JPH06234736A - Alicyclic amine derivative - Google Patents

Abstract

PURPOSE:To obtain a new alicyclic amine derivative useful in treatment and prevention for circulatory diseases as an excellent serotonin 2 receptor antagonistic agent and having dopamine 2 receptor antagonism and used also in treatment and prevention for schizophrenia. CONSTITUTION:A compound of formula I [R<1> is 5-7-membered heterocycle (hydrogen bonded to N atom on the ring may be substituted with alkyl or aryl or hydrogen bonded to C atom on the ring may be replaced with alkenyl, alkoxy, OH, etc.); R<2> to R<4> are H, lower alkyl, lower alkynyl, lower alkenyl, (halogen)lower alkoxy, (protected)OH, (substituted)carbamoyl, halogen, CN or aryl; m is 0-4] and its salt, e.g. 2-[2-[2-[2-(3-methoxyphenyl)ethyl) phenoxy]ethyl]-1-methylpiperidine hydrochloride. The compound is obtained by reacting a compound of formula II (R<2>a to R<4>a are as same as R<2> to R<4>, with the proviso that OH is protected) with a compound of formula III (R<1>a is as same as R<1>, with the proviso that OH and N on the ring are protected; Y is OH or eliminable group) and as necessary eliminating the protecting group.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

BACKGROUND OF THE INVENTION The present invention provides an excellent serotonin 2
Aryl having a receptor antagonism and useful for the treatment and prevention of cardiovascular diseases or having an excellent serotonin 2 receptor antagonism and dopamine 2 receptor antagonism and useful for the treatment and prevention of schizophrenia The present invention relates to an alkane derivative and a pharmaceutically acceptable salt thereof.

[0003]

BACKGROUND OF THE INVENTION Serotonin is classically classified as an autacoid, is also known as a neurotransmitter, and exhibits various physiological actions in vivo through various receptors. It is known that there are various subtypes of this serotonin receptor, but in the circulatory system, receptors classified as serotonin 2 receptors are distributed in vascular endothelial cells and platelets, and It is deeply involved in contraction and aggregation of platelets (for example, S. J. Peroutoka, et al., Federation Proceding, 42, 213 (198).
3 years): SJ Peroutka et. Al., Fed. Proc., 42 , 213
(1983)), the antagonist is useful for preventing vasoconstriction and inhibiting platelet aggregation. Currently, ketanserin is known as a serotonin 2 receptor antagonist (for example, J.
I S Robertson, Current Opinion in Cardiology, Volume 3, 702 (1988): J.
IS Robertson, Curr. Opinion Cardiol., 3 , 702 (198
8)), this drug was developed as an adrenergic α ₁ antagonist and has the drawback of having a strong antihypertensive effect. In addition, MCI-9042 and the like have recently been reported as platelet aggregation inhibitors having serotonin 2 receptor antagonistic activity (eg, Journal of Medicinal Chemistry, Vol. 35, p. 189, (1992): J. Med. Chem.,
35 , 189 (1992)), but these do not show an adrenergic α ₁ antagonism, but the serotonin 2 receptor antagonism is not sufficient. Therefore, in order to obtain clinical effects, development of a drug having a strong and selective serotonin 2 receptor antagonistic action has been desired. In addition, the above-mentioned prior art includes MCI-9042.
Etc. are not described as being useful for the treatment and prevention of schizophrenia.

[0004]

[Chemical 2]

[0005]

The present inventors have, over the years, synthesized a series of diarylalkane derivatives and investigated their pharmacological actions. As a result, the diarylalkane derivative has little adrenaline α ₁ antagonism and has a strong serotonin 2 receptor antagonism, or has excellent serotonin 2 receptor antagonism and dopamine 2 receptor antagonism. There are compounds, and they have found that they are useful for the treatment and prevention of cardiovascular diseases or the treatment and prevention of schizophrenia, and have completed the present invention.

[0006]

[Constitution of the invention]

[0007]

The novel alicyclic amine derivative of the present invention has the general formula

[0008]

[Chemical 3]

[Wherein R ¹ is a 5- to 7-membered heterocyclyl group (wherein a nitrogen atom on the ring may be substituted with a lower alkyl group or an aryl group, or a carbon atom on the ring may be substituted). A lower alkyl group, a lower alkynyl group, a lower alkenyl group, a lower alkoxy group, a hydroxyl group, a protected hydroxyl group,
The substituted hydroxyl group, carbamoyloxy group or substituted carbamoyloxy group may be substituted. )so,
A group bonded by a carbon atom on the ring is represented by R ² , R
³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkynyl group,
Lower alkenyl group, lower alkoxy group, hydroxyl group, protected hydroxyl group, carbamoyl group, substituted carbamoyl group, halogen atom, cyano group or aryl group, m
Represents an integer of 0 to 4. ] The novel serotonin 2 receptor antagonist or schizophrenia therapeutic and prophylactic drug of the present invention contains the compound of the above general formula (I).

The "5- to 7-membered heterocyclyl group" in the definition of R ¹ means a 5- to 7-membered heterocyclyl group containing a nitrogen atom and optionally an oxygen atom or a sulfur atom, for example, morpholinyl, thiomorpholinyl. , Pyrrolidinyl, piperidinyl, hexahydroazepinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, and the like, and preferably morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl or piperazinyl group. Preferred is a morpholinyl, thiomorpholinyl, pyrrolidinyl or piperidinyl group, and particularly preferred is morpholinyl, pyrrolidinyl or piperidinyl.

The "lower alkyl group" in the definition of R ¹ , R ² , R ³ and R ⁴ is, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2 -Methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-
Straight or branched chain having 1 to 6 carbon atoms such as dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl It represents an alkyl group, and is preferably a linear or branched alkyl group having 1 to 4 carbon atoms.

The "lower alkynyl group" in the definition of R ¹ , R ² , R ³ and R ⁴ is, for example, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2. -Butynyl, 1-ethyl-2-butynyl, 3-butynyl,
1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2- Methyl
-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl having 2 to 6 carbon atoms A straight chain or branched chain alkynyl group can be mentioned, and a straight chain or branched chain alkynyl group having 3 to 5 carbon atoms is preferable.

The "aryl group" in the definition of R ¹ , R ² , R ³ and R ⁴ is an aromatic hydrocarbon group having 5 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl. Of these, a phenyl group is preferred. Further, the ring may have a substituent, which is the above-mentioned lower alkynyl group, the below-mentioned lower alkoxy group or the below-mentioned halogen atom.

The "lower alkenyl group" in the definition of R ¹ , R ² , R ³ and R ⁴ is, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 1-methyl-2. -Propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-butenyl, 1-methyl-2-
Butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-
Butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl- 3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- A straight chain or branched chain alkenyl group having 2 to 6 carbon atoms such as hexenyl can be mentioned, and a straight chain or branched chain alkenyl group having 3 to 5 carbon atoms is preferable.

The "lower alkoxy group" in the definition of R ¹ , R ² , R ³ and R ⁴ is a group in which the above "lower alkyl group" is bonded to an oxygen atom, and examples thereof include methoxy, ethoxy and n-propoxy. , Isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentoxy,
Isopentoxy, 2-methylbutoxy, neopentoxy,
n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy,
Linear or branched chain having 1 to 6 carbon atoms such as 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy It represents an alkoxy group, preferably a linear or branched alkoxy group having 1 to 4 carbon atoms, and more preferably methoxy and ethoxy.

The protecting group of "protected hydroxyl group" in the definition of R ¹ , R ² , R ³ and R ⁴ is a group which is cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. The "protecting group in the reaction" and the "protecting group capable of being cleaved in vivo by a biological method such as hydrolysis" are shown. Examples of such "protecting group in reaction" include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl,
3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methyl Pentadecanoyl, 13,13-
Alkylcarbonyl groups such as dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, aicosanoyl and heneicosanoyl; carboxyalkylcarbonyl groups such as succinoyl, glutaroyl, adipoyl A halogeno lower alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; a lower alkoxylated lower alkylcarbonyl group such as methoxyacetyl; a non-alkyl group such as (E) -2-methyl-2-butenoyl "Aliphatic acyl group" such as saturated alkylcarbonyl group: arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl; halogenoaryl such as 2-bromobenzoyl, 4-chlorobenzoyl Carbonyl group; lower alkylated arylcarbonyl group such as 2,4,6-trimethylbenzoyl, 4-toluoyl; lower alkoxylated arylcarbonyl group such as 4-anisoyl; 2-carboxybenzoyl, 3-carboxy Carboxylated arylcarbonyl groups such as benzoyl and 4-carboxybenzoyl; Nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl; Lower alkoxycarbonyl such as 2- (methoxycarbonyl) benzoyl Arylcarbonyl group; “aromatic acyl group” such as arylphenylcarbonyl group such as 4-phenylbenzoyl: tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl: tetrahydrofuran-2
-Tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrothiofuran-2-yl: trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, tri A tri-lower alkylsilyl group such as isopropylsilyl; a tri-lower alkylsilyl group substituted with 1 to 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl, etc. Silyl group ": lower alkoxymethyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl; 2-methoxyeth "Alkoxymethyl group" such as lower alkoxylated lower alkoxymethyl group such as cimethyl; halogenated lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl: 1-ethoxyethyl , 1-methyl-1-
Lower alkoxylated ethyl group such as methoxyethyl, 1- (isopropoxy) ethyl; halogenated ethyl group such as 2,2,2-trichloroethyl; aryl-selenylated ethyl group such as 2- (phenylzenyl) ethyl “Substituted ethyl group” such as: 1 to 1 such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl group substituted with 3 aryl groups; 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl,
4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, lower alkyl such as piperonyl, lower alkoxy, nitro, halogen, and cyano group. "Aralkyl group" such as a lower alkyl group substituted with 1 to 3 aryl groups whose ring is substituted: a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl 2,2,2-trichloroethoxycarbonyl, 2-
"Alkoxycarbonyl group" such as lower alkoxycarbonyl group substituted by halogen or tri-lower alkylsilyl group such as trimethylsilylethoxycarbonyl: "alkenyloxycarbonyl group" such as vinyloxycarbonyl, allyloxycarbonyl: benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,
“Aralkyloxycarbonyl, which may have the aryl ring substituted with 1 to 2 lower alkoxy or nitro groups, such as 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl. Group ", but preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a linear or branched alkanoyloxy group having 1 to 20 carbon atoms or carboxy. A linear or branched alkanoyloxy group having 2 to 5 carbon atoms, which is substituted with, more preferably a linear or branched alkoxycarbonyl group having 1 to 4 carbon atoms, or 2 carbon atoms. To a straight-chain or branched alkanoyloxy group or a carboxy-substituted straight-chain alkanoyloxy group having 3 to 4 carbon atoms, and even more preferably Suitably, a linear or branched alkoxycarbonyl group having 1 to 4 carbon atoms, a linear alkanoyl group having 2 to 3 carbon atoms, a linear or branched alkanoyl group having 12 to 20 carbon atoms A straight-chain alkanoyl group having 3 to 4 carbon atoms, which is substituted with a group or carboxy, and even more preferably an ethoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group, and a carbon number of 2 to 3 Is a straight chain alkanoyl group having 14 to 20 carbon atoms, a straight chain or branched chain alkanoyl group having 14 to 20 carbon atoms, or a straight chain alkanoyl group having 3 to 4 carbon atoms substituted with carboxy. It is a propoxycarbonyl group, a t-butoxycarbonyl group, an acetyl group, a palmitoyl group, a stearoyl group or a succinyl group.

On the other hand, examples of the "protective group capable of being cleaved in vivo by a biological method such as hydrolysis" include, for example, the above "carbonyloxyalkyl group"; the above "aliphatic acyl group"; and the above "aromatic group". "Acyl group";"salt residue of carboxylated lower alkylcarbonyl group" such as half-ester salt residue of succinic acid; "phosphate ester salt residue";"ester forming residue of amino acid"; and pivalo A “carbonyloxyalkyloxycarbonyl group” such as yloxymethyloxycarbonyl can be mentioned. Whether or not such a derivative is administered to an experimental animal such as rat or mouse by intravenous injection, It can be determined by examining the body fluid and detecting the original compound or a pharmacologically acceptable salt thereof.

"Substituted hydroxyl group" in the definition of R ^1.
As the substituent of, for example, methanesulfonyloxy,
Lower alkanesulfonyloxy groups such as ethanesulfonyloxy, 1-propanesulfonyloxy; fluorinated lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy and benzenesulfonyloxy, such as p-toluenesulfonyloxy And an arylsulfonyloxy group, preferably methanesulfonyloxy,
It is an ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy group.

The "substituted carbamoyl group" in the definition of R ¹ , R ² , R ³ and R ⁴ is a carbamoyl group substituted with 1 to 2 "lower alkyl groups", and preferably, A methylcarbamoyl group and a dimethylcarbamoyl group.

The "halogeno lower alkoxy group" in the definition of R ² , R ³ and R ⁴ is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, 2-
It may be a fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy group, preferably fluoromethoxy. , Difluoromethoxy, trifluoromethoxy, chloromethoxy, 2-fluoroethoxy or 2-chloroethoxy group, more preferably fluoromethoxy, difluoromethoxy, 2-fluoroethoxy or 2-chloroethoxy group, particularly preferably Has
It is a difluoromethoxy group.

The "halogen atom" in the definitions of R ² , R ³ and R ⁴ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom. m is preferably 0-3, more preferably 0-
It is 2.

Further, specific examples of the 5- to 7-membered heterocyclyl group of R ¹ include, for example, pyrrolidinyl, methylpyrrolidinyl, ethylpyrrolidinyl, propylpyrrolidinyl, isopropylpyrrolidinyl, butylpyrrolidinyl,
Pentylpyrrolidinyl, hexylpyrrolidinyl, allylpyrrolidinyl, propargylpyrrolidinyl, hydroxypyrrolidinyl, methoxypyrrolidinyl, ethoxypyrrolidinyl, propoxypyrrolidinyl, isopropoxypyrrolidinyl, butoxypyrrolidinyl , Pentyloxypyrrolidinyl, hexyloxypyrrolidinyl, methoxycarbonyloxypyrrolidinyl, ethoxycarbonyloxypyrrolidinyl, propoxycarbonyloxypyrrolidinyl, isopropoxycarbonyloxypyrrolidinyl, butoxycarbonyloxypyrrolidinyl, t -Butoxycarbonyloxypyrrolidinyl, pentyloxycarbonyloxypyrrolidinyl, hexyloxycarbonyloxypyrrolidinyl, formyloxypyrrolidinyl, acetyloxypyrrolidinyl Le, propionyl Luo pyrrolidinylmethyl,
Butyryloxypyrrolidinyl, pivaloyloxypyrrolidinyl, valeryloxypyrrolidinyl, hexanoyloxypyrrolidinyl, heptanoyloxypyrrolidinyl,
Octanoyloxypyrrolidinyl, nonanoyloxypyrrolidinyl, decanoyloxypyrrolidinyl, lauroyloxypyrrolidinyl, myristoyloxypyrrolidinyl, palmitoyloxypyrrolidinyl, stearoyloxypyrrolidinyl, eicosanoyloxypyrrolidyl Dinyl, docosanoyloxypyrrolidinyl, (succinyloxy) pyrrolidinyl, (glutaryloxy) pyrrolidinyl, (carbamoyloxy) pyrrolidinyl, (N-methylcarbamoyloxy) pyrrolidinyl, (N-ethylcarbamoyloxy) pyrrolidinyl, (N, N-dimethylcarbamoyloxy) pyrrolidinyl, (N, N-diethylcarbamoyloxy) pyrrolidinyl, (N-methyl-
N-ethylcarbamoyloxy) pyrrolidinyl, 1-methyl-hydroxypyrrolidinyl, 1-methyl-methoxypyrrolidinyl, 1-methyl-ethoxypyrrolidinyl, 1
-Methyl-methoxycarbonyloxypyrrolidinyl, 1
-Methyl-ethoxycarbonyloxypyrrolidinyl, 1
-Methyl-propoxycarbonyloxypyrrolidinyl,
1-methyl-isopropoxycarbonyloxypyrrolidinyl, 1-methyl-butoxycarbonyloxypyrrolidinyl, 1-methyl-t-butoxycarbonyloxypyrrolidinyl, 1-methyl-acetyloxypyrrolidinyl,
1-methyl-propionyloxypyrrolidinyl, 1-methyl-lauroyloxypyrrolidinyl, 1-methyl-myristoyloxypyrrolidinyl, 1-methyl-palmitoyloxypyrrolidinyl, 1-methyl-stearoyloxypyrrolidinyl, 1-methyl-eicosanoyloxypyrrolidinyl, 1-methyl-docosanoyloxypyrrolidinyl, 1-methyl- (succinyloxy) pyrrolidinyl, 1-methyl- (glutaryloxy) pyrrolidinyl,
1-methyl- (carbamoyloxy) pyrrolidinyl, 1
-Methyl- (N-methylcarbamoyloxy) pyrrolidinyl, 1-methyl- (N-ethylcarbamoyloxy)
Pyrrolidinyl, 1-methyl- (N, N-dimethylcarbamoyloxy) pyrrolidinyl, 1-methyl- (N, N-
Diethylcarbamoyloxy) pyrrolidinyl, 1-methyl- (N-methyl-N-ethylcarbamoyloxy) pyrrolidinyl, 1-ethyl-hydroxypyrrolidinyl, 1
-Ethyl-methoxypyrrolidinyl, 1-ethyl-ethoxycarbonyloxypyrrolidinyl, 1-ethyl-isopropoxycarbonyloxypyrrolidinyl, 1-ethyl-
t-butoxycarbonyloxypyrrolidinyl, 1-ethyl-acetoxypyrrolidinyl, 1-ethyl-palmitoyloxyoxypyrrolidinyl, 1-ethyl-stearoyloxypyrrolidinyl, 1-ethyl- (succinyloxy) pyrrolidinyl, piperidinyl , Methylpiperidinyl, ethylpiperidinyl, propylpiperidinyl, isopropylpiperidinyl, butylpiperidinyl, pentylpiperidinyl, hexylpiperidinyl, allylpiperidinyl, propargylpiperidinyl, hydroxypiperidinyl , Methoxypiperidinyl, ethoxypiperidinyl,
Ethoxycarbonyloxypiperidinyl, isopropoxycarbonyloxypiperidinyl, t-butoxycarbonyloxypiperidinyl, acetyloxypiperidinyl, propionyloxypiperidinyl, palmitoyloxypiperidinyl, stearoyloxypiperidinyl, succinyl Oxypiperidinyl, glutaryloxypiperidinyl, carbamoyloxypiperidinyl, (N
-Methylcarbamoyloxy) piperidinyl, (N-ethylcarbamoyloxy) piperidinyl, (N, N-dimethylcarbamoyloxy) piperidinyl, (N-methyl-N-ethylcarbamoyloxy) piperidinyl, 1
-Methyl-hydroxypiperidinyl, 1-methyl-methoxypiperidinyl, 1-methyl-ethoxypiperidinyl, 1-methyl-ethoxycarbonyloxypiperidinyl, 1-methyl-isopropoxycarbonyloxypiperidinyl, 1 -Methyl-t-butoxycarbonyloxypiperidinyl, 1-methyl-acetyloxypiperidinyl, 1-methyl-propionyloxypiperidinyl, 1
-Methyl-palmitoyloxypiperidinyl, 1-methyl-stearoyloxypiperidinyl, 1-methyl-
(Succinyloxy) piperidinyl, 1-methyl- (N
-Methylcarbamoyloxy) piperidinyl, 1-methyl-carbamoyloxypiperidinyl, 1-methyl-
(N-ethylcarbamoyloxy) piperidinyl, 1-
Methyl- (N, N-dimethylcarbamoyloxy) piperidinyl, 1-methyl- (N-methyl-N-ethylcarbamoyloxy) piperidinyl, 1-ethyl-hydroxypiperidinyl, 1-ethyl-methoxypiperidinyl,
1-ethyl-ethoxypiperidinyl, 1-ethyl-ethoxycarbonyloxypiperidinyl, 1-ethyl-isopropoxycarbonyloxypiperidinyl, 1-ethyl-t-butoxycarbonyloxypiperidinyl, 1-ethyl-acetoxy Piperidinyl, 1-ethyl-palmitoyloxypiperidinyl, 1-ethyl-stearoyloxypiperidinyl, 1-ethyl-succinyloxypiperidinyl, hexahydroazepinyl, 1-methylhexahydroazepinyl, 1 -Ethylhexahydroazepinyl, piperazinyl, 1,4-dimethylpiperazinyl, morpholinyl, 4-methylmorpholinyl, 4-ethylmorpholinyl, 4-propylmorpholinyl, 4-isopropylmorpholinyl, 4 -Butylmorpholinyl, 4-pentylmorpholinyl, 4 Hexylmorpholinyl, 4-phenylmorpholinyl, thiomorpholinyl, 4-methylthiomorpholinyl, 4-ethylthiomorpholinyl, 4-propylthiomorpholinyl, 4-isopropylthiomorpholinyl, 4-butylthiomol It may be a folinyl, 4-pentylthiomorpholinyl, 4-hexylthiomorpholinyl, 4-phenylthiomorpholinyl group, preferably pyrrolidinyl, 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl. , 4-hydroxy-2-pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-methoxycarbonyloxy-2-pyrrolidinyl, 4-ethoxycarbonyloxy-
2-pyrrolidinyl, 4-isopropoxycarbonyloxy-2-pyrrolidinyl, 4-t-butoxycarbonyloxy-2-pyrrolidinyl, 4-formyloxy-2-
Pyrrolidinyl, 4-acetyloxy-2-pyrrolidinyl, 4-pivaloyloxy-2-pyrrolidinyl, 4-valeryloxy-2-pyrrolidinyl, 4-lauroyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-
Pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4-stearoyloxy-2-pyrrolidinyl, 4
-Eicosanoyloxy-2-pyrrolidinyl, 4-docosanoyloxy-2-pyrrolidinyl, 4- (succinyloxy) -2-pyrrolidinyl, 4- (glutaryloxy) -2-pyrrolidinyl, 4- (carbamoyloxy)
2-pyrrolidinyl, 4- (N-methylcarbamoyloxy) -2-pyrrolidinyl, 4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 4- (N-methyl-N-ethylcarbamoyloxy) -2 -Pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-methoxy-2-pyrrolidinyl, 1
-Methyl-4-methoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-ethoxycarbonyloxy-
2-pyrrolidinyl, 1-methyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-
t-butoxycarbonyloxy-2-pyrrolidinyl, 1
-Methyl-4-acetyloxy-2-pyrrolidinyl, 1
-Methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-succinonioxy-2-pyrrolidinyl, 1-methyl-4-glutaryloxy-2-pyrrolidinyl , 1-methyl-4- (carbamoyloxy)
2-pyrrolidinyl, 1-methyl-4- (N-methylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-
4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4- (N-methyl-N-ethylcarbamoyloxy) -2-pyrrolidinyl, 1-ethyl-4-hydroxy-2-pyrrolidinyl, 1-ethyl-
4-methoxy-2-pyrrolidinyl, 1-ethyl-4-ethoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-t-butoxycarbonyloxy-2 -Pyrrolidinyl, 1-ethyl-4-acetoxy-
2-pyrrolidinyl, 1-ethyl-4-palmitoyloxy-2-pyrrolidinyl, 1-ethyl-4-stearoyloxy-2-pyrrolidinyl, 1-ethyl-4-succinyloxy-2-pyrrolidinyl, piperidinyl, 1-methylpiperidin Nyl, 1-ethylpiperidinyl, hydroxypiperidinyl, methoxypiperidinyl, ethoxycarbonyloxypiperidinyl, isopropoxycarbonyloxypiperidinyl, t-butoxycarbonyloxypiperidinyl, acetyloxypiperidinyl, Palmitoyloxypiperidinyl, stearoyloxypiperidinyl, succinyloxypiperidinyl, glutaryloxypiperidinyl, carbamoyloxypiperidinyl,
(N-methylcarbamoyloxy) piperidinyl,
(N, N-dimethylcarbamoyloxy) piperidinyl, (N-methyl-N-ethylcarbamoyloxy) piperidinyl, 1-methyl-hydroxypiperidinyl, 1
-Methyl-methoxypiperidinyl, 1-methyl-ethoxycarbonyloxypiperidinyl, 1-methyl-isopropoxycarbonyloxypiperidinyl, 1-methyl-
t-butoxycarbonyloxypiperidinyl, 1-methyl-acetyloxypiperidinyl, 1-methyl-palmitoyloxypiperidinyl, 1-methyl-stearoyloxypiperidinyl, 1-methyl- (succinyloxy) piperidinyl, 1 -Methyl-carbamoyloxypiperidinyl, 1-methyl- (N-methylcarbamoyloxy) piperidinyl, 1-methyl- (N, N-dimethylcarbamoyloxy) piperidinyl, 1-ethyl-hydroxypiperidinyl, 1-ethyl- Methoxypiperidinyl, 1-ethyl-ethoxycarbonyloxypiperidinyl, 1-ethyl-isopropoxycarbonyloxypiperidinyl, 1-ethyl-t-butoxycarbonyloxypiperidinyl, 1-ethyl-acetoxypiperidinyl,
1-ethyl-palmitoyloxypiperidinyl, 1-ethyl-stearoyloxypiperidinyl, 1-ethyl-
Succinyloxypiperidinyl, piperazinyl, 1,4
-Dimethylpiperazinyl, morpholinyl, 4-methylmorpholinyl, 4-ethylmorpholinyl, 4-propylmorpholinyl, 4-isopropylmorpholinyl, 4-butylmorpholinyl, thiomorpholinyl, 4-methylthiomorpholinyl And a 4-ethylthiomorpholinyl, 4-propylthiomorpholinyl, 4-isopropylthiomorpholinyl or 4-butylthiomorpholinyl group, more preferably pyrrolidinyl and 1-methyl-2-. Pyrrolidinyl,
1-methyl-3-pyrrolidinyl, 4-hydroxy-2-
Pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-
Ethoxycarbonyloxy-2-pyrrolidinyl, 4-
Isopropoxycarbonyloxy-2-pyrrolidinyl,
4-t-butoxycarbonyloxy-2-pyrrolidinyl, 4-acetyloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4-stearoyloxy-
2-pyrrolidinyl, 4- (succinyloxy) -2-pyrrolidinyl, 4- (glutaryloxy) -2-pyrrolidinyl, 4- (carbamoyloxy) -2-pyrrolidinyl, 4- (N-methylcarbamoyloxy) -2- Pyrrolidinyl, 4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-methoxy-2-
Pyrrolidinyl, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl, 1-methyl -4-Acetyloxy-2-pyrrolidinyl, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-succinyloxypyrrolidinyl, 1- Methyl-4-glutaryloxy-2-pyrrolidinyl, 1-methyl-4-carbamoyloxy-2-
Pyrrolidinyl, 1-methyl-4- (N-methylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl-4-
(N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-ethyl-4-hydroxy-2-pyrrolidinyl, 1-ethyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-t-butoxy Carbonyloxy-2-pyrrolidinyl, 1-ethyl-4-
Acetoxy-2-pyrrolidinyl, 1-ethyl-4-palmitoyloxy-2-pyrrolidinyl, 1-ethyl-4-
Stearoyloxy-2-pyrrolidinyl, 1-ethyl-
4-succinyloxy-2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-piperidinyl, piperazinyl,
1,4-dimethylpiperazinyl, 2-morpholinyl, 4
-Methyl-2-morpholinyl, 4-ethyl-2-morpholinyl, 2-thiomorpholinyl or 4-methyl-2-thiomorpholinyl group, and even more preferably 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2- Pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-methoxy-2-pyrrolidinyl, 4-ethoxycarbonyloxy-2-pyrrolidinyl, 4-isopropoxycarbonyloxy-2-pyrrolidinyl, 4-t-butoxycarbonyloxy-2-pyrrolidinyl , 4-acetyloxy-2
-Pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl,
4-stearoyloxy-2-pyrrolidinyl, 4- (succinyloxy) -2-pyrrolidinyl, 4- (carbamoyloxy) -2-pyrrolidinyl, 4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 1-methyl -4-Hydroxy-2-pyrrolidinyl, 1-methyl-4-methoxy-2-pyrrolidinyl, 1-methyl-4-
Ethoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-acetyloxy-2- Pyrrolidinyl, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2-pyrrolidinyl, 1-methyl-4-succinyloxy-2-pyrrolidinyl, 1-methyl-4-
Carbamoyloxy-2-pyrrolidinyl, 1-methyl-
4- (N, N-dimethylcarbamoyloxy) -2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4
-Piperidinyl, 1-methyl-2-piperidinyl, 1-
A methyl-3-piperidinyl, 1-methyl-4-piperidinyl, 2-morpholinyl, 4-methyl-2-morpholinyl or 2-thiomorpholinyl group, particularly preferably,
2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4
-Hydroxy-2-pyrrolidinyl, 4-methoxy-2-
Pyrrolidinyl, 4-ethoxycarbonyloxy-2-pyrrolidinyl, 4-isopropoxycarbonyloxy-2
-Pyrrolidinyl, 4-t-butoxycarbonyloxy-
2-pyrrolidinyl, 4-acetyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4
-Stearoyloxy-2-pyrrolidinyl, 4- (succinyloxy) -2-pyrrolidinyl, 4- (carbamoyloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-isopropoxy Carbonyloxy-2-pyrrolidinyl, 1-methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy-2
-Pyrrolidinyl, 1-methyl-4-succinyloxy-
2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2-piperidinyl, 1-methyl-3-piperidinyl, 1-methyl-4-
Piperidinyl, 2-morpholinyl or 4-methyl-2-
It is a morpholinyl group.

The compound (I) of the present invention can be converted into a salt, and such salt is preferably a hydrogen halide such as hydrochloride, hydrobromide or hydroiodide. Inorganic acid salts such as acid salts, nitrates, perchlorates, sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate,
Benzene sulfonate, aryl sulfonate such as p-toluene sulfonate, acetate, benzoic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc. Examples thereof include organic acid salts and amino acid salts such as glutamate and aspartate. The compound (I) of the present invention has an asymmetric carbon atom in the molecule, and there exist stereoisomers each having R coordination and S coordination, and each of them or a mixture thereof is the present invention. Included in.

In the compound (I) of the present invention, preferred compounds are those having the general formula (I), preferably (1) R ¹ may be substituted, pyrrolidinyl group, piperidinyl Group, morpholinyl group, thiomorpholinyl group or piperazinyl group (wherein the substituent is a C1-4 alkyl group as a substituent on a carbon atom,
Hydroxy group, alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyloxy group having 1 to 4 carbon atoms, alkanoyloxy group having 2 to 20 carbon atoms, alkanoyloxy having 3 to 4 carbon atoms substituted with carboxy Group, carbamoyloxy group, mono- or di- (alkyl having 1 to 2 carbon atoms) carbamoyloxy group, fluoro atom or chloro atom, and the substituent on the nitrogen atom is an alkyl group having 1 to 4 carbon atoms. Group or a compound which is a phenyl group optionally substituted with methyl, methoxy, fluoro or chloro, (2) R ¹ is an optionally substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (the substituted The group is, as a substituent on a carbon atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a carbon number To 4 alkoxy groups, having 1 to 4 alkoxycarbonyloxy group having a carbon atoms 2
To 3 alkanoyloxy groups, 12 to 20 carbon atoms
Alkanoyloxy group, carboxy-substituted alkanoyloxy group having 3 to 4 carbon atoms, carbamoyloxy group or mono- or di (alkyl having 1 to 2 carbon atoms) carbamoyloxy group, As the substituent, an alkyl group having 1 to 4 carbon atoms is shown. And (3) R ¹ is an optionally substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (wherein the substituent has 1 to 2 carbon atoms as a substituent on a carbon atom). Alkyl groups, hydroxy groups, C1 to C2 alkoxy groups, ethoxycarbonyloxy groups, isopropoxycarbonyloxy groups, t-butoxycarbonyloxy groups, C2 to C3
Alkanoyloxy groups, C14 to C20 alkanoyloxy groups, carboxy-substituted C3
To 4 alkanoyloxy groups, carbamoyloxy groups or mono- or di (C1 to C2 alkyl) carbamoyloxy groups, and the substituent on the nitrogen atom is C1 to C2 alkyl group. . And (4) R ¹ is a pyrrolidinyl group, a 1-methylpyrrolidinyl group, a 4-hydroxy-1-methylpyrrolidinyl group, a 4-isopropoxycarbonyloxy-1-methylpyrrolidinyl group, 4-t-butoxycarbonyloxy-1-methylpyrrolidinyl group, 4-acetoxy-1-
Methylpyrrolidinyl group, 4-palmitoyloxy-1-
Methylpyrrolidinyl group, 4-stearoyloxy-1-
A compound which is a methylpyrrolidinyl group, a 4-succinyloxy-1-methylpyrrolidinyl group, a piperidinyl group, a 1-methylpiperidinyl group, a morpholinyl group or a 4-methylmorpholinyl group, (5) R ¹ is , A pyrrolidinyl group, 1
- methylpyrrolidinyl groups, 4-hydroxy-1-methyl-pyrrolidinylmethyl group, a piperidinyl group, 1-piperidinyl group, a compound morpholinyl group or a 4-methyl-morpholinylcarbonyl group, (6) R ^2, R ³ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
A hydroxy group, an alkoxy group having 1 to 4 carbon atoms, a halogenoalkoxy group having 1 to 4 carbon atoms, a halogen atom,
A compound having a cyano group or a carbamoyl group, (7) R ²
And R ³ are the same or different and each represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, a hydroxy group, an alkoxy group having 1 or 2 carbon atoms, a fluoromethoxy group, a difluoromethoxy group, a chloromethoxy group, 2- A fluoroethoxy group,
2-chloroethoxy group, fluoro atom, chloro atom, bromo atom or cyano group, R ⁴ is a hydrogen atom, (8) R ² and R ³ are the same or different, hydrogen atom, carbon number 1 to 2 alkyl group, hydroxy group, alkoxy group having 1 to 2 carbon atoms, fluoromethoxy group, difluoromethoxy group, 2-fluoroethoxy group, fluoro atom, chloro atom, bromo atom or cyano group, R A compound in which ⁴ is a hydrogen atom, (9) R ²
And R ³ are the same or different and are a hydrogen atom, a methyl group,
A hydroxy group, an alkoxy group having 1 to 2 carbon atoms, a fluoromethoxy group, a difluoromethoxy group, a fluoro atom, a chloro atom, a bromo atom or a cyano group, R ⁴
Is a hydrogen atom, (10) R ² and R ³
Are the same or different and are a hydrogen atom, a methyl group, a hydroxy group, an alkoxy group having 1 to 2 carbon atoms, a difluoromethoxy group, a fluoro atom, a chloro atom, a bromo atom or a cyano group, and R ⁴ is a hydrogen atom. A compound, (1
1) A compound in which m is 0-3, (12) m is 0-2
A compound that is

Representative compounds of the present invention include, for example:
The compounds listed in Table 1 can be mentioned, but the present invention is not limited to these compounds.

