JPH11147877A - Alkylenediamine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new alkylenediamine derivative having an action to inhibit the contraction for urination on elevation in the inner pressure of bladder and useful as a medicine for dysuria. SOLUTION: The compound of formula I [R<1> is H, an alkyl, (substituted) phenyl or the like; R<2> is (substituted) phenyl, naphthyl or an aromatic heterocyclic group; R<3> and R<4> are H, an alkyl, an aralkyl or an aryl, or R<3> and R<4> are bound to each other to form a (substituted) heterocyclic group; X is O, S or imino; Y is O or S; Z is CH2 , CO or CS; (m) and (n) are each 0-4; (r) is 0 or 1; (p) and (q) are 0-5, wherein (p)+(q)=1 to 5]. For example, 5-benzyl-3-(3- morpholino-1-phenylprophyl)-1,3-oxazolin-2-one, is obtained by reacting a compound of formula II with a compound of formula III (Q is a halogen or a releasable group such as tosyloxy or methyloxy).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel alkylenediamine derivative and a therapeutic agent for dysuria containing the novel alkylenediamine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, flavoxate hydrochloride and oxybutynin hydrochloride, which directly and peripherally act on the bladder, have been used as therapeutic agents for dysuria. However, they also affect other organs such as the digestive system, and there are concerns about side effects.

The applicant of the present invention has the following general formula (A):

[0004]

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Wherein R ^K represents a straight-chain or branched-chain alkyl group having 3 to 8 carbon atoms, X ^K represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
Has shown a 4,5 or 6) 1,3-oxazolidin-2-one derivative or a pharmacologically acceptable salt thereof as an active ingredient. See JP-A-1-319418).

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel alkylenediamine derivative having an action of suppressing urinary contraction caused by high pressure in the bladder and a therapeutic agent for dysuria containing the same as an active ingredient. is there.

[0007]

According to the present invention, there is provided a compound represented by the general formula (1):
Or the general formula (2):

[0008]

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Wherein R ¹ is a hydrogen atom, an alkyl group,
Or an alkyl group, halogen atom, haloalkyl group, hydroxyl group, alkoxyl group, aryloxy group, aralkyloxy group, nitro group, amino group, cyano group, alkylamino group, aralkylamino group, arylamino group, acylamino group, carboxyl Group, alkoxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, carbamoyl group, sulfo group, alkoxysulfonyl group, aralkyloxysulfonyl group, aryloxysulfonyl group, sulfonamide group and 1H
Selected from the group consisting of -tetrazol-5-yl group, represents a phenyl group, a naphthyl group or an aromatic heterocyclic group which may have 1 to 5 identical or different substituents, and R ² represents Alkyl group, halogen atom, haloalkyl group, hydroxyl group, alkoxyl group, aryloxy group, aralkyloxy group, nitro group, amino group, cyano group, alkylamino group, aralkylamino group, arylamino group, acylamino group, carboxyl group, Alkoxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, carbamoyl group, sulfo group,
It may have 1 to 5 identical or different substituents selected from the group consisting of an alkoxysulfonyl group, an aralkyloxysulfonyl group, an aryloxysulfonyl group, a sulfonamide group and a 1H-tetrazol-5-yl group. Represents a phenyl group, a naphthyl group or an aromatic heterocyclic group, and R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or
R ³ and R ⁴ are bonded together with the nitrogen atom to which R ³ and R ⁴ are bonded, optionally further oxygen atom, contains a sulfur atom or a nitrogen atom, an alkyl group, an aralkyl group, a phenyl group, a hydroxyl group, An alkoxyl group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, selected from the group consisting of an acyl group and a carbamoyl group, which may have 1 to 5 identical or different substituents, X represents a 5- to 7-membered ring group, X represents an oxygen atom, a sulfur atom or an imino group;
Represents an oxygen atom or a sulfur atom, Z is -CH ₂ -, - C
O- or -CS-, m represents an integer of 0 to 4, n
Represents an integer of 0 to 4, r is 0 or 1, p and q
Represents an integer of 0 to 5 independently. Provided that p + q is 1 to 5), or a pharmacologically acceptable salt thereof.

One of the typical compounds represented by the general formula (1) is represented by the general formula (3):

[0011]

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(Wherein R ¹ and R ² are each independently
Alkyl group, halogen atom, haloalkyl group, hydroxyl group, alkoxyl group, aryloxy group, aralkyloxy group, nitro group, amino group, alkylamino group,
Aralkylamino, arylamino, acylamino, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, carbamoyl, sulfo, alkoxysulfonyl, aralkyloxysulfonyl, aryloxysulfonyl, sulfonamide A phenyl group, a naphthyl group or an aromatic heterocyclic group, which may have 1 to 5 identical or different substituents, selected from the group consisting of a group and a 1H-tetrazol-5-yl group; ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or R ³ and R ⁴ are bonded to each other, and optionally together with a nitrogen atom to which R ³ and R ⁴ are bonded, Containing oxygen, sulfur or nitrogen atoms,
An alkyl group, an aralkyl group, a phenyl group, a hydroxyl group, an alkoxyl group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group and a carbamoyl group; 5 may have, represent a 5- to 7-membered cyclic group, X represents an oxygen atom, a sulfur atom or an imino group, Y represents an oxygen atom or a sulfur atom, Z is -CH ₂ -, - CO -Or -CS-, m
Represents an integer of 0 to 4, n represents an integer of 0 to 4, and p and q independently represent an integer of 0 to 5. However, p + q is 1-5
Or a pharmacologically acceptable salt thereof.

Another typical compound represented by the general formula (1) is represented by the general formula (4):

[0014]

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(R ¹ , R ² , R ³ , R ⁴ , X, Y, Z,
m, n, p and q have the same meaning as defined for the general formula (1)) or a pharmacologically acceptable salt thereof.

One of the typical compounds represented by the general formula (2) is represented by the general formula (5):

[0017]

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(R ¹ , R ² , R ³ , R ⁴ , X, Y, Z,
m, n, p and q have the same meaning as defined for the general formula (2)), or a pharmacologically acceptable salt thereof.

Other typical compounds represented by the general formula (2) are represented by the general formula (6):

[0020]

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(R ¹ , R ² , R ³ , R ⁴ , X, Y, Z,
m, n, p and q have the same meaning as defined for the general formula (2)), or a pharmacologically acceptable salt thereof.

The alkylenediamine derivative of the present invention represented by the general formula (1) or (2) has the general formula (7) or (8):

[0023]

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(Wherein R ¹ , X, Y, Z, m and r are
And a compound represented by the general formula (9):

[0025]

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Wherein R ² , R ³ , R ⁴ , n, p and q
Is as described above, and Q represents a leaving group such as a halogen atom, a tosyloxy group or a mesyloxy group).

The alkylenediamine derivative of the present invention represented by the general formula (1) or (2) is also represented by the general formula (10) or (11):

[0028]

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(Wherein R ¹ , R ² , X, Y, Z, Q,
m, n, p, q and r are as described above) and a compound represented by the general formula (12):

[0030]

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(Wherein R ³ and R ⁴ are as described above)
Can be produced by a method of reacting with a compound represented by the following formula:

The alkylenediamine derivative of the present invention represented by the general formula (3) is represented by the general formula (13):

[0033]

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Wherein R ¹ , X, Y, Z and m are as defined above, and a compound represented by the general formula (9):

[0035]

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Wherein R ² , R ³ , R ⁴ , n, p and q
Is as described above, and Q represents a leaving group).

The alkylenediamine derivative of the present invention represented by the general formula (3) is also represented by the general formula (14):

[0038]

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(Wherein R ¹ , R ² , X, Y, Z, Q,
m, n, p and q are as described above) and a compound represented by the general formula (12):

[0040]

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(Wherein R ³ and R ⁴ are as described above)
Can be produced by a method of reacting with a compound represented by the following formula:

The alkylenediamine derivative represented by the general formula (3) [X represents an oxygen atom, Y represents an oxygen atom, and Z represents -CH _2- ] is a compound represented by the following general formula (15):

[0043]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , m,
n, p and q are as defined above), and a reagent used for synthesizing 2-oxazolidone from 1,2-aminoalcohol.

The alkylenediamine derivative represented by the general formula (3) [X represents an oxygen atom, Y represents a sulfur atom, and Z represents -CH _2- ] is represented by the general formula (15). Can be prepared by reacting the compound to be prepared with carbon disulfide and an alkyl, phosgene or dialkyl carbonate.

The alkylenediamine derivative represented by the general formula (3) [X represents an oxygen atom, Y represents an oxygen atom, and Z represents -CH _2- ] is also represented by the general formula (16):

[0047]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , m,
n, p, and q are as described above, and R ⁵ represents an alkyl group). The compound can be produced by subjecting the compound to a ring-closing reaction under heating.

The alkylenediamine derivative represented by the general formula (3) [X represents an oxygen atom, Y represents an oxygen atom, and Z represents -CH _2- ] is a compound represented by the following general formula (17):

[0050]

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(Wherein R ¹ and m are as described above)
And a compound represented by the general formula (18):

[0052]

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Wherein R ² , R ³ , R ⁴ , n, p and q
Is as described above, and R ⁶ represents an alkyl group).

The general formulas (1) and (2) of the present invention
The alkylenediamine derivatives represented by (3), (4), (5) and (6) can be converted into pharmacologically acceptable salts.

The alkylenediamine derivative represented by the above general formula and the pharmacologically acceptable salt thereof of the present invention can be effectively used for the treatment of dysuria. A therapeutic agent for dysuria comprising the above-mentioned alkylenediamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel alkylenediamine derivative represented by the general formula (1) or (2) of the present invention will be described.

In the general formula (1) or the general formula (2),
R ¹ is a hydrogen atom, an alkyl group (preferably an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl); A phenyl group, a naphthyl group or an aromatic heterocyclic group (preferable examples include a phenyl group, a naphthyl group, a furan ring,
Represents a thiophene ring, a pyridine ring, a quinoline ring, or an indole ring, and R ² is a phenyl group, a naphthyl group, or an aromatic heterocyclic group which may have 1 to 5 identical or different substituents (preferred examples) Represents a phenyl group, a naphthyl group, a furan ring, a thiophene ring, a pyridine ring, a quinoline ring, an indole ring).

In particular, in the general formula (3), R ¹ or R ²
Is a phenyl group, a naphthyl group, or an aromatic heterocyclic group (preferable examples include a phenyl group, a naphthyl group, a furan ring, and a thiophene), which may have 1 to 5 identical or different substituents. Ring (ie, thienyl), pyridine ring, quinoline ring, indole ring).

The group represented by R ¹ or R ² is
It is preferably a phenyl group or a thienyl group which may have 1 to 5 identical or different substituents, and more preferably 1 to 5 as a phenyl group having no substituent or a substituent.
Phenyl group having one or more alkyl groups, alkoxyl groups, halogen atoms, haloalkyl groups or phenyl groups, and particularly preferably a phenyl group having no substituent.

Among the above substituents, the alkyl group is an alkyl group having 1 to 8 carbon atoms (for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, etc.), preferably, fluorine, chlorine, bromine, etc. as the halogen atom, and trifluoromethyl, chloromethyl, fluoromethyl, etc. as the haloalkyl group. Preferably, the alkoxyl group is preferably methoxy, ethoxy, propoxy and the like having 1 to 8 carbon atoms, the aryloxy group is preferably phenoxy and parachlorophenoxy, and the aralkyloxy group is preferably benzyloxy and the like.
Examples of the alkylamino group include methylamino having 1 to 8 carbon atoms, dimethylamino, ethylamino, propylamino,
Isobutylamino and the like are preferable, as the aralkylamino group, benzylamino and (4-chlorophenyl) methylamino and the like are preferable, and as the arylamino group, phenylamino and parachlorophenylamino and the like are preferable. Acetylamino, propionylamino and the like of Formulas 1 to 8 are preferable, and as the alkoxycarbonyl group, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are preferable, and as the aralkyloxycarbonyl group, benzyloxycarbonyl and the like are preferable, and the aryloxycarbonyl group is preferable. Is preferably phenoxycarbonyl, etc., and the alkoxysulfonyl group is preferably methoxysulfonyl, ethoxysulfonyl, etc., and the aralkyloxysulfonyl group is benzene. Le oxysulfonyl are preferable, aryloxy sulfonyl group, phenoxysulfonyl, and the like are preferable.

