MXPA06009656A - Indanol derivative - Google Patents

Abstract

A compound represented by the following general formula (I) is described (see formula (I)) which is useful as a neurokinin receptor antagonist; [in the above formula, R1 and R2 respectively represent an optionally substituted (hetero) aryl group; R 3 represents -CO-R 4, -CO-O-R 4 or the like, R 4 represents an alkyl group, cycloalkyl group or the like, A represents CH 2, CO or SO 2 B represents a single bond or the like, D represents an oxygen atom or CH 2; E represents an alkylene group or alkenylene group, and n represents an integer of 1-3

Description

DERIVED FROM INDANOL TECHNICAL FIELD The present invention relates to novel indanol derivatives having antagonistic activity against tachykinin receptors (NK-i, NK2 and NK3).

TECHNICAL BACKGROUND The patent of E.U.A. No. 6511975 describes indanol derivatives having antagonistic activity against NK receptors NK2 receptors and NK3 receptors. The present invention differs from the compounds of the prior art in that the hydroxyl group of indanol is substituted and there is no known prior art that motivates the introduction of this substituent (the group corresponding to R3 in the general formula (I) to be more fully described). forward) in a compound described in the US patent No. 6511975.

DESCRIPTION OF THE INVENTION As a result of conducting extensive studies over the course of many years of neurokinin receptor antagonists, the inventors of the present invention found compounds that have antagonistic activity against all NKi, NK2 and NK3 receptors, and demonstrate continuous pharmacological effects, leading to this way to complete the present invention. Moreover, another object of the present invention is to provide a novel pharmaceutical composition having a above-mentioned compound as an active ingredient thereof, and examples of diseases in which this pharmaceutical compound can be applied include diseases of the central nervous system including anxiety , depression, mental illness and schizophrenia; neurodegenerative diseases including dementia associated with AIDS, senile dementia of the Alzheimer's type, Alzheimer's disease, Down syndrome, de-diffusing disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases including chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchial constriction, asthma and cough; inflammatory diseases including inflammatory bowel disease (IBD), psoriasis, fibrositis, osteoarthritis, degenerative arthritis and rheumatoid arthritis; eczema; allergic diseases including rhinitis; hypersensitivity diseases including hypersensitivity diseases to vine plants; ophthalmological diseases including conjunctivitis, vernal conjunctivitis, vernal catarrh, destruction of the blood-aqueous barrier that accompanies various inflammatory eye diseases, increased intraocular pressure and miosis; skin diseases including contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis; addictions including alcoholism; somatic diseases induced by stress; sympathetic reflex dystrophy including shoulder-hand syndrome; dysthymia; diseases related to undesirable immune reactions including transplant rejection and immunoincrement or immunosuppression including systemic lupus erythematosus; diseases of digestive organs including diseases caused by abnormalities in nerves that regulate internal organs, colitis, ulcerative colitis, irritable bowel syndrome and Crohn's disease; emesis including that induced by X-ray irradiation and chemotherapeutic agents, poisons, toxins, pregnancy, vestibular disorders, post-operative disease, gastrointestinal obstruction, gastrointestinal dysmotility, visceralgia, migraine headache, increased intracranial pressure, decreased intracranial pressure or adverse side effects that accompany the administration of various pharmaceutical compounds; diseases of urinary bladder function including cystitis and incontinence, urinary; eosinophilia caused by collagen, scleroderma, or hepatic fasciola infection; diseases caused by abnormalities of the bloodstream due to vascular dilation or vascular constriction including angina pectoris, migraine headache and Raynaud's syndrome; pain associated with reception of pain penetration including migraine headache, headache and toothache; and, sleep apnea syndrome. A novel pharmaceutical composition of the present invention can be used as a prophylactic or therapeutic for respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disease; allergic diseases such as rhinitis; and / or urinary incontinence in particular. The present invention relates to: (1) a compound represented by the general formula (I): (wherein, R1 and R2 may be the same or different and each represents an aryl group, heteroaryl group, aryl group substituted with 1 to 3 groups selected from the substituent group a, or heteroaryl group substituted with 1 to 3 groups selected from the group substituent a; R3 represents any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N (R3) Rb, - (CH2) m-CO-R5 , - (CH2) mR.-CO-NH-CO-N (Ra) Rb, -CO-NH-SO2-N (Ra) R, -CO-NH-CO- (CH2) mN (Ra) Rb, and -CO-NH2; R4 represents a lower alkyl group, cycloalkyl group, cycloalkyl group substituted with 1 to 3 groups selected from the substituent group a, lower alkenyl group, lower alkynyl group, lower halogenoalkyl group, lower hydroxyalkyl group, lower alkoxyalkyl group, acyloxyalkyl lower group or lower alkoxycarbonyl group, R5 represents a hydroxyl group, a group -OR4, or a group -N (Ra) Rb; Ra and Rb may be the same or different and each represents an atom of hydrogen, hydroxyl group, lower alkoxy group, hydroxy-lower alkoxy group, hydroxy-lower alkoxyalkyl group, lower alkoxy-lower alkoxyalkyl group, cyano-lower alkyl group, cyano-alkoxyalkyl group Lower, carboxy-lower alkyl, carboxy-lower alkoxyalkyl group, lower alkoxycarbonyl-lower alkoxyalkyl group, carbamoyl-lower alkyl group, carbamoyl-lower alkoxyalkyl group, lower aliphatic acylamino-lower alkyl group, lower aliphatic acylamino-lower alkoxyalkyl group , lower alkylsulfonylamino-lower alkyl group, lower alkylsulfonylamino-lower alkoxyalkyl group, (N-hydroxy-N-methylcarbamoyl) -lower alkyl group, (N-hydroxy-N-methylcarbamoyl) -alkoxyalkyl lower group, (N-alkoxy) group -N-methylcarbamoyl) -lower alkyl, lower (N-alkoxy-N-methylcarbamoyl) -alkoxyalkyl or R 4 group, or together, including the nitrogen atom to which they are attached, represent a heterocyclic group containing nitrogen or heterocyclic group containing nitrogen substituted with 1 to 3 groups selected from the substituent group a; m represents an integer from 1 to 6; A represents a methylene group, carbonyl group or sulfonyl group; B represents a single bond, alkylene group of C -? - C4 or alkenylene group of C2-C4; D represents an oxygen atom or methylene group; E represents an alkylene group of C? -C or an alkenylene group of C2-C4; n represents an integer from 1 to 3; and the substituent group a represents a group of substituents consisting of halogen atoms; lower alkyl groups; lower hydroxy-lower alkyl groups, halogeno-lower alkyl groups, carboxy-lower alkyl groups, lower alkoxy groups, lower hydroxy-lower alkoxy groups; hydroxy-lower alkoxyalkyl groups; lower alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups, lower aliphatic acylamino groups; groups (N-hydroxy-N-methylcarbamoyl) -lower alkyl; groups (N-lower alkoxy-N-methylcarbamoyl) -lower alkyl, lower aliphatic hydroxy-acylamino groups, amino groups, carbamoyl groups, and cyano groups), or a pharmacologically acceptable salt thereof. Preferred compounds among the aforementioned compounds include: (2) a compound, wherein R1 is an aryl group or an aryl group substituted with 1 to 3 groups selected from the substituent group a, (3) a compound, wherein R1 is phenyl or phenyl substituted with 1 to 3 groups selected from the substituent group a, (4) a compound, wherein R 1 is phenyl or phenyl substituted with 1 to 3 groups selected from the group consisting of lower halogenoalkyl groups, lower alkoxy groups and lower groups hydroxy (5) a compound, wherein R 1 is phenyl substituted with 1 to 3 groups selected from the group consisting of lower halogenoalkyl groups and lower alkoxy groups, (6) a compound, wherein R 1 is 3,5-bis (trifluoromethyl) ) phenyl or 3,4,5-trimethoxyphenyl, (7) a compound, wherein R 2 is an aryl group substituted with 1 to 3 groups selected from the substituent group a, (8) a compound, wherein R 2 is a substituted phenyl group with 1 or 2 halogen atoms, (9) a compound, wherein R 2 is 3,4-difluorophenyl or 3,4-dichlorophenyl, (10) a compound, wherein A is a methylene group or carbonyl group, (11) a compound, wherein A is a carbonyl group, (12) a compound, wherein B is a single bond or alkylene group of C C4, (13) a compound, wherein B is a single bond, (14) a compound, wherein D is an oxygen atom or methylene group, (15) a compound, wherein E is an alkylene group of C1-C, (16) a compound, wherein E is ethylene or trimethylene, (17) a compound, wherein n is 1 or 2, (18) a compound, wherein n is 2, (19) a compound, wherein R3 is - (CH2) m-CO-R5, (20) a compound, wherein R3 is -CH2-CO-N (Ra) Rb, (21) a compound, wherein one of Ra and Rb represents a hydrogen atom, lower alkyl group, hydroxyl group or lower alkoxy group and the other represents a lower hydroxyalkyl group, lower hydroxy-alkoxyalkyl group, carboxy-lower alkyl group, g carboxy-lower alkoxyalkyl group, lower alkoxycarbonyl group-lower alkyl or lower alkoxycarbonyl group-lower alkoxyalkyl, or Ra and Rb together, including the nitrogen atom to which they are attached, form a heterocyclic group containing nitrogen or heterocyclic group containing substituted nitrogen with 1 to 3 groups selected from the substituent group a, and (22) a compound, wherein -N (Ra) Rb is N- (3-hydroxypropyl) -N-methylamino, N- (4-hydroxybutyl) -N-methylamino , N- (5-hydroxy-ethyl) -N-methylamino, N- (6-hydroxyhexyl) -N-methylamino, N- [2- (2-hydroxyethoxy) ethyl] -N-methylamino, N- (2 -hydroxyethyl) -N-methoxyamino, N- (3-carboxypropyl) -N-methylamino, 2- (3-hydroxypropyl) pyrrolidino, 4-hydroxymethylpiperidino, 4- (2-hydroxyethyl) piperidino, 4- (3-hydroxypropyl) ) piperidino, 4- (2-hydroxyethoxy) piperidino, 4- (hydroxyacetamido) piperidino, 4- (2-hydroxyethoxymethyl) piperidino or 4- (2-hydroxyethyl) piperazino, or a salt pharmacologically acceptable thereof. The present invention also relates to a pharmaceutical composition containing, as an active ingredient thereof, a pharmacologically acceptable compound or salt thereof as described in any of the aforementioned (1) to (22) (and particularly a composition Pharmaceutical for the treatment or prophylaxis of diseases mediated by NK-i, NK2 and / or NK3 receptors, a pharmaceutical composition for the prophylaxis or treatment of respiratory diseases, allergic diseases and / or urinary incontinence and, a pharmaceutical composition for the prophylaxis or treatment of asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence), and particularly to a pharmaceutical composition containing, as an active ingredient thereof, a pharmacologically acceptable compound or salt thereof as described in any of the above mentioned (1) to (22) for pulmonary administration for prophylaxis or treatment of respiratory diseases (particularly, asthma, bronchitis and / or chronic obstructive pulmonary disease). Furthermore, the present invention further relates to the use, as an active ingredient, of a compound or pharmacologically acceptable salt thereof as described in any of the aforementioned (1) to (22) to produce a pharmaceutical composition (particularly, A pharmaceutical composition for the treatment or prophylaxis of diseases mediated by NKi, NK2 and / or NK3 receptors, a pharmaceutical composition for the prophylaxis or treatment of respiratory diseases, allergic diseases and / or urinary incontinence, and a pharmaceutical composition for the prophylaxis or treatment of asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence), and particularly to the use, as an active ingredient, of a pharmacologically acceptable compound or salt thereof as described in any of the aforementioned (1) a (22) to produce a pharmaceutical composition for pulmonary administration for prophylaxis or treatment of respiratory diseases (particularly, asthma, bronchitis and / or chronic obstructive pulmonary disease). Moreover, the present invention furthermore relates to a method for preventing or treating diseases mediated by NKi, NK2 and / or NK3 receptors (particularly respiratory diseases, allergic diseases and / or urinary incontinence).; and asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence) by administering an effective amount of a compound or pharmacologically acceptable salt thereof as described in any of the aforementioned (1) to (22) to mammals ( particularly human), and particularly to a method for preventing or treating respiratory diseases (particularly asthma, bronchitis and / or chronic obstructive pulmonary disease) by administering an effective amount of a pharmacologically acceptable compound or salt thereof described in any of the aforementioned ( 1) to (22) to mammals (particularly humans). In the general formula (I) mentioned above, the "aryl group" and the aryl group of the "aryl group substituted with 1 to 3 groups selected from the substituent group a" in the definitions R1 and R2 means an aryl group of CQ-C10, and they are preferably phenyl, 1-naphthyl or 2-naphthyl, and in particular preferably phenyl. In addition, the aforementioned "C6-C10 aryl group" may be fused with an acycloalkyl group of C3-C ?O (preferably an acycloalkyl group of C5-C6). In the case where R1 is an "aryl group substituted with 1 to 3 groups selected from the substituent group a", it is preferably a phenyl group substituted with 1 to 3 groups selected from hydroxyl, methyl, ethyl, methoxy, ethoxy, difluoromethyl and trifluoromethyl, most preferably a phenyl group substituted with 1 to 3 groups selected from hydroxyl, methoxy and trifluoromethyl groups, and in particular preferably 3,4,5-trimethoxyphenyl or 3,5-bis (trifluoromethyl) phenyl. In the case where R2 is an "aryl group substituted with 1 to 3 groups selected from the substituent group a", it is preferably a phenyl group substituted with 1 to 3 groups selected from fluorine, chlorine, bromine and iodine atoms, most preferably group phenyl substituted with 1 or 2 groups selected from fluorine and chlorine atoms, most preferably still 3,4-difluorophenyl or 3,4-dichlorophenyl, and in particular preferably 3,4-dichlorophenyl. The "heteroaryl group" and the heteroaryl group of the "heteroaryl group substituted with 1 to 3 groups selected from the substituent group a" in the definitions of R1 and R2 means a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, examples of which include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and azepinyl groups, preferably a 5-6 membered heteroaryl group containing 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms such as a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl group , pyrimidinyl or pyrazinyl, and most preferably a pyridyl or pyrimidinyl group. In addition, the aforementioned "heteroaryl group" can be fused with another cyclic group [such as a C6-C? Ar ar aryl (preferably phenyl) or a C3-C10 cycloalkyl group (preferably C5-C6 cycloalkyl)], and examples of said groups include indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinazolinyl, tetrahydroquinolyl and tetrahydroisoquinol groups.

The "lower alkyl group" in the definitions of R 4 and substituent groups a means a straight or branched C 1 -C 6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1, 1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl or 3, 3-dimethylbutyl, and most preferably methyl, ethyl, propyl or isopropyl. The "cycloalkyl group" and the cycloalkyl group of "cycloalkyl group substituted with 1 to 3 groups selected from the substituent group a" in the definition of R4 means a C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably a C5-C6 cycloalkyl group, and most preferably cyclopentyl or cyclohexyl. The "lower alkenyl group" in the definition of R4 means a linear or branched C2-C6 alkenyl group, and is preferably vinyl or allyl. The "lower alkynyl group" in the definition of R4 means a linear or branched C2-C6 alkynyl group, and is preferably acetylenyl or propalgyl. The "halogeno-lower alkyl group" in the definitions of R4 and substituent group a means a group in which the "lower alkyl group" mentioned above is substituted with a halogen atom, examples of which include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl and 2-dibromoethyl . It is most preferably 2-fluoromethyl, 2-chloroethyl or 2-4 bromoethyl for R4. It is in particular preferably trifluoromethyl for the substituent group a. The "lower hydroxy alkyl group" in the definitions R4 and substituent group a means a group in which the "lower alkyl group" mentioned above is substituted with a hydroxyl group, examples of which include hydroxymethyl, 2-hydroxyethyl, , 3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl, preferably hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, and most preferably hydroxymethyl or 2-hydroxyethyl. The "lower alkoxy group" in the definitions of Ra, Rb and substituent group a; the lower alkyl portion of the "lower alkoxyalkyl group" and the "lower alkoxycarbonylalkyl group" in the definition of R4, and the lower alkoxy portion of the "lower alkoxycarbonyl group" in the definition of substituent group a means a group in which the "lower alkyl group" mentioned above is bonded to an oxygen atom, examples of which include a C6-C6 alkoxy group such as a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s- group 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 or 2,3-dimethylbutoxy, preferably a C 6 -alkoxy group, and most preferably methoxy or ethoxy group. The "lower alkoxyalkyl group" in the definition of R4 means a group in which the "lower alkyl group" mentioned above is substituted with the "lower alkoxy group" mentioned above, and is preferably a CC alkoxyalkyl group such as methoxymethyl , 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 2-ethoxyethyl or propoxymethyl, most preferably methoxymethyl, 2-methoxyethyl, ethoxymethyl or 2-ethoxyethyl, and most preferably still methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl. The "lower aliphatic acyl group" in the definition of substituent group a; the lower aliphatic acyl portion of the "lower acyloxyalkyl group" in the definition of R4; the lower aliphatic acyl portion of the "lower aliphatic acylamino-lower alkyl group" and the "lower aliphatic acylamine-lower alkoxyalkyl group" in the definitions of Ra and Rb, and the lower aliphatic acyl portion of the "lower aliphatic acylamino group" in the definition of substituent group a means an aliphatic acyl group of C -? - C6l examples of which include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl and isovaleryl, preferably formyl, acetyl or propionyl, and in particular preferably acetyl . The "lower aliphatic acyloxyalkyl group" in the definition of R4 means a group in which the above-mentioned "lower alkyl group" is substituted with C- | -C6 aliphatic acyloxy (such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, pivaloyloxy, valeryloxy or isovaleryloxy), preferably is an aliphatic C2-C6 acyloxyalkyl group, most preferably formyloxymethyl, 2-formyloxyethyl, acetyloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl or propionyloxymethyl, most preferably still an acetyloxymethyl, 2-acetyloxyethyl group or 3-acetyloxypropyl, and in particular preferably an acetyloxymethyl group. The "lower alkoxycarbonyl group" in the definition of substituent group a, the lower alkoxycarbonyl portion of the "lower alkoxycarbonyl group" in the definition of R 4, and the lower alkoxycarbonyl portion of the "lower alkoxycarbonyl group-lower alkoxyalkyl" in the definition of Ra and Rb means a group in which the "lower alkoxy group" mentioned above is bonded to a carbonyl group, and preferably is a C2-C5 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, tert-butoxycarbonyl or isobutoxycarbonyl. The "lower alkoxycarbonylalkyl group" in the definition of R 4 signifies a group in which the aforementioned "lower alkyl group" is substituted with the "lower alkoxycarbonyl group" mentioned above, preferably it is a C3-Cg-akoxycarbonylalkyl group, most preferably a C3-C-alkoxycarbonylalkyl group such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, ethoxylcarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, propoxycarbonylmethyl, 2-propoxycarbonylethyl or 3-propoxycarbonylpropyl, most preferably still a substituted CC alkyl group with ethoxycarbonyl, and in particular preferably ethoxycarbonylmethyl, 2-ethoxycarbonylethyl or 3-ethoxycarbonylpropyl. The "hydroxy-lower alkoxy group" in the definitions of Ra, Rb and substituent group a means a group in which the aforementioned "lower alkoxy group" is substituted with a hydroxyl group, examples of which include hydroxymethoxy, 2-hydroxyethoxy , 2,3-dihydroxypropoxy, 3-hydroxypropoxy, 3,4-dihydroxybutoxy and 4-hydroxybutoxy, preferably it is hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy or 4-hydroxybutoxy, and most preferably 2-hydroxyethoxy or 3-hydroxypropoxy. The "hydroxy-lower alkoxyalkyl group" in the definitions of Ra, Rb and substituent group a means a group in which the above-mentioned "lower alkoxyalkyl group" is substituted with a hydroxyl group, preferably it is a hydroxyalkyl group of C3-Cg, most preferably a hydroxyalkyl group of C3-C7 such as hydroxymethoxymethyl, - (hydroxymethoxy) ethyl, 3- (hydroxymethoxy) propyl, 2-hydroxyethoxymethyl, 2- (2-hydroxyethoxy) ethyl, 3- (2-hydroxyethoxy) propyl, 3-hydroxypropoxymethyl, 2- (3-hydroxypropoxy) ethyl or 3- (3-hydroxypropoxy) propyl, very preferably still a CC alkyl group substituted with 2-hydroxyethoxy, in particular preferably 2-hydroxyethoxymethyl, 2- (2-hydroxyethoxy) ethyl or 3- (2-hydroxyethoxy) propyl, and most preferably still 2- (2-hydroxyethoxy) ethyl. The "lower alkoxy lower alkoxyalkyl group" in the definitions of Ra and Rb means a group in which the aforementioned "lower alkoxyalkyl group" is substituted with a lower alkoxy group, preferably is an alkoxy group of C -? - C- C3-C9 alkoxyalkyl, most preferably C C-C2-alkoxy-C3-C alkoxy group, in particular preferably 2-methoxyethoxymethyl or 2- (2-methoxyethoxy) ethyl, and very preferably still 2- (2-methoxyethoxy) ethyl. The "cyano-lower alkyl group" in the definitions of Ra and Rb means a group in which the aforementioned "lower alkyl group" is substituted with a cyano group, examples of which include cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and 4-cyanobutyl, and preferably is 2-cyanoethyl or 3-cyanopropyl. The "cyano-lower alkoxyalkyl group" in the definitions of Ra and Rb means a group in which the above-mentioned "lower alkoxyalkyl group" is substituted with a cyano group, preferably it is a cyano-alkoxyalkyl group of C3-Cg, most preferably a cyano-alkoxyalkyl group of C3-C4, particularly preferably -cyanoethoxymethyl or 2- (2-cyanoethoxy) ethyl, and most preferably still 2- (2-cyanoethoxy) ethyl. The "carboxyl-lower alkyl group" in the definitions of Ra, Rb and substituent group a means a group in which the "lower alkyl group" mentioned above is substituted with a carboxy group, examples of which include carboxymethyl, 2- carboxyethyl, 3-carboxypropyl and 4-carboxybutyl, and preferably is 2-carboxyethyl or 3-carboxypropyl. The "lower carboxy-alkoxyalkyl group" in the definitions of Ra, Rb and substituent group a means a group in which the aforementioned "lower alkoxyalkyl group" is substituted with a carboxy group, preferably is a carboxy-alkoxyalkyl group of C3- Cg, most preferably a carboxy-alkoxyalkyl group of C3-C, in particular preferably 2-carboxyethoxymethyl or 2- (2-carboxyethoxy) ethyl; and most preferably still 2- (2-carboxyethoxy) ethyl. The "lower alkoxycarbonyl lower alkoxyalkyl group" in the definitions of Ra and Rb means a group in which the aforementioned "lower alkoxyalkyl group" is substituted with a lower alkoxycarbonyl group, preferably it is a methoxycarbonyl-alkoxyalkyl group of C3- Cg, most preferably a C3-C4 methoxycarbonyl-alkoxyalkyl group, in particular preferably 2-methoxycarbonylethoxymethyl or 2- (2-methoxycarbonylethoxy) ethyl, and most preferably still 2- (2-methoxycarbonylethoxy) ethyl. The "carbamoyl-lower alkyl group" in the definitions of Ra and Rb means a group in which the aforementioned "lower alkyl group" is substituted with a carbamoyl group, examples of which include carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl and 4-carbamoylbutyl, and preferably is 2-carbamoylethyl or 3- carbamoylpropyl. The "lower carbamoyl-alkoxyalkyl group" in the definitions of Ra and Rb means a group in which the above-mentioned "lower alkoxyalkyl group" is substituted with a carbamoyl group, preferably it is a C3-C9 carbamoyl-alkoxyalkyl group, very preferably a C3-C4 carbamoyl-alkoxyalkyl group, particularly preferably 2-carbamoylethoxymethyl or 2- (2-carbamoylethoxy) ethyl, and most preferably still 2- (2-carbamoylethoxy) ethyl. The "lower aliphatic acylamino group" in the definition of substituent group a and the lower aliphatic acylamino portion of the "lower aliphatic acylamino-lower alkyl group" and "lower aliphatic acylamino-lower alkoxyalkyl group" in the definitions of Ra and Rb means an amino group substituted with the aforementioned "lower aliphatic acyl group", examples of which include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, pivaloylamino, valerylamino and isovalerylamino, preferably is formylamino, acetylamino or propionylamino, and in particular preferably acetylamino. The "lower aliphatic acylamino-lower alkyl group" in the definitions of Ra and Rb means a group in which the aforementioned "lower alkyl group" is substituted with the aforementioned "lower aliphatic acylamino group", particularly preferably it is a group C? -C alkyl substituted with acetylamino, and most preferably still 2-acetylaminoethyl, 3-acetylaminopropyl or 4-acetylaminobutyl. The "lower aliphatic acylamino-lower alkoxyalkyl group" in the definitions of Ra and Rb means a group in which the "lower alkoxyalkyl group" mentioned above is substituted with a lower aliphatic acylamino group, preferably is an acetylamino-alkoxyalkyl group of C3 -C8, most preferably an acetylamino-alkoxyalkyl group of C3-C, in particular preferably 2-acetylaminoethoxymethyl or 2- (2-acetylaminoethoxy) ethyl, and most preferably still 2- (2-acetylaminoethoxy) ethyl. The "lower alkylsulfonylamino-lower alkyl group" in the definitions of Ra and Rb is preferably an alkyl group of C- | -C2-SO2NH-C- | -C4 alkyl, most preferably a substituted C-? -C4 alkyl group with methylsulfonylamino, and most preferably still 2-methylsulfonylaminoethyl, 3-methylsulfonylaminopropyl or 4-methylsulfonylaminobutyl. The "lower alkylsulfonylamine group-lower alkoxyalkyl" in the definitions of Ra and Rb is preferably a C 1 -C 2 alkyl group-SO 2 NH-C 3 -C 8 alkoxyalkyl, most preferably a C 3 -C 4 methylsulfonylamine-alkoxyalkyl group, particularly preferably 2- methylsulfonylaminoethoxymethyl or 2- (2-methylsulfonylaminoethoxy) ethyl, and most preferably still 2- (2-methylsulfonylaminoethoxy) ethyl. The "(N-hydroxy-N-methylcarbamoyl) -lower alkyl" group in the definitions of Ra, Rb and substituent group a is preferably a CC alkyl group substituted with N-hydroxy-N-methylcarbamoyl, and most preferably still 2- (N-hydroxy-N-methylcarbamoyl) ethyl, 3- (N-hydroxy-N-methylcarbamoyl) propyl or 4- (N-hydroxy-N-methylcarbamoyl) butyl. The "(N-hydroxy-N-methylcarbamoyl) -alkoxyalkyl group" in the definitions of Ra and Rb is preferably a C3-Cg alkoxyalkyl group substituted with N-hydroxy-N-methylcarbamoyl, most preferably an alkoxyalkyl group of C3- C substituted with N-hydroxy-N-methylcarbamoyl, in particular preferably 2- (N-hydroxy-N-methylcarbamoyl) ethoxymethyl or 2- [2- (N-hydroxy-N-methylcarbamoyl) ethoxy] ethyl, and very preferably still 2 - [2- (N-hydroxy-N-methylcarbamoyl) ethoxy] ethyl. The "lower (lower N-alkoxy-N-methylcarbamoyl) -alkyl" group in the definitions of Ra, Rb and substituent group a is preferably a N- (C1-C2 alkoxy) -N-methylcarbamoyl-alkyl group. of C -C4, most preferably a CC alkyl group substituted with N-methoxy-N-methylcarbamoyl, and most preferably 2- (N-methoxy-N-methylcarbamoyl) ethyl, 3- (N-methoxy-N-methylcarbamoyl) propyl or 4- (N-methoxy-N-methylcarbamoyl) butyl.

