JP2001131149A - Selective serotonine reuptake inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a selective serotonine reuptake inhibitor having an affinity for serotonine 1A receptors. SOLUTION: This selective serotonine reuptake inhibitor containing a compound represented by the formula [Cy1 is a cyclic group selected from the group consisting of a monocyclic aromatic group, a dicyclic condensed hydrocarbon ring group and a dicyclic condensed heterocyclic group, provided that the cyclic groups each may have one or more substituents and that at least one of the rings forming the condensed rings is an aromatic ring, when the cyclic group is the dicyclic condensed ring group; Cy2 is an aryl group which may be substituted; Y1 and Y2 are each a single bond, methylene or the like; Y3 is an alkylene or the like; Y4 is an alkylene or the like; Y5 is a single bond, an oxygen atom or the like; R1 and R2 are each H or a substituent; R3 and R4 are each H, a hydroxyl group or the like; Q and Z are each methine or nitrogen atom; (n) and (m) are each 1, 2 or 3], a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a serotonin reuptake inhibitor. The serotonin reuptake inhibitor of the present invention is a selective serotonin reuptake inhibitor having affinity for serotonin 1A receptor, weak dopamine and noradrenaline reuptake action, and strong serotonin reuptake inhibition. Further, the present invention relates to a novel compound having such a selective serotonin reuptake inhibitory action.

[0002]

BACKGROUND OF THE INVENTION Depression is a chronic disease that affects people of all ages. Currently, the most successful of various antidepressants used is a selective serotonin reuptake inhibitor (hereinafter sometimes abbreviated as SSRI). SSRI has a higher serotonin reuptake inhibitory action than dopamine and noradrenaline reuptake inhibitory action. The first drug marketed as SSRI was zimelidine. Other SSRIs subsequently marketed or under development include, for example, fluoxetine, fluvoxam
ine), citalopram (citalopram), sericlamin (c
ericlamine), femoxetine (femoxetine), ifoxetine (ifoxetine), cyanodothiepin (cyanodoth)
iepin), sertraline, paroxetine and litoxetine.

At present, SSRIs have been most successful as antidepressants, but some problems have been pointed out. The typical one is about 1 /
3 are refractory patients, and are unable to achieve a sufficient effect of SSRI and 3 years before a sufficient clinical effect appears.
Two weeks are required. In particular, the slow onset of this antidepressant action causes the following problems. Since the onset of antidepressant action is slow but side effects occur immediately,
This results in a vulnerable period in which the patient experiences only side effects without obtaining the therapeutic effect of the drug. This often places a heavy burden on the treating physician to persuade the patient to continue the same procedure during this period. In addition, in patients at risk of suicide, the gradual onset of action allows the patient to regain initiative before experiencing substantial improvement in depression,
The risk of suicide and the need for frequent hospitalization arise. Therefore, the development of an antidepressant drug that has a rapid onset of action is desired.

[0004] SSRIs require several weeks to develop antidepressant action for the following reasons. SSRIs inhibit acute serotonin reuptake of serotonin turnover.
This effect occurs at the nerve endings of serotonin neurons, thereby enhancing serotonin-induced neurotransmission. However, the inhibitory effect of SSRI on acute serotonin reuptake also occurs in serotonin neuron cell bodies and dendrites present in raphe nuclei.
-It also enhances HT _1A autoreceptor-mediated autoignition of serotonin neurons (negative feedback response).
As a result, initial administration of SSRIs does not enhance neurotransmission in serotonin neurons as expected as a whole. On the other hand, as SSRI is continued for several weeks, serotonin 1A autoreceptors on the serotonin neuron cell body and dendrites of the raphe nucleus are desensitized, and the negative feedback reaction disappears. At this time, the suppression of firing of serotonin neurons is finally released, and the enhancement of serotonin neuron activity and the inhibition of serotonin uptake at nerve endings work in harmony, thereby enhancing serotonin neurotransmission and exhibiting antidepressant action. Therefore, serotonin 1A receptor antagonists
Blockade of autoreceptor A and serotonin negative feedbac
By stopping the k response or by actively stimulating the serotonin 1A autoreceptor with a serotonin 1A receptor agonist to shorten the period until desensitization, the period until the onset of SSRI action can be shortened, Effects can be enhanced. That is, a compound having affinity for the serotonin 1A receptor and having a selective serotonin reuptake inhibitory action has a strong antidepressant action, and can be a therapeutic drug for mental disorders with a short onset of action. Indeed, it has been reported that pindolol, which has a high affinity for the serotonin 1A receptor, enhances the action of serotonin reuptake inhibitors in depressed patients and shortens the onset time (Arch). , Gen. Phsyc
hiatry, Vol. 51. Mar. 1994).

[0005] There are many references relating to arylalkyl, heteroarylalkyl or cycloalkylalkyl substituted nitrogen-containing saturated heterocyclic derivatives. However, there is little data on derivatives having two arylalkyl, heteroarylalkyl or cycloalkylalkyl-substituted nitrogen-containing saturated heterocycles in one molecule as in the present invention. WO 98/18788 and WO 98/8826 disclose piperazine derivatives as neurokinin antagonists. However, aryl or aralkyl substituents are required on the piperazine ring. WO 96/5185 discloses alkylamino derivatives as sigma 2 selective ligands. However, this is limited to those in which one of the two nitrogen-containing saturated heterocycles is substituted with a specific heteroarylalkyl such as naphthosultam. DE41
23599 discloses 2-aryl-2-hydroxy-1,3-bisamine derivatives as antibacterial agents. E
P428434 includes 1,4 as a neurokinin antagonist
-Dialkylpiperidine / piperazine derivatives are disclosed. It is essential that an aryl group and an acylaminomethyl group are simultaneously substituted on one carbon atom of a methylene chain connecting two nitrogen-containing saturated heterocycles.
EP 512901 discloses polycyclic amine compounds as neurokinin antagonists. This requires an aryl substituent at position 4 of the piperidine ring. WO95 / 24390 discloses phenyl (alkyl / alkoxy) -1- as a calcium channel antagonist.
Aminoalkyl-substituted piperidine / pyrrolidine derivatives are disclosed. WO 97/9308 discloses indolyl derivatives as neuropeptide Y antagonists.
None of these prior art documents discloses the compound according to the present invention as an exemplary compound, and none of the above prior art documents has an affinity for serotonin 1A receptor and inhibits selective serotonin reuptake. There is no description that it has an effect.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a selective serotonin reuptake inhibitor having an affinity for serotonin 1A receptor. The present invention specifically relates to mood disorders including depression, seasonal affective disorders and dysthymia in humans or animals;
Anxiety disorders, including obsessive-compulsive disorder and panic disorder; agoraphobia, avoidance personality abnormalities; social phobia; obsessive-compulsive disorder;
Post-traumatic stress disorder; psychosomatic disorder; memory impairment including dementia, amnesia and age-related memory impairment; disorders of eating behavior including anorexia nervosa and neural starvation; obesity; sleep disorders; Schizophrenia; Addiction to alcohol, tobacco, nicotine, etc .; Cluster headache; Migraine; Pain; Alzheimer's disease; Chronic seizure migraine; Headache associated with vascular disorders; Parkinson's disease, including induced Parkinson's syndrome and tardive dyskinesia; endocrine abnormalities such as hyperprolactinemia; vasospasm (especially of the cerebral vasculature); hypertension; Disorders; sexual dysfunction including premature ejaculation; and selective serotonin uptake with affinity for serotonin 1A receptor, useful as a therapeutic agent for drug dependence and the like The purpose is to provide an inhibitor.

[0007]

Means for Solving the Problems The present invention provides the following [1] to
The present invention relates to the invention as recited in the aforementioned Item [11]. That is, [1] Equation (1)

Embedded image (In the formula, Cy ¹ represents a cyclic group selected from the group consisting of a monocyclic aromatic group, a bicyclic fused hydrocarbon ring group and a bicyclic fused heterocyclic group. However, these cyclic groups are substituents. And when the cyclic group is a bicyclic fused ring group, at least one of the rings constituting the fused ring is an aromatic ring, and Cy ² may be substituted. Y ¹ and Y represent an aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted cycloalkyl group.
² independently represents a single bond, a methylene or an oxygen atom. Y ³ represents an optionally substituted alkylene. Y ⁴ represents an optionally substituted alkylene, an optionally substituted alkenylene or an optionally substituted alkynylene. Y ⁵ represents a single bond, an oxygen atom, a sulfur atom or -NH-. R ¹ and R ² each independently represent a hydrogen atom or a substituent. R ³ and R ⁴
Each independently represents a hydrogen atom, a hydroxyl group or an alkyl group. Q and Z each independently represent a methine or nitrogen atom. n and m are each independently 1, 2 or 3
Represents A) a serotonin reuptake inhibitor comprising, as an active ingredient, a compound represented by the formula, a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[2] The serotonin reuptake inhibitor according to [1], wherein one of Y ¹ and Y ² is a single bond and the other is an oxygen atom, or both are single bonds, [3]
The serotonin reuptake inhibitor according to [1] or [2], wherein R ³ and R ⁴ are hydrogen atoms, [4] [1], [2] or [3], wherein m is 2 and n is 2. [5] The serotonin reuptake inhibitor according to [1], [2], [3] or [4], wherein Z is a nitrogen atom; [6] Q is a nitrogen atom [1], [2], [3], [4] or [5] serotonin reuptake inhibitors described [7] Cy ² is an aromatic be the aryl group or substituted or optionally substituted Heterocyclic groups [1], [2], [3], [4],
[5] or [6], wherein the serotonin reuptake inhibitor, [8] ^{Y 5} is a single bond or an oxygen atom [1], [2], [3], [4], [5], [6 Or the serotonin reuptake inhibitor according to [7], [9]
[1], [2], [3], [4], wherein Y ⁵ is a single bond,
[5], the serotonin reuptake inhibitor according to [6] or [7], [10] the serotonin reuptake inhibitor according to [1], which is an anxiolytic or antidepressant;

