JP2000086603A - Cinnamamide derivatives and 3-phenylpropionamide derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having selective affinity to 5- hydroxytriptamine 1A receptor of central nervous system as well as antagonistic activity and useful as an antianxiety agent. SOLUTION: The objective compound is expressed by formula I [the dotted line is double bond or single bond; X is H, a 1-8C alkoxy or the like; R1 is HN-Y-R2 (Y is a 3-8C cycloalkyl or the like; R2 is an aryl or the like) or the like; R3 is H, a 1-18C alkyl or the like; R4 is N(R7)R8 (R7 and R8 are each H, a 1-18C alkyl or the like) or the like; Ra, Rb and Rc are each H, a 1-18C alkyl or the like], e.g. 3-(2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidin-1-yl) propyloxy)phenyl)propionylpyrrolidine. The compound of formula I can be produced by reacting a compound of formula II with a compound of formula III and reacting the resultant compound of formula IV with a compound of the formula H-R1.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to compounds that act on 5-hydroxytryptamine (5-HT) neurotransmission. In particular, the present invention is a compound having a selective affinity for the 5-hydroxytryptamine 1A (5-HT _1A ) receptor in the central nervous system, at the same time exhibiting antagonist activity, and inhibiting the uptake of 5-HT The present invention relates to novel cinnamamide derivatives and 3-phenylpropionamide derivatives useful as active pharmaceutical agents, and therapeutic agents for depression or the like containing the compounds. 5-
Hydroxytryptamine (5-HT) is "serotonin"
Also known as

[0002]

2. Description of the _Related Art Compounds which exhibit antagonist activity at the 5-HT _1A receptor and simultaneously inhibit 5-HT reuptake include, for example, 1- (4-indolyloxy) -3- (4 -(3,4-methylenedioxyphenyl) piperidin-1-yl) -2-propanol derivative (EP0722491), 4- (4-fluorophenyl) -1- (6-methylaminoindan-1-ylmethyl) piperidine derivative (WO95 / 33721),
3,6-dihydro-N-methyl-N- (5-chloro-2
-Pyridinyl) -4- (1-naphthalenyl) -1- (2
H) Pyridinepropanamine derivatives (US Pat. No. 547)
2966), 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-
b] Thiazole derivative (WO97 / 02269), S-
(-)-N- (2- (3- (2-naphthyl) pyrrolidino) ethyl) -N- (2-pyridyl) cyclohexanecarboxamide derivative (WO97 / 40038),
(R) -3- (N-cyclopentyl-Nn-propylamino) -8-fluoro-5-N-methylcarbamoyl-3,4-dihydro-2H-1-benzopyran derivative (WO96 / 33710), 3- (2- (4-methylpiperazin-1-yl) benzylidene) -1,3-dihydroindol-2-one derivative (WO97 / 3686)
7), 1- (4-Indolyloxy) -3- [4-hydroxy-4- (2-naphthyl) piperidin-1-yl]
Propan-2-ol derivative (WO97 / 48698)
Etc. are known.

Japanese Patent Application Laid-Open No. Sho 62-116557 discloses a compound having a binding ability to a serotonin receptor and a muscarinic acetylcholine receptor and used for treating senile dementia, Alzheimer's disease, cerebrovascular dementia and the like. Substituted benzyl lactams such as hydroxy-1- [2- (2-oxo-4-pyrrolidinylmethyl) phenoxy] -3- (4-diphenylmethyl-piperazin-1-yl) propane are disclosed.

[0004]

Various central nervous system diseases such as depression and anxiety may be caused by disorders of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT). . That is,
Enhanced 5-HT neurotransmission primarily affects depressed mood and anxiety, while enhanced noradrenaline neurotransmission appears to affect delayed symptoms in depressed patients. Drugs such as imipramine, desipramine, etc., which are most frequently used to treat depression, are thought to act by improving the neurotransmission of one or both of these. 5-HT activity is thought to be involved in many different types of mental disorders. In addition, 5-HT has been implicated in various conditions, such as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior. However, conventional antidepressants such as imipramine and desipramine are disadvantageous in that it takes 3 to 4 weeks or more to develop an antidepressant effect, which is a clinical problem.

[0005] In order to accelerate the onset of the effects of antidepressants or to improve the effective rate, the use of various drugs has been studied (Journal of C).
linear Psychiatry, Vol. 5
7; Suppliment 7; pp25-31). Among them, a selective serotonin (5-HT) reuptake inhibitor (selective serotonin reu)
ptake inhibitor (SSRI) to 5-H
It has been reported that the combined use of pindolol, a T _1A antagonist, markedly shortens the onset of clinical effects (Jou
rnal ofClinical Psychopha
rmology, Vol. 17, No. 6, pp.
446-450). On the other hand, the amount of 5-HT released in the brain is
It has been found that SSRI alone does not increase significantly, but increases significantly when a 5-HT _1A antagonist is used in combination (Neurochemical Research,
Vol. 21, No. 5, 1996, p. 557-5
62). Under these circumstances, regarding the onset of action of antidepressants, Bl
er and de Montigny proposed the “5-HT enhancement hypothesis” (Trends in Phar).
maclogical Sciences, 199
4, vol. 15, pp. 220-226). 5-HT
The hypothesis is that "the mechanism of response of antidepressants is 5 at the end.
-HT release enhancement. The above-mentioned antidepressants reduce 5-HT release in a single dose, and increase 5-HT release only by continuous administration, so that an antidepressant effect is exhibited. From these facts, it is expected that a drug that promotes 5-HT release in the brain from the beginning can be a rapid-acting antidepressant. That is, it is considered that a compound having both a serotonin reuptake inhibitory action and a 5-HT _1A antagonistic action can be a so-called immediate-acting antidepressant having a fast antidepressant action.

It is an object of the present invention to have an affinity for the 5-hydroxytryptamine (5-HT) receptor subgroup, a 5-HT _1A receptor in the central nervous system of mammals, including humans, Another object of the present invention is to find a compound which exhibits antagonist activity and has an activity of inhibiting 5-HT uptake. That is, the present invention provides a so-called immediate-acting antidepressant drug which has a rapid onset of antidepressant action, and a disease of the central nervous system mediated by 5-HT, for example, schizophrenia, anxiety, obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), seasonal affective disorder (seasonal affective disorder)
der), anorexia nervosa, bulimia, nocturnal enuresis, pediatric hyperactivity disorder, traumatic stress disorder (PTSD), senile dementia, migraine, stroke, Alzheimer's disease, cognitive dysfunction, hypertension, gastrointestinal dysfunction, feeding disorder
disorders), abnormal thermoregulation and sexual abnormalities,
It is intended to provide compounds useful for treating pain as well as for treating abnormalities in the cardiovascular system.

[0007]

Means for Solving the Problems As a result of diligent studies, the present inventors have found that novel cinnamamide derivatives and 3-phenylpropionamide derivatives represented by the general formula (I), optical isomers thereof or optical isomers thereof It has been found that a pharmaceutically acceptable salt has both a serotonin reuptake inhibitory action and a 5-HT _1A antagonistic action, and can be a so-called immediate-acting antidepressant with a rapid onset of antidepressant action.
HT-mediated diseases of the central nervous system such as schizophrenia, anxiety, threatening disorder (OCD), panic disorder, social phobic disorder
a), seasonal affective disorder (seasonal effect)
active disorder, anorexia nervosa, bulimia, nocturnal enuresis, pediatric hyperactivity disorder, traumatic stress disorder (PTSD), senile dementia, migraine, stroke, Alzheimer's disease, cognitive dysfunction, hypertension, gastrointestinal dysfunction, feeding disorders ), And found that it could be a useful agent for treating abnormal thermoregulation and sexual abnormalities, pain, and for treating abnormalities in the cardiovascular system, and completed the present invention. That is, the present invention is as follows. 1. General formula (I)

[0008]

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Or a pharmaceutically acceptable salt thereof or a hydrate thereof. In the above formula, the definition of each symbol is as follows. The bond represented by the solid line and the dotted line indicates a double bond or a single bond. X is
It represents a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 8 carbon atoms or a halogen. R ¹ represents a group represented by the following formula.

[0010]

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(Wherein, Y represents cycloalkyl having 3 to 8 carbon atoms which may have a substituent or alkylene having 1 to 8 carbon atoms which may be branched; m,
n represents 0, 1, or 2 each independently. Ar is
The aryl group which may have a substituent is shown. R ² is
It represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. R ⁵ is
It represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Z represents absent or CH _2. R ⁶ represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 8 carbon atoms. R ³ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms or a halogen atom. R ⁴ represents a group represented by the following formula.

[0012]

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(Wherein R ⁷ and R ⁸ are each independently
It represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl or aralkyl which may have a substituent. R ⁹ represents a hydrogen atom, an aryl group which may have a substituent, an alkyl group having 1 to 18 carbon atoms, an alkoxy group or an acyl group having 1 to 8 carbon atoms. Ra, Rb, Rc are the same or different and each is a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a hydroxy group, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an acyl group, a nitro group or an amino group. Is shown.
Alternatively, Ra and Rb or Rb and Rc are bonded to each other to form —CH ₂ CH ₂ CH ₂ CH ₂ — or —CH ＝ C
H-CH = CH- may be formed.

2. In the general formula (I), the compound according to the above 1, wherein each symbol is defined as follows, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The bond represented by the solid line and the dotted line indicates a double bond or a single bond. X represents a hydroxy group. R ¹ represents a group represented by the following formula.

[0015]

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(In the formula, R ⁵ represents a phenyl group or a naphthyl group which may have a substituent; Z does not exist; R ⁶ represents hydrogen.) R ³ represents a hydrogen atom or a carbon atom having 1 carbon atom. Represents up to 4 alkyl groups. R ⁴ represents a group represented by the following formula.

[0017]

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(Wherein R ⁷ and R ⁸ are each independently
It represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R
⁹ represents a phenyl group or an alkyl group having 1 to 4 carbon atoms. ) Ra, Rb and Rc all represent a hydrogen atom. Further, the present invention provides a pharmaceutical composition comprising a cinnamamide derivative and a 3-phenylpropionamide derivative of the general formula (I), an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and There is also provided a drug comprising a novel cinnamamide derivative and a 3-phenylpropionamide derivative of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION Specific examples of each group in the above general formula (I) are as follows. The cycloalkyl having 3 to 8 carbon atoms which may have a substituent in Y of R ¹ is
Represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
Examples of the substituent include alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, Examples thereof include alkoxy having 1 to 8 carbon atoms such as pentyloxy, hexyloxy, heptyloxy, and octyloxy, hydroxy, oxo, and hydrogen. Y of R ¹
And the alkylene having 1 to 8 carbon atoms which may be branched are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2- Methyl ethylene, 1,1
-Dimethylethylene, 2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene,
2-ethylethylene, 1-methyltrimethylene, 1,1
-Dimethyl trimethylene, 2-methyl trimethylene,
2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltrimethylene and the like, and ethylene, trimethylene or tetramethylene Is preferred.

The optionally substituted aryl in Ar, R ² , R ⁵ , R ⁷ , R ⁸ , and R ⁹ represents phenyl, naphthyl and the like. In R ⁵ , naphthyl (1-naphthyl, 2-naphthyl) and 3,4-dimethylphenyl are preferred. The aromatic heterocyclic group which may have a substituent in R ² and R ⁵ is pyridyl, furyl, thienyl, pyrimidinyl, indol-2-yl, benzo [b] thiophen-2-yl, benzo [b] Franc-2
-Yl, 3,4-methylenedioxyphenyl and the like. These substituents include halogen (such as fluorine, chlorine, and bromine), haloalkyl (such as fluoromethyl, difluoromethyl, and trifluoromethyl), and alkyl having 1 to 4 carbon atoms (methyl, ethyl, propyl, and isopropyl).
Butyl, isobutyl, tertiary butyl, etc.)
8 alkoxy (methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, etc.), hydroxy, nitro, cyano, amino, mono- or dialkylamino having 1 to 4 carbon atoms (methylamino, dimethyl) Amino, diethylamino, dipropylamino, etc.), acyl (acetyl, propionyl, butyryl, etc.), alkenyl having 2 to 6 carbons (vinyl, 1-propenyl, 2-propenyl, 3-propenyl, etc.), 2 to 6 carbons Alkynyl (ethynyl, 1-propynyl, 2-propynyl, etc.), phenyl, phenoxy, benzyloxy, C1-C4 alkyl-S (O) t-, phenyl-S (O) t- (where t is 0, 1
Or 2 is indicated. ), Carbamoyl, N, N-dialkylcarbamoyl (N, N-dimethylcarbamoyl, N, N
N-diethylcarbamoyl, N, N-dipropylcarbamoyl, etc.).

The alkoxy group having 1 to 8 carbon atoms in X, R ⁶ , R ⁹ , Ra, Rb and Rc means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, It represents hexyloxy, heptyloxy or octyloxy, and is preferably alkoxy having 1 to 4 carbon atoms, particularly preferably methoxy. X,
The halogen atom in R ³ , Ra, Rb and Rc represents fluorine, chlorine, bromine or iodine, and fluorine is preferred.
The alkyl group having 1 to 18 carbon atoms in R ³ , R ⁷ , R ⁸ , R ⁹ , Ra, Rb, and Rc means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl , Heptyl, octyl, decyl, hexadecyl, octadecyl, etc.
Preferred is 4 alkyl, especially methyl, ethyl. R
The acyl group in ⁹ , Ra, Rb and Rc refers to acetyl, propionyl, butyryl, pentanoyl, hexanoyl, benzoyl and the like, and an acyl group having 2 to 3 carbon atoms is particularly preferable. The aralkyl in R ⁷ and R ⁸ represents a group in which an alkyl having 1 to 4 carbon atoms is substituted with a phenyl group, and is benzyl, 2-phenylethyl, 1-phenylethyl, 1,1-dimethyl-2-phenylethyl. , 3
-Phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 1-phenylbutyl, etc., with benzyl being preferred. X represents a hydrogen atom, hydroxy, methoxy, ethoxy, isopropoxy, chlorine,
Bromine and the like are mentioned, and hydroxy is preferred.

Specific examples of R ¹ include 1-benzylpiperidin-4-ylamino, 4-phenylcyclohexyl-1-ylamino, indanone-2-ylamino and 4-phenylcyclohexyl-1-ylamino.
Hydroxy-4- (4-chlorophenyl) piperidine-
1-yl, 4-hydroxy-4- (2-naphthyl) piperidin-1-yl, 4-hydroxy-4- (benzo [b] thiophen-2-yl) piperidin-1-yl,
4-benzylpiperidin-1-yl, 4- (4-fluorobenzyl) piperidin-1-yl, 4- (4-chlorobenzyl) piperidin-1-yl, 4- (4-bromobenzyl) piperidin-1-yl , 4-phenylpiperidin-1-yl, 4- (4-fluorophenyl) piperidin-1-yl, 4- (4-chlorophenyl) piperidin-1-yl, 4- (4-bromophenyl) piperidin-
1-yl, 4- (4-methoxyphenyl) piperidine-
1-yl, 4- (4-methylphenyl) piperidine-1
-Yl, 4- (4-trifluoromethylphenyl) piperidin-1-yl, 4- (3-chlorophenyl) piperidin-1-yl, 4- (3-fluorophenyl) piperidin-1-yl, 4- (3 -Trifluoromethylphenyl) piperidin-1-yl, 4- (3-bromophenyl) piperidin-1-yl, 4- (3-methoxyphenyl) piperidin-1-yl, 4- (3-methylphenyl) piperidin- 1-yl, 4- (2-fluorophenyl) piperidin-1-yl,

4- (2-chlorophenyl) piperidine-
1-yl, 4- (2-bromophenyl) piperidine-1
-Yl, 4- (2-methylphenyl) piperidine-1-
Yl, 4- (2-methoxyphenyl) piperidine-1-
Yl, 4- (3,4-dichlorophenyl) piperidine-
1-yl, 4- (3,4-dimethylphenyl) piperidin-1-yl, 4- (3,4-dimethoxyphenyl) piperidin-1-yl, 4- (3,4-methylenedioxyphenyl) piperidin- 1-yl, 4- (2,3-dimethoxyphenyl) piperidin-1-yl, 4- (2,3
-Dimethylphenyl) piperidin-1-yl, 4-
(2,3-dichlorophenyl) piperidin-1-yl,
4- (3,5-dimethoxyphenyl) piperidine-1-
Yl, 4- (3,5-dimethylphenyl) piperidine-
1-yl, 4- (3,5-dichlorophenyl) piperidin-1-yl, 4- (2,6-dimethoxyphenyl) piperidin-1-yl, 4- (3,4,5-trimethoxyphenyl) piperidin- 1-yl, 4- (1-naphthyl) piperidin-1-yl, 4- (2-naphthyl) piperidin-1-yl, 4- (6-methoxynaphthalene-2
-Yl) piperidin-1-yl, 4- (benzo [b] thiophen-2-yl) piperidin-1-yl, 4- (benzo [b] furan-2-yl) piperidin-1-yl,
4- (indol-2-yl) piperidin-1-yl,
4- (4-fluorobenzyl) -3,6-dihydro-2
H-pyridin-1-yl, 4- (4-chlorobenzyl)
-3,6-dihydro-2H-pyridin-1-yl, 4-
(4-bromobenzyl) -3,6-dihydro-2H-pyridin-1-yl, 4-phenyl-3,6-dihydro-
2H-pyridin-1-yl, 4- (4-fluorophenyl) -3,6-dihydro-2H-pyridin-1-yl,

4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (4-bromophenyl) -3,6-dihydro-2H-pyridin-1-
Yl, 4- (4-methoxyphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (4-methylphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (4-trifluoromethylphenyl) -3,6
-Dihydro-2H-pyridin-1-yl, 4- (3-chlorophenyl) -3,6-dihydro-2H-pyridine-
1-yl, 4- (3-fluorophenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (3-trifluoromethylphenyl) -3,6-dihydro-2H-pyridin-1- Yl, 4- (3-bromophenyl) -3,
6-dihydro-2H-pyridin-1-yl, 4- (3-
Methoxyphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (3-methylphenyl) -3,6-
Dihydro-2H-pyridin-1-yl, 4- (2-fluorophenyl) -3,6-dihydro-2H-pyridin-
1-yl, 4- (2-chlorophenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (2-bromophenyl) -3,6-dihydro-2H-pyridin-1-yl, -(2-methylphenyl) -3,6-dihydro-
2H-pyridin-1-yl, 4- (2-methoxyphenyl) -3,6-dihydro-2H-pyridin-1-yl,
4- (3,4-dichlorophenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (3,4-dimethylphenyl) -3,6-dihydro-2H-pyridin-1-
Il,

4- (3,4-dimethoxyphenyl)-
3,6-dihydro-2H-pyridin-1-yl, 4-
(3,4-methylenedioxyphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (2,3-dimethoxyphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (2,3-dimethylphenyl) -3,
6-dihydro-2H-pyridin-1-yl, 4- (2,
3-dichlorophenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (3,5-dimethoxyphenyl) -3,6-dihydro-2H-pyridin-1-yl,
4- (3,5-dimethylphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (3,5-dichlorophenyl) -3,6-dihydro-2H-pyridin-1-
Yl, 4- (2,6-dimethoxyphenyl) -3,6-
Dihydro-2H-pyridin-1-yl, 4- (3,4,
5-trimethoxyphenyl) -3,6-dihydro-2H
-Pyridin-1-yl, 4- (1-naphthyl) -3,6
-Dihydro-2H-pyridin-1-yl, 4- (2-naphthyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (6-methoxynaphthalen-2-yl) -3,
6-dihydro-2H-pyridin-1-yl, 4- (benzo [b] thiophen-2-yl) -3,6-dihydro-
2H-pyridin-1-yl, 4- (benzo [b] furan-2-yl) -3,6-dihydro-2H-pyridin-1
-Yl, 4- (indol-2-yl) -3,6-dihydro-2H-pyridin-1-yl and the like.

R ¹ is 4- (3,4-dimethylphenyl) piperidin-1-yl, 4- (1-naphthyl) piperidin-1-yl, 4- (2-naphthyl) piperidin-1-yl, -(6-methoxynaphthalen-2-yl) piperidin-1-yl, 4- (3,4-dimethylphenyl) -3,6-dihydro-2H-pyridin-1-yl, 4- (1-naphthyl)- 3,6-dihydro-2H-
Pyridin-1-yl, 4- (2-naphthyl) -3,6-
Dihydro-2H-pyridin-1-yl, 4- (6-methoxynaphthalen-2-yl) -3,6-dihydro-2H
-Pyridin-1-yl and the like are particularly preferred.

R ³ is preferably a hydrogen atom or an alkyl having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl). Specific examples of R ⁴ include:
Amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, butylamino, dibutylamino, phenylamino, diphenylamino, benzylamino, dibenzylamino, phenethylamino, 3- Phenylpropylamino, 4-phenylbutylamino, N-methyl-N-phenylamino,
(1,1-dimethyl-2-phenylethyl) amino, 1
-Pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, 1-pyrrolyl, 1-pyrazolyl, 1-imidazolyl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl, 4-acetylpiperazin-1-
Yl, 4-methoxypiperidin-1-yl and the like. As Ra, Rb, and Rc, 0 to 3 may be present on the ring, and a hydrogen atom, fluorine, chlorine, bromine, methyl,
Ethyl, methoxy, methylenedioxy, hydroxy, acetyl and the like.

Preferred compounds of the general formula (I) include:
(18) 3- (2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) phenyl) propionylpyrrolidine, (2
1) 3- (2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) phenyl) propionylpiperidine, (27)
(3- (2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) phenyl) propionyl) morpholine, (34)
2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cinnamamide, (69) 1- (2 '-(3- (4- (naphthalen-1-yl) -3,6-dihydro-2H-pyridin-1-yl) ) -2-Hydroxypropyloxy) cinnamoyl) pyrrolidine, (70) 1- (2 ′-(3-
(4- (naphthalen-2-yl) -3,6-dihydro-
2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) pyrrolidine, (88) 1-
(2 ′-(2-hydroxy-3- (4- (naphthalene-
1-yl) piperidin-1-yl) propyloxy) cinnamoyl) pyrrolidine, (89) 1- (2 ′-(2-
Hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) pyrrolidine, (90) 1- (2 ′-(2-hydroxy-3)
-(4- (6-methoxynaphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) pyrrolidine, (124) 1- (2 '-(2-hydroxy-3)
-(4- (3,4-dimethylphenyl) -3,6-dihydro-2H-pyridin-1-yl) propyloxy) cinnamoyl) morpholine, (127) 1- (2 '-(3
-(3,6-dihydro-4- (naphthalen-1-yl)
-2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) morpholine, (128) 1-
(2 ′-(3- (3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) morpholine,

(144) 1- (2 '-(2-hydroxy-3- (4- (3,4-dimethylphenyl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (146) 1- (2 '-(2-hydroxy-3-
(4- (naphthalen-1-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (1
47) 1- (2 '-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (148) 1-
(2 ′-(2-hydroxy-3- (4- (6-methoxynaphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (171) 1-
(2 '-(3- (3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) -4-methylpiperazine, (173) 1- (2 ′-(2-hydroxy-
3- (4- (naphthalen-2-yl) piperidine-1-
Yl) propyloxy) cinnamoyl) -4-methylpiperazine, (177) 1- (2 ′-(2-hydroxy-
3- (4- (naphthalen-2-yl) piperidine-1-
Yl) propyloxy) cinnamoyl) -4-phenylpiperazine, (240) (+)-1- (2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyl (Oxy) cinnamoyl) morpholine, (241) (−)-1- (2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, 244) 2 '-(2-hydroxy-3- (4-
(Naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnam-N, N-dimethylamide and (248) 2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidine -1-yl) propyloxy) cinnam-a compound selected from N, N-diethylamide or a pharmaceutically acceptable salt thereof.
The number indicates the embodiment number.

