JPH08143557A - New phenylpiperazine derivative, its salt and its solvated material - Google Patents

Abstract

PURPOSE: To obtain a phenylpiperazine derivative having strong adrenaline α1 receptor-blocking action, hardly having adverse effect such as orthostatic hypotension and useful for preventing and treating cardiovascular functional disorder, etc. CONSTITUTION: This compound is expressed by formula I [R1 is H, etc.; R2 is H, an alkyl group, etc.; R3 and R4 are independently H or an alkyl group; R5 is H, an alkyl group, etc.; R6 is H, an alkyl group or a halogen; (n) is an integer of 3-5], e.g. 4-(4-acetoxy-2,3,5-trimethylphenoxy)-1= 4-(2-methoxyphenyl)- piperazino}butane. The compound of formula I is obtained by reacting a compound expressed by formula II, e.g. 4 (4-acetoxy-2,3,5-trimethylphenoxy)butyl chloride with a compound expressed by formula III, e.g. 4-(2-methoxyphenyl) piperazine or its acid addition salt in a solvent such as methanol in the presence of a base such as triethylamine at room temperature to under heating (reflux).

Description

Detailed Description of the Invention

[0001]

INDUSTRIAL APPLICABILITY The present invention has a superior blocking effect on adrenergic α receptors, especially adrenalgic α ₁ receptors, as a medicine, and has high blood pressure, pulmonary arterial hypertension, congestive heart failure, myocardial ischemia, Cardiovascular disorders due to changes in vascular resistance such as arrhythmia, angina and peripheral vascular disease, abnormal serum lipids, benign prostatic hypertrophy, dysuria, diabetes, glaucoma, ocular hypertension, obesity, colonic spasm, sensitive bowel Novel phenylpiperazine derivative useful for the prevention and treatment of sympathetic nerve-related symptoms such as gastrointestinal motility disorders including syndromes and constipation, impotence and central nervous system diseases such as depression and senile dementia, or a derivative thereof The present invention relates to salts and solvates thereof, and pharmaceutical compositions containing such compounds.

[0002]

2. Description of the Related Art Conventionally, various adrenergic α ₁ receptor blockers have been researched and developed, and many compounds have been reported. Examples of the compound having an adrenergic α ₁ receptor blocking action include, for example, Arzneimitter Forschung (Arzneim. Forsh.), Vol. 17, 305.
Page (1967) describes moxicilto hydrochloride, but it is hard to say that it shows a sufficient effect as an α ₁ receptor blocker. In addition, prazosin hydrochloride is used as a therapeutic drug for hypertension and dysuria, but side effects such as orthostatic hypotension have been reported.

[0003]

[Problems to be Solved by the Invention] Conventional adrenaline α
₁ receptor blockers, especially hypertension, pulmonary arterial hypertension, congestive heart failure, myocardial ischemia, arrhythmia, cardiovascular disorders due to changes in vascular resistance such as angina or peripheral vascular disease, abnormal serum lipids, benign prostatic hypertrophy, Sympathetic nervous system such as dysuria, diabetes, glaucoma, ocular hypertension, obesity, colonic spasm, gastrointestinal motility, including sensitive bowel syndrome and constipation, central nervous system diseases such as impotence or depression and senile dementia It is hard to say that it has been shown to be sufficiently effective in the treatment of symptoms associated with. In addition, conventional adrenergic α ₁ receptor blockers are
It is also known to cause side effects such as orthostatic hypotension.
The present invention overcomes the disadvantages of these conventional alpha ₁ receptor blockers, strong and has a adrenergic alpha ₁ receptor blocking action, to provide a orthostatic hypotension reduced side effects adrenergic alpha ₁ receptor blockers is there.

[0004]

The present inventors have found that hypertension,
Pulmonary arterial hypertension, congestive heart failure, myocardial ischemia, arrhythmia, cardiovascular disorders due to changes in vascular resistance such as angina and peripheral vascular disease, abnormal serum lipids, benign prostatic hypertrophy, dysuria,
Involves the sympathetic nervous system such as diabetes, glaucoma, ocular hypertension, obesity, colonic spasm, gastrointestinal motility disorders including sensitive bowel syndrome and constipation, impotence and depression and central nervous system diseases such as senile dementia Excellent adrenaline α ₁ for symptoms
As a result of synthesizing various compounds to obtain a drug having a receptor-blocking action and examining the pharmacological action, it was found that a specific phenylpiperazine derivative has an excellent adrenergic α ₁ receptor-blocking action and side effects of orthostatic hypotension. Therefore, the present invention has been completed.

That is, the present invention relates to a novel phenylpiperazine derivative represented by the following general formula (I), a salt thereof and a solvate thereof.

General formula (I):

[Chemical 5][Wherein, R¹Is a hydrogen atom or (CO) R⁷Indicated by
Group (R⁷Is a lower alkyl group or a phenyl group); R²Is
Hydrogen atom, lower alkyl group, (CO) R⁸Group represented by
Or (CO) OR⁹A group represented by (R⁸, R⁹Is hydrogen
Atom or lower alkyl group); R³, R^FourEach is German
Vertically hydrogen atom or lower alkyl group; R^FiveIs a hydrogen atom,
Lower alkyl group, (CO) NR^TenR¹¹A group represented by
(CO) OR ¹²A group represented by, a trifluoromethyl group,
NR¹³R¹⁴A group represented by NH (CO) R^FifteenIndicated by
Group, nitro group, OR¹⁶Group or halogen atom
(R^Ten, R¹¹Are each independently a hydrogen atom or a lower
Kill group, R¹²Is a hydrogen atom or a lower alkyl group, R¹³,
R¹⁴Are each independently a hydrogen atom or a lower alkyl group,
R^Fifteen, R¹⁶Is a lower alkyl group); R⁶Is a hydrogen atom, lower
Alkyl group or halogen atom; n is an integer of 3 to 5
Represent. ]

The present invention also relates to pharmaceutically acceptable salts of such compounds and their solvates, as well as to pharmaceutical compositions containing such compounds.

The "lower alkyl group" in the present invention means a linear or branched hydrocarbon having 1 to 4 carbon atoms. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s
An ec-butyl group, a tert-butyl group and the like, preferably a methyl group and an ethyl group are mentioned.

Further, the novel compound of the present invention includes a case where an asymmetric carbon atom is contained depending on the kind of the substituent. Therefore, the novel compound of the present invention includes a mixture of various optical isomers and an isolated one. The novel compounds of the present invention represented by the general formula (I) are in the form of their salts, for example, their acid addition salts,
In particular it can be in the form of its pharmaceutically acceptable non-toxic acid addition salts. Further, depending on the kind of the substituent, it may be a salt with a base, particularly a pharmaceutically acceptable non-toxic base addition salt thereof.

Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid and malonic acid.
Organic acid such as succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid and p-toluenesulfonic acid, and acid addition salt with acidic amino acid such as aspartic acid and glutamic acid Inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, organic bases such as methylamine, ethylamine and ethanolamine, salts with basic amino acids such as lysine and ornithine, and ammonium salts. The salt of the novel compound of the present invention can be a solvate thereof. Specific examples of such a solvent include water, methanol, ethanol, propanol, isopropyl alcohol and the like.

The compounds of the present invention include 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1-.
{4- (2-methoxyphenyl) piperazino} butane,
3- (4-hydroxy-2,3,5-trimethylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} propane, 4- (4-hydroxy-2-isopropyl-5-methylphenoxy) -1 -{4- (2-methoxyphenyl) piperazino} butane, 3- (4-hydroxy-2-isopropyl-5-methylphenoxy) -1-
{4- (2-Methoxyphenyl) piperazino} propane, 4- (4-hydroxy-2,3,5-trimethylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane, 1- {4- (5-Chloro-2-methylphenyl) piperazino} -3- (4-hydroxy-2,
3,5-Trimethylphenoxy) propane, 1- {4-
(5-Chloro-2-methylphenyl) piperazino} -4
-(4-hydroxy-2,3,5-trimethylphenoxy) butane, 4- (2-formyl-4-hydroxyphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane, 4- (5- Hydroxy-2-methoxycarbonylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane, 4- (2-carboxy-5
-Hydroxyphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane, 4- (4-hydroxy-2-methoxycarbonylphenoxy) -1- {4-
(2-Methoxyphenyl) piperazino} butane, 4-
(2-t-butyl-4-hydroxyphenoxy) -1-
{4- (2-methoxyphenyl) piperazino} butane,
4- (4-hydroxyphenoxy) -1- {4- (2-
Methoxyphenyl) piperazino} butane, 3- (4-hydroxyphenoxy) -1- {4- (2-methoxyphenyl) piperazino} propane, 3- (2-carboxy-
5-hydroxyphenoxy) -1- {4- (2-methoxyphenyl) piperazino} propane, 1- {4- (2-
Ethoxycarbonylphenyl) piperazino} -4- (4
-Hydroxyphenoxy) butane, 4- (4-acetoxyphenoxy) -1- {4- (2-ethoxycarbonylphenyl) piperazino} butane, 4- (4-benzoyloxy-2-t-butylphenoxy) -1- { 4- (2-
Ethoxycarbonylphenyl) piperazino} butane, 4
-(2-t-Butyl-4-hydroxyphenoxy) -1-
{4- (2-Ethoxycarbonylphenyl) piperazino} butane, 4- (4-acetoxy-2-t-butylphenoxy) -1- {4- (2-ethoxycarbonylphenyl) piperazino} butane, 4- (4- Hydroxyphenoxy) -1- (4-phenylpiperazino) butane, 4-
(4-acetoxyphenoxy) -1- (4-phenylpiperazino) butane, 4- (4-acetoxy-2,3,5
-Trimethylphenoxy) -1- {4- (2-carbamoylphenyl) piperazino} butane, 4- (2-t-butyl-4-hydroxyphenoxy) -1- {4- (2-chlorophenyl) piperazino} butane, 4 -(4-acetoxy-2,3,5-trimethylphenoxy) -1- {4
-(2-Ethoxycarbonylphenyl) piperazino} butane, 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-nitrophenyl) piperazino} butane, 4- (4-acetoxy) -2,3,5-
Trimethylphenoxy) -1- {4- (2-acetylaminophenyl) piperazino} butane, 4- (4-acetoxy-2-t-butylphenoxy) -1- {4- (2-chlorophenyl) piperazino} butane, 4 -(4-acetoxy-2,3,5-trimethylphenoxy) -1- {4
-(4-Fluorophenyl) piperazino} butane, 4-
(4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2,4-dimethylphenyl) piperazino} butane, 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1 -{4- (4-nitrophenyl) piperazino} butane, 4- (4-acetoxy-2,
3,5-Trimethylphenoxy) -1- {4- (4-aminophenyl) piperazino} butane, 4- (4-hydroxy-2,3,5-trimethylphenoxy) -1- {4
-(4-Nitrophenyl) piperazino} butane, 4-
(4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (4-acetylaminophenyl) piperazino} butane, 4- (4-acetoxy-2,3,5-
Trimethylphenoxy) -1- {4- (4-dimethylaminophenyl) piperazino} butane, 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4
Examples include-(3-trifluoromethylphenyl) piperazino} butane.

