JP2002293744A - Esophagitis regurgitica-preventing and treating medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an esophagitis regurgitica-preventing and treating medicine. SOLUTION: This esophagitis regurgitica-preventing and treating medicine contains a compound represented by the general formula (I) [R1 and R2 are H or a lower alkyl, or R1 and R2 together represent (CH2 )2 -NH-(CH2 )2 ; R3 is H or a lower alkyl; R4 , R5 and R6 are each H, a lower alkyl, a lower alkoxy, a halogen, amino or trifluoromethyl; W1 and W2 are N or C] or its pharmaceutically acceptable salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a piperazine derivative and a pharmaceutically acceptable salt thereof useful for the prevention and treatment of reflux esophagitis, and an agent for preventing and treating reflux esophagitis containing the same.

[0002]

2. Description of the Related Art Reflux esophagitis is a disease in which acid in the stomach flows back into the esophagus, causing inflammation and damage to mucous membranes in the lower esophagus. It is a disease frequently seen in the elderly, and heartburn and chest pain appear as subjective symptoms. The cause of reflux esophagitis is that gastric acid having a high acidity flows back into the esophagus, and reflux of gastric acid into the esophagus is also observed in healthy subjects after eating. However, in patients with reflux esophagitis, gastric acid reflux after meal is more remarkable than in healthy subjects, and nocturnal gastric acid reflux, which is not seen in healthy subjects, is observed in patients, although not remarkably. The promotion of acid secretion from gastric wall cells
It is caused by three kinds of stimuli, acetylcholine, gastrin and histamine. After eating, it is promoted by the coordination of three kinds of stimuli: acetylcholine secretion from vagus nerve endings, gastrin secretion from anterior fundus G cells and histamine secretion from ECL cells. Whereas nighttime promotion is
Made primarily by histamine. Therefore, the H ₂ receptor antagonist is effective for gastric acid secretion at night, but the effect of the H ₂ receptor antagonist is limited for gastric acid secretion after meal in the daytime. On the other hand, the proton pump inhibitor suppresses gastric acid secretion regardless of the type of stimulation, and thus can strongly suppress both gastric acid secretion at night and gastric acid secretion after eating. For this reason, proton pump inhibitors are currently the drug of choice for reflux esophagitis. However, the conventional proton pump inhibitors have a problem that reflux esophagitis recurs in a short period of time when administration is stopped. Therefore, there is a need for the development of a new drug for treating or preventing reflux esophagitis.

On the other hand, Japanese Patent Application Laid-Open No. 7-157455, GB
132,876 and Ind. J. Chem., 15B: 466-472 (1
977) describe piperazine derivatives useful as antihypertensives and intraocular pressure lowering agents, and JP-A-8-325241 describes piperazine derivatives having an antiallergic effect.

[0004]

SUMMARY OF THE INVENTION With the above background, an object of the present invention is to provide a preventive / therapeutic agent for reflux esophagitis.

[0005]

Means for Solving the Problems The present inventors have found that some piperazine derivatives have an anti-serotonin action and that they have a remarkable preventive / therapeutic effect on reflux esophagitis. The present invention was completed by further research based on the above.

That is, the present invention provides a compound represented by the general formula (I):

[0007]

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Wherein R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group,
When R2 together _{- (CH 2) 2 -NH- (} CH 2) 2
R 3 represents hydrogen or a lower alkyl group;
4, R5 and R6 each represent a hydrogen atom, or R4,
Two of R5 and R6 represent a hydrogen atom and the other represents a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group, or R4, R5 and R6
One of them is a hydrogen atom, and the other is the same or different and is a lower alkyl group, a lower alkoxy group, a halogen,
Represents an amino group or a trifluoromethyl group, or R4, R5 and R6 are all the same as each other and represent a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group, and W1 and W2 Represents the same or different and represents a nitrogen atom or a carbon atom. ) Or a pharmaceutically acceptable salt thereof (both are referred to as “the present compound”). W1 and W2 both represent a carbon atom and R4, R5
And when one of R6 and R6 represents a hydrogen atom and the remaining two each represent a lower alkoxy group, in a ring comprising W1 and W2, one of the two lower alkoxy groups is in the 2-position or One of the two alkoxy groups is 3
More preferably, the other is in position 4 in position.

In the present compound, R 1,
R2 and R3 both represent a hydrogen atom, W1 and W2 both represent a carbon atom, and R4, R5 and R6 represent
All represent a hydrogen atom, or R4, R5 and R6
Is a compound wherein one, two or three of them represent a lower alkoxy group, wherein one or two of R4, R5 and R6 represent a lower alkoxy group and the others represent a hydrogen atom or The pharmaceutically acceptable salts are a group of compounds that are particularly suitable for use in the prevention and treatment of reflux esophagitis.

In the present compound, R 1,
R2 and R3 both represent a hydrogen atom, W1 and W2 both represent a carbon atom, and R4, R5 and R6 represent
A compound or a drug thereof in which one, two or three of them represent a lower alkyl group, wherein one or two of R4, R5 and R6 represent a lower alkyl group and the others represent a hydrogen atom; Pharmaceutically acceptable salts are another group of compounds that are particularly suitable for use in the prevention and treatment of reflux esophagitis.

In the present compound, in the general formula (I), R1 and R2 each represent a lower alkyl group or
When R2 together _{- (CH 2) 2 -NH- (} CH 2) 2
-, R3 represents a hydrogen atom, W1 and W2 both represent a carbon atom, and R4, R5 and R6 represent one of them representing a lower alkoxy group and the other two representing a hydrogen atom. Certain compounds or pharmaceutically acceptable salts thereof are yet another group of compounds that are particularly suitable for use in the prevention and treatment of reflux esophagitis.

In the present compound, in the general formula (I), R1,
R2 and R3 both represent a hydrogen atom, W1 and W2 both represent a carbon atom, and R4, R5 and R6 represent
Compounds or pharmaceutically usable salts of which one of them represents a halogen and the other two represent a hydrogen atom are particularly suitable for use in the prevention and treatment of reflux esophagitis. Still another group of compounds.