The pharmaceutically acceptable salts of the compounds of general formula (I) include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Nitric acid and the like or organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfone) Acid, ascorbic acid, etc.). Since the compound of the general formula (I) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate, these hydrates and solvates are also included in the present invention. . When the compound of the formula (I) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention.

Compounds of general formula (I) and general formula (I)
Can be synthesized by the following method. Each symbol in the following reaction formulas has the same meaning as described above unless otherwise specified. Numerous general methods for synthesizing the compound represented by the general formula (I) are known.
B, C, D, E, and F are shown. In the formula, the symbol W represents a leaving group in organic synthesis, for example, chlorine, bromine, iodine, mesylate, tosylate, nosylate, triflate and the like. Leaving groups (or nucleophiles) are well known to those skilled in organic synthesis.

[0032]

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[0033]

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The phenol derivative (1), 1 to 2,3-epoxy propanes having a leaving group followed by reaction with (2) a method by reaction with H-R ¹ (Scheme A), H −
A method of reacting R ¹ with a 2,3-epoxypropane having a leaving group at the 1-position ( 2 ), followed by a reaction with a phenol derivative ( 1 ) (reaction formula B), a carboxylic acid derivative ( 5 ) Amidates the product ( 6 ) obtained by the reaction of the compound with a 2,3-epoxypropane having a leaving group at the 1-position ( 2 ), leading to an intermediate ( 3 ), and then HR ¹ (Reaction formula C), a phenol derivative ( 1 ),
- after reaction with position to have a leaving group or Hanarekakumoto 2-propanone compound (7), the reaction with H-R ^1, a method of reducing the resulting product (9) (Scheme D ), HR ¹
With a 2-propanone having a leaving group or a nucleophilic group at the 1,3-position ( 7 ), followed by a reaction with a phenol derivative ( 1 ) to reduce the resulting product ( 9 ). the method (Scheme E), as phenol derivative (1) and 3-allyl bromide, 3-position into a leaving group, or an aryl compound having a Hanarekakumoto (11) and the product obtained by reacting (1
2 ) epoxidation and subsequent reaction with HR ¹ (reaction formula F). However,
Many methods for synthesizing the compound of the general formula (I) are known to synthetic chemists other than the methods described here, and therefore, the method for obtaining the present compound is limited to the methods described here. Not something. In particular, the optically active compound of the general formula (I) (X = OH) can be prepared by the following reaction formulas G, H,
It can be synthesized as I, J, K, L, M.

[0035]

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[0036]

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[0037]

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[0038]

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In the above formula, the symbol R * represents a portion other than the carboxyl group of the optically active carboxylic acid. The intermediate ( 12 ) obtained by the reaction formula F is subjected to asymmetric epoxidation using a catalytic amount or a stoichiometric amount of an optically active base or an asymmetric ligand, and the obtained optically active intermediate ( 3 ) and H Method by reaction with -R ¹ (reaction formula G), phenol derivative ( 1 )
When, after reaction with 2,3-epoxypropane derivative having a leaving group in the optically active 1-position (2), a method of reacting with H-R ¹ (Scheme H), and H-R ^1, the optical 2,3-epoxypropane derivatives having an active leaving group at the 1-position ( 2 )
After the reaction with the phenol derivative ( 1 ), a racemic mixture represented by the formula (I)
After condensing with an optically active carboxylic acid ( 13 ) and converting it into an optically active ester ( 14 ), two diastereomers are separated by crystallization or column chromatography (reaction formula J), reaction formula A method of asymmetrically reducing the intermediate ( 9 ) obtained in D and E using a chiral ligand (reaction formula K), a racemic mixture represented by the formula (I), and an optically active carboxylic acid ( 13 ) A salt between the two isomers to separate both isomers by utilizing the difference in crystallinity (reaction formula L). The racemic mixture represented by the formula (I) is reacted with a carboxylic acid by a condensation reaction. A method of once converting an ester into an ester and then enantioselectively hydrolyzing the ester using an enzyme (reaction formula M). However, many methods for obtaining the optically active compound of the formula (I) are known to synthetic chemists other than the methods mentioned here, and therefore, the method for obtaining the present compound is based on the method shown here. It is not limited. Compounds of the general formula (I) wherein X is a hydrogen atom are represented by the following reaction formulas N, O, P
Can be synthesized as follows.

[0040]

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An intermediate ( 18 ) is synthesized by reacting the phenol derivative ( 1 ) with a propane derivative ( 17 ) having a leaving group or a nucleophilic group at the 1,3-position, and this intermediate ( 18 )
And H-R ¹ and a method of engaging the presence condensation of an acid acceptor (Scheme N) and a H-R ^1, the propane derivative having a leaving group or Hanarekakumoto 1,3-position (17) Intermediate ( 19 ) is synthesized by the reaction, and the intermediate ( 19 ) and the phenol derivative ( 1 ) are condensed in the presence of a deoxidizing agent (reaction formula O), and the formula (I, X = OH) A method of reducing the hydroxyl group of the compound represented (reaction formula P) and the like can be mentioned. Further, among the compounds represented by the general formula (I), X =
The compound of alkoxy and halogen is represented by the following formula Q.
It can be derived from a compound of general formula (I) where X = OH.

[0042]

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The symbol R ¹⁰ represents an alkyl group. By alkylating or halogenating the hydroxy group of the compound of the general formula (I) wherein X = OH, X is
A compound having an alkoxy group and a halogen atom can be synthesized (reaction formula Q). Reaction formulas A, B, D, E, F, H,
The phenol derivative (1) used for I, N, and O can be synthesized by the method of Reaction Formula R.

[0044]

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The phenol derivative ( 1 ) is prepared by reacting the carboxylic acid derivative ( 5 ) with HR ⁴ together with various condensing agents, by esterifying the carboxylic acid derivative ( 5 ) and then reacting with HR ⁴ , or once, such as an acid halide. after the state of being an activated, is reacted with H-R ^4, it can be synthesized by methods such as (Scheme R). However, many methods for obtaining the phenol derivative ( 1 ) are known to synthetic chemists other than the methods described here, and therefore, the method for obtaining the present compound is not limited to the methods described here. . In particular, the 3-phenylpropionamide derivative is a dihydrocoumarin derivative ( 2
And 2) can be obtained by reaction with H-R ^4.

[0046]

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The carboxylic acid derivative (5) used in Reaction Formulas C and R can be synthesized by the methods shown in Reaction Formulas T, U, V and W.

[0048]

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The symbol PG means a protecting group for isolating the nucleophilicity of the hydroxyl group. Examples of the protecting group include a methoxymethyl group, a benzyl group, a methyl group, an acetyl group, and a methoxyethyl group. The carboxylic acid intermediate ( 5 ) is ( 2 )
It can be derived by reacting the intermediate represented by 3 ) with a Horner Emmons reagent such as diethylphosphonoacetic acid ethyl ester ( 24 ) (reaction formula T). Also benzaldehyde derivatives ( 26 )
And an aldol reaction with an alkyl ester represented by the formula ( 27 ), and the resulting alcohol form ( 28 )
(Reaction formula U).
Similarly, after the aldol reaction of the intermediate ( 23 ) with the acetate ( 29 ), the alcohol ( 28 ) produced
(Reaction formula V).
By performing the hydrogenation reaction of the thus obtained intermediate (5), it is possible to obtain a single bond Intermediate (5) (Scheme W). Again, a number of methods for synthesizing these compounds are known to synthetic chemists besides those listed here, and thus the method of obtaining the present compounds is not limited to the methods shown here. Absent. These reactions and their application, which ultimately lead to the general formula (I) of the present invention, are well known to those skilled in organic chemical synthesis. Improvements in adapting the conditions and reagents to those described, as well as methods for synthesizing particular compounds of general formula (I), including compounds of the present invention, are known to synthetic chemists. . For a more detailed description, each synthesis example is described in the Examples section.

The compound of the general formula (I) obtained as described above has a high affinity for the 5-HT _1A receptor,
In addition, since it also has a strong inhibitory action on 5-HT reuptake, it can be an effective drug for diseases associated with dysfunction of serotonergic neurotransmission. That is, the compound of the present invention is useful as a so-called fast-acting antidepressant with a rapid onset of antidepressant action, and is a disease of the central nervous system mediated by 5-HT, such as schizophrenia, anxiety neurosis,
Threatening disorder (OCD), panic disorder, social anxiety disorder (social phobia), seasonal affective disorder (s
easy effective disorder
r), anorexia nervosa, bulimia, nocturnal enuresis, childhood hyperactivity disorder, traumatic stress disorder (PTSD), senile dementia, migraine, stroke,
Alzheimer's disease, cognitive impairment, hypertension, gastrointestinal disorders, feeding disorder
Orders), thermoregulatory and sexual abnormalities, pain and the treatment of mammals, including humans, including abnormalities in the cardiovascular system, drug abuse, and the like. The use of the compounds of the present invention as medicaments includes the systemic administration of a pharmaceutically acceptable amount of a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof to a mammal. The dosage must be carefully adjusted in each case, and generally takes into account parenteral administration, taking into account age, weight, and condition of the subject, the route of administration, and the nature and severity of the disease. The daily dose is 0.01-100 mg / k
g, preferably 0.1-1 mg / kg, and 0.5-10 mg / kg, preferably 1-5 mg for oral administration.
mg / kg. Administration includes oral, rectal and parenteral (including, for example, muscle, intravenous, transdermal and subcutaneous) administration.

The compounds of the present invention may be administered for the purpose of antidepressant as a single therapeutic agent or as a mixture with other therapeutic agents. Therapeutically, they are generally given as a pharmaceutical composition comprising an antidepressant amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. About 1 to 50 per unit dose
A pharmaceutical composition giving 0 mg of active ingredient is desirable,
It is prepared by conventional methods as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. The nature of the pharmaceutical composition employed will, of course, depend on the intended route of administration. For example, oral compositions may be tablets or capsules and may contain conventional excipients such as a binder (such as starch) and a humectant (such as sodium lauryl sulfate). Solutions or suspensions of the compounds, including conventional pharmaceutical vehicles, may be used for parenteral administration, such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injection.

[0052]

EXAMPLES The present invention will now be described by way of examples of raw material synthesis, working examples, and preparation processes.
The present invention will be described in detail with reference to
Is not limited in any way. In the following examples
Temperature is expressed in degrees Celsius, and the melting point is corrected
Not in. Nuclear magnetic resonance (NMR) spectral properties are
Lamethylsilane (TMS) was used as a standard for comparison.
Chemical shift (δ) is expressed in ppm. 1H-N
Relative area at various shifts in MR spectral data
Corresponds to the number of hydrogen atoms of the functional group in the molecule. shift
The multiplicity property of is broad, broad
Singlet (bs), singlet (s), multiplet (m), 5
Double line is (penth), quadruple line is (q), triple line is
(T) or the double line is described as (d). DMS
Od₆Is an abbreviation for deuterated dimethyl sulfoxide
And CDCl _ThreeIs an abbreviation for deuterated chloroform
And other abbreviations use conventional ones.
The unit of the coupling constant J is represented by. Analytical thin layer chromatography
Matography (TLC) is 0.25mm EM silica
Performed on a glass plate coated with Gel 60F-254. Ma
Preparative chromatography was performed using EM silica gel.
went. The solvent used was reagent grade.

Raw Material Synthesis Example 1 3- (2-hydroxyphenyl) propionamide Dihydrocoumarin 2 was added to 30 mL of aqueous ammonia under ice-cooling.
0 mL was added and stirred vigorously. When 5 mL of tetrahydrofuran was added to this heterogeneous mixture, heat was immediately generated, and the mixture became homogeneous. After confirming the completion of the reaction by TLC, the mixture was neutralized with hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain 19 g of a white solid. This crude product was used for the next reaction without purification. Melting point 71-73 ° C

Material Synthesis Example 2 4- (3- (2-hydroxyphenyl) propionyl)
Morpholine 15 mL of dihydrocoumarin was added to 10 mL of THF (tetrahydrofuran) containing 11 mL of morpholine under ice-cooling, followed by vigorous stirring. After confirming the completion of the reaction by TLC, the mixture was neutralized with hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a white solid 25%.
g was obtained. This crude product was used for the next reaction without purification. 63-66 ° C

Raw Material Synthesis Example 3 15 g of 2′-hydroxynamamide 2′-hydroxycinnamic acid methyl ester and 300 mL of aqueous ammonia were stirred at 40 to 50 ° C. for 7 days.
After confirming the disappearance of the starting material by TLC, the mixture was neutralized with hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain 10 g of a yellow solid. This crude product was used for the next reaction without purification.

Raw Material Synthesis Example 4 1- (2′-Hydroxycinnamoyl) pyrrolidine 30 g of 2′-hydroxycinnamic acid was suspended in 150 mL of chloroform and cooled to 0 ° C. Here thionyl chloride 1
8 mL and 0.5 mL of dimethylformamide were added, and the mixture was refluxed for 1 hour while gradually heating. After confirming that the suspension had become transparent, the solvent and excess thionyl chloride were concentrated under reduced pressure. Add 50 mL of tetrahydrofuran to this,
It was made into a tetrahydrofuran solution and stirred vigorously while cooling to 0 ° C. A solution of pyrrolidine (35 mL) in tetrahydrofuran (150 mL) was added dropwise to the above acid chloride in tetrahydrofuran. After completion of the dropwise addition, the reaction mixture is
The mixture was stirred at 30 ° C for 30 minutes, cooled and neutralized with hydrochloric acid, and the obtained crystals were washed with water and ethyl acetate to obtain 25 g of a white solid. This crude product was used for the next reaction without purification. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.
90 (m, 2H), 2.00 (m, 2H), 3.56
(T, J = 6.9, 2H), 3.63 (t, J = 6.9.
9, 2H), 6.82 (t, J = 7.8, 1H), 6.
90 (m, 2H), 7.15 (t, J = 7.3, 1
H), 7.42 (d, J = 5.9, 1H), 7.87
(D, J = 15.6, 1H), 9.43 (bs, 1H)

Raw Material Synthesis Example 5 25 g of 4- (2'-hydroxycinnamoyl) morpholine 2'-hydroxycinnamic acid was suspended in 150 mL of chloroform and cooled to 0 ° C. Here thionyl chloride 2
5 mL and 1.0 mL of dimethylformamide were added, and the mixture was refluxed for 1 hour while gradually heating. After confirming that the suspension had become transparent, the solvent and excess thionyl chloride were concentrated under reduced pressure. After adding 100 mL of tetrahydrofuran to make a tetrahydrofuran solution, the mixture was vigorously stirred while cooling to 0 ° C. 40 mL of morpholine was dropped into the above solution. After completion of the dropwise addition, the reaction mixture was stirred at 60 ° C. for 30 minutes, cooled and neutralized with hydrochloric acid, and the obtained crystals were washed with water and ethyl acetate to obtain 19 g of a white solid. This crude product was used for the next reaction without purification. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 3.
71 (bs, 8H), 6.83 (t, J = 7.3, 1
H), 6.92 (dd, J = 2.5, 7.3, 1H),
7.03-7.08 (m, 2H), 7.40-7.72
(M, 1H), 7.87 (d, J = 15.6, 1H),
9.43 (bs, 1H)

Raw Material Synthesis Example 6 1- (2′-Hydroxycinnamoyl) piperidine 10 g of 2′-hydroxycinnamic acid was suspended in 100 mL of chloroform and cooled to 0 ° C. Here thionyl chloride 1
0 mL and 0.5 mL of dimethylformamide were added, and the mixture was refluxed for 1 hour while gradually heating. After confirming that the suspension had become transparent, the solvent and excess thionyl chloride were concentrated under reduced pressure. After adding 100 mL of tetrahydrofuran to make a tetrahydrofuran solution, the mixture was vigorously stirred while cooling to 0 ° C. 15 mL of piperidine was dropped into the above solution. After completion of the dropwise addition, the reaction mixture was stirred at 60 ° C. for 30 minutes, cooled, neutralized with hydrochloric acid, and the obtained crystals were washed with water and ethyl acetate to obtain 13 g of an oil. This crude product was used for the next reaction without purification.

Material Synthesis Example 7 4- (5'-chloro-2'-hydroxycinnamoyl)
70 mL of 9 g of morpholine 5'-chloro-2'-hydroxycinnamic acid
And cooled to 0 ° C. Here, 6.6 mL of thionyl chloride and 0.5 mL of dimethylformamide
And refluxed for 1 hour while gradually heating. After confirming that the suspension had become transparent, the solvent and excess thionyl chloride were concentrated under reduced pressure. After adding 50 mL of tetrahydrofuran to make a tetrahydrofuran solution, the mixture was vigorously stirred while cooling to 0 ° C. 10 mL of morpholine was added dropwise into the above solution. After completion of the dropwise addition, the reaction mixture was stirred at 60 ° C. for 30 minutes, cooled and neutralized with hydrochloric acid, and the obtained crystals were washed with water and ethyl acetate to obtain 8.8 g of a white solid.
This crude product was used for the next reaction without purification.

Raw Material Synthesis Example 8 1- (2′-Hydroxy-β-methylcinnamoyl) pi
6 g of rolidine 2'-hydroxy-β- methylcinnamic acid is 1000 m
The resultant was suspended in L of chloroform and cooled to 0 ° C. 9 mL of thionyl chloride and 0.3 mL of dimethylformamide were added thereto, and the mixture was refluxed for 1 hour while gradually heating. After confirming that the suspension had become transparent, the solvent and excess thionyl chloride were concentrated under reduced pressure. After adding 50 mL of tetrahydrofuran to make a tetrahydrofuran solution, the mixture was vigorously stirred while cooling to 0 ° C. 10 mL of pyrrolidine was added dropwise into the above solution. After completion of the dropwise addition, the reaction mixture was heated at 60 ° C. for 3 hours.
The mixture was stirred for 0 minutes, cooled, neutralized with hydrochloric acid, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was collected, separated with saturated saline, and dried over anhydrous magnesium sulfate. After the solid matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained oily crude product was purified by silica gel column chromatography to obtain 2.0 g of white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.89 (m, 4
H), 2.39 (d, J = 1.5, 3H), 3.46
(T, J = 6.8, 2H), 3.56 (t, J = 6.8.
3, 2H), 6.12 (s, 1H), 6.88 (t, J
= 6.3, 1H), 6.95 (d, J = 7.8, 1
H), 7.11 (d, J = 7.8, 1H), 7.16
(T, J = 6.3, 1H)

Raw Material Synthesis Example 9 1- (3'-Hydroxyphenyl) cinnamamide 10 g of 3'-hydroxycinnamic acid methyl ester and 200 mL of aqueous ammonia were stirred at 40 to 50 ° C. for 5 days.
After confirming the disappearance of the starting material by TLC, the mixture was neutralized with hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain 5 g of a yellow solid. This crude solid was used for the next reaction without purification. Melting point 41-44 ° C

Raw Material Synthesis Example 10 1- (3′-Hydroxycinnamoyl) pyrrolidine 10 g of 3′-hydroxycinnamic acid was suspended in 100 mL of chloroform and cooled to 0 ° C. Here thionyl chloride 8
mL and 0.5 mL of dimethylformamide were added, and the mixture was refluxed for 2 hours while gradually heating. After confirming that the suspension had become transparent, the solvent and excess thionyl chloride were concentrated under reduced pressure. After adding 50 mL of tetrahydrofuran to make a tetrahydrofuran solution, the mixture was vigorously stirred while cooling to 0 ° C. 12 mL of pyrrolidine were dropped into the above solution. After completion of the dropwise addition, the reaction mixture was stirred at 60 ° C. for 30 minutes, cooled and neutralized with hydrochloric acid, and the obtained crystals were washed with water and ethyl acetate to obtain 9 g of a white solid. This crude product was used for the next reaction without purification.