The "lower (N-alkoxy-N-methylcarbamoyl) -alkoxyalkyl group" in the definitions of Ra and Rb is preferably an N- (C? -C2) alkoxy-N-methylcarbamoyl-C3-C9 alkoxy group, very preferably a C3-C4 alkoxyalkyl group substituted with N-methoxy-N-methylcarbamoyl, in particular preferably 2- (N-methoxy-N-methylcarbamoyl) ethoxymethyl or 2- [2- (N-methoxy-N-methylcarbamoyl) ethoxy] ethyl, and most preferably 2- [2- (N-methoxy-N-methylcarbamoyl) ethoxy] ethyl. The "nitrogen-containing heterocyclic group" and the nitrogen-containing heterocyclic group of the "nitrogen-containing heterocyclic group substituted with 1 to 3 groups selected from the substituent group a", which are formed by Ra and Rb, together with the nitrogen atom at which are attached, is a 4- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or sulfur atom, preferably a 4- to 6-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or sulfur atom, most preferably azetidino, pyrrolidino, imidazolidino, 1-pyrazolidinyl, piperidino, 4-oxopiperidino, piperazino, 3-oxopiperazino, morpholino or thiomorpholino, in particular preferably azetidino, pyrrolidino , piperidino, 4-oxopiperidino, piperazino, 3-oxopiperazino, morpholino or thiomorpholino, and most preferably pyrrolidino, piperidi no or piperazino. In the case of Ra and Rb, together with the nitrogen atom to which they are attached, forming a "heterocyclic group containing nitrogen substituted with 1 to 3 groups selected from the substituent group a", said group is preferably a heterocyclic group containing nitrogen substituted with a group selected from the substituent group, most preferably a nitrogen-containing heterocyclic group substituted with a lower hydroxy-lower alkyl group, hydroxy-lower alkoxy group, hydroxy-lower alkoxy-lower alkyl group, lower aliphatic acyl group, hydroxyl- lower aliphatic acylamino, hydroxyl group or carbamoyl group, and most preferably pyrrolidino, piperidino or piperazino substituted with a lower hydroxyalkyl group, hydroxy-lower alkoxy group, hydroxy-lower alkoxy-lower alkyl, lower aliphatic acyl group, lower aliphatic hydroxy-acylamino group or hydroxyl group. The "alkylene group of C? -C4" in the definitions of B and E is, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene or 3-methyltrimethylene, and preferably alkylene of CrC3. B is in particular preferably methylene. E is in particular preferably ethylene or trimethylene, and most preferably still ethylene. The "C2-C4 alkenylene group" in the definitions of B and E is, for example, ethenylene, 2-propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, 2-ethyl-2-propenylene or 2-butenylene, preferably ethenylene, 2-propenylene or 3-butenylene, and most preferably ethenylene or 2-propenylene. The "halogen atom" in the definition of substituent group a is a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferably a fluorine atom or a chlorine atom. The "lower aliphatic hydroxy-acylamino group" in the definition of substituent group a means a group in which the above-mentioned "lower aliphatic acylamino group" is substituted with a hydroxyl group, examples of which include hydroxy acetylamino, 3-hydroxypropionylamino, - hydroxybutyrylamino and 3-hydroxyisobutyrylamino, preferably it is hydroxyacetylamino or 3-hydroxypropionylamino, and in particular preferably a hydroxyacetylamino group. The "pharmacologically acceptable salt thereof" represents a salt of the compound (I) of the present invention since the compound (I) of the present invention can be converted to a salt by reacting with an acid in the case of a compound having a basic functional group such as an amino group, or by reacting with base in the case of a compound having an acid functional group such as a carboxyl group. Examples of salts based on basic functional groups include inorganic acid salts such as halohydrates, e.g., hydrochloride, bromohydrate or hydroiodide, nitrates, perchlorates, sulphates or phosphates; organic acid salts such as lower alken sulfonates, eg, methanesulfonate, trifluoromethanesulfonate or ethanesulfonate, arylsulfonates, e.g., benzenesulfonate or p-toluenesulfonate, or carboxylic acid salts, e.g., acetates maleates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates or maleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates or aspartates.

Examples of salts based on functional groups include metal salts such as alkali metal salts, e.g., sodium salts, potassium salts or lithium salts, alkaline earth metal salts, e.g., calcium salts or magnesium salts, aluminum salts, or iron salts; ammonium salts; organic amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosaline salts, alkyl ester salts of phenylglycine, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, salts of triethylamine, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts or tris (hydroxymethyl) aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates or aspartates. A compound having the general formula (I) of the present invention, or a pharmacologically acceptable salt thereof, can absorb moisture, retain adhered moisture or form a hydrate as a result of being exposed to the atmosphere or recrystallization, and said hydrates are They include in the present invention. A compound having the general formula (I) of the present invention can have optical isomers based on an asymmetric center in the molecule thereof. In a compound of the present invention, all these isomers and mixtures thereof are presented with a single formula, namely general formula (I). Therefore, the present invention includes all these isomers and mixtures of these isomers at arbitrary ratios. Specific examples of compounds having the general formula (I) of the present invention include those compounds in the following list of compounds 1 and list of compound 2. In the following lists of compounds, "Ac" represents acetyl, "Me" methyl , "Et" ethyl, "Pr" propyl, "Pr" aspropyl, "Bu" butyl, "Bu" isobutyl, "Pn" pentyl, "Pn" isopentyl, "tBu" tert-butyl, "cPr" cyclopropyl, "cBu" cyclobutyl, "cPn" cyclopentyl, "cHx" cyclohexyl, "Mor" morpholino, "Pip" piperidino (for example, "4- (H2NCO) -Pip" represents 4-aminocarbonylpiperazino), "Pipr" piperazino, "Aze" azetidino, and "Pyrr" pyrrolidino.

List of compounds 1 List of compounds 2 MODE FOR CARRYING OUT THE INVENTION A compound (I) of the present invention can be produced according to the methods described below. Among the compounds (I), a compound wherein R3 is -CO-R4 can be produced according to the following method A.

Method A In the above formulas, A, B, D, E, R1, R2, R4 and n are the same as defined above, and X represents a hydroxyl group or a residual group. There are no particular limitations on the "residual group" in the definition of X as long as it is a residual group that is used in the field of organic synthesis chemistry, and preferably it is a halogen atom such as a chlorine atom, bromine atom or iodine atom; a lower alkanesulfonyl group such as methanesulfonyl or ethanesulfonyl; a lower halogenoalkanesulfonyl group such as trifluoromethanesulfonyl or pentafluoroethanesulfonyl; or an arylsulfonyl group such as benzenesulfonyl, p-toluenesulfonyl or p-nitrobenzenesulfonyl, most preferably a halogen atom and particularly preferably a chlorine atom or a bromine atom.

Step A1 Step A1 is a step wherein a compound having the general formula (ai) is produced by condensing the compound (2) and compound (3) in an inert solvent in the presence or absence of a condensing agent and in the presence or absence of a base. There is no particular imitation of the inert solvent to be used as long as it is inert in the present reaction, examples of which include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; nitrile such as acetonitrile isobutylnitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulphonates such as sulfolane, preferably halogenated hydrocarbons, and most preferably methylene chloride. Examples of "condensing agents" to be used include: (1) combinations of phosphoric acid esters such as diethylphosphoryl or diphenylphosphoryl cyanide and the bases indicated below; (2) carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; combinations of the aforementioned carbodiimides and the bases indicated below; or combinations of the aforementioned carbodiimides and N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxyimide; (3) combinations of disulfides such as 2,2'-dipyridyl disulfide or 2,2'-dibenzothiazolyl disulfide and phosphines such as triphenylphosphine or tributylphosphine; (4) carbonates such as N, N'-disuccinimidyl carbonate, di-2-pyridyl carbonate or S, S'-bis (1-phenyl-1 H-tetrazol-5-yl) dithiocarbonate; (5) phosphinic acid chlorides such as N, N'-bis (2-oxo-3-oxazolidinyl) -phosphinic chloride; (6) oxalates such as N, N'-disuccinimidyl oxalate, N, N'-di-phthalimido oxalate, N, N'-bis (5-norbornene-2,3-d-carboxyimidyl) oxalate, oxalate of 1, 1'-bis (benzotriazolyl), 1,1'-bis (6-chlorobenzotriazolyl) oxalate or 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate; (7) combinations of the aforementioned phosphines and an azodicarboxylic acid ester or azodicarboxyamide such as diethyl diazocarboxylate or 1, 1 '- (azodicarbonyl) dipiperidine; or, a combination of the aforementioned phosphines and the bases indicated below; (8) N-lower alkyl-5-arylisoxazolium-3-sulfonates such as N-ethyl-5-phenylisoxazole-3'-sulfonate; (9) diheteroarlyldiselenides such as di-2-pyrridylselenide; (10) arylsulfonyltriazolides such as p-nitrobenzenesulfonyltriazolide; (1 1) 2-halogeno-1-lower alkyl-pyridinium halides such as 2-chloro-1-methyl pyridinium iodide; (12) imidazoles such as 1,1 '-oxalyldiimidazole or N, N'-carbonyldiimidazole; (13) 3-lower alkyl-2-halogeno-benzothiazolium fluoroborates such as 3-ethyl-2-chloro-benzothiazolium fluoroborate; (14) 3-lower alkyl-benzothiazole-2-selones such as 3-methyl-benzothiazole-2-selone; (15) phosphates such as phenyldichlorophosphate or polyphosphate esters; (16) halogensulfonyl isocyanates such as chlorosulfonyl isocyanate; (17) halogensilanes such as trimethylsilyl chloride or triethylsilyl chloride; (18) combinations of lower alkanesulfonyl halides such as methanesulfonyl chloride and the bases indicated below; and, (19) N, N, NSN'-tetra-lower alkyl-halogen formamide chlorides such as N, N, N'N'-tetramethylchloroformamide chloride, and (5) described above is preferred. There are no particular limitations on the basis provided it is a base to be used in ordinary alkylation reactions, examples of which include alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and, organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, NN-dimethylaniline, N, N-diphenylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] ] -7-undecene (DBU), preferably organic amines, and most preferably triethylamine. Although the reaction temperature varies depending on the type of starting materials, condensing agent, base, solvent, etc., it is usually from -20 ° C to 200 ° C (preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting materials, condensing agent, base, solvent, reaction temperature, etc., it is usually from 5 minutes to 48 hours (preferably from 15 minutes to 24 hours). In addition, in the case of using the compound (3) in which X is a hydroxyl group, the reaction is preferably carried out in the presence of a condensing agent. Further, in the present case, an acid anhydride (such as a compound having the general formula: R4-CO-O-CO-R4 or an acid anhydride of the compound (3) and an organic acid such as acetic acid) can be use instead of compound (3). After completion of the reaction, the desired compound is collected from the reaction mixture according to ordinary methods. For example, after adequately neutralizing the reaction mixture or removing insoluble material by filtration in cases where the insoluble material is present, an immiscible organic solvent such as water or ethyl acetate is added and after washing with water, etc. ., the organic layer containing the desired compound is separated, and after drying with anhydrous magnesium sulfate or anhydrous sodium sulfate, the desired compound is obtained by distilling off the solvent. The resulting desired compound is purified according to ordinary methods if necessary. For example, methods such as recrystallization, reprecipitation or methods used to separate and purify ordinary organic compounds can be suitably combined to separate and purify by eluting with a suitable eluent, examples of which include adsorption column chromatography using a vehicle such as a gel. silica, alumina, Florisil based on magnesium-silica gel; methods using synthetic adsorbent such as partition column chromatography using a vehicle such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm &Hass) or Diaion HP-20 (Mitsubishi Chemical); and methods using ion exchange chromatography or forward column / reverse phase chromatography using silica gel or alkylated silica gel (and preferably high performance liquid chromatography). Among the compounds (I), a compound in which R3 is -CO-O-R4 can be produced in accordance with the following method B.

Method B In the above formulas, A, B, D, E, R1, R2, R4, X and n are the same as defined above.

Step B1 Step B1 is a step wherein a compound having the general formula (Ib) is produced by condensing the compound (2) and the compound (4) in an inert solvent in the presence or absence of a condensing agent and in the presence of one base. In the present step, the same inert solvent, condensing agent and base described in "step A1" can be used. (However, the base used in the present step is most preferably still diisopropyethylamine.) Although the reaction temperature varies depending on the types of starting materials, condensing agent, base, solvent etc., it is usually -20 ° C. at 200 ° C (preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting materials, condensing agent, base, solvent, reaction temperature, etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary. Among the compounds (I), a compound in which R3 is -CO-NH-R4 or -CO-NH2 in the compound (I) can be produced according to the following method C.

Method C In the above formulas, A, B, D, E, R1, R2, R2 and n are the same as defined above, (step C1) Step C1 is a step wherein a compound having the general formula (le) is produces by reacting the compound (2) and the compound (5) in an inert solvent in the presence or absence of a base. In the present step, the same solvents and inert bases described in "step A1" can be used. (However, in the present step, preferably an aromatic hydrocarbon, halogenated hydrocarbon or nitrile (most preferably an aromatic hydrocarbon) is used as the solvent, and preferably an organic amine (most preferably diisopropyethylamine) is used as a base). Although the reaction temperature varies depending on the types of starting materials, base, solvent etc., it is usually from -20 ° C to 200 ° C (preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting materials, base, solvent, reaction temperature etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). In the present step, a compound in which R3 is -CO-NH2 can be produced if isocyanic acid is used in place of the compound (5). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" as necessary. Among the compounds (I), a compound in which R3 is -CO-CH-N (Ra) R can be produced in accordance with the following method D.

Method D In the above formulas, A, B, D, E, R1, R2, Ra, Rb, X and n are the same as defined above, and X 'represents a residual group. The same groups as the residual groups in the definition of X can be used for the "residual group" in the definition of XS and is preferably a halogen atom, particularly preferably a chlorine atom or a bromine atom, and most preferably still a bromine atom.

Step D1 Step D1 is a step wherein the compound (7) is produced by reacting the compound (2) and the compound (6) in an inert solvent in the presence of a base. In the present step, the same solvents and inert bases described in "step A1" can be used. (However, the base used in the present step is very preferably still diisopropyethylamine). Although the reaction temperature varies depending on the types of starting materials, base, solvent, etc., it is usually from -20 ° C to 200 ° C (and preferably from 0 to 120 ° C). Although the reaction time varies depending on the starting materials, base, solvent, reaction temperature etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary.

Step D2 Step D2 is a step wherein a compound having the general formula (Id) is produced by reacting the compound (7) and the compound (8) in an inert solvent in the presence or absence of a base. In the present step, the same solvents and inert bases described in "step A1" can be used. (However, in the present step, preferably nitrile (and particularly preferably acetonitrile) is used as the solvent.) Although the reaction temperature varies depending on the types of starting materials, base, solvent etc., it is usually -20 ° C to 200 ° C (and preferably 0 to 120 ° C).

Although the reaction time varies depending on the starting materials, base, solvent, reaction temperature etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary. Among the compounds (I), the compound in which R3 is - (CH2) m-CO-R5 can be produced according to the following method E.

Method E In the above formulas, A, B, D, E, R1, R2, R4, Ra, Rb, X, m and n are the same as defined above.

Step E1 Step E1 is a step wherein a compound having the general formula (le) is produced by reacting the compound (2) and the compound (9) in an inert solvent in the presence of a base. There is no particular limitation about the inert solvent that is to be used as long as it is inert in the present reaction, examples of which include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene , halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene, esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone, nitriles such as acetonitrile or isobutyl nitrile, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfones such as sulfolane; or mixed solvents thereof, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers or mixed solvents thereof, and most preferably aromatic hydrocarbons, ethers or mixed solvents thereof. There is no particular limitation on the base provided it is a base that is used in ordinary alkylation reactions, examples of which include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; organic amines such as triethylamine, tributylamine, diisopropyethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N / N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0 ] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); and, amides such as bis (trimethylsilyl) amide of potassium, preferably amides, and most preferably still potassium bis (trimethylsilyl) amide. Although the reaction temperature varies depending on the types of starting materials, base, solvent etc., it is usually from -20 ° C to 200 ° C (preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting materials, base, solvent, reaction temperature etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary.

Step E2 Step E2 is a step wherein a compound having the general formula (If) is produced by hydrolyzing a compound having the general formula (le) in an inert solvent in the presence of an acid or a base. There is no particular limitation about the inert solvent to be used as long as it is inert in the present reaction, examples of which include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; nitriles such as acetonitrile or isobutylnitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethyl-phophyric triamide; sulfoxides such as dimethyl sulfoxide; or sulfones such as sulfolane; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, ethylene glycol or diethylene glycol; Water; and mixed solvents of water and the aforementioned organic solvents, preferably halogenated hydrocarbons, and most preferably still methylene chloride. Examples of acids to be used include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; silphonic acids such as methanesulfonic acid or ethanesulfonic acid; and carboxylic acids such as acetic acid, propionic acid or trifluoroacetic acid, preferably is hydrochloric acid, sulfuric acid or trifluoroacetic acid, and in particular preferably trifluoroacetic acid. Examples of bases to be used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, and is preferably sodium hydroxide or potassium hydroxide. Although the reaction temperature varies depending on the types of starting material, acid, base, solvent, etc., it is usually from -20 ° C to 200 ° C (and preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting material, acid, base, solvent, reaction temperature etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary.

Step E3 Step E3 is a step wherein a compound having the general formula (Ig) is produced by reacting a compound having the general formula (If) with the compound (8) in an inert solvent, in the presence or absence of a condensing agent, and in the presence or absence of a base. There is no particular limitation about the inert solvent to be used as long as it is inert in the present reaction, examples of which include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; nitriles such as acetonitrile or isobutylnitrile; amides such as formamide, N, N-d, methylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; and mixed solvents thereof, preferably halogenated hydrocarbons, amides or mixed solvents thereof, and most preferably still methylene chloride, N, N-dimethylformamide or mixed solvents thereof. In the present step, the same condensation agent and bases can be used as those described in "step A1". Although the reaction temperature varies depending on the types of starting materials, condensing agent, base, solvent, etc., it is usually from -20 ° C to 200 ° C (preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting materials, condensing agent, base, solvent, reaction temperature, etc., it is usually from 5 minutes to 48 hours (preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary. In addition, the present step can also be carried out, for example, by reacting the compound (If) with a halogenating agent (such as thionyl chloride or oxalyl chloride) in the aforementioned solvents, and then reacting the reactive derivative resulting (acyl halide derivative) and compound (8) in the aforementioned solvents. Among the compounds (I), a compound in which R3 is - (CH2) m-RS and in which m is from 2 to 6 can be produced in accordance with the following method F.

Method F In the above formulas, A, B, D, E, R1, R2, R4, Ra, Rb, X, and m are the same as defined above (however, m is an integer from 2 to 6 in the reaction scheme mentioned above), and Y represents a residual group. There is no particular limitation about the "residual group" in the definition of Y as long as it is a residual group that is used in the field of organic synthesis chemistry, and is preferably a halogen atom such as a chlorine atom, bromine atom or iodine atom; a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; a halogeno-lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy; or an arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy or p-nitrobenzenesulfonyloxy, most preferably a halogen atom, lower alkanesulfonyloxy group or halogeno-lower alkanesulfonyloxy group, even very preferably a chlorine atom, bromine atom, methanesulfonyloxy or trifluoromethanesulfonyloxy , and in particular preferably methanesulfonyloxy.

Step F1 Step F1 is a step wherein a compound having the general formula (Ih) is produced by reacting a compound having the general formula (If) in an inert solvent using a reducing agent. There is no particular limitation about the inert solvent to be used as long as it is inert in the present reaction, examples of which include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; nitriles such as acetonitrile or isobutylnitrile; amides such as formamide, N, N-d-methylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl silhoxide; and sulfones such as sulfolane, preferably aromatic hydrocarbons or ethers, most preferably still ethers, and in particular preferably diethyl ether or tetrahydrofuran. Examples of reducing agents to be used include borane, diborane, dimethyl borane sulfoxide complex and borane-tetrahydrofuran complex; alkali metal boronides such as sodium cyanoborohydride, sodium borohydride, zinc borohydride or lithium borohydride; and aluminum hydride compounds such as lithium aluminum hydride or tri-tert-butyl aluminum hydride; preferably borane, borane-dimethyl sulfoxide complex and borane-tetrahydrofuran complex, and in particular preferably borane-tetrahydrofuran complex. Although the reaction temperature varies depending on the types of starting materials, reducing agent, solvent etc., it is usually from -20 ° C to 200 ° C (preferably from 0 ° C to 120 ° C). Although the reaction time varies depending on the starting material, reducing agent, solvent, reaction temperature, etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours).

After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary.

Step F2 Step F2 is a step wherein a compound having the general formula (li) is produced by reacting a compound having the general formula (Ih) with the compound (X) in an inert solvent, in the presence or absence of a condensing agent, and in the presence or absence of a base, and carried out in the same manner as "step A1" mentioned above. After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" if necessary.

Step F3 Step F3 is a step wherein the compound (10) is produced by reacting a compound having the general formula (Ih) with a halogenating agent (such as thionyl chloride or oxalyl chloride) or a sulfonilating agent (such as such as methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride) in an inert solvent in the presence or absence of a base. In the present step, the same inert solvent and base can be used as those described in "step A1". Although the reaction temperature varies depending on the types of the starting material, halogenating agent or sulfonilating agent, base, solvent, etc., it is usually from -20 ° C to 200 ° C (and preferably from 0 ° C to 120 ° C. ). Although the reaction time varies depending on the starting material, halogenating agent or sulfonilating agent, base, solvent, reaction temperature etc., it is usually from 5 minutes to 48 hours (and preferably from 15 minutes to 24 hours). After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" as necessary.

Step F4 Step F4 is a step wherein a compound having the general formula (Ij) is produced by reacting the compound (10) with the compound (8) in an inert solvent in the presence of a base, and carried out in the same way as "step D2" mentioned above. (However, in the present step, preferably an amide (particularly preferably N, N-dimethylacetamide) is used as the solvent, and preferably an alkali metal bicarbonate (particularly preferably sodium bicarbonate) is used as the base.) After completion of the reaction, the desired compound can be purified by the same methods as those described in "step A1" as necessary. Among the compounds (I), a compound in which R3 is -CO-NH-CO-N (Ra) Rb can be produced according to the following method G.

Method G In the above formulas, A, B, D, E, R1, R2, Ra, Rb, 'X' and n are the same as defined above.

Step G1 Step G1 is a step wherein the compound (12) is produced by reacting the compound (2) with the compound (11) in an inert solvent in the presence or absence of a base, and is carried out therefrom. way that the "step C1" mentioned above. (However, in the present step, preferably a halogenated hydrocarbon (particularly preferably methylene chloride) is used as the solvent.) After completion of the reaction, the desired compound can be purified by the same methods as those described in " Step A1"if necessary.

Step G2 Step G2 is a step wherein a compound having the general formula (Ik) is produced by reacting the compound (12) with the compound (8) in an inert solvent in the presence of a base; and it is carried out in the same manner as "step D2" mentioned above. (However, in the present step, preferably halogenated hydrocarbon (particularly preferably methylene chloride) is used as the solvent.) After completion of the reaction, the desired compound can be purified by the same methods as those described in " Step A1"if necessary. Among the compounds (I), a compound in which R3 is -co-NH-SO2-N (Ra) Rb can be produced according to the following H method.

Method H In the above formulas, A, B, D, E, R1, R2, Ra, Rb, X 'and n are the same as defined above.

Step H1 Step H1 is a step wherein compound (14) is produced by reacting compound (2) with compound (13) in an inert solvent in the presence or absence of a base, and is carried out therefrom. way that the "step C1" mentioned above. (However, in the present step, preferably a halogenated hydrocarbon (particularly preferably methylene chloride) is used as the solvent.) After completion of the reaction, the desired compound can be purified by the same methods as those described in " Step A1"if necessary.

Step H2 Step H2 is a step wherein a compound having the general formula (Im) is produced by reacting the compound (14) with the compound (8) in an inert solvent in the presence or absence of a base, and carried performed in the same way as "step D2" mentioned above. (However, in the present step, preferably a halogenated hydrocarbon (particularly preferably methylene chloride) is used as the solvent.) After completion of the reaction, the desired compound can be purified by the same methods as those described in " Step A1"if necessary. Among the compounds (I), a compound in which R3 is -CO-NH-CO- (CH2) m-N (Ra) Rb can be produced according to the following method I.

In the above formulas, A, B, D, E, R1, R2, Ra, R, XS m and n are the same as defined above.

Step 11 Step 11 is a step wherein the compound (16) is produced by reacting the compound (2) with the compound (15) in an inert solvent in the presence or absence of a base, and carried out therefrom. way that the "step C1" mentioned above. (However, in the present step, preferably a halogenated hydrocarbon, particularly preferably methylene chloride) is used as the solvent.) After completion of the reaction, the desired compound can be purified by the same methods as those described in " Step A1"if necessary.

Step 12 Step 12 is a step wherein a compound having the general formula (In) is produced by reacting the compound (16) with the compound (8) in an inert solvent in the presence or absence of a base (and it is carried performed in the same manner as the above-mentioned "step D2" (However, in the present step, preferably a halogenated hydrocarbon (particularly preferably methylene chloride) is used as the solvent.) After completion of the reaction, the The desired compound can be purified by the same methods as those described in step A1 if necessary: Among the compounds (I), a compound in which R3 is - (CH2) m -R5 and in which m is 1 to 6 can be produced according to the following method J.

Method J In the above formulas, A, B, D, E, R1, R2, R5, m and n are the same as defined above, and Y 'represents a residual group. The same groups as those described in the definition of Y can be used for the residual group in the definition of YS and is preferably a halogen atom, most preferably a chlorine atom or a bromine atom, and in particular preferably a hydrogen atom. chlorine.

Step J1 Step J1 is a step wherein a compound having the general formula (Ip) is produced by reacting the compound (2) with the compound (17) in an inert solvent, in the presence or absence of a condensing agent, and in the presence or absence of a base, and is carried out in the same manner as "step E1" mentioned above. After completion of the reaction, the desired compound can be purified by the same methods as those described in step A1 if necessary. Each starting material in the aforementioned methods A to J is a known compound or can be produced from a compound according to methods known in the field of organic chemistry. For example, the compound (2) can be produced according to the method described in columns 1 1 to 13 of the US patent. Do not. 6.51 1, 975. In addition, compounds having a residual group such as compounds (3), (4), (9) and (10) can be easily produced, for example, halogenation and sulfonylation of the corresponding carboxylic acid compound or alcohol compound of according to the method described in step F3 mentioned above. In addition, compounds (4), (5) and (9) can be easily produced by reacting R4-X (wherein, R4 and X are the same as defined above) with a suitable compound in accordance with the method described in Step A1 or step D2 mentioned above. Since a compound having the formula (I) and a pharmacologically acceptable salt thereof of the present invention have antagonistic activity or the neurokinin receptors (NKi receptors), NK2 and NK3), can be used as a pharmaceutical compound. Said pharmaceutical compound can be administered for diseases mediated by NK-i, NK2 and NK3 receptor, and examples of said diseases include diseases of the central nervous system including anxiety, depression, mental illness and schizophrenia; neurodegenerative diseases including dementia associated with AIDS, senile dementia of the Alzheimer's type, Alzheimer's disease, Down syndrome, de-diffusing disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases including chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchial constriction, asthma and cough; inflammatory diseases including inflammatory bowel disease (IBD), psoriasis, fibrositis, osteoarthritis, degenerative arthritis and rheumatoid arthritis; eczema; allergic diseases including rhinitis; hypersensitivity diseases including hypersensitivity diseases to vine plants; ophthalmological diseases including conjunctivitis, vernal conjunctivitis, vernal catarrh, destruction of the blood-aqueous barrier that accompanies various inflammatory eye diseases, increased infraocular pressure and miosis; skin diseases including contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis; addictions including alcoholism; somatic diseases induced by stress; sympathetic reflex dystrophy including shoulder-hand syndrome; dysthymia; diseases related to undesirable immune reactions including transplant rejection and immunoincrement or immunosuppression including systemic lupus erythematosus; diseases of digestive organs including diseases caused by abnormalities in nerves that regulate internal organs, colitis, ulcerative colitis, irritable bowel syndrome and Crohn's disease; emesis including that induced by X-ray irradiation and chemotherapeutic agents, poisons, toxins, pregnancy, vestibular disorders, post-operative disease, gastrointestinal obstruction, gastrointestinal dysmotility, visceralgia, migraine headache, increased intracranial pressure, decreased intracranial pressure or adverse side effects that accompany the administration of various pharmaceutical compounds; diseases of urinary bladder function including cystitis and urinary incontinence; eosinophilia caused by collagen, scleroderma, or hepatic fasciola infection; diseases caused by circulation abnormalities due to vascular dilation or vascular constriction including angina pectoris, migraine headache, and Raynaud's syndrome; pain associated with reception of pain penetration including migraine headache, headache and toothache; and, sleep apnea syndrome. The aforementioned pharmaceutical compounds can be used as a prophylactic or therapeutic for respiratory diseases such as asthma, bronchitis and chronic obstructive disease; allergic diseases such as rhinitis and / or urinary incontinence in particular. Examples of the manner of administration of a compound having the general formula (I) of the present invention, or pharmaceutically acceptable salt thereof, includes oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injection or suppositories . Moreover, a compound having the general formula (I) or a pharmacologically acceptable salt thereof of the present invention can also be administered by pulmonary administration in the form of a powder, solution or suspension. Preparations for these administrations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrective agents, diluents, etc. Examples of excipients include organic excipients such as sugar derivatives, e.g., lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g., corn starch, potato starch, α-starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g., crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally interlaced sodium carboxymethylcellulose and gum arabic, dextran or pullulan; and inorganic excipients such as silicate derivatives, e.g., light anhydrous silicic acid, synthetic aluminum silicate or magnesium aluminum metasilicate, phosphates, e.g., calcium phosphate, carbonates, e.g., carbonate calcium, or sulfates, e.g., calcium sulfate. Examples of lubricants include stearic acid and metal stearate such as calcium stearate or magnesium stearate; talcum powder; colloidal silica; waxes such as bee gum or spermaceti; boric acid; atypical acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; salts of sodium fatty acid; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or hydrated silicate; and, starch derivatives. Examples of binders include polyvinyl pyrrolidone, Macrogol and compounds similar to the aforementioned excipients. Examples of disintegrating agents include compounds similar to the aforementioned excipients, and chemically crosslinked starches and celluloses such as interlaced sodium carmellose, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone. Examples of stabilizers include esters of paraoxybenzoate such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and, sorbic acid. Examples of remedies include ordinarily used sweeteners, bitter flavors and fragrances. In the case of producing a solution or suspension for pulmonary administration of a compound having the general formula (I) or a pharmacologically acceptable salt thereof of the present invention, for example, said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g., ethanol, propylene glycol or polyethylene glycol). Said solution or suspension may also contain an antiseptic (e.g., benzalkonium chloride), solubilizing agent (e.g., a polysorbate such as Tween 80 or Span 80 or a surface activator such as benzalkonium chloride), regulator of pH, isotonic agent (e.g., sodium chloride), absorption promoter and / or thickener. In addition, the suspension may also contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethylcellulose). A composition for pulmonary administration produced in the manner described above is administered directly into the nasal cavity or oral cavity by a typical medium in the field of inhalants (using, for example, a dropper, pipette, cannula or atomizer). In the case of using an atomizer, the crystals of the present invention can be atomized as an aerosol in the form of a pressurized package together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or can be administered using a nebulizer.