The general formulas (1), (2), (3), (4),
In (5) and (6), the group represented by R ³ or R ⁴ is an alkyl group or a group formed by bonding R ³ and R ⁴ together with a nitrogen atom to which they are bonded. Seven-membered ring groups are preferred. As the alkyl group, an alkyl group having 1 to 8 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) is preferable, and as the aralkyl group, benzyl, phenylethyl, phenylpropyl, etc. is preferable, and as the aryl group Is preferably phenyl, pyridyl, naphthyl and the like, and particularly preferable are the above-mentioned alkyl groups. Also, bonded with R ³ and R ^4, formed together with the nitrogen atom to which R ³ and R ⁴ are bonded 5
As the 7-membered ring group, a 5- to 7-membered ring group which may have a hetero atom in the middle of the ring, for example, morpholino, piperidino, homomorpholino, 1-pyrrolidyl, thiomorpholino and 1-piperazinyl are preferable. These cyclic groups are
It has 1 to 5 substituents such as an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an acyl group (such as formyl, acetyl, propionyl, benzoyl, phthaloyl), and a hydroxyl group. May be. When two or more substituents are bonded, these substituents may be the same or different from each other. Particularly, a morpholino group having no substituent is preferable.

In the general formulas (1) and (3),
The following equation (19):

[0063]

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The cyclic portion represented by the following formula (20)
a), (20b), (20c) or (20d):

[0065]

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It is preferable to have a structure represented by the following formula:
In particular, it preferably has a structure represented by the formula (20a).

In the general formulas (1) to (6), m is 0,
It is preferably 1 or 2, and particularly preferably 1. n is preferably 0, 1 or 2, and particularly preferably 0. p is preferably 0, and q is preferably 2.

The compounds represented by the general formulas (1) to (6) have a carbon atom to which R ^1- (CH ₂ ) _m -is bonded and a carbon atom to which R ^2- (CH ₂ ) _n -is bonded. The carbon atom that is present is an asymmetric carbon atom and therefore has two diastereomers,
Although there are four types of optically active substances, general formulas (I) to (I)
The compound represented by (6) may be a racemate, an optically active substance, or a mixture of the optically active substances.

The pharmacologically acceptable salts of the alkylenediamine derivatives represented by the general formulas (1) to (6) include inorganic acids (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid) and organic acids ( Examples include acid addition salts of fumaric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, malic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid).

The alkylenediamine derivative of the present invention can be produced by a method of reacting the compound represented by the general formula (7) or (8) with the compound represented by the general formula (9). it can.

In this production method, a compound represented by the general formula (7) or (8) and a compound represented by the general formula (9) are converted into acetone, methyl ethyl ketone, isobutyl methyl ketone, dimethyl The reaction is carried out at room temperature to reflux temperature for 2 to 50 hours in an organic solvent such as formamide in the presence of a carbonate such as potassium carbonate, sodium carbonate or cesium carbonate for 2 to 50 hours. Is synthesized. In this reaction, 1 to 2 mol of the compound represented by the general formula (9) and 2 to 2 mol of the carbonate are added to 1 mol of the compound represented by the general formula (7) or (8). It is preferable to use 8 mol. General formula (9)
The compound represented by is preferably used in the form of a stable hydrochloride.

The alkylenediamine derivative of the present invention can be produced by a method of reacting the compound represented by the general formula (10) or (11) with the compound represented by the general formula (12). it can.

In this production method, the compound represented by the general formula (10) or (11) and the compound represented by the general formula (12) are usually dissolved in a solvent-free condition at 50 to 150 ° C. At a temperature of 1 to 7 hours to synthesize a compound represented by the general formula (1) or (2). If necessary, an inert solvent may be used in this reaction.

The alkylene diamine derivative of the general formula (3) of the present invention, wherein X represents an oxygen atom, Y represents an oxygen atom, and Z represents —CH ₂ —, has the general formula (1)
It can be produced by a method of reacting the compound represented by 5) with a reagent used for synthesizing 2-oxazolidone from 1,2-amino alcohol.

In this manufacturing method, 1, 2
Examples of the reagent used for synthesizing 2-oxazolidone from -amino alcohol include phosgene, trichloromethylchloroformate, diethyl carbonate, and urea. This reaction can be generally performed in a mixed solvent of an organic solvent and water in the presence of a base.

The alkylene diamine derivative of the general formula (3) of the present invention, wherein X represents an oxygen atom, Y represents a sulfur atom, and Z represents —CH ₂ —, has the general formula (1)
It can be produced by a method of reacting the compound represented by 5) with carbon disulfide and alkyl chloroformate.

In this production method, carbon disulfide and ethyl chloroformate are added to the compound represented by the general formula (15) in a mixed solvent such as dioxane-carbon tetrachloride in the presence of a base such as triethylamine. formula (3) [where, X represents an oxygen atom, Y represents a sulfur atom, Z is -CH ₂ - and represented] by reacting it is possible to produce a compound represented by the.

The alkylene diamine derivative of the general formula (3) of the present invention, wherein X represents an oxygen atom, Y represents an oxygen atom, and Z represents —CH ₂ —, has the general formula (1)
The compound represented by 6) can be produced by a method of subjecting the compound to a ring closure reaction under heating.

In this production method, the compound represented by the general formula (16) is synthesized by reacting the compound represented by the general formula (15) with the compound represented by the formula ClCO ₂ R ^5. Can be performed in an organic solvent such as toluene or xylene in the presence of a base such as sodium methoxide, sodium ethoxide or aluminum isopropoxide by heating at 50 ° C. to reflux temperature. Can be. This reaction is preferably carried out while removing by-product alcohol (R ⁵ OH) together with the reaction solvent.

The alkylenediamine derivative of the general formula (3) of the present invention, wherein X represents an oxygen atom, Y represents an oxygen atom, and Z represents —CH ₂ —, has the general formula (1)
It can be produced by a method of reacting the compound represented by 7) with the compound represented by the general formula (18).

In this production method, the compound represented by the general formula (17) and the compound represented by the general formula (18) are reacted by heating or melting under heating in the presence of a catalyst. Let it. As the catalyst, for example, triethylamine,
Quaternary ammonium halides, n-butoxylithium,
Bases such as sodium hydroxide and lithium hydroxide and Lewis acids such as zinc bromide, zinc chloride and iron chloride can be used. This reaction is preferably performed usually at a temperature of 100 to 150 ° C. for several hours.

The alkylenediamine derivative of the present invention can be produced by various production methods as described above and by combining unit reactions well known to those skilled in the art. 5-benzyl-3- (1-
FIG. 1 shows various routes for synthesizing phenyl-3-morpholinopropyl) -1,3-oxazolidine-2-one [compound (1)] as an example. In FIG. 1, the route for producing the compound (1) from the compound (2) and the compound (e) is the first method described above, and the compound (3) and the compound (a) obtained from the compound (2) are used. And the route for producing the compound (1) from the second method.
Note that the lowercase letters shown in FIG. 1 represent the compounds shown in FIG. 2, respectively.

In the optically active isomer of the alkylenediamine derivative of the present invention, first, the four optically active isomers are separated as two kinds of diastereomers using a silica gel column or the like, and each is separated by a usual optical resolution method. It can be produced by optically resolving a racemic alkylenediamine derivative or by using an optically active intermediate. For example, when a compound represented by the general formula (3) is synthesized by reacting a compound represented by the general formula (17) with a compound represented by the general formula (18),
By using both optically active compounds, an optically active compound represented by the general formula (3) can be obtained. Furthermore, the general formula (1)
When one optically active compound of the compound represented by 7) or the compound represented by the general formula (18) is used, the diastereomer is separated by ordinary silica gel column chromatography to obtain an optically active general formula. The compound represented by (3) can be obtained.

Table 1 shows typical examples of the alkylenediamine derivative of the general formula (3) corresponding to the alkylenediamine derivative of the general formula (1), wherein r is 0.

[0085]

[Table 1]

[0086]

[Table 2]

[0087]

[Table 3]

[0088]

[Table 4]

[0089]

[Table 5]

[0090]

[Table 6]

[0091]

[Table 7]

[0092]

[Table 8]

Table 2 shows typical examples of alkylenediamine derivatives having the general formula (1), where r is 0, but not included in the alkylenediamine derivatives of the general formula (3).

[0094]

[Table 9]

Table 3 shows typical examples of the alkylenediamine derivative of the general formula (4) corresponding to the alkylenediamine derivative of the general formula (1), wherein r is 1.

[0096]

[Table 10]

Table 4 shows typical examples of the alkylenediamine derivative of the general formula (5) corresponding to the alkylenediamine derivative of the general formula (2), wherein r is 0.

[0098]

[Table 11]

[0099]

[Table 12]

[0100]

[Table 13]

Table 5 shows typical examples of the alkylenediamine derivative of the general formula (6) corresponding to the alkylenediamine derivative of the general formula (2), wherein r is 1.

[0102]

[Table 14]

The effects of the compounds of the present invention on urinary contraction of the bladder were evaluated by the following test methods. Test Method Male Wistar rats were anesthetized with urethane (1.5 g /
kg, S.G. C. ) Fixed in a dorsal position below. A tracheal cannula was inserted to secure the airway, and a midline incision was made in the lower abdomen. After exposing the bladder and excreting urine by making a small hole at the top, a polyethylene cannula having an outer diameter of about 1 mm was inserted into the bladder. The urethra and ureter were ligated to make the bladder closed.

A saline solution was injected into the bladder of the rat at a rate of 0.05 ml / min using a continuous injector to induce periodic micturition contraction, and the change in bladder pressure was measured via a pressure transducer. And recorded on a pen recorder. The drug was dissolved in saline and administered via a polyethylene cannula into the femoral vein.

Evaluation Method The effect of suppressing micturition contraction was evaluated by measuring the time during which rhythmic bladder contraction was stopped after drug administration (contraction stop time).

The compounds obtained in the examples were used as drugs, and the contraction stop time measured for each compound is shown in Table 6.

[0107]

[Table 15]

The effect of the compound of the present invention on the isolated bladder smooth muscle was evaluated by the following test methods. Test method Japanese white male rabbit (weight: 2.00 to 2.80 kg)
Was exsanguinated, and the bladder was excised to prepare a specimen. Specimens were suspended in an organ bath filled with Krebs solution maintained at 37 ° C. aerated with carbogen. Acetylcholine and norepinephrine were applied cumulatively to determine concentration effect curves. As a test compound, the compound [5-
Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate] was pretreated for 5 minutes, and the effects of acetylcholine and norepinephrine on the contractile response were observed.

Evaluation Results The compound obtained in Example 2 had little effect on the contraction of acetylcholine and norepinephrine at a concentration of 10 ^{−5 to} 3 × 10 ⁻⁵ M. This confirmed that the test compound suppressed bladder contraction not by the peripheral nervous system but by the central nervous system.

From the above results, it is clear that the compounds of the present invention are effective for suppressing micturition contraction.

Further, regarding the toxicity of the compound of the present invention,
Table 6 shows the LD ₅₀ (mg / kg) calculated by the and down method.

Another object of the present invention is to provide a therapeutic agent for dysuria containing an alkylenediamine derivative represented by the general formula (1), (2) or (3) or a pharmaceutically acceptable salt thereof as an active ingredient. is there.

The therapeutic agent for dysuria of the present invention can be used by general oral or parenteral administration such as injection or suppository.

Examples of the dosage form of the oral administration preparation include tablets,
Capsules, powders, granules, syrups and the like can be mentioned, and examples of the dosage form of parenteral administration include injections, suppositories and the like. These preparations include the usual excipients, disintegrants,
Binders, lubricants, dyes, diluents and the like are used. As excipients, glucose, lactose, etc., as disintegrants,
Starch, carboxymethylcellulose calcium, etc., lubricants include magnesium stearate, talc, etc., and binders include hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc.

The dose is generally about 0.1 m / day in an adult using the compound of the formula (I) as an active ingredient in an injection.
g to 10.0 mg, about 1.0 mg to 50 mg / day by oral administration
0 mg, but it can be increased or decreased depending on age, symptoms and the like.

The therapeutic agent for dysuria of the present invention has no direct effect on bladder smooth muscle. It is a centrally acting drug that does not cause a decrease in blood pressure and is a drug that selectively acts on the bladder.

[0117]

Next, the present invention will be described in more detail by way of examples.

Example 1 5-Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one 5-benzyl-1,3-oxazolidine-2-one (8
25 mg, 4.7 mmol), 4-[(3-chloro-3
-Phenyl) propyl] morpholine hydrochloride (1415 m
g, 5.1 mmol), potassium carbonate (2.12 g, 1
5.4 mmol) and methyl ethyl ketone (25 ml)
And heated under reflux for 23 hours to cause a reaction. After the reaction solution was cooled to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified using silica gel column chromatography (ethyl acetate) to give diastereomer A (376 mg) as a colorless oil.
(Yield 21%) and diastereomer B as pale yellow oil
556 mg (31% yield) were obtained.

¹ H-NMR (CDCl ₃ ) δ: diastereomer A 1.8 to 2.5 (8H, m), 2.8 to 3.2 (4H,
m), 3.5-3.8 (4H, m), 4.64 (1H,
m), 5.00 (1H, t, J = 7 Hz), 7.0 to 7.0
7.4 (10H, m). Diastereomer B 1.7-3.1 (11H, m), 3.42 (1H, t,
J = 8 Hz), 3.5-3.8 (4H, m), 4.68
(1H, m), 5.00 (1H, t, J = 7 Hz),
6.8-7.4 (10H, m).

