SPIROPIPERIDINE DERIVATIVES

Abstract: [Object] To provide compounds exhibiting antagonism to each of NK 1 , NK 2 and NK 3 receptors. [Means for Solution] A compound represented by the formula (I): (wherein R 1 , R 2 : a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group; A: CH 2 , CO or SO 2 ; B: single bond, alkylene or alkenylene, D: O or S; E: alkylene or alkenylene; [wherein G: a substituted or unsubstituted cycloalkene ring, or a substituted cycloalkane ring; Ar: a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heteroaryl ring]; R 3 : alkyl; n: 1-3}, or a pharmacologically acceptable salt, ester or other derivative thereof

Description: The present invention relates to novel spiropiperidine derivatives which exhibit antagonistic action against tachykinin receptors (NK 1 , NK 2 and NK 3 ). It is already known that NK 1 receptors, NK 2 receptors and NK 3 receptors act as tachykinin receptors. A number of compounds are known to exhibit antagonistic action against one of these receptors. Recently, compounds which block as many subtypes as possible among these three subtypes have attracted a great deal of attention for use in methods of preventing or treating diseases induced by tachykinin. Compounds exhibiting antagonistic action against both NK 1 and NK 2 receptors are under investigation. As a compound having antagonistic activities against both NK 1 and NK 2 receptors, for example, Compound A shown below is disclosed in EP-776893. However, it is not reported that this compound exhibits an antagonistic activity against NK 3 receptor. The present invention relates to: (1) a compound represented by the formula (I): wherein: R 1 and R 2 are the same or different and each represents an aryl group defined below which may optionally be substituted with 1 to 3 groups selected from Substituent Group A defined below or a heteroaryl group defined below which may optionally be substituted with 1 to 3 groups selected from Substituent Group A defined below; A represents a methylene group, a carbonyl group or a sulfonyl group; B represents a single bond, a C 1-4 alkylene group or a C 2-4 alkenylene group; D represents an oxygen atom or a sulfur atom; E represents a C 1-4 alkylene or a C 2-4 alkenylene group; wherein, G represents a cyclopentane or cyclopentene ring which is substituted with a hydroxy group, Ar represents an aryl ring defined below which may optionally be substituted with 1 to 3 groups selected from Substituent Group A or a heteroaryl ring defined below which may optionally be substituted with 1 to 3 groups selected from Substituent Group A; R 3 represents a lower alkyl group defined below; and n represents an integer from 1 to 3; or a pharmacologically acceptable salt, ester or amide thereof; Substituent Group A consists of halogen atoms, lower alkyl groups defined below, halogeno-lower alkyl groups defined below, lower alkoxy groups defined below, lower alkoxycarbonyl groups comprising carbonyl groups substituted with a lower alkoxy group defined below, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups defined below, lower aliphatic acylamino groups comprising amino groups substituted with a lower aliphatic acyl group as defined below, amino groups and cyano groups; the aryl groups referred to in the definition of substituents R 1 and R 2 are (C 5-14 ) aromatic hydrocarbon groups which may optionally be fused with a (C 3-10 )cycloalkyl group; the heteroaryl groups referred to in the definition of substituents R 1 and R 2 are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 oxygen, sulfur and/or nitrogen atoms which may optionally be fused with another cyclic group; the lower alkyl groups referred to in the definition of substituent R 3 and Substituent Group A are straight or branched (C 1-6 )alkyl groups; the aryl rings which may optionally be substituted with 1 to 3 groups selected from Substituent Group A defined above which are referred to in the definition of substituent Ar are C 6-14 aromatic hydrocarbon rings; the heteroaryl rings which may optionally be substituted with 1 to 3 groups selected from Substituent Group A defined above which are referred to in the definition of substituent Ar are 5- to 7-membered aromatic heterocyclic rings containing 1 to 3 sulfur, oxygen and/or nitrogen atoms; the halogeno-lower alkyl groups referred to in the definition of Substituent Group A are lower alkyl groups as defined above which are substituted with 1 or more halogen atom; the lower alkoxy groups referred to in the definition of Substituent Group A and the lower alkoxy moiety of the lower alkoxycarbonyl groups referred to in the definition of Substituent Group A are lower alkyl groups as defined above which are attached to an oxygen atom; and the lower aliphatic acyl groups referred to in the definition of Substituent Group A and the lower aliphatic acyl moiety of the lower aliphatic acylamino groups referred to in the definition of Substituent Group A are C 2-7 aliphatic acyl groups. Among these, preferred compounds are: (2) compounds wherein R 1 represents an aryl group, a heteroaryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A, (3) compounds wherein R 1 represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A 1 defined below, (4) compounds wherein R 2 represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A, (5) compounds wherein R 2 represents an aryl group substituted with at least one group selected from Substituent Group A, (6) compounds wherein A represents a carbonyl group, (7) compounds wherein B represents a single bond, (8) compounds wherein D represents an oxygen atom, (9) compounds wherein E represents a C 1-4 alkylene group, (10) compounds wherein E represents a C 2-3 alkylene group, (11) compounds wherein n represents 1 or 2, and (12) compounds wherein n represents 2; and pharmacologically acceptable salts, esters or amides thereof. [Substituent Group A 1 ] lower alkyl groups, halogeno-lower alkyl groups and lower alkoxy groups as defined above. Of the above-described compounds, compounds which comprise a combination of factors selected from seven groups consisting of (2) and (3); (4) and (5); (6); (7); (8); (9) and (10); and (11) and (12) are also preferred. (13) The more preferred compounds are: 1-(2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine], 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], 1- {2-[(2R)-(3,4-dichlorophenyl}-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine], and 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], and pharmacologically acceptable salts, esters and amides thereof. (14) The most preferred compounds are: 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine] and 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], and pharmacologically acceptable salts, esters and amides thereof. A novel medicine of the present invention comprises as an effective ingredient a compound selected from any one of the compounds described above in (1) to (14), or a pharmacologically acceptable salt, ester or amide thereof, and it can be used particularly as a preventive agent or remedy for asthma and/or bronchitis, rhinitis, allergy and urinary incontinence. In the formula (I), examples of the "aryl group" in the definitions of R 1 and R 2 , the "aryl group" of the "aryl group substituted with 1 to 3 groups selected from Substituent Group A" in the definitions of R 1 and R 2 , and the "aryl group" of the "aryl group which may be substituted with a group selected from Substituent Group A" in the definition of "Substituent Group B", include C 5-14 aromatic hydrocarbon groups such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups, of which phenyl groups are preferred. Incidentally, the above-described "aryl group" may form a fused ring with a C 3-10 cycloalkyl group and examples of such a group include 5-indanyl groups. The "heteroaryl group" in the definitions of R 1 and R 2 , and the "heteroaryl group" of the "heteroaryl group substituted with 1 to 3 groups selected from Substituent Group A" in the definitions of R 1 and R 2 , mean a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms. Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Among these, 5- to 7-membered aromatic heterocyclic groups each of which contain at least one nitrogen atom and may further contain an oxygen atom or sulfur atom are preferred. Examples include pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups, of which pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl groups are more preferred. Incidentally, the above-described "heteroaryl group" may form a fused ring with another cyclic group. Examples of such a group include indolyl, benzofuryl, benzothienyl, benzoxazolyl, benzoimidazolyl, isoquinolyl, quinolyl and quinoxalyl groups. Examples of the "lower alkyl group" in the definition of R 3 , [Substituent Group A] and [Substituent Group A 1 ] include C 1-6 straight or branched chain alkyl groups such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups, of which C 1-4 straight or branched chain alkyl groups are preferred. Examples of the "C 1-4 alkylene group" in the definitions of B and E include C 1-4 straight or branched chain alkylene groups such as methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene and 3-methyltrimethylene groups. With reference to B, C 1-3 straight or branched chain alkylene groups are preferred. With reference to E, C 1-3 straight or branched chain alkylene groups are preferred, of which the ethylene and trimethylene groups are more preferred, and ethylene groups are most preferred. Examples of the "C 2-4 alkenylene group" in the definitions of B and E include C 2-4 straight or branched chain alkenylene groups such as ethenylene, 2-propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, 2-ethyl-2-propenylene and 2-butenylene groups, of which ethenylene, 2-propenylene and 3-butenylene groups are preferred, and ethenylene and 2-propenylene groups are more preferred. Examples of the "aryl ring", and the "aryl ring" of the "aryl ring substituted with 1 to 3 groups selected from Substituent Group A" in the definition of Ar, include C 6-14 aromatic hydrocarbon rings such as benzene, indene, naphthalene, phenanthrene and anthracenyl rings, of which benzene rings are preferred. The "heteroaryl ring", and the "heteroaryl ring" of the "heteroaryl ring substituted with 1 to 3 groups selected from Substituent Group A", each in the definition of Ar, means a 5- to 7-memered aromatic heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms or/and nitrogen atoms. Examples include such as furan, thiophene, pyrrole, azepine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine and pyrazine rings. Among these, 5- to 7-membered aromatic heterocyclic rings which contains at least one nitrogen atom and which may also contain an oxygen atom or a sulfur atom are preferred and examples include such as pyrrole, azepine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine rings, of which pyridine, imidazole, oxazole, pyrazine and thiazole rings are more preferred. Accordingly, examples of the group represented by the following formula: include 2-hydroxyindan-1,1-diyl (particularly, 2S-hydroxyindan-1,1-diyl) and 3-hydroxyindan-1,1-diyl. The "halogen atoms" in the definition of [Substituent Group A] include fluorine, chlorine, bromine and iodine atoms, of which the fluorine and chlorine atoms are preferred. The "halogeno-lower alkyl groups" in the definition of [Substituent Group A] and [Substituent Group A 1 ] mean the groups wherein a "halogen atom", described above is attached to a "lower alkyl group". Examples include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl and 2,2-dibromoethyl groups, of which trifluoromethyl, 2-bromoethyl, 2-chloroethyl and 2-fluoroethyl groups are preferred. The "lower alkoxy groups" in the definitions of [Substituent Group A] and [Substituent Group A 1 ], and the "lower alkoxy groups" of the "lower alkoxycarbonyl group" in the definition of [Substituent Group A] mean the group wherein a "lower alkyl group", described above, is attached to an oxygen atom. Examples include C 1-6 straight or branched chain alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy groups, of which C 1-4 straight or branched chain alkoxy groups are preferred. The "lower aliphatic acyl groups"; the "lower aliphatic acyl groups" of the "lower aliphatic acylamino groups" in the definition of [Substituent Group A] means a C 2-7 aliphatic acyl group. Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl and isovaleryl groups, of which acetyl and propionyl groups are preferred. R 1 is, preferably, an aryl group, a heteroaryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A; more preferably, is an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A 1 ; still more preferably, is an aryl group substituted with 1 to 3 groups selected from Substituent Group A 1 ; and, most preferably, is an aryl group substituted with I to 3 lower alkoxy groups. R 2 is, preferably, an aryl group substituted with 1 to 3 groups selected from Substituent Group A; more preferably, is an aryl group substituted with 1 to 3 groups selected from Substituent Group A; still more preferably, is an aryl group substituted with 1 to 3 halogen atoms; and, most preferably, is a phenyl group substituted with 1 to 3 halogen atoms. The following formula preferably represents a group wherein the carbon atom next to the carbon atom which constitutes the spiro bond between the group G and the piperidine ring, and the carbon atom next to the former carbon atom constitute a part of the cyclic group Ar and also a part of the cyclic group G. Since the compounds (I) of the present invention can form a salt, "pharmacologically acceptable salts thereof" represent such a salt. Preferred examples of the salt comprising the compounds (I) of the invention and an acid include inorganic acid salts such as hydrohalic acid salts (e.g. hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), nitrate, perchlorate, sulfate, phosphate and the like; organic acid salts such as lower alkanesulfonate (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.), arylsulfonate (e.g. benzenesulfonate, p-toluenesulfonate, etc.), acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate and the like; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, asparate and the like; of which the hydrohalic acid salts and organic acid salts are more preferred, the hydrohalic acid salts are still more preferred and the hydrochloride is most preferred. Preferred examples of the salt composed of the invention compound (I) and a base, on the other hand, include metal salts, for example, salts of an alkali metal such as sodium salts, potassium salts and lithium salts, salts of an alkaline earth metal such as calcium salts and magnesium salts, aluminum salts and iron salts; amine salts, for example, inorganic salts such as ammonium salts and organic salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts; aminoacid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts and aspartic acid salts. Since the compounds (I) of the invention can be converted into the corresponding quaternary amine by modifying the nitrogen atom of the piperidino group in the molecule with the group R 3 , salts between such a cation-containing compound and an anion (there is no particular limitation on the anion provided that it serves as an