Although the amount of a compound having the general formula (I) or pharmacologically acceptable salt thereof of the present invention used varies depending on the symptoms, age, method of administration, etc., it is desired to administer in an amount of 0.1 mg as a lower limit (preferably 1 mg and most preferably 5 mg) and 1000 mg as an upper limit (preferably 100 mg and most preferably 50 mg) per day to an adult human either in a single dose or dividing into multiple doses in accordance with the symptoms in the case of oral administration, for example. In the case of intravenous administration, it is desired to administer in an amount of 0.01 mg as a lower limit (preferably 0.1 mg) and 100 mg as an upper limit (preferably 10 mg) per day to an adult human in a single dose or dividing in multiple doses according to the symptoms. In addition, although the amount of a compound having the general formula (I) or pharmacologically acceptable salt used varies depending on the symptoms, age, gender, etc., it is desired to administer in an amount of 0.01 μg / kg as a lower limit ( preferably 0.05 μg / kg) and 1000 μg / kg as an upper limit (preferably 100 μg / kg and most preferably 20 μg / kg) per day to an adult human in a single dose or dividing into multiple doses in accordance with the symptoms, in the case of pulmonary administration.

BEST MODE FOR CARRYING OUT THE INVENTION Although the following provides a more detailed explanation of the present invention through its examples, reference examples, preparation examples and test examples, the present invention is not limited thereto.

EXAMPLES EXAMPLE 1 1- (2- (2R) -2-f3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl > etl) spiro. { (2S) -2-r (acetoxy) acetoxy-1-cranberry-1,4'-piperidine hydrochloride (hydrochloride of example compound No. 2-97) 0. 07 ml of acetoxyacetyl chloride was added to a solution of 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis ( trifluoromethyl) benzoyl) morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy) indane-1,4'-piperidine and 320 mg (1.07 mmol, 3.3 mmol / g) of PS-diisopropylethylamine in toluene (3.0 ml). After the mixture was stirred at room temperature for 20 hours, the resin was removed by filtration. After the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (eluent-solvent: methylene chloride / methanol = 10/1), it was dissolved in ethanol (5.0 ml) and a solution of 4N-dioxane hydrochloric acid (0.5 ml) thereto. The solvent was again distilled under reduced pressure, followed by azeotropy with diethyl ether twice. The residue thus obtained was recrystallized from hexane to obtain 171 mg (yield: 95%) of the title compound as a white crystal. Spectrum of 1 H-NMR (400 MHz, DMSO-d 6) d ppm: 8.45-8.01 (3H, m), 7.85-7.12 (7H, m), 5.43 (1 H, bs), 4.56 (2H, bs), 4.21 -1.62 (24H, m). IR v max cnO spectrum (KBr): 2961, 1748, 1646, 1474, 1439, 1376, 1282, 1186, 1137, 905, 681. Mass spectrum (FAB) m / z: 801 ((M + H) + , free form) Elemental analysis (for C38H37CI3F6N2? 6) Calculated (%): C: 54.46, H: 4.45, N: 3.34, R13.60, Cl: 12.69 Found (%): C.52.13, H: 4.54, N : 3.43, F: 12.23, Cl: 11.83 Optical rotation: [a] D20 = +39.5 (c = 1.00, methanol) EXAMPLE 2 1- (2- (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (tr? Fluoromethyl) benzoyl) morpholin-2-yl) ethyl) spiro ((2S) hydrochloride -2-f (3,3-dimethylbutanoyl) oxy) > Indane-1, 4'-piperidine (Example Compound Hydrochloride No. 2-106) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmoles) of 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4-piperidine and 3,3-dimethylbutanoic chloride to obtain 143 mg ( yield: 80%) of the title compound as a white crystal. IR spectrum v max crt? 1 (KBr): 2960, 2658, 2553, 1725, 1647, 1475, 1439, 1375, 1281, 1240, 1186, 1139, 905, 757, 681. Mass spectrum (FAB) m / z: 799 ((M + H) +, free form) EXAMPLE 3 1-f 2-f (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzo-morpholin-2-yl) ethyl) spirohydrochloride. { (2S) -2-r (cyclohexylcarbonyl) oxyl) indane-1,4'-piperidine (hydrochloride of example compound No. 2-110) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmoles) of 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl-3-morpholin-2-yl} ethyl) spiro ((2S) -2-hydroxy] indan-1,4'-piperidine and cyclohexanecarboxylic chloride to obtain 185 mg (yield: 99%) of the title compound as a white crystal, IR spectrum v max cm "1 (KBr): 2933, 2857, 2657, 2477, 1726, 1647, 1473, 1452, 1440, 1376, 1281, 1246, 1185, 1170, 1138, 1029, 905 , 757, 681. Mass Spectrum (FAB) m / z: 811 ((M + H) +, free form) EXAMPLE 4 1 - (2- (2R) -2- (3,4-) Hydrochloride dichlorophenyl) -4-r3,5-b1s (trifluoromethyl) benzo-morpholin-2-yl> ethyl) spiro { (2S) -2-f (methoxyacetyl) oxp) indane-1,4 ' - piperidine (example compound hydrochloride No. 2-111) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmoles) of 1- (2 { (2R) -2- (3,4-dichloropheni) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and methoxyacetyl chloride to obtain 98.0 mg (yield: 57%) of the Composed of the title as a white crystal. IR spectrum v max cm'1 (KBr): 2930, 2655, 2508, 1749, 1645, 1473, 1457, 1439, 1376, 1363, 1282, 1186, 1136, 1028, 905, 758, 681. Mass spectrum ( FAB) m / z: 773 ((M + H) +, free form) EXAMPLE 5 1 - (2. {(2R) -2- (3,4-dichlorophenyl) -4-r3,5-bs (trifluoromethyl) benzoinmorpholin-2-yl) ethyl chloride) spiro ((2S) -2-f (cyclopropylcarbonyl) oxyl> indane-1,4'-piperidine (hydrochloride of example compound No. 2-107) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmoles) of 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3.5 -b (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and cyclopropanecarboxylic chloride to obtain 72.0 mg (yield: 42 %) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 2926, 2482, 2406, 1724, 1646, 1473, 1439, 1392, 1376, 1281, 1172, 1139, 1071, 1029, 905, 758, 681. Mass spectrum ( FAB) m / z: 801 (M + H) +, free form) EXAMPLE 6 1 - (2 - ((2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spirof (2S) -2-ff (morpholin-1-yl) acetinoxy)) indane-1,4'-piperidine (dihydrochloride of example compound No. 2-112) 435 mg (1.71 mmol) of N, N-bis chloride. { 2-oxo-3-oxazolydinyl) -phosphinic acid and 7 mg (0.057 mmol) of 4- (dimethylamino) pyridine were added to a solution of 400 mg (0.57 mmol) of 1-. { 2-. { . { 2R) -2-. { 3,4-dichlorophenyl) -4- [3,5-b] s. { trifluoromethyl] benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine, 248 mg. { 1.71 mmoles) of 2-morpholineacetic acid and 0.48 ml (3.42 mmoles) of triethylamine in 12 ml of methylene chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (eluent-solvent: methylene chloride / methanol = 50 / 1-100 / 3) to obtain 337 mg (yield: 71%) of the form Free of the title compound. ml of ethanol was added to 336 mg (0.405 mmol) of the free form of the title compound thus obtained to dissolve it and 0.51 ml of 4N-dioxane hydrochloric acid solution was added thereto. After the reaction mixture was stirred under ice cooling for 10 minutes, the solvent was distilled off under reduced pressure, followed by azeotropy with diethyl ether. Ether was added to the residue thus obtained to be collected by filtration to obtain 341 mg (yield: 93%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CD3OD) d ppm: 8.20-7.92 (3H, m), 7.87-7.20 (7H, m), 5.70-5.40 (1 H, m), 4.55-1.80 (30H, m). IR spectrum v max cm "1 (KBr): 3422, 2928, 2873, 2646, 2551, 2424, 1750, 1695, 1645, 1473, 1457, 1440, 1376, 1281, 1240, 1224, 1206, 1186, 1138, 1109, 1098, 1073, 1049, 1027, 905, 757, 681. Mass spectrum (FAB) m / z: 828 ((M + H) +, free form) Elemental analysis (for C40H41CI2F6N3O5 2HCI) Calculated (%): C: 53.29, 1-1: 4.81, N.6.66, R12.64, Cl: 15.73 Found (%): C: 51.97, H: 5.05, N: 4.60, R11.48, CL15.39 Optical rotation: [a ] D20 = +44.2 (c = 1.00, methanol) EXAMPLE 7 1- (2-R (2R) -2- (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-ylletii) spirohydrochloride (2S) -2 - { r (morphoiin-y-ii) acetinoxi)) cranberry-1,4'-piperidine (dihydrochloride of Example Compound No. 1-112) The reaction was carried out with a procedure similar to that of Example 6 using 350 mg (0.534 mmol) of 1-. { 2 - [(2R) -2- (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} Spiro [(2S) -2-hydroxy] indane-1,4'-piperidine, 232 mg (1.60 mmol) of 2-morpholine acetic acid, 0.45 ml (3.20 mmol) of triethylamine, 408 mg (1.60 mmol) of N-chloride, N-bis (2-oxo-3-oxazolidinyl) -phosphinic acid and 7 mg (0.057 mmol) of 4- (dimethylamino) pyridine to obtain 404 mg (yield: 83%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CD3OD) d ppm: 7.87-7.20 (7H, m), 6.70-6.60 (2H, m), 5.70-5.38 (1 H, m), 4.50-1.80 (30H, m) IR spectrum v max cm "1 (KBr): 3426, 2936, 2872, 2644, 2537, 2423, 1750, 1634, 1583, 1505, 1462, 1427, 1415, 1380, 1330, 1269, 1228, 1207, 1125, 1075, 1026, 1004, 927, 901, 871, 831, 762, 723, 678. Mass spectrum (FAB) m / z: 782 ((M + H) +, free form) Elemental analysis (for C41H49CI2N3O8 2HCI 1.5H2O ) Calculated (%): C: 55.79, H: 6.17, N: 4.76, CL16.07 Found (%): C: 55.87, H: 6.07, N: 4.69, Cl: 16.37 Optical Rotation: [a] D20 = + 39.5 (c = 1.00, methanol) EXAMPLE 8 1 - (2 - ((2R) -2- (3,4-Dichlorophenyl) -4-f3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethychloride. l) spiro ((2S) -2-fr (4-morpholin-4-yl) butanoxynoxy)) indane-1,4'-piperidine fdihydrochloride of Example Compound No. 2-114) The reaction was carried out with a procedure similar to that of Example 6 using 212 mg (0.302 mmoles) of 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] -dane-1,4'-piperidine, 262 mg (1.51 mmol) of 4-acid morpholinbutyric acid, 0.42 ml (3.02 mmol) of triethylamine, 384 mg (1.51 mmol) of N, N-bis (2-oxo-3-oxazoiidinyl) -phosphinic chloride and 4 mg (0.03 mmol) of 4- (dimethylamino) pyridine for obtain 182 mg (yield: 67%) of the title compound as a white solid. IR spectrum v max cm "1 (KBr): 3436, 2927, 2874, 2653, 2558, 2461, 1733, 1644, 1472, 1457, 1440, 1376, 1282, 1243, 1183, 1138, 1108, 1096, 1028, 981, 928, 905, 759, 681. Mass spectrum (FAB) m / z: 856 ((M + H) +, free form) 0 EXAMPLE 9 1 - (2. {(2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spiro ((2S) - dihydrochloride 2- { Rí3-morpholin-4-yl) propanoinoxy » Cranberry-1,4'-piperidine (dihydrochloride of Example Compound No. 2-113) The reaction was carried out with a procedure similar to that of Example 6 using 218 mg (0.311 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3, S bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine, 247 mg (1.55 mmol) of 3-morpholinepropionic acid , 0.43 ml (3.10 mmol) of triethylamine, 395 mg (1.55 mmol) of N, N-bis (2-oxo-3-oxazolidinyl) -phosphinic chloride and 5 mg (0.03 mmol) of 4- (dimethylamino) pyridine to obtain 158 mg (yield: 63%) of the title compound as a white solid. IR spectrum v max cm "1 (KBr): 3438, 2928, 2873, 2653, 2560, 2458, 1737, 1644, 1473, 1458, 1440, 1376, 1319, 1282, 1185, 1137, 1110, 1095, 1047, 1028, 987, 905, 759, 707, 681. Mass spectrum (FAB) m / z: 842 ((M + H) \ free form) EXAMPLE 10 1 - (2-f (2R) -2- (3,4-dichlorophen-1, 3-bis (trifluoromethyl) benzo-morpholin-2-yl) ethyl) spiro (2S) hydrochloride -2- (í (2-methoxy) ethoxycarbonilloxy » Cranberry-1,4'-piperidine (example compound hydrochloride No. 2-122) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmoles) of 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] -dane-1,4, -piperidine and 2-methoxyethyl chloroformate to obtain 172 mg (yield: 96%) of the title compound as a white crystal. IR spectrum v max cm'1 (KBr): 2928, 248I, 2393, 1746, 1646, 1473, 1440, 1363, 1282, 1266, 1186, 1137, 1027, 905, 681. Mass spectrum (FAB) m / z: 803 ((M + H) +, free form) EXAMPLE 11 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bs (trifluoromethyl) benzoinmorpholin-2-yl) etl) chlorohydrate . { (2S) -2-f (ethoxycarbonyl) oxp > indane-1,4'-piperidine (example compound hydrochloride No. 2-121) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -βis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and ethyl chloroformate to obtain mg (yield: 93%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 2927, 2481, 2404, 1743, 1647, 1473, 1439, 1375, 1281, 1266, 1186, 1139, 905, 681. Mass spectrum (FAB) m / z: 773 ((M + H) +, free form) EXAMPLE 12 1 - (2. {(2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spirohydrochloride ((2S ) -2- (F (2-fluoro) ethoxycarboninoxy)) indane-1,4'-piperidine (hydrochloride of example compound No. 2-123) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -β (Trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine and ethyl chloroformate to obtain 50.0 mg (yield : 28%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 2960, 2481, 2400, 1748, 1646, 1473, 1440, 1377, 1282, 1267, 1186, 138, 905, 873, 681. Mass spectrum (FAB) m / z: 791 ((M + H) +, free form) EXAMPLE 13 1 - (2- (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spirohydrochloride (2S) -2- [(2-propargyl) oxycarboninoxy »indane-1,4'-piperidine (hydrochloride of example compound No. 2-124) The reaction was carried out with a procedure similar to that of Example 1 using 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and propargyl chloroformate to obtain 170 mg (yield: 97% ) of the title compound as a white crystal. Spectrum IR V max cm "1 (KBr): 2925, 2484, 2410, 1750, 1645, 1473, 1439, 1377, 1281, 1264, 1186, 1139, 905, 681. Mass spectrum (FAB) m / z: 783 ((M + H) +, free.form) EXAMPLE 14 1- (2 - ((2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethylbenzoyl) morpholin-2-yl} ethyl) -hydrochloride R (2S) -2 - ((f2- (ethoxycarbonyl) ethynycarbamoyl) oxy)] indane-1,4'-piperidine (hydrochloride of example compound No. 2-126) 0. 08 ml of ethoxycarbonylethyl isocyanate was added to a solution of 150 mg (0.214 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis ( trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy-oxy] indan-1,4'-piperidine and 320 mg (1.07 mmol, 3.3 mmol / g) of PS-diisopropylethylamine in toluene (3.0 ml). After the mixture was stirred at 80 ° C for 20 hours, the resin was removed by filtration. After the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (eluent-solvent: methylene chloride / methanol = 10/1), it was dissolved in ethanol (5.0 ml) and a solution of 4N-dioxane hydrochloric acid (0.5 ml) thereto. The solvent was again distilled under reduced pressure, followed by azeotropy with diethyl ether twice. The residue thus obtained was recrystallized from hexane to obtain 45.0 mg (yield: 24%) of the title compound as a white crystal. 1 H-NMR spectrum (400 MHz, DMSO-d 6) d ppm: 8.31-7.98 (3 H, m), 7.88-7.08 (7 H, m), 5.24 (1 H, bs), 4.18-1.57 (31 H, m ). IR spectrum v max cm "1 (KBr): 2958, 2657, 2564, 1723, 1644, 1525, 1376, 1282, 1 186, 1 139, 758, 681 Mass spectrum (FAB) m / z: 844 (( M + H) +, free form) Elemental analysis (for C40H42CI3F6N3O6) Calculated (%): C: 54.52, H: 4.80, N: 4.77, R12.94, Cl: 12.07 Found (%): C: 51.32, H: 4.77, N: 5.35, F: 10.92, CL12.04 Optical rotation: [a] D20 = +42.1 (c = 1.00, methanol) EXAMPLE 15 Hydrochloride of 1 - (2- { (2R) -2- (3.4 -dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro (2S) -2 - ((r3- (ethoxycarbonyl) propin carbamoyl) oxy) 1indane-1,4'-piperidine (Example compound hydrochloride No. 2-127) The reaction was carried out with a procedure similar to that of Example 14 using 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] -dane-1,4'-pperiodine and ethoxycarbonylpropyl socianate to obtain 38.0 mg ( yield: 20%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 2953, 2655, 2560, 1720, 1644, 1527, 1440, 1376, 1282, 1185, 1139, 1029, 758, 681. Mass spectrum (FAB) m / z: 858 ((M + H) +, free form) EXAMPLE 16 1 - (2-f (2R) -2- (3,4-dichlorophenyl -r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spirof (2S) -2- (2- (ethylcarbamoyloxy) -1indane-1,4'-piperidine (hydrochloride of example compound No. 2-128) The reaction was carried out with a procedure similar to that of Example 14 using 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} etl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine and ethyl isocyanate to obtain 68.0 mg (yield: 39% ) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 2971, 2495, 2417, 1714, 1645, 1518, 1473, 1440, 1376, 1281, 1186, 1139, 1029, 905, 681 Mass spectrum (FAB) m / z : 772 ((M + H) +, free form) EXAMPLE 17 1- (2 (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl> ethyl) espiror (2S) hydrochloride -2- (Ethoxycarbonylmethylcarbamoyloxy)) - indane-1,4'-piperidine (Example Compound Hydrochloride No. 2-125) The reaction was carried out with a procedure similar to that of Example 14 using 150 mg (0.214 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine and ethoxycarbonylmethyl isocyanate to obtain 53.0 mg ( yield: 29%) of the title compound as a white crystal. IR spectrum v max crt? 1 (KBr): 2961, 2657, 2562, 1722, 1645, 1521, 1474, 1440, 1376, 1282, 1186, 1139, 905, 758, 681. Mass spectrum (FAB) m / z: 830 ((M + H) +, free form) EXAMPLE 18 1 - (2 - ((2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorph in-2-yl} ethyl) spirof (2S) -2 - ((fN- (hydroxyethyl) -N-methylamino1 acetyl) oxy) 1indane-1,4'-piperidine (dihydrochloride of example compound No. 2 -129) EXAMPLE 18a 1- (2-f (2R) -2- (3,4-dichlorophenol) -4-r3,5-bis (trifluoromethyl) benzo-morpholin-2-yl) ethyl) -spiror (2S) -2 - (bromoacetyl) oxpindane-1,4'-piperidine Bromoacetyl bromide was added dropwise to a solution of 10.0 g (14.3 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis ( trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 2.78 ml of triethylamine in 200 ml of methylene chloride under cooling with ice with stirring and the mixture was stirred as such for 35 minutes. The reaction solution was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (eluent-solvent: methylene chloride / methanol = 25 / 1-20 / 1) to obtain 11.48 9 (yield: 98%) of the title as a white solid. 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.20-7.10 (10H, m), 5.80-5.30 (1 H, m), 4.65-1.40 (22H, m).

IR spectrum v max cm "1 (KBr): 2974, 1741, 1645, 1473, 1458, 1437, 1375, 1280, 1185, 1163, 1139, 1109, 1047, 1029, 992, 927, 905, 849, 758,722,705,681. Mass spectrum (FAB) m / z: 821 ((M + H) +) EXAMPLE 18b 1- (2 - ((2R) -2- (3,4-Dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) espiror (2S) -2 dihydrochloride - (fN- (2-hydroxyethyl) -N-methylamino1 acetyl) oxy) lindane-1,4'-piperidine 60 μl (0.75 mmol) of N-methylethanolamine was added to a solution of 200 mg (0.243 mmol) of 1- (2- {(2R.} -2- (3,4-dichlorophenyl) -4- [ 3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl.} Ethyl) espyro [(2S.) -2- (bromoacetyl) oxy] indane-1,4'-piperidine, obtained in the example 18a, in acetonitrile and the mixture was stirred at 50 ° C for 5 hours. Methylene chloride was added to the reaction solution and the organic layer was washed with a saturated NaCl solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (eluent-solvent: methylene chloride / 2-propanol = 10 / 1-5 / 1) and dissolved in 5.0 ml of methanol and added to the same 1.0 ml of 4N-dioxane hydrochloric acid solution. The solvent was distilled again under reduced pressure, followed by azeotropy twice with diethyl ether. Ether was added to the residue thus obtained to be collected by filtration to obtain 39 mg (yield: 18%) of the title compound as a white solid. 1H-NMR spectrum (400 MHz, CD3OD) d ppm: 8.20-7.91 (3H, m), 7.86-7.08 (7H, m), 5.72-5.32 (1H, m), 4.55-1.65 (29H, m) . IR spectrum v max cm "1 (KBr): 3344, 2926, 1645, 1474, 1458, 1439, 1376, 1281, 1 186, 1 165, 1 139, 1 109, 1047, 1029, 988, 972, 927, 905, 849, 830, 758, 722, 707, 681, 623. Mass spectrum (FAB) m / z: 816 ((M + H) +, free form) Elemental analysis (for C39H4? CI2F6N3O5 2HCI) Calculated: C .52.66, H: 4.87, N.4.72 Found: C: 52.72, H: 4.59, N: 3.73 Optical Rotation: [a] D20 = +36.3 (c = 1.00, methanol) EXAMPLE 19 1 - (2- (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spiro [(2S) -2- ( (f4- (aminocarbonyl) p.peridin-1-ipacetyl}. oxi? lindane-1,4'-piperidine (dihydrochloride of example compound No. 2-144) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5 -b¡s (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indan-1,4'-piperidine, obtained in example 18a, and 86 mg (0.75 mmole) of ioispectrophamide to obtain 43 mg (yield: 19%) of the title compound as a white solid. 1H-NMR spectrum (400 MHz, CD3OD) d ppm: 8.20-7.90 (3H, m), 7.86-7.11 (7H, m), 5.73-5.33 (1H, m), 4.55-1.70 (30H, m) . IR spectrum v max cm "1 (KBr): 3384, 3180, 2929, 2651, 2553, 1750, 1646, 1472, 1456, 1438, 1402, 1376, 1282, 1241, 1186, 1140, 1109, 1098, 1028, 952, 905, 757, 723, 707, 682, 637, 622, 543. Mass spectrum (FAB) m / z: 869 ((M + H) +, free form) Elemental analysis (for C 2H46CI2F6N O5 2HCI 5H2O) Calculated (%): C: 48.85, H: 5.47, N: 5.43 Found (%): C: 48.61, H: 5.23, N: 5.27 Optical Rotation: [a] D20 = +49.9 (c = 0.80, methanol) EXAMPLE 20 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl.} Ethyl) spiro ((2S) - dihydrochloride 2- (R (pyrrolidin-1-yl) acetyloxo] -dhane-1,4'-piperidine (dihydrochloride of Example Compound No. 2-142) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indan-1,4'-piperidine, obtained in example 18a, and 52 mg (0.73) mmoles) of pyrrolidine to obtain 91 mg (yield: 45%) of the title compound as a white solid.

