 Alkyl Ether Derivatives or Salts Thereof
专利摘要:
General formula [Wherein, R 1 and R 2 are hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, alkoxy group, aryloxy group, alkylthio group, arylthio group, alkenyl group, alkenyloxy group, amino group, alkylsulfo At least one group selected from a silyl group, an arylsulfonyl group, a carbamoyl group or a heterocyclic group, a hydroxyl group, or a carboxyl group, a nitro group, and an oxo group; R 3 is an alkylamino group, an amino group, a hydroxyl group, or the like; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n represent the integer of 1-6; p represents an integer of 1 to 3, respectively.] The alkyl ether derivative or its salt represented by the above has a neuroprotective action, a nerve regeneration promoting action and an neurite outgrowth effect and is useful as a therapeutic agent for diseases of the central and peripheral nerves. Do. 公开号:KR20040050919A 申请号:KR10-2004-7005687 申请日:2002-10-18 公开日:2004-06-17 发明作者:사이토아키히토；이와카미노보루；다카마츠다모츠 申请人:토야마 케미칼 컴퍼니 리미티드； IPC主号:
专利说明:
Alkyl Ether Derivatives or Salts Thereof} [2] Dementia is divided into cerebrovascular dementia and neurodegenerative dementia, and various drugs such as cerebral circulatory improvers and brain function improvers are used for these treatments. [3] The senile spots characteristic of Alzheimer's disease, the most neurodegenerative dementia, are composed mainly of amyloid β protein (Aβ) derived from β amyloid precursor protein. Aβ is a substance that causes symptoms such as dementia by depositing on nerve cells or blood vessels of the brain. It has also been reported that A [beta] itself interferes with neurons, and inhibitors of neurocytotoxicity induced by A [beta] are being studied as therapeutic drugs for Alzheimer's disease. [4] As a compound which has a neurocytotoxic inhibitory effect induced by A (beta), For example, the 1, 2- ethanediol derivative as described in Unexamined-Japanese-Patent No. 3-232830, 4-95070; N-alkoxyalkyl-N, N-dialkylamine derivatives described in International Publication WO00 / 75957 are known. [5] Among the 1,2-ethanediol derivatives described in Japanese Patent Application Laid-Open No. 3-232830, 4-95070, in particular, (R) -1- (benzo [b] thiophen-5-yl) -2- [2- ( N, N-diethylamino) ethoxy] ethanol hydrochloride protects against neuronal cell death by Aβ (SOCIETY FOR NEUROSCIENCE, Abstracts, Vol. 24, Part 1, p228, 1998) and nerve growth factor It has an augmentation effect of (NGF) (WO96 / 12717) and is useful as a drug for treating diseases of the central and peripheral nerves. However, there is a demand for the development of compounds having properties required as therapeutic agents for central and peripheral neurological diseases such as stronger neuronal cell protective action and neuronal regeneration promoting action. [1] The present invention relates to novel alkyl ether derivatives or salts thereof, preparation methods thereof, intermediates and therapeutic agents for central and peripheral nerves. [6] MEANS TO SOLVE THE PROBLEM As a result of earnestly researching in order to solve the said subject, the present inventors discovered that in the alkyl ether derivative | guide_body which has a calcium antagonist effect as described in international publication WO99 / 31056, in addition to a calcium antagonism, neuronal cytotoxicity induced by A (beta). It was found that there is a compound having an inhibitory action of. [7] Further this study, the following general formula [1] [8] [9] [Wherein, R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, which may be substituted; At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, amino, hydroxyl or carboxyl groups which may be protected, nitro groups and oxo groups; R <3> may be substituted alkylamino, the amino or hydroxyl group which may be protected; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n represent the integer of 1-6; p represents the integer of 1-3, respectively. ] [10] Discovered that the alkyl ether derivatives or salts thereof have neuroprotective action, nerve regeneration promoting action, neurite outgrowth activity, and also have excellent metabolic stability and are useful as therapeutic agents for diseases of the central and peripheral nerves. The present invention has been completed. [11] EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail. [12] In this specification, each term has the following meanings, unless specifically limited. [13] Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; An alkyl group is a linear or branched C 1-12 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups; Lower alkyl group is a linear or branched C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups; Alkoxy group is linear or branched C 1 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups -12 alkyloxy group; Lower alkoxy group is a linear or branched C 1-6 alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy groups; The alkenyl group refers to, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl and so on of the C 2-12 alkenyl group; Lower alkenyl group is a C 2-6 alkenyl group such as vinyl, propenyl, butenyl, pentenyl and hexenyl; Alkenyloxy group refers to vinyloxy, propenyloxy, butenyl oxy, pentenyloxy, hexenyloxy, heptenyl, and oxy okte group optionally including a C 2-12 aryloxy group Al alkenyl; Lower alkenyloxy group is a C 2-6 alkenyloxy group such as vinyloxy, propenyloxy, butenyloxy, pentenyloxy and hexenyloxy group; An alkynyl group is a C 2-6 alkynyl group such as ethynyl, 2-propynyl or 2-butynyl; A cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group; Alkylthio groups include C 1-12 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, bentylthio, hexylthio, heptylthio and octylthio; Lower alkylthio groups include C 1-6 alkylthio groups such as methylthio, ethylthio, propylthio, isobutylthio, butylthio, isobutylthio, tert-butylthio, pentylthio and hexylthio; An aryl group is a phenyl, naphthyl, indanyl and indenyl group; An aryloxy group is a phenyloxy, naphthyloxy, indanyloxy and indenyloxy group; An aralkyl group is an arC 1-6 alkyl group such as benzyl, diphenylmethyl, trityl and phenethyl group; An arylthio group is a phenylthio, naphthylthio, indanylthio and indenylthio group; Acyl groups include C 2-12 alkanoyl groups such as formyl, acetyl, isovaleryl, propionyl and pivaloyl, aralkylcarbonyl groups such as benzylcarbonyl, aroyl groups such as benzoyl and naphthoyl; Alkylsulfonyl group is methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl C 1-12 alkylsulfonyl groups such as heptylsulfonyl and octylsulfonyl; Lower alkylsulfonyl group is C such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl or pentylsulfonyl 1-6 alkylsulfonyl group; An arylsulfonyl group includes phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl group, etc .; Lower alkylsulfonyloxy group is methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsul C 1-16 alkylsulfonyloxy groups such as fonyloxy or bentylsulfonyloxy; An arylsulfonyloxy group is a phenylsulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy group, etc .; An alkylamino group; Mono or di-C 1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino and dibutylamino; Monoalkylamino is a mono C 1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino and butylamino; A dialkylamino group is a di-C 1-6 alkylamino group such as dimethylamino, diethylamino, diisopropylamino and dibutylamino; With heterocyclic group, pyrrolidinyl, piperidinyl, piperadinyl, homopyreradinyl, homopiperidinyl, morphoryl, thiomorphoryl, tetrahydroquinolinyl, tetrahydroisoquinoryl, quinuk Lidinyl, imidazolinyl, pyrrolyl, imidazoryl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazoryl, pyridinyl, pyrazorinyl, pyrazori Diyl, furinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl isoxoxazolyl, benzofuranyl, indoyl, benzoimidazoyl, benzooxazolyl, benzoisoxazolyl, benzo Thiazolyl, quinoxalyl, dihydroxyquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydroxybenzopyrrolyl, 2,3-4H-1-thianaphthyl, 2,3- Dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isooxazolyl, oxadizo 5 member containing at least one binary atom selected from nitrogen, oxygen or sulfur atoms, such as pyridadidinyl, isoindoryl, isoquinoryl, 1,3-benzodioxazonyl and 1,4-benzodioxanyl group Or a heterocyclic group of 6 membered ring, condensed ring or bridged ring; With cyclic amino groups, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morphoryl, thiomorphoryl, tetrahydroquinolinyl, tetrahydroisoquinoryl and imidasoridine Binary atoms which form the above-mentioned ring such as nil, and the like, a cyclic amino group of 5, 6 or 7 membered ring, condensed ring or bridged ring which may include one or more nitrogen atoms and may also include one or more oxygen or sulfur atoms. To; Each means. [14] As the 5 or 6 membered ring aromatic heterocyclic ring, a heterocyclic ring containing at least one binary atom selected from an oxygen atom, a nitrogen atom and a sulfur atom as a binary atom forming the ring, for example, triadine, 5- or 6-membered aromatic heterocycles such as pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole and pyran I can lift it. [15] Alkyl group, aryl group, aralkyl group, alkoxy group, aryloxy group, alkylthio group, arylthio group, alkenyl group, alkenylthio group, amino group, alkylsulfonyl group, arylsulfonyl group and carba in R 1 and R 2 Substituents for a sol group, a heterocyclic group, and an alkylamino group in R 3 include halogen atom, lower alkyl group, cycloalkyl group, aryl group, lower alkoxy group, aryloxy group, lower alkylthio group, arylthio group, lower alkenyl group, lower group Examples thereof include an alkylsulfonyl group, an arylsulfonyl group, an alkylamino group, an amino group which may be protected, a hydroxyl group which may be protected, a carboxyl group which may be protected, an acyl group and a heterocyclic group. [16] As a protecting group of a carboxyl group, all the groups which can be used as a protecting group of a normal carboxyl group are included, For example, Lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, 1, 1- dimethylpropyl, butyl, and tert- butyl; Aryl groups such as phenyl and naphthyl; Ar lower alkyl groups such as benzyl, diphenylmethyl, trityl, 4-nitrobenzyl, 4-methoxybenzyl and bis (4-methoxyphenyl) methyl; Acyl-lower alkyl groups such as acetylmethyl, benzoylmethyl, 4-nitrobenzoylmethyl, 4-bromobenzoylmethyl and 4-methanesulfonylbenzoylmethyl; Oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; Halogen-lower alkyl groups such as 2,2,2-trichloroethyl; Lower alkylsilyl-lower alkyl groups such as 2- (trimethylsilyl) ethyl; Acyloxy-lower alkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; Nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidemethyl and succinimidemethyl; Cycloalkyl groups such as cyclohexyl; Lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; Ar-lower alkoxy-lower alkyl groups such as benzoyloxymethyl; Lower alkylthio-lower alkyl groups such as methylthiomethyl and 2-methylthioethyl; Arylthio-lower alkyl groups such as phenylthiomethyl; Lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl and allyl; Substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl; Can be mentioned. [17] As a protecting group of a hydroxyl group, all the groups which can be used as a protecting group of a normal hydroxyl group include, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-meth Oxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, Isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-flufuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxy Al such as carbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl and S-benzylthiocarbonyl During and alkylthio-carbonyl group; Acyl groups such as acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; Lower alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl; Lower alkenyl groups such as allyl; Lower alkynyl groups such as propargyl; Ar-lower alkyl groups such as benzyl group, 4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; Oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; Methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1- Lower alkoxy- and lower alkylthio-lower alkyl groups such as methyl-1-methoxyethyl; Lower alkyl- and arylsulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; And substituted silyl groups such as trimethylsilyl, triethylsilyl, triisoprophylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl Etc. can be mentioned. [18] The protecting group of the amino group includes all groups which can be used as a normal amino protecting group, for example, methoxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, 2,2,2-trifluoro Roethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, tert-butoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1-adamantyloxycarbonyl , Benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, diphenylmethoxycarbonyl, 4 Alkoxycarbonyl groups such as-(phenylazo) benzyloxycarbonyl, 2-flufuryloxycarbonyl and 8-quinolyloxycarbonyl; Acyl groups such as (mono, di, tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, putaroyl, succinyl, aranyl and loisyl; Arseralkyl groups such as benzyl, diphenylmethyl and trityl; Arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio; Alkyl or arylsulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; Di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; Ar-lower alkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene; Nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; Cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxycyclohexylidene; Cycloalkylidene group; Diaryl or diar-lower alkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; Oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl; And substituted silyl groups such as trimethylsilyl, and the like. [19] As a salt of the compound of General formula [1], the salt in acidic groups, such as a basic group, such as an amino group, and hydroxyl or a carboxyl group, which are commonly known, are mentioned. [20] As a salt in a basic group, For example, salt with inorganic acids, such as hydrochloric acid, hydrobromic acid, acetic acid, and sulfuric acid; Salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, hydroxyl, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. [21] Moreover, as a salt in an acidic group, For example, salt with alkali metals, such as sodium and potassium; Salts with alkaline earth metals such as calcium and magnesium; Ammonium salts; And trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, And salts with nitrogen-containing organic acid salt groups such as N-benzyl-β-phenethylamine, 1-ephenamine and N, N'-dibenzylethylenediamine. [22] Among the salts mentioned above, preferred salts include pharmacologically acceptable salts. [23] In the alkyl ether derivative of the general formula [1] or a salt thereof, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present, the present invention includes all of these isomers and hydrates. It includes a thing, a solvate, and all the crystalline forms. [24] As the alkyl ether derivative of the general formula [1] or a salt thereof of the present invention, preferable ones in the general formula [1] [25] [26] The part shown by the following is mentioned. [27] [28] In said formula, R <1> is a hydrogen atom; It is mentioned as preferable that R <2> is a hydrogen atom, a halogen atom, and an alkoxy group. [29] Moreover, in general formula [1], the thing of m = 2 and n = 2-3 is preferable, and p = 1-2 are mentioned as a more preferable compound. [30] Most preferably, R <1> and R <2> in said (A) are a hydrogen atom; R 3 is hydroxyl group; m = 2; n = 3; p = 1. [31] Next, the manufacturing method of the alkyl ether derivative of general formula [1] or its salt is demonstrated. [32] The alkyl ether derivative of the general formula [1] or a salt thereof can be produced by, for example, a production method shown below by appropriately combining a method known per se or a combination thereof. [33] Manufacturing Method 1 [34] [35] Manufacturing Method 2 [36] [37] Manufacturing Method 3 [38] [39] Manufacturing Method 4 [40] [41] Manufacturing Method 5 [42] [43] "Wherein R 1 , R 2 , R 3 , R 4 , A, m, n and p have the same meaning as described above; R 3a is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; R 3b is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; R 3c is a protected hydroxyl group; R 3d is a monoalkylamino group, an amino group or a hydroxyl group; X 1 , X 2 and X 3 each represent a leaving group. [44] As a leaving group, a halogen atom, a lower alkylsulfonyloxy group, an alisulfonyloxy group, etc. are mentioned, for example. [45] Next, each manufacturing method is demonstrated. [46] Manufacturing Method 1 [47] The compound of General formula [4] can be manufactured by making the compound of General formula [3] react with the compound of (1-1)-general formula [2], or its reactive derivative. [48] This reaction can be carried out by a method known in the art, for example, the Experimental Chemistry Lecture, Vol. 22, Japanese Chemical Society, pp. 137-173, the method described in 1992 (Maruzen) or a method equivalent thereto. [49] As a reactive derivative of the compound of General formula [2], an acid halide, an acid anhydride, an active amide, an active ester, etc. are mentioned, for example. [50] When using the compound of General formula [2] in the form of a free acid, it is preferable to react in presence of a condensing agent. [51] As a condensing agent, For example, N, N'- dialkyl carboxylic diimides, such as N and N'- dicyclohexyl carbodiimide; Halogenating agents such as thionyl chloride and oxaryl chloride; Acid halides such as ethoxycarbonyl chloride; Active amide agents such as carbonyldiimidazole; And azide agents such as azide diphenyl phosphate. [52] The amount of the condensing agent may be used in an equimolar amount or more with respect to the compound of the general formula [2], preferably 1 to 5 times mole. [53] The solvent used in this reaction may be any one which does not adversely affect the reaction. For example, water; Halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; Amides such as N, N'-dimethylformamide; Esters such as ethyl acetate; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; And heteroaromatics such as pyridine, and the like may be used by mixing these solvents. [54] This reaction can be carried out in the presence of a base. [55] Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, tert-butoxy potassium, sodium carbonate, and carbonic acid. Organic acid salt groups, such as sodium hydrogen, potassium carbonate, and sodium hydroxide, or an inorganic acid salt group are mentioned. [56] The usage-amount of a base may use 0.5 times mole or more with respect to the compound of General formula [2], Preferably it is 1-10 times mole. [57] The usage-amount of the compound of General formula [3] is equimolar or more with respect to the compound of General formula [2], Preferably it is 1-20 times mole. [58] This reaction is usually performed at -100 to 200 ° C, preferably at -60 to 100 ° C for 10 minutes to 20 hours. [59] The obtained compound of the general formula [4] may be used for the following reaction without isolation. [60] (1-2) The compound of the hydroxyl group in which R < 3a is not protected in the compound of General formula [4] is made into the compound of General formula [4a] by attaching to the normal reaction of protecting a hydroxyl group. It can be derived. [61] This reaction is known in its own way, for example, Protective Groups in Organic Synthesis, pp. 10-118, 1991 Theodra W. Green, John Wiley & Sons. The method described in Inc. or a method similar thereto may be used. [62] As a compound used for the protection reaction of this hydroxyl group, For example, Acid anhydrides, such as acetic anhydride; Benzoyl chloride, pivaloyl chloride. Acid halides such as methoxycarbonyl chloride and ethoxycarbonyl chloride; Halides such as methoxymethyl chloride, benzoyloxymethyl chloride, benzyl chloride, benzylpromide, trityl chloride, triethylsilyl chloride, organic carboxylic acid compounds such as benzoic acid, dialkoxyalkyl compounds such as dimethoxymethane, 2- Acyclic and cyclic alkoxy vinyl compounds, such as a methoxy propene and 3, 4- dihydro-2H-pyran, etc. are mentioned. [63] The amount of the compound used for the protection reaction of the hydroxyl group may be used 1 mole or more with respect to the compound of the general formula [4a], preferably 1 to 2 moles. [64] The protection reaction of hydroxyl groups using acid anhydrides, acid halides and halides is usually carried out in the presence of a base or a dehalogenating agent, and examples of the base used include, for example, triethylamine, N, N-diiso. Propylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, tert-butoxypotassium, sodium hydroxide, potassium hydroxide and sodium hydride An organic base or an inorganic base, and as a dehalogenation agent, silver compounds, such as silver oxide, are mentioned. [65] The protective reaction of the hydroxyl group using the organic carboxylic acid compound is carried out in the presence of a dehydrating agent, and examples of the dehydrating agent used include triphenylphosphine-diisopropyl = azodicarboxylate and the like. [66] Moreover, the protection reaction of the hydroxyl group using an acid anhydride, dialkoxyalkyl compound, acyclic and cyclic alkoxy vinyl compound is normally performed in presence of an acid catalyst, As an acid used, Eutechonic acid, such as p-toluenesulfonic acid, is used. And inorganic acids such as hydrochloric acid and sulfuric acid, and Lewis acids such as boron trifluoride, boron trifluoride diethyl ether complex, and boron trifluoride tetrahydrofuran complex. [67] The amount of the base, the dehalogenating agent, and the dehydrating agent used in this reaction may be used 1 mole or more with respect to the compound used for the protection reaction of the hydroxyl group, preferably 1 to 2 moles. The acid amount of the catalyst may be used in an amount of 0.001 to 10 times or more, and preferably 0.01 to 1 times or more, based on the compound of the general formula [4a]. [68] As a solvent used for this reaction, what is necessary is just so long as it does not adversely affect reaction, For example, Halogenated hydrocarbons, such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; Amides such as N, N-dimethylformamide; Esters such as ethyl acetate; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; And heteroaromatics such as pyridine, and these solvents may be used by mixing. [69] This reaction is usually performed at -100 to 200 ° C, preferably at -60 to 100 ° C for 10 minutes to 30 hours. [70] The reaction reagent or base used in each of the above production methods may be used as a solvent depending on their properties. [71] The obtained compound of the general formula [4a] can also be used for the next reaction without being isolated. [72] (1-3) The compound of the general formula [1] can be prepared by adding the compound of the general formula [4] or the general formula [4a] to a normal reduction reaction. [73] This reduction reaction is a method described in a publicly known method, for example, New Experimental Chemistry Lecture, Vol. 15, [II] Japanese Chemical Society, pp. 29-244, 1977 (Maruzen), or What is necessary is just to carry out in a similar way. [74] As the solvent used in this reaction, any solvent may be used as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; And alcohols such as methanol, ethanol and isopropanol. These solvents may be used in combination. [75] As a