[0026]

[Chemical 4]

[0027]

[Table 1] ──────────────────────────────────── Example compounds R ¹ R ² R ³ R ⁴ m ──────────────────────────────────── 1 1-Me-2-Pyrd HHH 2 21- Me-3-Pyrd HHH 2 3 2-Pyrd HHH 2 4 3-Pyrd HHH 2 5 1-Et-2-Pyrd HHH 2 6 1-Pr-2-Pyrd HHH 2 7 2-Pip HHH 2 8 3-Pip HHH 2 9 4-Pip HHH 2 10 1-Me-2-Pip HHH 2 11 1-Me-3-Pip HHH 2 12 1-Me-4-Pip HHH 2 13 1-Et-2-Pip HHH 2 14 1- Pr-2-Pip HHH 2 15 2-Pip HHH 1 16 3-Pip HHH 1 17 4-Pip HHH 1 18 1-Me-2-Pip HHH 1 19 1-Me-3-Pip HHH 1 20 1-Me- 4-Pip HHH 1 21 1-Et-3-Pip HHH 1 22 1-Pr-3-Pip HHH 1 23 3-Pip HHH 0 24 4-Pip HHH 0 25 1-Me-3-Pip HHH 0 26 1- Me-4-Pip HHH 0 27 1-Et-4-Pip HHH 0 28 1-Pr-4-Pip HHH 0 29 2-Pyrd HHH 1 30 1-Me-2-Pyrd HHH 1 31 2-Mor HHH 1 32 4-Me-2-Mor HHH 1 33 4-Et-2-Mor HHH 1 34 2-Tmor HHH 1 35 4-Me-2-Tmor HHH 1 36 4-OH-1-Me-2-Pyrd HHH 1 37 4-OH-2-Pyrd HHH 1 38 4-OH-1-Me-2-Pyrd HHH 2 39 1-Me-2-Pyrd 3 -OH HH 2 40 1-Me-2-Pip 3-OH HH 2 41 4-Me-2-Mor 3-OH HH 1 42 4-OH-1-Me-2-Pyrd 3-OH HH 1 43 1- Me-2-Pip 2-OH HH 2 44 1-Me-2-Pyrd 2-OH HH 2 45 4-Me-2-Mor 2-OH HH 1 46 1-Me-2-Pip 4-OH HH 2 47 1-Me-2-Pyrd 4-OH HH 2 48 4-Me-2-Mor 4-OH HH 1 49 2-Pyrd 3-OH HH 2 50 1-Me-2-Pyrd 3-OMe HH 2 51 2- Pip 3-OMe HH 2 52 1-Me-2-Pip 3-OMe HH 2 53 1-Me-3-Pip 3-OMe HH 2 54 1-Me-4-Pip 3-OMe HH 2 55 1-Et- 2-Pip 3-OMe HH 2 56 1-Me-2-Pip 3-OMe HH 1 57 1-Me-3-Pip 3-OMe HH 1 58 1-Me-4-Pip 3-OMe HH 1 59 1- Me-3-Pip 3-OMe HH 0 60 1-Me-4-Pip 3-OMe HH 0 61 1-Me-2-Pyrd 3-OMe HH 1 62 4-OH-1-Me-2-Pyrd 3- OMe HH 1 63 4-Me-2-Mor 3-OMe HH 1 64 2-Mor 3-OMe HH 1 65 1-Me-2-Pyrd 3-OMe 4-OMe H 2 66 1-Me-2-Pip 3 -OMe 4-OMe H 2 67 4-Me-2-Mor 3-OMe 4-OMe H 1 68 1-Me-3-Pip 3-OMe 4-OMe H 1 69 3-Pip 3-OMe 4-OMe H 1 70 1-Me-2-Pyrd 3-OMe 5-OMe H 2 71 1-Me-2-Pip 3-OMe 5-OMe H 2 72 4-Me-2-Mor 3-OMe 5-OMe H 1 73 3-Pip 3-OMe 5-OMe H 1 74 1-Me-3-Pip 3-OMe 5-OMe H 1 75 1-Me-4-Pip 3-OMe 5-OMe H 0 76 1-Me-2- Pyrd 3-OMe 5-OMe H 1 77 4-OMe-1-Me-2-Pyrd 3-OMe 5-OMe H 2 78 1-Me-2-Pyrd 3-OMe 4-OMe 5-OMe 2 79 1-Me-2-Pip 3-OMe 4-OMe 5-OMe 2 80 4-Me-2 -Mor 3-OMe 4-OMe 5-OMe 1 81 1-Me-3-Pip 3-OMe 4-OMe 5-OMe 1 82 1-Me-4-Pip 3-OMe 4-OMe 5-OMe 0 83 1 -Me-2-Pyrd 3-OMe 4-OMe 5-OMe 1 84 1-Me-2-Pyrd 3-Me HH 2 85 1-Me-2-Pip 3-Me HH 2 86 4-Me-2-Mor 3-Me HH 1 87 1-Me-3-Pip 3-Me HH 1 88 1-Me-4-Pip 3-Me HH 0 89 1-Me-2-Pyrd 3-Me HH 1 90 1-Me-2 -Pyrd 3-Cl HH 2 91 1-Me-2-Pip 3-Cl HH 2 92 4-Me-2-Mor 3-Cl HH 1 93 1-Me-3-Pip 3-Cl HH 1 94 1-Me -4-Pip 3-Cl HH 0 95 1-Me-2-Pyrd 3-FHH 2 96 1-Me-2-Pip 3-FHH 2 97 4-Me-2-Mor 3-FHH 1 98 1-Me- 3-Pip 3-FHH 1 99 1-Me-2-Pyrd 3-FHH 1 100 1-Me-2-Pyrd 2-CN HH 2 101 1-Me-3-Pip 2-CN HH 1 102 1-Me- 2-Pip 2-CN HH 2 103 4-Me-2-Mor 2-CN HH 1 104 1-Me-4-Pip 2-CN HH 0 105 1-Me-2-Pyrd 2-CONH ₂ HH 2 106 1 -Me-3-Pip 2-CONH ₂ HH 1 107 1-Me-2-Pip 2-CONH ₂ HH 2 108 4-Me-2-Mor 2-CONH ₂ HH 1 109 1-Me-2-Pyrd 2- CONH ₂ HH 1 110 1-Me-2-Pyrd 3-OEt HH 2 111 1-Me-2-Pip 3-OEt HH 2 112 1-Me-3-Pip 3-OEt HH 1 113 4-Me-2- Mor 3-OEt HH 1 114 1-Me-4-Pip 3-OEt HH 0 115 1-Me-2-Pyrd 2-OMe HH 2 116 1-Me-2-Pip 2-OMe HH 2 117 4-Me-2-Mor 2-OMe HH 1 118 1-Me-3-Pip 2 -OMe HH 1 119 1-Me-2-Pyrd 2-OMe HH 1 120 1-Me-2-Pyrd 4-OMe HH 2 121 1-Me-2-Pip 4-OMe HH 2 122 1-Me-3- Pip 4-OMe HH 1 123 4-Me-2-Mor 4-OMe HH 1 124 1-Me-4-Pip 4-OMe HH 0 125 1-Me-2-Pyrd 3-Et HH 2 126 1-Me- 2-Pip 3-Et HH 2 127 1-Me-2-Pyrd 4-Et HH 2 128 1-Me-2-Pip 3-Et 5-OMe H 2 129 1-Me-2-Pyrd 4-Pr ⁱ HH 2 130 1-Me-2-Pyrd 4-Ph HH 2 131 1-Me-2-Pip 4-Ph HH 2 132 1-Me-2-Pyrd 3-Me 5-Me H 2 133 1-Me-2- Pyrd 3-OEt 5-OEt H 2 134 1-Me-2-Pyrd 3-OH 5-OH H 2 135 1-Me-2-Pyrd 4-Me HH 2 136 1-Me-2-Pyrd 2-Me HH 2 137 1-Me-2-Pyrd 3-Br HH 2 138 1-Me-2-Pip 3-Br HH 2 139 1-Et-2-Pyrd 2-Cl HH 2 140 1-Me-2-Pip 2- Cl HH 2 141 1-Me-2-Pyrd 4-Cl HH 2 142 1-Me-2-Pyrd 2-Cl 3-Cl H 2 143 1-Me-2-Pyrd 3-Cl 4-Cl H 2 144 1 -Me-2-Pyrd 3-Cl 5-Cl H 2 145 1-Me-4-OSuc-2-Pyrd HHH 1 146 1-Me-4-AcO-2-Pyrd HHH 1 147 1-Me-4-OSuc -2-Pyrd 3-OMe HH 1 148 1-Me-4-AcO-2-Pyrd 3-OMe HH 1 149 1-Me-4-OSuc-2-Pyrd HHH 2 150 1-Me-4-AcO-2 -Pyrd HHH 2 151 1-Me-3-Pip 3-OH HH 1 152 1-Me-4-Pip 3-OH HH 0 153 2-Pip 3-OH HH 2 154 1-Me-4-OSuc-2-Pyrd 3-OMe 5 -OMe H 1 155 1-Me-4-OGlu-2-Pyrd HHH 1 156 1-Me-4-OGlu-2-Pyrd 3-OMe HH 1 157 1-Me-4-OCONH ₂ -2-Pyrd HHH 1 158 1-Me-4-OCONH ₂ -2-Pyrd 3-OMe HH 1 159 1-Me-4-OCON (Me) ₂ -2-Pyrd HHH 1 160 1-Me-4-OCON (Me) ₂ -2 -Pyrd 3-OMe HH 1 161 4-Pip 3-OMe HH 0 162 2-Pyrd 3-OH HH 1 163 1-Me-2-Pyrd 3-OH HH 1 164 3-Pip 3-OMe HH 1 165 3- Pip 3-OMe HH 0 166 4-Pip 3-OMe HH 2 167 4-Pip 3-OH HH 2 168 1-Me-4-Pip 3-OH HH 2 169 2-Pip 3-OMe HH 1 170 4-OH -2-Pyrd 3-Me HH 1 171 2-Pip 4-Et HH 2 172 1-Me-2-Pip 4-Et HH 2 173 2-Pyrd 3-OMe HH 1 174 1-Me-4-OMe-2 -Pyrd 3-OMe 5-OMe H 1 175 4-OH-2-Pyrd HHH 2 176 4-EtOCOO-2-Pyrd HHH 2 177 4-Pr i OCOO-2-Pyrd HHH 2 178 4-Bu t OCOO-2 -Pyrd HHH 2 179 4-AcO-2-Pyrd HHH 2 180 4-PalO-2-Pyrd HHH 2 181 4-SteO-2-Pyrd HHH 2 182 1-Et-4-OH-2-Pyrd HHH 2 183 1 -Et-4-EtOCOO-2- Pyrd HHH 2 184 1-Et-4-Pr i OCOO-2-Pyrd HHH 2 185 1-Et-4-Bu t OCOO-2-Pyrd HHH 2 186 1-Et-4 -AcO-2-Pyrd HHH 2 187 1-Et-4-PalO-2-Pyrd H HH 2 188 1-Et-4-SteO-2-Pyrd HHH 2 189 3-Pip 3-OH HH 1 190 1-Me-3-Pip 3-OH 5-OH H 1 191 2-Mor 3-OH HH 1 192 2-Pyrd 3-OH 5-OH H 2 193 1-Et-2-Pyrd 3-OH HH 2 194 4-OH-2-Pyrd 3-OH HH 2 195 1-Me-4-OH-2-Pyrd 3-OH HH 2 196 4- EtOCOO-2-Pyrd 3-OH HH 2 197 4-Pr i OCOO-2-Pyrd 3-OH HH 2 198 4-Bu t OCOO-2-Pyrd 3-OH HH 2 199 4 -AcO-2-Pyrd 3-OH HH 2 200 4-PalO-2-Pyrd 3-OH HH 2 201 4-SteO-2-Pyrd 3-OH HH 2 202 1-Me-4-EtOCOO-2-Pyrd 3 -OH HH 2 203 1-Me-4-Pr ⁱ OCOO-2-Pyrd 3-OH HH 2 204 1-Me-4-Bu ^t OCOO-2-Pyrd 3-OH HH 2 205 1-Me-4-AcO -2-Pyrd 3-OH HH 2 206 1-Me-4-PalO-2-Pyrd 3-OH HH 2 207 1-Me-4-SteO-2-Pyrd 3-OH HH 2 208 3-Pip 2-OH HH 1 209 1-Me-3-Pip 2-OH HH 1 210 2-Mor 2-OH HH 1 211 2-Pyrd 2-OH HH 2 212 4-OH-2-Pyrd 2-OH HH 2 213 1-Me -4-OH-2-Pyrd 2 -OH HH 2 214 4-EtOCOO-2-Pyrd 2-OH HH 2 215 4-Pr i OCOO-2-Pyrd 2-OH HH 2 216 4-Bu t OCOO-2- Pyrd 2-OH HH 2 217 4-AcO-2-Pyrd 2-OH HH 2 218 4-PalO-2-Pyrd 2-OH HH 2 219 4-SteO-2-Pyrd 2-OH HH 2 220 1-Me- 4-EtOCOO-2-Pyrd 2-OH HH 2 221 1-Me-4-Pr ⁱ OCOO-2-Pyrd 2-OH HH 2 222 1- ^{Me-4-Bu t OCOO-} 2-Pyrd 2-OH HH 2 223 1-Me-4-AcO-2-Pyrd 2-OH HH 2 224 1-Me-4-PalO-2-Pyrd 2-OH HH 2 225 1-Me-4-SteO-2-Pyrd 2-OH HH 2 226 3-Pip 4-OH HH 1 227 1-Me-3-Pip 4-OH HH 1 228 2-Mor 4-OH HH 1 229 2 -Pyrd 4-OH HH 2 230 4-OH-2-Pyrd 4-OH HH 2 231 1-Me-4-OH-2-Pyrd 4-OH HH 2 232 4-EtOCOO-2-Pyrd 4-OH HH 2 ^{233 4-Pr i OCOO-2} -Pyrd 4-OH HH 2 234 4-Bu t OCOO-2-Pyrd 4-OH HH 2 235 4-AcO-2-Pyrd 4-OH HH 2 236 4-PalO-2- Pyrd 4-OH HH 2 237 4-SteO-2-Pyrd 4-OH HH 2 238 1-Me-4-EtOCOO-2-Pyrd 4-OH HH 2 239 1-Me-4-Pr ⁱ OCOO-2-Pyrd 4-OH HH 2 240 1-Me-4-Bu ^t OCOO-2-Pyrd 4-OH HH 2 241 1-Me-4-AcO-2-Pyrd 4-OH HH 2 242 1-Me-4-PalO- 2-Pyrd 4-OH HH 2 243 1-Me-4-SteO-2-Pyrd 4-OH HH 2 244 3-Pip 3-OMe 4-OMe 5-OMe 1 245 1-Et-3-Pip 3-OMe HH 1 246 1-Et-2-Pyrd 3-OMe HH 2 247 4-OH-2-Pyrd 3-OMe HH 2 248 1-Me-4-OH-2-Pyrd 3-OMe HH 2 249 1-Et- 4-OH-2-Pyrd 3 -OMe HH 2 250 4-EtOCOO-2-Pyrd 3-OMe HH 2 251 4-Pr i OCOO-2-Pyrd 3-OMe HH 2 252 4-Bu t OCOO-2-Pyrd 3-OMe HH 2 253 4-AcO-2-Pyrd 3-OMe HH 2 254 4-PalO-2-Pyrd 3-OMe HH 2 255 4-Ste O-2-Pyrd 3-OMe HH 2 256 1-Me-4-EtOCOO-2-Pyrd 3-OMe HH 2 257 1-Me-4-Pr ⁱ OCOO-2-Pyrd 3-OMe HH 2 258 1-Me -4-Bu ^t OCOO-2-Pyrd 3-OMe HH 2 259 1-Me-4-AcO-2-Pyrd 3-OMe HH 2 260 1-Me-4-PalO-2-Pyrd 3-OMe HH 2 261 1-Me-4-SteO-2-Pyrd 3-OMe HH 2 262 3-Pip 2-OMe HH 1 263 1-Me-3-Pip 2-OMe 3-OMe H 1 264 2-Mor 2-OMe HH 1 265 4-Me-2-Mor 2-OMe 3-OMe H 1 266 2-Pyrd 2-OMe HH 2 267 1-Me-2-Pyrd 2-OMe 3-OMe H 2 268 4-OH-2-Pyrd 2 -OMe HH 2 269 1-Me-4-OH-2-Pyrd 2-OMe HH 2 270 4-EtOCOO-2-Pyrd 2-OMe HH 2 271 4-Pr ⁱ OCOO-2-Pyrd 2-OMe HH 2 272 4-Bu ^t OCOO-2-Pyrd 2-OMe HH 2 273 4-AcO-2-Pyrd 2-OMe HH 2 274 4-PalO-2-Pyrd 2-OMe HH 2 275 4-SteO-2-Pyrd 2- OMe HH 2 276 1-Me-4-EtOCOO-2-Pyrd 2-OMe HH 2 277 1-Me-4-Pr ⁱ OCOO-2-Pyrd 2-OMe HH 2 278 1-Me-4-Bu ^t OCOO- 2-Pyrd 2-OMe HH 2 279 1-Me-4-AcO-2-Pyrd 2-OMe HH 2 280 1-Me-4-PalO-2-Pyrd 2-OMe HH 2 281 1-Me-4-SteO -2-Pyrd 2-OMe HH 2 282 3-Pip 4-OMe HH 1 283 1-Me-3-Pip 3-OMe 4-OMe H 1 284 2-Mor 4-OMe HH 1 285 4-Me-2- Mor 3-OMe 4-OMe H 1 286 2-Pyrd 4-OMe HH 2 287 1-Me-2-Pyrd 3-OMe 4-OMe H 2 288 4-OH-2-Pyrd 4-OMe HH 2 289 1-Me-4-OH-2-Pyrd 4-OMe HH 2 290 4-EtOCOO-2-Pyrd 4-OMe HH 2 291 4 -Pr ⁱ OCOO-2-Pyrd 4-OMe HH 2 292 4-Bu ^t OCOO-2-Pyrd 4-OMe HH 2 293 4-AcO-2-Pyrd 4-OMe HH 2 294 4-PalO-2-Pyrd 4 -OMe HH 2 295 4-SteO-2-Pyrd 4-OMe HH 2 296 1-Me-4-EtOCOO-2-Pyrd 4-OMe HH 2 297 1-Me-4-Pr ⁱ OCOO-2-Pyrd 4- OMe HH 2 298 1-Me-4-Bu ^t OCOO-2-Pyrd 4-OMe HH 2 299 1-Me-4-AcO-2-Pyrd 4-OMe HH 2 300 1-Me-4-PalO-2- Pyrd 4-OMe HH 2 301 1-Me-4-SteO-2-Pyrd 4-OMe HH 2 302 3-Pip 2-OMe 3-OMe H 1 303 2-Mor 2-OMe 3-OMe H 1 304 2- Pyrd 2-OMe 3-OMe H 2 305 4-OH-2-Pyrd 2-OMe 3-OMe H 2 306 1-Me-4-OH-2-Pyrd 2-OMe 3-OMe H 2 307 4-EtOCOO- 2-Pyrd 2-OMe 3- OMe H 2 308 4-Pr i OCOO-2-Pyrd 2-OMe 3-OMe H 2 309 4-Bu t OCOO-2-Pyrd 2-OMe 3-OMe H 2 310 4- AcO-2-Pyrd 2-OMe 3-OMe H 2 311 4-PalO-2-Pyrd 2-OMe 3-OMe H 2 312 4-SteO-2-Pyrd 2-OMe 3-OMe H 2 313 1-Me- 4-EtOCOO-2-Pyrd 2-OMe 3-OMe H 2 314 1-Me-4-Pr ⁱ OCOO-2-Pyrd 2-OMe 3-OMe H 2 315 1-Me-4-Bu ^t OCOO-2- Pyrd 2-OMe 3-OMe H 2 316 3-Pip 3-Me HH 1 317 2-Mor 3-Me HH 1 318 2-Pyrd 3-Me HH 2 319 4-OH-2-Pyrd 3-Me HH 2 320 1-Me-4-OH-2-Pyrd 3-Me HH 2 321 4-EtOCOO-2-Pyrd 3-Me ^{HH 2 322 4-Pr i OCOO} -2-Pyrd 3-Me HH 2 323 4-Bu t OCOO-2-Pyrd 3-Me HH 2 324 4-AcO-2-Pyrd 3-Me HH 2 325 4-PalO- 2-Pyrd 3-Me HH 2 326 4-SteO-2-Pyrd 3-Me HH 2 327 1-Me-4-EtOCOO-2-Pyrd 3-Me HH 2 328 1-Me-4-Pr ⁱ OCOO-2 -Pyrd 3-Me HH 2 329 1 -Me-4-Bu t OCOO-2-Pyrd 3-Me HH 2 330 3-Pip 3-FHH 1 331 2-Mor 3-FHH 1 332 2-Pyrd 3-FHH 2 333 4-OH-2-Pyrd 3-FHH 2 334 1-Me-4-OH-2-Pyrd 3-FHH 2 335 4-EtOCOO-2-Pyrd 3-FHH 2 336 4-Pr ⁱ OCOO-2-Pyrd 3-FHH 2 337 4-Bu t OCOO-2-Pyrd 3-FHH 2 338 4-AcO-2-Pyrd 3-FHH 2 339 4-PalO-2-Pyrd 3-FHH 2 340 4-SteO-2-Pyrd 3-FHH 2 341 1-Me -4-EtOCOO-2-Pyrd 3-FHH 2 342 1-Me-4-Pr i OCOO-2-Pyrd 3-FHH 2 343 1-Me-4-Bu t OCOO-2 -Pyrd 3-FHH 2 344 3-Pip 3-Cl HH 1 345 2-Mor 3-Cl HH 1 346 2-Pyrd 3-Cl HH 2 347 4-OH-2-Pyrd 3-Cl HH 2 348 1-Me -4-OH-2-Pyrd 3 -Cl HH 2 349 4-EtOCOO-2-Pyrd 3-Cl HH 2 350 4-Pr i OCOO-2-Pyrd 3-Cl HH 2 351 4-Bu t OCOO-2- Pyrd 3-Cl HH 2 352 4-AcO-2-Pyrd 3-Cl HH 2 353 4-PalO -2-Pyrd 3-Cl HH 2 354 4-SteO-2-Pyrd 3-Cl HH 2 355 1-Me-4-EtOCOO-2-Pyrd 3-Cl HH 2 356 1-Me-4-Pr ⁱ OCOO- 2-Pyrd 3-Cl HH 2 357 1-Me-4-Bu t OCOO-2-Pyrd 3-Cl HH 2 358 3-Pip 2-CN HH 1 359 2-Mor 2-CN HH 1 360 2-Pyrd 2 -CN HH 2 361 4-OH-2-Pyrd 2-CN HH 2 362 1-Me-4-OH-2-Pyrd 2-CN HH 2 363 4-EtOCOO-2-Pyrd 2-CN HH 2 364 4- ^{Pr i OCOO-2-Pyrd 2} -CN HH 2 365 4-Bu t OCOO-2-Pyrd 2-CN HH 2 366 4-AcO-2-Pyrd 2-CN HH 2 367 4-PalO-2-Pyrd 2- CN HH 2 368 4-SteO-2-Pyrd 2-CN HH 2 369 1-Me-4-EtOCOO-2-Pyrd 2-CN HH 2 370 1-Me-4-Pr ⁱ OCOO-2-Pyrd 2-CN HH 2 371 1-Me-4-Bu ^t OCOO-2-Pyrd 2-CN HH 2 372 3-Pip 3-OEt HH 1 373 2-Mor 3-OEt HH 1 374 2-Pyrd 3-OEt HH 2 375 4 -OH-2-Pyrd 3-OEt HH 2 376 1-Me-4-OH-2-Pyrd 3-OEt HH 2 377 4-EtOCOO-2-Pyrd 3-OEt HH 2 378 4-Pr ⁱ OCOO-2- Pyrd 3-OEt HH 2 379 4 -Bu t OCOO-2-Pyrd 3-OEt HH 2 380 4-AcO-2-Pyrd 3-OEt HH 2 381 4-PalO-2-Pyrd 3-OEt HH 2 382 4- SteO-2-Pyrd 3-OEt HH 2 383 1-Me-4-EtOCOO-2-Pyrd 3-OEt HH 2 384 1-Me-4-Pr ⁱ OCOO-2-Pyrd 3-OEt HH 2 385 1-Me -4-Bu ^t OCOO-2-Pyrd 3-OEt HH 2 386 3-Pip 2-C ONH ₂ HH 1 387 2-Mor 2-CONH ₂ HH 1 388 2-Pyrd 2-CONH ₂ HH 2 389 4-OH-2-Pyrd 2-CONH ₂ HH 2 390 1-Me-4-OH-2-Pyrd _{2-CONH 2 HH 2 391 4} -EtOCOO-2-Pyrd 2-CONH 2 HH 2 392 4-Pr i OCOO-2-Pyrd 2-CONH 2 HH 2 393 4-Bu t OCOO-2-Pyrd 2-CONH 2 HH 2 394 4-AcO-2-Pyrd 2-CONH ₂ HH 2 395 4-PalO-2-Pyrd 2-CONH ₂ HH 2 396 4-SteO-2-Pyrd 2-CONH ₂ HH 2 397 1-Me-4 -EtOCOO-2-Pyrd 2-CONH 2 HH 2 398 1-Me-4-Pr i OCOO-2-Pyrd 2-CONH 2 HH 2 399 1-Me-4-Bu t OCOO-2-Pyrd 2-CONH 2 HH 2 400 3-Pip 3-OCF ₂ HHH 1 401 1-Me-3-Pip 3-OCF ₂ HHH 1 402 2-Mor 3-OCF ₂ HHH 1 403 4-Me-2-Mor 3-OCF ₂ HHH 1 404 2-Pyrd 3-OCF ₂ HHH 2 405 1-Me-2-Pyrd 3-OCF ₂ HHH 2 406 1-Et-2-Pyrd 3-OCF ₂ HHH 2 407 4-OH-2-Pyrd 3-OCF ₂ HHH 2 408 1-Me-4-OH-2-Pyrd 3-OCF ₂ HHH 2 409 4-EtOCOO-2-Pyrd 3-OCF ₂ HHH 2 410 4-Pr ⁱ OCOO-2-Pyrd 3-OCF ₂ HHH 2 ^{411 4-Bu t OCOO-2} -Pyrd 3-OCF 2 HHH 2 412 4-AcO-2-Pyrd 3-OCF 2 HHH 2 413 4-PalO-2-Pyrd 3-OCF 2 HHH 2 414 4-SteO-2 -Pyrd 3-OCF ₂ HHH 2 415 1-Me-4-EtOCOO-2-Pyrd 3-OCF ₂ HHH 2 416 1-Me-4-Pr ⁱ OCOO-2-Pyrd 3-OCF ₂ HHH 2 417 1-Me - 4-Bu ^t OCOO-2-Pyrd 3-OCF ₂ HHH 2 418 1-Me-4-AcO-2-Pyrd 3-OCF ₂ HHH 2 419 1-Me-4-PalO-2-Pyrd 3-OCF ₂ HHH 2 420 1-Me-4-SteO-2-Pyrd 3-OCF ₂ HHH 2 421 3-Pip 2-OCF ₂ HHH 1 422 1-Me-3-Pip 2-OCF ₂ HHH 1 423 2-Mor 2-OCF ₂ HHH 1 424 4-Me-2-Mor 2-OCF ₂ HHH 1 425 2-Pyrd 2-OCF ₂ HHH 2 426 1-Me-2-Pyrd 2-OCF ₂ HHH 2 427 4-OH-2-Pyrd 2 -OCF ₂ HHH 2 428 1-Me-4-OH-2-Pyrd 2-OCF ₂ HHH 2 429 4-EtOCOO-2-Pyrd 2-OCF ₂ HHH 2 430 4-Pr ⁱ OCOO-2-Pyrd 2-OCF ^{_{2 HHH 2 431 4-Bu t}} OCOO-2-Pyrd 2-OCF 2 HHH 2 432 4-AcO-2-Pyrd 2-OCF 2 HHH 2 433 4-PalO-2-Pyrd 2-OCF 2 HHH 2 434 4- SteO-2-Pyrd 2-OCF ₂ HHH 2 435 1-Me-4-EtOCOO-2-Pyrd 2-OCF ₂ HHH 2 436 1-Me-4-Pr ⁱ OCOO-2-Pyrd 2-OCF ₂ HHH 2 437 1-Me-4-Bu ^t OCOO-2-Pyrd 2-OCF ₂ HHH 2 438 1-Me-4-AcO-2-Pyrd 2-OCF ₂ HHH 2 439 1-Me-4-PalO-2-Pyrd 2 -OCF ₂ HHH 2 440 1-Me-4-SteO-2-Pyrd 2-OCF ₂ HHH 2 441 3-Pip 4-OCF ₂ HHH 1 442 1-Me-3-Pip 4-OCF ₂ HHH 1 443 2- Mor 4-OCF ₂ HHH 1 444 4-Me-2-Mor 4-OCF ₂ HHH 1 445 2-Pyrd 4-OCF ₂ HHH 2 446 1-Me-2-Pyrd 4-OCF ₂ HHH 2 447 4-OH- 2-Pyrd 4-OCF ₂ HHH 2 448 1-Me-4-OH-2-Pyrd 4-OCF ₂ HHH 2 449 4-EtOCOO-2-Pyrd 4-OCF ₂ HHH 2 450 4-Pr ⁱ OCOO-2-Pyrd 4-OCF ₂ HHH 2 451 4- But ^t OCOO-2-Pyrd 4-OCF ₂ HHH 2 452 4-AcO-2-Pyrd 4-OCF ₂ HHH 2 453 4-PalO-2-Pyrd 4-OCF ₂ HHH 2 454 4-SteO-2-Pyrd 4 -OCF ₂ HHH 2 455 1-Me-4-EtOCOO-2-Pyrd 4-OCF ₂ HHH 2 456 1-Me-4-Pr ⁱ OCOO-2-Pyrd 4-OCF ₂ HHH 2 457 1-Me-4- But ^t OCOO-2-Pyrd 4-OCF ₂ HHH 2 458 1-Me-4-AcO-2-Pyrd 4-OCF ₂ HHH 2 459 1-Me-4-PalO-2-Pyrd 4-OCF ₂ HHH 2 460 1-Me-4-SteO-2-Pyrd 4-OCF ₂ HHH 2 461 3-Pip 3-OCFH ₂ HH 1 462 1-Me-3-Pip 3-OCFH ₂ HH 1 463 2-Mor 3-OCFH ₂ HH 1 464 4-Me-2-Mor 3-OCFH ₂ HH 1 465 2-Pyrd 3-OCFH ₂ HH 2 466 1-Me-2-Pyrd 3-OCFH ₂ HH 2 467 1-Et-2-Pyrd 3-OCFH ₂ HH 2 468 4-OH-2-Pyrd 3-OCFH ₂ HH 2 469 1-Me-4-OH-2-Pyrd 3-OCFH ₂ HH 2 470 4-EtOCOO-2-Pyrd 3-OCFH ₂ HH 2 471 ^{4-Pr i OCOO-2-} Pyrd 3-OCFH 2 HH 2 472 4-Bu t OCOO-2-Pyrd 3-OCFH 2 HH 2 473 4-AcO-2-Pyrd 3-OCFH 2 HH 2 474 4-PalO- 2-Pyrd 3-OCFH ₂ HH 2 475 4-SteO-2-Pyrd 3-OCFH ₂ HH 2 476 1-Me-4-EtOCOO-2-Pyrd 3-OCFH ₂ HH 2 477 1-Me-4-Pr ⁱ OCOO-2-Pyrd 3-OCFH ₂ HH 2 478 1-Me-4-Bu ^t OCOO-2-Pyrd 3-OCFH ₂ HH 2 479 1-Me-4-AcO-2-Pyrd 3-OCFH ₂ HH 2 480 1-Me-4-PalO- 2-Pyrd 3-OCFH ₂ HH 2 481 1-Me-4-SteO-2-Pyrd 3-OCFH ₂ HH 2 482 3-Pip 2-OCFH ₂ HH 1 483 1-Me-3-Pip 2-OCFH ₂ HH 1 484 2-Mor 2-OCFH ₂ HH 1 485 4-Me-2-Mor 2-OCFH ₂ HH 1 486 2-Pyrd 2-OCFH ₂ HH 2 487 1-Me-2-Pyrd 2-OCFH ₂ HH 2 488 4-OH-2-Pyrd 2-OCFH ₂ HH 2 489 1-Me-4-OH-2-Pyrd 2-OCFH ₂ HH 2 490 4-EtOCOO-2-Pyrd 2-OCFH ₂ HH 2 491 4-Pr ⁱ OCOO-2-Pyrd 2-OCFH 2 HH 2 492 4-Bu t OCOO-2-Pyrd 2-OCFH 2 HH 2 493 4-AcO-2-Pyrd 2-OCFH 2 HH 2 494 4-PalO-2-Pyrd 2 -OCFH ₂ HH 2 495 4-SteO-2-Pyrd 2-OCFH ₂ HH 2 496 1-Me-4-EtOCOO-2-Pyrd 2-OCFH ₂ HH 2 497 1-Me-4-Pr ⁱ OCOO-2- Pyrd 2-OCFH ₂ HH 2 498 1-Me-4-Bu ^t OCOO-2-Pyrd 2-OCFH ₂ HH 2 499 1-Me-4-AcO-2-Pyrd 2-OCFH ₂ HH 2 500 1-Me- 4-PalO-2-Pyrd 2-OCFH ₂ HH 2 501 1-Me-4-SteO-2-Pyrd 2-OCFH ₂ HH 2 502 3-Pip 4-OCFH ₂ HH 1 503 1-Me-3-Pip 4 -OCFH ₂ HH 1 504 2-Mor 4-OCFH ₂ HH 1 505 4-Me-2-Mor 4-OCFH ₂ HH 1 506 2-Pyrd 4-OCFH ₂ HH 2 507 1-Me-2-Pyrd 4-OCFH ₂ HH 2 508 4-OH-2-Pyrd 4- OCFH ₂ HH 2 509 1-Me-4-OH-2-Pyrd 4-OCFH ₂ HH 2 510 4-EtOCOO-2-Pyrd 4-OCFH ₂ HH 2 511 4-Pr ⁱ OCOO-2-Pyrd 4-OCFH ₂ ^{HH 2 512 4-Bu t OCOO} -2-Pyrd 4-OCFH 2 HH 2 513 4-AcO-2-Pyrd 4-OCFH 2 HH 2 514 4-PalO-2-Pyrd 4-OCFH 2 HH 2 515 4-SteO -2-Pyrd 4-OCFH ₂ HH 2 516 1-Me-4-EtOCOO-2-Pyrd 4-OCFH ₂ HH 2 517 1-Me-4-Pr ⁱ OCOO-2-Pyrd 4-OCFH ₂ HH 2 518 1 -Me-4-Bu ^t OCOO-2-Pyrd 4-OCFH ₂ HH 2 519 1-Me-4-AcO-2-Pyrd 4-OCFH ₂ HH 2 520 1-Me-4-PalO-2-Pyrd 4- OCFH ₂ HH 2 521 1-Me-4-SteO-2-Pyrd 4-OCFH ₂ HH 2 522 3-Pip 3-OCF ₃ HH 1 523 1-Me-3-Pip 3-OCF ₃ HH 1 524 2-Mor 3-OCF ₃ HH 1 525 4-Me-2-Mor 3-OCF ₃ HH 1 526 2-Pyrd 3-OCF ₃ HH 2 527 1-Me-2-Pyrd 3-OCF ₃ HH 2 528 1-Et-2 -Pyrd 3-OCF ₃ HH 2 529 4-OH-2-Pyrd 3-OCF ₃ HH 2 530 1-Me-4-OH-2-Pyrd 3-OCF ₃ HH 2 531 4-EtOCOO-2-Pyrd 3- _{OCF 3 HH 2 532 4-Pr} i OCOO-2-Pyrd 3-OCF 3 HH 2 533 4-Bu t OCOO-2-Pyrd 3-OCF 3 HH 2 534 4-AcO-2-Pyrd 3-OCF 3 HH 2 535 4-PalO-2-Pyrd 3-OCF ₃ HH 2 536 4-SteO-2-Pyrd 3-OCF ₃ HH 2 537 1-Me-4-EtOCOO-2-Pyrd 3-OCF ₃ HH 2 538 1-Me -4-Pr ⁱ OCOO-2-Pyrd 3-OCF ₃ HH 2 539 1-Me-4-Bu ^t OCOO-2-Pyrd 3-OCF ₃ HH 2 540 1-Me-4-AcO-2-Pyrd 3-OCF ₃ HH 2 541 1-Me-4-PalO-2 -Pyrd 3-OCF ₃ HH 2 542 1-Me-4-SteO-2-Pyrd 3-OCF ₃ HH 2 543 1-Et-3-Pip 3-OMe 5-OMe H 1 544 2-Mor 3-OMe 5 -OMe H 1 543 4-Et-2-Mor 3-OMe 5-OMe H 1 546 2-Pyrd 3-OMe 5-OMe H 2 547 1-Et-2-Pyrd 3-OMe 5-OMe H 2 548 4 -OH-2-Pyrd 3-OMe 5-OMe H 2 549 1-Me-4-OH-2-Pyrd 3-OMe 5-OMe H 2 550 1-Et-4-OH-2-Pyrd 3-OMe 5 -OMe H 2 551 4-EtOCOO- 2-Pyrd 3-OMe 5-OMe H 2 552 4-Pr i OCOO-2-Pyrd 3-OMe 5-OMe H 2 553 4-Bu t OCOO-2-Pyrd 3- OMe 5-OMe H 2 554 4-AcO-2-Pyrd 3-OMe 5-OMe H 2 555 4-PalO-2-Pyrd 3-OMe 5-OMe H 2 556 4-SteO-2-Pyrd 3-OMe 5 -OMe H 2 557 1-Me-4-EtOCOO-2-Pyrd 3-OMe 5-OMe H 2 558 1-Me-4-Pr ⁱ OCOO-2-Pyrd 3-OMe 5-OMe H 2 559 1-Me -4-Bu ^t OCOO-2-Pyrd 3-OMe 5-OMe H 2 560 1-Me-4-AcO-2-Pyrd 3-OMe 5-OMe H 2 561 1-Me-4-PalO-2-Pyrd 3-OMe 5-OMe H 2 562 1-Me-4-SteO-2-Pyrd 3-OMe 5-OMe H 2 563 1-Me-4-EtOCOO-2-Pyrd HHH 2 564 1-Me-4-Pr ⁱ OCOO-2-Pyrd HHH 2 565 1-Me-4-Bu ^t OCOO-2-Pyrd HHH 2 566 1-Me-4-PalO-2-Pyrd HHH 2 567 1 -Me-4-SteO-2-Pyrd HHH 2 568 1-Me-4-SucO-2-Pyrd 3-OMe HH 2 569 2-Pyrd 3-OMe HH 2 570 1-Me-4-SucO-2-Pyrd 3-OMe 5-OMe H 2 571 1-Me-2-Pyrd 2-FHH 2 572 2-Pyrd 2-FHH 2 573 3-Pip 2-FHH 1 574 1-Me-3-Pip 2-FHH 1 575 4 -Me-2-Mor 2-FHH 1 576 1-Me-4-OH-2-Pyrd 2-FHH 2 577 1-Me-4-SucO-2-Pyrd 2-FHH 2 578 1-Me-4-EtOCOO -2-Pyrd 2-FHH 2 579 1-Me-4-AcO-2-Pyrd 2-FHH 2 580 1-Me-4-PalO-2-Pyrd 2-FHH 2 581 1-Me-2-Pyrd 4- FHH 2 582 2-Pyrd 4-FHH 2 583 3-Pip 4-FHH 1 584 1-Me-3-Pip 4-FHH 1 585 4-Me-2-Mor 4-FHH 1 586 1-Me-4-OH -2-Pyrd 4-FHH 2 587 1-Me-4-SucO-2-Pyrd 4-FHH 2 588 1-Me-4-EtOCOO-2-Pyrd 4-FHH 2 589 1-Me-4-AcO-2 -Pyrd 4-FHH 2 590 1-Me-4-PalO-2-Pyrd 4-FHH 2 591 1-Me-2-Pyrd 2-Cl HH 2 592 2-Pyrd 2-Cl HH 2 593 3-Pip 2- Cl HH 1 594 4-Me-2-Mor 2-Cl HH 1 595 1-Me-4-OH-2-Pyrd 2-Cl HH 2 596 1-Me-4-SucO-2-Pyrd 2-Cl HH 2 597 1-Me-4-EtOCOO-2-Pyrd 2-Cl HH 2 598 1-Me-4-AcO-2-Pyrd 2-Cl HH 2 599 1-Me-4-PalO-2-Pyrd 2-Cl HH 2 600 2-Pyrd 4-Cl HH 2 601 3-Pip 4-Cl HH 1 602 1-Me-3-Pip 4-Cl HH 1 603 4-Me-2-Mor 4-Cl HH 1 604 1-Me- 4-O H-2-Pyrd 4-Cl HH 2 605 1-Me-4-SucO-2-Pyrd 4-Cl HH 2 606 1-Me-4-EtOCOO-2-Pyrd 4-Cl HH 2 607 1-Me-4 -AcO-2-Pyrd 4-Cl HH 2 608 1-Me-4-PalO-2-Pyrd 4-Cl HH 2 609 1-Me-2-Pyrd 4-CN HH 2 610 2-Pyrd 4-CN HH 2 611 3-Pip 4-CN HH 1 612 1-Me-3-Pip 4-CN HH 1 613 4-Me-2-Mor 4-CN HH 1 614 1-Me-4-OH-2-Pyrd 4-CN HH 2 615 1-Me-4-SucO-2-Pyrd 4-CN HH 2 616 1-Me-4-EtOCOO-2-Pyrd 4-CN HH 2 617 1-Me-4-AcO-2-Pyrd 4- CN HH 2 618 1-Me-4-PalO-2-Pyrd 4-CN HH 2 619 1-Me-2-Pyrd 3-CN HH 2 620 2-Pyrd 3-CN HH 2 621 3-Pip 3-CN HH 1 622 1-Me-3-Pip 3-CN HH 1 623 4-Me-2-Mor 3-CN HH 1 624 1-Me-4-OH-2-Pyrd 3-CN HH 2 625 1-Me-4 -SucO-2-Pyrd 3-CN HH 2 626 1-Me-4-EtOCOO-2-Pyrd 3-CN HH 2 627 1-Me-4-AcO-2-Pyrd 3-CN HH 2 628 1-Me- 4-PalO-2-Pyrd 3-CN HH 2 629 4-Me-2-Mor 3-Br HH 1 630 1-Me-4-OH-2-Pyrd 3-Br HH 2 631 1-Me-4-SucO -2-Pyrd 3-Br HH 2 632 1-Me-4-EtOCOO-2-Pyrd 3-Br HH 2 633 1-Me-4-AcO-2-Pyrd 3-Br HH 2 634 1-Me-4- PalO-2-Pyrd 3-Br HH 2 635 1-Me-3-Pip 2-Me HH 1 636 4-Me-2-Mor 2-Me HH 1 637 1-Et-4-OH-2-Pyrd 2- Me HH 2 638 1-Me-4-SucO- 2-Pyrd 2-Me HH 2 639 1-Me-4-EtOCOO-2-Pyrd 2-Me 3-OMe H 2 640 1-Me-4-AcO-2-Pyrd 2-Me HH 2 641 1-Me- 4-PalO-2-Pyrd 2-Me HH 2 642 1-Me-3-Pip 4-Me HH 1 643 4-Me-2-Mor 4-Me HH 1 644 1-Me-4-OH-2-Pyrd 4-Me HH 2 645 1-Me-4-SucO-2-Pyrd 4-Me HH 2 646 1-Me-4-EtOCOO-2-Pyrd 4-Me HH 2 647 1-Me-4-AcO-2- Pyrd 4-Me HH 2 648 1-Me-4-PalO-2-Pyrd 4-Me HH 2 649 2-Pyrd 3-Me 5-Me H 2 650 3-Pip 3-Me 5-Me H 1 651 1- Me-3-Pip 3-Me 5-Me H 1 652 4-Me-2-Mor 3-Me 5-Me H 1 653 1-Me-4-OH-2-Pyrd 3-Me 5-Me H 2 654 1-Me-4-SucO-2-Pyrd 3-Me 5-Me H 2 655 1-Me-4-EtOCOO-2-Pyrd 3-Me 5-Me H 2 656 1-Me-4-Pr ⁱ OCOO- 2-Pyrd 3-Me 5- Me H 2 657 1-Me-4-Bu t OCOO-2-Pyrd 3-Me 5-Me H 2 658 1-Me-4-AcO-2-Pyrd 3-Me 5- Me H 2 659 1-Me-4-PalO-2-Pyrd 3-Me 5-Me H 2 660 1-Me-4-SteO-2-Pyrd 3-Me 5-Me H 2 661 1-Me-3- Pip 4-Et HH 1 662 4-Me-2-Mor 4-Et HH 1 663 1-Me-4-OH-2-Pyrd 4-Et HH 2 664 1-Me-4-SucO-2-Pyrd 4- Et HH 2 665 1-Me-4-EtOCOO-2-Pyrd 4-Et HH 2 666 1-Me-3-Pip 3-Et HH 1 667 4-Me-2-Mor 3-Et HH 1 668 1-Me -4-OH-2-Pyrd 3-Et HH 2 669 1-Me-4-SucO-2-Pyrd 3-Et HH 2 670 1-Me-4-EtOCOO-2-Pyrd 3-Et HH 2 671 2-Pip 3-OMe HH 2 672 4-OH-2-Pyrd 3-OMe HH 1 673 1-Me-4 -SucO-2-Pyrd 2-OH HH 2 674 1-Me-4-SucO-2-Pyrd 4-OH HH 2 675 1-Me-4-SucO-2-Pyrd 3-OH HH 2 676 1-Me- 4-SucO-2-Pyrd 3-Me HH 2 677 1-Me-4-SucO-2-Pyrd 3-Cl HH 2 678 1-Me-4-SucO-2-Pyrd 3-FHH 2 679 1-Me- 4-SucO-2-Pyrd 2-CN HH 2 680 1-Me-4-SucO-2-Pyrd 3-Et HH 2 681 1-Me-4-SucO-2-Pyrd 2-OMe HH 2 682 1-Me -4-SucO-2-Pyrd 4-OMe HH 2 683 1-Me-4-OH-2-Pyrd 3-OH 5-OH H 2 684 1-Me-4-SucO-2-Pyrd 3-OH 5- OH H 2 685 1-Me-3-Pip 3-Br HH 1 686 1-Me-3-Pip 2-Cl HH 1 687 1-Me-4-SucO-2-Pyrd 2-OCHF ₂ HH 2 688 1- Me-4-SucO-2-Pyrd 4-OCHF ₂ HH 2 689 1-Me-4-SucO-2-Pyrd 3-OCHF ₂ HH 2 690 1-Me-4-SucO-2-Pyrd 3-OCF ₃ HH 2 691 1-Me-2-Pyrd 4-OEt HH 2 692 1-Me-3-Pip 4-OEt HH 1 693 4-Me-2-Mor 4-OEt HH 1 694 1-Me-4-OH-2 -Pyrd 4-OEt HH 2 695 1-Me-4-SucO-2-Pyrd 4-OEt HH 2 696 1-Me-2-Pyrd 2-OEt HH 2 697 1-Me-3-Pip 2-OEt HH 1 698 4-Me-2-Mor 2-OEt HH 1 699 1-Me-4-OH-2-Pyrd 2-OEt HH 2 700 1-Me-4-SucO-2-Pyrd 2-OEt HH 2 ─── ── ────────────────────────────.

