JPH05345772A - New heterocyclic compound - Google Patents

Abstract

PURPOSE:To obtain a new compound having strong acetylcholine esterase inhibiting activity and useful for prevention and treatment for diseases of central nervous system such as amnesia or dementia. CONSTITUTION:The compound of the formula M-W-Y-A-Q {M is formula I (R<1> is H, lower alkyl, aryl, etc.; R<2> is H, lower alkyl, aryl, etc.); W is bond, lower alkylene or lower alkenylene: Y is lower alkylene, NH, C(=O), formula II (R<3> is H or lower alkyl), etc.; A is bond or lower alkylene; Q IS formula III [R<8> is lower alkyl; R<9> is al(lower)alkyl], etc.}, e.g. 4,5-diphenyl-2-[{2-(1- benzylpiperidin-4-yl)ethyl}carbamoyl]thiazole. The compound of formula I is obtained by reacting, e.g. a compound of the formula M-W-COOH with a compound of formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel heterocyclic compound having an acetylcholinesterase inhibitory action and is used in the medical field.

[0002]

Many acetylcholinesterase inhibitors are known, but the heterocyclic compound represented by the following general formula (I) of the present invention is not known.

[0003]

Although an acetylcholinesterase inhibitor is known, this invention was made with the intention of developing a further excellent drug.

[0004]

The present invention relates to a novel heterocyclic compound and a pharmaceutically acceptable salt thereof. More specifically, the present invention is an acetylcholinesterase inhibitor,
Therefore, the present invention relates to a novel heterocyclic compound useful for the prevention and treatment of central nervous system diseases such as amnesia, dementia (eg, senile dementia of Alzheimer's type, vascular dementia, and cerebrovascular disorder) and a pharmaceutically acceptable salt thereof. The heterocyclic compound aimed at by the present invention is novel and represented by the following general formula: M-WYAQ (I) [wherein M is a formula:

[Chemical 10] (In the formula, R ¹ represents hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or aryl which may have a suitable substituent, and R ² represents hydrogen, a lower alkyl group. Represents an alkyl, a heterocyclic group which may have a suitable substituent, or an aryl which may have a suitable substituent, or
Alternatively, R ¹ and R ² are bonded to each other to form the formula:

[Chemical 11] And Z represents S or O respectively),

Formula:

[Chemical formula 12] Wherein R ¹ and R ² are each as defined above, or a formula:

[Chemical 13] (Wherein R ¹ and R ² are each as defined above), W is a bond, lower alkylene or lower alkenylene, Y is lower alkylene,

[Chemical 14] formula:

[Chemical 15] (Wherein R ³ represents hydrogen or lower alkyl) or a group:

[Chemical 16] (Wherein R ⁷ represents hydroxy or protected hydroxy), A is a bond or lower alkylene, and Q is of the formula:

[Chemical 17] Wherein R ⁸ represents lower alkyl and R ⁹ represents ar (lower) alkyl, or a group of the formula:

[Chemical 18] (Wherein R ⁴ represents lower alkyl or ar (lower) alkyl which may have a suitable substituent).] The object compound (I) of the present invention can be prepared by the following methods. Can be manufactured by

Manufacturing method (1)

[Chemical 19]

Manufacturing method (2)

[Chemical 20]

Manufacturing method (3)

[Chemical 21]

Manufacturing method (4)

[Chemical formula 22]

Manufacturing method (5)

[Chemical formula 23]

Manufacturing method (6)

[Chemical formula 24] In the above formula, R ¹ , R ² , R ³ , M, W, A, Q, and Y are as defined above, R ³ _a is lower alkyl, and X ¹ and X ² are acid residues. A group, W ¹ is a bond, C
The ₁ -C ₅ alkylene or C ₂ -C ₅ alkenylene,
R ⁷ _a represents protected hydroxy. The starting compounds or their salts can be prepared by the following methods.

Manufacturing method (A)

[Chemical 25]

Manufacturing method (B)

[Chemical formula 26]

Manufacturing method (C)

[Chemical 27]

Manufacturing method (D)

[Chemical 28]

Manufacturing method (E)

[Chemical 29]

Manufacturing method (F)

[Chemical 30]

Manufacturing method (G)

[Chemical 31]

Manufacturing method (H)

[Chemical 32]

Production method (I)

[Chemical 33] In the above formula, R ¹ , R ² , M, W, W ¹ , Z, Y, A, Q
And X ² are each as defined above, R ⁵ is carboxy or protected carboxy, R ⁶ is lower alkyl, R ¹⁰ is lower alkoxy, R ¹¹ is lower alkyl, W ² is a bond, C ₁ -C ₄ alkylene or C ₂ -C
₄ alkenylene, X ³ and X ⁴ each represent an acid residue.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts such as salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt etc.), Alkaline earth metal salts (eg calcium salt, magnesium salt etc.), ammonium salts; salts with organic bases, eg organic base salts (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine) Salt, N, N′-dibenzylethylenediamine salt, etc.); inorganic acid addition salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic acid or sulfonic acid addition salt (eg, formate, Acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzene It may include salts with bases or acid addition salts, such as salts with basic or acidic amino acids (eg arginine, aspartic acid, glutamic acid, etc.). In the above and subsequent description of the present specification, suitable examples and specific examples of various definitions that the present invention includes within the scope thereof will be described in detail below. The term "lower" is used to mean a group having 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise specified.

Suitable "lower alkyl" as well as preferred lower alkyl moieties in the term "ar (lower) alkyl" include methyl, ethyl, propyl, isopropyl,
Examples thereof include butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, and the like, which have 1 to 6 carbon atoms and which are linear or branched, preferably carbon. It has 1 to 4 atoms. Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, tertiary pentoxy, hexyloxy and the like having 1 to 6 carbon atoms. The straight-chain or branched-chain type of. Suitable "heterocyclic group" means a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as oxygen atom, sulfur atom and nitrogen atom. More preferred heterocyclic groups include the following heterocyclic groups: 3- to 8-membered unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, Pyridyl and its N-oxide, dihydropyridyl, tetrahydropyridyl, pyrimidyl,
Pyrazinyl, pyridazinyl, triazolyl (eg 4
H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),
Tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl etc.), dihydrotriazinyl (eg 4,5-dihydro-1,2,4-triazinyl, 2,5
-Dihydro-1,2,4-triazinyl etc.) and the like;

3- to 8-membered saturated heterocyclic groups containing 1 to 4 nitrogen atoms, such as azetidinyl, pyrrolidinyl,
Imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl and the like; fused unsaturated heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, Tetrazolopyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc .; 1-2 oxygen atoms and 1-3
A 3- to 8-membered unsaturated heterocyclic group containing 1 nitrogen atom, such as oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1,
3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); a 3- to 8-membered saturated heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl;

Fused unsaturated heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as benzoxazolyl, benzooxadiazolyl, etc .; 1-2 sulfur atoms and 1 A 3- to 8-membered unsaturated heterocyclic group containing 3 to 3 nitrogen atoms, for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,3). 4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc .; a 3-8 membered saturated heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, For example, thiazolidinyl, etc .; 3- to 8-membered unsaturated heterocyclic group containing one sulfur atom, for example, thienyl, etc .; condensed unsaturated heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. , For example Ben Thiazolyl, such as benzothiadiazolyl, etc.. Suitable "lower alkylene" includes straight chain or branched chain having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene and propylene. Examples thereof include C _{1 to} C ₄ alkylene.

Suitable "lower alkenylene" is vinylene, propenylene, 1- (or 2-) butenylene, 1- (or 2-or 3-) pentenylene, 1-.
(Or 2- or 3-) hexenylene, methylvinylene, ethylvinylene, 1- (or 2- or 3-) methylpropenylene, 1- (or 2- or 3-) ethylpropenylene, 1- (or 2- Or 3-or 4
-), such as methyl-1- (or 2-) butenylene, it includes those having 2 to 6 carbon atoms of straight or branched, include C ₂ -C ₄ alkenylene More preferred examples . Suitable "aryl" as well as suitable "aryl moieties" in the term "ar (lower) alkyl" include phenyl, naphthyl and the like, more preferred examples include phenyl. Suitable "protected carboxy" includes esterified carboxy and the like.

Suitable examples of esterified carboxy ester moieties include lower alkyl esters (eg methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, Hexyl ester, etc.), lower alkyl ester having at least one suitable substituent, eg lower alkanoyloxy lower alkyl ester [eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, Valoyloxymethyl ester, hexanoyloxymethyl ester, 1- (or 2-)
Acetoxyethyl ester, 1- (or 2- or 3
-) Acetoxypropyl ester, 1- (or 2- or 3- or 4-) acetoxybutyl ester, 1-
(Or 2-) propionylethyl ester, 1- (or 2-or 3-) propionyloxypropyl ester, 1- (or 2-) butyryloxyethyl ester, 1- (or 2-) isobutyryloxyethyl ester , 1- (or 2-) pivaloyloxyethyl ester, 1- (or 2-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyrate Ryloxymethyl ester, 1- (or 2-) pentanoyloxyethyl ester, etc.], lower alkanesulfonyl lower alkyl ester (eg, 2-mesylethyl ester), mono (or di or tri) halo lower alkyl ester (eg, 2 -Iodoethyl ester, 2,2,2 Such as trichloroethyl ester),
Lower alkoxycarbonyloxy lower alkyl ester [eg methoxycarbonyloxymethyl ester,
Ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1- (or 2-) methoxycarbonyloxyethyl ester, 1- (or 2
-) Ethoxycarbonyloxyethyl ester, 1-
(Or 2-) isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene (lower) alkyl ester, or (5-lower alkyl-2-oxo-1,
3-Dioxol-4-yl) (lower) alkyl ester [eg (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-
2-oxo-1,3-dioxol-4-yl) methyl ester; lower alkenyl ester (eg vinyl ester, allyl ester etc.); lower alkynyl ester (eg ethynyl ester, propynyl ester etc.); at least one suitable substitution Al (lower) alkyl ester which may have a group (for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3 , 4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); Aryl ester optionally having at least one suitable substituent (eg, phenyl ester, 4-chloro) Eniruesuteru, tolyl ester, t- butyl phenyl ester, xylyl ester,
Mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.

Suitable "acid residues" include halogen (eg chlorine, bromine, iodine or fluorine); acyloxy such as alkanoyloxy (eg acetoxy), lower alkanesulfonyloxy (eg methanesulfonyloxy) and the like. , Preferred is halogen. Suitable "protected hydroxy" includes acyloxy; conventional protection such as phenyl lower alkyl optionally having one or more appropriate substituents (eg, benzyl, 4-methoxybenzyl, etc.), tetrahydropyranyl, etc. Included are hydroxy substituted with groups. Suitable “acyl moiety” in the expression “acyloxy” is
Examples include carbamoyl, aliphatic acyl groups, and acyl groups containing an aromatic or heterocyclic ring. Suitable examples of the acyl include lower alkanoyl (eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl etc.); lower alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso Propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like); lower alkanesulfonyl (eg mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,
Butanesulfonyl, etc.); allylsulfonyl (eg, phenylsulfonyl, tosyl, etc.); aroyl (eg, benzoyl, toluoyl, xyloyl, naphthoyl,
Phthaloyl, indanecarbonyl, etc.); al (lower)
Examples thereof include alkanoyl (eg, phenylacetyl, phenylpropionyl, etc.); ar (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like.

Suitable "C ₁ -C ₅ alkylene" includes straight chain or branched chain such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, methylmethylene, ethylethylene and propylene. .. Suitable "C ₁ -C ₄ alkylene" includes:
Methylene, ethylene, trimethylene, tetramethylene,
Examples thereof include linear or branched ones such as ethylethylene and propylene. Suitable "C ₂ -C ₅ alkenylene", vinylene, propenylene, 1- (or 2-) butenylene, 1- (or 2- or 3-) pentenylene, methylvinylene, ethylvinylene, 1- (or 2- Or 3-) methylpropenylene, 1- (or 2-or 3-) ethylpropenylene, 1- (or 2-or 3-or 4-) methyl-1- (or 2
-) Linear or branched ones such as butenylene can be mentioned. Suitable “C ₂ -C ₄ alkenylene” includes linear chain such as vinylene, propenylene, 1- (or 2-) butenylene, methylvinylene, ethylvinylene, 1- (or 2- or 3-) methylpropenylene. Alternatively, a branched chain one may be mentioned.

Suitable "substituents" in the expression "aryl optionally having suitable substituents" include lower alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl). , Pentyl, neopentyl, tertiary pentyl, hexyl, etc.), lower alkoxy (eg methoxy, ethoxy, propoxy,
Isopropoxy, isobutoxy, tertiary butoxy, pentyloxy, neopentyloxy, tertiary pentyloxy, hexyloxy, etc., lower alkenyl (for example, vinyl, 1-propenyl, allyl, 1-methylallyl,
1- or 2- or 3-butenyl, 1- or 2- or 3- or 4-pentenyl, 1- or 2- or 3- or 4- or 5-hexenyl, lower alkynyl (e.g. ethynyl, 1-propynyl) , Propargyl, 1-methylpropargyl, 1- or 2- or 3-butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3- or 4- or 5-hexynyl, etc.), mono (Or di or tri) halo lower alkyl (eg, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1- or 2-fluoroethyl, 1- Or 2-bromoethyl, 1- or 2-chloroethyl, 1, - difluoroethyl, 2,2-difluoroethyl, etc.), halogen (e.g. chlorine, bromine,
Fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy as described above, aryl (eg phenyl, naphthyl etc.), ar lower alkyl such as phenyl lower alkyl (eg benzyl, phenethyl, phenylpropyl etc.), Carboxy (lower) alkyl (the lower alkyl moiety may be the one exemplified above), protected carboxy (lower) alkyl (the lower alkyl moiety may be the one exemplified above, protected carboxy moiety May also be cited as exemplified above), nitro, amino, protected amino, di-lower alkylamino (eg dimethylamino,
Diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylisopropylamino etc.), hydroxy lower alkyl, protected hydroxy lower alkyl, acyl, cyano, mercapto, lower alkylthio (eg methylthio, ethylthio, propylthio, isopropylthio, butylthio) Etc.) and imino.