reducing agent, For example, aluminum hydrides, such as lithium aluminum hydride; And boron hydrides such as diborane, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, and sodium borohydride. [76] When using sodium borohydride as a reducing agent, it is preferable to perform reaction in presence of Lewis acid, such as a boron trifluoride, a boron trifluoride diethyl ether complex, a boron trifluoride tetrahydrofuran complex, and the like. [77] The amount of the reducing agent used may be 0.2 times or more moles, preferably 0.5 to 10 times mole, based on the compound of the general formula [4] or the general formula [4a]. [78] The amount of Lewis acid to be used may be used in an equimolar amount or more with respect to the reducing agent, and preferably 4/3 to 2 times mole. [79] This reaction is usually performed at -50 to 200 ° C, preferably 0 to 110 ° C, for 10 minutes to 20 hours. [80] Manufacturing Method 2 [81] In the presence or absence of a base, the compound of the general formula [1a] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [3]. [82] The solvent used in this reaction may be any one which does not adversely affect the reaction. Examples of the solvent include halogenated hydrocarbons such as water, methyl chloride and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as tetrahydrofuran and dioxane; Alcohols such as methanol and ethanol; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide; And sulfoxides such as dimethyl sulfoxide, and the like, and these solvents may be mixed and used. [83] Examples of the base to be used as necessary include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, tert-butoxy Organic bases or inorganic bases such as potassium, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide. [84] The base may be used in an amount of 0.5 times or more based on the compound of the general formula [5], and preferably 1 to 20 times mole. [85] This reaction can also be carried out in the presence of a catalyst. [86] As a catalyst, potassium iodide, sodium iodide, etc. are mentioned, for example. [87] The amount of the catalyst to be used may be 0.01 to 10 moles or more, and preferably 0.1 to 1 moles, based on the compound of the general formula [5]. [88] The usage-amount of the compound of General formula [3] may use more than equimolar with respect to the compound of General formula [5], Preferably it is 1-20 times mole. [89] This reaction is usually performed at 0 to 200 ° C, preferably at 20 to 150 ° C for 10 minutes to 20 hours. [90] The reaction reagent or base used in each of the above production methods can be used as a solvent depending on their properties. [91] Manufacturing Method 3 [92] The compound of General formula [1b] can be manufactured by making the compound of General formula [7] react with the compound of General formula [6] in presence of a base. [93] This reaction is a method of self-announcement, for example, Tetrahedron Letters, Vol. 38, pp. 3151-3254, 1975 and New Experimental Chemistry Lectures, vol. 14 [I], Japanese Chemical Society, 567-611 May be carried out by the method described in 1977 (Maruzen) or a method equivalent thereto. [94] As a base, sodium hydride, sodium hydroxide, potassium hydroxide, tert-butoxy potassium, etc. are mentioned, for example. [95] As the solvent used in this reaction, any solvent may be used as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; Amides such as N, N-dimethylformamide; And water etc. are mentioned, These solvent may be mixed and used. [96] This reaction can also be carried out in the presence or absence of a catalyst. [97] As the catalyst to be used, a commonly known phase transfer catalyst of a quaternary ammonium salt may be mentioned. Preferably, tetrahydrogen sulfate-n-butylammonium, tetra-n-butylammonium bromide, etc. are mentioned. [98] In this reaction, the amount of the compound of the general formula [7] and the base may be used in an equimolar amount or more with respect to the compound of the general formula [6], preferably 1 to 20 times molar. The amount of catalyst is 0.001 to 1 molar. [99] This reaction is usually performed at -50 to 200 ° C, preferably 0 to 150 ° C, for 10 minutes to 20 hours. [100] Manufacturing Method 4 [101] In the presence or absence of a base, the compound of the general formula [1b] can be produced by reacting the compound of the general formula [8] with the compound of the general formula [9]. [102] This reaction may be carried out by a method known per se, for example, in the same manner as in Production Process 3. [103] Manufacturing Method 5 [104] (5-1) The compound of the general formula [1c] can be prepared by adding the compound of the general formula [1a] and the general formula [1b] to a normal deprotection reaction. [105] This reaction is known in the art, for example, Protective Groups in Organic Synthesis, pp. 10-118 and pp. 309-405, Theodra W. Green, 1991, John Wiley & Sons. Inc)] or a method similar thereto. [106] This deprotection reaction is carried out under conditions such as hydrolysis and transesterification in the presence of an acid or a base, substitution and desorption reactions under an acid catalyst, hydrolysis under a metal catalyst, and the like. Sodium hydroxide, potassium hydroxide, sodium hydride and the like are inorganic bases, and organic acids such as p-toluenesulfonic acid, organic carboxylic acids such as formic acid, acetic acid and trifluoroacetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and boron trifluoride And Lewis acids such as boron trifluoride ethyl ether complex and boron trifluoride tetrahydrofuran complex include transition metals such as platinum, palladium, palladium carbon, and palladium hydroxide. [107] The base used for this reaction is good to use 1 mol or more with respect to the compound of General formula [1a] and [1b], Preferably it is 1-5 times mole. The usage-amount of an acid may use 1 time mole or more with respect to the compound of General formula [1a] and [1b], Preferably it is 1.1-100 time mole. The amount of the acid of the metal catalyst used may be a catalyst amount based on the compounds of the general formulas [1a] and [1b], preferably 0.01 to 30% by weight. [108] As the solvent used in this reaction, any solvent may be used as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; Amides such as N, N-dimethylformamide; Esters such as ethyl acetate; Ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; Alcohols such as methanol and ethanol; Organic carboxylic acids such as formic acid and acetic acid; Water, and the like, and these solvents may be mixed and used. [109] The reaction is usually performed at -100 to 200 ° C, preferably at -60 to 120 ° C for 10 minutes to 20 hours. [110] In addition, the acid used in each said manufacturing method can be used using these as a solvent according to these properties. [111] (5-2) A compound of the general formula [1c] can be added to a compound of the general formula [1b] by attaching it to a protective reaction of a normal hydroxyl group and an amino group or an alkylation reaction of an amino group. [112] Protective reactions of these hydroxyl groups are known in their own way, for example, Protective Groups in Organic Synthesis, pp. 10-118, 1991 [Theodra W. Green], John Wiley & Sons. Inc)] or a method similar thereto, and may be carried out in the same manner as in Example (1-2). [113] The protective reaction of this amino group is known in its own way, for example, Protective Groups in Organic Synthesis, pp. 309-405, Theodra W. Green, 1991, John Wiley & Sons. Inc)] or a method similar thereto. [114] As a compound used for the protection reaction of an amino group, For example, Acid anhydrides, such as acetic anhydride; Acid halides such as acetyl chloride, benzoyl chloride, mesyl chloride and tosyl chloride, and the like, and the like may be used in an amount of at least 1 mole with respect to the compound of the general formula [1c], preferably 1 to 2 moles. . [115] This reaction is usually carried out in the presence of a base, and examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). ), Pyridine, tert-butoxy potassium, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydride such as organic bases and inorganic bases. [116] The amount of base to be used may be 0.5 molar or more, and preferably 1 to 10 molar, with respect to the compound of the general formula [1c]. [117] As a solvent used for this reaction, what is necessary is just so long as it does not adversely affect reaction, For example, Halogenated hydrocarbons, such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; Amides such as N, N-dimethylformamide; Esters such as ethyl acetate; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; Alcohols such as methanol and ethanol; Water etc. can be mentioned, and these solvent can also be mixed and used. [118] The reaction is usually performed at -100 to 200 ° C, preferably at -60 to 120 ° C for 10 minutes to 20 hours. [119] In addition, the alkylation reaction of this amino group can be carried out by a method known per se, for example, the New Experimental Chemistry Lecture, Volume 14 [III], Japanese Chemical Society, pp. 1332-1399 (1997, Maruzen). Or it may be carried out by a method similar thereto. [120] As a compound used for the alkylation reaction of an amino group, carbonyl compounds, such as formalin, pallaformaldehyde, acetaldehyde, acetone, are mentioned, for example. [121] The amount used may be usually 1 mole or more, and preferably 1 to 5 moles, relative to the compound of the general formula [1c]. [122] This reaction is usually performed in the presence of a reducing agent, and examples of the reducing agent include boron hydrides such as sodium borohydride. [123] The amount of the reducing agent used may be 0.5-fold molar or more with respect to the carbonyl compound, and preferably 1-10 moles. [124] The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as water, methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Alcohols, such as methanol and ethanol, etc. are mentioned, You may mix and use these solvent. [125] This reaction is usually performed at -100 to 200 ° C, preferably at 0 to 100 ° C for 10 minutes to 30 hours. [126] The reaction reagents used in each of the above production methods can be used as solvents depending on their properties. [127] In said manufacturing method, the compound of General formula [2]-[9] can also be used as a salt, As these salt, the same salt as the salt of the compound of General formula [1] is mentioned. Moreover, the salt similar to the salt of the compound of General formula [1] is mentioned as a salt of the compound of General formula [1a], [1b], and [1c]. [128] In the compounds of the general formulas [1a], [1b], [1c] and [2] to [9], when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present, all of these isomers And hydrates, solvates and all crystalline forms can be used. [129] In addition, the compounds of the general formulas [1a], [1b], [1c] and [2] to [9] are not isolated but may be used for the following reactions as they are. [130] In the compounds of the general formulas [1a], [1b], [1c] and [2] to [9], the compound having a hydroxyl group, an amino group or a carboxyl group is a hydroxyl group, an amino group or a carboxyl group in advance. Protected with a conventional protecting group, after the reaction, these protecting groups can be detached by a method known per se as necessary. [131] Further, alkyl ether derivatives of the general formulas [1], [1a], [1b] and [1c] or salts thereof, for example, oxidation reaction, reduction reaction, alkylation reaction, halogenation reaction, sulfonylation reaction and substitution reaction By appropriately combining methods known per se, such as dehydration reaction and hydrolysis reaction, it can be derived from another alkyl ether derivative of the general formula [1] or a salt thereof. [132] The alkyl ether derivatives of the general formulas [1], [1a], [1b] and [1c] obtained in this way or their salts can be isolated and purified by conventional methods such as extraction, crystallization, distillation and column chromatography. have. [133] Next, the manufacturing method of the compound of General formula [2] and [5] which is a raw material for manufacturing the compound of this invention is demonstrated. [134] The compound of General formula [2] can be manufactured by the manufacturing method A shown below by the well-known method or combining these suitably, for example. [135] Manufacturing Method A [136] [137] "Wherein R 1 , R 2 , A, X 3 , m and n have the same meaning as described above; R 4 is a cyano group, a lower alkoxycarbonyl group, a dialkylaminocarbonyl group or a cyclic aminocarbonyl group; X 4 means each leaving group. '' [138] (A-1) The compound of General formula [11] can be manufactured by making the compound of General formula [10] react with the compound of General formula [6] in presence of a base. [139] This reaction can be carried out by a method known per se, for example, the New Experimental Chemistry Lecture, Vol. 14, [I], Japanese Chemical Society, pp. 567-611, 1997 (Maruzen), or a method equivalent thereto. It is good to carry out. [140] (A-2) The compound of General formula [11] can be manufactured by making the compound of General formula [12] react with the compound of General formula [8] in presence of a base. [141] This reaction may be carried out by a method known per se, for example, in the same manner as in the production method (A-1). [142] (A-3) The compound of the formula [2] can be prepared by adding the compound of the formula [11] to a hydrolysis reaction of a common nitrile, ester or amide. [143] This reaction is a method of self-announcement, for example, New Experimental Chemistry Lecture, Volume 14 [II], Japanese Chemical Society, pp. 930-950, 1997 (Maruzen) and Protective Groups in Organic Synthesis, No. 152 192, Theodra W. Green, John Wiley & Sons. Inc)] or a method similar thereto. [144] (A-4) A compound of the formula [11a] can be prepared by subjecting the compound of the formula [16] to the compound of the formula [16] in the presence of a base by Michael addition. have. [145] This reaction is a method known per se, for example, Chemical & Pharmaceutical Bulletion, Vol. 41, pp. 1659-1663, 1993, New Experimental Chemistry Lecture, Vol. 14, [I], Japanese Chemical Society, The method described in pp. 585-587, 1997 (Maruzen) and Japanese Patent Laid-Open No. 3-99038 or a method equivalent thereto may be performed. [146] (A-5) A compound of the general formula [2a] can be prepared by applying the compound of the general formula [11a] to a hydrolysis reaction of a common nitrile, ester or amide. [147] This reaction may be carried out by a method known per se, for example, in the same manner as in (A-3). [148] The compound of General formula [5] can be manufactured by the manufacturing method B shown below, for example by a method known per se or by combining these suitably. [149] Manufacturing Method B [150] [151] "Wherein R 1 , R 2 , X 1 , A, m and n have the same meaning as described above; R 4a is an alkoxycarbonyl group; R 5 is a basic, stable hydroxyl protecting group; X 5 and X 6 each represent a leaving group. [152] As basic hydroxyl stable group, For example, Lower alkyl groups, such as tert- butyl; Lower alkenyl groups such as allyl; Ar-lower alkyl groups such as benzyl group, 4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; Oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; Lower alkoxy-lower alkyl groups such as methoxymethyl, 2- (trimethylsilyl) ethoxymethyl, and 1-methyl-1-methoxyethyl; And substituted silyl groups such as tert-butyldimethylsilyl and diphenylmethylsilyl. [153] (B-1) The compound of General formula [5] can be manufactured by making the compound of General formula [6] react with the compound of General formula [6]. [154] This reaction is known per se, for example in Tetrahedron. Letters. Vol. 38, pp. 3151-3254, 1975 and New Experimental Chemistry Lectures, Vol. 14 [I], Japanese Chemical Society, pp. 567-611, 1977 (Maruzen), or a method equivalent thereto. It is good to carry out. [155] (B-2) The compound of general formula [15] can be manufactured by making compound of general formula [14] react with compound of general formula [6], and then detaching a protecting group. [156] This reaction may be carried out by a method known per se, for example, in the same manner as in Production Method 3, to remove the protecting group. [157] (B-3) The compound of General formula [15] can be manufactured by adding the compound of General formula [2] or the compound of General formula [11b] to a normal reduction reaction. [158] This reduction reaction may be carried out by a method known per se, for example, the New Experimental Chemistry Lecture, Vol. 15, pp. 26 to 244, the method described in 1977 (Maruzen), or a method similar thereto. [159] (B-4) A compound of the general formula [5] can be prepared by reacting a compound of the general formula [15] with a halogenating agent or a sulfonylating agent in the presence or absence of a base. [160] As a solvent used for this reaction, For example, halogenated hydrocarbons, such as methylene chloride and chloroform; Ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; Amides such as N, N-dimethylformamide; Esters such as ethyl acetate; And nitriles such as acetonitrile, and these solvents may be mixed and used. [161] Moreover, as a base used as needed, for example, triethylamine, diisopropylethylamine, 1,8- diazabicyclo [5.4.0] undec-7-ene, pyridine, tert-butoxy potassium And organic or inorganic bases such as sodium carbonate, potassium carbonate and sodium hydride. [162] As a halogenating agent, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, carbon tetrabromide triphenylphosphine, thionyl chloride, etc. are mentioned, for example. [163] As a sulfonylating agent, methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. are mentioned, for example. [164] The usage-amount of a halogenating agent, a sulfonylating agent, and a base is good to use equimolar or more with respect to the compound of General formula [15], respectively, Preferably it is 1-2 times mole. [165] This reaction is usually performed at -50 to 200 ° C, preferably 0 to 50 ° C, for 10 minutes to 30 hours. [166] In the compounds of the general formulas [2], [2a], [6], [8], [10] to [16], [11a] and [11b] in the production methods A and B, a hydroxyl group, The compound which has an amino group or a carboxyl group can protect these hydroxyl groups, an amino group, or a carboxyl group by a normal protecting group previously, and can remove these protecting groups by a well-known method as needed after reaction. [167] Also, isomers (e.g., optical isomers, geometric isomers and tautomers) for the compounds of [2], [2a], [6], [8], [10] to [16], [11a] and [11b] Etc.), all these isomers can be used, and hydrates, solvates and all crystalline forms can be used. [168] In addition, the compounds of the general formulas [2], [2a], [6], [8], [10] to [16], [11a], and [11b] are not isolated but are used in the following reactions as they are. Also good. [169] Compounds of the present invention include excipients, binders, disintegrating agents, disintegrating inhibitors, anti-caking agents, lubricants, absorption and adhering agents, solvents, extenders, isotonic agents, dissolution aids, emulsifiers, suspending agents, thickeners, coating agents, and Accelerator, Gelation & Coagulation Accelerator, Light Stabilizer, Protective Agent, Desiccant, Emulsifying · Suspension · Dispersion Stabilizer, Coloring Agent, Deoxygenation · Antioxidant, Colic · Odor Agent, Colorant, Foaming Agent, Defoamer, Pain-proofing Agent, Antistatic Agent, Buffering · pH Formulated with various pharmaceutical additives such as regulators, oral preparations (tablets, capsules, powders, granules, granules, pills, suspensions, emulsions, solutions, syrups, etc.), injections, suppositories, external preparations (ointments, patches, etc.) And pharmaceutical preparations such as aerosols. [170] The said various preparations are formulated by a conventional method. [171] Oral solid preparations such as tablets, powders and granules include, for example, lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dicalcium phosphate, partially alpha starch, corn starch and Excipients such as alginic acid; Sweet syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, cerac, methyl cellulose, ethyl cellulose, sodium alginate, gum arabic Binders such as hydroxypropylmethylcellulose, hydroxypropylcellulose, water and ethanol; Disintegrating agents such as dried starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl cellulose sodium, carboxymethyl cellulose calcium and sodium starch glycolate; Disintegration inhibitors such as stearyl alcohol, stearic acid, cacao butter and hydrogenated oil; Anti-freezing and anti-sticking agents such as aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc and silicic anhydride; Carnabare, hard silicic anhydride, aluminum silicate, magnesium silicate, hardened oil, hardened plant fluid, sesame oil, white beewax, titanium oxide, dry aluminum hydroxide gel, stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate Lubricants such as sodium lauryl sulfate and polyethylene glycol; Absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate, urea and enzymes; If prepared according to a conventional method using pharmaceutical additives for solid preparation such as absorption and adsorption carriers such as starch, lactose, kaolin, bentonite, silicic anhydride, hydrous silicon dioxide, magnesium metasilicon aluminate and colloidal silicic acid, good. [172] If necessary, tablets may be conventionally coated tablets, for example, sugar-coated tablets, gelatin coated tablets, gastric coated tablets, enteric coated tablets, and water-soluble film coated tablets. [173] Capsules are prepared by mixing with various pharmaceutical products exemplified above, filling hard gelatine capsules and soft capsules. [174] In addition, the above-mentioned various additives for liquid papermaking, such as solvents, extenders, isotonic agents, dissolution aids, emulsifiers, suspending agents, and thickeners, may be prepared according to a conventional method, and used in aqueous or oily suspensions, solutions, syrups, and It can also be called elixir. [175] Suppositories may be prepared by, for example, adding an appropriate absorption accelerator to polyethylene glycol, cacao butter, lanolin, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glycide, and witezole. [176] Injectables include, for example, diluents such as ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, and sodium hydroxide; PH adjusters and buffers, such as sodium citrate, sodium acetate, and sodium phosphate; Stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid; Tonicity agents such as salt, glucose, mannitol or glycerin; Dissolution aids such as sodium carboxymethyl cellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin; Painless agents such as calcium glyconate, chlorobutanol, glucose and benzyl alcohol; And pharmaceutical additives for liquid preparation, such as a local anesthetic, may be prepared according to a conventional method. [177] Ointments in the form of pastes, creams and gels include, for example, bases such as white vaseline, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone and bentonite; Preservatives such as methyl paraoxybenzoate, ethyl paraoxybenzoate and propyl paraoxybenzoate; Stabilizer; What is necessary is just to mix and formulate by a conventional method using pharmaceutical additives, such as a humectant. [178] When manufacturing a patch, what is necessary is just to apply the said ointment, cream, gel, or paste to a normal support body by a conventional method. As a support body, Woven or nonwoven fabric which consists of cotton, staple fiber, and chemical fiber; Films or foam sheets such as soft vinyl chloride, polyethylene and polyurethane can be used. [179] The method of administering the above formulation is not particularly limited, but is appropriately determined according to the form of the formulation, the age of the patient, sex and other conditions, and the degree of symptoms of the patient. [180] The dosage of the active ingredient of the preparation of the present invention is appropriately selected according to the usage, the age, sex of the patient, the form of the disease and other conditions, and the like is usually divided into 0.1 to 500 mg once to several times per day for an adult. It is good to administer. [181] Next, an Example, a reference example, and a test example are given and this invention is demonstrated, but this invention is not limited to these illustrations. [182] In addition, all the mixing ratios in an eluent are volume ratios, and the support | carrier in column chromatography is B.W. Silica gel, BW-127ZH, and FL-100DX (manufactured by Fuji-Silica Kagakusha) were used. [183] In addition, the symbol in reaction drawing has the following meaning. [184] Ac: acetyl, Boc: tert-butoxycarbonyl, Bz: benzoyl, Piv: pivaloyl, Bn: benzyl, Tr: trityl, MOM: methoxymethyl, BOM: benzyloxymethyl, TES: triethylsilyl, THP: tetrahydropyranyl, Ms: mesyl, Me: methyl, Et: ethyl, Ph: phenyl, t-Bu: tert-butyl [185] Example 1 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-azetidinol [186] [187] (1) 1.20 g of 2- [2- (1-benzothiophen-5-yl) ethoxy] acetic acid was dissolved in 12 ml of methylene chloride, and 2.3 ml of triethylamine and 0.38 g of imidazole were added to this solution. After cooling to 5 ° C, 0.41 ml of thionyl chloride was added dropwise and stirred at the same temperature for 1 hour. After cooling to -60 ° C, 0.82 ml of triethylamine and 0.72 g of 3-azetidinol hydrochloride were added to the reaction mixture, which was stirred at the same temperature for 1 hour and at room temperature for 1.5 hours. Water was added to the reaction mixture, the pH was adjusted to 1.0 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and yellow oily 2 [2- (1-benzothiophen-5-yl) ethoxy] -1- (3- Hydroxy-1-azetidinyl) -1-ethanone was obtained. [188] (2) 12 ml of tetrahydrofuran in the above 2- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetidinyl) -1-ethanone It melt | dissolved in and cooled to 5 degreeC, Then, 12.7 ml of 1 mol / L tetrahydrofuran solutions of a borane- tetrahydrofuran complex were dripped, and it stirred at room temperature for 17 hours. 