In the present compound, in the general formula (I), R1 and R2 both represent a hydrogen atom, R3 represents a lower alkyl group, W1 and W2 both represent a carbon atom, and R4, R5 and R6 is a compound wherein one or two of them represent a lower alkoxy group and the other represents a hydrogen atom, or a pharmaceutically usable salt thereof is used for the prevention and treatment of reflux esophagitis Yet another group of compounds that are particularly suitable for

In the present compound, in the general formula (I), R1,
R2 and R3 each represent a hydrogen atom, and W1 and W2
Represents that one of them represents a carbon atom and the other represents a nitrogen atom, or both of them represent a nitrogen atom, and R4, R5 and R6 all represent a hydrogen atom, or R4, A compound in which one or two of R5 and R6 represent a lower alkoxy group and the other represents a hydrogen atom or a pharmaceutically usable salt thereof is used for prevention and treatment of reflux esophagitis. Yet another group of compounds which are particularly suitable for:

Among the present compounds, compounds selected from the following (1) to (23) or pharmaceutically acceptable salts thereof are particularly suitable for use in the prevention and treatment of reflux esophagitis. It is. (1) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (2) 3- [4- (2-methylphenyl) piperazinyl] -1- ( 4-aminophenoxy) propan-2-ol (3) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-dimethylaminophenoxy) propan-2-ol (4) 3- [4- ( 2-methoxyphenyl) piperazinyl] -1- (4-amino-3-methylphenoxy) propan-2-ol (5) 3- [4- (2-fluorophenyl) piperazinyl] -1- (4-aminophenoxy) Propan-2-ol (6) 3- [4- (3-methoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (7) 3- [4- (4-methoxyphenyl) pipe Radinyl] -1- (4-aminophenoxy) propan-2-ol (8) 3- [4- (2,3-dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane-
2-ol (9) 3- [4- (3,5-dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane-
2-ol (10) 3- [4- (2,3-dimethylphenyl) piperazinyl] -1- (4-aminophenoxy) propane-2
-Ol (11) 3- [4- (2,5-dimethylphenyl) piperazinyl] -1- (4-aminophenoxy) propane-2
-Ol (12) 3- [4- (4,6-dimethoxypyrimidine-2
-Yl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (13) 3- [4- (2,3,4-trimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane -2-ol (14) 3- [4- (2-pyridyl) piperazinyl] -1
-(4-Aminophenoxy) propan-2-ol (15) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-piperazinylphenoxy) propane-
2-ol (16) 3- [4-phenylpiperazinyl] -1- (4-
Aminophenoxy) propan-2-ol (17) 3- [4- (2-aminophenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (18) 3- [4- (3-methyl Phenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (19) 3- [4- (2-chlorophenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (20) 3- [4- (2-ethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (21) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (2-amino Phenoxy) propan-2-ol (22) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (3-aminophenoxy) propan-2-ol (23) 3- [4- (3-to Trifluoromethylphenyl)
Piperazinyl] -1- (4-aminophenoxy) propan-2-ol

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, a "lower alkyl group" refers to an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably 1 or 2 carbon atoms. 2 alkyl groups, ie, a methyl group or an ethyl group.

In the present specification, the term "lower alkoxy group" means an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, particularly preferably an alkoxy group having 1 or 2 carbon atoms. A methoxy or ethoxy group.

In the present specification, “halogen” is
Refers to fluorine, chlorine, bromine and iodine.

The production of this compound is carried out according to Ind. J. Chem., 15B:
466-472 (1977) or JP-A-8-325241 can be easily carried out by those skilled in the art by appropriately selecting starting materials corresponding to the substituents possessed by each target compound of the present invention. The outline is as follows.

Referring to the following synthesis scheme, a 2,3-epoxypropanol derivative as one of the starting materials can be prepared, for example, using a nitro group or a nitro group according to a known method (method described in JP-A-8-325241). It can be obtained by heating a phenol having a substituent R3 and a methyl oxirane halide in a solvent such as acetone or methyl ethyl ketone in the presence of an alkali carbonate. R4, R5, R6-substituted phenylpiperazine and R4, R5, R6-substituted pyridylpiperazine R4, R5, R6-substituted pyrimidylpiperazine represented by (IV), which are the other starting materials, are commercially available products or known ones. Method (JP-A-9-208)
570), for example, by heating N-monobenzylpiperazine and a halogenated benzene having R4, R5, and R6-substituents in an organic solvent or in the absence of a solvent to obtain [1. -Benzyl-4- (R4, R5,
[R6, substituted) phenyl] piperazine can be synthesized by catalytic reduction with palladium carbon (Pd-C) or the like. In a similar manner, R4, R5, R6-substituted pyridylpiperazine, and R4, R5, R6-substituted pyrimidylpiperazine can also be synthesized.

The compounds of formulas (III) and (IV) thus obtained are heated and stirred in a solvent such as dioxane or methanol for about 5 to 20 hours, then the solvent is distilled off and extracted with ethyl acetate or the like. Gives the compound of formula (V). After reducing this nitro group with a metal such as zinc or Pd-C and adding 2N hydrochloric acid to form a hydrochloride, alcohol (methanol, ethanol, propanol, etc.) / Acetone,
Alternatively, the desired compound can be obtained by recrystallization from an alcohol (such as methanol, ethanol, or propanol) / ethyl acetate. Furthermore, the amino group of the target compound is replaced with J.Or.
By dimethylation according to the method of g. Chem., 37: 1673 (1972), a dimethyl compound as another target compound can also be obtained.

[0022]

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The present compound having a piperazylphenoxy group can be synthesized, for example, as follows. That is, commercially available 4-hydroxyphenylpiperazine (VI) is dissolved in ethanol or the like, and di-t-
A urethane-type protecting group is introduced by adding butyl dicarbonate, benzyloxycarbonyl chloride or the like to obtain an N-protected compound (VII). The following reaction scheme shows the case where di-t-butyl dicarbonate is used. According to a known method (the method described in JP-A-8-325241), a halogenated methyl oxirane is heated in a solvent such as acetone or methyl ethyl ketone in the presence of an alkali carbonate to obtain a compound of the formula (VIII ) Can be obtained. The compound of the formula (IX) is obtained by heating and stirring the compound of the formula (IV), which can be obtained by the above-mentioned method, in a solvent such as dioxane or methanol for about 5 to 20 hours and distilling off the solvent with ethyl acetate or the like. Can be Next, this is dissolved in acetone or alcohol (methanol or ethanol), deprotected with an acid, and then recrystallized from, for example, water / acetone to obtain a target compound. Examples of the acid for deprotection include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as acetic acid and trifluoroacetic acid.

[0024]

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The present compound, either in free form or in the form of a pharmaceutically acceptable salt, can be used as an agent for preventing or treating reflux esophagitis. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloride, lead sulfate, nitrate or salts of organic acids such as acetate, maleate, tartrate and the like. Not done.

The present compound can be formulated as an agent for oral administration or an injection as a preventive / therapeutic agent for reflux esophagitis. Here, the “agent for oral administration” means various forms to be taken, for example, tablets, granules,
Appropriate solid preparations such as powders and capsules can be mentioned. The “injection preparations” also include those in the form of injections for normal intravenous injection, intramuscular injection, subcutaneous injection and the like and infusions for intravenous drip infusion. These preparations each include commonly used excipients, binders, disintegrants, dispersants, lubricants, diluents, absorption enhancers, buffers, surfactants, solubilizers, preservatives, emulsifiers, Various additives such as a tonicity agent, a stabilizer, a solubilizer for injection, and a pH adjuster may be used as appropriate.

The dosage of the preventive / therapeutic agent for reflux esophagitis of the present invention varies depending on the age, weight, condition and dosage form of the patient.
In the case of a drug for oral administration, the dosage is usually about several times a day, about 10 to 1000 mg.