anion, but examples include halogen ions such as a chloride ion and an iodide ion) are also embraced in the present invention. Additionally, the compounds (I) of the present invention absorb water and have adsorbed water added thereto or become a hydrate, when they are allowed to stand in the air. Such salts are also embraced in the present invention. The "ester or amide thereof" means a compound wherein a functional group (i.e. a hydroxy group, carboxy group or amino group) is modified with a protecting group or the like and which can be converted into a compound (I) of the present invention after it has been administered to a living body. It can be determined whether a compound is such a derivative by administering it to an experimental animal, such as a rat or mouse, by intravenous injection, examining the body fluid of the animal after administration and detecting the original compound or a pharmaceutically acceptable salt thereof. Since the compound (I) of the present invention can be converted into the corresponding ester, the "ester" thereof means such an ester. Examples of the ester include "esters of a hydroxyl group" and "esters of a carboxy group". It means an ester whose ester residue is a "conventional protecting group" or a "protecting group which can be cleaved in vivo by a biological method such as hydrolysis". The "conventional protecting group" means a protecting group which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. Preferred examples of the "conventional protecting group" for the "ester of a hydroxyl group" include the above-described "lower aliphatic acyl groups"; the above-described "aromatic acyl groups"; "tetrahydropyranyl or tetrahydrothiopyranyl groups" such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups; "tetrahydrofuranyl or tetrahydrothiofuranyl groups" such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl groups; "silyl groups", for example, tri(lower alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl and triisopropylsilyl groups and tri(lower alkyl)silyl groups substituted with 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; "alkoxymethyl groups", for example, lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl groups, lower alkoxymethyl groups substituted with lower alkoxy groups such as 2-methoxyethoxymethyl groups and (halogeno lower alkoxy)methyl groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; "substituted ethyl groups", for example, ethyl groups substituted with a lower alkoxy group such as 1-ethoxyethyl and 1-(isopropoxy)ethyl groups and halogenated ethyl groups such as 2,2,2-trichloroethyl groups; "aralkyl groups", for example, lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl groups and lower alkyl groups each substituted with 1 to 3 aryl groups having an aryl substituted with a lower alkyl, halogeno(lower alkyl), lower alkoxy, nitro, halogen or cyano group such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 3,5-di(trifluoromethyl)benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups; the above-described "lower alkoxycarbonyl groups"; the above-described "lower alkenyloxycarbonyl groups"; and the above-described "aralkyloxycarbonyl groups". Preferred examples of the "conventional protecting group" for the "ester of a carboxyl group" include the above-described "lower alkyl groups"; lower alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl; lower alkynyl groups such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl groups; the above-described "halogeno-lower alkyl groups"; hydroxy"lower alkyl groups" such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl groups; "lower aliphatic acyl" - "lower alkyl groups" such as acetylmethyl groups; the above-described "aralkyl groups"; and the above-described "silyl groups". The "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" means a protecting group which is cleaved in vivo by a biological method such as hydrolysis and forms a free acid or salt thereof. It can be determined whether an ester is such a derivative by administering it to an experimental animal, such as a rat or mouse, by intravenous injection, examining the body fluid of the animal after administration and detecting the original compound or a pharmaceutically acceptable salt thereof. Preferred examples of the "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" for the "ester of a hydroxyl group" include 1-(acyloxy)"lower alkyl groups", for example, 1-("lower aliphatic acyl"oxy)"lower alkyl groups" such as formyloxymethyl, acetoxymethyl, dimethylamino-acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyl-oxyhexyl groups, 1-("cycloalkyl"carbonyloxy)"lower alkyl groups" such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentyl-carbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexyl-carbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexyl-carbonyloxybutyl groups, and 1-("aromatic acyl"oxy)"lower alkyl groups" such as benzoyloxymethyl groups; (lower alkoxycarbonyloxy)alkyl groups such as methoxy-carbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxy-methyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)-ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(tert-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 2-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)-ethyl, 2-(propoxycarbonyloxy)ethyl, 2-(isopropoxycarbonyloxy)ethyl, 2-(butoxycarbonyloxy)ethyl, 2-(isobutoxycarbonyloxy)ethyl, 2-(pentyloxycarbonyloxy)ethyl, 2-(hexyloxycarbonyloxy)ethyl, 1-methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl groups; and oxodioxolenylmethyl groups such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl groups: "phthalidyl groups" such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups: the above-described "lower aliphatic acyl groups": the above-described "aromatic acyl groups": "half ester salt residue of succinic acid": "phosphate salt residues": "ester forming residues such as with amino acids": carbamoyl groups: carbamoyl groups substituted with 1 or 2 lower alkyl groups: and "1-(acyloxy)alkyloxycarbonyl groups" such as pivaloyloxymethyloxycarbonyl, of which the "carbonyloxyalkyl groups" are preferred. Preferred examples of the "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" for the "ester of a carboxy group" include "alkoxy lower alkyl groups", for example, (lower alkoxy)(lower alkyl) groups such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl and tert-butoxymethyl groups, (lower alkoxy)lower alkyl groups substituted with lower alkoxy such as 2-methoxyethoxymethyl, "aryl"oxy"lower alkyl groups" such as phenoxymethyl groups and (halogenated lower alkoxy)(lower alkyl) groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; " "lower alkoxy"carbonyl"lower alkyl groups"" such as methoxycarbonylmethyl groups; "cyano"lower alkyl groups"" such as cyanomethyl and 2-cyanoethyl groups; ""lower alkyl"thiomethyl groups" such as methylthiomethyl and ethylthiomethyl groups; ""aryl"thiomethyl groups" such as phenylthiomethyl and naphthylthiomethyl groups; "lower alkyl"sulfonyl"lower alkyl groups" which may be substituted with halogen" such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl groups; ""aryl"sulfonyl"lower alkyl groups"" such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl groups; the above-described "1-(acyloxy)"lower alkyl groups'"'; the above-described "phthalidyl groups"; the above-described "aryl groups"; the above-described "lower alkyl groups"; "carboxyalkyl groups" such as carboxymethyl groups; and "amide forming residues of amino acids" such as phenylalanine groups. When the compound (I) of the present invention contains an amino and/or carboxyl group, it can be converted into an amide derivative. The compound (I) of the present invention contains an asymmetric carbon atom in the molecule thereof and stereoisomers whose asymmetric carbon atom has the R or S configurations are present. The stereoisomers and a mixture thereof at any ratio are also included in the present invention. [Mode for carrying out the invention] The spiropiperidine derivative of the present invention can be prepared by the below-described method. [Method A] In the above reaction scheme, R 1 , R 2 , A, B, D, E, M and n have the same meanings as described above. Y' may be any group which is capable of being eliminated as a nucleophilic residue and is not specifically limited. Preferred examples of such groups include halogen atoms such as chlorine, bromine and iodine atoms; trihalomethoxy groups such as trichloromethoxy groups; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy groups; (halogeno lower alkane)sulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups; and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy groups, of which the halogen atoms and the lower alkanesulfonyloxy groups are still more preferred. Step A1 is a step of preparing the compound (I) of the present invention by reacting Compound (II) with Compound (III) in a solvent in the presence of a base. There is no particular limitation on the nature of the solvent to be employed, provided that it has no adverse effects on the reaction and can dissolve the starting materials at least to some extent. Preferred examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutylonitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide and sulfolane, of which the amides, ethers and nitriles are more preferred and the amides are most preferred. There is no particular limitation on the nature of the base to be employed provided that it is used in ordinary reactions. Preferred examples include combinations of a metal iodide (e.g. potassium iodide) and an inorganic base, such as an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate or lithium carbonate), an alkali metal hydrogencarbonate (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate or lithium hydrogencarbonate), an alkali metal hydride (e.g. lithium hydride, sodium hydride or potassium hydride), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide) or an alkali metal fluoride (e.g. sodium fluoride or potassium fluoride); or an organic base such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), of which the combination of a metal iodide and an inorganic base is still more preferred and the combination of a metal iodide and an alkali metal hydrogencarbonate is most preferred. The range of reaction temperature is from 0 to 150°C, from 20 to 120°C. Although the reaction time depends mainly on the reaction temperature and the nature of the raw materials, reaction reagents and solvent to be employed, the range is usually from 30 minutes to 48 hours, from 1 to 12 hours. A compound of the formula (I) wherein a carbon atom, which is a ring-atom of group G and which is not adjacent to the piperidine ring, has a hydroxyl group can be prepared by reduction of the corresponding ketone derivative, which is prepared in accordance with the above-described Method A. There is no particular limitation on the nature of the solvent to be employed provided that it has no adverse effects on the reaction and can dissolve the starting materials at least to some extent. Preferred examples include alcohols such as methanol and ethanol; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, of which the alcohols are preferred and the ethanol is most preferred. There is no particular limitation on the reducing agent to be employed provided that it is ordinarily used as a reducing agent. Preferred examples include hydride reagents such as alkali metal borohydrides (e.g. sodium borohydride or lithium borohydride), aluminum hydride compounds (e.g. lithium aluminum hydride or lithium triethoxyaluminum hydride), sodium tellurium hydride, and organic aluminum hydride reducing agents [e.g. diisobutylaluminum hydride or sodium di(methoxyethoxy)aluminum dihydride], of which the alkali metal borohydrides and organic aluminum hydride reducing agents are more preferred and the alkali metal borohydrides are most preferred. The range of reaction temperature is from -78 to 50°C, -20 to 20°C. The reaction time depends mainly on the reaction temperature, natures of the raw materials, reaction reagents and solvent to be employed. The range is usually from 5 minutes to 24 hours, 10 minutes to 2 hours. After the completion of the respective reactions, the compounds produced by the respective reactions may be collected from the reaction mixture by a conventional process. For example, the reaction mixture is appropriately neutralized and, after insoluble matter, if any, has been removed by filtration, a water immiscible organic solvent (e.g. ethyl acetate) is added. After washing with water and the like, the organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate and the like. Then, the solvent is distilled off to give the objective compound. The resultant desired compound can, if desired, be isolated and purified by using conventional procedures such as recrystallization and reprecipitation, or by procedures which are conventionally used for isolation and purification of organic compounds, for example, an adsorption column chromatography process using a carrier such as silica gel, alumina or magnesium-silica gel, Florisil; a process using a synthetic adsorbent, for example, partition column chromatography using Sephadex LH-20 (manufactured by Pharmacia Co.), Amberlite XAD-11 (manufactured by Rohm & Haas Co.), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.); a process using ion-exchange chromatography; or a normal/reversed phase liquid chromatography process ( high performance liquid chromatography) using silica gel or alkylated silica gel; or in combination using a suitable eluent. Incidentally, the raw materials are commercially available or can be prepared easily by a known method. For example, the compound of the formula (II) can be prepared by the method described in EP-776893 and the like, while the compound of the formula (III) can be prepared using methods well known in the art. See for example U.S. Patent No. 5,578,593 and the like. The novel spiropiperidine derivatives of the present invention exhibit excellent antagonism against tachykinin, excellent antagonistic activity against NK 1 , NK 2 and NK 3 receptors, excellent oral absorption and less toxicity so that they are useful as a medicament. Examples of the diseases for which the medicament is useful as a preventive or remedy include diseases of the central nervous system such as anxiety, depression, psychosis and schizophrenia; sleep apnea syndrome; neurodegenerative diseases such as dementia of AIDS, Alzheimer's senile dementia, Alzheimer's disease, Down's syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive lung diseases, bronchitis, pneumonia, bronchoconstriction, asthma and coughs; inflammatory diseases such as inflammatory bowel diseases (IBD), psoriasis, fibrositis, arthrosteitis, osteoarthritis and rheumatoid arthritis; allergic diseases such as rhinitis and eczema; hypersensitivity diseases such as hypersensitivity to vines; ophthalmological diseases such as conjunctivitis, vernal conjunctivitis, vernal catarrh, destruction of the blood-aqueous humor barrier caused by various inflammatory eye diseases, elevated in intraocular pressure and miosis; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addiction such as alcohol dependency; somatic diseases caused by stress; sympathetic reflex dystrophy such