In the above formula, Ac is an acetyl group and is represented by Bu ^t
Is a t-butyl group, Et is an ethyl group, Glu is
A glutaryl group, Me is a methyl group, Mor is a morpholinyl group, Pal is a palmitoyl group, and Ph is
Phenyl group, Pip is piperidinyl group, Pr is
Propyl group, Pr ⁱ is i-propyl group, Pyrd
Is a pyrrolidinyl group, Ste is a stearoyl group,
Suc represents a succinyl group, and Tmor represents a thiomorpholinyl group.

Of the above-exemplified compounds, as a prophylactic / therapeutic agent for cardiovascular diseases, compound Nos. 1, 5, 10,
16, 18, 19, 24, 26, 30, 31, 32, 3
5,36,38,39,41,44,45,50,5
2,57,60,62,63,64,65,66,6
7, 70, 72, 73, 74, 75, 78, 81, 8
2,84,86,87,88,90,92,93,9
4,95,97,98,100,101,103,10
4, 105, 106, 110, 111, 112, 11
3,114,115,117,118,120,12
1,122,123,124,125,127,13
0,132,133,134,135,136,13
7,141,149,150,151,152,16
1,164,175,189,190,195,20
2,209,213,247,248,256,25
7,258,259,260,261,262,26
3,265,267,268,269,276,27
7,280,282,288,289,296,29
9,306,320,327,330,334,34
1,348,355,362,369,372,37
3,375,376,383,384,390,40
0,401,402,403,404,405,40
8,415,416,417,418,419,42
0,422,424,426,428,435,43
9,442,444,446,448,455,45
8,459,461,462,464,466,46
9,476,479,480,483,485,48
7,489,496,503,505,507,50
9,523,525,527,530,537,53
8,540,541,548,549,557,55
8,560,561,562,563,564,56
5,566,567,568,569,570,57
1,574,575,576,577,578,58
0,581,584,585,586,587,58
8,591,593,594,595,596,59
7,598,599,602,603,604,60
5,606,607,608,609.612,61
3,614,615,616,619,622,62
3,624,625,626,628,629,63
0,631,633,634,635,636,63
7,642,643,644,649,650,65
1,652,653,661,662,663,66
4,665,666,667,668,669,67
0,675,676,677,678,679,68
0,681,682,683,685,686,68
7,688,689,690,691,694,696
And 699, and more preferable compounds include compound numbers 1, 16, 19, 26, 3
2,38,39,44,50,57,60,63,6
5,70,74,75,78,84,87,90,9
3,95,98,100,105,110,112,1
13, 115, 118, 120, 122, 125, 12
7,132,133,135,136,137,14
1,149,150,151,152,164,19
5,202,213,248,256,257,25
9, 260, 261, 269, 289, 296, 32
0,334,348,362,376,383,40
0,401,403,405,408,415,41
6,418,419,426,428,446,44
8,466,469,487,489,507,50
9,527,530,549,557,558,56
0,561,562,563,564,566,56
8,570,571,576,577,581,58
6,587,591,595,596,604,60
5,609,614,615,619,624,62
5,630,631,633,634,637,64
4,651,663,668,675,677,67
8,680,681,682,687,690,69
1,694,696 and 699 can be mentioned, and more preferable compounds are compound numbers 1,38,50,57,60,63,70,90,9.
5,100,110,135,137,141,14
9,164,248,256,257,259,26
0,269,334,348,376,400,40
1,405,408,415,418,469,54
9,557,560,568,570,571,57
6,581,586,591,595,604,60
9,614,619,630,631,632,68
Compounds 0,687,691 and 696 can be mentioned, and more preferable compounds include compound numbers 1,38,50,57,60,63,70,95,1.
00, 110, 135, 137, 248, 256, 25
9,334,401,405,408,549,56
8,570,571,630,687,691 and 69
6 can be mentioned, and particularly preferable compounds include compound numbers 1, 38, 50, 70, 95, 13
7,248,334,405,408,549,56
The compounds of 8,570,630 and 687 may be mentioned.

Further, as a prophylactic / therapeutic agent for mental illness, compound numbers 10, 19, 26, 44, 52, 5 are preferable.
4,57,60,70,74,75,78,81,8
2,87,88,93,94,98,112,114,
128, 172, 401, 422, 442, 462, 4
83, 503, 523, 571, 649, 685 and 6
The compound of No. 86 can be mentioned, and more preferable compounds include compound Nos. 10, 19, 44, 52, 54,
57, 70, 74, 78, 81, 93, 112, 17
The compounds of 2,401,571 and 685 can be mentioned, and as a particularly suitable compound, the compound of compound number 52 can be mentioned. The alicyclic amine derivative of the present invention can be easily produced by the method described below.

[0031]

[Chemical 5]

In the above formula, R ¹ , R ² , R ³ , R ⁴ and m
Represents the same meanings as defined above, R ¹ a is not hydroxy group is protected, in addition to the nitrogen atom of the ring (= NH) is protected, the same meaning as R ^1, R ² a, R ³ a and R ⁴ a and a hydroxy group are protected, and each has the same meaning as R ² , R ³ and R ⁴ , respectively, and Y is a hydroxyl group or a group which is usually eliminated as a nucleophilic residue. Preferred examples of the group that is usually eliminated as a nucleophilic residue include halogen atoms such as chlorine, bromine and iodine; alkylcarbonyloxy groups such as acetoxy and propionyloxy, chloroacetyloxy, dichloroacetyloxy and trichloroacetyl. Oxy, halogenated alkylcarbonyloxy groups such as trifluoroacetyloxy, lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy, (E) -2-methyl-2-butenoyl Aliphatic acyloxy groups such as unsaturated alkylcarbonyloxy groups such as Si; arylcarbonyloxy groups such as benzoyloxy, halogenated arylcarbonyloxy such as 2-bromobenzoyloxy, 4-chlorobenzoyloxy Group, lower alkylated arylcarbonyloxy group such as 2,4,6-trimethylbenzoyloxy, 4-toluoyloxy, lower alkoxylated arylcarbonyloxy group such as 4-anisoyloxy, 4- Aromatic acyloxy groups such as nitrated arylcarbonyloxy groups such as nitrobenzoyloxy and 2-nitrobenzoyloxy; trihalogenomethyloxy groups such as trichloromethyloxy; lower such as methanesulfonyloxy and ethanesulfonyloxy Alkanesulfonyloxy group; trifluoromethanesulfur Examples thereof include halogeno lower alkanesulfonyloxy groups such as phenyloxy and pentafluoroethanesulfonyloxy; arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy, and more preferably Is a halogen atom, a lower alkanesulfonyloxy group, a halogeno lower alkanesulfonyloxy group, and an arylsulfonyloxy group, and particularly preferably a chlorine, bromine or iodine atom.

The amino group-protecting group is not particularly limited as long as it is usually used as an amino group-protecting group, but is preferably the above "aliphatic acyl group"; the above "aromatic acyl group"; “Alkoxycarbonyl group”; the above “alkenyloxycarbonyl group”; the above “aralkyloxycarbonyl group”; the above “silyl group”; the above “aralkyl group”, and more preferably an aliphatic acyl having 1 to 5 carbon atoms. Group, an alkoxycarbonyl group having 1 to 6 carbon atoms, an arylmethoxycarbonyl group having 6 to 10 carbon atoms or an arylmethyl group having 6 to 10 carbon atoms, and particularly preferably acetyl, t-butoxycarbonyl, benzyl, p.
A methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl group.

The hydroxy-protecting group is preferably a cyclic ether group such as tetrahydrofuranyl or tetrahydropyranyl, a methoxymethyl group, a methoxymethoxymethyl group, an arylmethoxycarbonyl group having 6 to 10 carbon atoms or a carbon atom. An arylmethyl group of the formulas 6 to 10, particularly preferably tetrahydropyranyl, methoxymethyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyl. It is an oxycarbonyl group.

In the first step, the phenol derivative represented by the general formula (II) is reacted with the heterocyclyl compound represented by the general formula (III) to form an ether bond to form the compound represented by the general formula (Ia). This is a manufacturing process.

When Y represents a group capable of leaving as a nucleophilic residue, this reaction is preferably carried out in an inert solvent in the presence of a suitable base. As the base used, if used as a base in a normal reaction,
Although not particularly limited, preferably alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate;
Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, hydroxide Alkali metal hydroxides such as barium and lithium hydroxide; Inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium Alkali metal alkoxides such as methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, picoline, 4- (N, N-dimethylamino) pyridine,
2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline,
1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undesa-7-ene (DBU) Organic bases such as or butyllithium, lithium diisopropylamide,
Examples thereof include organic metal bases such as lithium bis (trimethylsilyl) amide, and more preferably, alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydrides, alkali metal fluorides, alkali metal alkoxides. And organic bases, most preferably alkali metal carbonates, alkali metal hydrides,
Alkali metal fluorides and alkali metal alkoxides. In order to effectively carry out the reaction, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like can be added. .

The inert solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but it is preferable to use a fat such as hexane, heptane, ligroin or petroleum ether. Group hydrocarbons; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitrites such as acetonitrile and isobutyronitrile Examples: amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide; sulphoxides such as dimethylsulfoxide and sulfolane, or a mixed solvent thereof. Are preferably ketones, ethers, amides and sulfoxides. The reaction temperature is usually 0 ° C. to 100 ° C. (preferably 10 to 80 ° C.), and the time required for the reaction varies depending on the reaction temperature, but is 30 minutes to 48 hours, and preferably 1 hour to 24 hours.

When Y is a hydroxyl group, azodicarboxylic acid esters such as diethyl azodicarboxylate and dimethyl azodicarboxylate are allowed to act in the presence of a phosphine such as triphenylphosphine to form an ether bond. Can be formed. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride. , Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, N-methyl-2
Examples include amides such as pyrrolidone and hexamethylphosphorotriamide, and mixed solvents thereof, but halogenated hydrocarbons and ethers are preferable. The reaction temperature is usually −20 ° C. to 100 ° C. (preferably 10 ° C. to 80 ° C.), and the time required for the reaction is 30 minutes to 48 hours, preferably 1 Hours to 24 hours.

After completion of the reaction, the target compound (Ia) of this reaction is
It is taken from the reaction mixture according to a conventional method. For example, when an insoluble substance is present, it is appropriately filtered off, and the solvent is distilled off under reduced pressure or after the solvent is distilled off under reduced pressure, water is added to the residue, and a water-immiscible organic substance such as ethyl acetate is added. It can be obtained by extraction with a solvent, drying over anhydrous magnesium sulfate and the like, and then distilling off the solvent. If necessary, it can be further purified by a conventional method such as recrystallization or column chromatography.

The second step is a step to be carried out if desired, and the reaction (a): a reaction for removing the hydroxy protecting group contained in R ¹ a, R ² a, R ³ a and / or R ⁴ a, a reaction (B): Reaction of alkylating, acylating or carbamoylating the hydroxy group generated by the reaction (a), Reaction (c): Reaction of removing the nitrogen atom-protecting group contained in R ¹ a, Reaction (d) A reaction for converting an alkoxycarbonyl group contained in R ¹ a to a methyl group or an alkanoyl group to an alkyl group, a reaction (e): a reaction for alkylating an = NH group contained in R ¹ a, and a reaction (f): cyano The method includes converting a group to a carbamoyl group, and the order is appropriately changed.

Reaction (a): R ¹ a, R in the reaction (a)
^The reaction for removing the hydroxy protecting group contained in ² a, R ³ a and / or R ⁴ a differs depending on the kind of the protecting group and is performed by a method well known in synthetic organic chemistry.

When a silyl group is used as a hydroxyl-protecting group, it is usually removed by treatment with a compound which produces a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable. The reaction temperature and reaction time are not particularly limited, but usually 10 to 18 at room temperature.
Will be carried out for hours.

When the hydroxyl-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by bringing it into contact with a reducing agent in a solvent (preferably, catalytic reduction at room temperature under a catalyst). A method or a method of removing using an oxidizing agent is preferable. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol and isopropanol, diethyl ether, Tetrahydrofuran, ethers such as dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, Preferred are amides such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide, formic acid, fatty acids such as acetic acid, water, or a mixed solvent thereof, and more preferred are , Alcohols, fatty acids, alcohols
It is a mixed solvent of alcohols and ethers, a mixed solvent of alcohols and water, or a mixed solvent of fatty acids and water. The catalyst used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney-nickel, platinum oxide,
Platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate are used, more preferably palladium carbon and palladium black. The pressure is not particularly limited, but is usually 1 to 1
It is carried out at 0 atm. The reaction temperature and reaction time will differ depending on the starting materials, solvent, type of catalyst, etc., but are usually 0 ° C.
To 100 ° C. (preferably 20 ° C. to 70 ° C.), 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but a water-containing organic solvent is preferable. Preferable examples of such an organic solvent include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran and dioxane. Ethers, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, and sulfoxides such as dimethylsulfoxide. The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation, but is preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro.
-5,6-Dicyano-p-benzoquinone (DDQ) is used.
The reaction temperature and the reaction time will differ depending on the starting materials, the solvent, the type of the catalyst and the like, but they are usually carried out at 0 to 150 ° C. for 10 minutes to 24 hours.

Also, in liquid ammonia or in methanol.
-78 in alcohols such as alcohol and ethanol
It can also be removed by reacting alkali metals such as lithium metal and sodium at -20 ° C.

Further, it can be removed by using aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide in a solvent. The solvent used is not particularly limited as long as it does not participate in this reaction, but preferably, nitriles such as acetonitrile, methylene chloride, halogenated hydrocarbons such as chloroform or a mixed solvent thereof. Is used. The reaction temperature and reaction time will differ depending on the starting materials, solvent, etc., but are usually 0 to 50 ° C., and 5 minutes to 3 minutes.
It is carried out for a day. When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treatment with a base in a solvent.

The base used is not particularly limited as long as it does not affect the other parts of the compound, but metal alkoxides such as sodium methoxide; sodium carbonate, potassium carbonate, Alkali metal carbonate such as lithium carbonate; Alkali metal hydroxide or ammonia water such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, concentrated ammonia-
Ammonia such as methanol is used. The solvent used is not particularly limited as long as it can be used in a usual hydrolysis reaction, and water; methanol, ethanol
Preferred are organic solvents such as alcohols such as alcohol and n-propanol, organic solvents such as ethers such as tetrahydrofuran and dioxane, or mixed solvents of water and the above organic solvents. The reaction temperature and the reaction time vary depending on the starting material, the solvent, the base used and the like and are not particularly limited, but in order to suppress side reactions, it is usually 0 to 150 ° C. and 30 minutes to 48 hours (preferably 1 to 24 hours).

The hydroxyl-protecting group is an alkoxymethyl group,
In the case of a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, it is usually removed by treating with an acid in a solvent. The acid used is not particularly limited as long as it is usually used as a Bronsted acid or a Lewis acid, and preferably,
Hydrogen chloride; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid; or Bronsted acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid: Lewis acids such as boron trifluoride However, Dowex 5
Strongly acidic cation exchange resins such as 0W® can also be used. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate,
Esters such as propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol , Glycerin, octanol, cyclohexanol,
Alcohols such as methyl cellosolve; acetone,
Ketones such as methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water, or
These mixed solvents are preferable, and halogenated hydrocarbons, esters or ethers are more preferable. The reaction temperature and the reaction time will differ depending on the starting materials, the solvent, the type and concentration of the acid used, etc., but are usually -10 to 1.
00 ° C (preferably -5 to 50 ° C) for 5 minutes to 48
Time (preferably 30 minutes to 10 hours).

When the hydroxyl-protecting group is an alkenyloxycarbonyl group, it is generally the same as the conditions for the removal reaction when the hydroxyl-protecting group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. And is treated with a base. In the case of allyloxycarbonyl, the method of removing it particularly using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

The protective group for the nitrogen atom may be simultaneously removed by the above-mentioned operation for removing the protective group for the hydroxyl group.

The above-mentioned reaction for removing a protective group for a hydroxyl group and the reaction for removing a protective group for a nitrogen atom described below can be carried out in any desired order in order. In addition, by selecting conditions for the protecting group and its removal reaction, R ¹ a, R ² a, R
^The hydroxy protecting group contained in ³ a and / or R ⁴ a can be selectively removed.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, by appropriately neutralizing the reaction mixture, or removing insolubles by filtration, an organic solvent immiscible with water such as ethyl acetate is added, and after washing with water, the solvent is distilled off. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (b): The reaction of alkylating, acylating or carbamoylating the hydroxy group produced by the reaction (a) is carried out by a method well known in synthetic organic chemistry. For example, inert solvents (preferably aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, esters such as ethyl acetate, ethers such as tetrahydrofuran and dioxane, Acetone, ketones such as methyl ethyl ketone, amides such as N, N-dimethylacetamide) in the presence or absence of a base (the base is preferably
Organic tertiary amines such as triethylamine, pyridine, diethylisopropylamine, and 4-dimethylaminopyridine) are present in the presence of alkylation, acylation, or reaction with a carbamoylating agent. Examples of the alkylating, acylating or carbamoylating agent used include alkyl halides having 1 to 6 carbon atoms such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentyl iodide and hexyl iodide, Halogenocarbons such as methyl chlorocarbonate, methyl bromocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isopropyl chlorocarbonate, butyl chlorocarbonate, t-butyl chlorocarbonate, pentyl chlorocarbonate, hexyl chlorocarbonate Alkyl having 1 to 6 carbon atoms, Acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, pivaloyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride Alkanoyl halides having 2 to 20 carbon atoms such as chlorochloride, palmitoyl chloride, stearoyl chloride, eicosanoyl chloride, docosanoyl chloride, mixed acid anhydrides of formic acid and acetic acid, acetic anhydride, propionic anhydride, valeric anhydride, anhydrous C2-6 carboxylic acid anhydrides such as pivalic acid, succinic anhydride, glutaric anhydride, cyclic acid anhydrides such as adipic anhydride, isocyanic acid, methyl isocyanate, ethyl isocyanate, propyl isocyanate, butyl isocyanate, C1 to C6 alkyl isocyanate such as pentyl isocyanate and hexyl isocyanate, N, N-dimethylcarbamoyl chloride, N,
Di- (having 1 to 6 carbon atoms) such as N-diethylcarbamoyl chloride, N, N-dipropylcarbamoyl chloride, N, N-dibutylcarbamoyl chloride, N, N-dipentylcarbamoyl chloride and N, N-dihexylcarbamoyl chloride. Alkyl) carbamoyl halides may be mentioned. The reaction temperature is 0 ° C to 120 ° C.
℃ (preferably 0 to 80 ℃), the reaction time is
It is 1 to 24 hours (preferably 1 to 16 hours).
After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method, for example, the same operation as the method for collecting the compound of the first step described above.

Reaction (c): The reaction for removing the protecting group of the nitrogen atom contained in R ¹ a in the reaction (c) depends on the kind of the protecting group and is carried out by a method well known in synthetic organic chemistry. . When the nitrogen atom-protecting group is a silyl group, it is carried out in the same manner as when the hydroxyl-protecting group is a silyl group.