Example 2 5-benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-one fumarate 5-benzyl-3- (3) obtained in Example 1 -Morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one (diastereomer A) (376 mg, 1.
0 mmol) was dissolved in ethanol (5 ml), and fumaric acid (115 mg, 1.0 mmol) was added to the solution and dissolved under heating. Ethanol was distilled off from the obtained solution under reduced pressure, and the residue was crystallized from ethanol / hexane (3/1).
/ 1). Drying under reduced pressure at room temperature overnight gave 234 mg (46% yield) of the title compound as white crystalline powder.

Melting point: 133-135 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.9-2.3 (2
H, m), 2.4 to 2.7 (2H, m), 2.7 to 3.
1 (6H, m), 3.1 to 3.4 (2H, m), 3.6
３3.9 (4H, m), 4.5-5.0 (2H, m),
6.84 (2H, s), 7.1 to 7.4 (10H,
m). IR (KBr) cm ^-1 : 3420, 2920, 258
0,1725,1425,1360,1290,125
0,1215,1040,980,970,750,7
00,640.

Example 3 (-)-5-benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-one fumarate Synthesized in the same manner as in Example 1. 5-benzyl-
3- (3-morpholino-1-phenylpropyl) -1,
3-Oxazolidin-2-one (diastereomer A)
(2.89 g) was dissolved in a mixed solution (isopropyl alcohol / acetone / water = 50 g / 20 g / 6.2 g) (15 ml), and D (−)-tartaric acid (1.17) was added to the resulting solution.
g) and the above mixture (30 ml), and the mixture was added at room temperature for 3 hours.
Left for hours. The precipitated crystals were collected by filtration and mixed with the above mixture (45).
ml) and air-dried to obtain a white powder (1.82 g).

The powder obtained as above (2.39 g)
Was added to the above mixture (65 ml), dissolved at 80 ° C., and the solution was left at room temperature overnight. The precipitated crystals were collected by filtration, washed with the above mixture (15 ml), and dried under reduced pressure to give a white powder (2.
1 g). The obtained powder was suspended in water (50 ml), made alkaline with a saturated aqueous solution of sodium hydrogencarbonate, and diluted with dichloromethane (3 ml).
0 ml). The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oil (1.5 g). This oil was dissolved in ethanol (10 ml), and fumaric acid (4
A solution of 58 mg) and ethanol (10 ml) was added, n-hexane (5 ml) was added, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with ethanol / n-hexane (4/1) (15 ml) and ethanol / n-hexane (1/1) (10 ml), air-dried, and then overnight at 50 ° C. under reduced pressure. Drying afforded the title compound (1.1 g).

Melting point: 131 to 132 ° C. (decomposition) [α] _D ²³ : -1 ° (c.0.6, methanol) HPLC: detected in a free form. Column: CHIRALCEL OG, detection: 254n
m, eluent: n-hexane / ethanol = 5/1, flow rate: 1 ml / min, temperature: room temperature, t _R: 19.5 minutes _{^{1 H-NMR (CD 3 OD}} ) δ: 2.1~2.2 (2
H, m), 2.4 to 2.6 (2H, m), 2.8 to 3.
3 (8H, m), 3.7 to 3.9 (4H, m), 4.7
4.9 (2H, m), 6.73 (2H, s), 7.2
~ 7.4 (10H, m). IR (KBr) cm ^-1 : 3400, 1730, 171
0,1425,1245,980,750,690,6
40.

Example 4 (+)-5-Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate Diastereomer A in Example 3 The filtrate obtained by reacting with D (-)-tartaric acid and collecting the crystals was filtered, and the solvent was removed under reduced pressure at 45 ° C or lower. Water was added to the resulting oil, and the mixture was made alkaline with saturated aqueous sodium hydrogen carbonate. Dichloromethane (3
0 ml). The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. An oil (1.64 g) obtained was mixed (isopropyl alcohol / acetone / water = 50 g / 20 g / water).
6.2 g) (15 ml).
(+)-Tartaric acid (647 mg) and the above mixture (16 ml)
And the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration, washed with the above mixture (25 ml), and air-dried to obtain a white powder (1.78 g).

The powder obtained as above (2.28 g)
Was added to the above mixture (62 ml), dissolved at 80 ° C., and the solution was left at room temperature overnight. The precipitated crystals were collected by filtration, washed with the above mixture (15 ml), and dried under reduced pressure to give a white powder (2.
08g). The resulting powder was suspended in water (50 ml), made alkaline with saturated aqueous sodium hydrogen carbonate, and extracted twice with dichloromethane (30 ml). The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oil (1.49 g). This oil was dissolved in ethanol (10 ml), a solution of fumaric acid (455 mg) and ethanol (10 ml) was added to the solution, n-hexane (5 ml) was added, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with ethanol / n-hexane (4/1) (15 ml) and ethanol / n-hexane (1/1) (10 ml), air-dried, and then dried under reduced pressure at 50 ° C. overnight. Thus, the title compound (1.08 g) was obtained.

Melting point: 133 to 135 ° C. (decomposition) [α] _D ²³ : + 1 ° (c.0.6, methanol) HPLC: detected in a free form. Column: CHIRALCEL OG, detection: 254n
m, eluent: n-hexane / ethanol = 5/1, flow rate: 1 ml / min, temperature: room temperature, t _R: 21.3 minutes _{^{1 H-NMR (CD 3 OD}} ) δ: 2.1~2.2 (2
H, m), 2.4 to 2.6 (2H, m), 2.8 to 3.
3 (8H, m), 3.7 to 3.9 (4H, m), 4.7
4.9 (2H, m), 6.73 (2H, s), 7.2
~ 7.4 (10H, m). IR (KBr) cm ^-1 : 3400, 1730, 171
0, 1440, 1420, 1240, 970, 745,
690, 625.

Example 5 5- (2-bromophenyl) methyl-3- [3- (4-
Hydroxypiperidino) -1-phenylpropyl]-
1,3-oxazolidin-2-one

(1) 5- (2-bromophenyl) methyl-3- (3-chloro-1-phenylpropyl) -1,
3-Oxazolidin-2-one 5- (2-bromophenyl) methyl-1,3-oxazolidin-2-one (256 mg, 1 mmol), 1-bromo-3-chloro-1-phenylpropane (234 m
g, 1 mmol), cesium carbonate (326 mg, 1 mmol) and 2 m of dimethylformamide dried on alumina
were mixed and the mixture was stirred and reacted at room temperature for 4 days.
Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated saline solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 470 mg of a colorless oil. After subjecting to medium pressure silica gel column chromatography, ethyl acetate / hexane =
Elution was carried out by 1/2 to obtain 121 mg of a colorless oily substance (yield: 2
9.7%).

¹ H-NMR (CDCl ₃ ) δ: 2.3
To 2.6 (2H, m), 2.9 to 3.4 (4H, m),
3.4 to 3.6 (2H, m), 4.7 to 4.8 (1H,
m), 5.0-5.1 (1H, m), 7.0-7.4
(8H, m), 7.5-7.6 (1H, m). IR (KBr) cm ^-1 : 2950, 1740, 148
5,1470,1420,1360,1240,103
0,750,695.

(2) 5- (2-bromophenyl) methyl-3- [3- (4-hydroxypiperidino) -1-phenylpropyl] -1,3-oxazolidine-2-one In the above (1) The obtained 5- (2-bromophenyl) methyl-
3- (3-chloro-1-phenylpropyl) -1,3-
Oxazolidin-2-one (0.81 g, 1.7 mmol) and 4-hydroxypiperidine (0.52 g, 5.
(1 mmol) was dissolved in dichloromethane and the dichloromethane was distilled off under reduced pressure. After the mixture was stirred at 110 ° C. for 5 hours, ethyl acetate was added thereto and extracted with 1N hydrochloric acid. The aqueous layer was made basic with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The obtained organic layer was washed with water and then with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off from this solution under reduced pressure to obtain a white amorphous (0.83
g) was subjected to medium pressure silica gel column chromatography. Elution with methanol / chloroform = 1/40 gave 0.41 g of a colorless oil (yield: 51%), which was designated as diastereomer A. Further, elution was performed with methanol / chloroform = 1/20 to obtain 0.36 g (yield: 45%) of a slightly yellow oily substance, which was designated as diastereomer B.

Diastereomer A ¹ H-NMR (CDCl ₃ ) δ: 1.5 to 1.7 (2
H, m), 1.8 to 2.0 (2H, m) 2.0 to 2.2 (4H, m), 2.2 to 2.4 (2H, m)
m) 2.6 (1H, broads), 2.7 to 2.9 (2
H, m), 3.1 to 3.3 (4H, m), 3.6 to 3.
8 (1H, m) 4.6 to 4.8 (1H, m), 5.00 (1H, dd,
J = 7 Hz, 9 Hz), 7.1 to 7.2 (1 H, m),
7.2 to 7.4 (7H, m), 7.54 (1H, d, J
= 8Hz). IR (neat) cm ^-1 : 3400, 2930, 281
0, 1730, 1470, 1420, 1360, 124
0,1070,1035,750,695,660.

Diastereomer B ¹ H-NMR (CDCl ₃ ) δ: 1.5 to 1.7 (2
H, m), 1.8 to 2.0 (2H, m) 2.0 to 2.3 (4H, m), 2.3 to 2.5 (2H, m)
m) 2.7-3.0 (5H, m), 3.04 (1H, dd,
J = 6 Hz, 14 Hz), 3.53 (1H, dd, J =
8 Hz, 9 Hz), 3.6 to 3.8 (1 H, m), 4.
7 to 4.9 (1H, m), 4.99 (1H, dd, J =
7 Hz, 8 Hz), 7.0 to 7.2 (3H, m), 7.
2 to 7.4 (5H, m), 7.45 (1H, dd, J =
1 Hz, 8 Hz). IR (neat) cm ^-1 : 3400, 2930, 281
0, 1730, 1470, 1420, 1360, 124
0,1070,1035,750,695,660.

Example 6 5- (2-bromophenyl) methyl-3- [3- (4-
Hydroxypiperidino) -1-phenylpropyl]-
1,3-Oxazolidin-2-one fumarate 5- (2-bromophenyl) methyl-3- [3- (4-hydroxypiperidino) -1-phenylpropyl obtained in the same manner as in Example 5. ] -1,3-Oxazolidin-2-one (237 mg, 0.5 mmol) and fumaric acid (58 mg, 0.5 mmol) in ethanol (3 m
1) Dissolved while heating. Ethanol was distilled off from the obtained solution under reduced pressure, and the residue was concentrated three times from water, dried under vacuum and then crushed to obtain 280 mg of the title compound as a white powder.

¹ H-NMR (D ₂ O) δ: 1.6 to
2.4 (6H, m), 2.7 to 3.6 (10H, m) 3.8 to 4.0 (1H, m), 4.1 to 4.3 (1H, m)
m) 6.67 (2H, s), 7.2-7.5 (8H, m),
3.1 to 3.3 (4H, m), 3.6 to 3.8 (1H,
m) 7.6-7.7 (1H, m). IR (neat) cm ^-1 : 3400, 2940, 173
5,1570,1425,1365,1250,104
0,980,755,700,645.

Example 7 3- (3-morpholino-1-phenylpropyl) -5
Phenyl-1,3-oxazolidine-2-one

(1) 2- (3-morpholino-1-phenylpropyl) amino-1-phenylethanol 2-amino-1-phenylethanol (2.50 g, 1
8.2 mmol) and 4- (3-chloro-3-phenylpropyl) morpholine (4.37 g, 18.2 mmol)
Were reacted at 110 ° C. for 40 minutes. After allowing the reaction product mixture to cool, it was dissolved in chloroform (200 ml). The solution was ice-cooled, 1N NaOH was added thereto to release the hydrochloride, and the chloroform layer was separated. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (chloroform / methanol = 100/1) to give the title compound (2.88 g, yield: 46.5%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.7
5 to 2.79 (10H, m), 3.67 to 3.72 (4
H, m) 3.80-3.84 (1H, m), 4.64-4.78
(1H, m) 7.24 to 7.34 (10H, m).

(2) 3- (3-morpholino-1-phenylpropyl) -5-phenyl-1,3-oxazolidine-2-one 2- (3-morpholino-1-phenylpropyl) obtained in the above (1) ) Amino-1-phenylethanol (2.2
g, 6.46 mmol), ether (100 ml) and 10% NaOH (50 ml) were added and stirred. To the resulting mixture was slowly added dropwise a solution of 20% trichloromethylchloroformate in toluene [14 ml (14 mmol)] over 1 hour while cooling with ice, followed by stirring at room temperature for 1 hour. Ethyl acetate (200 ml) was added to the reaction solution, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated saline (100 ml), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to medium pressure liquid chromatography (chloroform / methanol = 50
/ 1), and 510 mg of each of diastereomer A and diastereomer B of the title compound (yield: 2
1.5%) and 390 mg (yield: 16.5%) as an oil. In the TLC (chloroform / methanol = 10/1) development, those having an Rf value of about 0.6 were regarded as diastereomer A, and those having an Rf value of about 0.5 were regarded as diastereomer B.