[11] Formula (1-A)

Embedded image (In the formula, Cy ³ represents a cyclic group selected from the group consisting of a monocyclic aromatic group, a bicyclic fused hydrocarbon ring group and a bicyclic fused heterocyclic group, provided that these cyclic groups are substituents. And when the cyclic group is a bicyclic fused ring group, at least one of the rings constituting the fused ring is an aromatic ring, and Cy ⁴ may be substituted. Represents an aryl group, an optionally substituted aromatic heterocyclic group or an optionally substituted cycloalkyl group, wherein Y ⁶ and Y ⁷ are
One represents a single bond and the other represents a single bond or an oxygen atom.
Y ⁸ represents an optionally substituted alkylene. Y ⁹ represents a single bond, an optionally substituted alkylene, an optionally substituted alkenylene, or an optionally substituted alkynylene. Y ¹⁰ represents a single bond, an oxygen atom, a sulfur atom or —NH—. R ⁵ and R ⁶ each independently represent a hydrogen atom or a substituent. R ⁷ and R ⁸ are
Each independently represents a hydrogen atom, a hydroxyl group or an alkyl group. W represents a methine or nitrogen atom. n represents 1, 2 or 3. )), A prodrug thereof or a pharmaceutically acceptable salt thereof, and the present invention further includes the following embodiments [12] to [16].

[12] The compound according to [11], wherein R ⁷ and R ⁸ are hydrogen atoms, a prodrug thereof or a pharmaceutically acceptable salt thereof, and [13] Y ⁹ is an alkylene group having a substituent. , Y ¹⁰ is a single bond or an alkylene group having a substituent, the compound according to [11] or [12], a prodrug thereof or a pharmaceutically acceptable salt thereof, [14] W is a nitrogen atom [11] ], [12]
Or [13] the compound according, a prodrug thereof or their pharmaceutically acceptable salts, [15] Cy ⁴ is an aromatic heterocyclic group having an aryl group or a substituent having a substituent [11], [ 12], [13] or [1]
4] The compound according, a prodrug thereof or their pharmaceutically acceptable salts, ^{[16] Y 10} is a single bond or an oxygen atom [11], [12], [13], [14]
Or a compound according to [15], a prodrug thereof or a pharmaceutically acceptable salt thereof.

The groups in the formulas (1) and (1-A) will be specifically described below. As a monocyclic aromatic group, for example, an aryl group having 8 or less carbon atoms such as phenyl and tolyl, and pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazyl, pyrimidinyl, 5-6 having 1-4 heteroatoms selected from nitrogen, oxygen and sulfur such as tetrazolyl
And a membered heteroaromatic group. The bicyclic fused hydrocarbon ring group refers to a monovalent group having a free valence at a ring atom of a bicyclic hydrocarbon ring formed by condensing a benzo ring and a 5- to 7-membered hydrocarbon ring. The 5- to 7-membered hydrocarbon ring may be an aromatic ring or an aliphatic ring. Examples of the bicyclic fused hydrocarbon ring group include naphthyl, 1,4-dihydronaphthyl, 5,6,7,8-
Tetrahydronaphthyl and the like. A bicyclic fused heterocyclic group is a benzo ring and an aromatic or aliphatic heterocyclic ring,
A monovalent group having a free value at a ring atom of a bicyclic fused heterocyclic ring formed by condensing an aromatic heterocyclic ring with an aliphatic hydrocarbon ring or an aliphatic heterocyclic ring, or two aromatic heterocyclic rings. Examples of the aromatic or aliphatic heterocyclic ring constituting the bicyclic fused heterocyclic ring include a 5- or 6-membered aromatic or aliphatic heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. And more specifically, as the aromatic heterocyclic ring, for example, pyrrole, imidazole, pyrazole, furan, thiophene, oxazole,
Examples of isoxazole, thiazole, isothiazole, pyridine, pyrazine, pyrimidine and the like, and examples of the aliphatic heterocycle include pyrroline, imidazoline, pyrazoline, dihydropyridine, pyran and dioxane. As the aliphatic hydrocarbon ring constituting the bicyclic fused heterocyclic ring, cyclopentene, cyclopentadiene, cyclohexene,
Examples thereof include a hydrocarbon ring having 5 to 8 carbon atoms having 1 to 2 double bonds such as cycloheptene, cycloheptadiene, and cyclooctene. Representative examples of the bicyclic fused heterocyclic ring include, for example, a bicyclic fused heterocyclic ring containing one or two nitrogen atoms, and specifically, for example, indole, isoindole, indazole, quinoline, isoquinoline, Examples include phthalazine, quinoxaline, quinazoline and the like.

Examples of the substituent in the monocyclic aromatic group, the bicyclic fused hydrocarbon ring group and the bicyclic fused heterocyclic group include an alkyl group having 1 to 6 carbon atoms, and a substituent having 3 to 7 carbon atoms.
Cycloalkyl group, alkoxy group having 1 to 6 carbon atoms, hydroxyl group, halogen atom, acyl group having 2 to 7 carbon atoms, trifluoromethyl group, carboxyl group, amino group, alkylamino having 1 to 6 carbon atoms A dialkylamino group having 2 to 12 carbon atoms, a pyrrolidinyl group and the like.

As the aryl group, for example, one having 1 carbon atom
An aryl group of 0 or less is mentioned, and specific examples include phenyl and naphthyl. As the aromatic heterocyclic group, for example, a 5- to 6-membered monocyclic ring containing one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (however, the oxygen atom and the sulfur atom are not simultaneously contained) A monovalent group having a free value at a ring atom of an aromatic heterocyclic ring, and a bicyclic aromatic ring obtained by condensing such a monocyclic aromatic heterocyclic ring with an aromatic ring (benzo ring or monocyclic aromatic heterocyclic ring). Examples include a monovalent group having a free valence at a ring atom of the group heterocycle, and specifically, for example, pyrrole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyridazine, pyrazine, Indole, isoindole, benzimidazole, benzofuran, benzoxazole, benzothiazole, quinoline, isoquinoline, phthalazine, quinoxaline, Gelsolin, and the like.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The substituent in the substituted aryl group, the substituted aromatic heterocyclic group or the substituted cycloalkyl group in Cy ² and Cy ⁴ is, for example, one having 1 carbon atom.
An alkyl group having 6 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, a halogen atom, an acyl group having 2 to 7 carbon atoms, a trifluoromethyl group, a carboxyl group, Amino group, acylamino group having 2 to 7 carbon atoms, alkylamino group having 1 to 6 carbon atoms, dialkylamino group having 2 to 12 carbon atoms, carbamoyl group, alkylcarbamoyl group having 1 to 6 carbon atoms, carbon Examples thereof include a dialkylcarbamoyl group having 2 to 12 atoms and a pyrrolidinyl group.

As the alkylene, for example, one having 1 carbon atom
And 8 linear or branched alkylenes, specifically, for example, methylene, ethylene, trimethylene,
Tetramethylene, methylethylene (propylene), ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4- Methyltetramethylene, 2,3-dimethyltetramethylene and the like can be mentioned. Alkenylene includes, for example, alkenylene having 3 to 4 carbon atoms, and specific examples include propenylene and butenylene. Alkynylene includes, for example, propyne-
Alkynylene having 3 to 4 carbon atoms such as 1,3-diyl and butynylene is exemplified. Examples of the alkylene substituent include a hydroxyl group, a halogen atom, and a trifluoromethyl group. Examples of the substituent of alkenylene and alkynylene include a halogen atom.
Examples of the substituent in R ¹ , R ² , R ⁵ and R ⁶ include an alkyl group having 1 to 6 carbon atoms and a halogen atom. Examples of the alkyl group having 1 to 6 carbon atoms include linear or branched alkyl groups having 1 to 6 carbon atoms, and specifically, for example, methyl, ethyl, propyl, 1-methylethyl, butyl , 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Pentyl,
Examples thereof include 1-ethylbutyl and 2-ethylbutyl.

Examples of the alkoxy group having 1 to 6 carbon atoms include straight-chain or branched lower alkoxy groups having 1 to 6 carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy and 2-propoxy. , Butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. An alkylamino group having 1 to 6 carbon atoms is an amino group substituted with an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methylamino group, an ethylamino group, a propylamino group, a butylamino And the like. As the dialkylamino group having 2 to 12 carbon atoms, for example, an amino group substituted by the same or different two alkyl groups having 1 to 6 carbon atoms, and the like, more specifically, a dimethylamino group , Diethylamino group, ethylmethylamino group and the like. Examples of the acyl group having 2 to 7 carbon atoms include an alkanoyl group having 2 to 7 carbon atoms and an aroyl group having 7 or less carbon atoms, and more specifically, for example, formyl, acetyl, propanoyl, butanoyl, Pentanoyl, hexanoyl, heptanoyl, benzoyl and the like can be mentioned. Examples of the acyl group of the acylamino group having 2 to 7 carbon atoms include the same examples as described above. The alkylcarbamoyl group having 1 to 6 carbon atoms is a carbamoyl group substituted with an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a butylcarbamoyl group And the like. Examples of the dialkylcarbamoyl group having 2 to 12 carbon atoms include a carbamoyl group substituted by the same or different two alkyl groups having 1 to 6 carbon atoms, and more specifically, for example, dimethyl A carbamoyl group, a diethylcarbamoyl group, an ethylmethylcarbamoyl group and the like. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms.