IR spectrum v max cm "1 (KBr): 2955, 2927, 2647, 2555, 2468, 1751, 1645, 1472, 1457, 1438, 1376, 1282, 1237, 1186, 1138, 1109, 1029, 986, 905, 849, 757, 722, 707, 681. Mass spectrum (FAB) m / z: 812 ((M + H) +, free form) EXAMPLE 21 1 - (2 - ((2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro ((2S) -2-Dihydrochloride - { [(azetidin-1-yl) acetinoxy)) indane-1,4'-piperidine (dihydrochloride of Example Compound No. 2-141) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indan-1,4'-piperidine, obtained in example 18a , and 52 mg (0.75 mmol) of azetidine to obtain 37 mg (yield: 17%) of the title compound as a white solid. IR spectrum v max cm "1 (KBr): 3402, 2930, 2658, 2574, 2414, 1752, 1645, 1560, 1473, 1438, 1376, 1281, 1238, 1186, 1139, 1109, 1098, 1078, 1029, 985, 949, 905, 758, 722, 707, 681. Mass spectrum (FAB) m / z: 798 ((M + H) +, free form) EXAMPLE 22 Dihydrochloride of 1 - (2-f (2R) - 2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoyl-cymortolin-2-yl) eti) spiro (2S) -2 - ((4 - (hydroxymethyl) piper din-1-nacetyl) oxy!) 1indane-1,4'-piperidine (dihydrochloride of example compound No. 2-145) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indan-1,4'-piperidine, obtained in example 18a, and 96 mg (0.75) mmoles) of 4- (hydroxymethyl) piperidine to obtain 58 mg (yield: 26%) of the title compound as a white solid. Spectrum of IRv max cm "1 (KBr): 3374, 2927, 2876, 2650, 2552, 1751, 1645, 1473, 1457, 1439, 1405, 1376, 1330, 1281, 1241, 1186, 1164, 1 138, 1109, 1075, 1040, 1028, 1001, 985, 949, 905, 757, 722, 707, 681. Mass spectrum (FAB) m / z: 856 ((M + H) +, free form) EXAMPLE 23 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoylmorpholine-2-ii > etii) espirof (2S) -2- dihydrochloride ((rN- (2-Ethoxy-ethyl) -N-methylamino-acetyl) oxy) -lndan-1,4'-piperidine (dihydrochloride of Example Compound No. 2-130) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2- (bromoacetyl) -oxy] indan-1,4'-piperidine, obtained in the example 18a, and 105 μl (0.75 mmoles) of 2-ethoxyethylamine to obtain 68 mg (yield: 31%) of the title compound as a white solid. Spectrum of v max cm "1 (KBr): 3372, 3068, 2928, 2653, 2552, 1751, 1645, 1473, 1457, 1439, 1406, 1376, 1280, 1241, 1186, 1138, 1109, 1076, 1028, 987 , 905, 758, 681. Mass spectrum (FAB) m / z: 830 ((M + H) +, free form) EXAMPLE 24 Dihydrochloride of 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoii? Morfoiin-2-yl) etl) spiro (2S) - 2 - ((f4- (2-hydroxyethyl) piperidin-1-nacetyl > oxy) 1indane-1,4'-piperidine (dihydrochloride of example compound No. 2-146) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indane-1'-piperidine, obtained in example 18a, and 92 mg (0.75) mmoles) of 4-piperidinetanol to obtain 48 mg (yield: 21%) of the title compound as a white solid. IR spectrum v max cm "1 (KBr): 3372, 3068, 2928, 2653, 2552, 1751, 1645, 1473, 1457, 1439, 1406, 1376, 1280, 1241, 1186, 1138, 1109, 1076, 1028, 987, 905, 758, 681. Mass spectrum (FAB) m / z: 870 ((M + H) +, free form) EXAMPLE 25 1 - (2-f (2R) -2- (3,4-Dichlorophenyl) -3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro (2S) -2-f ( isopropylamino) acetyl] oxy »indane-1,4'-piperidine (dihydrochloride of Example Compound No. 2-134) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indan-1,4'-pperiodine obtained in the Example 18a, and 64 μl (0.75 mmoles) of 2-propylamine to obtain 50 mg (yield: 24%) of the title compound as a white solid. IR spectrum v max cm "1 (KBr): 3400, 2931, 2664, 2569, 2423, 1752, 1645, 1473, 1458, 1439, 1376, 1320, 1281, 1240, 1207, 1186, 1139, 1 109, 1098 , 1075, 1129, 905, 707, 681. Mass spectrum (FAB) m / z: 800 ((M + H) +, free form) EXAMPLE 26 1 - (2-f (2R) -2- (3,4-Dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzo-morpholin-2-yl> ethyl) spiro [(2S)] dihydrochloride -2- (frbis (2-methoxyethyl) amino1 acetyl) oxy) 1indane-1,4'-piperidine (dihydrochloride of example compound No. 2-140) The reaction was carried out with a procedure similar to that of Example 18b using 200 mg (0.243 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2- (bromoacetyl) oxy] indan-1,4'-piperidine, obtained in example 18a, and 97 μl (0.75) mmolesl) of bis (2-methoxyethyl) amine to obtain 74 mg (yield: 32%) of the title compound as a white solid. IR spectrum v max cm "1 (KBr): 3407, 2931, 2652, 2527, 2424, 1751, 1645, 1473, 1458, 1440, 1376, 1282, 1240, 1223, 1187, 1164, 1137, 1028, 989, 905, 757, 707, 681. Mass spectrum (FAB) m / z: 874 ((M + H) +, free form) EXAMPLE 27 Sodium salt of 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spirof (2S ) -2-r (carboxymethyl) oxi1 > indane-1,4'-piperidine (sodium salt of the example compound No. 2-147) EXAMPLE 27a 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spirof (2S) -2- (t-butoxycarbonylmethoxy) ] indane-1,4'-piperidine g (7.13 mmol) of 1- (2- { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl. The ether ((2S) -2-hydroxy] indane-1,4'-piperidine was dissolved in 6 ml of tetrahydrofuran and 21 ml (10.5 mmoles) of potassium bimes (trimethylsilyl) amide. (toluene solution 0.5 mol / l) was added dropwise thereto under ice cooling for 10 minutes after the mixture was stirred under ice cooling for 10 minutes.1.58 ml (10.7 mmoles) of t-butyl bromoacetate was added thereto. After the mixture was stirred under ice cooling for 10 minutes, the temperature of the mixture returned to room temperature and the mixture was stirred for 1 hour. Water was added and the mixture was quenched and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / n-hexane = 4/1) to obtain 3.45 9 (yield: 59%) of the title compound. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.34-7.98 (3H, m), 7.78-7.03 (7H, m), 4.52-4.33 (1 H, m), 4.15-1.65 (22H, m) , 1.39 (9H, s). IR spectrum v max cm "1 (KBr): 2926, 1749, 1646, 1473, 1375, 12BO, 1137. Mass spectrum (FAB) m / z: 815 ((M + H) +, free form) EXAMPLE 27b 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzo-morpholin-2-yl} ethyl) spirof (2S) -2 -r (carboxymethyl) oxy1} indane-1,4'-piperidine 7. 5 g (9.19 mmoles) of 1- (2- { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. ethyl) spiro [(2S) -2- (t-butoxycarbonylmethoxy)] rdan-1,4'-piperidine, obtained in example 27a, was dissolved in 75 ml of methylene chloride and 75 ml of a Aqueous solution of 90% trifluoroacetic acid was added dropwise thereto for 5 minutes. After the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl acetate, washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure to obtain 6.5 9 (yield: 96%) of the title compound. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.20-7.90 (3H, m), 7.86-7.10 (7H, m), 4.55-1.55 (23H, m). IR spectrum v max cm "1 (KBr): 2930, 1726, 1645, 1474, 1376, 1281, 1138. Mass spectrum (FAB) m / z: 759 ((M + H) +, free form) EXAMPLE 27c Sodium salt of 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzo-morpholin-2-yl) ethyl) spirof (2S) - 2-r (carboxymethyl) oxy1) indane-1,4'-piperidine 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro. { (2S) -2 - [(carboxymethyl) oxy]} Cranberry-1,4'-pyperidine, obtained in Example 27b, was dissolved in 15 ml of 1 N aqueous sodium hydroxide solution and the mixture was extracted twice with ethyl acetate, washed with a saturated NaCl solution. and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was recrystallized from n-hexane to obtain 135 mg (yield: 44%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.34-7.98 (3H, m), 7.79-7.01 (7H, m), 4.59-4.42 (1 H, m), 4.21-4.05 (2H, m) , 3.96-2.83 (10H, m), 2.70-1.60 (10H, m). IR spectrum v max cm "1 (KBr): 2922, 1645, 1615, 1280, 1 138. Mass spectrum (FAB) m / z: 759 ((M + H) +, free form) Elemental analysis (for C36H33CI2F6N2NaO5 4H2O) Calculated (%): C: 50.65, H: 4.84, CL8.31, F: 13.35, N: 3.28, Na: 2.69 Found (%): C: 50.59, H: 4.32, Cl: 7.94, R13.07, N: 3.36, Na: 3. 63 Optical rotation: [a] o20 = +43.4 (c = 0.50, methanol) EXAMPLE 28 1- (2-f (2R) -2- (3,4-dichlorofertl) -4-r3,5-bis (trifluoromethyl) benzoyl-1-morpholin-2-yl) ethyl) spirof (2S) -2 hydrochloride -f2- (morpholin-4-yl) -2-oxoethoxy1 > indane-1,4'-piperidine (example compound hydrochloride No. 2-156) 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. ethyl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-pperidine, obtained in Example 27b, was dissolved in 5 ml of methylene chloride and 57 μl (0.79 mmole) of thionyl chloride was added. added to it. A drop of dimethylformamide was added to the mixture, foll by stirring at room temperature for 2 hours. The solvent was distilled under reduced pressure, 5 ml of methylene chloride was added to the obtained residue and 103 μl (1.18 mmoles) of morpholine was added thereto under cooling with ice. After the mixture was stirred at room temperature for 2 hours, it was washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was purified by thin layer chromatography (eluent-solvent: methylene chloride / methanol = 9/1) to obtain 105 mg (yield: 32%) of 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) ester. { (2S) -2- [2- (morpholin-4-yl) -2-oxoethoxy]} indane-1, 4'-piperidine. 1- (2- {(2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl Spiro. { (2S) -2- [2- (Morpholin-4-yl) -2-oxoethoxy]} indane-1, 4'-piperidine thus obtained was dissolved in 4 ml of ethanol and 0.5 ml of hydrochloric acid 4N-dioxane was added thereto. The solvent was distilled under reduced pressure, followed by azeotropia twice with diethyl ether. The residue thus obtained was recrystallized from hexane to obtain 70 mg (yield: 64%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.35-8.00 (3H, m), 7.85-7.08 (7H, m), 4.37-1.58 (31 H, m). IR spectrum v max cm "1 (KBr): 2923, 1650, 1437, 1375, 1280, 1 138. Mass spectrum (FAB) m / z: 828 ((M + H) \ free form) Elemental analysis (for C40H42CI3F6N3O4 3H2O) Calculated (%): C: 52.27, H: 5.26, CI: I1.57, F: 12.40, N: 4.57 Found (%): C: 52.56, H: 5.05, CL 12.14, F: 12.67; N: 4.70 Optical rotation: [OC] D20 = +52.2 (c = 0.50, methanol) EXAMPLE 29 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis hydrochloride ( trifluoromethyl) benzoinmorpholin-2-ii > ethyl) spiro (2S) -2- (2-amino-2-oxoethoxy) 1indane-1? -piperidine (hydrochloride of example compound No. 2-150) The reaction was carried out with a procedure similar to that of Example 28 using 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3,4-dichloropheni) -4- [3.5 -bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-carboxymethoxy] indan-1,4'-piperidine and 2.5 ml of ammonia-water to obtain 162 mg (yield : 52%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD 3 OD) d ppm: 8.32-7.98 (3H, m), 7.87-6.88 (7H, m), 4.30-1.53 (23H, m). IR spectrum v max cm "1 (KBr): 2928, 1645, 1438, 1376, 1280, 1137. Mass spectrum (FAB) m / z: 758 ((M + H) \ free form) Elemental analysis (for C36H36CI3F6N3O4 4H2O) Calculated (%): C: 49.87, 1-1: 5.11, C 12.27, R13.15, N: 4.85 Found (%): C: 49.84, H: 4.81, CL14.91, R13.70, N: 4.83 Optical rotation: [a] o20 = +55.5 (c = 0.50, methanol) EXAMPLE 30 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) hydrochloride benzoipmorpholin-2-yl> ethyl) spirof (2S) -2-r2- (NN-dimethylamino) -2-oxoethoxy1) indane-1,4'-piperidine (hydrochloride of example compound No. 2-151) The reaction was carried out with a procedure similar to that of Example 28 using 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3, 4-dichlorophenyl) -4- [3, 5-bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) ester. { [(2S) -2-carboxymethoxy]]} indane-1, 4'-piperidine and 2.5 ml of an aqueous dimethylamine solution to obtain 166 mg (yield: 51%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.34-8.30 (3H, m), 7.85-7.05 (7H, m), 4.31-1.58 (29H, m). Spectrum of IR v max cm "1 (KBr): 2929, 1650, 1439, 1376, 1280, 1 137 Mass spectrum (FAB) m / z: 786 ((M + H) +, free form) Elemental analysis (for C38H40CI3F6N3O 2H O) Calculated (%): C: 53.13, 1-1: 5.16, 01: 12.38 , R13.27, N: 4.89 Found (%): C.53.37, H: 5.75, Cl.13.39, R12.96, N: 4.60 Optical Rotation: [] o20 = +49.1 (c = 0.50, methanol) EXAMPLE 31 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro (2S) -2-f2-rbis dichlorohydrate ( 2-hydroxyethyl) amino1-2-oxoethoxy)) indane-1,4'-piperidine (dihydrochloride of example compound No. 2-153) The reaction was carried out with a procedure similar to that of Example 28 using 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] indan-1,4'-piperidine and 113 μl (1.18 mmol) of diethanolamine to obtain 87 mg (yield : 25%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.33-8.01 (3H, m), 7.85-7.06 (7H, m), 4.41-1.58 (31 H, m). IR spectrum v max cm "1 (KBr): 2683, 1753, 1645, 1439, 1376, 1281, 1136. Mass spectrum (FAB) m / z: 846 ((M + H) +, free form) Elemental analysis (for C4oH45CI F6N3O6 4H O) Calculated (%): C: 48.45, H: 5.39, Cl: 14.30, F: 11.49, N: 4.24 Found (%): C: 48.51, H: 4.99, CL15.23, F: 11.77, N: 4.28 Optical rotation: [afo20 = +45.8 (c = 0.50, methanol) EXAMPLE 32 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5- hydrochloride bis (trifluoromethyl) benzoyl] morpholin-2-ii > ethyl) spiro ((2S) -2-ffN- (2-hydroxyethyl) -N-methylamino-2-oxoethoxy)) indane-1,4 ' -piperidine (example compound hydrochloride No. 2-155) The reaction was carried out with a procedure similar to that of Example 28 using 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} etl) spiro [(2S) -2-carboxymethoxy] -dane-1,4'-piperidine and 95 μl (1.18 mmoles) of 2 -. { methalamino) ethanol to obtain 162 mg (yield: 48%) of the title compound as a white crystal. Spectrum of 1 H-NMR (500 MHz, CD 3 OD) d ppm: 8.31-7.99 (3H, m), 7.88-7.06 (7H, m), 4.40-1.55 (30H, m). IR spectrum v max cm "1 (KBr): 2928, 1753, 1647, 1473, 1438, 1376, 1280, 1137. Mass spectrum (FAB) m / z: 816 ((M + H) +, free form) Elemental analysis (for C39H41CI2F6N3? 5 4 / 3HCI 3H2O) Calculated (%): C: 50.95, H : 5.30, 01: 12.85, F: 12.40, N.4.57 Found (%): C: 50.63, H: 5.13, CL13.77, F: 13.05, N: 4.49 Optical rotation: [a] D20 = +50.3 (c = 0.33, methanol) EXAMPLE 33 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzo-morpholin-2-yl) ethyl chloride ) spiro ((2S) -2-f2-rN- (2-hydroxyethyl) amino1-2-oxoethoxy)) indane-1,4'-piperidine (example compound hydrochloride No. 2-154) The reaction was carried out with a procedure similar to that of Example 28 using 300 mg (0.39 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -b, (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) esprro [(2S) -2-carboxymethoxy] indan-1,4'-piperidine and 71 μl (1.18 mmol) ) of ethanolamine to obtain 142 mg (yield: 43%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.33-7.98 (3H, m), 7.86-7.08 (7H, m), 4.32-1.53 (27H, m.). IR spectrum v max cm-1 (KBr): 2928, 1647, 1439, 1376, 1280, 1137. Mass spectrum (FAB) m / z: 802 ((M + H) +, free form) Elemental analysis (for C38H4oCI3F6N3? 5 3H2O) Calculated (%): C: 51.10, H: 5.19, CM 1.91, F: 12.76, N: 4.70 Found (%): C: 51.00, H: 4.95, CL12.76, F: 13.00, N : 4.72 Optical rotation: [CC] D20 = +58.4 (c = 0.50, methanol) EXAMPLE 34 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) hydrochloride ) benzoipromolin-2-yl) ethyl) spirof (2S) -2-r2- (piperidin-1-yl) -2-oxoethoxy1 > - indane-1,4'-piperidine (example compound hydrochloride No. 2-157) The reaction was carried out with a procedure similar to that of Example 28 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 119 μl (1.18 mmol) of piperidine to obtain 168 mg (yield: 50%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 3358, 2931, 1720, 1645, 1476, 1376, 1280, 1139. Mass spectrum (FAB) m / z: 831 ((M + H) +, free form) EXAMPLE 35 1 - (2-f (2R) -2- (3,4-Dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzopromolin-2-yl) ethyl) spirof (2S) -2 hydrochloride - (2-hydroxyethoxy) lindane-1,4'-piperidine (hydrochloride of example compound No. 2-159) EXAMPLE 35a 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) etl) spiro (2S) -2- (2- hydroxyethoxy) 1indane-1,4'-piperidine 3 g (3.95 mmol) of 1- (2- { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2- ethyl) spiro [(2S) -2-carboxymethoxy] indan-1,4'-piperidine, obtained in Example 27b, was dissolved in 30 ml of tetrahydrofuran and 5.9 ml (5.9 mmoles) ) of borane-tetrahydrofuran complex (1 mol / l tetrahydrofuran solution) was added dropwise thereto under ice cooling for 10 minutes. After the mixture was stirred under ice cooling for 30 minutes, the temperature of the mixture returned to room temperature, followed by stirring for 1 hour. Water was added thereto and the mixture was quenched and extracted with ethyl acetate. The extract was washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / methane 100/2) to obtain 2.1 9 (yield: 71%) of the title compound. 1 H NMR spectrum (500 MHz, CD3OD) d ppm: 8.20-7.90 (3H, m), 7.82-7.06 (7H, m), 4.40-1.42 (25H, m). IR spectrum v max cm "1 (KBr): 2924, 1645, 1473, 1375, 1281, 1 139. Mass spectrum (FAB) m / z: 745 ((M + H) +, free form) EXAMPLE 35b Hydrochloride 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoyl-1-morpholin-2-yl> ethyl) -spiror (2S) -2- (2- HydroxyethoxyHindane-1,4'-piperidine 300 mg (0.4 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. ethyl) spiro [(2S) -2- (2-hydroxyethoxy)] indane-1,4'-piperidine, obtained in example 35a, was dissolved in 6 ml of ethanol and 0.5 ml of hydrochloric acid 4N-dioxane was added to the same. The solvent was distilled under reduced pressure, followed by azeotropy twice with diethyl ether. The residue thus obtained was recrystallized from hexane to obtain 215 mg (yield: 68%) of the title compound as a white crystal. Spectrum of 1 H-NMR (500 MHz, CD 3 OD) d ppm: 8.31-8.00 (3H, m), 7.85-7.05 (7H, m), 4.20-1.50 (25H, m). IR spectrum v max cm "1 (KBr): 2928, 1645, 1438, 1376, 1280, 1 137. Mass spectrum (FAB) m / z: 745 ((M + H) +, free form) Elemental analysis ( for C 36 H 37 Cl 3 F 6 N 2 O 2 H 2 O) Calculated (%): C: 52.92, H.4.93, CM 3.02, F: 13.95, N: 3.43 Found (%): C: 52.61, H: 4.70, Cl: 12.68, R14.22, N. 3.48 Optical rotation: [a] D20 = +43.3 (c = 0.50, methanol) EXAMPLE 36 1 - (2-f (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spirof (2S) -2- dihydrochloride r 2 - (morpholin-4-yl) etox p) indane-1,4'-piperidine (dihydrochloride of example compound No. 2-166) 200 mg (0.27 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2- (2-hydroxyethoxy)] indane-1,4'-piperidine, obtained in example 35b, was dissolved in 4 ml of methylene chloride and 56 μl (0.4 mmol) of triethylamine was added thereto, and 27 μl (0.35 mmol) of methanesulfonyl chloride was added to the mixture under cooling with ice, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was dissolved in 6 ml of dimethylacetamide. 34 mg (0.35 mmol) of sodium bicarbonate, 66 mg (0.35 mmol) of potassium iodide and 35 μl (0.35 mmol) of morpholine were added to the solution, and the mixture was stirred at 80 ° C for 8 hours. The temperature of the reaction mixture returned to room temperature, and the mixture was poured into water, followed by extraction twice with ethyl acetate. The ethyl acetate layer was combined, washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the obtained residue was purified by thin layer chromatography (eluent-solvent: methylene chloride / methanol = 9/1) to obtain 125 mg (yield: 57%) of 1-. { 2-. { . { 2R) -2- (3,4-dichlorophenyl) -4- [3,5-b] s. { trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro. { . { 2S) -2- [2 - [(morpholin-4-yl) ethoxy]} Cranberry-1,4'-piperidine. 125 mg (0.15 mmoles) of 1- (2- { { 2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2 -il} ethyl) spiro. { . { 2S) -2- [2- (morpholin-4-yl) ethoxy]} Indane-1, 4'-piperidine obtained was dissolved in 3 ml of ethanol and 0.5 ml of hydrochloric acid 4N-dioxane was added thereto. The solvent was distilled under reduced pressure, followed by azeotropy twice with diethyl ether. The residue thus obtained was recrystallized from hexane to obtain 97 mg (yield: 74%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.35-8.01 (3H, m), 7.88-7.08. { 7H, m), 4.29-1.60 (33H, m). IR spectrum v max cm "1 (KBr): 2927, 2571, 1644, 1439, 1376, 1281, 1136. Mass spectrum (FAB) m / z: 814 ((M + H) +, free form) Elemental analysis (for C40H 5CI4F6N3O4 4H2O) Calculated (%): C: 50.06, H: 5.57, CL14.78, F: 1 1.88, N; 4.38 Found (%); C: 48.62, H: 5.03, Cl: 15.27, R11. 61, N: 3.48 Optical rotation: [a] D20 = +48.7 (c = 0.50, methanol) EXAMPLE 37 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spirof (2S) dihydrochloride -2-r2- (piperidin-1-yl) etoxp > indane-1,4'-piperidine (dihydrochloride of example compound No. 2-167) The reaction was carried out with a procedure similar to that of example 36 using 200 mg (0.27 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) espyro [(2S) -2- (2-hydroxyethoxy)] indane-1,4'-piperidine and 40 μl (0.4 mmol) of piperidine to obtain 32 mg (yield: 14%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.31-8.00 (3H, m), 7.88-7.07 (7H, m), 4.31-1.51 (35H, m). IR spectrum v max cm "1 (KBr): 2943, 2650, 1644, 1439, 1376, 1281, 1137. Mass spectrum (FAB) m / z: 812 ((M + H) \ free form) Elemental analysis ( for C4? H47CI4F6N3O3 8H2O) Calculated (%): C: 47.B2, H: 6.17, 01: 13.77, R11.07, N: 4.08 Found (%): C: 48.29, H: 5.26, 01: 15.53, R .11.03, N: 4.27 Optical rotation: [a] D20 = +44.0 (c = 0.50, methanol) EXAMPLE 38 1 - (2- (2R) -2- (3,4-dichlorophenyl) -4-r3.5- dihydrochloride bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spirof (2S) -2-r2- (N, N-dimethylamino) ethoxy p> - indane-1,4'-piperidine (dihydrochloride of compound of example No 2-61) The reaction was carried out with a procedure similar to that of example 36 using 200 mg. { 0.27 mmoles) of 1-. { 2-. { . { 2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis. { trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [. { 2S) -2-. { 2-hydroxyethoxy)] indane-1,4'-piperidine and 33 mg. { 0.4 mmoles) of dimethylamine hydrochloride to obtain 54 mg (yield: 25%) of the title compound as a white crystal. 1 H-NMR spectrum. { 500 MHz, CD3OD) d ppm: 8.31-8.00 (3H, m), 7.87-7.08 (7H, m), 4.35-1.53 (31H, m). IR spectrum v max cm "1 (KBr): 2927, 2654, 1644, 1474, 1376, 1281, 1137. Mass spectrum (FAB) m / z: 772 ((M + H) +, free form) Elemental analysis (for C38H43CI F6N3? 3 3H2O) Calculated (%): 0: 50.73, H.5.49, 01: 15.76, R.12.67, N.4.67 Found (%): 0: 47.55, H: 5.23, 01: 16.68, F : 12.43, N: 4.48 Optical rotation: [a] D20 = +50.5 (c = 0.50, methanol) EXAMPLE 39 Dihydrochloride of 1-f 2-ff 2R) -2-f3.4-dichlorophenyl) -4-r3.5 bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spirof2S) -2-f2- [N-f2-hydroxyethyl) -N-methylamino-1-ethoxy »indane-1.4'-piperidine (dihydrochloride of example compound No. 2 -165) The reaction was carried out with a procedure similar to that of example 36 using 200 mg (0.27 mmoles) of 1-. { 2-. { . { 2R) -2-. { 3,4-dichlorophenyl) -4- (3,5-bis { Trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [. { 2S) -2- (2-hydroxyethoxy)] indane-1,4, -piperidine and 32 μl (0.4 mmoles) of 2-. { methylamino) ethanol to obtain 158 mg (yield: 70%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.30-8.01 (3H, m), 7.87-7.08 (7H, m), 4.28-1.54 (32H, m). IR spectrum v max cm'1 (KBr): 2928, 2654, 1644, 1473, 1376, 1281, 1138. Mass spectrum (FAB) m / z: 802 ((M + H) +, free form) Elemental analysis (for C39H45CI4F6N3O4 3H2O) Calculated (%): 0: 50.39, H: 5.53, Cl: 15.25, F: 12.26, N: 4.52 Found (%): C: 50.00, H.5.50, 01: 15.22, F: 11.16, N: 4.30 Optical rotation: [a] D20: +52.3 (c: 0.50, methanol) EXAMPLE 40 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spiro (2S) -2- f2-rN- (2-hydroxyethyl) amino-1-ethoxy »indane-1,4'-piperidine (dihydrochloride of example compound No. 2-164) The reaction was carried out with a procedure similar to that of example 36 using 200 mg (0.27 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3, 5-bis (trifluoromethyl) benzoyl] morpholin-2-yl.} Ethyl) spiro [(2S) -2- (2-hydroxyethoxy)] indane-1,4'-pyperidine and 24 μl (0.4 mmol) of Ethanolamine to obtain 96 mg (yield: 43%) of the title compound as a white crystal. Spectrum of 1 H-NMR (500 MHz, CD 3 OD) d ppm: 8.30-8.02 (3H, m), 7.87-7.06 (7H, m), 4.28-1.50 (29H, m). IR spectrum v max cm "1 (KBr): 2930, 2681, 1644, 1439, 1376, 1280, 1138. Mass spectrum (FAB) m / z: 788 ((M + H) \ free form) Elemental analysis ( for C38H43CI4F6N3O 4H2O) Calculated (%): C: 48.89, H: 5.51, 01: 15.19, F: 12.21, N: 4.50 Found (%): 0: 48.75, H: 4: 79, 01: 15.85, R12.20 , N: 4.57 Optical rotation: [a] D20 = +52.5 (c = 0.50, methanol) EXAMPLE 41 Dihydrochloride of 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro ((2S) -2-f2-rbis (2-hydroxyethyl) amino-1-ethoxy »indane-1,4'-piperidine (dihydrochloride of example compound No. 2- 163) The reaction was carried out with a procedure similar to that of example 36 using 200 mg (0.27 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- (3.5 -b? s (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro ((2S) -2-hydroxy] indan-1,4'-piperidine and 33 μl (0.35 mmol) of diethanolamine to get 90 mg (yield: 39%) of the title compound as a white crystal. IR spectrum v max cm'1 (KBr): 3358, 2931, 1720, 1645, 1476, 1376, 1280, 1139 Mass spectrum (FAB) m / z: 832 ((M + H) +, free form) EXAMPLE 42 1 - (2- (2R) -2- (3,4-Dichlorophenyl) -4- (3,5-bis (trifluoromethyl) benzoyl-1-morpholin-2-yl> ethyl) spiro ((2S) -2-f ( f (bis (2-hydroxyethyl) aminolcarbonyl) amino) carbonyl] oxy)) indane-1,4'-piperidine (hydrochloride of example compound No. 2-172) 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. ethyl) spiro ((2S) -2-hydroxy] indane-1,4'-piperidine was dissolved in 5 ml of methylene chloride and 55 μl (0.64 mmoles) of N- (chlorocarbonyl) isocyanate was added thereto under ice cooling After the mixture was stirred under ice cooling for 30 minutes, 61 μl (0.64 mmol) of diethanolamine was added thereto and the mixture was stirred under ice cooling for 30 minutes. The mixture was returned to room temperature and the mixture was stirred for 1 hour, washed successively with 1 N aqueous hydrochloric acid, water and saturated NaCl solution and dried over anhydrous sodium sulfate.The solvent was distilled under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent-solvent: methylene chloride / methanol = 9/1) to obtain 223 mg (yield: 60%) of 1- ( 2- { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro. { (2S) -2-. { [( { [bis (2-hydroxyethyl) amino] carbonyl}. amino) carbonyl] oxy} lynde-1,4, -pyridine. 223 mg (0.25 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl. .}. etl) spiro [(2S) -2-. { [( { [bis (2-Hydroxyethyl) amino] carbonyl.} amino) carbonyl] oxy} Blueberry-1,4'-piperidine obtained was dissolved in 4 ml of ethanol and 0.5 ml of hydrochloric acid 4N-dioxane was added thereto. The solvent was distilled under reduced pressure, followed by azeotropy twice with diethyl ether. The residue thus obtained was recrystallized from hexane to obtain 179 mg (yield: 77%) of the title compound as a white crystal. Spectrum of 1 H-NMR (500 MHz, CD3OD) d ppm: 8.33-7.99 (3H, m), 7.85-7.06 (7H, m), 5.34-5.20 (1 H, m), 4.15-1.65 (29H, m) .

IR spectrum v max cm'1 (KBr): 3394, 2931, 1764, 1646, 1474, 1376, 1281, 1138. Mass spectrum (FAB) m / z: 875 ((M + H) +, free form) Elemental Analysis (for C40H 3OI3F6N O74H2O) Calculated (%): 0: 48.81, H: 5.22, 01: 10.81, R11.58, N: 5.69 Found (%): 0: 49.02, H: 4.92, 01: 11.62, R11 .50, N: 5.86 Optical Rotation: [a] D20 = +54.3 (c = 0.50, methanol) EXAMPLE 43 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4- (3,5-bis (trifluoromethyl) benzoyl-1-morpholin-2-yl> ethyl) spiro hydrochloride. (2S) -2- ((f [(morpholin-4-yl) carbonyl] amino > carbonyl) oxy1 > indane-1,4'-p-periadid (hydrochloride of example compound No. 2-175) The reaction was carried out with a procedure similar to that of Example 42 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spy [(2S) -2-hydroxy] indan-1,4, -piperidine and 56 μl (0.64 mmol) of morpholine to obtain 240 mg (yield: 63%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 3358, 2931, 1720, 1645, 1476, 1376, 1280, 1139. Mass spectrum (FAB) m / z: 857 ((M + H) +, free form) EXAMPLE 44 1 - (2-f (2R) -2- (3,4-dichlorophenyl) hydrochloride ) -4- (3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spirof (2S) -2-r (fr (piperidin-1-yl) carboninylamino) -carbonyl) oxyTlindane-1,4'-piperidine ( Example compound hydrochloride No. 2-176) The reaction was carried out with a procedure similar to that of Example 42 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spin [(2S) -2-hydroxy] indan-1,4'-piperidine and 64 μl (0.64 mmol) of piperidine to obtain 143 mg (yield: 38%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 3358, 2931, 1720, 1645, 1476, 1376, 1280, 1139. Mass spectrum (FAB) m / z: 855 (M + H) +, free form) EXAMPLE 45 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro ((2S) -2-fr hydrochloride (fN- (2-hydroxyethyl) -N-methylamino-1-carbonyl) amino) carbonyl] oxy)) indane-1,4'-piperidine (hydrochloride of example compound No. 2-174) The reaction was carried out with a procedure similar to that of Example 42 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3, 4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine and 52 μl (0.64 mmol) of 2- (methylamino) ethanol to obtain 181 mg (yield: 48%) of the title compound as a white crystal 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.34-7.98 (3H, m), 7.84-7.10 (7H, m), 5.34-5.20 (1 H, m), 4.17-1.64 (28H, m) . IR spectrum v max cm "1 (KBr): 3272, 2930, 1765, 1646, 1475, 1376, 1280, 1138. Mass spectrum (FAB) m / z: 845 ((M + H) +, free form) Elemental Analysis (for C39H4? C! 3F6N? 6 3H2O) Calculated (%): C: 50.04, H: 5.06, 01: 11.36, R12.18, N: 5.06 Found (%): 0: 50.69, H.4.82, Cl: 11.00, R 11.66, N: 6.20 Optical rotation: [a] D20 = +55.8 (c = 0.50, methanol) EXAMPLE 46 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spiro ((2S) -2-fr hydrochloride (frN- (2-hydroxyethyl) amino-1-carbonyl) amino) carbonyl-1oxy} ) indane-1, 4'-piperidine (hydrochloride of example compound No. 2-173) The reaction was carried out with a procedure similar to that of example 42 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -b¡s (trifluoromethyl) benzoyl) morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy) indane-1,4'-piperidine and 39 μl (0.64 mmole) of ethanolamine to obtain 192 mg (yield: 52%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.31-7.98 (3H, m), 7.90-7.10 (7H, m), 5.24-5.11 (1 H, m), 4.15-1.65 (25H, m) . IR spectrum v max cm "1 (KBr): 3358, 2931, 1720, 1645, 1476, 1 376, 1280, 1 139. Mass spectrum (FAB) m / z: 831 ((M + H) +, form free) Elemental analysis (for C38H39CI3F6N4O6 2H2O) Calculated (%): C: 50.48, H: 4.79, 01: 1 1.76, R12.61, N: 6.20 Found (%): C: 50.69, H: 4.82, 01: 11.93 , R 12.09, N: 6.20 Optical rotation: [a] D20 = +69.3 (c = 0.50, methanol) EXAMPLE 47 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoyl) morpholin-2-yl ethyl) esp? Rof hydrochloride (2S) - 2-f (ff (morpholin-4-ll) sulfoninamino-carbonyl) oxy)) indane-1,4'-pperidine (example compound hydrochloride No. 2-184) 300 mg (0.43 mmol) of 1-. { 2-. { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis. { trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine was dissolved in 5 ml of methylene chloride and 63 μl (0.64 mmoles) of isocyanate-sulfonyl chloride was added thereto under cooling with ice. After the mixture was stirred under ice cooling for 30 minutes, 56 μl (0.64 mmoles) of morpholine was added thereto and the mixture was stirred under ice cooling for 30 minutes. After the temperature of the mixture returned to room temperature and the mixture was stirred for 1 hour, the mixture was washed successively with 1N hydrochloric acid solution, water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was recrystallized from methanol-water to obtain 215 mg (yield: 56%) of 1- (2. {(2R) -2- (3,4- dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl-morpholin-2-yl} ethyl) -spray [(2S.) -2- ( { [(morpholin-4-yl) -sulfonyl) amino] carbonyl.} oxy) lndan-1,4'-pperiodine 215 mg (0.24 mmol) of 1- (2- ({2R) -2- (3 , 4-dichlorophen-I) -4- [3,5-bis (trifluoromethyl) benzoylmorpholin-2-yl} ethyl) spiro [(2S) -2- ( { [(Morpholin-4-yl) -sulfonyl) amino] carbonyl.}. oxy)] indane-1,4'-piperidine obtained was dissolved in 4 ml of ethanol and 0.5 ml of hydrochloric acid 4N-dioxane was added thereto The solvent was distilled under reduced pressure followed by azeotropy twice with diethyl ether The residue thus obtained was recrystallized from hexane to obtain 181 mg (yield: 81%) of the title compound as a white crystal, 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.31-7.99 (3H, m), 7.8 7-7.10 (7H, m), 5.35-5.25 (1 H, m), 4.21-1.68 (28H, m). IR spectrum v max cm "1 (KBr): 2926, 1741, 1645, 1455, 1375, 1281, 1 162. Mass spectrum (FAB) m / z: 893 ((M + H) +, free form) Elemental analysis (for C39H41CI3F6N4O7S 2H2O) Calculated (%): C: 48.48, H.4.69, 01: 11.01 , R11.80, N: 5.80, S: 3.32 Found (%.}.: 0: 48.11, H: 4.66, 01: 11.25, F: 11.83, N: 5.87, S: 3.38 Optical Rotation: [a] D20 = +61.7 (c = 0.50, DMSO) EXAMPLE 48 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoipmorpholin-2-yl.} Etl) espiror (2S) -2 hydrochloride - (f [(aminosulfonyl) aminocarbonyl> oxy) 1indane-1,4'-piperidine (example compound hydrochloride No. 2-178) The reaction was carried out with a procedure similar to that of Example 47 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 2.5 ml of ammonia-water to obtain 70 mg (yield: 12 %) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.35-7.97 (3H, m), 7.81-7.08 (7H, m), 5.48-5.19 (1H, m), 4.01-1.70 (20H, m). Spectrum of IR v rnax cm "1 (KBr): 2927, 1644, 1439, 1376, 1280, 1139 Mass spectrum (FAB) m / z: 823 ((M + H) +, free form) Elemental analysis (for C35H34CI2F6N4O6S 1 / 3HCI 2H2O) Calculated (%): C.48.22, H: 4.43, Cl: 9.49, F: 13.07, N: 6.43, S: 3.68 Found (%): 0: 48.21, H: 4.29, 01: 10.09, R13.39, N: 6.34, S: 3.58 Optical Rotation: [a] D20 = +55.0 ( c = 0.50, DMSO) EXAMPLE 49 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoyl-1-morpholin-2-yl} ethyl) spirof (2S) -2 hydrochloride - (fr (N, N-dimethylaminosulfonyl) amino1 carbonyl > oxy)] indane-1,4'-piperidine (hydrochloride of example compound No. 2-179) The reaction was carried out with a procedure similar to that of Example 47 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 2.5 ml of an aqueous dimethylamine solution to obtain 90 mg (yield : 25%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.36-7.98 (3H, m), 7.82-7.10 (7H, m), 5.35-5.29 (1 H, m), 3.99-1.65 (26H, m ). IR spectrum v max cm "1 (KBr): 2954, 1643, 1473, 1375, 1281, 1 138. Mass spectrum (FAB) m / z: 851 ((M + H) +, free form) Elemental analysis ( for C37H38CI2F6N4O6S 1 / 4HCI H2O) Calculated (%): C: 50.57, H: 4.62, Cl: 9.08, F: 12.97, N: 6.38, S.3.65 Found (%): C: 50.45, H: 4.43, 01: 9.12, F: 13.31, N; 6.24, S: 3.71 Optical rotation: [a] D20 = +57.8 (c = 0.50, DMSO) EXAMPLE 50 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spiro ((2S) -2-fr ( frN- (2-hydroxyethyl) -N-methylamino-sulfonyl > amino) carbonyl-1-oxy)) indane-1,4'-piperidine (example compound No. 2-183) The reaction was carried out with a procedure similar to that of Example 47 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -bis (trifluoromethyl) benzoyl] morpholin-2-yl.} etl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine and 52 μl (0.64) mmoles) of 2- (methylamino) ethanol to obtain 30 mg (yield: 8%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.35-7.98 (3H, m), 7.84-7.06 (7H, m), 5.38-5.23 (1H, m), 3.98-1.70 (27H, m). IR spectrum v max cm "1 (KBr): 2928, 1642, 1473, 1376, 1281, 1139. Mass spectrum (FAB) m / z: 881 ((M + H) +, free form) Elemental analysis (for C38H40CI2F6N O7S 3H2O) Calculated (%): C: 48.78, H: 4.95, Cl: 7.58, F: 12.18, N: 5.99, S: 3.43 Found (%): C: 48.52, H: 4.40, Cl: 7.81, F : 11.81, N: 6.22, S: 3.21 Optical rotation: [] D20 = +39.7 (c = 0.50, DMSO) EXAMPLE 51 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl) ethyl) spiro ((2S) -2-f [ (fN- (2-hydroxyethyl) amino] sulfonyl.) amino) carbonyl] -oxi »indane-1,4'-piperidine (example compound No. 2-182) The reaction was carried out with a procedure similar to that of Example 47 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 39 μl (0.64 mmol) of ethanolamine to obtain 67 mg (yield : 17%) of the title compound as a white crystal. 1H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.31-7.97 (3H, m), 7.78-7.03 (7H, m), 5.37-5.20 (1 H, m), 3.98-1.68 (24H, m) . IR spectrum v max cm'1 (KBr): 2927, 1642, 1475, 1376, 1281, 1138. Mass spectrum (FAB) m / z: 867 ((M + H) +, free form) Elemental analysis (for C 37 H 38 Cl 2 F 6 N O 7 S 2 H 2 O) Calculated (%): C: 49.18, H: 4.68, Cl: 7.85, F: 12.61, N: 6.20, S: 3.55 Found (%): C: 49.10, H: 4.45, Cl: 8.53, F : 12.67, N: 6.23, S: 3.29 Optical rotation: [a] D20 = +47.6 (c = 0.50, DMSO) EXAMPLE 52 1- (2-f (2R) -2- (3,4-dichlorophenyl) -4 hydrochloride -r3.5-bis (trifluoromethyl) benzoipmorpholin-2-yl ') ethyl) spiro ((2S) -2-ff (2-hydroxyethyl) aminol sulfonyl) amino) carbon.poxy} ) indane-1, 4'-piperidine (example compound hydrochloride No. 2-181) The reaction was carried out with a procedure similar to that of Example 47 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) espyr [(2S) -2-hydroxy] indane-1,4-piperidine and 61 μl (0.64 mmol) of diethanolamine to obtain 60 mg (yield: 16%) of the title compound as a white crystal. IR spectrum v max cm'1 (KBr): 3406, 2930, 1733, 1643, 1473, 1376, 1281, 1139. Mass spectrum (FAB) m / z: 911 ((M + H) +, free form) EXAMPLE 53 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl.} Ethyl) spirof (2S) -2-r hydrochloride (fr (morpholin-4-yl) acetynamino > -carbonyl) oxy]) indane-1,4'-piperidine (hydrochloride of example compound No. 2-187) 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indane-1,4'-piperidine was dissolved in 5 ml of methylene chloride and 55 μl (0.64 mmoles) of N- (chloroacetyl) isocyanate was added to the same under cooling with ice. After the mixture was stirred under ice cooling for 30 minutes, 56 μl (0.64 mmoles) of morpholine was added thereto, followed by stirring under ice cooling for 30 minutes. After the temperature of the mixture returned to room temperature and the mixture was stirred for 1 hour, it was washed successively with 1N hydrochloric acid solution, water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was purified by thin layer chromatography (eluent-solvent: methylene chloride / methanol = 9/1) to obtain 248 mg (yield: 67%) of 1- (2- . (2R) -2- (3,4-dichlorophenyl) -4- (3,5-bis (trifluoromethyl) benzoyl) morpholin-2-yl} ethyl) spiro. { (2S) -2 - [( { [(Morpholin-4-yl) acetyl) amino} carbonyl) oxy)} indane-1, 4'-pperidine. 248 mg (0.29 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- (3,5-bis (trifluoromethyl) benzoyl) morpholin-2-yl.} eti) spiro. { (2S) -2 - [( { [(Morpholin-4-yl) acetylamino.} Carbonyl) oxy]} Indane-1, 4'-piperidine obtained was dissolved in 4 ml of ethanol and 0.5 ml of hydrochloric acid 4N-dioxane was added thereto. The solvent was distilled under reduced pressure, followed by azeotropy twice with diethyl ether. The residue thus obtained was recrystallized from hexane to obtain 224 mg (yield: 84%) of the title compound as a white crystal. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 8.34-7.79 (3H, m), 7.86-7.1 1 (7H, m), 5.35-5.27 (1 H, m), 4.55-1.66 (30H, m ).

IR spectrum v max cm "1 (KBr): 2932, 1785, 171.9, 1644, 1475, 1376, 1281, 1137. Mass spectrum (FAB) m / z: 871 ((M + H) +, free form ) Elemental analysis (for C41H44CI4F6N4O6 3H2O) Calculated (%): C: 49.31, H: 5.05, Cl: 14.20, F: 11.41, N: 5.61 Found (%): 0: 49.21, H: 4.91, 01: 14.76, R11.62, N: 5.64 Optical rotation: [a] o20 = +59.4 (c = 0.50, methanol) EXAMPLE 54 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoyl] morpholin-2-yl> ethyl) spirof (2S) -2- hydrochloride [(aminocarbonyl) ox?) indane-1,4'-piperidine (hydrochloride of example compound No. 2-190) The reaction was carried out with a procedure similar to that of Example 53 using 300 mg (0.43.mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3, 5-bis (trifluoromethyl) benzoyl] morpholin-2-yl.} Ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 1 ml of ammonia-water to obtain 134 mg (yield : 40%) of the title compound as a white crystal. IR spectrum v max cm "1 (KBr): 2928, 1726, 1645, 1438, 1376, 1281, 1138. Mass spectrum (FAB) m / z: 744 ((M + H) +, free form) EXAMPLE 55 1 - (2-f (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoinmorpholin-2-yl> ethyl) spirof (2S) -2-f (ff piperidin-1-yl) acetylamino) carbonyl) oxy]) indane-1,4'-piperidine (example compound hydrochloride No. 2-188) The reaction was carried out with a procedure similar to that of Example 53 using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4'-piperidine and 64 μl (0.64 mmol) of piperidine to obtain 217 mg (yield : 56%) of the title compound as a white crystal. IR spectrum v max cm'1 (KBr): 3358, 2931, 1720, 1645, 1476, 1376, 1280, 1 139. Mass spectrum (FAB) m / z: 869 ((M + H) +, free form .}.

EXAMPLE 56 1- (2-f (2R) -2- (3,4-Dichlorophenyl) -4-r3.5-bis (trifluorornethyl) benzoinmorpholin-2-yl) ethyl) spirof (2S) -2-r (2- methoxyethoxy) methoxy1) indane-1,4'-piperidine (example compound No. 2-191) The reaction was carried out with a procedure similar to that of Example 27a using 300 mg (0.43 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S.) -2-hydroxy] indane-1,4'-piperidine and 73 μl (0.64 mmol. -methoxyethoxymethyl to obtain 110 mg (yield: 34%) of the title compound as a white crystal: IR spectrum v max cm "1 (KBr): 2926, 1645, 1472, 1375, 1280, 1 137. Mass spectrum ( FAB) m / z: 789 ((M + H) +, free form) EXAMPLE 57 1- (2-f (2R> -2- (3,4-dichlorophenol) -4-r3.5-bis (trifluoromethyl] -benzoyl-1-morpholin-2-yl) ethyl) spirof (2S) -2 - (2-methoxymethoxy) 1-amino-1,4'-piperidine (compound of example No. 2-192) The reaction was carried out with a procedure similar to that of example 27a using 300 mg (0.43 mmol.) Of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-hydroxy] indan-1,4-piperidine and 49 μl (0.64 mmol) of chloromethylmethyl ether to obtain 121 mg (yield: 37%) of the title compound as a white crystal: IR spectrum v max cm "1 (KBr): 2928, 1646, 1472, 1375, 1280, 1139. Mass spectrum (FAB) m / z: 745 ((M + H) \ free form) EXAMPLE 58 2-H (2S) -1 '-f 2-r (2R) ^ 4-r3.5-b¡s (trifluoromethyl) benzoyl hydrochloride n-2- (3,4-dichlorophenyl) morpholin-2-ipeti »-2,3-dihydrospirofindene-1,4'-piperidin] -2-yl) oxy-1 N- (4-hydroxybutyl) -N-methylacetamide (hydrochloride of example compound No 2-418) EXAMPLE 58a 4- (Methylamino) butan-1-ol hydrochloride 4. 00 g (0.045 mol) of 4-aminobutan-1-ol was dissolved in 10 ml of ethyl formate and the mixture was refluxed for 6 hours. After the temperature of the mixture returned to room temperature, the solvent was distilled under reduced pressure and the residue thus obtained was purified by column chromatography on silica gel (eluent-solvent: ethyl acetate / methylene chloride / methanol = 5: 5: 1) to obtain 4.16 g (yield: 79%) of 4-hydroxybutylformamide. 4.16 g (0.036 mole) of the obtained 4-hydroxybutylformamide was dissolved in 10 ml of anhydrous tetrahydrofuran and then the mixture was stirred at 0 ° C under nitrogen atmosphere. 1.35 g (0.036 mole) of lithium aluminum hydride was added to the reaction solution for 5 minutes and then the mixture was refluxed. After 6 hours, the reaction mixture was cooled to 0 ° C and 5.00 g of 10 sodium sulfate hydrates and 40 ml of tetrahydrofuran were slowly added thereto for 10 minutes. Then, the mixture was stirred until the reaction mixture became turbid white. The precipitated substance was removed by filtration and after 10 ml of 4N-dioxane hydrochloric acid were added thereto little by little while the residue was cooled to 0 ° C, the solvent was distilled to obtain 4.51 g (yield: 91% ) of the title compound. 1 H-NMR spectrum (400 MHz, CD3OD) d ppm: 3.61 (2H, t, J = 6.1 Hz), 3.02 (2H, t, 7.7 Hz), 2.70 (3H, s), 1.81-1.73 (2H, m), 1.65-1.58 (2H, m).

EXAMPLE 58b 2-f ((2S) -1 '-f 2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoyl-1-2- (3,4-dichlorophenol) hydrochloride morpholin-2-yl] ethyl) -2,3-dihydrospiro [indene-1,4'-p¡perdin1-2- 1) oxy1-N- (4-hydroxybutyl) -N-methylacetamide 3 g (3.95 mmol) of 1- (2- { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-piperidine, obtained in example 27b, was dissolved in 10 ml of methylene chloride and 406 ml (4.74 mmoles) of oxalyl chloride was added. added to it. A drop of dimethylformamide was added to the mixture, followed by stirring at room temperature for 20 minutes. 169 μl (1.98 mmol) of oxalyl chloride was added again thereto and the mixture was further stirred for 20 minutes The solution in which the residue obtained by distillation of the solvent under reduced pressure was dissolved in 10 ml of sodium chloride. methylene was added dropwise to a solution of 4- (methylamino) butan-1-ol hydrochloride, obtained in Example 58a, and 1.93 ml (13.9 mmol) of triethylamine in methylene chloride (5 ml) and the mixture was stirred for 30 minutes. The reaction mixture was washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was purified by column chromatography on silica gel (eluent-solvent: ethyl acetate / methylene chloride / methanol = 5/5 / 0-1) to obtain 1.89 g ( yield: 57%) of 2 - [((2S) -11- {2 - [(2R) -4- [3 [5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] etl.) -2,3-dihydrospyrro [indene-1,4'-piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide. The 2 - [((2S) -1'- { 2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-! I] ethyl.} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide thus obtained was dissolved in 20 ml of acetate of ethyl and the mixture was extracted with 20 ml of 1 N aqueous hydrochloric acid solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The amorphous material thus obtained was collected by filtration by the addition of n-hexane to obtain 1.89 g (yield: 96%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 8.20-7.14 (10H, m), 4.37-1.53 (34H, m). IR spectrum v max cm "1 (KBr): 3407, 2930, 1649; 1474, 1439, 1376, 1281, 1185, 1139, 1108 Mass Spectrum (FAB) m / z: 844 ((M + H) +, free form) Elemental Analysis (for C4? H45CI2F6N3? 5 HCl H2O) Calculated (% ): C: 54,771 H: 5,381 01: 11,831 N: 4.67. Found (%): 0: 54.921 H: 5.471 01: 11.591 N: 4.59.

EXAMPLE 59 2-r ((2S) -1, -f2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl) -2, 3-dihydro-spiro-denodene-1,4'-piperidin-1-yl) -oxi-N- (4-hydroxybutyl) -N-methylacetamide (example compound No. 2-418) 600 mg (0.68 mmol) of 2 - [((2S) -1 '-. {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4-dichlorophenyl) morpholin-2-yl] ethyl.} -2,3-dihydro-spiro [indene-1,4'-piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) - N-methylacetamide, obtained in example 58, was dissolved in 50 ml of ethyl acetate and the mixture was washed successively with 100 ml of a saturated aqueous sodium bicarbonate solution and a saturated NaCl solution and dried over sodium sulfate. anhydrous. The solvent was distilled under reduced pressure to obtain 575 mg (yield: 100%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.10-7.10 (10H, m), 4.70-1.20 (34H, m). IR spectrum v max cm "1 (KBr): 3431, 2928, 1645, 1473, 1440, 1375, 1281, 1184, 1138, 1097, 1030, 90g, 756, 707, 681.

Mass spectrum (FAB) m / z: 844 (M + H) + Elemental analysis (for C 1H 5Cl2F6N3O5 0.5H2O) Calculated (%): 0: 57.68, H: 5.43, 01: 8.31, R13.35, N: 4.92 Found (%): 0: 57.49, H: 5.34, Cl: 8.39, R13.73, N: 4.85 EXAMPLE 60 1/2 2-r ((2S) -1'-f2 - ((2R) -4-r3.5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholine- sulfate 2-inethyl) -2,3-dihydrospiro (indene-1,4'-piperidin] -2-yl) oxy-N- (4-hydroxybutyl) -N-methylacetamide (1/2 sulfate of compound of example No. 2 -418) 100 mg (0.12 mmol) of 2 - [((2S) -1 '-. {2 - [(2R) -4- (3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) ) morpholin-2-yl] ethyl.} -2,3-dihydroespyrro [indene-1,4-piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide, obtained in example 59, it was dissolved in 2 ml of ethanol and 30 μl (0.12 mmoles) of 4N sulfuric acid was added thereto under cooling with ice.The solvent was distilled under reduced pressure to obtain 104 mg (yield: 98% ) of the title compound as a white solid: 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.00-7.00 (10H, m), 4.40-1.40 (34H, m) IR spectrum v max cm "1 (KBr): 3412, 2932, 2561, 1649, 1474, 1439, 1376, 1281, 1 139, 1029, 905, 758, 681, 620. Mass spectrum (FAB) m / z: 844 ((M + H) +, free form) Elemental analysis (for C4? H45CI2F6N3? 5 0.5H2SO4 H2O) Calculated (%): C: 54.01, H: 5.31, 01: 7.78, F: 12.50, N: 4.61, S: 1.76 Found (%) : C: 53.54, H: 5.13, 01: 7.94, R12.53, N: 4.51, S: 1.88 EXAMPLE 61 Fumarate of 2-f (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-inethyl } -2.3-dihydrospyrorindene-1,4'-piperidin1-2-yl) oxp-N- (4-hydroxybutyl) -N-methylacetamide (example compound fumarate No. 2-418) 100 mg (0.12 mmol) of 2 - [(2S) -1'-. { 2 - [(2R) -4- [3,5-bis (trifluoromethy1) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide, obtained in Example 59, was dissolved in 1 ml of ethanol and 14 mg (0.12 mmoles) of fumaric acid was added thereto. The solvent was distilled under reduced pressure to obtain 114 mg (yield: 100%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CD3OD) d ppm: 8.20-7.30 (6H, m), 7.25-7.10 (4H, m), 6.71 (2H, s), 4.45-2.80 (24H, m), 2.70- 1.40 (10H, m) IR spectrum v max cm "1 (KBr): 3407, 2932, 2561, 1710, 1649, 1474, 1439, 1376, 1281, 1185, 1139, 1029, 983, 905, 757, 681, 648. Mass spectrum (FAB) rn / z: 844 ((M + H) +, free form) Elemental analysis (for C41H45CI2F6N3? 5 C H4O H2O) Calculated (%): C: 55.22, H: 5.25, Cl: 7.24, F: 11.65, N: 4.29 Found (%): C: 55.17, H: 5.14, 01: 7.42, F: 11.56, N: 4.17 EXAMPLE 62 L - (+) - 2-F tartrate ((2S) -1 '-f 2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl> -2.3-dihydrospiro [indene-1,4'-piperidin] -2-yl) oxy-N- (4-hydroxybutyl) -N-methylacetamide (L - (+) - tartrate of composed of example No. 2-418) 100 mg (0.12 mmol) of 2 - ((2S) -1'- {2 - ((2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4, -piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide, obtained in example 59, was dissolved in 1 ml of ethanol and 18 mg (0.12 mmol) of L - (+) - tartaric acid was added thereto. The solvent was distilled under reduced pressure to obtain 118 mg (yield: 100%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CD 3 OD) d ppm: 8.20-7.10 (10H, m), 4.50-1.40 (36H, m). Spectrum of IR v max cm "1 (KBr): 3321, 2932, 2560, 1734, 1648, 1438, 1376, 1281, 1137, 905, 681. Mass spectrum (FAB) m / z 844 ((M + H) +, free form) Elemental analysis (for C 1H 5CI2F6N3O5 C H6O6 H2O) Calculated (%): C : 53.36, H: 5.27, Cl: 7.00, R1 1.25, N: 4.15 Found (%): 0: 53.29, H.5.14, Cl: 7.36, R.11.04, N.4.03 EXAMPLE 63 2-K (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl ester Maleate ) -2.3-dihydro-spiro-indo-1,4'-piperidin-1-yl) oxy) -N- (4-hydroxybutyl) -N-methylacetamide (maleate of example compound No. 2-418) 200 mg (0.24 mmoles) of 2 - [((2S) -1'- { 2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) ) morpholin-2-yl] ethyl.} -2,3-dihydrospiro [indene-1,4-pyridin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide , obtained in example 59, was dissolved in 2 ml of ethanol and 27 mg (0.24 mmoles) of maleic acid was added thereto. The solvent was distilled under reduced pressure to obtain 227 mg (yield: 100%) of the title compound as a white solid. Spectrum of H-NMR (400 MHz, CD3OD) d ppm: 8.20-7.40 (6H, m), 7.25-7.10 (4H, m), 6.26 (2H, 8), 4.45-2.80 (24H, m), 2.65- 1.40 (10H, m). IR spectrum v max cm "1 (KBr): 3424, 2932, 2574, 1648, 1582, 1476, 1376, 1281, 1186, 1138, 1029, 905, 865, 757, 707, 681. Mass spectrum (FAB) m / z: 844 ((M + H) +, free form) Elemental analysis (for C4? H45CI2F6N3O5 C H4O H2O) Calculated (%): C: 55.22, H: 5.25, 01: 7.24, F: 11.65, N: 4.29 Found (%): C: 54.94, H: 5.06, 01: 7.38, R11.53, N: 4.19 EXAMPLE 64 2-K (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl) ethyl chloride > -2.3-dihydro-spiro-denodene-1,4'-piperidin-1-yl) -oxp-N- (3-hydroxypropyl) -N-methylacetamide (example compound hydrochloride No. 2-417) EXAMPLE 64a 3- (Methylamino) Propan-1-ol Hydrochloride The reaction was carried out with a procedure similar to that of Example 58a using 2 g (0.027 mol) of 4-aminopropan-1-ol to obtain 2.77 g (yield: 83%) of the title compound. Spectrum of 1 H-NMR (500 MHz, CD 3 OD) d ppm: 3.70 (2 H, t, 5.9 Hz), 3.12 (2H, t, 7.1 Hz), 2.70 (3H, s), 1.91-1.85 (2H, m).

EXAMPLE 64b 2-f ((2S) -1'-2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenii) morpholin-2-ethyl peptide hydrochloride > -2,3-dihydrospirofindeno-1,4'-piperidin-1-2-yl) oxp-N- (3-hydroxypropyl) -N-methylacetamide The reaction was carried out with a procedure similar to that of Example 58b using 2.86 g (3.76 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] -dandane-1,4'-piperidine, obtained in Example 27b, and hydrochloride of 3- (methylamino) propan-l-ol, obtained in example 64a, to obtain 1.62 g (yield: 52%) of 2 - [((2S) -1'- {2 - [(2R) -4 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidine] -2-yl) oxy] -N- (3-hydroxypropyl) -N-methylacetamide. 1 g (1.2 mmol) of 2 - [((2S) -1'- {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -dichlorophenyl) morpholin-2-yl] ethyl.} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) oxy] -N- (3-hydroxypropyl) -N-methylacetamide thus obtained was treated in a manner similar to Example 58b to obtain 956 mg (yield: 92%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CDCl 3) d pprn: 8.10-7.12 (10H, m), 4.45-1.64 (32H, m). IR spectrum v max cm "1 (KBr): 3384, 2927, 1649, 1474, 1439, 1376, 1282, 1185, 1139, 1109 Mass spectrum (FAB) m / z: 830 (M + H) +, form free) Elemental analysis (for C4oH43CI2F6N3O5 HCl 2H2O) Calculated (%): C: 53.19, H: 5.36, 01: 11.78, N: 4.65, Found (%): 0: 52.54, H: 5.04, 01: 11.27, N: 4.43.

EXAMPLE 65 2- (2S) -1 '- 2 - ((2R) -4- (3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-inethyl + gt hydrochloride; -2.3-dihydrospiro (indene-1,4'-piperidin1-2-yl) oxy1-N-f2- (2-hydroxyethoxy) etin-N-methylacetamide (hydrochloride of example compound No. 2-422) EXAMPLE 65a 2-r2- (Methylamino) ethoxylethanol hydrochloride The reaction was carried out with a procedure similar to that of Example 58a using 2 g (0.019 mol) of 2- (2-aminoethoxy) ethanol to obtain 1.99 9 (yield: 67%) of the title compound. Spectrum of 1 H-NMR (500 MHz, CD 3 OD) d ppm: 3.75-3.70 (4H, m), 3.60 (2H, t, J = 4.4), 3.22 (2H, t, J = 4.9 Hz), 2.73 (3H, s).

