WO2000006544A1 - Cyclic amine derivatives and process for the preparation thereof - Google Patents

Abstract

Cyclic amine derivatives represented by general formula (1) and salts thereof, which exhibit tachykinin antagonism, particularly antagonism against substance P and neurokinin A receptors; a process for the preparation of them; and drug compositions containing the compounds or medicinally useful salts thereof. In said formula, R1 is hydrogen or C¿1?-C6 alkyl; X is hydrogen, hydroxyl or C1-C6 alkoxy; Y is alkylene or alkenylalkylene; A is a five-, six- or seven-membered cyclic amine which contains one nitrogen atom and may be bridged at any positions; B is an optionally substituted homo- or hetero-cycle; C is an optionally substituted homo- or hetero-cycle except indole ring; and n is 1 or 2.

Description

 Satsuki Itoda 環状 Cyclic amine derivative and production method

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

Background art

Tachykinins (substance P, neurokinin A, neurokinin B) are a general term for neuropeptides, and each receptor (neurokinin 1 (NK js neurokinin 2 (NK 2). 3 (NK3)) is known to exert various physiological activities.These tachykinins act as transmitters of central and peripheral primary sensory neurons and enhance diuresis. It has physiological activities such as action, neuronal cell descending action, vascular permeability increasing action, vasodilator action, smooth muscle contraction action, immunity action, etc. It is considered to be deeply involved in respiratory tract diseases, pain, central nervous system diseases, etc. Therefore, tachykinin is an excellent prophylactic and therapeutic agent for the above various conditions. Having a body antagonism operation, and excellent safety, development of compounds having a persistent or the like is rarely Nozomu.

At present, the following compounds are disclosed as compounds having a substance P receptor antagonistic action.

(1) In Japanese Patent Application Laid-Open No. 1-28795, formula: R ¹ -AD-Trp (R ² G PhQ-R 3

(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 R ³ is an alk (lower) alkyl group, N (R ⁴ ) (R ⁵ ) group (wherein R ⁴ and R ⁵ are each hydrogen, aryl, or A good lower alkyl group, R ⁴ and R ⁵ combine with each other to form a benzene condensed lower alkylene group, or —OR ⁶ group, where R "is hydrogen, aryl, or Wherein A represents a single bond or one or two amino acid residues, and A represents D—T rp R ¹ is not hydrogen when it means one amino acid residue of the formula: ## STR00015 ## The compounds represented by the formula: and salts thereof are disclosed. Have been.

 (2) E P — A — 4 2 9 3 6 6 Formula:

Are disclosed.

(3) Formula in W091 / 09884:

Are disclosed.

(4) Ε Ρ— Α— 5 3 2 4 5 6 Formula

(5) EP—A— is represented by the formula

Are disclosed.

 (6) WO 93/0 1 1 69 No. formula:

Are disclosed.

 (7) In Japanese Patent Application Laid-Open No. Hei 8-67676, the formula is as follows:

(Wherein, ring A and ring B are homo or hetero rings, at least one of which is a heterocycle; ring C is a benzene ring; R is H or a hydrocarbon residue; one of X and Y is one NR ¹ - (R ¹ is H or a hydrocarbon residue) or - 0-, other guard CO- or - CS-, or one one N =, the other = CR ² i (1 ² 11, halogen, hydrocarbon A hydrogen residue, an amino group or a hydroxy group); n represents 1 or 2.) or a salt thereof.

(8) Japanese Patent Application Laid-Open No. 9-104646 describes the formula:

R ¹

(In the formula, x is a hydrogen atom or an oxygen atom, γ is a nitrogen atom or an oxygen atom which may be alkylated or acylated, and R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanol group, a nitrogen atom. An alkyl group containing an atom, a carbamoyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a (4-phenylbiperazine-1-yl) methyl group is a hydrogen atom, a lower alkyl group, A lower alkyl group, a lower alkanoyl group, or a lower alkoxy group containing a hydroxyl group, and the A ring and the B ring each represent a benzene ring which may have a substituent.

 (9) Japanese Patent Application Laid-Open No. Hei 9-2666387 describes the formula:

(In the formula, the M ring has a partial structure of X = Y and one N = C and one CO— N <or heterocycle having an CS- N rather; or R ^a and R ^h are combined together to form a ring A, or a substituent definitive same or different and each represents a hydrogen atom or M ring; ring A and ring B Is a heterocyclic or heterocyclic ring which may have a substituent, at least one of which is a heterocyclic ring which may have a substituent; and ring C is a heterocyclic or heterocyclic ring which may have a substituent. A prime or heterocycle, the 'Z ring may be an optionally substituted ring; and n represents 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) In Life Sciences, Volume 50, page 101 (1992):

 CI

Are disclosed.

(2) In Bioorganic 'And Medicinal Chemistry-Letters' (Vol. 6, Med. Chem. Lett.), Vol. O e

Are disclosed.

 (3) The formula in WO93 / 14804 is:

(In the formula, R ¹ is 1 or 2 and C, alkyl ~ C _4, C, § alkoxy group ~ C _4, Application Benefits Furuoromechiru group or a halogen atom which may be substituted phenylalanine radical, R ² is a hydrogen atom, a hydroxy group or an alkoxy group of C, to C ₄ , R ³ is a hydrogen atom or an alkyl group of C i to C ₄ , R ⁴ is a hydrogen atom, an alkyl group of C, to C 4 or C, alkoxy group ~ C _4, R ⁵ a hydrogen atom or an alkyl group C i to C 4, Application Benefits Furuoromechiru group Shiano group or a halogen atom, n represents ◦, represented Ru compound or in.) of 1 or 2 Salts are disclosed.

At present, it has excellent antagonism to tachykinin receptor as a preventive or therapeutic agent for the above-mentioned various disease states, and has safety, sustainability, etc. No compound has been found that can be a sufficiently satisfactory pharmaceutical in view of the above. An object of the present invention is to provide a pharmaceutical composition having a superior antagonism to a tachykinin receptor, which has a different chemical structure from a known compound containing the aforementioned compound, a tachykinin receptor antagonist, prevention of dysuria or An object of the present invention is to provide a therapeutic agent, a prophylactic or therapeutic agent for gastrointestinal diseases, a prophylactic or therapeutic agent for vomiting, and a prophylactic or therapeutic agent for central nervous system diseases. Disclosure of the invention

The present inventors have the following general formula (1)

(CVY-N A C

(In the formula, R ¹ may be a hydrogen atom or a C alkyl group, X may be a hydrogen atom hydroxy group, or a C ₆ to C ₆ alkoxy group, and Y may have a C i C y alkyl group. C i -C ₄ alkylene group or alkenylalkylene group, ring A may be cross-linked at any position containing one nitrogen atom 5-, 6- or 7-membered cyclic amine, ring B Is a homo- or heterocyclic ring which may have a substituent, C ring is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), and n is 1 or 2 The present invention provides a cyclic amine derivative represented by the formula or a salt, hydrate and solvate thereof.

We have:

A ring is a pyridin ring,

Ring B is a halogen atom, an optionally substituted C, to C ₆ alkyl group. 1 to 1 independently selected from an optionally substituted aryl group, a hydroxyl group, an optionally substituted CiCs alkoxy group, an amino group, a cyano group and a nitro group A homo- or heterocyclic ring optionally having three substituents,

C ring is halogen atom, optionally substituted C! To C _f; an alkyl group which may be substituted, independently from an aryl group, a hydroxyl group, an optionally substituted C t Ce alkoxy group, an amino group, a cyano group or a nitro group. A cyclic amine derivative of general formula (1) or a salt thereof, which represents a homo- or heterocyclic ring (excluding an indole ring) optionally having 1 to 3 substituents selected , Hydrates and solvates.

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

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

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

The present inventors have proposed a cyclic amine derivative of the general formula (1) or a salt thereof, in which ring A represents a piperidine ring and ring C represents a benzothiophene ring which may have a substituent. And solvates.

The present inventors have the following general formula (2)

(In the formula, R ¹ is a hydrogen atom or a C alkyl group, X is a hydrogen atom hydroxy group, or (^, ~. (; An alkoxy group, and A ring is any position including one nitrogen atom.) A 2- or 5-membered, 6- or 7-membered cyclic amide which may be crosslinked; a ring B being a homo- or heterocyclic ring which may have a substituent;

Indicates 1 or 2. ) And a compound represented by the following general formula (3)

(Wherein, gamma For c, may have an alkylene group or alkenyl alkylene group (alkyl group of C i C g of to c _4), z is reactive residue, c ring has a substituent A heterocyclic or heterocyclic ring (excluding an indole ring) which may be reacted with a compound represented by the general formula (1) in the presence of a base. Provided is a method for producing a derivative.

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. I do.

The present inventors have proposed a cyclic amine derivative represented by the general formula (1) or a salt thereof, Provided is a neurokinin A receptor antagonist, which comprises a hydrate and a solvate as a pharmaceutical composition.

Means for Solving the Problems The present inventors have disclosed a substance A and a neurokinin A receptor comprising a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide a body antagonist. The present inventors have found that a cyclic amine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition is included in a frequent urinary frequency, urinary incontinence, etc. And a preventive or therapeutic agent for dysuria including bladder dysfunction.

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

The present inventors have proposed a method for producing 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. Drugs for the prevention or treatment of vomiting induced by pregnancy, migraine, postoperative illness, gastrointestinal motility depression or side effects of drug administration.

The present inventors have anxiety, depression, Parkinson's disease characterized by comprising a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. And a preventive or therapeutic agent for central nervous system diseases including Huntington's disease, dementia and the like.

The present inventors have characterized in that a cyclic amine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof is contained as a pharmaceutical composition. Asthma involving tachykinin, Provide therapeutic agents for cough, pain, migraine, toothache, rheumatoid arthritis, etc.

The present inventors have the following general formula (4) R ¹ , NO OR ³

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C, to C ₆ , R ³ is an optionally substituted C, to C ₆ alkyl group or an optionally substituted benzyl group, Y is C i The C ^ alkylene group or alkenyl alkylene group (which may have a C 1 to C 3 alkyl group), ring A contains one nitrogen atom, and has 1 to 3 carbon atoms 5-membered, 6-membered or 7-membered cyclic amide which may be crosslinked at any position, ring B may be a homo- or heterocyclic ring which may have a substituent, ring C may have a substituent To provide a cyclic amide derivative represented by an allo- or heterocyclic ring (excluding an indole ring), or a salt, hydrate and solvate thereof.

We have:

A ring is a pyridin ring,

Ring B is a halogen atom, an optionally substituted C i C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C, -C ₆ alkoxy group, or an amino group A homo- or heterocyclic ring (excluding an indole ring) optionally having 1 to 3 substituents, each independently selected from among a cyano group or a nitro group; Provided is a cyclic amine derivative represented by the formula (4) or a salt, hydrate and solvate thereof.

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

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

The present inventors have the following general formula (5)

(Wherein, R ¹ is a hydrogen atom or a C alkyl group, R ³ is an optionally substituted C i -C _f; alkyl group or an optionally substituted benzyl group, and R ⁴ is t-butyl. Group or benzyl group, X ¹ is a halogen atom, ring A contains one nitrogen atom, and may be cross-linked at any position via 1 to 3 carbon atoms.5, 6 or 7 members Indicates a member's cyclic amine.)

The following general formula (6)

HS— ® (6)

(In the formula, ring B represents a homo- or heterocyclic ring which may have a substituent.) A method for producing a compound represented by the general formula 7) by reacting the compound represented by the general formula 7).

The present inventors have the following general formula (7)

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C ¹ to C 4, R ³ is an optionally substituted C i C g alkyl group or an optionally substituted benzyl group, and R ⁴ is t— Butyl or benzyl group, ring A contains one nitrogen atom and may be cross-linked at any position via 1 to 3 carbon atoms.5-, 6- or 7-membered cyclic amide And ring B represents an allo- or heterocyclic ring which may have a substituent.) A method for producing a compound represented by the general formula (8) by oxidizing the compound represented by the formula: I do. The present inventors provide a tachykinin receptor antagonist comprising a cyclic amine derivative represented by the general formula (4) 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 (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. provide.

The present inventors have disclosed a substance P and 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 a body antagonist. The present inventors are characterized in that a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof is contained as a pharmaceutical composition. Provided is a preventive or therapeutic agent for dysuria including urinary bladder dysfunction such as frequent urination and incontinence.

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

The present inventors have proposed an X-ray irradiation, chemotherapeutic agent comprising a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof as a pharmaceutical composition. It is intended to provide a preventive or therapeutic agent for vomiting induced by pregnancy, migraine, postoperative illness, gastrointestinal motility depression or side effects of drug administration.

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

The present invention is characterized in that a cyclic amine derivative represented by the general formula (4) or a salt, hydrate and solvate thereof is contained as a pharmaceutical composition. Asthma involving evening kikinin Provide a remedy for cough, pain, migraine, toothache, rheumatoid arthritis, etc.

Here, the alkyl group of C ₁ to C _4; 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, an isopropoxy group, a t-butoxy group, a hexyloxy group and the like. The alkylene group or alkenylalkylene group of C t C ^ which may have an alkyl group of C is a methylene group, an ethylene group which may be substituted with a methyl group, an ethyl group, a propyl group or an isopropyl group. Group, propylene group, aryl group and the like. With reactive residues A chlorine atom, a bromine atom, means iodine atom or 〇 S 0 ^₂ R ₂ (R ₂ is methylcarbamoyl group, Application Benefits Furuoromechiru group, phenyl group, 4-methylphenyl group or a 4 two preparative Rofueniru group) and the like. A 5-, 6-, or 7-membered cyclic amide which may be cross-linked at any position containing one nitrogen atom includes a pyrrolidine ring, a piperidine ring, a homopiperidine ring, Azabicyclo [3.2.1] means an octane ring or the like. The nitrogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The alkyl group which may be substituted with C,-(:(; is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a hydroxyl group, a C, -C ₆ alkoxy group, etc. A C ₁ -C _f ; alkyl group which may have 1 to 5 substituents selected from the group consisting of a halogen atom, a C _{1 to} C ₆ alkyl group, human Dorokishiru group, C i to alkoxy groups of C _6, amino group, Horumiruami amino group, an alkylcarbonyl § Mi amino group of C i~C ₆ (Asechiruami amino group, Puropioniruami cyano group, Buchirinoreami ), C, -C ₆ alkylsulfonylamino groups (methylsulfonylamino groups, ethylsulfonylamino groups, etc.), and optionally substituted arylsulfonylamino groups (phenylsulfonylamino groups) No group, 4-me Or a substituted or unsubstituted aryl group (phenyl group, naphthyl group, etc.) which may have 1 to 5 substituents selected from, for example, a phenyl group and a naphthyl group. ^ - (^; and alkoxy group, a halogen atom, arsenic mud hexyl group, C, alkoxy group-C _6, amino group, Horumiruami amino group, an alkylcarbonyl amino group of C-C _6, C, ~ _{C ί;} of Arukirusu Ruhoniruami amino group, which may have a substituent which may § Li one also be Rusuruhoniruami Bruno 1 selected from group 5 substituents

It means an alkoxy _group; f. The homologous ring of the ring B and the ring C means a benzene ring, a naphthalene ring or the like. Heterocycles of the B and C rings are 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from elementary, oxygen and sulfur atoms, or 9- or 10-membered aromatic It means a fused heterocycle.

As preferred compounds of the present invention,

4-Methoxy 11- (2-phenylethyl) 4-([phenylsulfinyl) methyl] piperidine, 1-1 [2- (3-chlorophenyl) ethyl] — 4-methoxy 4 — [(Phenylsulfinyl) methyl] bipyridine, 1- [2— (4-chlorophenyl) methyl] —4—methoxyl 4 -— [(phenylsulfinyl) methyl] piperidine 4-Methoxy 1- [2- (3-nitrophenyl) ethyl] -4-1 [(phenylsulfinyl) methyl] piperidine, 1-1 [2- (3-biphenyl) ethyl ] 4-Methoxy 4-[(phenylphenyl) methyl] piperidine, 1- [2- (4-biphenyl) methyl]-4-methoxy41-[(phenylsulfinyl) methyl] Bilidine, 1 — [2— (3,5-dichlorophenyl) ethyl] —4-me Xy 4-[(phenylsulfinyl) methyl] piperidine, 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] — 4-methoxy4 — [(phenylsulfinyl) methyl] Piperidine, 4-Methoxy 1- [2- (1-naphthyl) ethyl] —4 -— [(phenylsulfinyl) methyl] piperidine, 4-methoxy-1 1— [2— ( 2—naphthyl) ethyl] — 4 — [(phenylsulfinyl) methyl] bipyridine, 4-methoxy-1-41 [(phenylsulfinyl) methyl] 1 1— [2— (2 —Chenyl) ethyl] piperidine, 4-methoxy-14-[(phenylsulfinyl) methyl] 1-111 [2- (3-Chenyl) ethyl] piperidine, 1— [2— ( 1-d-yl-ethyl) 1-doxy 4--1 [(phenylsulfinyl) Methyl] Piperi gin, 1 one [2- (Benzofura down one 3 —Yl) ethyl——4-Methoxy 4 — [(phenylsulfinyl) methyl] bipyridine, 1- [2- (benzothiophene-3-yl) ethyl] 1-4-methoxy 4 1-[(phenylsulfinyl) methyl] piperidine, 1- [2 -— (5-fluorobenzothiophene-3-yl) ethyl] 1-4-methoxy-4-1 [ [Phenylsulfinyl) methyl] piperidine, 1- [2— (5-cyclobenzo-1-phenyl) ethyl] 14-methoxy41-[(phenylsulfinyl) methyl] Bilidine, 4-methoxy 11- [2- (5-Methylbenzothiophene 13-yl) ethyl] 1-41-[(phenylsulfinyl) methyl] piperidine, 1-1 [2 — (1,2-Benzoisoxazo—Lu-3-yl) ethyl] — 4-Methoxy 4 -— [(phenylsulfur Nyl) methyl] piperidine, 4-methoxy-1- 1- [2- (1-methylindazo-1-yl) ethyl] 1-41-[(phenylsulfinyl) methyl] piperidine , 1— [2— (1H—benzimidazole 1—yl) ethyl] —4-Methoxy 41 — ((phenylsulfinyl) methyl) methyl) pyridine, 1— [2— (2,3-Dihydrodol-3-yl) ethyl] 1-4-Methoxy 4-[(phenylsulfinyl) methyl] piperidine, 1-[(3,5-dichloro [Phenyl) methyl] 1-4-methoxy-14-[(phenylsulfinyl) methyl] piperidine, 1- [3— (3,5-dichlorophenyl) propyl] 1-4- Methoxy 4-([phenylsulfinyl) methyl] piperidine, 1- [1- (3,5-dichlorophenyl) bromide 1-3-yl] — 4-methoxy 4 — [(phenylsulfinyl) methyl] bipyridine, 1—2— (3,5-dichloromouth phenyl) ethyl] 1-4— 4-([phenylsulfonyl) methyl] biperidine, 1— [2— (benzothiophene-3

— (Yl) ethyl] 1—4—Methoxy 4 — ((phenylsulfonyl) Methyl] bipyridine, 1- [2- (benzofuran-3-yl) ethyl] 1-41-[(phenylsulfinyl) methyl] bipyridine-1-4-ol, 1— [2— (3,5-dichlorophenyl) ethyl] 1 4 1

[(Phenylsulfinyl) methyl] piperidine, 1- [2- (Benzothiophene-3-yl) ethyl] 1-4-[(Phenylsulfinyl) methyl] piperidine, 4— [ (4-Fluorophenylsulfinyl) methyl] —4-Methoxy-1— (2-Phenylethyl) biperidine, 1- [2— (Benzofuran-3-yl) ethyl] 1-41