When the nitrogen atom-protecting group is an aralkyl group or an aralkyloxycarbonyl group, the removal reaction is carried out in the same manner as in the reaction (a) of the second step when the hydroxy-protecting group is an aralkyl group. .

When the nitrogen-protecting group is a t-butoxycarbonyl group, it is carried out in the same manner as in the removal reaction when the hydroxy-protecting group in the reaction (a) in the second step is a methoxymethyl group or the like. .

When the nitrogen atom-protecting group is an alkenyloxycarbonyl group, the removal reaction conditions are usually the same when the nitrogen atom-protecting group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. Similarly, it is achieved by treating with a base.

Further, when the nitrogen atom-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl residue, an inert solvent (preferably alcohols such as methanol and ethanol, tetrahydrofuran, tetrahydrofuran, Ethers such as dioxane, water or a mixed solvent of water and the above organic solvent), a base (preferably, an alkali metal hydroxide or sodium carbonate such as lithium hydroxide, sodium hydroxide or potassium hydroxide, The corresponding protecting group is removed by reaction and hydrolysis with an alkali metal carbonate such as potassium carbonate).

The reaction temperature and reaction time will differ depending on the solvent and the like, but are usually 0 ° C. to 100 ° C. (preferably room temperature to 6 ° C.).
0 ° C.) and 1 hour to 24 hours (preferably 1 hour to 16 hours). After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method, for example, the same operation as the method for collecting the compound of the first step described above.

Reaction (d): The reaction for converting the alkoxycarbonyl group contained in R ¹ a into a methyl group or the alkanoyl group into an alkyl group in the reaction (d) is carried out in an inert solvent (preferably ether, tetrahydrofuran, It is carried out by reacting with a reducing agent (preferably an alkali aluminum hydride such as lithium aluminum hydride) in ethers such as dioxane). The reaction temperature and the reaction time will differ depending on the solvent and the like, but are usually 0 ° C.
To 100 ° C. (preferably room temperature to 80 ° C.) and 30 minutes to 24 hours (preferably 1 hour to 16 hours). After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method, for example, the same operation as the method for collecting the compound of the first step described above.

Reaction (e): The reaction for alkylating the = NH group contained in R ¹ a in the reaction (e) is carried out by using methyl iodide, ethyl iodide, propyl iodide, butyl iodide as an alkylating agent, Presence of alkyl halide having 1 to 6 carbon atoms such as pentyl iodide or hexyl iodide, and base (eg, alkali metal carbonate such as potassium carbonate or sodium carbonate; alkali metal hydride such as sodium hydride) The reaction is performed under the same conditions as in the reaction (b) of the second step.

Reaction (f): The reaction for converting a cyano group into a carbamoyl group in the reaction (f) is carried out by an inert solvent (for example, hydrous alcohols such as hydrous methanol and hydrous ethanol, hydrous ethers). , Water-containing tetrahydrofuran, water-containing ethers such as water-containing dioxane, or water, preferably water-containing alcohols, the corresponding compound is a base (for example, alkali metal water such as sodium hydroxide or potassium hydroxide). It is an alkali metal carbonate such as an oxide, sodium carbonate or potassium carbonate, and is preferably carried out by reacting with an alkali metal hydroxide). The reaction temperature and the reaction time are generally 10 ° C to 200 ° C (preferably 50 ° C to 150 ° C) and 30 minutes to 48.
Time (preferably 1 to 20 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, by appropriately neutralizing the reaction mixture, or removing insolubles by filtration, an organic solvent immiscible with water such as ethyl acetate is added, and after washing with water, the solvent is distilled off. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The compound (I) of the present invention can be converted into a pharmacologically acceptable salt by treating with an acid according to a conventional method. For example, compound (I) is dissolved in a suitable solvent (eg, esters, halogenated hydrocarbons, alcohols), and a necessary amount of acid, for example, inorganic acid such as hydrochloric acid or sulfuric acid; methanesulfonic acid, p Treatment with an organic acid such as toluenesulfonic acid, fumaric acid, maleic acid can give the desired acid addition salt. or,
Acidic resins such as CM-Sephadex C-25
Compound (I) or a salt addition salt thereof may be adsorbed on an (H ⁺ type: registered trademark) column and then eluted with dilute hydrochloric acid to be purified as a hydrochloride.

The starting compounds (II) and (II
I) is a known method or a known method (for example, JP-A-53-15364 and JP-A-55-2074).
No. 0, JP-A No. 3-4022, methods such as F. Loftus, Synthetic Communications, Volume 10, page 59 (1980)) or reference examples. It can be easily manufactured according to the above method.

[0067]

INDUSTRIAL APPLICABILITY As shown below, the compound of the present invention represented by the general formula (I) has little adrenergic α ₁ antagonism and has excellent serotonin 2 receptor antagonism. Therefore, by blocking the serotonin 2 receptor distributed in vascular endothelial cells and platelets, cardiovascular diseases such as arrhythmia, angina, ischemic heart disease such as myocardial infarction, cerebral infarction, and vasospasm after subarachnoid hemorrhage It is useful for the treatment of such cerebrovascular disorders, Raynaud's disease, peripheral circulatory disorders such as Buerger's disease, and the prevention of recurrence. Further, since it has an excellent serotonin 2 receptor antagonism as well as a dopamine 2 receptor antagonism, it is useful as a therapeutic drug for psychosis such as schizophrenia with weak side effects. An example of biological activity test is shown below.

Test Example 1 Vasoconstriction Experiment The smooth muscle contraction reaction was measured by Van Neuten et al. (J. Pharmacol. Exp.
Ther., 218 , 217-230, 1981).
An SD male rat with a body weight of about 500 g was exsanguinated to death, and the tail artery was extracted. After removing the incidental tissue from the artery, (2 x
20 mm) spiral specimens were prepared. This sample is Tyor
It was suspended in a Magnus tube containing 10 ml of ode solution and kept at 37 ° C., and a mixed gas (95% O ₂ , 5% CO ₂ ) was passed through the tube and left for 1 hour, and then used for the experiment. 0 as the initial tension.
5 g was loaded and the tension was recorded isometrically using a transducer. As a vasoconstrictor, serotonin 3x10 ^-6 M was added to the serotonin 2 receptor and phenylephrine 1x10 ^-6 M was added to the adrenary α ₁ receptor in the Magnus tube, and each test solution was added after the contraction reaction was stabilized. Cumulative additions were made and finally papaverine 10 ^-4 M was added. The tension was set to 100% before the addition of the test drug and the tension was set to 0% 5 minutes after the addition of papaverine. The concentration of the test drug required to reduce the tension to 50% was defined as an IC ₅₀ value, and the concentration was calculated by a least-squares regression line. The results are shown in Table 2.

[0069]

[Table 2] ────────────────────────────────── Compound IC ₅₀ nM serotonin 2 adrenaline α ₁ ─── ─────────────────────────────── Compound of Example 13 3.7 2,500 Compound of Example 15 4.3 3,700 Compound of Example 23 5.0 4,900 Compound of Example 48 6.5 860 Compound of Example 49 5.4 2,200 Compound of Example 50 6.1 1,300 Compound of Example 52 3.7 3,700 Compound of Example 59 2.2 1,700 Compound of Example 64 2.2 1,200 Compound of Example 65 5.7 1,100 Compound of Example 66 3.3 2,300 Compound of Example 67 2.2 -Compound of Example 68 1.8 5,900 Compound of Example 69 2.6 5,400 Compound of Example 71 4.2 -Compound of Example 72 2.2 -Compound of Example 74 5.7- Compound of Example 75 4.6-MCI-9042 72.0 50,000 ──────── ───────────────────────────.

Test Example 2 Receptor Binding Experiment This was carried out according to the method of Leysen et al. (Mol. Pharmacol., 21, 301-314, 1982). Male Wistar rats (weight 280-
320 g) was used. After decapitation, the removed cerebral cortex and striatum were frozen on dry ice and stored at -80 ° C until measurement. The cerebral cortex was used for serotonin receptors, and the striatum was used for dopamine receptors. For preparation of the membrane preparation, the frozen brain tissue was homogenized with 50 mM Tris-HCI buffer (pH 7.7) (Polytron PT-20) and then centrifuged at 49,000 g for 10 minutes. The precipitate was suspended in Tris buffer, centrifuged again, and then suspended in Tris buffer. The obtained membrane preparation is
After protein quantification, 0.57mg / protein / ml with Tris buffer
And stored at −80 ° C. In the receptor binding experiment, 440 μl of a membrane preparation was added to a test tube containing 50 μl of ³ H-ligand and 10 μl of a test compound (dissolved in DMSO) to start the reaction. After incubation for 1 hour at 30 ° C., the reaction was stopped by vacuum filtration on a Whatman GF / B glass filter. After washing the filter with ice-cold Tris buffer (4 ml x 2 times), ACS-
II was added and the radioactivity of the filter was measured with a liquid scintillation counter. 20 μM for non-specific binding
Determined by atropine. The binding inhibition rate (%) was determined from the binding rate in the presence of the test drug, and the concentration required to inhibit the binding by 50% was taken as the IC ₅₀ value, which was determined from the least-squares regression line.
The results are shown in Table 3.

[0071]

[Table 3] ────────────────────────────────── Compound IC ₅₀ ng / ml Serotonin 2 Dopamine 2 ── ──────────────────────────────── Compound of Example 27 1.7 168 Compound of Example 66 5.5 168 ──── ──────────────────────────────.

When the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as a prophylactic / therapeutic drug for cardiovascular disease or psychosis, itself or an appropriate pharmacologically acceptable carrier. , An excipient, a diluent and the like, and can be orally or parenterally administered as a pharmaceutical composition such as powder, granules, tablets, capsules and injections.

These formulations include excipients such as lactose,
Sugar derivatives such as sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α starch, dextrin, starch derivatives such as carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose. Cellulose derivatives such as carboxymethylcellulose calcium, sodium carboxymethylcellulose internally crosslinked; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, silicic acid such as magnesium aluminometasilicate. Inorganic excipients such as salt derivatives; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as bee gum and gay wax; boric acid; adipic acid; sodium sulfate) Sulfate; glycol;
Fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives. it can. ), A binder (for example, polyvinylpyrrolidone, macrogol, and a compound similar to the above-mentioned excipient), a disintegrant (for example, a compound similar to the above-mentioned excipient, and croscarmellose). Mention may be made of chemically modified starch / celluloses such as sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone), stabilizers (paraoxybenzoic acid esters such as methylparaben, propylparaben; chlorobutanol, benzyl alcohol). ,
Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.) and diluents and the like may be used to produce the compound by a known method. The dose varies depending on symptoms, age, etc., but, for example, in the case of oral administration, 1 to 1000 mg per dose
(Preferably 10-500 mg), 1 for intravenous administration
It is desirable to administer 0.1 to 500 mg (preferably 1 to 300 mg) per administration once to several times per day depending on the symptoms.

[0074]

The present invention will be described in more detail below with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0075]

Example 1 2- [2- [2- [2- (3-methoxyphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt (a) 2- [2- (3-methoxyphenyl) ethyl] phenol 20.0 g N, N-dimethylacetamide 50 ml
And potassium t-butoxide 9.83 under ice-cooled stirring.
g was added, and the mixture was stirred at the same temperature for 30 minutes. On the other hand, 16.1 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride was placed in 80 ml of N, N-dimethylacetamide with stirring under ice cooling.
9.83 g of potassium t-butoxide was added to give a free amine, which was added to the above-mentioned potassium salt solution of 2- [2- (3-methoxyphenyl) ethyl] phenol under stirring at room temperature,
Then, the mixture was stirred at 70 ° C. for 20 hours. After cooling, 500 ml of ethyl acetate was added to the reaction solution, and the mixture was washed successively with water and brine.
The extract layer was dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was treated by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 2-
[2- [2- [2- (3-methoxyphenyl) ethyl]]
Phenoxy] ethyl] -1-methylpyrrolidine 14.6 g
(Yield 49%) was obtained as a colorless liquid. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.55-2.6 (8H,
m), 2.42 (3H, s), 2.8-3.0 (4H, m), 3.1-3.3 (1H, m), 3.78
(3H, s), 3.9-4.15 (2H, m), 6.7-6.95 (5H, m), 7.1-7.3 (3H,
m). 14.5 g of the above 2- [2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 100 ml of ethyl acetate, and 11 ml of a 4N hydrogen chloride-ethyl acetate solution was dissolved. Was added under ice-cooling and the solution was allowed to stand to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (13.0 g, yield 81%) as colorless crystals. Melting point: 109-110 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.9-2.15 (2
H, m), 2.15-2.4 (2H, m), 2.4-2.65 (2H, m), 2.77 (3H, s),
2.7-3.0 (5H, m), 3.2-3.4 (1H, m), 3.78 (3H, s), 3.8-4.1 (2
H, m), 4.15-4.3 (1H, m), 6.7-7.0 (5H, m), 7.15-7.3 (3H,
m). (b) 2- [2- (3-Methoxyphenyl) ethyl] phenol 10.6 g, 1-methyl-2-pyrrolidine ethanol
8.4 g and triphenylphosphine 17 g were dissolved in 200 ml of methylene chloride, 11.3 g of azodicarboxylic acid diethyl ester was added dropwise under ice-cooling stirring, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, the extract layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This concentrate was subjected to silica gel column chromatography (methylene chloride / methanol = 10/1) to give 2- [2- [2- [2- (3-methoxyphenyl)).
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
5.70 g (36% yield) was obtained as a colorless liquid. The MMR spectrum was in agreement with that described in (a). This 2-
[2- [2- [2- (3-methoxyphenyl) ethyl]]
Phenoxy] ethyl] -1-methylpyrrolidine (5.70 g) was converted to a hydrochloride in the same manner as in (a) to obtain 4.89 g (yield 77%) of the title compound as colorless crystals. The melting point and the NMR spectrum were in agreement with those mentioned under (a).

[0076]

Example 2 4- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxy] piperidine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 456 mg, 1-t-butoxycarbonyl-4-hydroxypiperidine 600 mg and triphenylphosphine 8
65 mg was reacted in 30 ml of methylene chloride with 575 mg of azodicarboxylic acid diethyl ester in the same manner as in Example 1 (b), and after extraction, the concentrate was subjected to silica gel column chromatography (hexane / ethyl acetate = 4/1). )
Treat with 1-t-butoxycarbonyl-4- [2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
379 mg of piperidine (yield 46%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.47 (9H, s),
1.7-2.0 (4H, m), 2.8-3.0 (4H, m), 3.35-3.55 (2H, m), 3.6-
3.75 (2H, m), 3.78 (3H, s), 4.55-4.6 (1H, m), 6.7-6.9 (5H,
m), 7.1-7.3 (3H, m). The above 1-t-butoxycarbonyl-4- [2- [2-
379 mg of (3-methoxyphenyl) ethyl] phenoxy] piperidine was added to 5 ml of a 4N hydrogen chloride-dioxane solution.
It was dissolved in the solution and allowed to stand at room temperature for 1 hour. The reaction solution was concentrated, and the oily residue was dissolved in 10 ml of ethyl acetate and allowed to stand, whereby crystals were precipitated. This was collected by filtration and dried in vacuo to give the title compound (290 mg, yield 90%) as colorless crystals. Melting point: 121-122 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.05-2.2 (2H,
m), 2.25-2.4 (2H, m), 2.8-3.0 (4H, m), 3.2-3.4 (4H, m),
3.76 (3H, s), 4.55-4.6 (1H, m), 6.6-6.8 (4H, m), 6.92 (1H,
t, J = 7.3Hz), 7.1-7.3 (3H, m).

[0077]

Example 3 4- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxy] -1-methylpiperidine hydrochloride 482 mg of 1-t-butoxycarbonyl-4- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] piperidine obtained in the same manner as in Example 2 were added to 5 ml of tetrahydrofuran. Dissolved in. On the other hand, to the mixed solution prepared by adding 44.5 mg of lithium aluminum hydride to 5 ml of tetrahydrofuran under ice cooling, the above solution was added dropwise while stirring. After completion of the dropping, the reaction solution was heated under reflux for 1 hour, and then the reaction solution was cooled, and then sodium sulfate decahydrate was appropriately added to decompose excess hydride. The mixture was stirred for about 30 minutes, the insoluble material was filtered off, the filtrate was concentrated, and the oily residue obtained was subjected to silica gel column chromatography (methylene chloride / methanol = 1.
0/1) treated, 4- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -1-methylpiperidine 2
20 mg (yield 57%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.85-2.15 (4
H, m), 2.3-2.5 (2H, m), 2.33 (3H, s), 2.6-2.75 (2H, m), 2.
8-3.0 (4H, m), 3.79 (3H, s), 4.35-4.5 (1H, m), 6.7-6.9 (5
H, m), 7.1-7.3 (3H, m). 220 mg of the above 4- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -1-methylpiperidine,
Dissolved in ethyl acetate, 4N hydrogen chloride-dioxane solution
When 0.2 ml was added and left to stand, crystals were precipitated. This is filtered off and dried in vacuo, 170 mg (69%) of the title compound.
Was obtained as colorless crystals. Melting point: 147-148 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.0-2.25 (2H,
m), 2.5-2.8 (2H, m), 2.73 (3H, s), 2.8-3.1 (6H, m), 3.2-
3.4 (2H, m), 3.76 (3H, s), 3.6-3.8 (1H, m), 6.65-6.85 (4H,
m), 6.95 (1H, t, J = 7.3Hz), 7.15-7.3 (3H, m).

[0078]

Example 4 2- [2- [2- [2- (3-hydroxyphenyl) e]
Cyl] phenoxy] ethyl] -1-methylpyrrolidine salt
Acid salt 2- [2- (3-methoxymethoxyphenyl) ethyl]
Phenol 2.37 g, potassium t-butoxide 1.03 g and 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride 1.69 g were reacted in the same manner as in Example 1 (a) using 50 ml of N, N-dimethylacetamide. And extracted and purified by silica gel column chromatography to give 2- [2-
[2- [2- (3-Methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine 1.87
g (62% yield) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.5-2.4 (8H,
m), 2.39 (3H, s), 2.8-3.0 (4H, m), 3.05-3.2 (1H, m), 3.48
(3H, s), 3.95-4.15 (2H, m), 5.15 (2H, s), 6.8-6.95 (5H,
m), 7.1-7.3 (3H, m). 1.8 g of the above 2- [2- [2- [2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 20 ml of a 4N hydrogen chloride-dioxane solution, and the solution was stirred at room temperature for 30 minutes. After allowing to stand for a minute, it was concentrated under reduced pressure. The oil thus obtained was dissolved in 20 ml of methylene chloride, ethyl acetate was carefully added until just before cloudiness, and the mixture was allowed to stand at room temperature overnight to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (1.25 g, yield 71%) as colorless crystals. Melting point: 68-70 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.9-2.6 (6H,
m), 2.65-3.1 (5H, m), 2.83 (3H, s), 3.15-3.45 (1H, m), 3.
6-4.1 (3H, m), 6.57 (1H, d, J = 7.3Hz), 6.7-6.8 (2H, m), 6.9
2 (1H, t, J = 7.3Hz), 7.00 (1H, s), 7.05 (1H, t, J = 7.9Hz), 7.
1-7.25 (2H, m).

[0079]

Example 5 (S) -2- [2- [2- (3-hydroxyphenyl)
Ethyl] phenoxymethyl] pyrrolidine hydrochloride 2- [2- (3-methoxymethoxyphenyl) ethyl]
1.66 g of phenol was added to N, N-dimethylacetamide 5
Dissolve in 0.5 ml and under ice cooling, potassium t-butoxide 0.72 g
Was added and stirred for 15 minutes. To this, 2.28 g of (S) -1-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine was added, and the mixture was stirred at 50 ° C. for 2 hours. After cooling, ethyl acetate and water were added for liquid separation, the ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 4
(1) to give 1.70 g (yield 60%) of (S) -1-t-butoxycarbonyl-2- [2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxymethyl] pyrrolidine (60% yield) as colorless. Obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.47 (9H, s),
1.75-2.2 (4H, m), 2.8-3.0 (4H, m), 3.25-3.55 (2H, m), 3.4
8 (3H, s), 3.75-4.3 (3H, m), 5.15 (2H, s), 6.8-7.0 (5H, m),
7.05-7.3 (3H, m). The above (S) -1-t-butoxycarbonyl-2- [2-
[2- (3-Methoxymethoxyphenyl) ethyl] phenoxymethyl] pyrrolidine (630 mg) was dissolved in 4N hydrogen chloride-dioxane solution (10 ml) under cooling, and the mixture was mixed at room temperature for 3 times.
It was left to stand for a time and concentrated. The oily residue was dissolved in a small amount of isopropyl alcohol, and upon cooling and standing, crystals were precipitated. This was collected by filtration, dried in vacuo and the title compound (318 mg)
(Yield 66%) was obtained as colorless crystals. Melting point: 127-129 [deg.] C. [Α] _D ²⁵ : + 10.5 ° (c = 1.0, methanol). NMR spectrum (270 MHz, DMSO-d ₆ ) δppm: 1.8-2.0 (1
H, m), 2.05-2.2 (2H, m), 2.2-2.35 (1H, m), 2.7-3.1 (4H,
m), 3.2-3.35 (1H, m), 3.4-3.55 (1H, m), 4.05-4.25 (3H,
m), 6.61 (1H, d, J = 7.91Hz), 6.66 (1H, dd, J = 1.3,7.9Hz),
6.84 (1H, d, J = 7.9Hz,), 6.94 (1H, t, J = 7.3Hz), 7.0-7.25
(4H, m).

[0080]

Example 6 2- [2- [2- (3-hydroxyphenyl) ethyl]
Phenoxymethyl] -1-methylpyrrolidine hydrochloride 1.00 g of 1-t-butoxycarbonyl-2- [2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxymethyl] pyrrolidine prepared in the same manner as in Example 5.
Was treated with 88 mg of lithium aluminum hydride in tetrahydrofuran in the same manner as in Example 3, treated and purified by column chromatography to give 2- [2-
[2- (3-Methoxymethoxyphenyl) ethyl] phenoxymethyl] -1-methylpyrrolidine (668 mg, yield 83%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.7-2.0 (3H,
m), 2.0-2.2 (1H, m), 2.3-2.45 (1H, m), 2.53 (3H, s), 2.7-
3.0 (5H, m), 3.1-3.2 (1H, m), 3.48 (3H, s), 3.85 (1H, dd, J =
6.6,9.2Hz), 4.08 (1H, dd, J = 5.3,9.2Hz), 5.15 (2H, s),
6.8-6.9 (5H, m), 7.1-7.3 (3H, m). 660 mg of the above 2- [2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was dissolved in 5 ml of a 4N hydrogen chloride-dioxane solution, and the mixture was allowed to stand at room temperature for 30 minutes. After that, it was concentrated under reduced pressure.
The solid thus obtained was dissolved by heating in isopropyl alcohol and cooled to precipitate crystals. The crystals were collected by filtration and dried in vacuo to give the title compound (529 mg, yield 82%) as colorless needle crystals. Melting point: 232-233 ° C (decomposition). NMR spectrum (270 MHz, DMSO-d ₆ ) δppm: 1.8-2.2 (3
H, m), 2.2-2.4 (1H, m), 2.7-2.95 (4H, m), 2.97 (3H, s), 3.
05-3.25 (1H, m), 3.5-3.7 (1H, m), 3.8-3.95 (1H, m), 4.28
(1H, dd, J = 4.0,10.6Hz), 4.40 (1H, dd, J = 7.9,10.6Hz), 6.55
-6.7 (3H, m), 6.75-7.1 (3H, m), 7.15-7.3 (2H, m).

[0081]

Example 7 (R) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] morpholine hydrochloride 1.14 g 2- [2- (3-methoxyphenyl) ethyl] phenol, potassium t-butoxide 0.56 g and (R)-
1.86 g of 4-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) morpholine was reacted in 20 ml of N, N-dimethylacetamide in the same manner as in Example 5, extracted, and subjected to silica gel column chromatography (hexane). / Ethyl acetate = 4/1), (R)
-4-t-Butoxycarbonyl-2- [2- [2- (3
1.68 g (yield 79%) of -methoxyphenyl) ethyl] phenoxymethyl] morpholine was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.44 (9H,
s), 2.8-3.1 (6H, m), 3.5-3.7 (1H, m), 3.7-4.2 (6H, m), 3.
77 (3H, s), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m). The above (R) -4-t-butoxycarbonyl-2- [2
1.68 g of-[2- (3-methoxyphenyl) ethyl] phenoxymethyl] morpholine was dissolved in 10 ml of dioxane, and 10 ml of 4N hydrogen chloride-dioxane solution was added,
It was allowed to stand at room temperature for 30 minutes. This was concentrated under reduced pressure, dissolved in a small amount of methylene chloride, ethyl acetate was added, and the mixture was left standing to precipitate crystals. The crystals were collected by filtration and dried in vacuo to give the title compound (1.24 g, yield 86%) as colorless crystals. Melting point: 112-113 ° C. [Α] _D ²⁵ : −7.4 ° (c = 1.0, water). NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.75-2.95
(4H, m), 3.0-3.2 (2H, m), 3.35 (1H, d, J = 13.2Hz), 3.46 (1
H, d, J = 11.2Hz), 3.75 (3H, s), 3.95-4.2 (4H, m), 4.3-4.4
(1H, m), 6.65-6.95 (5H, m), 7.05-7.3 (3H, m).

[0082]

Example 8 (R) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl ] -4-methylmorpholine hydrochloride
Salt obtained in the same manner as in Example 7, (R) -2- [2- [2-
(3-Methoxyphenyl) ethyl] phenoxymethyl]
Morpholine hydrochloride (404 mg) was dissolved in N, N-dimethylacetamide (10 ml), potassium carbonate (152 mg) was added, and the mixture was stirred at room temperature for 1 hr. Methyl iodide 157
mg was added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction solution, which was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was treated with silica gel column chromatography (methylene chloride / methanol = 20/1) to give (R) -2- [2-
[2- (3-Methoxyphenyl) ethyl] phenoxymethyl] -4-methylmorpholine 310 mg (yield 82%)
Was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.0-2.25 (2
H, m), 2.32 (3H, s), 2.65-2.75 (1H, m), 2.8-3.05 (5H, m),
3.7-3.85 (1H, m), 3.78 (3H, s), 3.9-4.1 (4H, m), 6.7-6.95
(5H, m), 7.1-7.3 (3H, m). 310 mg of (R) -2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -4-methylmorpholine was dissolved in ethyl acetate, and 0.25 ml of 4N hydrogen chloride-ethyl acetate solution was added. Crystals were deposited on standing. This is filtered off and dried in vacuo to give the title compound 323
mg (yield 94%) was obtained as colorless needle crystals. Melting point: 184-185 [deg.] C. [Α] _D ²⁵ : −5.5 ° (c = 1.0, ethanol). NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.75 (3H,
s), 2.75-3.05 (6H, m), 3.38 (2H, t, J = 13.2Hz), 3.78 (3H,
s), 4.0-4.2 (3H, m), 4.3-4.45 (1H, m), 4.5-4.6 (1H, m),
6.7-6.9 (4H, m), 6.94 (1H, t, J = 7.3Hz), 7.1-7.3 (3H, m)
.

[0083]

Example 9 2- [2- [2- [2- (3,4-dimethoxypheny
Ru) ethyl] phenoxy] ethyl] -1-methylpyrroli
Zin hydrochloride 2- [2- (3,4-dimethoxyphenyl) ethyl] phenol 1.3 g, potassium t-butoxide 1.69 g and 2
-(2-Chloroethyl) -1-methylpyrrolidine hydrochloride
1.39 g was reacted in 30 ml of N, N-dimethylacetamide in the same manner as in Example 1 (a), extracted, and subjected to silica gel column chromatography (methylene chloride / methanol = 10).
/ (1) and then 2- [2- [2- [2- (3,4-
Dimethoxyphenyl) ethyl] phenoxy] ethyl]-
1.5 g (yield 80%) of 1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-2.4 (8
H, m), 2.41 (3H, s), 2.8-3.0 (4H, m), 3.15-3.25 (1H, m),
3.83 (3H, s), 3.86 (3H, s), 3.9-4.15 (2H, m), 6.6-6.9 (5H,
m), 7.05-7.25 (2H, m). 1.5 g of 2- [2- [2- [2- [2- (3,4-dimethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 20 ml of methylene chloride, and 2 ml of 4N hydrogen chloride-dioxane solution was added. Was added and concentrated. The oily residue was dissolved in ethyl acetate and left to stand to precipitate crystals. This is filtered off and dried in vacuum, 1.1 g of the title compound
(Yield 67%) was obtained as colorless crystals. Melting point: 147-148 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.15 (2
H, m), 2.2-2.4 (2H, m), 2.4-2.6 (2H, m), 2.76 and 2.78
(Total 3H, each s), 2.75-3.0 (5H, m), 3.15-3.35 (1H, m), 3.
80 (3H, s), 3.86 (3H, s), 3.8-4.1 (2H, m), 4.15-4.3 (1H,
m), 6.6-7.0 (5H, m), 7.1-7.3 (2H, m).

[0084]

Example 10 2- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxymethyl] morpholine hydrochloride 1.00 g of 2- [2- (3-methoxyphenyl) ethyl] phenol, 1.63 g of 4-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) morpholine and 0.49 g of potassium t-butoxide. , N, N-dimethylacetamide, reacted in the same manner as in Example 5, extracted and treated with silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-t-butoxycarbonyl-2. -[2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl] morpholine 1.87 g
(Yield 94.5%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ: ppm 1.45 (9H,
s), 2.8-3.1 (6H, m), 3.55-3.7 (1H, m), 3.7-4.2 (6H, m),
3.77 (3H, s), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m). The above 4-t-butoxycarbonyl-2- [2- [2-
(3-Methoxyphenyl) ethyl] phenoxymethyl]
Morpholine (0.99 g) was dissolved in dioxane (2 ml), 4N hydrogen chloride-dioxane solution (2 ml) was added, and the mixture was allowed to stand at room temperature and then concentrated under reduced pressure. When the oily residue was dissolved in ethyl acetate, crystals soon precipitated, so this was collected by filtration to give the title compound (0.42 g, yield 52%) as colorless crystals. Melting point: 110-112 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.8-3.0 (4H,
m), 3.0-3.2 (2H, m), 3.36 (1H, d, J = 12.5Hz), 3.48 (1H, d, J
= 13.2Hz), 3.76 (3H, s), 4.0-4.2 (4H, m), 4.25-4.4 (1H,
m), 6.7-7.0 (5H, m), 7.1-7.3 (3H, m).

[0085]

Example 11 2- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxymethyl] -4-methylmorpholine hydrochloride 870 mg of 4-t-butoxycarbonyl-2- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] morpholine, obtained in the same manner as in Example 10, Using 113 mg of lithium aluminum hydride, a reaction was performed in tetrahydrofuran in the same manner as in Example 3, and silica gel column chromatography (methylene chloride / methanol = 1)
0/1) to give 2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylmorpholine (620 mg, yield 94%) as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.0-2.3 (2H,
m), 2.33 (3H, s), 2.65-2.75 (1H, m), 2.8-3.0 (5H, m), 3.7
-3.85 (1H, m), 3.78 (3H, s), 3.9-4.1 (4H, m), 6.7-6.95 (5
H, m), 7.1-7.3 (3H, m). The above-mentioned 2- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylmorpholine 620.
mg in ethyl acetate, 4N hydrogen chloride-dioxane solution
After adding 0.5 ml and concentrating, a solid was obtained. this,
Recrystallize from ethyl acetate to give 476 mg of the title compound (yield 69
%) As colorless crystals. Melting point: 174-176 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.77 (3H, s),
2.7-3.1 (6H, m), 3.40 (2H, t, J = 11.9Hz), 3.79 (3H, s), 4.
0-4.2 (3H, m), 4.3-4.5 (1H, m), 4.5-4.65 (1H, m), 6.7-6.9
(4H, m), 6.95 (1H, t, J = 7.6Hz), 7.1-7.3 (3H, m).

[0086]

Example 12 2- [2- [2- [2- (3-methoxyphenyl) ethyl ]
L] phenoxy] ethyl] piperidine hydrochloride 1.0 g of 2- [2- (3-methoxyphenyl) ethyl] phenol, 1.51 g of 1-t-butoxycarbonyl-2- (2-hydroxyethyl) piperidine, 1.72 g of triphenylphosphine And azodicarboxylic acid diethyl ester 1.
Using 14 g, the reaction was carried out in 20 ml of methylene chloride in the same manner as in Example 1 (b), extracted, and treated with silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-
t-butoxycarbonyl-2- [2- [2- [2- (3
0.63 g (yield 32%) of -methoxyphenyl) ethyl] phenoxy] ethyl] piperidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.46 (9H, s),
1.4-2.0 (7H, m), 2.15-2.35 (1H, m), 2.65-3.0 (5H, m), 3.
78 (3H, s), 3.9-4.2 (3H, m), 4.35-4.45 (1H, m), 6.7-6.9 (5
H, m), 7.05-7.3 (3H, m). The above 1-t-butoxycarbonyl-2- [2- [2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
After dissolving 0.63 g of ethyl] piperidine in 1 ml of dioxane, 1 ml of 4N hydrogen chloride-dioxane solution was added,
The mixture was allowed to stand at room temperature for 2 hours and a half, and concentrated under reduced pressure. This was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate, the ethyl acetate extract layer was dehydrated and concentrated, and then CM-Sephadex C was added.
Ethanol was developed and adsorbed on a -25 (H ⁺ type: registered trademark) column as a solvent. The column was washed with ethanol and then eluted with 0.1N hydrogen chloride-ethanol solution. The eluate was concentrated under reduced pressure and dried in vacuo to give the title compound (0.22 g, yield 40%) as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.3-2.1 (6H,
m), 2.1-2.3 (1H, m), 2.5-2.7 (1H, m), 2.7-3.0 (5H, m), 3.
15-3.35 (1H, m), 3.4-3.55 (1H, d, J = 13.2Hz), 3.77 (3H, s),
4.0-4.25 (2H, m), 6.7-6.95 (5H, m), 7.05-7.3 (3H, m).
IR spectrum (film, ν _max cm ^-1 ): 1601, 1585,
1495, 1455, 1436, 1241.