In the present invention, the term "prodrug" refers to a derivative which is decomposed in vivo by acid hydrolysis or enzymatically to give the compound of the above formula (1). For example, when the compound of the formula (1) has a hydroxyl group or a carboxyl group, these groups can be modified to produce a prodrug.

The following starting compounds (2), (3),
(4), (5), (6), (7), (8), (9),
(10), (11), (12), (13), (14),
(15), (16), (17) and (18), some of which are novel, are produced by the methods described in the following Production Examples and Examples or by methods similar thereto, or by ordinary methods can do. The target compound (1) or a salt thereof can be produced by a method represented by the following formula. Manufacturing method 1

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y³,
Y⁴, Y⁵, R¹, R², R ³, R⁴, Q, Z, m and
And n are as described above, and X represents a leaving group. )
Examples of the leaving group include chloro, bromo and iodo.
Logen atom, for example, acetoxy, tosyloxy,
And acyloxy groups such as ruoxy.

Production method 1 (alkylation of amine) The target compound (1) or a salt thereof can be obtained by reacting the compound (2) or a salt thereof with the compound (3) or a salt thereof. The reaction is carried out in a suitable inert solvent at a temperature selected from the range of about −20 ° C. to the boiling point of the solvent used, for 10 minutes to 10 minutes, optionally in the presence of a base and optionally a phase transfer catalyst. The reaction can be performed for 48 hours. Examples of the base include organic bases such as triethylamine and pyridine; inorganic bases such as potassium carbonate, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide. Examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate. As the inert solvent, for example, acetonitrile, chloroform, halogenated hydrocarbons such as dichloromethane,
Aromatic hydrocarbons such as benzene and toluene, ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane, lower alcohols such as methanol, ethanol and isopropanol, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like Aprotic polar solvent or a mixed solvent thereof.

Manufacturing method 2

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y³,
Y⁴, Y⁵, R¹, R², R ³, R⁴, Z, X, m and
And n are as described above. )

Production Method 2 The target compound (1 ') or a salt thereof can be produced by reacting the compound (4) or a salt thereof with the compound (5) or a salt thereof. The reaction is carried out in a suitable inert solvent at a temperature selected from the range of about −20 ° C. to the boiling point of the solvent used, for 10 minutes to 10 minutes, optionally in the presence of a base and optionally a phase transfer catalyst. The reaction can be performed for 48 hours. Examples of the base, the phase transfer catalyst, and the inert solvent include the same examples as in the above-mentioned production method 1.

Manufacturing method 3

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y⁴,
Y⁵, R¹, R², R³, R ⁴, Z, X, m and n are
As described above, Y¹¹Is alkylene or a substituent
Represents an alkylene having )

Compound (2) or a salt thereof is converted to compound (6)
Alternatively, the intermediate (7) can be produced by reacting with a salt thereof. This reaction is carried out in a suitable inert solvent at a temperature selected from the range of about -20 ° C to the boiling point of the solvent used for 10 minutes in the presence of a base, if necessary, and optionally a phase transfer catalyst. The reaction can be carried out for up to 48 hours. Examples of the base, the phase transfer catalyst, and the inert solvent include the same examples as in the case of Production Method 1. The compound (1a) can be obtained by reducing the carbonyl group of the intermediate (7). The reduction reaction is carried out using a suitable reducing agent in a suitable inert solvent,
At a temperature between 20 ° C. and the boiling point of the solvent used,
The reaction can be performed for 48 hours. Suitable reducing agents include, for example, lithium aluminum hydride or diborane, and suitable inert solvents include
Diethyl ether, tetrahydrofuran (THF),
Examples thereof include ether solvents such as 1,4-dioxane. More specifically, the compound (1a) can be obtained by performing a reduction reaction with lithium aluminum hydride for 20 minutes to 1 hour under heating and refluxing tetrahydrofuran (THF).

Manufacturing method 4

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y⁴,
Y⁵, R¹, R², R³, R ⁴, Z, X, m and n are
As described above, Y¹²Is alkylene or substituted
Represents an alkylene having a group. ) Compound (8) or a compound (8)
Reacting the salt with compound (4) or a salt thereof to form an intermediate
By obtaining intermediate (9) and further reducing intermediate (9)
Thus, compound (1b) can be produced.

Production method 5

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y⁴,
Y⁵, R¹, R², R³, R ⁴, Z, m and n are as defined above.
And Y¹³Represents an alkylene group; X⁻Is
Represents an anion of X. )

The desired compound (Ic) or a salt thereof can be produced by reacting the compound (2) or a salt thereof with the compound (10) or a salt thereof in the presence of a base, if necessary, in an inert solvent. it can. As the base, for example, organic bases such as triethylamine and pyridine, inorganic bases such as potassium carbonate, sodium hydroxide and sodium hydride, bases such as sodium methoxide and metal alkoxides such as potassium tert-butoxide, etc. Basic alumina or potassium fluoride can be used. Examples of the inert solvent include acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-
Examples thereof include ether solvents such as dioxane, lower alcohols such as methanol, ethanol and isopropanol; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide; and mixed solvents thereof. The reaction can be carried out at a temperature between room temperature and the boiling point of the solvent used for 1 hour to 7 days.
More preferably, the compound (Ic) is reacted in an aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and the like at a temperature between 100 ° C. and the boiling point of the solvent used for 8 hours to 3 days. Can be obtained.

Manufacturing method 6

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y⁴,
Y⁵, R¹, R², R³, R ⁴, Z, Y¹³, X⁻, M
And n are as described above.) The target compound (Ic) or a salt thereof is prepared in the same manner as in Production Method 5.
Similarly, compound (5) or a salt thereof is converted to compound (1).
1) Production by reacting with or a salt thereof
Can be.

Manufacturing method 7

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y³,
Y⁴, Y⁵, R¹, R², R ³, R⁴, Q, X, m and
And n are as described above. The target compound (1d) or a salt thereof can be obtained by the method described in Production Method 1.
Compound (12) or a salt thereof is converted to compound
(13) or by reacting with a salt thereof
be able to.

Manufacturing method 8

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y⁴,
Y⁵, R¹, R², R³, R ⁴, Z, Y¹¹, M and
n is as described above. )

The intermediate (7) can be produced by reacting the compound (14) or a salt thereof with the compound (5) or a salt thereof to form an amide bond. This amide bond forming reaction is carried out by a usual method such as an acid chloride method using thionyl chloride, oxalyl chloride, or the like, a mixed acid anhydride method using chlorocarbonate ester, or a method using a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. It can be performed using: Intermediate (7) is prepared by using a suitable reducing agent (for example, lithium aluminum hydride, sodium borohydride, diborane, etc.) and a suitable inert solvent (for example, diethyl ether, tetrahydrofuran (THF), 1,4-
Compound (1a) can be obtained by reacting the mixture in an ether solvent such as dioxane) at a temperature between -20 ° C and the boiling point of the solvent used for 10 minutes to 48 hours. More specifically, the compound (1a) can be obtained by performing a reduction reaction with lithium aluminum hydride for 20 minutes to 1 hour under heating and refluxing tetrahydrofuran (THF).

Manufacturing method 9

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y⁴,
Y⁵, R¹, R², R³, R ⁴, Q, Z, Y¹², M
And n are as described above. ) Compound (2) or its compound
Is reacted with compound (15) or a salt thereof to give an amide
Intermediate (16) is prepared by forming a bond
be able to. Further reducing the intermediate (16)
Yields the compound (1e). Amide bond
The formation reaction and the reduction reaction were carried out in the same manner as in Production Method 8.
Can be done.

Manufacturing method 10

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y³,
Y⁵, R¹, R², R³, R ⁴, Q, Z, m and n are
As described above, Y¹⁴Is an alkylene or a substituent
Represents an alkylene having )

The target compound (If) or a salt thereof is prepared by converting the compound (12) or a salt thereof with the compound (17) or a salt thereof, if necessary, in the presence of a Lewis acid (eg, ytterbium triflate) and a suitable inert solvent. (For example, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (TH
F), ether solvents such as 1,4-dioxane, etc .; lower alcohols such as methanol, ethanol and isopropanol; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide; or mixed solvents thereof). It can be obtained by reacting at a temperature between 20 ° C. and the boiling point of the solvent used for 10 minutes to 48 hours.

Manufacturing method 11

Embedded image(In the above formula, Cy¹, Cy², Y¹, Y², Y³,
Y⁵, R¹, R², R³, R ⁴, Q, Z, Y¹⁴, M
And n are as described above. )

The target compound (1 g) or a salt thereof is obtained by reacting the compound (12) or a salt thereof with the compound (18) or a salt thereof under reductive amination conditions. As the reducing agent, sodium cyanoborohydride or sodium borohydride can be used.
2) and the compound (18) may be mixed as they are, or may be reacted after forming a Schiff base in advance. The reaction is carried out in a suitable inert solvent such as acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF),
Solvents used in ether solvents such as 4-dioxane, lower alcohols such as methanol, ethanol, and isopropanol; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide; At a temperature between the boiling points of
The reaction can be carried out for 10 minutes to 48 hours.