[0028]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples and Test Examples, but it is not intended that the present invention be limited to these.

Reference Example 1 3.5 g (0.025 mol) of 1- (4-nitrophenoxy) -2,3-epoxypropane 4-nitrophenol and 7 mL of chloromethyloxirane were dissolved in 40 mL of methyl ethyl ketone, and potassium hydroxide was added to the solution. g in 10 mL of water was added. After heating under reflux for 5 hours, the inorganic salt was filtered off, and the filtrate was concentrated. The residual oil was extracted with ethyl acetate, washed with a 1% aqueous sodium hydroxide solution and water in that order, and then ethyl acetate was distilled off. The obtained residue was recrystallized from ethanol to obtain 3.5 g of 1- (4-nitrophenoxy) -2,3-epoxypropane having pale yellow crystals and a melting point of 64 to 66 ° C.

Example 1 3- [4- (2-methoxyphenyl) piperazinyl]-
1- (4-aminophenoxy) propan-2-ol
Hydrochloride 1- (4-nitrophenoxy)-obtained in Reference Example 1
2.9 g of 2,3-epoxypropane and 3.1 g of (2-methoxyphenyl) piperazine were heated under reflux in 60 mL of methanol for 4 hours. After the reaction, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with a 3% aqueous sodium hydrogen carbonate solution and water in that order, and then the solvent was distilled off. The obtained residue was recrystallized from methanol-water to give pale yellow crystals, 3- [4- (2-methoxyphenyl) piperazinyl]-having a melting point of 164 to 166 ° C.
1- (4-nitrophenoxy) propan-2-ol 4.
6 g were obtained. This compound was dissolved in 80 mL of methanol, and 20 mL of 2N hydrochloric acid was added thereto.
-C) for catalytic reduction. Then, after filtering off Pd-C, the solvent was distilled off, and the obtained crystal was recrystallized from ethanol-isopropyl ether to obtain 3.0 g of the target compound having a white crystal and a melting point of 252 to 253 ° C (decomposition).

Example 2 3- [4- (2-methylphenyl) piperazinyl] -1
-(4-Aminophenoxy) propan-2-ol hydrochloride 1- (4-nitrophenoxy)-obtained in Reference Example 1
1.9 g of 2,3-epoxypropane, 2.2 g of (2-methylphenyl) piperazine hydrochloride and 1.5 m of triethylamine
L was dissolved in 100 mL of methanol and heated under reflux for 4 hours. After the reaction, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with a 3% aqueous sodium hydrogen carbonate solution and water in that order, and then the solvent was distilled off. Methanol was added to the residue to make it acidic with hydrochloric acid, and the solvent was distilled off. The resulting residue was recrystallized from ethanol to give white crystals, 3- [4
-(2-methylphenyl) piperazinyl] -1- (4-
Nitrophenoxy) propan-2-ol hydrochloride 3.9 g
I got 3.5 g of the compound thus obtained is 70%
Dissolve in 100 mL of ethanol and add palladium carbon (Pd-
Catalytic reduction using C). Next, after filtering off Pd-C, the solvent was distilled off, and the obtained crystal was recrystallized from ethanol to obtain 2.0 g of a target compound having white crystals and a melting point of 220 to 222 ° C (decomposition).

Elemental analysis: C ₂₂ H ₂₇ N ₃ O ₂ .HCl.
As 5H ₂ O Theoretical value (%): C, 62.08 H, 7.55 N, 10.86 Actual value (%): C, 62.03 H, 7.55 N, 10.88

Example 3 3- [4- (2-methoxyphenyl) piperazinyl]-
1- (4-dimethylaminophenoxy) propane-2-
All trihydrochloride 5.0 g of 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol obtained in Example 1 was dissolved in 100 mL of acetonitrile, and formaldehyde was added thereto. After dropping 5.2 mL, 1.6 g of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was cooled under ice cooling, neutralized with acetic acid, and the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with water, and the solvent was distilled off to obtain a brown oil. This was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1), converted into a hydrochloride with 2N hydrochloric acid, and recrystallized from methanol-ethyl acetate to give white crystals, melting point: 209 to 212 ° C. (decomposition) 2.9 g of the target compound was obtained.

Elemental analysis: C ₂₂ H ₃₁ N ₃ O ₃ .3HCl.
As 0.5 H ₂ O Theoretical value (%): C, 52.44 H, 7.00 N, 8.34 Actual value (%): C, 52.47 H, 7.12 N, 8.23

Example 4 3- [4- (2-methoxyphenyl) piperazinyl]-
1- (4-amino-3-methylphenoxy) propane-
Dissolve 3.1 g of 2-ol hydrochloride 4-nitro-3-methylphenol and 5 mL of chloromethyloxirane in 50 mL of dioxane,
After adding 2.8 g of potassium carbonate and heating to reflux for 10 hours,
The inorganic salt was removed by filtration, and the filtrate was concentrated. The residual oil was extracted with ethyl acetate, washed with a 1% aqueous sodium hydroxide solution and water in that order, and then ethyl acetate was distilled off to obtain a brown oil. This was dissolved in dioxane, 3.8 g of (2-methoxyphenyl) piperazine was added, and the mixture was heated under reflux for 8 hours. After the reaction, the solvent was distilled off, and the residue was recrystallized from ethyl acetate to give pale yellow crystals, 3- [4- (2
-Methoxyphenyl) piperazinyl] -1- (4-nitro-3-methylphenoxy) propan-2-ol 4.4
g was obtained. 3.2 g of this compound was dissolved in 80 mL of dioxane, and 20 mL of 2N hydrochloric acid was added thereto, followed by catalytic reduction using palladium carbon (Pd-C). Then, after filtering off Pd-C,
The solvent was distilled off, neutralized with 1N sodium hydroxide, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 0.5) and converted into a hydrochloride with 2N hydrochloric acid.
Recrystallized from methanol-acetone, white crystals, melting point 2
2.2 g of the target compound at 10-212 ° C (decomposition) was obtained.

Elemental analysis: C ₂₁ H ₂₉ N ₃ O ₃ .2HCl Theoretical value (%): C, 56.76 H, 7.03 N, 9.46 Actual value (%): C, 56.52 H, 7.09 N, 9.37

Example 5 3- [4- (2-fluorophenyl) piperazinyl]-
1- (4-aminophenoxy) propan-2-ol
Dihydrochloride 1- (4-nitrophenoxy)-obtained in Reference Example 1
3.9 g of 2,3-epoxypropane, 4.8 g of (2-fluorophenyl) piperazine hydrochloride and 2.2 g of triethylamine
g was heated to reflux in 20 mL of methanol and 80 mL of dioxane for 8 hours. After the reaction, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and then the solvent was distilled off. The obtained residue was recrystallized from ethyl acetate-isopropyl ether to give pale yellow crystals, 3- [4- (2-fluorophenyl) piperazinyl] -1- (4-nitrophenoxy) having a melting point of 138 to 142 ° C.
4.5 g of propan-2-ol were obtained. 3.4 g of this compound
Was dissolved in 70 mL of methanol, and 20 mL of 2N hydrochloric acid was added thereto.
And catalytically reduced using palladium on carbon (Pd-C). Next, Pd-C was filtered off, and the solvent was distilled off. The obtained residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, chloroform: methanol = 50: 1), and 2N hydrochloric acid was added to form a hydrochloride, which was then recrystallized from methanol-ethyl acetate to give white crystals. 1.9 g of the target compound having a melting point of 280-285 ° C. (decomposition) were obtained.