Raw Material Synthesis Example 11 1- (2 ′-(3-Chloropropyl-1-yl) cinnamo
Yl) pyrrolidine 1- (2′-hydroxycinnamoyl) pyrrolidine (raw material synthesis example 4) 7 g, potassium carbonate 13 g, 3-bromo-
20 g of 1-chloropropane is added to 50 parts of dimethylformamide.
Then, the mixture was heated and stirred at 90 ° C. for 5 hours. After cooling,
After pouring into water, the water tank was extracted three times with ethyl acetate, and the organic layer was collected and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solid was filtered off, and the filtrate was concentrated under reduced pressure.
10 g of the title compound were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.90 (t, J =
7.3H, 2), 2.01 (t, J = 7.3, 2H),
2.29 (m, 3H), 3.58 (m, 6H), 3.7
8 (t, J = 7.3, 2H), 4.19 (t, J = 7.
3, 2H), 6.84 (d, 1H, J = 14.4),
6.92-6.98 (m, 2H), 7.28-7.32
(M, 1H), 7.51 (d, J = 6.9, 1H),
7.95 (d, J = 14.4, 1H)

Material Synthesis Example 12 3- (2- (2,3-Epoxypropan-1-yloxy)
C) phenyl) propionamide 3- (2-hydroxyphenyl) propionamide 23
g was dissolved in an aqueous potassium hydroxide solution (15 g / 150 mL), and epichlorohydrin (16 g) was added thereto at room temperature, followed by further stirring for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate) to give the title compound (15 g). Melting point 56-58 ° C

Material Synthesis Example 13 4- (3- (2- (2,3-epoxypropane-1-i)
Loxy) phenyl) propionyl) morpholine 4- (3- (2-hydroxyphenyl) propionyl)
20 g of morpholine was added to an aqueous solution of potassium hydroxide (11 g / 1
00 mL) and add epichlorohydrin 19
After adding g at room temperature, the mixture was further stirred for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate) to give 16 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.60-2.75
(M, 2H), 2.95-3.05 (m, 2H), 3.
45-3.53 (m, 2H), 3.55 (bs, 4
H), 3.60 (bs, 4H), 3.89 (dd, J =
6.4, 11.3, 1H), 4.33 (dd, J = 2.
4, 11.3, 1H), 6.82 (d, J = 8.3, 1
H), 6.92 (t, J = 7.3, 1H), 7.17-
7.20 (m, 2H)

Material Synthesis Example 14 2 '-(2,3-epoxypropan-1-yloxy)
25 g of cinnamamide 2′-hydroxycinnamamide was dissolved in an aqueous potassium hydroxide solution (28 g / 200 mL), and 26 g of epichlorohydrin was added thereto at room temperature.
Stirred for hours. The reaction solution was extracted twice with ethyl acetate,
The organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solid was filtered. The solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate) to obtain 16 g of a yellow solid. 44-46 ° C

Raw Material Synthesis Example 15 1- (2 ′-(2,3-Epoxypropan-1-yl)
Xy) cinnamoyl) pyrrolidine 1- (2′-hydroxycinnamoyl) pyrrolidine 19
g was dissolved in an aqueous potassium hydroxide solution (20 g / 150 mL), and 25 g of epichlorohydrin was added thereto at room temperature, followed by further stirring for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate) to obtain 11 g of a yellow solid. Melting point 60-62 ° C

Raw Material Synthesis Example 16 4- (2 ′-(2,3-Epoxypropan-1-ylo)
Xy) cinnamoyl) morpholine 4- (2′-hydroxycinnamoyl) morpholine 30
g was dissolved in an aqueous potassium hydroxide solution (25 g / 300 mL), and after adding 35 g of epichlorohydrin at room temperature, the mixture was further stirred for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate) to obtain 16 g of a yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 2.80 (m, 1
H), 2.92 (t, J = 4.9, 1H), 3.72
(Bs, 8H), 4.03 (td, J = 5.4, 10.
7, 1H), 6.90 (d, J = 8.3, 1H), 6.
99 (t, J = 7.8, 1H), 7.10 (d, J = 1
5.1, 1H), 7.28 (t, J = 7.3, 1H),
7.48 (d, J = 7.8, 1H), 7.88 (d, J
= 15.7, 1H)

Raw Material Synthesis Example 17 1- (2 '-(2,3-epoxypropan-1-yl-
Xy) cinnamoyl) piperidine 1- (2′-hydroxycinnamoyl) piperidine 13
g was dissolved in an aqueous potassium hydroxide solution (20 g / 200 mL), 21 g of epichlorohydrin was added thereto at room temperature, and the mixture was further stirred for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate) to obtain 13 g of an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.58-1.78
(M, 6H), 2.78-2.2.83 (m, 1H),
2.90-2.94 (m, 1H), 3.40 (bs, 1
H) 3.58-3.77 (m, 4H), 4.02-
4.17) m, 1H), 4.21-4.33 (M, 1
H), 6.88-7.18 (m, 3H), 7.23-
7.38 (m, 1H), 7.43-7.58 (m, 1H)
H), 7.82-7.90 (m, 1H)

Raw Material Synthesis Example 18 4- (5′-Chloro-2 ′-(2,3-epoxypropane)
1-yl) oxycinnamoyl) morpholine 4- (5'-chloro-2'-hydroxycinnamoyl)
8.4 g of morpholine was added to an aqueous potassium hydroxide solution (3.3 g
/ 100 mL), 10 g of epichlorohydrin was added thereto at room temperature, and the mixture was further stirred for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure. The residue was used for the next reaction without purification.

Raw Material Synthesis Example 19 1- (2 ′-(2,3-Epoxypropan-1-yl)
Xy) -β-methylcinnamoyl ) pyrrolidine 2 g of 1- (2′-hydroxy-β-methylcinnamoyl) pyrrolidine was treated with an aqueous potassium hydroxide solution (1 g / 30 m
L), 2 g of epichlorohydrin was added thereto at room temperature, and the mixture was further stirred for 12 hours. The reaction solution was extracted twice with ethyl acetate, the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure to give an oil. 2 g were obtained. This crude product was used for the next reaction without purification.

Raw Material Synthesis Example 20 3 '-(2,3-epoxypropan-1-yloxy)
7 g of cinnamamide 3'-hydroxycinnamide was dissolved in an aqueous potassium hydroxide solution (10 g / 100 mL), and 10 g of epichlorohydrin was added thereto at room temperature, followed by stirring for further 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure to obtain 7 g of an oil. Obtained. This crude product was used for the next reaction without purification.

Raw Material Synthesis Example 21 1- (3 ′-(2,3-Epoxypropan-1-yl)
Xy) cinnamoyl) pyrrolidine 1- (3′-hydroxycinnamoyl) pyrrolidine 15
g was dissolved in an aqueous potassium hydroxide solution (8.5 g / 100 mL), and 10 g of epichlorohydrin was added thereto at room temperature, followed by further stirring for 12 hours. The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed once with a saturated saline solution, dried over anhydrous magnesium sulfate, the solid was filtered, and the solvent was concentrated under reduced pressure to obtain 7 g of an oil. Obtained. This crude product was used for the next reaction without purification.

Material Synthesis Example 22 (-)-4- (2 '-(2,3-epoxypropane-1)
-Yloxy) cinnamoyl) morpholinedimethylformamide in 70 mL of sodium hydride 0.
After 9 g was added and the mixture was cooled to zero temperature, 5.1 g of 4- (2′-hydroxycinnamoyl) morpholine was added, and stirring was continued at this temperature. After 30 minutes, 5.0 g of (2R)-(-)-glycidyl tosylate was added, the ice bath was removed, and the mixture was stirred at room temperature for 2 minutes.
After stirring for an hour, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The organic solvent was distilled off under reduced pressure to obtain pale yellow crystals. The crystals were recrystallized from ethyl acetate to give 5.2 g of the title compound. Melting point 112-114
° C, [α] _D ²⁵ −66.8 ゜ (c 0.1, methanol), 96% ee (DAICEL CHIRALPAK)
AS, hexane-isopropyl alcohol = 4/1,
flow rate 1.0mL / min, detec
t at 254 nm, 19.2 min (+)-for
m, 22min (-)-form)

Material Synthesis Example 23 (+)-4- (2 ′-(2,3-Epoxypropane-1)
-Yloxy) cinnamoyl) morpholinedimethylformamide in 70 mL of sodium hydride 0.
After 9 g was added and the mixture was cooled to zero temperature, 5.1 g of 4- (2′-hydroxycinnamoyl) morpholine was added, and stirring was continued at this temperature. After 30 minutes, 5.0 g of (2S)-(+)-glycidyl tosylate was added, the ice bath was removed, and the mixture was allowed to stand at room temperature for 2 minutes.
After stirring for an hour, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The organic solvent was distilled off under reduced pressure to obtain pale yellow crystals. The crystals were recrystallized from ethyl acetate to give 5.0 g of the title compound. 113-115
° C, [α] _D ²⁵ +65.5 ゜ (c0.1, methanol), 95% ee (DAICEL CHIRALPAK)
AS, hexane-isopropyl alcohol = 4/1,
flow rate 1.0mL / min, 19.2m
in (+)-form, 22 min (-)-form) The structural formula of the compound obtained in the above-mentioned raw material synthesis example is shown in Chemical formula 22.

[0076]

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Example 1 3- (2- (3- (4-benzylpiperidine-1-i)
Ru) -2-hydroxypropyloxy) phenyl) pro
2.0 g of pionamide / p-toluenesulfonate 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide and 2.0 g of 4-benzylpiperidine are dissolved in 50 mL of ethanol,
The mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product.
This oily product was dissolved in a small amount of acetone, and an acetone solution of paratoluenesulfonic acid was added dropwise to obtain a paratoluenesulfonic acid salt. The obtained pale yellow crystals were collected by filtration to give 3.6 g of the title compound. I got Melting point 139
-141 ° C

Example 2 3- (2- (3- (1-benzylpiperidin-4-yl)
Amino) -2-hydroxypropyloxy) phenyl)
Propionamide 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide (2.0 g) and 4-amino-1-benzylpiperidine (2.0 g) were dissolved in ethanol (50 m).
L and heated under reflux for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product. A small amount of acetone was added to this oily product and cooled to obtain 0.57 g of white crystals. 120
-121 ° C

Example 3 3- (2- (2-hydroxy-3- (indane-2-i)
Ruamino) propyloxy) phenyl) propionami
The de 3- (2- (2,3-epoxy-1-yloxy) phenyl) propionamide and 2-aminoindan is dissolved in methanol, the solvent then heated to reflux and concentrated under reduced pressure, the residue to silica gel column chromatography And purification yields the title compound.

Example 4 3- (2- (2-hydroxy-3-((4-phenylcy
Clohexyl) amino) propyloxy) phenyl) p
1.5 g of lopionamide 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide and 1.5 g of 1-amino-4-phenylcyclohexane were added to ethanol 5
It was dissolved in 0 mL and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, acetone was added to the residue, and the mixture was cooled to give pale yellow crystals. The crude compound was recrystallized from acetone to give 0.96 g of the title compound as white crystals.
103-105 ° C

Example 5 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (4-methylphenyl) -2H-pyridine-1-
Yl) propyloxy) phenyl) propionamide
1/4 hydrate 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide 1.1 g and 3,6-dihydro-4- (4-methylphenyl) -2H-pyridine 0 0.8 g was dissolved in 50 mL of methanol, and the mixture was refluxed for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound as white crystals.
26 g were obtained. 144-146 ° C

Example 6 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (3-trifluoromethylphenyl) -2H-pi
Lysin-1-yl) propyloxy) phenyl) propyl
Onamido 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide and 3,6-dihydro-
After dissolving 4- (4-trifluoromethylphenyl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 7 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) propyloxy) phenyl) propionamide
1/4 hydrate 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide 1.1 g and 3,6-dihydro-4- (naphthalen-2-yl) -2H- 0.8 g of pyridine was dissolved in 50 mL of methanol, and the mixture was refluxed for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.05 g of a white title compound. 156-158 ° C

Example 8 3- (2- (2-hydroxy-3- (4- (4-trif)
Fluoromethylphenyl) piperidin-1-yl) propi
Yloxy) phenyl) After propionamide 3- (2- (2,3-epoxy-1-yloxy) phenyl) propionamide and 4- (4-trifluoromethylphenyl) piperidine was dissolved in methanol and heated to reflux, The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 9 3- (2- (2-hydroxy-3- (4- (3-trif)
Fluoromethylphenyl) piperidin-1-yl) propi
Yloxy) phenyl) After propionamide 3- (2- (2,3-epoxy-1-yloxy) phenyl) propionamide and 4- (3-trifluoromethylphenyl) piperidine was dissolved in methanol and heated to reflux, The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 10 3- (2- (2-hydroxy-3- (4- (naphthalene)
-1-yl) piperidin-1-yl) propyloxy)
Phenyl) propionamide 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide and 4- (naphthalene-
After dissolving 1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 11 3- (2- (2-hydroxy-3- (4- (naphthalene)
-2-yl) piperidin-1-yl) propyloxy)
Phenyl) propionamide / p-toluenesulfonate 1.1 g of 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionamide and 0.8 g of 4- (naphthalen-2-yl) piperidine are dissolved in methanol. 5
It was dissolved in 0 mL and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and acetone-paratoluenesulfonic acid was added to obtain a paratoluenesulfonic acid salt. The obtained white crystals were collected by filtration to obtain 1.26 g of the title compound. Melting point 164-166
° C

Example 12 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) propyloxy) phenyl) propionyldim
Tylamine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyldimethylamine and 3,6-
After dihydro-4- (naphthalen-2-yl) -2H-pyridine is dissolved in methanol and heated under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 13 3- (2- (2-hydroxy-3- (4- (naphthalene)
-1-yl) piperidin-1-yl) propyloxy)
Phenyl) propionyldimethylamine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyldimethylamine and 4- (naphthalen-1-yl) piperidine are dissolved in methanol, and the mixture is heated under reflux and then dissolved in a solvent. Is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 14 3- (2- (2-hydroxy-3- (4- (naphthalene)
-2-yl) piperidin-1-yl) propyloxy)
Phenyl) propionyldimethylamine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyldimethylamine and 4- (naphthalen-2-yl) piperidine are dissolved in methanol, and the mixture is heated under reflux and then dissolved in a solvent. Is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 15 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (4-methylphenyl) -2H-pyridine-1-
Yl) propyloxy) phenyl) propionylpyrroli
Gin 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpyrrolidine 1.1 g and 3,
0.8 g of 6-dihydro-4- (4-methylphenyl) -2H-pyridine was dissolved in 50 mL of methanol and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.0 g of the title compound as an oily substance.

Example 16 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) propyloxy) phenyl) propionylpyro
Lysine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpyrrolidine and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine are dissolved in methanol and heated under reflux. After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 17 3- (2- (2-hydroxy-3- (4- (naphthalene)
-1-yl) piperidin-1-yl) propyloxy)
Phenyl) propionylpyrrolidine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpyrrolidine and 4- (naphthalen-1-yl) piperidine are dissolved in methanol, heated to reflux, and then the solvent is depressurized. After concentration, the residue is purified by silica gel column chromatography to give the title compound.

Example 18 3- (2- (2-hydroxy-3- (4- (naphthalene)
-2-yl) piperidin-1-yl) propyloxy)
Phenyl) propionylpyrrolidine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpyrrolidine and 4- (naphthalen-2-yl) piperidine are dissolved in methanol, heated to reflux, and then the solvent is depressurized. After concentration, the residue is purified by silica gel column chromatography to give the title compound.

Example 19 3- (2- (2-hydroxy-3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) propyloxy) phenyl) propionyl pipe
Lysine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpiperidine and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine are dissolved in methanol and heated to reflux. After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 20 3- (2- (2-hydroxy-3- (4- (naphthalene)
-1-yl) piperidin-1-yl) propyloxy)
( Phenyl) propionylpiperidine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpiperidine and 4- (naphthalen-1-yl) piperidine are dissolved in methanol, and the mixture is refluxed under heating. After concentration, the residue is purified by silica gel column chromatography to give the title compound.

Example 21 3- (2- (2-hydroxy-3- (4- (naphthalene)
-2-yl) piperidin-1-yl) propyloxy)
Phenyl) propionylpiperidine 3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionylpiperidine and 4- (naphthalen-2-yl) piperidine are dissolved in methanol, heated to reflux, and then the solvent is depressurized. After concentration, the residue is purified by silica gel column chromatography to give the title compound.

Example 22 4- (3- (2- (3- (4- (4-fluorophenyl)
Ru) piperazin-1-yl) -2-hydroxypropyl
Oxy) phenyl) propionyl) morpholine ・ 2 hydrochloric acid
Salt 1/2 hydrate 4- (3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyl) morpholine 2.0
g and 1.5 g of 4-fluorophenylpiperazine were dissolved in 50 mL of methanol, and the mixture was heated under reflux for 2 hours. After cooling,
The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 1.731 g of the title compound. 186-189 ° C

Example 23 4- (3- (2- (2-hydroxy-3- (3,6-di
Hydro-4- (4-methylphenyl) -2H-pyridine
-1-yl) propyloxy) phenyl) propioni
M) morpholine 4- (3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyl) morpholine 1.1
g and 3,6-dihydro-4- (4-methylphenyl)-
0.8 g of 2H-pyridine was dissolved in 50 mL of methanol and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.0 g of the title compound as an oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.94 (s, 3
H), 2.52-2.80 (m, 7H), 2.83-
3.20 (m, 3H), 3.16-3.22 (m, 1
H), 3.91-3.99 (m, 1H), 4.00-
4.11 (m, 2H), 4.13-4.26 (m, 1
H), 6.03 (s, 1H), 6.81-6.93
(M, 2H), 7.09-7.38 (m, 6H)

Example 24 4- (3- (2- (2-hydroxy-3- (3,6-di
Hydro-4- (naphthalen-2-yl) -2H-pyridi
1-yl) propyloxy) phenyl) propioni
Morpholine 4- (3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyl) morpholine and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
Pyridine was dissolved in 50 mL of methanol and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.82 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.55-3.11
(M, 10H), 3.18-3.44 (m, 6H),
3.57 (bs, 4H), 3.91-4.00 (m, 1
H), 4.01-4.12 (m, 2H), 4.14-
4.26 (m, 1H), 6.23 (s, 1H), 6.8
0-6.92 (m, 2H), 7.09-7.26 (m,
2H), 7.33-7.47 (m, 2H), 7.58
(D, J = 8.3, 1H), 7.70-7.84 (m,
4H)

Example 25 4- (3- (2- (3- (4-phenylpiperidine-1)
-Yl) -2-hydroxypropyloxy) phenyl)
Propionyl) morpholine 4- (3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyl) morpholine and 4-
After dissolving benzylpiperidine in methanol and heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 26 4- (3- (2- (2-hydroxy-3- (4- (naph
Taren-1-yl) piperidin-1-yl) propyl
Xy) phenyl) propionyl) morpholine 4- (3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyl) morpholine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 27 4- (3- (2- (2-hydroxy-3- (4- (naph
Taren-2-yl) piperidin-1-yl) propyl
Xy) phenyl) propionyl) morpholine 4- (3- (2- (2,3-epoxypropan-1-yloxy) phenyl) propionyl) morpholine 1.0
g and 4- (naphthalen-2-yl) piperidine 0.8 g
Was dissolved in 50 mL of methanol and heated under reflux for 5 hours.
After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.1 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.85-1.96
(M, 5H), 2.19 (t, J = 11.2, 1H),
2.43 (t, J = 11.2, 1H), 2.54-2.
71 (m, 5H), 2.95-3.06 (m, 3H),
3.15 (d, J = 11.3, 1H), 3.34-3.
44 (m, 4H), 3.60 (bs, 4H), 3.94
-4.06 (m, 2H), 4.12-4.17 (m, 1
H), 6.85-6.92 (m, 2H), 7.16-
7.22 (m, 2H), 7.37-7.47 (m, 3
H), 7.66 (s, 1H), 7.78 (dd, J =
2.9, 4.9, 1H)

Example 28 2 '-(3- (4-benzylpiperidin-1-yl)-
2-hydroxypropyloxy) cinnamamide / p-
Toluenesulfonate 1/4 hydrate 2 '-(2,3-epoxypropan-1-yloxy)
0.35 g of cinnamamide and 0.4 g of 4-benzylpiperidine were dissolved in 30 mL of ethanol and heated under reflux for 1 hour. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product. This oily product was dissolved in a small amount of acetone, and an acetone solution of paratoluenesulfonic acid was added dropwise to obtain a paratoluenesulfonic acid salt.The resulting white crystals were collected by filtration to give 0.2 g of the title compound. Obtained. 182-184 ° C

Example 29 2 '-(3- (1-benzylpiperidin-4-ylamido)
G) -2-Hydroxypropyloxy) cinnamamide
1/4 hydrate 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve 0.35 g of cinnamamide and 0.35 g of 4-amino-1-benzylpiperidine in 30 mL of ethanol,
The mixture was heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product.
This oily product was dissolved in a small amount of acetone and cooled to give 0.034 g of the title compound as white crystals. 139-141 ° C

Example 30 2 ′-(2-hydroxy-3-((4-phenylcyclo)
Hexyl) amino) propyloxy) cinnamamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve 1.0 g of cinnamamide and 1.0 g of 1-amino-4-phenylcyclohexane in 30 mL of ethanol,
The mixture was heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give an oily product of 0.2%.
6 g were obtained.

Example 31 2 '-(2-hydroxy-3- (3,6-dihydro-4)
-(Naphthalen-2-yl) -2H-pyridine-1-i
Propyloxy) cinnamamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnamamide and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol,
After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 32 2 '-(2-Hydroxy-3- (4-phenylpiperidinium)
1-yl) propyloxy) cinnamamide / 1
Tetrahydrate 2 '-(2,3-epoxypropan-1-yloxy)
1.0 g of cinnamamide and 4-phenylpiperidine
0 g was dissolved in 50 mL of ethanol, and the mixture was heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product. The oily product was dissolved in a small amount of acetone and cooled to give 0.56 g of the title compound as white crystals. Melting point 159-161 ° C

Example 33 2 '-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) cin
Namamide 2 '-(2,3-epoxypropan-1-yloxy)
After dissolving cinnamamide and 4- (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 34 2 '-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Namamide 1/4 hydrate 2 '-(2,3-epoxypropan-1-yloxy)
1.0 g of cinnamamide and 1.0 g of 4- (naphthalen-2-yl) piperidine were dissolved in methanol and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound. 178-180 ° C

Example 35 1- (2 '-(3- (4- (4-fluorophenyl) pi
Perazin-1-yl) -2-hydroxypropyloxy
C) Cinnamoyl) pyrrolidine hydrochloride 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine 2.0 g and 4-fluorophenylpiperazine 1.4 g are dissolved in methanol 50 mL and heated for 2 hours. Refluxed. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added to form a hydrochloride, and the obtained pale yellow crystals were collected by filtration to give 1.41 g of the title compound. Melting point 13
4-136 ° C

Example 36 1- (2 '-(2-hydroxy-3- (4-benzylpi)
Peridin-1-yl) propyloxy) cinnamoyl)
1.8 g of pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 1.5 g of 4-benzylpiperidine were dissolved in methanol and heated under reflux for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.8 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.39
(M, 2H), 1.48-1.73 (m, 6H), 1.
81-2.03 (m, 4H), 2.25 (t, J = 1
1.2, 1H), 2.44-2.60 (m, 4H),
2.78 (d, J = 7.8, 1H), 2.96 (d, J
= 7.8, 1H), 3.57-3.64 (m, 4H),
4.00-4.13 (m, 3H), 6.91-6.93
(M, 3H), 7.10-7.13 (m, 3H), 7.
23-7.38 (m, 3H), 7.48 (d, J = 7.
8, 1H), 7.89 (d, J = 15.6, 1H)

Example 37 1- (2 '-(3- (1-benzylpiperidine-4-i
Rumin) -2-hydroxypropyloxy) cinnamo
Yl) pyrrolidine dihydrochloride 1 / 2-hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine 0.8 g and 4-amino-1-benzylpiperidine 0.6 g in methanol 50m
L and heated under reflux for 6 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product. This oily product was dissolved in a small amount of isopropyl alcohol, and hydrochloric acid-isopropyl alcohol was added thereto.
The resulting white crystals were recrystallized from isopropyl alcohol to give 0.37 g of the title compound. Melting point 250 ° C or higher

Example 38 1- (2 '-(2-hydroxy-3- (indane-2-
Ilamino) propyloxy) cinnamoyl) pyrrolidi
Emissions hydrochloride 1- - (2 '(2,3-epoxy-1-yloxy) cinnamoyl) pyrrolidine 1.5g of 2-aminoindan 1.0g was dissolved in methanol 50 mL, was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added dropwise to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 0.27 g of the title compound. 210 ° C
(Disassembly)

Example 39 1- (2 '-(2-hydroxy-3- (4-phenylcyl)
Clohexane-1-ylamino) propyloxy) syn
Namoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 1-amino-4-phenylcyclohexane are dissolved in methanol, and the mixture is refluxed under heating. The residue is purified by silica gel column chromatography to give the title compound.