[(4-Fluorophenylsulfinyl) methyl] —4-methoxypiperidine, 1— [2- (5-Fluorobenzothiophene-3-yl) ethyl] —4 — [( 4-Fluorophenylsulfinyl) methyl] — 4-Methoxybiperidine, 4-Methoxy-1-41 [(4-Methoxyphenylsulfinyl) methyl] 111- (2-phenylethyl) biyl Resin, 1- [2- (Benzofuran-3-yl) ethyl] 1-4-Methoxy-14-[(4-Methoxyphenylsulfinyl) methyl] piperidine, 1— (2 —Phenylethyl) 1 4— [(4—Trifluoromethylphenylsulfinyl) methyl] piperidine 1—4,1— [2— (Benzofuran 1-3-yl) ethyl] —4 — [(4—Trifluoromethylphenylsulfinyl) methyl] piperidine 4-all, 4-methoxy-4-([2-naphthylsulfinyl) methyl] — 1- (2-phenylenyl) piperidine, 1— [2- (benzofuran-3-yl) ethyl] — 4-Methoxy 4-([2-naphthylsulfinyl) methyl] piperidine, 4-[(4-fluorophenylsulfinyl) methyl] 1-4-methoxy-11- (3-phenylbromide) Bill) Pyridine, 4-Methoxy 1- (2-phenylethyl) 1-4- [11- (phenylsulfinyl) ethyl] bipyridine,

1- [2- (Benzofuran-3-yl) ethyl] —4—Methoxy 4- [11- (phenylsulfinyl) ethyl] piperidine, 11- [21- (benzofuran-13-yl) ethyl] 13-methoxy-13-[(phenylsulfinyl) methyl ] Pyridine, 3-methoxy-1- (2-phenylenyl) -13- [1- (phenylsulfinyl) ethyl] -8-azabicyclo [3.2.1] octane, 8- [ 2- (Benzofuran-1-ethyl) ethyl] —3-Methoxy-3- (1- (phenylsulfinyl) ethyl] —8-azabicyclo [3.2.1] 4 — [(4-Fluorophenylsulfinyl) methyl] -1-4—Methoxy 1— [2— (3—Nitrophenyl) ethyl] Piberidine, 1— [2— (3—aminophene Nyl) ethyl] — 4 — [(4-Fluorophenylsulfinyl) methyl] 1-4-methoxypiperidine, 4-ethoxy-4 — [(4-fluorophenylsulfinyl) methyl] —1— (2-phenylenyl) piperidine, 4-[(4-fluorophenylsulfinyl) methyl] —1— (2 — (Phenylethyl) — 4—propoxypiperidine, 4-butoxy-1-41 [(4-fluorophenylsulfinyl) methyl] — 1 — (2—phenylethyl) piperidine, 4— [(4 _Fluorophenylsulfinyl) methyl]-1-(2 -phenylethyl) 1-4-(2-propoxy) piberidine, 4-cyclopropyl mouth pyrmethoxy 1 4-[(4-fluorophenylsulfenyl) methyl] — 1 — (2 — phenylethyl) piperidine, 4 — (2 — fluoroethoxy) 1 4 — [(4 — fluorophenylsulfinyl) methyl] — 1 1 (2 — phenylethyl) biphenyl Gin, 4— (2, 2, 2—Trifluoroethoxy) -4-1 [(4-Fluorophenylsulfinyl) methyl] —1— (2—phenylenyl) piperidine, 4 — [(4— Fluorophenylsulfinyl) methyl] — 41- (2-Methoxyethoxy) 1 1 — (2-phenylenyl) piperidine, 4-benzyloxy 4 — [(4-Funolerophenyls) (Phenyl) methyl] — 1 _ (2 —phenylethyl) piperidine, 1-1 [2 — (benzothiophene 3 — yl) ethyl] — 4 — ethoxy 4 _ [(4-fluorophenyl) Phenylsulfinyl) methyl] biperidine; [2— (Benzothiophene-3-ethyl) ethyl] — 4-butoxy-1-([4-fluorophenylsulfinyl) methyl] piperidine, 1-1 [2— (benzothiophene-3— Yl) — 4 — [(4-fluorophenylsulfinyl) methyl] 1-4- (2-propoxy) bipyridine, 1 — [2 — (benzothiophene-3-yl) ethyl] — 4 1 (2 — Fluoretoxy) 1 4 — [(4-fluorophenylsulfinyl) methyl] piperidine, 1— [2- (benzothiophene-3-yl) ethyl] — 4 — [(4-fluorophenylsulfinyl) methyl ] 1 4 1 (2,2,2—trifluoroethoxy) piperidine, 1 1 [2— (benzothiophene 3 —yl) ethyl] — 4 — [(4 fluorophenylsulfinyl) ) Methyl] — 4- (2-methoxyphenyl) piperidine, 1 — [2— (Benzothiophen-3-yl) ethyl] — 4 —Benzyloxy 4 — [(4-Fluorophenyl Sulfinyl) methyl] piperidine, 4-[((4-fluorophenylthio) methyl] —1— (2—phenylethyl) -14—methoxypyridine, 1_ [2— (3, 5 — Pistrifluoromethylphenyl) ethyl] 1 4 — methoxy 14-Frenylthiomethylbiperidine, 1_ [2— (3,5—Bistrifluoromethylphenyl) ethyl] 1-4 — [(4—Fluorophenylthio) methyl] —4—Methoxypyridine Gin, 1 [2 — (3, 5 — pristine trifluoromethylphenyl) methyl] — 4 — [(3 — fluorophenylthio) methyl Ί — 4 — Notoxypiperidine, 1 — [ twenty three, 5—Bis trifluoromethylphenyl) ethyl] —4 — [(2—Fluorophenylthio) methyl] —4—Toxipiperidine, 1— [2— (3,5—Bis trifluoromethylphenyl) ethyl] 1-4 _ [(4-bromophenylthio) methyl] — 4 — methoxypiperidine, 1 —

 [2- (3,5—bistrifluoromethylphenyl) ethyl] —4 — [(3—Bromophenylthio) methyl] —4—Methoxypiperidine, 1— [2— (3,5— Bis (trifluoromethylphenyl) ethyl] — 4-[(4-chlorophenyl) methyl] — 4—Methoxybipyridine, 1- [2— (3,5—Bistrifluoromethyl) Ethyl) ethyl] — 4 — [(3—Clofluorophenyl) methyl] — 4 Methoxypiperidine, 1 — [2 — (3, 5 — Bistrifluoromethylfenyl) ethyl ] — 4—Methoxy-1 4 — [(4-Methylphenylthio) methyl] piperidine, 1— [2— (3,5—bistrifluoromethylphenyl) ethyl] — 4- Methoxy 4-([3-methylphenylthio) methyl] bipyridine, 1— [2— (3,5-bis Trifluoromethylphenyl) _ethyl] _4-Methoxy-4-([2-methylphenylthio) methyl] piveridine, 1— [2— (3,5-bistrifluoromethylphenyl) Ethyl) — 4-Methoxy 4-([4-nitrophenylthio) methyl] piperidine, 1 — [2 —

(3,5—Bis trifluoromethylphenyl) ethyl] — 4—Methoxy 4 — [(4-Trifluoromethylphenylthio) methyl] piperidine, 1_ [2— (3,5—bis Trifluoromethylphenyl) ethyl] — 4 — [(2, 6 —dichlorophenyl) methyl] — 4 -methoxypiperidine, 1 — [2 — (3, 5 — bis trifluoromethyl) Enyl) ethyl] 1-41 [(3,5—bistrifluoromethylethylenthio) methyl] — 4 — methoxypiperidine, 1 — [2 —

(3, 5—bis trifluoromethylphenyl) ethyl] 1—4 Methoxyhexylthiomethyl-1-methoxypiperidine, 1- [2- (Benzofuran-3-yl) ethyl] —4—Methoxy-4—phenylthiomethylpiperidine, 1— [2— (benzofuran 1-3 —Yl) ethyl] 1-41 [(4-fluorophenylthio) methyl] — 4-methoxypiperidine, 1 — [2 — (benzofuran-3-yl) ethyl] 1-4 — [ (3-Fluorophenylthio) methyl] —4—Methoxybipyridine, 1- [2— (Benzofuran-3-yl) ethyl] —4 — [(2-Fluorophenylthio) methyl] —4-methyl Toxipiridine, 1-[2- (benzofuran-3-yl) ethyl]-4-[(4-bromophenylthio) methyl]-1-4-methoxypiperidine, 1-[2-(benzofuran-1 3- (ethyl)] — 4-([3-bromophenic Thio) methyl] — 4-Methoxypiperidine, 1- [2— (Benzofuran-3-yl) ethyl] — 4 -— [(4-chlorophenylthio) methyl] — 4-me Toxipiperidine, 1- [2— (Benzofuran-3-yl) ethyl] —4 — [(3-chlorophenythio) methyl] —4-Methoxylpiperidine, 1- [2— (benzofuran 1 3 —yl) ethyl] — 4 —Methoxy 1 4 1 [(4—Methylphenylthio) methyl] piperidine, 1 1 [2— (Benzofuran 3-yl) ethyl] — 4 —Methoxy 4 — [(3-Methylphenylthio) methyl] bipyridine, 1— [2— (benzofuran-3-yl) ethyl] 1-4—Methoxy 4 -— ((2—Methylphenyl Nilthio) methyl] piperidine, 1- [2- (benzofuran-3-yl) idyl] -14-methoxy-4-([412 Lofenylthio) methyl] piperidine, 1- [2- (benzofuran-3-yl) ethyl] — 4-methoxy-14 — [(4-trifluoromethylphenylthio) methyl] Pyridine, 1 — [2- (Benzofuran-3-yl) ethyl] 1-4 — [(2,6—dichroic phenylthio) methyl, 1-4 —Methoxypiridine, 1 — [2 — (Benzofuran-1-yl) ethyl] — 4 — [(3,5 —bistrifluoromethylphenylthio) methyl] — 4 — methoxypiperidine,

1 — [2- (Benzofuran-3-yl) ethyl] — 4—Cyclohexylthiomethyl-1-4—Methoxybiperidine, 4-Ethoxy-4_

[(4-Fluorophenylthio) methyl] —1— (2—phenylethyl) piperidine, 4-([4-Fluorophenylthio) methyl] —1— (2-phenylenyl) -1-4-propoxypiperi Gin, 4-butoxy-1-[(4-fluorophenylthio) methyl] 1-1- (2-phenylenyl) piperidine, 4-[(4-fluorophenylthio) methyl] — 1— (2— 4- (2-propoxy) piperidine, 4-cyclobutyr-pyrmethoxy-1-4 — [(4-Fluorophenylthio) methyl] 1-1— (2-phenylethyl) piperidine, 4 — (2—Fluoroethoxy) 1-4 — [(4-fluorophenylthio) methyl] —1— (2-phenylenyl) piperidine, 4-[(4-fluorophenylthio) methyl] —1— (2— Penny 1) 4-(2, 2, 2-trifluorethoxy) piperidine, 4-[(4-fluorophenylthio) methyl]-4-(2-methoxyshetoxy)-1 (2- (Phenylethyl) piperidine, 4-benziloxy-1 4 — [(4-fluorophenylthio) methyl] 1 1 —

(2-Phenylethyl) piperidine, 1- [2— (benzothiophen-3-yl) ethyl] —4-ethoxy-14-[(4-Fluorophenylthio) methyl] piperidine, 1 1 [2 — (benzothiophene — 3 — yl) ethyl] — 4 — [(4-fluorophenylthio) methyl] 1 4 — bropoxypiperidine, 1 — [2 — (benzothiophene 3 — yl) ) Ethyl] —4—butoxy-4-([(4-fluorophenylthio) methyl] pyridine, 1— [2— (benzothiophen-3-yl) ethyl] 1-4 — [(4 —Fluorophenylthio) methyl — 4- (2-propoxy) piperidine, 1— [2— (Benzothiophene-3-yl) ethyl] —4—Cyclopropyrmethoxy 4 — [(4-Fluorophenylthio) methyl] pi Peridine, 1 [2 — (Benzothiophene 3 — yl) ethyl] — 4 — (2 — Fluoroethoxy)-4-[(4-fluorophenylthio) methyl] piperidine, 1 – 1

 [2— (benzothiophene-3-yl) ethyl] —4-1 [(4-fluorophenylthio) methyl] —4— (2,2,2—trifluoroethoxy) piperidine, 1 — [2 — (benzothiophene 3 —yl) ethyl] — 4 — [(4-fluorophenylthio) methyl] 1-4 (2-methoxethoxy) piperidine, 1 1 [2 — ( Benzothiophene — 3-inethyl) ethyl] — 4 —Benzyloxy 4-41 [(4-fluorophenythio) methyl] bipyridine, +) — 1 _ [2-(Benzothiophene 3 — Yl) ethyl] — 4-1-[(4-Fluorophenylsulfinyl) methyl] 1-4-methoxypiperidine, (R) — 1 —

[2- (Benzothiophene-3-yl) ethyl] 4-methoxy [4- (phenylsulfinyl) methyl] bipyridine (S)-1-

[2 — (benzothiophene 3 — yl) ethyl 4 methoxy 4 1 [(phenylsulfinyl) methyl] piperidine (+) — 4 1

[(4-fluorophenylsulfenyl) methyl] 4-methoxy — 1 — (2-phenylethyl) piperidine, (1) 4-1 [(4-fluorophenylsulfinyl) methyl] — 4 — methoxy 1- (2-phenylethyl) piperidine and the like can be exemplified.

When a salt of the compound of the present invention is produced, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, lingoic acid, tartaric acid, citrate, Examples thereof include pharmacologically acceptable salts with organic acids such as tansulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid. The compounds of the present invention or salts thereof include optically active isomers and stereoisomers in addition to racemic isomers.

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.

 (I) (Hi)

In this step, compound (I) (rings Υ, Ζ and C are the same as described above) and compound (II) (R ′, X, ring A, ring B and n are the same as described above) are reacted in the presence of a base. This is the step of producing compound (III) (R ′, X, 、, Α, B, C and n are the same as 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, and carbonic acid. Inorganic bases such as sodium hydrogen, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and tricalcium phosphate are 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.

Compound (I) and compound (II) used in this step can be produced with reference to known methods.

(IV) (VI) This step, anti-compound (IV) (R Bruno, R ³ RX ¹ and ring A have the same meanings as defined above) with compound (V) (B rings the same) in the presence of a base In this step, the compound (VI) (RR ³ R ⁴ A ring and B ring are the same as described above) is produced. This step is carried out at room temperature to 150 ° C. using 110 equivalents, preferably 13 equivalents of compound (V) to compound (IV). Bases used in this step include triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and 1,8-diazabicyclo. [5.40] — 7-indene, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, sodium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, calcium carbonate, calcium carbonate, cesium carbonate, triphosphate Examples thereof include calcium, potassium fluoride, cesium fluoride, sodium hydride, potassium hydride, calcium hydride, and triton B. Alternatively, a polystyrene resin having a dimethylamino group, a biperidino group, a morpholino group, a 157-triazabicyclo [4,4,0] —5-deceno group, etc. (cross-linked with divielbenzene) Can also be used as a base. As the solvent, an inert solvent which does not participate in the reaction, for example, NN-dimethylformamide, N, N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane , Toluene, pyridine Are used. Compound (I) and compound () used in this step can be produced by referring to a known method.

(VI) (VII) The present step is the compound ^{(VI) (RR 3, R} 4, A ring and B ring are the same as defined above) Ri by the oxidizing the compound (VII) (R ', R 3, R ^4. Ring A and ring B are the same as described above, and m is a step for producing 1) or 2). The oxidizing agents used in this process include 3-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peracetic acid, aqueous hydrogen peroxide, hydrogen peroxide-urea complex, dimethyldioxolane And cumene hydroperoxide, t-butyl hydroperoxide, hypochlorous acid, and pseudosobenzen. The solvent may be an inert solvent that does not participate in the reaction, such as methanol, ethanol, isopronolol, t-butanol, ethoxyethanol, 2,2,2-trifluoroethanol, Acetone, N, N-Dimethylformamide, N, N-Dimethylacetamide, Sulfolane, Acetonitrile, Jetylether, Tetrahydrofuran, Dioxane, Dichloromethane, Toluene, carbon tetrachloride, water, etc. may be used alone or as a mixture of two or more solvents in any proportion. In the compound (VII), the compound in which m is 1 has an optical isomer based on a sulfur atom. When producing such an optical isomer based on a sulfur atom, asymmetric oxidation can be carried out using an optically active oxidizing agent or an optically active catalyst. Reagents used for asymmetric oxidation include camphorylsulfonyloxaziridine, dichlorocamylsulfonyloxaxiridine, and dimethoxycamphoryls. Ruphonyloxaziridine, tetrasopropoxytitanium and (+)

— Or (—) — getyl tartrate, (+) — or (—) — N, N, — bis (3, 5 — di t — butylsalicylidene) _ 1, 2-cyclohexandiamine manganese ( III) Chloride and the like. Of these, te-trisopropoxytitanium and (+)-or (-)-getyl tartrate or (+)-or (-) 1 N, N, 1 bis (3, 5-dit-butylsalicylidene When 1,2-cyclohexanediaminomanganese (III) chloride is used, the reaction is performed in the presence of a suitable oxidizing agent. Such oxidizing agents include 3-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peracetic acid, aqueous hydrogen peroxide, hydrogen peroxide-urea complex, dimethyldioxolan, Mention is made of, for example, methyl hydroperoxide, t-butyl hydroperoxide, hypochlorous acid, and ortho benzene. In addition, when (+)-or (-)-N, N, 1-bis (3,5-di-t-butylsalicylidene) 1-1,2-cyclohexanediaminomanganese (III) chloride or the like is used, the above oxidation Suitable additives can be added together with the agent. Such additives include formic acid, acetic acid, bivalic acid, benzoic acid, 4-chlorobenzoic acid, 2-phenylbenzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, Trifluoroacetic acid, cunic acid, malonic acid, succinic acid, lingic acid, tartaric acid, p-toluenesulfonic acid, boric acid, phosphoric acid, sulfuric acid, nitric acid, carbonic acid, etc., and their sodium salts, Calcium salt, lithium salt, ammonium salt, and trimethylamine N-oxide, N-methylmorpholine N-oxide, pyridine N-oxide, 4-methoxypyridine N-oxide, 4-nitrite Lopiridine N-oxide, 4-phenylvinylidine N-oxide, quinolin N-oxide, imidazole, N-methylimidazole and the like. These additives may be used in an amount of 0.001 to 1 ◦ equivalent, preferably 0.01. Used in the range of 1 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 (for example, neutralization).

The compound (1) or a salt thereof of the present invention can be used alone or together with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition, and comprises a pharmacologically acceptable carrier, Excipients (eg, starch, lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg, magnesium stearate, calcium stearate, talc, stearate, etc.); binders (eg, starch) , Microcrystalline cellulose, carboxymethylcellulose, gum arabic, polyvinyl viridone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose calcium, etc.), diluents (eg, physiological saline, glucose, mannitol, lactate) Tablets, tablets, granules, powders, etc. It can be administered orally or parenterally in the form of preparations, fine granules, ampules or injections. The dose varies depending on the kind of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, the symptoms, and the like. As salt 0. OOO l SOO mg / kg gZ day. Administration may be once or several times a day, for example.

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. BEST MODE FOR CARRYING OUT THE INVENTION

NK1 receptor antagonism The method of S. Dion et al. (“Life Sciences”, vol. 41, pp. 2269 (1989)) was partially modified.

After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The isolated ileum was suspended under a load of 1 g in a Magnus tube. Sample responses were recorded isotonic. Nutrient solution, using a T Yrode solution 〇 ₂ 95% was bubbled C 0 ₂ 5% of the mixed gas, liquid temperature and 3 2 ° 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 applied preliminarily with at least three concentrations of the test compound for 10 minutes and then cumulatively applied. The p A 2 value is the method of S child (“British Journal of Pharmaceuticals (Brit. J. Pharmacol.)”, Vol. 14, p. 48 (1959)) Table 1 shows the results.

The composition of the Tyrode solution was as follows. N a C l; 1 3 6. 9, KC 1;. 2. 7, C a C l 2 - 2 H 2 0; 2. 5 M g C 1 2 · 6 H 20; 1 0, N a H 2 _{.. PO 4 - 2 H 2} O 0. 4, N a HC_〇 _{3; 1 1 9, glucose;} 1 1 1 (m

NK 2 receptor antagonism

P. D, Orleans—Juste's Method (Eur. J. Pharmacol.), Vol. 125, p. 37 (1989) ) Was partially modified.

After the rabbit was anesthetized with pentonorbital (30 mg / kg, iv), blood was removed from the carotid artery and the pulmonary artery was removed. The removed pulmonary artery was suspended by applying 1 g of static tension to the Magnus tube after removing the endothelium. Specimen responses were recorded isometrically. Nutrient solution, using K Rebs solution 〇 ₂ 95%, bubbled C_〇 _25% of the mixed gas, the liquid temperature was set to 3 7 ° C. The experiment was started after the Persian pulmonary artery was suspended in a Magnus tube and allowed to equilibrate for 30 minutes. The presence or absence of endothelium, and check the options by the disappearance of the relaxation response by Asechiruko Li down 1 0- ⁶ M. Test compound in the absence [-? A 1 a ^8] and the concentration response curve of neurokinin A (4- 1 0) and con bets roll.

NK 2 receptor antagonistic action of the test compound was pretreated for 10 minutes with the test of compounds of 3 concentrations even rather small, and then cumulatively applied [One A la ^8?] Neurokinin A (4 - 1 0 ) Was determined from the concentration-response curve. to p A ₂ value is S chi 1 d of the method ( "Pretty Mesh Journal O Breakfast 'Famakoroji one (Brit. J. Pharmacol .;)" 1 4 Certificates, 4 page 8 (1 9 5 9 years)) Table 2 shows the results.

The composition of the K rebs solution was as follows. . N a C l; 1 4 3, KC 1;. 5 9, C a C l 2 - 2 H 2 0;. 2 5 5, M g S 0 4 - 2 H 2 0; 1 2, KH 2 P 04; 25 NaHC0; 1.18, g1 ucose; 11.1 (mM) Table 1

 Example number 卫 A value (nM)

 1 2 1 2 0

 3 2 9 5.5 Table 2

 Example number ^ A value (nM)

 4 7. 2 4

6 2 1.9 7 2. 6 3

 1 3 1 0.8

 1 6 1. 4 5

 1 7 6. 6 1

 3 9 7 5.7 Example 1

4-Methoxy-1-[(phenylsulfinyl) methyl] piperidine (133.39 mg, 0.533 mmol) and 2-phenylethyl bromide (97.3 mg, 0.53 mmo 1)

The mixture was dissolved in 10 ml, added with lithium carbonate (109.6 mg), and 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 a light yellow oil of 4-methoxy-1-1. (2-Phenylethyl) 1-41 [(phenylsulfinyl) methyl] piperidine (84.9 mg, 45%) was obtained.

1 H-NMR (400MHz, CDC1 3) δ: 1.70-1.75 (1Η, m), 1.88-1.95 (1H, m), 2.01-2.07 (1H, m), 2.13-2.19 (1H, m), 2.39- 2.50 (2H, m), 2.60-2.64 (2H, ra), 2.68-2.76 (2H, m), 2.79-2.83 (2H, ra), 2.87 (1H, d, J = 14.2Hz), 3.09 (1H, d, J2 14.2Hz), 3.25 (3H, s), 7.18-7.31 (5H, m), 7.49-7.56 (3H, m), 7.64-7.67 (2H, m).

_{HRMS (FAB +): C 21} H 28 N0 2 S and to Calculated: 358.1841 Observed value: 358.1844

Example 2

According to the same method as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] pyridine (154.0 mg, 0.61 mmol) and 2- (3-Cross-phenyl) ethylpromide (13.3.4 mg) was converted to yellow oily 1- [2- (3-chloromouth phenyl) ethyl] — 4-methoxy 4-([ [Ensylsulfinyl) methyl] biperidine (66.6 mg, 28%) was obtained.

_{HRMS (FAB +): C 21} H 27 C1N0 2 S and to Calculated: 392.1451

 Measured value: 392.1448 Example 3

According to the same method as in Example 1, 4-methoxy 4-[(phenylsulfinyl) methyl] piperidine (168.3 mg, 0.66 mmol) and 2 — (4-Cross-mouth phenyl) ethyl bromide (145.8 mg) Capella, yellow oily 1- [2- (4-Cross-mouth phenyl) ethyl 1-4-Methoxy-14-[(phenylsulfinyl) methyl] biberidine (63. 3 m: 25%) was obtained.

_{HRMS (FABi): C 21 H} 27 C1N0 2 S and to Calculated: 392.1451

 Obtained value: 392.1447 Example 4

According to the same method as in Example 1, 4-methoxy-4-[(phenylphenyl) methyl] piperidine (146.2 m: 0.58 mmol) and 2 — (3-Nitrophenyl) ethyl bromide (132.7 mg) was converted to yellow oily 4-methoxy-1- [2- (3--2-trifluorophenyl) ethyl] — 41- (phenylsulfuryl). Nyl) methyl] piperidine (63.3 mg, 27) was obtained.

_{HRMS (FABi): C 21 H} 27 N 2 0 4 S and to Calculated: 403.1692

Measured value: 403.1667 Example 5

In the same manner as in Example 1, 4-methoxy-1-([phenylphenyl) methyl] piperidine (192.7 mg, 0.76 mm〇1) and 3 — From biphenylethyl methanesulfonate (20.2 mg) to a colorless oil of 1- [2- (3-biphenyl) ethyl] ― 4-methoxy-14-[(phenylsulfinyl) methyl Piberidine (120.3 mg, 36%) was obtained. However, silica gel NH was used in place of alumina for the column chromatography.

_{HRMS (FABi): C 27 H} 32 N0 2 S and to Calculated: 434.2154

 Observed value: 434.2173 Example 6

According to the same method as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (73.9 mg, 0.29 mm 01) and 4 —Bifenylethyl methanesulfonate (80.6 mg) was converted to colorless scaly crystals of [1- (2- (4-biphenyl) ethyl)] — 4— methoxy 4 -— [(phenylsulfinyl) methyl 1 pi Gin (4 1.8 mg, 33%). However, for column chromatography, silica gel NH was used instead of alumina.

rap.108.0-109.0 ° C (Ethyl hexane monoacetate)

_{Anal: C 27 H 31 N0 2} S and to Calculated: C: 74.79 H: 7.21 N : 3.23

 Measured value: C: 74.69 H: 7.23 N: 3.27 Example Ί

According to the same method as in Example 1, 4-methoxy-4-([phenylphenyl) methyl] piperidine (1.10 g, 4.3 mmo1) and 2- (3, 5-Dichlorophenyl) ethyl methanesulfonate (1.17 g) was converted to light yellow oily 1- [2- (3,5-dichloromethylphenyl) ethyl] 1-4-methoxy-1-41 (Phenylsulfinyl) methyl] piperidine (52.6 mg, 28%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 21} H 26 C1 2 N0 2 S and to Calculated: 426.1061

Obtained value: 426.1056 Example 8

In the same manner as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (237.5 m: 0.94 mm 01) and 2 — (3,5-bistrifluoromethylphenyl) ethyl bromide (301.0 mg) from light yellow oily [2- (35-bistrifluoromethylphenyl) ethyl] — 4- 4-([phenylsulfinyl) methyl] piperidine (74.7 mg, 16%) was obtained.

_{HRMS (FABi): C 23 H} 26 F 6 N0 2 S and to Calculated: 494.1588

 Obtained value: 494.1562 Example 9

According to a method similar to that of Example 1, 4-methoxy-14-[(phenylsulfinyl) methyl] piperidine (127.8 mg, 0.50 mmo 1) and 2 — (1-Naphthyl) ethyl bromide (18.6 mg) from yellowish oily 4-methyxyl 1 — [2- (1-naphthyl) ethyl] 1-41 [(phenylsulfinyl) methyl] Thus, pigment (60.7 mg, 30%) was obtained. _{HRMS (FABi): C 25 H} 30 N0 2 S and to Calculated: 408.1997

 Obtained value: 408.1959 Example 10

According to the same method as in Example 1, 4-methoxy-14-[(phenylsulfinyl) methyl] piperidine (154.5 mg, 0.61 mmo1) and 2- ( 2-Naphthyl) ethyl bromide (143.4 mg) was converted to yellow oily 4-methoxy-1- [2- (2-naphthyl) ethyl] 1-41-[(phenylsulfinyl) methyl] biphenyl Resin (65.O mg, 26%) was obtained.

_{HRMS (FABi): C 25 H} :! () N0 2 S and to the calculated value: 408.1997

 Measured value: 408.1959 Example 11

According to a method similar to that of Example 1, 4-methoxy-14-[(phenylsulfinyl) methyl] piperidine (207.4 mg, 0.82 mmo 1) and 2 — (2-Chenyl) ethyl methane sulfonate (16 8.9 mg) to a colorless oil of 4-methoxy-4-[(phenylphenyl) methyl] 1-1-1 [2- (2-phenyl) ethyl] piperidine (155.3 mg , 52%). However, for column chromatography, silica gel NH was used in place of alumina. _{HRMS (FAB +): C 19} H 26 N0 2 S 2 and to Calculated: 364.1405

 Obtained value: 364.1407 Example 1 2

According to the same method as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (277.7 m: 1.1 mmol) was used.

1) and 2- (3-Chenyl) ethyl methanesulfonate (2 26.

1 mg) from colorless oil 4-methoxy [4-((phenylsulfinyl) methyl] 111] [2- (3-phenyl) ethyl] piberidine (209.5 mg, 53%). Obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FABi): C 19 H} 26 N0 2 S 2 and to Calculated: 364.1405

Obtained value: 364.1423 Example 13

According to a method similar to that of Example 1, 4-methoxy (4-phenyl) methyl] bipyridine (232.8 m; 0.92 mm 01) and 2- (indene-3-yl) ethylmethansulfonate (21.9.O mg) to brown oily 1- [2- (indene-3-yl) ethyl] —4—methoxy-1 41 [(Phenylsulfinyl) methyl] piperidine (70.3 mg, 19%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 24} H 30 N0 2 S and to Calculated: 396.1997

 Measured value: 396.1999 Example 14

According to the same method as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (149.2 mg: 0.59 mm 01) And 2- (benzofuran-3-yl) ethylmethansulfonate (132.5 mg) from yellow oily 1- [2- (benzofuran-3-yl) ethyl] — 4-methoxy 4— [(phenylsulf . I) methyl] Biperi Jin (6 7 9 mg, 2 9 %) The obtained _{HRMS (FAB +): C 23} H 28 N0 3 S and to Calculated: 398.1790

 Measured value: 398.1824 Example 15

According to the same method as in Example 1, 4-methoxy 4-[(phenylsulfinyl) methyl] bipyridine (1.94 g, 7.7 mm 01) and 2- (benzothiophene 13-yl) Le) ethyl bromide (1.85 g) from colorless prisms of 1- [2- (benzothiophene-3-yl) ethyl] 14-methoxy-14-[(phenylsulfinyl) methyl] Viridine (994.7 mg, 31%) was obtained.

mp.108.5-109.5 ° C (Ethyl hexane monoacetate)

_{Anal: C 23 H 2Y N0 2} S 2 and to Calculated: C: 66.79 H: 6.58 N : 3.39

Measured value: C: 66.74 H: 6.61: 3.54 Example 16

In the same manner as in Example 1, 4-methoxy-4-[(phenylphenyl) methyl] bipyridine (153.9 mg, 0.61 mmo1) and 2- (5 —Flurobenzothiophene-3-yl) ethyl bromide (157.4 mg) from yellow oily 1— [2— (5—Fluorobenzothiophene-3-yl) [Ethyl] —4-Methoxy—4-[(phenylsulfinyl) methyl] bipyridine (61.4 mg, 23%) was obtained.

_{HRMS (FAB +): C 23} H 27 FN0 2 S 2 and to Calculated: 432.1467

 Observed value: 432.1477

According to the same method as in Example 1, 4-methoxy-4-[(phenylsulfinyl) methyl] piperidine (182.5 mg, 0.72 mmo1) and 2- (5- Benzothiophene-3-ethyl) ethyl methanesulfonate (209.5 mg) from colorless oil 1- [2- (5- (benzo) thiophene-3-yl) ethyl] —4-methyl G Xyi 4-[((phenylsulfinyl) methyl] viridine (117.4 mg, 36%) was obtained. However, silica gel NH was used instead of alumina for column chromatography.

_{HRMS (FAB +): C 23} H 27 C1N0 2 S 2 and to Calculated: 448.1172

 Measured value: 448.1192 Example 18

According to a method similar to that of Example 1, 4-methoxy-4-([phenylsulfinyl) methyl] piperidine (290.0 mg, 1.1 mmol) and 2- (5-methylbenzo) were used. From thiophene-3-ethyl) ethyl bromide (292. lmg), yellow oily 4-methoxy-1-yl

 [2- (5-Methylbenzothiophene-3-yl) ethyl] -41-[(phenylsulfinyl) methyl] piperidine (289.7 mg, 59%) was obtained.

_{HRMS (FAB +): C 24} H 3. Calculated value as N0 ₂ S ₂ : 428.1718

Obtained value: 428.1719 Example 19

According to a method similar to that of Example 1, 4-methoxy-14-[(phenylphenyl) methyl] piperidine (86.2 mg, 0.34 mm 01) and 2- ( 1,2-Benzoisoxazolyl-3-yl) ethyl bromide (76.9 mg) from yellow oily [2- (1,2-Benzoisoxazolyl-3-yl) ethyl] 1-4-Methoxy-14-[(phenylsulfinyl) methyl] bipyridine (36.2 mg, 27%) was obtained.

_{HRMS (FABi): C 22 H} 27 N 2 0 3 S and to Calculated: 399.1742

 Obtained value: 399.1762 Example 20

According to the same method as in Example 1, 4-methoxy (4-phenyl) methyl] piperidine (225.4 mg: 0.89 mm 01) and 2 — (1-Methylindazolu-3-yl) Ethylpromide (22.7 mg) was converted to yellow oily 4-methoxy-1-yl (1-methylindazo-3-yl). 4-([phenylsulfinyl) methyl, piperidine (102.7 mg, 28%) I got

_{HRMS (FAB +): C 23} H 3. Calculated value for N ₃ 0 ₂ S: 412.2059

 Obtained value: 412.2039 Example 21

According to the same method as in Example 1, 4-methoxy 4-[(phenylphenyl) methyl] piperidine (13.2 mg, 0.45 mmol) and 2 — (1 H—benzimidazol-1-yl) ethyl bromide (10.6 mg) from yellow oily 1— [2 -— (1H—benzimidazol-1-yl) ethyl] — 4-Methoxy-4-[(phenylsulfinyl) methyl] piperidine (75.0 mg, 42%) was obtained.

_{HRMS (FAB +): C 22} H 28 N 3 0 2 S and to Calculated: 398.1902

 Measured value: 398.1869 Example 2 2

According to the same method as that of Example 1, 4-methoxy-14-[(phenylsulfinyl) methyldiviridine (335.2 mg, 1.32 mm ο 1) and 2— (1-trifluoroacetyl-1,2,3-dihydroindole-1-3-yl) ethylbromide (426.1 mg) Oroacetyl-2,3-dihydroxy-l-yl-3-ethyl) ethyl 4-methoxy [1- (phenylsulfinyl) methyl] piperidine was obtained. This product is treated with sodium carbonate (93.3 m) in methanol to give a yellow oily 1- [2- (2,3-dihydrin-de-l- 3-ethyl) ethyl] 4-methoxy [(phenylsulfinyl) methyl] bipyridine (146.65 mg, 28%, yield in two steps) was obtained.

_{HRMS (FABi): C 23 H} , N 2 0 2 S and to Calculated: 399.2106

 Observed value: 399.2119

According to the same method as in Example 1, 4-methoxy-4-[[phenylphenyl] methyl] piperidine (155.5 mg, 0.61 mmol) and 3,5- From dichlorobenzyl bromide (147.3 mg), yellow [1- (3,5-dichlorophenyl) methyl] 14-methoxy-14-[(phenylsulfinyl) methyl] piberidine as a yellow oil (143.4 mg, 57%).

_{HRMS (FABi): C 20 H} 24 C1 2 N0 2 S and to Calculated: 412.0905

Observed value: 412.0908 Example 2 4

According to the same method as in Example 1, 4-methoxy-14-[(phenylphenyl) methyl] piperidine (248.0 mg, 0.98 mmol) and 3- ( 3,5-Dichloromouth phenyl) propyl methanesulfonate (277.2 mg) from colorless oily 1- [3- (3,5-dichlorophenyl) propyl] —4-methoxy 4- [(Phenylsulfinyl) methyl] piperidine (145. 8 mg, 34%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 22} H 28 C1 2 N0 2 S and to Calculated: 440.1218

 Observed value: 440.1209

According to the same method as in Example 1, 4-methoxy-4-[(phenylphenyl) methyl] piperidine (187.8 mg, 0.74 mmol) and (1 1- (3,5-Dichloromouth phenyl) propene-1-3-ylbromide (197.1 mg) was converted to yellow oily 1- [1 (3 5-Dichlorophenyl) propene-3-yl] -14-methoxy-14-[(phenylsulfinyl) methyl] piperidine (131.6 mg 40%) was obtained.

_{HRMS (FAB +): C2 2} H 26 C1 2 N0 2 S and to Calculated: 438.1061

 Found: 438.1089 Example 26

According to a method similar to that of Example 1, 4-methoxy-14-[(phenylsulfonyl) methyl] piperidine (222.O mg, 0.82 mm 01) and 2- (3,5 —Dichlorophenyl) ethylmethanesulfone — Toluene (21.8 mg) was converted to yellow oily 1- [2- (3,5-dichloromouth phenyl) ethyl] —4-methoxy 4- ((Phenylsulfonyl) methyl] piperidine (71.3 mg, 18%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 21} H 26 C1 2 N0 3 S and to Calculated: 442.1010

Obtained value: 442.1068 Example 2 7

In the same manner as in Example 1, 4-methoxy-4-([phenylsulfonyl) methyl] piperidine (21.6 mg, 0.80 mm 01) and 2- (benzothiophene) 1- (2-yl) ethyl bromide (193.4 mg) was converted to yellow oily 1- [2- (benzothiophene-3-yl) ethyl] —4-methoxy 4 -— [(phenylsulfonimethyl) In addition, piperidine (175.0 mg, 51%) was obtained.

_{HRMS (FABi): C 23 H} 28 N0 3 S 2 and to Calculated: 430.1511

 Measured value: 430.1508 Example 2 8

In the same manner as in Example 1, 4-[(phenylsulfyl) methyl] bidinidine-41-ol (270.5 mg, 1.1 mmol) and 2- (benzofuran-l-3) were used. — (Ethyl) ethylmethansulfonate (271.5 mg) from colorless powdered 1- [2- (benzofuran-3-yl) ethyl] — 4 — [(phenylsulfinyl) methyl] pyridyl Thus, gin-1-ol (122.28 mg, 28%) was obtained. However, the ram chromatographic graph shows that silica kagel NH was used instead of alumina. Was used.

rap.134.0-135.0 ° C (Ethyl hexane monoacetate)

_{Anal: C 22 H 25 N0,} S 0.5H.0 and to Calculated: C: 67.32 H: 6.68 N : 3.57 Found: C: 67.11 H: 6.52 N : 3.44 Example 2 9

In the same manner as in Example 1, 4-[(phenylsulfinyl) methyl] piperidine (27.0 mg, 0.97 mmol) and 2- (3,5- Dichloromouth phenyl) ethyl methanesulfonate (261.5 mg) was converted to colorless prism crystals of 1- [2- (3,5-dichlorophenyl) ethyl] — 4-[(phenylsulfinyl) methyl In addition, pigment (48.0 mg, 12%) was obtained. However, silica gel NH was used in place of alumina for the column chromatography.

mp.90.5-92.5 ° C (hexane)

_{Anal: C 20 H 23 C1 2} NOS 0.1H 2 0 and to Calculated: C: 60.33 H: 5.87 N : 3.52 Found: C: 60.21 H: 5.78 N : 3.48 Example 3 0

In the same manner as in Example 1, 4-[(phenylsulfinyl) methyl] pyridine (28.0 mg, 0.98 mmo 1) and 2- (benzothiophene) 3- (yl) ethylmethansulfonate (235.4 mg) from yellow oily [2- (benzothiophene-3-yl) ethyl] — 4-[(phenylsulfinyl) methyl] piぺ Resin (153.7 mg, 41%) was obtained.

_{HRMS (FAB +): C 22} H 26 N0S 2 and to Calculated: 384.1456

 Measured value: 384.1425 Example 3 1

According to the same method as in Example 1, 4-[(4-fluorophenylsulfenyl) methyl] —4-methoxypyridine (331.8 mg, 1.2 mmol) and 2- From phenylethyl bromide (26.3 m), pale yellow powder of 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 Hv, FN0 2} S and to Calculated: C: 67.17 H: 6.98 N : 3.73

 Obtained value: C: 67.21 H: 7.00 N: 3.72

1 H-NMR (400MHz, CDC1 3) δ: 1.65-1.74 (1Η, m), 1.86-1.95 (1H, m), 1.99-2.06 (1H, m), 2.12-2.19 (1H, 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 = 14.2Hz), 3.08 (1H, d, J = 14.2Hz) , 3.23 (3H, s), 7.18-7.31 (7H, m), 7.64-7.69 (2H, m).

According to a method similar to that of Example 1, 4-[((4-fluorophenylsulfinyl) methyl] —4-methoxypiperidine (291.8 mg,

1 lmmol) and 2— (benzofuran-3-yl) ethyl sulfonate (258.4 mg) from light yellow oil 1— [2—

(Benzofuran-3-yl) ethyl] 1-41-[(4-fluorophenylsulfinyl) methyl] —4-methoxypiperidine (257.5 mg, 58%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 23} H 27 FN0 3 S and to Calculated: 416.1696

 Observed value: 416.1711

According to a method similar to that of Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -14-methoxypiperidine (316.8 mg,

From 1.2 mm 0 1) and 2— (5-fluorobenzofuran-3-yl) ethyl bromide (302.5 mg), yellow oily 1— [2—

(5-Fluorobenzothiophene-3-yl) ethyl] -14-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (85.0 mg, 16%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FABi): C 23 H} 26 F 2 N0 2 S 2 and to Calculated: 450.1373

 Observed value: 450.1367 Example 3 4

According to the same method as that of Example 1, 4- (4-methoxy) -4-[(4-methoxyphenylsulfinyl) methyl] piperidine (309.0 mg, 1.1 mmol) And 2-phenylethyl bromide (201.8 mg) were converted to colorless needles of 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 ° C (Hexane)

Anal: C ₂₂ H ₂ aN0 S and to Calculated: C: 68.18 H: 7.54 N : 3.61

Observed value: C: 68.06 H: 7.46 N: 3.59 Example 3 5

According to the same method as in Example 1, 4-methoxy-4-[(4-methoxyphenylsulfenyl) methyl] bipyridine (444.00 mg, 1.6 mmo 1) and 2- (Benzofuran-3-yl) ethylmethansulfonate (378.2 mg) was converted to a colorless oil of 1- [2- (benzofuran-3-yl) ethyl] —4-methoxy-1-4- [(4-Methoxyphenylsulfinyl) methyl] piperidine (330.7 mg 49%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

HRMS (CH): (Calculated as _{24 24 3 ()} Ν0 ^ ₎ : 428.1896

 Obtained value: 428.1872 Example 36

According to the same method as in Example 1, 4-[((4-trifluoromethylphenylsulfinyl) methyl] biridin-l-4-ol (200.O mg: 0.65 mmol) And 2-phenylethyl bromide (10.2 mg) from colorless needle-like 1- (2-phenylethyl) 4-[(4-Trifluoromethylphenylsulfinyl) methylpiridin-l-4-ol (185.3 mg: 69%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

mp.159.5-160.5 ° C (Ethyl hexane monoacetate)

Anal: calculated as C ₂₁ H ₂₄ F ₃ N0 ₂ S: C: 61.30 H: 5.88 N: 3.40

 Obtained value: C: 61.40 H: 5.76 N: 3.43 Example 37

According to the same method as in Example 1, 4-[(4-trifluoromethylphenylsulfinyl) methyl] piperidin-14-ol (200.0 mg, 0.65 mmol) and 2 — (Benzofuran-3-yl) ethyl methanesulfonate (156.4 mg) from colorless needles of 1- [2- (benzofuran-3-yl) ethyl] 1-4— [( 4-Trifluoromethylphenylsulfinyl) methyl] biridin-1-ol (112.lmg, 38%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina. mp.149.0-150.0 ° C (ethyl hexane monoacetate)

_{Anal: C 23 H 24 F 3} N0 3 S 0.1H 2 0 and to Calculated: C: 60.94 H: 5.38 N : 3.09 Found: C: 60.75 H: 5.24 N : 3.06 Example 3 8

According to the same method as in Example 1, 4-methoxy-4-([2-naphthylsulfinyl) methyl] piperidine (235.0 mg, 0.77 mmol) and 2-phenyl From enethylethyl bromide (143.3 mg), colorless needles of 4-methoxy-4-[(2-naphthylsulfinyl) methyl] — 1- (2-phenylethyl) piperidine (88.7 mg, 28%). However, silica gel NH was used in place of alumina for column chromatography.

mp.71.0-73.0 ° C (Hexane)

_{Anal: C 25 H 29 N0 2} S and to Calculated: C: 73.67 H: 7.17 N : 3.44

 Actual value: C: 73.39 H: 7.21: 3.39 Example 39

According to the same method as in Example 1, 4-methoxy-4-([2-naphthylsulfinyl) methyl] bipyridine (543.0 mg, 1.8 mmo 1) and 2- (benzofuran 1- [3- (yl) ethylmethanesulfonate (40.0. 0 mg) was converted to a colorless oily 1- [2- (benzofuran-3-yl) ethyl] — 4-methoxy-1 4- [ (2-Naphthylsulfinyl) methyl] viridin (319.4 mg, 40%) Obtained. However, for column chromatography, this silica gel NH was used instead of alna.

HRMS (CI +): Calculated as ϋ ₂₇ Η ₃₀ Ν0; ^: 448.1946

 Obtained value: 448.1986 Example 40

According to the same method as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4- (methoxybiperidine) (452.1 mg, 1.7 mmol) and 3-phenyl From propyl bromide (331.7 m), colorless oily 4-[(4-fluorophenylsulfinyl) methyl] -14-methoxy-11- (3-phenylpropyl) biperidine (17 1.1 mg, 26%). However, silica gel NH was used in place of alumina for column chromatography. _{HR S (FABi): C 22} H 29 FN0 2 S and to Calculated: 390.1903

 Actual value: 390.1923 Example 4 1

According to the same method as in Example 1, 4-methoxy-1- [1— Rusulfinyl) ethyl] colorless oil from piperidine (350.0 mg, 1.3 mmo 1) and 2-phenylethyl bromide (242.2 mg). Methoxy 1- (2-phenylethyl) 1-4- [1- (phenylsulfinyl) ethyl] viridine (164.1 mg, 34%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 22} H 30 N0 2 S and to Calculated: 372.1997

 Observed value: 372.2018 Example 4 2

According to the same method as in Example 1, 4-methoxy-1- [1- (phenylsulfinyl) ethyl] piperidine (360.0 mg, 1.4 mmo 1) and 2- (Benzofuran-3-yl) ethyl methanesulfonate (323.5 mg) from colorless oily 1- [2- (benzofuran-3-yl) ethyl] —4-methoxy-4- — [1— (Phenyl sulfiel) ethyl] biradidin (161.7 mg, 29%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FABi): C 24 H} :! () N0 3 S and to the calculated value: 412.1946

Obtained value: 412.1957 Example 4 3

According to the same method as in Example 1, 3-methoxy-3-([phenylsulfinyl) methyl] piperidine (13.6 mg, 0.54 mmo1) and 2- ( Benzofuran-3-yl) ethyl methanesulfonate (129.0 mg) was converted to yellow oily 1- [2- (benzofuran-3-yl) ethyl] 1-3-methoxy-3-. [(Phenylsulfinyl) methyl] piperidine (53.3 mg, 25%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 23} H 28 N0 3 S and to Calculated: 398.1790

 Obtained value: 398.1757 Example 4 4

According to a method similar to that of Example 1, 3-methoxy-3-[(phenylphenyl) methyl] -18-azabicyclo [3.2.1] octane (491.0 mg, 1.8 mm ol) and 2-phenylethyl bromide (325.2 mg) from colorless oily 3-methoxy-1- (2-phenylethyl) -1-3- (phenylsulfinyl) ethyl ] —8-Azabicyclo [3.2.1] octane (561.4 mg, 83%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (FAB +): C 23} H 30 N0 2 S and to Calculated: 384.1997

 Actual value: 384.1995 Example 4 5

According to a method similar to that of Example 1, 3-methoxy-3-[(phenylphenyl) methyl] -8-azabicyclo [3.2.1] octane (428.4 mg, 1.5 mmo 1 ) And 2- (benzofuran-3-yl) ethyl methanesulfonate (368.4 mg) from light yellow oily 8- [2- (benzofuran-3-yl) ethyl] — 3 —Methoxy-3- (1- (phenylsulfinyl) ethyl) -18-azabicyclo [3.2.1] octane (328.6 mg, 51%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

HRMS (FAB +): (: 25 Η 30 Ν0; ^ and to the calculated value: 424.1946

Measured value: 424.1935 Example 4 6

In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -4-methoxypiperidine (470 mg, 1.73 mmo 1) and 2- (3-ni (Trophenyl) ethyl bromide

(438 mg, 1.90 mm 0 1) shows that pale yellow oily 4-[(4-fluorophenylsulfinyl) methyl] — 4-methoxy-1- 1 —

[2- (3-Nitrophenyl) ethyl] piperidine (480 mg, 66%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (CI +): C 21} H 26 FN 2 0, S and to Calculated: 421.1597

 Measured value: 421.1605 Example 4 7

4 — [(4-Fluorophenylsulfinyl) methyl] —4—Methoxy-1- (2- (3-nitrophenyl) ethyl) piperidine (300 mg, 0.713 mm ol) in 10 ml of methanol, 60 mg of 10% palladium activated carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 15 hours. After removing the insoluble matter by filtration, the filtrate was concentrated, and the obtained residue was purified by silica gel NH column chromatography to give a pale yellow amorphous 1- [2— (3-aminophenol). ) Ethyl] 141-((4-fluorophenylsulfinyl) methyl] —4-methoxyethoxyperidine (240 mg, 86%) was obtained.

_{HRMS (CI +): C 21} H 28 FN 2 0 2 S and to Calculated: 391.1856

 Obtained value: 391.1848 Example 4 8

According to a method similar to that of Example 1, 4-ethoxy-1-[(4-fluorophenylsulfenyl) methyl] piperidine (150 mg, 0.526 mmol) and 2 —Phenylethyl bromide (97.4 mg) from light yellow solid 4-ethoxyethoxy 4-[(4-fluorophenylinolesulfinyl) methyl] — 1— (2-phenylethyl) piperidine (133 mg, 65%). However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (CI +): C 22} H 29 FN0 2 S and to Calculated: 390.1903

Measured value: 390.1876 Example 4 9

According to the same method as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -14-propoxypiperidine (80.0 mg, 0.267 mmol) and 2- From phenylethyl bromide (49.5 mg), 4-[(4-fluorophenylsulfinyl) methyl] — 1 — (2-phenylethyl) 1-4-propoxybiol as a pale yellow solid Resin (97.1 mg, 90%) was obtained. However, silica gel NH was used in place of alumina for column chromatography. _{HRMS (CI +): C 23} H 31 FN0 2 S and to Calculated: 404.2060

 Actual value: 404.2071 Example 50

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

_{HRMS (CI +): C 24} H 33 FN0 2 S and to Calculated: 418.2216

 Measured value: 418.2263 Example 5-1

According to the same method as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] 14- (2-propoxy) piperidine (98 mg, 0.327 mmol) And 2—phenylethyl bromide (60.6 mg) from light yellow solid 4-[(4-fluorophenylsulfenyl) methyl] 1-1— (2-phenylenyl) 14— (2 -Bropoxy) biligidine (105 mg, 80%) was obtained. However, silica gel NH was used in place of alumina for power column chromatography.

_{HRMS (CI +): C 23} H 31 FN0 2 S and to Calculated: 404.2060

Obtained value: 404.2077 Example 5 2 .

According to a method similar to that of Example 1, 4-cyclopropylmethoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (35.Om: 0.112 mmol) And 2-phenylethyl bromide (20.7 mg) from 4-cyclopropylmethoxyl 4-[((4-fluorophenylsulfinyl) methyl)]-l- (2-phenylethyl) as a pale yellow solid ) Piperidine (24.3 mg, 52) was obtained. However, for column chromatography, NH 3 was used instead of alumina.

_{HRMS (CI +): C 4} H 31 FN0 2 S and to Calculated: 416.2060

 Obtained value: 416.2029 Example 5 3

According to the same method as in Example 1, 4- (2-fluoroethoxy) -14-[(4-fluorophenylsolefinyl) methyl] piperidine (15 Om :, 0.49 4 mmol) and 2-phenylethyl bromide (91.5 mg) from 4- (2-fluoroethyl) as a pale yellow solid. B) 1-41-((4-Fluorophenylsulfinyl) methyl) -1- (2-phenylethyl) piperidine (147 mg, 73%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina.

Marauder S (CI +): Calculated as C ₂₂ H ₂₈ F ₂ N0 ₂ S: 408.1809

 Actual value: 408.1771 Example 5 4

According to a method similar to that of Example 1, 4- (2,2,2-trifluorethoxy) 141-((4-fluorophenylsulfinyl) methyl] bipyridine (150 mg, 0.5 mg) was used. 37.6 mmol) and 2—phenylethyl bromide (69.6 mg) from light yellow solid 4- (2,2,2-trifluoroethoxy) 1-4 — [(4—fluorophenylsulfuric acid) Nyl) methyl] — 1 — (2-phenylethyl) viridine (160 mg, 96%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina.

Image _{S (CI +): C 22} H 26 F "N0 2 S and to Calculated: 444.1620

Actual value: 444.1593 Example 5 5

According to the same method as in Example 1, 4-[((4-fluorophenylsulfinyl) methyl] _4- (2-methoxyethoxy) piperidine (150 mg: 0.47 6-mol) and 2-phenylethyl bromide (88.1 mg) were converted to 4-[(4-fluorophenylsulfinyl) methyl] —4 -— (2-methoxetoxy) 1-1- as a pale yellow solid. 2-Phenylethyl) piperidine (147 mg, 74%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina.

_{HRMS (CI +): C 23} H 31 FN0 3 S and to Calculated: 420.2009

 Measured value: 420.5684 Example 5 6

In the same manner as in Example 1, 4-benzyloxy 4-[(4-fluorophenylsulfinyl) methyl] bipyridine (115 mg 0.33 lmmol) and 2-phenyl Etil bromide (61. 2 mg) from the light yellow solid of 4-benzyloxy-4-1-[(4-fluorophenylsulfinyl) methyl] —111- (2-phenylene) piperidine (111 mg, 7 4%). However, silica gel NH was used in place of alumina for column chromatography. _{HRMS (CI +): C 27} H ,, FN0 2 S and to Calculated: 452.2060

 Obtained value: 452.2054 Example 5 7

According to a method similar to that of Example 1, 4-ethoxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (150 mg, 0.526 mmo1) and 2 — (Benzothiophene-3-yl) ethyl methanesulfonate (135 mg) from pale yellow oil 1— [2— (benzothiophene-3-yl) ethyl) —4-ethoxy-4 — [( 4-fluorophenylsulfinyl) methyl] piperidine (66.9 mg, 29%) was obtained. However, silica gel NH was used in place of aluminum for column chromatography.

_{HRMS (CI +): C 2} H 29 FN0, S 2 and to Calculated: 446.1624

Measured value: 446.1616 Example 5 8

In the same manner as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] -1-propoxypiperidine (80.0 mg, 0.267 mmol) and 2- ( Benzothiophene-3-ethyl) methylmethansulfonate (68.4 mg) from pale yellow oily 1- [2- (benzothiophene-3-yl) ethyl] —4-[[4-fluorophenyl Sulfiel) methyl] -1-propoxypiperidine (57.2 mg, 47%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina.

_{HRMS (CI +): C 25} H 31 FN0 2 S 2 and to Calculated: 460.1780

 Actual value: 460.1784 Example 5 9

In the same manner as in Example 1, 4-butoxy-4-([4-fluorophenylsulfinyl) methyl] piperidine (133 mg, 0.424 mmo 1) and 2 — (Benzothiophene-3-yl) ethyl methanesulfonate (109 mg) from 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.

_{HRMS (CI +): C 26} H 33 FN0 2 S 2 and to Calculated: 474.1937

 Measured value: 474.1922 Example 60

According to the same method as in Example 1, 4-[((4-fluorophenylsulfinyl) methyl] —4- (2-propoxy) piperidine (98.0 mg, 0.327 mm) was used. 0 1) and 2— (benzothiophene-3-yl) ethyl methanesulfonate (83.8 mg) from light yellow oily 1— [2— (benzothiophene-3-yl) ethyl ] -4 _ [(4-Fluorophenylsulfenyl) methyl] -4- (2-propoxy) piperidine (49.0 mg, 33%) was obtained. However Karamuku Kuchma the chromatograph I one may, HRMS using sheet Rikageru NH in place of alumina _{(CI +): C 25 H} 31 FN0 2 S 2 and to Calculated: 460.1780

Measured value: 460.1809 Example 6 1

According to the same method as in Example 1, 4-((2-fluoroethoxy))-4-([4-fluorophenylsulfinyl) methyl] bipyridine (150 mg, 0.494 mmol) And 2— (benzothiophene-3-yl) ethyl methanesulfonate (127 mg) from pale yellow oily 1— [2— (benzothiophene-3-yl) ethyl] —4— (2 —Fluoroethoxy) 1-41-((4-fluorophenylsulfinyl) methyl] piperidine (55.3 mg, 24%) was obtained. However, for column chromatography, NH 3 silica gel was used instead of alumina.

HR S (CI +): Calculated as C ₂₄ H ₂₈ F ₂ N0 ₂ S ₂ : 464.1530

 Measured value: 464.1530 Example 6 2

According to the same method as in Example 1, 4-[(4-fluorophenylsulfinyl) methyl] —4— (2,2,2—trifluoroethoxy) piperidine (150 mg) , 0.376 mm 0 1) and 2 — (benzo 1- [2— (Benzothiophene-3-yl) ethylenol] from light yellow oil from thiophene 1-yl) ethyl methanesulfonate (96.4 mg). —Fluorophenylsulfinyl) methyl] —4— (2,2,2—trifluorethoxy) piperidine (92.2 mg, 49%) was obtained. However, for column chromatography, silica gel NH was used instead of alumina.

Marauder S (CI +): Calculated as C ₂₄ H ₂₆ F N0 ₂ S ₂ : 500.1341

 Measured value: 500.1341 Example 6 3

According to the same method as in Example 1, 4 — [(4—fluorophenylsulfinyl) methyl] —4— (2—methoxyethoxy) bipyridine (150 m: 0.47) 6 mm 0 1) and 2- (benzothiophene-3-yl) ethyl methanesulfonate (112 mg) from light yellow oily 1- [2- (benzothiophene-3-yl) ethyl] One 4 — [(4-fluorophenylsulfinyl) methyl] —4— (2—methoxyethoxy) piperidine (68.2 mg, 30%) was obtained. However, silica gel NH was used in place of Alumina for ram chromatography.

_{HRMS (CI +): C 25} H:! 1 FN0 3 S 2 and to the calculated value: 476.1729

Observed value: 476.1751 Example 6 4

In the same manner as in Example 1, 4-benzyloxy-4-[(4-fluorophenylsulfinyl) methyl] piperidine (115 mg, 0.331 mmol) and 2 — (Benzothiophen-3-yl) ethyl methanesulfonate (84.8 m) from light yellow oily 1 — [2- (Benzothiophen-1-yl) ethyl] — 4-benzyloxy One-forty-four [(4-fluorophenylsulfinyl) methyl] piperidine (104 mg, 62%) was obtained. However, silica gel NH was used in place of alumina for column chromatography.