Elemental analysis: as C ₁₉ H ₂₄ N ₃ O ₂ F.2HCl Theoretical value (%): C, 54.55 H, 6.26 N, 10.04 Actual value (%): C, 54.29 H, 6.35 N, 10.24

Example 6 3- [4- (3-methoxyphenyl) piperazinyl]-
1- (4-aminophenoxy) propan-2-ol
Dihydrochloride 1- (4-nitrophenoxy)-obtained in Reference Example 1
3.9 g of 2,3-epoxypropane, 6.4 g of (3-methoxyphenyl) piperazine dihydrochloride, 4.9 g of triethylamine
g was heated to reflux in 100 mL of dioxane for 15 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate to give pale yellow crystals.
-[4- (3-methoxyphenyl) piperazinyl] -1
-(4-nitrophenoxy) propan-2-ol 2.2
g was obtained. 2.1 g of this compound was dissolved in 80 mL of dioxane, and catalytically reduced using palladium on carbon (Pd-C). Next, Pd-C was filtered off, and the solvent was distilled off. The obtained residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, chloroform: methanol = 20: 1), and 2N hydrochloric acid was added to form a hydrochloride, which was then recrystallized from methanol-ethyl acetate to give white crystals. 1.1 g of the target compound were obtained. Foaming at 130 ° C, 245-2
Decomposes at 50 ° C.

Elemental analysis: C ₂₀ H ₂₇ N ₃ O ₃ .2HCl.
As H ₂ O Theoretical value (%): C, 53.57 H, 6.96 N, 9.37 Actual value (%): C, 53.51 H, 6.88 N, 8.89

Example 7 3- [4- (4-methoxyphenyl) piperazinyl]-
1- (4-aminophenoxy) propan-2-ol
Trihydrochloride 1- (4-nitrophenoxy)-obtained in Reference Example 1
2.9 g of 2,3-epoxypropane, 4.8 g of (4-methoxyphenyl) piperazine dihydrochloride and triethylamine
3.6 g was heated under reflux in 100 mL of dioxane for 15 hours.
After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate to give yellow crystals, which had a melting point of 180 to 183 ° C.
-[4- (4-methoxyphenyl) piperazinyl] -1
-(4-nitrophenoxy) propan-2-ol 2.6
g was obtained. 1.9 g of this compound was dissolved in 80 mL of dioxane and catalytically reduced using palladium on carbon (Pd-C). Next, Pd-C was filtered off, and the solvent was distilled off. The obtained residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, chloroform: methanol = 30: 1), and 2N hydrochloric acid was added to form a hydrochloride, which was then recrystallized from methanol-ethyl acetate.
1.3 g of the target compound, white crystals, melting point 257-259 ° C (decomposition)
I got

Elemental analysis: As C ₂₀ H ₂₇ N ₃ O ₃ .3HCl Theoretical value (%): C, 51.46 H, 6.47 N, 9.00 Actual value (%): C, 51.43 H, 6.49 N, 8.97

Example 8 3- [4- (2,3-Dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol hydrochloride 1- (4) obtained in Reference Example 1 -Nitrophenoxy)-
1.6 g of 2,3-epoxypropane, 2.4 g of (2,3-dimethoxyphenyl) piperazine dihydrochloride and 1.8 g of triethylamine were heated to reflux in 100 mL of dioxane for 15 hours. After the reaction, the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with a 3% aqueous sodium hydrogen carbonate solution and water in that order, and then the solvent was distilled off. Methanol was added to the residue to make it acidic with hydrochloric acid, and the solvent was distilled off. The obtained residue was recrystallized from water to give white crystals, 3- [4-
(2,3-dimethoxyphenyl) piperazinyl] -1-
(4-nitrophenoxy) propan-2-ol hydrochloride
3.1 g were obtained. 2.9 g of this compound was dissolved in 80 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the obtained residue was recrystallized from isopropanol to give white crystals, melting point 240 to 245 (decomposition)
0.4 g of the desired compound was obtained.

Elemental analysis C ₂₁ H ₂₉ N ₃ O ₄ .HCl
・ As 0.25H ₂ O Theoretical value (%): C, 58.87 H, 7.17 N, 9.81 Actual value (%): C, 58.74 H, 7.21 N, 9.57

Example 9 3- [4- (3,5-dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol trihydrochloride 1- (obtained in Reference Example 1) 4-nitrophenoxy)-
2.0 g of 2,3-epoxypropane, 3.0 g of (3,5-dimethoxyphenyl) piperazine dihydrochloride and 1.5 g of triethylamine were heated under reflux in 100 mL of methanol for 15 hours. After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent was distilled off. The obtained residue is subjected to column chromatography (silica gel, ethyl acetate: hexane =
2: 1) and recrystallized from ethyl acetate to give pale yellow crystals, 3- [4- (3,5-dimethoxyphenyl) piperazinyl] -1- (4-nitrophenoxy) propane having a melting point of 143 to 145 ° C. 3.1 g of -2-ol was obtained. This compound
2.9 g was dissolved in 100 mL of methanol and catalytically reduced using palladium carbon (Pd-C). Then, after filtering off Pd-C,
After distilling off the solvent and adding 2N hydrochloric acid to the obtained residue to form a hydrochloride, the target compound 1.1 is recrystallized from isopropyl alcohol, white crystals, foams at around 215 ° C and decomposes at 217 to 219 ° C. g was obtained.

Elemental analysis: C ₂₁ H ₂₉ N ₃ O ₄ .3HCl.
0.5 H ₂ O Theoretical value (%): C, 49.86 H, 6.57 N, 8.31 Actual value (%): C, 49.73 H, 6.83 N, 8.23

Example 10 3- [4- (2,3-dimethylphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol dihydrochloride 1- (4 -Nitrophenoxy) -2,
3.9 g of 3-epoxypropane and 4.9 g of (2,3-dimethylphenyl) piperazine were added to 100 mL of methanol in 5 mL.
Heated to reflux for an hour. After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent was distilled off to obtain 3- [4- (2 , 3-Dimethylphenyl) piperazinyl] -1- (4-nitrophenoxy) propan-2-ol (6.5 g) was obtained. 5.8 g of this compound in methanol 100
It was dissolved in mL, and catalytically reduced using palladium carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off, and the obtained residue was added with 2N hydrochloric acid to form a hydrochloride, and then recrystallized from isopropyl alcohol to give white crystals, melting point 286 to 289.
5.8 g of the target compound at a temperature of ° C. (decomposition) was obtained. I of this compound
The R spectrum is shown in FIG.