EXAMPLE 65b 2 - ((2S) -1 '-f 2-r (2R) -4- (3,5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholine-2-inethyl + gt hydrochloride; -2,3-dihydrospiro (indene-1,4'-piperidin1-2-yl) oxp-N-f2- (2-hydroxyethoxy) ethyl] -N-methylacetamide The reaction was carried out with a procedure similar to that of example 58b using 100 mg (0.136 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- (3.5 bis (trifluoromethyl) benzoyl] morfoin-2-yl} ethyl) spiro (2S) -2-carboxymethoxy] indane-1,4'-piperidine, obtained in example 27b, and 106 mg (0.678 mmol) of 2- [2- (methylamino) ethoxy] ethanol hydrochloride, obtained in example 65a, to obtain 68.2 mg (yield: 58%) of 2 - [((2S) -1'- { 2 - [( 2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl.} -2,3-dihydrospiro [indene-1] , 4'-piperidin] -2-yl) oxy] - N - [2- (2-hydroxyethoxy) etl] -N-methylacetamide 68.2 mg (0.079 mmoles) of the 2 - [((2S ) -1 * - {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl.} -2 , 3-dihydrospiro [indene-1, 4'-piperidin] -2-yl) oxy] -N- [2- (2-hydroxyethoxy) ethyl] -N-methylacetamide obtained was dissolved in 5 ml of methylene chloride and 0.2 ml of 4N-dioxane hydrochloric acid solution was added dropwise The solvent was distilled under reduced pressure and the amorphous matter thus obtained was collected by filtration by the addition of n-hexane to obtain 63.6 mg (yield: 89%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CD3OD) d ppm: 8.07-7.14 (10H, m), 4.46-2.16 (34H, m). 1 7 IR spectrum v max cm "1 (KBr): 3384, 2927, 1650, 1474, 1439, 1376, 1282, 1185, 1137 Mass spectrum (FAB) m / z: 860 ((M + H) +, free form ) EXAMPLE 66 3- (1-ff ((2S) -1'-f 2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholine hydrochloride -2-yl] ethyl.} -2,3-dihydrospiro [indene-1,4'-piperidin1-2-yl) oxyacetylpiperidin-4-yl.] Propan-1-ol ( example compound hydrochloride No. 2-583) EXAMPLE 66a 3-piperidin-4-ylpropan-1-ol hydrochloride 1. 00 g (7.29 mmoles) of 4-pyridinepropanol was dissolved in 3N aqueous hydrochloric acid solution and 206 mg of platinum oxide was added thereto, followed by stirring the mixture at room temperature under a hydrogen atmosphere at an ordinary pressure for 12 hours. The reaction mixture was filtered with Celite and the filtrate was distilled under reduced pressure. The residue thus obtained was re-precipitated from methanol-ether to obtain 1.31 g (yield: quantitative) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CD3OD) d ppm: 6.45 (2H, t, J = 6.5 Hz), 3.42-3.33 (2H, m), 2.96 (3H, brt, J = 12.5 Hz), 1.96 (2H , brd, J = 13.7 Hz), 1.68-1.50 (3H, m), 1.44-1.30 (4H, m). IR spectrum v max cm "1 (KBr): 3440, 2945, 2851, 28021 2687, 2625, 2493, 1585, 1453, 1391, 1102, 1042, 978, 956, 592, 514. Mass spectrum (FAB) m / z: 143 (M +, free form) EXAMPLE 66b 3- (1 -ff ((2S) -1 '-f 2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholin-2 hydrochloride -yl1-ethyl} -2.3-dihydro-sspirorindene-1,4'-piperidin-2-yl) oxyacetylpperidin-4-yl> propan-1 -ol 2. 02 g (2.67 mmol) of 1- (2- { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. etl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-piperidine, obtained in example 27b, and 881 μl (8.02 mmol) of N-methylmorpholine were dissolved in 40 ml of methylene chloride and 263 μl (2.94 mmol) of ethyl chloroformate was added thereto under cooling with ice with stirring, followed by stirring the mixture for 15 minutes. 720 mg (4.01 mmol) of 3-piperidin-4-ylpropan-1-ol, obtained in Example 66b, was added to the reaction mixture under cooling with ice. After the mixture was stirred at room temperature for 1 hour, ethyl acetate was added thereto to dilute it and the mixture was washed successively with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue thus obtained was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / methanol = 88/12) to obtain 1.82 g of 3- (1- { [((2S) -1, -. { 2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenol) morpholin-2-yl) ethyl} -2,3-d, h, drospiro [indene-1, 4'-piperidin] -2-yl) oxyacetyl] picperidin-4-yl} propan-1-ol The 3- (1 - { [((2S) -1 '- {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -dichloropheni morpholin ^ -yljetyl ^. S -dihydrospirofindeno-l ^ '-piperidin] ^ - il) oxyacetyl) piperidin-4-yl.}. propan-1-ol thus obtained was dissolved in 40 ml of ethyl acetate and 1.00 ml of 4N-dioxane hydrochloric acid was added thereto The solvent was distilled off under reduced pressure and 30 ml of n-hexane-ethyl acetate (1: 1) was added thereto, followed by azeotropia. re-precipitate from methylene chloride-hexane to obtain 1.98 g (yield: 77%) of the title compound as a white solid.1H-NMR spectrum (400 MHz, CD3OD) d ppm: 8.14 (1H, brs) , 7.98 (2H, brs), 7.62 (1 H, brs), 7.70-7.45 (2H, m), 7.27-7.10 (4H, m), 4.45-0.85 (38H, m), IR spectrum v max cm " 1 (KBr): 3422, 2931, 2861, 2555, 1647, 1473, 1457, 1440, 1376, 1280, 1242, 1185, 1 166, 1139, 1 1 10, 1029, 904, 758, 681. Mass spectrum ( FAB) m / z: 884 ((M + H) +, free form) Analysis elementary system (for C 4H5oCI3F6N3O5 0.5H2O) Calculated (%): C: 56.81, H: 5.531 01: 1 1.43, F: 12.25, N: 4.52 Found (%): 0: 56.78, H: 5.80, 01: 1 1.37 , F: 12.22, N: 4.36 EXAMPLE 67 2- (4-ff ((2S) -1'-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3-hydrochloride , 4-dichlorophenyl) morpholin-2-yl-ethyl) -2,3-dihydrospiro [indene-1,4'-piperidin-1-yl) -oxaflacetyl} piperazin-1-yl) ethanol (example compound hydrochloride No. 2-614) 120 mg (0.158 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. ethyl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-piperidine, obtained in example 27b, was dissolved in 5 ml of methylene chloride and 27 μl (0.316 mmole) of oxalyl chloride was added to the same. A drop of dimethylformamide was added to the mixture, followed by stirring at room temperature for 1 hour. The residue obtained by distillation of the solvent under reduced pressure was dissolved in 5 ml of methylene chloride. 1- (2-hydroxyethyl) piperazine was added dropwise to the mixture, followed by stirring for 30 minutes. The mixture was washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was purified by column chromatography on silica gel (eluent-solvent: ethyl acetate / methylene chloride / methanol = 5/5 / 0-2) to obtain 60 mg ( yield: 44%) of 2- (4-. {[[((2S) -1 '- {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- ( 3,4-dichlorophenol) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl) oxy] acetyl] piperazine -1-l) ethanol. 2 - [((2S) -1 '- {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl. ] et.l.] -2,3-dhydroespyrro [ndeno-1, 4'-piperidin] -2-yl) oxy] -N- (4-hydroxybutyl) -N-methylacetamide obtained was dissolved in 5 ml of methylene chloride and 0.2 ml of 4N-dioxane hydrochloric acid solution was added dropwise thereto. The solvent was distilled off under reduced pressure and the obtained amorphous material was collected by filtration by the addition of n-hexane to obtain 50 mg (yield: 80%) of the title compound as a white solid. Spectrum of H-NMR (400 MHz, CDCl 3) d ppm: 8.28-7.95 (3H, m), 7.70-7.15 (7H, m), 4.65-1.66 (35H, m). IR spectrum v max cm "1 (KBr): 3342, 2927, 2578, 1649, 1473, 1439, 1376, 1282, 1139 Mass spectrum (FAB) m / z: 871 ((M + H) +, free form) Elemental analysis (for C42H46CI2F6N4? 5 2HCI H2O) Calculated (%): C: 52.40, H: 5.24, N: 5.82. Found (%): 0: 52.54, H: 5.04, N: 5.43.

EXAMPLE 68 3 - ((2R) -1 -f K2S) -1 '-f 2-r (2R) -4-r3,5-bis (trifluoromethyl) benzop- 2- (3,4-dichlorophenyl) hydrochloride ) morpholin-2-ethylhenyl} -2,3-dihydroes? Iro [indene-1,4'-piperidin] -2-yl) oxpacetl} pyrrolidin-2-yl) propan-1-ol (example compound hydrochloride No. 2-574) EXAMPLE 68a (2R) -2- (Hydroxymethyl) pyrrolidine-1-benzylcarboxylate 2 g (0.0198 moles) of (2R) -pyrrolidin-2-methanol dissolved in ml of ethyl acetate, 20 ml of water were added thereto, and the mixture was stirred. 3.3 g (0.30 mole) of sodium bicarbonate was added to the mixture, followed by stirring the mixture for 5 minutes. 4.24 ml (0.03 mole) of benzyl chloroformate was added dropwise to the mixture, followed by stirring for 5 hours. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain quantitatively the title compound. Spectrum of 1 H-NMR (500 MHz, CDCl 3) d ppm: 7.55-7.28 (5H, m), 5.16 (2H, s), 4.12-3.90 (1H, br), 3.83-3.33 (4H, m), 2.1. 9-1.51 (4H, m). 73 EXAMPLE 68b (2R) -2-formylpyrrolidin-1-benzylcarboxylate 1 g (4.25 mmol) of (2R) -2- (hydroxymethyl) pyrrolidine-1-benzyl carboxylate, obtained in Example 68a, was dissolved in 15 ml of methylene chloride and the mixture was stirred under ice-cooling. 1.98 g (4.68 mmoles) of Dess-Martin periodinane was added to the mixture, followed by stirring for 2 hours. After a solution of saturated aqueous sodium bicarbonate and an aqueous sodium thiosulfate solution (2 eq.) Were added to the mixture and the mixture was stirred for 30 minutes, the mixture was extracted with methylene chloride three times. After the methylene chloride layer was dried over anhydrous sodium sulfate, the solvent was distilled under reduced pressure to obtain a crude product of the title compound.

EXAMPLE 68c (2R) -2- (3-ethoxy-3-oxoprop-1-yl) pyrrolidine-1-benzylcarboxylate 929 μl (4.68 mmol) of triethyl phosphonoacetate was dissolved in 15 ml of tetrahydrofuran and 3.19 ml of a solution of n-butyllithium 1.6M in hexane was added dropwise thereto for 5 minutes while stirring at -50 °. C under a nitrogen atmosphere, followed by stirring the mixture for 20 minutes. 10 ml of a solution of benzyl- (2R) -2-formylpyrrolidine-1-carboxylic acid in tetrahydrofuran, obtained in example 68b, was added dropwise to the reaction mixture for 5 minutes and the temperature of the mixture rose at room temperature, followed by stirring for 8 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate three times. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (eluent-solvent: ethyl acetate / hexane = 1/5) to obtain 1.13 g (yield: 88%) of the title compound in the form mixture form (E) and (Z).

EXAMPLE 68d (2R) -2-r (1E) -3-hydroxypropyl-1-eninpyrrolidin-1-benzylcarboxylate 283 mg (0.933 mmoles) of (2R) -2- (3-ethoxy-3-oxoprop-1-enyl) pyrrolidine-1-benzylcarboxylate, obtained in example 68c, was dissolved in 5 ml of tetrahydrofuran and 1.85 ml (1.87 mmol) of a solution of 1.01 M diisobutylaluminum hydride in toluene was added dropwise thereto for 5 minutes while stirring at -78 ° C under a nitrogen atmosphere. After the mixture was stirred for 1 hour, the cooling bath was removed and the mixture was quenched by the slow addition of water dropwise. Water and ethyl acetate were added thereto and an extraction operation was carried out. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (eluent-solvent: ethyl acetate / hexane = 1/1) to obtain 135 mg (yield: 55%) of the title compound. Form (E) Spectrum of 1 H-NMR (400 MHz, CDCI3) d ppm: 7.49-7.25 (5H, m), 5.80-5.55 (2H, m), 5.26-5.00 (2H, m), 4.50- 4.30 (1 H, m), 4.19-3.88 (2H, m), 3.52-3.34 (2H, m), 2.11-1.67 (4H, m), Form (Z) 1H-NMR spectrum (400 MHz, CDCI3) d ppm: 7.64-7.25 (5H, m), 5.89-5.82 (1H, m), 5.39 (2H, t, J = 10.5 Hz), 5.16-5.08 (2H, dd, J = 32.0, 12.5 Hz), 4.86 (1 H, m), 4.53-4.48 (1 H, dd, J = 12.3, 8.8 Hz), 3.94-3.90 (1H, m), 3.59-3.30 (2H, m), 2.14-1.52 (4H, m), EXAMPLE 68e 3-r (2R) -pyrrolidin-2-n-propan-1-ol hydrochloride (2R) -2 - [(1 E) -3-Hydroxyprop-1-enyl] pyrrolidine-1-benzylcarboxylate, obtained in Example 68d, was dissolved in 5 ml of ethanol and 50 mg of palladium-carbon was added to 10% thereto, followed by vigorous stirring of the mixture under a hydrogen atmosphere. After 1 hour and 30 minutes, the palladium-carbon was removed by filtration and 0.5 ml of 4N hydrochloric acid / dioxane solution was added dropwise to the residue. The solvent was distilled under reduced pressure to obtain the title compound as a colorless oil. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 3.61 (2H, t), 3.44-3.51 (1H, m), 2.27-2.21 (35H, m), 2.12-1.99 (2H, m), 1.84-1.76 (2H, m), 1.69-1.60 (3H, m).

EXAMPLE 68f 3 - ((2R) -1 -ff ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophen) hydrochloride L) morpholin-2-yl-ethyl) -2,3-dihydrospiro [ndeno-1,4'-piperidin-1-yl) oxy-acetyl} pyrrolidin-2-yl) propan-1 -ol The reaction was carried out with a procedure similar to that of example 58b using 200 mg (0.263 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 -b (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] -dane-1,4'-piperidine, obtained in Example 27b, and hydrochloride of 3 - [(2R) -pyrrolidin-2-yl] propan-1-ol, obtained in example 68e, to obtain 102 mg (yield: 44%) of 3 - ((2R) -1- { [( (2S) -1'- { 2 - [(2R) -4- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-pyridin] -2-yl) oxy] acetyl} pyrrolidin-2-yl) propan-1-ol. 1 g (1.2 mmoles) of the 2 - [((2S) -1 '-. {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- dichlorophenyl) morpholin-2-yl] ethyl.} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) oxy] -N- (3-hydroxypropyl) -N-methyl The obtained lacetamide was treated in a manner similar to Example 58b to obtain 98 mg (yield: 93%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 8.15-7.14 (10H, m), 4.36-1.35 (36H, m). IR spectrum v max cm "1 (KBr): 3401, 2931, 2559, 1646, 1281, 1 185, 1139. Mass spectrum (FAB) m / z: 870 ((M + H) +, free form) Analysis elemental (for C43H47CI2F6N3? 5 HCl) Calculated (%): 0: 55.44, H: 5.27, N: 4.51, Found (%): 0: 55.17, H: 5.43, N: 4.47.

EXAMPLE 69 2- (1 -ff ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) -benzoin-2- (3,4-dichlorophen) hydrochloride L) morpholin-2-ineethyl> -2.3-dihydro-spiro-dindene-1,4'-piperidin-2-yl) -oxylacetyl> pperidin-4-yl) ethanol (example compound hydrochloride No. 2-582) 200 mg (0.26 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl}. ethyl) spiro [(2S) -2-carboxymethoxy] -dane-1,4-piperidine, obtained in example 27b, was dissolved in 4 ml of methylene chloride and 46 μl (0.53 mmole) of oxalyl chloride was added to the same under cooling with ice. A drop of dimethylformamide was added to the mixture, followed by stirring at room temperature for 30 minutes. The solvent was distilled under reduced pressure and the residue thus obtained was dissolved in 4 ml of methylene chloride. 68 mg (0.53 mmoles) of 4-piperidine ethanol and 110 μl (0.79 mmoles) of triethylamine were added to the solution under cooling with ice. After the mixture was stirred at room temperature for 2 hours, it was washed successively with water and with a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue thus obtained was purified by thin layer chromatography (eluent solvent: methylene chloride / methanol = 10/1). 2- (1- { [((2S) -1'- { 2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichloropheni The morpholinylcarbazyl-3-yl-dihydrospyrotindene-1'-piperidinyl] yl) oxy] acetyl] piperidin-4-yl) ethanol thus obtained was dissolved in 20 ml of ethyl acetate and the mixture was washed successively With 50 ml of 1N hydrochloric acid and a saturated NaCl solution and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue obtained was washed with hexane to obtain 129 mg (yield: 54%) of the title as a white solid: 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 12.05 (1 H, brs), 8.20-7.90 (3H, m), 7.70-7.10 (7H, m), 4.50-2.90 ( 23H, m), 2.80-2.10 (7H, m), 1.90-1.00 (6H, m), IR spectrum v max cm'1 (KBr): 3414, 2926, 2560, 1648, 1473, 1440, 1375, 1281 , 1139, 1029, 985, 905, 757, 681. Mass spectrum (FAB) m / z: 870 ((M + H) +, free form) Elemental analysis (for C43H 8CI3F6N3O5 1.5H2O) Calculated (%): C : 55.28, H: 5.50, 01: 11.38, F: 12. 20, N: 4.50 Found (%): C: 55.20, H: 5.53, 01: 11.24, R.12.53, N.4.33 EXAMPLE 70 2-f ((2S) -1 '-f 2-r (2R) -4-F3,5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholin-2-hydrochloride ipethyl) -2,3-dihydrospiroflndene-1,4'-piperidinyl-2-yl) oxp-N- (4-hydroxybutyl) -N-methoxyacetamide (Example Compound Hydrochloride No. 2-460) EXAMPLE 70a 4- (Metoxyamino) butan-1 -ol 1. 10 g (7.19 mmoles) of 4-bromo-1-butanol was dissolved in 20 ml of ethanol and 4.59 g (28.8 mmoles) of O-methylhydroxylamine hydrochloride and 6.02 ml (43.1 mmoles) of triethylamine were added thereto, followed by stirring the mixture at 70 ° C for 2 hours. Ethyl acetate was added to the reaction mixture, the precipitate was removed by filtration and the solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / methanol = 100 / 0-50 / 50) to obtain 52 mg (yield: 6%) of the title compound as a pale yellow oil. Spectrum of 1 H-NMR (400 MHz, CD3OD) d ppm: 3.72 (3H, s), 3.58 (2H, t, J = 6.1 Hz), 3.11 (2H, t, J = 7.2Hz), 1.76-1.56 (4H , m). Spectrum IR v max cm "1 (liquid film): 3390, 2946, 2726, 1637, 1465, 1445, 1035. Mass spectrum (El) m / z: 119 (M +) EXAMPLE 70b 2-r (2S) -1'-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-hydrochloride inethyl) -2.3-dihydrospirorindene-1,4'-piperidin1-2-yl) oxyl-N- (4-hydroxybutyl) -N-methoxyacetamide The reaction was carried out with a procedure similar to that of example 69 using 200 mg (0.26 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-piperidine, 46 μl (0.53 mmol) of oxalyl chloride, 47 mg (0.40 mmoles) of 4- (methoxyamino) butan-1-ol, obtained in example 70a, and 110 μl (0.79 mmoles) of triethylamine to obtain 86 mg (yield: 36%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.11 (1 H, brs), 8.10-7.90 (3 H, m), 7.70.7.10 (7 H, m), 4.50-2.90 (23 H, m), 2.85 -2.10 (5H, m), 1.80-1.50 (6H, m). IR spectrum v max cm'1 (KBr): 3394, 2936, 2555, 1649, 1473, 1440, 1376, 1281, 1138, 1029, 905, 758, 681. Mass spectrum (FAB) m / z: 860 ( M + H) +, free form) Elemental analysis (for C41H 6CI3F6N3? 6 H2O) Calculated (%): C: 53.81, H: 5.29, 01: 11.62, F: 12.46, N: 4.59 Found (%): C: 53.82, H: 5.22, 01: 11.31, F.12.40, N: 4.59 EXAMPLE 71 2-f ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl] et hydrochloride L) -2,3-dihydroespirofindene-1,4'-piperidin-1-yl) oxp-N- (5-hydroxypentyl) -N-methylacetamide (example compound hydrochloride No. 2-419) EXAMPLE 71a 5-Hydroxypentilformamide 2. 06 g (20.0 mmoles) of 5-amino-1-pentanol was dissolved in 5 ml of ethyl formate and the mixture was stirred at 90 ° C for 4 hours. The solvent was distilled off under reduced pressure and the obtained residue was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / methanol = 100 / 0-70 / 30) to obtain 1.90 g (yield: 73%) of the compound of the title as a pale yellow oil. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 8.14 (1 H, s), 5.69 (1 H, brs), 3.68-3.60 (2 H, m), 3.35-3.26 (2 H, m), 1.64-1.36 (6H, m). Mass spectrum (El) m / z: 131 (M +) 82 EXAMPLE 71b 5- (Methylamino) pentan-1 -ol 1. 90 g (14.5 mmol) of 5-hydroxypentilformamide, obtained in example 71a, was dissolved in 20 ml of tetrahydrofuran, and 17.4 ml (17.4 mmol) of 1M solution of lithium-aluminum hydride in tetrahydrofuran was added dropwise to the solution under cooling with ice, followed by stirring the mixture at 90 ° C for 2 hours. Then, 28 g (87 mmol) 10 sodium sulfate hydrates and 20 ml diethyl ether were added to the reaction mixture under cooling with ice and the mixture was stirred at room temperature for 18 hours. After the reaction mixture was filtered with Celite, the solvent was distilled off under reduced pressure and the obtained residue was purified by chromatography on silica gel (eluent solvent: dichloromethane / methanol / ammonia-water = 95/5 / 0- 80/19/1) to obtain 1.36 g (yield: 80%) of the title compound as a pale yellow oil. 1 H-NMR spectrum (400 MHz, CD3OD) d ppm: 3.54 (2H, t, J = 6.7Hz), 2.56-2.50 (2H, m), 2.35 (3H, s), 1.58-1.32 (6H, m ). Spectrum of IR v max cm "1 (liquid film): 3377, 3306, 2936, 2862, 1646, 1537, 1477, 1387, 1313, 1073, 1055. Mass spectrum (El) m / z: 117 (M +) EXAMPLE 71c 2-f ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ethyl) -2-hydrochloride 3-dihydrospirorindene-1,4 '-? Iperidin1-2-yl) oxy-N- (5-hydroxypentyl) -N-methylacetamide The reaction was carried out with a procedure similar to that of example 69 using 110 mg (0.15 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-pperidine, 25 μl (0.29 mmol) of oxalyl, 51 mg (0.43 mmol) of 5- (methoxyamino) pentan-1-ol, obtained in example 71b, and 91 μl (0.65 mmol) of triethylamine to obtain 29 mg (yield: 22%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.06 (1H, brs), 8.10-7.90 (3H, m), 7.70-7.10 (7H, m), 4.40-2.60 (29H, m), 2.50- 2.10 (3H, m), 1.80-1.20 (4H, m). IR spectrum v max cm "1 (KBr): 3409, 2931, 2561, 1649, 1474, 1439, 1376, 1281, 1185, 1139, 1029, 905, 757, 681. Mass spectrum (FAB) m / z: 858 ((M + H) +, free form) EXAMPLE 72 4-rfr Hydrochloride ((2S) -1'-f2-r (2R) ^ -r3.5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenol) morpholin-2-yl-ethyl) - 2,3-dihydrospiro [indene-1,4'-piperidin-1-yl) oxy-acetyl) (methyl) aminolbutanoic acid (hydrochloride of example compound No. 2-495) EXAMPLE 72a Ethyl 4- (methylamino) butanoate hydrochloride 2. 00 g (13.0 mmol) of 4- (methylamino) butanoic acid hydrochloride was dissolved in 40 ml of ethanol and 69 μl (1.30 mmol) of concentrated sulfuric acid was added thereto, followed by stirring the mixture at 90 ° C for 1 hour. The solvent was distilled under reduced pressure, followed by azeotropy with toluene. 3.02 g of the residue obtained was used as such for the subsequent reaction. Spectrum of 1 H-NMR (400 MHz, CD 3 OD) d ppm: 4.14 (2 H, q, J = 7.2 Hz), 3.03 (2 H, t, J = 7.6 Hz), 2.69 (3 H, s), 2.47 (2 H, t , J = 7.0Hz), 1.99-1.90 (2H, m), 1.25 (3H, t, J = 7.2Hz).

EXAMPLE 72b Hydrochloride of 4- (f (((2S) -1 '-f 2 - ((2R) -4- (3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl-1-yl) > Ethyl 2,3-dihydrospiro (indene-1,4'-piperidin-3-2-yl) oxy] acetyl] - (methyl) amino] butanoate The reaction was carried out with a procedure similar to that of example 69 using 200 mg (0.26 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- (3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro ((2S) -2-carboxymethoxy] indane-1,4'-piperidine, 46 μl (0.53 mmol) of oxalyl chloride, 96 mg (0.53 mmoles) of ethyl 4- (methylamino) butanoate hydrochloride, obtained in example 72a, and 184 μl (1.32 mmoles) of triethylamine to obtain 165 mg (yield: 68%) of the title compound as a white solid .

EXAMPLE 72c 4-rfr Hydrochloride ((2S) -1'-f2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ethylhexyl) > -2,3-dihydrospiro (indene-1,4'-piperidin-2-yl) -oxaflacetyl}. (methyl) ammolbutanoic acid 120 mg (0.13 mmol) of hydrochloride of 4- [. { [((2S) -1'- {2 - [(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl.} -2,3-dihydrospiro [indene-1,4-piperidine] -2-yl) oxy] acetyl} ethyl (methylal) butanoate, obtained in example 72b, was dissolved in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol, and 0.39 ml (0.39 mmoles) of 1 N aqueous sodium hydroxide solution was added. to it under cooling with ice, followed by stirring the mixture at room temperature for 18 hours. 20 ml of 1 N hydrochloric acid was added to the reaction mixture under cooling with ice and the mixture was extracted with ethyl acetate. The extract was washed successively with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue obtained was purified by thin layer chromatography (solvent-eluent: methylene chloride / methanol = 10/1). The obtained purified product was dissolved in 20 ml of ethyl acetate, the mixture it was washed successively with 50 ml of 1 N hydrochloric acid and a saturated NaCl solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with hexane to obtain 59 mg (yield: 51%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 11.82 (1 H, brs), 8.10-7.85 (3 H, m), 7.75-7.10 (7 H, m), 4.40-1.50 (32 H, m). IR spectrum v max cm "1 (KBr): 2930, 2576, 1731, 1650, 1474, 1439, 1376, 1282, 1029, 905, 756, 681. Mass spectrum (FAB) m / z: 858 (M + H) +, free form) Elemental analysis (for C - | H44CI3F6N3O6 2H2O) Calculated (%): C: 52.88, H: 5.20, 01: 1 1.42, F: 12.24, N: 4.51 Found (%): 0: 52.94 , H: 4.97, 01: 10.93, R12.66, N: 4.33 EXAMPLE 73 Hydrochloride of (1-fr ((2S) -1'-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ynethyl> -2,3-dihydrospyrorindene-1,4'-piperidin-1-2-yl) oxy] acetyl) piperidin-4-yl) methanol (hydrochloride compound example No. 2-581) The reaction was carried out with a procedure similar to that of example 69 using 200 mg (0.26 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-piperidine, 46 μl (0.53 mmol) oxalyl chloride, 61 mg ( 0.53 mmoles) of 4-piperidinemethanol and 110 μl (0.79 mmoles) of triethylamine to obtain 76 mg (yield: 32%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.00 (1H, brs), 8.15-7.90 (3H, m), 7.70-7.10 (7H, m), 4.50-2.90 (23H, m), 2.80- 2.10 (7H, m), 1.90-1.10 (4H, m). IR spectrum v max cm "1 (KBr): 3400, 2926, 2562, 1648, 1473, 1441, 1376, 1281, 1139, 1029, 905, 758, 681. Mass spectrum (FAB) m / z: 856 ( (M + H) +, free form) Elemental analysis (for C42H46CI3F6N3? 5 1.5H2O) Calculated (%): 0: 54.82, H: S.37, 01: 11.56, R12.39, N: 4.57 Found (%) : 0: 54.64, 1-1: 5.17, 01: 11.48, R12.82, N: 4.30 EXAMPLE 74 2-K (2S) -1 '-f 2 -r (2R) -4-r3,5- Hydrochloride bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl-ethyl} -2,3-dihydrospiro [indene-1,4 '-? iperidin1-2-yl) oxy] -N- (6 -hydroxyhexyl) -N-methylacetamide (example compound hydrochloride No. 2-421) EXAMPLE 74a 6-Hydroxyhexylformamide The reaction was carried out with a procedure similar to that of Example 71a using 1.50 g (12.8 mmoies) of 6-amino-1-hexanol and 3 ml of ethyl formate to obtain 1.34 g (yield: 72%) of the compound of the title as a white solid. Spectrum of 1 H-NMR (400 MHz, CD3OD) d ppm: 8.01 (1H, s), 3.54 (2H, t, J = 6.6Hz), 3.21 (2H, t, J = 6.8Hz), 1.60-1.30 (8H , m), IR spectrum v max cm "1 (KBr): 3376, 3311, 3040, 2936, 2857, 1655, 1526, 1464, 1385, .1242, 1063, 1049. Mass spectrum (El) m / z : 144 (MH) + 9 EXAMPLE 74b 6- (Methylamino) hexan-1 -ol The reaction was carried out with a procedure similar to that of Example 71b using 1.34 g (9.23 mmoles) of 6-hydroxyhexylformamide, obtained in example 74a, and 11.1 ml (11.1 mmoles) of a solution of 1 mol / l of sodium hydride. lithium-aluminum in tetrahydrofuran to obtain 0.89 g (yield: 74%) of the title compound as a pale yellow oil. 1H-NMR spectrum (400 MHz, CD3OD) d ppm: 3.53 (2H, t, J = 6.7Hz), 2.56-2.50 (2H, m), 2.35 (3H, s), 1.58-1.30 (8H, m). Spectrum of IR v max cm "1 (liquid film): 3299, 2932, 2858, 1650, 1539, 1475, 1379, 1059. Mass spectrum (El) m / z: 131 (M +) EXAMPLE 74c 2-f ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ethylhexyl chloride ) -2,3-dihydroespirorindene-1,4'-piperidin-2-yl) oxy-1 N- (6-hydroxyhexyl) -N-methylacetamide The reaction was carried out with a procedure similar to that of Example 69 using 110 mg (0.15 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- (3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.} ethyl) spiro ((2S) -2-carboxymethoxy] indane-1,4'-piperidine, 25 μl (0.29 mmol) oxalyl chloride, 57 mg ( 0.43 mmoles) of 6- (methylamino) hexan-1-ol, obtained in Example 74b, and 91 μl (0.65 mmoles) of triethylamine to obtain 54 mg (yield: 33%) of the title compound as a white solid. 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.05 (1H, brs), 8.15-7.90 (3H, m), 7.70-7.10 (7H, m), 4.40-2.60 (29H, m), 2.50- 2.10 (3H, m), 1.80-1.20 (6H, m) IR spectrum v max cm'1 (KBr): 3418, 2931, 2559, 1649, 1474, 1439, 1376, 1281, 1 185, 1 139, 1029, 905, 758, 681. Mass spectrum (FAB) m / z: 872 ((M + H) +, free form) EXAMPLE 75 Hydrochloride of 1 2 - ((1-f (((2S) -1'-f2 - ((2R) -4- (3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl)) morpholin-2-ylpethyl) -2,3-dihydro-spiro-dindene-1,4'-piperidin-1-yl) oxy-acetyl}. piperidin-4-yl) oxpetanol (hydrochloride of Example Compound No. 2-586) EXAMPLE 75a 4- (2-f-tert-Butyl (dimethyl) s-1-yloxy} -ethoxy) piperidin-1-tert-butylcarboxylate . 00 g (24.8 mmol) of tert-butyl 4-hydroxy-1-piperidoncarboxylate was dissolved in 100 ml of dimethylformamide and 1.08 g (24.8 mmol) of sodium hydride (55% or more, oily) was added. to it under cooling with ice, followed by stirring the mixture at room temperature for 4 hours. Then, 20 ml of a solution of 6.54 g (27.3 mmoles) of (2-bromoethoxy) -tert-butyldimethyl-silane in dimethylformamide was added dropwise to the reaction mixture under cooling with ice and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture under cooling with ice and the mixture was extracted with ethyl acetate, followed by washing successively with water and a saturated NaCl solution and drying over anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue obtained was purified by chromatography on silica gel (eluent-solvent: hexane / ethyl acetate = 100 / 0-90 / 10) to obtain 1.65 g (yield: 18%) of the compound of the title as a colorless oil. Spectrum of H-NMR (500 MHz, CDCl 3) d ppm: 3.80-3.68 (4H, m), 3.56-3.46 (3H, m), 3.14-3.04 (2H, m), 1.86-1.76 (2H, m), 1.58-1.46 (2H, m), 1.45 (9H, s), 0.90 (9H, s), 0.07 (6H, s). Spectrum of IR v max cm "1 (liquid film): 3475, 2953, 2931, 2859, 1699, 1422, 1366, 1253, 1237, 1175, 1111, 836, 777. Mass spectrum (FAB) m / z: 360 (M + H) + EXAMPLE 75b 4- (2-Hydroxyethoxy) piperidine-1-tert-butylcarboxylate 1. 65 g (4.59 mmol) of 4- (2. {[[Tert-butyl (dimethyl) silyl] -oxi} ethoxy) piperidine-1-tert-butylcarboxylate, obtained in Example 75a, was dissolved in 20 ml of tetrahydrofuran and 6.88 ml (6.88 mmoles) of a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran was added thereto under ice-cooling, followed by stirring the mixture at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, followed by washing successively with water and a saturated NaCl solution and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue obtained was purified by chromatography on silica gel (eluent solvent: hexane / ethyl acetate = 90 / 10-30 / 70) to obtain 0.94 g (yield: 84%) of the compound of the title as a colorless oil. Spectrum of 1 H-NMR (500 MHz, CDCl 3) d ppm: 3.84-3.68 (4H, m), 3.58 (2H, t, J = 4.6Hz), 3.54-3.46 (1H, m), 3.14-3.02 (2H, m), 2.01 (1 H, t, J = 6.1 Hz), 1.90-1.80 (2H, m), 1.58-1.40 (11 H, m). IR spectrum v max cm "1 (liquid film): 3458, 2933, 2867, 1695, 1426, 1367, 1276, 1240, 1173, 1141, 1114, 1067. Mass spectrum (FAB) m / z: 246 (M + H) + EXAMPLE 75c 2- (Piperidin-4-yloxy) ethanol 0. 94 g (3.83 mmol) of 4- (2-hydroxyethoxy) piperidine-1-carboxylate of tert-butyl, obtained in example 75b, was dissolved in 12 ml of dichloromethane and 6 ml of trifluoroacetic acid was added thereto under cooling with ice, followed by stirring the mixture at room temperature for 2 hours. The solvent was distilled under reduced pressure, followed by azeotropy with toluene. The residue obtained was purified by chromatography on silica gel (silica gel: Chromatrex NH, 100-200 mesh, eluent-solvent: dichloromethane / methanol = 10010-90 / 10) to obtain 564 mg (yield: 100%) of the compound of the title as a white solid. Spectrum of H-NMR (500 MHz, CD3OD) d ppm: 3.65 (2H, t, J = 4.9Hz), 3.55 (2H, t, J = 4.9Hz), 3.54-3.46 (1H, m), 3.12- 3.04 (2H, m), 2.72-2.64 (2H, m), 1.98-1.90 (2H, m), 1.58-1.50 (2H, m). IR spectrum v max cm "1 (liquid film): 3290, 2936, 2860, 1690, 1452, 1423, 1201, 1119, 1070. Mass spectrum (FAB) m / z: 146 (M + H) + EXAMPLE 75d 2-r hydrochloride (1-fr ((2S) -1, -f2-r (2R) -4-r3.5-bs (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) ) morpholin-2-yl] etl) -2,3-dihydro-sspirofindene-1,4'-piperidin-1-yl) oxylacetyl} piperidin-4-yl) oxyethanol The reaction was carried out with a procedure similar to that of Example 66b using 150 mg (0.20 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) spiro [(2S) -2-carboxymethoxy] indan-1,4'-piperidine, 21 μl (0.22 mmol) of ethyl chloroformate, 65 μl (0.59 mmoles) of N-methylmorpholine and 43 mg (0.30 mmoles) of 2- (piperidin-4-yloxy) ethanol, obtained in example 75c, to obtain 116 mg (yield: 4 64%) of the title compound as a white solid. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.11 (1H, brs), 8. 15-7.90 (3H, m), 7.70-7.10 (7H, m), 4.40-2.90 (25H, m), 2.80-2.60 (2H, m), 2. 50-2.10 (3H, m), 1.95-1.55 (6H, m). Spectrum of IR v max cm "1 (KBr): 3394, 2929, 2555, 1649, 1473, 1440, 1375, 1282, 1185, 1138, 1108, 1029, 905, 758, 681. Mass spectrum (FAB) m / z: 886 ((M + H) +, free form) Elemental analysis (for C43H48CI3F6N3O6 0.5H2O) Calculated (%): C: 55.40, H: 5.30, 01: 11.41, F. 2.23, N.4.51 Found (%): 0: 55.06, H: 5.30, 01: 11.22, R12.27, N: 4.35 EXAMPLE 76 N-K1 hydrochloride -ff ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichloropheni) morpholino- 2-yllethyl) -2,3-dihydrospyrorindene-1,4'-piperidin-2-yl) oxy] acetyl) piperidin-4-yl) -2-hydroxyacetamide (hydrochloride of example compound No. 2-590) EXAMPLE 76a 2- (Benzyloxy) -N- (1-benzylpiperidin-4-yl) acetamide 2. 00 g (12.0 mmoles) of benzyloxyacetic acid was dissolved in 40 ml of dichloromethane and 2.77 g (14.4 mmoles) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2.21 g (14.4 mmoles) of 1 Hydroxybenzotriazole hydrate, 2.52 ml (18.1 mmoles) of triethylamine and 2.52 g (13.2 mmoles) of 4-amino-1-benzylpiperidine were added thereto under ice-cooling, followed by stirring the mixture at room temperature for 18 hours. Dichloromethane was added to the reaction mixture and the mixture was washed successively with a saturated aqueous sodium bicarbonate solution, water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / meta nol = 100 / 0-90 / 10) to obtain 2.82 g (yield: 69%) of the composed of the title as a white solid. Spectrum of 1 H-NMR (500 MHz, CDCl 3) d ppm: 7.40-7.22 (10H, m), 6.46 (1 H, d, J = 7.3Hz), 4.56 (2H, s), 3.96 (2H, s), 3.90-3.80 (1 H, m), 3.49 (2H, s), 2.84-2.76 (2H, m), 2.18-2.08 (2H, m), 1.95-1.85 (2H, m), 1.53-1.43 (2H, m). Spectrum of IR v max cm "1 (KBr): 3309, 3025, 2931, 2795, 1643,1549, 1495, 1451, 133.7, 1283, 1105, 988, 736, 700, 652. Mass spectrum (FAB) m / z: 339 (M + H) + EXAMPLE 76b 2-Hydroxy-N-piperidin-4-ylacetamide 2. 82 g (8.33 mmoles) of 2- (benzyloxy) -N- (1-benzylpiperidin-4-yl) acetamide, obtained in example 76a, was dissolved in 60 ml of ethanol and 0.60 g of 10% palladium-carbon (wet content: 51.7%) was added thereto under a nitrogen atmosphere, followed by stirring the mixture at 50 ° C for 4 hours under a hydrogen atmosphere. After the reaction mixture was filtered with Celite, the solvent was distilled under reduced pressure to obtain 1.26 g (yield: 96%) of the title compound as a pale yellow solid. 1 H-NMR spectrum (500 MHz, CD3OD) d ppm: 3.94 (2H, s), 3.86-3.78 (1 H, m), 3.08-3.00 (2H, m), 2.68-2.60 (2H, m), 1.88 -1.80 (2H, m), 1.50-1.40 (2H, m). Spectrum of IR v max cm "1 (KBr): 3323, 3248, 2942, 2894, 1659, 1538, 1452, 1431, 1364, 1330, 1084, 1010, 437. Mass spectrum (FAB) m / z: 159 (M + H) + EXAMPLE 76c N- (1 -ff ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenol) morpholine hydrochloride -2-ethyl) -2,3-dihydrospirofindene-1,4'-piperidin-1-2-yl) oxylacetyl) piperidin-4-yl) -2-hydroxyacetamide The reaction was carried out with a procedure similar to that of Example 66b using 150 mg (0.20 mmol) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3,5 bis (trifluoromethyl) benzoyl] morpholin-2-yl.] etl) spiro [(2S) -2-carboxymethoxy] indane-1,4'-piperidine, 21 μl (0.22 mmoles) of ethyl chloroformate 65 μl (0.59 mmoles) of N-methylmorpholine and 37 mg (0.24 mmoles) of 2-hydroxy-N-piperidin-4-ylacetamide, obtained in example 76b, to obtain 89 mg (yield: 48%) of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 11.94 (1 H, brs), 8. 15-7.90 (3H, m), 7.75-7.10 (7H, m), 6.63-6.53 (1H, m) 4.50-1.20 (34H, m). Spectrum of IR v max cm "1 (KBr): 3340, 2928, 1650, 1529, 1473, 1440, 1375, 1282, 1185, 1139, 1029, 905, 758, 681. Mass spectrum (FAB) m / z: 899 ((M + H) +, free form) Elemental analysis (for C43H47CI3F6N 06 H2O) Calculated ( %): 0: 54.12, H: 5.18, 01: 11.15, F: 11.95, N: 5.87 Found (%): 0: 53.81, H: 5.22, 01: 10.72, R11.60, N: 5.50 EXAMPLE 77 2-f (1 -f K (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenii) morpholinohydrochloride 2-ipetp.} -2,3- [dihydrospyrofindeno-1,4'-piperidin-2-yl) oxy-acetyl} piperidin-4-yl) methoxy] ethanol (example compound hydrochloride No. 2-591) EXAMPLE 77a 4-f (2-f [Tert-butyl (dimethyl) silinoxy> ethoxy) methypiperidine-1-benzylcarboxylate The reaction was carried out with a procedure similar to that of Example 75a using 5.00 g (20.1 mmol) of 4- (hydroxymethyl) piperidine-1-benzyl carboxylate, 0.88 g (20.1 mmol) of sodium hydride (55% or more) , oily) and 5.28 g (22.1 mmol) of (2-bromoethoxy) -tert-butyldimethylsilane to obtain 237 mg (yield: 3%) of the title compound as a brown oil. Spectrum of 1 H-NMR (500 MHz, CDCl 3) d ppm: 7.40-7.28 (5H, m), 5.12 (2H, s), 4.28-4.10 (2H, m), 3.74 (2H, t, J = 5.4Hz) , 3.49 (2H, t, J = 5.4Hz), 3.31 (2H, d, J = 5.9Hz), 2.86-2.70 (2H, m), 1.82-1.68 (3H, m), 1.24-1.10 (2H, m ), 0.89 (9H, s), 0.06 (6H, s). Spectrum of IR v max cm "1 (liquid film): 3477, 2952, 2929, 2858, 1704, 1472, 1432, 1362, 1276, 1251, 1220, 1142, 1106, 941, 836, 778, 697. Mass spectrum (FAB) m / z: 408 (M + H) + EXAMPLE 77b 4-R (2-Hydroxyethoxy) methy1-piperidine-1-benzylcarboxylate The reaction was carried out with a procedure similar to that of Example 75b using 237 mg (0.58 mmoles) of 4 - [(2- ({(tert-butyl (dimethyl) silyl] oxy} ethoxy) methyl] piperidin-1-benzylcarboxylate obtained in example 77a and 0.87 ml (0.87 mmol) of a 1M tetrabutylammonium fluoride solution in tetrahydrofuran to obtain 133 mg (yield: 78%) of the title compound as a brown oil. Spectrum of 1 H-NMR (500 MHz, CDCl 3) d ppm: 7.40-7.28 (5H, m), 5.13 (2H, m), 4.28-4.10 (2H, m), 3.76-3.70 (2H, m), 3.56- 3.50 (2H, m), 3.33 (2H, d, J = 6.3Hz), 2.86-2.70 (2H, m), 1.89 (1 H, t, J = 6.1 Hz), 1.84-1.70 (3H, m), 1.26-1.10 (2H, m) IR spectrum v max cm "1 (liquid film): 3453, 2923, 2861, 1699, 1473, 1434, 1364, 1276, 1249, 1221, 1 151, 1 126, 1073, 765, 699. Mass spectrum (FAB) m / z: 294 (M + H) + EXAMPLE 77c 2- (Piperidin-4-ylmethoxy) ethanol 133 mg (0.45 mmol) of benzyl 4 - ((2-hydroxyethoxy) methyl] piperidine-1-carboxylate, obtained in Example 77b, was dissolved in 2 ml of ethanol and 20 mg of 10% palladium-carbon. (wet content: 51.7%) was added thereto under a nitrogen atmosphere, followed by stirring the mixture at room temperature under a hydrogen atmosphere for 2 hours.After the reaction mixture was filtered with Celite, the solvent was distilled under reduced pressure to obtain 70 mg (yield: 97%) of the title compound as a colorless oil Spectrum of 1 H-NMR (500 MHz, CD 3 OD) d ppm: 3.65 (2 H, t, J = 4.9 Hz) , 3.49 (2H, t, J = 4.9Hz), 3.31 (2H, d, J = 6.3Hz), 3.18-3.00 (2H, m), 2.64-2.56 (2H, m), 1.80-1.70 (3H, m ), 1.26-1.14 (2H, m) IR spectrum v max cm "1 (liquid film): 3296, 2920, 2856, 1598, 1449, 1359, 1319, 1 126, 1074, 846. Mass spectrum (The ) m / z: 159 (M +) EXAMPLE 77d Hydrochloride of 2-H1 -ff (2S) -1 '-f 2-r (2R) -4-r3,5-bis (trifluoromethyl) benzo ip-2- (3,4-dichlorophenyl) morpholin-2-ylethyl > -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) oxy-acetyl) piperidin-4-yl) methoxphletanol The reaction was carried out with a procedure similar to that of Example 66b using 239 mg (0.32 mmoles) of 1- (2 { (2R) -2- (3,4-dichlorophenyl) -4- [3.5 bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethyl) espyro [(2S) -2-carboxymethoxy] -dandane-1,4'-piperidine, 33 μl (0.35 mmol) of ethyl chloroformate, 52 μl (0.47 mmoles) of N-methylmorpholine and 60 mg (0.39 mmoles) of 2- (piperidin-4-ylmethoxy) ethanol, obtained in Example 77c, to obtain 206 mg (yield: 70%) of the title compound as a solid white. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.06 (1 H, brs), 8.15-7.90 (3 H, m), 7.70-7.10 (7 H, m), 4.50-1.50 (36 H, m), 1.30 -1.10 (2H, m). Spectrum of IR v max cm "1 (KBr): 3410, 2926, 2864, 1648, 1473, 1440, 1375, 128.1, 1185, 1137, 1029, 905, 758, 681. Mass spectrum (FAB) m / z: 900 (M + H) +, free form) Elemental analysis (for C44H5oC! 3F6N3? 6 H2O) Calculated (%): C: 55.32, H: 5.49, 01: 11.13, F: 11.93, N: 4.40 Found (%): C: 55.70, 1-1: 5.51, 01: 10.72, R11.84, N: 4.31 The reactions were carried out with a procedure similar to that of Example 58b, 66b or 69 to synthesize the following compounds.

EXAMPLE 78 Hydrochloride of 1-f H (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-yl-ethyl) -2,3-dihydrospiro [indene-1,4'-piperidin1-2- »l) oxyacetyl) p -peridin-4-one (hydrochloride of example compound No. 2-579) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.16-7.95 (3 H, m), 7.70-7.15 (7 H, m), 4.46-1.67 (31 H, m). IR spectrum v max cm "1 (KBr): 3414, 2926, 2553, 1719, 1651, 1282, 1138. Mass spectrum (FAB) m / z: 840 ((M + H) +, free form) Elemental analysis (for C4? H41CI2F6N3O5 HCl H2O) Calculated (%): 0: 55.01, H: 4.95, N: 4.69, Found (%): C: 55.08, H: 5.28, N: 4.28.

EXAMPLE 79 2-r (2S) -1'-f2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ethyl) -2.3-dihydrospiro hydrochloride [indeno-1,4'-piperidin1-2-yl) oxy] -N-ethyl-N- (2-hydroxyethyl) acetamide (example compound hydrochloride No. 2-424) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.15-7.95 (3H, m), 7.67-7.15 (7H, m), 4.48-1.21 (32H, m).

IR spectrum v max cm "1 (KBr): 3362, 2931, 2561, 1648, 1474, 143B, 1376, 1281, 1139. Mass spectrum (FAB) m / z: 830 ((M + H) +, form free) Elemental analysis (for C4oH43CI2F6N3O5 HCl) Calculated (%): C: 55.40, H: 5.11, N: 4.85, Found (%): C: 56.01, H: 5.67, N: 4.39.

EXAMPLE 80 2-f ((2S) -1 '-f 2-r (2R) -2- (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-hydrochloride il1ethyl) -2,3-dihydro-pyroxydene-1,4'-piperidin-1-yl) oxy-N- [2- (2-hydroxyethoxy) etn-methylacetamide (hydrochloride of example compound No 1-422) Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 7.70-7.14 (7H, m), 6.74 (2H, br), 4.45-2.15 (43H, m). IR spectrum v max cm "1 (KBr): 3410, 2935, 2567, 1646, 1583, 1464, 1427, 1330, 1239, 1125. Mass spectrum (FAB) m / z: 814 ((M + H) + , Free form) EXAMPLE 81 2-H (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-inethyl) hydrochloride - 2.3-dihydrospiro [indene-1,4'-piperidin-1-yl) oxy] -N-ethyl-N- (4-hydroxybutyl) acetamide (example compound hydrochloride No. 2-426) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.15-7.95 (3H, m), 7.68-7.14 (7H, m), 4.40-1.42 (36H, m). IR spectrum v max cm "1 (KBr): 3395, 2932, 2558, 1647, 1473, 1438, 1376, 1281, 1139. Mass spectrum (FAB) m / z: 858 ((M + H) +, form free) EXAMPLE 82 2-f ((2S) -1 '-f 2-r (2R) -2- (3,4-dichlorophenyl) -4- (3, 4,5-trimethoxybenzoyl) morpholin-2 hydrochloride yl] ethyl.} -2,3-dihydro-pyroxydene-1,4'-piperidin] -2-yl) oxy-N- (4-hydroxybutyl-N-methylacetamide (hydrochloride of example compound No 1-418) Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 7.75-7.14 (7H, m), 6.71 (2H, br), 4.53-1.48 (43H, m). IR spectrum v max cm "1 (KBr): 3399, 2934, 2562, 1647, 1583, 1463, 1426, 1330, .1238, 1125. Mass spectrum (FAB) m / z: 798 ((M + H) +, free form) EXAMPLE 83 Hydrochloride of 1 -ff ((2S) -1 '-f 2-r (2R) ^ - r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholine- 2-ineethyl> -2.3-dihydro-sspyrorindene-1,4'-piperidin-1-yl) -oxyacetyl) piperidin-4-ol (example compound hydrochloride No. 2-580) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.16-7.92 (3H, m), 7.71-7.13 (7H, m), 4.44-1.45 (31 H, m). IR spectrum v max cm "1 (KBr): 3397, 2927, 2563, 1648, 1473, 1440, 1375, 1282, 1 139. Mass spectrum (FAB) m / z: 842 (M + H) +, form free) Elemental analysis (for C41H43CI2F6N3O5 HCl) Calculated (%): 0: 54.89, 1-1: 5.17, N.4.68, found (%): 0: 54.91, H.5.37, N: 4.43.

EXAMPLE 84 2-f ((2S) -1'-f2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-inet hydrochloride 1.) -2,3-dihydrospiro [indene-1,4'-piperidin-2-yl) -oxp-N- (3-methoxypropyl) -N-methylacetamide (hydrochloride of compound of example No. 2- 466) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.14-7.90 (3H, m), 7.71-7.12 (7H, m), 4.45-1.55 (35H, m).

IR spectrum v max cm "1 (KBr): 2927, 1650, 1474, 1439, 1376, 1281, 1138 Mass spectrum (FAB) m / z: 844 (M + H) +, free form) Elemental analysis (for C? H 5Cl2F6N3O5 HCl) Calculated (%): 0: 55.88, H: 5.26, N: 4.77. Found (%): C: 55.56, H: 5.57, N: 4.54.

EXAMPLE 85 N- (1-f2-r ((2S) -1'-f2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholine- hydrochloride 2-inethyl.} -2,3-dihydrospyrorindene-1,4'-piperidm1-2-yl) oxy-acetyl) piperidin-4-yl) acetamide (example compound hydrochloride No. 2-589) Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 8.12-7.91 (3H, m) ,. 7.70-7.14 (7H, m), 6.48-6.27 (1 H, bs), 4.20-1.23 (34H, m). IR spectrum v max cm "1 (KBr): 2928, 1649, 1473, 1439, 1375, 1281, 1139. Mass spectrum (FAB) m / z: 883 (M + H) +, free form) Elemental analysis ( for C43H46CI2F6N4O5 HCl 3H2O) Calculated (%): C: 53.01, H: 5.4B, N: 5.75, Found (%): 0: 52.94, H: 5.53, N: 5.53.

EXAMPLE 86 2-f ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl-ethyl >hydrochloride; -2,3-dihydrospirophen-1,4'-p'iperidin) -2-yl) oxy-N- (2-methoxyethyl) -N-methylacetamide (hydrochloride of example compound No. 2-465) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.15-7.92 (3H, m), 7.72-7.11 (7H, m), 4.42-1.60 (33H, m). IR spectrum v max cm "1 (KBr): 2928, 1650, 1439, 1376, 1281, 1 138. Mass spectrum (FAB) m / z: 830 (M + H) +, free form) Elemental analysis (for C 0H43Cl2F6N3O5 HCl) Calculated (%): C: 55.40, H: 5.11, N: 4.85, Found (%): C: 56.11, H: 5.79, N: 4.38.

EXAMPLE 87 (2S) -2-F2- (4-Acetylpiperazin-1-yl) -2-oxoethoxy-1'-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoyl-2 hydrochloride - (3,4-dichlorophenyl) morpholin-2-yl) ethyl) -2.3- dihydrospirorindene-1,4'-piperidin-1 (example compound hydrochloride No. 2-613) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.17-7.91 (3H, m), 7.72-7.12 (7H, m), 4.48-1.94 (33H, m), 1.76-1.59 (1 H, m) .

IR spectrum v max cm "1 (KBr): 2926, .1650, 1472, 1438, 1282, 1138. Mass spectrum (FAB) m / z: 869 (M + H) +, free form) Elemental analysis (for C42H44Cl2F6N4O5 HCl 3H2O) Calculated (%): C: 52.54, H: 5.35, N: 5.85, Found (%): C: 53.00, H: 5.35, N: 5.50.

EXAMPLE 88 2-H (2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) -benzoin-2- (3,4-dichlorophenyl) morpholin-2 hydrochloride -yl-1-ethyl) -2,3-dihydro-spiro-3,4-N-bis (2-methoxyethyl) acetamide (Example Compound Hydrochloride No. 2-57) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.16-7.91 (3H, m), 7.66 (1 H, br), 7.58-7.14 (6H, m), 4.42-1.60 (37H, m). IR spectrum v max cm "1 (KBr): 2928, 1650, 1473, 1438, 1375, 1282, 1186, 1138. Mass spectrum (FAB) m / z: 874 (M + H) +, free form) Analysis elemental (for C 2 H 47 Cl 2 F 6 N 3 6 6 HCl) Calculated (%): 0: 55.36, 1-1: 5.31, N: 4.61, Found (%): C: 55.08, H: 5.76, N: 4.28.

EXAMPLE 89 2-r ((2S) -1'-f2-r (2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ethyl) -2. 3-dihydro-pyrophosphin-1,4'-piperidin-1-2-yl) -oxi-N- (3-hydroxypropoxy) -N-methylacetamide (example compound No. 2-550) Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 8.06-7.13 (10H, m), 4.79-1.74 (32H, m). IR spectrum v max cm "1 (KBr): 3438, 2926, 1646, 1473, 1440, 1375, 1281, 1184, 1139. Mass spectrum (FAB) m / z: 846 (M + H) \ free form) EXAMPLE 90 2-f ((2S) -1 '-f 2-r (2R) -4-r3.5-bis (trifluoromethyl) benzoyl-2- (3,4-dichlorophenyl) morpholin-2-inethyl} -hydrochloride - 2,3-dihydrospirorindene-1,4'-piperidin-1-yl) oxy-N- (3-hydroxypropyl) acetamide (hydrochloride of example compound No. 2-410) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 8.21-7.93 (3H, m), 7.70-7.16 (7H, m), 4.58-1.56 (29H, m). IR spectrum v max cm "1 (KBr): 3404, 2928, 1649, 1535, 1474, 1439, 1376, 128.1, 1139. Mass spectrum (FAB) m / z: 816 (M + H) +, free form ) Elemental Analysis (for C39H41CI2F6N3? 5 HCl) Calculated (%): 0: 54.91, H: 4.96, N: 4.93, Found (%): 0: 56.56, H: 6.03, N: 4.30.

EXAMPLE 91 2-f ((2S) -1 '-f2 - ((2R) -4-r3,5-bis (trifluoromethyl) benzoin-2- (3,4-dichlorophenyl) morpholin-2-ynyl > -2,3-dihydrospiro [indene-1,4'-piperidin1-2-yl) oxy] -N- (4-hydroxy-4-methylpentyl) -N-methylacetamide (hydrochloride of example compound No. 2-416) 1 H-NMR spectrum (400 MHz, CD3OD) d ppm: 8.13 (1H, brs), 7.98 (2H, brs), 7.81 (1 H, brs), 7.70-7.45 (2H, m), 7.28-7.10 (4H , m), 4.45-0.85 (38H, m). IR spectrum v max cm'1 (KBr): 3407, 2965, 2930, 1649, 1473, 1458, 1440, 1376, 1281, 1185, 1165, 1139, 681, 624. Mass spectrum (FAB.) M / z: 872 ((M + H) +, free form.] Elemental analysis (for C43H49CI2F6N3? 5 HCl) Calculated (%): C: 56.80, H: 5.54, N: 4.62. Found (%): 0: 57.38 , H: 6.16, N: 4.29.

EXAMPLE 92 3- (1 -ff ((2S) -1 '-f 2-r (2R) -2- (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-inethyl hydrochloride .) -2,3-dihydrospiro [indene-1,4'-piperidin-1-yl) oxy-acetyl) -piperidin-4-yl) -propan-1-ol (hydrochloride of example compound No. 1-587) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 7.95-7.10 (7H, m), 6.62-6.60 (2H, m), 4.50-0.85 (47H, m). IR spectrum v max cm'1 (KBr): 3400, 2931, 2856, 1644, 1583, 1463, 1427, 1377, 1330, 1269, 1236, 1125, 1028, 1005, 761. Mass spectrum (FAB) m / z: 838 ((M + H) +, free form) Elemental analysis (for C 5H57CI2N3O8 HCl H2O) Calculated (%): C: 60.50, H: 5.77, 01: 11.91, N: 4.70. Found (%): 0: 60.48, H: 6.72, 01: 11.85, N: 4.55.

EXAMPLE 93 N-r4- (Acetylamino) butp-2-r ((2S) -1 '-f 2 -f (2R) -4-r3.5-bis (trifluoromethyl) benzoin-2- (3.4) hydrochloride -dichlorophenyl) morpholin-2-ypethyl> -2.3- dihydro-sspyrorindene-1,4'-piperidin] -2-yl) oxy-1-N-methylacetamide (example compound hydrochloride No. 2-567) Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 12.07 (1H, brs), 8.15-7.90 (3H, m), 7.75-7.10 (7H, m), 5.90-5.50 (1 H, m), 4.45 -1.40 (37H, m).