Example 40 1- (2 ′-(3- (4- (4-fluorobenzyl) pi)
Peridin-1-yl) -2-hydroxypropyloxy
B) Cinnamoyl) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4-fluorobenzylpiperidine are dissolved in methanol, and the mixture is refluxed under heating, and the solvent is concentrated under reduced pressure. Is purified by silica gel column chromatography to give the title compound.

Example 41 1- (2 ′-(3- (4- (4-chlorophenyl) -4)
-Hydroxypiperidin-1-yl) -2-hydroxy
Propyloxy) cinnamoyl) pyrrolidine / p-tolu
Ensulfonate 1/4 hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine (1.0 g) and 4-chlorophenyl-4-hydroxypiperidine (1.0 g) in methanol (30 mL) And heated to reflux for 4 hours. After cooling,
The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product. This oily product was dissolved in a small amount of acetone, and an acetone solution of paratoluenesulfonic acid was added dropwise to obtain a paratoluenesulfonic acid salt. The obtained pale yellow crystals were collected by filtration to give the title compound 1.
146 g were obtained. Melting point 211-214 ° C

Example 42 1- (2 '-(3- (4- (4-bromophenyl) -4)
-Hydroxypiperidin-1-yl) -2-hydroxy
Propyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-bromophenyl) -4-hydroxypiperidine were dissolved in methanol and heated to reflux. Thereafter, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 43 1- (2 '-(3- (4- (4-fluorophenyl)-)
4-hydroxypiperidin-1-yl) -2-hydroxy
( Cipropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-fluorophenyl) -4-hydroxypiperidine are dissolved in methanol and heated to reflux. After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 44 1- (2 '-(3- (4- (4-methylphenyl) -4)
-Hydroxypiperidin-1-yl) -2-hydroxy
Propyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-methylphenyl) -4-hydroxypiperidine were dissolved in methanol and heated to reflux. Thereafter, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 45 1- (2 ′-(3- (4- (4-trifluoromethylphenyl)
Enyl) -4-hydroxypiperidin-1-yl) -2
-Hydroxypropyloxy) cinnamoyl) pyrrolidine
Emissions 1- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-trifluoromethylphenyl) -4-hydroxypiperidine was dissolved in methanol, after heating under reflux, the solvent Is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 46 1- (2 ′-(3- (4- (3-chlorophenyl) -4)
-Hydroxypiperidin-1-yl) -2-hydroxy
Propyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-chlorophenyl) -4-hydroxypiperidine are dissolved in methanol and heated under reflux. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 47 1- (2 ′-(3- (4- (3-methoxyphenyl)-)
4-hydroxypiperidin-1-yl) -2-hydroxy
( Cipropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-methoxyphenyl) -4-hydroxypiperidine are dissolved in methanol and heated to reflux. After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 48 1- (2 ′-(3- (4- (3-trifluoromethylphenyl)
Enyl) -4-hydroxypiperidin-1-yl) -2
-Hydroxypropyloxy) cinnamoyl) pyrrolidine
Emissions 1- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-trifluoromethylphenyl) -4-hydroxypiperidine was dissolved in methanol, after heating under reflux, the solvent Is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 49 1- (2 ′-(3- (4- (3,4-dichlorophenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 3,4-dichlorophenyl-4-hydroxypiperidine are dissolved in methanol and heated under reflux. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 50 1- (2 '-(3- (4- (3,4-dimethylphenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dimethylphenyl) -4-hydroxypiperidine are dissolved in methanol. After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 51 1- (2 ′-(3- (4- (3,4-dimethoxyphenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dimethoxyphenyl) -4-hydroxypiperidine are dissolved in methanol. After heating under reflux, the solvent was concentrated under reduced pressure,
The residue is purified by silica gel column chromatography to give the title compound.

Example 52 1- (2 ′-(3- (4- (3,4-methylenedioxy)
Phenyl) -4-hydroxypiperidin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) pyrroli
Gin 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-methylenedioxyphenyl) -4-hydroxypiperidine are dissolved in methanol and heated under reflux. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound. .

Example 53 1- (2 ′-(3- (4- (2,3-dichlorophenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (2,3-dichlorophenyl) -4-hydroxypiperidine are dissolved in methanol, After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 54 1- (2 ′-(2-hydroxy-3- (4-hydroxy
-4- (4-Naphthalen-2-yl) piperidine-1-
Yl) propyloxy) cinnamoyl) pyrrolidine ・ p
-Toluenesulfonate 1.5 g of 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 1.5 g of 4-hydroxy-4- (4-naphthalen-2-yl) piperidine It was dissolved in 50 mL of methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. The oily substance was dissolved in a small amount of acetone, and an acetone solution of paratoluenesulfonic acid was added dropwise to obtain a paratoluenesulfonic acid salt. The obtained pale yellow crystals were collected by filtration to give 1.54 g of the title compound. Obtained. 208-210 ° C

Example 55 1- (2 ′-(3- (4- (benzo [b] thiophene-
2-yl) -4-hydroxypiperidin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) pyrroli
Gin. P-toluenesulfonate 1.2 g of 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (benzo [b] thiophen-2-yl) -4-hydroxy 1.2 g of piperidine was dissolved in 30 mL of methanol, and the mixture was refluxed for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily product. This oily product was dissolved in a small amount of acetone, and an acetone solution of paratoluenesulfonic acid was added dropwise to form a paratoluenesulfonic acid salt, and the obtained pale yellow crystals were collected by filtration.
1.4 g of the title compound were obtained. 215-217 ° C

Example 56 1- (2 ′-(3- (4- (4-chlorophenyl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) pyrrolidine
P-toluenesulfonate 1/2 hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine 1.5 g and 4- (4-
1.2 g of (chlorophenyl) -3,6-dihydro-2H-pyridine was dissolved in 50 mL of methanol, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and acetone-paratoluenesulfonic acid was added to obtain a paratoluenesulfonic acid salt. The obtained white crystals were collected by filtration to obtain 1.8 g of the title compound. Melting point 150-152 ° C

Example 57 1- (2- (3- (3,6-dihydro-4-phenyl-)
2H-pyridin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 3,6-dihydro-
Dissolve 4-phenyl-2H-pyridine in methanol,
After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 58 1- (2 '-(3- (4- (4-bromophenyl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) pyrrolidine
Dihydrochloride 3/4 hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine 1.1 g and 4- (4-
0.8 g of (bromophenyl) -3,6-dihydro-2H-pyridine was dissolved in methanol and heated under reflux for 2 hours.
After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and hydrochloric acid-methanol was added to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 1.5 g of the dihydrochloride 3/4 hydrate of the title compound. . Melting point 225-228
° C

Example 59 1- (2 '-(3- (4- (4-fluorophenyl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-fluorophenyl) -3,6-dihydro-2H-pyridine in methanol After dissolving and heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 60 1- (2 '-(3- (4- (4-methylphenyl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) pyrrolidine
Hydrochloride 9/4 hydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-methylphenyl) -3,6-dihydro-2H-pyridine Was dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, hydrochloric acid-methanol was added to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 0.7 g of the hydrochloride 9/4 hydrate of the title compound. 138-140 ° C

Example 61 1- (2 '-(3- (4- (4-trifluoromethylphenyl)
Enyl) -3,6-dihydro-2H-pyridine-1-i
Ru) -2-hydroxypropyloxy) cinnamoyl)
Pyrrolidine hydrochloride 9/4 hydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-trifluoromethylphenyl) -3,6-dihydro-2H -Pyridine was dissolved in methanol and heated at reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oily substance was dissolved in a small amount of acetone, hydrochloric acid-methanol was added to form a hydrochloride, and the obtained white crystals were collected by filtration to give the hydrochloride of the title compound.
1.1 g of / 4 hydrate was obtained. 113-115 ° C

Example 62 1- (2 ′-(3- (4- (3-trifluoromethylphenyl)
Enyl) -3,6-dihydro-2H-pyridine-1-i
Ru) -2-hydroxypropyloxy) cinnamoyl)
Pyrrolidine hydrochloride 3/2 hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-trifluoromethylphenyl) -3,6-dihydro-2H -Pyridine was dissolved in methanol and heated at reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and hydrochloric acid-methanol was added to form a hydrochloride, and the obtained white crystals were collected by filtration to give the hydrochloride of the title compound.
1.0 g of / 2 hydrate was obtained. 134-136 ° C

Example 63 1- (2 '-(3- (4- (3-chlorophenyl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-chlorophenyl) -3,6-dihydro-2H-pyridine are dissolved in methanol And heated to reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.85 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.83-1.92
(M, 2H), 1.94-2.02 (m, 2H), 2.
55 (bs, 2H), 2.68-2.80 (m, 3
H) 2.83-2.98 (m, 1H), 3.19
(D, J = 17.1, 1H), 3.37 (d, J = 1
7.1, 1H), 3.58-3.69 (m, 4H),
4.03-4.12 (m, 2H), 4.10-4.15
(M, 1H), 6.09 (bs, 1H), 6.90-
7.01 (m, 3H), 7.10-7.18 (m, 5
H), 737 (s, 1H), 7.50 (d, J = 6.
4, 1H), 7.95 (d, J = 15.6, 1H)

Example 64 1- (2 '-(3- (4- (2,3-dichlorophenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-Hydroxypropyloxy) cinnamoyl) pyro
Lysine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (2,3-dichlorophenyl) -3,6-dihydro-2H-pyridine are dissolved in methanol and heated under reflux. After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 65 1- (2 '-(3- (4- (3,4-dimethylphenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-Hydroxypropyloxy) cinnamoyl) pyro
Lysine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dimethylphenyl) -3,6-dihydro-2H-pyridine were dissolved in methanol, Heated to reflux for an hour. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.85 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.81-2.03
(M, 4H), 2.25 (s, 3H), 2.27 (s,
3H), 2.49-2.60 (m, 2H), 2.66-
2.79 (m, 3H), 2.86-2.96 (m, 1
H), 3.12-3.22 (m, 1H), 3.18-
3.40 (m, 1H), 3.51-3.66 (m, 4
H), 3.92 (bs, 1H), 4.09 (d, J =
3.9, 2H), 4.20-4.30 (m, 1H),
6.01 (s, 1H), 6.93 (d, J = 15.6,
1H), 6.93-7.34 (m, 6H), 7.51
(D, J = 1.5, 1H), (d, J = 15.6, 1
H)

Example 66 1- (2 ′-(3- (4- (3,4-dichlorophenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-Hydroxypropyloxy) cinnamoyl) pyro
Lysine hydrochloride 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dichlorophenyl) -3,6-dihydro-2H-pyridine are dissolved in methanol, The mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oily substance was dissolved in a small amount of acetone, and hydrochloric acid-methanol was added to form a hydrochloride.
g was obtained. 152-154 ° C

Example 67 1- (2 ′-(3- (4- (3,4-dimethoxyphenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-Hydroxypropyloxy) cinnamoyl) pyro
Lysine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dimethoxyphenyl) -3,6-dihydro-2H-pyridine are dissolved in methanol and heated. After refluxing, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 68 1- (2 ′-(3- (4- (3,4-methylenedioxy)
Phenyl) -3,6-dihydro-2H-pyridine-1-
Yl) -2-hydroxypropyloxy) cinnamoy
L) Pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-methylenedioxyphenyl) -3,6-dihydro-2H-pyridine are converted to methanol. Dissolve and heat to reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.0 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.90-1.97
(M, 2H), 1.97-2.05 (m, 2H), 2.
55 (bs, 1H), 2.63-2.83 (m, 3
H), 2.91-2.99 (m, 1H), 3.20
(D, J = 11.2, 1H), 3.39 (d, J = 1
1.5, 1H), 3.58-3.69 (m, 4H),
4.10-4.18 (m, 2H), 4.21-4.28
(M, 1H), 5.98 (bs, 3H), 6.79
(D, J = 8.3, 1H), 6.85-7.03 (m,
4H), 7.29-7.38 (m, 1H), 7.53
(D, J = 7.8, 1H), 7.96 (d, J = 15.
6, 1H)

Example 69 1- (2 ′-(3- (4- (Naphthalen-1-yl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (naphthalene-
After dissolving 1-yl) -3,6-dihydro-2H-pyridine in methanol and heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 70 1- (2 ′-(3- (4- (naphthalen-2-yl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (naphthalene-
2-yl) -3,6-dihydro-2H-pyridine was dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.75 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.78-2.02
(M, 4H), 2.34 (bs, 1H), 2.66-
2.89 (m, 5H), 2.90-3.03 (m, 1
H) 3.21-3.46 (m, 2H), 3.50-
3.68 (m, 4H), 3.92 (bs, 1H),
10 (d, J = 4.9, 2H), 4.21-4.32
(M, 1H), 6.23 (s, 1H), 6.88-7.
03 (m, 3H), 7.23-7.37 (m, 1H),
7.39-7.66 (m, 4H), 7.71-7.88
(M, 4H), 7.97 (d, J = 15.6, 1H)

Example 71 1- (2 ′-(3- (4- (6-methoxynaphthalene-
2-yl) -3,6-dihydro-2H-pyridine-1-
Yl) -2-hydroxypropyloxy) cinnamoy
L) Pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (6-methoxynaphthalen-2-yl) -3,6-dihydro-2H-pyridine in methanol After dissolving and heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 72 1- (2 ′-(3- (4- (benz (b) thiophene-
2-yl) -3,6-dihydro-2H-pyridine-1-
Yl) -2-hydroxypropyloxy) cinnamoy
L) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (benz (b)
After dissolving (thiophen-2-yl) -3,6-dihydro-2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 73 1- (2 '-(3- (4- (Indol-2-yl)-)
3,6-dihydro-2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (indole-
After dissolving 2-yl) -3,6-dihydro-2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 74 1- (2 '-(3- (4- (4-chlorophenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
1.5 g of cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-
(Chlorophenyl) piperidine (1.2 g) in methanol (50)
It was dissolved in mL and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure to obtain 1.05 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.68-2.05
(M, 7H), 2.10-2.19 (m, 1H), 2.
29 (bs, 1H), 2.35-2.69 (m, 4
H), 2.98 (d, J = 11.7, 1H), 3.12
(D, J = 11.7, 1H), 3.52-3.67
(M, 4H), 3.94 (bs, 1H), 4.07
(D, J = 4.8, 1H), 4.16-4.22 (m,
1H), 6.90 (d, J = 16.1, 1H), 6.9
4-7.02 (m, 2H), 7.15 (d, J = 8.
3, 2H), 7.26 (d, J = 8.3, 2H), 7.
26-7.38 (m, 1H), 7.51 (d, J = 6.
3, 1H), 7.96 (d, J = 15.6, 1H)

Example 75 1- (2- (3- (4-phenylpiperidin-1-i)
Ru) -2-hydroxypropyloxy) cinnamoyl)
Pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4-phenylpiperidine were dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.3 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.75-2.00
(M, 10H), 2.03-2.74 (m, 4H),
2.98 (d, J = 11.2, 1H), 3.13 (d,
J = 11.2, 1H), 4.08 (d, J = 4.4, 1
H), 4.17-4.21 (m, 1H), 6.91-
6.98 (m, 3H), 7.18-7.50 (m, 6
H), 7.51 (d, J = 1.4, 1H), 7.95
(D, J = 15.6, 1H)

Example 76 1- (2 ′-(3- (4- (4-bromophenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
0.6 g of cinnamoyl) pyrrolidine hydrochloride 3/4 hydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-
0.6 g of (bromophenyl) piperidine in methanol,
By performing the same reaction procedure as in Example 22, 0.8 g of the title compound was obtained as white crystals. 127-129 ° C

Example 77 1- (2 '-(3- (4- (4-fluorophenyl) pi
Peridin-1-yl) -2-hydroxypropyloxy
B) Cinnamoyl) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-fluorophenyl) piperidine were dissolved in methanol, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.88 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.63-2.04
(M, 7H), 2.10-2.19 (m, 1H), 2.
21-2.32 (m, 1H), 2.35-2.70
(M, 4H), 2.97 (d, J = 11.2, 1H),
3.12 (d, J = 11.8, 1H), 3.51-3.
68 (m, 4H), 3.91 (bs, 1H), 4.08
(D, J = 4.4, 2H), 4.13-4.22 (m,
1H), 6.91 (d, J = 15.6, 1H), 6.9
2-7.05 (m, 2H), 7.12-7.37 (m,
5H), 7.52 (d, J = 2.4, 1H), 7.95
(D, J = 15.6, 1H)

Example 78 1- (2 '-(3- (4- (4-methylphenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
Cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-methylphenyl) piperidine are dissolved in methanol, heated to reflux, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.

Example 79 1- (2 ′-(3- (4- (4-trifluoromethylphenyl)
Enyl) piperidin-1-yl) -2-hydroxypro
Pyroxy) cinnamoyl) pyrrolidine hydrochloride monohydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-trifluoromethylphenyl) piperidine are dissolved in methanol, The mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil.
This oil was dissolved in a small amount of acetone, and hydrochloric acid-methanol was added to form a hydrochloride. The obtained white crystals were collected by filtration to obtain 1.1 g of the hydrochloride monohydrate of the title compound.
Melting point 167-169 ° C

Example 80 1- (2 '-(3- (4- (3-trifluoromethylphenyl)
Enyl) piperidin-1-yl) -2-hydroxypro
Pyroxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-trifluoromethylphenyl) piperidine were dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.43-2.08
(M, 9H), 1.27 (dt, J = 14.7, 2.
4, 1H), 2.42 (dt, J = 14.7, 2.4,
1H), 2.53-2.74 (m, 3H), 3.00
(D, J = 11.2, 1H), 3.14 (d, J = 1
1.2, 1H), 3.58-3.72 (m, 4H),
4.08 (d, J = 4.9, 2H), 4.16-4.2
7 (m, 1H), 6.89 (d, J = 15.6, 1
H), 6.90-7.04 (m, 2H), 7.23-
7.60 (m, 6H), 7.98 (d, J = 15.6,
1H)

Example 81 1- (2 '-(3- (4- (3-chlorophenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
Cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3-chlorophenyl) piperidine were dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.60 to 2.03
(M, 8H), 2.05-2.27 (m, 1H), 2.
32-2.68 (m, 4H), 2.94 (d, J = 9.
8, 1H), 3.11 (d, J = 9.4, 1H), 3.
48-3.69 (m, 4H), 3.70-3.93
(M, 1H), 4.00-4.22 (m, 3H), 6.
86-7.04 (m, 3H), 7.11-7.35
(M, 5H), 7.41-7.54 (m, 1H), 7.
85-7.98 (m, 1H)

Example 82 1- (2 '-(3- (4- (2,3-dichlorophenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (2,3-dichlorophenyl) piperidine were dissolved in methanol, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.95 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.62 to 2.07
(M, 7H), 2.13-2.34 (m, 2H), 2.
40-2.53 (m, 1H), 2.58-2.73
(M, 2H), 2.92-3.21 (m, 3H), 3.
49-3.74 (m, 4H), 3.93 (bs, 1
H), 4.07 (d, J = 4.9, 2H), 4.16−
4.28 (m, 1H), 6.90 (d, J = 15.6,
1H), 6.92-7.02 (m, 2H), 7.52
(D, J = 0.9, 1H), 7.97 (d, J = 15.
6,1H)

Example 83 1- (2 ′-(3- (4- (3,4-didimethylphenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
(Oxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-didimethylphenyl) piperidine are dissolved in methanol,
Heated to reflux for an hour. After cooling, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / chloroform).
Purification with methanol) yielded 0.9 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.68 to 2.04
(M, 7H), 2.07-2.21 (m, 2H), 2.
23 (s, 3H), 2.25 (s, 3H), 2.37-
2.52 (m, 2H), 2.55-2.70 (m, 2H)
H), 2.95 (d, J = 11.7, 1H), 3.12
(D, J = 11.2, 1H), 3.54-3.68
(M, 4H), 3.92 (bs, 1H), 4.08
(D, J = 4.9, 2H), 4.13-4.22 (m,
1H), 6.88-7.13 (m, 6H), 7.22-
7.35 (m, 1H), 7.51 (d, J = 1.5, 1
H), 7.96 (d, J = 15.6, 1H)

Example 84 1- (2 ′-(3- (4- (3,4-dichlorophenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) pyrrolidine hydrochloride / hemihydrate
The compound 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dichlorophenyl) piperidine were dissolved in methanol, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oily substance was dissolved in a small amount of acetone, hydrochloric acid-methanol was added to form a hydrochloride, and the obtained white crystals were collected by filtration.
1.2 g of the hydrochloride / hemihydrate of the title compound was obtained. 140-142 ° C

Example 85 1- (2 ′-(3- (4- (4-Chloro-2-methylphenyl)
Enyl) piperidin-1-yl) -2-hydroxypro
Pyroxy) cinnamoyl) pyrrolidine hydrochloride 1/2
Hydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (4-chloro-
2-Methylphenyl) piperidine was dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil.
This oil was dissolved in a small amount of acetone, and hydrochloric acid-methanol was added to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 1.0 g of the hydrochloride hemihydrate of the title compound. Melting point 162-163 ° C

Example 86 1- (2 ′-(3- (4- (3,4-dimethoxyphenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-dimethoxyphenyl) piperidine are dissolved in methanol, and the mixture is heated under reflux and then dissolved in methanol. Is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 87 1- (2 ′-(3- (4- (3,4-methylenedioxy)
Phenyl) piperidin-1-yl) -2-hydroxyp
1- (2 ′-(2,3- Epoxypropan -1-yloxy) cinnamoyl) pyrrolidine and 4- (3,4-methylenedioxyphenyl) piperidine are dissolved in methanol, and the mixture is heated under reflux. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 88 1- (2 '-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (naphthalene-
After dissolving 1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 89 1- (2 '-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
C) Cinnamoyl) pyrrolidine hydrochloride 1/2 hydrate 1
-1.1 g of (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 0.8 g of 4- (naphthalen-2-yl) piperidine are treated with 50 parts of methanol.
It was dissolved in mL and heated under reflux for 5 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 1.06 g of the title compound. 119-122 ° C

Example 90 1- (2 ′-(2-hydroxy-3- (4- (6-methoxy)
Xinaphthalen-2-yl) piperidin-1-yl) p
1- (2 ′-(2,3- Epoxypropan -1-yloxy) cinnamoyl) pyrrolidine and 4- (6-methoxynaphthalen-2-yl) piperidine are dissolved in methanol, and heated under reflux after heating. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 91 1- (2 ′-(3- (4- (benz [b] thiophene-
2-yl) piperidin-1-yl) -2-hydroxyp
Propyloxy) cinnamoyl) pyrrolidine 1- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) pyrrolidine and 4- (benz [b]
After dissolving thiophen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 92 1- (2 ′-(2-hydroxy-3- (4- (indo-
Ru-2-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (indole-
After dissolving 2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 93 1- (2 ′-(3- (4- (3,4-dimethylphenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-Hydroxypropyloxy) cinnamoyl) pipe
Lysine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperidine and 4- (3,4-dimethylphenyl) -3,6-dihydro-2H-pyridine are dissolved in methanol and heated. After refluxing, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 94 1- (2 '-(2-hydroxy-3- (4- (naphthalene)
-2-yl) -3,6-dihydro-2H-pyridine-
1-yl) propyloxy) cinnamoyl) piperidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperidine and 4- (naphthalene-
After dissolving 2-yl) -3,6-dihydro-2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 95 1- (2 ′-(3- (4- (3,4-dimethylphenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) piperidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperidine and 4- (3,4-dimethylphenyl) piperidine are dissolved in methanol, and the mixture is heated under reflux and then dissolved in methanol. Is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 96 1- (2 '-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) piperidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperidine and 4- (naphthalene-
After dissolving 1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 97 1- (2 '-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
C) 1.5 g of cinnamoyl) piperidine hydrochloride / 5/4 hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperidine and 4- (naphthalen-2-yl) piperidine 1 .1 g of methanol 5
It was dissolved in 0 mL and heated under reflux for 6 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 1.2 g of the title compound. 116-118 ° C

Example 98 4- (2 '-(3- (4- (4-fluorophenyl) pi
Perazin-1-yl) -2-hydroxypropyloxy
B) Cinnamoyl) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4-fluorophenylpiperazine are dissolved in methanol, heated to reflux and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.