Diastereomer A ¹ H-NMR (CDCl ₃ ) δ: 2.06 to 2.39
(8H, m), 3.36 to 3.58 (2H, m) 3.67 to 3.69 (4H, m), 5.12 (1H,
t, J = 7 Hz), 5.36 to 5.40 (1H, m),
7.26 to 7.41 (10H, m). Diastereomer B ¹ H-NMR (CDCl ₃ ) δ: 2.23 to 2.70
(8H, m), 3.73-3.82 (4H, m) 2.98-3.02 and 3.84-3.87 (2H, m
m), 5.07 to 5.11 (1H, m), 5.46 to
5.51 (1H, m), 7.16 to 7.34 (10H,
m).

Example 8 3- (3-morpholino-1-phenylpropyl) -5
Phenyl-1,3-oxazolidine-2-one fumarate 3- (3-morpholino-1-phenylpropyl) -5-phenyl-1,3- obtained in the same manner as in Example 7.
Diastereomer A of oxazolidin-2-one (48
0 mg, 1.31 mmol) and fumaric acid (152 mg,
1.31 mmol) was dissolved in ethanol (30 ml). The resulting solution was concentrated under reduced pressure to give the title compound 389
mg (yield: 61.5%) as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 2.3
1-2.78 (8H, m), 3.47-3.77 (6
H, m) 5.00 to 5.04 (1H, m), 5.50 to 5.54.
(1H, m), 6.71 (2H, s), 7.36-7.
42 (10H, m). IR (KBr) cm ^-1 : 3420, 1740, 125
0,990,700.

Example 9 5-Benzyl-3- (3-morpholino-3-phenylpropyl) -1,3-oxazolidin-2-one

(1) 5-benzyl-3- (3-oxo-3-phenylpropyl) -1,3-oxazolidine-
2-one 5-benzyl-1,3-oxazolidin-2-one (1.77 g, 10 mmol), 3-chloropropiophenone (1.69 g, 10 mmol), powdered potassium carbonate (2.76 g, 20 mmol) ) And methyl ethyl ketone (50 ml) were mixed and heated at reflux for 16 hours to react. The solvent was distilled off from the obtained reaction product under reduced pressure, and the residue was dissolved in ethyl acetate and water. The obtained organic layer was washed with water and then with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off from this solution under reduced pressure to obtain 3.00 g of a slightly yellow oily substance, which was subjected to silica gel column chromatography. Elution with hexane / ethyl acetate = 1/1 gave 2.05 g (yield: 66.3%) of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.9
To 3.3 (4H, m), 3.3 to 3.5 (1H, m),
3.5 to 3.7 (3H, m), 4.6 to 4.8 (1H,
m), 7.1-7.4 (5H, m), 7.4-7.7
(3H, m), 7.92 (7H, d, J = 7 Hz). IR (KBr) cm ^-1 : 1740, 1680, 159
0, 1480, 1440, 1360, 1250, 120
0, 1020, 740, 695.

(2) 5-benzyl-3- (3-hydroxy-3-phenylpropyl) -1,3-oxazolidine-2-one 5-benzyl-3- (3-oxo-one obtained in the above (1) 3
-Phenylpropyl) -1,3-oxazolidine-2-
On (0.31 g, 1 mmol) was dissolved in 3 ml of ethanol, and sodium borohydride (80 mg, 2 mmol) was added while stirring under water cooling, and the mixture was stirred and reacted at room temperature for 30 minutes. Water was added to the obtained reaction product, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off from this solution under reduced pressure to give the title compound 0.3 as a colorless oil.
1 g (yield: 100%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.7
１1.9 (2H, m), 2.8-3.1 (3H, m),
3.2 to 3.3 (2H, m), 3.4 to 3.6 (2H,
m), 4.5-4.6 (1H, m), 4.6-4.8
(1H, m), 7.2 to 7.4 (10H, m). IR (KBr) cm ^-1 : 3400, 3020, 292
0, 1730, 1480, 1445, 1370, 125
0, 1210, 1060, 1020, 750, 690.

(3) 5-benzyl-3- (3-chloro-3-phenylpropyl) -1,3-oxazolidine-
2-One 5-benzyl-3- (3-hydroxy-3-phenylpropyl) -1,3-oxazolidine- obtained in the above (2).
The 2-one (0.31 g, 1 mmol) was dissolved in dichloromethane (3 ml) and to the resulting solution was added thionyl chloride (0.08 ml, 1.1 mmol) and the solution was added at room temperature for 3 hours.
Stirred for 0 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over sodium sulfate. The solvent was distilled off from the obtained solution under reduced pressure to obtain 0.34 g of the title compound as a colorless oil.
(Yield: 100%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.1
~ 2.3 (2H, m), 2.8 ~ 3.2 (2H, m),
3.2 to 3.6 (4H, m), 4.6 to 4.9 (2H,
m), 7.1-7.4 (10H, m). IR (KBr) cm ^-1 : 3020, 2910, 174
0, 1485, 1450, 1430, 1370, 126
0,1025,750,695.

(4) 5-benzyl-3- (3-morpholino-3-phenylpropyl) -1,3-oxazolidin-2-one 5-benzyl-3- (3-chloro- obtained in the above (3). 3
-Phenylpropyl) -1,3-oxazolidine-2-
On (0.34 g, 1 mmol) and morpholine (0.
26 g, 3 mmol), and reacted by heating at 110 ° C. for 3 hours. The resulting reaction mixture was dissolved in ethyl acetate and 1N hydrochloric acid, the aqueous layer was basified with potassium carbonate,
Extracted twice with ethyl acetate. The obtained organic layers were combined, washed with water and then with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off from the solution under reduced pressure to obtain 0.31 g of a red oily substance, which was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 0.29 g of the title compound as a colorless oily substance (yield: 76%). %).

¹ H-NMR (CDCl ₃ ) δ: 1.8
To 2.1 (2H, m), 2.3 to 2.5 (4H, m),
2.8 to 3.3 (4H, m), 3.3 to 3.4 (1H,
m), 3.6-3.8 (4H, m), 4.5-4.7.
(1H, m), 7.1 to 7.4 (10H, m). IR (KBr) cm ^-1 : 2950, 2850, 280
0, 1740, 1490, 1450, 1430, 125
0, 1110, 1030, 750, 700.

Example 10 5-benzyl-3- (3-morpholino-3-phenylpropyl) -1,3-oxazolidine-2-one fumarate 5-benzyl obtained in the same manner as in Example 9. -3-
(3-morpholino-3-phenylpropyl) -1,3-
Oxazolidin-2-one (0.26 g, 0.68 mmol) and fumaric acid (0.08 g, 0.68 mmol) were dissolved in ethanol. Ethanol was distilled off from the obtained solution under reduced pressure, and the residue was concentrated from water three times under reduced pressure, and then dried under vacuum to obtain 0.34 g of the title compound (yield: 10%).
0%) as a slightly reddish amorphous.

¹ H-NMR (CDCl ₃ ) δ: 2.6
To 3.3 (8H, m), 3.4 to 4.2 (7H, m) 4.6 to 4.8 (1H, m), 6.69 (2H, s),
7.2 to 7.6 (10H, m). IR (KBr) cm ^-1 : 3420, 1735, 145
0,1270,1255,700.

Example 11 5-benzyl-3- (3-morpholino-2-phenylpropyl) -1,3-oxazolidin-2-one fumarate

(1) Ethyl 3-chloro-2-phenylpropionate A solution of ethyl 3-hydroxy-2-phenylpropionate (2.55 g, 13.1 mmol) and dichloromethane (15 ml) was added to a solution of SOCl under ice-cooling. ₂ (1.87
g, 15.7 mmol) and dichloromethane (1 ml)
Was added and stirred at room temperature for 3 hours to react. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution under ice-cooling, and the mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent from the solution under reduced pressure was subjected to silica gel column chromatography, and 1.27 g (yield: 45.5%) of the title compound was obtained from an eluted portion of acetone / hexane = 1/3. Was obtained as a colorless oil.

MS (m / e) 176 (M ⁺ -Cl) ¹ H-NMR (CDCl ₃ ) δ: 1.2 to 1.3 (3
H, m), 3.9 to 4.0 (1H, m) 4.1 to 4.3 (3H, m), 4.4 to 4.6 (1H,
m), 7.3-7.5 (5H, m).

(2) Ethyl 3-morpholino-2-phenylpropionate Ethyl 3-chloro-2-phenylpropionate (1 g, 4.72 mmol) obtained in the above (1) and morpholine (470 mg, 5.4 mmol) 110 ° C)
For 6 hours under heating for reaction. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl ether. The extract was washed with brine and dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent from the solution under reduced pressure was subjected to silica gel column chromatography, and acetone /
From the elution part of hexane = 1/6, 660 mg of the title compound was obtained.
(Yield: 53.2%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.2
~ 1.3 (3H, m), 2.4-2.5 (2H, m),
2.5 to 2.7 (3H, m), 3.16 (1H, dd,
J = 10 Hz, 5 Hz) 3.6 to 3.7 (4H, m), 3.82 (1H, dd,
J = 5 Hz, 5 Hz) 4.1 to 4.8 (2H, m), 7.2 to 7.4 (5H,
m).

(3) A suspension of 1-hydroxy-3-morpholino-2-phenylpropane LiAlH ₄ (110 mg, 2.89 mmol) and dry ether (10 ml) was obtained in the above (2) under ice-cooling. A solution of ethyl 3-morpholino-2-phenylpropionate (660 mg, 2.51 mmol) and dry ether (5 ml) was added dropwise, and the mixture was reacted by stirring at room temperature for 2 hours. A saturated sodium sulfate aqueous solution is added to the reaction product to decompose the remaining excess LiAlH ₄ ,
After filtering off the insoluble matter, it was dried over anhydrous sodium sulfate.
The solvent was distilled off from the solution under reduced pressure to give the title compound 660m
g (yield: 100%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.4
~ 2.5 (2H, m), 2.6-2.9 (3H, m),
2.69 (1H, t, J = 12 Hz), 3.2-3.3
(1H, m), 3.7 to 3.8 (4H, m), 3.8 to
3.9 (1H, m), 4.0 to 4.1 (1H, m),
7.2 to 7.4 (5H, m).

(4) 1-chloro-3-morpholino-2
-Phenylpropane 1-hydroxy-3-morpholino-2 obtained in the above (3)
-Phenylpropane (650 mg, 2.94 mmol)
And a solution of dichloromethane (10 ml) under ice-cooling.
A solution of OCl ₂ (420 mg, 3.53 mmol) and dichloromethane (5 ml) was added, and the mixture was stirred and reacted at room temperature for 23 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution under ice-cooling, and the mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the solution under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography, and acetone / hexane = 1
540 mg of the title compound (yield: 7)
6.6%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.3
-2.5 (2H, m), 2.5-2.6 (3H, m) 2.96 (1H, m), 3.1-3.2 (1H, m) 3.6-3.8 (4H, m), 3.8 to 3.9 (1H,
m) 3.9-4.0 (1H, m), 7.2-7.4 (5H,
m).

(5) 5-benzyl-3- (3-morpholino-2-phenylpropyl) -1,3-oxazolidine-2-one fumarate 1-chloro-3-morpholino-2- obtained in the above (4) Phenylpropane (478 mg), 5-benzyl-1,3
-Oxazolidine-2-one (354 mg), potassium carbonate (276 mg) and methyl ethyl ketone (10 m
The mixture of 1) was reacted under reflux for 15.5 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and n-hexane / acetone = 3/1.
268 mg of an oily substance obtained from the eluate of (yield: 35.
4%) was dissolved in ethanol (2 ml), a solution of fumaric acid (82 mg) and ethanol (3 ml) was added to the solution, and the mixture was stirred at room temperature. The precipitated crystals are collected by filtration, and 50
After drying under reduced pressure overnight at 250 ° C., 250 mg of the title compound (yield: 2
5.2%) as white crystals.

Melting point: 151-153 ° C. ¹ H-NMR (CD ₃ OD) δ: 2.5-2.9 (8
H, m), 3.1 to 3.3 (6H, m), 3.5 to 3.3.
8 (5H, m), 4.5 to 4.7 (1H, m), 6.7
0 (2H, s), 7.0-7.4 (10H, m). IR (KBr) cm ^-1 : 3420, 1735, 144
0, 1260, 1110, 1070, 980, 755,
695,620.

In the following Examples 12 to 80, only the names of the produced compounds, their physical properties and yields are shown. Examples 40, 44, and 45 are based on the method described in Examples 7 and 8, Examples 41, 42, 43, 52, and 53 are based on Examples 5 and 6, and the other examples are implemented. Performed according to Examples 1 and 2, respectively.

Example 12 5-benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2,4-dione
Fumarate yield: 68.7% (pale yellow powder) m. p. : 158 to 160 ° C IR (KBr) cm ^-1 : 1800, 1725, 144
5,1395,1370,1340,1255,116
5,1120,1065,975,745,690. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 2.6 (4
H, m), 2.6 to 2.8 (4H, m), 3.1 to 3.
4 (2H, m), 3.6 to 3.8 (4H, m), 4.9
To 5.1 (1H, m), 5.2 to 5.3 (1H, m),
6.73 (2H, s), 7.0-7.3 (10H,
m).

Example 13 5- (2-Bromophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 14.6% (white powder) m. p. 173-4 ° C (decomposition) IR (KBr, free form) cm ^-1 : 3500,295
0, 1740, 1440, 1360, 1240, 111
0, 1010, 920, 870, 750, 700. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 2.5 (2
H, m), 2.7 to 2.9 (2H, m), 2.9 to 3.
4 (8H, m), 3.7 to 3.9 (4H, m), 5.8
-5.9 (1H, m), 6.70 (2H, s), 7.0
８8.6 (9H, m).

Example 14 5- (2-Bromophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 11.2% (amorphous) IR (KBr, free body) cm ^-1 : 2950,285
5,2810,1740,1425,1370,124
5,1120,1040,750,700. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 2.5 (2
H, m), 2.7 to 3.4 (9H, m), 3.65 (1
H, t, J = 7 Hz), 3.75 to 3.85 (4H,
m), 4.7-5.0 (2H, m), 6.75 (2H,
s), 7.2-7.5 (9H, m).

Example 15 5- (2-chlorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-one fumarate (diastereomer A) Yield: 67 % (White powder) m. p. : 164 to 6 ° C IR (KBr) cm ^-1 : 3420, 1735, 172
0, 1425, 1250, 1050, 980, 755. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.6 (2
H, m), 2.6-3.5 (10H, m), 3.6-
4.1 (4H, m), 4.5 to 5.0 (2H, m),
6.68 (2H, s), 6.9-7.6 (9H, m).

Example 16 5- (2-chlorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 47 0.8% (white powder) m. p. : 162 to 164 ° C IR (KBr) cm ^-1 : 3430, 1735, 171
0,1425,1255,1075,760 ¹ H-NMR (D ₂ O) δ: 2.1 to 2.6 (2H,
m), 2.7-3.5 (9H, m), 3.72 (1H,
3. t, J = 8 Hz), 3.6-4.1 (4H, m),
8-5.1 (1H, m), 6.58 (2H, s), 7.
0-7.51 (9H, m).

Example 17 5- (2-bromophenyl) methyl-3- (3-diethylamino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 28.9% (amorphous) ¹ H-NMR (CD ₃ OD) δ: 1.30 (6H, t,
J = 8 Hz), 2.2 to 2.6 (2H, m), 2.9 to
3.4 (10H, m), 4.6-5.0 (2H, m),
6.64 (2H, s), 7.0-7.6 (9H, m).

Example 18 5- (2-Bromophenyl) methyl-3- (3-diethylamino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 37.4% (amorphous) ¹ H-NMR (CD ₃ OD) δ: 1.28 (6H, t,
J = 8 Hz), 2.2 to 2.6 (2H, m), 2.8 to
3.4 (9H, m), 3.63 (1H, t, J = 8H
z), 6.62 (2H, s), 6.9-7.5 (9H,
m).

Example 19 5- (2-bromophenyl) methyl-3- [1- (4-
Chlorophenyl) -3-morpholinopropyl] -1,3
-Oxazolidin-2-one fumarate (diastereomer A) Yield: 22.8% (white powder) m. p. : 150 to 5 ° C IR (KBr) cm ^-1 : 3425, 1730, 171
0,1560,1490,1425,1360,130
0, 1250, 1170, 1120, 1090, 98
0,830,755,640. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.4 (2
H, m), 2.5 to 2.9 (6H, m), 3.0 to 3.0.
5 (4H, m), 3.7 to 3.9 (4H, m), 4.6
~ 5.1 (2H, m), 6.60 (2H, s), 7.0
７7.6 (8H, m).

Example 20 5- (2-bromophenyl) methyl-3- [1- (4-
Chlorophenyl) -3-morpholinopropyl] -1,3
-Oxazolidin-2-one fumarate (diastereomer B) Yield: 40.5% (white powder) m. p. : 168-9 ° C IR (KBr) cm ^-1 : 3400, 1730, 169
0, 1565, 1420, 1300, 1240, 116
5,1035,975,750,630. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.4 (2
H, m), 2.6 to 3.1 (9H, m), 3.5 to 3.
9 (5H, m), 4.7 to 5.0 (2H, m), 6.6
4 (2H, s), 6.9-7.5 (8H, m).

Example 21 5- (2-Bromophenyl) methyl-3- (1-phenyl-3-piperidinopropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Rate: 26.7% (white powder) m. p. : 178 to 180 ° C (decomposition) IR (KBr) cm ^-1 : 1720, 1565, 142
0,1360,1300,1270,1245,117
5,1020,750. ¹ H-NMR (CD ₃ OD) δ: 1.4 to 2.0 (6
H, m), 2.0 to 2.6 (2H, m), 2.6 to 3.
4. (10H, m), 4.5-5.2 (2H, m), 6.
69 (2H, s), 6.9-7.5 (9H, m).

Example 22 5- (2-Bromophenyl) methyl-3- (1-phenyl-3-piperidinopropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Rate: 27.6% (white powder) m. p. : 155 to 6 ° C (decomposition) IR (KBr) cm ^-1 : 725, 1705, 157
0, 1420, 1360, 1290, 1240, 117
5, 1070, 1040, 1020, 980, 750,
745,690,625. ¹ H-NMR (CD ₃ OD) δ: 1.4 to 2.0 (6
H, m), 2.0 to 2.6 (2H, m), 2.6 to 3.
4 (9H, m), 3.4 to 3.7 (1H, m), 4.5
~ 5.2 (2H, m), 6.68 (2H, s), 6.9
~ 7.5 (9H, m).

Example 23 5- (4-Chlorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 9 0.8% (white powder) m. p. : 165 to 6 ° C (decomposition) IR (KBr) cm ^-1 : 1745, 1700, 152
0, 1410, 1290, 1240, 1120, 110
0,760. ¹ H-NMR (D ₂ O) δ: 2.2 to 2.4 (2H,
m), 2.9-3.3 (6H, m), 3.4-3.6.
(2H, m), 3.7-4.2 (6H, m), 5.0-5.0
5.1 (1H, m), 6.67 (1H, s), 7.3-
7.5 (9H, m).

Example 24 5- (4-Chlorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 9 0.6% (amorphous) IR (KBr) cm ^-1 : 1750, 1690, 154
0, 1400, 1290, 1240, 980, 760. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.3 (2
H, m), 2.7 to 3.1 (8H, m), 3.69 (1
H, d, d, J = 6 Hz, 10 Hz), 3.7 to 3.9.
(4H, m), 4.01 (1H, d, d, J = 6 Hz,
10Hz), 6.72 (2H, s), 7.2-7.4
(9H, m).

Example 25 5- [2- (2-bromophenyl) ethyl] -3- (3
-Morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 30.0% (amorphous) IR (KBr) cm ^-1 : 3425,1720,143
0, 1260, 980, 750, 700, 640. ¹ H-NMR (CD ₃ OD) δ: 1.7 to 3.1 (10
H, m), 3.1 to 3.3 (4H, m), 3.4 to 3.3.
9 (4H, m), 4.3 to 4.6 (1H, m), 4.8
-5.0 (1H, m), 6.64 (2H, s), 6.9
７7.6 (9H, m).

Example 26 5- [2- (2-bromophenyl) ethyl] -3- (3
-Morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 25.7% (amorphous) IR (KBr) cm ^-1 : 3425,2950,172
0, 1610, 1420, 1250, 1110, 98
0,750,700,640. ¹ H-NMR (CD ₃ OD) δ: 1.6 to 1.9 (2
H, m), 2.1 to 2.5 (2H, m), 2.5 to 2.
9 (9H, m), 3.5 to 3.9 (5H, m), 4.4
To 4.7 (1H, m), 4.8 to 5.1 (1H, m),
6.64 (2H, s), 6.9-7.5 (9H, m).

Example 27 5- [2- (2-chlorophenyl) ethyl] -3- (3
-Morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 14.8% (amorphous) IR (KBr) cm ^-1 : 3500, 2925, 172
0,1430,1240,1070,1040,97
0,750,690,640. ¹ H-NMR (CD ₃ OD) δ: 1.7 to 2.1 (2
H, m), 2.2 to 2.5 (2H, m), 2.5 to 3.
2 (10H, m), 3.7 to 3.9 (4H, m), 4.
2-4.6 (1H, m), 4.8-5.1 (1H,
m), 6.64 (2H, s), 7.0-7.4 (9H,
m).

Example 28 5- [2- (2-chlorophenyl) ethyl] -3- (3
-Morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 23.7% (amorphous) IR (KBr) cm ^-1 : 3400, 2925, 172
0,1430,1240,1070,1030,97
0,750,690,635. ¹ H-NMR (CD ₃ OD) δ: 1.6 to 1.9 (2
H, m), 2.1 to 2.5 (2H, m), 2.5 to 3.
2 (9H, m), 3.5 to 3.9 (5H, m), 4.4
４4.8 (1H, m), 4.8 to 5.1 (1H, m),
6.64 (2H, s), 7.0-7.4 (9H, m).

Example 29 5- (2-Bromophenyl) methyl-3- (1-phenyl-3-pyrrolidinopropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield : 4.4% (white powder) m. p. 144 to 9 ° C IR (KBr) cm ^-1 : 3400, 2950, 260
0, 1730, 1250, 980, 760. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 3.4 (16
H, m), 4.9-4.93 (2H, m), 6.71.
(2H, s), 7.2-7.6 (9H, m).

Example 30 5- (2-Bromophenyl) methyl-3- (1-phenyl-3-pyrrolidinopropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield : 16.1% (pale yellow powder) m. p. : 130 to 2 ° C IR (KBr) cm ^-1 : 3400, 2940, 260
0, 1740, 1260, 980, 750. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.5 and 3.1 to 3.4 (12H, m), 2.9 to 3.1 and 3.6 to 3.7 (4H, m), 4.9-5.0 (2H,
m), 6.69 (2H, s), 7.1-7.5 (9H,
m).

Example 31 5- (3-Chlorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 16 % (Amorphous) IR (KBr) cm ^-1 : 3400, 1730, 142
5,1365,1250,1080,980,760,
700,645. ¹ H-NMR (CD ₃ OD) δ: 2.0 to 2.5 (2H, m), 2.5 to 3.4 (8H,
m), 3.6-4.1 (6H, m), 4.5-4.8.
(1H, m), 6.73 (2H, s), 7.0-7.4
(9H, m).

Example 32 5- (3-Chlorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 14 0.8% (white powder) m. p. : 141 to 3 ° C (decomposition) IR (KBr) cm ^-1 : 3430, 1735, 142
0, 1300, 1240, 1075, 980. ¹ H-NMR (D ₂ O) δ: 2.3 to 2.5 (4H,
m), 2.70 (2H, d, d, J = 4 Hz, 5H
z), 2.9-4.3 (26H, m), 5.0-5.1.
(2H, m), 6.67 (2H, s), 7.0-7.3.
(3H, m), 7.30 to 7.5 (6H, m).

Example 33 5-Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 25.1% m.p. p. : 164-8 ° C (decomposition) IR (KBr) cm ^-1 : 3420, 2920, 260
0, 1725, 1675, 1610, 1450, 142
5,1250,1070,1040,980,750,
695. ¹ H-NMR (CD ₃ OD) δ: 2.0 to 2.4 (2
H, m), 2.6 to 3.4 (9H, m), 3.48 (1
H, t, J = 8 Hz), 3.6 to 3.9 (4H, m),
4.6-5.0 (2H, m), 6.71 (2H, s),
6.8-7.4 (10H, m).

Example 34 5- (2-Bromophenyl) methyl-3- [1- (4-
Methylphenyl) -3-morpholinopropyl] -1,3
-Oxazolidin-2-one fumarate (diastereomer A) Yield: 28.9% (amorphous) IR (KBr) cm ^-1 : 1730,1640,158
0, 1470, 1420, 1365, 1245, 113
0, 1080, 1020, 980, 750. ¹ H-NMR (D ₂ O) δ: 2.33 (3H, s),
2.2-2.4 and 2.8-4.2 (16H, m),
4.6-5.2 (2H, m), 6.69 (2H, s),
7.2 to 7.8 (8H, m).