as hand and shoulder syndrome; dysthymia; undesirable immune reactions including rejection of grafts, disease relating to immunopotentiation including systemic lupus erythematosus or immunosuppression; digestive diseases including diseases caused by abnormalities in nerves regulating the organs, colitis, ulcerative colitis and Crohn's disease; emesis including emesis induced by adverse effects of X-ray irradiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal occlusion, reduced gastrointestinal movement, visceral pain, migraines, increased intracranial pressure, reduced intracranial pressure or administration of various drugs; urinary bladder functional disease such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scleriasis or Fasciola hepatica infection; diseases caused by the abnormal blood flow due to vasodilation or vasoconstriction such as angina pectoris, migraines and Reynauds's disease; and pain of pain nociceptive reception such as migraines, headaches and toothache. The compound (I) of the present invention can be administered orally, for example, in the form of tablets, capsules, granules, powders or syrups, or administered parenterally, for example, in the form of injection preparations or suppositories. These preparations may be produced using additives, such as excipients [e.g. sugar derivatives, such as lactose, sucrose, glucose, mannitol, or sorbitol; starch derivatives, such as corn starch, potato starch, α-starch, dextrin or carboxymethyl starch; cellulose derivatives, such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl-cellulose, carboxymethylcellulose calcium or internally cross-linked carboxy-methylcellulose sodium; gum arabic; dextran; organic excipients, such as pullulan; silicate derivatives, such as light anhydrous silicic acid, synthetic aluminum silicate or magnesium aluminate metasilicate; phosphates, such as calcium phosphate; carbonates, such as calcium carbonate; inorganic excipients, such as sulfates (e.g. calcium sulfate)]; lubricants [e.g. metal stearates, such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silica; waxes, such as bee gum, and spermaceti; boric acid; adipic acid; sulfates, such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; laurylsulfates, such as sodium laurylsulfate, and magnesium laurylsulfate; silicic acids, such as anhydrous silicic acid, and silicate hydrate; and the above starch derivatives]; binders [e.g. polyvinyl pyrrolidone, macrogol and the same compounds as those of the above excipients]; disintegrators [e.g. the same compounds as those of the above excipients and chemically modified starchcelluloses, such as croscarmellose sodium, carboxymethylstarch sodium and cross-linked polyvinylpyrrolidone]; stabilizers [e.g. paraoxybenzoates, such as methylparaben, and propylparaben; alcohols, such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols, such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid]; corrigents [e.g. normally used sweetening agents, sour agents, and perfumes]; and diluents according to a per se known process. The dose varies depending on the severity of the diseases, the age, administration route and the like. For example, in the case of oral administration, it is advantageous that the compound of the present invention is administered one to several times per day with a dose of from 0.01 mg/kg body weight (0.1 mg/kg body weight, lower limit) to 100 mg/kg body weight ( 50 mg/kg body weight, upper limit) according to the severity of the diseases. In the case of intravenous administration, it is advantageous that the compound of the present invention is administered one to several times per day with a dose of 0.01 mg/kg body weight ( 0.05 mg/kg body weight, lower limit) to 100 mg/kg body weight ( 50 mg/kg body weight, upper limit) according to the severity of the diseases. [Best mode for carrying out the invention] The present invention will hereinafter be described in further detail with reference to examples, formulation examples and test examples. However, these are not intended to limit the scope of the present invention. [Examples] [Example 1] 1-{2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine] (The below-described Compound No. 138) In 4 ml of anhydrous dimethylformamide, 200 mg (0.37 mmol) of 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol methanesulfonate, 96 mg (0.40 mmol) of spiro[(2-hydroxy)indane-1,4'-piperidine] hydrochloride obtained in Referential Example 3, 92 mg (1.10 mmol) of sodium bicarbonate and 91 mg (0.55 mmol) of potassium iodide were suspended, followed by heating at 80°C for 8 hours under a nitrogen atmosphere. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing agent; methylene chloride : methanol = 10:1), whereby 175 mg (73%) of the title compound were obtained as white crystals. [α] D 25 +11.8° (c=0.56, chloroform) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.16-7.67 (7H,m), 6.52 (2H,s), 4.40 (1H,s), 3.85 (9H,s), 3.37-4.04 (6H,m), 3.27 (1H,dd,J=16.7,5.3Hz), 2.82 (1H,d,J=16.7Hz), 2.62-2.88 (2H,m), 1.49-2.40 (10H,m). Infrared absorption spectrum ν max cm -1 (KBr): 3432, 2934, 1634, 1584 Mass spectrometric analysis (FAB) m/z: 655 ((M+H) + ) Elemental analysis (% based on C 35 H 40 N 2 O 6 C 12 ·0.5H 2 O) Calculated C; 63.25, H; 6.22, N; 4.21, Cl; 10.67 Found C; 63.24, H; 6.37, N; 4.14, Cl; 10.41 [Example 2] 1-{2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine] (The below-described Compound No. 106) [Example 2a] 1-{3-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethyoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-indanone)-1,4'-piperidine] In 4 ml of anhydrous dimethylformamide, 200 mg (0.37 mmol) of 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol methanesulfonate, 95 mg (0.40 mmol) of spiro[(3-indanone)-1,4'-piperidine] hydrochloride obtained in Referential Example 5,92 mg (1.10 mmol) of sodium bicarbonate and 91 mg (0.55 mmol) of potassium iodide were suspended, followed by heating at 80°C for 8 hours under a nitrogen atmosphere. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing agent; methylene chloride : methanol = 10:1), whereby 167 mg (70%) of the title compound were obtained as white crystals. [α] D 25 +4.3° (c 0.53, chloroform) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.29-7.78 (7H,m), 6.49 (2H,s), 3.85 (9H,s), 3.30-3.92 (6H,m), 2.74-2.96 (2H,m), 2.52 (2H,s), 1.93-2.30 (8H,m), 1.47-1.50 (2H,m). Infrared absorption spectrum ν max cm -1 (KBr): 3416, 2933, 1714, 1637, 1603 Mass spectrometric analysis (FAB) m/z: 653 ((M+H) + ) Elemental analysis (% based on C 35 H 38 N 2 O 6 C 12 ·0.5H 2 O) Calculated C; 63.44, H; 5.93, N; 4.22, Cl; 10.70 Found C; 63.63, H; 6.20, N; 4.11, Cl; 10.26 [Example 2b] 1-{2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine] In 1 ml of ethanol, 24 mg (0.62 mmol) of sodium borohydride were dissolved. To the resulting solution, an ethanol (1ml) solution of 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-indanone)-1,4'-piperidine] (100 mg (0.16 mmol)), which had been prepared in Example 2a, was added under ice cooling, followed by stirring for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing agent; methylene chloride : methanol = 10:1), whereby 80 mg (78%) of the title compound were obtained as white crystals. [α] D 25 +8.3° (c 0.52, chloroform) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.19-7.69 (7H,m), 6.50 (2H,s), 5.23 (1H,t,J=5.9Hz), 3.85 (9H,s), 3.41-4.02 (6H,m), 2.78-2.89 (2H,m), 1.37-2.45 (12H,m) Infrared absorption spectrum ν max cm -1 (KBr): 3424, 2928, 1634, 1584 Mass spectrometric analysis (EI) m/z: 654 (M + ) Elemental analysis (% based on C 35 H 40 N 2 O 6 C 12 ·0.5H 2 O) Calculated C; 63.25, H; 6.22, N; 4.21, Cl; 10.67 Found C; 63.62, H; 6.35, N; 4.05, Cl; 10.22 [Example 3] 1-{2-[(2R)-(3,4-Dichlorophenyl-4 -(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[((2S)-hydroxy)indane-1,4'-piperidine] (The below-described Compound No. 138) In 6.0 ml of dimethylacetamide, 300 mg (0.547 mmol) of 2-[(2R)-(3,4-dichlorophenyl-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol methanesulfonate, 144 mg (0.602 mmol) of spiro[((2S)-hydroxy)indane-1,4'-piperidine] hydrochloride obtained in Referential Example 7, 138 mg (1.64 mmol) of sodium bicarbonate and 136 mg (0.821 mmol) of sodium iodide were suspended, followed by heating at 80°C for 8 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl aqueous solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (silica gel; 15 g, eluent; hexane : ethyl acetate = 1:1 → 1:3, methylene chloride : methanol = 50:1 →20:1), whereby 297 mg (yield: 83%) of 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[((2S)-hydroxy)indane-l,4'-piperidine] were obtained as white crystals. Melting point: 121°C [α] D 24 +23.6° (c=0.96, chloroform) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.67-7.16 (7H,m), 6.52 (2H,br.s), 4.40 (1H,br.s), 3.85 (9H,s), 4.04-3.37 (6H,m), 3.27 (1H,dd,J=16.7Hz,5.3Hz), 2.82 (1H,d,J=16.7Hz), 2.88-2.62 (2H,m), 2.40-1.49 (10H,m) Infrared absorption spectrum ν max cm -1 (KBr): 3427, 2933, 1634, 1584, 1465, 1428, 1415, 1330, 1237, 1128 Mass spectrometric analysis (FAB) m/z: 655 ([M+H] + ) Elemental analysis (% based on C 35 H 40 C 12 N 2 O 6 ·H 2 O) Calculated C; 62.41, H; 6.29, N; 4.16, Cl; 10.53 Found C; 62.33, H; 6.27, N; 3.90, Cl; 10.49 [Example 4] 1-{2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[((2S)-hydroxy)indane-1,4'-piperidine] hydrochloride (the below-described Compound No. 138·hydrochloride) In 3.0 ml of ethanol, 297 mg (0.453 mmol) of 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[((2S)-hydroxy)indane-1,4'-piperidine] obtained in Example 3 were dissolved. To the resulting solution, 0.57 ml of 4N hydrogen chloride - 1,4-dioxane solution were added under ice cooling, followed by stirring for 30 minutes. After the solvent was distilled off under reduced pressure, the residue was washed with ether, whereby 304 mg (yield: 97%) of 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl} spiro[((2S)-hydroxy)indane-1,4'-piperidine] hydrochloride were obtained as white crystals. Melting point: 169°C [α] D 24 +30.5° (c=1.0, methanol) Nuclear magnetic resonance spectrum (400 MHz, DMSO) δppm: 10.78 (1H,m), 7.88-7.32 (3H,m), 7.27-7.06 (4H,m), 6.76-6.61 (2H,m), 4.93-4.92 (1H,m), 4.39-4.38 (1H,m), 3.81 (6H,s), 3.70 (3H,s), 4.22-2.58 (15H,m), 2.41-1.18 (4H,m), 1.69-1.48 (1H,m) Infrared absorption spectrum ν max cm -1 (KBr): 3360, 2937, 2561, 1635, 1584, 1464, 1427, 1330, 1237, 1127 Mass spectrometric analysis (FAB) m/z: 655 ([M+H] + free form) Elemental analysis (% based on C 35 H 40 Cl 12 N 2 O 6 ·1/2H 2 O) Calculated C; 59.96, H; 5.89, N; 4.00, Cl; 15.17 Found C; 59.94, H; 5.81, N; 3.94, Cl; 15.22 The compounds which will be described below are synthesized in a similar manner to that described in the above examples. Incidentally, in the below-described table, "Ac" represents an acetyl group, "Me" represents a methyl group, "Ph" means a phenyl group, "iPr" means an isopropyl group and each substituent (in the table, described as "sub") represents the following group. Cpd No. R 1 R 2 A B n D E Z 1 sub.1 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 2 sub.2 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 3 sub.3 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 4 sub.4 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 5 sub.5 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 6 sub.6 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 7 sub.7 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 8 sub.8 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 9 sub.9 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 10 sub.10 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 11 sub.11 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 12 sub.12 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 13 sub.13 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 14 sub.14 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 15 sub.15 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 16 sub.16 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 17 sub.17 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 18 sub.18 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 19 sub.19 3,4-diClPh CO bond I O CH 2 CH 2 sub.33 20 sub.20 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 21 sub.21 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 22 sub.22 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 23 sub.23 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 24 sub.24 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 25 sub.25 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 26 sub.26 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 27 sub.27 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 28 sub.28 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 29 sub.29 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 30 sub.30 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 31 sub.31 3.4-diClPh CO bond 1 O CH 2 CH 2 sub.33 32 sub.32 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 33 sub.1 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 34 sub.2 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 35 sub.3 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 36 sub.4 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 37 sub.5 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 38 sub.6 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 39 sub.7 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 40 sub.8 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 41 sub.9 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 42 sub.10 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 43 sub.11 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 44 sub.12 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 45 sub.13 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 46 sub.14 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 47 sub.15 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 48 sub.16 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 49 sub.17 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 50 sub.18 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 51 sub.19 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 52 sub.20 3,4-diClPh CO bond I O CH 2 CH 2 sub.34 53 sub.21 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 54 sub.22 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 55 sub.23 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 56 sub.24 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 57 sub.25 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 58 sub.26 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 59 sub.27 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 60 sub.28 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 61 sub.29 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 62 sub.30 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 63 sub.31 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 64 sub.32 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 97 sub.1 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 98 sub.2 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 99 sub.3 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 100 sub.4 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 101 sub.5 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 