Example 99 1- (2 '-(3- (1-benzylpiperidine-4-i
Rumin) -2-hydroxypropyloxy) cinnamo
Il) morpholine dihydrochloride 1/2 hydrate 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine 1.6 g and 4-amino-1-benzylpiperidine 1.6 g 50m methanol
L and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added to form a hydrochloride, and the obtained pale yellow crystals were collected by filtration to give 1.23 g of the title compound. 245-246 ° C

Example 100 4- (2 '-(2-hydroxy-3- (4-phenylcyl)
Clohexane-1-ylamino) propyloxy) syn
Namoyl) morpholine 1.7 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 1.4 g of 1-amino-4-phenylcyclohexane are dissolved in methanol 5
The mixture was dissolved in 0 mL and heated under reflux for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.26 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.15 to 1.30
(M, 2H), 1.35-2.15 (m, 8H), 2.
45-2.65 (m, 2H), 2.65-3.18
(M, 4H), 3.70 (bs, 6H), 4.07 (b
s, 3H), 6.95 (m, 2H), 7.00-7.4.
1 (m, 7H), 7.46 (d, J = 5.9, 1H),
7.92 (d, J = 15.8, 1H)

Example 101 4- (2 ′-(2-hydroxy-3- (4-benzylpi)
Peridin-1-yl) propyloxy) cinnamoyl)
Morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) was obtained by heating 1.5 g of morpholine and 0.9 of benzylpiperidine in methanol under reflux.

Example 102 4- (2 '-(3- (4- (4-fluorobenzyl) pi
Peridin-1-yl) -2-hydroxypropyloxy
B) Cinnamoyl) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4-fluorobenzylpiperidine are dissolved in methanol, heated to reflux, and the solvent is concentrated under reduced pressure. Is purified by silica gel column chromatography to give the title compound. Is dissolved in methanol, the mixture is refluxed under heating, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 103 4- (2 ′-(3- (4- (2,3-dichlorophenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (2,3-dichlorophenyl) -4-hydroxypiperidine are dissolved in methanol, After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 104 4- (2 '-(3- (4- (3,4-dichlorophenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3,4-dichlorophenyl) -4-hydroxypiperidine are dissolved in methanol, After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 105 4- (2 ′-(3- (4- (2,3-dimethylphenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (2,3-dimethylphenyl) -4-hydroxypiperidine are dissolved in methanol. After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 106 4- (2 ′-(3- (4- (3,4-dimethylphenyl)
Ru) -4-hydroxypiperidin-1-yl) -2-hi
( Droxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3,4-dimethylphenyl) -4-hydroxypiperidine are dissolved in methanol. After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 107 4- (2 ′-(3- (4- (3,4-methylenedioxy)
Phenyl) -4-hydroxypiperidin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) morpho
Phosphorus 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3,4-methylenedioxyphenyl) -4-hydroxypiperidine were dissolved in methanol and heated to reflux. Thereafter, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 108 4- (2 ′-(3- (4- (naphthalen-1-yl)-)
4-hydroxypiperidin-1-yl) -2-hydroxy
Cypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (naphthalene-
After dissolving 1-yl) -4-hydroxypiperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 109 4- (2 ′-(3- (4- (naphthalen-2-yl)-)
4-hydroxypiperidin-1-yl) -2-hydroxy
Cypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (naphthalene-
After dissolving 2-yl) -4-hydroxypiperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 110 4- (2 ′-(3- (4- (6-methoxynaphthalene-
2-yl) -4-hydroxypiperidin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) morpho
Phosphorus 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (6-methoxynaphthalen-2-yl) -4-hydroxypiperidine are dissolved in methanol, and the mixture is heated under reflux. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 111 4- (2 ′-(3- (4- (benzo [b] thiophene-
2-yl) -4-hydroxypiperidin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) morpho
Phosphorus 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (benzo [b]
After dissolving (thiophen-2-yl) -4-hydroxypiperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 112 4- (2 '-(3- (4- (Indol-2-yl)-)
4-hydroxypiperidin-1-yl) -2-hydroxy
Cypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (indole-
After dissolving 2-yl) -4-hydroxypiperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 113 4- (2 ′-(3- (4- (naphthalen-2-yl)-)
4-methoxypiperidin-1-yl) -2-hydroxy
Propyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (naphthalene-
After dissolving 2-yl) -4-methoxypiperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 114 4- (2 '-(3- (3,6-dihydro-4-phenyl)
-2H-pyridin-1-yl) -2-hydroxypropyl
Yloxy) cinnamoyl) morpholine 4- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro -
After dissolving 4- (4-chlorophenyl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure.
The residue is purified by silica gel column chromatography to give the title compound.

Example 115 4- (2 '-(3- (4- (4-chlorophenyl)-
3,6-dihydro-2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) morpholine Dissolve 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4-chlorophenyl) -3,6-dihydro-2H-pyridine in methanol After heating under reflux, the solvent was concentrated under reduced pressure,
The residue is purified by silica gel column chromatography to give the title compound.

Example 116 4- (2 ′-(3- (4- (4-bromophenyl)-
3,6-dihydro-2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4-bromophenyl) -3,6-dihydro-2H-pyridine in methanol After dissolving and heating to reflux, the solvent was concentrated under reduced pressure,
The residue is purified by silica gel column chromatography to give the title compound.

Example 117 4- (2 ′-(3- (3,6-dihydro-4- (4-f
(Fluorophenyl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (4-fluorophenyl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 118 4- (2 ′-(3- (3,6-dihydro-4- (4-meth)
Tylphenyl) -2H-pyridin-1-yl) -2-h
( Droxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (4-methylphenyl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure.
The residue is purified by silica gel column chromatography to give the title compound.

Example 119 4- (2 ′-(3- (3,6-dihydro-4- (4-t)
(Trifluoromethylphenyl) -2H-pyridine-1-i
Ru) -2-hydroxypropyloxy) cinnamoyl)
Morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (4-trifluoromethylphenyl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 120 4- (2 '-(3- (3,6-dihydro-4- (3-t)
(Trifluoromethylphenyl) -2H-pyridine-1-i
Ru) -2-hydroxypropyloxy) cinnamoyl)
Morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (3-trifluoromethylphenyl) -2H-pyridine in methanol and heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 121 4- (2 '-(3- (4- (3-chlorophenyl)-
3,6-dihydro-2H-pyridin-1-yl) -2-
Hydroxypropyloxy ) cinnamoyl) morpholine 1.5 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3-
1.0 g of the title compound was obtained by heating and refluxing 1.0 g of (chlorophenyl) -3,6-dihydro-2H-pyridine in methanol. ¹ H-NMR (CDCl ₃ ) δ: 2.56 (bs, 2
H), 2.63-2.78 (m, 4H), 2.90-
2.98 (m, 1H), 3.19 (d, J = 16.1,
1H), 3.27 (d, J = 16.1, 1H), 3.7
2 (bs, 8H), 4.01-4.08 (m, 2H),
4.19-4.22 (m, 1H), 6.09 (bs, 1
H), 6.90-7.00 (m, 2H), 7.13
(D, J = 15.6, 1H), 7.20-7.38
(M, 4H), 7.39 (s, 1H), 7.48 (d,
J = 7.3, 1H), 7.91 (d, J = 15.6, 1
H)

Example 122 4- (2 ′-(3- (4- (2,3-dichlorophenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-hydroxypropyloxy) cinnamoyl) mol
Folin 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (2,3-dichlorophenyl) -3,6-dihydro-2H-pyridine are dissolved in methanol and heated under reflux. After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 123 4- (2 ′-(3- (4- (3,4-dichlorophenyl)
) -3,6-dihydro-2H-pyridin-1-yl)
-2-hydroxypropyloxy) cinnamoyl) mol
Holin 4 - (2 '(2,3-epoxy-1-yloxy) cinnamoyl) morpholine and 4- (3,4-dichlorophenyl) -3,6-dihydro -2H- pyridine was dissolved in methanol and heated to reflux After that, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 124 4- (2 '-(3- (3,6-dihydro-4- (3,4
-Dimethylphenyl) -2H-pyridin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) morpho
1.5 g of phosphorus 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 1.0 g of 3,6-dihydro-4- (3,4-dimethylphenyl) -2H-pyridine It was obtained by heating to reflux in methanol.

Example 125 4- (2 ′-(3- (3,6-dihydro-4- (3,4
-Dimethoxyphenyl) -2H-pyridin-1-yl)
-2-hydroxypropyloxy) cinnamoyl) mol
Holin 4- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) morpholine 1.5g and 3,6-dihydro-4- (3,4-dimethoxyphenyl) -2H-
1.0 g of pyridine was heated under reflux in methanol to obtain 1.0 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.57 (bs, 2
H) 2.68-2.78 (m, 3H), 2.91-
2.99 (m, 1H), 3.20 (d, J = 11.7,
1H), 3.35 (d, J = 11.7, 1H), 3.8
8 (s, 3H), 3.91 (s, 3H), 4.03-
4.17 (m, 2H), 4.21-4.25 (m, 1
H), 5.99 (bs, 1H), 6.88 (d, J =
7.3, 1H), 6.90-6.99 (m, 4H),
7.18 (d, J = 15.6, 1H), 7.27-7.
33 (m, 1H), 7.47 (d, J = 7.8, 1
H), 7.90 (d, J = 15.7, 1H)

Example 126 4- (2 ′-(3- (3,6-dihydro-4- (3,4
-Methylenedioxyphenyl) -2H-pyridine-1-
Yl) -2-hydroxypropyloxy) cinnamoy
) Morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine 1.5 g and 3,6-dihydro-4- (3,4-methylenedioxyphenyl)-
1.0 g of 2H-pyridine was heated and refluxed in methanol to obtain 1.0 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (bs, 1
H), 2.63-2.74 (m, 3H), 2.91-
2.98 (m, 1H), 3.16 (d, J = 15.6,
1H), 3.38 (d, J = 15.2, 1H), 3.7
2 (bs, 8H), 4.02-4.17 (m, 2H),
4.20-4.23 (m, 1H), 5.96 (bs, 3
H), 6.78 (d, J = 7.8, 1H), 6.83-
7.00 (m, 4H), 7.16 (d, J = 11.6,
1H), 7.28-7.35 (m, 1H), 7.47
(D, J = 7.3, 1H), 7.89 (d, J = 15.
6, 1H)

Example 127 4- (2 '-(3- (3,6-dihydro-4- (naphtha)
Len-1-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (naphthalen-1-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 128 4- (2 '-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
(Hydroxypropyloxy ) cinnamoyl) morpholine 1.2 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-4- (naphthalen-2-yl) -2H- By heating and refluxing 0.8 g of pyridine in methanol, 1.0 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.59 (bs, 2
H), 2.78-2.83 (m, 2H), 3.00-
3.03 (m, 1H), 3.23-3.30 (m, 1
H), 3.40 (bs, 2H), 3.73 (bs, 8
H) 4.05-4.19 (m, 2H), 4.20-
4.33 (m, 1H), 5.77 (bs, 1H), 6.
93-7.03 (m, 3H), 7.19 (d, J = 1
5.7, 1H), 7.28-7.38 (m, 2H),
7.40-7.58 (m, 3H), 7.78-8.03
(M, 4H)

Example 129 4- (2 ′-(3- (3,6-dihydro-4- (6-meth)
Toxinaphthalen-2-yl) -2H-pyridine-1-
Yl) -2-hydroxypropyloxy) cinnamoy
M) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (6-methoxynaphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 130 4- (2 '-(3- (4- (benzo (b) thiophene-
2-yl) -3,6-dihydro-2H-pyridine-1-
Yl) -2-hydroxypropyloxy) cinnamoy
M) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (benzo (b)
After dissolving (thiophen-2-yl) -3,6-dihydro-2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 131 4- (2 '-(3- (3,6-dihydro-4- (indone)
2-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (indol-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 132 4- (2 '-(2-Hydroxy-3- (4-phenylpypi)
Peridin-1-yl) propyloxy) cinnamoyl)
Morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) 1.2 g of morpholine and 1.0 g of 4-phenylpiperidine are dissolved in 50 mL of methanol,
The mixture was heated under reflux for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2.21 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.61-1.74
(M, 5H), 1.76-1.80 (m, 4H), 1.
88-2.18 (m, 2H), 2.43 (dt, J =
2.5, 11.1, 1H), 2.51-2.67 (m,
3H), 2.97 (d, J = 11.3, 1H), 3.1
3 (d, J = 11.3, 1H), 3.63 (d, J = 1
7.1, 1H), 4.07 (d, J = 5.4, 2H),
4.18 (m, 1H), 695 (m, 2H), 7.15
(D, J = 15.7, 1H), 7.19-7.33
(M, 5H), 7.49 (d, J = 7.3, 1H),
7.87 (d, J = 15.7, 1H)

Example 133 4- (2 '-(3- (4- (4-fluorophenyl) pi
Peridin-1-yl) -2-hydroxypropyloxy
B) Cinnamoyl) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4-fluorophenyl) piperidine are dissolved in methanol, heated to reflux, and then the solvent is depressurized. After concentration, the residue is purified by silica gel column chromatography to give the title compound.

Example 134 4- (2 '-(3- (4- (4-chlorophenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
Dissolve cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4-chlorophenyl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, The residue is purified by silica gel column chromatography to give the title compound.

Example 135 4- (2 ′-(3- (4- (4-bromophenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
Cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4-bromophenyl) piperidine are dissolved in methanol, heated to reflux, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.

Example 136 4- (2 ′-(2-hydroxy-3- (4- (4-methyl
Ruphenyl) piperidin-1-yl) propyloxy)
Cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4-methylphenyl) piperidine are dissolved in methanol, heated to reflux, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.

Example 137 4- (2 '-(2-hydroxy-3- (4- (4-tri
Fluoromethylphenyl) piperidin-1-yl) pro
Pyroxy) cinnamoyl) morpholine monohydrochloride / 1 water
Hydrate 4- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) morpholine 1.2 g of 4- (4-
It was obtained by heating and refluxing 1.0 g of (trifluoromethylphenyl) piperidine in methanol. Melting point 1
74-178 ° C

Example 138 4- (2 ′-(2-hydroxy-3- (4- (3-tri
Fluoromethylphenyl) piperidin-1-yl) pro
Pyroxy) cinnamoyl) morpholine 1.2 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3-
1.0 g of (trifluoromethylphenyl) piperidine was dissolved in methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.98
(M, 5H), 2.12-2.22 (m, 1H), 2.
40-2.52 (m, 1H), 2.62-2.71
(M, 3H), 2.99 (d, J = 11.2, 1H),
3.15 (d, J = 11.2, 1H), 3.73 (br
s, 8H), 4.07 (d, J = 5.4, 2H), 4.
12-4.22 (m, 1H), 6.90-7.01
(M, 2H), 7.11 (d, J = 15.6, 1H),
7.23-7.35 (m, 1H), 7.38-7.54
(M, 5H), 7.92 (d, J = 15.6, 1H)

Example 139 4- (2 ′-(3- (4- (3-chlorophenyl) pipe)
Lysin-1-yl) -2-hydroxypropyloxy)
Cinnamoyl) morpholine 1.2 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3-
1.0 g of (chlorophenyl) piperidine in methanol,
By heating under reflux, 1.0 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.66-1.91
(M, 5H), 2.11-2.22 (m, 1H), 2.
40-2.63 (m, 6H), 2.96 (d, J = 1
1.2, 1H), 3.06 (d, J = 11.7, 1
H), 3.72 (bs, 8H), 4.00-4.08
(M, 2H), 4.15-4.18 (m, 1H), 6.
89-7.00 (m, 2H), 7.05-7.41
(M, 6H), 7.50-7.59 (m, 1H), 7.
88 (dd, J = 15.1, 4.9, 1H)

Example 140 4- (2 ′-(3- (4- (3,4-dimethoxyphenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) morpholine 1.5 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3
By heating 0.9 g of 4-dimethoxyphenyl) piperidine in methanol under reflux, 0.55 g of the title compound was obtained.
g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.86
(M, 5H), 2.12 (t, J = 11.7, 1H),
2.18-2.62 (m, 4H), 2.93 (d, J =
11.7, 1H), 3.11 (d, J = 11.2, 1
H), 3.62 (bs, 8H), 3.84 (s, 3
H), 3.87 (s, 3H), 4.01-4.05
(M, 2H), 4.13-4.19 (m, 1H), 6.
70-6.83 (m, 3H), 6.90-7.01
(M, 1H), 7.13 (d, J = 15.6, 1H),
7.28-7.36 (m, 1H), 7.40-7.50
(M, 1H), 7.93 (d, J = 15.6, 1H)

Example 141 4- (2 ′-(3- (4- (2,3-dichlorophenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
Oxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (2,3-dichlorophenyl) piperidine are dissolved in methanol, and the mixture is refluxed with heating. The title compound is obtained by concentrating under reduced pressure and purifying the residue by silica gel column chromatography. .

Example 142 4- (2 '-(2-hydroxy-3- (4- (3,4-
Methylenedioxyphenyl) piperidin-1-yl) p
Ropyloxy) cinnamoyl) morpholine / p-tolue
1.3 g of sulfonic acid salt of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3
It was obtained by heating and refluxing 1.0 g of 4-methylenedioxyphenyl) piperidine in methanol. 207-209 ° C

Example 143 4- (2 ′-(3- (4- (3,4-dichlorophenyl)
Ru) piperidin-1-yl) -2-hydroxypropyl
1.3 g of oxy) cinnamoyl) morpholine monohydrochloride monohydrate 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (3
It was obtained by heating and refluxing 1.0 g of 4-dichlorophenyl) piperidine in methanol. Melting point 147-
149 ° C

Example 144 4- (2 ′-(2-hydroxy-3- (4- (3,4-
Dimethylphenyl) piperidin-1-yl) propyl
Carboxymethyl) cinnamoyl) morpholine 4- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) morpholine 1.3g and 4- (3,
It was obtained by heating and refluxing 1.0 g of 4-dimethylphenyl) piperidine in methanol. ¹ H-NMR (CDCl ₃ ) δ: 1.64-1.90
(M, 4H), 2.08-2.18 (m, 1H), 2.
24 (s, 3H), 2.26 (s, 3H), 2.38-
2.68 (m, 4H), 2.92 (d, J = 11.2,
1H), 3.12 (d, J = 11.2, 1H), 3.7
2 (bs, 8H), 3.98 (bs, 1H), 4.01
-4.12 (m, 2H), 4.13-4.22 (m, 1
H), 6.89-7.34 (m, 7H), 7.48
(D, J = 1.5, 1H), 7.88 (d, J = 15.
6, 1H)

Example 145 4- (2 ′-(3- (4- (5-chloro-2-methylphenyl
Enyl) piperidin-1-yl) -2-hydroxypro
Pyroxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (5-chloro-
After dissolving 2-methylphenyl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 146 4- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B ) Cinnamoyl) morpholine 1.3 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 1.0 g of 4- (naphthalen-1-yl) piperidine are heated under reflux in methanol. Thereby, 1.1 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.94 to 2.05
(M, 6H), 2.33 (t, J = 11.6, 1H),
2.58-2.70 (m, 2H), 3.05 (d, J =
11.2, 1H), 3.20 (d, J = 11.2, 1
H), 3.30-3.39 (m, 1H), 3.72 (b
s, 8H), 4.01-4.19 (m, 2H), 4.1
9-4.30 (m, 1H), 6.94-6.98 (m,
2H), 7.15 (d, J = 15.6, 1H), 7.3
1 (t, J = 6.2, 1H), 7.41-7.58
(M, 5H), 7.72 (d, J = 7.7, 1H),
7.86-7.94 (m, 2H), 8.09 (d, J =
8.3, 1H)

Example 147 4- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
B) 1.2 g of cinnamoyl) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 0.8 g of 4- (naphthalen-2-yl) piperidine in methanol 5
It was dissolved in 0 mL and heated under reflux for 5 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.1 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.99
(M, 4H), 2.18-2.22 (m, 2H), 2.
47-2.58 (m, 1H), 2.59-2.80
(M, 3H), 3.00 (d, J = 8.2, 1H),
3.19 (d, J = 8.2, 1H), 3.73 (b, 8
H) 4.05-4.11 (m, 2H), 4.18-
4.25 (m, 1H), 5.17 (b, 1H), 6.9
3-7.00 (m, 2H), 7.16 (d, J = 15.
6, 1H), 7.27-52 (m, 4H), 7.66
(S, 1H), 7.80 (d, J = 8.3, 4H),
7.90 (d, J = 15.6, 1H)