Suitable "protected amino" includes acylamino (the acyl moiety may be exemplified by those exemplified above) and the like. Suitable "substituent" in the expression "heterocyclic group optionally having substituent (s)" includes lower alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, Pentyl, neopentyl, tertiary pentyl, hexyl etc.), lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tertiary butoxy, pentyloxy, neopentyloxy, tertiary pentyloxy, hexyloxy etc.) , Lower alkenyl (eg vinyl, 1-propenyl, allyl, 1
-Methylallyl, 1- or 2- or 3-butenyl,
1-or 2-or 3-or 4-pentenyl, 1-
Or 2- or 3- or 4- or 5-hexenyl), lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1-
Or 2- or 3-butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3-
Or 4- or 5-hexynyl), mono (or di or tri) halo lower alkyl (eg fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl etc.), halogen (eg chlorine, bromine, Fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (eg phenyl, naphthyl etc.), ar lower alkyl such as phenyl lower alkyl (eg benzyl, phenethyl, phenylpropyl etc.), carboxy (lower ) Alkyl, protected carboxy (lower) alkyl, nitro, amino, protected amino, di (lower) alkylamino (eg dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isoprene) Pyrmethylamino, ethylisopropylamino etc.), hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, cyano, mercapto, lower alkylthio (eg methylthio, ethylthio, propylthio, isopropylthio, butylthio etc.), imino etc. Be done.

Suitable "substituent" in the expression "ar (lower) alkyl optionally having substituent (s)" includes lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc.), lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tertiary butoxy, pentyloxy, neopentyloxy, tertiary pentyloxy) , Hexyloxy, etc.), lower alkenyl (eg vinyl, 1-propenyl, allyl, 1
-Methylallyl, 1- or 2- or 3-butenyl,
1-or 2-or 3-or 4-pentenyl, 1-
Or 2- or 3- or 4- or 5-hexenyl), lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1-
Or 2- or 3-butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3-
Or 4- or 5-hexynyl), mono (or di or tri) halo lower alkyl (eg fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl etc.), halogen (eg chlorine, bromine, Fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (eg phenyl, naphthyl etc.), ar lower alkyl such as phenyl lower alkyl (eg benzyl, phenethyl, phenylpropyl etc.), carboxy (lower ) Alkyl, protected carboxy (lower) alkyl, nitro, amino, protected amino, di (lower) alkylamino (eg dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isoprene) Pyrmethylamino, ethylisopropylamino etc.), hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, cyano, mercapto, lower alkylthio (eg methylthio, ethylthio, propylthio, isopropylthio, butylthio etc.), imino etc. Be done. The method for producing the target compound and the starting compound will be described in detail below.

Process (1) Compound (Ia) or a salt thereof is prepared by reacting compound (IIa) or its reactive derivative at the carboxy group or a salt thereof with compound (III) or a reactive derivative thereof or a salt thereof. It can be manufactured. Suitable reactive derivatives of the compound (III) include a Schiff base type imine formed by the reaction of the compound (III) with a carbonyl compound such as an aldehyde or a ketone or an enamine type tautomer thereof, the compound (III) , Bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide [eg N- (trimethylsilyl) acetamide], silyl derivative formed by reaction with silyl compound such as bis (trimethylsilyl) urea, compound (III) and phosphorus trichloride or Examples include derivatives formed by the reaction with phosgene. Suitable reactive derivative at the carboxy group of the compound (IIa) includes acid halide, acid anhydride, active amide, active ester and the like. Suitable examples of these reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid,
Dibenzylphosphoric acid, halogenated phosphoric acid, etc., dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (eg methanesulfonic acid etc.), aliphatic carboxylic acid (eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentane) Acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), mixed acid anhydride with an acid such as aromatic carboxylic acid (eg, benzoic acid, etc.); symmetrical acid anhydride; imidazole, 4-substituted imidazole, dimethylpyrazole,
Triazoles, active amide with 1-hydroxy -1H- benzotriazole or tetrazole; active ester [e.g. methyl ester, ethyl ester, cyanomethyl ester, methoxymethyl ester, dimethyl imino-methyl ^{_{[(CH 3) 2 N +}} = CH-] Ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p- Cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.] or N-hi Proxy compound [e.g. N, N-dimethylhydroxylamine, 1-hydroxy-2 (1
H) -pyridone, N-hydroxysuccinimide, N-
Hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and the like] and the like.
These reactive derivatives may be appropriately selected depending on the type of compound (IIa) used.

The reaction is usually carried out in a conventional solvent such as water,
Alcohol (eg methanol, ethanol, etc.),
It is carried out in acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, or any other organic solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when compound (IIa) is used in the form of a free acid or a salt thereof, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-
Cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N
-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide, N, N'-carbonylbis (2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1 -Alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, lower alkyl haloformates (eg ethyl chloroformate, chloroformate). Isopropyl formate), triphenylphosphine, 2
-Ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H -Reacting in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of benzotriazole, N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. Is preferred. When the starting compound is liquid, it can also be used as a solvent. The reaction is carried out using alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N
It can also be carried out in the presence of an inorganic or organic base such as lower alkylmorpholine or N, N-di (lower) alkylbenzylamine. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Production Method (2) Compound (Ic) or a salt thereof can be produced by reacting compound (Ib) or a salt thereof with compound (IV) or a salt thereof. The reaction is usually carried out in a conventional solvent such as alcohol (eg methanol, ethanol, ethylene glycol etc.), chloroform, ether, tetrahydrofuran, benzene, N, N-dimethylformamide, or any other organic solvent which does not adversely influence the reaction. Done in. The reaction temperature is not particularly limited, but usually,
The reaction is carried out under cooling or heating. The reaction is usually carried out by alkali metal hydroxide, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal acetate, tri (lower) alkylamine, alkali metal hydride, pyridine, lutidine,
It is carried out in the presence of an inorganic or organic base such as picoline, dimethylaminopyridine, N-lower alkylmorpholine, N, N-di (lower) alkylbenzylamine, N, N-di (lower) alkylaniline. When the base and / or the starting compound are liquid, they can also be used as a solvent.

Production Method (3) Compound (Id) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (VIII) or a salt thereof. The reaction is usually an alcohol (eg, methanol, ethanol, etc.), benzene, N, N
It is carried out in a solvent such as dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under heating or heating.

Process (4) Compound (Ie) or a salt thereof is prepared by reacting compound (IX) or a salt thereof with compound (IIIa) or a salt thereof,
It can be produced by subjecting the resulting compound to a reduction reaction. This reduction is performed by a conventional method including chemical reduction and catalytic reduction. Suitable reducing agents to be used for the chemical reduction include hydrides (eg hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or metals (eg tin,
Zinc, iron, etc.) or metal compounds (eg, chromium chloride, chromium acetate, etc.) and organic or inorganic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.) It is a combination with. Suitable catalysts to be used for catalytic reduction include platinum catalysts (eg platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg sponge palladium, palladium black, palladium oxide). ,
Palladium on charcoal, colloidal palladium, palladium / barium sulfate, palladium / barium carbonate, etc., nickel catalysts (eg reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalysts (eg reduced cobalt, Raney cobalt etc.), iron catalysts (eg reduction) iron,
Raney iron, etc.), copper catalysts (eg reduced copper, Raney copper,
Ullman copper etc.) and other conventional ones. The reaction is usually carried out in a solvent such as water, alcohol (eg, methanol, ethanol, etc.), N, N-dimethylformamide, tetrahydrofuran, a mixture thereof, or any other solvent which does not adversely influence the reaction. Further, when the acids to be used for the chemical reduction are liquid, they can be used as a solvent. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Production Method (5) The compound (Ig) or a salt thereof can be produced by subjecting the compound (If) or a salt thereof to a reaction for eliminating a hydroxy protecting group. Suitable methods of this elimination reaction include conventional methods such as hydrolysis and reduction. (I) In the case of hydrolysis: The hydrolysis is preferably carried out in the presence of a base or an acid including a Lewis acid. Suitable bases include alkali metals (eg sodium,
Potassium, etc.), alkaline earth metals (eg magnesium, calcium etc.), their hydroxides, carbonates or hydrogencarbonates, tri (lower) alkylamines (eg trimethylamine, triethylamine etc.), picoline, 1,5-diazabicyclo [4.3.0] Non-5-
Inorganic and organic bases such as ene are mentioned. Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride,
Hydrogen bromide). The elimination using a Lewis acid such as trihaloacetic acid (eg trichloroacetic acid, trifluoroacetic acid etc.) is preferably carried out in the presence of a cation trapping agent (eg anisole, phenol etc.). The reaction is usually carried out in a conventional solvent such as water, alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, etc. It is carried out in any other organic solvent that does not adversely influence the reaction. Of these solvents, the hydrophilic solvent may be used as a mixture with water. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. (Ii) In the case of reduction: Reduction is performed by a conventional method including chemical reduction and catalytic reduction. Suitable reducing agents to be used for chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid, propionic acid,
Trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts to be used for catalytic reduction include platinum catalysts (eg platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg sponge palladium, palladium black, palladium oxide). , Palladium charcoal, colloidal palladium, palladium / barium sulfate, palladium / barium carbonate, etc.), nickel catalysts (eg reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalysts (eg reduced cobalt, Raney cobalt etc.), copper catalysts (eg Reduced copper, Raney copper, Ullmann copper, etc.), iron catalysts (eg, reduced iron, Raney iron, Ullmann iron, etc.) and the like. This reduction is usually
Water, methanol, ethanol, propanol, N, N-
It is carried out in a conventional solvent which does not adversely influence the reaction, such as dimethylformamide, diethyl ether, dioxane, tetrahydrofuran and a mixture thereof. Furthermore, when the acid to be used for the chemical reduction is liquid,
They can also be used as solvents. The reaction temperature for this reduction is not particularly limited, but usually the reaction is carried out under cooling or heating.

Production Method (6) Compound (Ih) or a salt thereof can be produced by subjecting compound (Ig) or a salt thereof to an oxidation reaction. Oxidation is performed according to a conventional method. Suitable oxidizing agents include dimethylsulfoxide and N, N'-dicyclohexylcarbodiimide, lower alkanoic acid anhydrides (such as acetic anhydride), phosphorus pentoxide, sulfur trioxide-pyridine, N-halosuccinimide (such as N-chlorosuccinimide). Etc.) and oxalyl chloride and the like. The reaction may be carried out in the presence of acid. Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.) Is mentioned. The reaction includes alkali metal (eg sodium, potassium etc.), alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide etc.),
Alkali metal hydrogen carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), Alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), Tri-lower alkylamine (eg, trimethylamine, triethylamine, diisopropylamine, etc.), Alkali metal hydride (Eg sodium hydride), alkali metal lower alkoxide (eg sodium methoxide, sodium ethoxide etc.), pyridines (eg pyridine, lutidine, picoline, dimethylaminopyridine etc.), N-lower alkylmorpholine, N, N- It may be carried out in the presence of an inorganic base or an organic base such as di-lower alkylbenzylamine and N, N-di-lower alkylaniline. When the base, acid and / or starting compound are in liquid form, they can also be used as solvents. This reaction is usually carried out with water, alcohol (eg methanol,
It is carried out in a solvent such as ethanol), benzene, N, N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether, or any other solvent which does not adversely influence the reaction. These conventional solvents may be used in a mixture with water. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Process (A) Compound (IIb) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (VI) or a salt thereof. The reaction is usually water, alcohol (eg, methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethylacetamide, N, N-.
It is carried out in a conventional solvent such as dimethylformamide, or any other organic solvent that does not adversely influence the reaction. Among these solvents, the hydrophilic solvent may be mixed with water and used. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Process (B) Compound (IId) or a salt thereof can be prepared by reacting compound (IIc) or a salt thereof with compound (VII) or a salt thereof. The reaction is usually carried out in a conventional solvent such as alcohol (eg, methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran, benzene, acetone, or any other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. The reaction includes alkali metal hydroxide, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal acetate, tri (lower) alkylamine, pyridine, lutidine, picoline, dimethylaminopyridine, N-lower alkylmorpholine, N, It can also be carried out in the presence of an inorganic or organic base such as N-di-lower alkylbenzylamine, N, N-di-lower alkylaniline. Base and /
Alternatively, when the starting compounds are liquid, they can be used as a solvent.

Process (C) Compound (IIe) or a salt thereof can be produced by subjecting compound (IId) or a salt thereof to a reduction reaction. The reduction is carried out according to a conventional method that includes reducing the pyridine ring to a 1,2,5,6-tetrahydropyridine ring, including chemical reduction and catalytic reduction. Suitable reducing agents to be used for chemical reduction are hydrides (eg hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, etc.).
Alternatively, a metal (eg, tin, zinc, iron, etc.) or a metal compound (eg, chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (eg, formic acid, acetic acid, propionic acid, etc.)
Trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts to be used for catalytic reduction are platinum catalysts (eg platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg spongy palladium, palladium black, palladium oxide). , Palladium charcoal, colloidal palladium, palladium / barium sulfate, palladium / barium carbonate, etc.), nickel catalysts (eg reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalysts (eg reduced cobalt, Raney cobalt etc.), iron catalysts (eg (Reduced iron, Raney iron, etc.), copper catalyst (for example, reduced copper, Raney copper, Ullmann copper, etc.) and the like. The reduction is usually carried out in a conventional solvent such as water, alcohol (eg, methanol, ethanol, etc.), N, N-dimethylformamide, tetrahydrofuran, a mixture thereof, or any other solvent which does not adversely influence the reaction. Among these solvents, the hydrophilic solvent may be mixed with water and used. When the above acids to be used for chemical reduction are liquid, they can also be used as a solvent. The reaction temperature for this reduction is not particularly limited, but usually the reaction is carried out under cooling or heating.

Production Method (D) Compound (IXa) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (X) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation Example 7 or a method similar thereto.

Process (E) -Compound (XII) or a salt thereof is compound (IXb)
Alternatively, it can be produced by reacting a salt thereof with compound (XI) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation Example 8 or a method similar thereto. Production method (E) -Compound (XIII) or a salt thereof is compound (XII)
Alternatively, it can be produced by subjecting the salt to a reduction reaction.
This reaction can be carried out by the method disclosed in Preparation Example 9 or a method similar thereto.

Process (F) -Compound (XVI) or a salt thereof can be prepared by reacting compound (XIV) or a salt thereof with compound (XV) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation Example 11 or a method similar thereto. Production method (F) -Compound (XVII) or a salt thereof is compound (XVI)
Alternatively, it can be produced by subjecting the salt to a reduction reaction.
This reaction can be carried out by the method disclosed in Preparation Example 12 or a method similar thereto.

Process (G) Compound (VIII) or a salt thereof can be prepared by reacting compound (XVII)
It can be produced by reacting I) or a salt thereof with compound (XIX) or a salt thereof. This reaction corresponds to Production Example 1
7 or a method similar thereto.

Process (H) Compound (VIII) or a salt thereof can be prepared by reacting compound (XVII)
It can be produced by reacting I) or a salt thereof with compound (XX) or a salt thereof. This reaction corresponds to Production Example 19
Can be carried out by the method disclosed in or similar method.

Process (I) Compound (VIIIa) or a salt thereof can be prepared by reacting compound (III)
It can be produced by reacting a) or a salt thereof with compound (XXI). This reaction can be carried out by the method disclosed in Preparation Example 20 or a method similar thereto. Method (1)
Examples of suitable salts of the target compound and the starting compound in to (6) and (A) to (I) include those exemplified for compound (I). Preferred specific examples of the target compound (I) are as follows. M is the formula:

[Chemical 34] (In the formula, R ¹ is hydrogen; lower alkyl; 1 to 4 containing 1 to 4 nitrogen atoms and selected from the group consisting of lower alkyl, lower alkoxy, nitro and halogen (more preferably 1 or 2 3-8-membered (more preferably 5- or 6-membered) unsaturated heterocyclic group optionally having a substituent (more preferably pyridyl or lower alkyltetrahydropyridyl]; or lower alkyl, lower alkoxy , Phenyl optionally having 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of acylamino, lower alkylthio, halogen and nitro [more preferably phenyl and lower alkylphenyl. ,
Mono (or di) lower alkoxyphenyl, halophenyl, nitrophenyl, lower alkylthiophenyl, or lower alkanoylaminophenyl], and R ² is hydrogen; lower alkyl; containing 1 to 4 nitrogen atoms, lower alkyl, lower Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) complex optionally having 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of alkoxy, nitro and halogen. A cyclic group [more preferably pyridyl or lower alkyltetrahydropyridyl];
Or lower alkyl, lower alkoxy, acylamino,
Is phenyl which may have 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of halogen and nitro [more preferably phenyl, nitrophenyl or lower alkoxyphenyl] , Or

When R ¹ and R ² are bonded to each other, the formula:

[Chemical 35] A group represented by the formula:

[Chemical 36] Where R ¹ and R ² are each as defined above, or a formula:

[Chemical 37] (Wherein R ¹ and R ² are each as defined above), W is a bond, lower alkylene or lower alkenylene, Y is lower alkylene,

[Chemical 38] formula:

[Chemical Formula 39] Where R ³ is hydrogen or lower alkyl or a group or formula:

[Chemical 40] Wherein R ⁷ is hydroxy or protected hydroxy [more preferably acyloxy, particularly preferably lower alkanoyloxy], A is a bond or lower alkylene and Q is of the formula:

[Chemical 41] (Wherein R ⁸ is lower alkyl, R ⁹ is ar (lower) alkyl [more preferably phenyl (lower) alkyl, particularly preferably benzyl] or the formula:

[Chemical 42] (In the formula, R ⁴ is lower alkyl, or ar (lower) alkyl which may have a suitable substituent. [More preferably, it is selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen and nitro. 1 to 2 (more preferably 1 or 2) phenyl (lower) alkyl optionally having a substituent; particularly preferably benzyl or halobenzyl].

The object compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a strong acetylcholinesterase inhibitory action, but little butyrylcholinesterase inhibitory action. That is, the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are selective inhibitors of acetylcholinesterase, and therefore amnesia, dementia (for example, Alzheimer-type senile dementia, vascular dementia and cerebrovascular disease). It is useful for the treatment of central nervous system diseases such as disorders, etc. In order to show the usefulness of the target compound (I), the pharmacological test data of the compound (I) is shown below: Example 2- (1) ) Means the compound produced in Example 2- (1) [A] Inhibition of acetylcholinesterase (I) Test method: Acetylcholinesterase inhibitory action is Clinica Chimica Acta, 115.
(Enzyme analysis method) described in (1981) 163-170. The acetylcholinesterase used in this test was obtained from rat striatum.

(II) Test results:

[Table 1] The object compound (I) or a pharmaceutically acceptable salt thereof is used in mammals including human, usually in conventional pharmaceutical preparations such as capsules, microcapsules, tablets, granules,
It is administered in the form of powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion and the like. Various organic or inorganic carriers conventionally used for pharmaceutical use in the pharmaceutical composition of the present invention, such as excipients (for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.). ), Binders (eg cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch etc.), disintegrants (eg sucrose, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch) , Sodium glycol-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc., lubricants (eg magnesium stearate, talc, sodium lauryl sulfate) Helium, etc.), flavoring (e.g. citric acid, menthol, glycine, orange powder etc.), preservatives (e.g. sodium benzoate, sodium bisulfite,
Methylparaben, propylparaben etc.), stabilizers (eg citric acid, sodium citrate, acetic acid etc.), suspending agents (eg methylcellulose, polyvinylpyrrolidone, aluminum stearate etc.), dispersants, aqueous diluents (eg water), A base wax (for example, cocoa butter, polyethylene glycol, white petrolatum, etc.) may be added. In general, a single dose of 0.01 mg / kg to 10 mg / kg as an active ingredient is 1 to 1 times daily.
It may be administered four times, but the dose may be increased or decreased depending on the age, weight, condition or administration method of the patient. The following Manufacturing Examples and Examples are provided to illustrate the present invention.

Production Example 1 (1) Bromine (4.0 ml) was added to a solution of 3-propionylpyridine (10 g) in chloroform (100 ml) at room temperature over 15 minutes, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was evaporated under reduced pressure and the residue was N, N-dimethylformamide (5 ml).
After being dissolved in ethyl acetate, ethyl 2-amino-2-thioxoacetate (14.8 g) was added thereto. The mixture is stirred and heated at 100 ° C. for 30 minutes. After cooling, the mixture was poured into water, washed with ethyl acetate and the pH was adjusted with aqueous potassium carbonate solution.
After adjusting to 8.0, it is extracted with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue was recrystallized from ether to give 2-ethoxycarbonyl-
5-Methyl-4- (pyridin-3-yl) thiazole (5.38 g) is obtained. mp: 71-72 ° C IR (nujol): 1700, 1590, 1565 cm ^-1 NMR (CDCl ₃ , δ): 1.37 (3H, t, J = 7.2Hz), 2.67 (3H, s),
4.49 (2H, q, J = 7.2Hz), 7.39 (1H, dd, J = 4.8, 7.9Hz),
8.04 (1H, d, J = 7.9Hz), 8.62 (1H, d, J = 4.8Hz), 8.90 (1H,
s) Elemental analysis: Calculated as C ₁₂ H ₁₂ N ₂ O ₂ S: C 58.04, H 4.87, N 11.28 Measured value: C 58.01, H 4.57, N 11.16 Same as Production Example 1- (1) below. Obtain the compound. (2) 2-Ethoxycarbonyl-4- (pyridine-3
-Yl) thiazole mp: 65-66 ° C IR (nujol): 1725, 1590, 1570 cm ^-1 NMR (CDCl ₃ , δ): 1.47 (3H, t, J = 7.1Hz), 4.52 (2H, q, J
= 7.1Hz), 7.37 (1H, dd, J = 5.0, 8.0Hz), 7.87 (1H, s),
8.29 (1H, d, J = 8.0Hz), 8.61 (1H, d, J = 5.0Hz), 9.15 (1
H, s) Mass (M / Z): 234 (M ⁺ ) Elemental analysis: Calculated as C ₁₁ H ₁₀ N ₂ O ₂ S: C 56.39, H 4.30, N 11.95 Found: C 56.15, H 4.26, N 12.03

Production Example 2 (1) 2-Ethoxycarbonyl-5-methyl-4-
A solution of (pyridin-3-yl) thiazole (1.0 g) and methyl iodide in acetone is stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was recrystallized from ether to give 2-
Ethoxycarbonyl-4- (1-methyl-3-pyridinio) -5-methylthiazole iodide (1.2 g) is obtained. mp: 208-209 ° C (decomposition) IR (nujol): 1720, 1640, 1495 cm ^-1 NMR (DMSO-d ₆ , δ): 1.35 (3H, t, J = 7.1Hz), 2.79 (3H,
s), 4.42 (2H, q, J = 7.1Hz), 4.47 (3H, s), 8.26 (1H, dd,
J = 6.0, 8.2Hz), 8.87 (1H, d, J = 8.2Hz), 9.05 (1H, d, J =
6.0Hz), 9.34 (1H, s) Elemental analysis: Calculated as C ₁₃ H ₁₅ IN ₂ O ₂ S: C 40.01, H 3.87, N 7.18 Measured value: C 40.10, H 3.80, N 6.94 Production example 2- ( The following compound is obtained in the same manner as in 1). (2) 2-ethoxycarbonyl-4- (1-methyl-
3-pyridinio) thiazole / iodide mp: 151-153 ° C (decomposition) IR (nujol): 1730, 1630, 1590, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.38 (3H, t, J = 7.1 Hz), 4.45 (2H,
q, J = 7.1Hz), 4.47 (3H, s), 8.25 (1H, dd, J = 6.1, 8.2Hz),
8.97 (1H, s), 9.02 (1H, d, J = 6.1Hz), 9.10 (1H, d, J = 8.
2Hz), 9.61 (1H, s) Elemental analysis: Calculated as C ₁₂ H ₁₃ IN ₂ O ₂ S: C 38.31, H 3.48, N 7.45 Measured value: C 38.39, H 3.38, N 7.08

Production Example 3 2-Ethoxycarbonyl-4- (1-methyl-3-pyridinio) -5-methylthiazole iodide (1.0
g) methanol (15 ml) -water (8 ml) solution
Cool to ° C and stir. Sodium borohydride (0.
19 g) is added over 30 minutes. Mix 30 more
After stirring for 10 minutes, 10% hydrochloric acid (15 ml) is added thereto. The pH of the mixture is adjusted to 10.5 with an aqueous solution of potassium carbonate and then extracted with ethyl acetate (50 ml). The extract was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-ethoxycarbonyl-4.
-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl) -5-methylthiazole (0.6g) is obtained as an oil. IR (thin layer): 1705, 1510 cm ^-1 NMR (CDCl ₃ , δ): 1.42 (3H, t, J = 7.1Hz), 2.40-2.45 (2
H, m), 2.47 (3H, s), 2.57 (3H, s), 2.59-2.67 (2H, m),
3.34-3.38 (2H, m), 4.44 (2H, q, J = 7.1Hz), 5.95-6.01
(1H, m) Mass (M / Z): 266 (M ⁺ )

Production Example 4 A solution of 2-ethoxycarbonyl-4- (1-methyl-3-pyridinio) thiazole iodide (3.0 g) in methanol (30 ml) -water (15 ml) was cooled to 0 ° C.
Stir. Sodium borohydride (0.6g) 30
Add over minutes. After stirring the mixture for another 30 minutes,
To this is added 10% hydrochloric acid (10 ml). The mixture is adjusted to pH 10.0 with aqueous potassium carbonate solution and extracted with ethyl acetate (50 ml). The extract was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-methoxycarbonyl-4- (1-methyl-1,
2,5,6-Tetrahydropyridin-3-yl) thiazole (0.9 g) is obtained. mp: 83-84 ° C IR (nujol): 3200, 1725 cm ^-1 NMR (CDCl ₃ , δ): 2.40-2.45 (2H, m), 2.47 (3H, s), 2.
59 (2H, t, J = 5.2Hz), 3.50 (2H, m), 4.01 (3H, s), 6.76
(1H, m), 7.29 (1H, s) Mass (M / Z): 238 (M ⁺ ) Elemental analysis: Calculated as C ₁₁ H ₁₄ N ₂ O ₂ S: C 55.44, H 5.92, N 11.75 Measured value : C 55.18, H 5.98, N 11.61