102 sub.6 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 103 sub.7 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 104 sub.8 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 105 sub.9 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 106 sub.10 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 107 sub.11 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 108 sub.12 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 109 sub.13 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 110 sub.14 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 111 sub.15 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 112 sub.16 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 113 sub.17 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 114 sub.18 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 115 sub.19 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 116 sub.20 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 117 sub.21 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 118 sub.22 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 119 sub.23 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 120 sub.24 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 121 sub.25 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 122 sub.26 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 123 sub.27 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 124 sub.28 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 125 sub.29 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 126 sub.30 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 127 sub.31 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 128 sub.32 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 129 sub.1 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 130 sub.2 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 131 sub.3 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 132 sub.4 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 133 sub.5 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 134 sub.6 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 135 sub.7 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 136 sub.8 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 137 sub.9 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 138 sub.10 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 139 sub.11 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 140 sub.12 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 141 sub.13 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 142 sub.14 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 143 sub.15 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 144 sub.16 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 145 sub.17 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 146 sub.18 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 147 sub.19 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 148 sub.20 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 149 sub.21 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 150 sub.22 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 151 sub.23 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 152 sub.24 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 153 sub.25 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 154 sub.26 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 155 sub.27 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 156 sub.28 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 157 sub.29 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 158 sub.30 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 159 sub.31 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 160 sub.32 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 193 sub.1 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 194 sub.2 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 195 sub.3 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 196 sub.4 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 197 sub.5 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 198 sub.6 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 199 sub.7 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 200 sub.8 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 201 sub.9 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 202 sub.10 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 203 sub.11 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 204 sub.12 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 205 sub.13 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 206 sub.14 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 207 sub.15 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 208 sub.16 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 209 sub.17 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 210 sub.18 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 211 sub.19 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 212 sub.20 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 213 sub.21 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 214 sub.22 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 215 sub.23 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 216 sub.24 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 217 sub.25 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 218 sub.26 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 219 sub.27 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 220 sub.28 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 221 sub.29 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 222 sub.30 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 223 sub.31 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 224 sub.32 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 225 sub.1 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 226 sub.2 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 227 sub.3 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 228 sub.4 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 229 sub.5 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 230 sub.6 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 231 sub.7 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 232 sub.8 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 233 sub.9 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 234 sub.10 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 235 sub.11 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 236 sub.12 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 237 sub.13 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 238 sub.14 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 239 sub.15 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 240 sub.16 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 241 sub.17 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 242 sub.18 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 243 sub.19 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 244 sub.20 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 245 sub.21 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 246 sub.22 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 247 sub.23 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 248 sub.24 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 249 sub.25 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 250 sub.26 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 251 sub.27 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 252 sub.28 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 253 sub.29 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 254 sub.30 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 255 sub.31 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 256 sub.32 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 289 sub.1 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 290 sub.2 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 291 sub.3 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 292 sub.4 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 293 sub.5 4-CIPh CO bond 2 O CH 2 CH 2 sub.33 294 sub.6 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 295 sub.7 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 296 sub.8 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 297 sub.9 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 298 sub.10 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 299 sub.11 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 300 sub.12 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 301 sub.13 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 302 sub.14 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 303 sub.15 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 304 sub.16 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 305 sub.17 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 306 sub.18 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 307 sub.19 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 308 sub.20 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 309 sub.21 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 310 sub.22 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 311 sub.23 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 312 sub.24 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 313 sub.25 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 314 sub.26 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 315 sub.27 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 316 sub.28 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 317 sub.29 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 318 sub.30 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 319 sub.31 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 320 sub.32 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 321 sub.1 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 322 sub.2 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 323 sub.3 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 324 sub.4 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 325 sub.5 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 326 sub.6 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 327 sub.7 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 328 sub.8 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 329 sub.9 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 330 sub.10 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 331 sub.11 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 332 sub.12 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 333 sub.13 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 334 sub.14 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 335 sub.15 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 336 sub.16 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 337 sub.17 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 338 sub.18 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 339 sub.19 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 340 sub.20 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 341 sub.21 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 342 sub.22 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 343 sub.23 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 344 sub.24 4-CIPh CO bond 2 O CH 2 CH 2 sub.34 345 sub.25 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 346 sub.26 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 347 sub.27 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 348 sub.28 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 349 sub.29 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 350 sub.30 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 351 sub.31 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 352 sub.32 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 Cpd No. R 1 R 2 A B n D E Z 385 sub.1 4-FPh CO bond 2 O CH 2 CH 2 sub.33 386 sub.2 4-FPh CO bond 2 O CH 2 CH 2 sub.33 387 sub.3 4-FPh CO bond 2 O CH 2 CH 2 sub.33 388 sub.4 4-FPh CO bond 2 O CH 2 CH 2 sub.33 389 sub.5 4-FPh CO bond 2 O CH 2 CH 2 sub.33 390 sub.6 4-FPh CO bond 2 O CH 2 CH 2 sub.33 391 sub.7 4-FPh CO bond 2 O CH 2 CH 2 sub.33 392 sub.8 4-FPh CO bond 2 O CH 2 CH 2 sub.33 393 sub.9 4-FPh CO bond 2 O CH 2 CH 2 sub.33 394 sub.10 4-FPh CO bond 2 O CH 2 CH 2 sub.33 395 sub.11 4-FPh CO bond 2 O CH 2 CH 2 sub.33 396 sub.12 4-FPh CO bond 2 O CH 2 CH 2 sub.33 397 sub.13 4-FPh CO bond 2 O CH 2 CH 2 sub.33 398 sub.14 4-FPh CO bond 2 O CH 2 CH 2 sub.33 399 sub.15 4-FPh CO bond 2 O CH 2 CH 2 sub.33 400 sub.16 4-FPh CO bond 2 O CH 2 CH 2 sub.33 401 sub.17 4-FPh CO bond 2 O CH 2 CH 2 sub.33 402 sub.18 4-FPh CO bond 2 O CH 2 CH 2 sub.33 403 sub.19 4-FPh CO bond 2 O CH 2 CH 2 sub.33 404 sub.20 4-FPh CO bond 2 O CH 2 CH 2 sub.33 405 sub.21 4-FPh CO bond 2 O CH 2 CH 2 sub.33 406 sub.22 4-FPh CO bond 2 O CH 2 CH 2 sub.33 407 sub.23 4-FPh CO bond 2 O CH 2 CH 2 sub.33 408 sub.24 4-FPh CO bond 2 O CH 2 CH 2 sub.33 409 sub.25 4-FPh CO bond 2 O CH 2 CH 2 sub.33 410 sub.26 4-FPh CO bond 2 O CH 2 CH 2 sub.33 411 sub.27 4-FPh CO bond 2 O CH 2 CH 2 sub.33 412 sub.28 4-FPh CO bond 2 O CH 2 CH 2 sub.33 413 sub.29 4-FPh CO bond 2 O CH 2 CH 2 sub.33 414 sub.30 4-FPh CO bond 2 O CH 2 CH 2 sub.33 415 sub.31 4-FPh CO bond 2 O CH 2 CH 2 sub.33 416 sub.32 4-FPh CO bond 2 O CH 2 CH 2 sub.33 417 sub.1 4-FPh CO bond 2 O CH 2 CH 2 sub.34 418 sub.2 4-FPh CO bond 2 O CH 2 CH 2 sub.34 419 sub.3 4-FPh CO bond 2 O CH 2 CH 2 sub.34 420 sub.4 4-FPh CO bond 2 O CH 2 CH 2 sub.34 421 sub.5 4-FPh CO bond 2 O CH 2 CH 2 sub.34 422 sub.6 4-FPh CO bond 2 O CH 2 CH 2 sub.34 423 sub.7 4-FPh CO bond 2 O CH 2 CH 2 sub.34 424 sub.8 4-FPh CO bond 2 O CH 2 CH 2 sub.34 425 sub.9 4-FPh CO bond 2 O CH 2 CH 2 sub.34 426 sub.10 4-FPh CO bond 2 O CH 2 CH 2 sub.34 427 sub.11 4-FPh CO bond 2 O CH 2 CH 2 sub.34 428 sub.12 4-FPh CO bond 2 O CH 2 CH 2 sub.34 429 sub.13 4-FPh CO bond 2 O CH 2 CH 2 sub.34 430 sub.14 4-FPh CO bond 2 O CH 2 CH 2 sub.34 431 sub.15 4-FPh CO bond 2 O CH 2 CH 2 sub.34 432 sub.16 4-FPh CO bond 2 O CH 2 CH 2 sub.34 433 sub.17 4-FPh CO bond 2 O CH 2 CH 2 sub.34 434 sub.18 4-FPh CO bond 2 O CH 2 CH 2 sub.34 435 sub.19 4-FPh CO bond 2 O CH 2 CH 2 sub.34 436 sub.20 4-FPh CO bond 2 O CH 2 CH 2 sub.34 437 sub.21 4-FPh CO bond 2 O CH 2 CH 2 sub.34 438 sub.22 4-FPh CO bond 2 O CH 2 CH 2 sub.34 439 sub.23 4-FPh CO bond 2 O CH 2 CH 2 sub.34 440 sub.24 4-FPh CO bond 2 O CH 2 CH 2 sub.34 441 sub.25 4-FPh CO bond 2 O CH 2 CH 2 sub.34 442 sub.26 4-FPh CO bond 2 O CH 2 CH 2 sub.34 443 sub.27 4-FPh CO bond 2 O CH 2 CH 2 sub.34 444 sub.28 4-FPh CO bond 2 O CH 2 CH 2 sub.34 445 sub.29 4-FPh CO bond 2 O CH 2 CH 2 sub.34 446 sub.30 4-FPh CO bond 2 O CH 2 CH 2 sub.34 447 sub.31 4-FPh CO bond 2 O CH 2 CH 2 sub.34 448 sub.32 4-FPh CO bond 2 O CH 2 CH 2 sub.34 481 sub.1 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 482 sub.2 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 483 sub.3 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 484 sub.4 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 485 sub.5 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 486 sub.6 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 487 sub.7 