Example 148 4- (2 ′-(2-hydroxy-3- (4- (6-methoxy)
Xinaphthalen-2-yl) piperidin-1-yl) p
Dissolve propyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (6-methoxynaphthalen-2-yl) piperidine in methanol and heat to reflux. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 149 4- (2 ′-(3- (4- (benzo (b) thiophene-
2-yl) piperidin-1-yl) -2-hydroxyp
Ropyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (benzo (b)
After dissolving thiophen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 150 4- (2 ′-(2-hydroxy-3- (4- (indole)
Ru-2-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (indole-
After dissolving 2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 151 2 '-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
(Xypropyloxy) -β-methylcinnamamide 2 ′-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnamamide and 3,6-dihydro-4-
After dissolving (naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 152 2 ′-(2-Hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) -β
-Methylcinnamamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnamamide and 4- (naphthalene-1-
Il) Piperidine is dissolved in methanol, heated under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 153 2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) -β
-Methylcinnamamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnamamide and 4- (naphthalene-2-
Il) Piperidine is dissolved in methanol, heated under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 154 2 '-(2-hydroxy-3- (4- (6-methoxyna
Phthalen-2-yl) piperidin-1-yl) propyl
Oxy) -β-methylcinnamamide 2 ′-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnamamide and 4- (6-methoxynaphthalen-2-yl) piperidine are dissolved in methanol,
After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 155 2 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
(Xypropyloxy) -β-methylcinnam-N, N-
Dimethylamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-dimethylamide and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 156 2 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) -β
-Methylcinnam-N, N-dimethylamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-dimethylamide and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 157 2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) -β
-Methylcinnam-N, N-dimethylamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-dimethylamide and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 158 2 ′-(2-hydroxy-3- (4- (6-methoxyna
Phthalen-2-yl) piperidin-1-yl) propyl
Oxy) -β-methylcinnam-N, N-dimethylami
Do 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-dimethylamide and 4-
After dissolving (6-methoxynaphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 159 2 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
(Xypropyloxy) -β-methylcinnam-N, N-
Diethylamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-diethylamide and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 160 2 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) -β
-Methylcinnam-N, N-diethylamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-diethylamide and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 161 2 '-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) -β
-Methylcinnam-N, N-diethylamide 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-diethylamide and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 162 2 ′-(2-hydroxy-3- (4- (6-methoxyna
Phthalen-2-yl) piperidin-1-yl) propyl
Oxy) -β-methylcinnam-N, N-diethylamido
Do 2 '-(2,3-epoxypropan-1-yloxy)
-Β-methylcinnam-N, N-diethylamide and 4-
After dissolving (6-methoxynaphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 163 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) -β-methylcinnamoy
3) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) pyrrolidine and 3,6
After dissolving -dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 164 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) -β-methylcinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) pyrrolidine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 165 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
B) -β-methylcinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) pyrrolidine and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 166 1- (2 ′-(2-hydroxy-3- (4- (6-methoxy)
Xinaphthalen-2-yl) piperidin-1-yl) p
1- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) pyrrolidine and 4- ( roxypropyl) -β-methylcinnamoyl) pyrrolidine
The title compound was obtained by heating (6-methoxynaphthalen-2-yl) piperidine in methanol under reflux.
0 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.83-1.97
(M, 10H), 2.18 (t, J = 11.2, 1
H), 2.43 (s, 3H), 2.45-2.48
(M, 2H), 2.56-2.61 (m, 1H), 2.
67-2.71 (m, 2H), 3.49 (t, J = 6.
8, 2H), 3.55 (t, J = 6.8, 2H), 4.
00-4.06 (m, 2H), 4.07-4.14
(M, 1H), 6.04 (s, 1H), 6.05-6.
97 (m, 2H), 7.17 (d, J = 1.9, 1
H), 7.18-7.19 (m, 1H), 7.27-
7.47 (m, 3H), 7.65 (s, 1H), 7.7
8-7.81 (m, 1H)

Example 167 4- (2 ′-(2-hydroxy-3- (3,6-dihydrido)
B-4- (Naphthalen-2-yl) -2H-pyridine-
1-yl) propyloxy) -β-methylcinnamoy
M) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) morpholine and 3,6
After dissolving -dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 168 4- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) -β-methylcinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) morpholine and 3,6
After dissolving -dihydro-4- (naphthalen-1-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound. .

Example 169 4- (2- (2-hydroxy-3- (4- (naphthalene)
-2-yl) piperidin-1-yl) propyloxy)
-Β-methylcinnamoyl) morpholine 1/4 hydrate 4- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) morpholine 1.0 g
And 0.7 g of 4- (naphthalen-2-yl) piperidine
Was subjected to the same reaction procedure as in Example 2 in methanol to give 0.62 g of the title compound as yellow crystals.
95-98 ° C

Example 170 4- (2 ′-(2-hydroxy-3- (4- (6-methoxy)
Xinaphthalen-2-yl) piperidin-1-yl) p
Ropyloxy) -β-methylcinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) morpholine and 4-
After dissolving (6-methoxynaphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 171 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) -β-methylcinnamoy
) -4-Methylpiperazine 1- (2 ′-(2,3-epoxypropan-1-yloxy) -β-methylcinnamoyl) -4-methylpiperazine and 3,4-dihydro-4- (naphthalene-2 After dissolving -yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 172 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
C) Cinnamoyl) -4-methylpiperazine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-methylpiperazine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 173 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
C ) Cinnamoyl) -4-methylpiperazine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-methylpiperazine and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 174 1- (2 ′-(2-hydroxy-3- (4- (6-methoxy)
Xinaphthalen-2-yl) piperidin-1-yl) p
Ropyloxy) cinnamoyl) -4-methylpiperazine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-methylpiperazine and 4-methylpiperazine
After dissolving (6-methoxynaphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 175 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) -4-fe
Nilpiperazine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-phenylpiperazine and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 176 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
C) Cinnamoyl) -4-phenylpiperazine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-phenylpiperazine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 177 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
C) Cinnamoyl) -4-phenylpiperazine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-phenylpiperazine and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 178 1- (2 ′-(2-hydroxy-3- (4- (6-methoxy)
Xinaphthalen-2-yl) piperidin-1-yl) p
Ropyloxy) cinnamoyl) -4-phenylpiperazine
Emissions 1- (2 '- (2,3-epoxy-1-yloxy) cinnamoyl) -4- phenylpiperazine and 4-
After dissolving (6-methoxynaphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 179 1-acetyl-4- (2 ′-(3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) -2-hydroxypropyloxy) cinnamoy
L) piperazine 1-acetyl-4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperazine and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 180 1-acetyl-4- (2 ′-(2-hydroxy-3-
(4- (naphthalen-1-yl) piperidin-1-i
L) propyloxy) cinnamoyl) piperazine 1-acetyl-4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperazine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 181 1-acetyl-4- (2 ′-(2-hydroxy-3-
(4- (naphthalen-2-yl) piperidin-1-i
L) propyloxy) cinnamoyl) piperazine 1-acetyl-4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) piperazine and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 182 4- (5′-chloro-2 ′-(2-hydroxy-3-
(4-phenylpiperidin-1-yl) propyloxy
B) Cinnamoyl) morpholine 4- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine 1.2
g and 4-phenylpiperidine 0.7 g in methanol 50
It was dissolved in mL and heated under reflux for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.76 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.64-1.90
(M, 5H), 2.15 (dt, J = 1.5, 9.9,
1H), 2.45 (dt, J = 1.5, 9.9, 1H)
2.48-2.60 (m, 3H), 2.97 (d, J =
12.6, 1H) 3.13 (d, J = 12.6, 1
H), 3.70 (bs, 8H), 3.98-4.20
(M, 3H), 6.88 (d, J = 7.2, 1H),
7.12 (d, J = 12.6, 1H), 7.18-7.
43 (m, 8H), 7.82 (d, 1H, J = 12.
6)

Example 183 4- (5′-Chloro-2 ′-(3- (4-benzylpipe)
Lysin-1-yl) -2-hydroxypropyloxy)
Cinnamoyl) morpholine 4- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine 1.2
g and 4-benzylpiperidine 0.7 g in methanol 50
It was dissolved in mL and heated under reflux for 3 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.67 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.30
(M, 2H), 1.540-1.54 (m, 1H),
1.63 (d, J = 13.2, 2H), 1.92 (t,
J = 11.3, 1H), 2.21 (t, J = 11.2,
1H), 2.40-2.50 (m, 4H), 2.67
(D, J = 9.7, 1H), 2.93 (d, J = 11.1.
2, 1H), 3.69 (bs, 8H), 3.93-4.
01 (m, 2H), 4.04-4.09 (m, 1H),
6.82 (d, J = 8.4, 1H), 7.06-7.2
8 (m, 7H), 7.39 (d, J = 2.5, 1H),
7.77 (d, J = 15.6, 1H)

Example 184 4- (5′-Chloro-2 ′-(3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) -2-hydroxypropyloxy) cinnamoy
Morpholine 4- (5′-chloro-2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 185 4- (5′-Chloro-2 ′-(2-hydroxy-3-
(4- (naphthalen-1-yl) piperidin-1-i
L) propyloxy) cinnamoyl) morpholine 4- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 186 4- (5′-Chloro-2 ′-(2-hydroxy-3-
(4- (naphthalen-2-yl) piperidin-1-i
L) propyloxy) cinnamoyl) morpholine 4- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 187 1- (5′-Chloro-2 ′-(3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) -2-hydroxypropyloxy) cinnamoy
L) pyrrolidine 1- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 188 1- (5′-Chloro-2 ′-(2-hydroxy-3-
(4- (naphthalen-1-yl) piperidin-1-i
L) propyloxy) cinnamoyl) pyrrolidine 1- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4-
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 189 1- (5′-Chloro-2 ′-(2-hydroxy-3-
(4- (naphthalen-2-yl) piperidin-1-i
L) propyloxy) cinnamoyl) pyrrolidine 1- (5'-chloro-2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4-
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 190 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) -3'-methoxycinnamo
Yl) pyrrolidine 1- (2 '-(2,3-epoxypropan-1-yloxy) -3'-methoxycinnamoyl) pyrrolidine and 3,6-dihydro-4- (naphthalen-2-yl) -2
After dissolving H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 191 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) -3′-Methoxycinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) -3′-methoxycinnamoyl) pyrrolidine and 4
After dissolving-(naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 192 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
B) -3′-Methoxycinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) -3′-methoxycinnamoyl) pyrrolidine and 4
After dissolving-(naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 193 1- (2 ′-(3- (4-phenylpiperidin-1-i)
Ru) propyloxy) cinnamoyl) pyrrolidine monohydrochloride
1.5 g of salt / hemihydrate 1- (2 ′-(3-chloropropyloxy) cinnamoyl) pyrrolidine and 0.1 g of 4-phenylpiperidine.
8 g of the title compound was heated and refluxed in methanol to obtain 0.72 g of the title compound. 217-219 ° C

Example 194 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Len-2-yl) -2H-pyridin-1-yl) prop
Yloxy) cinnamoyl) pyrrolidine 1- (2 '- (3-chloro-propyloxy) cinnamoyl) pyrrolidine and 3,6-dihydro-4- (naphthalen-2-yl) -2H- pyridine was dissolved in methanol,
After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 195 1- (2 ′-(3- (4- (Naphthalen-1-yl) pi)
Peridin-1-yl) propyloxy) cinnamoyl)
Pyrrolidine 1- (2 ′-(3-Chloropropyloxy) cinnamoyl) pyrrolidine and 4- (naphthalen-1-yl) piperidine are dissolved in methanol, heated to reflux, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. Purification by chromatography affords the title compound.

Example 196 1- (2 ′-(3- (4- (Naphthalen-2-yl) pi
Peridin-1-yl) propyloxy) cinnamoyl)
1.0 g of pyrrolidine 1- (2 '-(3-chloropropyloxy) cinnamoyl) pyrrolidine and 1.0 g of 4- (naphthalen-2-yl) piperidine were dissolved in methanol and heated to reflux. After cooling, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol).
The title compound was obtained by refine | purifying in. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.91
(M, 2H), 1.92-2.02 (m, 2H), 2.
05-2.22 (m, 2H), 2.25-2.30
(M, 2H), 2.50-2.55 (m, 2H), 2.
63-2.80 (m, 1H), 2.98-3.23
(M, 4H), 3.28-3.55 (m, 2H), 3.
62-3.72 (m, 4H), 4.18-4.23
(M, 2H), 6.95-7.20 (m, 3H), 7.
38-7.60 (m, 4H), 7.62-7.80
(M, 2H), 7.81-7.90 (m, 4H)

Example 197 4- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Len-2-yl) -2H-pyridin-1-yl) prop
Yloxy) cinnamoyl) morpholine 4- (2 '- (3-chloro-propyloxy) cinnamoyl) morpholine and 3,6-dihydro-4- (naphthalen-2-yl) -2H- pyridine was dissolved in methanol,
After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 198 4- (2 ′-(3- (4- (naphthalen-1-yl) pi
Peridin-1-yl) propyloxy) cinnamoyl)
Morpholine 4- (2 '-(3-chloropropyloxy) cinnamoyl) morpholine and 4- (naphthalen-1-yl) piperidine are dissolved in methanol, heated to reflux, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. Purification by chromatography affords the title compound.

Example 199 4- (2 '-(3- (4- (naphthalen-2-yl) pi
Peridin-1-yl) propyloxy) cinnamoyl)
1.5 g of morpholine 4- (2 '-(3-chloropropyloxy) cinnamoyl) morpholine and 1.0 g of 4- (naphthalen-2-yl) piperidine were dissolved in methanol and heated to reflux. After cooling, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol).
The title compound was obtained by refine | purifying in. ¹ H-NMR (CDCl ₃ ) δ: 1.75-1.83
(M, 2H), 1.85-1.99 (m, 4H), 2.
01-2.20 (m, 4H), 2.58-2.78
(M, 3H), 3.10 (d, J = 11.7, 2H),
3.60-3.80 (b, 10H), 4.13 (t, J
= 6.3, 3H), 6.93-7.00 (m, 3H),
7.01 (d, J = 15.7, 1H), 7.30-7.
58 (m, 4H), 7.66 (s, 1H), 7.76-
7.82 (m, 3H), 7.94 (d, J = 15.7, 1
H)

Example 200 4- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
Methoxypropyloxy) cinnamoyl) morpholine is obtained by reacting the compound obtained in Example 128 with methyl iodide in dimethylformamide in the presence of sodium hydride.

Example 201 4- (2 ′-(2-methoxy-3- (4- (naphthalene)
-1-yl) piperidin-1-yl) propyloxy)
Cinnamoyl) morpholine Obtained by reacting the compound obtained in Example 146 with methyl iodide in dimethylformamide in the presence of sodium hydride.

Example 202 4- (2 ′-(2-methoxy-3- (4- (naphthalene)
-2-yl) piperidin-1-yl) propyloxy)
Cinnamoyl) morpholine Obtained by reacting the compound obtained in Example 147 with methyl iodide in dimethylformamide in the presence of sodium hydride.

Example 203 4- (2 ′-(2-chloro-3- (3,6-dihydro-
4- (naphthalen-2-yl) -2H-pyridine-1-
Yl) propyloxy) cinnamoyl) morpholine Obtained by heating the compound obtained in Example 128 in thionyl chloride.

Example 204 4- (2 ′-(2-chloro-3- (4- (naphthalene-
1-yl) piperidin-1-yl) propyloxy) cy
(Nnamoyl) morpholine Obtained by heating the compound obtained in Example 146 in thionyl chloride.

Example 205 4- (2 ′-(2-chloro-3- (4- (naphthalene-
2-yl) piperidin-1-yl) propyloxy) si
(Nannamoyl) morpholine Obtained by heating the compound obtained in Example 147 in thionyl chloride.

Example 206 4- (2 '-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) -β-fluorocinnamoy
G) Morpholine Obtained by treating the compound obtained in Example 128 with fluorine gas in acetic acid.

Example 207 4- (2 '-(3- (4- (naphthalen-1-yl) pi
Peridin-1-yl) -2-hydroxypropyloxy
B) -β-fluorocinnamoyl) morpholine Obtained by treating the compound obtained in Example 146 with fluorine gas in acetic acid.

Example 208 4- (2 ′-(3- (4- (Naphthalen-2-yl) pi)
Peridin-1-yl) propyloxy) -β-fluoro
Cinnamoyl) morpholine Obtained by treating the compound obtained in Example 147 with fluorine gas in acetic acid.

Example 209 2 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
( Xypropyloxy) cinnam-N-methylanilide 2 '-(2,3-epoxypropan-1-yloxy)
Cinnam-N-methylanilide and 3,6-dihydro-4
After dissolving-(naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent was concentrated under reduced pressure.
The residue is purified by silica gel column chromatography to give the title compound.

Example 210 2 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N-methylanilide 2 '-(2,3-epoxypropan-1-yloxy)
Cinnam-N-methylanilide and 4- (naphthalene-1
After dissolving -yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 211 2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N-methylanilide 2 '-(2,3-epoxypropan-1-yloxy)
Cinnam-N-methylanilide and 4- (naphthalene-2
After dissolving -yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 212 N-benzyl-N- (2 ′-(3- (3,6-dihydro
-4- (Naphthalen-2-yl) -2H-pyridine-1
-Yl) -2-hydroxypropyloxy) cinnam)
Amide N-benzyl-N- (2 '-(2,3-epoxypropan-1-yloxy) cinnam) amide and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine are dissolved in methanol. After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 213 N-benzyl-N- (2 ′-(2-hydroxy-3-
(4- (naphthalen-1-yl) piperidin-1-i
Propyloxy) cinnam) amide N-benzyl-N- (2 ′-(2,3-epoxypropan-1-yloxy) cinnam) amide and 4- (naphthalen-1-yl) piperidine are dissolved in methanol, After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 214 N-benzyl-N- (2 ′-(2-hydroxy-3-
(4- (naphthalen-2-yl) piperidin-1-i
Propyloxy) cinnam) amide N-benzyl-N- (2 ′-(2,3-epoxypropan-1-yloxy) cinnam) amide and 4- (naphthalen-2-yl) piperidine are dissolved in methanol, After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 215 2 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
Xypropyloxy) cinnam-N- (α, α-dimethyl)
Ruphenethyl) amide 2 '-(2,3-epoxypropan-1-yloxy)
Cinnam-N- (α, α-dimethylphenethyl) amide and 3,6-dihydro-4- (naphthalen-2-yl)-
After dissolving 2H-pyridine in methanol and heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 216 2 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N- (α, α-dimethylphenethyl) amide 2 ′-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N- (α, α-dimethylphenethyl) amide and 4- (naphthalen-1-yl) piperidine in methanol, heat and reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography. To give the title compound.

Example 217 2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N- (α, α-dimethylphenethyl) amide 2 ′-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N- (α, α-dimethylphenethyl) amide and 4- (naphthalen-2-yl) piperidine in methanol, heat and reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography. To give the title compound.

Example 218 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) pyrrole 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrole and 3,6-dihydro-4
After dissolving-(naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent was concentrated under reduced pressure.
The residue is purified by silica gel column chromatography to give the title compound.

Example 219 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) pyrrole 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrole and 4- (naphthalene-1
After dissolving -yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 220 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) pyrrole 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrole and 4- (naphthalene-2)
After dissolving -yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 221 1- (2 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) -4-meth
Xypiperidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-methoxypiperidine and 3,
6-dihydro-4- (naphthalen-2-yl) -2H-
After dissolving pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 222 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
C) Cinnamoyl) -4-methoxypiperidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-methoxypiperidine and 4-methoxypiperidine
After dissolving (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 223 1- (2 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
C) Cinnamoyl) -4-methoxypiperidine 1- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) -4-methoxypiperidine and 4-methoxypiperidine
After dissolving (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 224 3 ′-(2-Hydroxy-3- (4-phenylpiperididi)
N-1-yl) propyloxy) cinnamamide / p-
Toluenesulfonate 3 '-(2,3-epoxypropan-1-yloxy)
2.0 g of cinnamamide and 4-phenylpiperidine
5 g was dissolved in 50 mL of methanol and heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. This oil was dissolved in a small amount of acetone, and acetone-paratoluenesulfonic acid was added to obtain a paratoluenesulfonic acid salt, and the obtained white crystals were collected by filtration to obtain 0.73 g of the title compound.
Melting point 181-183 ° C

Example 225 3 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
( Xypropyloxy) cinnamamide 3 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnamamide and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol,
After heating under reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound.

Example 226 3 ′-(2-hydroxy-3- (4- (na
Phthalen-1-yl) piperidin-1-yl) propyl
Oxy) cinnamamide 3 '-(2,3-epoxypropan-1-yloxy)
After dissolving cinnamamide and 4- (naphthalen-1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 227 3 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Namamide 3 '-(2,3-epoxypropan-1-yloxy)
After dissolving cinnamamide and 4- (naphthalen-2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 228 3 '-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
Xypropyloxy) cinnam-N, N-dimethylami
Do 3 '-(2,3-epoxypropan-1-yloxy)
After dissolving cinnam-N, N-dimethylamide and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol, heating and refluxing, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. Purification by chromatography affords the title compound.

Example 229 3 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N, N-dimethylamide 3 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-dimethylamide and 4- (naphthalen-1-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography to give the title compound. Is obtained.

Example 230 3 ′-(2-Hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N, N-dimethylamide 3 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-dimethylamide and 4- (naphthalen-2-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography to give the title compound. Is obtained.