_{HRMS (CI +):! C} 29 H; 1 FN0 2 S 2 and to Calculated: 508.1780

 Measured value: 508.1791 Example 6 5

2-phenylethyl bromide (87.0 mg, 0.470 mm 0 1) and 4 — [(4-Fluorophenylthio) methyl] —4-methoxypiperidine (180 mg, 0.705 mmol) in acetonitrile 5 ml solution (piperidinomethyl ) Polystyrene (600 mg) was added and shaken at 80 ° C for 6 hours. The residue obtained by concentrating the reaction solution from which the insoluble matter was removed by filtration was purified by silica gel NH column chromatography to obtain a colorless oil of 4-[(4-fluorophenylthio) methyl] 1-1. — (2-phenylethyl) 4- 4-methoxypiperidine (1

19 mg, 70%).

_{HRMS (CI +): C 21} H 27 FN0S and to Calculated: 360.1797

 Measured value: 360.1789 Example 6 6

In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150 mg, 0.467 mmo 1) and 4-methoxy-1- 1- [2- (35-bistrifluoromethylphenyl) ethyl] pale yellow oil was obtained from phenylthiomethylbiperidine (166 mg, 0.7000 mmol). —Methoxy-1-4-thiophenylthiomethylbiperidine (94.0 mg, 42%) was obtained.

_{HRMS (CI +): C 23} H 2 N0S and to Calculated: 478.1639

Observed value: 478.1640 Example 6 7

In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (550 mg, 1.71 mm 01) and 4-[(4-fluoro Phenylthio) methyl] 1-4-methoxypiperidine (437 mg, 1.71 mmo1) from light yellow solid 1_ [2- (3,5-bistrifluoromethylphenyl)] [Ethyl] —4 — [(4-fluorophenylthio) methyl] -14-methoxypiperidine (350 mg, 41%) was obtained.

_{HRMS (CI +): C 23} H 25 F 7 N0S and to Calculated: 496.1545

 Measured value: 496.1555 Example 6 8

According to a method similar to that of Example 65, 2- (3,5-bistrifluoromethinolephenyl) ethyl bromide (150 mg, 0.467 mmo1) and 4-([3- Fluorophenylthio) methyl] — 4-Methoxypiperidine (179 mg, 0.7000 mmol) Colored solid 1- [2_ (3,5-bistrifluoromethylphenyl) ethyl] -4-1 [(3-fluorophenylthio) methyl] -14-methoxybiperidine (124 mg, 54%) I got

_{HRMS (CI +): C 23} H 25 F 7 N0S and to Calculated: 496.1545

 Observed value: 496.1504

In the same manner as in Example 65, 2— (3,5-bistrifluoromethylphenyl) ethyl bromide (150 mg :, 0.467 mm 01) and 4 — [(2-fluorophenyl Thio) methyl] — 4—Methoxypiperidine (179 mg, 0.7000 mmol) from a pale yellow oil containing 1- [2— (3,5-bistrifluoromethylphenyl) ) Ethyl] 1-4-[(2-fluorophenylthio) methyl]-4-methoxypiperidine (130 mg, 56%) was obtained.

_{HRMS (CI +): C 23} H 2 F 7 N0S and to Calculated: 496.1545

Observed value: 496.1533 Example Ί 0

According to a method similar to that of Example 65, 2— (3,5-bistrifluoromethylphenyl) ethyl bromide (120 mg, 0.374 mmo 1) and 4-[(4-bromophene) 2- (thiol) methyl] -1-4-methoxypyperidin (177 mg, 0.561 mm 01) Capella, pale yellow oil 1— [2— (3,5-bistrifluo) [Romethylphenyl) ethyl] _4-[(4-bromophenylthio) methyl] -4--4-methoxypiperidine (79.0 mg, 38%) was obtained.

_{HRMS (CI +): C 23} H 25 BrF 6 N0S and to Calculated: 556.0744

 Observed value: 556.0707 Example Ί 1

In the same manner as in Example 65, 2— (3,5—bistrifluoromethylphenyl) ethyl bromide (150 mg, 0.467 mmo 1) and 4-([3— Bromophenylthio) methyl] 1-4 — methoxypiperidine (221 mg, 0.7000 mmo 1), pale yellow Oily 1— [2— (3,5—bis trifluoromethylphenyl) ethyl] —4 — [(3—Bromophenylthio) methyl] 14 methoxypiperidine (104 mg, 4 0%).

_{HRMS (CI +): C 23} H 25 BrF 6 N0S and to Calculated: 556.0744

 Measured value: 556.0739 Example 例 2

According to a method similar to that of Example 65, 2— (3,5—bistrifluoromethylphenyl) ethyl bromide (12Om: 0.3734 mmo1) and 4 — [(4 — Clo-mouth phenylthio) methyl] — 4—Methoxybiperidine (152 mg, 0.561 mmo 1) from a pale yellow oil containing 1- [2— (3,5-bistri) Fluoromethylphenyl) ethyl] —4 — [(4—Clo- mouth phenylthio) methyl] —4-methoxythipiperidine (96.Om, 50%) was obtained.

_{HRMS (CI +): C 23} H 25 ClF fi N0S and to Calculated: 512.1250

Measured value: 512.1251 Example 7 3

In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (150 mg, 0.467 mmo1) and 4-[(3-chloro Methyl phenylthio) methyl] — 4-Methoxypiperidine (190 mg, 0.70 mmol) from 1- [2— (3,5-bistrifluoromethylphenyl) as pale yellow oil [Ethyl] — 4— [(3-chlorophenylthio) methyl] — 4-methoxythiperiperidine (131 mg, 55%) was obtained.

Negation _{S (CI +): C 23} H 25 C1F 6 N0S and to Calculated: 512.1250

 Measured value: 512.1212 Example 7 4

In the same manner as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120 mg, 0.374 mmo 1) and 4-methoxy-1- [(4-Methylphenylthio) methyl] pale yellow from viridine (141 mg, 0.561 mmo 1) Oily 1- [2— (3,5-bistrifluoromethylphenyl) ethyl] —4-Methoxy-4-([4-methylphenylthio) methyl] piperidine ( 118 mg, 64%).

_{HRMS (CI +): C 24} H 28 F 6 N0S and to Calculated: 492.1796

 Observed value: 492.1753 Example Ί 5

According to a method similar to that of Example 65, 2— (3,5-bistrifluoromethylphenyl) ethyl bromide (120 mg, 0.374 mmo 1) and 4-methoxy-1- 4 — [(3—Methylphenylthio) methyl] piperidine (141 mg, 0.561 mmo 1) was converted to 1— [2— (3,5—bis trifluo) as a pale yellow oil. [4-Methylphenyl) ethyl] -4- (methoxy) -4-[(3-methylphenylthio) methyl] piperidine (96.0 mg, 52%) was obtained.

HRMS (CI +): C ₂₄ H, ₈ F (; calculated as 0S: 492.1796

Measured value: 492.1819 Example Ί 6

According to the same method as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (120 mg, 0.374 mmo 1) and 4-methoxy-14 [(2-Methylphenylthio) methyl] piperidine (141 mg, 0.561 mmo 1) was converted to a light yellow oil from 1 [2— (3,5-bistrifluo). (4-Methylphenyl) ethyl] 14-methoxy-14-[(2-methylphenylthio) methyl] piperidine (95.0 mg, 52%) was obtained.

_{HRMS (CI +): C 24} H 28 F 6 N0S and to Calculated: 492.1796

 Found: 492.1771 Example 7 7

In the same manner as in Example 65, 2— (3,5—bistrifluoromethylphenyl) ethyl bromide (128 mg, 0.40 mmo 1) and 4—methoxy-1- [(4-nitrophenylthio) methyl] pale yellow from viridine (147 mg, 0.520 mmo 1) Oily 1- [2— (3,5-bistrifluoromethylphenyl) ethyl] —4—Methoxy 4-([4-nitrophenylthio) methyl] piperidine (13 3 mg, 65%).

HR S (CI +): C 23 H 25 F 6 N 2 0 3 S and to Calculated: 523.1490

 Obtained value: 523.1491 Example Ί 8

In the same manner as in Example 65, 2— (3,5-bistrifluoromethylphenyl) ethyl bromide (128 mg, 0.4000 mmo 1) and 4—methoxy 4-— (4-Trifluoromethylphenylthio) methyl] piperidine (159 mg, 0.520 mm 01) was converted to 1— [2— (3,5—) as a pale yellow oil. Bis (trifluoromethylphenyl) ethyl] —4—methoxy-4-((4—trifluoromethylphenylthio) methyl] bipyridine (137 mg, 64%) was obtained.

HRMS (CI +): Calculated for C, H _2fl F ₉ N0S: 546.1513

Measured value: 546.1489 Example 7 9

According to the same method as in Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128 mg, 0.4000 mmo1) and 4-([2, 6 —Dichlorophenylthio) methyl] —4—Methoxypiperidine (159 mg, 0.520 mmol) and a pale yellow oil from 1— [2— (3,5-bistrifluoro) Methylphenyl) ethyl] —4-[(2,6-dichloroperthiol) methyl] —4-methoxypyrididine (138 mg, 65%) was obtained.

Marauder S (CI +): Calculated as C ₂₃ H ₂ C1 ₂ F ₆ N0S: 546.0860

 Observed value: 546.0840 Example 80

According to the same method as in Example 65, 2— (3,5-bistrifluoromethylphenyl) ethyl bromide (128 mg: 0.40 mm 01) and 4 — [(3, 5 — Bistrifluoromethylphenylthio) methyl] ー 4 — Methoxypiridine (194 mg, 0.520 mm o 1) from light yellow oil of 1- [2— (3,5-bistrifluoromethylphenyl) ethyl] —4 — [(3,5-bistrifluoromethylphenylphenyl) methyl] 1—4-methyl Toxibiperidine (170 mg, 71%) was obtained.

_{HRMS (CI +): C2 5} H 24 F 12 N0S and to Calculated: 614.1387

 Measured value: 614.1352 Example 8 1

According to a method similar to that of Example 65, 2- (3,5-bistrifluoromethylphenyl) ethyl bromide (128 mg, 0.400 mmo1) and 4-cyclohexylthiomethyl-1- From methoxypiberidine (127 mg, 0.520 mmol), pale yellow oily 1- [2- (3,5-bistrifluoromethylphenyl) ethyl] —4-cis Clohexylthiomethyl-14-methoxypiperidine (73.0 mg, 39%) was obtained.

_{HRMS (CI +): C 23} H 32 F 6 N0S and to Calculated: 484.2109

Obtained value: 484.2074 Example 82

In the same manner as in Example 65, 2- (benzofuran-3-ethylmethylsulfonate (112 m: 0.467 mmol)) and 4-methoxy-14-phenyl From luthiomethylbiperidine (166 mg, 0.70 mm 0 1), pale yellow oily [2- (benzofuran-3-yl) ethyl] 4--4-methoxy-1- Phenylthiomethylpiperidine (130 mg, 73%) was obtained.

Image _{S (CI +): C 23} H 28 N0 2 S and to Calculated: 382.1841

 Measured value: 382.1840 Example 8 3

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethanesulfonate (144 m: 0.60 mm 01) and 4-[( 4-Fluorophenylthio) methyl] — 4-Methoxypiperidine (230 mg, 0.9000 mm 01) from pale yellow oil 1- [2- (benzo-furan-1-yl) ) Ethyl] 1-41 [(4-fluorophenylthio) methyl] — 4-methoxypiperidine (202) mg, 84%).

_{HRMS (CI +): C 23} H 27 FN0 2 S and to Calculated: 400.1747

 Measured value: 400.1737 Example 8 4

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethanesulfonate (112 mg, 0.467 mmol) and 4-[(3-fluorophenyl) Ruthio) methyl] — 4— methoxypiperidine (179 mg, 0.70 mm 0 1) from light yellow oily [2- (benzfuran-1-yl) ethyl] 1-4— [(3-Fluorophenylthio) methyl] —4-methoxybenzylidine (122 mg, 65%) was obtained.

_{HRMS (CI +): C 23} H 27 FN0 ;; S and to Calculated: 400.1747

Measured value: 400.1758 Example 8 5

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethanesulfonate (112 mg, 0.467 mmol) and 4-[(2 1- [2- (Benzofuran-3-ylyl) ethyl], a pale yellow oil, from 4-methoxyphenylperidine (179 mg, 0.7000 mmol). — [(2-Fluorophenylthio) methyl] — 4-methoxypyrididine (161 mg, 87%) was obtained.

Marauder S (CI +): Calculated as C ₂₃ H ₂₇ FN0 ₂ S: 400.1747

 Measured value: 400.1730 Example 8 6

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethansulfonate (90.0 mg, 0.374 mm 01) and 4 — [(4-bromophenyl Enilthio) methyl] — 4—Methoxy xyperidine (177 mg, 0.561 mmo 1) from a pale yellow oil 1— [2- (Benzofuran-3-yl) ethyl] —4 — [(4-Bromofenylthio) methyl] —4-Methoxypiperidine (69.0 mg, 40% ).

_{HRMS (CI +): C 23} H 27 BrN0 2 S and to Calculated: 460.0946

 Measured value: 460.0938 Example 8 7

In the same manner as in Example 65, 2- (benzofuran-3-ethylmethansulfonate (112 mg, 0.467 mmol)) and 4-[(3-bromophenylthio) ) Methyl] — 4—Methoxybipyridine (221 mg, 0.70 mmol) from light yellow oily 1- [2- (benzofuran-3-yl) ethyl] — 4— [ (3-Bromofenylthio) methyl] —4-methoxypiperidine (190 mg, 88%) was obtained.

_{HRMS (CH): C 23 H} 27 BrN0vS and to Calculated: 460.0946

Actual value: 460.0927 Example 8 8

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethansulfonate (90.0 mg, 0.374 mm 01) and 4-[(4- B) Methyl] —4-Methoxybiperidine (152 mg, 0.561 mmol) was converted to a light yellow oil of 1- [2- (benzofuran-3-yl) ethyl. ] — 4 — [(4-Chlorofluorothio) methyl] 1-4-methoxypiperidine (72.0 mg, 60%) was obtained.

_{HRMS (CI +): C 23} H 27 C1N0 2 S and to Calculated: 416.1451

 Measured value: 416.1426 Example 8 9

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethansulfonate (112 m: 0.467 mmol) and 4-[[3- Methyl thiophene) methyl] — 4— methoxypiperidine (190 mg, 0.70 mmo 1) from light yellow oil -[2- (Benzofuran-3-yl) ethyl]-4-[(3-chlorophenylthio) methyl]-4-methoxypiperidine (17 lmg, 88%) was obtained.

_{HRMS (CI +): C 23} H 27 C1N0 2 S and to Calculated: 416.1451

 Obtained value: 416.1430 Example 90

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethyl methanesulfonate (90.0 mg, 0.374 mm 01) and 4-methoxy4 — [(4-Methylphenylthio) methyl] biperidine (141 mg, 0.561 mmol) from a pale yellow oil containing 1- [2- (benzofuran-3-yl) ethyl ] — 4-Methoxy-1- 4-((4-methylphenylthio) methyl] piperidine (85.0 mg, 57%) was obtained.

_{HRMS (CI +): C 2} H 30 N0 2 S and to Calculated: 396.1997

Obtained value: 396.1972 Example 9 1

In the same manner as in Example 65, 2- (benzofuran-3-ethylmethanesulfonate (90.0 mg, 0.374 mm 01)) and 4-methoxy-14-[( 3- (Methylphenylthio) methyl] biperidine (141 mg, 0.561 mmo 1) from light yellow oily 1- [2- (benzofuran-3-yl) ethyl] 1-4-methyl Toxic 4-[(3-methylphenylthio) methyl] piperidine (98.0 mg, 66%) was obtained.

_{HRMS (CI +): C 24} H 30 N0 2 S and to Calculated: 396.1997

 Measured value: 396.2015 Example 9 2

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethansulfonate (90.0 mg, 0.374 mm 01) and 4-methoxy-14-[(2 —Methylphenirthio) methyl] biperidine (141 mg, 0.561 mmo 1) from a pale yellow oil 1— [2- (Benzofuran-3-yl) ethyl] —4-Methoxy-4 — [(2-Methylphenylthio) methyl] piperidine (98.0 mg, 66%) Obtained.

_{HRMS (CI +): C 24} H 30 N0 2 S and to Calculated: 396.1997

 Obtained value: 396.1968 Example 9 3

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethansulfonate (120 m :, 0.50 mmol) and 4-methoxy-14- [ (4-122 thiophenylthio) methyl] piperidine (184 mg, 0.650 mm 01) from light yellow solid 1- [2- (benzofuran-3-yl) ethyl] 1-4 —Methoxy-1-[(4-nitrophenylthio) methyl] piperidine (121 mg, 57%) was obtained.

_{HRMS (CI +): C 23} H 27 N 2 0, S and to Calculated: 427.1692

Observed value: 427.1696

In the same manner as in Example 65, 2- (benzofuran-3-ethylmethylsulfonate (120 mg, 0.5000 mmol)) and 4-methoxy-14- [ (4-Trifluoromethylphenylthio) methyl] piperidine (19.8 mg, 0.650 mmo 1) from a pale yellow oil containing 1- [2- (benzofuran-3-yl) 4- (Methoxy) 4-[(4-trifluoromethylphenylthio) methyl] piperidine (138 mg, 61%) was obtained.

_{HRMS (CI +): C 24} H 27 F 3 N0 2 S and to Calculated: 450.1715

 Measured value: 450.1721 Example 9 5

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethanesulfonate (120 mg, 0.5000 mmol) and 4-[[2, 6-Dichlorophenylthio) methyl] — 4-Methoxy sibiperidin (199 mg, 0.650 mmol) from light yellow oily 1- [2- (benzofuran-3-yl) Etil] — 4-1 [(2, 6-Dichlorophenylthio) methyl] —4-methoxypiperidine (142 mg, 63%) was obtained.

_{HRMS (CI +): C 23} H 26 C1 2 N0 2 S and to Calculated: 450.1061

 Measured value: 450.1049 Example 9 6

In the same manner as in Example 65, 2- (benzofuran-3-ethylmethylsulfonate (120 mg, 0.5000 mmol)) and 4-[(3,5-bistrifluoromethyl) 1- [2- (benzofuran-3-yl) ethyl] as pale yellow oil from 4-methylethoxybiperidine (243 mg, 0.650 mmol) —4-[(3,5-bistrifluoromethylphenylthio) methyl] -14-methoxybiperidine (210 mg, 81%) was obtained.

_{HRMS (CI +): C 25} H 26 F 6 N0 2 S and to Calculated: 518.1588

Observed value: 518.1586

In the same manner as in Example 65, 2- (benzofuran-3-yl) ethylmethanesulfonate (120 mg, 0.5000 mmol) and 4-cyclohexylthio were used. Methyl_4-methoxypiperidine (158 mg, 0.650 mm 01) was converted to a light yellow oil from 1- [2- (benzofuran-3-yl) ethyl] —4-cyclohexylthio. Methyl-4-methoxypyrididine (78.0 mg, 40%) was obtained.

_{HRMS (CI +): C 23} H 34 N0 2 S and to Calculated: 388.2310

 Measured value: 388.2310 Example 9 8

In the same manner as in Example 65, 2-phenylethyl bromide (206 mg, 1.11 mmol) and 4-ethoxy-4-[(4-fluorophenylthio) methyl] biphenyl were used. From peridine (300 mg, 1.1 1 mmo 1), pale yellow oil of 4 _ ethoxy—4 — [(4-fluorene phenylthio) methyl] — 1- (2-phenylethyl) ) Beveridine (311 mg, 75%) was obtained. _{HRMS (CI +): C 22} H 29 FN0S and to Calculated: 374.1954

 Obtained value: 374.1935 Example 9 9

In the same manner as in Example 65, 2-phenylethyl bromide (196 mg, 1.06 mmol) and 4-[(4-fluorophenylthio) methyl] —4-propoxypiperi Gin (300 mg, 1.06 mmo 1) from pale yellow oily 4-[(4-fluorophenylthio) methyl] — 1 — (2-phenylethyl) 1-4-propoxybipyridine ( 276 mg, 67%).