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 488 sub.8 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 489 sub.9 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 490 sub.10 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 491 sub.11 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 492 sub.12 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 493 sub.13 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 494 sub.14 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 495 sub.15 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 496 sub.16 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 497 sub.17 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 498 sub.18 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 499 sub.19 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 500 sub.20 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 501 sub.21 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 502 sub.22 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 503 sub.23 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 504 sub.24 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 505 sub.25 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 506 sub.26 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 507 sub.27 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 508 sub.28 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 509 sub.29 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 510 sub.30 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 511 sub.31 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 512 sub.32 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 513 sub.1 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 514 sub.2 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 515 sub.3 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 516 sub.4 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 517 sub.5 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 518 sub.6 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 519 sub.7 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 520 sub.8 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 521 sub.9 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 522 sub.10 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 523 sub.11 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 524 sub.12 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 525 sub.13 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 526 sub.14 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 527 sub.15 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 528 sub.16 3,4-diClPh CO bond 1 O (CR 2 ) 3 sub.34 529 sub.17 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 530 sub.18 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 531 sub.19 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 532 sub.20 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 533 sub.21 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 534 sub.22 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 535 sub.23 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 536 sub.24 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 537 sub.25 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 538 sub.26 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 539 sub.27 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 540 sub.28 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 541 sub.29 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 542 sub.30 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 543 sub.31 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 544 sub.32 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 577 sub.1 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 578 sub.2 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 579 sub.3 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 580 sub.4 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 581 sub.5 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 582 sub.6 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 583 sub.7 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 584 sub.8 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 585 sub.9 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 586 sub.10 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 587 sub.11 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 588 sub.12 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 589 sub.13 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 590 sub.14 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 591 sub.15 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 592 sub.16 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 593 sub.17 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 594 sub.18 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 595 sub.19 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 596 sub.20 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 597 sub.21 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 598 sub.22 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 599 sub.23 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 600 sub.24 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 601 sub.25 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 602 sub.26 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 603 sub.27 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 604 sub.28 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 605 sub.29 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 606 sub.30 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 607 sub.31 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 608 sub.32 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 609 sub.1 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 610 sub.2 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 611 sub.3 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 612 sub.4 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 613 sub.5 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 614 sub.6 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 615 sub.7 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 616 sub.8 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 617 sub.9 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 618 sub.10 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 619 sub.11 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 620 sub.12 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 621 sub.13 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 622 sub.14 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 623 sub.15 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 624 sub.16 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 625 sub.17 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 626 sub.18 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 627 sub.19 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 628 sub.20 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 629 sub.21 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 630 sub.22 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 631 sub.23 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 632 sub.24 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 633 sub.25 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 634 sub.26 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 635 sub.27 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 636 sub.28 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 637 sub.29 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 638 sub.30 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 639 sub.31 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 640 sub.32 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 673 sub.1 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 674 sub.2 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 675 sub.3 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 676 sub.4 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 677 sub.5 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 678 sub.6 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 679 sub.7 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 680 sub.8 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 681 sub.9 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 682 sub.10 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 683 sub. 11 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 684 sub. 12 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 685 sub.13 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 686 sub.14 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 687 sub.15 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 688 sub.16 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 689 sub.17 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 690 sub. 18 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 691 sub.19 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 692 sub.20 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 693 sub.21 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 694 sub.22 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 695 sub.23 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 696 sub.24 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 697 sub.25 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 698 sub.26 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 699 sub.27 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 700 sub.28 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 701 sub.29 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 702 sub.30 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 703 sub.31 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 704 sub.32 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 705 sub.1 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 706 sub.2 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 707 sub.3 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 708 sub.4 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 709 sub.5 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 710 sub.6 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 711 sub.7 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 712 sub.8 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 713 sub.9 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 714 sub.10 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 715 sub.11 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 716 sub.12 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 717 sub.13 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 718 sub.14 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 719 sub.15 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 720 sub.16 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 721 sub.17 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 722 sub.18 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 723 sub.19 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 724 sub.20 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 725 sub.21 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 726 sub.22 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 727 sub.23 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 728 sub.24 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 729 sub.25 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 730 sub.26 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 731 sub.27 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 732 sub.28 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 733 sub.29 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 734 sub.30 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 735 sub.31 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 736 sub.32 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 Cpd No. R 1 R 2 A B n D E Z 769 sub.1 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 770 sub.2 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 771 sub.3 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 772 sub.4 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 773 sub.5 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 774 sub.6 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 775 sub.7 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 776 sub.8 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 777 sub.9 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 778 sub.10 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 779 sub.11 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 780 sub.12 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 781 sub.13 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 782 sub.14 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 783 sub.15 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 784 sub.16 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 785 sub.17 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 786 sub.18 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 787 sub.19 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 788 sub.20 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 789 sub.21 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 790 sub.22 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 791 sub.23 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 792 sub.24 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 793 sub.25 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 794 sub.26 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 795 sub.27 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 796 sub.28 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 797 sub.29 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 798 sub.30 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 799 sub.31 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 800 sub.32 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 801 sub.1 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 802 sub.2 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 803 sub.3 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 804 sub.4 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 805 sub.5 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 806 sub.6 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 807 sub.7 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 808 sub.8 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 809 sub.9 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 810 sub.10 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 811 sub.11 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 812 sub.12 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 813 sub.13 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 814 sub.14 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 815 sub.15 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 816 sub.16 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 817 sub.17 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 818 sub.18 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 819 sub.19 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 820 sub.20 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 821 sub.21 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 