10 ml of acetone was added to the reaction mixture, stirred for 30 minutes, and 6.0 ml of 6 mol / L hydrochloric acid was added thereto, followed by heating to reflux for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 13 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and yellow oily 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl}. 1.13 g of 3-azetidinol were obtained. [189] IR (neat) cm -1 : 3378, 2943, 1438, 1193, 1119, 703 [190] NMR (CDCl 3 ) δ value: 2.66 (2H, t, J = 6 Hz), 2.9-3.1 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.46 (2H, t, J = 6 Hz), 3.6-3.7 (2H, m), 3.67 (2H, t, J = 7 Hz), 4.41 (1H, qn, J = 6 Hz), 7.20 (1H, dd, J = 2.8 Hz), 7.27 (1H, d, J = 5 Hz), 7.41 (1 H, d, J = 5 Hz), 7.66 (1 H, d, 2 Hz), 7.78 (1 H, d, J = 8 Hz). [191] Example 2 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-azetidinol hydrochloride [192] [193] 1.03 g of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-azetidinol is dissolved in 4.2 ml of ethyl acetate, and 4.76 mol / L dry hydrogen chloride is added to this solution. 0.86 ml of ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour and again at 5 ° C for 1 hour. The precipitated crystals were filtered, washed with ethyl acetate and dried to obtain 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-azetidinol hydrochloride 0.98 g was obtained. [194] Melting Point: 101-102 ℃ [195] IR (KBr) cm -1 : 3132, 2952, 1423, 1340, 1158, 814, 701 [196] NMR (CDCl 3 ) δ value: 2.97 (2H, t, J = 7 Hz), 3.2-3.3 (2H, m), 3.69 (2H, t, J = 7 Hz), 3.6-3.8 (2H, m), 3.9- 4.1 (2H, m), 4.2-4.4 (2H, m), 4.6-4.8 (1H, m), 7.18 (1H, dd, J = 1.8 Hz), 7.29 (1H, d, J = 5 Hz), 7.41 ( 1 H, d, J = 5 Hz), 7.65 (1 H, d, 1 Hz), 7.78 (1 H, d, J = 8 Hz). [197] Example 3 Preparation of 1- {3- [2- (1-benzothiophen-6-yl) ethoxy] propyl} -3-azetidinol [198] [199] 1.00 g of 6- [2- (3-chloropropoxy) ethyl] 1-benzothiophene was dissolved in 5 ml of dimethyl sulfoxide, and 0.86 g of 3-azetidinol hydrochloride and 1.63 g of potassium carbonate were added to this solution. The mixture was stirred at 75 ° C. for 25 hours and at 95 ° C. for 1.5 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L hydrochloric acid, and the water layer was separated therefrom. Ethyl acetate was added to the water layer, the pH was adjusted to 10 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 30: 1-5: 1) to give a colorless oily 1- {3- [2- (1-benzothiophen-6yl) ethoxy] propyl. } 8-azetidinol 0.28 g was obtained. [200] IR (neat) cm -1 : 3398, 2940, 2867, 1197, 1107, 820, 757 [201] NMR (CDCl 3 ) δ value: 1.60 (2H, t, J = 7 Hz), 2.45 (2H, t, J = 7 Hz), 2.7-2.8 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.45 (2H, t, J = 7 Hz), 3.5-3.6 (2H, m), 3.66 (2H, t, J = 7 Hz), 4.37 (1H, qn, J = 6 Hz), 7.23 (1H, dd, J = 1, 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.37 (1H, d, J = 5 Hz), 7.73 (1H, d, 1 Hz), 7.74 (1H, d, J = 8 Hz). [202] Example 4 Preparation of 1- {3- [2- (1-benzothiophen-6-yl) ethoxy] propyl} -3-azetidinol hydrochloride [203] [204] 0.28 g of 1- {3- [2- (1-benzothiophen-6-yl) ethoxy] propyl} -3-azetidinol is dissolved in 3.0 ml of ethyl acetate and 3.25 mol / L dry hydrogen chloride is added to this solution. 0.35 ml of ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, the solvent was removed under reduced pressure to obtain 0.30 g of pale yellow oily 1- {3- [2- (1-benzothiophen-6-yl) ethoxy] propyl} -3-azetidinol hydrochloride. [205] IR (neat) cm -1 : 3264, 2866, 2596, 1398, 1109, 1048, 821 [206] NMR (CDCl 3 ) δ Value: 1.81 (2H, qn, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 2.98 (2H, t, J = 6 Hz), 3.46 (2H, t, J = 6 Hz ), 3.68 (2H, t, J = 6 Hz), 3.8-3.9 (2H, m), 3.8-4.0 (2H, m), 4.4-4.6 (1H, m), 7.23 (1H, dd, J = 1, 8 Hz), 7.31 (1H, d, J = 5 Hz), 7.39 (1H, d, J = 5 Hz), 7.74 (1H, d, 1 Hz), 7.76 (1H, d, J = 8 Hz). [207] Example 5 Preparation of 1- {3- [2- (1-benzothiophen-2-yl) ethoxy] propyl} -3-azetidinol [208] [209] In the same manner as in Example 3, colorless oily 1- {3- [2- (1-benzothiophen-2-yl) ethoxy] propyl} -3-azetidinol was obtained. [210] IR (neat) cm -1 : 3366, 2942, 2856, 1458, 1436, 1113, 750 [211] NMR (CDCl 3 ) δ value: 1.64 (2H, qn, J = 7 Hz), 2.49 (2H, t, J = 7 Hz), 2.7-2.8 (2H, m), 3.15 (2H, t, J = 7 Hz), 3.50 (2H, t, J = 7 Hz), 3.5-3.7 (2H, m), 3.71 (2H, t, J = 7 Hz), 4.3-4.4 (1H, m), 7.06 (1H, s), 7.2-7.4 (2H, m), 7.67 (1H, dd, J = 1, 7 Hz), 7.77 (1H, dd, J = 1, 7 Hz) [212] Example 6 Preparation of 1- {3- [2- (1-benzothiophen-2-yl) ethoxy] propyl} -3-azetidinol hydrochloride [213] [214] In the same manner as in Example 4, 1- {3- [2- (1-benzothiophen-2-yl) ethoxy] propyl} -3-azetidinol hydrochloride as pale yellow oil was obtained. [215] IR (neat) cm -1 : 3290, 2868, 1457, 1436, 1113, 751 [216] NMR (CDCl 3 ) δ Value: 1.83 (2H, qn, J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.16 (2H, t, J = 6 Hz), 3.52 (2H, t, J = 7 Hz ), 3.74 (2H, t, J = 6 Hz), 3.7-3.8 (2H, m), 3.7-3.9 (2H, m), 4.3-4.5 (1H, m), 7.09 (1H, s), 7.27 (1H) , dt, J = 1,8 Hz), 7.33 (1H, dt, J = 1, 8 Hz), 7.69 (1H, dd, J = 1, 8 Hz), 7.78 (1H, dd, J = 1, 8 Hz) [217] Example 7 Preparation of 1- {3- [2- (1-benzothiophen-7-yl) ethoxy] propyl} -3-azetidinol [218] [219] In the same manner as in Example 3, colorless oily 1- {3- [2- (1-benzothiophen-7-yl) ethoxy] propyl} -3-azetidinol was obtained. [220] IR (neat) cm -1 : 3368, 2942, 2856, 1458, 1105, 796, 755, 700 [221] NMR (CDCl 3 ) δ value: 1.61 (2H, qn, J = 7 Hz), 2.45 (2H, t, J = 7 Hz), 2.7-2.8 (2H, m), 3.17 (2H, t, J = 7 Hz), 3.48 (2H, t, J = 7 Hz), 3.5-3.7 (2H, m), 3.79 (2H, t, J = 7 Hz), 4.3-4.5 (1H, m), 7.20 (1H, dd, J = 1, 8 Hz), 7.32 (1H, t, J = 8 Hz), 7.36 (1H, d, J = 5 Hz), 7.43 (1H, d, J = 5 Hz), 7.70 (1H, dd, J = 1, 8 Hz) [222] Example 8 Preparation of 1- {3- [2- (1-benzothiophen-7-yl) ethoxy] propyl} -3-azetidinol hydrochloride [223] [224] In the same manner as in Example 2, colorless oily 1- {3- [2- (1-benzothiophen-7-yl) ethoxy] propyl} -3-azetidinol hydrochloride was obtained. [225] Melting Point: 105-106 ℃ [226] IR (KBr) cm -1 : 3252, 2806, 2620, 1398, 1130, 1106, 811, 708 [227] NMR (CDCl 3 ) δ value: 1.82 (2H, qn, J = 6 Hz), 2.8-3.0 (2H, m), 3.16 (2H, t, J = 6 Hz), 3.47 (2H, t, J = 6 Hz), 3.83 (2H, t, J = 6 Hz), 3.7-4.1 (4H, m), 4.5-4.7 (1H, m), 7.21 (1H, d, J = 8 Hz), 7.36 (1H, dd, J = 8 Hz) , 7.38 (1H, d, J = 5 Hz), 7.46 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 8 Hz) [228] Example 9 Preparation of (a) 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol 1 [229] [230] 6.50 g of 5- [2- (3-chloropropoxy) ethyl] -1-benzothiophene is dissolved in 30 ml of dimethyl sulfoxide, and 5.60 g of 3-azetidinol hydrochloride and 5 mol / L sodium hydroxide are dissolved in this solution. 15.3 ml of aqueous solution was added, and it stirred at 65 degreeC for 3.5 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L hydrochloric acid, and the water layer was separated therefrom. Ethyl acetate was added to the water layer, the mixture was adjusted to pH 10 with 5 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 30: 1-10: 1), and 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl}- 4.77 g of 3-azetidinol were obtained. [231] (b) Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol 2 [232] [233] (1) 100 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid was dissolved in 300 ml of tetrahydrofuran, 0.1 ml of N, N'-dimethylformamide was added, followed by jade 41.8 mL of salyl chloride was added dropwise over 10 minutes, and stirred at room temperature for 1.5 hours. This solution was dripped at 600 degreeC solution of 65.7 g of 3-hydroxyazine hydrochloride and 59.5 g of sodium hydroxide at 10 degreeC, and it stirred at room temperature for 1 hour. 600 ml of water, 500 ml of ethyl acetate and salt were added to the reaction mixture, and the organic layer was separated therefrom. 100 ml of ethyl acetate was added to the water layer, the organic layer was separated, and the obtained organic layer was combined. 100 ml of water was added to the organic layer, the mixture was adjusted to pH 3.5 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was concentrated to about 200 ml, washed successively with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. 300 ml of toluene was added to the residue, and after heating and dissolving at 50 ° C, seed crystals were added at 40 ° C and gradually cooled, followed by stirring for 30 minutes under ice-cooling. The precipitated crystals were filtered out, and 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetidinyl) -1-propanone 96.6 of light brown crystals. g was obtained. [234] (2) 30.0 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetidinyl) -1-propanone was added to chlorotrahydrofuran 60 It dissolved in ml, 274 ml of 1 mol / L tetrahydrofuran solution of borane-tetrahydrofuran complex was dripped, and it stirred at room temperature for 5 minutes. 81.9 ml of 6 mol / L hydrochloric acid was added dropwise to the reaction solution, and the mixture was refluxed for 1.5 hours. After cooling, about 290 mL of the solvent was concentrated under reduced pressure, and the insolubles were filtered off. 120 ml of water and 60 ml of toluene were added to the filtrate, and the water layer was separated and washed with 600 ml of toluene. 90 ml of ethyl acetate was added to the water layer, the pH was adjusted to 9.5 with 5 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, 5.35 g of fumaric acid and 54 ml of ethanol were added to the obtained residue, and the resulting residue was heated and dissolved at 74 ° C, followed by dropwise addition of 161 ml of ethyl acetate. After cooling gradually, the mixture was stirred at 5 to 10 ° C. for 30 minutes, and the precipitated crystals were filtered to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl}-as pale brown crystals. 22.7 g of 3-azetidinol 1/2 fumarate was obtained. [235] (3) 22.7 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol 1 / 2fumalate was suspended in 45 ml of water and acetic acid 68 ml of ethyl was added, the pH was adjusted to 9.5 with 1 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 20: 1-10: 1) and crystallized from 40 ml of diisopropyl ether to give solid-{3- [2- (1-benzothiophene). 16.0 g of 5-5-)) ethoxy] propyl} -3-azetidinol was obtained. [236] Melting Point: 60-62 ℃ [237] IR (KBr) cm -1 : 3095, 2944, 2769, 1361, 1191, 1098, 810, 709 [238] NMR (CDCl 3 ) δ value: 1.61 (2H, qn, J = 7 Hz), 2.45 (2H, t, J = 7 Hz), 2.7-2.9 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.45 (2H, t, J = 7 Hz), 3.5-3.6 (2H, m), 3.66 (2H, t, J = 7 Hz), 4.3-4.4 (1H, m), 7.22 (1H, dd, J = 1, 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 7.67 (1H, d, J = 1 Hz). 7.79 (1H, d, J = 8 Hz) [239] Example 10 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol hydrochloride [240] [241] In the same manner as in Example 2, colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol hydrochloride were obtained. [242] Melting Point: 71-73 ℃ [243] IR (KBr) cm -1 : 3301, 2937, 2809, 2631, 1125, 1099, 818, 765, 710 [244] NMR (CDCl 3 ) δ Value: 1.8-1.9 (2H, m), 2.98 (2H, t, J = 7 Hz), 2.9-3.1 (2H, m), 3.48 (2H, t, J = 6 Hz), 3.69 ( 2H, t, J = 7 Hz, 3.6-4.4 (4H, m), 4.5-4.7 (1H, m), 7.22 (1H, dd, J = 1, 8 Hz), 7.31 (1H, d, J = 5 Hz) , 7.44 (1H, d, J = 5 Hz), 7.68 (1H, d, J = 1 Hz), 7.81 (1H, d, J = 8 Hz) [245] Example 11 Preparation of 1- {3- [2- (1-benzothiophen-4-yl) ethoxy] propyl} -3-azetidinol [246] [247] In the same manner as in Example 3, colorless oily 1- {3- [2- (1-benzothiophen-4-yl) ethoxy] propyl} -3-azetidinol was obtained. [248] IR (neat) cm -1 : 3368, 2946, 2856, 1457, 1107, 759 [249] NMR (CDCl 3 ) δ value: 1.60 (2H, qn, J = 7 Hz), 2.44 (2H, t, J = 7 Hz), 2.7-2.9 (2H, m), 3.22 (2H, t, J = 7 Hz), 3.45 (2H, t, J = 7 Hz), 3.5-3.6 (2H, m), 3.70 (2H, t, J = 7 Hz), 4.3-4.5 (1H, m), 7.19 (1H, d, J = 7 Hz) , 7.28 (1H, d, J = 7 Hz), 7.44 (1H, d, J = 6 Hz), 7.46 (1H, d, J = 7 Hz), 7.76 (1H, d, J = 7 Hz) [250] Example 12 Preparation of 1- {3- [2- (1-benzothiophen-4-yl) ethoxy] propyl} -3-azetidinol hydrochloride [251] [252] In the same manner as in Example 4, 1- {3- [2- (1-benzothiophen-4-yl) ethoxy] propyl} -3-azetidinol hydrochloride as pale yellow oil was obtained. [253] IR (neat) cm -1 : 3303, 2966, 2877, 2954, 1412, 1108, 766 [254] NMR (CDCl 3 ) δ Value: 1.78 (2H, qn, J = 6 Hz), 2.82 (2H, t, J = 7 Hz), 3.21 (2H, t, J = 6 Hz), 3.43 (2H, t, J = 6 Hz ), 3.73 (2H, t, J = 6 Hz), 3.7-3.9 (2H, m), 3.8-4.0 (2H, m), 4.5-4.7 (1H, m), 7.21 (1H, d, J = 7 Hz) , 7.30 (1H, t, J = 7 Hz), 7.49 (2H, s), 7.78 (1H, d, J = 7 Hz) [255] Example 13 Preparation of 1- {3- [2- (1-benzothiophen-3-yl) ethoxy] propyl} -3-azetidinol [256] [257] 1.00 g of 3-2- (3-chloropropoxy) ethyl] -1-benzothiophene was dissolved in 5 ml of dimethyl sulfoxide, and 1.10 g of 3-azetidinol-trifluoroacetate and potassium carbonate were dissolved in this solution. 1.63 g was added and it stirred at 70 degreeC for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L hydrochloric acid, and the water layer was separated therefrom. Ethyl acetate was added to the water layer, the mixture was adjusted to pH 10 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The remaining mule was purified by column chromatography (eluent: chloroform: methanol = 30: 1-10: 1) to obtain colorless oily 1- {3- [2- (1-benzothiophen-3-yl) ethoxy]. 0.55 g of propyl} -3-azetidinol was obtained. [258] IR (neat) cm -1 : 3368, 2942, 2845, 1427, 1191, 1109, 759 [259] NMR (CDCl 3 ) δ value: 1.62 (2H, qn, J = 7 Hz), 2.47 (2H, t, J = 7 Hz), 2.7-2.9 (2H, m), 3.11 (2H, t, J = 7 Hz), 3.48 (2H, t, J = 6 Hz), 3.5-3.7 (2H, m), 3.74 (2H, t, J = 7 Hz), 4.3-4.5 (1H, m), 7.18 (1H, s), 7.33 (1H , dt, J = 1, 7 Hz), 7.39 (1H, dt, J = 1, 7 Hz), 7.77 (1H, dd, J = 1, 7 Hz), 7.86 (1H, dd, J = 1, 7 Hz) [260] Example 14 Preparation of 1- {3- [2- (1-benzothiophen-3-yl) ethoxy] propyl} -3-azetidinol hydrochloride [261] [262] In the same manner as in Example 4, pale yellow oily 1- {3- [2- (1-benzothiophen-3-yl) ethoxy] propyl} -3-azetidinol hydrochloride was obtained. [263] IR (neat) cm -1 : 3284, 2966, 2596, 1428, 1112, 1049, 765, 734 [264] NMR (CDCl 3 ) δ Value: 1.83 (2H, qn, J = 6 Hz), 2.96 (2H, t, J = 6 Hz), 3.12 (2H, t, J = 6 Hz), 3.48 (2H, t, J = 6 Hz ), 3.76 (2H, t, J = 6 Hz), 3.8-3.9 (2H, m), 3.9-4.1 (2H, m), 4.5-4.7 (1H, m), 7.21 (1H, s), 7.35 (1H) , dt, J = 1, 7 Hz), 7.40 (1H, dt, J = 1, 7 Hz), 7.78 (1H, dd, J = 1, 7 Hz), 7.86 (1H, dd, J = 1, 7 Hz) [265] Example 15 Preparation of N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol) acetamide [266] [267] 0.80 g of 5- [2- (3-cyclopropoxy) ethyl] -1-benzothiophene is dissolved in 8 ml of N, N-dimethylformamide, and N- (3-azetynyl) acetamide 1.20 is added to this solution. g was added and stirred at 90 ° C for 12 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; chloroform: methanol = 7: 1) to give N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl as pale yellow oil. } -3-azetidinol) acetamide was obtained. [268] IR (neat) cm -1 : 3276, 2941, 2860, 1654, 1559, 1111, 756, 703 [269] NMR (CDCl 3 ) δ Value: 1.59 (2H, qn, J = 7 Hz), 1.97 (3H, s), 2.42 (2H, t, J = 7 Hz), 2.7-2.9 (2H, m), 2.98 (2H, t, J = 7 Hz, 3.45 (2H, t, J = 7 Hz), 3.4-3.6 (2H, m), 3.66 (2H, t, J = 7 Hz), 4.4-4.5 (1H, m), 7.22 (1H , dd, J = 1, 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.67 (1H, d, J = 1 Hz), 7.80 (1H, d, J = 8Hz) [270] Example 16 Preparation of 1- {2- [2-1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol [271] [272] (1) 0.74 g of 2- [2- (1-benzothiophen-6-yl) ethoxy] acetic acid was dissolved in 7.4 mL of methylene chloride, 1.36 mL of triethylamine and 0.22 g of imidazole were added to this solution. Subsequently, after cooling to 5 degreeC, 0.24 ml of thionyl chlorides were dripped, and it stirred at the same temperature for 1 hour. After cooling to -50 ° C, 0.45 ml of triethylamine and 0.32 ml of 3-pyrrolidinol were added to the reaction mixture, which was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Water was added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed with 1 mol / L hydrochloric acid, 2 mol / L aqueous sodium hydroxide solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and 2- [2- (1-benzothiophen-6-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanol as light yellow oil was obtained. Got a rice paddy. [273] IR (neat) cm -1 : 3386, 2942, 1636, 1106, 758 [274] (2) 7.4 mL of the above 2- [2- (1-benzothiophen-6-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanone with tetrahydrofuran It melt | dissolved in 7.4 ml of 1 mol / L tetrahydrofuran solutions of borane-tetrahydrofuran complex, was dripped under ice-cooling, and it stirred at room temperature for 17 hours. 10 ml of acetone was added to the reaction mixture, stirred for 30 minutes, and then 1.5 ml of 6 mol / L hydrochloric acid was added thereto, followed by heating to reflux for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and the water layer was separated therefrom. Acetic acid ether was added to the water layer, and after adjusting to pH9.5 with 2 mol / L aqueous sodium hydroxide solution, the organic layer was isolate | separated. [275] The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 30: 1-20: 1) to obtain 1- {2- [2- (1-benzothiophen-6-yl) ethoxy] as a yellow oil. 0.53 g of ethyl} -3-pyrrolidinol was obtained. [276] IR (neat) cm -1 : 3386, 2940, 2867, 1110, 820, 756 [277] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.0-2.2 (1H, m), 2.31 (1H, dt, J = 7, 9Hz), 2.53 (1H, dd, J = 5, 10Hz ), 2.6-2.7 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.01 (2H, t, J = 7 Hz), 3.58 (2H, t, J = 6 Hz), 3.71 (2H, t, J = 7 Hz), 4.2-4.3 (1H, m), 7.23 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.37 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 8 Hz), 7.73 (1H, s) [278] Example 17 Preparation of 1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol oxalate [279] [280] 0.48 g of 1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol is dissolved in 2.0 ml of ethyl acetate, and 0.15 g of hydroxide is contained in this solution. A 2.8 ml solution of ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour and again at 5 ° C for 1 hour. The precipitated crystals were filtered, washed with ethyl acetate, dried and colorless crystals 1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol 0.42 g of oxalate was obtained. [281] IR (neat) cm -1 : 3384, 2862, 2687, 1717, 1636, 1400, 1200, 1114, 720 [282] NMR (DMS0-d 6 ) δ Value: 1.7-1.8 (1H, m), 1.9-2.1 (1H, m), 2.96 (2H, t, J = 7, 9Hz), 3.0-3.2 (1H, m), 3.1-3.4 (5H, m), 3.6-3.8 (4H, m), 4.3-4.4 (1H, m), 7.29 (1H, d, J = 8 Hz), 7.41 (1H, d, J = 5 Hz), 7.68 (1H, d, J = 5 Hz), 7.80 (1H, d, J = 8 Hz), 7.87 (1H, s) [283] Example 18 Preparation of 1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol [284] [285] In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanone Got. [286] NMR (CDCl 3 ) δ values: 1.6-2.2 (2H, m), 2.9-4.0 (8H, m), 4.0-4.2 (2H, m), 4.0-4.2 (2H, m), 4.2-4.5 (1H, m), 7.1-7.4 (2H, m), 7.42 (1H, d, J = 5 Hz), 7.69 (1H, s), 7.79 (1H, d, J = 8 Hz) [287] Then, in the same manner as in Example 16 (2), pale yellow oily 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol was obtained. [288] IR (neat) cm -1 : 3386, 2941, 2864, 1438, 1112, 755, 702 [289] NMR (CDCl 3 ) δ Value: 1.5-2.0 (1H, m), 2.0-2.9 (7H, m), 3.00 (2H, t, J = 7Hz), 3.58 (2H, t, J = 6Hz), 3.71 ( 2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 7.21 (1H, d, J = 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz) , 7.67 (1H, s), 7.79 (1H, d, J = 8 Hz) [290] Example 19 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide [291] [292] In the same manner as in Example 17, colorless crystals of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [293] IR (KBr) cm -1 : 3347, 2943, 2687, 1719, 1404, 1119, 720 [294] NMR (CDCl 3 ) δ Value: 1.7-2.2 (2H, m), 2.9-3.8 (6H, m), 2.94 (2H, t, J = 6Hz), 3.68 (4H, t, J = 6Hz), 4.2- 4.5 (1H, m), 7.17 (1H, d, J = 8 Hz), 7.26 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.62 (1H, s), 7.78 (1H , d, J = 8 Hz) [295] Example 20 Preparation of Preparation of 1- {2- [2- (1-benzothiophen-4-yl) ethoxy] ethyl} -3-pyrrolidinol [296] [297] In the same manner as in Example 16 (1), the oily 2- [2- (1-benzothiophen-4yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl} -1-eta Got a rice paddy. [298] IR (neat) cm -1 : 3374, 2944, 1637, 1107, 761 [299] Subsequently, in the same manner as in Example 16 (2), light yellow oily 1- {2- [2- (1-benzothiophen-4yl) ethoxy] ethyl} -3-pyrrolidinol was obtained. [300] IR (neat) cm -1 : 3376, 2939, 2867, 1452, 1413, 1111, 760 [301] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.30 (1H, dt, J = 6, 9Hz), 2.53 (1H, dd, J = 5, 10Hz ), 2.6-2.7 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.25 (2H, t, J = 7 Hz), 3.58 (2H, t, J = 6 Hz), 3.75 (2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 7.20 (1H, d, J = 7 Hz), 7.27 (1H, t, J = 7 Hz), 7.44 (1H, d, J = 6 Hz), 7.46 (1H, d, J = 6 Hz), 7.75 (1H, d, J = 7 Hz) [302] Example 21 Preparation of 1- {2- [2- (1-benzothiophen-4-yl) ethoxy] ethyl} -3-pyrrolidinol hydrochloride [303] [304] 0.63 g of 1- {2- [2- (1-benzothiophen-4-yl) ethoxy] ethyl} -3-pyrrolidinol was dissolved in 5.0 ml of ethyl acetate, and the solution was dissolved in 3.25 mol / L dry hydrogen chloride. 