Elemental analysis: C ₂₁ H ₂₉ N ₃ O ₂ .2HCl Theoretical value (%): C, 58.88 H, 7.29 N, 9.81 Actual value (%): C, 58.78 H, 7.42 N, 9.79

Example 11 3- [4- (2,5-dimethylphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol hydrochloride 1- (4- Nitrophenoxy) -2,3
-3.9 g of epoxypropane and 4.6 g of (2,5-dimethylphenyl) piperazine were heated under reflux in 100 mL of methanol for 15 hours. After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1) to give 3- [4-
(2,5-dimethylphenyl) piperazinyl] -1-
6.8 g of (4-nitrophenoxy) propan-2-ol
I got This compound was converted into a hydrochloride with 2N hydrochloric acid, and then recrystallized from methanol-ethyl acetate to obtain a hydrochloride having a melting point of 177 to 179 (decomposition). 6.3 g of this compound was added to methanol 1
It was dissolved in 00 mL and catalytically reduced using palladium carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off, and the obtained residue was recrystallized from isopropyl alcohol.
Pale red crystal, target compound with melting point 260-263 ℃ (decomposition) 4.1
g was obtained.

Elemental analysis: C ₂₁ H ₂₉ N ₃ O ₂ .HCl 1.
As 75H ₂ O Theoretical value (%): C, 59.56 H, 7.97 N, 9.92 Actual value (%): C, 59.40 H, 7.61 N, 9.79

Example 12 3- [4- (4,6-Dimethoxypyrimidin-2-yl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol hydrochloride Obtained in Reference Example 1. 1- (4-nitrophenoxy)-
2.3 g of 2,3-epoxypropane, 4.3 g of (4,6-dimethoxypyrimidin-2-yl) piperazine dihydrochloride and 2.9 g of triethylamine were dissolved in 50 mL of methanol in 50 mL of methanol.
Heated to reflux for an hour. After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and then the solvent was distilled off. The resulting residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1), melting point 126-129 ° C
3.8 g of 3- [4- (4,6-dimethoxypyrimidin-2-yl) piperazinyl] -1- (4-nitrophenoxy) propan-2-ol as yellow crystals was obtained. 2.7 g of the hydrochloride of this compound was dissolved in 50 mL of methanol, and catalytically reduced using palladium carbon (Pd-C). Next, after Pd-C filtration, the residue obtained by evaporating the solvent was recrystallized from ethyl alcohol to obtain 2.0 g of a target compound having white crystals and a melting point of 171 to 174 ° C (decomposition).

Elemental analysis: C ₁₉ H ₂₇ N ₅ O ₄ .HCl.
As 75H ₂ O Theoretical value (%): C, 51.93 H, 6.76 N, 15.94 Actual value (%): C, 52.18 H, 6.87 N, 16.01

Example 13 3- [4- (2,3,4-trimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane-
2-ol dihydrochloride 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
1.6 g of epoxypropane, 2.8 g of (2,3,4-trimethoxyphenyl) piperazine hydrochloride and 1.9 g of triethylamine were heated under reflux in 50 mL of methanol for 15 hours. After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent was distilled off. The obtained residue is subjected to column chromatography (silica gel, ethyl acetate: hexane =
2: 1) to give 3-yellow crystals with a melting point of 159 to 163 ° C.
[4- (2,3,4-trimethoxyphenyl) piperazinyl] -1- (4-nitrophenoxy) propane-2-
2.5 g of all were obtained. 2.4 g of the hydrochloride of this compound was dissolved in 50 mL of methanol, and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off,
The obtained residue is recrystallized from isopropyl alcohol to give the target compound having pale red crystals and a melting point of 231 to 233 ° C (decomposition).
1.8 g were obtained.

[0054] Elemental Analysis _{C 22 H 31 N 3 O 5} · 2HCl
・ As 0.75H ₂ O Theoretical value (%): C, 52.44 H, 6.90 N, 8.34 Actual value (%): C, 52.69 H, 7.16 N, 8.19

Example 14 3- [4- (2-pyridyl) piperazinyl] -1- (4
-Aminophenoxy) propan-2-ol trihydrochloride 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
-2.1 g of epoxypropane and 2.2 g of (2-pyridyl) piperazine were heated under reflux in 50 mL of dioxane for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was recrystallized from ethyl acetate to give pale yellow crystals, 3- [4] having a melting point of 140 to 142 ° C.
2.5 g of-(2-pyridyl) piperazinyl] -1- (4-nitrophenoxy) propan-2-ol were obtained. Dissolve 3.5 g of the hydrochloride of this compound in 50 mL of methanol,
Catalytic reduction was performed using palladium on carbon (Pd-C). Then
After filtering off Pd-C, the solvent was distilled off. The obtained residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, ethyl acetate), and 2N hydrochloric acid was added thereto to form a hydrochloride, which was then recrystallized from methanol-ethyl acetate to give pale red crystals, melting point 210-215. ° C
1.2 g of the target compound (decomposition) was obtained.

Elemental analysis: C ₁₈ H ₂₄ N ₄ O ₂ .3HCl.
0.25H theory as _{2 O (%): C,} 48.88 H, 6.26 N, 12.67 Found (%): C, 48.89 H , 6.66 N, 12.43

Example 15 3- [4- (2-methoxyphenyl) piperazinyl]-
1- (4-piperazinylphenoxy) propan-2-ol tetrahydrochloride 4.2 g of tert-butyl 4- (4-hydroxyphenyl) piperazine-1-carboxylate and 4.2 g of chloromethyloxirane were dissolved in 100 mL of methyl ethyl ketone, After adding 2.1 g of potassium carbonate and heating under reflux for 12 hours, the inorganic salts were separated by filtration and the filtrate was concentrated. The residual oil was extracted with ethyl acetate, washed sequentially with a 1% aqueous sodium hydroxide solution and water, and the ethyl acetate was distilled off to obtain 4.9 g of a brown oil.
This was dissolved in dioxane, 2.9 g of (2-methoxyphenyl) piperazine was added thereto, and the mixture was heated under reflux for 12 hours.
After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent was distilled off. The obtained residue was subjected to column chromatography (silica gel, ethyl acetate: hexane = 1: 1).
Purified in 1), 3- [4-
(2-methoxyphenyl) piperazinyl] -1- [4-
(4-tert-butoxycarbonyl) piperazinylphenoxy] propan-2-ol (4.8 g) was obtained. This compound 4.5
g in 50 mL of methanol and 20 mL of 2N hydrochloric acid.
Was added, and the mixture was stirred at room temperature for 20 hours. Evaporate the solvent,
The obtained residue was recrystallized from water-acetone to obtain 4.7 g of a target compound having white crystals and a melting point of 240 to 245 ° C (decomposition).

Elemental analysis C ₂₄ H ₃₄ N ₄ O ₃ .4HCl
· 2.5H ₂ O theoretically (%): C, 46.69 H , 7.02 N, 9.07 Found (%): C, 46.63 H , 7.00 N, 8.99

Example 16 3- [4-phenylpiperazinyl] -1- (4-aminophenoxy) propan-2-ol dihydrochloride 1- (4-nitrophenoxy)-obtained in Reference Example 1 Two, three
-3.9 g of epoxypropane and 3.9 g of phenylpiperazine
Was heated to reflux in 80 mL of dioxane for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate to give pale yellow crystals having a melting point of 150 to 153 ° C.
4.5 g of [4-phenylpiperazinyl] -1- (4-nitrophenoxy) propan-2-ol were obtained. 3.0 g of this compound was dissolved in 80 mL of dioxane, and catalytically reduced using palladium on carbon (Pd-C). Next, Pd-C was filtered off, and the solvent was distilled off. The obtained residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, chloroform: methanol = 20: 1), and 2N hydrochloric acid was added to form a hydrochloride, which was then recrystallized from ethanol-ethyl acetate to give white crystals. Melting point 275
1.1 g of the target compound at 278278 ° C. (decomposition) was obtained.

Elemental analysis: C ₁₉ H ₂₅ N ₃ O ₂ .2HCl.
As H ₂ O Theoretical value (%): C, 54.55 H, 6.98 N, 10.04 Actual value (%): C, 54.67 H, 6.88 N, 9.85

Example 17 3- [4- (2-aminophenyl) piperazinyl] -1
-(4-Aminophenoxy) propan-2-ol dihydrochloride 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
-2.9 g of epoxypropane and 3.4 g of 1- (2-nitrophenyl) piperazine were heated under reflux in 80 mL of dioxane for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate to give yellow crystals, melting point 13
3- [4- (2-nitrophenyl) piperazinyl] -1- (4-nitrophenoxy) propane-2- at 6-139 ° C.
All obtained 3.1 g. 2.9 g of this compound was added to 80 m of ethanol.
L and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with water, and then the solvent was distilled off. The obtained residue was added with 2N hydrochloric acid to form a hydrochloride, and then recrystallized from isopropanol to obtain 2.4 g of a target compound having pale red crystals and a melting point of 269 to 271 ° C (decomposition).

Elemental analysis: C ₁₉ H ₂₆ N ₃ O ₂ .2HCl.
As H ₂ O Theoretical value (%): C, 52.66 H, 6.97 N, 12.93 Actual value (%): C, 53.06 H, 7.04 N, 12.81

Example 18 3- [4- (3-methylphenyl) piperazinyl] -1
-(4-Aminophenoxy) propan-2-ol dihydrochloride 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
-2.9 g of epoxypropane, 4.1 g of 1- (3-methylphenyl) piperazine dihydrochloride and 3.3 g of triethylamine
g was heated to reflux in 80 mL of methanol for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate-isopropyl ether to give yellow crystals.
3.0 g of 3- [4- (3-methylphenyl) piperazinyl] -1- (4-nitrophenoxy) propan-2-ol having a melting point of 117-120 ° C. were obtained. 3.0 g of this compound was dissolved in 80 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with water, and then the solvent was distilled off. The obtained residue was added with 2N hydrochloric acid to form a hydrochloride, and then recrystallized from ethanol-isopropanol-ethyl acetate to obtain 2.7 g of the desired compound having white crystals and a melting point of 245 to 249 ° C (decomposition).

Elemental analysis: C ₂₀ H ₂₇ N ₃ O ₂ .2HCl.
As 0.25H ₂ O Theoretical value (%): C, 57.35 H, 7.09 N, 10.03 Actual value (%): C, 57.57 H, 7.16 N, 9.72

Example 19 3- [4- (2-chlorophenyl) piperazinyl] -1
-(4-Aminophenoxy) propan-2-ol dihydrochloride 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
4.9 g of epoxypropane and 5.4 g of 1- (2-chlorophenyl) piperazine were heated under reflux in 80 mL of methanol for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate-isopropyl ether to give pale yellow crystals, 3- [4- (2
-Chlorophenyl) piperazinyl] -1- (4-nitrophenoxy) propan-2-ol (7.0 g) was obtained. 3.3 g of this compound was dissolved in 80 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with water, and then the solvent was distilled off. 2N hydrochloric acid was added to the obtained residue to form a hydrochloride, which was then recrystallized from methanol-isopropanol to give white crystals, melting point 280-284 ° C.
3.1 g of the target compound (decomposition) was obtained.

Elemental analysis: As C ₁₉ H ₂₄ N ₃ O ₂ .2HCl Theoretical value (%): C, 52.49 H, 6.02 N, 9.66 Actual value (%): C, 52.44 H, 6.16 N, 9.58

Example 20 3- [4- (2-ethoxyphenyl) piperazinyl]-
1- (4-aminophenoxy) propan-2-ol 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
-Epoxypropane 4.9 g, 1- (2-ethoxyphenyl) piperazine hydrochloride 5.3 g and triethylamine 2.2 g
Was heated to reflux in 80 mL of methanol for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate-isopropyl ether to give pale yellow crystals, 3- [4- (2-ethoxyphenyl) having a melting point of 126 to 128 ° C. Piperazinyl] -1- (4-nitrophenoxy) propan-2-ol (3.4 g) was obtained. Dissolve 3.2 g of this compound in 80 mL of methanol and add palladium carbon (Pd-C)
Was used for catalytic reduction. Then, after filtering off Pd-C, the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with water, and then the solvent was distilled off. The obtained residue was recrystallized from ethyl acetate-isopropyl ether to give pale red crystals, melting point
2.6 g of the target compound at 126-129 ° C (decomposition) was obtained.

Elemental analysis: C ₂₁ H ₂₉ N ₃ O ₃ Theoretical value (%): C, 67.90 H, 7.87 N, 11.31 Actual value (%): C, 67.97 H, 8.00 N, 11.27

Example 21 3- [4- (2-methoxyphenyl) piperazinyl]-
1- (2-Aminophenoxy) propan-2-ol trihydrochloride 7.0 g of 2-nitrophenol and 13.88 g of chloromethyloxirane were dissolved in 100 mL of methyl ethyl ketone, and an aqueous solution obtained by dissolving 3.1 g of potassium hydroxide in 10 mL of water was added thereto. In addition, after heating under reflux for 15 hours, the inorganic salts were filtered off, and the filtrate was concentrated. The residual oil was extracted with ethyl acetate, washed sequentially with a 1% aqueous sodium hydroxide solution and water, and the ethyl acetate was distilled off. The obtained residue was dissolved in 100 mL of methanol, and 1- (2-methoxyphenyl) piperazine was added thereto.
8 g was added, and the mixture was heated under reflux for 8 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from isopropyl ether to give pale yellow crystals, 3- [4] having a melting point of 110 to 114 ° C.
-(2-methoxyphenyl) piperazinyl] -1- (2
9.1 g of -nitrophenoxy) propan-2-ol were obtained. 5.0 g of this compound was dissolved in 100 mL of methanol, and catalytically reduced using palladium on carbon (Pd-C). Next, Pd-C was removed by filtration, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1), and 2N hydrochloric acid was added to form a hydrochloride. Thereafter, recrystallization from methanol-acetone gave 4.2 g of the target compound having white crystals and a melting point of 235 to 240 ° C. (decomposition).