822 sub.22 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 823 sub.23 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 824 sub.24 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 825 sub.25 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 826 sub.26 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 827 sub.27 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 828 sub.28 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 829 sub.29 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 830 sub.30 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 831 sub.31 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 832 sub.32 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 865 sub.1 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 866 sub.2 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 867 sub.3 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 868 sub.4 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 869 sub.5 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 870 sub.6 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 871 sub.7 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 872 sub.8 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 873 sub.9 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 874 sub.10 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 875 sub.11 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 876 sub.12 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 877 sub.13 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 878 sub.14 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 879 sub.15 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 880 sub.16 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 881 sub.17 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 882 sub.18 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 883 sub.19 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 884 sub.20 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 885 sub.21 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 886 sub.22 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 887 sub.23 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 888 sub.24 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 889 sub.25 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 890 sub.26 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 891 sub.27 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 892 sub.28 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 893 sub.29 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 894 sub.30 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 895 sub.31 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 896 sub.32 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 897 sub.1 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 898 sub.2 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 899 sub.3 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 900 sub.4 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 901 sub.5 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 902 sub.6 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 903 sub.7 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 904 sub.8 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 905 sub.9 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 906 sub.10 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 907 sub.11 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 908 sub.12 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 909 sub.13 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 910 sub.14 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 911 sub.15 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 912 sub.16 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 913 sub.17 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 914 sub.18 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 915 sub.19 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 916 sub.20 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 917 sub.21 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 918 sub.22 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 919 sub.23 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 920 sub.24 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 921 sub.25 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 922 sub.26 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 923 sub.27 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 924 sub.28 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 925 sub.29 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 926 sub.30 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 927 sub.31 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 928 sub.32 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 961 sub.36 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 962 sub.37 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 963 sub.38 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.33 964 sub.36 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 965 sub.37 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 966 sub.38 3,4-diClPh CO bond 1 O CH 2 CH 2 sub.34 970 sub.36 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 971 sub.37 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 972 sub.38 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.33 973 sub.36 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 974 sub.37 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 975 sub.38 3,4-diClPh CO bond 2 O CH 2 CH 2 sub.34 979 sub.36 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 980 sub.37 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 981 sub.38 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.33 982 sub.36 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 983 sub.37 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 984 sub.38 3,4-diFPh CO bond 2 O CH 2 CH 2 sub.34 988 sub.36 4-CIPh CO bond 2 O CH 2 CH 2 sub.33 989 sub.37 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 990 sub.38 4-ClPh CO bond 2 O CH 2 CH 2 sub.33 991 sub.36 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 992 sub.37 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 993 sub.38 4-ClPh CO bond 2 O CH 2 CH 2 sub.34 997 sub.36 4-FPh CO bond 2 O CH 2 CH 2 sub.33 998 sub.37 4-FPh CO bond 2 O CH 2 CH 2 sub.33 999 sub.38 4-FPh CO bond 2 O CH 2 CH 2 sub.33 1000 sub.36 4-FPh CO bond 2 O CH 2 CH 2 sub.34 1001 sub.37 4-FPh CO bond 2 O CH 2 CH 2 sub.34 1002 sub.38 4-FPh CO bond 2 O CH 2 CH 2 sub.34 1006 sub.36 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 1007 sub.37 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 1008 sub.38 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.33 1009 sub.36 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 1010 sub.37 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 1011 sub.38 3,4-diClPh CO bond 1 O (CH 2 ) 3 sub.34 1015 sub.36 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 1016 sub.37 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 1017 sub.38 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.33 1018 sub.36 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 1019 sub.37 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 1020 sub.38 3,4-diClPh CO bond 2 O (CH 2 ) 3 sub.34 1024 sub.36 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 1025 sub.37 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 1026 sub.38 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.33 1027 sub.36 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 1028 sub.37 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 1029 sub.38 3,4-diFPh CO bond 2 O (CH 2 ) 3 sub.34 1033 sub.36 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 1034 sub.37 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 1035 sub.38 4-ClPh CO bond 2 O (CH 2 ) 3 sub.33 1036 sub.36 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 1037 sub.37 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 1038 sub.38 4-ClPh CO bond 2 O (CH 2 ) 3 sub.34 1042 sub.36 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 1043 sub.37 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 1044 sub.38 4-FPh CO bond 2 O (CH 2 ) 3 sub.33 1045 sub.36 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 1046 sub.37 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 1047 sub.38 4-FPh CO bond 2 O (CH 2 ) 3 sub.34 In the above table, the compounds of Compound Nos. 1 to 192 and Compound Nos. 321 to 384 are preferred, of which the compounds of Compound Nos. 97 to 192 are still more preferred and the compounds of Compound Nos. 101 to 106, 133 to 138 and 165 to 170 are still more preferred. The most preferred compounds are: 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)mdane-1,4'-piperidine], 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine], and 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], particularly preferred compounds are 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine] and 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine]. [Referential Examples] The present invention will hereafter be described with reference to referential examples. [Referential Example 1] N-t-Butoxycarbonyl-spiro(1H-indene-1,4'-piperidine) In 60 ml of anhydrous tetrahydrofuran, 11.6 g (0.10 mole) of indene were dissolved, followed by the gradual dropwise addition of 200 ml (0.20 mole) of lithium bistrimethylsilylamide (a 1.0M tetrahydrofuran solution) for one hour under ice cooling. After stirring the reaction mixture for 30 minutes, 50 ml of a tetrahydrofuran solution of 24.2 g (0.10 mole) of N-t-butoxycarbonyl-bis(2-chloroethyl)amine were added dropwise to the reaction mixture for 20 minutes. The resulting mixture was further stirred for 2 hours under ice cooling. The reaction mixture was distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate = 97:3), whereby 21.3 g (89%) of the title compound were obtained as white crystals. Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.21-7.41 (4H,m), 6.85 (1H,d,J=5.7Hz), 6.79 (1H,d,J=5.7Hz), 4.11-4.28 (2H,m), 3.07-3.23 (2H,m), 2.01 (2H,dt,J=12.8,4.5Hz), 1.51 (9H,s), 1.47-1.50(2H,m) Infrared absorption spectrum ν max cm -1 (KBr): 2965, 1680, 1425, 1365, 1245, 1165 Mass spectrometric analysis (EI) m/z: 285 (M + ) [Referential Example 2] N-t-Butoxycarbonyl-spiro[(2-hydroxy)indane-1,4'-piperidine] and N-t-Butoxycarbonyl-spiro[(3-hydroxy)indane-1,4'-piperidine] In 100 ml of anhydrous tetrahydrofuran, 10.0 g (35.0 mmol) ofN-t-butoxycarbonyl-spiro(1H-indene-1,4'-piperidine), prepared as described in Referential Example 1, were dissolved, followed by the dropwise addition of 52.5 ml (52.5 mmol) of borane·tetrahydrofuran complex (a 1.0M tetrahydrofuran solution) for 1.5 hours under ice cooling. The resulting mixture was stirred for 30 minutes under ice cooling and then for 4 hours at room temperature. Under ice cooling, 5 ml of ethanol were added to the reaction mixture. After stirring for a further 5 minutes, 13 ml of a 6N aqueous solution of sodium hydroxide were added dropwise to the reaction mixture for 20 minutes. Then, 13.0 ml of 30% aqueous hydrogen peroxide were added dropwise for 25 minutes, followed by stirring for 20 minutes under ice cooling and 3 hours at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate = 70:30 - 60:40), whereby 5.83 g (55%) of N-t-butoxycarbonyl-spiro[(2-hydroxy)indane-1,4'-piperidine] were obtained as a nonpolar substance and 4.20 g (40%) of N-t-butoxycarbonyl-spire[(3-hydroxy)indane-1,4'-piperidine] as a polar substance, each as white crystals. N-t-Butoxycarbonyl-spiro[(2-hydroxy)indane-1,4'-piperidine] Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.20-7.29 (4H,m), 4.48-4.52 (1H,m), 3.96 (2H,brs), 3.32 (1H,dd,J=16.7,5.3Hz), 3.24 (2H,m), 2.86 (1H,dd,J=16.7,1.0Hz), 2.02-2.06 (1H,m), 1.84 (1H,m), 1.52-1.65 (3H,m), 1.49 (9H,s) Infrared absorption spectrum ν max cm -1 (KBr): 3620, 2980, 2935, 1680, 1430, 1365 Mass spectrometric analysis (EI) m/z: 303 (M + ). N-t-Butoxycarbonyl-spire[(3-hydroxy)indane-1,4'-piperidine] Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.42 (1H,d,J=7.0Hz), 7.26-7.36 (2H,m), 7.23 (1H,d,J=7.0Hz), 5.29 (1H,d,J=6.2Hz), 4.12 (2H,m), 2.95 (2H,m), 2.53 (1H,q,J=6.9Hz), 1.91-1.98 (2H,m), 1.72-1.80 (2H,m), 1.61-1.67 (1H,m), 1.49 (9H,s), 1.38-1.42 (1H,m) Infrared absorption spectrum ν max cm -1 (KBr): 3605, 2980, 2935, 1680, 1430, 1365 Mass spectrometric analysis (EI) m/z: 303 (M + ) [Referential Example 3] Spiro[(2-hydroxy)indane-1,4'-piperidine]hydrochloride In 10 ml of ethanol, 2.51 g (8.27 mmol) of N-t-butoxycarbonyl-spiro[(2-hydroxy)indane-1,4'-piperidine], prepared as described in Referential Example 2, were dissolved, followed by the dropwise addition of 10.0 ml (40.0 mmol) of 4N hydrochloric acid/dioxane solution for 5 minutes under ice cooling. After stirring it for 30 minutes under ice cooling, the mixture was further stirred at room temperature for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was recrystallized from methanol/diethyl ether, whereby 1.64 g (83%) of the title compound were obtained as white crystals. Melting point: 250 - 251°C Nuclear magnetic resonance spectrum (400 MHz, DMSO-d 6 ) δppm: 8.99 (2H,m), 7.13-7.22 (4H,m), 5.19 (1H,s), 4.38 (1H,s), 3.13-3.26 (5H,m), 2.77 (1H,dd,J=16.5,3.2Hz), 2.07 (1H,d,J=14.0Hz), 1.82-1.99 (2H,m), 1.60 (d,J=14.0Hz) Infrared absorption spectrum ν max cm -1 (KBr): 3390, 2973, 2826, 1598. Mass spectrometric analysis (EI) m/z: 203 (M + )(free form) [Referential Example 4] N -t-Butoxycarbonyl-spiro[(3-indanone)-1,4'-piperidine] In 40 ml of methylene chloride, 2.00 g (6.59 mmol) of N-t-butoxycarbonyl-spiro[(3-hydroxy)indane)-1,4'-piperidine], prepared as described in Referential Example 2, were dissolved. To the resulting solution, 12.0 g of powdered molecular sieves 4A and 2.84 g (13.2 mmol) of pyridinium chlorochromate were added under ice cooling, followed by stirring for 30 minutes. The mixture was further stirred for 2 hours at room temperature. After the addition of 80 ml of diethyl ether to the reaction mixture, the resulting mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate = 75:25), whereby 1.98 g (99%) of the title compound were obtained as white crystals. Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.75 (1H,d,J=8.0Hz), 7.65 (1H,dd,J=8.0,8.0Hz), 7.49 (1H,d, J=8.0Hz), 7.42 (1H,dd,J=8.0,8.0Hz), 4.23 (2H,brs), 2.86 (2H,m), 2.64 (2H,s), 1.99 (2H,dt,J=13.2,4.4Hz), 1.50-1.53 (11H,m) Infrared absorption spectrum ν max cm -1 (CHCl 3 ): 2980, 2940, 1710, 1685, 1430 Mass spectrometric analysis (FAB) m/z: 301 (M + ) [Referential Example 5] Spiro [ (3-indanone)-1,4'-piperidine] hydrochloride In 20 ml of ethanol, 1.94 g (6.50 mmol) of N-t-butoxycarbonyl-spiro[(3-indanone)-1,4'-piperidine], prepared as described in Referential Example 4, were dissolved, followed by the dropwise addition of 17.0 ml (65.0 mmol) of 4N hydrogen chloride /dioxane for 5 minutes under ice cooling. After stirring for 30 minutes, the mixture was further stirred for 2 hours at room temperature. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was recrystallized from methanol/diethyl ether, whereby 1.46 g (94%) of the title compound were obtained as white crystals. Melting point: 227 - 228°C Nuclear magnetic resonance spectrum (400 MHz, DMSO-d 6 ) δppm: 9.07 (2H,brs), 7.78 (1H,dd,J=7.8,7.8Hz), 7.65 (1H,d,J=7.8Hz), 7.59 (1H,d,J=7.8Hz), 7.50 (1H,dd,J=7.8,7.8Hz), 3.34-3.37 (2H,m), 2.99-3.05 (2H,m), 2.76 (2H,s), 2.27 (2H,dt,J=13.8,4.1Hz), 1.64-1.68 (2H,m) Infrared absorption spectrum ν max cm -1 (KBr): 3030, 2703, 2500, 1690, 1610, 1470 Mass spectrometric analysis (EI) m/z: 201 (M + )(free form) [Referential Example 6] N-t-Butoxycarbonyl-spiro[((2S)-hydroxy)indane-1,4'-piperidine] To 0.42 ml (0.42 mmol) of a 1.0M toluene solution of (R)-2-methyl-CBS-oxazaborolidine, a tetrahydrofuran (8.3 ml) solution of 2.5 g (8.30 mmol) of N-t-butoxycarbonyl-spiro[(2-indanone)-1,4'-piperidine] and 4.2 ml of a 1M tetrahydrofuran solution of boranetetrahydrofuran complex were added, each at a rate of 1.0 ml/min. The resulting mixture was stirred at room temperature for 1 hour, followed by the addition of water under ice cooling. After extraction of the reaction mixture with ethyl acetate, the organic layer was washed with saturated NaCI solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1:1), whereby 2.51 g (yield: 100%, optical purity: 89% ee) of N-t-butoxycarbonyl-spiro[((2S)-hydroxy)indane-1,4'-piperidine] were obtained as white crystals. The resulting crystals were dissolved in 5.0 ml of ethyl acetate under heating in a water bath. After the addition of 150 ml of hexane, the resulting mixture was allowed to stand, whereby 1.9 g of white crystals were obtained. The same procedure was repeated again, whereby 1.52 g (yield: 61%, optical purity: 100% ee) of N-t-butoxycarbonyl-spiro[((2S)-hydroxy)indane-1,4'-piperidine] were obtained as white crystals. (Incidentally, the optical purity of the title compound was determined by subjecting the nitrobenzoyl derivative of the title compound, which is prepared as described in Referential Example 8, to high-performance liquid chromatography (HPLC).) Melting point: 106°C [α] D 24 +50.0° (c=1.0, methanol) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.28-7.18 (4H,m), 4.50 (1H,dd,J=4.9,1.9Hz), 4.07-3.83 (2H,m), 3.32 (1H,dd,J=16.7Hz,4.9Hz), 3.30-3.12 (2H,m), 2.86 (1H,dd,J=16.7Hz,1.9Hz), 2.08-1.99 (1H,m), 1.89-1.78 (1H,m), 1.49(9H,s), 1.64-1.42 (2H,m) Infrared absorption spectrum ν max cm -1 (KBr): 3349, 2934, 1698, 1425, 1367, 1168, 1162 Mass spectrometric analysis (FAB) m/z: 304 ([M+H] + ) Elemental analysis (% based on C 18 H 25 NO 3 ) Calculated C; 71.26 H; 8.31, N; 4.62 Found C; 70.99, H; 8.24, N; 4.68 [Referential Example 7] Spiro[((2S)-hydroxy)indane-1,4'-piperidine]hydrochloride In 12.4 ml of ethanol, 1.5 g (1.95 mmol) of N-t-butoxycarbonyl-spiro[((2S)-hydroxy)indane-1,4'-piperidine], prepared as described in Referential Example 6, were dissolved. To the resulting solution, 6.2 ml of 4N hydrogen chloride-1,4-dioxane were added under ice cooling, followed by stirring at room temperature for 5 hours. The solvent was then distilled off under reduced pressure. The residue was washed with ether, whereby 1.1 g (yield: 93%) of spiro[((2S)-hydroxy)indane-1,4'-piperidine] hydrochloride were obtained as white crystals. Melting point: 247°C [α] D 24 +46.2° (c=0.50, methanol) Nuclear magnetic resonance spectrum (400 MHz, DMSO) δppm: 8.98 (2H,m), 7.22-7.17 (4H,m), 5.20 (1H,d,J=5.0Hz), 4.40-4.37 (1H,m), 3.26-3.13 (5H,m), 2.77 (1H,dd,J=16.5 Hz,3.2 Hz), 2.07 (1H,d,J=14.0Hz), 1.99-1.82 (2H,m), 1.60 (1H,d,J=14.0Hz) Infrared absorption spectrum ν max cm -1 (KBr): 3413, 3269, 2937, 1607, 1431, 1074, 765 Mass spectrometric analysis (EI) m/z: 203 (M + free form) Elemental analysis (% based on C 13 H 17 NO·HCl) Calculated C; 65.13, H; 7.57, N; 5.84, Cl; 14.79 Found C; 64.89, H; 7.48, N; 5.82, Cl; 15.01 [Referential Example 8] N-t-Butoxycarbonyl-spiro[(2S)-(4-nitrobenzoyloxy)indane-1,4'-piperidine] In 2.0 ml of methylene chloride, 30.3 mg (0.1 mmol) of N-t-butoxycarbonyl-spiro[((2S)-hydroxy)indane-1,4'-piperidine], prepared as described in Referential Example 6, were dissolved. To the resulting solution, 0.042 ml (0.3 mmol) of triethylamine, 1.2 mg (0.01 mmol) of 4-dimethylaminopyridine and 28 mg (0.15 mmol) of 4-nitrobenzoyl chloride were added, followed by stirring at room temperature for 3 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2:1), whereby 42 mg (yield: 93%, optical purity: 100% ee) of N-t-butoxycarbonyl-spiro[(2S)-(4-nitrobenzoyloxy)indane-1,4'-piperidine] were obtained as white crystals. The optical purity of the compound was determined by HPLC analysis. Melting point: 75.6°C [α] D 24 +141.5° (c=1.18, chloroform) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 8.25 (2H,d,J=8.9Hz), 8.11 (2H,d,J=8.9Hz), 7.34-7.17 (4H,m), 5.83 (1H,d,J=5.3Hz), 4.11-3.84 (2H,m), 3.52 (1H,dd,J=17.4Hz,5.3Hz), 3.32-3.13 (1H,m), 3.04 (1H,d,J=17.4Hz), 3.02-2.92 (1H,m), 2.16-1.97 (2H,m), 1.73-1.58 (2H, m), 1.47 (9H, s) Infrared absorption spectrum ν max cm -1 (KBr): 2975, 1723, 1695, 1530, 1279, 1167 Mass spectrometric analysis (FAB) m/z: 452 ([M+H] + ) Elemental analysis (% based on C 25 H 28 N 2 O 6 ) Calculated C; 66.36, H; 6.24, N; 6.19, O; 21.21 Found C; 66.33, H; 6.37, N; 5.95 HPLC analysis: Column; Chiral Cel AD (product of Daicel Chemical Industries, Ltd., inner diameter: 4.6 mm, length: 250 mm) Eluent; hexane : 2-propanol = 50:50 Flow rate; 0.5 ml/min. Temperature; 40°C Detection; 254 nm Retention time; 17.1 min. [Referential Example 9] N -t-Butoxycarbonyl-spiro[((2R)-hydroxy)indane-1,4'-piperidine] Using 0.083 ml (0.083 mmol) of a 1.0M toluene solution of (S)-2-methyl-CBS-oxazaborazine and 0.5 g (1.66 mmol) of N-t-butoxycarbonyl-spiro[(2-indanone)-1,4'-piperidine], 215 mg (yield: 43%, optical purity: 100% ee) ofN-t-butoxycarbonyl-spiro[((2R)-hydroxy)-indane-1,4'-piperidine] were obtained as white crystals in a similar manner to that described in Referential example 6. (The optical purity of the title compound was determined by subjecting the nitrobenzoyl derivative of the title compound, which is prepared as described in Referential Example 10, to HPLC.) The melting point, Nuclear Magnetic Resonance spectrum, Infrared absorption spectrum and Mass spectrometric analysis of the resulting compound coincided with those of the (S)-form prepared in Referential Example 6. [α] D 24 -51.7° (c=1.0, methanol) Elemental analysis (% based on C 18 H 25 NO 3 ) Calculated C; 71.26, H; 8.31, N; 4.62 Found C; 71.09, H; 8.25, N; 4.68 [Referential Example 10] N -t-Butoxycarbonyl-spiro[(2R) - (4-nitrobenzoyloxy)indane-1,4'-piperidine] Using 30.3 mg (0.1 mmol) of N-t-butoxycarbonyl-spiro[((2R)-hydroxy)indane-1,4'-piperidine], prepared as described in Referential Example 9, 43 mg (yield: 95%, optical purity: 100% ee) of N-t-butoxycarbonyl-spiro[(2R)-(4-nirrobenzoyloxy)indane-1,4'-piperidine] were obtained as white crystals in a similar manner to that described in Referential Example 7. The optical purity of the compound was determined by HPLC analysis. The melting point, Nuclear Magnetic Resonance spectrum, Infrared absorption spectrum and Mass spectrometric analysis of the resulting compound coincided with those of the (S)-form prepared in Referential Example 7. [α] D 24 -139.9° (c=0.76, chloroform) Elemental analysis (% based on C 25 H 28 N 2 O 6 ·1/4H 2 O) Calculated C; 65.70, H; 6.29, N; 6.13 Found C; 65.97, H; 6.38, N; 6.01 HPLC analysis: Column; Chiral Cel AD (product of Daicel Chemical Industries, Ltd., inner diameter: 4.6 mm, length: 250 mm) Eluent; hexane: 2-propanol = 50:50 Flow rate; 0.5 ml/min. Temperature; 40°C Detection; 254 nm Retention time; 10.1 min. [Referential Example 11] N-t-Butoxycarbonyl-spiro[((2R,3S)-epoxy)indane-1,4'-piperidine] In 2.0 ml of methylene chloride, 100 mg (0.35 mmol) of N-t-butoxycarbonyl-spiro[1H-indene-1,4'-piperidine] were dissolved. To the resulting solution, 11.4 mg (0.018 mmol) of (S,S)-(+)-N,N'-bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexane-diaminomanganese (III) chloride were added, followed by the addition of 19 mg (0.11 mmol) of 4-phenylpyridine-N-oxide. The resulting mixture was stirred for 10 minutes. After the addition of 1.1 ml (0.7 mmol) of a 1.0M aqueous solution of sodium hypochlorite to the mixture, the resulting mixture was stirred for 2 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCI aqueous solution and then dried over anhydrous sodium sulfate. The solvent of the extract was distilled off under reduced pressure. The residue was subjected to preparative thin layer chromatography (developing agent; hexane : ethyl acetate = 2:1), whereby 53.6 mg (yield: 51%, optical purity: 91% ee) ofN-t-butoxycarbonyl-spiro[((2R,3S)-epoxy)indane-1,4'-piperidine] were obtained as white crystals. The optical purity of the compound was determined by HPLC analysis. Melting point: 149°C [α] D 25 +62.2° (c=1.0, methanol, 99% ee) Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δppm: 7.49 (1H,d,J=7.3Hz), 7.32-7.15 (3H,m), 4.28 (1H,d,J=2.9Hz), 4.11 (1H,d,J=2.9Hz), 4.30-4.03 (2H,m), 3.15 (2H,br.t,J=12.0Hz), 1.95-1.74 (3H,m), 1.51 (9H,s), 1.58-1.50 (1H,m) Infrared absorption spectrum ν max cm -1 (KBr): 2949, 1679, 1424, 1365, 1244, 1168, 765 Mass spectrometric analysis (EI) m/z: 301 (M + free form) Elemental analysis (% based on C 18 H 23 NO 3 ) Calculated C; 71.74, H; 7.69, N; 4.65 Found C; 71.62, H; 7.67, N; 4.59 HPLC analysis: Column; Chiral Cel AD (product of Daicel Chemical Industries, Ltd., inner diameter: 4.6 mm, length: 250 mm) Eluent; hexane: 2-propanol = 80:20 Flow rate: 0.5 ml/min. Temperature: 40°C Detection: 210 nm Retention time: 13.2 min. [Referential Example 12] N-t-Butoxycarbonyl-spiro[((2S)-hydroxy)indane-1,4'-piperidine] In 5.0 ml of 1,4-dioxane, 125 mg (0.415 mmol) of N-t-butoxycarbonyl-spiro[((2R,3S)-epoxy)indane-1,4'-piperidine] were dissolved. To the resulting solution, 151 mg (2.49 mmol) of ammonium formate and 10 mg of 5% palladium-carbon were added, followed by stirring at 80°C for 1 hour. To the reaction mixture, 120 mg of ammonium formate and 10 mg of 5% palladium-carbon were further added and the resulting mixture was stirred for one hour. After the reaction mixture was allowed to stand at room temperature, it was filtered. The solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane : ethyl acetate = 3:1), whereby 118 mg (yield: 94%) of N-t-butoxycarbonylspiro[((2S)-hydroxy)indane-1,4'-piperidine] were obtained as white crystals. The physical data of the title compound all coincided with those of the compound of Referential Example 6. [Referential Example 13] N -t-Butoxycarbonyl-spiro[((2S,3R) -epoxy)indane-1,4'-piperidine] Using 100 mg (0.35 mmol) ofN-t-butoxycarbonyl-spiro[1H-indene-1,4'-piperidine] and 11.4 mg (0.018 mmol) of (R,R)-(-)-N,N'-bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexane-diaminomanganese (III) chloride, 52.4 mg (yield: 50%, optical purity: 87% ee) ofN-t-butoxycarbonylspiro[((2S,3R)-epoxy)indane-1,4'-piperidine] were obtained as white crystals in a similar manner to that described in Referential Example 11. The optical purity of the compound was determined by HPLC analysis. The melting point, Nuclear Magnetic Resonance spectrum, Infrared absorption spectrum and Mass spectrometric analysis coincided with those of the (2R,3S) form prepared in Referential Example 11. [α] D 25 -63.5° (c=0.50, methanol, 99% ee) Elemental analysis (% based on C 18 H 23 NO 3 ·1/3 H 2 O) Calculated C; 70.33, H; 7.76, N; 4.56 Found C; 70.22, H; 7.79, N; 4.53 HPLC analysis: Column; Chiral Cel AD (product of Daicel Chemical Industries, Ltd., inner diameter: 4.6 mm, length:250 mm) Eluent; hexane : 2-propanol = 80:20 Flow rate; 0.5 ml/min. Temperature; 40°C Detection; 210 nm Retention time; 10.9 min. [Formulation example] Pharmaceutical formulations containing the compound (I) of the present invention, or an ester or another derivative thereof as an active ingredient are prepared as follows: [Formulation Example 1] Powder Powders can be obtained by mixing the compound of Example 1 (5 g), lactose (895 g) and corn starch (100 g) in a blender. [Formulation Example 2] Granules Granules can be prepared by mixing the compound of Example 2 (5 g), lactose (865 g) and low-substituted hydroxylpropylcellulose (100 g), adding 300g of a 10% aqueous solution of hydroxypropylcellulose to the mixture, kneading the mixture, granulating the kneaded mass using an extrusion granulator and then drying the granulated product. [Formulation Example 3] Capsules Capsules can be obtained by mixing the compound of Example 3 (5 g), lactose (115 g), corn starch (58 g) and magnesium stearate (2 g) in a V-shaped mixer and then filling the resulting mixture, in 180 mg portions, into No. 3 capsules. [Formulation Example 4] Tablets Tablets can be obtained by mixing the compound of Example 4 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) in a blender and then tableting the resulting mixture using a tableting machine. [Test example] [Test example 1] NK 1 receptor binding test (a) Preparation of Crude Pulmonary Membrane Specimens Crude pulmonary membrane specimens were prepared from the lungs of male Hartley guinea pigs. Namely, the animals were sacrificed by exsanguination from the abdominal aorta under chloroform anesthesia followed promptly by excision of lung and respiratory tract tissue. After perfusing the excised lungs in buffer (1) (50 mM Tris-HCl, pH 7.4), the lungs were sliced into thin sections and then homogenized in a buffer (2) (buffer (1) containing 120 mM sodium chloride and 5 mM potassium chloride) using a Polytron. The tissue mass was removed from the homogenate by passing through a Nylon mesh (50 µm) and separating by centrifugation (30,000 x g, 30 minutes, 4°C). The pellet was re-suspended in an ice-cooled Buffer (3) (Buffer (1) containing 10 mM EDTA and 300 mM potassium chloride) and after allowing to stand undisturbed for 60 minutes at 4°C, the resulting suspension was centrifuged and washed twice (30,000 x g, 15 minutes, 4°C). The crude membrane specimens were stored at -80°C until the time of use. (b) Receptor binding test 250 µl of crude pulmonary membrane specimen solution were added to 250 µl of a mixed solution of test drug and [ 3 H]-substance P (final concentration: 1 nM) (50 mM Tris-HCl, pH 7.4, 6 mM manganese chloride, 800 µg/ml BSA, 8 µg/ml chemostatin, 8 µg/ml leupeptin, 80 µg/ml bacitracin and 20 µg/ml phosphoramidone) followed by incubation for 30 minutes at room temperature. After the reaction, the membrane component was recovered on a GF/B glass fiber filter (Whatman) using an automatic filtration system (Brandel). Incidentally, the glass filter was pretreated for about 4 hours with 0.1% polyethyleneimine solution to minimize non-specific binding. The filter containing the membrane component was transferred to a mini plastic vial containing 4 ml of Picoflow and radioactivity was measured with a liquid scintillation counter (Beckman, LCS3500). [Experiment 2] NK 2 receptor binding test (a) Preparation of Crude Ileal Membrane Specimens Crude membrane specimens were prepared from the ileum of male Hartley guinea pigs. Namely, the animals were sacrificed by exsanguination from the abdominal aorta under chloroform anesthesia followed promptly by excision of the ileum. The excised ileum was separated into its contents, secretions and epithelium by scraping with a slide glass. After slicing into thin sections in buffer (1) (50 mM Tris-HCl, pH 7.4), it was homogenized in buffer (2) (buffer (1) containing 120 mM sodium chloride and 5 mM potassium chloride) using a Polytron. The tissue mass was removed from the homogenate by passing through a Nylon mesh (50 µm) and separating by centrifugation (30,000 x g, 30 minutes, 4°C). The pellet was re-suspended in an ice-cooled Buffer (3) (Buffer (1) containing 10 mM EDTA and 300 mM potassium chloride) and after allowing to stand undisturbed for 60 minutes at 4°C, the resulting suspension was centrifuged and washed twice (30,000 x g, 15 minutes, 4°C). The crude membrane specimens were stored at -80°C until the time of use. (b) Receptor binding test 250 ml of crude ileal membrane specimen solution was added to 250 ml of a mixed solution of test drug and [ 3 H]-SR-48968 (Amersham, final concentration: 1 nM) (50 mM Tris-HCl pH 7.4, 6 mM manganese chloride, 800 µg/ml BSA, 8 µg/ml chemostatin, 8 µg/ml leupeptin, 80 µg/ml bacitracin and 20 µg/ml phosphoramidone) followed by incubation for 30 minutes at room temperature. After the reaction, the membrane component was recovered on a GF/B glass fiber filter (Whatman) using an automatic filtration system (Brandel). Incidentally, the glass filter was pretreated for about 4 hours with 0.1% polyethyleneimine solution to minimize non-specific binding. The filter containing the membrane component was transferred to a mini plastic vial containing 4 ml of Picoflow and radioactivity was measured with a liquid scintillation counter (Beckman, LSC3500). [Experiment 3] Inhibitory Effect on Increased Vascular Permeability The inhibitory effect on increased vascular permeability induced by NK 1 receptor antagonist substance P (SP) was assessed based on the amount of leaked pigment obtained using normal guinea pigs (male Hartley guinea pigs, body weights: approx. 