Example 35 5- (2-bromophenyl) methyl-3- [1- (4-
Methylphenyl) -3-morpholinopropyl] -1,3
-Oxazolidin-2-one fumarate (diastereomer B) Yield: 26.9% (white powder) m. p. : 152 to 3 ° C (decomposition) IR (KBr) cm ^-1 : 1730, 1710, 142
0, 1390, 1360, 1300, 1260, 120
5,1180,1130,1080,1040,76
5. ¹ H-NMR (D ₂ O) δ: 2.38 (3H, s),
2.2 to 2.5 (2H, m), 3.0 to 3.7 (9H,
m), 3.6-4.2 (4H, m), 3.7-3.8
(1H, m), 4.7-5.0 (1H, m), 6.58
(2H, s), 7.0-7.5 (8H, m).

Example 36 5- (2-Bromophenyl) methyl-3- [1-phenyl-3- (4-thiomorpholinyl) propyl] -1,3
-Oxazolidin-2-one mesylate (diastereomer A) Yield: 21.8% (white powder) m. p. 183-5 ° C IR (KBr) cm ^-1 : 1745, 1430, 126
0,1220,1150,1060,1035,77
0,740,700,560. ¹ H-NMR (D ₂ O) δ: 2.1 to 2.4 (2H,
m), 2.81 (3H, s), 2.8-3.1 (8H,
m), 3.2-3.8 (8H, m), 4.9-5.0
(1H, m), 7.3 to 7.5 (8H, m), 7.73
(1H, d, J = 8Hz).

Example 37 5- (2-Bromophenyl) methyl-3- [1-phenyl-3- (4-thiomorpholinyl) propyl] -1,3
-Oxazolidin-2-one mesylate (diastereomer B) Yield: 20.0% (amorphous) IR (KBr) cm ^-1 : 3420,1730,147
0,1420,1235,1200,1190,105
5,1030,780,755,695. ¹ H-NMR (D ₂ O) δ: 2.4 to 2.5 (2H,
m), 2.83 (3H, s), 3.6-3.9 (2H,
m), 6.7-7.4 (9H, m).

Example 38 5- (3-Methylphenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-one fumarate (diastereomer A) Yield: 22.1% (amorphous) IR (KBr) cm ^-1 : 1730, 1485, 142
0, 1370, 1240, 1070, 1020, 98
0, 970, 780, 750, 690. ¹ H-NMR (D ₂ O) δ: 1.9 to 4.3 (16H,
m), 2.32 and 2.35 (3H, s), 4.6-.
5.1 (2H, m), 6.67 (2H, s), 7.1 to
7.6 (9H, m).

Example 39 5- (3-Methylphenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-one fumarate (diastereomer B) Yield: 18.4% (white powder) m. p. : 142 to 3 ° C (decomposition) IR (KBr) cm ^-1 : 1730, 1705, 157
0,1420,1405,1370,1300,126
0, 1240, 1175, 1075, 790, 750,
630. ¹ H-NMR (D ₂ O) δ: 2.22 (3H, s),
2.3 to 2.5 (2H, m), 2.0 to 3.6 (9H,
m), 3.6-3.8 (1H, m), 3.8-4.2
(4H, m), 4.6-4.9 (1H, m), 4.9-
5.1 (1H, m), 6.57 (2H, s), 6.8-
7.5 (9H, m).

Example 40 3- (3-morpholino-1-phenylpropyl) -5
Phenyl-1,3-oxazolidine-2-one fumarate (diastereomer B) Yield: 9.9% (pale yellow amorphous) IR (KBr) cm ^-1 : 3420, 1730, 123
0,980,690. ¹ H-NMR (CD ₃ OD) δ: 2.4 to 3.1 (8
H, m), 3.6-4.1 (6H, m), 5.0-5.0.
1 (1H, m), 5.5 to 5.6 (1H, m), 6.7
2 (2H, s), 7.1 to 7.4 (10H, m).

Example 41 5- (2-bromophenyl) methyl-3- [3- (4-
Hydroxypiperidino) -1-phenylpropyl]-
1,3-Oxazolidin-2-one fumarate (diastereomer B) Yield: 45.0% (amorphous) IR (KBr) cm ^-1 : 3400, 1730, 157
0,1430,1370,1250,1040,98
0,760. ¹ H-NMR (CD ₃ OD) δ: 1.7 to 2.1 (4
H, m), 2.3 to 2.6 (2H, m), 2.8 to 3.
5 (9H, m), 3.6 to 3.7 (1H, m), 3.8
~ 4.0 (1H, m), 6.69 (2H, s), 7.0
~ 7.5 (9H, m).

Example 42 5- (2-Bromophenyl) methyl-3- [3- (4-
Methoxypiperidino) -1-phenylpropyl] -1,
3-Oxazolidin-2-one fumarate (diastereomer A) Yield: 42.0% (amorphous) IR (KBr) cm ^-1 : 3420,2940,174
0,1430,1365,1250,1105,108
0,1025,985,760,700,645. ¹ H-NMR (D ₂ O) δ: 1.6 to 1.8 (1H,
m), 1.8-2.0 (1H, m), 2.1-2.4
(4H, m), 2.6 to 3.8 (1H, m), 3.41
(3H, s), 6.67 (2H, s), 7.2-7.5
(8H, m), 7.7 (1H, d, J = 8 Hz).

Example 43 5- (2-bromophenyl) methyl-3- [3- (4-
Methoxypiperidino) -1-phenylpropyl] -1,
3-Oxazolidin-2-one fumarate (diastereomer B) Yield: 43.0% (amorphous) IR (KBr) cm ^-1 : 3430,2980,174
0, 1470, 1425, 1360, 1240, 110
0,1075,1025,980,755,700,6
40. ¹ H-NMR (CD ₃ OD) δ: 1.8 to 2.2 (4
H, m), 2.3 to 2.6 (2H, m), 2.8 to 3.
8 (11H, m), 3.35 (3H, s), 6.69
(2H, s), 7.0-7.6 (9H, m).

Example 44 5- (2-Bromophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-thione mesylate (diastereomer A) Yield: 28.0% (white powder) m. p. 184-5 ° C (decomposition) IR (KBr) cm ^-1 : 1485,1445,131
0,1235,1215,1150,1130,112
0, 1020, 760, 755. ¹ H-NMR (CD ₃ OD) δ: 2.4 to 2.6 (2
H, m), 2.71 (3H, s), 3.0 to 4.2 (1
4H, m), 4.9-5.1 (1H, m), 5.8-
5.9 (1H, m), 7.1 to 7.3 (1H, m),
7.3 to 7.7 (8H, m).

Example 45 5- (2-Bromophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-2-thione mesylate (diastereomer B) Yield: 24.3% (white powder) m. p. 179-180 ° C (decomposition) IR (KBr) cm ^-1 : 1480, 1440, 132
0, 1220, 1190, 1160, 1150, 113
0,1015,750,550. ¹ H-NMR (CD ₃ OD) δ: 2.4 to 2.6 (2
H, m), 2.7 (3H, s), 2.9 to 4.1 (14
H, m), 5.1 to 5.2 (1H, m), 5.8 to 5.
9 (1H, m), 7.0 to 7.5 (9H, m).

Example 46 5- (1-Naphthyl) methyl-3- (3-morpholino-
1-phenylpropyl) -1,3-oxazolidine-2
-On mesylate (diastereomer A) yield: 3
7.3% (amorphous) IR (KBr) cm ^-1 : 3430, 2960, 287
0, 1740, 1250, 980, 780, 700. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.9 (8
H, m), 3.2 to 3.8 (8H, m), 4.8 to 5.
0 (2H, m), 6.72 (2H, s), 7.3-8.
1 (12H, m).

Example 47 5- (1-Naphthyl) methyl-3- (3-morpholino-
1-phenylpropyl) -1,3-oxazolidine-2
-On mesylate (diastereomer B) Yield: 24.3% (amorphous) IR (KBr) cm ^-1 : 3430, 2960, 287
0, 1730, 1250, 980, 780, 700. ¹ H-NMR (CD ₃ OD) δ: 2.0 to 3.9 (16
H, m), 4.7 to 5.0 (2H, m), 6.70 (2
H, s), 7.1-7.9 (12H, m).

Example 48 5- (4-Fluorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) Yield: 16.9% (white powder) IR (KBr) cm ^-1 : 2850, 2420, 174
0, 1720, 1570, 1450, 1430, 130
5,1270,1180,1120,1045,99
0,750,640. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.3 (2
H, m), 2.5 to 2.7 (3H, m), 2.8 to 3.
4 (8H, m), 3.8 to 3.9 (4H, m), 4.7
4.9 (2H, m), 6.73 (2H, s), 7.0
~ 7.4 (9H, m).

Example 49 5- (4-Fluorophenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer B) Yield: 38.3% (white powder) m. p. : 157 ~ 9 ° C (decomposition) IR (KBr) cm ^-1 : 2950,2430,174
0, 1730, 1580, 1510, 1430, 130
5,1250,1225,1180,850,760,
640. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.4 (2
H, m), 2.7 to 3.1 (9H, m), 3.61 (1
H, t, J = 9 Hz), 3.7 to 3.9 (4H, m),
4.7-5.0 (2H, m), 6.72 (2H, s),
6.8-7.4 (9H, m).

Example 50 3- (3-morpholino-1-phenylpropyl) -5
(2-phenylethyl) -1,3-oxazolidine-2
-On fumarate (diastereomer A) Yield: 10.4% (white powder) m. p. : 168.5 to 170 ° C (decomposition) IR (KBr) cm ^-1 : 2950, 2450, 174
5,1450,1420,1395,1270,124
5,1210,1145,1090,990,760,
700,635,460. ¹ H-NMR (CD ₃ OD) δ: 1.9 to 2.1 (2
H, m), 2.2 to 2.5 (2H, m), 2.6 to 3.
0 (8H, m), 3.2 to 3.4 (2H, m), 3.7
３3.9 (4H, m), 4.45 (1H, m), 4.9
6 (1H, m), 6.72 (2H, s), 7.1 to 7.
5 (10H, m).

Example 51 3- (3-morpholino-1-phenylpropyl) -5
(2-phenylethyl) -1,3-oxazolidine-2
-On fumarate (diastereomer B) yield: 1
4.4% (white powder) m. p. : 142 to 3 ° C IR (KBr) cm ^-1 : 2950, 2450, 174
0,1420,1400,1260,1240,114
0, 1090, 1050, 1020, 750, 700,
640, 446. ¹ H-NMR (CD ₃ OD) δ: 1.7 to 1.9 (2
H, m), 2.2 to 2.5 (2H, m), 2.5 to 2.
7 (2H, m), 2.7 to 3.0 (7H, m), 3.6
5 (1H, t, J = 9 Hz), 3.7 to 3.9 (4H,
m) 4.55 (1H, m), 5.00 (1H, m),
6.72 (2H, s), 7.0-7.5 (10H,
m).

Example 52 5- (2-Bromophenyl) methyl-3- [3- (hexahydro-1,4-oxazepin-4-yl) -1-phenylpropyl] -1,3-oxazolidin-2 -On fumarate (diastereomer A) Yield: 16.4% (white powder) m. p. : 145 to 7 ° C IR (KBr) cm ^-1 : 3400, 2950, 173
0, 1420, 1250, 1130, 1070, 102
0,980,920,760,695,640. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.2 (2
H, m), 2.3 to 2.5 (2H, m), 3.0 to 3.0.
3. 5 (10H, m), 3.8-3.9 (4H, m),
8-5.6 (2H, m), 6.76 (2H, s), 7.
1-7.7 (9H, m).

Example 53 5- (2-Bromophenyl) methyl-3- [3- (hexahydro-1,4-oxazepin-4-yl) -1-phenylpropyl] -1,3-oxazolidin-2 -On fumarate (diastereomer B) Yield: 20.5% (amorphous) IR (KBr) cm ^-1 : 3400, 2925, 173
0,1425,1370,1240,1135,98
0,750,695,640. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.2 (2
H, m), 2.5 to 2.8 (2H, m), 2.9 to 3.
5 (9H, m), 3.62 (1H, t, J = 8 Hz),
4.9-5.0 (2H, m), 6.70 (2H, s),
7.1 to 7.5 (9H, m).

Example 54 5- (4-Methoxyphenyl) methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate Yield: 5.6% (amorphous) ) IR (KBr) cm ^-1 : 3440, 2930, 173
0, 1620, 1520, 1250, 1250, 99
0,650. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 3.0 (10
H, m), 3.0 to 3.8 (6H, m), 3.76 (3
H, s), 4.7-4.9 (2H, m), 6.71 (2
H, s), 6.7-7.3 (9H, m).

Example 55 3- (3-morpholino-1-phenylpropyl) -5
(2-thenyl) -1,3-oxazolidin-2-one
Fumarate (diastereomer A) Yield: 19.7% (white powder) m. p. : 141 to 146 ° C (decomposition) IR (KBr) cm ^-1 : 3400, 1720, 165
0, 1565, 1490, 1430, 1365, 130
5,1250,1180,1125,1095,92
0,790,755,725,695. ¹ H-NMR (CD ₃ OD) δ: 2.1 to 2.2 (2
H, m), 2.3 to 2.9 (6H, m), 3.1 to 3.
3 (4H, m), 3.7 to 3.8 (4H, m), 4.7
4.9 (2H, m), 6.72 (2H, s), 6.9
~ 7.4 (8H, m).

Example 56 3- (3-morpholino-1-phenylpropyl) -5
(2-thenyl) -1,3-oxazolidin-2-one
Fumarate (diastereomer B) Yield: 16.1% (white powder) m. p. : 160 to 165 ° C (decomposition) IR (KBr) cm ^-1 : 3400, 1730, 165
0,1570,1425,1365,1290,124
5,1070,1035,980,790,750,6
90,630. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 2.4 (2
H, m), 2.8 to 3.2 (9H, m), 3.5 to 3.
6 (1H, m), 3.7 to 3.9 (4H, m), 4.8
４4.9 (2H, m), 6.72 (2H, s), 6.8
~ 7.4 (8H, m).

Example 57 3- (3-morpholino-1-phenylpropyl) -5
(3-phenylpropyl) -1,3-oxazolidine-
2-one fumarate (diastereomer A) Yield: 31% (white powder) m. p. : 165 to 167 ° C IR (KBr) cm ^-1 : 3420, 1720, 144
5,1425,1255,695. ¹ H-NMR (CD ₃ OD) δ: 1.6 to 1.8 (4
H, m), 2.2 to 2.4 (2H, m), 2.6 to 2.
8 (8H, m), 3.1 to 3.3 (2H, m), 3.7
To 3.8 (4H, m), 4.4 to 4.5 (1H, m),
4.9-5.0 (1H, m), 6.73 (2H, s),
7.1 to 7.4 (10H, m).

Example 58 3- (3-morpholino-1-phenylpropyl) -5
(3-phenylpropyl) -1,3-oxazolidine-
2-one fumarate (diastereomer B) Yield: 42% (amorphous) IR (KBr) cm ^-1 : 3420, 2920, 173
0, 1440, 1420, 1370, 1240, 98
0,695. ¹ H-NMR (CD ₃ OD) δ: 1.4 to 1.6 (4
H, m), 2.3 to 2.6 (4H, m), 2.6 to 2.
8 (1H, m), 2.8 to 3.2 (6H, m), 3.6
To 3.7 (1H, m), 3.8 to 3.9 (4H, m),
4.5-4.6 (1H, m), 4.9-5.0 (1H,
m), 6.72 (2H, s), 7.0-7.4 (10
H, m).

Example 59 3- [3- (4-Acetylpiperazinyl) -1-phenylpropyl] -5-benzyl-1,3-oxazolidin-2-one (diastereomer A) m. p. : Oil ¹ H-NMR (CDCl ₃ ) δ: 2.08 (3H,
s), 2.1 to 2.3 (2H, m), 2.3 to 2.5
(6H, m), 2.9-3.1 (2H, m), 3.1-
3.2 (2H, m), 3.4 to 3.5 (2H, m),
3.6 to 3.7 (2H, m), 4.6 to 4.7 (1H,
m), 5.0 to 5.1 (1H, m), 7.1 to 7.3
(10H, m),

Example 60 3- [3- (4-acetylpiperazinyl) -1-phenylpropyl] -5-benzyl-1,3-oxazolidin-2-one (diastereomer B) m. p. : Oil ¹ H-NMR (CDCl ₃ ) δ: 2.07 (3H,
s), 2.1 to 2.2 (2H, m), 2.3 to 2.5
(6H, m), 2.7 to 2.75 (1H, m), 2.8
To 3.0 (2H, m), 3.4 to 3.45 (1H,
m), 3.4-3.5 (2H, m), 3.55-3.6
(2H, m), 4.6-4.7 (1H, m), 5.0-5.0
5.1 (1H, m), 7.1 to 7.3 (10H, m),

Example 61 5-Benzyl-3- [3-morpholino-1- (2-thienyl) propyl] -1,3-oxazolidin-2-one (diastereomer A) m. p. : 143-145 ° C IR (KBr) cm ^-1 : 3400,1715,156
0, 1480, 1420, 1360, 1300, 125
0, 1180, 1120, 1090, 1005, 99
0,910,840,790,750,695,64
0. ¹ H-NMR (DMSO-d ₆ ) δ: 1.8 to 2.0
(1H, m), 2.0 to 2.1 (1H, m), 2.1 to
2.2 (2H, m), 2.3 to 2.4 (4H, m),
2.9-3.0 (2H, m), 3.2-3.7 (6H,
m), 4.7-4.8 (1H, m), 5.0-5.1.
(1H, m), 6.60 (2H, s), 7.0 to 7.1
(2H, m), 7.2 to 7.5 (6H, m).

Example 62 5-Benzyl-3- [3-morpholino-1- (2-thienyl) propyl] -1,3-oxazolidin-2-one (diastereomer B) m. p. : 135 to 136 ° C IR (KBr) cm ^-1 : 3400, 1730, 142
0, 1360, 1290, 1240, 1170, 108
0, 1040, 980, 790, 750, 690, 64
0. ¹ H-NMR (CDCl ₃ ) δ: 2.0 to 2.1 (2
H, m), 2.2 to 2.4 (6H, m), 2.8 to 3.
0 (2H, m), 3.4 to 3.6 (6H, m), 4.7
-4.8 (1H, m), 5.0-5.1 (1H, m),
6.60 (2H, s), 6.9-7.0 (2H, m),
7.1 to 7.5 (6H, m).

Example 63 5-Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-thiazolidine-2-one fumarate (diastereomer A) m. p. : 150 to 155 ° C IR (KBr) cm ^-1 : 3400, 1700, 164
0, 1440, 1395, 1290, 1250, 116
5,1070,985,740,690,630. ¹ H-NMR (CD ₃ OD) δ: 2.3 to 2.4 (2
H, m), 2.7 to 3.5 (10H, m), 3.8 to
3.9 (4H, m), 3.9 to 4.6 (1H, m),
5.2 to 5.3 (1H, m), 6.75 (2H, s),
7.2 to 7.4 (10H, m),

Example 64 5-Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-thiazolidine-2-one fumarate (diastereomer B) m.p. p. : 148 to 150 ° C IR (KBr) cm ^-1 : 3400, 1695, 165
0, 1395, 1260, 1200, 1120, 107
0,970,740,685,620. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 2.3 (2
H, m), 2.5 to 3.1 (9H, m), 3.6 to 3.
7 (1H, m), 3.7 to 3.9 (5H, m), 5.3
５5.4 (1H, m), 6.72 (2H, s), 7.1
~ 7.5 (10H, m).

Example 65 3- (3-morpholino-1-phenylpropyl) -1,
3-oxazolidine-2-one fumarate m. p. : Amorphous IR (KBr) cm ^-1 : 3420, 1730, 142
0, 1250, 1070, 1040, 980, 760,
695,640. ¹ H-NMR (D ₂ O) δ: 2.4 to 2.6 (2H,
m), 3.1 to 3.7 (8H, m), 3.8 to 4.2
(4H, m), 4.3-4.5 (2H, m), 4.96
(1H, t, J = 8 Hz), 6.69 (2H, s),
7.4 to 7.6 (5H, m),

Example 66 5-Methyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (mixture of diastereomers) m. p. : Amorphous IR (KBr) cm ^-1 : 3400, 2955, 172
0, 1630, 1560, 1480, 1420, 136
0,1240,1120,970,905,865,7
90,750,690,640,540. ¹ H-NMR (DMSO-d ₆ ) δ: 1.1 to 1.3
(3H, m), 2.0-2.2 (2H, m), 2.2-
2.6 (6H, m), 3.1 to 3.2 (1H, m),
3.27 to 3.33 (1H, m), 3.5 to 3.7 (4
H, m), 4.5 to 4.6 (1H, m), 4.8 to 4.
9 (1H, m), 6.60 (2H, s), 7.2 to 7.
4 (5H, m).

Example 67 4-Isobutyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (mixture of diastereomers A and B, A / B =
10/6) m. p. 133-143 ° C (decomposition) IR (KBr) cm ^-1 : 3420, 2950, 175
0, 1580, 1420, 1260, 1170, 113
0, 1070, 980, 790, 760, 700, 63
0. ¹ H-NMR (CD ₃ OD) δ: 0.6 to 0.9 (9.
6H, m), 1.2 to 1.7 (4.8H, m), 2.3
To 3.0 (3.2H, m), 2.9 to 3.1 (9.6
H, m), 3.5-3.8 (1.6H, m), 3.8-
3.9 (6.4H, m), 3.9 to 4.0, 4.3 to
4.4 (3.2H, m), 4.5 to 4.7, 4.8 to
4.9 (1.6H, m), 6.72 (3.2H, s),
7.3-7.5 (8H, m).

Example 68 3- (3-morpholino-1-phenylpropyl) -4-
Phenyl-1,3-oxazolidine-2-one fumarate (diastereomer A) m. p. : 155 to 167 ° C (decomposition) IR (KBr) cm ^-1 : 3400, 1735, 172
0,1425,1075,695. ¹ H-NMR (CD ₃ OD) δ: 1.9 to 2.1 (2
H, m), 2.6 to 2.9 (6H, m), 3.7 to 3.
8 (4H, m), 4.16 (1H, dd, J = 6 Hz,
8 Hz), 4.4 to 4.6 (2H, m), 4.97 (1
H, dd, J = 7 Hz, 8 Hz), 6.71 (2H,
s), 7.1 to 7.5 (10H, m),

Example 69 4-Benzyl-3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidin-2-one fumarate (diastereomer A) m. p. : 170 to 172 ° C IR (KBr) cm ^-1 : 3430, 1745, 172
0, 1425, 1305, 1260, 1250, ¹ H-NMR (CD ₃ OD) δ: 2.3 to 2.5 (1
H, m), 2.6 to 2.7 (2H, m), 2.8 to 3.
0 (6H, m), 3.20 (1H, dd, J = 4 Hz,
13 Hz), 3.7-3.9 (5H, m), 4.04
(2H, d, J = 7 Hz) 4.97 (1H, dd, J =
6 Hz, 8 Hz), 6.72 (2H, s), 6.9-
7.0 (2H, m), 7.1 to 7.3 (3H, m),
7.4-7.6 (5H, m).

Example 70 2- (2-bromobenzyl) -4- (3-morpholino-
1-phenylpropyl) -5-morpholinone fumarate (diastereomer A) m. p. : Amorphous IR (KBr) cm ^-1 : 3400, 1700, 164
0,1425,1270,1130,1070,75
0,690,640. ¹ H-NMR (CD ₃ OD) δ: 2.3 to 2.5 (2
H, m), 2.8 to 3.3 (8H, m), 3.3 to 3.
4 (2H, m), 3.8 to 4.0 (4H, m), 4.1
To 4.3 (2H, m), 4.8 to 4.9 (1H, m),
6.8 to 6.9 (1H, m), 6.73 (2H, s),
7.1 to 7.6 (9H, m).

The above fumarate was synthesized 2- (2-bromobenzyl) -5-morpholinone IR (KBr) cm ^-1 : 3200, 3050, 168
5,1490,1460,1420,1100,103
5,1015,900,820,750,730,45
0. ¹ H-NMR (CD ₃ OD) δ: 2.9 to 3.1 (2
H, m), 3.2 to 3.3 (1H, m), 3.3 to 3.3.
4 (1H, m), 3.9 to 4.0 (1H, m), 4.1
0 (1H, d, J = 4 Hz), 4.26 (1H, d, J
= 4 Hz), 6.71 (1H, broads), 7.
1-7.6 (4H, m).

Example 71 2- (2-bromobenzyl) -4- (3-morpholino-
1-phenylpropyl) -5-morpholinone fumarate (diastereomer B) m. p. : 103 to 107 ° C IR (KBr) cm ^-1 : 3450, 1640, 144
0, 1350, 1270, 1120, 1090, 107
0,1040,980,755,700,640. ¹ H-NMR (CD ₃ OD) δ: 2.2 to 2.4 (2
H, m), 2.7-3.0 (8H, m), 3.3-3.0.
4 (2H, m), 3.7 to 3.9 (4H, m), 4.1
To 4.3 (2H, m), 4.8 to 4.9 (1H, m),
6.8 to 6.9 (1H, m), 6.74 (2H, s),
7.1 to 7.6 (9H, m).

Examples 72 and 73 5-Benzyl-4- (3-morpholino-1-phenylpropyl) -3-morpholinone 60% NaH in dry dimethylformamide (8 ml)
(80 mg, 2 mmol) in 5-benzyl-
3-morpholinone (880 mg, 2 mmol) was added. The mixture was stirred at room temperature for 1 hour. To this, 4- (3-
Chloro-3-phenylpropyl) morpholine (480 m
g, 2 mmol) and dry dimethylformamide (1 m
l) was added. The mixture was then stirred at 60 ° C. overnight. The stirred mixture was reduced in pressure to evaporate the solvent.
Water was added to the residue and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was removed from the dried extract under reduced pressure. The oily residue was applied to a silica gel column, and ethyl acetate / methanol (2
0/1), diastereomer A of the title compound
(168 mg, 21.3%) and diastereomer B
(156 mg, 19.8%).

5-Benzyl-3-morpholinone ¹ H-NMR (CDCl ₃ ) δ: 2.6 to 2.7 (1
H, m), 2.8 to 2.9 (1H, m), 3.5 to 3.0.
6 (1H, m), 3.7 to 3.8 (1H, m), 3.8
To 3.9 (1H, m), 4.1 to 4.27 (2H,
m), 6.1 (1H, broads), 7.1 to 7.
4 (5H, m, aryl H).

Diastereomer A (Example 72) ¹ H-NMR (CDCl ₃ ) δ: 2.3 to 2.5 (8
H, m), 3.0 to 3.2 (4H, m), 3.5 to 3.3.
7 (1H, m), 3.6 to 3.8 (4H, m), 4.2
0 (1H, d, J = 7 Hz), 4.35 (1H, d, J
= 7 Hz), 5.7 to 5.8 (1H, m), 7.0 to 7.0
7.4 (10H, m).

Diastereomer B (Example 73) ¹ H-NMR (CDCl ₃ ) δ: 2.3 to 2.5 (8
H, m), 2.62 to 2.75 (1H, m), 3.5 to
3.7 (2H, m), 3.6 to 3.8 (6H, m),
4.20 (1H, d, J = 6 Hz), 4.35 (1H,
d, J = 6 Hz), 5.75-5.85 (1H, m),
6.8 to 7.0 (2H, m), 7.1 to 7.6 (8H,
m).

Example 74 5-Benzyl-4- (3-morpholino-1-phenylpropyl) -3-morpholinone fumarate (diastereomer A) m.p. p. : 173 to 175 ° C IR (KBr) cm ^-1 : 3400, 1700, 164
0, 1440, 1300, 1160, 1120, 108
5,980,870,790,745,690,63
0. ¹ H-NMR (CD ₃ OD) δ: 2.5 to 2.7 (2
H, m), 2.8-3.2 (10H, m), 3.50
(1H, d, J = 12 Hz), 3.8-3.9 (1H,
m), 4.20 (1H, d, J = 17 Hz), 4.34
(1H, d, J = 17 Hz), 5.5 to 5.7 (1H,
m), 6.71 (2H, s), 7.0-7.6 (10
H, m).

Example 75 5-Benzyl-4- (3-morpholino-1-phenylpropyl) -3-morpholinone fumarate (diastereomer B) m.p. p. : 168 to 176 ° C IR (KBr) cm ^-1 : 3400, 1710, 163
0, 1440, 1420, 1290, 1250, 116
0, 1120, 1090, 1065, 970, 900,
860, 745, 690, 630. ¹ H-NMR (CD ₃ OD) δ: 2.4 to 2.6 (2
H, m), 2.6 to 2.9 (8H, m), 3.5 to 3.
6 (2H, m), 3.65 (1H, d, J = 12H
z), 3.7-3.9 (4H, m), 4.21 (1H,
d, J = 17 Hz), 4.32 (1H, d, J = 17H)
z), 5.5-5.6 (1H, m), 6.72 (2H,
s), 6.9-7.6 (10H, m).

Example 76 3- (3-morpholino-1-phenylpropyl) -4-
Phenethyl-1,3-oxazolidin-2-one fumarate (mixture of diastereomers A and B, A / B =
10/4) m. p. : Amorphous IR (KBr) cm ^-1 : 3410, 2910, 250
0, 1720, 1380, 1240, 980, 750,
700,640. ¹ H-NMR (CD ₃ OD) δ: 1.5 to 2.1 (2.
8H, m), 2.3 to 3.1 (14H, m), 3.5 to
3.9 (7H, m), 4.09 (1.4H, dd, J =
6 Hz and 9 Hz), 4.33 (1H, dd, J = 9H)
z and 9 Hz), 4.37 (0.4H, dd, J = 9H)
z and 9 Hz), 4.69 (0.4 H, dd, J = 6 H)
z and 10 Hz), 6.72 (2H, s), 6.9-
7.6 (14H, m).

Example 77 3- (3-morpholino-1-phenylpropyl) -4-
(1-naphthylmethyl) -1,3-oxazolidine-2
-On fumarate (mixture of diastereomers A and B, A / B = 10/3) m. p. : 205 to 208 ° C IR (KBr) cm ^-1 : 3400, 1725, 155
0, 1440, 1395, 1240, 1160, 112
0,1065,1020,970,865,780,7
50,690,630. ¹ H-NMR (CD ₃ OD) δ: 2.4 to 3.1 (10
H, m), 3.6-3.9 (6H, m), 4.5-4.0.
6 (0.2H, m), 5.1 to 5.2 (0.8H,
m), 6.71 (2H, s), 7.1-7.9 (12
H, m).

Example 78 5- (3-Indolylmethyl) -3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-
2-one fumarate (diastereomer A) m.
p. : Amorphous IR (KBr) cm ^-1 : 3350, 1720, 157
0, 1425, 1360, 1250, 980, 740,
700,640. ¹ H-NMR (D ₂ O) δ: 2.0 to 2.5 (2H,
m), 2.9-3.6 (9H, m), 3.64 (1H,
dd, J = 9 Hz and 9 Hz), 3.6 to 4.2 (4
H, m), 4.56 (1H, m), 5.06 (1H,
m), 6.67 (1H, s), 6.8-6.9 (2H,
m), 6.93 (1H, s), 7.09 (1H, dd,
J = 7 Hz and 8 Hz), 7.2 to 7.4 (4H,
m), 7.45 (1H, d, J = 8 Hz), 7.52
(1H, d, J = 8Hz).

Example 79 5- (3-Indolylmethyl) -3- (3-morpholino-1-phenylpropyl) -1,3-oxazolidine-
2-one fumarate (diastereomer B) m.
p. : Amorphous IR (KBr) cm ^-1 : 3300, 1720, 157
0, 1420, 1360, 1240, 980, 740,
700,640. ¹ H-NMR (D ₂ O) δ: 1.69 (1 H, m),
1.8 to 2.0 (2H, m), 2.3 to 2.5 (2H,
m), 2.6-3.4 (7H, m), 3.6-4.2
(4H, m), 5.00 (1H, m), 6.66 (2
H, s), 7.2 to 7.5 (8H, m), 7.56 (1
H, d, J = 8 Hz), 7.78 (1 H, d, J = 8 H)
z).

Example 80 4- (2-bromobenzyl) -3- (3-morpholino-
1-phenylpropyl) -1,3-oxazolidine-2
-On fumarate (diastereomer A) IR (KBr) cm ^-1 : 3420,2910,174
0,1430,1400,1240,1070,98
0,750,700,640. ¹ H-NMR (D ₂ O) δ: 2.1 to 2.5 (8H,
m), 2.7-3.3 (2H, m), 3.5-3.7
(4H, m), 3.9 to 4.1 (3H, m), 4.7 to
4.9 (1H, m), 6.33 (2H, s), 7.1-
7.6 (9H, m),

Example 81 Formulation Example (Tablet) One tablet (100 mg) contains the following components. Active ingredient 10mg Lactose 55mg Crystalline cellulose 20mg Carboxymethylcellulose calcium 10mg Hydroxypropylcellulose 4mg Magnesium stearate 1mg

Example 82 Formulation Example (Granules) The following components are contained in 1 g of granules. Active ingredient 100mg Lactose 450mg Maize starch 400mg Hydroxypropyl cellulose 50mg

[0240]

The alkylenediamine derivative represented by the general formula (1), (2) or (3) and the pharmacologically acceptable salt thereof can suppress micturition contraction caused when the intravesical pressure is high, It can improve dysuria, urinary incontinence, urinary urgency and residual urine in diseases or conditions such as neurological dysuria, chronic prostatitis, chronic cystitis, neurogenic bladder and unstable bladder. It is a therapeutic agent for dysuria.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows 5-benzyl-3-
(1-phenyl-3-morpholinopropyl) -1,3-
It is a figure which shows the various routes for synthesize | combining oxazolidin-2-one [compound (1)].

FIG. 2 shows the compounds indicated by the lower case alphabets in FIG.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/47 A61K 31/47 31/495 31/495 31/535 31/535 31/54 31/54 C07D 239/26 C07D 239 / 26 241/08 241/08 263/16 263/16 263/20 263/20 263/24 263/24 263/44 263/44 263/46 263/46 265/30 265/30 265/32 265/32 277/14 277/14 277/16 277/16 277/36 277/36 279/12 279/12 413/06 307 413/06 307 333 333 413 413/12 213 413/12213 307 307 307 333 333 413/14 307 413/14 307 333 333 (72) Inventor Michiko Ishida 3-9-1-312 Nakaaogi, Kawaguchi City, Saitama Prefecture (72) Inventor Yasuhiko Shinozaki 477-17-15-507, Imabachi-cho, Omiya City, Saitama Prefecture

Claims (6)

[Claims] 1. A compound of the general formula (2): (Wherein R ¹ is a hydrogen atom, an alkyl group, or an alkyl group, a halogen atom, a haloalkyl group, a hydroxyl group, an alkoxyl group, an aryloxy group, an aralkyloxy group, a nitro group, an amino group, a cyano group, an alkylamino Group, aralkylamino group, arylamino group, acylamino group, carboxyl group, alkoxycarbonyl group,
An aralkyloxycarbonyl group, an aryloxycarbonyl group, a carbamoyl group, a sulfo group, an alkoxysulfonyl group, an aralkyloxysulfonyl group, an aryloxysulfonyl group, a sulfonamide group and a 1H-tetrazol-5-yl group, Represents a phenyl group, a naphthyl group or an aromatic heterocyclic group which may have 1 to 5 identical or different substituents, and R ² represents an alkyl group, a halogen atom, a haloalkyl group, a hydroxyl group, an alkoxyl group, Aryloxy, aralkyloxy, nitro, amino, cyano, alkylamino, aralkylamino, arylamino, acylamino, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, carbamo 1 to 5 identical or different substituents selected from the group consisting of a thiol group, a sulfo group, an alkoxysulfonyl group, an aralkyloxysulfonyl group, an aryloxysulfonyl group, a sulfonamide group and a 1H-tetrazol-5-yl group. May have a phenyl group, a naphthyl group or an aromatic heterocyclic group, and R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or R ³ and and R ⁴ is attached, together with the nitrogen atom to which R ³ and R ⁴ are bonded, optionally further oxygen atom, contains a sulfur atom or a nitrogen atom, an alkyl group, an aralkyl group, a phenyl group, a hydroxyl group, an alkoxyl group, Carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, acyl and carba groups The same or different substituents selected from the group consisting of
To five and may have, represent a 5- to 7-membered cyclic group, X represents an oxygen atom, a sulfur atom or an imino group, Y represents an oxygen atom or a sulfur atom, Z is -CH ₂ -, - CO- or -C
Represents S-, m represents an integer of 0 to 4, n represents an integer of 0 to 4, r is 0 or 1, p and q are independently 0 to
Represents an integer of 5. Wherein p + q is 1 to 5), or a pharmacologically acceptable salt thereof. 2. The alkylenediamine derivative according to claim 1, wherein in the general formula (2), X represents an oxygen atom, Y represents an oxygen atom, and Z represents —CH ₂ —. Physically acceptable salts. 3. In the general formula (2), R ¹ is phenyl, thienyl, an alkyl group having 1 to 5 carbon atoms, an alkoxyl group having 1 to 5 carbon atoms, a halogen atom or a haloalkyl having 1 to 5 carbon atoms. The alkylenediamine derivative according to claim 1, which is a phenyl group or a thienyl group substituted with a group, or a pharmacologically acceptable salt thereof. 4. In the general formula (2), R ² is phenyl, thienyl, an alkyl group having 1 to 5 carbon atoms, an alkoxyl group having 1 to 5 carbon atoms, a halogen atom or a haloalkyl having 1 to 5 carbon atoms. The alkylenediamine derivative according to claim 1, which is a phenyl group or a thienyl group substituted with a group, or a pharmacologically acceptable salt thereof. 5. In the general formula (2), bonded to the R ³ and R ^4, together with the nitrogen atom to which R ³ and R ⁴ are attached, morpholino, piperidino, homomorpholino, 1-pyrrolidyl, thiomorpholino, 1-piperazinyl or carbon number 1
Forming a morpholino substituted with an alkyl group of ~ 5,
The alkylenediamine derivative according to claim 1, or a pharmacologically acceptable salt thereof. 6. A therapeutic agent for dysuria comprising the alkylenediamine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.