Example 231 1- (3 ′-(3- (4-benzylpiperidin-1-i)
Ru) -2-hydroxypropyloxy) cinnamoyl)
1.5 g of pyrrolidine 1- (3 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 1.5 g of 4-benzylpiperidine are dissolved in 50 mL of methanol,
The mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.7 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.15 to 1.40
(M, 2H), 1.12-1.65 (m, 2H), 1.
75-2.03 (m, 6H), 2.20 (t, J = 9.
9, 1H), 2.38-2.62 (m, 4H), 2.8
2 (d, J = 11.2, 1H), 2.96 (d, J = 1
1.2, 1H), 3.56 (m, 4H), 3.96
(T, J = 4.6, 2H), 3.99-4.10 (m,
1H), 6.69 (d, J = 15.2, 1H), 6.9
0 (d, J = 7.3, 1H), 7.0-7.30 (m,
8H), 7.65 (d, 15.2, 1H)

Example 232 1- (3 ′-(3- (1-benzylpiperidin-4-i)
Rumin) -2-hydroxypropyloxy) cinnamo
Yl) pyrrolidine dihydrochloride 1/2 hydrate 1- (3 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine 1.7 g and 4-amino-1-benzylpiperidine 2.0 g 50m methanol
L and heated under reflux for 4 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.7 g of the title compound as an oil. This oil was dissolved in a small amount of acetone, and methanol-hydrochloric acid was added dropwise to form a hydrochloride, and the obtained white crystals were collected by filtration to obtain 0.90 g of the title compound. Melting point 220 ° C or higher (decomposition)

Example 233 1- (3 ′-(2-hydroxy-3- (4-phenylpyridine)
Peridin-1-yl) propyloxy) cinnamoyl)
1.5 g of pyrrolidine 1- (3 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 2.0 g of 4-phenylpiperidine are dissolved in 50 mL of methanol,
The mixture was heated under reflux for 2 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 0.73 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.70-1.99
(M, 8H), 2.10 (dt, J = 10.5, 3.
3, 1H), 2.25-2.65 (m, 4H), 2.9
7 (d, J = 11.2, 1H), 09 (d, J = 11.
2, 1H), 3.54 (m, 4H), 4.01 (d, J
= 4.6, 2H), 4.02-4.16 (m, 1H),
6.70 (d, J = 15.2, 1H), 6.91 (d
d, J = 2.0, 8.6, 1H), 7.10-7.62.
(M, 8H), 7.66 (d, J = 15.2, 1H)

Example 234 1- (3 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) pyrrolidine 1- (3 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 3,6-dihydro-
After dissolving 4- (naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 235 1- (3 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) pyrrolidine 1- (3 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (naphthalene-
After dissolving 1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 236 1- (3 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) pyrrolidine 1- (3 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (naphthalene-
After dissolving 2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 237 4- (3 ′-(3- (3,6-dihydro-4- (naphtha)
Ren-2-yl) -2H-pyridin-1-yl) -2-
Hydroxypropyloxy) cinnamoyl) morpholine 4- (3 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 3,6-dihydro-
After dissolving 4- (naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 238 4- (3 ′-(2-hydroxy-3- (4- (naphthalene)
1-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) morpholine 4- (3 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (naphthalene-
After dissolving 1-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 239 4- (3 ′-(2-hydroxy-3- (4- (naphthalene)
2-yl) piperidin-1-yl) propyloxy
B) Cinnamoyl) morpholine 4- (3 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (naphthalene-
After dissolving 2-yl) piperidine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound.

Example 240 (+)-4- (2 ′-(2-hydroxy-3- (4-
(Naphthalen-2-yl) piperidin-1-yl) pro
Pyroxy) cinnamoyl) morpholine maleate
-1/4 hydrate (-)-4- (2 '-(2,3-epoxypropane-1)
-Yloxy) cinnamoyl) morpholine 1.1 g and 4
0.8 g of-(naphthalen-2-yl) piperidine was dissolved in 50 mL of methanol and heated under reflux for 5 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. The oil was dissolved in a small amount of acetone, and a maleic acid salt was obtained by adding an acetone solution of maleic acid. The obtained white crystals were collected by filtration to obtain 1.5 g of the title compound. 158-160 ° C [α] _D ²⁵ + 13.4 ° (c1.0, methanol), 9
8% ee (DAICEL CHIRALPAK AS, hexane-isopropyl alcohol-diethylamine = 8
0/20 / 0.15, flow rate 1.0mL
/ Min, 27.0 min (-)-form, 36.2
min (+)-form)

Example 241 (−)-4- (2 ′-(2-hydroxy-3- (4-
(Naphthalen-2-yl) piperidin-1-yl) pro
Pyroxy) cinnamoyl) morpholine maleate
1/4 hydrate (+)-4- (2 '-(2,3-epoxypropane-1)
-Yloxy) cinnamoyl) morpholine 1.1 g and 4
0.8 g of-(naphthalen-2-yl) piperidine was dissolved in 50 mL of methanol and heated under reflux for 5 hours. After cooling, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oil. The oil was dissolved in a small amount of acetone, and a maleic acid salt was prepared by adding an acetone solution of maleic acid. The resulting white crystals were collected by filtration to obtain 1.2 g of the title compound. 158-160 ° C [α] _D ²⁵ -13.1 ° (c0.9, methanol), 9
8% ee (DAICEL CHIRALPAK AS, hexane-isopropyl alcohol-diethylamine = 8
0/20 / 0.15, flow rate 1.0mL
/ Min, 27.0 min (-)-form, 36.2
min (+)-form)

Example 242 2 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
Xypropyloxy) cinnam-N, N-dimethylami
Do 2 '-(2,3-epoxypropan-1-yloxy)
After dissolving cinnam-N, N-dimethylamide and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol, heating and refluxing, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. Purification by chromatography affords the title compound.

Example 243 2 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N, N-dimethylamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-dimethylamide and 4- (naphthalen-1-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography to give the title compound. Is obtained.

Example 244 2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N, N-dimethylamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-dimethylamide and 4- (naphthalen-2-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography to give the title compound. Is obtained.

Example 245 2 ′-(2-hydroxy-3- (4- (6-methoxyna
Phthalen-2-yl) piperidin-1-yl) propyl
Oxy) cinnam-N, N-dimethylamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-dimethylamide and 4- (6-methoxynaphthalen-2-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography. Affords the title compound.

Example 246 2 ′-(3- (3,6-dihydro-4- (naphthalene-
2-yl) -2H-pyridin-1-yl) -2-hydro
Xypropyloxy) cinnam-N, N-diethylami
Do 2 '-(2,3-epoxypropan-1-yloxy)
After dissolving cinnam-N, N-diethylamide and 3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine in methanol and heating to reflux, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. The title compound is obtained by purifying under the conditions described above.

Example 247 2 ′-(2-hydroxy-3- (4- (naphthalene-1)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N, N-diethylamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-diethylamide and 4- (naphthalen-1-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography to obtain the title compound. can get.

Example 248 2 ′-(2-hydroxy-3- (4- (naphthalene-2)
-Yl) piperidin-1-yl) propyloxy) cin
Nam-N, N-diethylamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-diethylamide and 4- (naphthalen-2-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography to obtain the title compound. can get.

Example 249 2 ′-(2-hydroxy-3- (4- (6-methoxyna
Phthalen-2-yl) piperidin-1-yl) propyl
Oxy) cinnam-N, N-diethylamide 2 '-(2,3-epoxypropan-1-yloxy)
Dissolve cinnam-N, N-diethylamide and 4- (6-methoxynaphthalen-2-yl) piperidine in methanol, heat to reflux, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography. The title compound is obtained.

Example 250 2- (2-hydroxy-3- (4- (naphthalene-2-)
Yl) piperidino) propyloxy) -N- (2-meth
Xyethyl) cinnamamide 1/4 hydrate 2- (2-hydroxy-3- (4- (naphthalene-2-
Il) piperidino) propyloxy) cinnamic acid 0.8
Using 0 g, 0.21 g of 2-methoxyethylamine, 0.60 g of diethyl cyanophosphate, and 10 ml of DMF, a crude crystal obtained by performing the same reaction operation as in Example 2 was obtained.
By recrystallizing from acetonitrile, 0.26 g of the title compound was obtained as white crystals. 138-139
° C

Example 251 N-ethyl- (2-hydroxy-3- (4- (naphthalene)
2-yl) piperidino) propyloxy) cinnam
Amide 2- (2-hydroxy-3- (4- (naphthalene-2-
Il) piperidino) propyloxy) cinnamic acid 0.8
Using 0 g, 0.23 g of ethylamine hydrochloride, 0.60 g of diethyl cyanophosphate, and 10 ml of DMF, the crude crystals obtained by performing the same reaction procedure as in Example 2 were recrystallized with acetonitrile to obtain the title compound 0.1. 41
g were obtained as white crystals. 145-146 ° C

Example 252 N, N-bis (2-hydroxyethyl) -2- (2-h
Droxy-3- (4- (naphthalen-2-yl) piperi
Dino) propyloxy) cinnamamide hemihydrate 2- (2-hydroxy-3- (4- (naphthalene-2-
Il) piperidino) propyloxy) cinnamic acid 0.8
0g, N, N-bis (2-hydroxyethyl) amine 0.39g, diethyl cyanophosphate 0.50g, DMF
Crude crystals obtained by performing the same reaction operation as in Example 2 using 15 ml were recrystallized with ethyl acetate / diethyl ether to obtain 0.22 g of the title compound as white crystals. 127-129 ° C

Example 253 (S) -4- (2- (2-hydroxy-3- (4-
(5,6,7,8-tetrahydronaphthalene-2-i
Ru) piperidino) propyloxy) cinnamoyl) mol
Using folin 3/2 maleate (S) -4- (2-glycidyloxycinnamoyl) morpholine 3.4 g and 4- (5,6,7,8-tetrahydronaphthalen-2-yl) piperidine 2.5 g By performing the same reaction operation as in Example 240,
(S) -4- (2- (2-hydroxy-3- (4-
4.6 g of (5,6,7,8-tetrahydronaphthalen-2-yl) piperidino) propyloxy) cinnamoyl) morpholine were obtained as a pale yellow oil. This was dissolved in ethyl acetate, 1.0 g of maleic acid was added, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain 2.5 g of the title compound as white crystals. Melting point 98-
100 ℃

Example 254 (R) -4- (2- (2-hydroxy-3- (4-
(5,6,7,8-tetrahydronaphthalene-2-i
Ru) piperidino) propyloxy) cinnamoyl) mol
Folin 3/2 maleate monohydrate (R) -4- (2-glycidyloxycinnamoyl) morpholine 1.5 g and 4- (5,6,7,8-tetrahydronaphthalen-2-yl) piperidine 1 By performing the same reaction operation as in Example 240 using 0.1 g,
(R) -4- (2- (2-hydroxy-3- (4-
2.3 g of (5,6,7,8-tetrahydronaphthalen-2-yl) piperidino) propyloxy) cinnamoyl) morpholine were obtained as a pale yellow oil. This was dissolved in ethyl acetate, 0.47 g of maleic acid was added, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain 0.64 g of the title compound as white crystals. Melting point 9
5-97 ° C

Example 255 (S) -2- (2-hydroxy-3- (4- (naphthalene)
2-yl) piperidino) propyloxy) -N-meth
Toxi-N-methylcinnamamide maleate (S) -2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnam hydrochloride 3.0 g, N, The same operation as in Example 240 was performed using 0.63 g of O-dimethylhydroxyamine hydrochloride, 1.0 g of diethyl cyanophosphate, 2.7 ml of triethylamine, and 50 ml of DMF to obtain (S)
-2- (2-hydroxy-3- (4- (naphthalene-2)
3.0 g of -yl) piperidino) propyloxy) -N-methoxy-N-methylcinnamamide were obtained as a brown oil. This was dissolved in ethyl acetate and maleic acid 0.54
g, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to give 1.7 g of the title compound as white crystals. 146-147 ° C

Example 256 (S) -N- (2-acetylaminoethyl) -2- (2
-Hydroxy-3- (naphthalen-2-yl) piperidi
No) propyloxy) cinnamamide 1/5 pentahydrate (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 1.5 g, N-acetyl 2 ml of ethylenediamine,
Using 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide,
By performing the same reaction procedure as in Example 2, 0.79 g of the title compound was obtained. 148-150 ° C

Example 257 1- (2- (2-hydroxy-3- (N- (4,4-bi
(4-fluorophenyl) cyclohexyl) -N-meth
Tylamino) propyloxy) cinnamoyl) pyrrolid
Emissions monohydrate 1- - (2 '(2,3-epoxy-1-yloxy) cinnamoyl) pyrrolidine 0.5 g, N-
By subjecting 0.5 g of (4,4-bis (4-fluorophenyl) cyclohexyl) -N-methylamine to the same operation as in Example 2 in methanol, 0.49 g of the title compound was obtained as white crystals. . Melting point 103-106
° C

Example 258 1- (2- (3- (4- (6-fluoro-1,2-benzene)
Zoisoxazol-3-yl) piperidin-1-yl)
-2-Hydroxypropyloxy) cinnamoyl) pyro
1.1 g of lysine hydrochloride pentahydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (6
-Fluoro-1,2-benzisoxazol-3-yl) piperidine (1.3 g) in methanol was subjected to the same reaction procedure as in Example 22 to give the title compound (1.02).
g were obtained as white crystals. 138-140 ° C

Example 259 1- (2- (3- (4- (6-fluorobenzo (b) phenyl)
Lan-3-yl) piperidin-1-yl) -2-hydro
Xypropyloxy) cinnamoyl) pyrrolidine hydrochloride
1.1 g of monohydrate 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and 4- (6
The same reaction procedure as in Example 22 was performed on 1.3 g of -fluorobenzo (b) furan-3-yl) piperidine in methanol to obtain 1.25 g of the title compound as white crystals. 126-128 ° C

Example 260 (R) -2- (2-hydroxy-3- (4-naphthalene)
-2-yl) piperidino) propyloxy) -N-meth
0.9 g of xy-N-methylcinnamamide maleate (R) -2 '-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid, N, O -Dimethylamine hydrochloride 0.21
g, 0.56 ml of triethylamine, 0.39 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide, by performing the same reaction operation as in Example 240,
0.22 g of the title compound was obtained. 145-147 ° C

Example 261 (S) -4- (2- (3- (4- (3-fluoro-4-
Methylphenyl) piperidin-1-yl) -2-hydro
Xypropyloxy) cinnamoyl) morpholine male
1.0 g of 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine folate salt hemihydrate and 4- (3
-Fluoro-4-methylphenyl) piperidine 1.0 g
Was subjected to the same reaction procedure as in Example 240 in methanol to give 0.42 g of the title compound as white crystals. Melting point 98-100 ° C

Example 262 (S) -4- (2- (3- (4- (3,4-difluoro
Phenyl) piperidin-1-yl) -2-hydroxyp
Ropyloxy) cinnamoyl) morpholine / maleic acid
1.0 g of salt 2/5 hydrate 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine
1.09 g of (3,4-difluorophenyl) piperidine was subjected to the same reaction procedure as in Example 240 in methanol to give 0.99 g of the title compound as white crystals. 116-118 ° C

Example 263 (S) -4- (2- (3- (4- (4-chloro-3-f)
(Fluorophenyl) -3,6-dihydro-2H-pyridine
-1-yl) -2-hydroxypropyloxy) cinna
0.8 g of moyl) morpholine hydrochloride 3/4 hydrate 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4
-Chloro-3-fluorophenyl) -3,6-dihydro-2H-pyridine in methanol, Example 22
By performing the same reaction operation as described above, the title compound 0.5
1 g was obtained as white crystals. Melting point 184-185 ° C

Example 264 (S) -4- (2- (3- (4- (4-chloro-3-to
(Trifluoromethylphenyl) -3,6-dihydro-2H
-Pyridin-1-yl) -2-hydroxypropyloxy
B) 0.8 g of cinnamoyl) morpholine hydrochloride monohydrate 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4
-Chloro-3-trifluoromethylphenyl) -3,6
-Dihydro-2H-pyridine 1.0 g in methanol,
By performing the same reaction procedure as in Example 22, 0.53 g of the title compound was obtained as white crystals. Melting point 190-1
92 ° C

Example 265 (S) -4- (2- (3- (4- (4-chloro-3-f)
Fluorophenyl) piperidin-1-yl) -2-hydro
Xypropyloxy) cinnamoyl) morpholine hydrochloride
1.2 g of 3/4 hydrate 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4
-Chloro-3-fluorophenyl) piperidine 1.0 g
Was subjected to the same reaction procedure as in Example 22 in methanol to give 0.53 g of the title compound as white crystals. 129-131 ° C

Example 266 (S) -4- (2- (3- (4- (4-chloro-3-to
Trifluoromethylphenyl) piperidin-1-yl)-
2-hydroxypropyloxy) cinnamoyl) morpho
1.2 g of phosphorus hydrochloride monohydrate 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4
-Chloro-3-trifluoromethylphenyl) piperidine (1.0 g) was subjected to the same reaction procedure as in Example 22 in methanol to give the title compound (0.82 g) as white crystals. 145-147 ° C

Example 267 4- (2- (2-hydroxy-3- (3- (2-naphtho)
Xy) propylamino) propyloxy) cinnamoy
Morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine 0.6 g;
-Naphthoxy) propylamine in methanol was subjected to the same reaction operation as in Example 2 in methanol to give 0.18 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.98-2.05
(M, 2H), 2.83-2.97 (m, 4H), 3.
58-3.70 (m, 10H), 4.01-4.08
(M, 1H), 4.15-4.23 (m, 2H), 6.
88 (d, 1H, J = 8.2), 6.95 (t, 1H,
J = 1.3), 7.00 (d, 1H, J = 15.6),
7.11-7.13 (m, 2H), 7.25-7.35
(M, 2H), 7.42 (t, 1H, J = 1.5),
7.46 (d, 1H, J = 1.0), 7.68-7.8
0 (m, 3H), 7.95 (d, 1H, J = 15.6)

Example 268 cis-1- (2- (3- (N-benzyl-N- (4-f
Enylcyclohexyl) amino) -2-hydroxypro
1.0 g of pyroxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and N-benzyl-N- (4-phenylcyclohexyl) amine
0 g of the title compound was subjected to the same reaction procedure as in Example 2 in methanol to obtain 0.53 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.80
(M, 8H), 1.82-2.00 (m, 4H), 2.
18-2.30 (m, 2H), 2.58-2.63
(M, 1H), 2.69-2.78 (m, 2H), 2.
92-2.99 (m, 1H), 3.50 (m, 4H),
3.93-3.98 (m, 3H), 6.82 (d, 1
H, J = 7.8), 6.90-6.96 (m, 2H),
7.15-7.38 (m, 11H), 7.45 (d, 1
H, J = 6.3), 7.86 (d, 1H, J = 15.
6)

Example 269 1- (2- (2-hydroxy-3- (N- (4,4-bi
(4- (fluorophenyl) cyclohexyl) amino)
0.5 g of propyloxy) cinnamoyl) pyrrolidine 1- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) pyrrolidine and N-
(0.6 g of 4,4-bis (4-fluorophenyl) cyclohexylamine was treated in methanol in the same manner as in Example 2 to obtain 0.05 g of the title compound. ¹ H-NMR (CDCl ₃ ) Δ: 1.28-1.38
(M, 2H), 1.75-1.99 (m, 8H), 2.
50-2.63 (m, 3H), 2.70-2.78
(M, 1H), 2.83-2.90 (m, 1H), 3.
42-3.60 (m, 4H), 3.95-3.99
(M, 2H), 4.02-4.05 (m, 1H), 6.
75 (d, 1H, J = 16.2), 6.80-6.98
(M, 5H), 7.00-7.10 (m, 2H), 7.
21-7.30 (m, 4H), 7.43-7.55
(M, 1H), 7.97 (d, 1H, J = 16.2)

Example 270 4- (2- (2-hydroxy-3- (2- (2-naphtho)
Xy) ethylamino) propyloxy) cinnamoyl)
Morpholine 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine 0.7 g and 2- (2
-Naphthoxy) ethylamine 0.7 g in methanol,
By performing the same reaction procedure as in Example 2, 0.38 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.83-2.97
(M, 2H), 3.08-3.15 (m, 2H), 3.
50-3.80 (m, 12H), 4.01-4.08
(M, 1H), 4.15-4.23 (m, 2H), 6.
82-6.90 (m, 1H), 6.91-7.00
(M, 2H), 7.08-7.18 (m, 2H), 7.
25-7.38 (m, 2H), 7.40-7.50
(M, 2H), 7.65-7.80 (m, 3H), 7.
95 (d, 1H, J = 15.6)

Example 271 (S) -4- (2- (3- (4- (p-biphenylyl))
Piperidin-1-yl) -2-hydroxypropyloxy
B) Cinnamoyl) morpholine hydrochloride (S) -4- (2 ′-(2,3-epoxypropane-1)
-Yloxy) cinnamoyl) morpholine 1.0 g;
The same reaction procedure as in Example 22 was carried out in 1.0 g of 4- (p-biphenylyl) piperidine in methanol to obtain 0.18 g of the title compound. 135-138
° C

Example 272 (S) -N-benzyl-2- (2-hydroxy-3-
(4- (naphthalen-2-yl) piperidino) propyl
1.5 g of oxy) -N-methylcinnamamide hydrochloride (R) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid, N-methylbenzyl 0.42 g of amine,
Using 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide,
By performing the same reaction operation as in Example 22, 0.21 g of the title compound was obtained as white crystals. Melting point 112-1
15 ℃

Example 273 (S) -3-acetylamino-1- (2- (2-hydro
Xy-3- (4- (naphthalen-2-yl) piperidi
No) propyloxy) cinnamoyl) pyrrolidine (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 1.5 g, 3-acetamidopyrrolidine 0.45
g, 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide, and the same reaction procedure as in Example 2 was performed to obtain 0.36 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.38
(M, 2H), 1.85-1.99 (m, 6H), 2.
00 (s, 3H), 2.05-2.13 (m, 2H),
2.40-2.47 (m, 1H), 2.50-2.57
(M, 1H), 2.60-2.72 (m, 1H), 2.
93-3.03 (m, 1H), 3.09-3.20
(M, 1H), 3.52-3.75 (m, 2H), 3.
99-4.21 (m, 3H), 4.50-4.61
(M, 1H), 6.85-7.00 (m, 3H), 7.
38-7.55 (m, 3H), 7.65 (s, 1H),
7.75-7.82 (m, 2H), 7.85-7.97
(M, 1H)

Example 274 (S) -4- (2- (2-hydroxy-3- (4- (5
-Methylbenzo (b) furan-3-yl) piperidine-
1.3 g of 1-yl) propyloxy) cinnamoyl) morpholine 4- (2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (5
-Methylbenzo (b) furan-3-yl) piperidine (0.9 g) was subjected to the same reaction procedure as in Example 2 in methanol to give 1.45 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.90
(M, 3H), 2.09 (m, 2H), 2.21 (t,
1H, J = 9.7), 2.46 (s, 3H), 2.50
-2.70 (m, 3H), 2.71-2.80 (m, 1
H), 2.93-2.97 (m, 1H), 3.10-
3.15 (m, 1H), 3.72 (bs, 8H),
05-4.10 (m, 2H), 4.15-4.20
(M, 1H), 6.90-7.00 (m, 2H), 7.
10 (d, 1H, J = 8.3), 7.16 (d, 1H,
J = 15.7), 7.30-7.40 (m, 3H),
7.49 (d, 1H, J = 6.4), 7.92 (d, 1
H, J = 15.7)