400 g). Increased vascular permeability was induced by sequential administration of pigment (Evans blue: 20 mg/kg) to guinea pigs anesthetized with pentobarbital (25 mg/kg, i.p.) followed immediately by intravenous injection of SP (1 µg/kg). After 15 minutes, the guinea pigs were sacrificed under chloroform anesthesia and the amount of pigment that had leaked into the major areas of the respiratory tract was measured according to the method of Harada (J. Pharm. Pharmacol 23 , 218 (1971)). A test compound was suspended in a 0.5% tragacanth suspension and the resulting suspension was orally administered one hour before induction by SP. The inhibitory effect was based on the amounts of the leaked pigment in the guinea pigs to which a test compound was administered. [Experiment 4] Inhibitory Effect on Respiratory Tract Contraction The inhibitory effect of a test drug on respiratory tract contraction induced by neurokinin A (NKA), which is an NK 2 receptor agonist, was assessed based on respiratory tract internal pressure in accordance with a variation of the method of Konzett-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195 , 71 (1940)) using normal guinea pigs (male Hartley guinea pigs, body weights: approx. 500 g). Namely, after implanting a respiratory tract cannula in the guinea pigs anesthetized with pentobarbital (30 mg/kg, i.p.) and administering gallamine (20 mg/kg, i.v.), the animals were immediately subjected to positive pressure breathing at 8 ml/kg and 60 cycles/minute (Ugo-Basile, 7025). Respiratory tract internal pressure during artificial respiration was amplified by means of a pressure transducer (Nippon Denko, TP-200T) installed in the side branch of the respiratory tract cannula, received (Nippon Denko, AP-601G) and recorded with a recorder (Nippon Denko, WT-685G). Five minutes after pretreatment with atropine (1 mg/kg, i.v.) and propranolol (1 mg/kg, i.v.), 4 µg/kg of NKA were intravenously administered to induce respiratory tract contraction. Respiratory tract internal pressure was then measured for 10 minutes. A test compound was prepared in a similar manner to that described in Experiment 3 and orally administered one hour before the induction by NKA. The inhibitory activity was determined by a comparison in the area of respiratory tract internal pressure between the group to which a test compound was administered and the non-administered group. [Experiment 5] NK 3 receptor binding test (a) Preparation of Crude Cerebral Membrane Specimens Crude membrane specimens were prepared from the brain of male Hartley guinea pigs. Namely, the animals were sacrificed by exsanguination from the abdominal aorta under chloroform anesthesia After perfusing with Buffer (1) (50 mM Tris-HCl, pH 7.4) from the right ventricle, the brain was enucleated immediately. The excised brain was homogenized in buffer (2) (buffer (1) containing 120 mM sodium chloride and 5 mM potassium chloride) using a Polytron. Tissue mass was removed from the homogenate by passing through a Nylon mesh (50 µm) and separating by centrifugation (30,000 x g, 30 minutes, 4°C). The pellet (membrane component) was suspended in an ice-cooled Buffer (3) (Buffer (1) containing 10 mM EDTA and 300 mM potassium chloride) and after allowing to stand undisturbed for 60 minutes at 4°C, the resulting suspension was centrifuged and washed twice (30,000 x g, 15 minutes, 4°C). This was suspended in Buffer (1) to prepare the crude membrane specimens. It was stored at -80°C until the time of use in the receptor binding test. (b) Receptor binding test A test tube to be used for the reaction was treated in advance with Buffer (1) containing 5 mg/ml of bovine serum albumin (BSA). To 100 µl of Buffer (1) containing [ 3 H]-senktide, 6mM of manganese chloride, 800 µg/ml of BSA, 8 µg/ml of chimostatin, 8 µg of leupeptin, 80 µg/ml of bacitracin and 20 µg/ml of phosphoramidone, 150 µl of Buffer (1) containing 400 µg/ml of BSA and a test compound were added. To the resulting mixture, 250 µl of the crude brain membrane specimen (adjusted to 1 mg/ml of a protein concentration) were added to start the reaction (at that time, the final concentration of the [ 3 H]-senktide in the reaction phase was 2.5 nM). After incubation at room temperature for 60 minutes, the membrane component was recovered on a GF/B glass fiber filter (Whatman) using an automatic filtration system (Brandel), which had been pre-treated with 0.1% polyethyleneimine for more than 4 hours, followed by washing three times with 5 ml of ice-cooled Buffer (4) (5 mM tris-hydrochloric acid containing 400 µg/ml of BSA and 0.01% of sodium dodecylsulfate, pH 7.4). The filter containing the membrane component was transferred to a mini plastic vial containing 4 ml of Picoflow and radioactivity was measured with a liquid scintillation counter (Aloka, LSC 3500). In order to determine the radioactivity due to non-specific binding of [ 3 H]-senktide (binding to sites other than the receptor, for example, the filter), the Experiment was carried out by adding an excess amount of senktide (final concentration: 10 µM), and the radioactivity was measured. The inhibitory ratio of senktide-receptor binding due to a test compound was calculated by the following equation. Inhibitory ratio (%) = [1-(C-A)/(B-A)] x 100 A: radioactivity due to nonspecific binding B: radioactivity in the test without the addition of a test compound C: radioactivity in the test with the addition of a test compound The compounds of the present invention exhibited, against all of NK 1 , NK 2 and NK 3 receptors, antagonistic activities superior to those of Compound A. [Industrial applicability] Since the spiropiperidine derivatives of the present invention exhibit excellent antagonistic activity against NK 1 , NK2 and NK 3 receptors, have less toxicity and superior pharmacokinetics, they are useful as a medicament, particularly as a preventive or remedy for asthma and/or bronchitis, rhinitis, allergies or urinary incontinence.

Claims: A compound represented by the following formula (I): wherein: R 1 and R 2 are the same or different and each represents an aryl group defined below which may optionally be substituted with 1 to 3 substituents selected from Substituent group A defined below, or a heteroaryl group defined below which may optionally be substituted with I to 3 substituents selected from Substituent group A defined below; A represents a methylene group, a carbonyl group or a sulfonyl group; B represents a single bond, a C 1-4 alkylene group or a C 2-4 alkenylene group; D represents an oxygen atom or a sulfur atom; E represents a C 1-4 alkylene or a C 2-4 alkenylene group; wherein, G represents a cyclopentane or cyclopentene ring which is substituted with a hydroxy group, and Ar represents an aryl ring defined below which is optionally substituted with 1 to 3 groups selected from Substituent Group A defined below or a heteroaryl ring defined below which is optionally substituted with 1 to 3 groups selected from Substituent Group A defined below; R 3 represents a lower alkyl group defined below; and n represents an integer from 1 to 3; or a pharmacologically acceptable salt, ester or amide thereof; Substituent Group A consists of halogen atoms, lower alkyl groups defined below, halogeno-lower alkyl groups defined below, lower alkoxy groups defined below, lower alkoxycarbonyl groups comprising carbonyl groups substituted with a lower alkoxy group defined below, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups defined below, lower aliphatic acylamino groups comprising amino groups susbstituted with a lower aliphatic acyl group defined below, amino groups and cyano groups; the aryl groups referred to in the definition of substituents R 1 and R 2 are (C 5-14 ) aromatic hydrocarbon groups which may optionally be fused with a (C 3-10 )cycloalkyl group; the heteroaryl groups referred to in the definition of substituents R 1 and R 2 are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 oxygen, sulfur and/or nitrogen atoms which may optionally be fused with another cyclic group; the lower alkyl groups referred to in the definition of substituent R 3 and Substituent Group A are straight or branched (C 1-6 )alkyl groups; the aryl rings which may optionally be substituted with 1 to 3 groups selected from Substituent Group A defined above which are referred to in the definition of substituent Ar are C 6-14 aromatic hydrocarbon rings; the heteroaryl rings which may optionally be substituted with 1 to 3 groups selected from Substituent Group A defined above which are referred to in the definition of substituent Ar are 5- to 7-membered aromatic heterocyclic rings containing 1 to 3 sulfur, oxygen and/or nitrogen atoms; the halogeno-lower alkyl groups referred to in the definition of Substituent Group A are lower alkyl groups as defined above which are substituted with 1 or more halogen atom; the lower alkoxy groups referred to in the definition of Substituent Group A and the lower alkoxy moiety of the lower alkoxycarbonyl groups referred to in the definition of Substituent Group A are lower alkyl groups as defined above which are attached to an oxygen atom; and the lower aliphatic acyl groups referred to in the definition of Substituent Group A and the lower aliphatic acyl moiety of the lower aliphatic acylamino groups referred to in the definition of Substituent Group A are C 2-7 aliphatic acyl groups. A compound according to claim 1, wherein R 1 represents an aryl group, a heteroaryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A as defined in claim 1, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to claim 1, wherein R 1 represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A 1 defined below, or a pharmacologically acceptable salt, ester or amide thereof; Substituent Group A 1 consists of lower alkyl groups, halogeno-lower alkyl groups and lower alkoxy groups as defined in claim 1. A compound according to any one of claims 1 to 3, wherein R 2 represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A as defined in claim 1, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 3, wherein R 2 represents an aryl group substituted with at least one group selected from Substituent Group A as defined in claim 1, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 5, wherein A represents a carbonyl group, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 6, wherein B represents a single bond, or a pharmacologically acceptable salt, ester or amide thereof A compound according to any one of claims 1 to 7, wherein D represents an oxygen atom, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 8, wherein E represents a C 1-4 alkylene group, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 8, wherein E represents a C 2-3 alkylene group, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 10, wherein n represents 1 or 2, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to any one of claims 1 to 10, wherein n represents 2, or a pharmacologically acceptable salt, ester or amide thereof. A compound according to claim 1, which is selected from the group consisting of the following compounds: 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine], 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], 1- (2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4'-piperidine], and 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl} spiro[(3-hydroxy)indane-1,4'-piperidine], or a pharmacologically acceptable salt, ester or amide thereof. A compound according to claim 1, which is selected from the group consisting of the following compounds: 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spire[(2-hydroxy)indane-1,4'-piperidine] and 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4'-piperidine], or a pharmacologically acceptable salt, ester or amide thereof. A medicine comprising a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof as an effective ingredient. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for use in the prevention or treatment of asthma and/or bronchitis. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for use in the prevention or treatment of rhinitis. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for use in the prevention or treatment of allergic diseases. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for use in the prevention or treatment of urinary incontinence. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for use in the prevention or treatment of respiratory diseases. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for use in the prevention or treatment of inflammatory bowel disease. Use of a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for manufacturing a preventive or therapeutic agent for asthma and/or bronchitis. Use of a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for manufacturing a preventive or therapeutic agent for rhinitis. Use of a compound according to one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for manufacturing a preventive or therapeutic agent for allergic diseases. Use of a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for manufacturing a preventive or therapeutic agent for urinary incontinence. Use of a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for manufacturing a preventive or therapeutic agent for respiratory diseases. Use of a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt, ester or amide thereof for manufacturing a preventive or therapeutic agent for inflammatory bowel disease.

Inventors: IIO YUKIKO, NAKAJIMA KATSUYOSHI, NISHI TAKAHIDE, TAKEMOTO TOSHIYASU, YAMAGUCHI TAKESHI, IIO, YUKIKO, NAKAJIMA, KATSUYOSHI, NISHI, TAKAHIDE, TAKEMOTO, TOSHIYASU, YAMAGUCHI, TAKESHI
Applicants: SANKYO CO, SANKYO COMPANY LIMITED
Application year: 1999
Main classification: C07D413
IPC codes: C07D413, A61P11