Throughout this specification, amino acids, peptides,
Protecting groups, condensing agents, and the like may be abbreviated by IUPAC-IUB (Biochemical Nomenclature Committee) commonly used in this technical field. Suitable salts and pharmaceutically acceptable salts of the starting compounds and the intended compounds are the conventional non-toxic salts, which include organic acid salts (eg acetate, trifluoroacetate, maleate, fumarate) ,
Citrate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.),
Acid addition salts such as inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.);
Salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) or metal salts such as alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium Those skilled in the art can appropriately select salts, organic base salts (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.) and the like.

In the above-described production method, if any functional group other than the reaction site changes under the reaction conditions described or is inappropriate for carrying out the described method, the other site is protected. After the reaction, the target compound can be obtained by deprotection. Examples of the protecting group include Protective Groups in Organic Synthesis (e.g., ethoxycarbonyl, t-butoxycarbonyl, acetyl, benzyl, etc.).
oups in Organic Synthesis), Green (T.W./), John Wiley & Sons Inc. (1981), and the like. . Methods for introducing and removing protecting groups are commonly used in organic synthetic chemistry [for example, Protective Groups in Organic Synthesis].
s), by TW Greene, John Wiley & Sons Incorporated (John Wiley & So
ns Inc.) (1981)] and the like, or according to them.

In the compound of the formula (1) or (1-A), by converting a functional group, the compound of the formula (1)
Or it may be another compound of (1-A). The functional group can be converted by a general method commonly used [e.g., Comprehensive Organic Transformations (Communication).
prehensive Organic Transformations); C. Larock, 1989). Intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. can do. Also,
The intermediate can be subjected to the next reaction without purification.

Some of the compounds (1) may exist as tautomers, and the present invention includes all possible isomers and mixtures thereof, including these. When it is desired to obtain a salt of compound (1), if compound (1) is obtained in the form of a salt, it may be purified as it is,
When it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a usual method. The compound (1) and a pharmaceutically acceptable salt thereof may be present in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Compound (1) and other compounds may include one or more stereoisomers based on asymmetric carbon atoms, and all such isomers and mixtures thereof are included in the scope of the present invention.

The target compound (1) and a pharmaceutically acceptable salt thereof have pharmacological actions such as SRI (serotonin reuptake inhibition) action. Therefore, diseases mediated by the serotonin nervous system, for example, mood disorders including depression, seasonal affective disorders and dysthymia; anxiety disorders including generalized anxiety disorders and panic disorders; agoraphobia, avoidance personality abnormalities; It is useful for treating or preventing phobias, obsessive-compulsive disorders, post-traumatic stress disorders, and psychosomatic disorders. Furthermore, the target compound (1) of the present invention and a pharmaceutically acceptable salt thereof may be used as a memory disorder including dementia, amnesia and age-related memory disorder; eating behavior including anorexia nervosa and neural starvation. Disorders of obesity; sleep disorders; schizophrenia; drug dependence such as alcohol, tobacco, nicotine, etc .; cluster headache; migraine; pain; Alzheimer's disease; It is also useful for treating or preventing dementia, depression, anxiety, Parkinson's disease including neuroleptic-induced Parkinson's syndrome and tardive dyskinesia. The target compound (1) of the present invention and a pharmaceutically acceptable salt thereof further include:
Endocrine abnormalities such as hyperprolactinemia; vasospasm (especially of the cerebral vasculature); hypertension; disorders of the gastrointestinal tract involving altered motility and secretion; sexual dysfunction, including premature ejaculation; It is useful for treating or preventing drug dependence.

For medical purposes, compound (1) of the present invention and its pharmaceutically acceptable salts can be used topically, enterally, intravenously, intramuscularly, inhalation, nasal drops, intraarticularly, intrathecally, transtracheally Alternatively, it can be used in the form of a pharmaceutical preparation as a mixture with a pharmaceutically acceptable carrier such as a solid or liquid organic or inorganic excipient suitable for oral or parenteral administration including ophthalmic administration, or external use. As the pharmaceutical preparations, capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops Liquid, syrup, aerosol, suspension, emulsion and the like, solid, semi-solid or liquid. If desired, these preparations may contain auxiliaries, stabilizers,
Wetting or emulsifying agents, buffers and other conventional additives can be added. The dose of compound (1) increases or decreases depending on the age and condition of the patient.
mg, 250 mg, 500 mg and 1000 mg
It is effective against diseases such as depression, mood disorders including seasonal affective disorder and dysthymia; anxiety including general anxiety disorder and panic disorder. Generally, an amount of from 0.1 mg / individual to about 1,000 mg / individual can be administered per day.

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Examples. Test Example 1: Screening using [ ³ H] citalopram binding
( ¹⁾ Preparation of cerebral cortical membrane preparation A membrane preparation was prepared according to the method ¹⁾ of D'amato et al. That is, SD male rats weighing around 200 g (Japan SLC
Was killed by decapitation, the whole brain was immediately removed, and the cerebral cortex was fractionated under ice cooling. 25 to wet weight
Double volume of buffer (50 mM Tris-HCl (pH = 7.4), 120 mM NaCl, 5 mM
KCl) was added, and the mixture was homogenized using a Teflon-glass homogenizer in an ice bath. This is 45,000 xg at 4 ° C for 10
The precipitate obtained by centrifugation for 10 minutes is ice-cold buffer (50 mM Tr).
Dispersed in is-HCl (pH = 7.4), 120 mM NaCl, 5 mM KCl) using Hiscotron (registered trademark) and 15,000 × 45,000 × g at 4 ° C.
Centrifuged for 0 minutes. After resuspension, the washing operation was repeated. The membrane preparation thus obtained was suspended in the above buffer solution and stored frozen at -80 ° C. 1-2 Measurement of receptor binding experiments ^[3 H] citalopram binding was performed according to the method ¹⁾ of D'amato et al. That is, 120 mM NaCl and 5 mM KCl
[ ³ H] c diluted with 50 mM Tris-HCl (pH = 7.4) buffer containing
5 μl of italopram (final concentration 0.7 nM), 146 μl of a cerebral cortical membrane sample (72 μg / well as a protein amount), and 4 μl of a test drug solution dissolved in dimethyl sulfoxide were added to give a total volume of 200 μl.
μl. After reacting this solution at room temperature for 60 minutes, it was quickly filtered under low pressure using glass fiber filter paper. After washing the glass fiber filter paper twice with 250 μl of the same buffer, ACS-I
It was transferred to a glass vial containing 4 ml of I (Amersham), and the radioactivity remaining on the filter paper was measured using a liquid scintillation counter. The non-specific binding of [ ³ H] citalopram was defined as the amount of binding in the presence of 100 μM 5-HT. The binding inhibition rate was calculated according to the following formula: Binding inhibition rate (%) = 100−100 × ｛[[ ³ H] citalopram binding amount in the presence of test substance] − [[ ³ H in the presence of 100 μM 5-HT] ] citalopram binding amount]} / {[test substance in the absence ^[3 H] citalopram binding amount] - [100μM 5-HT [ 3 H] citalopram binding amount in the presence]} references 1) D'amato RJ et al., J. Pharm. Exp. Ther., 24
2 , 364-371 (1987)

1-3 Test results

[0044]Test example 2: [ ³ H] 8-OH-DPAT binding test  2-1 Test method The method of Hall M.D.²⁾It went according to. About 1 week
After breeding, the animals were decapitated and their brains were immediately removed. This
Then, the hippocampus was separated on ice, and 40 times the wet weight.
 50 mM Tris-HCl (pH = 7.4) was added, and Teflon-
Homogenize using glass homogenizer (3 min, 1 s
troke / min), and then centrifuge at 40,000 xg for 10 minutes.
(4 ° C). The resulting sediment is washed with ice-cold buffer (50 mM T
ris-HCl (pH = 7.4)) using Hiscotron (registered trademark)
And centrifuged (4 ° C) at 40,000 xg for 10 minutes.
Was. Furthermore, it was resuspended and the washing operation was repeated once. Profit
The resulting precipitate is ice-cold buffer (50 mM Tris-HCl (pH = 7.4))
Was dispersed using Hiscotron (registered trademark) at 37 ° C.
Incubate for 1 hour, then at 40,000 xg for 10 minutes
Centrifugation (4 ° C.). In addition, resuspend and wash operation
Was repeated once. The obtained membrane preparation was added to the above buffer solution.
After the suspension, the suspension was stored frozen at -80 ° C. 50 mM Tris-HCl
(pH = 7.4), 4mM CaCl_Two In a buffer containing^ThreeH] 8-OH-D
50 μl of PAT (final concentration 2 nM), 4 μl of test drug solution,
146 μl of hippocampal membrane preparation (80 μg / tube as protein content)
 Was added, and the measurement was performed using a total volume of 200 μl of the reaction solution. Anti
After reacting the reaction solution at room temperature for 30 minutes,
The mixture was quickly filtered under reduced pressure. Glass fiber filter paper is buffered
After washing twice with 250 μl of the solution, ACS-II (Amersham
 ) Add to 4ml of counting vial and filter paper
Receptor-bound radioactivity remaining on the surface was determined by liquid scintillation.
It was measured with a counter. Non-specific binding is 1 μM 8-OH-D
The binding amount was determined in the presence of PAT. The binding inhibition rate is calculated by the following equation.
Calculated: binding inhibition rate (%) = 100−100 × ｛[test substance present
Below [^ThreeH] 8-OH-DPAT binding amount]-[1 μM 8-OH-DPAT present
Amount in the presence of the test substance]^ThreeH] 8-OH
-DPAT binding amount]-[Binding in the presence of 1 µM 8-OH-DPAT
Amount]｝ References 2) Hall M.D. et al., J. Neurochem.,44, 1685-1696
(1985)