_{HRMS (CI +): C 23} H 3I FN0S and to Calculated: 388.2110

 Measured value: 388.2110 Example 1 100

According to a method similar to that of Example 65, 2-phenylethyl bromide (1 8 7 mg, 1.0 Olmmol) and 4_butoxy-4-([4-fluorophenylthio) methyl] piperidine (300 mg, 1.01 mm01) 4-Butoxy-l 4-[((4-fluorophenyl) thio) methyl] -1-(2-phenylethyl) piperidine (281 mg, 69%) was obtained as a pale yellow oil.

_{HRMS (CI +): C 24} H 33 FN0S and to Calculated: 402.2267

 Measured value: 402.2267 Example 1 01

In the same manner as in Example 65, 2-phenylethyl bromide (196 mg, 1.06 mmol) and 4-[(4-fluorophenylthio) methyl] 14- (2- Propoxy) piperidine (300 mg, 1.06 mmo 1) was converted to 4-[(4-fluorophenylthio) methyl] 1 1— (2-phenylenyl) 1-4— ( 2-Bropoxy) viridin (255 mg, 63%) was obtained.

_{HRMS (CI +): C 23} H 31 FN0S and to Calculated: 388.2110

Obtained value: 388.2126 Example 1 102

By a method similar to that of Example 65, 2-phenylethyl bromide (188 mg, 1.02 mmol) and 4-cyclopropylmethoxy-4-[(4-fluorophenylthio) methyl] Piperidine (300 mg, 1. ◦ 2 mmo 1) was converted to pale yellow oil 4-cyclobutyral methoxy-4-[(4-fluorophenylthio) methyl] ― 1- (2-phenylethyl) Piperidine (253 mg, 62%) was obtained. _{HRMS (CI +): C 24} H 31 FN0S and to Calculated: 400.2110

 Measured value: 400.2104 Example 1 0 3

By the same method as in Example 65, 2-phenylethyl bromide (192 mg, 1.04 mm 01) and 4- (2-fluoroethoxy) —4 -— ((4-fluorophenylthio) ) Methyl] piperidine (30 mg, 1.04 mm 01) from pale yellow oily 4- (2-fluoroethoxy) methyl 4-([4-fluorophenylthio) methyl] — 1 -(2-Phenylethyl) piperidine (244 mg, 60%) was obtained.

_{HRMS (CI +): C 22} H 28 F 2 N0S and to Calculated: 392.1860

 Actual value: 392.1863 Example 1 104

In the same manner as in Example 65, 2-phenylene bromide (172 mg, 0.928 mm 01) and 4-[(4-fluorophenylthio) methyl] —4 -— (2, 2, 2-Trifluoroethoxy) piperidine (300 mg, 0.928 mmol) from light yellow oily 4-[(4-fluorofurnylthio) methyl] — 1 — (2 — Phenyl leethyl) 1-4- (2,2,2-trifluoroethoxy) piberidine (282 mg, 71%) was obtained.

_{HRMS (CI +): C 22} H 26 F 4 N0S and to Calculated: 428.1671

Measured value: 428.1688 Example 1 105

According to a method similar to that of Example 65, 2-phenylethyl bromide (186 mg, 1.00 mmol) and 4-[(4-fluorophenylthio) methyl] -4-1 (2-me Toxietoxy) piperidine (300 mgs 1. OO mmol) was converted to pale yellow oily 4-[(4-fluorophenylthio) methyl] — 4- (2-methoxhetoxy) 1 1- (2-Phenylethyl) piperidine (238 mg, 59%) was obtained.

_{HRMS (CI +): C 23} H 3I FN0 2 S and to Calculated: 404.2060

 Measured value: 404.2055 Example 1 106

According to the same method as in Example 65, 2-phenylethyl bromide (168 mg, 0.905 mm 01) and 4-benzyloxy 4-[(4-fluorophenylthio) methyl] biphenyl were used. From peridine (300 mg, 0.905 mm 01), pale yellow oily 4-benzyloxy 4-[(4 —Fluorophenylthio) methyl] —1-1 (2-phenylethyl) piperidine (284 mg, 72%) was obtained.

_{HRMS (CI +): C 27} H 31 FN0S and to Calculated: 436.2110

 Observed value: 436.2109 Example 10 0

In the same manner as in Example 65, 2- (benzothiophene-3-ethyl) ethyl methanesulfonate (103 mg, 0.402 mm 01) and 4-ethoxy 1 — [(4-Fluorophenylthio) methyl] bipyridine (100 mg, 0.371 mmol) was converted to 1— [2— (benzothiophen-1-yl) as a colorless oil. 4) [4- (ethoxy) methyl] piperidine (100 mg, 36%) was obtained.

_{HRMS (CI +): C 24} H 29 FN0S 2 and to Calculated: 430.1675

 Obtained value: 430.1645 Example 1 08

In the same manner as in Example 65, 2- (benzothiophene-3-yl) ethylmethanesulfonate (103 mg, 0.402 mm 01) and 4- [(4-fluorophenyl) Ruthio) methyl] — 4-propoxysibiperidine (100 mg, 0.353 mmo 1) from a colorless oil of 1- [2- (benzothiophene-3-yl) ethyl] — 4— [( [4-fluorophenylthio) methyl]-4-propoxypiperidine (87.7 mg, 56%) was obtained.

Marauder S (CI +): Calculated as C ₂₅ H ₃₁ FN0S ₂ : 444.1831

 Found: 444.1812 Example 1 09

In the same manner as in Example 65, 2- (benzothiophene-3-yl) ethylmethanesulfonate (103 mg, 0.402 mm 01) and 4-butoxy-14 were used. — [(4-Fluorophenylthio) methyl] piperidine (100 mg, 0.336 mmol) from colorless oil 1 — [2- (benzothiophene-3-yl) ethyl] 4-butoxy-4-([4-fluorophenylthio) methyl] piperidine (78.0 mg, 51%) was obtained.

_{HRMS (CI +): C 26} H 33 FN0S 2 and to Calculated: 458.1988

Observed value: 458.1979 Example 1 1 0

In the same manner as in Example 65, 2- (benzothiophene-3-yl) ethylmethanesulfonate (103 mg, 0.402 mm 01) and 4-([4- Fluorophenylthio) methyl] — 4— (2-Bropoxy) piperidine (100 mg, 0.353 mmo 1) from a colorless oil of 1- [2-—benzothiophene-3- L) ethyl]-4-[(4-fluorophenylthio) methyl] -14- (2-propoxy) piperidine (75.2 mg, 48%) was obtained.

_{HRMS (CI +): C 25} H 31 FN0S 2 and to Calculated: 444.1831

 Measured value: 444.1823 Example 1 1 1

In the same manner as in Example 65, 2- (benzothiophene-3-yl) ethyl methanesulfonate (103 m: 0.42 mm 01) and 4-cyclobutyrazine Toxin 4-[((4-fluorophenylthio) methyl] piperidine (100 mg, 0.339 mm 01) is a colorless oily 1- [2- (benzophenenephene) 1-3-yl) ethyl] — 4-—Cyclopropylmethoxy-4-([4-fluorophenylthio) methyl] piperidine (35.5 mg, 23%) was obtained.

_{HRMS (CI +): C 26} H 31 FN0S 2 and to Calculated: 456.1831

 Measured value: 456.1840 Example 1 1 2

In the same manner as in Example 65, 2— (benzothiophene-3-yl) ethylmethansulfonate (206 mg, 0.804 mmo 1) and 4— (2—fluoroethoxy) 1) [1- (4-Fluorophenylthio) methyl] piperidine (200 mg, 0.696 mm 01) was converted to a colorless oil from 1— [2— (benzothiophene-3—). (Ethyl) ethyl 4- (2-fluoroethoxy) -14-[(4-fluorophenylthio) methyl] piperidine (162 mg, 52%) was obtained. _{HRMS (CI +): C 24} H 28 F 2 N0S 2 and to Calculated: 448.1580

 Measured value: 448.1577 Example 1 1 3

In the same manner as in Example 65, 2- (benzothiophene-3-ethyl) ethyl bromide (74.6 mg, 0.309 mmol) and 4-[(4-fluorophenyl) Thio) methyl] 1- (2,2,2-trifluoroethoxy) piperidine (100 mg, 0.309 mmol) was converted to 1- [2— (benzothiophene) as a colorless oil. 3- (yl) ethyl] —4-[(4-fluorofluorothio) methyl] —4— (2,2,2—trifluoroethoxy) viridine (120 mg, 80%) Obtained.

_{HRMS (CI +): C 24} H 26 F 4 N0S 2 and to Calculated: 484.1392

 Obtained value: 484.6022 Example 1 1 „4

In the same manner as in Example 65, 2- (benzothiophene-3-yl) ethylmethanesulfonate (103 mg: 0.402 mm 01) and 4-[(4 —Fluorophenylthio) methyl] —4— (2-Methoxyethoxy) piperidine (100 mg, 0.33 mm 4) from 1- [2— (benzothiophene) as a colorless oil 1—3—yl) ethyl] —4 — [(4—fluorophenylthio) methyl] 14— (2—methoxetoxy) viridin (99.6 mg, 63%) was obtained. Was. _{HRMS (CI +): C 25} H 31 FN0 2 S 2 and to Calculated: 460.1780

Observed value: 460.1796 Example 1 1 5

According to a method similar to that of Example 65, 2- (benzothiophene-3-yl) ethylmethanesulfonate (103 mg, 0.402 mm 01) and 4-benzyloxy-141 were used. [(4-Fluorophenylthio) methyl] piperidine (100 mg, 0.32 mmo 1) from colorless oily 1- [2- (benzothiophene-3-yl) ethyl] —4-Benzyloxy-4 -— [(4-fluorophenylthio) methyl] piperidine (75.7 mg, 51%) was obtained.

_{HRMS (CI +): C 29} H 1 FN0S 2 and to Calculated: 492.1831

 Measured value: 492.1857 Example 1 1-6

According to a method similar to that of Example 1, (+) — 4 — [(4—fluorophenylsulfinyl) methyl] —4—methoxypiperidine (98.6% ee) (603 mg, 2.22 mmol) and 2- (benzothiophene-3-yl) ethyl methanesulfonate (626 mg, 2.44 mm 01) (+)-1- [2- (Benzothiophene-3-yl) ethyl] 1-4-[(4-fluorophenylsulfyl) methyl] —4—Methoxybiperidine (78) 2 mg, 82%). However, for column chromatography, silica gel NH was used instead of alumina.

_{HRMS (FAB +): C 23} H 27 FN0 2 S 2 and to Calculated: 432.1467

 Observed value: 432.1438

[a] _D ²³ +95.9 (c = 0.75, CHCl _{; i} ) (98.6% ee) Reference Example 1

By the same method as in Example 1, (+) — 4-methoxy-4-phenylphenylmethylbiperidine (100% ee) (1.79 g, 7.07 mmol) and 2 — (5 — Fluoroid dol — 3-yl) ethyl bromide (1.88 g, 7.78 mmo 1), colorless, morphous (+)-1-[2 — (5 — Fluoroydol And 4-ethyl) —4—methoxy 4—phenylsulfinylmethylbiperidine (2.05 g, 70%) was obtained. However, silica gel NH was used instead of alumina for column chromatography. Anal: C ₂₃ H ₂₇ FN ₂ 0 ₂ S Calculated as 1.5H ₂ 0: C: 62.56 H: 6.85 N: 6.35 Measured value: C: 62.79 H: 6.63 N:

6.32

[a] _D ²⁴ + 105.4 (c = 0.368, CHC1) (100% ee) Example 1 1 Ί

1-t-Butoxycarbonyl 2- 4-methylenepiperidine (55.0 mg, 0.279 mmo 1) is dissolved in 0.5 ml of methanol, and N-promosqueimide ( 49.6 mg, 0.279 mmo 1) were added, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and then 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 a colorless syrup-like 4-bromoethyl-1-t— Butoxycarbonyl-14-methoxybiperidine (77.0 mg, 90%) was obtained.

lH-NMR (400 MHz, CDC13) δ: 1.42-1.50 (2Η, 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 (100MHz, CDC13) δ: 28.4, 31.8, 32.6, 37.9, 38.7, 39.1, 48.7, 72.1, 79.5, 154.7.

MS: 307 (M +) Example 1 1 8

Example 11 1-t-butoxycarbonyl-14-methylene pyridine (960 mg, 4.87 mm 01), methanol 5 ml and N-odosuccine were prepared in the same manner as in Example 11 From the mid (1.42 g, 6.33 mmo 1), a colorless, syrupy form of 1-t-butoxycarbonyl-14-odomethyl-14-methoxypiperidine (1.28 g, 7 4%).

 1H-NMR (400 MHz, CDC13) δ: 1.40-1.50 (2H, m), 1.45 (9H, s), 1.85-1.95 (2H, in), 3.01 (2H, brs), 3.19 (3H, s), 3.26 (2H, s), 3.83 (2H, brs).

According to a method similar to that in Example 117, 1-t-butoxycarbonyl-14-methylenepiperidine (2.0 g, 10-lmmol), ethanol From 5 ml of N-promosque imide (2.16 g 12.2 mmo 1), a colorless sirobe form of 4-bromomethyl-11-t-butoxycarbonyl-14-ethoxybiperidine ( 1.95 g, 58%).

lH-NMR (400 MHz, CDC13) δ: 1.23 (3Η, t, J = 6.8 Hz), 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 (ZH, brs).

 S (CI +): 322 (M + 1).

In the same manner as in Example 11, 17-t-butoxycarbonyl-14-methylenepiperidine (2.00 g, 10-lmmol), 6 ml of prononol and N-promosuccinimide (2 From 16 g (12.2 mmol), a colorless syrup of 4-bromomethyl-1-t-butoxycarbonyl-14-propoxybiperidine (1.95 g, 58%) was obtained. Was.

lH-NMR (400 MHz, CDC13) δ: 0.96 (3Η, t, J = 7.3 Hz), 1.42-1.50 (2H, m), 1.46 (9H, s), 1.55-1.65 (2H, m), 1.87-1.90 (2H, in), 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) . Example 1 2 1

Example 11 1-t-Butoxycarbonyl-14-methylenebipyridine (2.0 g: 10 lmmol), 8 ml of butanol, From N-promosquimid (2.16 g, 12.2 mmo 1), a pale yellow chipped 4-bromomethyl-1-butoxy 1-butoxycarbonylbiperidine (2 .77 g, 78%).

lH-NMR (400 MHz, CDC13) δ: 0.93 (3H, t, J = 7.8 Hz), 1.37-1.47 (4H, m), 1.46 (9H, s), 1.49-1.61 (2H, 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). S (CI +): 350 (M + 1) Example 1 2 2

Boc

In the same manner as in Example 11, 17 1-t-butoxycarbonyl-14-methylpyridin (2.00 g 10 .1 mmol), 2 -phenol 6 ml and N —Promosquimid (2.16 g 12.2 mm 01) from pale yellow syrup 4 —Promomethyl-1 —t —Butoxycarbonyl-14 2 —Proboxoxy) pyridine ( 1.65 g 48%).

lH-NMR (400MHz CDC13) δ: 1.21 (6Η, d J = 6.3 Hz), 1.46 (9H, s), 1.54-1.62 (2H, m), 1.79-1.82 (2H, m), 3.16 (2H, brs ), 3.31 (2H, t J = 6.3 Hz), 3.40 (2H, s), 3.86 (2H, brs).

MS (CH): 336 (M + 1).

Boc-N

According to a method similar to that in Example 11-17, 1-t-butoxycarbonyl-14-methylpyridinine (2.00 g10.lmmol), cyclobutyrolmethanol 10m From 1 and N-promosque imide (2.16, 12.2 mmol), colorless syrup-like 4-bromomethyl 1-t-butoxycarboryl 4-cyclopropylpyrmetoxypipiperidine (2.75 g 78%).

1H-title R (400MHz CDC13) δ 0.23 (2H dd, J = 4.9, 10.3 Hz), 0.55 (2H dd, 5.4, 13.2 Hz), 1.43-1.91 (1H 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 (CH): 348 (M + 1).

In the same manner as in Example 117, 1-t-butoxycarbonyl-4-methylenepyridine (2.00 g, 10-lmmol), 2-fluoroethanol 8 ml and N- From the mosquisimid (2.16 g, 12.2 mmol), colorless sylobic 4- (bromomethyl-1-t-butoxycarbonyl-14- (2-fluoroethoxy) biperidine (2.75) g, 78%).

lH-NMR (400MHz CDC13) δ: 1.45-1.56 (2H, m), 1.46 (9H, s), 1.89-1.92 (2H, in), 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 Hz).

MS (CI +): 340 (M + 1).

According to a method similar to that in Example 117, 1-t-butoxycarbonyl-14-methylenebipyridine (2.0 g, 10 lmmol), 2, 2, 2—trifluoroeta 8 ml of Nol and N-Promosque

(2.16 g, 12.2 mmol) from a colorless syrup of 4-bromomethyl-111-t-butoxycarbonyl-141 (2,2,2-trifluroyl ethoxy) Piperidine (1.68 g, 44%) was obtained. lH-NMR (400MHz, CDC13) δ: 1.42-1.59 (2Η, m), 1.46 (9H, s), 1.89-1.93 (2H, m), 3.07 (2H, brs), 3.38 (2H, s), 3.81 (2H, q, J 2 8.3 Hz), 3.84 (2H, brs).

MS (CI +): 376 (M + 1).

According to a method similar to that of Example 11-17, 1-t-butoxycarbonyl 4-methylenepiperidine (2.0 g, 10.1 mm 01), 2-methoxyethanol 10 ml and N-promosquimid (2.16 g, 12.2 mmol) from a pale yellow lipo-form of 4-promomethyl-1 1-t-butoxycarbone 4-(2-methoxycarbonyl) piperidine ( 2.96 g, 83%).

lH-NMR (400 MHz, CDC13) δ: 1.46 (9Η, 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 (CH): 352 (M + 1).

In the same manner as in Example 117, 1-t-butoxycarbonyl 4-methylenepyridine (2.00 g, 10 .1 mmol), benzyl alcohol 10 m1 and N-bromosuccimid (2.71 g,

15.2 mm 0 1), a pale yellow syrup-like 4-benziloxy — 4 — bromomethyl-1- 1 — t-butoxycarbonylbiperidine

(2.95 g, 76%).

lH-NMR (400 MHz, CDC13) δ: 1.46 (9Η, 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).

To a suspension of sodium hydride (oil-based, approx. 60%) (0.93 g, 23.2 mmol) in 5 ml of N, N-dimethylformamide was added 4-fluorothiophene. After addition of ethanol (2.47 ml, 23.2 mmo 1), 4-bromomethyl-1-t-butoxycanolebonyl-14-methoxypiperidine (6.80 g, A solution of 22.1 mm 01) in 10 ml of N, dimethylformamide was added, and the mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 4: 1) to give a colorless syrup-like 1-t-butoxycarbonyl-14_ (4-fluorophenyl). Thio) methyl-41-methoxypiperidine (7.56 g, 96%) was obtained.

lH-NMR (400MHz, CDC13) δ: 1.45 (9Η, 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 +).