0.80 ml of ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour and again at 5 ° C for 1 hour, and then the precipitated crystals were filtered. The precipitated crystals were washed with ethyl acetate and then dried to give 0.43 g of colorless crystals, 1- {2- [2- (1-benzothiophen-4-yl) ethoxy] ethyl} -3-pyrrolidinol hydrochloride. Got. [305] IR (KBr) cm -1 : 3229, 2872, 2625, 1451, 1413, 1119, 771 [306] NMR (DMSO-d 6 ) δ Value: 1.7-2.2 (1H, m), 2.9-3.6 (6H, m), 3.22 (2H, t, J = 7Hz), 3.74 (4H, t, J = 7Hz), 4.3-4.4 (1H, m), 7.27 (1H, d, J = 8z), 7.30 (1H, t, J = 8 Hz), 7.61 (1H, d, J = 5 Hz), 7.77 (1H, d, J = 5 Hz), 7.86 (1H, d, J = 8 Hz) [307] Example 22 Preparation of 1- {2- [2- (1-benzothiophen-7-yl) ethoxy] ethyl} -3-pyrrolidinol [308] [309] In the same manner as in Example 16 (1), the oily 2- [2- (1-benzothiophen-7-yl) ethoxy] -1- [3-hydroxy-1-pyrrolidinyl) -1- Obtained ethanone. [310] NMR (CDCl 3 ) δ Value: 1.8-2.0 (2H, m), 3.1-3.3 (3H, m), 3.3-3.6 (3H, m), 3.8-4.0 (2H, m), 4.0-4.2 (2H, m), 4.3-4.5 (1H, m), 7.23 (1H, d, J = 7 Hz), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 7.6-7.8 (1H, m) [311] Then, in the same manner as in Example 16 (2), colorless oily 1- {2- [2- (1-benzothiophen-7-yl) ethoxy] ethyl} -3-pyrrolidinol was obtained. [312] IR (neat) cm -1 : 3385, 2941, 2867, 1459, 1395, 1106, 795, 754, 701 [313] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.30 (1H, dt, J = 7, 9Hz), 2.52 (1H, dd, J = 5, 10Hz ), 2.6-2.7 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.19 (2H, t, J = 7 Hz), 3.59 (2H, t, J = 6 Hz), 3.84 (2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 7.20 (1H, d, J = 8 Hz), 7.32 (1H, t, J = 8 Hz), 7.35 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.69 (1H, d, J = 8 Hz) [314] Example 23 Preparation of 1- {2- [2- (1-benzothiophen-7-yl) ethoxy] ethyl} -3-pyrrolidinol hydrochloride [315] [316] In the same manner as in Example 21, colorless crystals 1- {2- [2- (1-benzothiophen-7-yl) ethoxy] -3-pyrrolidinol hydrochloride were obtained. [317] IR (KBr) cm -1 : 3283, 2938, 2706, 1395, 1358, 1125, 810, 720 [318] NMR (DMSO-d 6 ) δ Value: 1.7-2.2 (2H, m), 2.8-3.7 (6H, m), 3.12 (2H, t, J = 7Hz), 3.7-3.8 (2H, m), 3.82 ( 2H, t, J = 7 Hz, 4.3-4.4 (1H, m), 7.29 (1H, d, J = 7 Hz), 7.36 (1H, t, J = 7 Hz), 7.49 (1H, d, J = 5 Hz) , 7.76 (1H, d, J = 5 Hz), 7.77 (1H, d, J = 7 Hz) [319] Example 24 Preparation of 1- {2- [2- (1-benzothiophen-2-yl) ethoxy] ethyl} -3-pyrrolidinol [320] [321] In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-2-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanone Got. [322] NMR (CDCl 3 ) δ Value: 1.8-2.0 (2H, m), 3.1-3.3 (3H, m), 3.3-3.7 (3H, m), 3.8-4.0 (2H, m), 4.1-4.2 (2H, m), 4.2-4.5 (1H, m), 7.10 (1H, s), 7.2-7.4 (2H, m), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m) [323] Then, in the same manner as in Example 16 (2), light yellow oily 1- {2- [2- (1-benzothiophen-7-yl) ethoxy] ethyl} -3-pyrrolidinol was obtained. [324] IR (neat) cm -1 : 3396, 2939, 1458, 1438, 1113, 747, 727 [325] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.34 (1H, dt, J = 6, 9Hz), 2.55 (1H, dd, J = 5, 10Hz ), 2.6-2.8 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.18 (2H, dt, J = 1, 7 Hz), 3.62 (2H, t, J = 6 Hz), 3.77 ( 2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 7.07 (1H, s), 7.26 (1H, dt, J = 1, 8 Hz), 7.31 (1H, dt, J = 1, 8 Hz) , 7.67 (1H, dd, J = 1, 8 Hz), 7.76 (1H, dd, J = 1, 8 Hz) [326] Example 25 Preparation of 1- {2- [2- (1-benzothiophen-2-yl) ethoxy] ethyl} -3-pyrrolidinol oxalate [327] [328] In the same manner as in Example 17, colorless crystals of 1- {2- [2- (1-benzothiophen-2-yl) ethoxy] -3-pyrrolidinol hydroxide were obtained. [329] IR (KBr) cm -1 : 3432, 2871, 1716, 1436, 1127, 827, 760, 706 [330] NMR (DMSO-d 6 ) δ Value: 1.7-1.8 (1H, m), 1.9-2.2 (1H, m), 3.0-3.4 (8H, m), 3.73 (4H, t, J = 6Hz), 4.2- 4.4 (1H, m), 7.23 (1H, s), 7.28 (1H, t, J = 7 Hz), 7.33 (1H, d, J = 7 Hz), 7.74 (1H, d, J = 7 Hz), 7.87 (1H , d, J = 7 Hz) [331] Example 26 Preparation of 1- {2- [2- (1-benzothiophen-3-yl) ethoxy] ethyl} -3-pyrrolidinol [332] [333] In the same manner as in Example 16 (1), the oily 2- [2- (1-benzothiophen-3-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1- Obtained ethanone. [334] NMR (CDCl 3 ) δ Value: 1.8-1.9 (1H, m), 1.9-2.0 (1H, m), 3.1-3.6 (6H, m), 3.8-4.0 (2H, m), 4.09 (1H, s) , 4.13 (1H, s), 4.3-4.5 (1H, m), 7.26 (1H, s), 7.3-7.4 (2H, m), 7.7 (1H, d, J = 8 Hz), 7.85 (1H, d, J = 8Hz) [335] Then, in the same manner as in Example 16 (2), light yellow oily 1- {2- [2- (1-benzothiophen-7-yl) ethoxy] ethyl} -3-pyrrolidinol was obtained. [336] IR (neat) cm -1 : 3388, 2934, 1426, 1112, 761, 733 [337] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.33 (1H, dt, J = 6, 9Hz), 2.56 (1H, dd, J = 5, 10Hz ), 2.6-2.8 (3H, m), 2.87 (1H, dt, J = 5, 9 Hz), 3.14 (2H, dt, J = 1, 7 Hz), 3.61 (2H, t, J = 6 Hz), 3.80 ( 2H, t, J = 7 Hz, 4.3-4.4 (1H, m), 7.20 (1H, s), 7.34 (1H, dt, J = 1, 7 Hz), 7.38 (1H, dt, J = 1, 7 Hz) , 7.77 (1H, dd, J = 1, 7 Hz), 7.85 (1H, dd, J = 1, 7 Hz) [338] Example 27 Preparation of 1- {2- [2- (1-benzothiophen-3-yl) ethoxy] ethyl} -3-pyrrolidinol oxalate [339] [340] In the same manner as in Example 17, colorless crystals of 1- {2- [2- (1-benzothiophen-3-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [341] IR (KBr) cm -1 : 3363, 2922, 2691, 1718, 1636, 1427, 1404, 1119, 767, 721 [342] NMR (DMSO-d 6 ) δ Value: 1.7-1.8 (1H, m), 2.0-2.2 (1H, m), 3.10 (2H, t, J = 7Hz), 3.1-3.4 (6H, m), 3.72 ( 2H, t, J = 5 Hz, 3.78 (2H, t, J = 7 Hz), 4.3-4.4 (1H, m), 7.37 (1H, d, J = 8 Hz), 7.42 (1H, d, J = 8 Hz) , 7.51 (1H, s), 7.85 (1H, d, J = 8 Hz), 7.98 (1H, d, J = 8 Hz) [343] Example 28 Preparation of 1- {2- [2- (1-naphthyl) ethoxy] ethyl} -3-pyrrolidinol [344] [345] In the same manner as in Example 16 (1), yellow oily 2- [2- (1-naphthyl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanone was obtained. . [346] IR (neta) cm -1 : 3392, 2946, 1645, 1133, 800, 779 [347] Subsequently, in the same manner as in Example 16 (2), light yellow oily 1- {2- [2- (1-naphthyl) ethoxy] ethyl} -3-pyrrolidinol was obtained. [348] IR (neat) cm -1 : 3395, 2944, 1107, 778 [349] NMR (CDCl 3 ) δ Value: 1.5-1.9 (1H, m), 2.0-2.5 (3H, m), 2.5-3.0 (4H, m), 3.37 (2H, t, J = 7Hz), 3.59 (2H, t, J = 6 Hz), 3.80 (2H, t, J = 7 Hz), 4.2-4.4 (1H, m), 7.4-7.6 (4H, m), 7.6-8.0 (2H, m), 8.0-8.2 (1H , m) [350] Example 29 Preparation of 1- {2- [2- (1-naphthyl) ethoxy] ethyl} -3-pyrrolidinol oxalate [351] [352] In the same manner as in Example 17, colorless crystals 1- {2- [2- (1-naphthyl) ethoxy] -3-pyrrolidinol hydroxide were obtained. [353] IR (KBr) cm -1 : 3366, 1400, 1116, 780, 720 [354] NMR (DMSO-d 6 ) δ Value: 1.6-2.3 (1H, m), 2.7-3.5 (8H, m), 3.5-3.9 (4H, m), 4.2-4.5 (1H, m), 7.4-7.6 ( 4H, m), 7.7-8.0 (2H, m), 8.0-8.2 (1H, m) [355] Example 30 Preparation of (3S) -1- {2- [2- (1-benzothiophen5-yl) ethoxy] ethyl} -3-pyrrolidinol [356] [357] In the same manner as in Example 16 (1), light yellow oily 2- [2- (1-benzothiophen-5-yl) ethoxy] -1-[(3S) -3-hydroxy-1-pyrroli Dinyne) -1-ethanone was obtained. [358] Subsequently, in the same manner as in Example 16 (2), light yellow oily (3S) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol Got. [359] IR (neat) cm -1 : 3386, 2936, 2867, 1438, 1111, 755, 702 [360] NMR (CDCl 3 ) δ Value: 1.5-2.0 (1H, m), 2.0-3.0 (5H, m), 2.66 (2H, t, J = 6Hz), 3.00 (2H, t, J = 7Hz), 3.58 ( 2H, t, J = 6 Hz, 3.71 (2H, t, J = 7 Hz), 4.2-4.4 (1H, m), 7.21 (1H, d, J = 8 Hz), 7.28 (1H, d, J = 5 Hz) , 7.42 (1H, d, J = 5 Hz), 7.67 (1H, s), 7.79 (1H, d, J = 8 Hz) [361] Example 31 Preparation of (3S) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol oxalate [362] [363] In the same manner as in Example 17, colorless crystals (3S) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [364] IR (KBr) cm -1 : 3366, 2914, 2867, 2686, 1718, 1701, 1404, 1114, 720 [365] NMR (DMSO-d 6 ) δ Value: 1.5-2.2 (2H, m), 2.8-3.5 (8H, m), 3.70 (4H, t, J = 6Hz), 4.2-4.5 (1H, m), 7.28 ( 1H, d, J = 8 Hz, 7.40 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 5 Hz), 7.76 (1H, s), 7.91 (1H, d, J = 8 Hz) [366] Example 32 Preparation of (3R) -1- {2- [2- (1-benzothiophen5-yl) ethoxy] ethyl} -3-pyrrolidinol [367] [368] In the same manner as in Example 16 (1), colorless crystal 2- [2- (1-benzothiophen-5-yl) ethoxy] -1-[(3R) -3-hydroxy-1-pyrroli Dinyne) -1-ethanone was obtained. [369] IR (KBr) cm -1 : 3408, 2937, 1637, 1137, 1108, 812, 703 [370] Subsequently, in the same manner as in Example 16 (2), light yellow oily (3R) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol Got. [371] IR (neat) cm -1 : 3373, 2940, 1438, 1111, 755, 702 [372] NMR (CDCl 3 ) δ Value: 1.5-2.0 (1H, m), 2.0-3.0 (5H, m), 2.68 (2H, t, J = 6Hz), 3.01 (2H, t, J = 7Hz), 3.59 ( 2H, t, J = 6 Hz, 3.71 (2H, t, J = 7 Hz), 4.2-4.4 (1H, m), 7.21 (1H, d, J = 8 Hz), 7.28 (1H, d, J = 5 Hz) , 7.42 (1H, d, J = 5 Hz), 7.67 (1H, s), 7.79 (1H, d, J = 8 Hz) [373] Example 33 Preparation of (3R) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol hydrate [374] [375] In the same manner as in Example 17, colorless crystals (3R) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [376] IR (KBr) cm -1 : 3318, 2870, 1718, 1114, 720 [377] NMR (DMSO-d 6 ) δ Value: 1.5-2.2 (2H, m), 2.8-3.5 (8H, m), 3.70 (4H, t, J = 6Hz), 4.2-4.5 (1H, m), 7.28 ( 1H, d, J = 8 Hz, 7.40 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 5 Hz), 7.76 (1H, s), 7.91 (1H, d, J = 8 Hz) [378] Example 34 Preparation of (3S) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol [379] [380] In the same manner as in Example 16 (1), colorless oily 2- [2- (1-benzothiophen-6-yl) ethoxy] -1-[(3S) -3-hydroxy-1-pyrroli Dinyne) -1-ethanone was obtained. [381] IR (KBr) cm -1 : 3385, 2944, 1637, 1133, 820, 699 [382] Then, in the same manner as in Example 16 (2), colorless oily (3S) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol Got. [383] IR (neat) cm -1 : 3385, 2940, 2867, 1110, 820, 757 [384] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.32 (1H, dt, J = 6, 9Hz), 2.54 (1H, dd, J = 5, 10Hz ), 2.6-2.7 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.01 (2H, t, J = 7 Hz), 3.58 (2H, t, J = 6 Hz), 3.71 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 8 Hz), 7.74 (1H, s) [385] Example 35 Preparation of (3S) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide [386] [387] In the same manner as in Example 17, colorless crystals (3S) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [388] IR (KBr) cm -1 : 3364, 2938, 2692, 1718, 1400, 1201, 1114, 720 [389] NMR (DMSO-d 6 ) δ Value: 1.7-1.8 (1H, m), 1.9-2.1 (1H, m), 2.96 (2H, t, J = 7Hz), 3.0-3.1 (1H, m), 3.1- 3.5 (5H, m), 3.70 (4H, t, J = 7 Hz), 4.2-4.3 (1H, m), 7.29 (1H, d, J = 8 Hz), 7.41 (1H, d, J = 5 Hz), 7.68 (1H, d, J = 5 Hz), 7.80 (1H, d, J = 8 Hz), 7.87 (1H, s) [390] Example 36 Preparation of (3R) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol [391] [392] In the same manner as in Example 16 (1), the oily 2- [2- (1-benzothiophen-6-yl) ethoxy] -1-[(3R) -3-hydroxy-1-pyrrolidinyl ] -1-ethanone was obtained. [393] IR (neat) cm -1 : 3386, 2940, 1637, 1107, 820, 758 [394] Then, in the same manner as in Example 16 (2), colorless oily (3R) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol Got. [395] IR (neat) cm -1 : 3385, 2940, 2867, 1110, 820, 757 [396] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.32 (1H, dt, J = 6, 9Hz), 2.54 (1H, dd, J = 5, 10Hz ), 2.6-2.7 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.01 (2H, t, J = 7 Hz), 3.58 (2H, t, J = 6 Hz), 3.71 (1H, d, J = 5 Hz), 4.2-4.3 (1H, m), 7.23 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.37 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 8 Hz), 7.74 (1H, s) [397] Example 37 Preparation of (3R) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol hydrate [398] [399] In the same manner as in Example 17, colorless crystals (3R) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [400] IR (KBr) cm -1 : 3364, 2938, 2692, 1718, 1400, 1201, 1114, 720 [401] NMR (DMSO-d 6 ) δ Value: 1.7-1.8 (1H, m), 1.9-2.1 (1H, m), 2.96 (2H, t, J = 7Hz), 3.0-3.1 (1H, m), 3.1- 3.3 (5H, m), 3.70 (4H, t, J = 7 Hz), 4.2-4.3 (1H, m), 7.29 (1H, d, J = 8 Hz), 7.41 (1H, d, J = 5 Hz), 7.68 (1H, d, J = 5 Hz), 7.80 (1H, d, J = 8 Hz), 7.87 (1H, s) [402] Example 38 Preparation of (3R) -1- {2- [2- (1-benzothiophen-3-yl) ethoxy] ethyl} -3-pyrrolidinol [403] [404] In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-6-yl) ethoxy] -1-[(3R) -3-hydroxy-1-pyrrolidinyl]- 1-ethanone was obtained. [405] NMR (CDCl 3 ) δ Value: 1.8-1.9 (1H, m), 1.9-2.0 (1H, m), 3.1-3.4 (3H, m), 3.3-3.7 (3H, m), 3.8-4.0 (2H, m), 4.0-4.2 (2H, m), 4.3-4.5 (1H, m), 7.27 (1 / 2H, s), 7.28 (1 / 2H, s), 7.3-7.5 (2H, m), 7.7- 7.8 (1H, m), 7.8-7.9 (1H, m) [406] Subsequently, in the same manner as in Example 16 (2), yellow oily (3R) -1- {2- [2- (1-benzothiophen-6-yl) ethoxy] ethyl} -3-pyrrolidinol Got. [407] IR (neat) cm -1 : 3386, 2942, 1458, 1429, 1113, 759, 733 [408] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.34 (1H, dt, J = 6,9Hz), 2.55 (1H, dd, J = 5, 10Hz ), 2.6-2.8 (3H, m), 2.85 (1H, dt, J = 5, 9 Hz), 3.14 (2H, t, J = 7 Hz), 3.61 (2H, t, J = 6 Hz), 3.80 (2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 7.21 (1H, s), 7.34 (1H, dt, J = 1, 7 Hz), 7.38 (1H, d, J = 1, 7 Hz), 7.76 (1H, dd, J = 1, 7 Hz), 7.85 (1H, dd, J = 1, 7 Hz) [409] Example 39 Preparation of (3R) -1- {2- [2- (1-benzothiophen-3-yl) ethoxy] ethyl} -3-pyrrolidinol hydrochloride [410] [411] 0.99 g of (3R) 1- {2- [2- (1-benzothiophen-3-yl) ethoxy] ethyl} -3-pyrrolidinol was dissolved in 5.0 ml of ethyl acetate and 3.25 mol / 1.10 ml of L dry hydrogen chloride-ethyl acetate solution was added, the mixture was stirred at room temperature for 1 hour, and then the solvent was removed under reduced pressure to obtain a pale yellow oily (3R) -1- {2- [2- (1-benzothiophene- 1.05 g of 3-yl) ethoxy] ethyl} -3-pyrrolidinol hydrochloride was obtained. [412] IR (neat) cm -1 : 3368, 2946, 1560, 1430, 1121, 765, 734 [413] NMR (CDCl 3 ) δ values: 1.9-2.1 (1H, m), 2.1-2.3 (1H, m), 2.8-3.0 (2H, m), 3.0-3.1-3.2 (4H, m), 3.29 (1H, d, J = 12 Hz), 3.3-3.5 (1H, m), 3.8-3.9 (4H, m), 4.3-4.4 (1H, m), 7.24 (1H, s), 7.35 (1H, t, J = 8 Hz ), 7.40 (1H, t, J = 8 Hz), 7.76 (1H, d, J = 8 Hz), 7.86 (1H, d, J = 8 Hz) [414] Example 40 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -4-piperidinol [415] [416] In the same manner as in Example 16 (1), oily 2- [2- (1-benzothiophen-5-yl) ethoxy] -1- (4-hydroxy-1-piperidinyl) -1- Obtained ethanone. [417] Then, in the same manner as in Example 16 (2), yellow oily 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -4-piperidinol was obtained. [418] IR (neat) cm -1 : 3386, 2939, 1110, 1071, 754, 701 [419] NMR (CDCl 3 ) δ value: 1.5-2.3 (6H, m), 2.5-3.0 (2H, m), 2.56 (2H, dt, J = 6, 6Hz), 3.00 (2H, t, J = 7Hz), 3.5-3.9 (1H, m), 3.58 (2H, t, J = 6 Hz), 3.70 (2H, t, J = 7 Hz), 7.19 (1H, t, J = 8 Hz), 7.27 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 7.65 (1H, s), 7.78 (1H, d, J = 8 Hz) [420] Example 41 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -4-piperidinol hydrochloride [421] [422] In the same manner as in Example 21, hydrochloride of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -4-piperidinol as light brown crystals was obtained. [423] IR (neat) cm -1 : 3312, 2946, 2691, 1457, 1124, 1043, 769, 712 [424] NMR (CDCl 3 ) δ Value: 1.5-2.5 (4H, m), 2.8-3.2 (6H, m), 2.99 (2H, t, J = 6Hz), 3.76 (2H, t, J = 6Hz), 3.8- 4.2 (3H, m), 7.19 (1H, d, J = 8 Hz), 7.30 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 7.67 (1H, s), 7.80 (1H , t, J = 8 Hz) [425] Example 42 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-piperidinol [426] [427] In the same manner as in Example 16 (1), yellow oily 2- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-piperidinyl) -1 -Got ethanone. [428] IR (neat) cm -1 : 3486, 2938, 1637, 1114, 704 [429] Then, in the same manner as in Example 16 (2), yellow oily 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-piperidinol was obtained. [430] IR (neat) cm -1 : 3387, 2937, 1438, 1109, 703 [431] NMR (CDCl 3 ) δ Value: 1.4-2.0 (4H, m), 2.0-2.7 (6H, m), 2.57 (2H, dt, J = 6Hz), 3.00 (2H, t, J = 7Hz), 3.56 ( 2H, t, J = 6Hz), 3.6-3.9 (1H, m), 3.70 (2H, t, J = 7Hz), 7.20 (1H, t, J = 8Hz), 7.28 (1H, d, J = 5Hz) , 7.42 (1H, d, J = 5 Hz), 7.66 (1H, s), 7.79 (1H, d, J = 8 Hz) [432] Example 43 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-piperidinol hydrochloride [433] [434] In the same manner as in Example 21, colorless crystals of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-piperidinol hydrochloride were obtained. [435] IR (KBr) cm -1 : 3260, 2949, 2638, 1433, 1129, 1045, 702, 668 [436] NMR (CDCl 3 ) δ Value: 1.5-2.0 (4H, m), 2.1-2.8 (2H, m), 2.99 (2H, t, J = 6Hz), 3.1-3.6 (4H, m), 3.76 (2H, t, J = 6 Hz, 3.8-4.1 (3HJ, m), 7.20 (1H, d, J = 8 Hz), 7.30 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 7.67 (1H, s), 7.80 (1H, t, J = 8 Hz) [437] Example 44 Preparation of 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -4-piperidinol [438] [439] In the same manner as in Example 16 (1), 2- [2- (1-benzofuran-5-yl) ethoxy] -1- (4-hydroxy-1-piperidinyl) -1-ethanone was prepared. Got it. [440] IR (neat) cm -1 : 3406, 2931, 1636, 1110, 771, 740 [441] Subsequently, in the same manner as in Example 16 (2), a colorless oily 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -4-piperidinol was obtained. [442] IR (neat) cm -1 : 3359, 2939, 1468, 1078, 882, 768, 739 [443] NMR (CDCl 3 ) δ Value: 1.5-2.2 (6H, m), 2.5-3.0 (2H, m), 2.57 (2H, t, J = 6Hz), 2.97 (2H, t, J = 7Hz), 3.5- 3.8 (1H, m), 3.58 (2H, t, J = 6 Hz), 3.68 (2H, t, J = 7 Hz), 6.71 (1H, dd, J = 1, 2 Hz), 7.13 (1H, dd, J = 2, 8 Hz), 7.40 (1H, d, J = 8 Hz), 7.42 (1H, dd, J = 1, 2), 7.55 (1H, d, J = 2 Hz) [444] Example 45 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -4-piperidinol hydrochloride [445] [446] In the same manner as in Example 21, light yellow oily 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -4-piperidinol hydrochloride was obtained. [447] IR (neat) cm -1 : 3366, 2938, 2638, 1458, 1126, 776, 742 [448] NMR (CDCl 3 ) δ Value: 1.6-2.4 (4H, m), 2.8-3.2 (8H, m), 3.71 (2H, t, J = 6Hz), 3.7-4.1 (3H, m), 6.72 (1H, dd, J = 1, 2 Hz), 7.12 (1H, dd, J = 2, 8 Hz), 7.44 (1H, d, J = 8 Hz), 7.42 (1H, dd, J = 1, 2), 7.60 (1H, d, J = 2 Hz) [449] Example 46 Preparation of 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -3-piperidinol [450] [451] (1) 1.28 g of 2- [2- (1-benzofuran-5-yl) ethoxy] acetic acid was dissolved in 13.0 ml of tetrahydrofuran, cooled to 5 ° C, and then 1.1'-carbonyldiimidazole 1.41 g was added and stirred for 2 hours at room temperature. To the reaction mixture, 1.22 ml of triethylamine and 0.72 ml of 3-pyrrolidinol were added, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L acetic acid, and the organic layer was separated therefrom. The organic layer was washed successively with saturated sodium bicarbonate water and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the colorless oily 2- [2- (1-benzofuran-5-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanone Obtained 1.39 g [452] IR (neat) cm -1 : 3398, 2943, 1637, 1467, 1128, 1030, 771, 741 [453] (2) 1.39 g of 2- [2- (1-benzofuran-5-yl) ethoxy] -1- (3-hydroxy-1-pyrrolidinyl) -1-ethanone was added to 14.0 ml of tetrahydrofuran. It melt | dissolved and it was dripped at 14.4 ml of 1 mol / L tetrahydrofuran solutions of a poran- tetrahydrofuran complex under ice-cooling, and it stirred at room temperature for 17 hours. 8.0 ml of 6 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was heated to reflux for 1 hour. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 10 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 30: 1-10: 1) and colorless oily 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl } -3-pyrrolidinol 0.96 g was obtained. [454] IR (neat) cm -1 : 3386, 2941, 1468, 1261, 1110, 1030, 882, 769, 738 [455] NMR (CDCl 3 ) δ Value: 1.5-2.0 (1H, m), 1.9-3.0 (5H, m), 2.68 (2H, t, J = 6Hz), 2.98 (2H, t, J = 7Hz), 3.58 ( 2H, t, J = 6 Hz, 3.70 (2H, t, J = 7 Hz), 4.2-4.4 (1H, m), 6.71 (1H, dd, J = 1, 2 Hz), 7.14 (1H, d, J = 8 Hz), 7.42 (1H, d, J = 8 Hz), 7.4-7.5 (1H, m), 7.59 (1H, d, J = 2 Hz) [456] Example 47 Preparation of 1- {2- [2- (1-benofuran-5-yl) ethoxy] ethyl} -3-pyrrolidinol hydrate [457] [458] In the same manner as in Example 17, colorless crystals of 1- {2- [2-benzofuran-5-yl) ethoxy} ethyl} -3-pyrrolidinol hydroxide were obtained. [459] IR (KBr) cm -1 : 3418, 2945, 2698, 1715, 1197, 1111, 720 [460] NMR (DMS0-d 6 ) δ Value: 1.6-2.3 (2H, m), 2.92 (2H, t, J = 7Hz), 3.0-3.5 (6H, m), 3.5-3.8 (4H, m), 4.2- 4.5 (1H, m), 6.89 (1H, dd, J = 1, 2 Hz), 7.19 (1H, dd, J = 1, 8 Hz), 7.50 (1H, d, J = 8 Hz), 7.5-7.6 (1H, m), 7.94 (1H, doublet, J = 2 Hz) [461] Example 48 Preparation of (3R * , 4R * )-1- {2- [2- (1-benzothiophen-5-yl) ethoxy} ethyl} -3,4-pyrrolidinediol [462] [463] In the same manner as in Example 46 (1), yellow oily 2- [2- (1-benzothiophen-5-yl) ethoxy] -1-[(3R * , 4R * )-3,4-di Hydroxy-1-pyrrolidinyl] -1-ethanone was obtained. [464] IR (neat) cm -1 : 3370, 2935, 2874, 1636, 1131, 756, 701 [465] Then, in the same manner as in Example 46 (2), a yellow oily (3R * , 4R * )-1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3 , 4-pyrrolidinediol was obtained. [466] IR (neat) cm -1 : 3386, 2938, 2866, 1438, 1113, 756, 703 [467] NMR (CDCl 3 ) δ Value: 2.5-3.0 (5H, m), 3.00 (2H, t, J = 7Hz), 3.2-3.7 (1H, m), 3.56 (2H, t, J = 6Hz), 3.71 ( 2H, t, J = 7 Hz, 3.9-4.4 (2H, m), 7.20 (1H, d, J = 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.43 (1H, d, J = 5 Hz) , 7.66 (1H, s), 7.80 (1H, d, J = 8 Hz) [468] Example 49 Preparation of (3R * , 4R * )-1- {2- [2- (1-benzothiophen-5-yl) ethoxy} ethyl} -3,4-pyrrolidinediol oxalate [469] [470] In the same manner as in Example 17, the colorless crystals of ((3R * , 4R * )-1- {2- [2- (1-benzothiophen-5-yl) ethoxy} ethyl} -3,4-py Lolidinediol oxalate was obtained. [471] IR (KBr) cm -1 : 3309, 2929, 1718, 1617, 1199, 1104, 702 [472] NMR (DMS0-d 6 ) δ Value: 2.8-3.2 (6H, m), 3.2-3.8 (6H, m), 4.1-4.4 (2H, m), 7.26 (1H, d, J = 8Hz), 7.39 ( 1H, d, J = 5Hz), 7.72 (1H, d, J = 5Hz), 7.75 (1H, s), 7.90 (1H, d, J = 8Hz) [473] Example 50 Preparation of 1- {2- [2- (5-methoxy-1-benzofuran-6-yl) ethoxy} ethyl} -3,4-pyrrolidinol [474] [475] In the same manner as in Example 46 (1), colorless oily 2- [2- (5-methoxy-1-benzofuran-6-yl) ethoxy] -1- (3-hydroxy-1-pyrroli Dinyne) 1-ethanone was obtained. [476] IR (neat) cm -1 : 3394, 2941, 1637, 1465, 1197, 1131, 1015, 841, 759 [477] Subsequently, in the same manner as in Example 46 (2), colorless oily 1- {2- [2- (5-methoxy-1-benzofuran-6-yl) ethoxy] ethyl} -3,4-py Obtained lollidinol. [478] IR (neat) cm -1 : 3386, 2940, 1466, 1430, 1198, 1131, 1015, 837, 762 [479] NMR (CDCl 3 ) δ Value: 1.5-2.4 (3H, m), 2.5-3.0 (5H, m), 2.99 (2H, t, J = 7Hz), 3.59 (2H, t, J = 6Hz), 3.67 ( 2H, t, J = 7Hz, 3.85 (3H, s), 4.2-4.4 (1H, m), 6.68 (1H, d, J = 2Hz), 6.99 (1H, s), 7.34 (1H, s), 7.54 (1H, d, J = 2 Hz) [480] Example 51 Preparation of 1- {2- [2- (5-methoxy-1-benzofuran-6-yl) ethoxy} ethyl} -3-pyrrolidinol hydroxide [481] [482] In the same manner as in Example 17, colorless crystals of 1- {2- [2- (5-methoxy-1-benzofuran-6-yl) ethoxy} ethyl} -3-pyrrolidinol hydroxide were obtained. [483] IR (KBr) cm -1 : 3396, 2942, 1718, 1636, 1465, 1198, 1130, 720 [484] NMR (DMS0-d 6 ) δ Value: 1.7-2.3 (2H, m), 2.8-3.6 (6H, m), 2.91 (2H, t, J = 6Hz), 3.5-3.9 (4H, m), 3.83 ( 3H, s), 4.2-4.5 (1H, m), 6.86 (1H, d, J = 2 Hz), 7.17 (1H, s), 7.43 (1H, s), 7.88 (1H, d, J = 2 Hz) [485] Example 52 Preparation of 1- {2- [2- (6-methoxy-1-benzofuran-5-yl) ethoxy} ethyl} -3-pyrrolidinol [486] [487] In the same manner as in Example 46 (1), colorless oily 2- [2- (6-methoxy-1-benzofuran-5-yl) ethoxy] -1- (3-hydroxy-1-pyrroli Dinyne) 1-ethanone was obtained. [488] IR (neat) cm -1 : 3381, 2944, 1638, 1475, 1201, 1125, 1011, 758 [489] Subsequently, in the same manner as in Example 46 (2), colorless oily 1- {2- [2- (6-methoxy-1-benzofuran-5-yl) ethoxy] ethyl} -3-pyrrolidinol Got. [490] IR (neat) cm -1 : 3397, 2938, 1475, 1202, 1094, 757, 730 [491] NMR (CDCl 3 ) δ Value: 1.5-2.4 (3H, m), 2.5-3.0 (5H, m), 2.98 (2H, t, J = 7Hz), 3.59 (2H, t, J = 6Hz), 3.68 ( 2H, t, J = 7 Hz, 3.86 (3H, s), 4.2-4.4 (1H, m), 6.65 (1H, d, J = 2 Hz), 7.00 (1H, s), 7.35 (1H, s), 7.50 (1H, d, J = 2 Hz) [492] Example 53 Preparation of 1- {2- [2- (6-methoxy-1-benzofuran-5-yl) ethoxy} ethyl} -3-pyrrolidinol hydrochloride [493] [494] In the same manner as in Example 21, colorless oily 1- {2- [2- (6-methoxy-1-benzofuran-5-yl) ethoxy} ethyl} -3-pyrrolidinol hydrochloride was obtained. [495] IR (KBr) cm -1 : 3377, 2938, 2694, 1475, 1202, 1124, 1093, 1011 [496] NMR (CDCl 3 ) δ Value: 1.7-2.2 (2H, m), 2.8-3.6 (6H, m), 2.96 (2H, t, J = 6Hz), 3.5-4.2 (4H, m), 3.86 (3H, s), 4.3-4.6 (1H, m), 6.6-6.7 (1H, m), 7.01 (1H, s), 7.34 (1H, d, J = 1 Hz), 7.51 (1H, d, J = 2 Hz) [497] Example 54 Preparation of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy} ethyl} -3-pyrrolidinamine [498] [499] (1) 1.00 g of 2- [2- (1-benzothiophen-5-yl) ethoxy} acetic acid was dissolved in 10.0 ml of tetrahydrofuran, cooled to 5 ° C, and then 1,1'-carbonyldi 1.03 g of imidazole was added, and the mixture was stirred at room temperature for 1 hour. After cooling to 5 ° C., 0.88 ml of triethylamine and 1.18 g of tert-butyl = 3-pyrrolidinylcarbamate were added to the reaction mixture, which was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 4 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed successively with saturated brine and brine, and then dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and the pale yellow oil was tert-butyl = 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] acetyl} -3-pyrrolidinylcarbamate 2.00 g was obtained. [500] (2) 2.0 ml of tetrahydrofuran in 2.00 g of tert-butyl = 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] acetyl} -3-pyrrolidinyl carbamate It melt | dissolved in and cooled to 5 degreeC, Then, 10.6 ml of 1 mol / L tetrahydrofuran solutions of borane-tetrahydrofuran complex were dripped, and it stirred at room temperature for 17 hours. 3.5 ml of 6 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was heated to reflux for 3 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 10 with 5 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 30: 1-15: 1), and pale yellow oily 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] 1.01 g of ethyl} -3-pyrrolidinamine was obtained. [501] IR (neat) cm -1 : 3358, 2938, 2891, 2861, 1438, 1112, 1052, 755, 703 [502] NMR (CDCl 3 ) δ Value: 1.2-1.7 (1H, m), 1.9-3.0 (7H, m), 2.01 (2H, s), 3.00 (2H, t, J = 7Hz), 3.3-3.7 (1H, m), 3.57 (2H, t, J = 6 Hz), 3.71 (2H, t, J = 7 Hz), 7.20 (1H, d, J = 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.41 (1H) , d, J = 5 Hz), 7.66 (1H, s), 7.78 (1H, d, J = 8 Hz) [503] Example 55 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinamine dihydrate [504] [505] 0.71 g of 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidinamine was dissolved in 3.0 ml of ethyl acetate, and the solution contained 0.44 g of hydroxide. 4.0 ml of ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour and again at 5 ° C for 1 hour. The precipitated crystals were filtered, washed with ethyl acetate and dried to give 1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3-pyrrolidine as colorless crystals. 1.03 g of amine dihydrate was obtained. [506] IR (KBr) cm -1 : 3457, 2938, 1406, 1279, 1115, 720 [507] NMR (DMSO-d 6 ) δ Value: 1.7-2.5 (2H, m), 2.5-3.5 (8H, m), 3.5-4.0 (5H, m), 7.27 (1H, d, J = 8Hz), 7.40 ( 1H, d, J = 5 Hz, 7.72 (1H, d, J = 5 Hz), 7.75 (1H, s), 7.90 (1H, d, J = 8 Hz) [508] Example 56 Preparation of 1- {2- [2- (1-benzofuran-5-yl) ethoxy} ethyl} -3-pyrrolidinamine [509] [510] In the same manner as in Example 54 (1), tert-butyl = 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -3-pyrrolidinylcarbamate was obtained. [511] Then, in the same manner as in Example 54 (2), yellow oily 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -3-pyrrolidinamine was obtained. [512] IR (neat) cm -1 : 3356, 2938, 1467, 1261, 1111, 1030, 882, 769, 740 [513] NMR (CDCl 3 ) δ Value: 1.2-1.7 (1H, m), 2.02 (2H, s), 2.1-3.0 (7H, m), 2.98 (2H, t, J = 7Hz), 3.3-3.7 (1H, m), 3.57 (2H, t, J = 6 Hz), 3.69 (2H, t, J = 7 Hz), 6.71 (1H, dd, J = 1, 2 Hz), 7.15 (1H, dd, J = 1, 7 Hz) , 7.40 (1H, d, J = 7 Hz), 7.4-7.5 (1H, m), 7.59 (1H, d, J = 2 Hz) [514] Example 57 Preparation of 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -3-pyrrolidinamine oxalate [515] [516] In the same manner as in Example 17, colorless crystals of 1- {2- [2- (1-benzofuran-5-yl) ethoxy] ethyl} -3-pyrrolidinamine hydrate were obtained. [517] IR (KBr) cm -1 : 3408, 2952, 1615, 1311, 1127, 769 [518] NMR (DMSO-d 6 ) δ Value: 1.5-1.9 (1H, m), 1.8-2.4 (1H, m), 2.1-3.0 (6H, m), 2.89 (2H, t, J = 7Hz), 3.4- 3.8 (5H, m), 6.89 (1H, dd, J = 1, 2 Hz), 7.18 (1H, d, J = 8 Hz), 7.50 (1H, d, J = 8 Hz), 7.4-7.6 (1H, m) , 7.94 (1H, d, J = 2 Hz) [519] Example 58 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol [520] [521] 1.20 g of 5- [2- (3-chloropropoxy) ethyl] -1-benzothiophene is dissolved in 12 ml of N, N-dimethylformamide, and 0.82 g of 3-pyrrolidinol and 1.30 of potassium carbonate are dissolved in this solution. g was added and stirred at 85 ° C. for 2.5 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 20: 1-10: 1) to obtain a colorless oily 1- {3- [2- (1-benzothiophen-5-yl) ethoxy]. 0.78 g of propyl} -3-pyrrolidinol was obtained. [522] IR (neat) cm -1 : 3386, 2943, 1438, 1106, 1052, 755, 701 [523] NMR (CDCl 3 ) δ Value: 1.5-2.0 (3H, m), 2.0-3.0 (7H, m), 2.98 (2H, t, J = 7Hz), 3.49 (2H, t, J = 6Hz), 3.67 ( 2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 7.1-7.3 (2H, m), 7.41 (1H, d, J = 6 Hz), 7.66 (1H, s), 7.78 (1H, d , J = 8 Hz) [524] Example 59 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol hydrochloride [525] [526] In the same manner as in Example 21, colorless crystals 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol hydrochloride were obtained. [527] IR (KBr) cm -1 : 3368, 2937, 2695, 1438, 1108, 821, 764, 708 [528] NMR (CDCl 3 ) δ Value: 1.8-2.3 (4H, m), 2.3-3.6 (6H, m), 2.96 (2H, t, J = 6Hz), 3.50 (2H, t, J = 6Hz), 3.68 ( 2H, t, J = 7 Hz, 4.3-4.7 (1H, m), 7.21 (1H, d, J = 8 Hz), 7.30 (1H, d, J = 5 Hz), 7.43 (1H, d, J = 5 Hz) , 7.67 (1H, s), 7.80 (1H, d, J = 8 Hz) [529] Example 60 Preparation of 1- {3- [2- (1-benzofuran-5-yl) ethoxy] propyl} -3-pyrrolidinol [530] [531] In the same manner as in Example 58, 1- {3- [2- (1-benzofuran-5-yl) ethoxy] propyl} -3-pyrrolidinol as pale yellow oil was obtained. [532] IR (KBr) cm -1 : 3386, 2942, 1467, 1261, 1108, 1030, 883, 740 [533] NMR (CDCl 3 ) δ Value: 1.5-2.0 (3H, m), 2.0-3.0 (7H, m), 2.95 (2H, t, J = 7Hz), 3.49 (2H, t, J = 6Hz), 3.65 ( 2H, t, J = 7 Hz, 4.2-4.4 (1H, m), 6.71 (1H, d, J = 1, 2 Hz), 7.14 (1H, dd, J = 1, 8 Hz), 7.3-7.5 (2H, m), 7.58 (1H, doublet, J = 2 Hz) [534] Example 61 Preparation of 1- {3- [2- (1-benzofuran-5-yl) ethoxy] propyl} -3-pyrrolidinol hydrochloride [535] [536] In the same manner as in Example 39, pale yellow oily 1- {3- [2- (1-benzofuran-5-yl) ethoxy] propyl} -3-pyrrolidinol hydrochloride was obtained. [537] IR (neat) cm -1 : 3339, 2941, 2605, 1468, 1262, 1110, 773, 742 [538] NMR (CDCl 3 ) δ Value: 1.6-2.4 (4H, m), 2.4-4.0 (12H, m), 4.4-4.8 (1H, m), 6.72 (1H, d, J = 2Hz), 7.12 (1H, d, J = 8 Hz), 7.3-7.6 (2H, m), 7.59 (1H, d, J = 2 Hz) [539] Example 62 Preparation of 1- {3- [2- (6-fluoro-1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol [540] [541] In the same manner as in Example 58, yellow oily 1- {3- [2- (6-fluoro-1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol was obtained. [542] IR (neat) cm -1 : 3422, 2952, 1458, 1257, 1106, 838, 747, 711 [543] NMR (CDCl 3 ) δ Value: 1.5-3.0 (10H, m), 3.00 (2H, t, J = 7Hz), 3.4-3.6 (2H, m), 3.68 (2H, t, J = 7Hz), 4.2- 4.4 (1H, m), 7.23 (1H, d, J = 5 Hz), 7.36 (1H, d, J = 5 Hz), 7.51 (1H, dd, J = 10 Hz), 7.66 (1H, d, J = 7 Hz) [544] Example 63 Preparation of 1- {3- [2- (6-fluoro-1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol hydrochloride [545] [546] In the same manner as in Example 39, yellow oily 1- {3- [2- (6-fluoro-1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinol hydrochloride was obtained. . [547] IR (neat) cm -1 : 3377, 2954, 2702, 1458, 1257, 1107, 750, 712 [548] NMR (CDCl 3 ) δ Value: 1.8-2.3 (4H, m), 2.8-3.6 (8H, m), 3.53 (2H, t, J = 6Hz), 3.69 (2H, t, J = 7Hz), 4.3- 4.4 (1H, m), 7.27 (1H, d, J = 5 Hz), 7.39 (1H, d, J = 5 Hz), 7.52 (1H, d, J = 10 Hz), 7.67 (1H, d, J = 7 Hz) [549] Example 64 Preparation of (3R, 4S) -1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3,4-pyrrolidinol [550] [551] In the same manner as in Example 58, colorless oily (3R, 4S) -1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3,4-pyrrolidinol was obtained. Got it. [552] IR (neat) cm -1 : 3387, 2940, 1438, 1159, 1108, 1051, 703 [553] NMR (CDCl 3 ) δ value: 1.5-1.9 (2H, m), 2.4-2.8 (6H, m), 2.98 (2H, t, J = 1, 7 Hz), 3.47 (2H, t, J = 6H7z), 3.67 (2H, t, J = 7 Hz), 4.1-4.3 (2H, m), 7.20 (1H, dd, J = 1, 8 Hz), 7.27 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.65 (1H, d, J = 1 Hz), 7.79 (1H, d, J = 8 Hz) [554] Example 65 Preparation of (3R, 4S) -1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3,4-pyrrolidinol hydrochloride [555] [556] In the same manner as in Example 21, colorless oily (3R, 4S) -1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3,4-pyrrolidinol Hydrochloride was obtained. [557] IR (KBr) cm -1 : 3381, 2871, 2602, 1120, 808, 768, 718 [558] NMR (DMSO-d 6 ) δ Value: 1.8-2.0 (2H, m), 2.8-3.8 (12H, m), 3.9-4.3 (2H, m), 7.25 (1H, dd, J = 2, 8Hz), 7.39 (1H, d, J = 5 Hz), 7.72 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 2 Hz), 7.90 (1H, d, J = 8 Hz) [559] Example 66 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -4-pyrrolidinol [560] [561] In the same manner as in Example 58, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -4-pyrrolidinol as pale yellow oil was obtained. [562] IR (neat) cm -1 : 3385, 2935, 1438, 1364, 1111, 755, 701 [563] NMR (CDCl 3 ) δ Value: 1.4-2.2 (8H, m), 2.1-2.5 (2H, m), 2.5-3.0 (2H, m), 2.98 (2H, t, J = 7Hz), 3.48 (2H, t, J = 6 Hz), 3.5-3.8 (1H, m), 3.67 (2H, d, J = 7 Hz), 7.1-7.3 (2H, m), 7.42 (1H, d, J = 5 Hz), 7.66 (1H , s), 7.79 (1H, d, J = 8 Hz) [564] Example 67 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -4-piperidinol hydrate [565] [566] In the same manner as in Example 17, colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -4-piperidinol hydroxide were obtained. [567] IR (KBr) cm -1 : 3420, 2866, 1718, 1616, 1190, 1120, 705 [568] NMR (DMSO-d 6 ) δ Value: 1.5-2.0 (6H, m), 2.8-3.1 (8H, m), 3.4-3.8 (1H, m), 3.44 (2H, t, J = 6Hz), 3.64 ( 2H, t, J = 6 Hz, 7.24 (2H, t, J = 6 Hz), 7.24 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 5 Hz), 7.6-7.8 (2H, m) , 7.91 (1H, d, J = 8 Hz) [569] Example 68 Preparation of 1- {2- [2-naphthyl) ethoxy] ethyl) -3-pyrrolidinol [570] [571] 0.80 g of 2- [2- (2-naphthyl) ethoxy] ethyl = methanesulfonate was dissolved in 8 ml of N, N-dimethylformamide, and 0.45 ml of 3-pyrrolidinol and 0.75 g of potassium carbonate were dissolved in this solution. Was added, and it stirred at 90 degreeC for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 8: 1-5: 1), and colorless oily 1- {2- [2- (2-naphthyl) ethoxy] ethyl) -3- 0.51 g of pyrrolidinol was obtained. [572] IR (neat) cm -1 : 3422, 2938, 1112, 820, 749 [573] NMR (CDCl 3 ) δ Value: 1.5-1.9 (1H, m), 2.0-2.5 (3H, m), 2.5-3.0 (4H, m), 3.05 (2H, t, J = 7Hz), 3.59 (2H, t, J = 6 Hz, 3.75 (2H, t, J = 7 Hz), 4.2-4.4 (1H, m), 7.2-7.6 (4H, m), 7.6-8.0 (3H, m) [574] Example 69 Preparation of 1- {2- [2- (2-naphthyl) ethoxy] ethyl} -3-pyrrolidinol oxalate [575] [576] In the same manner as in Example 17, colorless crystals 1- {2- [2- (2-naphthyl) ethoxy] ethyl} -3-pyrrolidinol hydroxide were obtained. [577] IR (KBr) cm -1 : 3366, 2945, 1405, 1113, 820, 720 [578] NMR (DMSO-d 6 ) δ values: 1.6-2.3 (2H, m), 2.7-3.5 (8H, m), 3.5-3.9 (4H, m), 4.2-4.5 (1H, m), 7.4-7.6 ( 3H, m), 7.7-8.0 (4H, m) [579] Example 70 Preparation of (3R, 4S) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3,4-pyrrolidinediol [580] [581] 2.50 g of 2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl = methanesulfonate are dissolved in 25 ml of N, N'-dimethylformamide, and the solution is dissolved in (3R, 4S)-. 1.40 g of 3,4-pyrrolidinediol hydrochloride and 4.70 ml of triethylamine were added, and the mixture was stirred at 90 ° C for 1 hour. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 10 with 2 mol / L sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: chloroform: methanol = 8: 1-5: 1) to obtain a yellow oily compound (3R, 4S) -1- {2- [2- ( 0.84 g of 1-benzothiophen-5-yl) ethoxy] ethyl} -3,4-pyrrolidinediol was obtained. [582] IR (neat) cm -1 : 3390, 2940, 1438, 1111, 1050, 703 [583] NMR (CDCl 3 ) δ value: 2.5-3.0 (6H, m), 3.00 (2H, t, J = 7Hz), 3.55 (2H, t, J = 6Hz), 3.70 (2H, t, J = 7Hz), 4.0-4.3 (2H, m), 7.21 (1H, dd, J = 1, 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.43 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 1 Hz), 7.80 (1H, d, J = 8 Hz) [584] Example 71 Preparation of (3R, 4S) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3,4-pyrrolidinediol hydrochloride [585] [586] In the same manner as in Example 21, colorless crystals (3R, 4S) -1- {2- [2- (1-benzothiophen-5-yl) ethoxy] ethyl} -3,4-pyrrolidinediol Hydrochloride was obtained. [587] IR (KBr) cm -1 : 3194, 2854, 1365, 1348, 1130, 1111, 820, 712 [588] NMR (DMSO-d 6 ) δ Value: 2.8-4.0 (12H, m), 3.9-4.3 (2H, m), 7.2-7.6 (2H, m), 7.7-8.2 (3H, m) [589] Example 72 Preparation of tert-Butyl = 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinylcarbamate [590] [591] 0.70 g of 3- [3- (1-benzotheophen-5-yl) ethoxy] propyl = methanesulfonate was dissolved in 7 ml of N, N'-dimethylformamide, and tert-butyl = 3- in this solution. 1.03 g of pyrrolidinyl carbonate and hydrochloride and 1.86 ml of triethylamine were added, and the mixture was stirred at 90 ° C for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 10 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure and yellow oily tert-butyl = 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinylcarbamate 1.12 g was obtained. [592] NMR (CDCl 3 ) δ Value: 1.2-1.9 (3H, m), 1.44 (9H, s), 1.9-3.0 (7H, m), 2.99 (2H, t, J = 7Hz), 3.49 (2H, t, J = 6 Hz), 3.67 (2H, t, J = 7 Hz), 4.0-4.3 (1H, m), 7.19 (1H, d, J = 8 Hz), 7.27 (1H, d, J = 5 Hz), 7.42 (1H , d, J = 5 Hz), 7.66 (1H, s), 7.79 (1H, d, J = 8 Hz) [593] Example 73 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinamine [594] [595] 1.12 g of tert-butyl = 1- {3- [2- (1-benzotheophen-5-yl) ethoxy] propyl} -3-pyrrolidinylcarbamate was dissolved in 7.0 ml of ethyl acetate, and this solution 1.86 ml of 6 mol / L hydrochloric acid was added to the mixture, and the mixture was heated and refluxed for 1 hour. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 10 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 30: 1-20: 1), and pale yellow oily 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] 0.38 g of propyl} -3-pyrrolidinamine was obtained. [596] IR (neat) cm -1 : 3357, 2937, 2861, 2796, 1146, 1108, 755, 701 [597] NMR (CDCl 3 ) δ Value: 1.2-1.9 (4H, m), 1.9-2.8 (7H, m), 2.97 (2H, t, J = 7 Hz), 3.48 (2H, t, J = 6 Hz), 3.66 ( 2H, t, J = 7 Hz, 7.19 (1H, t, J = 8 Hz), 7.23 (1H, d, J = 6 Hz), 7.19 (1H, d, J = 8 Hz), 7.23 (1H, d, J = 5 Hz), 7.39 (1H, d, J = 5 Hz), 7.64 (1H, s), 7.77 (1H, d, J = 8 Hz) [598] Example 74 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinamine oxalate [599] [600] In the same manner as in Example 17, colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinamine hydrate were obtained. [601] IR (KBr) cm -1 : 3390, 2871, 1614, 1310, 1122, 766 [602] NMR (DMSO-d 6 ) δ Value: 1.5-1.9 (2H, m), 1.9-2.9 (8H, m), 2.92 (2H, t, J = 7Hz), 3.3.-3.7 (1H, m), 3.43 (2H, t, J = 6 Hz), 3.62 (2H, t, J = 7 Hz), 7.25 (1H, d, J = 8 Hz), 7.39 (1H, d, J = 5 Hz), 7.72 (1H, d, J = 5 Hz), 7.73 (1 H, s), 7.90 (1 H, d, J = 8 Hz) [603] Example 75 Preparation of N- (1- {3- [2-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) acetamide [604] [605] 0.50 g of 1- {3- [2-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidineamine was dissolved in 5 ml of methylene chloride, cooled to -60 ° C, and then added to this solution. 0.27 ml of triethylamine and 0.14 ml of acetyl chloride were added and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: methanol = 50: 1-10: 1), and yellow oily N- (1- {3- [2-benzothiophen-5-yl) ethoxy] 0.55 g of propyl} -3-pyrrolidinyl) acetamide was obtained. [606] IR (neat) cm -1 : 3292, 2946, 1654, 1560, 1110, 757, 702 [607] NMR (CDCl 3 ) δ Value: 1.5-1.7 (1H, m), 1.7-1.8 (2H, m), 1.94 (3H, s), 2.13 (1H, q, J = 9 Hz), 2.2-2.3 (1H, m), 2.4-2.5 (3H, m), 2.59 (1H, dd, J = 2, 10 Hz), 2.86 (1H, dt, J = 4, 9 Hz), 2.99 (2H, t, J = 7 Hz), 3.49 (2H, t, J = 6 Hz), 3.67 (2H, t, J = 7 Hz), 4.3-4.5 (1H, m), 5.8-5.9 (1H, m), 7.22 (1H, dd, J = 1, 8 Hz ), 7.28 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.67 (1H, d, J = 1 Hz), 7.79 (1H, d, J = 8 Hz) [608] Example 76 Preparation of N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) acetamide hydrochloride [609] [610] In the same manner as in Example 21, N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) acetamide hydrochloride of light brown crystals was prepared. Got it. [611] IR (KBr) cm -1 : 3422, 2868, 2475, 1664, 1542, 1343, 1117, 711 [612] NMR (CDCl 3 ) δ Value: 1.9-2.1 (3H, m), 2.05 (3H, s), 2.3-2.4 (1H, m), 2.4-2.5 (1H, m), 2.6-2.7 (1H, m) , 2.8-2.9 (2H, m), 2.97 (2H, t, J = 6 Hz), 3.4-3.5 (1H, m), 3.51 (2H, t, J = 6 Hz), 3.6-3.7 (1H, m), 3.70 (2H, t, J = 6 Hz), 4.6-4.8 (1H, m), 7.22 (1H, dd, J = 1, 8 Hz), 7.31 (1H, dd, J = 5 Hz), 7.46 (1H, d, J = 5 Hz), 7.67 (1 H, s), 7.81 (1 H, d, J = 8 Hz) [613] Example 77 Preparation of N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) methanesulfonamide [614] [615] In the same manner as in Example 75, yellow oily N- (1- {3- [2-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) methanesulfonamide was obtained. [616] IR (neat) cm -1 : 3270,2927, 2856, 1320, 1148, 1110, 756 [617] NMR (CDCl 3 ) δ value: 1.6-1.8 (3H, m), 2.1-2.3 (2H, m), 2.44 (2H, t, J = 7 Hz), 2.50 (1H, dd, J = 6, 10 Hz), 2.60 (1H, dd, J = 3, 10 Hz), 2.77 (1H, dt, J = 4, 9 Hz), 2.94 (3H, s), 2.99 (2H, t, J = 7 Hz), 3.48 (2H, t, J = 6 Hz), 3.68 (2H, t, J = 7 Hz), 3.9-4.0 (1H, m), 4.6-4.8 (1H, m), 7.22 (1H, dd, J = 1, 8 Hz), 7.28 (1H , d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.67 (1H, d, J = 1 Hz), 7.79 (1H, d, J = 8 Hz) [618] Example 78 Preparation of N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) methanesulfonamide oxalate [619] [620] In the same manner as in Example 17, a colorless crystal N- (1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-pyrrolidinyl) methanesulfonamide oxalate Got. [621] IR (KBr) cm -1 : 3250, 2968, 1718, 1314, 1165, 1119, 707 [622] NMR (CDCl 3 ) δ Value: 1.5-2.0 (3H, m), 2.2-2.3 (1H, m), 2.93 (2H, t, J = 7Hz), 2.97 (3H, s), 3.0-3.1 (3H, m), 3.1-3.2 (1H, m), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.45 (2H, t, J = 6 Hz), 3.63 (2H, t, J = 7 Hz ), 4.0-4.1 (1H, m), 7.26 (1H, dd, J = 1, 8 Hz), 7.40 (1H, d, J = 5 Hz), 7.4-7.6 (1H, m), 7.72 (1H, d, J = 5 Hz), 7.74 (1H, d, J = 1 Hz), 7.90 (1H, d, J = 8 Hz) [623] Example 79 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -N, N-dimethyl-3-pyrrolidinamine [624] [625] 0.43 g of 1- {3- [2- (1-benzotheophen-5-yl) ethoxy] propyl} -3-pyrrolidineamine was dissolved in 8.6 ml of methanol, cooled to 5 ° C, and then this solution. 0.35 ml of 37% formalin and 0.09 g of sodium borohydride were added thereto, and the resultant was stirred at room temperature for 17 hours. Under ice-cooling, 2.6 ml of 2 mol / L hydrochloric acid was added to the reaction mixture, the mixture was stirred at room temperature for 30 minutes, and then water and acetethyl were added, and the water layer was partitioned. Ethyl acetate was added to the water layer, the pH was adjusted to 9.5 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; chloroform: methanol = 50: 1-10: 1), and colored 1- {3- [2- (1-benzoteofen-5-yl) ethoxy] as a yellow oil. 0.39 g of propyl} -N, N'-dimethyl-3-pyrrolidinamine was obtained. [626] IR (neat) cm -1 : 2945, 2862, 2786, 1458, 1111, 700 [627] NMR (CDCl 3 ) δ Value: 1.6-1.8 (3H, m), 1.9-2.0 (1H, m), 2.20 (6H, s), 2.2-2.3 (1H, m), 2.3-2.5 (2H, m) , 2.50 (1H, dt, J = 8, 12 Hz), 2.7-2.8 (2H, m), 2.8-2.9 (1H, m), 2.99 (2H, t, J = 7 Hz), 3.49 (2H, t, J = 7 Hz), 3.67 (2H, t, J = 7 Hz), 7.22 (1H, dd, J = 1, 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 7.67 (1H, d, J = 1 Hz), 7.79 (1H, d, J = 8 Hz) [628] Example 80 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -N, N-dimethyl-3-pyrrolidinamine dihydrochloride [629] [630] 0.39 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -N, N-dimethyl-3-pyrrolidineamine was dissolved in 4.0 ml of ethyl acetate, and this solution 0.825 mL of 3.25 mol / L dry hydrogen chloride-ethyl acetate solution was added to the mixture, and the resultant was stirred at room temperature for 1 hour and again at 5 ° C for 1 hour. The precipitated crystals were filtered, washed with ethyl acetate and dried to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -N, N-dimethyl as colorless crystals. 0.32 g of 3-pyrrolidinamine dihydrochloride were obtained. [631] IR (KBr) cm -1 : 2986, 1437, 1101, 701 [632] NMR (CDCl 3 ) δ Value: 1.9-2.1 (2H, m), 2.4-2.6 (2H, m), 2.84 (6H, s), 2.98 (2H, t, J = 7Hz), 3.1-3.2 (2H, m), 3.4-3.9 (4H, m), 3.54 (2H, t, J = 5 Hz), 3.72 (2H, t, J = 3, 7 Hz), 4.2-4.3 (1H, m), 7.24 (1H, d , J = 8 Hz, 7.35 (1H, d, J = 5 Hz, 7.43 (1H, d, J = 5 Hz), 7.71 (1H, s), 7.84 (1H, d, J = 8 Hz) [633] Example 81 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol 1 / 2fumalate [634] [635] 5.00 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol was dissolved in 10.0 ml of ethanol, heated to 70 ° C., and then 0.99 g of fumaric acid was added and stirred for 30 minutes. 30.0 ml of ethyl acetate was dripped at this solution, and it stirred at 60 degreeC for 15 minutes, cooled to 5 degreeC over 1 hour, and stirred at the same temperature for 1 hour. The precipitated crystals were filtered, washed with ethyl acetate, and dried to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol as colorless crystals. 