Example 275 (S) -4- (2- (3- (4- (4-tert-butyl)
Enyl) piperidin-1-yl) -2-hydroxypro
Pyroxy) cinnamoyl) morpholine (S) -4- (2 ′-(2,3-epoxypropane-1)
-Yloxy) cinnamoyl) morpholine 1.2 g;
1.0 g of 4- (4-tert-butylphenyl) piperidine
Was subjected to the same reaction procedure as in Example 2 in methanol to give 1.1 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (s, 9
H) 1.60-1.70 (m, 2H), 1.80-
1.88 (m, 2H), 2.58-2.62 (m, 1
H) 2.69-2.80 (m, 2H), 3.15-
3.23 (m, 2H), 3.42-3.50 (m, 2
H), 3.72 (bs, 8H), 4.05-4.10
(M, 2H), 4.15-4.20 (m, 1H), 6.
90-7.00 (m, 2H), 7.16 (d, 1H, J
= 15.7), 7.17 (d, 2H, J = 8.6),
7.33 (d, 2H, J = 8.6), 7.33-7.4
0 (m, 2H), 7.49 (d, 2H, J = 6.4),
7.92 (d, 1H, J = 15.7)

Example 276 (S) -4-benzyl-1- (2- (2-hydroxy-
3- (4- (naphthalen-2-yl) piperidino) pro
1.5 g of pyroxy) cinnamoyl) piperidine hydrochloride (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid, 0.73 g of 4-benzylpiperidine, Using 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide,
By performing the same reaction procedure as in Example 22, 0.91 g of the title compound was obtained as white crystals. Melting point 135-1
38 ° C

Example 277 Ethyl (S) -1- (2- (2-hydroxy-3-
(4- (naphthalen-2-yl) piperidino) propyl
Oxy) cinnamoyl) piperidine-4-carboxyle
Sodium maleate (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 1.5 g, isonipecotic acid ethyl ester 0.6
Using 6 g, 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide, 1.0 g of the title compound was obtained as white crystals by performing the same reaction operation as in Example 240. Melting point 1
47-150 ° C

Example 278 (S) -N-phenyl-2- (2-hydroxy-3-
(4- (naphthalen-2-yl) piperidino) propyl
( Oxy) cinnamamide (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 1.5 g, aniline 0.66 g, triethylamine 0.98 ml, cyanophosphoric acid The same reaction procedure as in Example 2 was carried out using 0.67 ml of diethyl and 20 ml of dimethylformamide to obtain 0.44 g of the title compound as pale yellow crystals. 118-120 ° C

Example 279 (S) -1-benzyl-4- (2- (2-hydroxy-
3- (4- (naphthalen-2-yl) piperidino) pro
Pyroxy) cinnamoyl) piperazine (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 1.5 g, 1-benzylpiperazine 0.70 g, triethylamine 0 .98 ml, 0.67 ml of diethyl cyanophosphate, 20 ml of dimethylformamide,
By performing the same reaction procedure as in Example 2, 1.37 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.78-2.00
(M, 4H), 2.18-2.30 (m, 1H), 2.
38-2.57 (m, 5H), 2.58-2.77
(M, 2H), 2.98-3.03 (m, 1H), 3.
17-3.22 (bs, 2H), 3.47 (s, 2
H) 3.77 (bs, 4H), 3.98-4.17
(M, 3H), 4.18-4.23 (m, 1H), 6.
97-7.03 (m, 2H), 7.18-7.50
(M, 11H), 7.68 (s, 1H), 7.79-
7.90 (m, 4H)

Example 280 (S) -1,2,3,4-tetrahydro-2- (2-
(2-hydroxy-3- (4- (naphthalene-2-i
Ru) piperidino) propyloxy) cinnamoyl) iso
Quinoline (S) -2 '-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 1.5 g, 1,2,3,4-tetrahydroisoquinoline 0.474 g, Using the same reaction procedure as in Example 2 using 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide, 0.38 g of the title compound was obtained as white crystals. Melting point 98-101 ° C

Example 281 (S) -4- (2- (2-hydroxy-3)
-(4- (naphthalen-2-yl) piperidino) propyl
Loxy) -α-methylcinnamoyl) morpholine (S) -4- (2 ′-(2,3-epoxypropane-1)
-Yloxy) -α-methylcinnamoyl) morpholine (1.4 g) and 4- (naphthalen-2-yl) piperidine (1.0 g) in methanol were reacted in the same manner as in Example 2 to give the title compound 1. 2 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.82 to 2.03
(M, 4H), 2.15 to 2.20 (m, 1H), 2.
45-2.60 (m, 4H), 2.62-2.78
(M, 1H), 2.97-3.00 (m, 1H), 3.
15-3.18 (m, 1H), 3.78 (bs, 8
H), 3.99-4.03 (m, 2H), 4.10-
4.18 (m, 1H), 6.66 (s, 1H), 6.9
0 (d, 1H, J = 7.9), 6.97 (t, 1H, J
= 7.3), 7.13-7.15 (m, 2H), 7.3
5-7.50 (m, 3H), 7.66 (s, 1H),
7.78-7.82 (m, 2H)

Example 282 (S) -4- (2- (2-hydroxy-3- (4- (6
-Methoxynaphthalen-2-yl) piperidin-1-i
L) propyloxy) cinnamoyl) morpholine 0.9 g of 4- (2 '-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine and 4- (4
0.88 g of the title compound was obtained as white crystals by subjecting 0.8 g of-(6-methoxynaphthalen-2-yl) piperidine to the same operation as in Example 2 in methanol. 146-148 ° C

Example 283 (R) -2- (2-hydroxy-3- (4- (naphthalene)
N-2-yl) piperidino) propyloxy) -N, N
-Dimethylcinnamamide maleate (R) -2 '-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 0.9 g, dimethylamine hydrochloride 0.1 g 19g, triethylamine 0.56ml, diethyl cyanophosphate 0.
The same reaction procedure as in Example 240 was carried out using 39 ml and dimethylformamide 20 ml to obtain 0.63 g of the title compound. Melting point 171-172 ° C

Example 284 (R) -N, N-diethyl-2- (2-hydroxy-3
-(4- (naphthalen-2-yl) piperidino) propyl
( Roxy) cinnamamide maleate (R) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamic acid 0.9 g, diethylamine 0.16 g, triethylamine 0.1 g 56 ml, diethyl cyanophosphate 0.39 m
l, using dimethylformamide 20 ml, Example 24
By performing the same reaction procedure as in Step 0, the title compound 0.1.
51 g were obtained. 156-158 ° C

Example 285 (S) -N, N-diethyl-2- (2-hydroxy-3
-(4- (naphthalen-2-yl) piperidino) propyl
Leoxy) cinnamamide maleate hemihydrate (S) -2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnam hydrochloride 3.0 g, diethylamine 0.47 g, diethyl cyanophosphate 1.0 g, triethylamine 0.9 m
1 and 50 ml of DMF, and by performing the same reaction operation as in Example 240, (S) -N, N-diethyl-2
-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamamide 2.
3 g were obtained as a brown oil. This was dissolved in ethyl acetate, 0.48 g of maleic acid was added, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile / diethyl ether to obtain 0.94 g of the title compound as white crystals. 148-150 ° C

Example 286 (S) -4- (5-Chloro-2- (2-hydroxy-3)
-(4- (naphthalen-2-yl) piperidin-1-i
Le) propyloxy) cinnamoyl) morpholine 3 /
2-maleate hemihydrate 4- (5'-chloro-2'-hydroxycinnamoyl)
4- (5′-Chloro-2 ′-(2,3-epoxypropan-1-yloxy) cinnamoyl) morpholine obtained from morpholine and (S) -glycidyl nosylate
2 g and 4- (naphthalen-2-yl) piperidine 1.
By performing the same reaction operation as in Example 240 in 0 g of methanol, 2.5 g of the title compound was obtained as white crystals. 155-158 ° C

Example 287 (S) -1- (2- (2-hydroxy-3- (4- (na
Phthalen-2-yl) piperidino) propyloxy) si
Nannamoyl) -4-phenylpiperazine (S) -2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnamate 1.5 g, 1-phenylpiperazine 0.68 g, Using 0.98 ml of triethylamine, 0.67 ml of diethyl cyanophosphate, and 20 ml of dimethylformamide,
By performing the same reaction procedure as in Example 2, 1.17 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.75-2.00
(M, 4H), 2.18-2.05 (m, 1H), 2.
43-2.58 (m, 1H), 2.59-2.78
(M, 3H), 2.90-3.03 (m, 4H), 3.
10-3.25 (m, 8H), 3.85-3.98
(M, 8H), 4.05-4.18 (m, 2H);
19-4.23 (m, 1H), 6.83-7.00
(M, 4H), 7.20-7.60 (m, 6H), 7.
61-7.65 (m, 1H), 7.78-7.82
(M, 3H), 7.88-7.95 (m, 2H)

Example 288 (S) -2- (2-hydroxy-3- (4- (naphthalene)
N-2-yl) piperidino) propyloxy) -N, N
-Dimethylcinnamamide maleate (S) -2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) cinnam hydrochloride 3.0 g, dimethylamine hydrochloride 0 .52 g,
1. 1.0 g of diethyl cyanophosphate, triethylamine
Using the same reaction procedure as in Example 240 using 7 ml and 50 ml of DMF, (S) -2- (2-hydroxy-3- (4- (naphthalen-2-yl) piperidino) propyloxy) -N, 3.0 g of N-dimethylcinnamamide was obtained as a pale brown oil. This was dissolved in ethyl acetate, 0.54 g of maleic acid was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1.9 g of the title compound as white crystals. Melting point 172-17
3 ° C. The structural formulas of the compounds obtained in the above Examples are represented by
Shown in

[0365]

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[0366]

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[0367]

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[0368]

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[0369]

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[0370]

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[0371]

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[0372]

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[0373]

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[0374]

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[0375]

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[0376]

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[0377]

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[0378]

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[0379]

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[0380]

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[0381]

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[0382]

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[0383]

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[0384]

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Formulation Formulation Example 1 Among the compounds of the present invention, compound 50 represented by the general formula (I)
lactose 98mg and corn starch 45mg,
It is thoroughly kneaded with 3 mg of hydroxypropylcellulose in a kneading machine. Pass the wrought product through a 200 mesh comb, 50
Dry at ℃ and pass through a 24 mesh comb. Talc 3
mg and magnesium stearate 1 mg,
A tablet weighing 200 mg is obtained using a 9 mm diameter punch.
The tablets can be sugar-coated or film-coated as required.

Experimental Example 1: 5-HT _1A receptor binding test D. The method of Hall et al. (J. Neurochem.
44, 1685-1696 (1985)). Rat hippocampus frozen and stored
0 volumes of 50 mM Tris-HCl buffer (pH 7.
4) The homogenate was centrifuged at 500 × g for 10 minutes. The supernatant was centrifuged at 40,000 × g for 10 minutes, the precipitate was incubated at 37 ° C. for 10 minutes, and then centrifuged at 40,000 × g for 10 minutes. Further, the precipitate was added to a 20-fold volume of 50 mM Tris-HCl buffer (pH
7.4) was added and homogenized, and again 40,000 × g
For 10 minutes. Add 100 volumes of 1 mM Mn to the sediment
50 mM Tris-HCl buffer containing Cl ₂ (pH
7.4) was added and homogenized to obtain a membrane solution.
96well pre - test substance solution 25ml was added to the preparative, 25ml of the ^{(3 H) -8-OH-} DPAT solution (final concentration 2 nM) was added, 0.45 ml of membrane solution which had been pre-incubated at 37 ° C. In addition, 12
Incubated for minutes. After completion, the reaction solution was GF /
Filter through a B glass filter and add 50 mM Tris-H
The filter was washed five times with a Cl buffer (pH 7.4). The radioactivity remaining on the filter was measured by TopCount. 25 ml of 0.005N hydrochloric acid for total binding measurement
And 25 ml of WAY-1 for non-specific binding measurement
00635 (final concentration 1M) was used instead of the test substance. The measurement of total binding or non-specific binding is quadruplicate, and the measurement of test substance is d.
performed in duplicate. The IC ₅₀ value was calculated using a two-point complementary interpolation method, and the Ki value was calculated from the Kd value of each test using the following equation. _{Ki = IC 50 / (1 +} C / Kd) IC 50: 50% binding inhibitory concentration, C: concentration of ligand

Experimental Example 2: 5-HT transporter binding test (Eur. J. Pharm)
acol. , 118; 107-114 (1985)). 50 m ice-cooled rat cerebral cortex
Homogenize with polytron in mol / L Tris-HCl buffer (pH 7.4). 1000 × g, 10
Centrifugation at 4 ° C for 10 minutes, and transfer the supernatant to another centrifuge tube.
After centrifugation at 40000 × g for 20 minutes at 4 ° C., a 50 mmol / L Tris-HCl buffer solution (pH
Add 7.4) and suspend. After incubating at 37 ° C. for 10 minutes, centrifugation was performed at 40000 × g for 20 minutes at 4 ° C. to obtain 120 mmol / L NaCl and 5 mmol / L
The suspension is suspended in a 50 mmol / L Tris-HCl buffer (pH 7.4) containing KCl. (Diluted to 100 times the wet weight of the brain) This was used as a membrane fluid. For the binding inhibition test, a final concentration of 0.
It was prepared in 2nmol / L ⁽³ H) paroxetine and 25
React in plastic test tube at 90 ° C. for 90 minutes. Solvent for total binding, final concentration 10 μmo for non-specific binding
1 / L of fluvoxamine is used. Using a cell harvester, the reaction was terminated by filtering through a GF / B glass filter treated with 0.1% polyethyleneimine, and the ice-cooled 50 m
mol / L Tris-HCl buffer station (pH 7.4) 3
Wash three times with mL. Radioactivity was measured on β-plate. As a result of Experimental Examples 1 and 2, 5-HT of the compound of the present invention
Both Ki values for the _1A receptor binding test and the 5-HT transporter binding test showed 0.1 to 100 nM or less.

Experimental Example 3: Antagonism of lowering of body temperature The antagonism of the test compound against the decrease in body temperature caused by 8-OH-DPAT proved that the test compound was able to enter the brain and that the test compound had 5-HT _1A receptor. It was determined whether it acts as an agonist or an antagonist on the body. The rectal temperature of ddY male mice was measured using a digital thermistor thermometer (KN-91, Natsume Seisakusho)
Was measured (previous value). Thereafter, the test compound is orally or parenterally administered, and after a certain time, 8-OH-DPAT.
1 mg / kg was administered subcutaneously, and the rectal temperature (post-value) was measured 30 minutes later. As a result of Experimental Example 3, the compound of the present invention
By oral administration of 0.1-100 mg / kg, 8-O
By antagonizing the hypothermia caused by H-DPAT, it is an antagonist to the 5-HT _1A receptor, and this indicates that the compound of the present invention has excellent bioavailability and brain-localization. It was suggested.

Experimental Example 4: Forced swimming test A test substance was orally or parenterally administered to a ddY male mouse, and after a certain period of time, the mouse was placed in an aquarium (material: vinyl chloride, color: black, inner diameter: 10 cm, height: 25 cm) , Water depth:
15 cm, water temperature: 25 ° C.), and a 6-minute test trial was performed. The movement of the animal is recorded on a video via a CCD camera installed directly above the aquarium, and the image analysis system / forced swimming analysis program (NeuroScience Inc .: Vi)
deoimage motion analyzer
(AXIS series) / (TARGET / 7
Using M)), an analysis of the immobility time for 2 to 4 minutes from the start of swimming was performed. As a result of Experimental Example 4, the compound of the present invention significantly reduced the immobility time by a single oral administration of 0.1 to 100 mg / kg, whereas the conventional SSRI took several days for the onset of action. This suggests that the compound of the present invention can be a so-called immediate-acting antidepressant having a faster onset of antidepressant action than conventional SSRIs.

[0390]

The compound of the present invention is useful as a so-called immediate-acting antidepressant having a rapid onset of antidepressant action.
-HT-mediated diseases of the central nervous system such as schizophrenia, anxiety, obsessive-compulsive disorder (OCD), panic disorders, social anxiety disorders (social phobi)
a), seasonal affective disorder (seasonal effect)
active disorder, anorexia nervosa, bulimia, nocturnal enuresis, pediatric hyperactivity disorder, traumatic stress disorder (PTSD), senile dementia, migraine, stroke, Alzheimer's disease, cognitive impairment, hypertension, gastrointestinal dysfunction, feeding disorder ), Thermoregulatory and sexual abnormalities, pain and the treatment of cardiovascular abnormalities, drug abuse and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31/40 A61K 31/40 31/44 31/44 31/445 31/445 605 605 610 610 611 611 611 613 613 614 614 31/495 31/495 31/535 605 31/535 605 C07D 211/14 C07D 211/14 211/18 211/18 211/52 211/52 211/58 211/58 211/70 211/70 295 / 18 295/18 Z 401/04 401/04 209 209 401/12 401/12 207 207 405/04 405/04 211 211 409/04 409/04 211 211 (72) Inventor Akira Nishiyama Koyata, Iruma, Saitama 3-7-25 Yoshitomi Pharmaceutical Co., Ltd.Drug Discovery Research Laboratory (72) Inventor Yasunori Morio 3-7-25 Koyata, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd.

Claims (6)

[Claims] 1. A compound of the general formula (I) Or an optically active form thereof or a pharmaceutically acceptable salt thereof and a hydrate thereof. In the above formula, the definition of each symbol is as follows. The bond represented by the solid line and the dotted line indicates a double bond or a single bond. X is a hydrogen atom,
It represents a hydroxy group, an alkoxy group having 1 to 8 carbon atoms or a halogen. R ¹ represents a group represented by the following formula. Embedded image (In the formula, Y has 3 to 5 carbon atoms which may have a substituent.
It represents 8 cycloalkyl or alkylene having 1 to 8 carbon atoms which may be branched. m and n each independently represent 0, 1 or 2. Ar represents an aryl group which may have a substituent. R ² represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. R ⁵ represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Z represents absent or CH _2. R ⁶ represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 8 carbon atoms. R ³ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms or a halogen atom. R ⁴ represents a group represented by the following formula. Embedded image (Wherein, R ⁷ and R ⁸ are each independently a hydrogen atom,
And represents an alkyl group having 1 to 18 carbon atoms, an aryl or aralkyl which may have a substituent. R ⁹ is
A hydrogen atom, an aryl group which may have a substituent,
It represents an alkyl group having 1 to 18 carbon atoms, an alkoxy group or an acyl group having 1 to 8 carbon atoms. Ra, Rb, Rc are the same or different and each is a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a hydroxy group, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an acyl group, a nitro group or an amino group. Is shown.
Alternatively, Ra and Rb or Rb and Rc are bonded to each other to form —CH ₂ CH ₂ CH ₂ CH ₂ — or —CH ＝ C
H-CH = CH- may be formed. 2. The compound according to claim 1, wherein each symbol in the formula (I) is defined as follows, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
The bond represented by the solid line and the dotted line indicates a double bond or a single bond. X represents a hydroxy group. R ¹ represents a group represented by the following formula. Embedded image (In the formula, R ⁵ represents a phenyl group or a naphthyl group which may have a substituent; Z does not exist; R ⁶ represents hydrogen.) R ³ represents a hydrogen atom or 1 to 4 carbon atoms. Represents an alkyl group. R ⁴ represents a group represented by the following formula. Embedded image (In the formula, R ⁷ and R ⁸ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R ⁹ represents a phenyl group or an alkyl group having 1 to 4 carbon atoms.) ,
Rb and Rc both represent a hydrogen atom. (18) 3- (2- (2-hydroxy-
3- (4- (naphthalen-2-yl) piperidin-1
-Yl) propyloxy) phenyl) propionylpyrrolidine, (21) 3- (2- (2-hydroxy-3-
(4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) phenyl) propionylpiperidine, (27) (3- (2- (2-hydroxy-3- (4
-(Naphthalen-2-yl) piperidin-1-yl) propyloxy) phenyl) propionyl) morpholine,
(34) 2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamamide, (69) 1- (2 ′-(3- (4
-(Naphthalen-1-yl) -3,6-dihydro-2H
-Pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) pyrrolidine, (70) 1- (2′-
(3- (4- (naphthalen-2-yl) -3,6-dihydro-2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) pyrrolidine, (88)
1- (2 ′-(2-hydroxy-3- (4- (naphthalen-1-yl) piperidin-1-yl) propyloxy) cinnamoyl) pyrrolidine, (89) 1- (2′-
(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) pyrrolidine, (90) 1- (2 ′-(2-hydroxy-3- (4- ( 6-methoxynaphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) pyrrolidine, (124) 1- (2 ′-(3-
(127) (3,6-dihydro-4- (3,4-dimethylphenyl) -2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) morpholine
1- (2 ′-(3- (3,6-dihydro-4- (naphthalen-1-yl) -2H-pyridin-1-yl) -2-
(Hydroxypropyloxy) cinnamoyl) morpholine, (128) 1- (2 ′-(3- (3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridine-1)
-Yl) -2-hydroxypropyloxy) cinnamoyl) morpholine, (144) 1- (2 '-(2-hydroxy-3- (4- (3,4-dimethylphenyl) piperidin-1-yl) propyloxy) Cinnamoyl) morpholine, (146) 1- (2 ′-(2-hydroxy-3)
-(4- (naphthalen-1-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (1
47) 1- (2 '-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (148) 1-
(2 ′-(2-hydroxy-3- (4- (6-methoxynaphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, (171) 1-
(2 '-(3- (3,6-dihydro-4- (naphthalen-2-yl) -2H-pyridin-1-yl) -2-hydroxypropyloxy) cinnamoyl) -4-methylpiperazine, (173) 1- (2 ′-(2-hydroxy-
3- (4- (naphthalen-2-yl) piperidine-1-
Yl) propyloxy) cinnamoyl) -4-methylpiperazine, (177) 1- (2 ′-(2-hydroxy-
3- (4- (naphthalen-2-yl) piperidine-1-
Yl) propyloxy) cinnamoyl) -4-phenylpiperazine, (240) (+)-1- (2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyl (Oxy) cinnamoyl) morpholine, (241) (−)-1- (2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnamoyl) morpholine, 244) 2 '-(2-hydroxy-3- (4-
(Naphthalen-2-yl) piperidin-1-yl) propyloxy) cinnam-N, N-dimethylamide and (248) 2 ′-(2-hydroxy-3- (4- (naphthalen-2-yl) piperidine The compound according to claim 1, which is selected from -1-yl) propyloxy) cinnam-N, N-diethylamide, an optically active form thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof. 4. A medicament comprising the compound according to claim 1, an optically active form thereof or a pharmaceutically acceptable salt thereof and a hydrate thereof. 5. The medicament according to claim 4, which is a therapeutic agent for depression which improves depression symptoms in mammals including humans. 6. A compound having an antidepressant action selected from the compound according to claim 1, an optically active form thereof or a pharmaceutically acceptable salt thereof and a hydrate thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition.