JP2000103782A - Cyclic amine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject low-toxic, safe new compound exhibiting excellent antagonism against tachykinin receptors, and useful in preventing or treating dysuria, digestive system diseases, vomiting, or the like. SOLUTION: This new compound is represented by formula I [R1 is H or a 1-6C alkyl; X is H, OH or the like; Y is a 1-4C alkylene or alkenylalkylene (may bear a 1-3C alkyl); ring A is a 5 to 7-membered cyclic amine which contains one N-atom and may be crosslinked at any site via 1-3C atom(s); ring B is a substitutable homocyclic or heterocyclic ring; ring C is a substitutable homocyclic or heterocyclic ring (except indole); (n) is 1 or 2], e.g. 4-methoxy-1-(2- phenylethyl)-1-4-[(phenylsulfinyl)methyl]piperidine. The compound of formula I is obtained by reaction between a compound of formula II e.g. 4- methoxy-4-[(phenylsulfinyl)methyl]piperidine} and a compound of formula III (Z is a reactive residue) (e.g. 2-phenylenthyl bromide) in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel cyclic amine derivative having a tachykinin receptor antagonistic activity or a pharmacologically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition containing the cyclic amine derivative. is there.

[0002]

2. Description of the Related Art Tachykinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their respective receptors (neurokinin 1 (NK ₁ ), neurokinin 2 (NK) ₂ ) It is known that various physiological activities are expressed by binding to neurokinin 3 (NK ₃ )). These tachykinins act as mediators of central and peripheral primary sensory neurons and have physiological activities such as hyperdiuresis, neuronal excitability, vascular hyperpermeability, vasodilation, smooth muscle contraction, and immunity. Have various pathological conditions (frequent urination,
Urinary incontinence, vomiting, inflammation, allergies, airway disease, pain, central nervous system disease, etc.). Therefore, development of a compound having an excellent tachykinin receptor antagonistic activity as an agent for preventing and treating various pathological conditions as described above, and having excellent safety, long-lasting properties and the like is desired. At present, the following compounds and the like have been disclosed as compounds having a substance P receptor antagonistic action.

(1) Japanese Patent Application Laid-Open No. 1-287095 discloses a formula: (Wherein, R ¹ is hydrogen or an amino protecting group, R ² is hydrogen, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R ³ is (Lower) alkyl group, -N
An (R ⁴ ) (R ⁵ ) group (wherein R ⁴ and R ⁵ each represent hydrogen, an aryl group or a lower alkyl group optionally having a suitable substituent, or R ⁴ and R ⁵ represent Combine with each other to form a benzene condensed lower alkylene group), or-
A group represented by an OR ⁶ group (wherein R ⁶ represents hydrogen, an aryl group or a lower alkyl group which may have a suitable substituent), wherein A is a single bond or one or two amino acids; means residues, if a is meant a single amino acid residue 1 of D-Trp R ⁴ represents a non-hydrogen). ) And salts thereof are disclosed.

(2) Formulas described in EP-A-429366: Are disclosed.

(3) In WO 91/09844, the formula is: Are disclosed.

(4) EP-A-532456 has the formula: Are disclosed.

(5) EP-A-522808 describes the formula: Are disclosed.

(6) In WO 93/01169, the formula is: Are disclosed.

(7) JP-A-8-67678 discloses a formula: (Wherein, A ring and B ring are homo or hetero rings, at least one of which is a hetero ring; C ring is a benzene ring; R is H or a hydrocarbon residue; one of X and Y is -NR ^1- (R ¹ is H or a hydrocarbon residue) or —O—, and the other is —CO— or —C
S-, or one -N =, the other ⁼ CR ² - ^(R 2
Is H, a halogen, a hydrocarbon residue, an amino group or a hydroxyl group); n represents 1 or 2. ) Or a salt thereof is disclosed.

(8) Japanese Patent Application Laid-Open No. 9-104674 shows the formula: (Wherein, X represents a hydrogen atom or an oxygen atom, Y represents a nitrogen atom or an oxygen atom which may be alkylated or acylated, and R ¹ contains a hydrogen atom, a lower alkyl group, a lower alkanoyl group, and a nitrogen atom. Alkyl group, carbamoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, (4-phenylpiperazine-1
-Yl) methyl group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkyl group containing a hydroxyl group, a lower alkanoyl group, or a lower alkoxy group. Rings A and B represent a benzene ring which may have a substituent. ) Is disclosed.

(9) JP-A-9-263587 describes the formula: (Wherein the M ring has a partial structure -X = Y <, -N = C
A heterocyclic ring having <, -CO-N <or -CS-N <;
^a and R ^b are linked together to form ring A, or are the same or different and are a hydrogen atom or a substituent on ring M;
Ring and ring B are each an optionally substituted homo- or heterocyclic ring, at least one of which is an optionally substituted heterocyclic ring; ring C may have an optionally substituted substituent; A good homo or heterocyclic ring; a ring Z is an optionally substituted ring; and n is an integer of 1 to 6. ) Is disclosed.

Further, the following compounds and the like are disclosed as compounds having a neurokinin A receptor antagonistic action. (1) "Life Sciences" 50 volumes,
On page 101 (1992): Are disclosed.

(2) “Bioorganic and Medicinal Chemistry Letters (Bioorg. Med. Che.
m. Lett.), Vol. 6, pp. 951 (1996): Are disclosed.

(3) In WO93 / 14084, the formula is: (Wherein R ¹ is one or two C ₁ -C ₄ alkyl groups,
A C ₁ -C ₄ alkoxy group, a trifluoromethyl group or a phenyl group optionally substituted with a halogen atom, R ²
Is a hydrogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group, R ³ is a hydrogen atom or a C ₁ -C ₄ alkyl group, R ⁴
Is a hydrogen _atom, an alkyl group or a _C 1 -C ₄ alkoxy group C 1 ~C _4, ^{R 5} a hydrogen atom or an alkyl group _C 1 -C _4, a trifluoromethyl group, a cyano group or a halogen atom, n represents Indicates 0, 1 or 2. ) Or a salt thereof is disclosed.

[0015]

At present, it has excellent antagonism against tachykinin receptor as a preventive or therapeutic agent for the above-mentioned various disease states, and has sufficient safety and sustainability. No compounds have been found that can be satisfactory pharmaceuticals. An object of the present invention is to provide a pharmaceutical composition having a different chemical structure from known compounds including the above-mentioned compounds and having an excellent antagonism to a tachykinin receptor, a tachykinin receptor antagonist, a prophylactic or therapeutic agent for dysuria, digestion, An object of the present invention is to provide an agent for preventing or treating organ diseases, an agent for preventing or treating emesis, and an agent for preventing or treating central nervous system diseases.

[0016]

Means for Solving the Problems The present inventors have the following general formula (1): (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C ₁ -C ₆ alkoxy group, Y is a C ₁ -C ₄ alkylene group or an alkenyl alkylene group which may have a C ₁ -C ₃ alkyl group, A ring Is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, ring B is a homo- or heterocyclic ring which may have a substituent, ring C Represents an optionally substituted homo- or heterocyclic ring (however, excluding an indole ring), and n represents 1 or 2. And a salt, hydrate and solvate thereof.

The present inventors have found that ring A is a piperidine ring, ring B is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, A homo- or heterocyclic ring optionally having 1 to 3 substituents each independently selected from a C _{1 to} C ₆ alkoxy group, an amino group, a cyano group or a nitro group are shown, C ring is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted aryl group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkoxy group , An amino group, a cyano group or a nitro group, each independently selected from a homo- or heterocyclic ring optionally having 1 to 3 substituents (provided that
A cyclic amine derivative of the general formula (1) or a salt, hydrate or solvate thereof.

The present inventors have proposed a cyclic amine derivative of the general formula (1) wherein Ring A represents a piperidine ring and Ring C represents a benzene ring which may have a substituent, or salts, hydrates and solvates thereof. Offer things.

The present inventors have proposed a cyclic amine derivative of the general formula (1) in which ring A represents a piperidine ring and ring C represents an indene ring which may have a substituent, or salts, hydrates and solvates thereof. Offer things.

The present inventors have proposed a cyclic amine derivative of the general formula (1) wherein Ring A represents a piperidine ring and Ring C represents a benzofuran ring which may have a substituent, or a salt, hydrate and solvate thereof. Offer things.

The present inventors have proposed a cyclic amine derivative of the general formula (1) wherein ring A represents a piperidine ring and ring C represents a benzothiophene ring which may have a substituent, or a salt, hydrate and solvate thereof. Offer things.

The present inventors have the following general formula (2)(Where R¹Is a hydrogen atom or C₁~ C₆An alkyl group of
X represents a hydrogen atom, a hydroxy group, or C₁~ C₆Arco
Xyl group, Ring A is bridged at any position containing one nitrogen atom
5-, 6- or 7-membered cyclic amine, B-ring which may be
Is an homo or heterocyclic ring which may have a substituent, n is 1 or
Indicates 2. ) And the following general formula (3)(Where Y is C₁~ C₄Alkylene group or alkenyl of
Alkylene group (C₁~ C ₃Having an alkyl group of
Good), Z is a reactive residue, and C ring may have a substituent.
Good homo or heterocyclic ring (excluding indole ring)
Show. ) In the presence of a base.
To produce a cyclic amine derivative of the general formula (1)
provide.

The present inventors provide a tachykinin receptor antagonist comprising a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. .

The present inventors have developed a neurokinin A receptor antagonist comprising a cyclic amine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. provide.

The present inventors have disclosed a substance P and a neurokinin A receptor comprising a cyclic amine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. Provide an antagonist.

The present inventors have proposed a bladder for pollakiuria, urinary incontinence and the like, characterized by containing a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provided is an agent for preventing or treating dysuria including a functional disease.

The present inventors have developed ulcerative colitis and Crohn's disease characterized by containing a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. And / or a prophylactic or therapeutic agent for gastrointestinal diseases.

The inventors of the present invention have provided a pharmaceutical composition comprising the cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provided is a preventive or therapeutic agent for vomiting induced by pregnancy, migraine, postoperative disease, gastrointestinal motility, side effects of drug administration, and the like.

The present inventors have developed anxiety, depression, Parkinson disease, Provided is an agent for preventing or treating central nervous system diseases including Huntington's disease, dementia and the like.

The present inventors have ascertained tachykinin-related asthma and cough, comprising a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. And a therapeutic agent for pain, migraine, toothache, rheumatoid arthritis and the like.

The present inventors have the following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
The present invention provides a cyclic amine derivative represented by the following formula (excluding the indole ring)) or a salt, hydrate and solvate thereof.

The present inventors have found that ring A is a piperidine ring, ring B is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, A homo- or heterocyclic ring optionally having 1 to 3 substituents each independently selected from a C _{1 to} C ₆ alkoxy group, an amino group, a cyano group or a nitro group Provided is a cyclic amine derivative represented by the general formula (4) or a salt, hydrate or solvate thereof (excluding an indole ring).

The present inventors have proposed a cyclic amine derivative of the general formula (4) wherein Ring A represents a piperidine ring and Ring C represents a benzene ring which may have a substituent, or salts, hydrates and solvates thereof. Offer things.

The present inventors have proposed a cyclic amine derivative of the general formula (4) wherein ring A represents a piperidine ring and ring C represents a benzofuran ring which may have a substituent, or a salt, hydrate and solvate thereof. Offer things.

The present inventors have proposed a cyclic amine derivative of the general formula (4) in which ring A represents a piperidine ring and ring C represents a benzothiophene ring which may have a substituent, or a salt, hydrate and solvent thereof. Provide Japanese food.

The present inventors have made the following general formula (5) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group; R ⁴ is a t-butyl group or a benzyl group; X ¹ is a halogen atom; A 5-, 6-, or 7-membered cyclic amine containing a nitrogen atom, which may be cross-linked at any position via 1 to 3 carbon atoms. The compound represented by the following general formula (6) (Wherein ring B represents a homo- or heterocyclic ring which may have a substituent (s)). provide.

The present inventors have the following general formula (7) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and R ⁴ is t A butyl or benzyl group, the A ring contains one nitrogen atom,
A 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position via 1 to 3 carbon atoms, and ring B represents a homo- or heterocyclic ring which may have a substituent . A method for producing the compound represented by the general formula (8) by oxidizing the compound represented by the general formula (8).

The present inventors provide a tachykinin receptor antagonist comprising a cyclic amine derivative represented by the general formula (4) or a salt, hydrate or solvate thereof as a pharmaceutical composition. .

The present inventors have developed a neurokinin A receptor antagonist comprising a cyclic amine derivative represented by the general formula (4) or a salt, hydrate or solvate thereof as a pharmaceutical composition. provide.

The present inventors have disclosed a substance P and a neurokinin A receptor comprising a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide an antagonist.

The present inventors have proposed a bladder for pollakiuria and urinary incontinence characterized by containing a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provided is an agent for preventing or treating dysuria including a functional disease.

The present inventors have developed ulcerative colitis and Crohn's disease characterized by containing a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. And / or a prophylactic or therapeutic agent for gastrointestinal diseases.

The present inventors have provided a pharmaceutical composition comprising the cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition, Provided is a preventive or therapeutic agent for vomiting induced by pregnancy, migraine, postoperative illness, gastrointestinal motility depression, side effects of drug administration, and the like.

The present inventors have anxiety, depression, Parkinson's disease, characterized by containing a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provided is a preventive or therapeutic agent for central nervous system diseases including Huntington's disease, dementia and the like.

The present inventors have ascertained tachykinin-related asthma and cough, comprising a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. For improving pain, migraine, toothache, rheumatoid arthritis and the like.

Here, the C ₁ -C ₆ alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group and the like. The C ₁ -C ₆ alkoxy group means a methoxy group, an ethoxy group, a propoxy group,
It means an isopropoxy group, a t-butoxy group, a hexyloxy group and the like. The C ₁ -C ₃ alkylene group or alkenyl alkylene group of the alkyl group which may have a C ₁ -C _4, a methyl group, an ethyl group, a propyl group, methylene group which may be substituted with an isopropyl group , Ethylene, propylene, allyl and the like. The reactive residue is a chlorine atom, a bromine atom, an iodine atom or OSO ₂ R
² (R ² is a methyl group, a trifluoromethyl group, a phenyl group, a 4-methylphenyl group or a 4-nitrophenyl group)
And so on. A 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom is
It means a pyrrolidine ring, piperidine ring, homopiperidine ring, azabicyclo [3.2.1] octane ring and the like. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Optionally substituted C₁~ C₆Archi
Is a halogen atom (fluorine atom, chlorine atom, bromine
Atom, iodine atom), hydroxyl group, C₁~ C₆No
It has 1 to 5 substituents selected from alkoxy groups and the like.
May be C₁~ C₆Means an alkyl group. Replaced
Aryl group which may be a halogen atom, C₁~ C
₆Alkyl group, hydroxyl group, C₁~ C₆Arco
Xy group, amino group, formylamino group, C₁~ C₆No
Alkylcarbonylamino group (acetylamino group, propyl
Onylamino group, butyrylamino group, etc.), C₁~ C₆of
Alkylsulfonylamino group (methylsulfonylamino
Group, ethylsulfonylamino group, etc.)
Good arylsulfonylamino group (phenylsulfonyl
Amino group, 4-methylphenylsulfonylamino group, etc.)
And may have 1 to 5 substituents selected from
It means a reel group (phenyl group, naphthyl group, etc.). Place
C which may be replaced₁~ C₆Is an alkoxy group
Logen atom, hydroxyl group, C₁~ C₆The alkoxy of
Group, amino group, formylamino group, C₁~ C₆Archi
Carbonylamino group, C₁~ C₆Alkylsulfoni
Amino group, optionally substituted arylsulfonyl
Having 1 to 5 substituents selected from amino groups, etc.
Good C₁~ C₆Means an alkoxy group. Ring B and
The homocyclic ring of the C ring means a benzene ring, a naphthalene ring, etc.
I do. Heterocycles of ring B and ring C are nitrogen atom, oxygen atom
1 to 3 hetero atoms arbitrarily selected from
A 5- or 6-membered aromatic monocyclic heterocycle containing atoms, or
Represents a 9- or 10-membered fused aromatic heterocycle.

As a preferred compound of the present invention, 4-methoxy-1- (2-phenylethyl) -4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (3-chlorophenyl) ethyl] -4-methoxy-4-[(phenyl Sulfinyl) methyl] piperidine, 1- [2- (4-chlorophenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 4-methoxy-1- [2- (3-nitrophenyl) ethyl]
-4-[(Phenylsulfinyl) methyl] piperidine, 1- [2- (3-biphenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (4-biphenyl) ethyl] -4 -Methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (3,5 dichlorophenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl)
Methyl] piperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 4-methoxy-1- [2- (1-naphthyl) ethyl] -4 -[(Phenylsulfinyl) methyl] piperidine, 4-methoxy-1- [2- (2-naphthyl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine, 4-methoxy-4-[(phenylsulfinyl) methyl] -1- [ 2- (2-thienyl) ethyl] piperidine, 4-methoxy-4-[(phenylsulfinyl) methyl] -1- [2- (3-thienyl) ethyl] piperidine, 1- [2- (inden-3-yl) ethyl] -4-methoxy- 4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (be Zofran-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (5-Fluorobenzothiophen-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (5-chlorobenzothiophen-3-yl) ethyl] -4-methoxy-4 -[(Phenylsulfinyl) methyl] piperidine, 4-methoxy-1- [2- (5-methylbenzothiophen-3-yl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (1,2 -Benzisoxazole-3
-Yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 4-methoxy-1- [2- (1-methylindazol-3-yl) ethyl]
4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (1H-benzimidazol-1-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (2, 3-dihydroindol-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1-[(3,5 dichlorophenyl) methyl] -4
-Methoxy-4-[(phenylsulfinyl) methyl]
Piperidine, 1- [3- (3,5 dichlorophenyl)
Propyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, 1- [1- (3,5 dichlorophenyl) propen-3-yl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine,
1- [2- (3,5 dichlorophenyl) ethyl] -4
-Methoxy-4-[(phenylsulfonyl) methyl] piperidine, 1- [2- (benzothiophen-3-yl)
Ethyl] -4-methoxy-4-[(phenylsulfonyl) methyl] piperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-[(phenylsulfinyl)
Methyl] piperidin-4-ol, 1- [2- (3,5
Dichlorophenyl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine, 4-[(4-fluoro Phenylsulfinyl) methyl] -4-methoxy-1- (2-phenylethyl) piperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine, 1- [ 2- (5-fluorobenzothiophene-3
-Yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine, 4-methoxy-4-[(4-methoxyphenylsulfinyl)
Methyl] -1- (2-phenylethyl) piperidine, 1
-[2- (benzofuran-3-yl) ethyl] -4-methoxy-4-[(4-methoxyphenylsulfinyl)
Methyl] piperidine, 1- (2-phenylethyl) -4
-[(4-trifluoromethylphenylsulfinyl)
Methyl] piperidin-4-ol, 1- [2- (benzofuran-3-yl) ethyl] -4-[(4-trifluoromethylphenylsulfinyl) methyl] piperidin-4-ol, 4-methoxy-4-[(2naphthylsulfinyl) methyl] -1- (2-phenylethyl) piperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4-[(2naphthylsulfinyl) methyl] piperidine, 4-[(4-fluorophenylsulfinyl) methyl]- 4-methoxy-1- (3-phenylpropyl) piperidine, 4-methoxy-1- (2-phenylethyl) -4- [1- (phenylsulfinyl) ethyl] piperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4 -[1- (phenylsulfinyl) Ethyl] piperidine, 1 over [2 chromatography (Benzofuran 3 Iru) ethyl] -3 Metokishi 3 over [(phenylsulfinyl) methyl] piperidine, 3 Metokishi 8-1 (2-phenylethyl) -3
-[1- (phenylsulfinyl) ethyl] -8-azabicyclo [3.2.1] octane, 8- [2- (benzofuran-3-yl) ethyl] -3-methoxy-3- [1
-(Phenylsulfinyl) ethyl] -8-azabicyclo [3.2.1] octane, 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxy-1- [2
-(3-nitrophenyl) ethyl] piperidine, 1-
[2- (3-aminophenyl) ethyl] -4-[(4-
Fluorophenylsulfinyl) methyl] -4-methoxypiperidine, 4-ethoxy-4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) piperidine, 4-[(4-fluorophenylsulfinyl) methyl ] -1- (2-phenylethyl) -4
-Propoxypiperidine, 4-butoxy-4-[(4-
Fluorophenylsulfinyl) methyl] -1- (2-
Phenylethyl) piperidine, 4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) -4- (2-propoxy) piperidine, 4-cyclopropylmethoxy-4-[(4-fluorophenyl Sulfinyl) methyl] -1- (2-phenylethyl) piperidine, 4- (2-fluoroethoxy) -4-[(4
-Fluorophenylsulfinyl) methyl] -1- (2
-Phenylethyl) piperidine, 4- (2,2,2-trifluoroethoxy) -4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl)
Piperidine, 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-methoxyethoxy) -1-
(2-phenylethyl) piperidine, 4-benzyloxy-4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) piperidine, 1-
[2- (benzothiophen-3-yl) ethyl] -4-
Ethoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4-propoxypiperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-butoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine, 1- [2- (benzothiophen-3-yl) ethyl]- 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-propoxy) piperidine, 1- [2- (benzothiophene-3)
-Yl) ethyl] -4- (2-fluoroethoxy) -4
-[(4-fluorophenylsulfinyl) methyl] piperidine, 1- [2- (benzothiophen-3-yl)
Ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4- (2,2,2-trifluoroethoxy) piperidine, 1- [2- (benzothiophen-3-
Yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4- (2-methoxyethoxy) piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-benzyloxy-4 -[(4-fluorophenylsulfinyl) methyl] piperidine, 4-[(4
-Fluorophenylthio) methyl] -1- (2-phenylethyl) -4-methoxypiperidine, 1- [2-
(3,5-bistrifluoromethylphenyl) ethyl]
-4-methoxy-4-phenylthiomethylpiperidine,
1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(4-fluorophenylthio) methyl] -4-methoxypiperidine, 1- [2- (3,5
-Bistrifluoromethylphenyl) ethyl] -4-
[(3-fluorophenylthio) methyl] -4-methoxypiperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(2-fluorophenylthio) methyl] -4-methoxy Piperidine, 1-
[2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(4-bromophenylthio) methyl]-
4-methoxypiperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(3-bromophenylthio) methyl] -4-methoxypiperidine, 1- [2- (3,5 -Bistrifluoromethylphenyl) ethyl] -4-[(4-chlorophenylthio) methyl] -4-methoxypiperidine, 1- [2- (3,5
-Bistrifluoromethylphenyl) ethyl] -4-
[(3-chlorophenylthio) methyl] -4-methoxypiperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-methoxy-4-[(4-
Methylphenylthio) methyl] piperidine, 1- [2-
(3,5-bistrifluoromethylphenyl) ethyl]
-4-methoxy-4-[(3-methylphenylthio) methyl] piperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-methoxy-4-
[(2-methylphenylthio) methyl] piperidine, 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-methoxy-4-[(4-nitrophenylthio) methyl] piperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-methoxy-4-[(4-tri Fluoromethylphenylthio) methyl] piperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(2,6-dichlorophenylthio) methyl] -4-methoxypiperidine,
1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine,
1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-cyclohexylthiomethyl-4-methoxypiperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4- Phenylthiomethylpiperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-[(4-fluorophenylthio) methyl]
4-methoxypiperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-[(3-fluorophenylthio) methyl] -4-methoxypiperidine, 1- [2-
(Benzofuran-3-yl) ethyl] -4-[(2-fluorophenylthio) methyl] -4-methoxypiperidine, 1- [2- (benzofuran-3-yl) ethyl]-
4-[(4-bromophenylthio) methyl] -4-methoxypiperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-[(3-bromophenylthio) methyl] -4-methoxypiperidine 1- [2- (benzofuran-3-yl) ethyl] -4-[(4-chlorophenylthio) methyl] -4-methoxypiperidine, 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(3-
Chlorophenylthio) methyl] -4-methoxypiperidine, 1- [2- (benzofuran-3-yl) ethyl]-
4-methoxy-4-[(4-methylphenylthio) methyl] piperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4-[(3-methylphenylthio) methyl] piperidine , 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4-[(2
-Methylphenylthio) methyl] piperidine, 1- [2
-(Benzofuran-3-yl) ethyl] -4-methoxy-4-[(4-nitrophenylthio) methyl] piperidine, 1- [2- (benzofuran-3-yl) ethyl]-
4-methoxy-4-[(4-trifluoromethylphenylthio) methyl] piperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-[(2,6-dichlorophenylthio) methyl] -4 -Methoxypiperidine, 1-
[2- (Benzofuran-3-yl) ethyl] -4-
[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine, 1- [2- (benzofuran-3-yl) ethyl] -4-cyclohexylthiomethyl-4-methoxypiperidine, 4-ethoxy- 4-
[(4-fluorophenylthio) methyl] -1- (2-
Phenylethyl) piperidine, 4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl)-
4-propoxypiperidine, 4-butoxy-4-[(4
-Fluorophenylthio) methyl] -1- (2-phenylethyl) piperidine, 4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl) -4-
(2-propoxy) piperidine, 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl]
-1- (2-phenylethyl) piperidine, 4- (2-
Fluoroethoxy) -4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl) piperidine, 4-[(4-fluorophenylthio) methyl] -1
-(2-phenylethyl) -4- (2,2,2-trifluoroethoxy) piperidine, 4-[(4-fluorophenylthio) methyl] -4- (2-methoxyethoxy)
-1- (2-phenylethyl) piperidine, 4-benzyloxy-4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl) piperidine, 1-
[2- (benzothiophen-3-yl) ethyl] -4-
Ethoxy-4-[(4-fluorophenylthio) methyl] piperidine, 1- [2- (benzothiophen-3-
Yl) ethyl] -4-[(4-fluorophenylthio)
Methyl] -4-propoxypiperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-butoxy-
4-[(4-fluorophenylthio) methyl] piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-[(4-fluorophenylthio) methyl]-
4- (2-propoxy) piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] piperidine, 1- [2- (Benzothiophene-3-
Yl) ethyl] -4- (2-fluoroethoxy) -4-
[(4-fluorophenylthio) methyl] piperidine,
1- [2- (benzothiophen-3-yl) ethyl]-
4-[(4-fluorophenylthio) methyl] -4-
(2,2,2-trifluoroethoxy) piperidine, 1
-[2- (benzothiophen-3-yl) ethyl] -4
-[(4-fluorophenylthio) methyl] -4- (2
-Methoxyethoxy) piperidine, 1- [2- (benzothiophen-3-yl) ethyl] -4-benzyloxy-4-[(4-fluorophenylthio) methyl] piperidine, +)-1- [2- ( Benzothiophen-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine, (R) -1
-[2- (benzothiophen-3-yl) ethyl-4-
Methoxy-4-[(phenylsulfinyl) methyl] piperidine, (S) -1- [2- (benzothiophene-3)
-Yl) ethyl-4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, (+)-4-[(4-
Fluorophenylsulfinyl) methyl] -4-methoxy-1- (2-phenylethyl) piperidine, (-)-
4-[(4-fluorophenylsulfinyl) methyl]
4-methoxy-1- (2-phenylethyl) piperidine and the like can be exemplified.

When preparing a salt of the compound of the present invention, hydrochloric acid,
Hydrobromic acid, sulfuric acid, inorganic acids such as nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid,
Examples thereof include pharmacologically acceptable salts with organic acids such as citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid. The compound of the present invention or a salt thereof includes an optically active form and a stereoisomer in addition to the racemic form.

The compound of the present invention can be produced by various synthetic methods. Next, typical production steps of the compound of the present invention and a salt thereof will be described.

In this step, compound (I) (rings Y, Z and C are the same as described above) and compound (II) (R ¹ , X, ring A, ring B and n are the same as described above) The compound (III) (R ¹ , X, Y, A ring, B ring, C ring and n
Is the same as described above). This step is performed at room temperature to 100 ° C. using 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (II) relative to compound (I). Examples of the base used in this step include organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, and collidine;
Sodium hydrogen carbonate, sodium carbonate, potassium carbonate,
An inorganic base such as calcium carbonate, cesium carbonate or tripotassium phosphate is used. As the solvent, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used. Compound (I) and compound (II) used in this step can be produced by referring to a known method.

In this step, compound (IV) (R ¹ , R ³ ,
R ⁴ , X ¹ and ring A are the same as described above) and compound (V) (B
This is a step of producing a compound (VI) (R ¹ , R ³ , R ⁴ , ring A and ring B are the same as described above) by reacting the same ring as described above in the presence of a base. In this step, compound (IV)
Compound (V) is used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents.
The reaction is performed at room temperature to 150 ° C. using an equivalent amount. As the base used in this step, triethylamine, tributylamine,
Diisopropylethylamine, N-methylmorpholine,
Pyridine, lutidine, collidine, 1,8-diazabicyclo [5.4.0] -7-undecene, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, water Sodium oxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate,
Tripotassium phosphate, potassium fluoride, cesium fluoride,
Sodium hydride, potassium hydride, calcium hydride, Triton B and the like can be mentioned. Alternatively, a polystyrene resin (crosslinked with divinylbenzene) having a dimethylamino group, a piperidino group, a morpholino group, a 1,5,7-triazabicyclo [4.4.0] -5-deceno group, or the like may be used as a base. Can also be used. As the solvent, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used. Compound (IV) and compound (V) used in this step can be produced by referring to a known method.

In this step, compound (VI) (R ¹ , R ³ , R
⁴ , ring A and ring B are the same as described above, to thereby give compound (VII) (R ¹ , R ³ , R ⁴ , ring A and ring B).
The ring is the same as described above, and m is a step for producing 1 or 2). As the oxidizing agent used in this step, 3-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peracetic acid, aqueous hydrogen peroxide, hydrogen peroxide-urea complex, dimethyldioxolan, cumene hydroperoxide, Examples include t-butyl hydroperoxide, hypochlorous acid, iodosobenzene and the like. As the solvent, an inert solvent which does not participate in the reaction, for example, methanol, ethanol, isopropanol, t-butanol, ethoxyethanol, 2,2,2
-Trifluoroethanol, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, toluene, carbon tetrachloride, water alone, or two or more kinds Are used in a mixture at an arbitrary ratio. Compound (VI
In the compound of the formula (I) wherein m is 1, an optical isomer based on a sulfur atom exists. When producing such an optical isomer based on a sulfur atom, asymmetric oxidation can be performed using an optically active oxidizing agent or an optically active catalyst. Reagents used for asymmetric oxidation include camphorylsulfonyloxaziridine, dichlorocamforylsulfonyloxaziridine, dimethoxycamphorylsulfonyloxaziridine, tetraisopropoxytitanium and (+)-or (-)-tartaric acid Diethyl, (+)-or (-)-N,
N'-bis (3,5-di-tert-butylsalicylidene)-
1,2-cyclohexanediaminomanganese (II
I) Chloride and the like. Of these, tetraisopropoxytitanium and (+)-or (-)-diethyl tartrate, or (+)-or (-)-N, N'-bis (3,5-di-tert-butylsalicylidene)- When 1,2-cyclohexanediaminomanganese (III) chloride or the like is used, the reaction is performed in the presence of an appropriate oxidizing agent.
Examples of such oxidizing agents include 3-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peracetic acid, aqueous hydrogen peroxide, hydrogen peroxide-urea complex, dimethyldioxolan,
Cumene hydroperoxide, t-butyl hydroperoxide, hypochlorous acid, iodosobenzene and the like can be mentioned.
Also, (+)-or (-)-N, N'-bis (3,5-
When (di-t-butylsalicylidene) -1,2-cyclohexanediaminomanganese (III) chloride or the like is used, a suitable additive can be added together with the oxidizing agent. Examples of such additives include formic acid, acetic acid, pivalic acid, benzoic acid, 4-chlorobenzoic acid, 2-phenylbenzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, citric acid, malonic acid, and succinic acid. Acid, malic acid, tartaric acid, p-toluenesulfonic acid, boric acid, phosphoric acid, sulfuric acid, nitric acid, carbonic acid and the like, and their sodium, potassium, lithium, ammonium salts, and trimethylamine N-oxide, N-methyl Morpholine N-oxide, pyridine N-oxide, 4-methoxypyridine N-oxide, 4-nitropyridine N-oxide, 4-phenylpyridine N-oxide, quinoline N
-Oxide, imidazole, N-methylimidazole and the like. These additives are used in the range of 0.001 to 10 equivalents, preferably 0.01 to 5 equivalents.

The compound (1) of the present invention can be isolated and purified by usual separation means (eg, extraction, recrystallization, distillation, chromatography, etc.). In the case of producing a salt of the compound (1) of the present invention, various salts can be produced by a usual method or a method analogous thereto (eg, neutralization).

The compound (1) of the present invention or a salt thereof can be used alone or in combination with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition. For example, starch, lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg, magnesium stearate, calcium talc, stearic acid, etc.), binders (eg, starch, crystalline cellulose, carboxymethyl cellulose, gum arabic,
Polyvinylpyrrolidone, alginic acid, etc.), disintegrants (eg, talc, carboxymethylcellulose calcium, etc.), diluents (eg, physiological saline, glucose, mannitol, aqueous solution of lactose, etc.) and the like, and tablets, It can be administered orally or parenterally in the form of capsules, granules, powders, fine granules, ampules or injections. The dose varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, symptoms, and the like. ~ 3
00 mg / kg / day. The administration is performed, for example, once or several times a day.

[0056]

The compounds of the present invention and salts thereof have excellent antagonism to tachykinin receptors, have low toxicity, and are safe as pharmaceuticals. Accordingly, the compounds of the present invention and salts thereof are useful as pharmaceutical compositions, tachykinin receptor antagonists and preventive or therapeutic agents for dysuria, preventive or therapeutic agents for gastrointestinal disorders, and preventive or therapeutic agents for emesis. The usefulness of the present invention is shown by the following experimental examples and examples, but the present invention is not limited to the experimental examples and examples.

[0057]

[Experimental method] NK1 receptor antagonism The method of Dion et al. (“Life Scie
vol. 41, p. 2269 (1987)). After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The removed ileum is placed in a Magnus tube.
g and suspended. Specimen responses were recorded isotonic. The nutrient solution uses Tyrode solution, O ₂ 95%,
A mixed gas of 5% CO ₂ was passed, and the liquid temperature was 32 ° C. The experiment started after the guinea pig ileum was suspended in a Magnus tube and allowed to equilibrate for 20 minutes. The concentration-response curve of substance P in the absence of the test compound was used as a control.

The NK1 receptor antagonism of the test compound was determined from a concentration-response curve of substance P, which was pretreated with at least three concentrations of the test compound for 10 minutes and then applied cumulatively. The pA2 value was determined according to the method of Schild ("Brit. J. Pharmacol.
Pharmacol.), Vol. 14, p. 48 (1959)), and the results are shown in Table 1.

The composition of the Tyrode solution is as follows:
Was. NaCl; 136.9, KCl; 2.7, CaCl
₂・ 2H₂O; 2.5, MgCl₂・ 6H₂O;
0, NaH ₂PO₄・ 2H₂O; 0.4, NaHC
O₃11.9, glucose; 11.1 (mM)

NK2 receptor antagonism The method of D'Orleans-Juste (“European Journal of Pharmacology (Eur. J.
Pharmacol.), Vol. 125, p. 37 (1985)).

Rabbits were pentobarbital (30 mg /
kg, i. v. After anesthesia, blood was removed from the carotid artery to remove the pulmonary artery. After removing the endothelium, the removed pulmonary artery was suspended in the Magnus tube by applying a static tension of 1 g. Specimen responses were recorded isometrically. Nutrient solution, using Krebs _solution, O 2 95%, and the _CO 2 5% of the mixed gas venting, liquid temperature and 37 ° C.. The experiment was started after the rabbit pulmonary artery was suspended in the Magnus tube and allowed to equilibrate for 30 minutes. The presence or absence of endothelium was confirmed by disappearance of the relaxation reaction by acetylcholine ^10-6M . [Β-Ala ⁸ ] in the absence of test compound
The concentration response curve of neurokinin A (4-10) was used as a control.

The NK2 receptor antagonism of the test compound is low.
Pre-treat at least 3 concentrations of test compound for 10 minutes,
Applied post-cumulatively [β-Ala⁸] Neurokinin A
It was determined from the concentration-response curve of (4-10). pA₂Value is S
child's method ("British Journal
B. Pharmacol. "14
Volume, p. 48 (1959)), and the results are tabulated.
2 The composition of the Krebs solution was as follows.
NaCl; 143, KCl; 5.9, CaCl₂・ 2H
₂O; 2.55, MgSO₄・ 2H₂O; 1.2, KH
₂PO ₄25, NaHCO₃1.18, gluco
se; 11.1 (mM)

Table 1Example No. pA ₂ value (nM)  12 120 32 95.5

Table 2Example No. pA ₂ value (nM)  4 7.24 6 21.9 7 2.63 13 10.8 16 1.45 17 6.61 39 75.7

[0065]

Embodiment 1 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (133.9 mg, 0.53 mmol)
And 2-phenylethyl bromide (97.3 mg,
0.53 mmol) was dissolved in 10 ml of acetonitrile, potassium carbonate (109.6 mg) was added, and the mixture was heated and stirred at 80 ° C. for 3 hours. The reaction solution was filtered through celite and the solvent was concentrated. The residue obtained was purified by column chromatography (alumina, hexane: ethyl acetate = 1: 1) to give 4-methoxy-1- (2-phenylethyl)-as a pale yellow oil. 4-[(Phenylsulfinyl) methyl] piperidine (84.9 mg, 45%) was obtained. 1H-NMR (400 MHz, CDCl ₃ ) δ: 1.70-1.75 (1H, m),
1.88-1.95 (1H, m), 2.01-2.07 (1H, m), 2.13-2.19 (1
H, m), 2.39-2.50 (2H, m), 2.60-2.64 (2H, m), 2.68-
2.76 (2H, m), 2.79-2.83 (2H, m), 2.87 (1H, d, J = 1
4.2Hz), 3.09 (1H, d, J = 14.2Hz), 3.25 (3H, s), 7.18-
7.31 (5H, m), 7.49-7.56 (3H, m), 7.64-7.67 (2H,
m).

Embodiment 2 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (15
4.0 mg, 0.61 mmol) and 2- (3-chlorophenyl) ethyl bromide (133.4 mg) from
1- [2- (3-chlorophenyl) ethyl] as yellow oil
4-Methoxy-4-[(phenylsulfinyl) methyl] piperidine (66.6 mg, 28%) was obtained.

Embodiment 3 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (16
From 8.3 mg, 0.66 mmol) and 2- (4-chlorophenyl) ethyl bromide (145.8 mg)
1- [2- (4-chlorophenyl) ethyl] as yellow oil
4-Methoxy-4-[(phenylsulfinyl) methyl] piperidine (63.3 mg, 25%) was obtained.

Embodiment 4 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (14
6.2 mg, 0.58 mmol) and 2- (3-nitrophenyl) ethyl bromide (132.7 mg)
4-Methoxy-1- [2- (3-nitrophenyl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine (63.3 mg, 27%) was obtained as a yellow oil.

Embodiment 5 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (19
2.7 mg (0.76 mmol) and 3-biphenylethyl methanesulfonate (210.2 mg) from colorless oily 1- [2- (3-biphenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine ( 120.3 mg, 36%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 6 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (7
3.9 mg (0.29 mmol) and 4-biphenylethyl methanesulfonate (80.6 mg) were converted to colorless, scaly 1- [2- (4-biphenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine. (41.8 mg, 33%). However, silica gel NH was used in place of alumina for column chromatography. mp.108.0-109.0 ° C (hexane-ethyl acetate) Anal: Calculated as C ₂₇ H ₃₁ NO ₂ S: C: 74.79 H: 7.21 N: 3.23 Found: C: 74.69 H: 7.23 N: 3.27

Embodiment 7 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (1.
From 10 g, 4.3 mmol) and 2- (3,5 dichlorophenyl) ethyl methanesulfonate (1.17 g), 1- [2- (3,5 dichlorophenyl) ethyl] -4-methoxy-4- [ (Phenylsulfinyl) methyl] piperidine (512.6 mg, 28
%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 8 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (23
7.5 mg, 0.94 mmol) and 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (3
01.0 mg) to 1- [2- (3,5
-Bistrifluoromethylphenyl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (74.7 mg, 16%) was obtained.

Embodiment 9 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (12
From 7.8 mg, 0.50 mmol) and 2- (1-naphthyl) ethyl bromide (118.6 mg), 4-methoxy-1- [2- (1-naphthyl) ethyl] -4-[(phenylsulfinyl) methyl] as yellow oil Piperidine (60.7 mg, 30%) was obtained.

Embodiment 10 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (15
From 4.5 mg, 0.61 mmol) and 2- (2-naphthyl) ethyl bromide (143.4 mg), 4-methoxy-1- [2- (2-naphthyl) ethyl] -4-[(phenylsulfinyl) methyl] as yellow oil Piperidine (65.0 mg, 26%) was obtained.

Embodiment 11 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (20
From 7.4 mg, 0.82 mmol) and 2- (2-thienyl) ethyl methanesulfonate (168.9 mg), colorless oily 4-methoxy-4-[(phenylsulfinyl) methyl] -1- [2- (2-thienyl) ethyl ] Piperidine (155.3 mg, 52%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 12 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (27
From 7.7 mg, 1.1 mmol) and 2- (3-thienyl) ethyl methanesulfonate (226.1 mg), colorless oily 4-methoxy-4-[(phenylsulfinyl) methyl] -1- [2- (3-thienyl) ethyl ] Piperidine (209.5 mg, 53%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 13 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (23
2.8 mg, 0.92 mmol) and 2- (inden-3-yl) ethyl methanesulfonate (219.0 m
g), 1- [2- (Inden-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine as a brown oil (70.3 mg, 19%)
I got However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 14 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (14
9.2 mg, 0.59 mmol) and 2- (benzofuran-3-yl) ethylmethanesulfonate (132.5
mg) from yellow oily 1- [2- (benzofuran-3
-Yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (67.9 mg, 29
%).

Embodiment 15 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (1.
From 94 g (7.7 mmol) and 2- (benzothiophen-3-yl) ethyl bromide (1.85 g), colorless prisms of 1- [2- (benzothiophen-3-yl) ethyl] -4-methoxy-4-[( Phenylsulfinyl) methyl] piperidine (994.7 mg, 31
%). mp.108.5-109.5 ° C (hexane-ethyl acetate) Anal: C ₂₃ H ₂₇ NO ₂ S ₂ Calculated: C: 66.79 H: 6.58 N: 3.39 Found: C: 66.74 H: 6.61 N: 3.54

Embodiment 16 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (15
3.9 mg, 0.61 mmol) and 2- (5-fluorobenzothiophen-3-yl) ethyl bromide (1
57.4 mg) to give 1- [2- (5-fluorobenzothiophen-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (61.4 mg, 23%) as a yellow oil. .

Embodiment 17 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (18
From 2.5 mg, 0.72 mmol) and 2- (5-chlorobenzothiophen-3-yl) ethyl methanesulfonate (209.5 mg), 1- [2- (5
-Chlorobenzothiophen-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (117.4 mg, 36%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 18 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (29
0.0 mg, 1.1 mmol) and 2- (5-methylbenzothiophen-3-yl) ethyl bromide (29
2.1 mg) from 4-methoxy-1- [2
-(5-methylbenzothiophen-3-yl) ethyl]
-4-[(Phenylsulfinyl) methyl] piperidine (289.7 mg, 59%) was obtained.

Embodiment 19 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (8
6.2 mg, 0.34 mmol) and 2- (1,2-benzoisoxazol-3-yl) ethyl bromide (7
6.9 mg) to 1- [2- (1,2-benzoisoxazol-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine as a yellow oil (36.2 mg, 27%). I got

Embodiment 20 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (22
5.4 mg, 0.89 mmol) and 2- (1-methylindazol-3-yl) ethyl bromide (212.
7 mg) from 4-methoxy-1- [2- (1-methylindazol-3-yl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine (10%) as a yellow oil.
(2.7 mg, 28%).

Embodiment 21 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (11
3.2 mg, 0.45 mmol) and 2- (1H-benzimidazol-1-yl) ethyl bromide (10
0.6 mg) to give 1- [2- (1H-benzimidazol-1-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (75.0 mg, 42%) as a yellow oil.

Embodiment 22 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (33
From 5.2 mg, 1.32 mmol) and 2- (1-trifluoroacetyl-2,3 dihydroindol-3-yl) ethyl bromide (426.1 mg), 1- [2- (1-trifluoroacetyl-2 Thus, 3-dihydroindol-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine was obtained. This was dissolved in methanol in sodium carbonate (93.
1- [2- (2,3, dihydroindole-3-yl) ethyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (146.5 mg, 28%, 2 steps) Was obtained.

Embodiment 23 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (15
From 5.5 mg (0.61 mmol) and 3,5 dichlorobenzyl bromide (147.3 mg), yellow oily 1-[(3,5 dichlorophenyl) methyl] -4-methoxy-4-[(phenylsulfinyl) methyl] Piperidine (143.4 mg, 57%) was obtained.

Embodiment 24 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (24
8.0 mg, 0.98 mmol) and 3- (3,5 dichlorophenyl) propyl methanesulfonate (27
7.2 mg) from 1- [3- (3,5 dichlorophenyl) propyl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (14) as a colorless oil.
(5.8 mg, 34%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 25 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (18
From 7.8 mg, 0.74 mmol) and (1- (3,5 dichlorophenyl) propene) -3-ylbromide (197.1 mg), 1- [1- (3,
5-Dichlorophenyl) propen-3-yl] -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (131.6 mg, 40%) was obtained.

Embodiment 26 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfonyl) methyl] piperidine (22
2.0 mg, 0.82 mmol) and 2- (3,5 dichlorophenyl) ethyl methanesulfonate (221.
8 mg) from 1- [2- (3,5-dichlorophenyl) ethyl] -4-methoxy-4-[(phenylsulfonyl) methyl] piperidine (71.3 mg, 1
8%). However, for column chromatography,
Silica gel NH was used instead of alumina.

Embodiment 27 In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfonyl) methyl] piperidine (21
6.0 mg, 0.80 mmol) and 2- (benzothiophen-3-yl) ethyl bromide (193.4 m
g), 1- [2- (benzothiophen-3-yl) ethyl] -4-methoxy-4-[(phenylsulfonyl) methyl] piperidine (175.0 mg, 5
1%).

Embodiment 28 In the same manner as in Example 1, 4-[(phenylsulfinyl) methyl] piperidin-4-ol (270.5
mg, 1.1 mmol) and 2- (benzofuran-3-yl) ethyl methanesulfonate (271.5 mg) from colorless powdery 1- [2- (benzofuran-3-yl) ethyl] -4-[(phenylsulfinyl) methyl] Piperidin-4-ol (122.8 mg, 28
%). However, silica gel NH was used in place of alumina for column chromatography. mp.134.0-135.0 ℃ (hexane-ethyl _{acetate) Anal: C 22 H 25 NO} 3 S 0.5H 2 O Calculated: C: 67.32 H: 6.68 N : 3.57 Found: C: 67.11 H: 6.52 N : 3.44

Embodiment 29 In the same manner as in Example 1, 4-[(phenylsulfinyl) methyl] piperidine (217.0 mg, 0.9
7 mmol) and 2- (3,5 dichlorophenyl) ethyl methanesulfonate (261.5 mg), 1- [2- (3,5 dichlorophenyl) of colorless prism crystals
Ethyl] -4-[(phenylsulfinyl) methyl] piperidine (48.0 mg, 12%) was obtained. However, silica gel NH was used in place of alumina for column chromatography. mp.90.5-92.5 ℃ _{(hexane) Anal: C 20 H 23 Cl} 2 NOS 0.1H 2 O Calculated: C: 60.33 H: 5.87 N : 3.52 Found: C: 60.21 H: 5.78 N : 3.48

Embodiment 30 In the same manner as in Example 1, 4-[(phenylsulfinyl) methyl] piperidine (218.0 mg, 0.9
8 mmol) and 2- (benzothiophen-3-yl)
From ethyl methanesulfonate (235.4 mg), 1- [2- (benzothiophen-3-yl) ethyl] -4-[(phenylsulfinyl) methyl] piperidine (153.7 mg, 41%) was obtained as a yellow oil.

Embodiment 31 In the same manner as in Example 1, pale yellow was obtained from 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (331.8 mg, 1.2 mmol) and 2-phenylethyl bromide (226.3 mg). Powdered 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxy-1- (2-phenylethyl) piperidine (275.8 mg, 60%) was obtained. However, silica gel NH was used in place of alumina for column chromatography. mp.114.5-115.0 ° C (hexane) Anal: C ₂₁ H ₂₆ FNO ₂ S Calculated: C: 67.17 H: 6.98 N: 3.73 Observed: C: 67.21 H: 7.00 N: 3.72 1H-NMR (400 MHz, CDCl ₃ ) δ: 1.65-1.74 (1H, m),
1.86-1.95 (1H, m), 1.99-2.06 (1H, m), 2.12-2.19 (1
H, m), 2.37-2.51 (2H, m), 2.59-2.64 (2H, m), 2.66
2.74 (2H, m), 2.76-2.81 (2H, m), 2.85 (1H, d, J = 1
4.2Hz), 3.08 (1H, d, J = 14.2Hz), 3.23 (3H, s), 7.18-
7.31 (7H, m), 7.64-7.69 (2H, m).

Embodiment 32 In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (291.8 mg, 1.1 mmol) and 2- (benzofuran-3-yl) ethylmethanesulfonate (25
8.4 mg) to give 1- [2- (benzofuran-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (257.5 mg, 58%) as a pale yellow oil. Was. However, for column chromatography, silica gel N was used instead of alumina.
H was used.

Embodiment 33 In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (316.8 mg, 1.2 mmol) and 2- (5-fluorobenzofuran-3-yl) ethyl bromide ( 302.5 mg) to give 1- [2- (5-fluorobenzothiophen-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4 as a yellow oil.
-Methoxypiperidine (85.0 mg, 16%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 34 In the same manner as in Example 1, colorless needles were obtained from 4-methoxy-4-[(4-methoxyphenylsulfinyl) methyl] piperidine (309.0 mg, 1.1 mmol) and 2-phenylethyl bromide (201.8 mg). 4-methoxy-4-[(4-methoxyphenylsulfinyl) methyl] -1- (2-phenylethyl)
Piperidine (158.4 mg, 37%) was obtained. However, silica gel NH was used in place of alumina for column chromatography. mp.80.5-81.0 ℃ _{(hexane) Anal: C 22 H 29 NO} 3 S Calculated: C: 68.18 H: 7.54 N : 3.61 Found: C: 68.06 H: 7.46 N : 3.59

Embodiment 35 In the same manner as in Example 1, 4-methoxy-4-[(4-methoxyphenylsulfinyl) methyl] piperidine (446.0 mg, 1.6 mmol) and 2- (benzofuran-3-yl) ethyl methanesulfonate (378.2 mg) were used. Thus, 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4-[(4-methoxyphenylsulfinyl) methyl] piperidine (330.7 mg, 49%) was obtained as a colorless oil. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 36 A colorless needle was prepared from 4-[(4-trifluoromethylphenylsulfinyl) methyl] piperidin-4-ol (200.0 mg, 0.65 mmol) and 2-phenylethyl bromide (120.4 mg) in the same manner as in Example 1. 1- (2-phenylethyl) -4-[(4-trifluoromethylphenylsulfinyl) methyl] piperidin-4-ol (185.3 mg, 69)
%). However, silica gel NH was used in place of alumina for column chromatography. mp.159.5-160.5 ° C (hexane-ethyl acetate) Anal: C ₂₁ H ₂₄ F ₃ NO ₂ S Calculated: C: 61.30 H: 5.88 N: 3.40 Actual: C: 61.40 H: 5.76 N: 3.43

Embodiment 37 In the same manner as in Example 1, 4-[(4-trifluoromethylphenylsulfinyl) methyl] piperidin-4-ol (200.0 mg, 0.65 mmol) and 2- (benzofuran-3-yl) ethyl methanesulfonate (156.4 mg) ) To give 1- [2- (benzofuran-3-yl) ethyl] -4-[(4-trifluoromethylphenylsulfinyl) methyl] piperidin-4-ol (112.1 mg, 38%) as colorless needles. However, silica gel NH was used in place of alumina for column chromatography. mp.149.0-150.0 ° C (hexane-ethyl acetate) Anal: Calculated as C ₂₃ H ₂₄ F ₃ NO ₃ S 0.1H ₂ O: C: 60.94 H: 5.38 N: 3.09 Found: C: 60.75 H: 5.24 N: 3.06

Embodiment 38 In the same manner as in Example 1, colorless needles were obtained from 4-methoxy-4-[(2naphthylsulfinyl) methyl] piperidine (235.0 mg, 0.77 mmol) and 2-phenylethyl bromide (143.3 mg). 4-methoxy-4-[(2-naphthylsulfinyl) methyl] -1- (2-phenylethyl) piperidine (88.7 mg, 28%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina.
Was used. mp. 71.0-73.0 ° C (hexane) Anal: Calculated as C ₂₅ H ₂₉ NO ₂ S: C: 73.67 H: 7.17 N: 3.44 Found: C: 73.39 H: 7.21 N: 3.39

Embodiment 39 In the same manner as in Example 1, 4-methoxy-4-[(2naphthylsulfinyl) methyl] piperidine (543.0 mg, 1.8 mmol) and 2- (benzofuran-3-yl) ethylmethanesulfonate (43
0.0 mg) from 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4-[(2naphthylsulfinyl) methyl] piperidine (319.
4 mg, 40%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 40 A colorless oil was obtained from 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (452.1 mg, 1.7 mmol) and 3-phenylpropylbromide (331.7 mg) in the same manner as in Example 1. Of 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxy-1- (3-phenylpropyl) piperidine (171.1 mg, 26%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 41 In the same manner as in Example 1, 4-methoxy-4- [1
-(Phenylsulfinyl) ethyl] piperidine (35
0.0 mg, 1.3 mmol) and 2-phenylethyl bromide (242.2 mg) from colorless oil of 4-methoxy-1- (2-phenylethyl) -4- [1- (phenylsulfinyl) ethyl] piperidine (164.1).
mg, 34%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 42 In the same manner as in Example 1, 4-methoxy-4- [1
-(Phenylsulfinyl) ethyl] piperidine (36
0.0mg, 1.4mmol) and 2- (benzofuran-3-yl) ethyl methanesulfonate (323.5m
g), colorless oily 1- [2- (benzofuran-3-yl) ethyl] -4-methoxy-4- [1- (phenylsulfinyl) ethyl] piperidine (161.7 mg,
29%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 43 In the same manner as in Example 1, 3-methoxy-3-[(phenylsulfinyl) methyl] piperidine (13
6.0 mg, 0.54 mmol) and 2- (benzofuran-3-yl) ethyl methanesulfonate (129.0).
mg) from yellow oily 1- [2- (benzofuran-3
-Yl) ethyl] -3-methoxy-3-[(phenylsulfinyl) methyl] piperidine (53.3 mg, 25
%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 44 In the same manner as in Example 1, 3-methoxy-3-[(phenylsulfinyl) methyl] -8-azabicyclo [3.2.1] octane (491.0 mg, 1.8 m
mol) and 2-phenylethyl bromide (325.
2 mg) from 3-methoxy-8- (2-phenylethyl) -3- [1- (phenylsulfinyl) as a colorless oil
Ethyl] -8-azabicyclo [3.2.1] octane (561.4 mg, 83%) was obtained. However, for column chromatography, silica gel N was used instead of alumina.
H was used.

Embodiment 45 In the same manner as in Example 1, 3-methoxy-3-[(phenylsulfinyl) methyl] -8-azabicyclo [3.2.1] octane (428.4 mg, 1.5 m
mol) and 2- (benzofuran-3-yl) ethyl methanesulfonate (368.4 mg) from a pale yellow oil of 8- [2- (benzofuran-3-yl) ethyl] -3.
-Methoxy-3- [1- (phenylsulfinyl) ethyl] -8-azabicyclo [3.2.1] octane (32
8.6 mg, 51%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 46 In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (470 mg, 1.73 mmol) and 2- (3-nitrophenyl) ethyl bromide (438 mg, 1.9)
0 mmol) from 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxy-1- as a pale yellow oil.
[2- (3-nitrophenyl) ethyl] piperidine (4
80 mg, 66%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 47 4-[(4-fluorophenylsulfinyl) methyl]
-4-Methoxy-1- [2- (3-nitrophenyl) ethyl] piperidine (300 mg, 0.713 mmol)
Was dissolved in 10 ml of methanol, and 60 mg of 10% palladium activated carbon was added.
Stir for 5 hours. The residue obtained by removing the insoluble material by filtration and concentrating the filtrate was purified by silica gel NH column chromatography, and 1- [2- (3-aminophenyl) ethyl] -4-[(4 -Fluorophenylsulfinyl) methyl] -4-methoxypiperidine (2
(40 mg, 86%).

Embodiment 48 In the same manner as in Example 1, 4-ethoxy-4-
From [(4-fluorophenylsulfinyl) methyl] piperidine (150 mg, 0.526 mmol) and 2-phenylethyl bromide (97.4 mg), 4-ethoxy-4-[(4-fluorophenylsulfinyl) methyl as a pale yellow solid was obtained. ] -1- (2-Phenylethyl) piperidine (133 mg, 65%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 49 By a method similar to that in Example 1, pale yellow was obtained from 4-[(4-fluorophenylsulfinyl) methyl] -4-propoxypiperidine (80.0 mg, 0.267 mmol) and 2-phenylethyl bromide (49.5 mg). Solid 4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) -4-propoxypiperidine (97.1 mg, 90%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 50 In the same manner as in Example 1, 4-butoxy-4-
From [(4-fluorophenylsulfinyl) methyl] piperidine (133 mg, 0.424 mmol) and 2-phenylethyl bromide (78.5 mg), 4-butoxy-4-[(4-fluorophenylsulfinyl) methyl as a pale yellow solid was obtained. ]-(2-Phenylethyl) piperidine (160 mg, 90%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 51 In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-propoxy) piperidine (98 mg, 0.327 mmol) and 2-phenylethyl bromide (60.6 mg) were obtained.
4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) -4- (2
-Propoxy) piperidine (105 mg, 80%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 52 According to a method similar to that of Example 1, 4-cyclopropylmethoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (35.0 mg, 0.112 mmol)
l) and 2-phenylethyl bromide (20.7 m
g) from 4-cyclopropylmethoxy- as a pale yellow solid
4-[(4-fluorophenylsulfinyl) methyl]
-1- (2-phenylethyl) piperidine (24.3 m
g, 52%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 53 According to a method similar to that in Example 1, 4- (2-fluoroethoxy) -4-[(4-fluorophenylsulfinyl)
Methyl] piperidine (150 mg, 0.494 mmol
l) and 2-phenylethyl bromide (91.5 m
g), 4- (2-fluoroethoxy) as a pale yellow solid
-4-[(4-Fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) piperidine (147
mg, 73%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 54 According to a method similar to that of Example 1, 4- (2,2,2-trifluoroethoxy) -4-[(4-fluorophenylsulfinyl) methyl] piperidine (150 mg, 0.3
76 mmol) and 2-phenylethyl bromide (6
9.6 mg) from light yellow solid 4- (2,2,2-trifluoroethoxy) -4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl)
Piperidine (160 mg, 96%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 55 According to a method similar to that of Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-methoxyethoxy) piperidine (150 mg, 0.476 mmol)
l) and 2-phenylethyl bromide (88.1 m
g), 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-methoxyethoxy) -1- (2-phenylethyl) piperidine (147) as a pale yellow solid
mg, 74%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 56 In the same manner as in Example 1, 4-benzyloxy-4
-[(4-fluorophenylsulfinyl) methyl] piperidine (115 mg, 0.331 mmol) and 2-
From phenylethyl bromide (61.2 mg), 4-benzyloxy-4-[(4-fluorophenylsulfinyl) methyl] -1- (2-phenylethyl) piperidine (111 mg, 74%) was obtained as a pale yellow solid. . However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 57 In the same manner as in Example 1, 4-ethoxy-4-
[(4-Fluorophenylsulfinyl) methyl] piperidine (150 mg, 0.526 mmol) and 2-
From (benzothiophen-3-yl) ethyl methanesulfonate (135 mg), 1- [2- (benzothiophen-3-yl) ethyl] -4-ethoxy- as a pale yellow oil was obtained.
4-[(4-fluorophenylsulfinyl) methyl]
Piperidine (66.9 mg, 29%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 58 In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4-propoxypiperidine (80.0 mg, 0.267 mmol) and 2-
From (benzothiophen-3-yl) ethyl methanesulfonate (68.4 mg), 1- [2-
(Benzothiophen-3-yl) ethyl] -4-[(4
-Fluorophenylsulfinyl) methyl] -4-propoxypiperidine (57.2 mg, 47%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 59 In the same manner as in Example 1, 4-butoxy-4-
[(4-Fluorophenylsulfinyl) methyl] piperidine (133 mg, 0.424 mmol) and 2-
From (benzothiophen-3-yl) ethyl methanesulfonate (109 mg), pale yellow oily 1- [2- (benzothiophen-3-yl) ethyl] -4-butoxy-
4-[(4-fluorophenylsulfinyl) methyl]
Piperidine (82.0 mg, 41%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 60 According to a method similar to that of Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-propoxy) piperidine (98.0 mg, 0.327 mmol)
And 2- (benzothiophen-3-yl) ethyl methanesulfonate (83.8 mg) from light yellow oil 1-
[2- (benzothiophen-3-yl) ethyl] -4-
[(4-fluorophenylsulfinyl) methyl] -4
-(2-propoxy) piperidine (49.0 mg, 33
%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 61 According to a method similar to that in Example 1, 4- (2-fluoroethoxy) -4-[(4-fluorophenylsulfinyl)
Methyl] piperidine (150 mg, 0.494 mmol
l) and 2- (benzothiophen-3-yl) ethyl methanesulfonate (127 mg) from 1) as a pale yellow oil.
-[2- (benzothiophen-3-yl) ethyl] -4
-(2-Fluoroethoxy) -4-[(4-fluorophenylsulfinyl) methyl] piperidine (55.3 m
g, 24%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 62 In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4- (2,2,2-trifluoroethoxy) piperidine (150 mg, 0.3
76 mmol) and 2- (benzothiophen-3-yl) ethyl methanesulfonate (96.4 mg)
1- [2- (Benzothiophen-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4- (2,2,2-trifluoroethoxy) piperidine (92. 2 mg, 49%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 63 According to a method similar to that of Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4- (2-methoxyethoxy) piperidine (150 mg, 0.476 mmol)
1) and 2- (benzothiophen-3-yl) ethyl methanesulfonate (112 mg) to give 1 as a pale yellow oil.
-[2- (benzothiophen-3-yl) ethyl] -4
-[(4-fluorophenylsulfinyl) methyl]-
4- (2-methoxyethoxy) piperidine (68.2 m
g, 30%). However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 64 In the same manner as in Example 1, 4-benzyloxy-4
-[(4-fluorophenylsulfinyl) methyl] piperidine (115 mg, 0.331 mmol) and 2-
From (benzothiophen-3-yl) ethyl methanesulfonate (84.8 mg), 1- [2-
(Benzothiophen-3-yl) ethyl] -4-benzyloxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (104 mg, 62%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

Embodiment 65 2-phenylethyl bromide (87.0 mg, 0.4
70 mmol) and 4-[(4-fluorophenylthio) methyl] -4-methoxypiperidine (180 mg,
(Piperidinomethyl) polystyrene (600 mg) was added to a solution of 0.705 mmol) in 5 ml of acetonitrile and shaken at 80 ° C. for 6 hours. The residue obtained by concentrating the reaction solution from which the insolubles were removed by filtration was purified by silica gel NH column chromatography to give 4-[(4-
Fluorophenylthio) methyl] -1- (2-phenylethyl) -4-methoxypiperidine (119 mg, 70
%).

Embodiment 66 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150
mg, 0.467 mmol) and 4-methoxy-4-phenylthiomethylpiperidine (166 mg, 0.700
mmol) from 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-methoxy-4-phenylthiomethylpiperidine (94.0 m) as a pale yellow oil.
g, 42%).

Embodiment 67 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (550)
mg, 1.71 mmol) and 4-[(4-fluorophenylthio) methyl] -4-methoxypiperidine (43
7 mg, 1.71 mmol) from 1-
[2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(4-fluorophenylthio) methyl]
4-methoxypiperidine (350 mg, 41%) was obtained.

Embodiment 68 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150
mg, 0.467 mmol) and 4-[(3-fluorophenylthio) methyl] -4-methoxypiperidine (1
79 mg, 0.700 mmol) from 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-[(3-fluorophenylthio) methyl] -4-methoxypiperidine (124 mg, 54%)
I got

Embodiment 69 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150
mg, 0.467 mmol) and 4-[(2-fluorophenylthio) methyl] -4-methoxypiperidine (1
79 mg, 0.700 mmol) from 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-[(2-fluorophenylthio) methyl] -4-methoxypiperidine (130 mg, 56%)
I got

Embodiment 70 In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120
mg, 0.374 mmol) and 4-[(4-bromophenylthio) methyl] -4-methoxypiperidine (17
7 mg, 0.561 mmol) from 1-
[2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(4-bromophenylthio) methyl]-
4-methoxypiperidine (79.0 mg, 38%) was obtained.

Embodiment 71 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150
mg, 0.467 mmol) and 4-[(3-bromophenylthio) methyl] -4-methoxypiperidine (22
1 mg, 0.700 mmol) from 1-
[2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(3-bromophenylthio) methyl]-
4-methoxypiperidine (104 mg, 40%) was obtained.

Embodiment 72 In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120
mg, 0.374 mmol) and 4-[(4-chlorophenylthio) methyl] -4-methoxypiperidine (15
2 mg, 0.561 mmol) from 1-
[2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(4-chlorophenylthio) methyl]-
4-methoxypiperidine (96.0 mg, 50%) was obtained.

Embodiment 73 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150
mg, 0.467 mmol) and 4-[(3-chlorophenylthio) methyl] -4-methoxypiperidine (19
0 mg, 0.700 mmol) from 1-
[2- (3,5-bistrifluoromethylphenyl) ethyl] -4-[(3-chlorophenylthio) methyl]-
4-Methoxypiperidine (131 mg, 55%) was obtained.

Embodiment 74 In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120
mg, 0.374 mmol) and 4-methoxy-4-
[(4-methylphenylthio) methyl] piperidine (1
41 mg, 0.561 mmol) from 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-methoxy-4-[(4-methylphenylthio) methyl] piperidine (118 mg, 64%) was obtained.

Embodiment 75 In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120
mg, 0.374 mmol) and 4-methoxy-4-
[(3-methylphenylthio) methyl] piperidine (1
41 mg, 0.561 mmol) from 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-methoxy-4-[(3-methylphenylthio) methyl] piperidine (96.0 mg, 52%) was obtained.

Embodiment 76 In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120
mg, 0.374 mmol) and 4-methoxy-4-
[(2-methylphenylthio) methyl] piperidine (1
41 mg, 0.561 mmol) from 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-methoxy-4-[(2-methylphenylthio) methyl] piperidine (95.0 mg, 52%) was obtained.

Embodiment 77 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128
mg, 0.400 mmol) and 4-methoxy-4-
[(4-nitrophenylthio) methyl] piperidine (1
47 mg, 0.520 mmol) from 1
-[2- (3,5-bistrifluoromethylphenyl)
Ethyl] -4-methoxy-4-[(4-nitrophenylthio) methyl] piperidine (133 mg, 65%) was obtained.

Embodiment 78 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128
mg, 0.400 mmol) and 4-methoxy-4-
From [(4-trifluoromethylphenylthio) methyl] piperidine (159 mg, 0.520 mmol), 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] -4-methoxy-4-yl as a pale yellow oil was obtained. [(4-Trifluoromethylphenylthio) methyl] piperidine (137 mg, 64%) was obtained.

Embodiment 79 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128
mg, 0.400 mmol) and 4-[(2,6-dichlorophenylthio) methyl] -4-methoxypiperidine (159 mg, 0.520 mmol) from 1- [2- (3,5-bistrifluoro) as a pale yellow oil. Methylphenyl) ethyl] -4-[(2,6-dichlorophenylthio) methyl] -4-methoxypiperidine (138 mg,
65%).

Embodiment 80 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128
mg, 0.400 mmol) and 4-[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine (194 mg, 0.520 mmol) from 1- [2- (3,5 -Bistrifluoromethylphenyl) ethyl] -4-[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine (170 mg, 71%).

Embodiment 81 By a method similar to that in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128
mg, 0.400 mmol) and 4-cyclohexylthiomethyl-4-methoxypiperidine (127 mg, 0.1 mg).
520 mmol) from 1- [2- (3,
5-bistrifluoromethylphenyl) ethyl] -4-
Cyclohexylthiomethyl-4-methoxypiperidine (73.0 mg, 39%) was obtained.

Embodiment 82 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (112 mg,
0.467 mmol) and 4-methoxy-4-phenylthiomethylpiperidine (166 mg, 0.700 mmol)
1), 1- [2- (benzofuran-3) as a pale yellow oil
-Yl) ethyl] -4-methoxy-4-phenylthiomethylpiperidine (130 mg, 73%).

Embodiment 83 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (144 mg,
0.600 mmol) and 4-[(4-fluorophenylthio) methyl] -4-methoxypiperidine (230 m
g, 0.900 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(4-
Fluorophenylthio) methyl] -4-methoxypiperidine (202 mg, 84%).

Embodiment 84 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (112 mg,
0.467 mmol) and 4-[(3-fluorophenylthio) methyl] -4-methoxypiperidine (179 m
g, 0.700 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(3-
Fluorophenylthio) methyl] -4-methoxypiperidine (122 mg, 65%).

Embodiment 85 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (112 mg,
0.467 mmol) and 4-[(2-fluorophenylthio) methyl] -4-methoxypiperidine (179 m
g, 0.700 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(2-
Fluorophenylthio) methyl] -4-methoxypiperidine (161 mg, 87%).

Embodiment 86 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (90.0 mg,
0.374 mmol) and 4-[(4-bromophenylthio) methyl] -4-methoxypiperidine (177 m
g, 0.561 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(4-
[Bromophenylthio) methyl] -4-methoxypiperidine (69.0 mg, 40%).

Embodiment 87 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (112 mg,
0.467 mmol) and 4-[(3-bromophenylthio) methyl] -4-methoxypiperidine (221 m
g, 0.700 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(3-
Bromophenylthio) methyl] -4-methoxypiperidine (190 mg, 88%).

Embodiment 88 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (90.0 mg,
0.374 mmol) and 4-[(4-chlorophenylthio) methyl] -4-methoxypiperidine (152 m
g, 0.561 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(4-
Chlorophenylthio) methyl] -4-methoxypiperidine (72.0 mg, 60%) was obtained.

Embodiment 89 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (112 mg,
0.467 mmol) and 4-[(3-chlorophenylthio) methyl] -4-methoxypiperidine (190 m
g, 0.700 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-[(3-
Chlorophenylthio) methyl] -4-methoxypiperidine (171 mg, 88%) was obtained.

Embodiment 90 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (90.0 mg,
0.374 mmol) and 4-methoxy-4-[(4-
Methylphenylthio) methyl] piperidine (141 m
g, 0.561 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-methoxy-4-[(4-methylphenylthio) methyl] piperidine (85.0 mg, 57%) was obtained.

Embodiment 91 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (90.0 mg,
0.374 mmol) and 4-methoxy-4-[(3-
Methylphenylthio) methyl] piperidine (141 m
g, 0.561 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-methoxy-4-[(3-methylphenylthio) methyl] piperidine (98.0 mg, 66%) was obtained.

Embodiment 92 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (90.0 mg,
0.374 mmol) and 4-methoxy-4-[(2-
Methylphenylthio) methyl] piperidine (141 m
g, 0.561 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-methoxy-4-[(2-methylphenylthio) methyl] piperidine (98.0 mg, 66%) was obtained.

Embodiment 93 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (120 mg,
0.500 mmol) and 4-methoxy-4-[(4-
Nitrophenylthio) methyl] piperidine (184m
g, 0.650 mmol) from 1- [2
-(Benzofuran-3-yl) ethyl] -4-methoxy-4-[(4-nitrophenylthio) methyl] piperidine (121 mg, 57%) was obtained.

Embodiment 94 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (120 mg,
0.500 mmol) and 4-methoxy-4-[(4-
From trifluoromethylphenylthio) methyl] piperidine (198 mg, 0.650 mmol), pale yellow oily 1- [2- (benzofuran-3-yl) ethyl] -4.
-Methoxy-4-[(4-trifluoromethylphenylthio) methyl] piperidine (138 mg, 61%) was obtained.

Embodiment 95 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (120 mg,
0.500 mmol) and 4-[(2,6-dichlorophenylthio) methyl] -4-methoxypiperidine (19
9 mg, 0.650 mmol) from 1-
[2- (Benzofuran-3-yl) ethyl] -4-
[(2,6-Dichlorophenylthio) methyl] -4-methoxypiperidine (142 mg, 63%) was obtained.

Embodiment 96 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (120 mg,
0.500 mmol) and 4-[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine (243 mg, 0.650 mmol) from light yellow oil, 1- [2- (benzofuran-3-yl). ) Ethyl] -4-[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine (210 m
g, 81%).

Embodiment 97 According to a method similar to that in Example 65, 2- (benzofuran-
3-yl) ethyl methanesulfonate (120 mg,
0.500 mmol) and 4-cyclohexylthiomethyl-4-methoxypiperidine (158 mg, 0.650
mmol), 1- [2- (benzofuran-3-yl) ethyl] -4-cyclohexylthiomethyl-4-methoxypiperidine (78.0 mg, 40%) as a pale yellow oil.
I got

Embodiment 98 By a method similar to that in Example 65, 2-phenylethyl bromide (206 mg, 1.11 mmol) and 4-ethoxy-4-[(4-fluorophenylthio) methyl]
Piperidine (300 mg, 1.11 mmol) gave 4-ethoxy-4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl) piperidine (311 mg, 75%) as a pale yellow oil.

Embodiment 99 According to a method similar to that in Example 65, 2-phenylethyl bromide (196 mg, 1.06 mmol) and 4-phenylethyl bromide were used.
From [(4-fluorophenylthio) methyl] -4-propoxypiperidine (300 mg, 1.06 mmol), 4-[(4-fluorophenylthio) was obtained as a pale yellow oil.
Methyl] -1- (2-phenylethyl) -4-propoxypiperidine (276 mg, 67%) was obtained.

Embodiment 100 By a method similar to that in Example 65, 2-phenylethyl bromide (187 mg, 1.01 mmol) and 4-butoxy-4-[(4-fluorophenylthio) methyl]
From piperidine (300 mg, 1.01 mmol), 4-butoxy-4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl) piperidine (281 mg, 69%) was obtained as a pale yellow oil.

Embodiment 101 According to a method similar to that in Example 65, 2-phenylethyl bromide (196 mg, 1.06 mmol) and 4-phenylethyl bromide were used.
[(4-fluorophenylthio) methyl] -4- (2-
Propoxy) piperidine (300 mg, 1.06 mmol)
1) shows that 4-[(4-fluorophenylthio) methyl] -1- (2-phenylethyl) -4- as a pale yellow oil
(2-propoxy) piperidine (259 mg, 63%)
I got

Embodiment 102 By a method similar to that in Example 65, 2-phenylethyl bromide (188 mg, 1.02 mmol) and 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] piperidine (300 mg, 1.02 mm)
ol) from 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] -1- as a pale yellow oil.
(2-phenylethyl) piperidine (253 mg, 62
%).

Embodiment 103 According to a method similar to that in Example 65, 2-phenylethyl bromide (192 mg, 1.04 mmol) and 4-phenylethyl bromide were used.
(2-Fluoroethoxy) -4-[(4-fluorophenylthio) methyl] piperidine (300 mg, 1.04
mmol), 4- (2-fluoroethoxy) -4-[(4-fluorophenylthio) methyl] as pale yellow oil
-1- (2-phenylethyl) piperidine (244 m
g, 60%).

Embodiment 104 By a method similar to that in Example 65, 2-phenylethyl bromide (172 mg, 0.928 mmol) and 4-phenylethyl bromide were used.
[(4-fluorophenylthio) methyl] -4- (2,
2,2-trifluoroethoxy) piperidine (300 m
g, 0.928 mmol) from light yellow oily 4-
[(4-fluorophenylthio) methyl] -1- (2-
Phenylethyl) -4- (2,2,2-trifluoroethoxy) piperidine (282 mg, 71%) was obtained.

Embodiment 105 In the same manner as in Example 65, 2-phenylethyl bromide (186 mg, 1.00 mmol) and 4-phenylethyl bromide
[(4-fluorophenylthio) methyl] -4- (2-
Methoxyethoxy) piperidine (300 mg, 1.00
mmol), 4-[(4-fluorophenylthio) methyl] -4- (2-methoxyethoxy) as a pale yellow oil
-1- (2-phenylethyl) piperidine (238 m
g, 59%).

Embodiment 106 By a method similar to that in Example 65, 2-phenylethyl bromide (168 mg, 0.905 mmol) and 4-phenylethyl bromide were used.
Benzyloxy-4-[(4-fluorophenylthio)
Methyl] piperidine (300 mg, 0.905 mmol
l) shows that 4-benzyloxy-4-
[(4-fluorophenylthio) methyl] -1- (2-
Phenylethyl) piperidine (284 mg, 72%) was obtained.

Embodiment 107 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-ethoxy-4-
From [(4-fluorophenylthio) methyl] piperidine (100 mg, 0.371 mmol), colorless oily 1- [2- (benzothiophen-3-yl) ethyl]-
4-Ethoxy-4-[(4-fluorophenylthio) methyl] piperidine (100 mg, 36%) was obtained.

Embodiment 108 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-[(4-fluorophenylthio) methyl] -4-propoxypiperidine (1
00 mg, 0.353 mmol) from 1-
[2- (benzothiophen-3-yl) ethyl] -4-
[(4-Fluorophenylthio) methyl] -4-propoxypiperidine (87.7 mg, 56%) was obtained.

Embodiment 109 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-butoxy-4-
From [(4-fluorophenylthio) methyl] piperidine (100 mg, 0.336 mmol), colorless oily 1- [2- (benzothiophen-3-yl) ethyl]-
4-Butoxy-4-[(4-fluorophenylthio) methyl] piperidine (78.0 mg, 51%) was obtained.

Embodiment 110 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-[(4-fluorophenylthio) methyl] -4- (2-propoxy) piperidine (100 mg, 0.353 mmol) from 1- [2- (benzothiophene-3) as a colorless oil. -Yl) ethyl] -4-[(4-fluorophenylthio) methyl]-
4- (2-propoxy) piperidine (75.2 mg, 4
8%).

Embodiment 111 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] piperidine (100 mg, 0.339 mmol) as colorless oily 1- [2- (benzothiophen-3-yl). ) Ethyl] -4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] piperidine (35.5 m
g, 23%).

Embodiment 112 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (206 m
g, 0.804 mmol) and 4- (2-fluoroethoxy) -4-[(4-fluorophenylthio) methyl]
From piperidine (200 mg, 0.696 mmol)
1- [2- (benzothiophen-3-yl) as a colorless oil
Ethyl] -4- (2-fluoroethoxy) -4-[(4
-Fluorophenylthio) methyl] piperidine (162
mg, 52%).

Embodiment 113 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl bromide (74.6 mg, 0.1%) was used.
309 mmol) and 4-[(4-fluorophenylthio) methyl] -4- (2,2,2-trifluoroethoxy) piperidine (100 mg, 0.309 mmol) to give 1- [2- (benzothiophene) as a colorless oil. -3-yl) ethyl] -4-[(4-fluorophenylthio) methyl] -4- (2,2,2-trifluoroethoxy) piperidine (120 mg, 80%).

Embodiment 114 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-[(4-fluorophenylthio) methyl] -4- (2-methoxyethoxy)
From piperidine (100 mg, 0.334 mmol)
1- [2- (benzothiophen-3-yl) as a colorless oil
Ethyl] -4-[(4-fluorophenylthio) methyl] -4- (2-methoxyethoxy) piperidine (9
9.6 mg, 63%).

Embodiment 115 By a method similar to that in Example 65, 2- (benzothiophen-3-yl) ethyl methanesulfonate (103 m
g, 0.402 mmol) and 4-benzyloxy-4
From 1-[(4-fluorophenylthio) methyl] piperidine (100 mg, 0.302 mmol), 1- [2- (benzothiophen-3-yl) ethyl]-as a colorless oil.
4-Benzyloxy-4-[(4-fluorophenylthio) methyl] piperidine (75.7 mg, 51%) was obtained.

Embodiment 116 By the same method as in Example 1, (+)-4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (98.6% ee) (603 mg, 2.22)
mmol) and 2- (benzothiophen-3-yl) ethyl methanesulfonate (626 mg, 2.44 mmol)
1), (+)-1- [2- (benzothiophen-3-yl) ethyl] -4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (782 mg, 82%) as pale yellow oil ) Got. However, for column chromatography, use silica gel NH instead of alumina.
Was used. [α] _D ²³ +95.9 (c = 0.75, CHCl ₃ ) (98.6% ee)

Reference Example 1 By the same method as in Example 1, (+)-4-methoxy-
4-phenylsulfinylmethylpiperidine (100%
ee) (1.79 g, 7.07 mmol) and 2- (5
From (-fluoroindol-3-yl) ethyl bromide (1.88 g, 7.78 mmol), a colorless amorphous (+)-1- [2- (5-fluoroindol-3-yl) ethyl] -4-methoxy was obtained. 4-Phenylsulfinylmethylpiperidine (2.05 g, 70%) was obtained. However, silica gel NH was used in place of alumina for column chromatography. Anal: C ₂₃ H ₂₇ FN ₂ O ₂ S 1.5H ₂ O Calculated: C: 62.56 H: 6.85 N: 6.35 Actual: C: 62.79 H: 6.63 N: 6.32 [α] _D ²⁴ +105.4 (c = 0.368, CHCl ₃ ) (100% ee)

Embodiment 117 1-t-butoxycarbonyl-4-methylenepiperidine (55.0 mg, 0.279 mmol) was dissolved in 0.5 ml of methanol, and N-bromosuccinimide (49.6 mg, 0.279 mmol) was added under ice cooling. And stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 4: 1) to give 4-bromomethyl-1-t- as a colorless syrup.
Butoxycarbonyl-4-methoxypiperidine (77.
0 mg, 90%). 1H-NMR (400 MHz, CDCl3) δ: 1.42-1.50 (2H, m), 1.46
(9H, s), 1.86-1.96 (2H, m), 3.05 (2H, brs), 3.23
(3H, s), 3.40 (2H, s), 3.85 (2H, brs) .13C-NMR (100 MHz, CDCl3) δ: 28.4, 31.8, 32.6, 37.9,
38.7, 39.1, 48.7, 72.1, 79.5, 154.7. MS: 307 (M +)

Embodiment 118 According to a method similar to that of Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (960 mg, 4.
87 mmol), 5 ml of methanol and N-iodosuccinimide (1.42 g, 6.33 mmol) from 1-t-butoxycarbonyl-4-iodomethyl-4-methoxypiperidine (1.28 g, 74) as a colorless syrup.
%). 1H-NMR (400 MHz, CDCl3) δ: 1.40-1.50 (2H, m), 1.45
(9H, s), 1.85-1.95 (2H, m), 3.01 (2H, brs), 3.19
(3H, s), 3.26 (2H, s), 3.83 (2H, brs).

Embodiment 119 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 5 ml of ethanol and N-bromosuccinimide (2.16 g, 12.2 mmol) from 4-bromomethyl-1-t-butoxycarbonyl-4-ethoxypiperidine (1.95 g, 5%) as a colorless syrup.
8%). 1H-NMR (400 MHz, CDCl3) δ: 1.23 (3H, t, J = 6.8 H
z), 1.42-1.50 (2H, m), 1.46 (9H, s), 1.86-1.89 (2H,
m), 3.05 (2H, brs), 3.39 (2H, q, J = 6.8 Hz), 3.40
(2H, s), 3.86 (2H, brs). MS (CI +): 322 (M + 1).

Embodiment 120 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 6 ml of propanol and N-bromosuccinimide (2.16 g, 12.2 mmol)
4-bromomethyl-1-t-butoxycarbonyl-4-propoxypiperidine as a colorless syrup (1.95
g, 58%). 1H-NMR (400 MHz, CDCl3) δ: 0.96 (3H, t, J = 7.3 H
z), 1.42-1.50 (2H, m), 1.46 (9H, s), 1.55-1.65 (2
H, m), 1.87-1.90 (2H, m), 3.04 (2H, brs), 3.20 (2H,
t, J = 6.8 Hz), 3.40 (2H, s), 3.87 (2H, brs). MS (CI +): 336 (M + 1).

Embodiment 121 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 8 ml of butanol and N-bromosuccinimide (2.16 g, 12.2 mmol) from 4-bromomethyl-4-butoxy- as a pale yellow syrup.
1-t-butoxycarbonylpiperidine (2.77 g,
78%). 1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.8 H
z), 1.37-1.47 (4H, m), 1.46 (9H, s), 1.49-1.61 (2
H, m), 1.86-1.89 (2H, m), 3.04 (2H, brs), 3.31 (2H,
t, J = 6.3 Hz), 3.40 (2H, s), 3.86 (2H, brs). MS (CI +): 350 (M + 1).

Embodiment 122 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 6 ml of 2-propanol and N-bromosuccinimide (2.16 g, 12.2 mmol) from 4-bromomethyl-1-t- as a pale yellow syrup.
Butoxycarbonyl-4- (2-propoxy) piperidine (1.65 g, 48%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 1.21 (6H, d, J = 6.3 H
z), 1.46 (9H, s), 1.54-1.62 (2H, m), 1.79-1.82 (2
H, m), 3.16 (2H, brs), 3.31 (2H, t, J = 6.3 Hz),
3.40 (2H, s), 3.86 (2H, brs). MS (CI +): 336 (M + 1).

Embodiment 123 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), cyclopropylmethanol 10m
l and N-bromosuccinimide (2.16 g, 12.2
mmol) from 4-bromomethyl- as a colorless syrup.
1-t-butoxycarbonyl-4-cyclopropylmethoxypiperidine (2.75 g, 78%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 0.23 (2H, dd, J = 4.9, 1
0.3 Hz), 0.55 (2H, dd, 5.4, 13.2 Hz), 1.43-1.91 (1
H, m), 1.42-1.50 (2H, m), 1.46 (9H, s), 1.87-1.90
(2H, m), 3.07 (2H, brs), 3.17 (2H, d, J = 6.3 Hz),
3.87 (2H, brs). MS (CI +): 348 (M + 1).

Embodiment 124 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 8 ml of 2-fluoroethanol and
N-bromosuccinimide (2.16 g, 12.2 mmol
From 1), 4-bromomethyl-1-- as a colorless syrup
t-butoxycarbonyl-4- (2-fluoroethoxy) piperidine (2.75 g, 78%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 1.45-1.56 (2H, m), 1.46
(9H, s), 1.89-1.92 (2H, m), 3.09 (2H, brs), 3.40
(2H, s), 3.62 (2H, ddd, J = 3.9, 3.9, 28.8 Hz), 3.
86 (2H, brs), 4.58 (2H, ddd, J = 3.9, 3.9, 47.9 H
z) .MS (CI +): 340 (M + 1).

Embodiment 125 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 8 ml of 2,2,2-trifluoroethanol and N-bromosuccinimide (2.16 g, 1
2.2 mmol) from 4-bromomethyl-1-t-butoxycarbonyl-4- (2,2,
2-trifluoroethoxy) piperidine (1.68 g,
44%). 1H-NMR (400 MHz, CDCl3) δ: 1.42-1.59 (2H, m), 1.46
(9H, s), 1.89-1.93 (2H, m), 3.07 (2H, brs), 3.38
(2H, s), 3.81 (2H, q, J = 8.3 Hz), 3.84 (2H, brs). MS (CI +): 376 (M + 1).

Embodiment 126 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 10 ml of 2-methoxyethanol and N-bromosuccinimide (2.16 g, 12.2 mm
ol) from 4-bromomethyl- as a pale yellow syrup
1-t-butoxycarbonyl-4- (2-methoxyethoxy) piperidine (2.96 g, 83%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.46-1.55
(2H, m), 1.88-1.91 (2H, m), 3.09 (2H, brs), 3.39
(3H, s), 3.40 (2H, s), 3.50-3.58 (4H, m), 3.86 (2H,
brs) .MS (CI +): 352 (M + 1).

Embodiment 127 In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepiperidine (2.00 g, 1
0.1 mmol), 10 ml of benzyl alcohol and N
-Bromosuccinimide (2.71 g, 15.2 mmol
1), 4-benzyloxy-4 in the form of a pale yellow syrup
-Bromomethyl-1-t-butoxycarbonylpiperidine (2.95 g, 76%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.52-1.58
(2H, m), 1.99-2.02 (2H, m), 3.11 (2H, brs), 3.52
(2H, s), 3.90 (2H, brs), 4.43 (2H, s), 7.27-7.41
(5H, m). MS (CI +): 384 (M + 1).

Embodiment 128 Sodium hydride (oil-based, about 60%) (0.93 g, 2
3.2 mmol) of N, N-dimethylformamide 5m
1 suspension to 4-fluorothiophenol (2.47 m
After adding 23.2 mmol), a solution of 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (6.80 g, 22.1 mmol) in 10 ml of N, N-dimethylformamide was added, and the mixture was heated at 70 ° C. Stir for 30 minutes. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 4: 1) to give 1-t-butoxycarbonyl-4 as a colorless syrup.
-(4-Fluorophenylthio) methyl-4-methoxypiperidine (7.56 g, 96%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 1.45 (9H, s), 1.45-1.54
(2H, m), 1.86-1.90 (2H, m), 3.04 (4H, brs), 3.16
(3H, s), 3.85 (2H, brs), 6.99 (2H, dd, J = 8.3, 8.
3 Hz), 7.38 (2H, dd, J = 4.9, 8.3 Hz). MS: 355 (M +).

Embodiment 129 Sodium hydride (oily, about 60%) (120 mg,
3.00 mmol) of N, N-dimethylformamide 2
Add thiophenol (331 mg, 3.00
mmol), and then add 4-bromomethyl-1-t-
Butoxycarbonyl-4-methoxypiperidine (616
mg, 2.00 mmol) in 2 ml of N, N-dimethylformamide and shaken at 80 ° C. for 12 hours, and then p-toluenesulfonic acid monohydrate (1.9
0 g, 10.0 mmol) and shaken at 80 ° C. for 2 hours. After adding 1N hydrochloric acid to the reaction solution and washing with diethyl ether, the aqueous layer was made alkaline by adding potassium carbonate, and extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and 4-methoxy-4-phenylthiomethylpiperidine (400 mg, 8
4%).

Embodiment 130 According to a method similar to that in Example 129, 3-fluorothiophenol (385 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were used as a brown oil. -[(3-fluorophenylthio) methyl] -4-methoxypiperidine (358 mg, 70
%).

Embodiment 131 According to a method similar to that in Example 129, 2-fluorothiophenol (385 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were used as a brown oil. -[(2-fluorophenylthio) methyl] -4-methoxypiperidine (409 mg, 80
%).

Embodiment 132 According to a method similar to that of Example 129, 4-bromothiophenol (567 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-[(4-bromophenylthio) methyl] as a brown oil
4-Methoxypiperidine (512 mg, 81%) was obtained.

Embodiment 133 According to a method similar to that in Example 129, 3-bromothiophenol (567 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-[(3-bromophenylthio) methyl] as a brown oil
4-Methoxypiperidine (502 mg, 79%) was obtained.

Embodiment 134 According to a method similar to that of Example 129, 4-chlorothiophenol (434 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-[(4-chlorophenylthio) methyl] as a brown oil
4-Methoxypiperidine (413 mg, 76%) was obtained.

Embodiment 135 According to a method similar to that in Example 129, 3-chlorothiophenol (434 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-[(3-chlorophenylthio) methyl] as a brown oil
4-Methoxypiperidine (457 mg, 84%) was obtained.

Embodiment 136 According to a method similar to that in Example 129, 4-methylthiophenol (373 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-methoxy-4-[(4-methylphenylthio) methyl] piperidine (392 mg, 78%) was obtained as a brown oil.

Embodiment 137 By a method similar to that in Example 129, 3-methylthiophenol (373 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-methoxy-4-[(3-methylphenylthio) methyl] piperidine (377 mg, 75%) was obtained as a brown oil.

Embodiment 138 By a method similar to that in Example 129, 2-methylthiophenol (373 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
4-methoxy-4-[(2-methylphenylthio) methyl] piperidine (417 mg, 83%) was obtained as a brown oil.

Embodiment 139 By a method similar to that in Example 129, 4-nitrothiophenol (466 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol) were obtained.
A brown solid of 4-methoxy-4-[(4-nitrophenylthio) methyl] piperidine (310 mg, 55%) was obtained.

Embodiment 140 By a method similar to that in Example 129, 4-trifluoromethylthiophenol (535 mg, 3.00 mmol)
And 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mm
ol) from 4-methoxy-4-[(4-
Trifluoromethylphenylthio) methyl] piperidine (500 mg, 82%).

Embodiment 141 In the same manner as in Example 129, 2,6-dichlorothiophenol (537 mg, 3.00 mmol) and 4
-Bromomethyl-1-t-butoxycarbonyl-4-
Methoxypiperidine (616 mg, 2.00 mmol)
From 4-[(2,6-dichlorophenylthio) methyl] -4-methoxypiperidine (500 m
g, 82%).

Embodiment 142 According to a method similar to that in Example 129, 3,5-bistrifluoromethylthiophenol (739 mg, 3.00 m
mol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.
00 mmol) to give 4-[(3,5-bistrifluoromethylphenylthio) methyl] -4-methoxypiperidine (620 mg, 83%) as a pale yellow oil.

Embodiment 143 By a method similar to that in Example 129, 4-cyclohexyl as a pale yellow oil was obtained from cyclohexylmercaptan (349 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-4-methoxypiperidine (616 mg, 2.00 mmol). Thiomethyl-4-
Methoxypiperidine (350 mg, 72%) was obtained.

Embodiment 144 1-t-butoxycarbonyl-4- (4-fluorophenylthio) methyl-4-methoxypiperidine (45.0
mg, 0.127 mmol) in 1 ml of methylene chloride, and m-chloroperbenzoic acid (70% content) (31.2 mg, 0.127 mmol) was added thereto under ice cooling to give 1
Stirred for 0 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed successively with 5% sodium thiosulfate, 5% sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3), and 1-t-butoxycarbonyl-4- (4-fluorophenylsulfinyl) methyl as a pale yellow oil was obtained. 4-Methoxypiperidine (38.0 mg, 81%) was obtained. 1H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.50-1.65
(1H, brm), 1.65-1.80 (1H, m), 1.90-2.00 (1H, m),
2.00-2.15 (1H, brm), 2.75-2.90 (1H, brm), 3.00-3.2
5 (3H, brm), 3.25 (3H, s), 3.83 (2H, brs), 7.24 (2
H, dd, J = 7.3, 16.1 Hz), 7.66 (2H, dd, J = 5.4, 8.
8 Hz). MS (CI +): 372 (M + 1).

Embodiment 145 1-t-butoxycarbonyl-4- (4-fluorophenylthio) methyl-4-methoxypiperidine (6.00
g, 16.9 mmol) and (S, S) -N, N'-bis (3,5-di-t-butylsalicylidene) -1,2-
Cyclohexanediaminomanganese (III) chloride (268 mg, 0.420 mmol) was dissolved in 80 ml of methanol, and trisodium citrate (496 m
g, 1.69 mmol) in 20 ml of water.
Under ice cooling, 30% aqueous hydrogen peroxide (5.7 ml, 50.6 m
mol) was added and stirred at room temperature for 30 minutes. 5% in the reaction solution
An aqueous solution of sodium hydrogen sulfite was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3). The purified product was recrystallized three times from diisopropyl ether to give (+)-1-
t-butoxycarbonyl-4- (4-fluorophenylsulfinyl) methyl-4-methoxypiperidine (0.
86 g, 14%). [α] _D ²³ +138.8 (c = 1.00, CHCl ₃ ) (98.6% ee)

Embodiment 146 Sodium hydride (oily, about 60%) (4.00 g, 1
00 mmol) N, N-dimethylformamide 40m
1-Suspension was added to 4-fluorothiophenol (1
0.65 ml, 100 mmol), and the mixture was stirred at room temperature for 1 hour, and stirred at room temperature for 2 M sodium 4-fluorothiophenoxide N, N-dimethylformamide solution (hereinafter, 2M-4F)
TPNa solution). 4-bromomethyl-
To a solution of 1-t-butoxycarbonyl-4-ethoxypiperidine (1.95 g, 6.05 mmol) in 1 ml of N, N-dimethylformamide was added a 2M-4FTPNa solution (3.03 ml, 6.06 mmol) and the mixture was heated at 80 ° C. Shake for 12 hours. The reaction solution was diluted with diethyl ether, and insolubles were removed by filtration using Celite. The filtrate was concentrated under reduced pressure.
p-Toluenesulfonic acid monohydrate (1.73 g, 9.0
8 mmol) and shaken at 80 ° C. for 1 hour. The supernatant of the reaction solution was removed, and the lower layer was washed with diethyl ether, made alkaline with a 10% aqueous potassium carbonate solution, and extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and 4-ethoxy-4-[(4-fluorophenylthio) methyl] as a brown oil was obtained.
Piperidine (1.16 g, 71%) was obtained. To a solution of 4-ethoxy-4-[(4-fluorophenylthio) methyl] piperidine (1.80 g, 6.68 mmol) in 10 ml of methylene chloride was added triethylamine (1.39 ml, 1
0.0 mmol) and a 1 M solution of di-t-butyl dicarbonate in methylene chloride (8.02 ml, 8.02 mmol).
l) was added and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride.
The organic layer was washed successively with 1N hydrochloric acid and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to give a pale yellow oily 1-t-butoxycarbonyl-4-ethoxy-4-.
[(4-Fluorophenylthio) methyl] piperidine was obtained. To a solution of the obtained 1-t-butoxycarbonyl-4-ethoxy-4-[(4-fluorophenylthio) methyl] piperidine in 10 ml of methylene chloride under ice-cooling, m-chloroperbenzoic acid (1.15 g, 6. 68 mmol) and stirred for 1 hour. The reaction solution was poured into a 1: 1 mixture of 5% sodium thiosulfate and 5% sodium hydrogen carbonate, extracted with methylene chloride, and the organic layer was washed successively with 5% sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. did. The residue obtained by evaporating the solvent was purified by silica gel column chromatography, and 1-t-butoxycarbonyl-4-ethoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (1. 42
g, 55%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (9H, s), 1.45-1.54
(2H, m), 1.86-1.90 (2H, m), 3.04 (4H, brs), 3.16
(3H, s), 3.85 (2H, brs), 6.99 (2H, dd, J = 8.3, 8.
3 Hz), 7.38 (2H, dd, J = 4.9, 8.3 Hz). MS: 355 (M +).

Embodiment 147 According to a method similar to that in Example 146, 4-bromomethyl-
1-t-butoxycarbonyl-4-propoxypiperidine (1.67 g, 4.97 mmol) and 2M-4F
From the TPNa solution (2.49 ml, 4.98 mmol),
4-[(4-fluorophenylthio) methyl] -4-propoxypiperidine as a brown oil (0.986 g, 70
%). The obtained 4-[(4-fluorophenylthio) methyl] -4-propoxypiperidine (1.00
g, 3.53 mmol) from light yellow oily 1-t-butoxycarbonyl-4-[(4-fluorophenylthio)
Methyl] -4-propoxypiperidine provided 1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] -4-propoxypiperidine (0.676 g, 48%) as a pale yellow oil. MS (CI +): 400 (M + 1).

Embodiment 148 According to a method similar to that in Example 146, 4-bromomethyl-
4-butoxy-1-t-butoxycarbonylpiperidine (2.77 g, 7.91 mmol) and 2M-4FT
From the PNa solution (3.96 ml, 7.92 mmol), 4-butoxy-4-[(4-fluorophenylthio) methyl] piperidine (1.72 g, 73%) was obtained as a brown oil. The resulting 4-butoxy-4-[(4-fluorophenylthio) methyl] piperidine (0.650 g, 2.1
8 mmol) to 4-butoxy-1-t- as a pale yellow oil.
Via butoxycarbonyl-4-[(4-fluorophenylthio) methyl] piperidine, pale yellow oil of 4-butoxy-1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] piperidine (0.5
57 g, 62%). MS (CI +): 414 (M + 1).

Embodiment 149 According to a method similar to that in Example 146, 4-bromomethyl-
1-t-butoxycarbonyl-4- (2-propoxy) piperidine (1.65 g, 4.91 mmol) and 2M-4FTPNa solution (2.46 ml, 4.92 mmol)
l) gave 4-[(4-fluorophenylthio) methyl] -4- (2-propoxy) piperidine (1.71 g, 76%) as a brown oil. The obtained 4-[(4-
Fluorophenylthio) methyl] -4- (2-propoxy) piperidine (0.747 g, 2.64 mmol) from pale yellow oily 1-t-butoxycarbonyl-4-.
[(4-fluorophenylthio) methyl] -4- (2-
Through propoxy) piperidine, 1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] -4- (2-propoxy) piperidine (0.394 g, 37%) was obtained as a pale yellow oil. MS (CI +): 400M + 1).

Embodiment 150 According to a method similar to that in Example 146, 4-bromomethyl-
1-t-butoxycarbonyl-4-cyclopropylmethoxypiperidine (2.83 g, 8.13 mmol) and 2M-4FTPNa solution (4.07 ml, 8.14 mm)
ol) from 4-cyclopropylmethoxy- as a brown oil.
4-[(4-Fluorophenylthio) methyl] piperidine (1.38 g, 58%) was obtained. The obtained 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] piperidine (0.687 g, 2.33 mm
ol) to 1-t-butoxycarbonyl- as a pale yellow oil
Via 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] piperidine, pale yellow oil 1
-T-butoxycarbonyl-4-cyclopropylmethoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (0.362 g, 38%) was obtained. MS (CI +): 412 (M + 1).

Embodiment 151 According to a method similar to that in Example 146, 4-bromomethyl-
1-t-butoxycarbonyl-4- (2-fluoroethoxy) piperidine (2.65 g, 7.79 mmol)
And 2M-4FTPNa solution (3.90 ml, 7.80 m
mol) yielded 4- (2-fluoroethoxy) -4-[(4-fluorophenylthio) methyl] piperidine (1.71 g, 76%) as a brown oil. The obtained 4-
(2-Fluoroethoxy) -4-[(4-fluorophenylthio) methyl] piperidine (0.783 g, 2.7
2 mmol) via pale yellow oily 1-t-butoxycarbonyl-4- (2-fluoroethoxy) -4-[(4-fluorophenylthio) methyl] piperidine to give pale yellow oily 1-t-butoxycarbonyl-4. -(2-Fluoroethoxy) -4-[(4-fluorophenylsulfinyl) methyl] piperidine (0.782 g, 71%) was obtained. MS (CI +): 404 (M + 1).

Embodiment 152 According to a method similar to that in Example 146, 4-bromomethyl-
1-t-butoxycarbonyl-4- (2,2,2-trifluoroethoxy) piperidine (1.62 g, 4.3
1 mmol) and a 2M-4FTPNa solution (2.16 m
1, 4.32 mmol) from 4-[(4-
Fluorophenylthio) methyl] -4- (2,2,2-
(Trifluoroethoxy) piperidine (1.10 g, 79
%). From the obtained 4-[(4-fluorophenylthio) methyl] -4- (2,2,2-trifluoroethoxy) piperidine (0.782 g, 2.42 mmol), 1-t-butoxycarbonyl as a pale yellow oil -4-
[(4-fluorophenylthio) methyl] -4- (2,
Via 2,2-trifluoroethoxy) piperidine, 1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] -4- (2,
2,2-trifluoroethoxy) piperidine (0.82
9g, 78%). MS (CI +): 440 (M + 1).

Embodiment 153 According to a method similar to that in Example 146, 4-bromomethyl-
1-t-butoxycarbonyl-4- (2-methoxyethoxy) piperidine (3.15 g, 8.94 mmol)
And 2M-4FTPNa solution (4.47 ml, 8.94 m
mol) yielded 4-[(4-fluorophenylthio) methyl] -4- (2-methoxyethoxy) piperidine (1.72 g, 65%) as a brown oil. The obtained 4-
[(4-fluorophenylthio) methyl] -4- (2-
(Methoxyethoxy) piperidine (1.06 g, 3.54
mmol) to 1-t-butoxycarbonyl-4-[(4-fluorophenylthio) methyl] -4 as a pale yellow oil.
Via 1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] -4- (2-methoxyethoxy) piperidine (1.08 g, 69%) as pale yellow oil via-(2-methoxyethoxy) piperidine. ) Got. MS (CI +): 416 (M + 1).

Embodiment 154 According to a method similar to that in Example 146, 4-benzyloxy-4-bromomethyl-1-t-butoxycarbonylpiperidine (2.17 g, 5.65 mmol) and 2M-4
From the FTPNa solution (2.83 ml, 5.66 mmol), brown oily 4-benzyloxy-4-[(4-fluorophenylthio) methyl] piperidine (0.768).
g, 41%). 4-benzyloxy-4 obtained
From-[(4-fluorophenylthio) methyl] piperidine (1.00 g, 3.02 mmol), 4
-Benzyloxy-1-t-butoxycarbonyl-4-
Via [(4-fluorophenylthio) methyl] piperidine, 4-benzyloxy-1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] piperidine as a pale yellow oil (0.651 g, 48%) I got MS (CI +): 448 (M + 1).

Embodiment 155 (R) -1-t-butoxycarbonyl-4-methoxy-prepared from (R) -phenylmethylsulfoxide
4-[(Phenylsulfinyl) methyl] piperidine (1.37 g, 3.88 mmol) was treated with trifluoroacetic acid to give (R) -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine. From the obtained (R) -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, in the same manner as in Example 15, light brown needle-like crystals of (R) -1- [2- (benzothiophene- 3-yl) ethyl-4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (0.555
g, 35%). [α] _D ²⁴ + 108 (c = 0.49, EtOH) (99.8% ee)

Embodiment 156 (S) -1-t-butoxycarbonyl-4-methoxy-prepared from (S) -phenylmethylsulfoxide
4-[(Phenylsulfinyl) methyl] piperidine (3.05 g, 8.63 mmol) was treated with trifluoroacetic acid to give (S) -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine. From the obtained (S) -4-methoxy-4-[(phenylsulfinyl) methyl] piperidine, a pale orange yellow needle-like (S) -1- [2- (benzothiophene) was obtained in the same manner as in Example 15. -3-yl) ethyl-4-methoxy-4-
[(Phenylsulfinyl) methyl] piperidine (1.
70 g, 52%).

Embodiment 157 Treatment of 1-tert-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (705 mg, 1.90 mmol) prepared from (+)-4-fluorophenylmethylsulfoxide with trifluoroacetic acid. Thus, 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine was obtained. Example 31 was obtained from the obtained 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine.
(+)-4-[(4
-Fluorophenylsulfinyl) methyl] -4-methoxy-1- (2-phenylethyl) piperidine (528
mg, 74%). [α] _D ²² +117 (c = 0.40, CHCl ₃ ) (95% ee)

Embodiment 158 1-t-butoxycarbonyl-4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (1.98 g, 5.33 mmol) produced from (−)-4-fluorophenylmethylsulfoxide was treated with trifluoroacetic acid. To give 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine. Example 31 was obtained from the obtained 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine.
(-)-4-[(4
-Fluorophenylsulfinyl) methyl] -4-methoxy-1- (2-phenylethyl) piperidine (0.5
37 g, 27%). [α] _D ²² −111 (c = 0.39, CHCl ₃ ) (92% ee)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/46 A61K 31/46 A61P 1/00 A61P 1/00 1/04 1/04 1/08 1 / 08 11/06 11/06 13/10 13/10 25/04 25/04 25/06 25/06 25/14 25/14 25/16 25/16 25/22 25/22 25/24 25/24 29 / 00 101 29/00 101 43/00 111 43/00 111 C07D 211/20 C07D 211/20 211/42 211/42 401/06 401/06 405/06 405/06 409/06 409/06 413/06 413/06 451/06 451/06 (72) Inventor Yasuji Fukuda 3-21-13-202, Otome, Oyama City, Tochigi Prefecture

Claims (31)

[Claims] [Claim 1] The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C ₁ -C ₆ alkoxy group, Y is a C ₁ -C ₄ alkylene group or an alkenyl alkylene group (which may have a C ₁ -C ₃ alkyl group), Ring A contains one nitrogen atom and has 1 to 3 carbon atoms.
A 5-, 6-, or 7-membered cyclic amine which may be cross-linked at any position via the ring, the ring B is a homo- or heterocyclic ring which may have a substituent, and the ring C is a substituent. A homo- or heterocyclic ring (optionally excluding an indole ring), n is 1
Or 2. Or a salt, hydrate or solvate thereof. 2. Ring A is a piperidine ring, ring B is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, or an optionally substituted A homo- or heterocyclic ring optionally having 1 to 3 substituents, each independently selected from C _{1 to} C ₆ alkoxy, amino, cyano or nitro, ring a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted aryl group, a hydroxyl group, which may C ₁ ~ be substituted
A homo- or heterocyclic ring optionally having 1 to 3 substituents each independently selected from a C ₆ alkoxy group, amino group, cyano group or nitro group (excluding indole ring The cyclic amine derivative according to claim 1, or a salt, hydrate and solvate thereof. 3. The cyclic amine derivative or a salt, hydrate or solvate thereof according to claim 1, wherein the ring A represents a piperidine ring and the ring C represents a benzene ring which may have a substituent. 4. The cyclic amine derivative or a salt, hydrate or solvate thereof according to claim 1, wherein ring A represents a piperidine ring and ring C represents an indene ring which may have a substituent. 5. The cyclic amine derivative or a salt, hydrate or solvate thereof according to claim 1, wherein the ring A represents a piperidine ring and the ring C represents a benzofuran ring which may have a substituent. 6. The cyclic amine derivative or a salt, hydrate or solvate thereof according to claim 1, wherein ring A represents a piperidine ring and ring C represents a benzothiophene ring which may have a substituent. 7. The following general formula (2)(Where R¹Is a hydrogen atom or C₁~ C₆An alkyl group of
X represents a hydrogen atom, a hydroxy group, or C₁~ C₆Arco
Xyl group, Ring A is bridged at any position containing one nitrogen atom
5-, 6- or 7-membered cyclic amine, B-ring which may be
Is an homo or heterocyclic ring which may have a substituent, n is 1 or
Indicates 2. ) And the following general formula (3)(Where Y is C₁~ C₄Alkylene group or alkenyl of
Alkylene group (C₁~ C ₃Having an alkyl group of
Good), Z is a reactive residue, and C ring may have a substituent.
Good homo or heterocyclic ring (excluding indole ring)
Show. ) In the presence of a base.
The method for producing a cyclic amine derivative according to claim 1, wherein 8. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. A) a tachykinin receptor antagonist, which comprises a cyclic amine derivative represented by the formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. 9. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. A neurokinin A receptor antagonist comprising a cyclic amine derivative represented by the formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. 10. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. ), Or a salt, hydrate or solvate thereof, as a pharmaceutical composition. 11. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. Or a salt, hydrate or solvate thereof as a pharmaceutical composition for preventing or treating dysuria including bladder dysfunction such as pollakiuria and urinary incontinence. . 12. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. Or a salt, a hydrate or a solvate thereof, as a pharmaceutical composition, for preventing or treating digestive diseases including ulcerative colitis and Crohn's disease. 13. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. X-ray irradiation, a chemotherapeutic agent, pregnancy, migraine, postoperative disease, gastrointestinal motility, which comprises the cyclic amine derivative represented by the formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. An agent for preventing or treating emesis induced by a decrease or side effects of drug administration. 14. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. Central nervous system diseases including anxiety, depression, Parkinson's disease, Huntington's disease, dementia and the like, characterized by containing a cyclic amine derivative represented by the formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Prophylactic or therapeutic agent. 15. The following general formula (1) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
X is a hydrogen atom, a hydroxy group, or a C _{1 to} C ₆ alkoxy group, Y is a C _{1 to} C ₄ alkylene group or an alkenyl alkylene group (which may have a C _{1 to} C ₃ alkyl group), Ring A is a 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position containing one nitrogen atom, Ring B is a homo- or heterocyclic ring which may have a substituent, The ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n represents 1 or 2. ) Or a salt, hydrate or solvate thereof as a pharmaceutical composition, wherein asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc., involving tachykinin are provided. Improver. 16. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
And a salt, hydrate and solvate thereof. 17. Ring A may be a piperidine ring, ring B may be a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, or an optionally substituted A homo- or heterocyclic ring optionally having 1 to 3 substituents each independently selected from a C _{1 to} C ₆ alkoxy group, amino group, cyano group or nitro group (provided that indole (Excluding a ring).
Or a salt, hydrate or solvate thereof. 18. The cyclic amine derivative according to claim 16, wherein ring A represents a piperidine ring and ring C represents a benzene ring which may have a substituent, or a salt, hydrate or solvate thereof. 19. The cyclic amine derivative according to claim 16, wherein ring A represents a piperidine ring and ring C represents a benzofuran ring which may have a substituent, or a salt, hydrate or solvate thereof. 20. The cyclic amine derivative or a salt, hydrate or solvate thereof according to claim 16, wherein the ring A represents a piperidine ring and the ring C represents a benzothiophene ring which may have a substituent. 21. The following general formula (5) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group; R ⁴ is a t-butyl group or a benzyl group; X ¹ is a halogen atom; A 5-, 6-, or 7-membered cyclic amine containing a nitrogen atom, which may be cross-linked at any position via 1 to 3 carbon atoms. ). 22. The following general formula (5) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group; R ⁴ is a t-butyl group or a benzyl group; X ¹ is a halogen atom; A 5-, 6-, or 7-membered cyclic amine containing a nitrogen atom, which may be cross-linked at any position via 1 to 3 carbon atoms. The compound represented by the following general formula (6) (Wherein ring B represents a homo- or heterocyclic ring which may have a substituent) by reacting a compound represented by the following general formula (7): (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and R ⁴ is t A butyl or benzyl group, the A ring contains one nitrogen atom,
A 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position via 1 to 3 carbon atoms, and ring B represents a homo- or heterocyclic ring which may have a substituent . )). 23. The following general formula (7) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and R ⁴ is t A butyl or benzyl group, the A ring contains one nitrogen atom,
A 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position via 1 to 3 carbon atoms, and ring B represents a homo- or heterocyclic ring which may have a substituent . ) By oxidizing the compound represented by the following general formula (8) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and R ⁴ is t A butyl or benzyl group, the A ring contains one nitrogen atom,
A 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position via 1 to 3 carbon atoms, a ring B, a homo- or heterocyclic ring which may have a substituent, m Represents 1 or 2. )). 24. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
A tachykinin receptor antagonist comprising a cyclic amine derivative represented by the following formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. 25. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
A neurokinin A receptor antagonist comprising, as a pharmaceutical composition, a cyclic amine derivative represented by (excluding the indole ring))), or a salt, hydrate or solvate thereof. 26. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
A substance P and neurokinin A receptor antagonist comprising a cyclic amine derivative represented by the following formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. 27. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
Dysuria including bladder dysfunction such as pollakiuria and urinary incontinence characterized by containing a cyclic amine derivative represented by)) or a salt, hydrate and solvate thereof as a pharmaceutical composition Prophylactic or therapeutic agent. 28. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
Prevention of gastrointestinal diseases including ulcerative colitis and Crohn's disease, characterized by containing a cyclic amine derivative represented by)) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Or therapeutic agents. 29. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
X-ray irradiation, a chemotherapeutic agent, pregnancy, migraine, surgery, which comprises a cyclic amine derivative represented by the following formula) or a salt, hydrate and solvate thereof as a pharmaceutical composition: An agent for preventing or treating vomiting induced by post-disease, gastrointestinal motility, or side effects of drug administration. 30. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
Anxiety, depression, Parkinson's disease, characterized by containing a cyclic amine derivative represented by the following formula) or a salt, hydrate and solvate thereof as a pharmaceutical composition:
An agent for preventing or treating central nervous system diseases including Huntington's disease, dementia and the like. 31. The following general formula (4) (Wherein, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ is an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted benzyl group, and Y is a C ₁ -C ₄ alkylene group or an alkenylalkylene group (C ₁ -C
₃ ring), ring A contains one nitrogen atom and may be bridged at any position via 1 to 3 carbon atoms to form a 5-, 6- or 7-membered Membered cyclic amine,
Ring B is a homo- or heterocyclic ring which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however,
Asthma involving tachykinin, characterized by containing a cyclic amine derivative represented by:
An improving agent for cough, pain, migraine, toothache, rheumatoid arthritis and the like.