5.83 g of 1/2 fumarate was obtained. [636] IR (KBr) cm -1 : 3258, 2936, 2862, 1578, 1360, 1114, 1109, 707, 665 [637] NMR (DMSO-d 6 )) δ Value: 1.5-1.6 (2H, m), 2.60 (2H, t, J = 7Hz), 2.91 (2H, t, J = 7Hz), 2.9-3.1 (2H, m) , 3.39 (2H, t, J = 7 Hz), 3.60 (2H, t, J = 7 Hz), 3.6-3.8 (2H, m), 4.1-4.3 (1H, m), 6.50 (1H, s), 7.25 ( 1H, dd, J = 1, 8 Hz), 7.39 (1H, d, J = 5 Hz), 7.72 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 1 Hz), 7.89 (1H, d, J = 8Hz) [638] Example 82 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol [639] [640] (1) 5.00 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid is suspended in 12.5 ml of toluene, and 0.1 ml of N, N'-dimethylformamide is added, followed by 15 ° C. 1.68 ml of thionyl chloride was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was added dropwise to 10 ml of a solution of 4.44 g of 3-hydroxyazitidine ½ tin salt and 3.76 g of sodium hydroxide at 10 ° C., followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: chloroform: acetone = 3: 1-1: 1), and crystallized from diisopropyl ether to give colorless crystals of 3- [2- (1-benzothiophen-5-yl. 5.48 g of) ethoxy] -1- (3-hydroxy) -1-azetidinyl-propanone was obtained. [641] IR (KBr) cm -1 : 3316, 2875, 1610, 1481, 1112, 992, 706 [642] NMR (CDCl 3 ) δ Value: 2.2-2.4 (2H, m), 2.98 (2H, t, J = 7Hz), 3.6-3.8 (5H, m), 3.8-4.0 (1H, m), 4.1-4.3 ( 2H, m), 4.4-4.4 (1H, m), 7.20 (1H, dd, J = 1, 8 Hz), 7.28 (1H, dd, J = 1, 5 Hz), 7.41 (1H, d, J = 5 Hz) , 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [643] (2) 20 ml of tetrahydrofuran 5.00 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetidinyl) -1-propanone After dissolving in, and adding 1.09 g of sodium borohydride, 4.25 ml of boron trifluoride-tetrahydrofuran complex was added dropwise at 10 ° C, and stirred at 40 ° C for 1 hour at 3 ° C. After cooling to 10 ° C, 30 ml of 6 mol / L hydrochloric acid was added dropwise to the reaction mixture, and the mixture was refluxed for 1 hour. After cooling, the solvent was concentrated under reduced pressure, ethyl acetate was added, the pH was adjusted to 9.4 with 20% aqueous sodium hydride solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then purified by column chromatography (eluent; chloroform: methanol = 20: 1-10: 1), and crystallized from toluene-diisopropyl ether (1: 3, 14 mL). This gave 2.31 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol. [644] Example 83 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol maleate [645] [646] 8.00 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol was dissolved in 56 ml of acetone, and 3.19 g of maleic acid was added thereto to 60 ° C. Heated to dissolve. The reaction mixture was cooled slowly and stirred at 5 ° C for 30 minutes. The precipitated crystals were filtered to give 9.89 g of colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol maleate. [647] NMR (DMSO-d 6 )) δ Value: 1.6-1.8 (2H, m), 2.93 (2H, t, J = 7Hz), 3.13 (2H, t, J = 7Hz), 3.48 (2H, t, J = 6 Hz), 3.63 (2H, t, J = 7 Hz), 3.7-3.9 (2H, m), 4.1-4.3 (2H, m), 4.4-4.5 (1H, m), 6.04 (2H, s), 7.26 ( 1H, dd, J = 1, 8 Hz), 7.40 (1H, d, J = 5 Hz), 7.7-7.8 (1H, m), 7.74 (1H, d, J = 5 Hz), 7.92 (1H, d, J = 8 Hz) [648] Example 84 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol-hydrate [649] [650] 10.0 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol was dissolved in 20 ml of ethyl acetate, 20 ml of isopropanol was added, and then room temperature. 2.60 mL of concentrated aquatic acid (61%) was added dropwise. 60 ml of ethyl acetate was dripped at this reaction mixture, and it stirred at the same temperature for 1 hour and 5 degreeC for 1 hour. The precipitated crystals were filtered to give 11.3 g of colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol hydroxide. [651] IR (KBr) cm -1 : 3354, 2880, 1385, 1107, 712 [652] NMR (DMSO-d 6 )) δ Value: 1.6-1.8 (2H, m), 2.93 (2H, t, J = 7Hz), 3.1-3.2 (2H, m), 3.44 (2H, t, J = 6Hz) , 3.64 (2H, t, J = 7 Hz), 3.7-3.9 (2H, m), 4.0-4.4 (2H, m), 4.4-4.5 (1H, m), 7.27 (1H, d, J = 8 Hz), 7.41 (1H, d, J = 5 Hz), 7.74 (1H, d, J = 5 Hz), 7.74 (1H, s), 7.92 (1H, d, J = 8 Hz) [653] Example 85 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol-L-Tartrate [654] [655] 10.0 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol is dissolved in 40 ml of ethyl acetate, 5.15 g of L-tartrate and 40 ml of ethanol Was added and heated to 65 ° C. to dissolve. After stirring 20 minutes at 50 degreeC, 40 ml of ethyl acetate was dripped at the same temperature, and it stirred at 20-30 degreeC for 1 hour. The precipitated crystals were filtered to give 13.9 g of colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol-L-tartrate. [656] IR (KBr) cm -1 : 3318, 2807, 1305, 1126, 679, 483 [657] NMR (DMSO-d 6 )) δ Value: 1.5-1.7 (2H, m), 2.82 (2H, t, J = 7 Hz), 2.92 (2H, t, J = 7 Hz), 3.2-3.4 (2H, m) , 3.41 (2H, t, J = 6 Hz), 3.61 (2H, t, J = 7 Hz), 3.8-4.0 (2H, m), 4.02 (2H, s), 4.2-4.4 (1H, m), 7.26 ( 1H, dd, J = 2, 8 Hz), 7.40 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 5 Hz), 7.7-7.8 (1H, m), 7.91 (1H, d, J = 8 Hz) [658] Example 86 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol 1/2 pumpkin [659] [660] 10.0 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol is dissolved in 30 ml of ethyl acetate, 2.03 g of succinic acid and 35 ml of isopropanol are added. And refluxed to dissolve. 40 ml of ethyl acetate was added dropwise to the reaction mixture, which was then cooled slowly and stirred at 5 ° C for 30 minutes. Precipitated crystals were filtered to give 11.1 g of colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol 1/2 pumpkin salt . [661] IR (KBr) cm -1 : 3250, 2936, 1576, 1361, 1109, 707, 652 [662] NMR (DMSO-d 6 )) δ Value: 1.4-1.6 (2H, m), 2.35 (2H, s), 2.46 (2H, t, J = 7Hz), 2.7-2.9 (2H, m), 2.91 (2H , t, J = 7 Hz), 3.38 (2H, t, J = 6 Hz), 3.5-4.6 (2H, m), 3.59 (2H, t, J = 7 Hz), 4.1-4.2 (1H, m), 7.25 ( 1H, dd, J = 2, 8 Hz), 7.39 (1H, d, J = 5 Hz), 7.72 (1H, d, J = 5 Hz), 7.7-7.8 (1H, m), 7.90 (1H, d, J = 8 Hz) [663] Example 87 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol citrate [664] [665] Dissolve 10.0 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol in 14.4 ml of ethanol, and add 7.21 g of citric acid monohydrate. Heated to ° C. to dissolve. 35 ml of ethyl acetate and 5.6 ml of ethanol were added at 50 degreeC, and it stirred at 25 degreeC. After heating the reaction mixture to 40 ° C, ethyl acetate (45 ml) was added dropwise, and stirred at 40 ° C for 10 minutes and at 10 to 20 ° C for 1 hour. The precipitated crystals were filtered to give 14.9 g of colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol citrate. [666] IR (KBr) cm -1 : 3374, 2943, 1720, 1224, 1104, 706 [667] NMR (DMSO-d 6 )) δ Value: 1.6-1.7 (2H, m), 2.50 (2H, d, J = 15 Hz), 2.58 (2H, d, J = 15 Hz), 2.93 (2H, t, J = 7 Hz), 2.99 (2H, t, J = 7 Hz), 3.42 (2H, t, J = 6 Hz), 3.5-3.6 (2H, m), 3.63 (2H, t, J = 7 Hz), 4.0-4.1 (2H , m), 4.3-4.4 (1H, m), 7.26 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 5 Hz), 7.7-7.8 ( 1H, m), 7.91 (1H, d, J = 8 Hz) [668] Example 88 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = benzoate [669] [670] (1) 0.70 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetinyl) -1-propanone was dissolved in 7 ml of methylene chloride 0.57 ml of triethylamine was added to this solution, and after cooling to 5 degreeC, 0.42 ml of benzoyl chlorides were added and it stirred at the same temperature for 1 hour. Water was added to the reaction mixture, the mixture was adjusted to pH 1 with 2 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1 = 2: 1) to give a colorless oily 1- {3- [2- (1-benzothiophen-5-yl) ethoxy. ] 0.45 g of propanoyl} -3-azetidinyl = benzoate was obtained. [671] IR (neat) cm -1 : 2873, 1719, 1654, 1451, 1274, 1117, 714 [672] NMR (CDCl 3 ) δ Value: 2.3-2.4 (2H, m), 2.99 (2H, t, J = 7Hz), 3.72 (2H, t, J = 7Hz), 3.7-3.8 (2H, m), 4.0- 4.3 (2H, m), 4.3-4.4 (1H, m), 4.4-4.6 (1H, m), 5.2-5.4 (1H, m), 7.1-7.3 (2H, m), 7.41 (1H, d, J = 5 Hz), 7.46 (1H, d, J = 8 Hz), 7.5-7.7 (2H, m), 7.78 (1H, d, J = 8 Hz), 8.0-8.1 (2H, m) [673] (2) 0.51 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propanoyl} -3-azetidinyl = benzoate was dissolved in 1 ml of tetrahydrofuran, 6.8 ml of 1 mol / L tetrahydrofuran solution of the borane-tetrahydrofuran complex was added dropwise under ice cooling, and the mixture was stirred at room temperature for 22 hours. 6.2 mL of ethanol was added to the reaction mixture, and the mixture was refluxed for 4 hours. After cooling, the solvent was removed under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1-chloroform) to give a colorless oily 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl. } -3-azetidinyl = benzoate 0.33 g was obtained. [674] IR (neat) cm -1 : 2941, 1718, 1174, 1115, 755, 713 [675] NMR (CDCl 3 ) δ values: 1.6-1.7 (2H, m), 2.54 (2H, t, J = 7 Hz), 3.00 (2H, t, J = 7 Hz), 3.0-3.2 (2H, m), 3.49 ( 2H, t, J = 6 Hz, 3.67 (2H, t, J = 7 Hz), 3.7-3.8 (2H, m), 5.2-5.3 (1H, m), 7.22 (1H, dd, J = 2, 8 Hz) , 7.28 (1H, d, J = 5 Hz), 7.40 (1H, d, J = 5 Hz), 7.45 (2H, t, J = 8 Hz), 7.5-7.6 (1H, m), 7.6-7.7 (1H, m ), 7.79 (1H, d, J = 8 Hz), 8.0-8.1 (2H, m) [676] Example 89 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = benzoate maleate [677] [678] 0.25 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = benzoate was dissolved in 3 ml of ethyl acetate, 0.07 g of maleic acid was added, And dissolved by heating. The reaction mixture was cooled and the precipitated crystals were filtered to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = benzoate maleate. . [679] IR (KBr) cm -1 : 2872, 1732, 1454, 1358, 1270, 1119 [680] NMR (DMSO-d 6 ) δ Value: 1.6-1.8 (2H, m), 2.94 (2H, t, J = 7Hz), 3.1-3.3 (2H, m), 3.46 (2H, t, J = 6Hz), 3.65 (2H, t, J = 7 Hz), 4.1-4.3 (2H, m), 4.4-4.6 (2H, m), 5.3-5.5 (1H, m), 6.04 (2H, s), 7.26 (1H, d , J = 8 Hz), 7.39 (1H, d, J = 5 Hz), 7.58 (2H, t, J = 8 Hz), 7.7-7.8 (3H, m), 7.91 (1H, d, J = 8 Hz), 8.0- 8.1 (2H, m) [681] Example 90 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = pivalate [682] [683] (1) 1.00 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetidinyl) -1-propanone was added to 8 ml of methylene chloride. It dissolved, 0.40 ml of pyridine was added to this solution, 0.48 ml of pivaloyl chloride was added under ice cooling, and it stirred at room temperature for 22 hours. Water was added to the reaction mixture, acidified with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed with 2 mol / L aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1: 2: 1), and colorless oily 1- {3- [2- (1-benzothiophen-5-yl) ethoxy ] 1.20 g of propanoyl} -3-azetidinyl = pivalate. [684] IR (neat) cm -1 : 2972, 1730, 1655, 1458, 1282, 1151, 1112, 703 [685] NMR (CDCl 3 ) δ Value: 1.21 (9H, s), 2.2-2.4 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.6-3.8 (4H, m), 3.8-4.1 (2H, m), 4.2-4.3 (1H, m), 4.3-4.5 (1H, m), 4.9-5.1 (1H, m), 7.1-7.3 (2H, m), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.80 (1H, d, J = 8 Hz) [686] (2) In the same manner as in Example 88 (2), 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = pivalate was obtained. [687] IR (neat) cm -1 : 2938, 1727, 1283, 1156, 1110, 702 [688] NMR (CDCl 3 ) δ Value: 1.20 (9H, s), 1.5-1.7 (2H, m), 2.50 (2H, t, J = 7 Hz), 2.8-3.0 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.47 (2H, t, J = 6 Hz), 3.6-3.8 (4H, m), 4.9-5.1 (1H, m), 7.22 (1H, dd, J = 2, 8 Hz), 7.2-7.3 (1H, m), 7.42 (1H, d, J = 6 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [689] Example 91 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = pivalate maleate [690] [691] In the same manner as in Example 89, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = pivalate maleate was obtained. [692] IR (KBr) cm -1 : 2866, 1740, 1578, 1452, 1356, 1165, 1120, 870 [693] NMR (DMSO-d 6 ) δ Value: 1.18 (9H, s), 1.6-1.8 (2H, m), 2.8-3.0 (2H, m), 3.0-3.3 (2H, m), 3.3-3.6 (2H, m), 3.5-3.7 (2H, m), 3.9-4.1 (2H, m), 4.3-4.5 (2H, m), 5.0-5.2 (1H, m), 6.05 (2H, s), 7.26 (1H, d, J = 8 Hz), 7.40 (2H, t, J = 5 Hz), 7.7-7.8 (2H, m), 7.91 (1H, d, J = 8 Hz) [694] Example 92 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = methyl = carbonate [695] [696] (1) 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propanoyl} -3-azetidinyl = methyl = carbonate in the same manner as in Example 90 (1); Got it. [697] IR (neat) cm -1 : 2943, 1751, 1272, 1110, 791, 705 [698] NMR (CDCl 3 ) δ Value: 2.2-2.4 (2H, m), 2.99 (2H, t, J = 7Hz), 3.7-3.8 (2H, m), 3.71 (2H, t, J = 7Hz), 3.82 ( 3H, s), 3.9-4.0 (1H, m), 4.0-4.3 (2H, m), 4.3-4.4 (1H, m), 4.9-5.1 (1H, m), 7.21 (1H, dd, J = 1 , 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.80 (1H, d, J = 8 Hz) [699] (2) In the same manner as in Example 88 (2), 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = methyl = carbonate was obtained. . [700] IR (neat) cm -1 : 2952, 2858, 1749, 1442, 1271, 1109, 792, 704 [701] NMR (CDCl 3 ) δ Value: 1.5-1.7 (2H, m), 2.49 (2H, t, J = 7 Hz), 2.9-3.1 (4H, m), 3.46 (2H, t, J = 6 Hz), 3.6- 3.7 (4H, m), 3.78 (3H, s), 4.9-5.1 (2H, m), 7.21 (1H, dd, J = 2, 8 Hz), 7.28 (1H, dd, J = 1, 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [702] Example 93 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = methyl = carbonate [703] [704] 0.31 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = methyl = carbonate was dissolved in 7 ml of ethyl acetate and dissolved in this solution A solution of 1 ml of ethyl acetate containing 0.10 g was added and stirred at room temperature. The precipitated crystals were filtered to give 0.34 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = methyl = carbonate oxalate. [705] IR (KBr) cm -1 : 2863, 2594, 1753, 1444, 1278, 1112, 719 [706] NMR (DMSO-d 6 ) δ Value: 1.6-1.8 (2H, m), 2.92 (2H, t, J = 7 Hz), 3.0-3.1 (2H, m), 3.42 (2H, t, J = 6 Hz), 3.62 (2H, t, J = 7 Hz), 3.74 (3H, s), 3.9-4.0 (2H, m), 4.2-4.3 (2H, m), 5.0-5.2 (1H, m), 7.26 (2H, dd , J = 1, 8 Hz), 7.40 (1H, dd, J = 1, 5 Hz), 7.7-7.8 (2H, m), 7.90 (1H, d, J = 8 Hz) [707] Example 94 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = ethyl = carbonate [708] [709] (1) In the same manner as in Example 90 (1), 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propanoyl} -3-azetidinyl = ethyl = carbonate Got. [710] IR (neat) cm -1 : 2942, 2873, 1747, 1654, 1450, 1260, 1111, 791, 704 [711] NMR (CDCl 3 ) δ Value: 1.32 (3H, t, J = 7Hz), 2.2-2.4 (2H, m), 2.99 (2H, t, J = 7Hz), 3.7-3.8 (2H, m), 3.71 ( 2H, t, J = 7Hz), 3.9-4.0 (1H, m), 4.0-4.2 (1H, m), 4.2-4.3 (1H, m), 4.22 (2H, q, J = 7Hz), 4.3-4.4 (1H, m), 4.9-5.1 (1H, m), 7.21 (1H, dd, J = 2, 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.80 (1H, d, J = 8 Hz) [712] (2) In the same manner as in Example 88 (2), 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = ethyl = carbonate was obtained. . [713] IR (neat) cm -1 : 2941, 1750, 1262, 1110, 1049, 792, 704 [714] NMR (CDCl 3 ) δ Value: 1.31 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 2.50 (2H, t, J = 7 Hz), 2.9-3.1 (4H, m), 3.46 ( 2H, t, J = 6 Hz, 3.6-3.7 (4H, m), 4.19 (2H, q, J = 7 Hz), 4.9-5.1 (1H, m), 7.21 (1H, dd, J = 2, 8 Hz) , 7.28 (1H, dd, J = 1, 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, s), 7.79 (1H, d, J = 8 Hz) [715] Example 95 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = ethyl = carbonate oxalate [716] [717] In the same manner as in Example 93, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = ethyl = carbonate oxalate was obtained. [718] IR (KBr) cm -1 : 2932, 2864, 2583, 1748,789, 719 [719] NMR (DMSO-d 6 ) δ Value: 1.23 (3H, t, J = 7 Hz), 1.6-1.8 (2H, m), 2.92 (2H, t, J = 7 Hz), 3.0-3.1 (2H, m), 3.43 (2H, t, J = 6 Hz), 3.62 (2H, t, J = 7 Hz), 3.9-4.0 (2H, m), 4.16 (2H, q, J = 7 Hz), 4.2-4.3 (2H, m) , 5.0-5.2 (1H, m), 7.26 (1H, dd, J = 2, 8 Hz), 7.40 (1H, d, J = 6 Hz), 7.7-7.8 (2H, m), 7.90 (1H, d, J = 8 Hz) [720] Example 96 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (methoxymethoxy) azetidine [721] [722] (1) 1.52 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetiyl) -1-propanone was dissolved in 8.5 ml of methylene chloride To the solution was added 2.6 ml of N, N'-diisopropylethylamimi, cooled to 5 ° C, 1.0 ml of chloromethyl methyl ether was added and stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1-1: 1) to obtain oily 3- [2- (1-benzothiophen-5-yl) ethoxy] -1. 1.40 g of-[3- (methoxymethoxy) -1-azetiyl] -1-propanone was obtained. [723] IR (neat) cm -1 : 2941, 2867, 1654, 1112, 1055, 919, 704 [724] NMR (CDCl 3 ) δ Value: 2.3-2.4 (2H, m), 2.99 (2H, t, J = 7Hz), 3.37 (3H, s), 2.9-3.7-3.8 (2H, m), 3.72 (2H, t, J = 7 Hz, 3.8-4.1 (2H, m), 4.1-4.4 (3H, m), 4.60 (2H, s), 7.21 (1H, dd, J = 2, 8 Hz), 7.29 (1H, dd , J = 1, 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, s), 7.79 (1H, d, J = 8 Hz) [725] (2) 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (methoxymethoxy) azetidine in the same manner as in Example 88 (2) Got it. [726] IR (neat) cm -1 : 2943, 1113, 1059, 1012, 109, 703 [727] NMR (CDCl 3 ) δ Value: 1.5-1.7 (2H, m), 2.49 (2H, t, J = 7 Hz), 2.8-2.9 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.36 ( 3H, s), 3.47 (2H, t, J = 6 Hz), 3.5-3.7 (4H, m), 4.2-4.3 (1H, m), 4.59 (2H, s), 7.22 (1H, dd, J = 1 , 8 Hz), 7.28 (1H, dd, J = 1, 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [728] Example 97 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (methoxymethoxy) azetidine-hydrate [729] [730] In the same manner as in Example 93, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (methoxymethoxy) azetidine-hydrate was obtained. [731] IR (KBr) cm -1 : 2866, 1719, 1624, 1112, 989, 920, 707 [732] NMR (DMSO-d 6 ) δ Value: 1.6-1.8 (2H, m), 2.92 (2H, t, J = 7Hz), 3.0-3.1 (2H, m), 3.29 (3H, s), 3.43 (2H, t, J = 6 Hz, 3.63 (2H, t, J = 7 Hz), 3.7-3.9 (2H, m), 4.1-4.3 (2H, m), 4.3-4.5 (1H, m), 4.60 (2H, s ), 7.26 (1H, dd, J = 2, 8 Hz), 7.40 (1H, d, J = 5 Hz), 7.7-7.8 (2H, m), 7.90 (1H, d, J = 8 Hz) [733] Example 98 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (benzyloxy) methoxy] azetidine [734] [735] (1) In the same manner as in Example 96 (1), 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- {3-[(benzyloxy) methoxy] -1- Azetidinyl} -1-propanone was obtained. [736] IR (neat) cm -1 : 2872, 1654, 1112, 700 [737] NMR (CDCl 3 ) δ Value: 2.3-2.4 (2H, m), 2.99 (2H, t, J = 7Hz), 3.7-3.8 (2H, m), 3.71 (2H, t, J = 7Hz), 3.8- 4.3 (4H, m), 4.3-4.4 (1H, m), 4.60 (2H, s), 4.73 (2H, s), 7.21 (1H, dd, J = 1, 8 Hz), 7.2-7.4 (6H, m ), 7.40 (1H, dd, J = 5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [738] (2) 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-[(benzyloxy) methoxy] ase in the same manner as in Example 88 (2) Tidin was obtained. [739] IR (neat) cm -1 : 2942, 1196, 1115, 1060, 700 [740] NMR (CDCl 3 ) δ Value: 1.5-1.7 (2H, m), 2.49 (2H, t, J = 7 Hz), 2.8-3.0 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.47 ( 2H, t, J = 6 Hz, 3.5-3.7 (2H, m), 3.66 (2H, t, J = 7 Hz), 4.2-4.4 (1H, m), 4.60 (2H, s), 4.72 (2H, s ), 7.2-7.4 (6H, m), 7.22 (1H, dd, J = 1, 8 Hz), 7.41 (1H, d, J = 6 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8Hz) [741] Example 99 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine [742] [743] (1) 0.85 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetinyl) -1-propanone was dissolved in 6.8 ml of toluene; 0.34 ml of pyridine, 0.02 g of 4- (dimethylamino) pyridine and 0.93 g of trityl chloride were added to the solution, followed by stirring at 50 ° C for 3 hours. 0.85 ml of N, N'-dimethylformamide was added, followed by further stirring at 50 ° C for 24 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1-3: 1) to obtain oily 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- [ 1.15 g of 3- (trityloxy) -1-azetiyl] -1-propanone were obtained. [744] IR (neat) cm -1 : 2940, 2870, 1654, 1106, 762, 707 [745] NMR (CDCl 3 ) δ Value: 2.18 (2H, t, J = 6 Hz), 2.94 (2H, t, J = 7 Hz), 3.5-3.8 (8H, m), 4.2-4.4 (1H, m), 7.1- 7.5 (18H, m), 7.6-7.7 (1H, m), 7.73 (1H, d, J = 8 Hz) [746] (2) In the same manner as in Example 88 (2), 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine was obtained. . [747] IR (neat) cm -1 : 2943, 1492, 1146, 1104, 706 [748] NMR (CDCl 3 ) δ Value: 1.4-1.6 (2H, m), 2.3-2.4 (2H, m), 2.5-2.7 (2H, m), 2.95 (2H, t, J = 7Hz), 3.0-3.1 ( 2H, m), 3.37 (2H, t, J = 7 Hz), 3.61 (2H, t, J = 7 Hz), 4.1-4.3 (1H, m), 7.1-7.3 (11H, m), 7.3-7.5 (7H , m), 7.6-7.7 (1H, m), 7.77 (1H, d, J = 8 Hz) [749] Example 100 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine-hydrate [750] [751] In the same manner as in Example 93, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine-hydrate was obtained. [752] IR (KBr) cm -1 : 2866, 1491, 1451, 1155, 1110, 704 [753] NMR (DMSO-d 6 ) δ Value: 1.4-1.6 (2H, m), 2.8-3.0 (4H, m), 3.34 (2H, t, J = 6Hz), 3.4-3.6 (6H, m), 4.2- 4.4 (1H, m), 7.73 (1H, d, J = 8 Hz), 7.3-7.5 (16H, m), 7.6-7.8 (2H, m), 7.88 (1H, d, J = 8 Hz) [754] Example 101 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (triethylsilyl) oxy] azetidine [755] [756] (1) 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- {3-[(triethylsilyl) oxy] -1-ase in the same manner as in Example 99 (1) Tidinyl} -1-propanone was obtained. [757] IR (neat) cm -1 : 2954, 2875, 1654, 1458, 1113, 1004, 750 [758] NMR (CDCl 3 ) δ value: 0.57 (6H, q, J = 8 Hz), 0.94 (9H, t, J = 8 Hz), 2.2-2.4 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.6-3.9 (5H, m), 3.9-4.0 (1H, m), 4.1-4.3 (2H, m), 4.4-4.6 (1H, m), 7.21 (1H, dd, J = 2, 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [759] (2) 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (triethylsilyl) oxy] azetidine in the same manner as in Example 88 (2) Got. [760] IR (neat) cm -1 : 2951, 1380, 1201, 1114, 865, 747, 701 [761] NMR (CDCl 3 ) δ value: 0.57 (6H, q, J = 8 Hz), 0.94 (9H, t, J = 8 Hz), 1.5-1.7 (2H, m), 2.48 (2H, t, J = 7 Hz), 2.7-2.8 (2H, m), 2.99 (2H, t, J = 7 Hz), 3.46 (2H, t, J = 6 Hz), 3.5-3.7 (2H, m), 3.66 (2H, t, J = 7 Hz) , 4.3-4.5 (1H, m), 7.21 (1H, dd, J = 2, 8 Hz), 7.28 (1H, dd, J = 1, 8 Hz), 7.41 (1H, d, J = 6 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [762] Example 102 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (benzyloxy) azetidine [763] [764] (1) 1.00 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1- (3-hydroxy-1-azetinyl) -1-propanone was added N, N'-dimethyl It dissolved in 8 ml of formamide, 1.90 g of silver oxide (I) and 0.97 ml of benzyl bromide were added to this solution, and it stirred at room temperature for 31 hours. The insolubles were filtered off, water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1-1: 4) to obtain oily 3- [2- (1-benzothiophen-5-yl) ethoxy] -1-. 