[0045]Test Example 3: 5-HT _1A receptor operation test  3-1 Preparation of cells used and membrane preparation Human 5-HT was used for the experiment._1AReceptor-expressing CHO cells (human 5-HT_1A
/ CHO) was used. Cells are 5% CO_TwoIn the incubator,
10% FCS, 500 μg / ml Geneticin and 100 U / ml
F12 containing penicillin-100μg / ml streptmycin (all
And gibco), and the membrane preparation is the method of A. Newman et al.³⁾
Was prepared according to the following procedure. That is, buffer A (20 mM HEP
ES, 5mM MgSO_FourThe cells detached and collected in
After homogenizing with a (registered trademark) homogenizer,
A centrifugation operation (50,000 × g, 30 min, 4 ° C.) was performed. sediment
Is resuspended in an appropriate amount of buffer A and stored at -80 ° C until use
did. The amount of protein in the membrane standard
Using Bovine (SIGMA), Dye ReagentConcentrate (BIO-
RAD). 3-2 Experimental method Human 5-HT_1AFor the receptor³⁵The measurement of S] GTPγS binding
Using the above membrane preparation, A. Newman et al.³⁾According to
Done. That is, 10^-FiveBuffer containing M test substances
Liquid B (20 mM HEPES, 3 mM MgSO_Four, 3μM GDP, 1mM DTT)
In addition, 0.05 nM [^{Three Five}S] GTPγS (Dupont NEN) and
And a certain amount (about 50 μg / tube) of membrane preparation
The reaction was incubated at 22 ° C. for 20 minutes. End of reaction
After that, the reaction solution was diluted with 5 ml of ice-cold buffer B, and
Suction filter quickly using fiber filter paper (Whatman, GF / B)
The reaction was terminated by passing. Wash twice with the same buffer
Put the purified glass fiber filter paper into a vial and add 4 ml of ACS-I
I was added. On the filter paper³⁵S] GTPγS radioactivity
It was measured by a scintillation counter. 10 μM GTPγ
From the non-specific binding obtained in the presence of S (Sigma)³⁵S] GTP
Specific binding of γS was determined. 5-HT for each test substance_1AReceptor
Agonist activity was determined by 10 μM 5-HT [³⁵[S] GTPγS binding increase
Is expressed as an increase rate when 100% is taken. References: 3) Adrian Newman-Tancredi et al., Eur. J. Pharmac
ol.,307, 107-111 (1996)

With respect to the compounds obtained in the examples, the results of Test Example 1, Test Example 2 and Test Example 3 are as shown in Table 1. Table 1: Test results

[Table 1] ───────────────────────────────── Compound [ ³ H] citalopram [ ³ H] 8-OH -DPAT 5-HT _1A receptor (Example number) Binding inhibition rate (%) Binding inhibition rate (%) Agonist activity (%) ──────────────────── ３ 3 9874 44 697 59 09 9 100 46 56 12 12 100 56 35 15 97 66 44 21 99 46 42 28 98 98 72 85 34 84 60 76 76 40 99 99 76 56 45 98 89 35 52 93 79 79 26 56 98 54 49 ─────────────────────────────────

Reference Example 1 N-tert-butoxycarbonyl-4-piperidone

Embedded image Ice-cooled 4-piperidone hydrochloride monohydrate (29 g, 189 mmo
l) and 1,4-dioxane (120 mL)
1,4 of t-butyl dicarbonate (41.3 g, 189 mmol)
A dioxane (120 mL) solution and a 1N aqueous sodium hydroxide solution (200 mL) were simultaneously added dropwise, and the mixture was stirred for 30 minutes. 1,
After distilling off 4-dioxane under reduced pressure, the residue was washed with ethyl acetate.
Extracted twice. The organic layers were combined, washed sequentially with a 5% aqueous solution of potassium hydrogen sulfate, distilled water, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-tert-butoxycarbonyl-4-piperidone (34.8 g, 92.5%) as white crystals. ¹ H-NMRδ (CDCl ₃ , ppm): 3.72 (t, J = 6.3Hz, 4H), 2.44 (t,
J = 6.3Hz, 4H), 1.50 (s, 9H).

Reference Example 2 2-Naphthylmethyltriphenylphosphonium bromide

Embedded image A mixture of 2-bromomethylnaphthalene (44.2 g, 200 mmol), triphenylphosphine (52.4 g, 200 mmol), and xylene (200 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. After allowing to cool to room temperature, diethyl ether was added to the resulting solid to form a uniform slurry, which was collected by filtration, washed with diethyl ether, dried and dried to give 2-naphthylmethyltriphenylphosphonium bromide (89.9 g, 93.0 g). %).

Reference Example 3 4- (2-naphthylmethyl) piperidine hydrochloride

Embedded image 2-naphthylmethyltriphenylphosphonium bromide (40.0 g, 82.7 mmol), potassium tert-butoxide (10.
23 g, 91.1 mmol) and tetrahydrofuran (240 m
The mixture of L) was heated to 60 ° C under a nitrogen atmosphere,
t-butoxycarbonyl-4-piperidone (10.08 g, 50.
6 mmol) was added. After stirring at that temperature for 6 hours, the mixture was allowed to cool to room temperature, subsequently poured into water, and extracted twice with diethyl ether. The organic layers were combined, washed sequentially with distilled water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were separated by filtration. After the filtrate was treated with activated carbon, the solvent was distilled off under reduced pressure, and crude 1-tert-butoxycarbonyl-4- (2-naphthylmethyl) piperidine (20.8
g) was obtained. This was used for the next reaction without purification. ¹ H-NMRδ (CDCl ₃ , ppm): 7.82-7.77 (m, 3 H), 7.63 (s,
1 H), 7.48-7.41 (m, 2 H), 7.33 (dd, J = 8.6, 1.6
Hz, 1 H), 6.51 (s, 1 H), 3.54 (t, J = 5.6 Hz, 2
H), 3.43 (t, J = 5.6 Hz, 2 H), 2.55 (t, J = 5.6 H
z, 2 H), 2.39 (t, J = 5.6 Hz, 2 H), 1.49 (s, 9 H). Crude 1-tert-butoxycarbonyl-4- (2-naphthylmethyl) piperidine (18.4 g), oxidized Platinum (33% water content)
(1.25 g), ethyl acetate (20 mL), methanol (20 mL),
The mixture of acetic acid (20 mL) was stirred under a 1 atmosphere of hydrogen atmosphere for 6 hours. After the catalyst was filtered off on celite, the filtrate was concentrated under reduced pressure to obtain crude 1-tert-butoxycarbonyl-4- (2-naphthylmethyl) piperidine (19.1 g). This was used for the next reaction without purification. ¹ H-NMRδ (CDCl ₃ , ppm): 7.82-7.75 (m, 3 H), 7.57 (s,
1 H), 7.48-7.39 (m, 2 H), 7.29 (dd, J = 8.1, 1.6
Hz, 1 H), 4.08 (dm, J = 12.5 Hz, 2 H), 2.70 (d, J
= 7.2 Hz, 2 H), 2.64 (tm, J = 12.5 Hz, 2 H), 1.84
− 1.70 (m, 1H), 1.65 (dm, J = 12.5 Hz, 2 H), 1.4
9 (s, 9 H), 1.23 (qd, J = 12.5, 3.0 Hz, 2 H). Crude 1-tert-butoxycarbonyl-4- (2-naphthylmethyl) piperidine (19.1 g), acetic acid (40 mL) , And a mixture of 4N hydrochloric acid / 1,4-dioxane (20 mL) were heated and stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and a white precipitate was collected by filtration, washed with ethyl acetate, and dried.
-(2-Naphthylmethyl) piperidine hydrochloride (9.05 g, 8
2.1%). ¹ H-NMRδ (DMSO-d ₆ , ppm): 8.92 (br, 1 H), 8.68 (br,
1 H), 7.89-7.82 (m, 3H), 7.68 (s, 1 H), 7.52-7.
41 (m, 2 H), 7.36 (dd, J = 8.3, 1.6 Hz, 1 H), 3.20
(dm, J = 12.5 Hz, 2 H), 2.80 (tm, J = 12.5 Hz, 2
H), 2.70 (d, J = 7.2 Hz, 2 H), 1.98 − 1.84 (m, 1
H), 1.72 (dm, J = 12.5 Hz, 2 H), 1.41 (qd, J = 12.
5, 3.0 Hz, 2 H).

Reference Example 4 8-benzyl-5,8-diazaspiro [4.5] decane iodide

Embedded image 1-benzylpiperazine (35.25 g, 200 mmol), 1-bromo-4-chlorobutane (34.3 g, 200 mmol), potassium carbonate (69 g, 500 mmol), and acetonitrile (250
mL) was stirred at 50 ° C. under a nitrogen atmosphere for 4 hours.
After the inorganic substances were filtered off, the filtrate was treated with sodium iodide (30.0 g,
200 mmol) and stirred at 50 ° C. for 3 hours. After the inorganic substances were filtered off while hot, the filtrate was concentrated under reduced pressure, ethyl acetate was added to the residue, a white precipitate was collected by filtration, washed with ethyl acetate, dried and dried with 8-benzyl-5,8-diazaspiro [4]. .5] decane iodide (63.0 g, 87.9%) was obtained.

Reference Example 5 8- (2-bromo-5-methoxybenzyl) -5,8-diazaspiro [4.5] decane 5-a) 2-bromo-5-methoxybenzylpiperazine dihydrochloride

Embedded image 2-bromo-5-methoxybenzyl chloride [JP-A-9
-Synthesized according to the method described in -169750] (23.77 g, 10
0 mmol), 1-tert-butoxypiperazine (20 g, 107 m
mol), potassium carbonate (37.1 g, 269 mmol), and acetonitrile (10 mL) were heated to reflux for 4 hours under a nitrogen atmosphere. After allowing to cool to room temperature, the inorganic substances were separated by filtration, and the filtrate was concentrated under reduced pressure to give crude 1-tert-butoxycarbonyl-4-.
(2-bromo-5-methoxybenzyl) piperazine (31.5
g) was obtained. This was used for the next reaction without purification. Crude 1-tert-butoxycarbonyl-4- (2
-Bromo-5-methoxybenzyl) piperazine (31.5 g)
Acetic acid (40 mL) and 4N hydrochloric acid / 1,4-dioxane (20
The mixture was heated and stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and a white precipitate was collected by filtration, washed with ethyl acetate, dried and dried to give 2-bromo-5-methoxybenzylpiperazine 2 The hydrochloride (25.34 g, 86.6%) was obtained.

5-b) 8- (2-bromo-5-methoxybenzyl) -5,8-diazaspiro [4.5] decane iodide

Embedded image 2-bromo-5-methoxybenzylpiperazine dihydrochloride (11.0 g, 30.7 mmol), 1-bromo-4-chlorobutane (5.26 g, 30.7 mmol), potassium carbonate (20 g, 145 mm)
ol) and acetonitrile (50 mL) was stirred at 50 ° C. for 4 hours under a nitrogen atmosphere. After inorganic substances were filtered off, sodium iodide (4.50 g, 30 mmol) was added to the filtrate, and the mixture was stirred at 50 ° C for 3 hours. After the inorganic matter was filtered off while hot, the filtrate was concentrated under reduced pressure, ethyl acetate was added to the residue, a white precipitate was collected by filtration, washed with ethyl acetate, dried and dried with 8- (2-bromo-
5-methoxybenzyl) -5,8-diazaspiro [4.
5] Decane iodide (8.52 g, 59.4%) was obtained.

Reference Example 6 1-benzyl-4- (3-chloropropyl) piperazine

Embedded image 1-benzylpiperazine (17.6 g, 100 mmol), 1-bromo-3-chloropropane (15.7 g, 100 mmol), potassium carbonate (27.8 g, 200 mmol), and acetonitrile
(250 mL) was stirred for 4 hours under a nitrogen atmosphere. After filtering off the inorganic substance, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate) to give an oily 1-benzyl-4- (3-chloropropyl) piperazine (13.4 g, 53%). I got ¹ H-NMRδ (CDCl ₃ , ppm): 7.32-7.24 (m, 5 H), 3.58 (t,
J = 6.6 Hz, 2 H), 3.51 (s, 2 H), 2.50-2.45 (m,
10 H), 1.94 (app.quint, J = 6.6 Hz, 2 H).

Reference Example 7 1- (3- (4-benzylpiperidino) propyl) piperazine trihydrochloride 7-a) 1-tert-butoxycarbonyl-4-
(3- (4-benzylpiperidino) propyl) piperazine

Embedded image 4-benzyl-1- (3-chloropropyl) piperidine
(10.17 g, 40.4 mmol), 1-tert-butoxycarbonylpiperazine (9.03 g, 48.5 mmol), potassium carbonate (1
3.40 g, 97 mmol), potassium iodide (674 mg, 4.06 mmo
l), tetra n-butylammonium hydrogen sulfate (687 mg, 2.0
2 mmol) and acetonitrile (80 mL) were heated at reflux for 4 hours. After allowing the reaction solution to cool to room temperature, the inorganic salts were separated by filtration. The residue obtained by concentrating the filtrate under reduced pressure was subjected to flash silica gel column chromatography (ethyl acetate, then ethyl acetate: triethylamine 20: 1).
To give oily 1-tert-butoxycarbonyl-4
-(3- (4-benzylpiperidino) propyl) piperazine (1
1.10 g, 68.4%). 7-b) 1- (3- (4-benzylpiperidino) propyl) piperazine trihydrochloride

Embedded image 1-tert-butoxycarbonyl-4- (3- (4-benzylpiperidino) propyl) piperazine (11.09 g, 27.6 mmol
l), a mixture of 2N hydrogen chloride-1,4-dioxane (100 mL), and acetic acid (20 mL) was stirred at 50 ° C. for 3.5 hours. The reaction solution was allowed to cool to room temperature, diethyl ether (100 mL) was added, and a white solid was collected by filtration, washed with diethyl ether, dried, and dried with 1- (3- (4-benzylpiperidino) propyl). Piperazine trihydrochloride (11.40 g, quantitative) was obtained.

Reference Example 8 1- (4- (4-benzylpiperidino) butyl) piperazine trihydrochloride

Embedded image 4-benzyl-1- (4- (4-benzylpiperidino) butyl)
Piperazine (20.81 g, 51.3 mmol), 10% palladium on carbon (50% water-containing) (20.52 g), and acetic acid (200 mL)
Was stirred at room temperature under a hydrogen atmosphere at 1 atm for 4 hours to perform catalytic reduction. The catalyst was filtered off, toluene was added to the filtrate, and the solvent was distilled off under reduced pressure. The residue was made alkaline by adding a 1N aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure to give an oily 1- (4-
(4-benzylpiperidino) butyl) piperazine (19.77 g,
quant). 2N hydrogen chloride-1,4-dioxane (140mL)
1- (4- (4-benzylpiperidino) butyl) piperazine
(19.77 g) in 1,4-dioxane solution (70 mL) under a nitrogen atmosphere
The mixture was added dropwise at 5 ° C over 15 minutes, and stirred at that temperature for 30 minutes.
Diethyl ether (300 mL) was added, and the mixture was further stirred for 30 minutes.
The white solid was collected by filtration, washed with diethyl ether and dried to give 1- (4- (4-benzylpiperidino) butyl) piperazine 3
The hydrochloride (20.47 g, 93.9%) was obtained.

Reference Example 9 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionic acid 9-a) 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionitrile

Embedded image Di-tert-butyl dicarbonate (11.0 mL, 47.9 mmol) was added dropwise to a chloroform solution (40 mL) of 4-piperidineethanol (5.91 g, 45.7 mmol) under a nitrogen atmosphere at room temperature over 25 minutes. After the obtained mixture was further stirred at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. Methylene chloride
(80 mL) and triethylamine (8.30 mL, 59.5 mm
ol). The obtained mixture was immersed in an ice bath, cooled to 5 ° C, and methanesulfonyl chloride (3.9
0 mL, 50.4 mmol) was added dropwise, and the mixture was stirred at that temperature for 30 minutes.
Pour the reaction mixture into a 5% aqueous potassium carbonate solution and use ethyl acetate
Extracted twice. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with N, N-dimethylformamide (30 m
L) and sodium cyanide (2.90 g, 59.2 mmol)
Was added and stirred at 50 ° C. for 6 hours under a nitrogen atmosphere. The reaction solution was allowed to cool to room temperature, and then poured into distilled water.
Extracted twice. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to flash silica gel column chromatography (hexane: ethyl acetate 5: 2 followed by 2: 2).
Purified in 1) to give oily 2- (1-tert-butoxycarbonylpiperidin-4-yl) propionitrile (7.27 g, 6
6.7%). 9-b) 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionic acid

Embedded image 2- (1-tert-butoxycarbonylpiperidin-4-yl) propionitrile (7.26 g, 30.5 mmol), 2N aqueous potassium hydroxide (70 mL), and ethanol (35 mL)
Was stirred at 90 ° C. for 6 hours under a nitrogen atmosphere. The reaction solution was allowed to cool to room temperature, then poured into a 5% aqueous potassium hydrogen sulfate solution, and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 3- (1-te) as a white solid.
rt-butoxycarbonylpiperidin-4-yl) propionic acid (8.13 g, quantitative) was obtained.

Reference Example 10 4-benzyl-1- (3- (piperidin-4-yl) propionyl) piperidine 10-a) 4-Benzyl-1- (3- (1-tert-butoxycarbonylpiperidin-4-yl) ) Propionyl) piperidine

Embedded image 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionic acid (805 mg, 3.13 mmol), 4-benzylpiperidine (550 mg, 3.14 mmol), 1- [3- (dimethylamino) propyl] -3- Ethyl carbodiimide hydrochloride (663
mg, 3.46 mmol), 1-hydroxybenztriazole (424 mg, 3.13 mmol), and N, N-dimethylformamide (7.0 mL) were stirred overnight at room temperature under a nitrogen atmosphere. Pour the reaction solution into a 5% aqueous solution of potassium hydrogen sulfate,
Extracted twice with toluene-ethyl acetate (1: 1). The organic layers were combined, washed sequentially with saturated aqueous sodium bicarbonate and saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain oily 4-benzyl-1- (3- (1-tert-butoxycarbonylpiperidin-4-yl) propionyl) piperidine (1.44 g, quantitative). This was used for the next reaction without purification. 10-b) 4-benzyl-1- (3- (piperidine-4
-Yl) propionyl) piperidine

Embedded image 4-benzyl-1- (3- (1-tert-butoxycarbonylpiperidin-4-yl) propionyl) piperidine
(1.34 mg, 3.13 mmol), 4N hydrogen chloride in 1,4-dioxane (4.0 mL), and 1,4-dioxane (4.0 m
The mixture of L) was stirred at 50 ° C for 1 hour under a nitrogen atmosphere. The reaction solution was allowed to cool to room temperature, then poured into a 1N aqueous sodium hydroxide solution, and extracted twice with diethyl ether. The organic layers were combined, washed with saturated saline, and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure to give oily 4-benzyl-1- (3- (piperidin-4-yl) propionyl).
Piperidine (809 mg, 80%) was obtained.

Reference Example 11 4-benzyl-1- (3-
(Piperidin-4-yl) propyl) piperidine

Embedded image Lithium aluminum hydride (88.5 mg, 2.33 mmol) in tetrahydrofuran (2.5 m
L) Add 4-benzyl-1- (3- (piperidine-4) to the suspension.
-Yl) propionyl) piperidine (362 mg, 1.15 mmol)
Of tetrahydrofuran (4 mL) was added dropwise, and the resulting mixture was further heated to reflux for 30 minutes. The reaction solution was allowed to cool to room temperature, then poured into a 1N aqueous sodium hydroxide solution, and extracted twice with diethyl ether. The organic layers were combined, washed with saturated saline, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure to give oily 4-benzyl-1- (3- (piperidin-4-yl) propyl) piperidine. (270 mg, 78
%).

Reference Example 12 4- (1-tert-butoxycarbonylpiperidin-4-yl) butanoic acid 12-a) 4- (1-tert-butoxycarbonylpiperidin-4-yl) -2-butenoic acid methyl ester

Embedded image To a chloroform solution (30 mL) of 4-piperidineethanol (3.62 g, 28.0 mmol) was added di-tert-
Butyl dicarbonate (6.76 mL, 29.4 mmol) was added dropwise over 25 minutes. After the obtained mixture was further stirred at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. This residue was dissolved in methylene chloride (50 mL) to obtain a solution A. A methylene chloride solution (50 mL) of dimethyl sulfoxide (4.80 mL) was immersed in a dry ice-acetone bath, cooled to −78 ° C., oxalyl chloride (2.90 mL, 33.7 mmol) was added dropwise under a nitrogen atmosphere, and the temperature was maintained for 15 minutes. Stirred. To the mixture, the solution A was added dropwise at -78 ° C over 20 minutes.
Stirred for 0 minutes. Then add triethylamine (19.5 mL)
The solution was added dropwise over 0 minutes, and the temperature was raised to room temperature. The reaction solution was poured into water and extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the corresponding aldehyde (6.87 g). To a solution of this aldehyde (2.74 g) in tetrahydrofuran (30 mL) was added methyl triphenylphosphoranylidene acetate (3.73 g), and the mixture was stirred at room temperature under a nitrogen atmosphere at room temperature for 24 hours. After the reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, triphenylphosphine oxide was separated by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to flash silica gel column chromatography (hexane: ethyl acetate 6: 1). Purified oily 4- (1-ter
(t-butoxycarbonylpiperidin-4-yl) -2-butenoic acid methyl ester (1.93 g, 60.9%) was obtained. 12-b) 4- (1-tert-butoxycarbonylpiperidin-4-yl) butanoic acid

Embedded image 4- (1-tert-butoxycarbonylpiperidin-4-yl) -2-butenoic acid methyl ester (1.17 g, 4.13 mmol
l), 10% palladium carbon (50% water-containing product) (130m
g) and a mixture of ethyl acetate (10 mL) were stirred at room temperature under a hydrogen atmosphere at 1 atm for 1 hour to perform catalytic reduction. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give oily methyl 4- (1-tert-butoxycarbonylpiperidin-4-yl) butanoate.
(1.21 g, quant) was obtained. A mixture of this and a 1 N aqueous solution of sodium hydroxide (10 mL) and 1,2-dimethoxyethane (10 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted twice with toluene. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4- (1-tert-butoxycarbonylpiperidin-4-yl) butanoic acid (1.24 g, quantitative) as a white solid.

The measurement conditions of the LC-MS analysis performed on the compounds obtained in the following Examples were as follows.

[Table 2] --------------------------------------------------------- Apparatus: Measurement method: Ion spray method MS measurement conditions: Molecular weight measurement Range: 100-800 amu Measurement interval: 0.28 amu Scan time: 1.253 sec Orifice voltage: 40 V LC measurement conditions: Column: YMC CombiScreen ODS, 50 × 4.6 mm ID, S-5 μm, 120 A Flow rate: 3.5 ml / min Measurement wavelength: 220, 254 nm Moving layer: Liquid A + Liquid B Liquid A: ion-exchanged water containing 0.05% trifluoroacetic acid Liquid B: acetonitrile containing 0.035% trifluoroacetic acid (for HPLC) The ratio is varied from 10% to 99% over time. 0min → 0.5min → 4.2min → 4.4min → 4.8min → 5.6min 10% 10% 99% 99% 10% 10% −−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−

Example 1 1- (2-bromo-5-methoxybenzyl) -4- (3
-(4- (2-fluoro-5-methoxybenzyl) piperidino) propyl) piperazine

Embedded image 1- (2-bromo-5-methoxybenzyl) -4- (3
-Chloropropyl) piperazine (303 mg, 0.84 mmol), 2
-Fluoro-5-methoxypiperidine (198 mg, 0.86 mmol
l) [synthesized by the method of JP-A-9-169731], potassium carbonate (30
A mixture of 2 mg, 2.18 mmol), potassium iodide (15 mg, 0.09 mmol), and acetonitrile (3.0 mL) was heated under reflux for 2 hours. After allowing the reaction solution to cool to room temperature, the inorganic salts were separated by filtration.
The residue obtained by concentrating the filtrate under reduced pressure was purified by flash silica gel column chromatography (ethyl acetate: triethylamine 20: 1) to give oily 1- (2-bromo-5-methoxybenzyl) -4- (3- ( 4- (2-fluoro-5-methoxybenzyl) piperidino) propyl)
Piperazine (313 mg, 68%) was obtained. Retention time (RT): 3.18 minutes M + H / Z: 54
8.2 (Mw: 547.22)

In the same manner as in Example 1, the following Examples 2 to
24 compounds were prepared. Table 3: Examples 2-20

[Table 3]

Embodiment 21

Embedded image ¹ H NMR (CDCl ₃ , δ) 8.11 (brs, 1H), 7.57 (d, 1H, J = 7.
3Hz), 7.42-7.35 (m, 2H), 7.21-7.05 (m, 3H), 6.97 (s,
1H), 6.67 (dd, 1H, J = 3.1, 8.7Hz), 3.79 (s, 3H), 3.55
(s, 2H), 3.11 (d, 2H, J = 11.5Hz), 2.71 (d, 2H, J = 5.9H
z), 2.54-2.47 (m, 10H), 2.39 (t, 2H, J = 7.3Hz), 2.15-
2.05 (m, 2H), 1.89-1.48 (m, 7H).

Table 4: Examples 22 to 24

[Table 4]

Example 25 1- (2-bromo-5-methoxybenzyl) -4- (3
-(4-benzyl) piperidino) propyl) piperazine

Embedded image 1- (3- (4-benzyl) piperidino) propyl) piperazine trihydrochloride (532 mg, 1.30 mmol), potassium carbonate
(1.08 g, 7.81 mmol) and N, N-dimethylformamide (7.0 mL) were added to 2-bromo-5-methoxybenzyl chloride (336 mg, 2.0 mmol), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction solution was poured into a 5% aqueous potassium carbonate solution and extracted twice with toluene. The organic layers were combined, washed with saturated saline, and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure to obtain oily 1- (2-bromo-5).
-Methoxybenzyl) -4- (3- (4-benzyl) piperidino) propyl) piperazine (596 mg, 91.6%) was obtained. ¹ H NMR (CDCl ₃ , δ) 7.40 (d, 1H, J = 8.6 Hz), 7.30-7.
12 (m, 5H), 7.07 (d, 1H, J = 3.3Hz), 6.67 (dd, 1H, J = 3.
3, 8.6Hz), 3.79 (s, 3H), 3.55 (s, 2H), 2.89 (d, 2H, J
= 11.6Hz), 2.55 (br, 4H), 2.52 (d, 2H, J = 6.9Hz), 2.
48 (br, 4H), 2.37-2.28 (m, 4H), 1.89-1.79 (m, 2H),
1.74-1.42 (m, 5H), 1.36-1.21 (m, 2H).