Production Example 5 (1) 4'-chloropropiophenone (5.43 g)
Pyridinium hydrobromide perbromide (10.3 g) and 30% hydrogen bromide / acetic acid (5 ml) are added to a methylene chloride (50 ml) solution of the above at room temperature. After 2 hours, pour the mixture into ice water. The organic layer is separated, washed with water, saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5 ml), and ethyl 2-amino-2-thioxoacetate (2.76) was added to this solution.
g) is added. The mixture is heated at 60 ° C. for 2 hours. After cooling, the mixture is poured into water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue was chromatographed on silica gel eluting with chloroform / methanol (98: 2) to give 4- (4-
Chlorophenyl) -2-ethoxycarbonyl-5-methylthiazole (1.98g) is obtained. IR (thin layer): 1720 cm ^-1 NMR (CDCl ₃ , δ): 1.43 (3H, t, J = 7.1Hz), 2.62 (3H, s),
4.47 (2H, q, J = 7.1Hz), 7.41 (2H, d, J = 8.7Hz), 7.61 (2
H, d, J = 8.7 Hz) Mass (m / z): 281 (M ^{+ of} free compound) The following compound is obtained in the same manner as in Production Example 5- (1). (2) 2-Ethoxycarbonyl-4- (2-methoxyphenyl) -5-methylthiazole IR (thin layer): 1710 cm ^-1 NMR (CDCl ₃ , δ): 1.41 (3H, t, J = 7.2Hz) , 2.38 (3H, s),
3.79 (3H, s), 4.46 (2H, q, J = 7.2Hz), 6.96 (1H, d, J = 8.0
Hz), 7.03 (1H, d, J = 7.4Hz), 7.33-7.41 (2H, m) Mass (m / z): 277 (M ⁺ ) (3) 2-ethoxycarbonyl-5-methyl-4-
(4-Nitrophenyl) thiazole mp: 109-111 ° C IR (nujol): 1730, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.36 (3H, t, J = 7.1Hz), 2.72 (3H,
s), 4.40 (2H, q, J = 7.1Hz), 7.99 (2H, d, J = 9.0Hz), 8.33
(2H, d, J = 9.0Hz) Elemental analysis: Calculated as C ₁₃ H ₁₂ N ₂ O ₄ S: C 53.41, H 4.13, N 9.58 Measured value: C 53.50, H 3.98, N 9.53 Mass (m / z ): 292 (M ⁺ ) (4) 2-ethoxycarbonyl-4- (4-methylphenyl) -5-methylthiazole IR (thin layer): 1700 cm ^-1 NMR (CDCl ₃ , δ): 1.43 (3H, t, J = 7.1Hz), 2.39 (3H, s),
2.62 (3H, s), 4.47 (2H, q, J = 7.1Hz), 7.24 (2H, d, J = 7.4
Hz), 7.55 (2H, d, J = 7.4Hz) Mass (m / z): 261 (M ⁺ )

(5) 2-ethoxycarbonyl-4-
(4-Acetylaminophenyl) -5-methylthiazole mp: 186-188 ° C IR (nujol): 3450, 1710, 1680, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 1.34 (3H, t, J = 7.1Hz), 2.08 (3H,
s), 2.63 (3H, s), 4.37 (2H, q, J = 7.1Hz), 7.61 (2H, d, J =
6.7Hz), 7.71 (2H, d, J = 6.7Hz), 10.10 (1H, s) Mass (m / z): 304 (M ⁺ ) (6) 2-ethoxycarbonyl-4- (3-methoxyphenyl) 5-methylthiazole mp: 70-72 ℃ IR ^{(Nujol): 1730, 1600 cm -1 NMR} (CDCl 3, δ): 1.43 (3H, t, J = 7.1Hz), 2.62 (3H, s),
3.85 (3H, s), 4.43 (2H, q, J = 7.1Hz), 6.89-6.95 (1H,
m), 7.19-7.39 (3H, m) Mass (m / z): 277 (M ⁺ ) (7) 2-ethoxycarbonyl-5,6-dihydro-
4H-benzo [6,7] cyclohepta [1,2-d] thiazole IR (thin layer): 1730 cm ^-1 NMR (CDCl ₃ , δ): 1.45 (3H, t, J = 7.1Hz), 2.22-2.36 (2
H, m), 2.70-2.85 (2H, m), 2.92-3.07 (2H, m), 4.48 (2
H, q, J = 7.1Hz), 7.20-7.38 (3H, m), 7.96-8.01 (1H, m) Mass (m / z): 273 (M ⁺ ) (8) 2-Ethoxycarbonyl-4-phenyl Thiazole IR (thin layer): 1710 cm ^-1 NMR (CDCl ₃ , δ): 1.46 (3H, t, J = 7.1Hz), 4.50 (2H, q, J
= 7.1Hz), 7.33-7.50 (3H, m), 7.74 (1H, s), 7.92-7.98
(2H, m) Mass (m / z): 233 (M ⁺ )

Production Example 6 The following compounds were obtained in the same manner as in Production Example 1- (1) and Production Example 5- (1). 2-ethoxycarbonyl-4-
(3,4-dimethoxyphenyl) -5-methylthiazole mp: 93-94 ° C IR (nujol): 1710, 1600, 1590 cm ^-1 NMR (CDCl ₃ , δ): 1.44 (3H, t, J = 7.1Hz ), 2.62 (3H, s),
3.93 (3H, s), 3.94 (3H, s), 4.47 (2H, q, J = 7.1Hz), 6.9
2 (1H, d, J = 8.5Hz), 7.15 (1H, d, J = 8.5Hz), 7.24 (1H, s) Mass (m / z): 307 (M ⁺ )

Production Example 7 (2-Bromopropionyl) benzene (8.1 g) and 2,2-di (methoxy) thioacetamide (10.28)
The mixture of g) in N, N-dimethylformamide (25 ml) is heated at 50 ° C. for 30 minutes. The mixture is then poured into water, extracted with ethyl acetate and concentrated under reduced pressure. The residue is dissolved in a mixture of concentrated sulfuric acid (0.5 ml) and acetone (50 ml). The solution is stirred for 30 minutes, then evaporated under reduced pressure and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography,
Elute with chloroform to give 2-formyl-5-methyl-
4-Phenylthiazole (2.7 g) is obtained. mp: 47-48 ° C IR (nujol): 1670 cm ^-1 NMR (CDCl ₃ , δ): 2.68 (3H, s), 7.37-7.54 (3H, m), 7.
65-7.70 (2H, m), 9.96 (1H, s) Mass (m / z): 203 (M ⁺ ) Elemental analysis: Calculated as C ₁₁ H ₉ NOS ・ 0.1H ₂ O: C 64.43, H 4.52, N 6.83 Found: C 64.55, H 4.38, N 6.82

Preparation 8 A mixture of 2-formyl-5-methyl-4-phenylthiazole (1.0 g), malonic acid (2.05 g) and piperidine (0.24 ml) in pyridine (10 ml) is refluxed for 1 hour. . After cooling, the mixture is evaporated under reduced pressure, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to give 2-[(E) -2-Carboxyethenyl] -4-phenyl-5-methylthiazole (0.68
g) is obtained. mp: 211-213 ° C IR (nujol): 1680, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.60 (3H, s), 6.61 (1H, d, J = 15.8H
z), 7.37-7.72 (6H, m), 12.78 (1H, s) Mass (m / z): 245 (M ⁺ )

Production Example 9 2-[(E) -2-Carboxyethenyl] -4-phenyl-5-methylthiazole (0.7 g) and palladium (II) hydroxide (0.15 g) in tetrahydrofuran (1
The mixture in 5 ml) is hydrogenated under normal pressure for 8 hours. Palladium (II) hydroxide is removed by filtration, and the filtrate is concentrated under reduced pressure.
The obtained precipitate is washed with ether to give 2- (2-carboxyethyl) -4-phenyl-5-methylthiazole (0.7 g). mp: 172-174 ° C IR (thin layer): 3460, 1720 cm ^-1 NMR (DMSO-d ₆ , δ): 2.51 (3H, s), 2.78 (2H, t, J = 7.1H)
z), 3.25 (2H, t, J = 7.1Hz), 7.36-7.53 (3H, m), 7.64-7.
69 (2H, m) Mass (m / z): 247 (M ⁺ )

Production Example 10 (1) A solution of sulfuryl chloride (3.33 ml) in methylene chloride (5 ml) was mixed with 3-acetylmethylpyridine (5.
60 g) in methylene chloride (50 ml) at room temperature. The mixture is stirred for 2 hours and then evaporated under reduced pressure. A mixture of the residue and ethyl 2-amino-2-thioxoacetate (6.62 g) in N, N-dimethylformamide (5 ml) is stirred at 100 ° C. for 1 hour. After cooling the mixture to room temperature, it is poured into water, adjusted to pH 9.5 with aqueous potassium carbonate solution and extracted with ethyl acetate. The extract is washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform to give 2-
Ethoxycarbonyl-4-methyl-5- (pyridine-3
-Yl) thiazole (2.7 g) is obtained. mp: 67-69 ° C IR (nujol): 1740, 1580, 1560 cm ^-1 NMR (CDCl ₃ , δ): 4.44 (3H, t, J = 7.1Hz), 2.61 (3H, s),
4.51 (2H, q, J = 7.1Hz), 7.45 (1H, ddd, J = 0.8, 4.8, 8.0
Hz), 7.83 (1H, ddd, J = 0.8,8.0Hz), 8.67 (1H, dd, J = 0.8,
4.8Hz), 8.77 (1H, dd, J = 0.8, 0.8Hz) Mass (m / z): 248 (M ⁺ ) Elemental analysis: Calculated as C ₁₂ H ₁₂ N ₂ O ₂ S: C 58.04, H 4.87 , N 11.28 Found: C 57.91, H 4.87, N 11.29 The following compounds are obtained in the same manner as in Production Example 10- (1). (2) 2-Ethoxycarbonyl-5- (4-methoxyphenyl) -4-methylthiazole mp: 55-56 ° C IR (nujol): 1720, 1600 cm ^-1 NMR (CDCl ₃ , δ): 1.44 (3H, t, J = 7.1Hz), 2.57 (3H, s),
3.86 (3H, s), 4.52 (2H, q, J = 7.1Hz), 6.97 (2H, d, J = 10.
3Hz), 7.40 (2H, d, J = 10.3Hz)

Production Example 11 A solution of 2-ethoxycarbonyl-4-methyl-5- (pyridin-3-yl) thiazole (2.0 g) and methyl iodide (1.26 g) in acetone (20 ml) was stirred overnight at room temperature. After that, concentrate under reduced pressure. The residue was recrystallized from ether-acetone to give 2-ethoxycarbonyl-4-methyl-5- (1-methyl-3-pyridinio) thiazole.
Iodide (2.26 g) is obtained. mp: 209-210 ° C IR (nujol): 1720, 1640, 1500 cm ^-1 NMR (DMSO-d ₆ , δ): 1.36 (3H, t, J = 7.0Hz), 2.60 (3H,
s), 4.43 (2H, q, J = 7.0Hz), 4.45 (3H, s), 8.29 (1H, dd,
J = 6.0, 8.0Hz), 8.81 (1H, d, J = 8.0Hz), 9.09 (1H, d, J =
6.0Hz), 9.36 (1H, s)

Production Example 12 2-Ethoxycarbonyl-4-methyl-5- (1-methyl-3-pyridinio) thiazole iodide (1.0
To a solution of g) in methanol (15 ml) -water (8 ml) is added sodium borohydride (0.2 g) at 0 ° C over 30 minutes. The mixture was stirred for 30 minutes, then 10% hydrochloric acid (10 ml) was added, and then the pH was adjusted with aqueous potassium carbonate solution.
Adjust to 9.5 and extract with ethyl acetate. The extract is washed successively with water and brine, dried over magnesium sulfate,
Concentrated under reduced pressure to give 2-ethoxycarbonyl-4-methyl-
5- (1-Methyl-1,2,5,6-tetrahydropyridin-3-yl) thiazole (0.6 g) is obtained as an oil. NMR (CDCl ₃ , δ): 4.42 (3H, t, J = 7.1Hz), 2.44 (3H, s),
2.47 (3H, s), 2.53 (2H, s), 2.60 (2H, t, J = 5.3Hz), 3.1
7 (2H, dd, J = 2.6, 4.5Hz), 4.44 (2H, q, J = 7.1Hz), 6.08
(1H, m) Mass (m / z): 266 (M ⁺ )

Preparation Example 13 A mixture of 1-benzyl-4- (3-cyanopropylidene) piperidine (8.13 g) and platinum dioxide (0.8 g) in methanol (160 ml) is hydrogenated at atmospheric pressure for 30 minutes. The catalyst is filtered off and the filtrate is evaporated under reduced pressure.
The residue was chromatographed on silica gel eluting with chloroform / methanol (98: 2) to give 4- (1
-Benzylpiperidin-4-yl) butyronitrile (7.80 g) is obtained. IR (thin layer): 2250 cm ^-1 NMR (CDCl ₃ , δ): 1.27-1.43 (5H, m), 1.59-1.66 (4H,
m), 1.78-2.00 (2H, m), 2.32 (2H, t, J = 7.0Hz), 2.86-2.9
2 (2H, m), 3.50 (2H, s), 7.20-7.33 (5H, m) Mass (m / z): 241 (M ⁺ -1)

Production Example 14 A solution of 4- (1-benzylpiperidin-4-yl) butyronitrile (7.71 g) in toluene (80 ml) was charged with 0.
95M diisobutylaluminum hydride-hexane (3
5.1 ml) is added at −60 ° C. and the mixture is stirred at room temperature for 1 hour. Saturated ammonium chloride solution (100m
l) is added. The mixture is stirred for 1 hour and then 5% sulfuric acid (150 ml) is added. The aqueous layer is separated, made basic with saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4- (1-benzylpiperidin-4-yl) butanal (4.70 g) as an oil. IR (thin layer): 1720 cm ^-1 NMR (CDCl ₃ , δ): 1.25-1.28 (6H, m), 1.56-1.67 (4H,
m), 1.88-1.93 (2H, m), 2.37-2.48 (1H, m), 2.85-2.91
(2H, m), 3.49 (2H, s), 7.19-7.32 (5H, m), 9.74-9.76 (1
H, m) Mass (m / z): 244 (M ⁺ -1)

Production Example 15 4- (1-benzylpiperidin-4-yl) butanal (4.66 g), trimethylsilyl cyanide (3.04)
ml) and zinc iodide (100 mg) are stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was converted to 10%.
Dissolve in a mixture of hydrochloric acid (30 ml) and acetone (15 ml). The solution is stirred for 1 hour, then made basic with saturated potassium carbonate solution and extracted with ethyl acetate. The extract is washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was recrystallized from hexane to give 5- (1-benzylpiperidin-4-yl) -2-
Hydroxypentanenitrile (3.90 g) is obtained. mp: 92-94 ° C IR (nujol): 3400 cm ^-1 NMR (CDCl ₃ , δ): 1.26-1.32 (5H, m), 1.47-1.50 (2H,
m), 1.64-1.83 (4H, m), 1.92-2.02 (2H, m), 2.89-2.94
(2H, m), 3.52 (2H, s), 4.35 (1H, t, J = 6.6Hz), 7.19-7.4
1 (5H, m) FAB Mass: 273 (M ⁺ +1)

Preparation 16 A mixture of 5- (1-benzylpiperidin-4-yl) -2-hydroxypentanenitrile (3.77 g) and triethylamine (2.31 ml) in methylene chloride (40 ml) was added to acetyl chloride (1. A solution of 18 ml) in methylene chloride (5 ml) is added dropwise at 0 ° C. Mix the mixture at room temperature 1
After stirring for an hour, water is added to this. The mixture was extracted with methylene chloride, the extract was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-acetoxy-5- (1-benzylpiperidin-4-yl).
Pentanenitrile (3.50 g) is obtained as an oil. IR (thin layer): 1750 cm ^-1 NMR (CDCl ₃ , δ): 1.24-1.31 (5H, m), 1.42-1.66 (4H,
m), 1.82-1.98 (4H, m), 2.13 (3H, s), 2.85-2.90 (2H,
m), 3.48 (2H, s), 5.31 (1H, t, J = 6.7Hz), 7.19-7.41 (5
H, m) Mass (m / z): 314 (M ⁺ )

Production Example 17 2-acetoxy-5- (1-benzylpiperidine-4-
A mixture of (yl) pentanenitrile (3.33 g) and triethylamine (20 ml) in ethanol (40 ml) is bubbled with hydrogen sulfide at 5 ° C. for 2 hours and the mixture is stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with cold ethanol and ether to give 2-acetoxy-5- (1-benzylpiperidin-4-yl) pentanethioamide (2.59).
g) is obtained. mp: 135-137 ° C IR (nujol): 3480, 3130, 1740, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 1.16-1.28 (7H, m), 1.56-1.61 (2
H, m), 1.70-1.93 (3H, m), 2.08 (3H, m), 2.74-2.80 (2
H, m), 3.31-3.35 (1H, m), 3.42 (2H, s), 5.11 (1H, dd, J =
4.6, 7.8Hz), 7.20-7.39 (5H, m), 9.19 (1H, s), 9.76 (1
H, s) FAB Mass: 349 (M ⁺ +1)

Production Example 18 An ethanol solution of thiobenzamide (3.0 g) and ethyl bromopyruvate (2.7 ml) is heated under reflux for 2 hours. After cooling, the mixture is subjected to an evaporation operation, then ethyl acetate and water are added to the residue and the layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a mixture of chloroform and methanol (98: 2) to collect fractions containing the target compound, and the solvent was distilled off to give 4-ethoxycarbonyl-2-phenylthiazole ( 3.1 g) is obtained as an oil. IR (thin layer): 1720 cm ^-1 NMR (CDCl ₃ , δ): 1.434 (3H, t, J = 7.1Hz), 4.45 (2H, q,
J = 7.1Hz), 7.42-7.49 (3H, m), 7.97-8.06 (2H, m), 8.16
(1H, s) Mass (m / z): 233 (M ⁺ )

Production Example 19 1N-benzyl-4- (4-cyanobutyl) piperidine (2.0 g) and thioacetamide (1.76 g) in 4N
The mixture in hydrogen chloride-dioxane (20 ml) is heated under reflux for 3 hours. After cooling, the solvent is evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution is added to the residue, and this is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a mixture of chloroform and methanol (98: 2), the fractions containing the target compound were collected, and the solvent was evaporated to give 5- (1
-Benzylpiperidin-4-yl) pentanethioamide (0.8g) is obtained. mp: 124-127 ° C IR (nujol): 3200, 1640, 1580 cm ^-1 NMR (DMSO-d ₆ , δ): 1.06-1.21 (7H, m), 1.56-1.65 (4
H, m), 1.81-2.01 (2H, m), 2.42-2.51 (2H, m), 2.73-2.7
9 (2H, m), 3.41 (2H, s), 7.17-7.34 (5H, m) Mass (m / z): 290 (M ⁺ )

Production Example 20 1-Benzyl-4- (2-aminoethyl) piperidine (2.0 g) in acetone (6 ml) was added to a solution of benzoyl isothiocyanate (1.27 ml) in acetone (6 ml).
The solution is added at room temperature. After 1 hour, the solvent is distilled off under reduced pressure.
Add to water and residue and extract with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue is dissolved in 2.5N sodium hydroxide (10 ml) and the solution is refluxed for 30 minutes. After cooling, the mixture is extracted with ethyl acetate, the organic layer is washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of chloroform and methanol (95: 5) to collect fractions containing the target compound,
The solvent was evaporated to give N- [2- (1-benzylpiperidin-4-yl) ethyl] thiourea (1.2 g) as an oil. IR (thin layer): 3500, 3400, 1600, 1500 cm ^-1 NMR (CDCl ₃ , δ): 1.21-1.33 (3H, m), 1.49-1.67 (4H,
m), 1.90-2.00 (2H, m), 2.85-2.91 (2H, m), 3.10-3.20
(2H, m), 3.49 (2H, s), 5.96 (2H, s), 6.48 (1H, m), 7.21
-7.32 (5H, m) Mass (m / z): 277 (M ⁺ )

Example 1 (1) 4,5-Diphenyl-2-ethoxycarbonylthiazole (0.50 g) and 1-benzyl-4- (2-
1 mixture of aminoethyl) piperidine (0.42 g)
Stir and heat at 00 ° C. for 3 hours. After cooling, this mixture is dissolved in ethyl acetate and washed with water. The organic layer is separated and the solvent is evaporated under reduced pressure. Recrystallize the residue with ether to give 4,
5-Diphenyl-2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole (0.32 g) is obtained. mp: 109-111 ° C IR (nujol): 3300, 1640 cm ^-1 NMR (CDCl ₃ , δ): 1.28-1.40 (3H, m), 1.54-1.75 (4H,
m), 1.90-2.02 (2H, m), 2.85-2.91 (2H, m), 3.49 (2H,
s), 3.45-3.56 (2H, m), 7.23-7.34 (14H, m), 7.45-7.52
(2H, m) Mass (M / Z): 481 (M ⁺ ) Elemental analysis: Calculated as C ₃₀ H ₃₁ N ₃ OS: C 74.81, H 6.48, N 8.72 Measured value: C 74.46, H 6.45, N 8.43 The following compound is obtained in the same manner as in Example 1- (1). (2) 4,5-bis (4-methoxyphenyl) -2-
[{2- (1-Benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole IR (CHCl ₃ ): 3400, 1660, 1600 cm ⁻¹ NMR (CDCl ₃ , δ): 1.30-1.48 (3H, m), 1.55-1.74 (4H,
m), 1.90-2.00 (2H, m), 2.85-2.91 (2H, m), 3.44-3.54
(2H, m), 3.49 (2H, s), 3.82 (3H, s), 3.83 (3H, s), 6.82
-6.88 (4H, m), 7.25-7.46 (10H, m) Mass (M / Z): 541 (M ⁺ ) (3) 4,5-diphenyl-2-[{2- (1-methylpiperidine-4 -Yl) ethyl} carbamoyl] thiazole mp: 85-87 ° C IR (nujol): 3290, 1640 cm ^-1 NMR (CDCl ₃ , δ): 1.12-1.37 (3H, m), 1.55-1.62 (2H,
m), 1.73-1.78 (2H, m), 1.86-2.04 (2H, m), 2.26 (3H,
s), 2.81-2.87 (2H, m), 3.50 (2H, dd, J = 7Hz, 14Hz), 7.
24-7.35 (9H, m), 7.45-7.52 (2H, m) Mass (M / Z): 405 (M ⁺ ) Elemental analysis: C ₂₄ H ₂₇ N ₃ OS ・ Calculated as 1 / 5H ₂ O: C 70.77, H 6.81, N 9.80 Found: C 70.45, H 6.74, N 10.26

Example 2 (1) 2-Ethoxycarbonyl-5-methyl-4-
(Pyridin-3-yl) thiazole (0.8 g) and 1-
Benzyl-4- (2-aminoethyl) piperidine (0.
84 g) is stirred and heated at 100 ° C. for 2 hours.
After cooling, the mixture was subjected to column chromatography on alumina, eluting with chloroform to give 4- (pyridin-3-yl) -5-methyl-2-[{2- (1-benzylpiperidin-4-yl) ethyl. } Carbamoyl] thiazole (0.9 g) is obtained as an oil. This compound (0.2 g) was treated with a solution of hydrogen chloride in ethanol, then evaporated under reduced pressure and the residue was recrystallized from ether to give 4- (pyridin-3-yl) -5-methyl. -2
-[{2- (1-Benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole dihydrochloride (0.12
g) is obtained. mp: 135 ° C NMR (DMSO-d ₆ , δ): 1.42-1.76 (5H, m), 1.80-1.92 (2
H, m), 2.72 (3H, s), 2.75-3.10 (2H, m), 3.25-3.35 (4H,
m), 4.22 (2H, d, J = 6Hz), 7.43-7.62 (3H, m), 7.60-7.62
(2H, m), 8.04 (1H, dd, J = 5Hz, 8Hz), 8.75 (1H, d, J = 8H
z), 8.87 (1H, d, J = 5Hz), 9.00 (1H, t, J = 7Hz), 9.26 (1
H, s) Mass (M / Z): 420 (M ^{+ of} free compound) Elemental analysis: C ₂₄ H ₂₈ N ₄ OS ・ 2HCl ・ 3.5H ₂ O Calculated value: C 51.79, H 6.70, N 10.06 Measured value : C 51.77, H 6.66, N 9.85 The following compound is obtained in the same manner as in Example 2- (1). (2) 4- (1-Methyl-1,2,5,6-tetrahydropyridin-3-yl) -2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole dihydrochloride Salt mp: 158-161 ° C (decomposition) IR (nujol): 1660, 1525 cm ^-1 NMR (DMSO-d ₆ , δ): 1.44-1.75 (5H, m), 1.80-1.95 (2
H, m), 2.52-2.86 (2H, m), 2.86, 2.88 (total 3H, s), 3.05
-3.49 (6H, m), 3.70 (2H, s), 3.85-3.95 (1H, m), 4.21,
4.24 (2H, s), 4.34 (1H, s), 6.86 (1H, br), 7.42-7.45
(3H, m), 7.62-7.66 (2H, m), 7.96 (1H, s), 8.87 (1H, t,
J = 5.8Hz), 10.99 (1H, br), 11.60 (1H, br) Mass: 424 (M ⁺ ) Elemental analysis: C ₂₄ H ₃₂ N ₄ OS ・ 2HCl ・ 1.3H ₂ O Calculated: C 55.33, H 7.08, N 10.75 Found: C 55.27, H 7.21, N 10.46 (3) 4- (1-methyl-1,2,5,6-tetrahydropyridin-3-yl) -5-methyl-2-[{ 2-
(1-Benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole dihydrochloride mp: 150 ° C IR (thin layer): 3400, 1640, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.45-1.75 (5H, m), 1.85-1.95 (2
H, m), 2.55 (3H, s), 2.70-2.80 (2H, m), 2.84, 2.87 (total
3H, s), 3.17-3.49 (6H, m), 3.63 (2H, br), 3.80-3.92
(1H, m), 4.21, 4.23 (total 2H, s), 4.28-4.36 (1H, m), 6.2
8 (1H, br), 7.42-7.46 (3H, m), 7.61-7.64 (2H, m), 8.8
0 (1H, t, J = 6Hz), 10.92 (1H, br), 11.51 (1H, br) Mass (M / Z): 438 (M ^{+ of} free compound) Elemental analysis: C ₂₅ H ₃₄ N ₄ OS Calculated as 2HCl ・ 0.5C ₂ H ₅ OH ・ 1.5H ₂ O: C 55.60, H 7.53, N 9.97 Found: C 55.57, H 7.52, N 9.79

Example 3 (1) 2-Ethoxycarbonyl-5-methyl-4-phenylthiazole (0.5 g) and 1-benzyl-4-
A mixture of (2-aminoethyl) piperidine (0.53g) is stirred and heated at 100 ° C for 1 hour. After cooling, the mixture is subjected to column chromatography with alumina,
Elute with chloroform to give 4-phenyl-5-methyl-
2-[{2- (1-Benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole (0.8 g) is obtained.
This compound is dissolved in ethanol (5 ml), maleic acid (0.22 g) is added thereto, and the mixture is stirred for 30 minutes.
The solvent was removed under reduced pressure and the residue was triturated to give 4-phenyl-5-methyl-2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole.
Maleate (0.40 g) is obtained. mp: 75 ° C IR (nujol): 3300, 1700, 1650 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.02-1.36 (5H, m), 1.90-1.96 (2
H, m), 2.61 (3H, s), 3.30-3.35 (4H, m), 4.28 (2H, s),
6.08 (2H, s), 7.42-7.54 (8H, m), 7.73-7.76 (2H, m), 8.
77 (1H, br) Mass (M / Z): 419 (M ^{+ of} free compound) In the same manner as in Example 3- (1), the following compound is obtained. (2) 4-phenyl-5-methyl-2-[{2- (1
-Benzylpiperidin-4-yl) methyl} carbamoyl] thiazole maleate mp: 162-163 ° C IR (nujol): 3350, 1660, 700 cm ^-1 NMR (DMSO-d ₆ , δ): 1.2-1.6 ( 2H, m), 1.7-2.0 (3H, m),
2.61 (3H, s), 2.7-3.1 (2H, m), 3.1-3.4 (4H, m), 4.24
(2H, s), 6.02 (2H, s), 7.4-7.6 (8H, m), 7.7-7.9 (2H, s
m), 8.86 (1H, br) Elemental analysis: Calculated as C ₂₈ H ₃₁ N ₃ O ₅ S: C 64.47, H 5.98, N 8.05 Measured value: C 64.54, H 5.95, N 7.93

Example 4 4,5-Diphenyl-2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole (1.2 g) in N, N-dimethylformamide (10 m
l) The solution is cooled to 0 ° C., to which sodium hydride (0.1 g) is added and the mixture is stirred at 0 ° C. for 1 hour.
Add methyl iodide (0.16 ml) and stir for 1 hour. The mixture is quenched with aqueous ammonium chloride solution (10 ml) and extracted with ethyl acetate (50 ml). The extract is washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is recrystallized from hexane to give 4,5-diphenyl-2- [N-methyl-N- {2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] thiazole (0.9g). . mp: 92-93 ° C IR (nujol): 1610, 1495 cm ^-1 NMR (CDCl ₃ , δ): 1.21-1.40 (3H, m), 1.61-1.80 (4H,
m), 1.82-1.94 (2H, m), 2.77-2.90 (2H, m), 3.14, 3.45
(Total 3H, s), 3.48, 3.65 (Total 2H, s), 3.55-3.60 (1H, m),
4.11-4.19 (1H, m), 7.23-7.35 (13H, m), 7.45-7.50 (2H, m
m) Mass (M / Z): 495 (M ⁺ )

Example 5 (1) A mixture of 2-ethoxycarbonyl-5-methyl-4-phenylthiazole (1.0 g) and 4-amino-1-benzylpiperidine (1.0 ml) is heated at 100 ° C. After 1 hour, the cooled mixture was chromatographed on alumina, eluting with chloroform, recrystallized from ether-hexane to give 2-[(1-benzylpiperidin-4-yl) carbamoyl] -5-methyl-.
4-Phenylthiazole (1.12 g) is obtained. mp: 120-122 ° C IR (thin layer): 3380, 3300, 1650, 1590 cm ^-1 NMR (CDCl ₃ , δ): 1.52-1.72 (2H, m), 1.97-2.03 (2H,
m), 2.10-2.27 (2H, m), 2.60 (3H, s), 2.83-2.89 (2H,
m), 3.52 (2H, s), 3.87-4.04 (1H, m), 7.16-7.66 (11H,
m) Mass (m / z): 391 (M ⁺ ) Elemental analysis: C ₂₃ H ₂₅ N ₃ OS 0.5H ₂ O Calculated value: C 68.97, H 6.54, N 10.49 Measured value: C 69.11, H 6.31, N 10.51 The following compound is obtained in the same manner as in Example 5- (1). (2) 2-[{2- (1-benzylpiperidine-4-
(Yl) ethyl} carbamoyl] -5-methyl-4-phenyloxazole IR (thin layer): 3400, 1680, 1335 cm ^-1 NMR (DMSO-d ₆ , δ): 1.0-1.3 (3H, m), 1.3- 1.5 (2H, m),
1.55-1.7 (2H, m), 1.8-2.0 (2H, m), 2.60 (3H, s), 2.7-
2.9 (2H, m), 3.2-3.5 (4H, m), 3.44 (2H, s), 7.2-7.6 (8
H, m), 7.7-7.8 (2H, m), 8.84 (1H, t, J = 6Hz) Mass (m / z): 403 (M ⁺ )

Example 6 The following compound was obtained in the same manner as in Example 3- (1). (1) 2-[{3- (1-benzylpiperidine-4-
(Yl) propyl} carbamoyl] -5-methyl-4-phenylthiazole maleate IR (thin layer): 3300, 1700, 1650, 1580 cm ^-1 Mass (m / z): 433 (M ^{+ of} free compound) NMR (DMSO-d ₆ , δ): 1.06-1.27 (7H, m), 1.82-1.88 (2
H, m), 2.61 (3H, s), 2.91 (2H, m), 3.25-3.36 (4H, m),
4.29 (2H, s), 6.07 (2H, s), 7.42-7.49 (8H, m), 7.73-7.
77 (2H, m), 8.77 (1H, br) (2) 2-[{5- (N-ethyl-N-benzylamino) pentyl} carbamoyl] -5-methyl-4-phenylthiazole maleate IR (Thin layer): 1710, 1660, 865 cm ^-1 NMR (DMSO-d ₆ , δ): 1.23 (3H, t, J = 7.2Hz), 1.2-1.4 (2
H, m), 1.4-1.8 (4H, m), 2.61 (3H, s), 2.9-3.2 (4H, m),
3.25 (2H, q, J = 7.2Hz), 4.31 (2H, s), 6.08 (2H, s), 7.4
-7.6 (8H, m), 7.7-7.8 (2H, m), 8.76 (1H, t, J = 6Hz) Mass (m / z): 421 (M ⁺ ) (3) 2-[{2- (1 -Benzylpiperidine-4-
Ill) ethyl] carbamoyl] -5-methyl-4-phenylthiazole fumarate mp: 165-168 ° C IR (nujol): 1710, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 1.06-1.48 ( 5H, m), 1.75-1.81 (2
H, m), 2.35-2.46 (2H, m), 2.53 (3H, s), 3.01-3.07 (2
H, m), 3.29-3.32 (2H, m), 3.85 (2H, s), 6.60 (2H, s),
7.31-7.54 (8H, m), 7.72-7.77 (2H, m), 8.75 (1H, t, J =
5.9Hz) Mass (m / z): 419 (M ^{+ of} free compound)

(4) 2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] -4- (4
-Methoxyphenyl) -5-methylthiazole fumarate mp: 193-195 ° C IR (nujol): 3350, 1720, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 1.03-1.31 (5H, m) , 1.47-1.50 (2
H, m), 2.17-2.27 (2H, m), 2.57 (3H, s), 2.91-2.97 (2H,
m), 3.28, 3.30 (2H, m), 3.70 (2H, s), 3.81 (3H, s), 6.
59 (2H, s), 7.04 (2H, d, J = 8.8Hz), 7.28-7.45 (5H, m),
7.67 (2H, d, J = 8.8Hz), 8.71 (1H, t, J = 5.9Hz) Mass (m / z): 449 (M ^{+ of} free compound) (5) 2-[{2- (1- Benzylpiperidine-4-
Ill) ethyl} carbamoyl] -4- (4-chlorophenyl) -5-methylthiazole fumarate mp: 199-201 ° C IR (nujol): 3320, 1680, 1650 cm ^-1 NMR (DMSO-d ₆ , δ) ): 1.30-1.48 (5H, m), 1.72-1.78 (2
H, m), 2.22-2.33 (2H, m), 2.61 (3H, s), 2.95-3.00 (2
H, m), 3.29-3.32 (2H, m), 3.75 (2H, s), 6.59 (2H, s),
7.34-7.38 (5H, m), 7.55 (2H, d, J = 8.4Hz), 7.79 (2H, d,
J = 8.4Hz), 8.75-8.78 (1H, m) Mass (m / z): 454 (M ^{+ of} free compound) (6) 2-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -4- (4-methylphenyl) -5-methylthiazole fumarate mp: 200-202 ° C IR (nujol): 3350, 1720, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 1.13-1.47 (5H, m), 1.71-1.77 (2
H, m), 2.20-2.31 (2H, m), 2.36 (3H, s), 2.59 (3H, s),
2.93-2.99 (2H, m), 3.28-3.40 (2H, m), 3.73 (2H, s), 6.
59 (2H, s), 7.28-7.35 (7H, m), 7.64 (2H, d, J = 8.1Hz),
8.71 (1H, t, J = 5.9Hz) Mass (m / z): 433 (M ^{+ of} free compound)

(7) 4- (4-acetylaminophenyl) -2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] -5-methylthiazole.
Fumarate IR (nujol): 1640 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.26-1.47 (5H, m), 1.71-1.76 (2
H, m), 2.08 (3H, s), 2.15-2.56 (2H, m), 2.59 (3H, s),
2.91-2.96 (2H, m), 3.28-3.36 (2H, m), 3.74 (2H, s), 6.
59 (2H, s), 7.34-7.45 (5H, m), 7.69-7.80 (4H, m), 8.70
-8.72 (1H, m), 10.11 (1H, s) Mass (m / z): 476 (M ^{+ of} free compound) (8) 2-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -4-phenylthiazole fumarate mp: 198-200 ° C IR (nujol): 3320, 1670 cm ^-1 NMR (DMSO-d ₆ , δ): 1.31-1.51 (5H, m) , 1.74-1.80 (2
H, m), 2.23-2.34 (2H, m), 2.95-3.01 (2H, m), 3.33-3.5
6 (2H, m), 3.75 (2H, s), 6.60 (2H, s), 7.36-7.49 (8H,
m), 8.06-8.10 (2H, m), 8.39 (1H, s), 8.88-8.90 (1H,
m) Mass (m / z): 405 (M ^{+ of} free compound) (9) 2-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -5-methyl-4- (4
-Nitrophenyl) thiazole fumarate mp: 168-170 ° C IR (nujol): 1700, 1660, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.20-1.49 (5H, m), 1.78-1.85 (2
H, m), 2.20-2.25 (2H, m), 2.69 (3H, s), 3.05-3.10 (2
H, m), 3.30-3.35 (2H, m), 3.92 (2H, s), 6.61 (2H, s),
7.37-7.45 (5H, m), 8.07 (2H, d, J = 8.5Hz), 8.35 (2H, d,
J = 8.5Hz), 8.86-8.88 (1H, m) Mass (m / z): 464 (M ^{+ of} free compound) (10) 2-[{2- (1-benzylpiperidine-4
-Yl) ethyl} carbamoyl] -4- (3-methoxyphenyl) -5-methylthiazole fumarate mp: 207-208 ° C IR (nujol): 3440, 1700, 1650, 1600 cm ^-1 NMR (DMSO- d ₆ , δ): 1.03-1.30 (5H, m), 1.47-1.50 (2
H, m), 2.12-2.23 (2H, m), 2.61 (3H, s), 2.89-2.95 (2
H, m), 3.15-3.25 (2H, m), 3.66 (2H, s), 3.82 (3H, s),
6.59 (2H, s), 6.96-7.02 (1H, m), 7.28-7.45 (8H, m),
8.73 (1H, t, J = 5.9Hz) Mass (m / z): 449 Elemental analysis (M ⁺ of free _{compound): C 26 H 31 N 3} O 2 S · C 4 H 4 O 4 Calculated: C, 63.69, H 6.23, N 7.42 Found: C 63.77, H 6.46, N 7.47

(11) 2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] -5,6
-Dihydro-4H-benzo [6.7] cyclohepta [1,2-d] thiazole fumarate mp: 155-157 ° C IR (nujol): 3350, 1650 cm ^-1 NMR (DMSO-d ₆ , δ). : 1.35-1.49 (5H, m), 1.70-1.76 (2
H, m), 2.12-2.28 (4H, m), 2.77-3.04 (6H, m), 3.30-3.3
4 (2H, m), 3.76 (2H, s), 6.59 (2H, s), 7.29-7.36 (8H,
m), 8.09-8.10 (1H, m), 8.76-8.78 (1H, br) Mass (m / z): 445 (M ⁺ ) Elemental analysis: C ₂₇ H ₃₁ N ₃ OS ・ C ₄ H ₄ O ₄ Calculated value: C 66.28, H 6.28, N 7.48 Found value: C 66.27, H 6.56, N 7.46 (12) 2-[{2- (1-benzylpiperidine-4
-Yl) ethyl} carbamoyl] -5- (4-methoxyphenyl) -4-methylthiazole fumarate mp: 166-167 ° C IR (nujol): 3420, 1700, 1650, 1600 cm ^-1 NMR (DMSO- d ₆ , δ): 1.03-1.47 (5H, m), 1.72-1.78 (2
H, m), 2.22-2.33 (2H, m), 2.47 (3H, s), 2.96-3.01 (2
H, m), 3.28-3.31 (2H, m), 3.78 (2H, s), 3.82 (3H, s),
6.59 (2H, s), 7.06 (2H, d, J = 8.7Hz), 7.34-7.38 (5H,
m), 7.47 (2H, d, J = 8.7Hz), 8.78 (1H, t, J = 5.8Hz) Mass (m / z): 449 (M ^{+ of} free compound) Elemental analysis: C ₂₆ H ₃₁ N ₃ Calculated value as O ₂ S / C ₄ H ₄ O ₄ : C 63.69, H 6.23, N 7.42 Measured value: C 63.40, H 6.27, N 7.34 (13) 2-[{2- (1-benzylpiperidine-4
-Yl) ethyl} carbamoyl] -4- (2-methoxyphenyl) -5-methylthiazole fumarate mp: 153-155 ° C IR (nujol): 3420, 1700, 1640 cm ^-1 NMR (DMSO-d ₆ , δ): 1.06-1.44 (5H, m), 1.71-1.76 (2
H, m), 2.22-2.28 (2H, m), 2.29 (3H, s), 2.94-2.99 (2
H, m), 3.25-3.28 (2H, m), 3.75 (2H, s), 3.77 (3H, s),
6.59 (2H, s), 7.04 (1H, t, J = 7.3Hz), 7.13 (1H, d, J = 8.2
Hz), 7.33-7.47 (7H, m), 8.67 (1H, t, J = 5.8Hz) Mass (m / z): 449 (M ^{+ of} free compound)

Example 7 (1) 2-[(1-benzylpiperidin-4-yl)
Carbamoyl] -5-methyl-4-phenylthiazole (0.4 g) and maleic acid (0.12 g) are dissolved in warm ethanol (10 ml). After standing at room temperature for 4 hours, the resulting precipitate was collected by filtration, washed with ether and washed with 2
-[(1-Benzylpiperidin-4-yl) carbayl] -5-methyl-4-phenylthiazole maleate (0.45g) is obtained. mp: 212-213 ° C IR (nujol): 3240, 1690, 1640, 1610 cm ^-1 NMR (DMSO-d ₆ , δ): 1.98 (4H, br), 2.60 (3H, s), 3.08
(2H, br), 3.30-3.47 (2H, m), 4.03 (1H, br), 4.27 (2H,
s), 6.07 (2H, s), 7.40-7.55 (8H, m), 7.71-7.76 (2H,
m), 8.83 (1H, d, J = 7.0Hz) Mass (m / z): 391 (M ^{+ of} free compound) In the same manner as in Example 7- (1), the following compound is obtained. (2) 2-[(E) -2-{(1-benzylpiperidin-4-yl) carbamoyl} ethenyl] -4-phenyl-5-methylthiazole maleate mp: 202-204 ° C IR (nujol) : 3330, 1680, 1650, 1610, 1570 cm
^-1 NMR (DMSO-d ₆ , δ): 1.60-1.70 (2H, m), 2.00-2.06 (2
H, m), 2.60 (3H, s), 3.00-3.15 (2H, m), 3.30-3.43 (2H,
m), 3.90-3.94 (1H, m), 4.26 (2H, s), 6.08 (2H, s), 6.8
6 (1H, d, J = 15.4Hz), 7.37-7.53 (9H, m), 7.69 (2H, m),
8.49 (1H, d, J = 7.1Hz) Mass (m / z): 417 (M ^{+ of} free compound)