[0087]

Example 13 2- [2- [2- [2- (3-methoxyphenyl) ethyl ]
Lu] phenoxy] ethyl] -1-methylpiperidine hydrochloride
Salt 1.7 g of 1-t-butoxycarbonyl-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] piperidine, obtained as in Example 12.
Was reacted with 0.29 g of lithium aluminum hydride in tetrahydrofuran in the same manner as in Example 3 and purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 2- [2- [ 2- [2
0.73 g (yield 53%) of-(3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpiperidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.2-2.0 (7H,
m), 2.05-2.35 (3H, m), 2.34 (3H, s), 2.8-3.0 (5H, m), 3.7
8 (3H, s), 4.04 (2H, t, J = 7.3Hz), 6.7-6.9 (5H, m), 7.1-7.2
5 (3H, m). The above 2- [2- [2- [2- (3-methoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpiperidine
0.73 g was dissolved in ethyl acetate, 1 ml of a 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated. The oily residue was dissolved in ethyl acetate, and upon standing, crystals were precipitated. This was collected by filtration to give the title compound (0.56 g, yield 69%) as colorless crystals. Melting point: 115-117 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.3-2.2 (5H,
m), 2.2-2.45 (2H, m), 2.45-2.7 (2H, m), 2.75 (3H, s), 2.8
-3.2 (5H, m), 3.4-3.55 (1H, m), 3.78 (3H, s), 3.95-4.2 (2
H, m), 6.65-6.8 (3H, m), 6.84 (1H, d, J = 7.9Hz), 6.93 (1H,
t, J = 7.3Hz), 7.1-7.3 (3H, m).

[0088]

Example 14 3- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxymethyl] piperidine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 790 mg, potassium t-butoxide 388 mg and 1-
Using 1280 mg of tert-butoxycarbonyl-3- (p-toluenesulfonyloxymethyl) piperidine, N, N-
The reaction was carried out in the same manner as in Example 5 in 15 ml of dimethylacetamide and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-t-butoxycarbonyl-3- [2- [2- (3 1090 mg (yield 74%) of -methoxyphenyl) ethyl] phenoxymethyl] piperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.8 (3H,
m), 1.43 (9H, m), 1.85-2.15 (2H, m), 2.7-3.0 (6H, m), 3.7
9 (3H, s), 3.85 (2H, d, J = 5.9Hz), 3.9-4.25 (2H, m), 6.7-6.
95 (5H, m), 7.1-7.3 (3H, m). The above 1-t-butoxycarbonyl-3- [2- [2-
(3-Methoxyphenyl) ethyl] phenoxymethyl]
240 mg of piperidine was dissolved in 4 ml of 4N hydrogen chloride-dioxane solution, allowed to stand at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and upon standing, crystals precipitated, which were collected by filtration to give the title compound (183 mg)
(Yield 76%) was obtained as colorless crystals. Melting point: 155-157 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.4-2.2 (4H,
m), 2.45-2.6 (1H, m), 2.7-3.0 (6H, m), 3.4-3.6 (2H, m),
3.76 (3H, s), 3.86 (2H, d, J = 4.6Hz), 6.65-6.85 (4H, m), 6.
89 (1H, t, J = 7.3Hz), 7.1-7.3 (3H, m).

[0089]

Example 15 3- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxymethyl] -1-methylpiperidine hydrochloride 850 mg of 1-t-butoxycarbonyl-3- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] piperidine, obtained in the same manner as in Example 14, was hydrogenated. The reaction was carried out in the same manner as in Example 3 using 113 mg of lithium aluminum bromide, and purified by silica gel column chromatography (methylene chloride / methanol = 10/1).
520 mg (yield 76%) of 3- [2- [2- (3- (methoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was obtained as a solid. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.3 (1H,
m), 1.6-2.3 (6H, m), 2.31 (3H, s), 2.75-3.0 (5H, m), 3.0-
3.1 (1H, m), 3.78 (3H, s), 3.8-3.95 (2H, m), 6.7-6.9 (5H,
m), 7.1-7.3 (3H, m). The above 3- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine 520
mg was dissolved in ethyl acetate, 0.5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated to give hydrochloride as a solid.
This was dissolved in a small amount of methylene chloride, ethyl acetate was added and the mixture was left to stand, and crystals were precipitated. Thus, the crystals were collected by filtration to give the title compound (443 mg, yield 77%) as colorless crystals. Melting point: 191-193 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.44-2.1 (3
H, m), 2.2-3.0 (8H, m), 2.75 (3H, s), 3.4-3.6 (2H, m), 3.7
9 (3H, s), 3.85-4.0 (2H, m), 6.7-6.9 (4H, m), 6.94 (1H, t, J
= 7.6Hz), 7.1-7.3 (3H, m).

[0090]

Example 16 3- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxy] piperidine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 1.50 g, 1-t-butoxycarbonyl-3-hydroxypiperidine 2.64 g, triphenylphosphine 3.44 g and azodicarboxylic acid diethyl ester 2.29 g Used and reacted in the same manner as in Example 1 (b), and after extraction, silica gel column chromatography (hexane / ethyl acetate = 7 /
Treated with 1) to give 1-t-butoxycarbonyl-3-
[2- [2- (3-Methoxyphenyl) ethyl] phenoxy] piperidine (1.68 g, yield 62%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.37 (9H, s),
1.4-2.4 (4H, m), 2.75-2.95 (4H, m), 3.0-3.8 (4H, m), 3.7
9 (3H, s), 4.2-4.4 (1H, m), 6.7-6.95 (5H, m), 7.05-7.25 (3
H, m). The above 1-t-butoxycarbonyl-3- [2- [2-
800 mg of (3-methoxyphenyl) ethyl] phenoxy] piperidine was added to 8 ml of 4N hydrogen chloride-dioxane solution.
Was dissolved in the solution, allowed to stand at room temperature for 2 hours, and then concentrated under reduced pressure.
This was dissolved in ethyl acetate and left standing to precipitate a crystal, which was collected by filtration to give the title compound (300 mg, yield 44%) as a colorless crystal. Melting point: 130-132 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-1.8 (1H,
m), 1.9-2.3 (3H, m), 2.8-3.1 (6H, m), 3.25-3.4 (1H, m),
3.55 (1H, dd, J = 3.3,12.6Hz), 3.77 (3H, s), 4.7-4.85 (1H,
m), 6.7-6.8 (3H, m), 6.85-7.0 (2H, m), 7.1-7.3 (3H, m).

[0091]

Example 17 3- [2- [2- (3-methoxyphenyl) ethyl] phenyl
Enoxy] -1-methylpiperidine hydrochloride 880 mg of 1-t-butoxycarbonyl-3- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] piperidine obtained in the same manner as in Example 16 was hydrogenated. Reaction was carried out in the same manner as in Example 3 using 162 mg of lithium aluminum, and purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 3- [2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
360 mg (yield 51%) of 1-methylpiperidine was obtained as a colorless oil. NMR spectrum (60 MHz, CDCl ₃ ) δppm: 1.1-2.4 (6H,
m), 2.28 (3H, s), 2.5-3.3 (6H, m), 3.77 (3H, s), 4.1-4.7
(1H, m), 6.6-7.4 (8H, m). To the above 3- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -1-methylpiperidine 360 mg,
0.4 ml of 4N hydrogen chloride-dioxane solution in ethyl acetate
Was added and the mixture was concentrated to give an oily substance. This was dissolved in ethyl acetate and left standing at room temperature to precipitate crystals, which were collected by filtration to give the title compound (383 mg, yield 95%) as colorless crystals. Melting point: 158-160 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.4-1.65 (1
H, m), 1.9-2.1 (1H, m), 2.2-2.6 (3H, m), 2.6-2.8 (1H, m),
2.8-3.0 (4H, m), 2.82 (3H, s), 3.4-3.7 (2H, m), 3.78 (3H,
s), 4.9-5.3 (1H, m), 6.7-6.8 (3H, m), 6.94 (1H, t, J = 7.3H
z), 7.0-7.3 (4H, m).

[0092]

Example 18 4- [2- [2- [2- (3-methoxyphenyl) ethyl ]
L ] phenoxy] ethyl] piperazine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 1.20 g, 1-t-butoxycarbonyl-4- [2-
Example 5 using 2 g of (p-toluenesulfonyloxy) ethyl] piperidine as the base in 0.5 ml of potassium t-butoxide in 20 ml of N, N-dimethylacetamide.
The reaction was performed in the same manner as above, and the product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-
t-butoxycarbonyl-4- [2- [2- [2- (3
-Methoxyphenyl) ethyl] phenoxy] ethyl] piperidine (2.00 g, yield 86%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.1-1.3 (2H,
m), 1.45 (9H, s), 1.6-1.85 (5H, m), 2.68 (2H, t, J = 12.5H
z), 2.8-3.0 (4H, m), 3.78 (3H, s), 4.0-4.2 (2H, m), 4.18
(2H, t, J = 5.9Hz), 6.7-6.9 (5H, m), 7.1-7.3 (3H, m). The above 1-t-butoxycarbonyl-4- [2- [2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
2.00 g of ethyl] piperidine was dissolved in 10 ml of a 4N hydrogen chloride-dioxane solution, and the mixture was allowed to stand at room temperature for 4 hours. The solid obtained by removing the solvent under reduced pressure was dissolved in a small amount of methylene chloride, ethyl acetate was added and allowed to stand, and the precipitated crystals were collected by filtration to give 1.59 g of the title compound (yield 93%) as colorless crystals. Got as. Melting point: 119-121 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.05 (7
H, m), 2.7-2.95 (6H, m), 3.47 (2H, d, J = 12.5Hz), 3.79 (3H,
s), 4.00 (2H, t, J = 5.9Hz), 6.7-7.0 (5H, m), 7.1-7.3 (3H,
m).

[0093]

Example 19 4- [2- [2- [2- (3-methoxyphenyl) ethyl ]
Lu] phenoxy] ethyl ] -1-methylpiperidine hydrochloride
Obtained in the same manner as salt in Example 18, 1-t - butoxycarbonyl-4- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] piperidine 2.15g
Was treated with 0.37 g of lithium aluminum hydride in tetrahydrofuran in the same manner as in Example 3 and purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 4- [2- [2- [2-
1.53 g (yield 90%) of (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpiperidine was obtained as an oil. This was added with 1.5 ml of a 4 N hydrogen chloride-dioxane solution in ethyl acetate and concentrated. The obtained oily substance was dissolved in ethyl acetate and allowed to stand to precipitate crystals. This was collected by filtration to give the title compound (1.06 g, yield 61%) as colorless crystals. Melting point: 97-99 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.75-2.2 (7
H, m), 2.56 (2H, t, J = 11.2Hz), 2.70 (3H, s), 2.8-3.0 (4H,
m), 3.47 (2H, d, J = 11.2Hz), 3.79 (3H, s), 4.02 (2H, t, J = 5.
9Hz), 6.7-7.0 (5H, m), 7.1-7.3 (3H, m).

[0094]

Example 20 4- [2- [2- [2- (3-hydroxyphenyl) e]
Cyl] phenoxy] ethyl] piperidine hydrochloride 2- [2- (3-methoxymethoxyphenyl) ethyl]
Phenol 1.58 g, 1-t-butoxycarbonyl-4-
2.34 g of [2- (p-toluenesulfonyloxy) ethyl] piperidine was added to 10 ml of N, N-dimethylacetamide.
Among them, potassium t-butoxide (0.69 g) was used as a base and reacted in the same manner as in Example 5, and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1).
1-t-butoxycarbonyl-4- [2- [2- [2-
(3-Methoxymethoxyphenyl) ethyl] phenoxy] ethyl] piperidine (1.96 g, yield 68%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.1-1.3 (2H,
m), 1.45 (9H, s), 1.65-1.85 (5H, m), 2.68 (2H, t, J = 12.5H
z), 2.8-3.0 (4H, m), 3.48 (3H, s), 4.0-4.2 (2H, m), 4.02
(2H, t, J = 5.9Hz), 5.15 (2H, s), 6.8-6.95 (5H, m), 7.1-7.3
(3H, m). The above 1-t-butoxycarbonyl-4- [2- [2-
890 mg of [2- (3-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] piperidine was added to dioxane 8
It was dissolved in 8 ml of 4N hydrogen chloride-dioxane solution and left standing at room temperature to precipitate crystals. This was collected by filtration, washed with ethyl acetate, and dried in vacuo to give the title compound (651 mg, yield 95%) as colorless needle crystals. Melting point: 156-158 [deg.] C. NMR spectrum (270MHz, DMSO-d ₆ ) δppm: 1.3-1.5 (2
H, m), 1.65-1.95 (5H, m), 2.65-2.9 (6H, m), 3.24 (2H, d, J =
12.5Hz), 4.02 (2H, t, J = 5.9Hz), 6.55-6.7 (3H, m), 6.84 (1
H, t, J = 7.3Hz), 6.95 (1H, d, J = 7.9Hz), 7.06 (1H, t, J = 7.3H
z), 7.1-7.2 (2H, m).

[0095]

Example 21 4- [2- [2- [2- (3-hydroxyphenyl) e]
Cyl] phenoxy] ethyl] -1-methylpiperidine salt
Acid salt 1-t-butoxycarbonyl-4- [2- [2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] piperidine 1.
Using 40 g of lithium aluminum hydride 240 mg,
The reaction was conducted in tetrahydrofuran in the same manner as in Example 3, and the product was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 4- [2- [2-
710 mg of [2- (3-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpiperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.3-1.9 (7H,
m), 1.95-2.1 (2H, m), 2.32 (3H, s), 2.75-3.0 (6H, m), 3.4
8 (3H, s), 4.02 (2H, t, J = 6.3Hz), 5.16 (2H, s), 6.8-6.95 (5
H, m), 7.1-7.3 (3H, m). The above-mentioned 4- [2- [2- [2- (2- (3-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpiperidine (710 mg) was dissolved in dioxane (2.3 ml) to prepare a 4N hydrogen chloride-dioxane solution 2 0.3 ml was added, and the mixture was left standing at room temperature for 1 hour. This was concentrated under reduced pressure, dissolved in a small amount of methylene chloride, ethyl acetate was added, and the mixture was left standing to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (294 mg, yield 42%) as a crystalline powder. Melting point: 130-132 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.2 (7H,
m), 2.6-2.9 (6H, m), 2.74 (3H, s), 3.45 (2H, d, J = 11.9Hz),
3.96 (2H, t, J = 5.0Hz), 6.62 (1H, d, J = 7.3Hz), 6.7-6.85 (2
H, m), 6.91 (1H, t, J = 7.3Hz), 6.95-7.0 (1H, m), 7.08 (1H,
t, J = 7.3Hz), 7.1-7.25 (2H, m), 8.05 (1H, br.s).

[0096]

Example 22 (S) -2- [2- [2- (3-methoxyphenyl) e
Tyl] phenoxymethyl] pyrrolidine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 2.00 g, (S) -1-t-butoxycarbonyl-2-
(P-Toluenesulfonyloxymethyl) pyrrolidine 3.
74 g were reacted in 20 ml of N, N-dimethylacetamide with 0.98 g of potassium t-butoxide in the same manner as in Example 5 and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). hand,
(S) -1-t-butoxycarbonyl-2- [2- [2
1.65 g (yield 45%) of-(3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.47 (9H, s),
1.8-2.2 (4H, m), 2.8-3.0 (4H, m), 3.3-3.5 (2H, m), 3.7-
4.3 (3H, m), 3.78 (3H, s), 6.7-7.0 (5H, m), 7.05-7.3 (3H,
m). The above (S) -1-t-butoxycarbonyl-2- [2
1.65 g of-[2- (3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 2 hours and a half. The reaction solution was concentrated, and the oily residue was treated with silica gel column silica gel column chromatography (methylene chloride / methanol = 20: 1) to obtain (S) -2- [2- [2- (3-methoxyphenyl) ethyl. ] Phenoxymethyl] pyrrolidine 910 mg
(Yield 73%) was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.7-2.05 (4
H, m), 2.8-3.0 (4H, m), 3.05-3.25 (2H, m), 3.65-3.8 (1H,
m), 3.76 (3H, s), 3.95-4.1 (2H, m), 6.7-6.8 (3H, m), 6.85
-6.95 (2H, m), 7.1-7.25 (3H, m). The above (S) -2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine (410 mg) was dissolved in ethyl acetate to prepare a 4N hydrogen chloride-dioxane solution.
0.5 ml was added to form the hydrochloride, and the solvent was removed under reduced pressure to quantitatively obtain the title compound (458 mg) as a colorless oil. [Α] _D ²⁵ : + 6 ° (c = 1.0, ethanol). NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.8-2.2 (4H,
m), 2.8-3.1 (4H, m), 3.29 (2H, t, J = 6.6Hz), 3.75 (3H, s),
3.9-4.0 (1H, m), 4.11 (1H, dd, J = 5.3,9.9Hz), 4.22 (1H, dd,
J = 5.3,9.9Hz), 6.65-6.75 (3H, m), 6.85-6.95 (2H, m), 7.0
5-7.2 (3H, m).

[0097]

Example 23 (S) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] -1-methylpyrrolidine hydrochloride
Salt obtained in the same manner as in Example 22, (S) -2- [2- [2
500 mg of-(3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine was dissolved in 5 ml of N, N-dimethylacetamide, 130 mg of potassium carbonate was added, and the mixture was stirred at room temperature. To this, 288 mg of methyl iodide was added, and the mixture was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction solution, which was successively washed with water and brine, and then the extract layer was dehydrated and concentrated under reduced pressure. The obtained oily substance was treated with silica gel column chromatography (methylene chloride / methanol = 20: 1) to give (S) -2- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1. 320 mg (61% yield) of methylpyrrolidine were obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (3H,
m), 2.0-2.2 (1H, m), 2.34 (1H, q, J = 8.6Hz), 2.52 (3H, s),
2.65-2.8 (1H, m), 2.8-3.0 (4H, m), 3.05-3.2 (1H, m), 3.79
(3H, s), 3.85 (1H, dd, J = 6.6,9.2Hz), 4.07 (1H, dd, J = 5.3,
9.2Hz), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m). 320 mg of the above (S) -2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylpyrrolidine was dissolved in ethyl acetate, and 0.37 ml of 4N hydrogen chloride-dioxane solution was added. Crystals were deposited on standing. This was collected by filtration and 101 mg of the title compound (yield 28
%) As colorless needles. Melting point: 124-126 ° C. [Α] _D ²⁵ : + 3.8 ° (c = 1.0, ethanol). NMR spectrum (270 MHz, DMSO) δppm: 1.75-2.2 (3H,
m), 2.2-2.4 (1H, m), 2.75-3.0 (4H, m), 2.95 (3H, s), 3.0-
3.2 (1H, m), 3.72 (3H, s), 3.5-3.7 (1H, m), 3.75-3.95 (1H,
m), 4.2-4.45 (2H, m), 6.7-6.85 (3H, m), 6.91 (1H, t, J = 7.
3Hz), 7.00 (1H, d, J = 7.9Hz), 7.15-7.3 (3H, m).

[0098]

Example 24 1-Methyl-2- [2- [2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine hydrochloride 900 mg of 2- (2-phenylethyl) phenol, 1.02 g of potassium t-butoxide and 836 mg of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were added to N, N.
-React in 10 ml of dimethylacetamide in the same manner as in Example 1 (a), purify by silica gel column chromatography (methylene chloride / methanol = 10/1), and
480 mg of methyl-2- [2- [2- [2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-2.05 (5
H, m), 2.2-2.4 (2H, m), 2.4-3.0 (1H, m), 2.42 (3H, s), 2.8
-3.0 (4H, m), 3.1-3.25 (1H, m), 3.9-4.2 (2H, m), 6.8-6.95
(2H, m), 7.1-7.35 (7H, m). To 1-methyl-2- [2- [2- (2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine (480 mg) described above was added 4N hydrogen chloride-dioxane solution (0.5 ml) in ethyl acetate.
Was added and the mixture was concentrated to give an oily substance. This was dissolved in ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration to give the title compound (130 mg, yield 24%) as colorless needle crystals. Melting point: 154-156 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.9-2.15 (2
H, m), 2.15-2.4 (2H, m), 2.4-2.6 (2H, m), 2.7-3.0 (5H, m),
2.75 (3H, s), 3.2-3.4 (1H, m), 3.8-4.05 (2H, m), 4.15-4.
3 (1H, m), 6.85 (1H, d, J = 7.9Hz), 6.93 (1H, t, J = 7.6Hz),
7.1-7.35 (7H, m).

[0099]

Example 25 1-Methyl-2- [2- [2- [2- (3-methylphen
Nyl) ethyl] phenoxy] ethyl] pyrrolidine hydrochloride 2- [2- (3-methylphenyl) ethyl] phenol
Using 1.00 g, potassium t-butoxide 1.05 g, and 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride 0.87 g, in the same manner as in Example 1 (a) in 10 ml of N, N-dimethylacetamide. And purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 150 mg of 1-methyl-2- [2- [2- [2- [2- (3-methylphenyl) ethyl] phenoxy] ethyl] pyrrolidine. (Yield 11%) was obtained as an oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.15 (1H, m), 2.2-2.55 (3H, m), 2.33 (3H, s), 2.4
2 (3H, s), 2.8-3.0 (4H, m), 3.15-3.25 (1H, m), 3.95-4.2 (2
H, m), 6.8-6.95 (2H, m), 7.0-7.1 (3H, m), 7.1-7.25 (3H,
m). The above 1-methyl-2- [2- [2- [2- [2- (3-methylphenyl) ethyl] phenoxy] ethyl] pyrrolidine (150 mg) was converted to a hydrochloride using 0.2 ml of 4N hydrogen chloride-dioxane solution, and acetic acid was added. Recrystallization from ethyl gave 87 mg (52% yield) of the title compound as a colorless crystalline solid. Melting point: 128-130 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2
H, m), 2.15-2.4 (2H, m), 2.33 (3H, s), 2.4-2.65 (2H, m),
2.7-3.0 (5H, m), 2.75 (3H, s), 3.2-3.4 (1H, m), 3.8-4.1 (2
H, m), 4.2-4.3 (1H, m), 6.8-7.1 (5H, m), 7.1-7.3 (3H,
m).

[0100]

Example 26 2- [2- [2- (2-phenylethyl) phenoxy]
Ethyl] piperidine hydrochloride 2- (2-phenylethyl) phenol 0.93 g, potassium t - butoxycarbonyl-2-[2- (p-toluenesulfonyloxy) ethyl] piperidine 1.66 g, - butoxide 0.53g and 1-t The reaction was carried out in the same manner as in Example 5 in 20 ml of N, N-dimethylacetamide, followed by silica gel column chromatography (hexane / ethyl acetate = 4).
/ 1) and 1-t-butoxycarbonyl-2-
1.32 g (yield 75%) of [2- [2- (2-phenylethyl) phenoxy] ethyl] piperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.3-1.8 (6H,
m), 1.38 (9H, s), 1.8-2.0 (1H, m), 2.15-2.35 (1H, m), 2.7
-3.0 (5H, m), 3.9-4.15 (3H, m), 4.4-4.6 (1H, m), 6.75-6.9
(2H, m), 7.05-7.35 (7H, m). The above 1-tert-butoxycarbonyl-2- [2- [2
440 mg of-(2-phenylethyl) phenoxy] ethyl] pyrrolidine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 2 hours and then concentrated under reduced pressure. The solid thus obtained was dissolved in a small amount of methylene chloride, ethyl acetate was added, and the mixture was left standing to precipitate crystals. This was collected by filtration to give the title compound (214 mg, yield 53%) as colorless crystals. Melting point: 95-97 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.3-1.5 (1H,
m), 1.7-2.1 (5H, m), 2.15-2.3 (1H, m), 2.5-2.7 (1H, m),
2.7-3.0 (5H, m), 3.2-3.35 (1H, m), 3.45 (1H, d, J = 12.5Hz),
4.0-4.2 (2H, m), 6.8-6.9 (2H, m), 7.05-7.35 (7H, m).

[0101]

Example 27 1-Methyl-2- [2- [2- (2-phenylethyl)
Phenoxy] ethyl] piperidine hydrochloride 1.34 g of 1-t-butoxycarbonyl-2- [2- [2- (2-phenylethyl) phenoxy] ethyl] piperidine obtained in the same manner as in Example 26 was added to lithium hydride. After reacting with 0.27 g of aluminum in tetrahydrofuran in the same manner as in Example 3, the product was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 1-methyl-2- [2- [2 1.10 g (96% yield) of-(2-phenylethyl) phenoxy] ethyl] piperidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2-2.4 (10H,
m), 2.35 (3H, s), 2.8-3.0 (5H, m), 4.0-4.1 (2H, m), 6.8-
6.95 (2H, m), 7.1-7.35 (7H, m). The above-mentioned 1-methyl-2- [2- [2- (2-phenylethyl) phenoxy] ethyl] piperidine (670 mg) was dissolved in ethyl acetate to prepare a 4N hydrogen chloride-dioxane solution (0.6).
The mixture was added with ml to give a hydrochloride and concentrated under reduced pressure. The solid thus obtained was recrystallized from ethyl acetate to give 350 mg of the title compound.
(Yield 47%) was obtained as colorless crystals. Melting point: 128-130 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.2-2.4 (8H,
m), 2.4-2.65 (1H, m), 2.74 (3H, s), 2.8-3.2 (5H, m), 3.2-
3.6 (1H, m), 3.95-4.2 (2H, m), 6.84 (1H, d, J = 7.9Hz), 6.92
(1H, t, J = 7.3Hz), 7.1-7.35 (7H, m).

[0102]

Example 28 2- [2- [2- [2- (2-methoxyphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
1.00 g of salt 2- [2- (2-methoxyphenyl) ethyl] phenol, 1.47 g of potassium t-butoxide and 2- (2
-Chloroethyl) -1-methylpyrrolidine hydrochloride 1.61 g
Example 1 in N, N-dimethylacetamide using
The reaction was performed in the same manner as in (a), and the product was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 2- [2- [2- [2- [2- (2-methoxyphenyl) ethyl] phenoxy] ethyl. ] 300 mg (yield 20%) of 1-methylpyrrolidine was obtained as an oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.5-1.95 (4
H, m), 2.0-2.15 (1H, m), 2.2-2.55 (3H, m), 2.38 (3H, s),
2.89 (4H, s), 3.1-3.2 (1H, m), 3.82 (3H, s), 3.9-4.15 (2H,
m), 6.8-6.9 (4H, m), 7.1-7.25 (4H, m). 300 mg of the above 2- [2- [2- [2- [2- (2-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in ethyl acetate to prepare 4N hydrogen chloride-
A solid was obtained by adding 0.3 ml of dioxane solution and concentrating as a hydrochloride. This was recrystallized using ethyl acetate,
The title compound (186 mg, yield 56%) was obtained as colorless needle crystals. Melting point: 143-145 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.7-2.65 (6H,
m), 2.65-2.95 (5H, m), 2.74 (3H, s), 3.25-3.4 (1H, m), 3.
75-3.9 (1H, m), 3.80 (3H, s), 3.9-4.05 (1H, m), 4.15-4.3
(1H, m), 6.8-7.0 (4H, m), 7.05-7.3 (4H, m).

[0103]

Example 29 1-Methyl-2- [2- [2- [2- (2-methylphene
Nyl) ethyl] phenoxy] ethyl] pyrrolidine hydrochloride 2- [2- (2-methylphenyl) ethyl] phenol
1.00 g, potassium t-butoxide 1.59 g and 2- (2-
Example 1 (a) in N, N-dimethylacetamide using 1.73 g of chloroethyl) -1-methylpyrrolidine hydrochloride.
1-methyl-2- [2- [2- [2- [2- (2-methylphenyl) ethyl] phenoxy by reacting in the same manner as above, purified by silica gel column chromatography (methylene chloride / methanol = 10/1). ] Ethyl] pyrrolidine 3
Obtained 50 mg (23% yield) as a solid. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.5-1.9 (4H,
m), 1.95-2.5 (4H, m), 2.34 (3H, s), 2.37 (3H, s), 2.86 (4
H, s), 3.1-3.2 (1H, m), 3.9-4.2 (2H, m), 6.8-6.95 (2H, m),
7.1-7.25 (6H, m). 350 mg of the above 1-methyl-2- [2- [2- [2- [2- (2-methylphenyl) ethyl] phenoxy] ethyl] pyrrolidine was dissolved in ethyl acetate, and 0.3 ml of 4N hydrogen chloride-dioxane solution was added. Concentration as the hydrochloride gave an oil. This was dissolved in ethyl acetate, and crystals were deposited when left standing. Therefore, the crystals were collected by filtration to give the title compound (212 mg, yield 5
4%) as colorless crystals. Melting point: 163-165 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.85-2.6 (6
H, m), 2.29 (3H, s), 2.6-2.95 (5H, m), 2.73 (3H, s), 3.2-
3.4 (1H, m), 3.8-4.1 (2H, m), 4.2-4.3 (1H, m), 6.86 (1H, d,
J = 7.9Hz), 6.93 (1H, t, J = 7.6Hz), 7.1-7.3 (6H, m).

[0104]

Example 30 (4R) -4-hydroxy-2- [2- (2-phenyl)
Ethyl) phenoxymethyl] pyrrolidine hydrochloride 2- (2-phenylethyl) phenol 200 mg, potassium t-butoxide 124 mg and (4R) -4-benzyloxy-1-t-butoxycarbonyl-2- (p-
Toluenesulfonyloxymethyl) pyrrolidine 500mg
In 10 ml of N, N-dimethylacetamide,
The reaction was carried out in the same manner as in Example 5, purified by silica gel column chromatography (hexane / ethyl acetate = 4/1), and then (4R) -4-benzyloxy-1-t-butoxycarbonyl-2- [2- ( 400 mg (yield 81%) of 2-phenylethyl) phenoxymethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.45 (9H, s),
2.15-2.35 (2H, m), 2.75-3.0 (4H, m), 3.4-4.6 (8H, m), 6.
8-6.95 (2H, m), 7.05-7.4 (12H, m). 390 mg of the above (4R) -4-benzyloxy-1-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine was added to 25 ml of ethanol.
And was stirred at 60 ° C. for 5 hours under normal hydrogen pressure using 5% palladium carbon as a catalyst. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and this was treated with silica gel column chromatography (hexane / ethyl acetate = 1/1),
(4R) -1-t-butoxycarbonyl-4-hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine (310 mg, yield 97%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.46 (9H, s),
2.0-2.4 (2H, m), 2.8-3.0 (4H, m), 3.4-3.7 (2H, m), 4.0-
4.6 (4H, m), 6.87 (2H, t, J = 7.3Hz), 7.05-7.35 (7H, m). 200 mg of the above (4R) -1-t-butoxycarbonyl-4-hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine was dissolved in 3 ml of dioxane, and 3 ml of 4N hydrogen chloride-dioxane solution was added. After standing at room temperature for 2 hours, the mixture was concentrated under reduced pressure. This was dissolved in a small amount of methylene chloride, ethyl acetate was added, and the mixture was allowed to stand to precipitate crystals. This was collected by filtration to give the title compound (133 mg, yield 79%) as colorless crystals. Melting point: 143-145 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.8-2.0 (1H,
m), 2.13 (1H, dd, J = 7.3,13.9Hz), 2.85-3.0 (4H, m), 3.21
(1H, dd, J = 3.3,11.9Hz), 3.51 (1H, d, J = 11.9Hz), 4.01 (1
H, dd, J = 5.3,10.6Hz), 4.10 (1H, dd, J = 4.0,10.6Hz), 4.2-
4.35 (1H, m), 4.4-4.5 (1H, m), 6.75-6.95 (2H, m), 7.0-7.3
(7H, m).

[0105]

Example 31 (4R) -4-Hydroxy-1-methyl-2- [2-
(2-Phenylethyl) phenoxymethyl] pyrrolidine
Hydrochloride (300 mg) of (4R) -1-t-butoxycarbonyl-4-hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine obtained in the same manner as in Example 30.
And 86 mg of lithium aluminum hydride were reacted in tetrahydrofuran in the same manner as in Example 3, and then purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (4R) -4-hydroxy-1. 150 mg (63% yield) of -methyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.1 (2
H, m), 2.38 (1H, dd, J = 5.3,9.9Hz), 2.51 (3H, s), 2.8-3.0
(4H, m), 3.0-3.15 (1H, m), 3.42 (1H, dd, J = 5.9,10.6Hz),
3.85 (1H, dd, J = 5.9,9.2Hz), 4.02 (1H, dd, J = 5.3,9.2Hz),
4.35-4.5 (1H, m), 6.8-6.95 (2H, m), 7.05-7.35 (7H, m). The above (4R) -4-hydroxy-1-methyl-2-
[2- (2-Phenylethyl) phenoxymethyl] pyrrolidine (150 mg) was dissolved in dioxane, and a 4N hydrogen chloride-dioxane solution was added to give a hydrochloride, which was concentrated under reduced pressure. This was recrystallized from ethyl acetate to give the title compound (92 mg, yield 55%) as colorless crystals. Melting point: 97-99 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.1-2.4 (2H,
m), 2.7-3.3 (5H, m), 2.89 (3H, s), 3.8-4.3 (3H, m), 4.5-
4.8 (2H, m), 6.8-7.0 (2H, m), 7.05-7.35 (7H, m).

[0106]

Example 32 (4R) -4-hydroxy-2- [2- [2- (3-me
Tylphenyl) ethyl] phenoxymethyl] pyrrolidine
Hydrochloride 2- [2- (3-methylphenyl) ethyl] phenol 400 mg, potassium t-butoxide 232 mg and (4
R) -4-Benzyloxy-1-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine (870 mg) was reacted in N, N-dimethylacetamide in the same manner as in Example 5 and subjected to silica gel column chromatography. After purification with (hexane / ethyl acetate = 4/1), 4 (R) -4-benzyloxy-1-t-butoxycarbonyl-2- [2- [2- (3-methylphenyl)
560 mg (59% yield) of ethyl] phenoxymethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.45 (9H, s),
2.15-2.4 (2H, m), 2.31 (3H, s), 2.75-3.0 (4H, m), 3.4-4.
6 (8H, m), 6.8-7.55 (13H, m). 550 mg of the above (4R) -4-benzyloxy-1-t-butoxycarbonyl-2- [2- [2- (3-methylphenyl) ethyl] phenoxymethyl] pyrrolidine
Was reacted in the same manner as in Example 30 with 5% palladium carbon as a catalyst in ethanol under normal pressure hydrogen pressure, and subjected to silica gel column chromatography (hexane /
Purified with ethyl acetate = 1/1), (4R) -1-t-
Butoxycarbonyl-4-hydroxy-2- [2- [2
-(3-Methylphenyl) ethyl] phenoxymethyl]
370 mg (82% yield) of pyrrolidine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.46 (9H, s),
2.0-2.4 (2H, m), 2.34 (3H, s), 2.75-3.0 (4H, m), 3.4-4.6
(6H, m), 6.8-7.3 (8H, m). The above (4R) -1-t-butoxycarbonyl-4-hydroxy-2- [2- [2- (3-methylphenyl) ethyl] phenoxymethyl] pyrrolidine (348 mg) was dissolved in dioxane (3 ml) to prepare 4N hydrogen chloride- Dioxane solution 3
ml was added and the mixture was allowed to stand at room temperature for 3 hours. The solid obtained by removing the solvent under reduced pressure was dissolved in methylene chloride, ethyl acetate was added, and the mixture was left standing to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (208 mg, yield 70%) as a colorless crystalline solid. Melting point: 141-143 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.85-2.05 (1
H, m), 2.15 (1H, dd, J = 6.6,13.2Hz), 2.27 (3H, s), 2.7-2.9
5 (4H, m), 3.18 (1H, dd, J = 4.0,12.5Hz), 3.49 (1H, d, J = 12.5
Hz), 4.01 (1H, dd, J = 4.6,10.6Hz), 4.12 (1H, dd, J = 4.6,10.
6Hz), 4.2-4.35 (1H, m), 4.4-4.5 (1H, m), 6.75-7.2 (8H,
m).

[0107]

Example 33 2- [2- [2- [2- (3,5-dimethoxyphenyl
Ru) ethyl] phenoxy] ethyl] -1-methylpyrroli
Zine hydrochloride 2- [2- (3,5-dimethoxyphenyl) ethyl] phenol 1.00 g, potassium t-butoxide 1.3 g and 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride 1.06 g were added to N, N. Reaction in the same manner as in Example 1 (a) in 10 ml of dimethylacetamide and silica gel column chromatography (methylene chloride / methanol = 10 /
1-) to give 2- [2- [2- [2- (2- (3,5-dimethoxyphenyl) ethyl] phenoxy] ethyl] -1.
1.15 g (80% yield) of -methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.5-2.5 (8H,
m), 2.39 (3H, s), 2.75-3.0 (4H, m), 3.1-3.2 (1H, m), 3.76
(6H, s), 3.95-4.15 (2H, m), 6.3-6.4 (3H, m), 6.8-6.95 (2
H, m), 7.1-7.25 (2H, m). 1.15 g of the above 2- [2- [2- [2- (2- (3,5-dimethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 4N hydrogen chloride-dioxane solution.
The crystals were recrystallized from ethyl acetate using 9 ml as a hydrochloride to obtain 0.66 g (yield 52%) of the title compound as a colorless crystalline solid. Melting point: 99-101 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.9-2.6 (6H,
m), 2.7-3.0 (5H, m), 2.78 (3H, s), 3.35-3.45 (1H, m), 3.7
6 (6H, s), 3.8-4.05 (2H, m), 4.15-4.3 (1H, m), 6.25-6.35
(3H, m), 6.8-7.0 (2H, m), 7.15-7.25 (2H, m).

[0108]

Example 34 2- [2- [2- [2- (4-ethylphenyl) ethyl ]
Lu] phenoxy] ethyl] piperidine hydrochloride 2- [2- (4-ethylphenyl) ethyl] phenol
1.00 g, potassium t-butoxide 0.496 g and 1-t-
1.70 g of butoxycarbonyl-2- [2- (p-toluenesulfonyloxy) ethyl] piperidine was reacted with 20 ml of N, N-dimethylacetamide in the same manner as in Example 5 and subjected to silica gel column chromatography (hexane / Ethyl acetate = 4/1) and treated with 1-t-butoxycarbonyl-2- [2- [2- [2- (4-ethylphenyl) ethyl] phenoxy] ethyl] piperidine 1.
92 g (yield 99%) was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.23 (3H, t, J
= 7.3Hz), 1.3-1.8 (6H, m), 1.38 (9H, s), 1.8-2.0 (1H, m),
2.15-2.35 (1H, m), 2.63 (2H, q, J = 7.3Hz), 2.75-3.0 (5H,
m), 3.9-4.15 (3H, m), 4.4-4.6 (1H, m), 6.75-6.9 (2H, m),
7.1-7.25 (6H, m). The above 1-t-butoxycarbonyl-2- [2- [2-
[2- (4-Ethylphenyl) ethyl] phenoxy] ethyl] piperidine (0.910 g) was dissolved in dioxane (5 ml), 4N hydrogen chloride-dioxane solution (5 ml) was added, and the mixture was allowed to stand at room temperature for 1 hr. After concentration under reduced pressure, the obtained oily substance was dissolved in a small amount of ethyl acetate, ether was added, and the mixture was left standing to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (687 mg, yield 88%) as a colorless crystalline solid. Melting point: 74-76 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.21 (3H, t, J
= 7.6Hz), 1.3-1.5 (1H, m), 1.7-2.1 (6H, m), 2.15-2.3 (1H,
m), 2.61 (2H, q, J = 7.6Hz), 2.6-3.0 (5H, m), 3.2-3.35 (1H,
m), 3.4-3.55 (1H, m), 4.0-4.2 (2H, m), 6.8-6.95 (2H, m),
7.05-7.2 (6H, m).

[0109]

Example 35 2- [2- [2- [2- (4-ethylphenyl) ethyl ]
Lu] phenoxy] ethyl] -1-methylpiperidine hydrochloride
Salt 1-t-butoxycarbonyl-2- [2- [2- [2- (4-ethylphenyl), obtained in the same manner as in Example 34.
Ethyl] phenoxy] ethyl] piperidine (1.0 g) was added to lithium aluminum hydride 0.17 in tetrahydrofuran.
g in the same manner as in Example 3 and silica gel column chromatography (methylene chloride / methanol =
Purified by 10/1), 2- [2- [2- [2- (4-
Ethylphenyl) ethyl] phenoxy] ethyl] -1-
0.65 g (yield 81%) of methylpiperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.23 (3H, t, J
= 7.6Hz), 1.2-2.35 (10H, m), 2.36 (3H, s), 2.63 (2H, q, J =
7.6Hz), 2.8-3.0 (5H, m), 4.0-4.15 (2H, m), 6.8-7.0 (2H,
m), 7.1-7.25 (6H, m). The above 2- [2- [2- [2- (4-ethylphenyl)
Ethyl] phenoxy] ethyl] -1-methylpiperidine
0.65 g of 4N hydrogen chloride-dioxane solution (0.6 ml) was added to ethyl acetate in ethyl acetate to give a hydrochloride, which was concentrated under reduced pressure. The obtained oily substance was dissolved in ethyl acetate, a small amount of ether was added, and the mixture was left standing to precipitate crystals. This was collected by filtration and dried in vacuum to give the title compound 0.59 g (yield 82%).
Was obtained as a colorless crystalline solid. Melting point: 101-103 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.23 (3H, t, J
= 7.6Hz), 1.25-1.55 (1H, m), 1.6-2.7 (8H, m), 2.63 (2H, q,
J = 7.6Hz), 2.74 (3H, s), 2.8-3.2 (5H, m), 3.3-3.55 (1H,
m), 3.95-4.2 (2H, m), 6.8-7.0 (2H, m), 7.05-7.25 (6H, m)
.

[0110]

Example 36 (S) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl ] morpholine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 1.14 g, potassium t-butoxide 0.56 g and (S)-
1.86 g of 4-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) morpholine was reacted in 25 ml of N, N-dimethylacetamide in the same manner as in Example 5, extracted, and subjected to silica gel column chromatography (hexane). / Ethyl acetate = 5/1), (S)
-4-t-Butoxycarbonyl-2- [2- [2- (3
1.97 g (yield 92%) of -methoxyphenyl) ethyl] phenoxymethyl] morpholine was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.44 (9H,
s), 2.8-3.1 (6H, m), 3.5-3.7 (1H, m), 3.7-4.2 (6H, m), 3.
77 (3H, s), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m). The above (S) -4-t-butoxycarbonyl-2- [2
420 mg of-[2- (3-methoxyphenyl) ethyl] phenoxymethyl] morpholine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 1 hour. The oily substance obtained by concentrating the reaction solution under reduced pressure was dissolved in 20 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (279 mg, yield 78%) as colorless needle crystals. Melting point: 105-106 ° C. [Α] _D ²⁰ : + 7.3 ° (C = 1.0, water). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.75-2.95
(4H, m), 3.0-3.2 (2H, m), 3.35 (1H, d, J = 12.5Hz), 3.46 (1
H, d, J = 12.5Hz), 3.76 (3H, s), 3.95-4.2 (4H, m), 4.3-4.4
(1H, m), 6.65-6.95 (5H, m), 7.05-7.3 (3H, m).

[0111]

Example 37 (S) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] -4-methylmorpholine hydrochloride
Salt (S) -4-t-butoxycarbonyl-2- [2- [2- (3-methoxyphenyl) obtained in the previous stage of Example 36.
1.5 g of ethyl] phenoxymethyl] morpholine was treated with 167 mg of lithium aluminum hydride in 20 ml of tetrahydrofuran in the same manner as in Example 3 and treated,
After extraction, purification by silica gel column chromatography (methylene chloride / methanol = 20/1),
(S) -2- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] -4-methylmorpholine 1.04
g (yield 87%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.0-2.25 (2
H, m), 2.31 (3H, s), 2.65-2.75 (1H, m), 2.8-3.0 (5H, m),
3.7-3.85 (1H, m), 3.77 (3H, s), 3.9-4.1 (4H, m), 6.7-6.95
(5H, m), 7.1-7.3 (3H, m). 1.04 g of the above (S) -2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -4-methylmorpholine was dissolved in 20 ml of ethyl acetate, and 1 ml of 4N hydrogen chloride-dioxane solution was added. When left to stand at room temperature, crystals were precipitated. This is filtered off, dried and the title compound 1.05 g
(Yield 91%) was obtained as colorless crystals. Melting point: 186-187 [deg.] C. [Α] _D ²⁰ : + 5.7 ° (C = 1.0, ethanol). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.77 (3H,
s), 2.7-3.1 (6H, m), 3.41 (2H, t, J = 10.2Hz), 3.78 (3H, s),
4.0-4.2 (3H, m), 4.3-4.45 (1H, m), 4.5-4.6 (1H, m), 6.7-
6.9 (4H, m), 6.94 (1H, t, J = 7.4Hz), 7.1-7.3 (3H, m).

[0112]

Example 38 1-Methyl-2- [2- [2- [2- (3,4,5-to
Limethoxyphenyl) ethyl] phenoxy] ethyl] pi
Roridin hydrochloride 2- [2- (3,4,5-trimethoxyphenyl) ethyl] phenol 1.0 g, potassium t-butoxide 1.18
and 0.96 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were added to N, N-dimethylacetamide 10
After reacting and treating in the same manner as in Example 1 (a) in ml, the residue was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 1-methyl-2- [2.
-[2- [2- (3,4,5-trimethoxyphenyl)
Ethyl] phenoxy] ethyl] pyrrolidine (0.90 g, yield 65%) was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.6-2.6 (8
H, m), 2.46 (3H, s), 2.75-3.0 (4H, m), 3.25-3.35 (1H, m),
3.81 (6H, s), 3.82 (3H, s), 3.9-4.2 (2H, m), 6.35 (2H, s),
6.8-6.95 (2H, m), 7.05-7.25 (2H, m). The above 1-methyl-2- [2- [2- [2- (3,4,
0.90 g of 5-trimethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was added to 0.84 ml of a 4N hydrogen chloride-dioxane solution in dioxane to give a hydrochloride. The solid obtained by removing the solvent under reduced pressure was dissolved in a small amount of methylene chloride, ethyl acetate was added, and the mixture was left standing at room temperature. The crystals formed were collected by filtration and dried in vacuo to give the title compound (755 mg, yield 7).
7%) as colorless crystals. Melting point: 130-131 ° C. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.9-2.1 (2
H, m), 2.1-2.35 (2H, m), 2.35-2.55 (2H, m), 2.70 (3H, s),
2.75-2.95 (5H, m), 3.0-3.1 (1H, m), 3.7-4.0 (2H, m), 3.77
(6H, s), 3.81 (3H, s), 4.1-4.2 (1H, m), 6.27 (2H, s), 6.83
(1H, d, J = 8.6Hz), 6.94 (1H, t, J = 7.9Hz), 7.1-7.25 (2H,
m).

[0113]

Example 39 (R) -2- [2- (2-phenylethyl) phenoxy
Methyl] pyrrolidine hydrochloride 2- (2-phenylethyl) phenol 1.00 g, 1-t
-Butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine (2.89 g) and potassium t-butoxide (0.91 g) were used to prepare N, N-dimethylacetamide 1
After reacting in 0 ml in the same manner as in Example 5 and treating, the product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give (R) -1-t-butoxycarbonyl-2- [. 2- (2-Phenylethyl) phenoxymethyl] pyrrolidine as a colorless oil 1.77
g (yield 92%) was obtained. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.47 (9H,
s), 1.8-2.2 (4H, m), 2.8-3.0 (4H, m), 3.3-3.5 (2H, m), 3.
8-4.3 (3H, m), 6.8-7.0 (2H, m), 7.05-7.35 (7H, m). The above (R) -1-t-butoxycarbonyl-2- [2
630 mg of-(2-phenylethyl) phenoxymethyl] pyrrolidine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and the obtained oily substance was solidified when cooled. This was crushed in pentane and collected by filtration to give the title compound as a colorless solid (360 mg, yield 68%). Softening point: 73-88 ° C. [Α] _D ²⁵ : −7.5 ° (C = 3.76, ethanol). NMR spectrum (270MHz, DMSO-d ₆ ) δ ppm: 1.75-2.1
(3H, m), 2.1-2.25 (1H, m), 2.8-3.0 (4H, m), 3.15-3.3 (2H,
m), 3.9-4.05 (1H, m), 4.1-4.3 (2H, m), 6.89 (1H, t, J = 6.9H
z), 6.97 (1H, d, J = 7.3Hz), 7.1-7.35 (7H, m).

[0114]

Example 40 (R) -1-methyl-2- [2- (2-phenylethyl)
(L) Phenoxymethyl] pyrrolidine hydrochloride 1.14 g of (R) -1-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine obtained in the previous stage of Example 39 was added to tetrahydrofuran 10
After reacting with 0.23 g of lithium aluminum hydride in ml in accordance with Example 3, treating and extracting, the product was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to obtain (R). -1-methyl-2-
[2- (2-Phenylethyl) phenoxymethyl] pyrrolidine (0.67 g, yield 76%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.6-1.95 (3
H, m), 2.0-2.2 (1H, m), 2.25-2.4 (1H, m), 2.52 (3H, s), 2.
65-2.8 (1H, m), 2.8-3.0 (4H, m), 3.05-3.2 (1H, m), 3.84 (1
H, dd, J = 6.6,9.2Hz), 4.06 (1H, dd, J = 5.3,9.2Hz), 6.8-6.9
(2H, m), 7.1-7.35 (7H, m). 670 mg of the above-mentioned (R) -1-methyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine was dissolved in a small amount of dioxane, and 0.63 ml of 4N hydrogen chloride-dioxane solution was added to give a hydrochloride salt. The solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of methanol, ethyl acetate was added, and the mixture was allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (596 mg, yield 85%) as colorless crystals. Melting point: 211-212 ° C. [Α] _D ²⁵ : −5.6 ° (C = 3.42, methanol). NMR spectrum (270MHz, DMSO-d ₆ ) δ ppm: 1.8-2.2
(3H, m), 2.2-2.4 (1H, m), 2.8-3.0 (4H, m), 2.94 (3H, s),
3.0-3.3 (1H, m), 3.5-3.7 (1H, m), 3.75-3.95 (1H, m), 4.2-
4.45 (2H, m), 6.91 (1H, t, J = 6.9Hz), 6.99 (1H, d, J = 7.9H
z), 7.15-7.35 (7H, m).

[0115]

Example 41 (R) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] pyrrolidine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 1.00 g, potassium t-butoxide 0.74 g and (R)-
Using 2.33 g of 1-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine, N,
After reacting and treating in the same manner as in Example 5 in 10 ml of N-dimethylacetamide, silica gel column chromatography (hexane / hexane / ethyl acetate = 4/1).
Purified by (R) -1-t-butoxycarbonyl-2
1.54 g of-[2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine as a colorless oil.
(Yield 85%) was obtained. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.47 (9H,
s), 1.8-2.2 (4H, m), 2.8-3.0 (4H, m), 3.3-3.5 (2H, m), 3.
7-4.3 (3H, m), 3.78 (3H, s), 6.7-7.0 (5H, m), 7.05-7.3 (3
H, m). The above (R) -1-t-butoxycarbonyl-2- [2
540 mg of-[2- (3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dried under vacuum to quantitatively obtain 456 mg of the title compound as a colorless oily substance. [Α] _D ²⁵ : −5.5 ° (C = 2.04, ethanol). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.75-2.2 (4
H, m), 2.8-3.1 (4H, m), 3.30 (2H, t, J = 6.6Hz), 3.75 (3H,
s), 3.85-4.0 (1H, m), 4.11 (1H, dd, J = 4.6,9.9Hz), 4.23 (1
H, dd, J = 5.3,9.9Hz), 6.65-6.75 (3H, m), 6.85-6.95 (2H,
m), 7.05-7.3 (3H, m).

[0116]

Example 42 (R) -2- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] -1-methylpyrrolidine hydrochloride
Salt (R) -1-t-butoxycarbonyl-2- [2- [2- (3-methoxyphenyl), obtained in the previous stage of Example 41.
Ethyl] phenoxymethyl] pyrrolidine 1.0 g in tetrahydrofuran 10 ml lithium aluminum hydride
Using 0.18 g, the reaction was carried out in the same manner as in Example 3, treated, and then purified by silica gel column chromatography (methylene chloride / methanol = 20/1) to give (R) -2-
[2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl] -1-methylpyrrolidine 0.75 g (yield 95
%) As a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.6-1.95 (3
H, m), 2.0-2.2 (1H, m), 2.25-2.4 (1H, m), 2.52 (3H, s), 2.
65-2.8 (1H, m), 2.8-3.0 (4H, m), 3.05-3.2 (1H, m), 3.79
(3H, s), 3.84 (1H, dd, J = 6.6,9.2Hz), 4.06 (1H, dd, J = 5.9,
9.2Hz), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m). 750 mg of the above (R) -2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylpyrrolidine was added to 0.7 g of 4N hydrogen chloride-dioxane solution in ginoxane to give the hydrochloride salt. The solvent was distilled off under reduced pressure to obtain an oily product. This was dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. The crystals were collected by filtration and dried in vacuum to give 686 mg of the title compound (yield 82
%) As a colorless powder. Melting point: 124-125 ° C. [Α] _D ²⁵ : −4.2 ° (C = 3.45, ethanol). NMR spectrum (270MHz, DMSO-d ₆ ) δ ppm: 1.75-2.2
(3H, m), 2.2-2.4 (1H, m), 2.75-3.0 (4H, m), 2.94 (3H, s),
3.0-3.2 (1H, m), 3.5-3.7 (1H, m), 3.72 (3H, s), 3.75-3.95
(1H, m), 4.2-4.45 (2H, m), 6.7-6.85 (3H, m), 6.92 (1H, t,
J = 7.3Hz), 7.00 (1H, d, J = 7.9Hz), 7.15-7.3 (3H, m).

[0117]

Example 43 2- [2- [2- [2- (3-chlorophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt 2- [2- (3-chlorophenyl) ethyl] phenol
1.00 g was dissolved in 20 ml of N, N-dimethylacetamide, cooled with ice-salt and stirred. To this, 1.06 g of potassium t-butoxide was added, and to the resulting solution was added 2-
(2-Chloroethyl) -1-methylpyrrolidine hydrochloride 0.
95 g was added and dissolved. The solution thus obtained was heated to 50 ° C. and stirred for 3 hours. The reaction mixture is cooled and ethyl acetate 1
00 ml and 50 ml of water were added and mixed by shaking to separate the organic solvent layer. The extract thus obtained was washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. This is methylene chloride-methanol (2
Silica gel column chromatography purification using 0: 1) to give 2- [2- [2- [2-
(3-Chlorophenyl) ethyl] phenoxy] ethyl]
0.77 g of -1-methylpyrrolidine was obtained. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.55-1.95 (4H,
m), 1.95-2.15 (1H, m), 2.2-2.5 (3H, m), 2.42 (3H, s), 2.7
5-3.0 (4H, m), 3.1-3.25 (1H, m), 3.9-4.15 (2H, m), 6.8-
6.95 (2H, m), 7.0-7.3 (6H, m). The above 2- [2- [2- [2- (3-chlorophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.75 g was dissolved in 15 ml of ethyl acetate, and 4N hydrogen chloride was added.
After adding 0.6 ml of a dioxane solution, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 20 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.53 g of the title compound as colorless crystals. Melting point: 119-121 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.2 (2H,
m), 2.2-2.4 (2H, m), 2.4-2.6 (2H, m), 2.7-3.0 (5H, m), 2.
79 (3H, s), 3.15-3.4 (1H, m), 3.8-4.1 (2H, m), 4.15-4.3 (1
H, m), 6.84 (1H, d, J = 7.9Hz), 6.93 (1H, tJ = 7.9Hz), 6.95
-7.05 (1H, m), 7.1-7.3 (5H, m).

[0118]

Example 44 2- [2- [2- [2- (2-chlorophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt In the same manner as in Example 43, 0.95 g of 2- [2- (2-chlorophenyl) ethyl] phenol, 1.15 g of potassium t-butoxide, and 1.13 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were added. Used, reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Then, 2- [2- [2- [2- (2-chlorophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.41 g was obtained as a colorless solid. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.15 (1H, m), 2.2-2.4 (2H, m), 2.4-2.6 (1H, m),
2.44 (3H, s), 2.85-3.05 (4H, m), 3.15-3.3 (1H, m), 3.9-
4.1 (2H, m), 6.8-6.95 (2H, m), 7.1-7.2 (5H, m), 7.3-7.4
(1H, m). The above 2- [2- [2- [2- (2-chlorophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
Dissolve 0.41 g in 5 ml of methylene chloride and add 4N hydrogen chloride-
After adding 0.35 ml of a dioxane solution, the solution was concentrated under reduced pressure. The solid thus obtained was again dissolved in a small amount of methylene chloride, 30 ml of ethyl acetate was added, and the mixture was allowed to stand at room temperature to precipitate crystals. This was collected by filtration, dried in vacuo and the title compound 0.41
g was obtained as colorless crystals. Melting point: 187-188 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.4-2.6 (2H, m), 2.7-3.1 (5H, m),
2.78 (3H, s), 3.3-3.5 (1H, m), 3.8-4.0 (2H, m), 4.1-4.2 (1
H, m), 6.82 (1H, d, J = 7.9Hz), 6.94 (1H, tJ = 7.6Hz), 7.05
-7.25 (5H, m), 7.3-7.4 (1H, m).

[0119]

Example 45 2- [2- [2- [2- (4-chlorophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt In the same manner as in Example 43, 1.00 g of 2- [2- (4-chlorophenyl) ethyl] phenol, 1.21 g of potassium t-butoxide, and 1.19 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were added. Used, reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Then, 2- [2- [2- [2- (4-chlorophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.45 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.7 (8H,
m), 2.47 (3H, s), 2.86 (4H, s), 3.2-3.35 (1H, m), 3.9-4.
15 (2H, m), 6.8-6.95 (2H, m), 7.0-7.3 (6H, m). The above 2- [2- [2- [2- (4-chlorophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.45 g was dissolved in a small amount of dioxane, and 4N hydrogen chloride was added.
After adding 0.36 ml of a dioxane solution, the mixture was concentrated under reduced pressure. The oily material thus obtained was dissolved again by adding 15 ml of ethyl acetate, and the solution was allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.35 g of the title compound as colorless crystals. Melting point: 145-146 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.2-2.4 (2H, m), 2.4-2.65 (2H, m), 2.7-3.0 (1H, m),
2.77 (3H, s), 2.86 (4H, s), 3.15-3.3 (1H, m), 3.8-4.1 (2H,
m), 4.1-4.25 (1H, m), 6.84 (1H, d, J = 8.6Hz), 6.92 (1H, t.
J = 7.6Hz), 7.0-7.15 (3H, m), 7.15-7.3 (3H, m).

[0120]

Example 46 2- [2- [2- [2- (3-fluorophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt As in Example 43, 1.00 g of 2- [2- (3-fluorophenyl) ethyl] phenol, 1.14 g of potassium t-butoxide, and 2- (2-chloroethyl) -1-
Methylpyrrolidine hydrochloride (1.02 g) was reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20 /
After 1), 0.94 g of 2- [2- [2- [2- [2- (3-fluorophenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.1 (1H, m), 2.2-2.4 (2H, m), 2.4-2.6 (1H, m),
2.44 (3H, s), 2.8-3.0 (4H, m), 3.15-3.3 (1H, m), 3.9-4.2
(2H, m), 6.8-7.0 (5H, m), 7.05-7.3 (3H, m). 0.92 g of the above 2- [2- [2- [2- (2- (3-fluorophenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 15 ml of ethyl acetate, and 0.8 ml of a 4N hydrogen chloride-dioxane solution was added. After adding, it was concentrated under reduced pressure.
The oil thus obtained was again dissolved in 25 ml of ethyl acetate,
Crystals were precipitated when left to stand at room temperature. This was collected by filtration and dried in vacuum to obtain 0.53 g of the title compound as colorless crystals. Melting point: 135-136 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.2 (2H,
m), 2.2-2.4 (2H, m), 2.4-2.65 (2H, m), 2.7-3.0 (1H, m),
2.78 (3H, s), 2.88 (4H, s), 3.2-3.4 (1H, m), 3.8-4.1 (2H,
m), 4.15-4.3 (1H, m), 6.8-7.0 (5H, m), 7.1-7.3 (3H, m)
.

[0121]

Example 47 2- [2- [2- [2- (4-fluorophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt As in Example 43, 1.00 g of 2- [2- (4-fluorophenyl) ethyl] phenol, 1.3 g of potassium t-butoxide and 2- (2-chloroethyl) -1-
Methylpyrrolidine hydrochloride 1.27 g was reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain a mixture containing the target substance as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20 /
After 1), 0.56 g of 2- [2- [2- [2- (2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-1.95 (4H,
m), 1.95-2.15 (1H, m), 2.15-2.5 (3H, m), 2.40 (3H, s), 2.
75-2.95 (4H, m), 3.1-3.2 (1H, m), 3.9-4.15 (2H, m), 6.8-
7.0 (4H, m), 7.05-7.25 (4H, m). 0.56 g of the above 2- [2- [2- [2- (2-fluorophenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 10 ml of ethyl acetate, and 0.5 ml of a 4N hydrogen chloride-dioxane solution was added. After adding, it was concentrated under reduced pressure.
The oil thus obtained was again dissolved in 15 ml of ethyl acetate,
Crystals were precipitated when left to stand at room temperature. This was collected by filtration and dried in vacuum to obtain 0.48 g of the title compound as colorless crystals. Melting point: 114-115 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.2 (2H,
m), 2.2-2.4 (2H, m), 2.4-2.65 (2H, m), 2.7-3.0 (1H, m),
2.78 (3H, s), 2.86 (4H, s), 3.15-3.35 (1H, m), 3.8-4.1 (2
H, m), 4.15-4.3 (1H, m), 6.8-7.0 (4H, m), 7.0-7.2 (4H,
m).

[0122]

Example 48 2- [2- [2- [2- (2-fluorophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt In the same manner as in Example 43, 1.00 g of 2- [2- (2-flurophenyl) ethyl] phenol, 1.3 g of potassium t-butoxide, and 1.26 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were added. Used, reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Thus, 0.316 g of 2- [2- [2- [2- [2- (2-fluorophenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.6 (7H,
m), 2.54 (3H, s), 2.6-2.9 (1H, m), 2.90 (4H, s), 3.3-3.4
5 (1H, m), 3.9-4.2 (2H, m), 6.8-6.95 (2H, m), 6.95-7.1 (2
H, m), 7.1-7.25 (4H, m). 0.31 g of 2- [2- [2- [2- [2- (2-fluorophenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine above was dissolved in 10 ml of ethyl acetate, and 0.36 ml of 4N hydrogen chloride-dioxane solution was added. In addition, crystals were precipitated when left at room temperature. This was collected by filtration and dried in vacuum to obtain 0.29 g of the title compound as colorless crystals. Melting point: 178-180 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.2 (2H,
m), 2.2-2.7 (4H, m), 2.7-3.0 (1H, m), 2.84 (3H, s), 2.87
(4H, s), 3.4-3.65 (1H, m), 3.8-4.1 (2H, m), 4.2-4.3 (1H,
m), 6.8-7.3 (8H, m).

[0123]

Example 49 2- [2- [2- [2- (3-bromophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt As in Example 43, 1.00 g of 2- [2- (3-bromophenyl) ethyl] phenol, 1.01 g of potassium t-butoxide and 1.0 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride. Was reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Then, 2- [2- [2- [2- (3-bromophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.45 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.6 (4H, m), 2.44 (3H, s), 2.8-2.95 (4H, m), 3.15
-3.3 (1H, m), 3.9-4.15 (2H, m), 6.8-6.95 (2H, m), 7.1-7.
4 (6H, m). The above 2- [2- [2- [2- (3-bromophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.45 g was dissolved in a small amount of dioxane, and 4N hydrogen chloride was added.
After adding 0.4 ml of dioxane solution, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in about 15 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.39 g of the title compound as colorless crystals. Melting point: 127-129 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.2 (2H,
m), 2.2-2.4 (2H, m), 2.4-2.7 (2H, m), 2.75-3.1 (5H, m),
2.79 (3H, s), 3.2-3.4 (1H, m), 3.8-4.1 (2H, m), 4.15-4.3
(1H, m), 6.85 (1H, d, J = 7.9Hz), 6.93 (1H, t, J = 7.3Hz), 7.
05 (1H, d, J = 7.3Hz), 7.1-7.4 (5H, m).

[0124]

Example 50 2- [2- [2- [2- (3-ethoxyphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt 2- [2- (3-ethoxyphenyl) ethyl] phenol 1.78 g, potassium t-butoxide 2.06 g, and 2-
(2-chloroethyl) -1-methylpyrrolidine hydrochloride 2.
Using 03 g, the reaction was performed in 40 ml of N, N-dimethylacetamide in the same manner as in Example 43, and extraction was performed to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20 / 1) and then 2- [2- [2- [2- (3-ethoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.90 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J =
7.3Hz), 1.6-2.0 (4H, m), 2.0-2.15 (1H, m), 2.2-2.4 (2H,
m), 2.4-2.6 (1H, m), 2.45 (3H, s), 2.75-3.0 (4H, m), 3.1
5-3.3 (1H, m), 3.9-4.2 (2H, m), 4.00 (2H, q, J = 7.3Hz), 6.
7-7.0 (5H, m), 7.05-7.25 (3H, m). 0.89 g of the above 2- [2- [2- [2- (2- (3-ethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in a small amount of ethyl acetate, and 4N hydrogen chloride-dioxane solution 0.76 ml was dissolved. After adding, the mixture was concentrated under reduced pressure.
The oil thus obtained was again dissolved in 25 ml of ethyl acetate,
Crystals were precipitated when left to stand at room temperature. This was collected by filtration and dried in vacuo to give the title compound (0.52 g) as colorless crystals. Melting point: 120-121 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.39 (3H, t, J =
7.3Hz), 1.9-2.15 (2H, m), 2.15-2.4 (2H, m), 2.4-2.65 (2
H, m), 2.7-3.0 (5H, m), 2.78 (3H, s), 3.2-3.4 (1H, m), 3.
8-4.1 (2H, m), 4.00 (2H, q, J = 7.3Hz), 4.1-4.2 (1H, m), 6.
65-6.8 (3H, m), 6.84 (1H, d, J = 7.9Hz), 6.93 (1H, t, J = 7.9H
z), 7.1-7.25 (3H, m).

[0125]

Example 51 2- [2- [2- [2- (2-ethoxyphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt 2- [2- (2-ethoxyphenyl) ethyl] phenol 1.10 g, potassium t-butoxide 1.27 g and 2-
(2-Chloroethyl) -1-methylpyrrolidine hydrochloride 1.
26 g of N, N-dimethylacetamide was reacted in 15 ml in the same manner as in Example 43 and extracted to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20 / 1) and then 2- [2- [2- [2- (2-ethoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.636 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J =
7.2Hz), 1.55-2.0 (4H, m), 2.0-2.15 (1H, m), 2.2-2.55 (3
H, m), 2.40 (3H, s), 2.90 (4H, s), 3.1-3.25 (1H, m), 3.9-
4.15 (2H, m), 4.02 (2H, q, J = 7.2Hz), 6.8-6.95 (4H, m), 7.
1-7.25 (4H, m). This 2- [2- [2- [2- (2-ethoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
Dissolve 0.60 g in a small amount of ethyl acetate and add 4N hydrogen chloride-
After adding 0.41 ml of dioxane solution, the mixture was concentrated under reduced pressure. The solid thus obtained was again dissolved in a small amount of methanol, 30 ml of ethyl acetate was added, and the mixture was allowed to stand at room temperature to precipitate crystals.
This was collected by filtration and dried in vacuum to obtain 0.42 g of the title compound as colorless crystals. Melting point: 148-150 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J =
7.3Hz), 1.9-2.15 (2H, m), 2.15-2.4 (2H, m), 2.4-2.65 (2
H, m), 2.65-3.0 (5H, m), 2.71 (3H, s), 3.2-3.4 (1H, m),
3.8-4.1 (2H, m), 4.02 (2H, q, J = 7.3Hz), 4.15-4.3 (1H, m),
6.8-7.0 (4H, m), 7.05-7.25 (3H, m).

[0126]

Example 52 2- [2- [2- [2- (4-ethoxyphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
2- (2- (4-ethoxyphenyl) ethyl] phenol salt 1.00 g, potassium t-butoxide 1.16 g and 2-
(2-Chloroethyl) -1-methylpyrrolidine hydrochloride 1.
14 g of N, N-dimethylacetamide was reacted in 15 ml in the same manner as in Example 43 and extracted to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20 / 1) and then 2- [2- [2- [2- (4-ethoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
1.00 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J =
7.2Hz), 1.55-1.95 (4H, m), 1.95-2.15 (1H, m), 2.15-2.5
(3H, m), 2.40 (3H, s), 2.75-2.95 (4H, m), 3.1-3.25 (1H,
m), 3.9-4.15 (2H, m), 4.00 (2H, q, J = 7.2Hz), 6.75-6.9 (4
H, m), 7.05-7.2 (4H, m). 1.00 g of the above 2- [2- [2- [2- (2-ethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 10 ml of ethyl acetate, and 0.8 ml of a 4N hydrogen chloride-dioxane solution was added. After adding, it was concentrated under reduced pressure.
The solid thus obtained was again dissolved in a small amount of methanol, 30 ml of ethyl acetate was added, and the mixture was allowed to stand at room temperature to precipitate crystals. This is collected by filtration, dried in vacuo and the title compound 0.81 g
Was obtained as colorless crystals. Melting point: 131-132 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J =
7.2Hz), 1.9-2.15 (2H, m), 2.15-2.4 (2H, m), 2.4-2.65 (2
H, m), 2.7-3.0 (5H, m), 2.76 (3H, s), 3.2-3.4 (1H, m), 3.
8-4.1 (2H, m), 4.01 (2H, q, J = 7.2Hz), 4.15-4.3 (1H, m),
6.75-6.9 (3H, m), 6.92 (1H, t, J = 7.3Hz), 7.04 (2H, d, J = 8.
6Hz), 7.1-7.25 (2H, m).

[0127]

Example 53 (R) -2- [2- (2-phenylethyl) phenoxy
Methyl] morpholine hydrochloride 2- (2-phenylethyl) phenol 1.00 g, (R)
Using 2.33 g of -4-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) morpholine and 0.743 g of potassium t-butoxide, the reaction was conducted in 20 ml of N, N-dimethylacetamide in the same manner as in Example 5, and extraction was performed. To give a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 5 /
1) and then (R) -4-t-butoxycarbonyl-2-
1.96 g of [2- (2-phenylethyl) phenoxymethyl] morpholine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.45 (9H, s),
2.8-3.1 (6H, m), 3.5-3.7 (1H, m), 3.75-4.2 (6H, m), 6.8-
6.95 (2H, m), 7.1-7.3 (7H, m). The above (R) -4- (t-butoxycarbonyl) -2-
0.92 g of [2- (2-phenylethyl) phenoxymethyl] morpholine was dissolved in 5 ml of dioxane, 5 ml of a 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 1 hour. This was concentrated under reduced pressure, the solvent was removed, and 25 ml of ethyl acetate was added to the obtained oily substance to dissolve it, and crystals were deposited when left standing at room temperature. This was collected by filtration and dried in vacuo to give the title compound (0.69 g) as colorless crystals. [Α] _D : −7.94 ° (c = 1.0, H ₂ O). Melting point: 150-151 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.8-3.0 (4H,
m), 3.0-3.2 (2H, m), 3.33 (1H, d, J = 12.5Hz), 3.45 (1H, d, J
= 12.5Hz), 3.9-4.2 (4H, m), 4.25-4.4 (1H, m), 6.79 (1H, d,
J = 7.9Hz), 6.91 (1H, t, J = 7.9Hz), 7.1-7.4 (7H, m).

[0128]

Example 54 (R) -4-Methyl-2- [2- (2-phenylethyl)
) Phenoxymethyl] morpholine hydrochloride 1.03 g of (R) -4-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine obtained in Example 53 was hydrogenated in 20 ml of tetrahydrofuran. The reaction product was treated with 0.2 g of lithium aluminum in the same manner as in Example 3, and the oily substance obtained by the treatment was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (R) -4-methyl- 2- [2-
(2-Phenylethyl) phenoxymethyl] morpholine
0.82 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.2-2.4 (2H,
m), 2.44 (3H, s), 2.8-3.0 (5H, m), 3.08 (1H, d, J = 11.2H
z), 3.8-4.2 (5H, m), 6.8-6.95 (2H, m), 7.1-7.35 (7H,
m). 0.82 g of the above (R) -4-methyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine was dissolved in 10 ml of dioxane to prepare a 4N hydrogen chloride-dioxane solution.
After 0.8 ml was added, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 15 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.54 g) as colorless crystals. [Α] _D : −5.08 ° (c = 1.3, ethanol). Melting point: 123-125 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.7-3.0 (6H,
m), 2.73 (3H, s), 3.40 (2H, t, J = 11.9Hz), 4.0-4.2 (3H,
m), 4.37 (1H, t, J = 11.9Hz), 4.5-4.6 (1H, m), 6.83 (1H, d,
J = 7.9Hz), 6.94 (1H, t, J = 7.9Hz), 7.1-7.3 (7H, m).

[0129]

Example 55 (S) -2- [2- (2-phenylethyl) phenoxy
Methyl] morpholine hydrochloride 2- (2-phenylethyl) phenol 0.62 g, (S)
-4-t-Butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) morpholine (1.51 g) and potassium t-butoxide (0.46 g) were reacted in 16 ml of N, N-dimethylacetamide in the same manner as in Example 5 and extracted. To give a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 5 /
1) Then, (S) -4-t-butoxycarbonyl-2-
1.23 g of [2- (2-phenylethyl) phenoxymethyl] morpholine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.45 (9H, s),
2.8-3.1 (6H, m), 3.5-3.7 (1H, m), 3.75-4.2 (6H, m), 6.8-
6.95 (2H, m), 7.1-7.3 (7H, m). The above (S) -4-t-butoxycarbonyl-2- [2
0.50 g of (2-phenylethyl) phenoxymethyl] morpholine was dissolved in 2 ml of dioxane, and 4N hydrogen chloride was added.
4 ml of dioxane solution was added, and the mixture was left standing at room temperature for 1 hour.
This was concentrated under reduced pressure, 15 ml of ethyl acetate was added to the oily substance obtained by removing the solvent to dissolve it, and crystals were deposited when left standing at room temperature. This was collected by filtration, dried in vacuo and the title compound 0.
35 g was obtained as colorless crystals. [Α] _D : + 7.25 ° (c = 1.49, H ₂ O). Melting point: 143-145 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.8-3.0 (4H,
m), 3.0-3.2 (2H, m), 3.33 (1H, d, J = 12.5Hz), 3.45 (1H, d, J
= 12.5Hz), 3.9-4.2 (4H, m), 4.25-4.4 (1H, m), 6.79 (1H, d,
J = 7.9Hz), 6.91 (1H, t, J = 7.9Hz), 7.1-7.4 (7H, m).

[0130]

Example 56 (S) -4-Methyl-2- [2- (2-phenylethyl)
Phenoxymethyl] morpholine hydrochloride 0.72 g of (S) -4-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine obtained in Example 55 was hydrogenated in 15 ml of tetrahydrofuran. The reaction product was treated with 0.142 g of lithium aluminum in the same manner as in Example 3, and the oily substance obtained by the treatment was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (S) -4-methyl- 2- [2
0.58 g of-(2-phenylethyl) phenoxymethyl] morpholine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.2-2.4 (2H,
m), 2.44 (3H, s), 2.8-3.0 (5H, m), 3.08 (1H, d, J = 11.2H
z), 3.8-4.2 (5H, m), 6.8-6.95 (2H, m), 7.1-7.35 (7H,
m). 0.58 g of the above (S) -4-methyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine was dissolved in 5 ml of dioxane, and 4N hydrogen chloride-dioxane solution was added.
After adding 56 ml, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.45 g of the title compound as colorless crystals. [Α] _D : + 5.29 ° (c = 1.36, ethanol). Melting point: 125-127 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.7-3.0 (6H,
m), 2.73 (3H, s), 3.40 (2H, t, J = 11.9Hz), 4.0-4.2 (3H,
m), 4.38 (1H, t, J = 11.9Hz), 4.5-4.6 (1H, m), 6.83 (1H, d,
J = 7.9Hz), 6.94 (1H, t, J = 7.9Hz), 7.1-7.3 (7H, m).

[0131]

Example 57 2- [2- [2- [2- (4-methoxyphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
1.00 g of salt 2- [2- (4-methoxyphenyl) ethyl] phenol, 1.23 g of potassium t-butoxide, and 2-
(2-Chloroethyl) -1-methylpyrrolidine hydrochloride 1.
Using 61 g, the reaction was performed in 20 ml of N, N-dimethylacetamide in the same manner as in Example 43, and extraction was performed to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20 / 1) and then 2- [2- [2- [2- (4-methoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.60 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.5-2.7 (8H,
m), 2.65 (3H, s), 2.75-3.0 (4H, m), 3.5-3.7 (1H, m), 3.8
3 (3H, s), 3.95-4.1 (1H, m), 4.15-4.25 (1H, m), 6.8-7.0 (4
H, m), 7.1-7.3 (4H, m). 0.60 g of the above 2- [2- [2- [2- (2- (4-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in a small amount of dioxane, and 0.66 ml of a 4N hydrogen chloride-dioxane solution was added. After adding, it was concentrated under reduced pressure.
The oil thus obtained was again dissolved in 15 ml of ethyl acetate,
Crystals were precipitated when left to stand at room temperature. This was collected by filtration and dried in vacuo to give the title compound (0.33 g) as colorless crystals. Melting point: 136-138 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.4-2.6 (2H, m), 2.7-2.95 (5H, m),
2.78 (3H, s), 3.2-3.35 (1H, m), 3.79 (3H, s), 3.8-4.1 (2H,
m), 4.15-4.3 (1H, m), 6.8-6.9 (3H, m), 6.92 (1H, t, J = 7.6
Hz), 7.0-7.25 (4H, m).

[0132]

Example 58 2- [2- [2- [2- (4-methylphenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt 2- [2- (4-methylphenyl) ethyl] phenol
1.00 g, potassium t-butoxide 1.32 g and 2-
(2-Chloroethyl) -1-methylpyrrolidine hydrochloride 1.
Using 3 g, the reaction was carried out in 20 ml of N, N-dimethylacetamide in the same manner as in Example 43, extraction was carried out to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20). / 1) and 2- [2- [2- [2- (2- (4-methylphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine.
81 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.2 (1H, m), 2.2-2.4 (2H, m), 2.32 (3H, s), 2.45
-2.65 (1H, m), 2.46 (3H, s), 2.75-2.95 (4H, m), 3.2-3.35
(1H, m), 3.9-4.3 (2H, m), 6.8-6.95 (2H, m), 7.05-7.25 (6
H, m). The above 2- [2- [2- [2- (4-methylphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.81 g was dissolved in 5 ml of dioxane, 0.95 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 15 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.74 g of the title compound as colorless crystals. Melting point: 137-138 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.33 (3H, s), 2.4-2.65 (2H, m), 2.7
-3.0 (5H, m), 2.75 (3H, s), 3.2-3.4 (1H, m), 3.8-4.1 (2H,
m), 4.2-4.3 (1H, m), 6.85 (1H, d, J = 7.9Hz), 6.93 (1H, t, J
= 6.9Hz), 7.0-7.3 (6H, m).

[0133]

Example 59 2- [2- [2- [2- (2-cyanophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt As in Example 43, 1.00 g of 2- [2- (2-cyanophenyl) ethyl] phenol, 1.26 g of potassium t-butoxide and 1.24 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride. Was reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Then, 2- [2- [2- [2- (2-cyanophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.21 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-1.95 (4H,
m), 1.95-2.2 (1H, m), 2.2-2.35 (2H, m), 2.35-2.55 (1H,
m), 2.43 (3H, s), 2.9-3.3 (5H, m), 3.95-4.15 (2H, m),
6.8-6.9 (2H, m), 7.05-7.35 (4H, m), 7.47 (1H, t, J = 7.6H
z), 7.60 (1H, d, J = 8.6Hz). The above 2- [2- [2- [2- (2-cyanophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.20 g was dissolved in a small amount of dioxane, and 4N hydrogen chloride-
After adding 0.25 ml of dioxane solution, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.17 g) as colorless crystals. Melting point: 172-173 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.2 (2H,
m), 2.2-2.7 (4H, m), 2.75-3.2 (5H, m), 2.88 (3H, s), 3.55
-3.8 (1H, m), 3.8-4.1 (2H, m), 4.15-4.3 (1H, m), 6.85 (1
H, d, J = 7.9Hz), 6.92 (1H, t, J = 7.6Hz), 7.1-7.4 (4H, m),
7.52 (1H, t, J = 7.6Hz), 7.61 (1H, d, J = 7.9Hz).

[0134]

Example 60 2- [2- [2- [2- (3-cyanophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt As in Example 43, 1.00 g of 2- [2- (3-cyanophenyl) ethyl] phenol, 1.26 g of potassium t-butoxide and 1.24 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride. Was reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Then, 2- [2- [2- [2- (3-cyanophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.51 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-1.95 (4H,
m), 1.95-2.15 (1H, m), 2.15-2.5 (3H, m), 2.40 (3H, s), 2.
91 (4H, s), 3.1-3.2 (1H, m), 3.95-4.15 (2H, m), 6.8-6.9 (2
H, m), 7.04 (1H, d, J = 5.9Hz), 7.19 (1H, t, J = 7.2Hz), 7.25
-7.55 (4H, m). The above 2- [2- [2- [2- (3-cyanophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
Dissolve 0.50 g in a small amount of dioxane and add 4N hydrogen chloride-
After adding 0.56 ml of dioxane solution, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 20 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.41 g of the title compound as colorless crystals. Melting point: 101-102 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.2 (2H,
m), 2.2-2.45 (2H, m), 2.45-2.65 (2H, m), 2.8-3.0 (1H, m),
2.83 (3H, s), 2.90 (4H, s), 3.2-3.4 (1H, m), 3.85-4.1 (2
H, m), 4.15-4.3 (1H, m), 6.85 (1H, d, J = 7.9Hz), 6.91 (1H,
t, J = 7.3Hz), 7.06 (1H, d, J = 7.3Hz), 7.21 (1H, t, J = 7.9Hz),
7.3-7.45 (3H, m), 7.50 (1H, d, J = 6.9Hz).

[0135]

Example 61 2- [2- [2- [2- (4-cyanophenyl) ethyl ]
] Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride
Salt As in Example 43, 1.00 g of 2- [2- (4-cyanophenyl) ethyl] phenol, 1.26 g of potassium t-butoxide and 1.24 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride. Was reacted in 20 ml of N, N-dimethylacetamide and extracted to obtain an oily mixture containing the desired product, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1).
Then, 2- [2- [2- [2- (4-cyanophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.31 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-1.95 (4H,
m), 1.95-2.15 (1H, m), 2.2-2.5 (3H, m), 2.42 (3H, s), 2.8
-3.05 (4H, m), 3.15-3.3 (1H, m), 3.9-4.15 (2H, m), 6.8-
6.9 (2H, m), 7.03 (1H, d, J = 5.9Hz), 7.19 (1H, t, J = 7.9Hz),
7.25 (2H, d, J = 7.9Hz), 7.55 (2H, d, J = 7.9Hz). The above 2- [2- [2- [2- (4-cyanophenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
Dissolve 0.30 g in a small amount of dioxane and add 4N hydrogen chloride-
After adding 0.25 ml of dioxane solution, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.17 g) as colorless crystals. Melting point: 137.5-139 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.2 (2H,
m), 2.2-2.45 (2H, m), 2.45-2.65 (2H, m), 2.75-3.1 (5H,
m), 2.81 (3H, s), 3.15-3.35 (1H, m), 3.8-4.1 (2H, m), 4.
15-4.3 (1H, m), 6.8-7.0 (2H, m), 7.02 (1H, d, J = 7.3Hz),
7.15-7.3 (3H, m), 7.56 (2H, d, J = 7.9 Hz).

[0136]

Example 62 2- [2- [2- [2- (2-hydroxyphenyl) e]
Cyl] phenoxy] ethyl] -1-methylpyrrolidine salt
In the same manner as in Example 43, 1.00 g of 2- [2- (2-methoxymethoxyphenyl) ethyl] phenol, 1.09 g of potassium t-butoxide, and 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride. Using 1.07 g, N,
The mixture was reacted in 20 ml of N-dimethylacetamide and extracted to obtain a mixture containing the target substance as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 20/1) to give 2- [2- [2 -[2- (2-Methoxymethoxyphenyl) ethyl] phenoxy] ethyl]
0.66 g of -1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.2 (1H, m), 2.2-2.4 (2H, m), 2.46 (3H, s), 2.45
-2.65 (1H, m), 2.91 (4H, s), 3.2-3.35 (1H, m), 3.48 (3H,
s), 3.9-4.2 (2H, m), 5.12 (2H, s), 6.8-7.0 (3H, m), 7.05
-7.2 (5H, m). 0.66 g of 2- [2- [2- [2- [2- (2-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine above was dissolved in 5 ml of dioxane, and 5 ml of 4N hydrogen chloride-dioxane solution was added. The mixture was allowed to stand at room temperature for 30 minutes and concentrated under reduced pressure to give a colorless solid. The solid thus obtained was again dissolved in a small amount of a mixture of methylene chloride and methanol, and about 30 ml of ethyl acetate was added thereto, and the mixture was allowed to stand to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.56 g) as colorless crystals. Melting point: 168.5-171 ° C. NMR spectrum (270MHz, DMSO-d ₆ ) δppm: 1.7-2.5 (6H,
m), 2.65-2.9 (4H, m), 2.79 (3H, s), 2.9-3.15 (1H, m), 3.3
-3.65 (2H, m), 3.9-4.2 (2H, m), 6.69 (1H, t, J = 7.3Hz), 6.
8-7.2 (7H, m).

[0137]

Example 63 2- [2- [2- [2- (4-hydroxyphenyl) e]
Cyl] phenoxy] ethyl] -1-methylpyrrolidine salt
In the same manner as in Example 43, 1.10 g of 2- [2- (4-methoxymethoxyphenyl) ethyl] phenol, 1.20 g of potassium t-butoxide and 2- (2-chloroethyl).
Using 1.18 g of -1-methylpyrrolidine hydrochloride, N, N-
React in 20 ml of dimethylacetamide and extract to obtain a mixture containing the desired product as an oil, which was purified by silica gel column chromatography (methylene chloride / methanol = 2).
0/1) and then 2- [2- [2- [2- (4-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1.
-0.41 g of methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.7-2.2 (5H,
m), 2.25-2.5 (2H, m), 2.54 (3H, s), 2.6-2.95 (5H, m), 3.3
5-3.5 (1H, m), 3.48 (3H, s), 3.95-4.05 (1H, m), 4.05-4.2
(1H, m), 5.15 (2H, s), 6.8-7.0 (4H, m), 7.05-7.25 (4H,
m). 0.40 g of 2- [2- [2- [2- [2- (4-methoxymethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine above was dissolved in 5 ml of dioxane, and 5 ml of 4N hydrogen chloride-dioxane solution was added. The mixture was allowed to stand at room temperature for 30 minutes and concentrated under reduced pressure to give a colorless solid. The solid thus obtained was dissolved in a small amount of methanol, about 50 ml of ethyl acetate was added, and the mixture was left standing to precipitate crystals. this,
The crystals were collected by filtration and dried in vacuum to obtain 0.22 g of the title compound as colorless crystals. Melting point: 132-133.5 ° C. NMR spectrum (270MHz, DMSO-d ₆ ) δppm: 1.7-2.5 (6H,
m), 2.6-2.9 (4H, m), 2.80 (3H, s), 2.95-3.15 (1H, m), 3.2
5-3.45 (1H, m), 3.45-3.65 (1H, m), 3.95-4.15 (2H, m), 6.
67 (2H, d, J = 8.6Hz), 6.86 (1H, t, J = 6.9Hz), 6.9-7.05 (3H,
m), 7.1-7.25 (2H, m).

[0138]

Example 64 (S) -2- [2- [2- [2- (3-methoxyphenyl)
Ethyl) phenoxy] ethyl] -1-methylpyrroli
Zin hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 0.700 g, (S) -1-ethoxycarbonyl-2-
[2- (p-Toluenesulfonyloxy) ethyl] pyrrolidine (1.15 g) and potassium t-butoxide (0.378 g) were reacted in 20 ml of N, N-dimethylacetamide in the same manner as in Example 5 and extracted to contain the desired product. A mixture was obtained, which was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give (S) -1-
1.08 g of ethoxycarbonyl-2- [2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.35 (3H,
m), 1.75-2.1 (5H, m), 2.1-2.45 (1H, m), 2.8-3.0 (4H, m),
3.3-3.55 (2H, m), 3.88 (3H, s), 3.95-4.2 (5H, m), 6.7-6.
95 (5H, m), 7.05-7.25 (3H, m). The above (S) -1-ethoxycarbonyl-2- [2-
[2- [2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine (1.06 g) was reacted in the same manner as in Example 3 with 0.303 g of lithium aluminum hydride in 40 ml of tetrahydrofuran to obtain a product. The oily substance was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (S) -2- [2-
[2- [2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine 0.850 g Obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-2.0 (4H,
m), 2.0-2.15 (1H, m), 2.2-2.4 (2H, m), 2.4-2.6 (1H, m),
2.43 (3H, s), 2.8-3.0 (4H, m), 3.15-3.3 (1H, m), 3.78 (3H,
s), 3.9-4.15 (2H, m), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m)
. 0.829 g of the above (S) -2- [2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was dissolved in 10 ml of dioxane to prepare a 4N hydrogen chloride-dioxane solution. After adding 1.83 ml, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 15 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.741 g of the title compound as colorless crystals. [Α] _D : -18.4 ° (c = 1.29, methanol). Melting point: 133-135 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.4-2.6 (2H, m), 2.7-3.0 (5H, m),
2.76 (3H, s), 3.2-3.4 (1H, m), 3.78 (3H, s), 3.8-4.05 (2
H, m), 4.15-4.3 (1H, m), 6.65-6.8 (3H, m), 6.84 (1H, d, J =
7.9Hz), 6.93 (1H, t, J = 7.9Hz), 7.1-7.3 (3H, m).

[0139]

Example 65 (R) -2- [2- [2- [2- (3-methoxyphenyl)
Ethyl) phenoxy] ethyl] -1-methylpyrroli
Zin hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 0.320 g, (R) -1-ethoxycarbonyl-2-
[2- (p-toluenesulfonyloxy) ethyl] pyrrolidine (0.526 g) and potassium t-butoxide (0.173 g)
Was reacted in 15 ml of N, N-dimethylacetamide in the same manner as in Example 5, and extraction was performed to obtain a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). , (R) -1-
0.475 g of ethoxycarbonyl-2- [2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.35 (3H,
m), 1.75-2.1 (5H, m), 2.1-2.45 (1H, m), 2.8-3.0 (4H, m),
3.3-3.55 (2H, m), 3.78 (3H, s), 3.95-4.2 (5H, m), 6.7-6.
95 (5H, m), 7.05-7.25 (3H, m). The above (R) -1-ethoxycarbonyl-2- [2-
[2- [2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine (0.460 g) was treated in 20 ml of tetrahydrofuran with 0.132 g of lithium aluminum hydride in the same manner as in Example 3 to obtain a product. The oily substance was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (R) -2- [2-
0.410 g of [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-2.0 (4H,
m), 2.0-2.15 (1H, m), 2.2-2.4 (2H, m), 2.4-2.6 (1H, m),
2.42 (3H, s), 2.8-3.0 (4H, m), 3.15-3.3 (1H, m), 3.78 (3H,
s), 3.9-4.15 (2H, m), 6.7-6.95 (5H, m), 7.1-7.3 (3H, m)
. The above (R) -2- [2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine (0.392 g) was dissolved in dioxane (7 ml) to prepare a 4N hydrogen chloride-dioxane solution. After adding 0.87 ml, the mixture was concentrated under reduced pressure. The oil thus obtained was again dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.272 g) as colorless crystals. [Α] _D : + 18.8 ° (c = 1.08, methanol). Melting point: 133-136 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.4-2.6 (2H, m), 2.7-3.0 (5H, m),
2.77 (3H, s), 3.2-3.4 (1H, m), 3.77 (3H, s), 3.8-4.05 (2
H, m), 4.15-4.3 (1H, m), 6.65-6.8 (3H, m), 6.84 (1H, d, J =
7.9Hz), 6.93 (1H, t, J = 7.3Hz), 7.1-7.3 (3H, m).

[0140]

Example 66 (S) -2- [2- [2- [2- (3,5-dimethoxy
Phenyl) ethyl] phenoxy] ethyl] -1-methyl
Pyrrolidine hydrochloride 2- [2- (3,5-dimethoxyphenyl) ethyl] phenol 0.450 g, (S) -1-ethoxycarbonyl-
2- [2- (p-toluenesulfonyloxy) ethyl]
Pyrrolidine 0.773 g and potassium t-butoxide 0.25
Using 4 g, the reaction was carried out in 20 ml of N, N-dimethylacetamide in the same manner as in Example 5, and extraction was performed to obtain a mixture containing the desired product. ), Then (S) -1
-Ethoxycarbonyl-2- [2- [2- [2- (3,
0.723 g of 5-dimethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.35 (3H,
m), 1.75-2.1 (5H, m), 2.1-2.45 (1H, m), 2.75-3.0 (4H, m),
3.3-3.55 (2H, m), 3.76 (3H, s), 3.95-4.2 (5H, m), 6.3-
6.4 (3H, m), 6.8-6.9 (2H, m), 7.05-7.25 (2H, m). The above (S) -1-ethoxycarbonyl-2- [2-
[2- [2- (3,5-dimethoxyphenyl) ethyl]
Phenoxy] ethyl] pyrrolidine (0.704 g) in tetrahydrofuran (35 ml) was charged with lithium aluminum hydride (0.18 g).
The reaction product was treated in the same manner as in Example 3 using 7 g, and the oily substance obtained by the treatment was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (S) -2-
[2- [2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine 0.
565 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.0-2.2 (1H, m), 2.2-2.4 (2H, m), 2.4-2.65 (1H, m),
2.46 (3H, s), 2.75-2.95 (4H, m), 3.2-3.35 (1H, m), 3.76 (6
H, s), 3.9-4.2 (2H, m), 6.3-6.4 (3H, m), 6.8-6.95 (2H,
m), 7.05-7.25 (2H, m). (S) -2- [2- [2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy] ethyl] -1-
Dissolve 0.545 g of methylpyrrolidine in 8 ml of dioxane,
After adding 4.11 ml of 4N hydrogen chloride-dioxane solution, the mixture was concentrated under reduced pressure. The oily material thus obtained was again added with ethyl acetate 10
Dissolved in ml and allowed to stand at room temperature, crystals precipitated. This was collected by filtration and dried in vacuo to give the title compound (0.361 g) as colorless crystals. [Α] _D : -19.0 ° (c = 1.15, methanol). Melting point: 125-126 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.9-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.4-2.65 (2H, m), 2.7-3.0 (5H, m),
2.78 (3H, s), 3.2-3.4 (1H, m), 3.76 (6H, s), 3.8-4.05 (2H,
m), 4.15-4.3 (1H, m), 6.25-6.35 (3H, m), 6.84 (1H, d, J =
8.6Hz), 6.94 (1H, t, J = 7.3Hz), 7.15-7.25 (2H, m).

[0141]

Example 67 (S) -2- [2- [2- [2- (3-difluoromethoxy)
Cyphenyl) ethyl] phenoxy] ethyl] -1-methyl
Lupyrrolidine hydrochloride 2- [2- (3-difluoromethoxyphenyl) ethyl]
Phenol 0.53 g, (S) -1-ethoxycarbonyl-
2- [2- (p-toluenesulfonyloxy) ethyl]
Pyrrolidine 0.68 g and potassium t-butoxide 0.23 g
Was reacted in the same manner as in Example 5 in 10 ml of N, N-dimethylacetamide and extracted to obtain a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). , (S) -1-
0.87 g of ethoxycarbonyl-2- [2- [2- [2- [2- (3-difluoromethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.35 (3H,
m), 1.75-2.1 (5H, m), 2.1-2.45 (1H, m), 2.90 (4H, s), 3.3
-3.55 (2H, m), 3.9-4.2 (5H, m), 6.47 (1H, t, J = 74.6Hz),
6.8-7.0 (4H, m), 7.0-7.1 (2H, m), 7.1-7.3 (2H, m). The above (S) -1-ethoxycarbonyl-2- [2-
[2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine (0.85 g) in tetrahydrofuran (10 ml) was charged with lithium aluminum hydride (0.15 g).
The reaction product was treated in the same manner as in Example 3 using 18 g, and the oily substance obtained by the treatment was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (S) -2-
[2- [2- [2- (3-difluoromethoxyphenyl)
Ethyl] phenoxy] ethyl] -1-methylpyrrolidine
0.69 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.55-1.95 (4H,
m), 1.95-2.15 (1H, m), 2.15-2.45 (2H, m), 2.40 (3H, s),
2.5-2.75 (1H, m), 2.8-3.0 (4H, m), 3.1-3.3 (1H, m), 3.9-
4.15 (2H, m), 6.45 (1H, t, J = 74.2Hz), 6.8-7.0 (4H, m), 7.
0-7.1 (2H, m), 7.15-7.3 (2H, m). (S) -2- [2- [2- [2- (3-difluoromethoxyphenyl) ethyl] phenoxy] ethyl] -1 above.
-Dissolve 0.69 g of methylpyrrolidine in 5 ml of dioxane,
After adding 0.55 ml of a 4N hydrogen chloride-dioxane solution, the mixture was concentrated under reduced pressure. The oily material thus obtained was again added with ethyl acetate 15
Dissolved in ml and allowed to stand at room temperature, crystals precipitated. This was collected by filtration and dried in vacuo to give the title compound (0.38 g) as colorless crystals. [Α] _D : -16.9 ° (c = 2.38, methanol). Melting point: 119-120 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.95-2.15 (2H,
m), 2.15-2.4 (2H, m), 2.4-2.65 (2H, m), 2.75-3.0 (5H, m),
2.79 (3H, s), 3.2-3.4 (1H, m), 3.8-4.1 (2H, m), 4.15-4.
3 (1H, m), 6.49 (1H, t, J = 73.9Hz), 6.75-7.05 (5H, m), 7.1
-7.35 (3H, m).

[0142]

Example 68 (2R, 4R) -4-Hydroxy-2- [2- [2-
[2- (3-Methoxyphenyl) ethyl] phenoxy]
Ethyl] -1-methylpyrrolidine hydrochloride 2- [2- (3-methoxyphenyl) ethyl] phenol 0.500 g, (2R, 4R) -4-benzyloxy-1
-Ethoxycarbonyl-2- [2- (p-toluenesulfonyloxy) ethyl] pyrrolidine (1.19 g) and potassium t-butoxide (0.270 g) were reacted in 20 ml of N, N-dimethylacetamide in the same manner as in Example 5 and extracted. To obtain a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 4 /
1) and then (2R, 4R) -4-benzyloxy-1-
0.860 g of ethoxycarbonyl-2- [2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.35 (3H,
m), 1.75-2.1 (2H, m), 2.2-2.6 (2H, m), 2.8-3.0 (4H, m),
3.43 (1H, dd, J = 4.6 and 11.9Hz), 3.55-4.3 (7H, m), 3.
75 (3H, s), 4.45 (2H, s), 6.65-6.9 (5H, m), 7.05-7.4 (8H,
m). The above (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine
0.853 g was stirred in 6 ml of ethanol using 85 mg of 5% palladium-carbon catalyst at 60 ° C. for 7 hours under a hydrogen atmosphere to remove the benzyl group. The reaction solution was cooled, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [2- [2- [2-
0.650 g of (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.35 (3H,
m), 1.7-2.3 (3H, m), 2.3-2.6 (1H, m), 2.8-3.0 (4H, m), 3.
46 (1H, dd, J = 4.6 and 11.9Hz), 3.5-3.8 (1H, m), 3.78 (3
H, s), 3.95-4.3 (5H, m), 4.35-4.5 (1H, m), 6.7-6.95 (5H,
m), 7.1-7.3 (3H, m). The above (2R, 4R) -1-ethoxycarbonyl-4-
Hydroxy-2- [2- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine 0.64
0 g of the product was reacted in the same manner as in Example 3 with 0.176 g of lithium aluminum hydride in 30 ml of tetrahydrofuran, and the oily product obtained by the treatment was purified by silica gel column chromatography (methylene chloride / methanol = 10/1).
Then, (2R, 4R) -4-hydroxy-2- [2-
0.523 g of [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.7-2.5 (5H,
m), 2.48 (3H, s), 2.8-3.0 (5H, m), 3.59 (1H, dd, J = 5.9 and 10.6Hz), 3.78 (3H, s), 3.9-4.2 (2H, m), 4.4 -4.5 (1H,
m), 6.7-7.0 (5H, m), 7.1-7.3 (3H, m). The above (2R, 4R) -4-hydroxy-2- [2-
[2- [2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine (0.520 g) was dissolved in dioxane (5 ml) to prepare a 4N hydrogen chloride-dioxane solution.
After adding 1.1 ml, the mixture was concentrated under reduced pressure. The oil thus obtained was dissolved in 2 ml of methylene chloride, 40 ml of ethyl acetate was added, and the mixture was allowed to stand at room temperature to precipitate crystals. This is filtered,
After drying in vacuum, 0.420 g of the title compound was obtained as colorless crystals. [Α] _D : -12.20 (c = 1.06, methanol). Melting point: 100-102 ° C. NMR spectrum (400MHz, CDCl ₃ + D ₂ O) δppm: 2.0-2.2 (1
H, m), 2.3-2.65 (3H, m), 2.75-3.1 (5H, m), 2.88 (3H, s),
3.77 (3H, s), 3.8-4.3 (4H, m), 4.55-4.7 (1H, m), 6.7-6.8
(3H, m), 6.83 (1H, d, J = 8.1Hz), 6.92 (1H, t, J = 7.3Hz), 7.
1-7.3 (3H, m).

[0143]

[Example 69] (2R, 4R) -2- [2- [2- [2- (3,5-di
Methoxyphenyl) ethyl] phenoxy] ethyl] -4
-Hydroxy-1-methylpyrrolidine hydrochloride 2- [2- (3,5-dimethoxyphenyl) ethyl] phenol 0.605 g, (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- ( p-toluenesulfonyloxy) ethyl] pyrrolidine (1.15 g) and potassium t-butoxide (0.289 g) were reacted in 20 ml of N, N-dimethylacetamide in the same manner as in Example 5 and extracted to obtain a mixture containing the desired product. This was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- [2- [2-
(3,5-Dimethoxyphenyl) ethyl] phenoxy]
Obtained 0.980 g of ethyl] pyrrolidine as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.3 (3H,
m), 1.75-2.1 (2H, m), 2.2-2.55 (2H, m), 2.75-3.0 (4H, m),
3.43 (1H, dd, J = 4.6 and 11.9Hz), 3.55-4.3 (7H, m),
3.74 (3H, s), 4.45 (2H, s), 6.25-6.4 (3H, m), 6.75-6.95
(2H, m), 7.05-7.4 (7H, m). 0.951 g of the above (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- [2- [2- (2- (3,5-dimethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine in 6 ml of ethanol. 5% palladium-
The benzyl group was removed by stirring with 95 mg of carbon catalyst at 60 ° C. for 9 hours under a hydrogen atmosphere. The reaction solution was cooled, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [2-
0.717 g of [2- (3,5-dimethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.1-1.3 (3H,
m), 1.75-2.3 (3H, m), 2.3-2.65 (1H, m), 2.75-3.0 (4H, m),
3.46 (1H, dd, J = 4.6 and 11.9Hz), 3.5-3.8 (1H, m), 3.7
7 (6H, s), 3.95-4.3 (3H, m), 4.12 (2H, q, J = 7.3Hz), 4.35-
4.5 (1H, m), 6.25-6.4 (3H, m), 6.83 (1H, d, J = 8.6Hz), 6.89
(1H, d, J = 6.6Hz), 7.1-7.25 (2H, m). The above (2R, 4R) -1-ethoxycarbonyl-4-
0.62 g of hydroxy-2- [2- [2- [2- (2- (3,5-dimethoxyphenyl) ethyl] phenoxy] ethyl] pyrrolidine in 30 ml of tetrahydrofuran as in Example 3 using 0.178 g of lithium aluminum hydride. The oily substance obtained by reacting with and treated with silica gel was purified by silica gel column chromatography (methylene chloride / methanol = 10 /
1) and then (2R, 4R) -4-hydroxy-2- [2
-[2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy] ethyl] -1-methylpyrrolidine 0.54
7 g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.75-2.5 (5H,
m), 2.51 (3H, s), 2.75-3.1 (5H, m), 3.62 (1H, dd, J = 5.9
And 10.6Hz), 3.77 (6H, s), 3.9-4.2 (2H, m), 4.4-4.55
(1H, m), 6.3-6.4 (3H, m), 6.84 (1H, d, J = 7.9Hz), 6.91 (1
H, d, J = 7.3Hz), 7.1-7.25 (2H, m). The above (2R, 4R) -4-hydroxy-2- [2-
[2- [2- (3,5-dimethoxyphenyl) ethyl]
Phenoxy] ethyl] -1-methylpyrrolidine 0.535 g
Was dissolved in 5 ml of dioxane, 1.04 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was concentrated under reduced pressure. The oil thus obtained was dissolved in 2 ml of methylene chloride and 40 ml of ethyl acetate.
Was added and the mixture was allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.501 g) as colorless crystals. [Α] _D : -12.1 ° (c = 1.15, methanol). Melting point: 134-136 ° C. NMR spectrum (400MHz, CDCl ₃ + D ₂ O) δppm: 2.0-2.2 (1
H, m), 2.3-2.65 (3H, m), 2.75-3.1 (5H, m), 2.89 (3H, s),
3.76 (6H, s), 3.8-4.3 (4H, m), 4.55-4.65 (1H, m), 6.25-
6.4 (3H, m), 6.83 (1H, d, J = 8.0Hz), 6.92 (1H, t, J = 7.3Hz),
7.1-7.3 (2H, m).

[0144]

Example 70 (S) -2- [3- [2- [2- (3,5-dimethoxy
(Phenyl) ethyl] phenoxy] propyl] -1-methyl
Lupyrrolidine hydrochloride 2- [2- (3,5-dimethoxyphenyl) ethyl] phenol 1.00 g, (S) -1-ethoxycarbonyl-2
-[3- (p-toluenesulfonyloxy) propyl]
Pyrrolidine 1.51 g and potassium t-butoxide 0.478
g and reacting in 17 ml of N, N-dimethylacetamide in the same manner as in Example 5 and extracting to obtain a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). Then, (S) -1-
Ethoxycarbonyl-2- [3- [2- [2- (3,5
1.68 g of -dimethoxyphenyl) propyl] phenoxy] ethyl] pyrrolidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.15-1.3 (3H,
m), 1.5-2.1 (8H, m), 2.75-3.0 (4H, m), 3.25-3.6 (2H, m),
3.76 (6H, s), 3.8-4.2 (5H, m), 6.25-6.4 (3H, m), 6.8-6.9
5 (2H, m), 7.05-7.25 (2H, m). (S) -1-Ethoxycarbonyl-2- [3- [2-
An oil obtained by reacting 1.63 g of [2- (3,5-dimethoxyphenyl) propyl] phenoxy] ethyl] pyrrolidine in 35 ml of tetrahydrofuran with 0.419 g of lithium aluminum hydride in the same manner as in Example 3 and treating. The product was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give (S) -2- [3-
[2- [2- (3,5-Dimethoxyphenyl) propyl] phenoxy] ethyl] -1-methylpyrrolidine 1.22
g was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.4-2.3 (8H,
m), 2.35 (3H, s), 2.4-2.65 (2H, m), 2.75-3.0 (4H, m), 3.
1-3.25 (1H, m), 3.76 (6H, s), 3.9-4.1 (2H, m), 6.25-6.4 (3
H, m), 6.8-6.95 (2H, m), 7.05-7.25 (2H, m). (S) -2- [3- [2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy] propyl] -1 above
-Dissolve 1.19 g of methylpyrrolidine in 8 ml of dioxane,
After adding 2.33 ml of 4N hydrogen chloride-dioxane solution, the mixture was concentrated under reduced pressure. The oily material thus obtained was again added with ethyl acetate 20
It was dissolved in ml, about 4 ml of ether was added, and the mixture was allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.536 g) as colorless crystals. [Α] _D : -19.7 ° (c = 0.94, methanol). Melting point: 101-102 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.75-2.4 (8H,
m), 2.7-3.0 (5H, m), 2.72 (3H, s), 3.0-3.2 (1H, m), 3.77
(6H, s), 3.8-4.15 (3H, m), 6.25-6.4 (3H, m), 6.82 (1H, d, J
= 7.9Hz), 6.91 (1H, t, J = 7.3Hz), 7.1-7.25 (2H, m).

[0145]

Example 71 (S) -3- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] piperidine hydrochloride 1.55 g of 2- [2- (3-methoxyphenyl) ethyl] phenol was dissolved in 60 ml of N, N-dimethylacetamide, and 0.295 g of 55% sodium hydride was added under ice-cooling stirring. And stirred for 15 minutes. To this mixture, (S) -1-t
-Butoxycarbonyl-3- (p-toluenesulfonyloxymethyl) piperidine (2.50 g) was added at the same temperature, and the mixture was stirred for 30 minutes and further stirred for 6 hours at room temperature. 250 ml of ethyl acetate and 150 ml of water were added to the reaction solution and stirred, and the ethyl acetate layer was separated. The aqueous layer was extracted once again with 50 ml of ethyl acetate, the ethyl acetate extracted layers were combined, washed twice with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture containing substances was obtained. This is purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give (S) -1-t-butoxycarbonyl-3- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl]. 2.78 g of piperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.4-1.8 (3H,
m), 1.42 (9H, s), 1.85-2.15 (2H, m), 2.75-3.0 (6H, m),
3.78 (3H, s), 3.8-4.25 (4H, m), 6.7-6.9 (5H, m), 7.1-7.25
(3H, m). The above (S) -1-t-butoxycarbonyl-3- [2
1.00 g of-[2- (3-methoxyphenyl) ethyl] phenoxymethyl] piperidine was dissolved in 10 ml of dioxane, 10 ml of 4N hydrogen chloride-dioxane solution was added at room temperature, and the mixture was left standing for 1 hour. This was concentrated under reduced pressure, the obtained solid was dissolved in a small amount of methylene chloride, 50 ml of ethyl acetate was added, and the mixture was left standing at room temperature to precipitate crystals, which were collected by filtration and dried in vacuo to give the title compound 0.638 g Was obtained as colorless crystals. [Α] _D : −7.46 ° (c = 2.44, methanol). Melting point: 150-152 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.4-1.7 (1H,
m), 1.85-2.15 (3H, m), 2.45-2.65 (1H, m), 2.7-3.0 (6H,
m), 3.4-3.6 (2H, m), 3.76 (3H, s), 3.8-3.95 (2H, m), 6.6
5-6.85 (4H, m), 6.89 (1H, t, J = 7.3Hz), 7.05-7.3 (3H, m).

[0146]

Example 72 (S) -3- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] -1-methylpiperidine hydrochloride
Salt Obtained in Example 71 (S) -1-t-butoxycarbonyl-3- [2- [2- (3-methoxyphenyl) ethyl]
2.35 g of phenoxymethyl] piperidine in 40 ml of tetrahydrofuran, 0.210 g of lithium aluminum hydride
Was treated in the same manner as in Example 3, and the oily substance obtained by the treatment was purified by silica gel column chromatography (methylene chloride / methanol = 9/1) to give (S) -3- [2-
1.82 g of [2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.05-1.3 (1H,
m), 1.6-2.3 (6H, m), 2.28 (3H, s), 2.7-3.1 (6H, m), 3.75-
3.9 (2H, m), 3.78 (3H, s), 6.7-6.9 (5H, m), 7.1-7.3 (3H, m)
. 1.80 g of the above (S) -3- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was dissolved in 10 ml of dioxane, and 1.5 ml of 4N hydrogen chloride-dioxane solution was added. After that, it was concentrated under reduced pressure. The oil thus obtained was again dissolved in 25 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (1.18 g) as colorless crystals. [Α] _D : −4.48 ° (c = 2.1, methanol). Melting point: 206-207 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.5-1.75 (1H,
m), 1.85-2.05 (2H, m), 2.25-2.7 (2H, m), 2.7-3.0 (6H, m),
2.74 (3H, s), 3.4-3.6 (2H, m), 3.78 (3H, s), 3.85-4.0 (2
H, m), 6.7-6.85 (4H, m), 6.93 (1H, d, J = 7.2Hz), 7.1-7.3
(3H, m).

[0147]

Example 73 (R) -3- [2- [2- (3-methoxyphenyl) e
Cyl] phenoxymethyl] -1-methylpiperidine hydrochloride
Salt [2- (2- (3-methoxyphenyl) ethyl] phenol 0.53 g, (R) -1- in the same manner as in Example 1 (b).
Reaction was carried out using 0.50 g of t-butoxycarbonyl-3-hydroxymethylpiperidine, 0.67 g of triphenylphosphine, 0.45 g of diethyl azodicarboxylate and 15 ml of methylene chloride and extraction to obtain a mixture containing an oily target substance. Silica gel column chromatography purification (hexane / ethyl acetate = 10/1), and (R) -1-t-butoxycarbonyl-3- [2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] piperidine 0.64 g
Was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.4-1.8 (3H,
m), 1.42 (9H, s), 1.85-2.15 (2H, m), 2.75-3.0 (6H, m),
3.78 (3H, s), 3.84 (2H, d, J = 5.9Hz), 3.85-4.25 (2H, m),
6.7-6.9 (5H, m), 7.1-7.25 (3H, m). The above (R) -1-t-butoxycarbonyl-3- [2
-[2- (3-Methoxyphenyl) ethyl] phenoxymethyl] piperidine 0.63 g In 12 ml of tetrahydrofuran, 0.06 g of lithium aluminum hydride was reacted in the same manner as in Example 3, and the oil obtained by the treatment was treated with silica gel. Purification by column chromatography (methylene chloride / ethanol = 10/1), and then (R) -3- [2- [2- (3-
Methoxyphenyl) ethyl] phenoxymethyl] -1-
0.43 g of methylpiperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.05-1.3 (1H,
m), 1.55-2.3 (6H, m), 2.31 (3H, s), 2.65-3.1 (6H, m), 3.7
5-3.95 (2H, m), 3.78 (3H, s), 6.7-6.9 (5H, m), 7.1-7.3 (3
H, m). 0.43 g of the above (R) -3- [2- [2- (2- (3-methoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was dissolved in 1 ml of dioxane to prepare 4N hydrogen chloride-
After adding 0.38 ml of a dioxane solution, the solution was concentrated under reduced pressure. The oil thus obtained was again dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature to precipitate crystals. This was collected by filtration and dried in vacuo to give the title compound (0.39 g) as colorless crystals. [Α] _D : + 4.56 ° (c = 2.41, methanol). Melting point: 190-193 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.5-1.75 (1H,
m), 1.85-2.05 (2H, m), 2.25-2.7 (2H, m), 2.7-3.0 (6H, m),
2.74 (3H, s), 3.4-3.6 (2H, m), 3.78 (3H, s), 3.85-4.0 (2
H, m), 6.7-6.85 (4H, m), 6.93 (1H, d, J = 7.3Hz), 7.1-7.3
(3H, m).

[0148]

Example 74 3- [2- [2- (3-difluoromethoxyphenyl) e
Cyl] phenoxymethyl] piperidine hydrochloride 2- [2- (3-difluoromethoxyphenyl) ethyl]
Phenol 1.05 g, 1-t-butoxycarbonyl-3-
(P-Toluenesulfonyloxymethyl) piperidine 1.
Using 47 g and 0.45 g of potassium t-butoxide, N,
Reaction was carried out in the same manner as in Example 5 in 20 ml of N-dimethylacetamide and extraction was performed to obtain a mixture containing the desired product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-t. -Butoxycarbonyl-3- [2- [2- (3-difluoromethoxyphenyl)
1.55 g of ethyl] phenoxymethyl] piperidine was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.35-1.8 (3H,
m), 1.42 (9H, s), 1.85-2.15 (2H, m), 2.7-3.0 (6H, m), 3.
75-4.3 (4H, m), 6.46 (1H, t, J = 74.6Hz), 6.8-7.0 (4H, m),
7.0-7.1 (2H, m), 7.1-7.3 (2H, m). The above 1-t-butoxycarbonyl-3- [2- [2-
0.83 g of (3-difluoromethoxyphenyl) ethyl] phenoxymethyl] piperidine was dissolved in 8 ml of dioxane,
8N of 4N hydrogen chloride-dioxane solution was cooled and added,
This was left to stand at room temperature for 1 hour and concentrated under reduced pressure to obtain an oily substance. When this was dissolved in 50 ml of ethyl acetate, crystals immediately precipitated, so this was collected by filtration and dried in vacuo to give 0.68 g of the title compound as colorless crystals. Melting point: 153-154 ° C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.4-1.65 (1H,
m), 1.85-2.2 (3H, m), 2.45-2.65 (1H, m), 2.7-3.0 (6H, m),
2.87 (4H, s), 3.4-3.6 (2H, m), 3.8-3.95 (2H, m), 6.49 (1
H, t, J = 73.9Hz), 6.75-7.35 (8H, m).

[0149]

Example 75 3- [2- [2- (3-difluoromethoxyphenyl) e
Cyl] phenoxymethyl] -1-methylpiperidine hydrochloride
Salt 1-t-butoxycarbonyl-3-obtained in Example 74
[2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxymethyl] piperidine (0.64 g) in tetrahydrofuran (10 ml) was added to lithium aluminum hydride (0.05).
The oily substance obtained by the reaction in the same manner as in Example 3 using g was purified by silica gel column chromatography (methylene chloride / methanol = 10/1) to give 3- [2- [2
0.56 g of-(3-difluoromethoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was obtained as a colorless oil. 0.56 g of the above 3- [2- [2- (3-difluoromethoxyphenyl) ethyl] phenoxymethyl] -1-methylpiperidine was dissolved in 5 ml of dioxane, and 0.45 ml of 4N hydrogen chloride-dioxane solution was added. , Concentrated under reduced pressure. The solid thus obtained was dissolved in a small amount of methanol, about 50 ml of ethyl acetate was added, and the mixture was allowed to stand overnight at room temperature to precipitate crystals. This was collected by filtration and dried in vacuum to obtain 0.43 g of the title compound as colorless crystals. Melting point: 174-175 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.45-1.7 (1H,
m), 1.85-2.05 (2H, m), 2.3-3.0 (4H, m), 2.76 (3H, s), 2.8
9 (4H, s), 3.4-3.6 (2H, m), 3.8-4.05 (2H, m), 6.51 (1H, t, J
= 73.9Hz), 6.75-7.35 (8H, m).

[0150]

[Reference Example 1] 2-benzyloxybenzyl triphenylphosphonium
152 g of chloride salicyl alcohol was dissolved in 600 ml of N, N-dimethylformamide, and 151 g of potassium tert-butoxide was added under ice-cooling stirring. After stirring for 30 minutes at room temperature, 160 ml of benzyl bromide was added dropwise to the reaction mixture, and the mixture was stirred for 2 hours at 30-40 ° C. The reaction mixture was partitioned between ethyl acetate and water, and the extract was washed twice with brine, dehydrated and concentrated under reduced pressure. The oil obtained is
It was treated by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain 228.5 g (yield 87%) of 2-benzyloxybenzyl alcohol as a colorless oily substance. This was dissolved in 500 ml of tetrahydrofuran, 85 ml of thionyl chloride was added dropwise under ice cooling, the mixture was allowed to stand overnight at room temperature, and concentrated under reduced pressure to obtain a dark oily substance. This was dissolved in toluene, filtered over silica gel for chromatography, decolorized, and the filtrate was concentrated under reduced pressure to give 2-benzyloxybenzyl chloride as a yellowish oil. It was dissolved in 500 ml of toluene without further purification,
When 420 g of triphenylphosphine was added and the mixture was heated under reflux for 3 hours, a white insoluble matter gradually appeared. After cooling the reaction solution, the resulting precipitate was collected by filtration, washed and dried in vacuo to give the title compound (539.9 g, yield 96%) as a colorless solid. NMR spectrum (60 MHz, CDCl ₃ ) δppm: 4.46 (2H, s),
5.28 (2H, d, J = 14Hz), 6.5-8.0 (24H, m).

[0151]

[Reference Example 2] 5.09 g of 2- (2-phenylethyl) phenolbenzaldehyde and 26.12 g of 2-benzyloxybenzyltriphenylphosphonium chloride were dissolved in 100 ml of acetonitrile with heating, and then 1,8- Diazabicyclo [5.4.0] undec-
8.04 g of 7-ene was added dropwise, and the mixture was further stirred for 40 minutes at the same temperature. After reducing the pressure of the reaction liquid, the residue was subjected to liquid separation treatment with ethyl acetate and water. After concentration, hexane-ethyl acetate (2: 1) was added again.
Was added and the precipitated crystals were filtered off. The filtrate was concentrated and subjected to silica gel column chromatography (hexane /
Treatment with ethyl acetate = 30/1) gave 10.4 g of 2-benzyloxystilbene (yield 76%). This was stirred in 300 ml of ethanol using 5% palladium carbon as a catalyst in a hydrogen atmosphere at atmospheric pressure at 60 ° C. for 3 hours and a half. After cooling, the catalyst was filtered off and concentrated, which was subjected to silica gel column chromatography (hexane / ethyl acetate = 4).
/ 1) to obtain 6.41 g (yield 89%) of the title compound as a colorless solid. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.92 (4H, s),
4.64 (1H, s, -OH), 6.74 (1H, d, J = 7.9Hz), 6.86 (1H, t, J = 7.
3Hz), 7.0-7.4 (7H, m).

[0152]

Reference Example 3 In the same manner as in Reference Example 2, the following phenol derivatives were synthesized using the corresponding aldehyde and 2-benzyloxybenzyltriphenylphosphonium chloride. (A) 2- [2- (3-methoxyphenyl) ethyl] phenyl
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 2.91 (4H, s),
3.37 (3H, s), 4.65 (1H, s, -OH), 6.7-6.95 (5H, m), 7.05-
7.3 (3H, m). (B) 2- [2- (3-methoxymethoxyphenyl) e
Chill] phenol NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.90 (4H, s),
3.47 (3H, s), 4.78 (1H, s, -OH), 5.15 (2H, s), 6.73 (1H, d,
J = 7.9Hz), 6.8-6.95 (4H, m), 7.0-7.3 (3H, m). (C) 2- [2- (3,4-dimethoxyphenyl) ethyl
Phenol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.8-3.0 (4H,
m), 3.81 (3H, s), 3.86 (3H, S), 4.71 (1H, s, -OH), 6.6-6.9
(5H, m), 7.05-7.15 (2H, m). (D) 2- [2- (2-methoxyphenyl) ethyl] phenyl
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 2.7-2.9 (4H,
m), 3.94 (3H, s), 6.25 (1H, s, -OH), 6.7-7.0 (4H, m), 7.05
-7.3 (4H, m). (E) 2- [2- (2-methylphenyl) ethyl] fe
Nol NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.31 (3H, s),
2.8-3.0 (4H, m), 4.70 (1H, s, -OH), 6.74 (1H, d, J = 7.9Hz),
6.87 (1H, t, J = 7.6Hz), 7.0-7.2 (6H, m). (F) 2- [2- (3-methylphenyl) ethyl] fe
Nol NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.33 (3H, s),
2.89 (4H, s), 4.63 (1H, s), 6.75 (1H, d, J = 7.9Hz), 6.87 (1
H, t, J = 7.9Hz), 7.0-7.25 (6H, m). (G) 2- [2- (4-ethylphenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.23 (3H, t, J
= 7.6Hz), 2.63 (2H, q, J = 7.6Hz), 2.89 (4H, s), 4.64 (1H, s,
-OH), 6.75 (1H, d, J = 7.9Hz), 6.87 (1H, t, J = 7.6Hz), 7.05-
7.2 (6H, m). (H) 2- [2- (3,5-dimethoxyphenyl) ethyl
Phenol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.8-3.0 (4H,
m), 3.75 (6H, s), 4.78 (1H, s, -OH), 6.3-6.4 (3H, m), 6.74
(1H, d, J = 8.6Hz), 6.86 (1H, t, J = 8.6Hz), 7.05-7.2 (2H,
m). (I) 2- [2- (3,4,5-trimethoxyphenyl
) Ethyl] phenol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.8-3.0 (4H,
m), 3.81 (6H, s), 3.83 (3H, s), 4.76 (1H, s, -OH), 6.38 (2
H, s), 6.75 (1H, d, J = 9.9Hz), 6.86 (1H, t, J = 6.9Hz), 7.05-
7.15 (2H, m). (J) 2- [2- (3-ethoxyphenyl) ethyl] fluoro
Phenol NMR spectrum _{(270MHz, CDCl 3) δ ppm} : 1.39 (3H, t, J =
7.3Hz), 2.89 (4H, s), 4.00 (2H, q, J = 7.3Hz), 4.65 (1H, s),
6.7-6.9 (5H, m), 7.05-7.25 (3H, m). (K) 2- [2- (2-ethoxyphenyl) ethyl] fur
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 1.52 (3H, t, J =
6.9Hz), 2.82 (4H, s), 4.18 (2H, q, J = 6.9Hz), 5.90 (1H, s),
6.8-7.0 (4H, m), 7.1-7.3 (4H, m). (L) 2- [2- (4-ethoxyphenyl) ethyl] phenyl
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 1.40 (3H, t, J =
7.2Hz), 2.87 (4H, s), 4.01 (2H, q, J = 7.2Hz), 4.57 (1H, s),
6.7-6.9 (4H, m), 7.05-7.15 (4H, m). (M) 2- [2- (4-methoxyphenyl) ethyl] phenyl
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 2.87 (4H, s),
3.79 (3H, s), 4.58 (1H, s), 6.75 (1H, d, J = 7.9Hz), 6.8-6.9
(3H, m), 7.05-7.15 (4H, m). (N) 2- [2- (4-methylphenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.32 (3H, s),
2.88 (4H, s), 4.57 (1H, s), 6.75 (1H, d, J = 7.9Hz), 6.86 (1
H, t, J = 6.9Hz), 7.0-7.2 (6H, m). (O) 2- [2- (2-methoxymethoxyphenyl) e
Chill] phenol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.75-2.95 (4H,
m), 3.53 (3H, s), 5.30 (2H, s), 5.95 (1H, s), 6.8-7.05 (3
H, m), 7.1-7.3 (5H, m). (P) 2- [2- (4-methoxymethoxyphenyl) e
Chill] phenol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.87 (4H, s),
3.48 (3H, s), 4.68 (1H, s), 5.15 (2H, s), 6.74 (1H, d, J = 7.9
Hz), 6.85 (1H, t, J = 6.9Hz), 6.9-7.0 (2H, m), 7.05-7.15
(4H, m). (Q) 2- [2- (2-cyanophenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.9-3.2 (4H,
m), 4.99 (1H, s), 6.76 (1H, d, J = 7.9Hz), 6.83 (1H, t, J = 7.
3Hz), 7.04 (1H, d, J = 7.3Hz), 7.10 (1H, t, J = 7.9Hz), 7.2-
7.35 (2H, m), 7.49 (1H, t, J = 7.3Hz), 7.61 (1H, d, J = 7.9H
z). (R) 2- [2- (3-cyanophenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.75-3.1 (4H,
m), 4.87 (1H, s), 6.74 (1H, d, J = 7.9Hz), 6.84 (1H, t, J = 7.
3Hz), 7.01 (1H, d, J = 7.3Hz), 7.09 (1H, t, J = 7.9Hz), 7.3-
7.55 (4H, m). (S) 2- [2- (4-cyanophenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.85-3.1 (4H,
m), 4.81 (1H, s), 6.74 (1H, d, J = 7.9Hz), 6.84 (1H, t, J = 7.
3Hz), 7.01 (1H, d, J = 7.3Hz), 7.09 (1H, t, J = 7.9Hz), 7.27
(2H, d, J = 8.6Hz), 7.55 (2H, d, J = 8.6Hz). (T) 2- [2- (3-difluoromethoxyphenyl)
Ethyl] phenol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.91 (4H, s),
4.90 (1H, s), 6.44 (1H, t, J = 74.6Hz), 6.7-7.2 (6H, m), 7.
25 (1H, t, J = 7.6Hz).

[0153]

Reference Example 4 14 g of 2- [2- (3-chlorophenyl) ethyl] phenol 3-chlorobenzaldehyde and 2-benzyloxybenzyltriphenylphosphonium chloride 59.4
18 g of 1,8-diazabicyclo [5.4.0] undesa-7-ene in 300 ml of acetonitrile was reacted in the same manner as in Reference Example 2, extraction operation was performed, and the extract was subjected to silica gel column chromatography treatment ( Solvent system: hexane / ethyl acetate = 9/1) to give 2-benzyloxy-
28.8 g of 3'-chlorostilbene was obtained. Of this, 5.4 g
Is dissolved in a mixture of 60 ml of benzene and 40 ml of ethanol,
300 mg of tris (triphenylphosphine) rhodium (I) chloride was used as a catalyst and stirred under a hydrogen atmosphere for 1 day. The reaction solution was treated by adding an aqueous solution of sodium hydrogen sulfite in which a small amount of sodium metabisulfite was suspended, insoluble matter was removed by filtration, and ethyl acetate was added to the filtrate, which was washed with water. The extract layer was washed twice more with brine, dried and concentrated. The residue thus obtained was subjected to silica gel column chromatography treatment (solvent system: hexane / ethyl acetate = 20/1) to obtain 5.35 g of benzyl 2- [2- (3-chlorophenyl) ethyl] phenyl ether. This was dissolved in 50 ml of methylene chloride, 17 ml of a 1M boron tribromide-methylene chloride solution was added under ice cooling, and the mixture was allowed to stand at room temperature for 2 hours. The reaction solution was removed under reduced pressure, and the residue was subjected to silica gel column chromatography treatment (solvent system: hexane / ethyl acetate = 10/1) to obtain 3.8 g of the title compound as a solid. NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.89 (4H, s),
4.5-4.9 (1H, br), 6.74 (1H, d, J = 7.9Hz), 6.86 (1H, t, J = 7.
9Hz), 7.0-7.3 (6H, m).

[0154]

Reference Example 5 In the same manner as in Reference Example 4, the following phenols were synthesized using the corresponding aldehyde and 2-benzyloxybenzyltriphenylphosphonium chloride. (A) 2- [2- (2-chlorophenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.85-3.1 (4H,
m), 4.77 (1H, s), 6.78 (1H, d, J = 7.9Hz), 6.87 (1H, t, J = 7.
6Hz), 7.1-7.3 (5H, m), 7.3-7.4 (1H, m). (B) 2- [2- (4-chlorophenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.89 (4H, s),
4.61 (1H, s), 6.74 (1H, d, J = 7.9Hz), 6.85 (1H, t, J = 7.3H
z), 7.0-7.15 (4H, m), 7.2-7.3 (2H, m). (C) 2- [2- (2-fluorophenyl) ethyl] fluoro
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 2.85-3.05 (4H,
m), 4.72 (1H, s), 6.77 (1H, d, J = 7.9Hz), 6.86 (1H, t, J = 7.
3Hz), 7.0-7.25 (6H, m). (D) 2- [2- (3-fluorophenyl) ethyl] fluoro
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 2.91 (4H, s),
4.65 (1H, s), 6.7-7.3 (8H, m). (E) 2- [2- (4-fluorophenyl) ethyl] fluoro
Phenol NMR spectrum _{(270MHz, CDCl 3) δppm:} 2.89 (4H, s),
4.61 (1H, s), 6.74 (1H, d, J = 8.6Hz), 6.8-7.3 (7H, m). (F) 2- [2- (3-bromophenyl) ethyl] fe
Nol NMR spectrum (270MHz, CDCl ₃ ) δppm: 2.89 (4H, s),
4.67 (1H, s), 6.74 (1H, d, J = 7.9Hz), 6.86 (1H, t, J = 7.3H
z), 7.0-7.2 (4H, m), 7.3-7.4 (2H, m).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location A61K 31/55 ABN 7431-4C C07D 207/12 8217-4C 211/22 9165-4C 211/40 9165 -4C 223/04 265/30 279/12 521/00 8314-4C (72) Inventor Fukumi Ito Fukumi 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Hiroyuki Koike Tokyo 1-2-2 Hiromachi, Shinagawa-ku Sankyo Co., Ltd.

Claims (4)

[Claims] 1. A general formula: [In the formula, R ¹ represents a 5- to 7-membered heterocyclyl group (wherein a nitrogen atom on the ring may be substituted with a lower alkyl group or an aryl group, and a carbon atom on the ring may be a lower alkyl group; An alkyl group,
A lower alkynyl group, a lower alkenyl group, a lower alkoxy group, a hydroxyl group, a protected hydroxyl group, a substituted hydroxyl group, a carbamoyloxy group or a substituted carbamoyloxy group may be substituted. ) Is a group bonded at a carbon atom on the ring, R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom,
Lower alkyl group, lower alkynyl group, lower alkenyl group, lower alkoxy group, halogeno lower alkoxy group, hydroxyl group, protected hydroxyl group, carbamoyl group, substituted carbamoyl group, halogen atom, cyano group or aryl group, and m is , 0 to 4 are shown. ] The alicyclic amine derivative represented by these, and its salt. 2. A 5- to 7-membered heterocyclyl group (wherein R ¹ has a lower alkyl group or an aryl group at the nitrogen atom on the ring, and a lower alkyl group at the carbon atom on the ring), A lower alkoxy group, a hydroxyl group, a protected hydroxyl group, or a substituted hydroxyl group may be substituted), which is a group bonded at a carbon atom on the ring, and R ² , R ³ and R ⁴ are , The same or different, a hydrogen atom,
The alicyclic amine derivative or a salt thereof according to claim 1, which is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a hydroxyl group, a protected hydroxyl group or an aryl group, and m is an integer of 0 to 3. 3. A 5- to 6-membered heterocyclyl group (wherein R ¹ has a lower alkyl group at the nitrogen atom on the ring;
The carbon atom on the ring may be substituted with a hydroxyl group or a protected hydroxyl group. ), A group bonded at a carbon atom on the ring, wherein R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom,
The alicyclic amine derivative and salt thereof according to claim 1, wherein the alicyclic amine derivative is a lower alkoxy group, a halogeno lower alkyl group, or a hydroxyl group, and m is an integer of 0 to 2. 4. A serotonin 2 receptor antagonist comprising the compound according to claim 1 selected from claims 1 to 3.