Elemental analysis: C ₂₀ H ₂₇ N ₃ O ₃ .3HCl
・ As 0.25H ₂ O Theoretical value (%): C, 50.97 H, 6.52 N, 8.92 Actual value (%): C, 50.96 H, 6.53 N, 8.69

Example 22 3- [4- (2-methoxyphenyl) piperazinyl]-
1- (3-aminophenoxy) propan-2-ol
7.0 g of 3-nitrophenol trihydrochloride and 13.88 g of chloromethyloxirane were dissolved in 100 mL of methyl ethyl ketone, and an aqueous solution of 3.1 g of potassium hydroxide dissolved in 10 mL of water was added thereto. After heating under reflux for 15 hours, inorganic salts were filtered off. And the filtrate was concentrated. The residual oil was extracted with ethyl acetate, washed with a 1% aqueous sodium hydroxide solution and water in that order, and then ethyl acetate was distilled off. The obtained residue was dissolved in 100 mL of methanol, and 1- (2-methoxyphenyl) piperazine was added thereto.
5.8 g was added, and the mixture was heated under reflux for 15 hours. After the reaction, the solvent was distilled off, and the obtained residue was washed with water and recrystallized from ethyl acetate to give yellow crystals, 3- [4- (2-methoxyphenyl) piperazinyl] -1 having a melting point of 115 to 118 ° C. 7.6 g of-(3-nitrophenoxy) propan-2-ol were obtained. 5.0 g of this compound was dissolved in 100 mL of methanol, and catalytically reduced using palladium on carbon (Pd-C). Next, Pd-C was filtered off, the solvent was distilled off, and the obtained residue was added with 2N hydrochloric acid to form a hydrochloride, and then recrystallized from methanol-acetone to obtain 3.5 g of a white crystalline target compound. . Foaming at 125 ° C,
Decomposes at 225-230 ° C.

Elemental analysis: C ₂₀ H ₂₇ N ₃ O ₃ .3HCl
· 1.25H ₂ O theoretically (%): C, 49.09 H , 6.69 N, 8.59 Found (%): C, 49.36 H , 6.98 N, 8.73

Example 23 3- [4- (3-trifluoromethylphenyl) piperazinyl] -1- (4-aminophenoxy) propane-2
-All trihydrochloride 1- (4-nitrophenoxy) -2,3 obtained in Reference Example 1
-2.9 g of epoxypropane and 4.1 g of 1- (3-trifluorophenyl) piperazine in 100 ml of methanol
The mixture was refluxed for 15 hours. After the reaction, the solvent was distilled off, the obtained residue was extracted with ethyl acetate, washed with 1% aqueous sodium hydroxide solution and water in that order, and the ethyl acetate was distilled off. The obtained residue was subjected to column chromatography (silica gel). , Ethyl acetate: hexane = 1: 1) to give 3-yellow oil.
[4- (3-trifluorophenyl) piperazinyl]-
1- (4-nitrophenoxy) propan-2-ol 3.
6 g were obtained. 3.4 g of this compound was dissolved in 150 mL of methanol, and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed with water, and then the solvent was distilled off. To the obtained residue, 2N hydrochloric acid was added to form a hydrochloride, which was then recrystallized from methanol-ethyl acetate to obtain 2.8 g of the target compound having white crystals and a melting point of 218 to 222 ° C (decomposition).

Elemental analysis: C ₂₀ H ₂₄ N ₃ O ₃ .3HCl
As H ₂ O Theoretical value (%): C, 45.95 H, 5.59 N, 8.04 Observed value (%): C, 46.13 H, 5.40 N, 7.80

[0075] and the effect of Test Example 1] The present compounds on the effect of serotonin 5-HT _1A receptors of the compounds for the serotonin 5-HT _1A receptors was investigated as follows. (Test substance) The compound of Example 1 or 2 was dissolved in DMSO to a concentration of 0.4% and used. (Test method) Martin GR, Humphrey PPA: Ne
uropharmacol., 33: 261-273 (1993). That is, using human recombinant CHO-K1 cells, 50 mM Tris-
HCl, 10 mM MgSO ₄ , 0.5 mM EDTA, 0.1%
Acetate, in a buffer of pH 7.4, 25 ° C., at incubation conditions of 60 minutes to determine the effect against specific binding of ³ H-8-OH-DPAT in 1.5 nM. Judgment of effect is IC
_50, was carried out by K _1, n _H. IC ₅₀ represents the concentration of the antagonist that inhibits the response of the agonist alone by 50%, and K ₁ represents the dissociation constant of the inhibitor. n _H represents Hill count.

(Test Results) The results are shown in the following table.

[0077]

[Table 1]

As can be seen from the above table, Examples 1 and 2
Were found to have an antagonistic effect on serotonin 5-HT _1A receptor.

Test Example 2 Effect of the present compound on a rat reflux esophagitis model (acid reflux model) The effect of the present compound on a rat reflux esophagitis model (acid reflux model) was examined as follows. (Test substance) As a test substance, the compounds of Examples 1 to 23 were used by dissolving them in distilled water to a concentration of 10 mg / 5 mL. As a positive control, omeprazole (proton pump inhibitor) was added at 10 mg / 5 mL or 30 mg / 5 mL.
It was used by suspending it in a 0.5% CMC-Na (sodium carboxymethylcellulose) aqueous solution to a concentration of mL. Distilled water was used as a control. (Test method) The test was performed by Inatomi, N. et al., Jpn. Pharmac.
ol. Ther., 25: (10), p.2445-2455 (1997), according to the method described below. That is, 8-week-old male Wistar rats purchased from Japan SLC, Inc. were used for the test. The rats were fasted for 24 hours and then further water-free for 2 hours before use in the test. After laparotomy of the rat under ether anesthesia and ligation of the pyloric ring and the boundary region between the forestomach and the gastric body, the test substance (10 mg / kg) was intraduodenally administered.
The laparotomy was sutured. Five hours later, the rats were exsanguinated and killed under ether anesthesia, and the stomach and thoracic esophagus were removed. The degree of damage to the thoracic esophagus was observed and evaluated by using the five-stage esophagitis index shown in Table 2.