Example 8 The following compound was obtained in the same manner as in Example 4 and Example 7- (1). 2- [N- {2- (1-benzylpiperidin-4-yl) ethyl} -N-methylcarbamoyl] -4-phenyl-5-methylthiazole fumarate mp: 167-169 ° C IR (nujol): 1705, 1650 cm ^-1 NMR (DMSO-d ₆ , δ): 1.10-1.29 (3H, m), 1.50-1.73 (4
H, m), 2.11-2.25 (2H, m), 2.60 (3H, s), 2.81-2.94 (3
H, m), 3.02, 3.52 (total 3H, s), 3.65,3.72 (total 2H, s),
4.03-4.05 (1H, m), 6.59 (2H, s), 7.33-7.49 (8H, m), 7.
64-7.72 (2H, m) Mass (m / z): 433 (M ^{+ of} free compound) Elemental analysis: C ₂₆ H ₃₁ N ₃ OS ・ C ₄ H ₄ O ₄ Calculated value: C 65.55, H 6.41, N 7.64 Found: C 65.94, H 6.59, N 7.59

Example 9 4- (2) was added to a solution of 2-formyl-5-methyl-4-phenylthiazole (0.30 g) in methanol (5 ml).
-Aminoethyl) -1-benzylpiperidine (0.38
g) is added at room temperature. After 1 hour, the mixture is added to sodium borohydride (0.06g) and stirred at room temperature for 1 hour. Then the mixture is poured into water and extracted with ethyl acetate.
The extract is washed successively with water and brine, dried over magnesium sulfate and concentrated. The residue was treated with an ethanol solution of hydrogen chloride, the solvent was distilled off under reduced pressure, and the residue was triturated with ether to give 2-[{2- (1-benzylpiperidine-
4-yl) ethyl} aminomethyl] -5-methyl-4-
Phenylthiazole dihydrochloride (0.30 g) is obtained. mp: 265-267 ℃ IR (Nujol): 3420, 2720, 2550, 2420, 1600, 15
30 cm ^-1 NMR (DMSO-d ₆ , δ): 1.58-1.82 (7H, m), 2.58 (3H, s),
2.80-2.90 (2H, m), 2.98-3.02 (2H, m), 3.24-3.40 (2H, m
m), 4.24 (2H, s), 4.50 (2H, s), 7.35-7.53 (6H, m), 7.6
8-7.71 (4H, m), 9.79 (2H, br), 11.61 (1H, br) Mass (m / z): 405 (M ^{+ of} free compound)

Example 10 (1) 2-Ethoxycarbonyl-4-methyl-5-
(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl) thiazole (0.50 g) and 4- (2-aminoethyl) -1-benzylpiperidine (0.49 g)
Is heated at 100 ° C. for 2 hours. After cooling, the mixture is chromatographed on alumina, eluted with chloroform and treated with a solution of hydrogen chloride in ethanol to give 2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] -5-. (1-methyl-1,
2,5,6-Tetrahydropyridin-3-yl) -4-
Methyl thiazole dihydrochloride (0.30 g) is obtained. NMR (DMSO-d ₆ , δ): 1.02-1.49 (7H, m), 2.45 (3H, s),
2.60-2.80 (2H, m), 2.83, 2.86 (total 3H, s), 3.00-3.50
(6H, m), 3.93-3.97 (2H, m), 4.22 (2H, d, J = 4.8Hz), 4.38
(2H, s), 6.22 (1H, m), 7.43-7.46 (3H, m), 7.61-7.64 (2H, m), 8.85 (1H, m) Mass (m / z): 438 (M ⁺ ) The following compounds are obtained in the same manner as in Example 10- (1). (2) 2-[{2- (1-Methylpiperidin-4-yl) ethyl} carbamoyl] -5-methyl-4-phenylthiazole / hydrochloride IR (nujol): 3350, 1640, 1520 cm ^-1 NMR ( DMSO-d ₆ , δ): 1.45-1.73 (5H, m), 1.89-1.90 (2
H, m), 2.61 (3H, s), 2.64, 2.67 (total 3H, s), 2.85-3.00
(2H, m), 3.31-3.36 (4H, m), 7.38-7.55 (3H, m), 7.73-
7.78 (2H, m), 8.80 (1H, t, J = 5.9Hz) Mass (m / z): 343 (M ^{+ of} free compound) (3) 2-[{2- (1-benzylpiperidine-4-
Yield) ethyl} carbamoyl] -4- (4-methoxyphenyl) -5-methylthiazole hydrochloride hydrochloride (DMSO-d ₆ , δ): 1.45-1.85 (7H, m), 2.58 (3H, s),
2.86-3.30 (6H, m), 3.81 (3H, s), 4.21-4.36 (2H, m), 7.
04 (2H, d, J = 8.8Hz), 7.42-7.45 (3H, m), 7.61-7.70 (4H,
m), 8.76 (1H, t, J = 6.0Hz), 10.90 (1H, s) Mass (m / z): 449 (M ^{+ of} free compound) (4) 2-[{2- (1-benzylpiperidine -4-
Ile) ethyl} carbamoyl] -4-methyl-5- (pyridin-3-yl) thiazole dihydrochloride IR (nujol): 3400, 1640, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.35- 1.85 (7H, m), 2.53 (3H, s),
2.86-3.04 (2H, m), 3.30-3.42 (4H, m), 4.22 (2H, m), 7.
42-7.46 (3H, m), 7.61-7.64 (2H, m), 7.89-7.92 (1H, m),
8.43 (1H, d, J = 7.6Hz), 8.81-8.83 (1H, m), 8.98-9.02
(2H, m) Mass (m / z): 420 (M ^{+ of} free compound) (5) 2-[{5- (N-ethyl-N-benzylamino) pentyl} carbamoyl] -5-methyl-4- Phenyloxazole / hydrochloride IR (thin layer): 3400, 1680, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J = 7.2Hz), 1.4-1.6 (2
H, m), 1.6-1.8 (2H, m), 2.61 (3H, s), 2.8-3.1 (4H, m),
3.25 (2H, q, J = 7.2Hz), 4.29 (2H, s), 7.2-7.6 (8H, m),
7.7-7.8 (2H, m), 8.84 (1H, t, J = 6Hz) Mass (m / z): 405 (M ⁺ ) (6) 2-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -4- (3,4-dimethoxyphenyl) -5-methylthiazole hydrochloride hydrochloride (thin layer): 3400, 3330, 1650, 1600 cm ^-1 (free compound) NMR (DMSO-d ₆ , δ): 1.51-1.90 (7H, m), 2.59 (3H, s),
2.81-2.86 (2H, m), 3.24-3.33 (2H, m), 3.81 (3H, s), 3.
83 (3H, s), 4.13-4.15 (2H, m), 4.21-4.34 (2H, m), 7.03
-7.66 (8H, m), 8.76 (1H, t, J = 5.8Hz) Mass (m / z): 479 (M ^{+ of} free compound)

Example 11 2-((E) -2-Carboxyethenyl) -4-phenyl-5-methylthiazole (0.50 g), 4-amino-1-benzylpiperidine (0.42 ml), 3- (3
A mixture of -dimethylaminopropyl) -1-ethylcarbodiimide (0.37 ml) and 1-hydroxybenzotriazole hydrate (0.31 g) in N, N-dimethylformamide (10 ml) is stirred at room temperature for 1 hour.
The mixture is evaporated under reduced pressure and then extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-[(E)
2-{(1-benzylpiperidin-4-yl) carbamoyl} ethenyl] -5-methyl-4-phenylthiazole (0.60 g) is obtained. mp: 187-188 ° C NMR (DMSO-d ₆ , δ): 1.14-1.21 (2H, m), 1.36-1.51 (2
H, m), 1.99-2.09 (2H, m), 2.59 (3H, s), 2.73-2.79 (2
H, m), 3.66 (2H, s), 4.01-4.05 (1H, m), 6.87 (1H, d, J = 1
5.6Hz), 7.21-7.71 (11H, m), 8.29 (1H, d, J = 7.6Hz) Mass (m / z): 417 (M ⁺ )

Example 12 The following compound is obtained in the same manner as in Example 11 and Example 7- (1). (1) 2- [2-{(1-benzylpiperidine-4-
Ill) carbamoyl} ethyl] -4-phenyl-5-methylthiazole maleate mp: 154-157 ° C IR (nujol): 3300, 1680, 1660, 1620, 1570 cm
^-1 NMR (DMSO-d ₆ , δ): 1.60-1.70 (2H, m), 1.90-1.96 (2
H, m), 2.50 (3H, s), 2.54-2.61 (2H, m), 3.02-3.26 (4H,
m), 3.78-3.82 (1H, m), 4.23 (2H, s), 6.06 (2H, s), 7.3
1-7.48 (8H, m), 7.64 (2H, d, J = 7.0Hz), 8.09 (1H, d, J =
7.1Hz) Elemental analysis: C ₂₅ H ₂₉ N ₃ OS ・ C ₄ H ₄ O ₄ Calculated value: C 65.02, H 6.20, N 7.84 Measured value: C 64.89, H 6.24, N 7.80 Mass (m / z): 419 (M ^{+ of} free compound) (2) 2- [2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] ethyl] -5-methyl-4-phenylthiazole fumarate mp : 115-117 ° C NMR (DMSO-d ₆ , δ): 1.06-1.31 (5H, m), 1.64-1.69 (2
H, m), 2.21-2.32 (2H, m), 2.49 (3H, s), 2.51-2.58 (2
H, s), 2.94-3.46 (6H, m), 3.77 (2H, s), 6.60 (2H, s),
7.31-7.49 (8H, m), 7.62-7.67 (2H, m), 7.92 (1H, t, J =
5.4Hz) Mass (m / z): 447 (M ^{+ of} free compound) (3) 2-[(E) -2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] ethenyl] -5-Methyl-4-phenylthiazole maleate NMR (DMSO-d ₆ , δ): 1.12-1.44 (5H, m), 1.85-1.92 (2
H, m), 2.59 (3H, s), 2.86-2.90 (2H, s), 3.21-3.28 (4H,
m), 4.27 (2H, s), 6.06 (2H, s), 6.84 (1H, d, J = 15.5Hz),
7.37-7.53 (9H, m), 7.67-7.71 (2H, m), 8.34-8.36 (1H,
m) Mass (m / z): 445 (M ^{+ of} free compound)

Example 13 (1) 2-acetoxy-5- (1-benzylpiperidin-4-yl) pentanethioamide (1.30 g) and 1
1- (2-bromopropanoyl-4-methoxybenzene (1.00 g) in ethanol (20 ml))
Reflux for 8 hours. The solvent is distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, then dried over magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixture of methanol and chloroform (3: 100) to give 2- [1-acetoxy-
4- (1-benzylpiperidin-4-yl) butyl]-
4- (4-Methoxyphenyl) -5-methylthiazole (1.20 g) is obtained as an oil. IR (thin layer): 1740, 1600 cm ^-1 NMR (CDCl ₃ , δ): 1.25-1.61 (9H, m), 1.82-2.02 (4H,
m), 2.13 (3H, s), 2.51 (3H, s), 2.85-2.90 (2H, s), 3.5
0 (2H, s), 3.84 (3H, s), 6.01 (1H, t, J = 6.5Hz), 6.94
(2H, d, J = 8.9Hz), 7.26-7.57 (5H, m), 7.92 (2H, d, J = 8.9
Hz) Mass (m / z): 493 (M ⁺ +1) In the same manner as in Example 13- (1), the following compound was obtained. (2) 2- [4- (1-benzylpiperidin-4-yl) butyl] -5-methyl-4-phenylthiazole.
Hydrochloride IR (thin layer): 3050, 3010, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.26-1.75 (11H, m), 2.62 (3H, s),
2.76-3.03 (4H, m), 3.22-3.28 (2H, m), 4.21-4.35 (2H,
m), 7.34-7.67 (10H, m) Mass (m / z): 404 (M ^{+ of} free compound) (3) 2- [2- (1-benzylpiperidin-4-yl) ethylamino] -5 Methyl-4-phenylthiazole dihydrochloride mp: 194-196 ° C IR (nujol): 3450, 3400, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 1.57-1.62 (7H, m), 2.25 ( 3H, s),
2.85-2.90 (2H, m), 3.25-3.50 (4H, m), 4.24-4.36 (2H,
m), 7.43-7.70 (10H, m), 11.20 (1H, m) Mass (m / z): 391 (M ^{+ of} free compound)

Example 14 2- [1-Hydroxy-4- (1-benzylpiperidin-4-yl) butyl] -4- (4-methoxyphenyl)
1,3-Dicyclohexylcarbodiimide (1.0 g) and orthophosphoric acid (0.13 g) were added to a solution of -5-methylthiazole (0.20 g) in dimethyl sulfoxide (5 ml).
g) is added and the mixture is stirred at room temperature for 24 hours. The precipitate is filtered off and ethyl acetate is added to the filtrate. The mixture is washed with water and brine, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixture of methanol and chloroform (3: 100) to give 2- [1-oxo-4-].
(1-Benzylpiperidin-4-yl) butyl] -4-
(4-Methoxyphenyl) -5-methylthiazole is obtained as an oil (0.18 g). This compound was dissolved in a solution of fumaric acid (46.6 mg) in ethanol (1 ml), and the crystals were collected by filtration to give 2- [1-oxo-4- (1-benzylpiperidin-4-yl) butyl] -4. -(4-Methoxyphenyl) -5-methylthiazole fumarate (0.15 g) is obtained. mp: 172-173 ° C IR (nujol): 1705, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.10-1.28 (5H, m), 1.65-1.70 (4
H, m), 2.10-2.20 (2H, m), 2.62 (3H, s), 2.88-2.94 (2
H, m), 3.08-3.12 (2H, m), 3.65 (2H, s), 3.82 (3H, s),
6.58 (2H, s), 7.05 (2H, d, J = 8.8Hz), 7.30-7.35 (5H,
m), 7.65 (2H, d, J = 8.8Hz) Mass (m / z): 448 (M ^{+ of} free compound) Elemental analysis: Calculated as C ₂₇ H ₃₂ N ₂ O ₂ S ・ C ₄ H ₄ O _4. Value: C 65.93, H 6.42, N 4.96 Actual value: C 65.93, H 6.49, N 4.93

Example 15 2- [1-acetoxy-4- (1-benzylpiperidin-4-yl) butyl] -4- (4-methoxyphenyl)
A solution of 5-methylthiazole (0.90 g) in methanol (15 ml) was added with 4N sodium hydroxide (1.0 m).
l) is added at 0 ° C. After stirring the mixture at room temperature for 3 hours, the solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. Residue (0.38g)
(0.18 g) was dissolved in a solution of fumaric acid (26 mg) in ethanol (5 ml), and the crystals were collected by filtration to give 2-
[1-hydroxy-4- (1-benzylpiperidine-4
-Yl) butyl] -4- (4-methoxyphenyl) -5
-Methyl thiazole fumarate (0.15 g) is obtained. mp: 114-116 ° C IR (nujol): 3200, 1710 cm ^-1 NMR (CDCl ₃ , δ): 1.10-1.45 (7H, m), 1.64-1.80 (4H,
m), 2.40-2.50 (2H, m), 2.49 (3H, s), 3.01-3.07 (2H,
m), 3.79 (3H, s), 3.89 (2H, s), 4.70-4.74 (1H, m), 6.6
1 (2H, s), 7.00 (2H, d, J = 8.5Hz), 7.39-7.42 (5H, m),
7.56 (2H, d, J = 8.5Hz) Mass (m / z): 450 (M ^{+ of} free compound)

Production Example 21 2-Ethoxycarbonyl-4-phenyl-5-methyloxazole (4.0 g) was added to a fuming nitric acid (d = 1.52) (30 ml) solution at -30 ° C to -20 ° C. The mixture is stirred under the same conditions for 20 minutes. The reaction mixture is poured into cold water and the precipitate is filtered off. The precipitate is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate to give 2-ethoxycarbonyl-4-
(4-Nitrophenyl) -5-methyloxazole (3.85 g) is obtained. mp: 160-162 ℃ IR (nujor): 1720, 1600, 1545, 1510, 1350 cm
^-1 NMR (DMSO-d ₆ , δ): 1.35 (3H, t, J = 7.1Hz), 2.72 (3H,
s), 4.39 (2H, q, J = 7.1Hz), 8.00 (2H, d, J = 9.0Hz), 8.30
(2H, d, J = 9.0Hz) Mass (m / z): 276 (M ⁺ )

Production Example 22 Ethyl 4- (4-nitrophenyl) -2,4-dioxo-butanoate (1.65 g) and hydroxylamine hydrochloride (1.73 g) in ethanol (20 ml)
The mixture is refluxed with stirring. After 3 hours, the mixture is concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-ethoxycarbonyl-5- (4-nitrophenyl).
Obtained isoxazole (0.71 g). mp: 176-177 ° C IR (nujol): 1720, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 (3H, t, J = 7.1Hz), 4.50 (2H,
q, J = 7.1Hz), 7.12 (1H, s), 8.00 (2H, d, J = 9.0Hz), 8.37
(2H, d, J = 9.0Hz) Mass (m / z): 262 (M ⁺ )

Example 16 The following compound is obtained in the same manner as in Example 2- (1) and 10- (1). (1) 3-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -5- (4-nitrophenyl) isoxazole hydrochloride mp: 233-234 ° C IR (nujol): 3360, 3130, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 1.50 -1.65 (5H, m), 1.85-1.90 (2
H, m), 2.75-2.90 (2H, m), 3.27-3.36 (4H, m), 4.23-4.3
8 (2H, m), 7.44-7.47 (3H, m), 7.61-7.66 (2H, m), 7.67
(1H, s), 8.21 (2H, d, J = 8.7Hz), 8.39 (2H, d, J = 8.7Hz),
8.94-8.98 (1H, m) Elemental analysis: Calculated as C ₂₄ H ₂₆ N ₄ O ₄・ HCl: C 61.20, H 5.77, N 11.89 Found: C 61.12, H 5.89, N 11.83 Mass (m / z) : 434 (M ^{+ of} free compound) (2) 2-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -4- (4-nitrophenyl) -5-methyloxazole-hydrochloride mp: 240-242 ° C (decomposition) IR (nujol): 3300, 1680, 1600, 1560, 1510 cm
^-1 NMR (DMSO-d ₆ , δ): 1.03-1.10 (5H, m), 1.48-1.52 (2
H, m), 2.69 (3H, s), 2.82-2.87 (2H, m), 3.29-3.32 (4H,
m), 4.24 and 4.33 (total 2H, d, J = 4.9Hz respectively),
7.44 (3H, m), 7.63 (2H, m), 7.99 (2H, d, J = 8.9Hz), 8.3
5 (2H, d, J = 8.9Hz), 9.00 (1H, m) Mass (m / z): 448 (M ⁺ )

Example 17 The following compound was obtained in the same manner as in Example 3- (1). (1) 2-[[2- {1- (4-fluorobenzyl)
Piperidin-4-yl} ethyl] carbamoyl] -4-
(4-Nitrophenyl) -5-methylthiazole fumarate mp: 213-214 ° C IR (nujol): 3260, 1710, 1655 cm ^-1 NMR (DMSO-d ₆ , δ): 1.09-1.27 (3H, m), 1.47-1.51 (2
H, m), 1.69-1.74 (2H, m), 2.02-2.13 (2H, m), 2.69 (3
H, s), 2.83-2.89 (2H, m), 3.29-3.32 (2H, m), 3.58 (2H,
s), 6.60 (2H, s), 7.11-7.20 (2H, m), 7.32-7.40 (2H,
m), 8.07 (2H, d, J = 8.9Hz), 8.35 (2H, d, J = 8.9Hz), 8.83
-8.87 (1H, m) Elemental analysis: C ₂₅ H ₂₇ FN ₄ O ₃ S ・ C ₄ H ₄ O ₄ Calculated value: C 58.18, H 5.22, N 9.36 Measured value: C 58.02, H 5.08, N 9.27 ( 2) 2-[[2- {1- (4-fluorobenzyl)
Piperidin-4-yl} ethyl] carbamoyl] -5-
(4-Nitrophenyl) oxazole fumarate mp: 181-182 ° C IR (nujol): 3220, 1700, 1670 cm ^-1 NMR (DMSO-d ₆ , δ): 1.25-1.32 (3H, m), 1.48 -1.55 (2
H, m), 1.71-1.76 (2H, m), 2.05-2.16 (2H, m), 2.88-2.9
4 (2H, m), 3.33-3.70 (2H, m), 3.65 (2H, s), 6.59 (2H,
s), 7.13-7.21 (2H, m), 7.32-7.40 (2H, m), 8.08 (2H, d,
J = 8.5Hz), 8.18 (1H, s), 8.37 (2H, d, J = 8.5Hz), 9.09
(1H, br) Elemental analysis: C ₂₄ H ₂₅ FN ₄ O ₄ · C ₄ H ₄ O ₄ Calculated value: C 59.15, H 5.14, N 9.85 Measured value: C 59.15, H 5.27, N 9.83 (3) 2 -[[2- {1- (4-fluorobenzyl)
Piperidin-4-yl} ethyl] carbamoyl] -4-
(4-Nitrophenyl) -5-methyloxazole fumarate mp: 140-143 ° C (decomposition) IR (nujol): 1660, 1600, 1550, 1500 cm ^-1 NMR (DMSO-d ₆ , δ): 1.15 -1.25 (3H, m), 1.46-1.49 (2
H, m), 1.67-1.93 (2H, m), 1.91-2.03 (2H, m), 2.69 (3
H, s), 2.81-2.87 (2H, m), 3.27-3.30 (2H, m), 3.54 (2H,
s), 6.59 (2H, s), 7.10-7.19 (2H, m), 7.31-7.39 (2H,
m), 8.01 (2H, d, J = 9.0Hz), 8.35 (2H, d, J = 9.0Hz), 8.95
(1H, m) Mass (m / z): 466 (M ⁺ )

(4) 2-[{2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] -4- (4
-Methoxyphenyl) -5-methyloxazole fumarate mp: 155-156 ° C IR (nujol): 3350, 1710, 1670, 1250 cm ^-1 NMR (DMSO-d ₆ , δ): 1.05-1.60 (5H, m), 1.6-1.8 (2H,
m), 2.1-2.3 (2H, m), 2.56 (3H, s), 2.9-3.0 (2H, m), 3.
2-3.4 (2H, m), 3.80 (3H, m), 6.59 (2H, s), 7.05 (2H, d,
J = 8.8Hz), 7.34 (5H, s), 7.63 (2H, d, J = 8.8Hz), 8.82 (1
(H, t, J = 5.9Hz) (5) 2-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -4- (4-chlorophenyl) -5-methyloxazole fumarate mp: 167-170 ° C IR (nujol): 3300, 1700, 1660, 1550, 830 cm ^-1 NMR (DMSO- d ₆ , δ): 1.10-1.60 (5H, m), 1.65-1.80 (2
H, m), 2.1-2.35 (2H, m), 2.60 (3H, s), 2.90-3.10 (2H,
m), 3.20-3.40 (2H, m), 3.73 (2H, s), 6.59 (2H, s), 7.3
-7.4 (5H, m), 7.53 (2H, d, J = 6.7Hz), 7.72 (2H, d, J = 6.7)
Hz), 8.89 (1H, t, J = 5.8Hz) (6) 5-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -3- (4-nitrophenyl) pyrazole fumarate mp: 232-233 ° C (decomposition) IR (nujol): 3400, 1645, 1570, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.06-1.50 (5H, m), 1.69-1.75 (2
H, m), 2.04-2.15 (2H, m), 2.85-2.91 (2H, m), 3.29-3.4
7 (2H, m), 3.60 (3H, s), 6.58 (1H, s), 7.26-7.37 (6H,
m), 8.06 (2H, d, J = 9.0Hz), 8.32 (2H, d, J = 9.0Hz), 8.48
(1H, m) Mass (m / z): 433 (M ⁺ ) (7) 5-[{2- (1-benzylpiperidine-4-
Ill) ethyl} carbamoyl] -3- (4-methylthiophenyl) pyrazole fumarate mp: 220-222 ° C (decomposition) NMR (DMSO-d ₆ , δ): 1.09-1.48 (5H, m), 1.69- 1.75 (2
H, m), 2.06-2.17 (2H, m), 2.87-2.93 (2H, m), 3.27-3.4
4 (2H, m), 3.62 (2H, s), 6.58 (1H, s), 7.09 (1H, s), 7.
27-7.36 (7H, m), 7.54 (2H, d, J = 8.4Hz), 8.27 (1H, m)

Example 18 The following compound was obtained in the same manner as in Examples 4 and 7- (1). 2- [N-methyl-N- {2- (1-benzylpiperidin-4-yl) ethyl} carbamoyl] -4- (4
-Methoxyphenyl) -5-methyloxazole fumarate mp: 124-126 ° C IR: 3375, 1700, 1640, 1250 cm ^-1 NMR (DMSO-d ₆ , δ): 1.0-1.9 (7H, m), 1.9-2.4 (2H, m),
2.55 (3H, s), 2.7-3.1 (2H, m), 2.99, 3.36 (Total 3H,
S), 3.3-3.6 (2H, m), 3.61, 3.67 (total 2H,
S), 6.59 (2H, s), 6.9-7.2 (2H, m), 7.2-7.5, respectively
(5H, m), 7.5-7.7 (2H, m)

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication C07D 261/20 263/32 263/34 263/48 263/52 277/60 401/12 8829-4C 413/12 8829-4C 417/12 9051-4C // A61K 31/415 AED 9360-4C 31/42 AAM 9360-4C 31/425 ABN 9360-4C 31/445 9360-4C

Claims (1)

[Claims] 1. A general formula: MWYAQ [wherein M
Is the formula: (In the formula, R ¹ represents hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or aryl which may have a suitable substituent, and R ² represents hydrogen, a lower alkyl group. Represents an alkyl, a heterocyclic group which may have a suitable substituent, or an aryl which may have a suitable substituent, or R ¹ and R ² are bonded to each other to give a compound represented by the formula: : [Chemical 2] And Z represents S or O, respectively),
Formula: Wherein R ¹ and R ² are each as defined above, or a group of the formula: A group represented by the formula: wherein R ¹ and R ² are each as defined above, W is a bond, lower alkylene or lower alkenylene, Y is lower alkylene, Formula: (Wherein R ³ represents hydrogen or lower alkyl) or a group of the formula: (Wherein R ⁷ represents hydroxy or protected hydroxy), A is a bond or lower alkylene, and Q is of the formula: Wherein R ⁸ represents lower alkyl and R ⁹ represents ar (lower) alkyl, or a group of the formula: (In the formula, R ⁴ represents lower alkyl or ar (lower) alkyl which may have a suitable substituent), and a new heterocyclic compound represented by salt.