1.00 g of [3- (benzyloxy) -1-azetidinyl] -1-propanone was obtained. [765] IR (neat) cm -1 : 2869, 1654, 1112, 754, 700 [766] NMR (CDCl 3 ) δ Value: 2.2-2.4 (2H, m), 2.98 (2H, t, J = 7Hz), 3.6-3.8 (4H, m), 3.8-3.9 (1H, m), 3.9-4.0 ( 1H, m), 4.0-4.1 (1H, m), 4.1-4.3 (2H, m), 4.40 (1H, d, J = 12 Hz), 4.44 (1H, d, J = 12 Hz), 7.20 (1H, dd , J = 1, 8 Hz), 7.2-7.5 (7H, m), 7.6-7.7 (1H, m), 7.78 (1H, d, J = 8 Hz) [767] (2) In the same manner as in Example 1 (2), 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (benzyloxy) azetidine was obtained. [768] IR (neat) cm -1 : 2939, 1355, 1194, 1110, 754, 700 [769] NMR (CDCl 3 ) δ Value: 1.5-1.7 (2H, m), 2.48 (2H, t, J = 7 Hz), 2.8-2.9 (2H, m), 2.98 (2H, t, J = 7 Hz), 3.46 ( 2H, t, J = 6 Hz, 3.5-3.7 (2H, m), 3.65 (2H, t, J = 7 Hz), 4.1-4.3 (1H, m), 4.42 (2H, s), 7.21 (1H , dd, J = 1, 8 Hz), 7.2-7.4 (6H, m), 7.41 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [770] Example 103 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (benzyloxy) azetidine-hydrate [771] [772] In the same manner as in Example 93, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (benzyloxy) azetidine-hydrate was obtained. [773] IR (KBr) cm -1 : 2859, 1111, 700 [774] NMR (DMSO-d 6 ) δ Value: 1.6-1.8 (2H, m), 2.92 (2H, t, J = 7Hz), 3.06 (2H, t, J = 7Hz), 3.42 (2H, t, J = 6Hz ), 3.62 (2H, t, J = 7 Hz), 3.7-3.9 (2H, m), 4.1-4.2 (2H, m), 4.3-4.4 (1H, m), 4.46 (2H, s), 7.26 (1H) , d, J = 8 Hz), 7.3-7.5 (6H, m), 7.7-7.8 (2H, m), 7.90 (1H, d, J = 8 Hz) [775] Example 104 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine [776] [777] 0.54 g of 2- (1-benzothiophen-5-yl) -1-ethanol is suspended in 0.4 ml of toluene and 7 ml of 50% (W / V) aqueous sodium hydroxide solution, and 1- (3-chloropropyl) -3 1.45 g of-(trityloxy) azetidine hydrate and 0.03 g of tetra-n-butylammonium bromide were added and refluxed for 7 hours. After cooling, water and toluene were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; chloroform: methanol = 75: 1) to obtain 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3 as a pale yellow oil. 0.59 g of-(trityloxy) azetidine was obtained. [778] Example 105 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidinemaleate [779] [780] In the same manner as in Example 89, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine maleate was obtained. [781] IR (KBr) cm -1 : 3059, 1346, 1119, 871, 706 [782] NMR (CDCl 3 ) δ value: 1.6-1.8 (2H, m), 2.8-3.0 (4H, m), 3.1-3.3 (2H, m), 3.40 (2H, t, J = 6Hz), 3.63 (2H, t, J = 7 Hz, 3.8-4.0 (2H, m), 4.4-4.6 (1H, m), 6.23 (2H, s), 7.18 (1H, d, J = 8 Hz), 7.2-7.5 (17H, m ), 7.64 (1H, s), 7.79 (1H, d, J = 8 Hz) [783] Example 106 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (tetrahydro-2H-pyran-2-yloxy) azetidine [784] [785] In the same manner as in Example 104, 2- (1-benzothiophen-5-yl) -1-ethanol and 1- (3-chloropropyl) -3- (tetrahydro-2H-pyran-2-yloxy) 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (tetrahydro-2H-pyran-2-yloxy) azetidine was obtained from azetidine. [786] IR (neat) cm -1 : 2943, 2853, 1201, 1115, 1037, 975, 703 [787] NMR (CDCl 3 ) δ Value: 1.4-1.9 (8H, m), 2.49 (2H, t, J = 7 Hz), 2.8-3.0 (2H, m), m 2.98 (2H, t, J = 7 Hz), 3.4 -3.6 (1H, m), 3.46 (2H, t, J = 6 Hz), 3.5-3.7 (4H, m), 3.8-3.9 (1H, m), 4.2-4.4 (1H, m), 4.5-4.6 ( 1H, m), 7.21 (1H, dd, J = 2, 8 Hz), 7.28 (1H, dd, J = 1, 6 Hz), 7.41 (1H, d, J = 6 Hz), 7.6-7.7 (1H, m) , 7.78 (1H, doublet, J = 8 Hz) [788] Example 107 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = pyvarate [789] [790] 0.75 g of 5- [2- (3-bromopropoxy) ethyl] -1-benzothiophene was dissolved in 3.75 ml of dimethylsulfoxide, and 0.63 g of sodium hydrogencarbonate and 3-azetidinyl = pibarate in this solution 0.73 g of hydrochloride was added and stirred at 70 ° C for 4 hours. After cooling, 20 ml of water and 15 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 1: 1: 1: 5) to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy as a pale yellow oil. ] Propyl} -3-azetidinyl = pibarate 0.78 g. [791] Example 108 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetidine [792] [793] 2.69 g of 3- (trityloxy) azetidine hydrochloride was suspended in 15 ml of water, 20 ml of ethyl acetate was added to adjust pH to 9 with 2 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was dissolved in 10 ml of dimethyl sulfoxide, and 0.80 g of sodium hydrogencarbonate and 2.00 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] propyl = methanesulfonate were added to the solution. And it stirred at 50 degreeC for 3 hours. 20 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1 = 1: 3) to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy as a pale yellow oil. ] Propyl} -3- (trityloxy) azetidine was obtained. [794] Example 109 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = acetate [795] [796] 1.50 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol is dissolved in 15 ml of tetrahydrofuran, and on ice cooling, 0.73 ml of acetic anhydride and 0.06 ml of boron trifluoride-diethyl ether complex was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; chloroform: methanol = 100: 1-50: 1) to obtain 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] as a pale yellow oil. 1.63 g of propyl} -3-azetidinyl = acetate was obtained. [797] IR (neat) cm -1 : 2941, 2859, 1741, 1375, 1239, 1109, 756, 703 [798] NMR (CDCl 3 ) δ Value: 1.5-1.7 (2H, m), 2.06 (3H, s), 2.49 (2H, t, J = 7 Hz), 2.91-3.1 (4H, m), 3.46 (2H, t, J = 6 Hz), 3.5-3.7 (4H, m), 3.66 (2H, t, J = 7 Hz), 4.9-5.1 (1H, m), 7.21 (1H, dd, J = 1, 8 Hz), 7.28 (1H , d, J = 1, 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J = 8 Hz) [799] Example 110 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = acetate [800] [801] In the same manner as in Example 93, 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = acetate hydrate was obtained. [802] IR (KBr) cm -1 : 2862, 1745, 1253, 1108, 711 [803] NMR (DMSO-d 6 ) δ Value: 1.6-1.8 (2H, m), 2.06 (3H, s), 2.92 (2H, t, J = 7Hz), 3.05 (2H, t, J = 7Hz), 3.43 ( 2H, t, J = 6 Hz, 3.62 (2H, t, J = 7 Hz), 3.8-4.0 (2H, m), 4.2-4.3 (2H, m), 5.0-5.2 (1H, m), 7.26 (1H , dd, J = 1, 8 Hz), 7.40 (1H, d, J = 6 Hz), 7.7-7.8 (2H, m), 7.91 (1H, d, J = 8 Hz) [804] Example 111 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinylmaleate [805] [806] 1.30 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = pibarate maleate was suspended in 2.6 ml of isopropanol and 5 mol at 20 ° C. 2.1 ml / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed successively with water and brine. 0.29 g of maleic acid was added to the organic layer, and after heating and melting, the solvent was removed under reduced pressure. 5.2 ml of ethyl acetate and 1.3 ml of isopropanol were added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes under ice cooling for 1 hour. The precipitated crystals were filtered to give 0.76 g of colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol maleate. [807] Example 112 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol maleate [808] [809] 2.00 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinyl = benzoate maleate was suspended in 1.00 ml of isopropanol, followed by 2 mol / L hydroxide. 7.82 ml of aqueous sodium solution was added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. 0.43 g of maleic acid was added to the residue and crystallized from ethyl acetate-isopropanol (4: 1, 10 mL) to give 1- {3- [2- (1-benzothiophen-5-yl) ethoxy as colorless crystals. ] Propyl} -3-azetidinol maleate 1.29g was obtained. [810] Example 113 Preparation of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3-azetidinol maleate [811] [812] 0.83 g of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy] propyl} -3- (trityloxy) azetididine is dissolved in 4.00 ml of chloroform, and 4.75 mol / L dried. 1.66 ml of hydrogen chloride-ethanol solution was added, and it stirred at room temperature for 6 hours. Water and chloroform were added to the reaction mixture to separate the water layer. Ethyl acetate was added to the water layer, the mixture was adjusted to pH 10 with 5 mol / L aqueous sodium hydroxide solution, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. 0.11 g of maleic acid was added to the residue and crystallized from ethyl acetate-isopropanol (4: 1, 5 mL) to give colorless crystals of 1- {3- [2- (1-benzothiophen-5-yl) ethoxy. ] Propyl} -3-azetidinol maleate 0.33 g was obtained. [813] Reference Example 1 Preparation of 3- [2- (1-benzothiophen-4-yl) ethoxy] -1-propanol [814] [815] 2.2 g of 2- (1-benzothiophen-4-yl) -1-ethanol was suspended in 2.2 ml of toluene and 8 ml of 50% (W / V) aqueous sodium hydroxide solution, and 2- (3-chloropropoxy) tetra 4.41 g of hydro-2H-pyran and 0.42 g of tetrahydrogen tetra-n-butylammonium sulfate were added, and it heated and refluxed for 2 hours. After cooling, water and toluene were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure to afford 2- {3- [2- (1-benzothiophen-4-yl) ethoxy] propoxy} tetrahydro-2H-pyran and 2- (3-chloro in the light brown oil phase. 6.50 g of a mixture of propoxy) tetrahydro-2H-pyran were obtained. [816] 6.50 g of this mixture was dissolved in 8.0 ml of methanol, 8.0 ml of water and 0.70 g of p-toluenesulfonic acid monohydrate were added, followed by stirring at room temperature for 12 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: toluene: ethyl acetate = 4: 1-3: 1), and the oily 3- [2- (1-benzothiophen-4-yl) ethoxy] -1- 1.42 g of propanol were obtained. [817] IR (neat) cm -1 : 3394, 2943, 2867, 1413, 1110, 761 [818] NMR (CDCl 3 ) δ Value: 1.81 (2H, qn, J = 6 Hz), 2.1 (1H, brs), 3.26 (2H, t, J = 7 Hz), 3.63 (2H, t, J = 6 Hz), 3.69 ( 2H, t, J = 7 Hz, 3.76 (2H, t, J = 6 Hz), 7.0-7.4 (2H, m), 7.45 (2H, s), 7.77 (1H, dd, J = 2, 7 Hz) [819] Reference Example 2 [820] In the same manner as in Reference Example 1, the following compounds were obtained. [821] ※ 3- [2- (1-benzothiophen-2-yl) ethoxy] -1-propanol [822] NMR (CDCl 3 ) δ Value: 1.68 (1H, brs), 1.86 (2H, qn, J = 6 Hz), 3.17 (2H, t, J = 6 Hz), 3.67 (2H, t, J = 6 Hz), 3.76 ( 4H, t, J = 6Hz), 7.07 (1H, s), 7.2-7.4 (2H, m), 7.67 (1H, d, J = 8Hz), 7.77 (1H, d, J = 8Hz) [823] ※ 3- [2- (1-benzothiophen-3-yl) ethoxy] -1-propanol [824] IR (neat) cm -1 : 3395, 2942, 2897, 1427, 1113, 762, 732 [825] NMR (CDCl 3 ) δ Value: 1.83 (2H, qn, J = 6Hz), 2.27 (1H, t, J = 6Hz), 3.13 (2H, t, J = 7Hz), 3.65 (2H, t, J = 6Hz ), 3.74 (2H, t, J = 6 Hz), 3.78 (2H, t, J = 7 Hz), 7.18 (1H, s), 7.34 (1H, dt, J = 1, 7 Hz), 7.39 (1H, dt, J = 1, 7 Hz), 7.76 (1H, dd, J = 1, 7 Hz), 7.86 (1H, dd, J = 1, 7 Hz) [826] ※ 3- [2- (1-benzothiophen-5-yl) ethoxy] -1-propanol [827] IR (neat) cm -1 : 3398, 2939, 2866, 1438, 1110, 704 [828] NMR (CDCl 3 ) δ Value: 1.82 (2H, qn, J = 6 Hz), 2.29 (1H, t, J = 6 Hz), 3.00 (2H, t, J = 7 Hz), 3.64 (2H, t, J = 6 Hz ), 3.71 (2H, t, J = 7 Hz), 3.73 (2H, q, J = 6 Hz), 7.22 (1H, dd.J = 1, 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.28 ( 1H, d, J = 5 Hz, 7.42 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 1 Hz), 7.80 (1H, d, J = 8 Hz) [829] ※ 3- [2- (1-benzothiophen-6-yl) ethoxy] -1-propanol [830] IR (neat) cm -1 : 3389, 2942, 2865, 1397, 1111, 819, 693 [831] NMR (CDCl 3 ) δ Value: 1.82 (2H, qn, J = 6 Hz), 2.24 (1H, t, J = 6 Hz), 3.00 (2H, t, J = 7 Hz), 3.64 (2H, t, J = 6 Hz ), 3.71 (2H, t, J = 7 Hz), 3.74 (2H, q, J = 6 Hz), 7.21 (1H, d, J = 5 Hz), 7.28 (1H, d, J = 5 Hz), 7.38 (1H, d, J = 5 Hz), 7.70 (1H, s), 7.75 (1H, d, J = 8 Hz) [832] ※ 3- [2- (1-benzothiophen-7-yl) ethoxy] -1-propanol [833] Reference Example 3 Preparation of 4- [2- (3-chloropropoxy) ethyl] benzothiophene [834] [835] Dissolve 1.40 g of 3- [2- (1-benzothiophen-4-yl) ethoxy] -1-propanol in 7.0 ml of methylene chloride, 1.10 ml of thionyl chloride and 0.05 ml of N, N'-dimethylformamide Was added and heated to reflux for 5 hours. Then the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 20: 1) to obtain 1.43 g of yellow oily 4- [2- (3-chloropropoxy) ethyl) -1-benzothiophene. [836] IR (neat) cm -1 : 2867, 1413, 1113, 760 [837] NMR (CDCl 3 ) δ Value: 1.99 (2H, qn, J = 6 Hz), 3.23 (2H, t, J = 7 Hz), 3.58 (2H, t, J = 6 Hz), 3.59 (2H, t, J = 6 Hz ), 3.75 (2H, t, J = 7 Hz), 7.18 (1H, dd, J = 2, 7 Hz), 7.29 (1H, d, J = 7 Hz), 7.1-7.3 (2H, m), 7.45 (2H, s), 7.76 (1H, doublet of doublets, J = 2, 8 Hz) [838] Reference Example 4 [839] In the same manner as in Reference Example 3, the following compounds were obtained. [840] 2- [2- (3-chloropropoxy) ethyl] -1-benzothiophene [841] NMR (CDCl 3 ) δ Value: 2.04 (2H, qn, J = 6 Hz), 3.16 (2H, t, J = 7 Hz), 3.62 (2H, t, J = 6 Hz), 3.66 (2H, t, J = 6 Hz ), 3.75 (2H, t, J = 7 Hz), 7.06 (1H, s), 7.25 (1H, dt, J = 1, 7 Hz), 7.30 (1H, dt, J = 1, 7 Hz), 7.67 (1H, dd, J = 1, 7 Hz), 7.77 (1H, dd, J = 1, 7 Hz) [842] ※ 3- [2- (3-chloropropoxy) ethyl] -1-benzothiophene [843] IR (neat) cm -1 : 2865, 1427, 1115, 762, 732 [844] NMR (CDCl 3 ) δ Value: 2.02 (2H, qn, J = 6 Hz), 3.13 (2H, t, J = 7 Hz), 3.61 (2H, t, J = 6 Hz), 3.62 (2H, t, J = 6 Hz ), 3.78 (2H, t, J = 7 Hz), 7.19 (1H, s), 7.34 (1H, dt, J = 1, 7 Hz), 7.39 (1H, dt, J = 1, 7 Hz), 7.77 (1H, dd, J = 1, 7 Hz), 7.86 (1H, dd, J = 1, 7 Hz) [845] ※ 5- [2- (3-chloropropoxy) ethyl] -1-benzothiophene [846] IR (neat) cm -1 : 2864, 1438, 1113, 755, 701 [847] NMR (CDCl 3 ) δ Value: 2.01 (2H, qn, J = 6 Hz), 3.00 (2H, t, J = 7 Hz), 3.59 (2H, t, J = 6 Hz), 3.61 (2H, t, J = 6 Hz ), 3.70 (2H, t, J = 7 Hz), 7.22 (1H, dd, J = 1, 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.68 ( 1H, d, J = 1 Hz), 7.79 (1H, d, J = 8 Hz) [848] ※ 6- [2- (3-chloropropoxy) ethyl] -1-benzothiophene [849] IR (neat) cm -1 : 2864, 1113, 820, 761, 695, 652 [850] NMR (CDCl 3 ) δ Value: 2.00 (2H, qn, J = 6Hz), 3.00 (2H, t, J = 7Hz), 3.58 (2H, t, J = 6Hz), 3.61 (2H, t, J = 6Hz ), 3.70 (2H, t, J = 7 Hz), 7.21 (1H, d, J = 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.37 (1H, d, J = 5 Hz), 7.72 (1H, s), 7.73 (1H, d, J = 8 Hz) [851] ※ 7- [2- (3-chloropropoxy) ethyl] -1-benzothiophene [852] IR (neat) cm -1 : 2866, 1460, 1395, 1115, 795, 701 [853] NMR (CDCl 3 ) δ Value: 2.00 (2H, qn, J = 6 Hz), 3.17 (2H, t, J = 7 Hz), 3.60 (4H, t, J = 6 Hz), 3.82 (2H, t, J = 7 Hz ), 7.20 (1H, t, J = 8 Hz), 7.33 (1H, d, J = 8 Hz), 7.35 (1H, dd, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.70 (1H, d, J = 8 Hz) [854] Reference Example 5 Preparation of 3- [2- (1-benzothiophen-5-yl) ethoxy] propyl = methanesulfonate [855] [856] 2.03 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1-propanol was dissolved in 16.8 ml of methylene chloride, and ice-cooled; 2.43 ml of methanesulfonyl chloride and triethylamine in this solution. 4.37 mL and 0.10 g of 4- (dimethylamino) pyridine were added, followed by stirring at the same temperature for 30 minutes and again at room temperature for 12 hours. Methylene chloride and water were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 5: 1) to obtain 1.40 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] propyl = methanesulfonate. [857] IR (neat) cm -1 : 2937, 2866, 1352, 1174, 1114, 943, 705, 529 [858] NMR (CDCl 3 ) δ Value: 1.97 (2H, qn, J = 6 Hz), 2.81 (3H, s), 2.98 (2H, t, J = 7 Hz), 3.54 (2H, t, J = 6 Hz), 3.70 ( 2H, t, J = 6 Hz), 4.26 (2H, t, J = 7 Hz), 7.20 (1H, dd, J = 1, 8 Hz), 7.28 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.65 (1H, d, J = 1 Hz), 7.79 (1H, d, J = 8 Hz) [859] Reference Example 6 In 2- [2- (6-methoxy-1benzofuran-5-yl) ethoxy] acetic acid and 2- [2- (5-methoxy-1-benzofuran-6-yl) Preparation of oxy] acetic acid [860] (1) Preparation of 2,4-dimethoxyphenethyl = acetate [861] [862] 15.0 g of 2- (2,4-dimethoxyphenyl) -1-ethanol was dissolved in 150 ml of methylene chloride, and under ice-cooling, 9.32 ml of acetic anhydride, 13.8 ml of triethylamine, and 4- (dimethylamino) pyridine were dissolved in ice solution. 0.10 g was added and stirred at the same temperature for 30 minutes, and again at room temperature for 12 hours. Water was added to the reaction mixture, the pH was adjusted to 1.5 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 5: 1) to give 17.2 g of colorless oily 2,4-dimethoxyphenethyl = acetate. [863] IR (neat) cm -1 : 2958, 1736, 1509, 1243, 1035, 834 [864] NMR (CDCl 3 ) δ Value: 2.03 (3H, s), 2.87 (2H, t, J = 7Hz), 3.80 (6H, s), 4.22 (2H, t, J = 7Hz), 6.41 (1H, d, J = 9 Hz), 6.46 (1H, s), 7.05 (1H, d, J = 9 Hz) [865] In the same manner, 2,5-dimethoxyphenethyl = acetate was obtained. [866] IR (neat) cm -1 : 2952, 1736, 1502, 1226, 1048, 802, 710 [867] NMR (CDCl 3 ) δ Value: 2.01 (3H, s), 2.90 (2H, t, J = 7Hz), 3.74 (3H, s), 3.76 (3H, s), 4.25 (2H, t, J = 7Hz) , 6.74 (3H, s) [868] (2) Preparation of 5-acetyl-2,4-dimethoxyphenethyl = acetate [869] [870] 17.0 g of 2,4-dimethoxyphenethyl = acetate was dissolved in 170 ml of methylene chloride, and 5.93 ml of acetyl chloride and 12.1 g of aluminum chloride were added to the solution under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into iced water, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was added to diisopropyl ether, and the precipitated crystals were filtered out, washed with diisopropyl ether, dried, and 13.9 g of 5-acetyl-2,4-dimethoxyphenethyl = yellow crystals were obtained. Got it. [871] NMR (CDCl 3 ) δ Value: 2.01 (3H, s), 2.57 (3H, s), 2.88 (2H, t, J = 7Hz), 3.90 (3H, s), 3.93 (3H, s), 4.21 (2H , t, J = 7 Hz), 6.42 (1H, s), 7.86 (1H, s) [872] In the same manner, 4-acetyl-2,5-dimethoxyphenethyl = acetate was obtained. [873] (3) Preparation of 5-acetyl-4-hydroxy-2-methoxyphenethyl = acetate [874] [875] 13.9 g of 5-acetyl-2,4-dimethoxyphenethyl = acetate was dissolved in 70 ml of acetonitrile, and 13.9 g of aluminum chloride and 7.82 g of sodium iodide were added to the solution under ice cooling, followed by stirring at 50 ° C. for 3 hours. It was. The reaction mixture was poured into iced water, ethyl acetate was added to the mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 13.3 g of a yellow oily 5-acetyl-4-hydroxy-2-methoxyphenethyl = acetate. . [876] In the same manner, 4-acetyl-5-hydroxy-2-methoxyphenethyl = acetate was obtained. [877] (4) Preparation of 1- [2-hydroxy-5- (2-hydroxyethyl) -4-methoxyphenyl] -1-ethanol [878] [879] 13.3 g of the above 5-acetyl-4-hydroxy-2-methoxyphenethyl = acetate was dissolved in 30 ml of ethanol, 21 ml of a 5 mol / L aqueous sodium hydroxide solution was added to the solution, followed by stirring at room temperature for 17 hours. . Water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were filtered, washed with diisopropyl ether, and dried to give 1- [2-hydroxy-5- (2-hydroxyethyl) as yellow crystals. 8.30 g of 4-methoxyphenyl] -1-ethanone were obtained. [880] In the same manner, 1- [2-hydroxy-4- (2-hydroxyethyl) -5-methoxyphenyl] -1-ethanone was obtained. [881] NMR (CDCl 3 ) δ Value: 1.6-1.8 (1H, m), 2.61 (3H, s), 2.90 (2H, t, J = 7Hz), 3.8-4.1 (2H, m), 3.84 (3H, s) , 6.84 (1H, s), 7.06 (1H, s), 11.98 (1H, s) [882] (5) Preparation of 2-bromo-1- [2-hydroxy-5-yl (2-hydroxyethyl) -4-methoxyphenyl] -1-ethanone [883] [884] 10.0 g of 1- [2-hydroxy-5- (2-hydroxyethyl) -4-methoxyphenyl] -1-ethanone is dissolved in 100 ml of methylene chloride, 2.94 ml of bromine is added dropwise to this solution, Stirred at room temperature for 1 hour. The reaction mixture was introduced into iced water, and the organic layer was separated therefrom. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily 2-bromo-1- [2-hydroxy-5- (2-hydroxyethyl 16.4 g of) -4-methoxyphenyl] -1-ethanone was obtained. [885] In the same manner, 2-bromo-1- [2-hydroxy-4- (2-hydroxyethyl) -5-methoxyphenyl] -1-ethanone was obtained. [886] IR (neat) cm -1 : 3376, 2941, 1644, 1496, 1243, 1034, 757, 690 [887] NMR (CDCl 3 ) δ Value: 1.5-1.8 (1H, m), 2.91 (2H, t, J = 7Hz), 3.8-4.1 (2H, m), 3.85 (3H, s), 4.40 (2H, s) , 6.89 (1H, s), 7.07 (1H, s), 11.51 (1H, s) [888] (6) 2- (6-methoxy-1-benzofuran-5-yl) -1-ethanol [889] [890] 16.4 g of the above 2-bromo-1- [2-hydroxy-5- (2-hydroxyethyl) -4-methoxyphenyl] -1-ethanone is dissolved in 70 ml of methanol, and acetic acid is added to this solution. 17.3 g of sodium was added and the mixture was heated to reflux for 5 minutes. After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 150 ml of methanol, and 6.30 g of sodium borohydride was added to the solution in portions and stirred at room temperature for 1 hour. Subsequently, 6 mol / L hydrochloric acid was added to this solution, it adjusted to pH1, and it stirred for 1 hour again. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 4: 1) to obtain 1.48 g of 2- (6-methoxy-1-benzofuran-5-yl) -1-ethanol as pale yellow crystals. [891] NMR (CDCl 3 ) δ Value: 1.79 (1H, brs), 2.97 (2H, t, J = 7 Hz), 3.84 (2H, t, J = 7 Hz), 3.86 (3H, s), 6.66 (1H, d, J = 3 Hz), 7.03 (1H, s), 7.35 (1H, s), 7.51 (1H, d, J = 3 Hz) [892] In the same manner, 2- (5-methoxy-1-benzofuran-6-yl) -1-ethanol was obtained. [893] NMR (CDCl 3 ) δ Value: 2.04 (1H, brs), 2.98 (2H, t, J = 6 Hz), 3.86 (2H, t, J = 7 Hz), 3.86 (3H, s), 6.68 (1H, d, J = 2Hz), 7.02 (1H, s), 7.31 (1H, s), 7.55 (1H, d, J = 2Hz) [894] (7) Preparation of 2- [2- (6-methoxy-1-benzofuran-5-yl) ethoxy] acetic acid [895] [896] 1.75 g of 2- (6-methoxy-1-benzofuran-5-yl) -1-ethanol is dissolved in a mixed solution of 7.0 ml of tert-butanol and 1.75 ml of N, N'-dimethylformamide. 2.2 g of 1-chloroacetyl piperidine and 1.54 g of tert-butoxy potassium were added to the solution, followed by stirring at the same temperature for 30 minutes and again at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 10.5 ml of 90% ethanol aqueous solution, 0.91 g of sodium hydroxide was added, and the mixture was heated to reflux for 3 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the mixture was adjusted to pH 1 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, the precipitated crystals were filtered, washed with diisopropyl ether, and dried to give 2- [2- (6-methoxy-1-benzofuran-5-yl) as a yellow crystal. ) Ethoxy] acetic acid obtained 1.42 g. [897] IR (neat) cm -1 : 2942, 1731, 1466, 1431, 1249, 1132, 1013, 955, 832, 760 [898] NMR (DMSO-d 6 ) δ Value: 2.90 (2H, t, J = 7 Hz), 3.66 (2H, t, J = 7 Hz), 3.82 (3H, s), 4.02 (2H, s), 6.86 (1H, d, J = 2 Hz), 7.15 (1H, s), 7.46 (1H, s), 7.88 (1H, d, J = 2 Hz) [899] Reference Example 7 Preparation of 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid [900] [901] (1) 45 to 50 mg of potassium hydroxide, 83 mg of tetra-n-butylammonium bromide and 5.67 ml of tert-butyl acrylate were added to 4.60 g of 2- (1-benzothiophen-5-yl) -1-ethanol. It stirred at 2 degreeC. After cooling, water and toluene were added to the reaction mixture, adjusted to pH 1 with 6 mol / L hydrochloric acid, and the organic layer was separated therefrom. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give 7.70 g of colorless oily 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid tert-butyl. Got. [902] IR (neat) cm -1 : 2978, 2867, 1729, 1368, 1159, 1112, 702 [903] NMR (CDCl 3 ) δ Value: 1.42 (9H, m), 2.49 (2H, t, J = 6 Hz), 2.99 (2H, t, J = 7 Hz), 3.70 (2H, t, J = 6 Hz), 3. 70 (2H, t, J = 7 Hz), 7.21 (1H, dd, J = 2, 8 Hz), 7.27 (1H, dd, J = 1, 5 Hz), 7.41 (1H, d, J = 5 Hz), 7.6- 7.7 (1 H, m), 7.78 (1 H, d, J = 8 Hz) [904] (2) 7.60 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] propioic acid tert-butyl are dissolved in 22.8 ml of toluene, 94 mg of p-toluenesulfonic acid monohydrate is added, It was refluxed for 6 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from a toluene-dicyclohexane mixture (1: 4, 23 mL) to obtain 5.30 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid as light red crystals. [905] IR (KBr) cm -1 : 2860, 1719, 1273, 1128, 706 [906] NMR (CDCl 3 ) δ Value: 2.63 (2H, t, J = 6 Hz), 3.00 (2H, t, J = 7 Hz), 3.73 (2H, t, J = 7 Hz), 3.74 (2H, t, J = 6 Hz ), 7.20 (1H, dd, J = 1, 8 Hz), 7.28 (1H, dd, J = 1, 5 Hz), 7.41 (1H, d, J = 5 Hz), 7.6-7.7 (1H, m, 7.79) (1H, d, J = 8 Hz) [907] Reference Example 8 Preparation of 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid [908] [909] (1) To 2.00 g of 2- (1-benzothiophen-5-yl) -1-ethanol, 13 mg of potassium hydroxide, 36 mg of tetra-n-butylammonium bromide and 1.11 ml of acrylonitrile were added at 45 ° C. Stir for 3 hours. After cooling, water and ethyl acetate were added to the reaction mixture, the pH was adjusted to 1 with 2 mol / L hydrochloric acid, the insolubles were filtered off, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 3: 1) to obtain 2.46 g of colorless oily 3- [2- (1-benzothiophen-5-yl) ethoxy] propiononitrile. Got it. [910] IR (neat) cm -1 : 2870, 2251, 1114, 757, 704 [911] NMR (CDCl 3 ) δ Value: 2.58 (2H, t, J = 6 Hz), 3.02 (2H, t, J = 7 Hz), 3.66 (2H, t, J = 6 Hz), 3.75 (2H, t, J = 7 Hz ), 7. 