To a suspension of sodium hydride (oil-based, approx. 60%) (120 mg, 3.00 mm 01) in 2 ml of N, N-dimethylformamide was added thiophenol ( After adding 3 1 mg :, 3.000 mmol), N, N of 4-bromomethyl-11-t-butoxycarbonyl-14-methoxypiperidine (6 16 mg, 2.000 mmol) — Add 2 ml of dimethylformamide solution, shake for 12 hours at 80 ° C, and add p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mm0 1) was added and shaken at 80 ° C for 2 hours. After adding 1N hydrochloric acid to the reaction solution and washing with ethyl 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 to obtain a brown oily 4-methoxy-4-phenylthiomethylpiperidine (400 mg, 84%). Example 1 3 0

In the same manner as in Example 12 9, 3-fluorothioenol (3 8 5 mg, 3. OO mmol) and 4-bromomethyl-1-t-butoxycarbonyl- 14-methoxypiperidine (6 16 mg, 2. OO mmol) were converted to brown oily 4-[(3-fluorophenyl). [Methyl] methyl] —4-methoxypiperidine (358 mg, 70%) was obtained. Example 1 3 1

In the same manner as in Example 12 29, 2-fluorothiophenol (385 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-14-methoxypiperidine ( The brown oily 4-[(2-fluorophenylthio) methyl] -14-methoxypiperidine (409 mg, 80%) was obtained from 616 mg (2.00 mmol). Example 1 3 2

O e According to a method similar to that of Example 12-29, 4-promothiophenol (567 mg, 3.00 mm 01) and 4-promomethyl-11-t-butoxycarboryl 4-4-methoxypiperi Gin (6 16 mg: 2.00 mm 01) was converted to brown oil of 4 _ [(4-bromophenylthio) methyl] — 4- methoxypiperidine (512 mg, 81%). Obtained. Example 1 3 3

In the same manner as in Example 12 29, 3-promothiophenol (566 mg, 3.00 mmol) and 4-promomethyl-111-butoxycarbonyl-14-methoxypiperidine (6 From 16 mg, 2.00 mmol), brown oily 4-[(3-bromophenylthio) methyl] —4-methoxypiperidine (502 mg, 79%) was obtained. Example 1 3 4

OMe In the same manner as in Example 12 29, 4-chlorothiophenol (434 mg, 3.00 mmol) and 4-bromomethyl-11-t-butoxycarbonyl-14-methoxypiperidine (616) mg, 2.0 mmo 1), to give brown oily 4-[(4-chlorophenylthio) methyl "1-4-4-methoxypiperidine (4 13 mg, 76%). Example 1 3 5

In the same manner as in Example 12-29, 3-chlorothiophenol (434 mg, 3.000 mmol) and 4-bromomethyl-1-t-butoxycarbonyl 4-methoxypiperidine (616 mg , 2.0 mmo 1) to give 4-[(3-chlorofluorothio) methyl] —4-methoxypyrididine (457 mg, 84%) as a brown oil. Example 1 3 6

OMe According to a method similar to that of Example 12-29, 4-methylthiopheneol (373 mg, 3.00 mmol) and 4-bromomethyl-1—t-butoxycarboryl 4-methoxypiperidine (616 mg) were used. , 2. OO mmol) to give 4-methoxy-14-[(4-methylthiolthio) methyl] piperidine (392 mg, 78) as a brown oil. Example 1 3 7

According to a method similar to that of Example 12-29, 3-methylthiophenol (373 mg, 3.00 mmol) and 4-bromoethyl-11-t-butoxycarbonyl-14-methoxypiperidine ( 6 16 mg: 2. OO mmol) from brown oily 4-methoxy-14-[(3-methylphenylthio) methyl] piperidine (377 mg, 75%) Was obtained. Example 1 3 8

According to a method similar to that of Example 12-29, 2-methylthiophenol (373 mg, 3.00 mmol) and 4-bromomethyl-1 1-t-butoxycarbonyl 4-methoxypiperidine (6 16 mg, 2.

OO mmol) to give brown oily 4-methoxy-4-[(2-methylphenylthio) methyl] piperidine (4 17 mg, 83%) ο Example 13 9

According to a method similar to that in Example 12-29, 4-nitrothioenol (466 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-14-methoxypiperidine were obtained. Gin (6 16 mg, 2.000 mmol) from brown solid 4-methoxy-4-([4-nitrate phenylthio) methyl] piperidine (310 mg, 5 5%). Example 1 4 0

According to a method similar to that of Example 12-29, 4-trifluoromethylthiol enol (535 mg, 3.00 mm 01) and 4-bromomethyl-1-t-butoxycarbonyl 4-Methoxypiperidine (6.16 mg, 2.000 mmol) was converted to 4-methoxy-14-[(4-trifluoromethylphenylthio) methyl] pale yellow oil Gin (500 mg, 82%) was obtained. Example 1 4 1

According to a method similar to that of Example 12 29, 2,6-dichlorothiophenol (5337 mg, 3.00 mmol) and 4-bromomethyl-1-t-butoxycarbonyl-1-methyl Toxipiperidine (6 16 mg 2.0 MMol) was converted from pale yellow oil to 4-[(2,6-dichloro- [Fenrylthio) methyl] 4--4-methoxypirididine (500 mg 82%) was obtained. Example 1 4 2

According to a method similar to that of Example 12 29, 3,5-bistrifluoromethylthioofenol (739 mg, 3.00 mol) and 4-bromomethyl-1-t-butoxycarbonyl-1-4- From methoxypiberidine (6 16 mg, 2.000 mmol), pale yellow oily 4-[(35-bistrifluoromethylphenylthio) methyl] 14-methoxypiperidine ( 62 mg, 83%). Example 1 4 3

In the same manner as in Example 12 29, cyclohexylmercaptan (3 49 mg, 3.0 mmO 1) and 4-bromomethyl-11-t-butoxycarbonyl-14-methoxypiperidine (616 mg, 2.0 mmO 1) 4-cyclohexylthiomethyl-4--4-methoxypiperidine (350 mg, 72%) was obtained. Example 1 4 4

Dissolve 1-t-butoxycarbonyl-1- (4-fluorophenylthio) methyl-1-methoxybiperidine (45.0 mg, 0.127 mmo1) in 1 ml of methylene chloride Under ice-cooling, m-chloroperbenzoic acid (a product containing 70%) (31.2 mg 0.127 mmol) was added, and the mixture was stirred for 10 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 5% sodium thiosulfate, 5% sodium hydrogen carbonate, and saturated saline sequentially. It was dried with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3), and the light yellow oily 1-t-butoxycarbonyl-1- (4-fluoro) was obtained. Methyl phenylsulfinyl) methyl-14-methoxypiperidine (38 mg, 81%) was obtained.

lH-NMR (400MHz, CDC13) δ: 1.46 (9Η, 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), 3.00-3.25 (3H, brm), 3.25 (3H, s), 3.83 (2H, brs), 7.24 (2H, dd, J = 7.3, 16.1 Hz), 7.66 (2H, dd, J = 5.4: 8.8 Hz).

 MS (CI +): 372 (M + 1).

l — t—butoxycarbonyl 4- (4-fluorophenyl)

Methyl 4-methoxypyridine (6.00 g, 16.9 mmo 1) and (S, S) -Ν, Ν'-bis (3,5-di-t-butylsalicylidene) 1,2-cyclohexanediaminomanganese (III) chloride (268 mg, 0.420 mm 01) is dissolved in 80 ml of methanol, and trinatto citrate is dissolved. After adding a solution of lithium (496 mg, 1.69 mm 01) in 20 ml of water, 30% hydrogen peroxide solution (5.7 m1, 50.6 mm 01) was added, and the mixture was stirred at room temperature for 30 minutes. A 5% aqueous solution of sodium hydrogen sulfite was added to the reaction mixture, 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 distilling off 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 (+)-111-butoxycarbonyl-14- (4-fluorophenylsenorefinyl) methyl-4-methylethoxypipe as a colorless powder. Resin (0.86 g, 14%).

[] _D ²³ + 138.8 (c = 1.00, CHC1,) (98.6% ee) Example 1 4 6

A suspension of sodium hydride (oil-based, approx. 60%) (4.00 g, 100 mmo1) in N, N-dimethylformamide (40 ml) was added under ice-cooling. Add 1-fluorothiophenol (10.65 ml, 100 mmol), stir at room temperature for 1 hour, and add 2 M sodium 4-fluorofluorophenol N, N-dimethylformamide A solution (hereinafter abbreviated as 2M-4 FTPNa solution) was prepared.

To a solution of 4-bromomethyl-1—t-butoxycarbonyl-4-ethoxyethoxylidine (1.95 g, 6.05 mm 01) in 1 ml of N, N-dimethylformamide, add 2 M— 4 FTPNa solution (3.03 ml, 6.06 mmo1) was added, and the mixture was shaken at 80 ° C. for 12 hours. The reaction solution was diluted with getyl ether, and the insolubles were removed by filtration using celite. The filtrate was concentrated under reduced pressure. To the residue obtained, 10 ml of dibutyl ether-toluenesulfonic acid monohydrate (1.73 g, 9.08 mm 01) was added, and the mixture was heated at 80 ° C. Shake for 1 hour. The supernatant of the reaction solution was removed, and the lower layer was washed with getyl ether, made alkaline by adding a 10% aqueous solution of potassium carbonate, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. 4-[(4-Fluorofluorothio) methyl] piperidine (1.16 g, 71%) was obtained.

 4-Ethoxy 4-([4-fluorophenylthio) methyl] bipyridine (1.80 g, 6.68 mmol) in methylene chloride (10 ml) was added to triethylamine (1.3). Add 9 ml, 10.0 mmo 1) and 1 M di-t-butyl dicarbonate methylene chloride solution (8.02 ml, 8.02 mmo 1) and stir at room temperature for 1 hour did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain pale yellow oily 1-t-butoxycarbonyl-4-ylethoxy [41- (4-fluorophenylthio) methyl] piperidine.

The obtained 1-t-butoxycarbonyl-14-ethoxy-14-[((4-fluorophenylthio) methyl] piperidine) methylene chloride solution in methylene chloride (10 ml) was cooled under ice-cooling to obtain m-chloroperbenzoic acid. An acid (1.15 g, 6.68 mmo1) was added and stirred for 1 hour. The reaction mixture was poured into a 1: 1 mixture of 5% sodium thiosulfate and 5% sodium bicarbonate, extracted with methylene chloride, and the organic layer was extracted with 5% sodium bicarbonate, saturated saline. And dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and 1-t-butoxycarbonyl-2-ethoxy-4-([4-fluorophenylsulfinyl) as a pale yellow oil was obtained. ) Methyl] piperidine (1.42 g, 5

5%).

1H- 丽 R (400MHz, CDC13) δ: 1.45 (9Η, 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 +). Example 1 4 7

In the same manner as in Example 14 46, 4-bromomethyl-1-t-butoxycarbonyl-14-propoxypiperidine (1.67 g, 4.97 mmol) and 2M-4 From the FTPNa solution (2.49 ml, 4.98 mmo 1), brown oily 4-[(4-fluorofluorothio) methyl] —4-propoxypiperidine (0.986 g, 70 %). From the obtained 4-[[(4-fluorophenylthio) methyl] -4-propoxypiperidine (1.00 g, 3.53 mm 01), a pale yellow oily 1-t-butoxycarbonyl-1 4 — [(4-fluorophenylthio) methyl] — 1-t-butoxycarbonyl 4-([4-fluorophenylsulfinyl) methyl] — 4-propoxypiperidine (0) as pale yellow oil via 4-propoxypiperidine .676 g (48%).

MS (CI +): 400 (M + 1).

Example 1 According to the same method as in 46, 4-bromomethyl-4-butoxy-11-t-butoxycarbonylbiperidine (2.77 g, 7.91 mmol) and 2M-4 FTPN From solution a (3.96 ml, 7.92 mmo1), a brown oil of 4-butoxy_4 — [(4-fluorene phenylthio) methyl] piperidine (1.72 g, 73%). From the obtained 4-butoxy-4-[(4-fluorophenylthio) methyl] piperidine (0.650 g, 2.18 mmol), 4-butoxy-1 1 as a pale yellow oil was obtained. 4-butoxycarbonyl-1- 4-((4-fluorophenylthio) methyl) piperidine and pale yellow oily 4-butoxy-1 1-t-butoxycarbonyl 4 -— [(4-fluorophenylphenylsulfinyl ) Methyl] piperidine (0.557 g, 62%) was obtained.

MS (CI +): 414 (M + 1). Boc-N

According to a method similar to that in Example 1 46, 4-bromomethyl-1-t-butoxycarbonyl 4- (2-propoxy) piberidine (1.65 g, 4.91 mmol) And 2 M—4 FTPN a solution (2.46 m 1, 4.92 mm 01) from brown oily 4-([4-funolethiophenylthio) methyl] — 4- (2-propoxy) ) Piperidine (1.7 lg, 76%) was obtained. From the obtained 4-[(4-fluorophenylthio) methyl] —4- (2-propoxy) piperidine (0.747 g, 2.64 mmol), 1 t of pale yellow oil was obtained. 1-t-butoxycarbonyl 4-([4-fluorophenyl) 2-butoxycarboyl 4-[(4-fluorophenylthio) methyl] 1- (2-propoxy) piperidine [Sulfinyl) methyl] -4- (2-propoxy) piperidine (0.394 g, 37%) was obtained.

MS (CI +): 400M + 1).

In the same manner as in Example 1, 46, 4-bromomethyl-1-t-butoxycarbonyl-1-cyclopropylmethoxypiperidine (2.

83 g, 8.13 mmol) and 2 M_4 FTPNa solution (4.07 m1, 8.14 mm01) from a brown oil of 4-cyclobutyral methoxyl 4-[( [4-fluorophenylthio) methyl] piperidine (1.38 g, 58%) was obtained. From the obtained 4-cyclobutanevirmethoxyl 4-[(4-fluorophenylthio) methyl] piperidine (0.687 g, 2.33 mm 01), a pale yellow oily 1-t-one was obtained. Butoxy carboxyl 4-cyclocyclopropyl methoxy 4- 4-[(4-fluorophenylthio) methyl] piperidine and pale yellow oil 1-t-butoxycarbonyl 1-4-cyclobutyryl methoxy 4- [(4-Fluorophenylsulfinyl) methyl] piperidine (0.362 g, 38%) was obtained.

412 (M + 1). Example 1 5 1

In the same manner as in Example 14 46, 4-bromomethyl-1-t-butoxycarbonyl-14- (2-fluoroethoxy) piperidine (265 g, 7.79 mmol) and From 2 M—4 FTPN a solution (3.90 ml, 7.80 mm 01), 4_ (2-fluoroethoxy) methyl 4-pi (2-fluorophenylthio) pibelidine as brown oil (1.71 g, 76%) was obtained. From the obtained 4-((2-fluoroethoxy))-1-[(4-fluorophenylthio) methyl] piberidine (0.783 g, 2.72 mmol), 1-t was obtained as a pale yellow oil. 1-butoxycarbonyl -4- 4- (2-fluoroethoxy) 1-t-butoxycarbonyl 4- (2-fluoroethoxy) as a pale yellow oil via 4-[(4-fluorophenylthio) methyl] pyridine 1) 4-[(4-Fluorophenylsulfinyl) methyl] piperidine (0782 g, 71%) was obtained.

MS (CI +): 404 (M + 1).

According to a method similar to that of Example 14 46, 4-bromomethyl-1-t-butoxycarbonyl-41- (2,2,2-trifluoroethoxy) bipyridine (1.62 g, 4.31 mm 01) and 2M—4 FTPN a solution (2.16 ml, 4.32 mm 01)

[(4-Fluorofluorothio) methyl] —4- (2,2,2-trifluoroethoxy) piperidine (1.10 g, 79%) was obtained. From the obtained 4-[(4-fluorophenylthio) methyl] _4— (2,2,2-trifluoroethoxy) piperidine (0.782 g, 2.42 mm 01), 1-t-butoxycarbonyl 1- [1- (4-fluorophenylthio) methyl] yellow oily — 4- (2,2,2-trifluoroethoxy) piperidine 1-t-butoxycarbonyl 1-4 _ [(4-fluorophenylsulfinyl) methyl] — 4 -— (2,2,2-trifluoroethoxy) piperidine

(0.829 g, 78%).

MS (CI +): 440 (M + 1).

According to a method similar to that in Example 1 46, 4-bromomethyl-1-t-butoxycarbonyl-14- (2-methoxetoxy) piperidine (315 g, 8.94 mmol) ) And 2 M—4 FTPN a solution (4.47 ml, 8.94 mmo 1) from a brown oil of 4 -— [(4-fluorophenylthio) methyl] —4 -— (2-methoxetoxy) ) Piberidine (1.72 g, 65%) was obtained. From the obtained 4-[(4-fluorofluorothio) methyl] —4- (2-methoxyethoxy) biveridine (1.06 g, 3.54 mmol), a pale yellow oil was obtained. — 1-t-Butoxycarbonyl 1-4-[(4-fluorophenylthio) methyl] — 4- (2-Methoxyxoxy) piperidine 4-fluorophenylsulfinyl) methyl] 141- (2-methoxetoxy) viridine (1.08 g, 69%) was obtained.

S (CI +): 416 (M + 1).

According to a method similar to that of Example 14 46, 4-benzyloxy-4-bromomethyl-111-t-butoxycarbonylbiperidine (2.17 g,

5.65 mm o l) and 2 M—4 F T PNa solution (2.83 ml, 5.

From 66 mm o 1), brown oily 4-benzyloxy 4-[(4-fluorophenylthio) methyl] piperidine (0.768 g, 41%) was obtained. From the obtained 4-benzyloxy-4-([4-fluorophenylthio) methyl] piperidine (1.00 g, 3.02 mmo1), 4-benzyloxy 11 t as a pale yellow oil was obtained. —Butoxycarbonyl-1-yl 4 -— (4-fluorophenylthio) methyl] Piberidine and pale yellow oil of 4-benzyloxy-1-t—butoxycarbonyl-1-yl 4 -— ((4-fluorophenylsulfinyl) methyl Thus, piperidine (0.651 g, 48%) was obtained.

 MS (CI +): 448 (M + 1).

(R) —Prepared from phenylmethylsulfoxide (R) —1—t —Butoxycarbonyl 1-4—Methoxy-4 — [(phenylsulfinyl) methyl] piperidine (1.37 g, 3.88 mm 01) is treated with trifluoroacetic acid and treated with (R ) —4-Methoxy 4-([phenylsulfenyl) methyl] piperidine was obtained. From the obtained (R) —4—methoxy-4 -— [(phenylsulfinyl) methyl] piperidine, by the same method as in Example 15, (R) —1— [2- (Benzothiophen-3-yl) ethyl-14-methoxy-14-[(phenylsulfinyl) methyl] piperidine (0.555 g, 35%) was obtained.

[a] _D ²⁴ + 108 (c = 0.49, EtOH) (99.8% ee) Example 1 5 6

(S)-(1-)-t-butoxycarbonyl-14-methoxy-14-[(phenylsulfinyl) methyl] piperidine prepared from (S) -phenylmethylsulfoxide (3. 0.5 g, 8.63 mm 0 1) was treated with trifluoroacetic acid to obtain (S) —4-methoxy-14-[(phenylsulfiel) methyl] piperidine. Was. From the obtained (S) -4-methoxy-14-[(phenylsulfinyl) methyl] piperidine, a pale orange yellow needle-like (S) was obtained in the same manner as in Example 15. — 1 — [2— (Benzochifen 1—3 yl) Ethyl 1—Methoxy

4 -— [(phenylsulfinyl) methyl] piperidine (1.70 g,

5 2 "%). Example 1 5 7

(+) — 4—Fluorophenylmethylsulfoxide prepared from 1—t—Butoxycarbonyl-14 — [(4—Fluorophenylsulfinyl) methyl] —4—Methoxypiperidine (705 mg, 1.90 mm 01) was treated with trifluoroacetic acid to obtain 4-[(4-fluorophenylsulfinyl) methyl] -14-methoxypiperidine. From the obtained 4-[(4-fluorophenylsulfinyl) methyl] -14-methoxypiperidine, in the same manner as in Example 31, (+) — 4— [(4-Fluorophenylsulfinyl) methyl] -4- (methoxy-1-)-(2-phenylethyl) piperidine (528 mg, 74%) was obtained.

^{[] ,, 22 +117 (c =} 0A, CHC1 3) (95% ee) Example 1 5 8

(1) 1-t-butoxycarbonyl 1-[(4-fluorophenylsulfinyl) methyl] 4- 4-methoxypiperidine prepared from 14-fluorophenylmethylsulfoxide (1.98 g, 5.3

3mmo1) was treated with trifluoroacetic acid to obtain 4-[(4-fluorophenylsulfinyl) methyl] -4-4-methoxypiperidine. The resulting 4 — [(4-fluorophenylsulfinyl) methyl] ―

In the same manner as in Example 31 from 4-methoxypiperidine, colorless plate-like (1)-4-[(4-fluorophenylsulfinyl) methyl] 1-4-methoxy-1 1 — (2-Phenylethyl) bipyridine (0537 g, 27%) was obtained.

^{_{[] D 22 - 111 (c}} = 0.39, CHC1 3) (92 ¾ee) Industrial Applicability

 The compounds of the present invention and salts thereof have excellent antagonistic activity against tachykinin receptors, have low toxicity, and are safe as pharmaceuticals. Therefore, 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. is there.

Claims

Range of blue seeking

1. The following general formula (1)

R 1 (3 ー @ ("

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C! To ^; X is a hydrogen atom hydroxy group or an alkoxy group of C, to C ₆ ; Y is an alkylene group or an alkenyl alkylene group of C! CA) (It may have an alkyl group of c ₁ to c ₃ ), Ring A contains one nitrogen atom, and may be cross-linked at any position via 1 to 3 carbon atoms. , A 6- or 7-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 n represents 1 or 2.) or a salt, hydrate or solvate thereof.

2. A ring is piperidine ring,

A ring B is a halogen atom, an optionally substituted C, -C _fi alkyl group. An optionally substituted aryl group, a hydroxyl group, an optionally substituted 〇,-(alkoxy group of 6. A homo- or heterocyclic ring optionally having 1 to 3 substituents, each independently selected from an amino group, a cyano group or a nitro group,

Ring C is a halogen atom, optionally substituted C, to (: alkyl group of ₆ . Independently selected from an optionally substituted aryl group, a hydroxyl group, an 'optionally substituted CtCs alkoxy group, an amino group, a cyano group and a nitro group The cyclic amine derivative or a salt, hydrate and a cyclic amine derivative thereof according to claim 1, which represents a homo- or heterocyclic ring (excluding an indole ring) which may have 1 to 3 substituents. Solvate.

3. The cyclic amine derivative or a salt, hydrate and 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 and solvate thereof according to claim 1, wherein the ring A represents a piperidine ring and the ring C represents an indene ring which may have a substituent. object.

5. The cyclic amine derivative or a salt, hydrate and 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. object.

6. The cyclic amine derivative or a salt, hydrate and solvate thereof according to claim 1, wherein ring A represents a piberidine ring and ring C represents a benzothiophene ring which may have a substituent. object.

7. The following general formula (2) ) A

 c

X) ⁿ

 : S

(In the formula, R ¹ is a hydrogen atom or a Ct-C ₆ alkyl group, X is a hydrogen atom hydroxy group, or an alkoxy group of, and the A ring is cross-linked at any position including one nitrogen atom. A 5-, 6- or 7-membered cyclic amine which may be substituted, a ring B being a homo- or heterocyclic ring which may have a substituent, and n

Indicates 1 or 2. ) And the compound represented by

The following general formula (3)

Y

One Z (3)

(Where Y is an alkylene or alkenylalkylene group of C!

(May have a C! Ca alkyl group), Z is a reactive residue, and C ring is a homo- or heterocyclic ring which may have a substituent (however, an indole ring Excluding). 2. The method for producing a cyclic amine derivative according to claim 1, wherein the compound represented by the formula is reacted in the presence of a base.

8. The following general formula (1)

(In the formula, R ¹ is a hydrogen atom or a C t Ce alkyl group, X is a hydrogen atom hydroxy group, or a C 1 to C ₄ alkoxy group, and Y is a C 1 to C ₄ alkylene group or an alkenylalkylene group. (The ring A may have a C 3 to C 3 alkyl group), and the ring A may be bridged at any position including one nitrogen atom, and may be a 5-, 6- or 7-membered cyclic amine. Ring B is a homo- or heterocyclic ring which may have a substituent, ring C is a homo- or hetero ring which may have a substituent (excluding an indole ring), and n is Or 1 or 2.) A kinkinin receptor antagonist comprising a cyclic amine derivative represented by the formula: or a salt, hydrate and solvate thereof as a pharmaceutical composition.

9 · General formula (1)

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C, to C ₆ , X is a hydrogen atom of a hydroxyl group, or an alkoxy group of C, to C, Y is a C! To C ₄ alkylene group or alkenyl Alkylene group (C t to C alkyl group Ring A may be bridged at any position containing one nitrogen atom, and may be a 5-, 6- or 7-membered cyclic amine, and ring B may have a substituent. An optionally substituted homo- or heterocyclic ring, the ring C represents an optionally-substituted allo- or heterocyclic ring (excluding an indole ring), and n represents 1 or 2. A neurokinin A receptor antagonist comprising a cyclic amine derivative represented by the formula or a salt, hydrate and solvate thereof as a pharmaceutical composition.

10. The following general formula (1)

(Wherein, R 'is a hydrogen atom or a C! Alkyl ~ C _6, X is a hydrogen atom arsenide Dorokishi group, or a C i to alkoxy groups of C _6, Y is § alkylene group or alkenyl C ₁ ~ C ₄ An alkylene group (which may have a C i C g alkyl group), ring A may be bridged at any position containing one nitrogen atom, a 5-, 6- or 7-membered ring Rings of amine and B are homo- or heterocyclic rings which may have a substituent, and ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring) And n represent 1 or 2. The substance P and the neuron, which contain the cyclic amine derivative represented by the formula or a salt, hydrate and solvate thereof as a pharmaceutical composition. Kinin A receptor antagonist.

1 1. The following general formula (1)

R.

(In the formula, R ¹ is a hydrogen atom or a C ^{1 to} C ₆ alkyl group, X is a hydrogen atom hydroxy group, or a C 1 to C ₆ alkoxy group, Y is a C t C alkylene group or an alkenylalkylene. Ring A), ring A may be bridged at any position containing one nitrogen atom, and may be a 5-, 6- or 7-membered cyclic amine, ring B Is an optionally substituted homo- or heterocyclic ring, C is an optionally substituted homo- or heterocyclic ring (excluding an indole ring), and n is 1 or 2. Show. ) Including urinary frequency including urinary frequency, urinary incontinence, and other bladder dysfunction characterized by containing a cyclic amine derivative or a salt, hydrate and solvate thereof represented by the formula (1) as a pharmaceutical composition. Agent for preventing or treating disorders.

1 2. The following general formula (1)

(CVY-N A C I ®

 x

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C, to C ₆ , X is a hydrogen atom, a hydroxy group, or an alkoxy group of C: to _{Cί ;} , and Υ is an alkylene group of C i to C 4. Or an alkenylalkylene group (C! ~ C _:! Ring A may be bridged at any position including one nitrogen atom, and may be a 5-, 6- or 7-membered cyclic amine, and ring B may have a substituent. An optionally substituted homo- or heterocyclic ring, the ring C represents an optionally-substituted allo- or heterocyclic ring (excluding an indole ring), and n represents 1 or 2. ) Or a salt, hydrate or solvate thereof as a pharmaceutical composition, for preventing gastrointestinal diseases including ulcerative colitis and Crohn's disease; Therapeutic agent.

1 3. The following general formula (1)

C, / ~ S— B

 θ- Υ -Ν A C

 X

(Wherein, R ¹ is a hydrogen atom or a C ¹ to C ₆ alkyl group, X is a hydrogen atom hydroxy group, or a C 1 to C ₆ alkoxy group, and Y is a C t C alkylene group or alkenylalkylene group. (It may have a C! Cg alkyl group.) Ring A may be bridged at any position containing one nitrogen atom. 5-, 6- or 7-membered cyclic amino Ring B is a homo- or heterocyclic ring which may have a substituent, ring C is a homo- or hetero ring which may have a substituent (excluding an indole ring), and n is X-irradiation, chemotherapeutic agent, pregnancy characterized by containing a cyclic amine derivative represented by or a salt, hydrate and solvate thereof as a pharmaceutical composition An agent for preventing or treating vomiting induced by migraine, postoperative illness, decreased gastrointestinal motility or side effects of drug administration.

1 4. The following general formula (1)

R

R

OM S— @

 (Ch-Y-N A C

 ^ X

(Wherein, R ¹ is a hydrogen atom or a C ¹ to C ₆ alkyl group, X is a hydrogen atom hydroxy group, or a C t to C ₆ alkoxy group, and Y is a C 1 to C ₄ alkylene group or alkenyl. An alkylene group (which may have a C! Cs alkyl group) and a ring A which may be bridged at any position including one nitrogen atom, a 5-, 6- or 7-membered ring Amine and ring B are homo- or heterocyclic rings which may have a substituent, ring C is a homo- or heterocyclic ring which may have a substituent (however, excluding an indole ring), n Represents 1 or 2.) An anxiety, depression, Parkinson's disease, characterized by containing a cyclic amine derivative represented by the 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.

1 5. The following general formula (1)

(CVY-N AC (Wherein, R ¹ is a hydrogen atom or a C! Ce alkyl group, 'X is a hydrogen atom hydroxy group, or a C i -C ₆ alkoxy group, and Y is a C t C alkylene group or an alkenylalkylene group. (C! may have an alkyl group ~ C _3), a ring any 5-membered also be cross-linking at a position containing a single nitrogen atom, 6-membered or 7-membered cyclic amino Ring B is a homo- or heterocyclic ring which may have a substituent, ring C is a homo- or hetero ring which may have a substituent (excluding an indole ring), and n is Or 1 or 2.) A cyclic amine derivative represented by the formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition, characterized by containing tachykinin-related asthma, cough, Remedy for pain, migraine, toothache, rheumatoid arthritis, etc.

1 6. The following general formula (4)

( ⁴ )

(Wherein, R ¹ is a hydrogen atom or a C ¹ to C ₆ alkyl group, R ³ is an optionally substituted C i to C ₆ alkyl group or an optionally substituted benzyl group, Y is C alkylene group or alkenyl Al sharp emission group i~ C ₄ (C i~ may have an alkyl group of C _3), a ring contains one nitrogen atom, via a 1-3 carbon atoms 5-, 6-, or 7-membered cyclic amine which may be cross-linked at any position, ring B may be a homo- or heterocyclic ring which may have a substituent, and ring C may have a substituent A ring represented by a homo- or heterocyclic ring (excluding an indole ring) Amide derivatives or salts, hydrates and solvates thereof.

1 7. A ring is a pyridin ring,

 A halogen atom in the ring B, an optionally substituted C i C e alkyl group; an optionally substituted aryl group, a hydroxyl group, an optionally substituted C i C f; alkoxy group, A homo- or heterocyclic ring (excluding an indole ring), which may have 1 to 3 substituents, each independently selected from the group consisting of a hetero group, a cyano group and a nitro group; The cyclic amine derivative according to claim 16, or a salt, hydrate or solvate thereof.

18. The cyclic amine derivative or a salt, hydrate and solvate thereof according to claim 16, wherein the ring A represents a piperidine ring and the ring C represents a benzene ring which may have a substituent. object.

19. The cyclic amine derivative or the salt, hydrate and solvent thereof according to claim 16, wherein the ring A represents a piperidine ring and the ring C represents a benzofuran ring which may have a substituent. Japanese food.

20. The cyclic amine derivative according to claim 16 or a salt, hydrate and a cyclic amine derivative thereof wherein the ring A represents a piperidine ring and the ring C represents a benzothiophene ring which may have a substituent. Solvate.

2 1. The following general formula (5) (Five)

(Wherein, R ¹ is a hydrogen atom or a C ¹ to C ₆ alkyl group, R ³ is an optionally substituted C ₁ to C _{1 ;} 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, ring A contains one nitrogen atom, and may be cross-linked at any position via 1 to 3 carbon atoms. Shows a 6- or 7-membered cyclic amine.

2 2. The following general formula (5)

 R,

 (Five)

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C, to C ₆ , R ³ is an optionally substituted 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, ring A contains one nitrogen atom and may be cross-linked at any position via 1 to 3 carbon atoms. A cyclic amine is shown.) The following general formula (6)

(In the formula, ring B represents an optionally substituted homo- or heterocyclic ring.) By reacting a compound represented by the formula

The following general formula (Ί)

R

R ⁴ 00C-NAC _,

No OR ³

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C t to C ′, R ³ is an optionally substituted C, to C ₆ alkyl group or an optionally substituted benzyl group, and R ⁴ is t-Butyl or benzyl group, Ring A contains one nitrogen atom, and may be cross-linked at any position via 1 to 3 carbon atoms. 5-, 6- or 7-membered ring And a ring B or a homocyclic or heterocyclic ring which may have a substituent.).

2 3. The following general formula (7)

(In the formula, R ¹ is a hydrogen atom or a C! Cs alkyl group, R ³ is an optionally substituted C alkyl group or an optionally substituted benzyl group, R ⁴ is a t-butyl group or Benzyl group, ring A contains one nitrogen atom and may be cross-linked at any position via 1-3 carbon atoms, 5-, 6- or 7-membered cyclic amine, B The ring represents an allo- or heterocyclic ring which may have a substituent.) By oxidizing a compound represented by

The following general formula (8)

'

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C! To ( ₆ , R ³ is an optionally substituted C ₁ to C ₆ alkyl group or an optionally substituted benzyl group, and R ⁴ is t-Butyl or benzyl group, Ring A contains one nitrogen atom, and may be cross-linked at any position via 1 to 3 carbon atoms. 5-, 6- or 7-membered ring And a ring B or a homo- or heterocyclic ring which may have a substituent, and m represents 1 or 2.)

2 4. The following general formula (4)

(Four)

© -Y-

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C, to C ₆ , R ³ is an optionally substituted C i C f; alkyl group or an optionally substituted benzyl group, and Y is C ! ~ alkylene group or alkenyl Al sharp emission group C ₄ (C! may have an alkyl group of - C _3), a ring contains one nitrogen atom, via three 1 carbon atoms 5-, 6-, or 7-membered cyclic amine which may be cross-linked at any position, ring B may be a homo- or heterocyclic ring which may have a substituent, and ring C may have a substituent. A cyclic amide derivative represented by an allo- or heterocyclic ring (excluding an indole ring)) or a salt, hydrate and solvate thereof may be used as a pharmaceutical composition. A tachykinin receptor antagonist characterized by containing.

2 5. The following general formula (4)

{ ^V

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C, C ₆ , and R ³ is an optionally substituted alkyl group or an optionally substituted alkyl group. Benzyl group, Y For c, alkylene group or alkenyl Al sharp emission group ~ c ₄ (C ₁ may have an alkyl group ~ C), A ring contains one nitrogen atom, carbon atom 1 A 5-, 6- or 7-membered cyclic amine which may be cross-linked at any position through 3 to 3, a ring B is a homo- or heterocyclic ring which may have a substituent, a ring C Represents a cyclic amide derivative represented by an allo- or heterocyclic ring (optionally excluding an indole ring) which may have a substituent, or a salt, hydrate or solvate thereof, in a pharmaceutical composition A neurokinin A receptor antagonist characterized by containing:

26. The following general formula (4)

Y-N A C '. (

\ ノ OR ³

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C! To C ₆ , R ³ is an optionally substituted C 1 to C ₆ alkyl group or an optionally substituted benzyl group, and Y is C _{A 1} to C ₄ alkylene group or alkenyl alkylene group (which may have a C 1 to C 3 alkyl group), ring A contains one nitrogen atom, and has 1 to 3 carbon atoms. 5-, 6-, or 7-membered cyclic amine which may be crosslinked at any position, ring B may be a homo- or heterocyclic ring which may have a substituent, and ring C may have a substituent. A cyclic amide derivative represented by an allo- or heterocyclic ring (excluding an indole ring)) or a salt, hydrate or solvate thereof as a pharmaceutical composition A substance P and neurokinin A receptor antagonist, characterized in that:

2 7. The following general formula (4

R

C S— (B) / ₄ )

 ©-Y-N A C. Re

 No 0R.

(Wherein, R ¹ is a hydrogen atom or an alkyl group of C; to C ₆ , R ³ is an optionally substituted C t to C alkyl group or an optionally substituted benzyl group, and Y is (, An alkylene group or an alkenylalkylene group (which may have an alkyl group of C i C ^), the ring A contains one nitrogen atom, and is optionally bonded through 1 to 3 carbon atoms. A 5-, 6- or 7-membered cyclic amide which may be cross-linked at the position, ring B may be a homo- or heterocyclic ring which may have a substituent, and ring C may have a substituent. It is characterized by containing as a pharmaceutical composition a cyclic amide derivative represented by allo- or heterocyclic ring (excluding indole ring)) or a salt, hydrate and solvate thereof. For preventing or treating dysuria including urinary frequency, urinary incontinence and other bladder dysfunctions.

2 8. The following general formula (4)

R ¹

 >-S- {B) (4)

OR ³ (Wherein, R is a hydrogen atom or an alkyl group of C! To Cκ, R ³ is an optionally substituted C i C e; alkyl group or an optionally substituted benzyl group, and Y is C alkylene group or alkenyl Al sharp emission group t~ C ₄ (C i may have an alkyl group of C _3), a ring contains one nitrogen atom, via 1 to 3 carbon atoms 5-membered, 6-membered or 7-membered cyclic amide which may be crosslinked at any position, ring B may be a homo- or heterocyclic ring which may have a substituent, ring C may have a substituent A cyclic amide derivative represented by an allo- or heterocyclic ring (excluding indole ring) which may be present, or a salt, hydrate or solvate thereof, may be contained as a pharmaceutical composition. A preventive or therapeutic agent for digestive diseases including ulcerative colitis and Crohn's disease, characterized by the following.

2 9. The following general formula (4)

(In the formula, R ¹ is a hydrogen atom or an alkyl group of C! To C _fi , R ³ is an _optionally substituted C t Ce alkyl group or an optionally substituted benzyl group, and Y is C! An alkylene group or an alkenylalkylene group (which may have a C ₁ to C ₃ alkyl group), the ring A contains one nitrogen atom, and can be any group through 1 to 3 carbon atoms. A 5-, 6- or 7-membered cyclic amide which may be cross-linked at the position, ring B may be a homo- or heterocyclic ring which may have a substituent, and ring C may have a substituent. Cyclic represented by allo- or heterocyclic ring (however, excluding indole ring) X-ray irradiation, chemotherapeutic agents, pregnancy, migraine, postoperative disease, decreased gastrointestinal motility characterized by containing an amide derivative or a salt, hydrate and solvate thereof as a pharmaceutical composition. Or a prophylactic or therapeutic agent for vomiting induced by side effects of drug administration.

30. The following general formula (4)

(Wherein, R ¹ is a hydrogen atom or a C i -C ₆ alkyl group, R ³ is an optionally substituted C i -C ₆ alkyl group or an optionally substituted benzyl group, and Y is C _A C ₁ to C ₄ alkylene group or alkenyl alkylene group (which may have a C ₁ to C ₃ alkyl group), the ring A contains one nitrogen atom, and has 1 to 3 carbon atoms; 5-, 6-, or 7-membered cyclic amine which may be cross-linked at any position, ring B may be a homo- or heterocyclic ring which may have a substituent, and ring C may have a substituent. A cyclic amide derivative represented by an allo- or heterocyclic ring (excluding indole ring)) or a salt, hydrate or solvate thereof may be contained as a pharmaceutical composition. A preventive or therapeutic agent for central nervous system diseases including anxiety, depression, Parkinson's disease, Huntington's disease, dementia, etc.

3 1. The following general formula (4)

(Wherein, R ¹ is a hydrogen atom or a C i Cs alkyl group, R ³ is an optionally substituted C t -C ₆ alkyl group or an optionally substituted benzyl group, and γ is ctc ^ the alkylene down group or alkenyl Al sharp emission group (which may have an alkyl group of ci~ c _3), a ring contains one nitrogen atom, any position via 1 to 3 carbon atoms A 5-, 6- or 7-membered cyclic amide, a ring B may be a homo- or heterocyclic ring which may have a substituent, and a ring C may have a substituent It is characterized in that it contains a cyclic amide derivative represented by a good homo- or heterocyclic ring (excluding an indole ring)) or a salt, hydrate or solvate thereof as a pharmaceutical composition. An agent for improving asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc. in which tachykinin is involved.