In the same manner as in Example 25, the following compounds of Examples 26 to 35 were produced. Table 5: Examples 26-28

[Table 5]

Embodiment 29

Embedded image ¹ H NMR (CDCl ₃ , δ) 7.47 (d, 1H, J = 8.3 Hz), 7.37 (s, 1
H), 7.30-7.12 (m, 6H), 7.05 (d, 1H, J = 7.3 Hz), 3.48
(s, 2H), 2.88 (d, 2H, J = 11.6Hz), 2.52 (d, 2H, J = 6.9H
z), 2.46 (br, 8H), 2.36-2.26 (m, 4H), 2.16 (s, 3H),
1.87-1.77 (m, 2H), 1.64-1.42 (m, 7H), 1.36-1.21 (m, 2
H).

Table 6: Examples 30 to 34

[Table 6]

Embodiment 35

Embedded image

Example 36 1- (2-Bromo-5-methoxybenzyl) -4- (4-
(4- (2,4-dimethylbenzyl) piperidino) butyl) piperazine

Embedded image 4- (2,5-dimethylbenzyl) piperidine hydrochloride (480 m
g, 2.00 mmol), 1N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous potassium carbonate, and the solvent was concentrated under reduced pressure.
-(2-Bromo-5-methoxybenzyl) -5,8-diazaspiro [4.5] decane iodide (940 mg, 2.01 mmol)
l), 37% potassium fluoride-activated alumina (basic) (1.0%)
g), and dimethyl sulfoxide (4.0 mL)
Heated to reflux for an hour. After allowing the reaction solution to cool to room temperature,
After pouring into a mixture of diethyl ether (1: 1) and stirring for 30 minutes, the inorganic substances were separated by filtration and separated. The aqueous layer was extracted with diethyl ether, combined with the organic layer, washed with brine, and dried over anhydrous potassium carbonate. The residue obtained by evaporating the solvent under reduced pressure was subjected to flash silica gel column chromatography (ethyl acetate: triethylamine 20:
1, then purified with ethyl acetate: ethanol: triethylamine 20: 1: 1) to give an oily 1- (2-bromo-5).
-Methoxybenzyl) -4- (4- (4- (2,4-dimethylbenzyl) piperidino) butyl) piperazine (455 mg, 41.
9%). RT 3.37 M + H / Z 542.3 MW 541.29

In the same manner as in the above Example 36, the following compounds of Examples 37 to 53 were produced. Table 7: Examples 37-51

[Table 7]

Table 8: Examples 52-53

[Table 8]

Example 54 1- (3- (4-benzylpiperidino) propyl) -4
-(3- (4-indoleoxy) -2-hydroxypropyl) piperazine

Embedded image 1- (3- (4-benzylpiperidino) propyl) piperazine (300 mg, 1.0 mmol), indole-4-oxymethyloxirane (189 mg, 1.0 mmol), ytterbium trifluoromethanesulfonate (60 mg, 0.097 mmol), dichloromethane (3.0 mL) was stirred overnight under a nitrogen atmosphere. Pour the reaction solution into 1N aqueous sodium hydroxide solution,
Extracted twice with chloroform. The organic layers were combined, washed with saturated saline, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The residue is purified by flash silica gel column chromatography (ethyl acetate: triethylamine 2
0: 1 then purified with ethyl acetate: ethanol: triethylamine 20: 1: 1) to give an oily 1- (3- (4-benzylpiperidino) propyl) -4- (3- (4-indoleoxy)- 2-hydroxypropyl) piperazine (15
9 mg, 32.4%). ¹ H-NMRδ (CDCl ₃ , ppm): 8.38 (br, 1H), 7.30-7.24 (m, 2
H), 7.20-7.00 (m, 6H), 6.65 (br, 1H), 6.53 (dd, J = 7.
6, 1.0Hz, 1H), 4.20-4.08 (m, 3H), 3.26 (br, 1H), 2.9
3 (dm, J = 11.5Hz, 2H), 2.70 (br, 2H), 2.61 (d, J = 5.3H
z, 2H), 2.53 (d, J = 5.6Hz, 2H), 2.48 (br, 6H), 2.41-2.2
8 (m, 4H), 1.89 (t, J = 11.5Hz, 2H), 1.71 (app.quint,
J = 7.0Hz, 2H), 1.64 (dm, J = 12.5Hz, 2H), 1.59-1.45 (m,
1H), 1.33 (qd, J = 12.5, 3.5Hz, 2H).

In the same manner as in the above Example 54, the following compounds of Examples 55 to 56 were produced. Table 9: Examples 55-56

[Table 9]

Embodiment 57

Embedded image 289.7 mg of the compound obtained in Example 26, 48% hydrobromic acid 2.0
A mixture of 1.0 ml of acetic acid and 1.0 ml of acetic acid was stirred at about 100 ° C. for 4.5 hours. 1.0 ml of 48% hydrobromic acid was added, and the mixture was further stirred at the same temperature for 1 hour. Cool the reaction to room temperature, 5%
The mixture was poured into an aqueous solution of calcium carbonate and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by TLC preparative (CHCl ₃ : MeOH: Et ₃ N = 40: 2: 1) to give an oily 1- (2-bromo-5-hydroxybenzyl) -4- (4- (4-benzylpi Peridino) butyl) piperazine (174.4 mg, RT: 3.12 min) was obtained.

Example 58 A compound of the following formula was obtained in the same manner as in Example 57.

Embedded image

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/28 A61P 25/28 25/30 25/30 43/00 114 43/00 114 C07D 211/14 C07D 211/14 211/18 211/18 211/44 211/44 401/06 401/06 401/12 401/12 401/14 401/14 (72) Inventor Atsushi Kojima 4-2-1 Takashi Takarazuka City, Hyogo Prefecture No. Sumitomo Techno Service Co., Ltd. F-term (reference) 4C054 AA02 CC06 DD01 EE01 FF04 FF08 FF12 FF25 4C063 AA01 AA03 BB03 BB07 CC10 DD06 EE01 4C086 AA01 AA02 AA03 BC21 BC50 GA07 GA12 MA01 MA04 ZA14 Z15ZA ZA36 ZA42 ZA66 ZA70 ZA81 ZC14 ZC39

Claims (11)

[Claims] (1) Formula (1) (In the formula, Cy ¹ represents a cyclic group selected from the group consisting of a monocyclic aromatic group, a bicyclic fused hydrocarbon ring group and a bicyclic fused heterocyclic group. However, these cyclic groups are substituents. And when the cyclic group is a bicyclic fused ring group, at least one of the rings constituting the fused ring is an aromatic ring, and Cy ² may be substituted. Y ¹ and Y represent an aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted cycloalkyl group.
² independently represents a single bond, a methylene or an oxygen atom. Y ³ represents an optionally substituted alkylene. Y ⁴ represents an optionally substituted alkylene, an optionally substituted alkenylene or an optionally substituted alkynylene. Y ⁵ represents a single bond, an oxygen atom, a sulfur atom or -NH-. R ¹ and R ² each independently represent a hydrogen atom or a substituent. R ³ and R ⁴
Each independently represents a hydrogen atom, a hydroxyl group or an alkyl group. Q and Z each independently represent a methine or nitrogen atom. n and m are each independently 1, 2 or 3
Represents ) A serotonin reuptake inhibitor comprising, as an active ingredient, a compound represented by the formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof. 2. The serotonin reuptake inhibitor according to claim 1, wherein one of Y ¹ and Y ² is a single bond and the other is an oxygen atom, or both are single bonds. 3. The serotonin reuptake inhibitor according to claim 1, wherein R ³ and R ⁴ are hydrogen atoms. 4. The method of claim 1, wherein m is 2 and n is 2.
4. The serotonin reuptake inhibitor according to 2 or 3. 5. The serotonin reuptake inhibitor according to claim 1, wherein Z is a nitrogen atom. 6. The method according to claim 1, wherein Q is a nitrogen atom.
6. The serotonin reuptake inhibitor according to 4 or 5. 7. The serotonin reuptake inhibitor according to claim 1, wherein Cy ² is an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group. . 8. The serotonin reuptake inhibitor according to claim 1, wherein Y ⁵ is a single bond or an oxygen atom. 9. The method according to claim 1, wherein Y ⁵ is a single bond.
The serotonin reuptake inhibitor according to 4, 5, 6, or 7. 10. The serotonin reuptake inhibitor according to claim 1, which is an anxiolytic or an antidepressant. 11. The formula: (In the formula, Cy ³ represents a cyclic group selected from the group consisting of a monocyclic aromatic group, a bicyclic fused hydrocarbon ring group and a bicyclic fused heterocyclic group, provided that these cyclic groups are substituents. And when the cyclic group is a bicyclic fused ring group, at least one of the rings constituting the fused ring is an aromatic ring, and Cy ⁴ may be substituted. Represents an aryl group, an optionally substituted aromatic heterocyclic group or an optionally substituted cycloalkyl group, wherein Y ⁶ and Y ⁷ are
One represents a single bond and the other represents a single bond or an oxygen atom.
Y ⁸ represents an optionally substituted alkylene. Y ⁹ represents a single bond, an optionally substituted alkylene, an optionally substituted alkenylene, or an optionally substituted alkynylene. Y ¹⁰ represents a single bond, an oxygen atom, a sulfur atom or —NH—. R ⁵ and R ⁶ each independently represent a hydrogen atom or a substituent. R ⁷ and R ⁸ are
Each independently represents a hydrogen atom, a hydroxyl group or an alkyl group. W represents a methine or nitrogen atom. n represents 1, 2 or 3. Or a prodrug thereof or a pharmaceutically acceptable salt thereof.