22 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.68 (1H, s), 7.80 (1H, d, J = 8Hz) [912] (2) 200 mg of 3- [2- (1-benzothiophen-5-yl) ethoxy] propiononitrile was dissolved in 0.6 ml of acetic acid, 0.4 ml of water and 0.184 ml of sulfuric acid were added, and 90 to 100 ° C. Stirred for 1 hour. After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1) to obtain 140 mg of colorless crystals of 3- [2- (1-benzothiophen-5-yl) ethoxy] propionic acid. [913] Reference Example 9 Preparation of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1-propanol [914] [915] 2.00 g of (3- [2- (1-benzothiophen-5-yl) ethoxy] -1-propanoic acid was dissolved in 8 ml of tetrahydrofuran and 1.31 ml of triethylamine was added. After cooling to -25 DEG C, 0.88 mL of ethyl chloro formate 2 mL tetrahydrofuran solution was added dropwise and stirred for 1 hour at 5 DEG C. 15 mL of ethyl acetate and 10 mL of saturated saline were added to the reaction mixture, and the organic layer was added. After cooling the organic layer to 5 DEG C, 0.36 g of sodium borohydride was added and stirred for 1 hour at room temperature 20 ml of water and 10 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure, and the yellow oily 3- [2- (1-benzothiophene- 1.89 g of 5-yl) ethoxy] -1-propanol were obtained. [916] Reference Example 10 Preparation of 5- [2- (3-bromopropoxy) ethyl] -1-benzothiophene [917] [918] 2.00 g of 3- [2- (1-benzothiophen-5-yl) ethoxy] -1-propanol is dissolved in 40 ml of methylene chloride, and 5.55 g of triphenylphosphine is added to this solution, followed by ice On cooling, it was dripped at 10 ml of methylene chloride of 8.42 g of carbon tetrabromide, and it stirred at room temperature for 20 minutes. 20 ml of water was added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diethyl ether was added to the residue, the insolubles were filtered off, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 20: 1 = 10: 1) to give a colorless oily 5- [2- (3-bromopropoxy) ethyl] -1-benzothiophene. 1.93 g was obtained. [919] IR (neat) cm -1 : 2863, 1437, 1112, 1051, 701 [920] NMR (CDCl 3 ) δ value: 2.0-2.0 (2H, m), 3.00 (2H, t, J = 7Hz), 3.48 (2H, t, J = 6Hz), 3.58 (2H, t, J = 6Hz), 3.70 (2H, t, J = 7 Hz), 7. 22 (1H, dd, J = 8 Hz), 7.28 (1H, dd, J = 1, 5 Hz), 7.42 (1H, d, J = 5 Hz), 7.6- 7.7 (1 H, m), 7.79 (1 H, d, J = 8 Hz) [921] REFERENCE EXAMPLE 11 Preparation of 3-azetidinyl = Pivarate Hydrochloride [922] [923] (1) 50.0 g of 1-[(1R) -1-phenylethyl] azetididin-3-ol is dissolved in a mixed solution of 200 ml of toluene and 100 ml of tert-butanol, and under ice-cooling, tert-butoxy potassium 41.2 g was added separately and stirred at the same temperature for 1.5 hours. Under ice-cooling, 41.7 ml of pivaloyl chloride was added dropwise to the reaction mixture, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into 300 ml of water, the insolubles were filtered off, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained oily substance was dissolved in 200 ml of ethyl acetate, 258 ml of 1.15 mol / L dry hydrogen chloride-ethyl acetate solution was added at 10 ° C, and stirred for 20 minutes at the same temperature. The precipitated crystals were filtered to give 70.8 g of colorless crystals of 1-[(1R) -1-phenylethyl] -3-azetidinyl = pibarate hydrochloride. [924] IR (KBr) cm -1 : 2963, 2509, 2436, 1731, 1284, 1161, 699 [925] NMR (DMS-d 6 ) δ Value: 1.16 (9H, m), 1.49 (3H, t, J = 7 Hz), 3.6-4.3 (3H, m), 4.4-4.7 (2H, m), 4.9-5.2 ( 1H, m), 7.3-7.5 (3H, m), 7.6-7.7 (2H, m) [926] (2) 1-[(1R) -1-phenylethyl] -3-azetidinyl = pibarate-5 g of ethanol 250 ml of ethanol was added to 5 ml of 10% palladium-activated carbon, and 1 atmosphere of pressure under hydrogen atmosphere. It stirred at 50 degreeC for 9 hours. After cooling, the insolubles were filtered off and the solvents were removed under reduced pressure. A mixed solution of ethyl acetate and hexane (1: 2) was added to the residue, and the precipitated crystals were filtered to give 23.1 g of colorless crystals of 3-azetidinyl = pibarate hydrochloride. [927] IR (KBr) cm -1 : 2988, 1718, 1156, 877, 789 [928] NMR (CDCl 3 ) δ Value: 1.23 (9H, s), 4.0-4.2 (2H, m), 4.3-4.5 (2H, m), 5.2-5.4 (1H, m) [929] Reference Example 12 Preparation of 3- (trityloxy) azetidine hydrochloride [930] [931] (1) 10.0 g of 1- (3-hydroxy-1-azetidinyl) -1-ethanone is dissolved in 50 ml of methylene chloride, and then cooled on ice to yield 1,8-diazabichlor [5, 4, 0]. 31.2 ml of Undec-7-ene and 29.1 g of trityl chloride were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water, and the organic layer was separated therefrom. The organic layer was washed with dilute hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were filtered to give 21.7 g of 1- [3- (trityloxy) -1-azetidinyl] -1-ethanone as pale yellow crystals. [932] IR (KBr) cm -1 : 1646, 1450, 1124, 750, 711 [933] NMR (CDCl 3 ) δ Value: 1.74 (3H, s), 3.6-3.8 (4H, m), 4.4-4.5 (1H, m), 7.2-7.5 (15H, m) [934] (2) 22.0 g of 1- [3- (trityloxy) -1-azetidinyl) -1-ethanone was suspended in 88 ml of methanol, 66 ml of 5 mol / L sodium hydroxide solution was added, and the mixture was refluxed for 9 hours. . The reaction mixture was evaporated under reduced pressure, 110 ml of water and 220 ml of ethyl acetate were added, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate to remove the solvent under reduced pressure. The obtained oily substance was dissolved in 154 ml of ethyl acetate, 25 ml of 2.95 mol / L dry hydrogen chloride-ethyl acetate solution was added to this solution, and the mixture was stirred at room temperature. The precipitated crystals were filtered to give 13.7 g of 3- (trityloxy) azetidine hydrochloride as colorless crystals. [935] IR (KBr) cm -1 : 2900, 2620, 1447, 751, 700 [936] NMR (DMS0-d 5 ) δ Value: 3.4-3.6 (4H, m), 4.3-4.5 (1H, m), 7.2-7.5 (15H, m) [937] Reference Example 13 Preparation of 3- (tetrahydro-2H-pyran-2-yloxy) azetidine hydrochloride [938] [939] (1) 1.00 g of 1- (3-hydroxy-1-azetidinyl) -1-ethanone is dissolved in 10 ml of methylene chloride, and 1.19 ml of 3.4-dihydro-2H-pyran and p-toluene are dissolved in this solution. 0.08 g of sulfonic acid monohydrate was added and stirred overnight at room temperature. 10 ml of water was added to the reaction mixture, the mixture was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate, and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent; chloroform-chloroform: methanol = 25: 1) to give 1- [3- (tetrahydro-2H-pyran-2yloxy) 1-azetidinyl]-as a yellow oil. 1.79 g of 1-ethanone were obtained. [940] IR (KBr) cm -1 : 2945, 2875, 1654, 1458, 1138, 1036, 971 [941] NMR (CDCl 3 ) δ Value: 1.5-1.9 (6H, m), 1.87 (3H, s), 3.4-3.6 (1H, m), 3.8-4.4 (5H, m), 4.5-4.7 (2H, m) [942] (2) 3- (tetrahydro-2H from 1- [3- (tetrahydro-2H-pyran-2yloxy) -1-azetidinyl] -1-ethanone in the same manner as in Reference Example 12 (2) Pyran-2yloxy) azetidine hydrochloride was obtained. [943] IR (KBr) cm -1 : 2945, 2627, 1036, 976, 915 [944] NMR (DMS0-d 5 )) δ Value: 1.7-1.8 (6H, m), 3.3-3.5 (1H, m), 3.7-4.2 (5H, m), 4.4-4.7 (2H, m) [945] Reference Example 14 Preparation of 1- (3-chloropropyl) -3- (trityloxy) azetidine-oxalate [946] [947] (1) 0.50 g of 3- (trityloxy) azetidine hydrochloride was dissolved in 5 ml of dimethyl sulfoxide, and 0.49 g of potassium carbonate, 0.35 g of potassium iodide, and 0.22 ml of 1-bromo-3-chloropropane were dissolved in this solution. Was added and stirred at room temperature for 2 hours. 15 ml of water and 10 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated therefrom. The organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1- (3-chloropropyl) -3- (trityloxy) azetidine. [948] (2) 1- (3-chloropropyl) 3- (trityloxy) azetidine was dissolved in 10 ml of ethyl acetate, 0.15 g of hydroxyl acid was added to this solution, and the mixture was stirred at room temperature. The precipitated crystals were filtered to give 0.39 g of 1- (3-chloropropyl) -3- (trityloxy) azetidine-hydrate. [949] IR (KBr) cm -1 : 3033, 1491, 1449, 1139, 706 [950] NMR (DMS0-d 5 )) δ Value: 1.7-1.9 (2H, m), 3.0-3.1 (2H, m), 3.5-3.7 (6H, m), 4.3-4.5 (1H, m), 7.2-7.4 (15H, m) [951] Reference Example 15 Preparation of 1- (3-chloropropyl) -3- (tetrahydro-2H-pyran-2-yloxy) azetidine [952] [953] In the same manner as in Reference Example 14 (1), 1- (3-chloropropyl) -3- (tetrahydro-2H-pyran-2 from 3- (tetrahydro-2H-pyran-2yloxy) azetidine hydrochloride Iloxy) azetidine was obtained. [954] IR (neta) cm -1 : 2943, 2834, 1203, 1038, 975, 914, 871 [955] NMR (CDCl 3 ) δ values: 1.4-1.8 (6H, m), 1.8-1.9 (2H, m), 2.59 (2H, t, J = 7 Hz), 2.8-3.0 (2H, m), 3.4-3.5 ( 1H, m), 3.57 (2H, t, J = 7 Hz), 3.6-3.7 (2H, m), 3.8-3.9 (1H, m), 4.3-4.4 (1H, m), 4.5-4.6 (1H, m ) [956] <Test Example 1> [957] [Neural dendritic extension] [958] 5% heat inactivation (56 ° C, 30 minutes) horse serum (Bio-Uitaka Co., Ltd.), 5% heat inactivation (56 ° C, 30 minutes) fetal bovine serum (Manufactured by Sigma Co., Ltd.) and RPMI 1640 medium (manufactured by Nisui Pharmaceutical Co., Ltd.) containing 25 µg / ml gentamicin (manufactured by Chibuco BRL Co., Ltd.) were used and cultured in a 5% CO 2 , 37 ° C incubator. [959] The cultured PC12 cells were kept at 37 ° C. for 30 minutes in a phosphate buffered saline solution containing 1 mM EDTA, and separated from the culture bottle. 2 ml in a 35 mm tissue culture dish (manufactured by Falcon Corporation) coated with 0.01% polyornithine [dissolved in 150 mM boric acid buffer solution (pH8.4)] prepared at 5 × 10 4 cells / ml in RPMI1640 medium containing mycin. After spraying, add 2.5s-NGF (made by Wako Pure Chemicals Co., Ltd.) (soluble in 0.1% bovine serum albumin-containing phosphate buffered saline solution) to 40 ng / ml, and simultaneously add the test compound to a final concentration of 10 μm. And incubated at 5% CO 2 , 37 ° C. After 48 hours of culture, the cells were fixed in 10% neutral formalin solution for 30 minutes, washed with phosphate buffered saline and distilled water, and dried. Under the phase contrast microscope, an arbitrary 4 field of view was selected, and 50 or more cells were observed in each field of view, and the ratio of the number of cells protruding neurites beyond the diameter of the cell body to the total number of observation cells (neurogenesis rate) was determined. Calculated. [960] The neurite outgrowth activity was calculated by the following equation as the neurite outgrowth rate by the addition of each test compound when the neurite outgrowth rate by NGF was 100%. [961] (Nerve projection elongation by test compound addition) / (NGF proliferation rate by NGF) X 100 (%) [962] As a result, the neurite outgrowth ratio was 265% compound of Example 2, 300% compound of Example 6, 299% compound of Example 12, 207% compound of Example 14, 207% compound of Example 29 : 212%, compound of Example 51: 216%, compound of Example 59: 241%, compound of Example 69: 233%, compound of Example 71 183%, compound of Example 74: 246%, Example 80 compound: 190%, Example 81 compound: 190%. [963] <Test Example 2> [964] [Nerve regeneration] [965] The test was conducted by J. Pharmaco.Exp. Ther., Vol. 290, p. 348, 1999 and Neuroscience, vol. 88, p. 257, 1999. [966] Pentobarbital anesthesia for SD rats (male 6-7 weeks, weight 170-280 g), exposing the left sciatic nerve in the thigh, separating the nerves from the surrounding connective tissue, about 1 cm peripheral in the hip muscles The side was cut off. Both ends of the cut nerves are fixed by inserting 3.5 mm so that a 1 mm gap is made at the center of a sterile silicon tube having a length of 8 mm (inner diameter of 1.3 mm and outer diameter of 1.8 mm), and the nerve is returned to the muscle tissue with the tube again, and dissected. Wealth was sealed. After 7 days, the test compound dissolved in distilled water was orally administered at a dose of 1 mg / kg, and then the same administration was performed once a day for 13 days. [967] After 21 days of nerve cutting, the sciatic nerve was again exposed under pentobarbital anesthesia, and the nerves of the thigh and lower thighs were separated from the surrounding connective tissue to remove the silicon tube of the cut portion. The stimulation electrode was placed at the central side rather than the cut portion, and the recording electrode was placed at the distal end of the lower thigh, and the action potential was recorded by stimulation (voltage: 2V, delay: 1 msec, duration: 100 μsec). The recording electrode was gradually moved to the central side, and the distance from the most distal point at which the action potential was obtained to the cut portion was measured to be the reproduction distance. Only distilled water was administered to the control group. [968] The sciatic nerve regeneration rate of the test compound was calculated by the following equation. [969] (Release of the troops) / (Control of the control) x 100 (%) [970] As a result, the sciatic nerve regeneration rate was 167% compound of Example 4, 186% compound of Example 10, 142% compound of Example 12, 142% compound of Example 14, 150% compound of Example 31: 155%, and the compound of Example 33: 161%. [971] <Test Example 3> [972] [Inhibits neuronal cell death induced by Aβ] [973] The control effect on the cultured neuronal cell death by Aβ, Brain Res. Vol. 639, p. 240, carried out with modifications to the method described in 1994. The cerebral cortex extracted from the Wistar rat brain (17-19 years old) was finely cut, and neurons were dissociated by tripucine treatment. Cells were seeded 1 × 10 5 per well of 48 blood tissue culture plates, and under Dulbecco's modified Eagle's medium supplemented with B27 additive (manufactured by Jibuco BRL Co., Ltd.) and 3.6 mg / ml glucose, 5% CO 2 , The culture was carried out under 37 ° C. [974] After 12-13 days of culture, potassium chloride solution was added to a final concentration of 25 mmol / L, and test compounds were immediately added thereto. After 24 hours, Aβ (25-35 residue peptide) dissolved in distilled water was added to a final concentration of 20 μmol / L. After 24 hours, Dulbecco's modified Eagle's medium supplemented with B27 additive and 3.6 mg / ml glucose was exchanged in the medium to which the test compound was added. [975] The control effect of the test compound on media neuronal cell death was based on the inhibitory effect of MTT reduction ability. That is, the MTT assay developed by Mossman 48 hours after medium exchange [J. Immuno.Methods, Vol. 65, p. 55, 1983] and calculated the percent inhibition of the test compound against the decrease of the MTT assay value induced by Aβ. [976] Inhibition rate = [(Aβ + MTT assay value of drug addition group)-(MTT assay value of Aβ addition group)] ÷ [MTT assay value of no addition group-MTT assay value of Aβ addition group] x 100 (%) [977] As a result, at a concentration of 1 μm, the inhibition rate was 63% for the compound of Example 4, 48% for the compound of Example 6, 42% for the compound of Example 10, 48% for the compound of Example 14, and 31%. Compound: 50%, compound of Example 33: 54%, compound of Example 61: 52%, compound of Example 69: 70%, compound of Example 74: 50%, compound of Example 80 were 75% . [978] <Test Example 4> [979] [Human Liver Microsomal Metabolism] [980] 50 μl of 100 mmol / L potassium phosphate buffer (pH 7.4) and 25 μl of 3 mg protein / ml pleated human liver microsomes (manufactured by Zentest) were added to the test tube, followed by 10 μl of 66 mmol / L glucose hexahexaphosphate, 10. Mixed μl of 10 units / ml glucose hexaphosphate dehydrogenase, 10 μl of 26 mmol / L nicotinamide andenine dinucleotide phosphate, 10 μl of 66 mmol / L magnesium chloride and 135 μl of 100 mmol / L potassium phosphate buffer (pH 7.4) One solution was added and preincubated for 5 minutes. 50 µl of the test compound at 6 µmol / L was added to initiate the reaction and incubated at 37 ° C for 60 minutes (final volume 300 µl). 600 µl of acetonitrile was added to stop the reaction, the mixture was centrifuged at 12000xg for 15 minutes at 4 ° C, the supernatant was collected, centrifuged under reduced pressure, and subjected to liquid high-speed chromatography. Obtained. [981] The residual ratio was calculated by the following formula. [982] Residual rate (%) = [(peak area by test compound after 60 minutes reaction) ÷ (peak area by test compound when the reaction was stopped by adding acetonitrile at the same time as the test compound was added after pre-incubation)] x 100 [983] As a result, the residual ratio after 60 minutes was 80% of the compound of Example 4, 70% of the compound of Example 10, 12: 83% of the compound of Example 14, 75% of the compound of Example 14, 74 of the compound of Example 61, 74 %, The compound of Example 69: 74%, the compound of Example 71: 80%, the compound of Example 74: 71%. [984] Alkyl ether induction or salt thereof represented by the general formula [1] of the present invention has excellent neurogenesis extension action, nerve regeneration promoting action and neuroprotective action, and is also excellent in metabolic stability and prevents diseases of central and peripheral nerves. It is useful as a therapeutic drug.
权利要求:
Claims (9) [1" claim-type="Currently amended] General formula [Wherein, R 1 and R 2 are the same or different and are hydrogen atom, halogen atom, alkyl which may be substituted, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, akenyloxy, amino, At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, optionally protected amino, hydroxyl or carboxyl groups, nitro groups and oxo groups; R 3 is an alkylamino group which may be substituted, an amino or hydroxyl group which may be protected; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n represent the integer of 1-6; p represents the integer of 1-3, respectively.] The alkyl ether derivative or its salt represented by. [2" claim-type="Currently amended] The method according to claim 1, wherein in the general formula of claim 1 The alkyl ether derivative or its salt whose part represented by any of the following (A), (B), and (C). [3" claim-type="Currently amended] The compound according to claim 1 or 2, wherein R 1 is a hydrogen atom; Alkyl ether derivative or its salt whose R <2> is a hydrogen atom, a halogen atom, and an alkoxy group. [4" claim-type="Currently amended] The alkyl ether derivative or salt thereof according to any one of claims 1 to 3, wherein m is 2, n is 2 to 3 and p is an integer of 1 to 2. [5" claim-type="Currently amended] General formula [Wherein, R 1 and R 2 are the same or different, hydrogen atom, halogen atom, alkyl which may be substituted, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, optionally protected amino, hydroxyl or carboxyl groups, nitro groups and oxo groups; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n each represent an integer of 1 to 6; and a carboxylic acid derivative represented by General formula [Wherein, R 3a is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; p represents an integer of 1 to 3, respectively.] or a salt thereof General formula Wherein R 1 , R 2 , R 3a , A ring, m, n, and p have the same meaning as described above; or an alkylamide derivative or a salt thereof, or R 3a hydroxyl group The hydroxy group may be subsequently added to the protective reaction to form an alkylamide derivative or a salt thereof, wherein R 3a is a protected hydroxyl group, and then the obtained alkylamide derivative is added to the reduction reaction. [Wherein, R 3 is an alkylamino group which may be substituted, an amino or hydroxyl group which may be protected; R <1> , R <2> , A ring, m, n, and p have the same meaning as the above. The manufacturing method of the alkyl ether derivative or its salt represented by. [6" claim-type="Currently amended] General formula [Wherein, R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, which may be substituted; At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, optionally protected amino, hydroxyl or carboxyl groups, nitro groups and oxo groups; An alkylamino group which may be substituted, a protected amino group, or the protected hydroxyl group; R 3a is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n represent the integer of 1-6; p represents the integer of 1-3, respectively.] The alkylamide derivative or its salt represented by. [7" claim-type="Currently amended] General formula [Wherein, R 1 and R 2 are the same or different and are hydrogen atom, halogen atom, alkyl which may be substituted, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, akenyloxy, amino, At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, optionally protected amino, hydroxyl or carboxyl groups, nitro groups and oxo groups; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; X- 1 represents a leaving group; m and n each represent an integer of 1 to 6; and an ether derivative or a salt thereof represented by General formula [Wherein, R 3a is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; p represents an integer of 1 to 3, respectively.] A general formula characterized by reacting a carboxylic acid derivative or a salt thereof. A method for producing an alkyl ether derivative or its salt represented by [wherein R 1 , R 2 , R 3a , A ring, m, n and p have the same meaning as described above]. [8" claim-type="Currently amended] General formula [Wherein, R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, which may be substituted; At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, optionally protected amino, hydroxyl or carboxyl groups, nitro groups and oxo groups; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n represent the integer of 1-6, respectively.] to the alcohol derivative or its salt represented by General formula [Wherein, R 3b is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; X 2 represents a leaving group; n is an integer of 1 to 6; p represents an integer of 1 to 3, respectively.] A general formula characterized by reacting an N-alkyl cyclic amino derivative represented by A method for producing an alkyl ether derivative or its salt represented by [wherein R 1 , R 2 , R 3b , A ring, m, n and p have the same meaning as described above]. [9" claim-type="Currently amended] General formula [Wherein, R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, which may be substituted; At least one group selected from alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic groups, optionally protected amino, hydroxyl or carboxyl groups, nitro groups and oxo groups; R 3 is an alkylamino group which may be substituted, an amino or hydroxyl group which may be protected; Ring A is a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n represent the integer of 1-6; p represents an integer of 1 to 3, respectively.] A therapeutic agent for the central and / or peripheral nerves containing an alkyl ether derivative or a pharmacologically acceptable salt thereof.
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同族专利:
公开号 | 公开日 CN100500662C|2009-06-17| NZ532328A|2005-07-29| AU2002344107B2|2007-11-01| KR100956990B1|2010-05-11| IL161308D0|2004-09-27| DE60220694D1|2007-07-26| US20090111992A1|2009-04-30| NO325780B1|2008-07-14| US20050070521A1|2005-03-31| RO122203B1|2009-02-27| PL217872B1|2014-08-29| PT1437353E|2007-08-28| JPWO2003035647A1|2005-07-28| DK1437353T3|2007-08-06| BR0213393A|2005-01-11| PL215264B1|2013-11-29| DE60220694T2|2008-02-07| EP1437353A1|2004-07-14| US20060194781A1|2006-08-31| WO2003035647A1|2003-05-01| CN101643470B|2012-08-01| HU0500017A2|2005-04-28| AT364604T|2007-07-15| ZA200402806B|2005-06-29| HU230407B1|2016-04-28| CN101643470A|2010-02-10| EP1437353A4|2005-01-19| PL369601A1|2005-05-02| PL402986A1|2013-04-29| US8129535B2|2012-03-06| JP4398247B2|2010-01-13| IL161308A|2011-06-30| USRE43676E1|2012-09-18| US7087594B2|2006-08-08| EP1437353B1|2007-06-13| CA2464358C|2011-05-24| MXPA04003541A|2004-07-22| CN1571786A|2005-01-26| BRPI0213393B1|2018-12-04| CA2464358A1|2003-05-01| HU0500017A3|2011-07-28| US7468443B2|2008-12-23| NO20041531L|2004-04-15| ES2287324T3|2007-12-16|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2001-10-19|Priority to JP2001321381 2001-10-19|Priority to JPJP-P-2001-00321381 2002-10-18|Application filed by 토야마 케미칼 컴퍼니 리미티드 2002-10-18|Priority to PCT/JP2002/010827 2004-06-17|Publication of KR20040050919A 2010-05-11|Application granted 2010-05-11|Publication of KR100956990B1
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