[0080]

[Table 2]

(Test Results) The results are shown in the following table.

[0082]

[Table 3]

As can be seen in Table 3, test substances 1 to 8,
In rats in the group to which 10 to 23 were administered, suppression of reflux esophagitis was observed. Test substances 1, 3, 4, 5, 1
1,14,18,19,20,21,22,23 showed almost the same effect as the positive control omeprazole.

Test Example 3 Effect of Compound of Example 9 on Rat Reflux Esophagitis Model (Acid Reflux Model) The effect of the compound of Example 9 on the rat reflux esophagitis model (acid reflux model) was as follows. Reexamined as follows. (Test substance and method) As a test substance, the compound of Example 9 was used by dissolving it in distilled water to a concentration of 30 mg / 5 mL or 100 mg / 5 mL. As a positive control,
Omeprazole was added to a concentration of 30 mg / 5 mL to give a concentration of 0.
It was used by suspending it in a 5% CMC-Na aqueous solution. Distilled water was used as a control. The test method was as described in Test Example 2 above.

(Test Results) The results are shown in the following table.

[Table 4]

As shown in Table 4, in the rats to which the compound of Example 9 was administered, reflux esophagitis was significantly suppressed.
In particular, complete suppression was observed in the 100 mg / kg administration group.

[Formulation Example 1] Oral tablet Compound of any of Examples 1 to 23: 100 mg Lactose: 75 mg Starch: 20 mg polyethylene glycol 6000 5 mg The above ingredients are mixed by a conventional method to make one tablet. Sugar coating may be applied if desired.

Formulation Example 2 Injection Compound of any of Examples 1 to 23: 200 mg Mannitol: 5.0 g 1N sodium hydroxide・ ・ Appropriate amount (pH5) distilled water ・ ・ ・ ・ ・ ・ ・ 100ml total amount The above components are mixed by a conventional method to form a solution, and sterile filtered.
Aseptically fill 5 ml glass ampules and seal the ampules.

[0089]

Industrial Applicability The present invention enables the manufacture of a medicament useful for the prevention and treatment of reflux esophagitis.

[Brief description of the drawings]

FIG. 1 is an IR spectrum of the compound of Example 10.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Masahito Iemura 55F F-term (reference) 4C086 AA01 AA02 BC50 GA07 MA01 MA04 NA14 ZA66 ZB11

Claims (8)

[Claims] (1) An active ingredient represented by the following general formula (I): (Wherein, R1 and R2, identical or different, represent a hydrogen atom or a lower alkyl group, or, R1 and R2 together _{- (CH 2) 2 -NH- (} CH 2) 2 - and R3 represents hydrogen or a lower alkyl group; R4, R5 and R6 all represent a hydrogen atom,
4, two of R5 and R6 represent a hydrogen atom and the other represents a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group, or one of R4, R5 and R6 represents a hydrogen atom and Is the same or different from each other, represents a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group,
Or, R4, R5 and R6 are all the same as each other;
Represents a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group, and W1 and W2 are the same or different from each other and represent a nitrogen atom or a carbon atom. Or a pharmaceutically acceptable salt thereof, for preventing or treating reflux esophagitis. 2. In the general formula (I), R1, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 each represent a hydrogen atom. Or R4, R5 and R6 are one of them
, Two or three represent lower alkoxy groups, where R
4. The preventive / therapeutic agent for reflux esophagitis according to claim 1, wherein when one or two of R5 and R6 represent a lower alkoxy group, the other represents a hydrogen atom. 3. In the general formula (I), R1, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent one of them.
, Two or three represent lower alkyl groups, where R
4. The preventive / therapeutic agent for reflux esophagitis according to claim 1, wherein when one or two of R5 and R6 represent a lower alkyl group, the other represents a hydrogen atom. During wherein general formula (I), R1 and R2, or even a lower alkyl group, or, R1 and R2 together _{- (CH 2) 2 -NH- (} CH 2) 2 -, R3 represents a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent one of them representing a lower alkoxy group and the other two representing a hydrogen atom. The preventive / therapeutic agent for reflux esophagitis according to claim 1. 5. In the general formula (I), R1, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent one of them being halogen. The preventive / therapeutic agent for reflux esophagitis according to claim 1, wherein the other two represent a hydrogen atom. 6. In the general formula (I), R1 and R2 each represent a hydrogen atom, R3 represents a lower alkyl group, W1 and W2 each represent a carbon atom, and R4, R5 and R
6. The preventive / therapeutic agent for reflux esophagitis according to claim 1, wherein one or two of them represent a lower alkoxy group and the other represents a hydrogen atom. 7. In the general formula (I), R1, R2 and R3 all represent a hydrogen atom, and W1 and W2 represent one of them representing a carbon atom and the other representing a nitrogen atom, or Both represent nitrogen atoms and R4, R5 and R6
Represents any of them representing a hydrogen atom, or R4, R5
The agent for preventing or treating reflux esophagitis according to claim 1, wherein one or two of R6 and R6 represent a lower alkoxy group and the other represents a hydrogen atom. 8. The method according to claim 1, wherein the active ingredient is (1) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (2) 3- [4- (2 -Methylphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (3) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-dimethylaminophenoxy) propane-2- All (4) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-amino-3-methylphenoxy) propan-2-ol (5) 3- [4- (2-fluorophenyl) piperazinyl ] -1- (4-Aminophenoxy) propan-2-ol (6) 3- [4- (3-methoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (7) 3- [4- 4-methoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (8) 3- [4- (2,3-dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane -
2-ol (9) 3- [4- (3,5-dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane-
2-ol (10) 3- [4- (2,3-dimethylphenyl) piperazinyl] -1- (4-aminophenoxy) propane-2
-Ol (11) 3- [4- (2,5-dimethylphenyl) piperazinyl] -1- (4-aminophenoxy) propane-2
-Ol (12) 3- [4- (4,6-dimethoxypyrimidine-2
-Yl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (13) 3- [4- (2,3,4-trimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane -2-ol (14) 3- [4- (2-pyridyl) piperazinyl] -1
-(4-Aminophenoxy) propan-2-ol (15) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (4-piperazinylphenoxy) propane-
2-ol (16) 3- [4-phenylpiperazinyl] -1- (4-
Aminophenoxy) propan-2-ol (17) 3- [4- (2-aminophenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (18) 3- [4- (3-methyl Phenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (19) 3- [4- (2-chlorophenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (20) 3- [4- (2-ethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol (21) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (2-amino Phenoxy) propan-2-ol (22) 3- [4- (2-methoxyphenyl) piperazinyl] -1- (3-aminophenoxy) propan-2-ol, and (23) 3- [4- ( - trifluoromethylphenyl)
The preventive / therapeutic agent for reflux esophagitis according to claim 1, which is a compound selected from the group consisting of piperazinyl] -1- (4-aminophenoxy) propan-2-ol or a pharmaceutically acceptable salt thereof.