IR spectrum v max cm "1 (KBr): 3284, 2930, 2558, 1651, 1546, 1475, 1439, 1375, 1282, 1185, 1138, 1109, 1029, 905, 758, 707, 681. Mass spectrum ( FAB) m / z: 885 ((M + H) +, free form) Elemental analysis (for C 3H 8CI3F6N3? 6 H2O) Calculated (%): C: 54.93, H: 5.47, 01: 11.31, R12.12, N: 5.96 Found (%): C: 54.84, H: 5.56, 01: 11.03, R12.12, N: 5.81 EXAMPLE 94 2-f ((2S) -1 '-f 2 -f (2R) -4-r3,5-bis (trifluoromethyl) benzoip-2-f 3,4-dichlorophenyl) morpholin-2-inethyl) -2-hydrochloride , 3-dihydro-spiro-1,3-indo-1,4'-piperidin-1-yl) -oxp-N-hydroxy-N- (4-hydroxybutyl) acetamido (hydrochloride of Example Compound No. 2-453) IR spectrum v max cm "1 (KBr): 3414, 2931, 2683, 2578, 1650, 1474, 1439, 1376, 1281, 1186, 1140, 1029, 905, 758, 681. Mass spectrum (FAB) m / z 846 ((M + H) +, free form) EXAMPLE 95 2-f ((2S) -1 '-f 2-r (2R) -4-r3,5-bis (trifluoromethy1) benzoin-2- (3,4-dichlorophenyl) morpholine hydrochloride 2-yl-ethyl-2-dihydro-spiro [indene-1,4'-piperidin] -2-yl) oxy] -N-methyl-N-f4 - [(methylsulfonyl) aminolbutyl) acetamide (hydrochloride) of example compound No. 2-569) 1 H-NMR spectrum (400 MHz, CDCl 3) d ppm: 11.96 (1 H, brs), 8.15-7.90 (3 H, m), 7.75-7.10 (7 H, m), 5.20-4.80 (1 H, m), 4.40 -1.45 (37H, m). IR spectrum v max cm "1 (KBr): 3429, 2930, 2561, 1649, 1474, 1439, 1376, 1321, 1282, 1185, 1142, 1108, 1029, 976, 905, 758, 681. Mass spectrum ( FAB) m / z: 921 ((M + H) +, free form) Elemental analysis (for C43H48CI3F6N3O6 HO) Calculated (%): 0: 51.67, H: 5.27, 01: 10.89, R11.68, N: 5.74, S: 3.28 Found (%): 0: 51.44, H: 5.40, C 10.51, FH21, N: 5.61, S: 3.18 REFERENCE EXAMPLES REFERENCE EXAMPLE 1 1-f2-r (2R) -2- (3,4-dichlorophenyl) -4-r3.5-bis (trifluoromethyl) benzoylmorpholin-2-yl-ethyl) -spiror (2S) -2-hydroxy1indan-1, 4'-piperidine REFERENCE EXAMPLE 1a 2-f (2R) -2- (3,4-Dichlorophenyl) -4-r3,5-bis (trifluoromethyl) benzoyl-1-morpholin-2-yl) methanesulfonate ethanol . 60 g (20.3 mmol) of 2 - [(2R) -2- (3,4-dichlorophenyl) morpholin-2-yl-ethanol (specification of USP 6 / 159,967, example 51 (d)) was dissolved in methylene chloride (60 mg). ml) and 2.83 ml (24.3 mmoles) of triethylamine were added thereto. 5.60 g (20.3 mmol) of 3,5-bis (trifluoromethyl) benzoyl chloride and 248 mg (2.03 mmol) of 4-dimethylaminopyridine were added to the mixture under cooling with ice and the mixture was stirred at room temperature for 2 hours under an atmosphere of nitrogen. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (eluent-solvent: hexane / ethyl acetate = 1/1) to obtain 5.68 g (yield: 54%) of 2-. { (2R) -2- (3,4-Dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethanol. 5.68 g (11 mmol) of the obtained alcohol form was dissolved in methylene chloride (60 ml) and 2.3 ml (16.5 mmol) of triethylamine were added thereto under a nitrogen atmosphere. 1.02 ml (13.2 mmol) of methanesulfonyl chloride was added to the mixture under cooling with ice and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (eluent-solvent: hexane / ethyl acetate = 3/2) to obtain 6.09 g (yield: 93%) of the composed of the title. Spectrum of 1 H-NMR (400 MHz, CDCl 3) d ppm: 8.05-7.71 (3H, m), 7.70-7.29 (3H, m), 4.56-4.19 (2H, m), 4.08-3.23 (6H, m), 2.95 (3H, s), 2.52-2.16 (2H, m). Mass spectrum (FAB +) m / z: 594 ((M + H) +) REFERENCE EXAMPLE 1b 1-f 2 -r (2R) -2- (3,4-dichlorophenyl) -4-r 3,5-bis (trifluoromethyl) benzoinmorpholin-2-yl] ethyl} esprof (2S) -2-hydroxy1indane-1,4'-piperidine 126 mg (212 mmol) of 2- methanesulfonate. { (2R) -2- (3,4-Dichlorophenyl) -4- [3,5-bis (trifluoromethyl) benzoyl] morpholin-2-yl} ethanol, obtained in reference example 1a, was dissolved in 1300 ml of dimethylacetamide and 26.7 g (318 mmoles) of sodium bicarbonate, 52.8 g (318 mmoles) of potassium iodide and 43.1 g (212 mmoles) of spiro [( 2S) -2- hydroxy] indane-1,4'-piperidine] were added thereto, followed by stirring the mixture at 80 ° C for 8 hours. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was combined and the mixture was washed with water and a saturated NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled under reduced pressure and the residue was purified by chromatography on silica gel (eluent-solvent: ethyl acetate / methanol = 100/1) to obtain 129 g (yield: 87%) of the title compound as a white amorphous solid. Spectrum of 1 H-NMR (500 MHz, CD3OD) d ppm: 8.35-8.20 (1 H, m), 8.06-7.99 (2H, m), 7.81-7.28 (3H, m), 7.24-7.04 (4H, m ), 4.54-4.40 (1H, m), 4.29-3.04 (8H, m), 2.72-2.37 (3H, m), 2.30-1.58 (9H, m). IR spectrum v max cm "1 (KBr): 3448, 2923, 1645, 1473, 1375, 1280, 1139. Mass spectrum (FAB) m / z: 701 ((M + H) +) Elemental analysis (for C34H32CI2F6N2? 3 1 / 2H2O) Calculated: C: 57.47, H: 4.68, Cl: 9.98, F: 16.04, N: 3.94 Found: C: 57.76, H: 4.63, Cl: 9.54, F: 15.78, N: 3.86 Optical Rotation: [a] D20 = +37.20 (c = 1.00, methanol) EXAMPLES OF PREPARATION EXAMPLE OF PREPARATION 1 Powder A powder can be obtained by mixing 5 g of the compound of example 1, 895 g of lactose and 100 g of corn starch in a blender.

EXAMPLE OF PREPARATION 2 Granules g of the compound of Example 3, 865 g of lactose and 100 g of hydroxypropyl cellulose substituted with low substituent are mixed followed by the addition of 300 g of 10% aqueous hydroxypropyl cellulose solution and kneading. The product thus kneaded is then extruded and granulated using a granulation machine followed by drying to obtain granules.

EXAMPLE OF PREPARATION 3 Tablets g of the compound of Example 5, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, followed by tabletting with a tablet press to obtain tablets EXAMPLE OF PREPARATION 4 Liquid for inhalation 1 A liquid is prepared so as to contain 10% (w / w) of the compound of Example 6, 0.04% (w / w) of benzalkonium chloride, 0.40% (w / w) of phenethyl alcohol and 89.56% (w / w) ) of purified water.

EXAMPLE OF PREPARATION 5 Liquid for inhalation 2 A liquid is prepared in a manner that contains 10% (w / w) of the compound of Example 31, 0.04% (w / w) of benzalkonium chloride, 10% (w / w) of polyethylene glycol, 30% (w / w) of propylene glycol and 49.96% (w / w) of purified water.

EXAMPLE OF PREPARATION 6 Powder for inhalation A liquid is prepared so as to contain 40% (w / w) of the compound of Example 32 and 60% (w / w) of lactose.

EXAMPLE OF PREPARATION 7 Aerosol An aerosol is prepared so as to contain 10% (w / w) of the compound of Example 33, 0.5% (w / w) of lecithin, 34.5% (w / w) of chlorofluorocarbon 11 and 55% (w / w) of chlorofluorocarbon 12.

TEST EXAMPLES TEST EXAMPLE 1 NK1 receptor binding test. { in vitro) Preparation of crude lung membrane specimen A pulmonary membrane specimen was prepared from the lungs of a male Hartley guinea pig. Namely, blood was extracted from the abdominal aorta of the animal under anesthesia with chloroform followed by timely extirpation of lung and respiratory tract tissue. The excised lungs were perfused with pH regulator a (50 mM pH regulator Tris-HCl, pH 7.4) and then sliced into thin sections followed by homogenization using a Polytron in pH regulator (pH regulator containing 120 mM sodium chloride and 5 mM chloride of potassium). The tissue masses were removed from the homogenate by filtering through a Nylon mesh (50 μm) followed by centrifugation (30,000 x g, 30 minutes, 4 ° C). The resulting pellet was resuspended in pH regulator cooled in ice? (pH regulator a containing 10 mM EDTA and 300 mM potassium chloride) followed by undisturbed rest at 4 ° C for 60 minutes and then washing twice with centrifugation (30,000 x g, 15 minutes, 4 ° C). The crude lung membrane specimen was stored at -80 ° C until the time of use. 250 μl receptor binding assay of crude lung membrane specimen fluid was added to 250 μl of a mixture of test substance and [3 H] -substance P (final concentration: 1 nM) (containing 50 mM Tris-HC1 , pH 7.4, 6 mM manganese chloride, 800 μl / ml BSA, 8 μg / ml chymostatin, 8 μg / ml leupeptin, 80 μg / ml bacitracin and 20 μg / ml phosphoramidon) followed by incubation room temperature for 30 minutes. After the reaction, the membrane component was recovered on a GF / B glass fiber filter (Whatman) using an automatic filtration system (Brandel). In addition, the glass filter was used after pre-treating for about 4 hours with a 0.1% solution of polyethylenimine to suppress non-specific binding at a low level.

The filter used to recover the membrane component was transferred to a plastic mini-vial containing 4 ml of Picoflow followed by measurement of radioactivity with a liquid scintillation counter (Beckman, LSC3500).

TEST EXAMPLE 2 NK2 receptor binding test (in vitro) Preparation of crude ileum membrane specimen A membrane specimen was prepared from the ileum of a male Hartley guinea pig. Namely, blood was extracted from the abdominal aorta under anesthesia with chloroform followed by timely extirpation of the ileum. The contents of lumen, secretions and epithelium were removed from the ileum by rubbing with a slide, and then sliced in sections at pH regulator a (50 mM Tris-HCl pH regulator, pH 7.4), the thin sections were homogenized using Polytron in pH regulator ß (pH regulator containing 120 mM of sodium chloride and 5 mM of potassium chloride). The tissue masses were removed from the homogenate by filtering through a Nylon mesh (50 μm) followed by centrifugal separation (30,000 x g, 30 minutes, 4 ° C). The resulting pellet was resuspended in pH regulator cooled in ice? (pH buffer containing 10 mM EDTA and 300 mM potassium chloride) followed by resting undisturbed at 4 ° C for 60 minutes and then washing twice with centrifugation (30,000 x g, 15 minutes, 4 ° C). The crude membrane specimen was stored at -80 ° C until the time of use. 250 μl receptor binding test of crude ileum membrane specimen fluid was added to 250 μl of a mixture of test substance and [3HJ-SR-48968 (Amersham, final concentration: 1 nM) (containing 50 mM of Tris-HC1, pH 7.4, 6 mM manganese chloride, 800 μl / ml BSA, 8 μg / ml chymostatin, 8 μg / ml leupeptin, 80 μg / ml bacitracin and 20 μg / ml phosphoramidon) followed by incubation at room temperature for 30 minutes. After the reaction, the membrane component was recovered on a GF / B glass fiber filter (Whatman) using an automatic filtration system (Brandel). In addition, the glass filter was used after pre-treating for about 4 hours with a 0.1% solution of polyethylenimine to suppress non-specific binding at a low level. The filter used to recover the membrane component was transferred to a plastic mini-vial containing 4 ml of Picoflow followed by measurement of radioactivity with a liquid scintillation counter (Beckman, LSC3500).

EXAMPLE OF TEST 3 Inhibitory action on increased vascular permeability (oral administration in vivo) The inhibitory action on increased vascular permeability can be investigated using the amount of escape dye as an indicator of the inhibitory action on increased vascular permeability induced by the NK1 receptor agent, substance P (SP), using normal guinea pigs (body weights: approximately 400 g, male Hartley guinea pigs). Dye (Evans blue: 40 mg / kg iv) was administered to the guinea pig femoral vein under anesthesia with pentobarbital (30 mg / kg, ip) followed immediately by intravenous injection of SP (1 μg / kg) to induce a ncrement in vascular permeability. 15 minutes later, the guinea pigs were sacrificed under anesthesia with chloroform and the amount of dye that escapes at the site of the primary bronchus is measured according to the Harada method (J. Pharm, Pharmacol 23, 218 (1971)). The test substance is suspended in a 0.5% tragacanth suspension and orally administered 1 hour before challenge by SP. The inhibitory action can be evaluated using the amount of escape dye in guinea pigs to which the test substance is administered as an indicator.

EXAMPLE OF TEST 4 Inhibitory action on contraction of airways (oral administration in vivo) The inhibitory action on airway contraction can be investigated using internal airway pressure as an indicator of the inhibitory effects of a test substance on airway contraction induced by the NK2 receptor agent, neurokinin A (NKA), using normal guinea pigs (body weights: approximately 500 g, male Hartley guinea pigs) in accordance with a variation of the Konzett-Roessler method (Naunyn-Schmiedegergs Arch. Exp. Pathol. Pharmakol., 195, 71 (1940 )). Namely, after implanting a trachea cannula in the guinea pigs under anesthesia with pentobarbital (30 mg / kg, ip) and treating with gallamine (20 mg / kg, iv), positive pressure ventilation (Ugo-Basile Biological Research Apparatus, Cat. No.7025) was carried out rapidly at 8 ml / kg and 60 times / minute. The internal airway pressure during artificial respiration is recorded with a recording device (Nihon Koden, WT-645G or WT-685G) by amplification and sensitization (Nihon Koden, AP-601G) by means of a pressure transducer (Nihon Koden, TP-200T or TP-400T) implanted to the lateral branch of the trachea cannula. Five minutes of penetration with atropine (1 mg / kg, iv) and propranolol (1 mg / kg, iv), NKA is administered intravenously at 4 μg / kg to induce contraction of airways followed by measurement of internal pressure of the tract over the next 10 minutes.

The test substance is prepared in the same manner as test example 3 and administered orally 1 hour before challenge by NKA. The inhibitory action can be compared by comparing the surface area values of internal airway pressure between a group of doses of test substance and a group without dose.

TEST EXAMPLE 5 NK3 receptor binding test (in vitro) Preparation of raw brain membrane specimen A membrane specimen was prepared from the brain of a male Hartley guinea pig. Namely, blood was extracted from the abdominal aorta under anesthesia with chloroform, and after perfusing the right ventricle with pH regulator to (50 mM pH buffer Tris-HCl, pH 7.4), the brain was removed opportunely. The excised brain was homogenized with Polytron (Kinematica) in pH regulator (pH regulator containing 120 mM of sodium chloride and 5 mM of potassium chloride) followed by removal of masses of tissue filtering with gauze and a mesh of Nylon (50 μm) and centrifugation (30,000 xg, 30 minutes, 4 ° C). The resulting pellet (membrane component) was resuspended in pH regulator cooled in ice? (pH regulator a containing 10 mM EDTA and 300 mM potassium chloride) followed by resting undisturbed at 4 ° C for 60 minutes and then washing twice with centrifugation (30,000 x g, 15 minutes, 4 ° C). This was then used as a crude membrane specimen by suspending in pH regulator a, and stored at -80 ° C in the receptor binding test until the time of use.

Receiver binding test The test tube used in the reaction was previously treated with a pH regulator a containing 5 mg / ml bovine serum albumin (BSA). A test substance and 150 μl of pH regulator a containing 400 μg / ml of BSA were added to 100 μl of pH regulator containing [3 H] -senctide, 6 mM manganese chloride, 800 μg / ml of BSA, 8 μg / ml of chymostatin, 8 μg / ml of leupeptin, 80 μg / ml of bacitracin and 20 μg / ml of phosphoramidon followed by the addition of 250 μl of the crude brain membrane specimen (adjusted to protein concentration of 1 mg / ml) to initiate the reaction (at this time, the final concentration of [3 H] -senctide in the reaction phase is 2.5 nM). After incubating at room temperature for 60 minutes, the membrane component was recovered on a GF / B glass fiber filter (Whatman) previously treated for 4 hours or more with 0.1% polyethylenimine using an automatic filtration system (Brandel) , and then washed three times with 5 ml of ice-cooled pH regulator or (5 mM Tris-HCl pH buffer containing 400 μg / ml BSA and 0.01% sodium dodecyl sulfate, pH 7.4). The glass fiber filter GF / B to which the membrane component was adhered was transferred to a plastic mini-vial containing 4 ml of Picoflow followed by measurement of radioactivity with a liquid scintillation counter (Aloka, LSC3500). The test was carried out by adding an excessive amount of senctide (final concentration: 10 μM) followed by measurement of radioactivity to determine radioactivity attributable to non-specific binding of [3 H] -senctide (binding to sites other than receptors (such as the filter)). The rate of inhibition of senctide-receptor binding by the test substance was determined according to the following equation. Inhibition rate (%) = [1- (CA) / (BA)] x 100 A: Radioactivity attributable to non-specific binding B: Radioactivity in test carried out without adding test substance C: Radioactivity in test in which added the test substance EXAMPLE OF TEST 6 Inhibitory action on increased vascular permeability (transtracheal administration in vivo) A test substance was dissolved in 5% aqueous solution of glucose, and 0.5 ml / kg of solution was administered transtracheally to guinea pigs (body weights: approximately 400 g, male Hartley guinea pigs) using an intratracheal dosing instrument (1A- 1 B, Penn-Century) under anesthesia with pentobarbital (0.2 to 0.25 ml / body, i.p.). Immediately after administration of the drug, Evans blue (40 mg / 2 ml / kg, iv) and then the NK1 receptor agonist, substance P (1 μg / 2 ml / kg, iv) were administered via a femoral vein ( inside). The animals were sacrificed with gaseous carbon dioxide 15 minutes after the administration of the substance Ge P1 and approximately 2 cm of the primary bronchus was excised from the neck. The excised primary bronchus was immersed for approximately 24 hours in 4 ml of a 7: 3 mixture of acetone and 0.5% Na2SO4 to extract the dye followed by measurement of the optical density (OD 620 nm) of the extract. The amount of dye was converted using a calibration curve, and the amount of dye that escaped per 0.1 g of trachea was taken to represent the concentration of the increase in vascular permeability followed by calculation of the rate of inhibition relative to a control (group of transtracheal dose of 5% glucose).

EXAMPLE OF TEST 7 Inhibitory action on contraction of airways (transtracheal administration in vivo) The inhibitory action on airway contraction by the NK2 receptor agonist, neurokinin A (NKA) was investigated using internal airway pressure as an indicator normal guinea pigs (body weights: approximately 500 g, male Hartley guinea pigs) using a variation of the method by Konzett-Roessler (Naunyn-Schmiedebergs Arch. Exp. .Pathol. Pharmakol., 1951 71 (1940) A tracheal cannula and venous cannula were implanted in guinea pigs under pentobarbital anesthesia (50 mg / ml liquid, 0.40 to 0.50 ml In addition, an arterial cannula carried with physiological saline containing heparin (100 U / ml) was implanted to monitor blood pressure and heart rate by means of an amplifier and instant cardiograph, and then, after administering gallamine (20 mg / kg, iv) and interrupting spontaneous respiration, positive pressure ventilation was rapidly carried out (Ugo-Basile Biological Research Apparatus, Cat. No.7025) a 10 ml / kg and 60 times / minute The internal airway pressure during artificial respiration was detected with a pressure transducer (Nihon Koden, TP-200T or TP-400T) implanted in the lateral branch of the trachea cannula, it was amplified (Nihon Koden, AP-601 G) and registered with a recording device (Nihon Koden, WT-645G or WT-685G). After the internal airway pressure, blood pressure and heart rate had stabilized, the standard tracheal contraction substance methacholine was administered at 10 μg / kg (100 μg / ml, 0.10 ml / kg) to confirm path response aerial In the event that the prescribed contraction response was not obtained, methacholine was additionally administered at 12 μg / kg (120 μg / ml, 0.10 ml / kg) followed by confirmation of airway response. Five minutes after confirming the airway response, NKA was administered intravenously through the intravenous cannula at 4 μg / kg to induce airway contraction followed by measurement of internal airway pressure during the following minutes. The test substance was dissolved in 5% glucose, and 0.5 ml / kg of solution was administered into the airways using an intratracheal delivery instrument (IA-1 B, Penn-Century). The surface value over which the internal airway pressure had increased to 10 minutes after administration of NKA was taken to represent the airway concentration induced by NKA, and the inhibition rate was calculated for a control group (5% glucose trans-tracheal dose group). Rates of inhibition of airway contraction when the preferred compounds of the present invention were administered followed 16 hours later by administration of NKA are shown below.

Industrial Applicability Since a compound having the general formula (I) of the present invention or pharmacologically acceptable salt thereof demonstrates antagonistic action on neurokinin receptors (NK < \ NK2 and NK3), has low toxicity and has superior pharmacokinetics, it is useful as a pharmaceutical compound, and is particularly useful as a preventive or treatment agent for respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disease; allergic diseases such as rhinitis and / or urinary incontinence in particular.

Claims (34)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- A compound represented by the general formula (I): (wherein, R1 and R2 may be the same or different and each represents an aryl group, heteroaryl group, aryl group substituted with 1 to 3 groups selected from the a substitution group, or heteroaryl group substituted with 1 to 3 groups selected from the group substituent a; R3 represents any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N (Ra) Rb, - (CH2) m-CO-R5 , - (CH2) m-R5, -CO-NH-CO-N (Ra) Rb, -CO-NH-SO2-N (Ra) Rb, -CO-NH-CO- (CH2) mN (Ra) Rb , and -CO-NH2; R4 represents a lower alkyl group, cycloalkyl group, cycloalkyl group substituted with 1 to 3 groups selected from substituent group a, lower alkenyl group, lower alkynyl group, lower halogenoalkyl group, lower hydroxyalkyl group, alkoxyalkyl group lower , lower acyloxyalkyl group or lower alkoxycarbonyl group, R5 represents a hydroxyl group, a group -OR4, or a group -N (Ra) Rb; Ra and Rb may be the same or different and each represents a hydrogen atom, hydroxyl group, lower alkoxy group, hydroxy group-lower alkoxy, lower alkoxyalkyl hydroxyalkyl group, alkoxy group inferiori-lower alkoxyalkyl, lower alkoxyalkyl group lower-alkyl carboxy-cyano, cyano-alkoxyalkyl group nferior, carboxy- lower alkyl group, group , lower-alkoxyalkyl lower alkoxycarbonyl group, carbamoyl group-lower alkyl group, carbamoyl-lower alkoxyalkyl, acylamino lower aliphatic-lower alkyl, acylamino lower aliphatic-alkoxyalkyl lower alkylsulfonylamino group lower-alkyl lower alkylsulfonylamino group lower-alkoxyalkyl nferior group (Nh¡droxi-N-metilcarbamo¡lo) lower -alqu¡lo, (N-hydroxy-N-methylcarbamoyl) -alcoxialquilo nferior group (N-alkoxy-N-methylcarbamoyl lower) alkyl, group (N-alkoxy-N-methylcarbamoyl nferor) -alkoxyalkyl lower or R4, or together, including the nitrogen atom to which they are attached, represent a a heterocyclic group containing nitrogen or heterocyclic group containing nitrogen substituted with 1 to 3 groups selected from the substituent group a; m represents an integer from 1 to 6; A represents a methylene group, carbonyl group or sulfonyl group; B represents a single bond, alkylene group of C -? - C or C2-C4 alkenyl group; D represents an oxygen atom or methylene group; E represents an alkylene group of C? -C or an alkenylene group of C2-C4; n represents an integer from 1 to 3; and the substituent group a represents a group of substituents consisting of halogen atoms; lower alkyl groups; hydroxy-lower alkyl groups, halogeno-lower alkyl groups, lower carboxyalkyl groups, lower akoxy groups, hydroxy-lower alkoxy groups; lower hydroxy-alkoxyalkyl groups; lower alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups, lower aliphatic acylamino groups; groups (N-hydroxy-N-methylcarbamoyl) -lower alkyl; groups (lower N-alkoxy-N-methylcarbamoyl) -lower alkyl, lower aliphatic hydroxy-acylamino groups, amino groups, carbamoyl groups, and cyano groups), or a pharmacologically acceptable salt or other derivative thereof.
2. 2. The compound or pharmacologically acceptable salt thereof according to claim 1, further characterized in that R1 is an aryl group or an aryl group substituted with 1 to 3 groups selected from the substituent group a.
3. 3. The compound or pharmacologically acceptable salt thereof according to claim 1, further characterized in that R1 is phenyl or phenyl substituted with 1 to 3 groups selected from the substituent group a.
4. 4. The compound or pharmacologically acceptable salt thereof according to claim 1, further characterized in that R1 is phenyl; or phenyl substituted with 1 to 3 groups selected from the group consisting of halogeno-lower alkyl groups, lower alkoxy groups and hydroxyl groups.
5. 5. The compound or pharmacologically acceptable salt thereof according to claim 1, further characterized in that R1 is phenyl substituted with 1 to 3 groups selected from the group consisting of halogeno-lower alkyl groups and lower alkoxy groups.
6. 6. The compound or pharmacologically acceptable salt thereof according to claim 1, further characterized in that R1 is 3,5-bis (trifluoromethyl) phenyl or 3,4,5-trimethoxyphenyl.
7. 7. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 6, further characterized in that R2 is an aryl group substituted with 1 to 3 groups selected from the substituent group a.
8. 8. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 6, further characterized in that R2 is a phenyl group substituted with 1 or 2 halogen atoms.
9. 9. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 6, further characterized in that R2 is 3,4-difluorophenyl or 3,4-dichlorophenyl.
10. 10. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 9, further characterized in that A is a methylene group or carbonyl group.
11. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 9, further characterized in that A is a carbonyl group.
12. 12. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 11, further characterized in that B is a single bond or alkylene group of C -? - C.
13. 13. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 11, further characterized in that B is a single bond.
14. 14. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 13, further characterized in that D is an oxygen atom or a methylene group.
15. 15. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 14, further characterized in that E is an alkylene group of CrC4.
16. 16. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 14, further characterized in that E is ethylene or trimethylene.
17. 17. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 16, further characterized in that n is 1 or 2.
18. 18. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 16, further characterized in that n is 2.
19. 19. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 18, further characterized in that R3 is - (CH2) m-CO-R5.
20. 20. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 18, further characterized in that R3 is -CH2-CO-N (Ra) Rb.
21. 21. - The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 18, further characterized in that one of Ra and Rb represents a hydrogen atom, lower alkyl group, hydroxyl group or lower alkoxy group and the other represents a lower hydroxyalkyl group, lower hydroxy-alkoxyalkyl group, carboxy lower alkyl group, lower carboxy-alkoxyalkyl group, lower alkoxycarbonyl group-lower alkyl or lower alkoxycarbonyl group-lower alkoxyalkyl, or Ra and Rb together, including the nitrogen atom to which they are attached joined, they form a heterocyclic group containing nitrogen or heterocyclic group containing nitrogen substituted with 1 to 3 groups selected from the substituent group a.
22. 22. The compound or pharmacologically acceptable salt thereof according to any of claims 1 to 18, further characterized in that -N (Ra) Rb is N- (3-hydroxypropyl) -N-methylamino, N- (4-hydroxybutyl) ) -N-methylamino, N- (5-hydroxypentyl) -N-methylamino, N- (6-hydroxyhexyl) -N-methylamino, N- [2- (2-hydroxyethoxy) ethyl] -N-methylamino, N- ( 2-hydroxyethyl) -N-methoxyamino, N- (3-carboxypropyl) -N-methylamino, 2- (3-hydroxypropyl) pyrrolidino, 4-hydroxymethylpiperidino, 4- (2-hydroxyethyl) piperidino, 4- ( 3-hydroxypropyl) piperidino, 4- (2-hydroxyethoxy) piperidino, 4- (hydroxyacetamido) piperidino, 4- (2-hydroxyethoxymethyl) piperidino or 4- (2-hydroxyethyl) piperazino.
23. 23. A pharmaceutical composition containing, as an active ingredient, a pharmacologically acceptable compound or salt thereof according to any of claims 1 to 22.
24. 24.- The pharmaceutical composition according to claim 23, for the treatment or prophylaxis of diseases mediated by NKi, NK2 and / or NK3 receptors.
25. 25. The pharmaceutical composition according to claim 23, for the prophylaxis or treatment of respiratory diseases, allergic diseases and / or urinary incontinence.
26. 26. The pharmaceutical composition according to claim 23, for the prophylaxis or treatment of asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence.
27. 27. The pharmaceutical composition according to claim 23, for the prophylaxis or treatment of respiratory diseases.
28. 28. The pharmaceutical composition according to claim 23, for the prophylaxis or treatment of asthma, bronchitis and / or chronic obstructive pulmonary disease.
29. 29. The pharmaceutical composition according to claim 27 or claim 28, in a form suitable for pulmonary administration.
30. The use of a compound or pharmacologically acceptable salt thereof according to any of claims 1 to 22, in the manufacture of a medicament for the treatment or prophylaxis of diseases mediated by NK-i, NK2 and / or NK3 receptors. .
31. 31. The use of a compound or pharmacologically acceptable salt thereof according to any of claims 1 to 22, in the manufacture of a medicament for the prophylaxis or treatment of respiratory diseases, allergic diseases and / or urinary incontinence.
32. 32. The use of a compound or pharmacologically acceptable salt thereof according to any of claims 1 to 22, in the manufacture of a medicament for the prophylaxis or treatment of asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence.
33. 33. The use of a compound or pharmacologically acceptable salt thereof according to any of claims 1 to 22, in the manufacture of a medicament for the prophylaxis or treatment of respiratory diseases.
34. 34. The use of a compound or pharmacologically acceptable salt thereof according to any of claims 1 to 22, in the manufacture of a medicament for the prophylaxis or treatment of asthma, bronchitis and / or chronic obstructive pulmonary disease. 35.- The use as claimed in claim 33 or claim 34, wherein the medicament is for pulmonary administration.