[Production Method] The novel compound of the present invention and a salt thereof can be produced by utilizing various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. The typical manufacturing method is illustrated below.

[0013]

[Chemical 6]

[Wherein R¹Is a hydrogen atom or (CO) R
⁷A group represented by (R⁷Is a lower alkyl group or phenyl
Group); R²Is a hydrogen atom, a lower alkyl group, (CO) R⁸
A group represented by or (CO) OR⁹Group represented by
(R⁸, R⁹Is a hydrogen atom or a lower alkyl group);
R³, R^FourAre each independently a hydrogen atom or a lower alkyl
R group; R^FiveIs a hydrogen atom, a lower alkyl group, (CO) NR
^TenR¹¹A group represented by (CO) OR ¹²Group represented by
Lifluoromethyl group, NR¹³R¹⁴A group represented by
(CO) R^FifteenGroup represented by, nitro group, OR¹⁶Indicated by
Group or halogen atom (R^Ten, R¹¹Each independently
Hydrogen atom or lower alkyl group, R¹²Is a hydrogen atom or
Lower alkyl group, R¹³, R¹⁴Are each independently a hydrogen atom
Or a lower alkyl group, R^Fifteen, R¹⁶Is lower alkyl
Group); R⁶Is a hydrogen atom, a lower alkyl group or halogen
Represents an atom; R^{1 '}Is a hydrogen atom or (CO) R^{7 '}Indicated by
Group (R^{7 '}Is a lower alkyl group or a phenyl group);
R^{2 '}Is a hydrogen atom, a lower alkyl group, (CO) R ^{8 '}Indicated by
Group or (CO) OR^{9 '}A group represented by (R^{8 '}, R^{9 '}
Is a hydrogen atom or a lower alkyl group); R^{3 '}, R^Four'Is it
Each independently a hydrogen atom or a lower alkyl group; X is a halogen
Alkyl atom, an alkylsulfonione having 1 to 4 carbon atoms
An aryloxy group or an aryl having 6 to 10 carbon atoms
Represents a sulfonylsulfonyl group. ; R^Five'Is a hydrogen atom, lower
Alkyl group, (CO) NR^Ten'R^{11 '}A group represented by
(CO) OR^{12 '}Group represented by, trifluoromethyl
Group, NR^13'R^14'A group represented by NH (CO) R^{15 '}
Group represented by, nitro group, OR^{16 '}Group represented by or
Halogen atom (R^Ten', R^{11 '}Are independent hydrogen
Child or lower alkyl group, R^{12 '}Is a hydrogen atom or lower
Alkyl group, R^13', R^14'Are each independently a hydrogen atom
Or a lower alkyl group, R^{15 '}, R^{16 '}Is lower alkyl
Group); R^{6 '}Is a hydrogen atom, a lower alkyl group or halogen
Represents an atom. ]

The production method is as follows: the compound represented by the above formula (IV) and the compound represented by (V) or an acid addition salt thereof are reacted in a suitable solvent or without solvent in the presence or absence of a base. And a method for obtaining the novel compound of the present invention represented by the general formula (I), wherein these free compounds are, if desired, added with a suitable organic or inorganic acid or base.
A method for obtaining a pharmaceutically acceptable salt and a solvate thereof.

Among the compounds represented by the general formula (I) produced in this manner, those compounds in which R ¹ is a hydrogen atom have R ¹ of (CO) R due to an acylation reaction or the like.
⁷ (R ⁷ is a lower alkyl group or a phenyl group) can be converted into a compound having a group. Furthermore, R ¹
Is a group represented by (CO) R ⁷ (wherein R ⁷ is a lower alkyl group or a phenyl group),
R ¹ can be converted into a compound having a hydrogen atom or a group represented by (CO) R ⁷ (R ⁷ is a lower alkyl group or a phenyl group different from those shown above).

A compound in which R ² is a group represented by (CO) OR ⁹ (R ⁹ is a hydrogen atom) can be prepared by a general method in which R ² is (CO) OR ⁹ (R ⁹ is a lower alkyl group). It can be converted into a compound having the group represented by. Furthermore, compounds represents a group represented by R ² is (CO) OR ⁹ (R ⁹ is a lower alkyl group) is by customary methods, R ² is (CO) OR ⁹ (R ⁹ represents a hydrogen atom or a previously And a lower alkyl group different from the above).

Further, the compound represents a group R ⁵ is represented by (CO) OR ¹² (R ¹² is a hydrogen atom) is by customary methods, R ⁵ is (CO) OR ¹² (R ¹² is a lower alkyl group) Alternatively, it can be converted to a compound having a group represented by (CO) NR ¹⁰ R ¹¹ (R ¹⁰ and R ¹¹ are each independently a hydrogen atom or a lower alkyl group). Furthermore, R ⁵ is (CO) O
In the compound showing the group represented by R ¹² (R ¹² is a lower alkyl group), R ⁵ is (CO) OR ¹² (R ¹²
Can be converted into a compound showing a hydrogen atom or a group represented by a lower alkyl group different from those shown above.

Further, in the compound in which R ⁵ represents a nitro group, R ⁵ is NR ¹³ R ¹⁴ (R ¹³ and R ¹⁴ are independently hydrogen by a general reduction reaction or subsequent alkylation or acylation. Atom or lower alkyl group) or NH (C
O) R ¹⁵ (R ¹⁵ is a lower alkyl group) can be converted to a compound having a group.

If desired, these free compounds can be converted into their pharmaceutically acceptable salts or their solvates by the addition of suitable organic or inorganic acids or bases.

In the reaction of the compound represented by the formula (IV) in the formula (6) with the compound represented by the formula (V) or an acid addition salt thereof, alcohols such as methanol, ethanol, propanol and isopropyl alcohol, benzene, Hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as tetrahydrofuran, dioxane and ether, acetonitrile, N, N-dimethylformamide ( A solvent inert to the reaction such as DMF), dimethylsulfoxide, and ethyl acetate can be appropriately used, or the reaction can be performed without a solvent. When the reaction is carried out in the presence of a base, it is desirable to add organic bases such as triethylamine and pyridine, inorganic bases such as sodium carbonate, potassium carbonate and sodium hydride, or n-butyllithium. If the base is liquid at the reaction temperature, the base may be used as a solvent. In addition,
These reactions proceed under cooling or heating, but they are usually carried out under heating (under reflux) to accelerate the reaction. It is desirable to carry out the reaction preferably at room temperature or under heating (under reflux).

[0022]

INDUSTRIAL APPLICABILITY The compound of the present invention has a blocking effect on the adrenergic α receptor, and particularly exhibits a very strong blocking action on the adrenergic α ₁ receptor which is a subtype of the adrenergic α receptor. Therefore, the compounds of the present invention can be used for the treatment of various diseases involving the sympathetic nervous system, particularly the adrenergic α receptor. Such diseases include, for example, hypertension, pulmonary arterial hypertension, congestive heart failure, myocardial ischemia, arrhythmia, cardiovascular disorders due to changes in vascular resistance such as angina and peripheral vascular disease, abnormal serum lipids, benign prostatic hypertrophy, Examples thereof include urinary disorders, diabetes, glaucoma, ocular hypertension, obesity, colonic spasm, gastrointestinal motility disorders including sensitive bowel syndrome and constipation, impotence and central nervous system diseases such as depression and senile dementia. The strength of the blocking action of the novel compound of the present invention on the adrenergic α ₁ receptor and the effect of orthostatic hypotension was confirmed below.

[Experimental Example 1] Blocking action on adrenaline α ₁ receptor 1) Experimental method The blocking action on adrenaline α ₁ receptor was determined by measuring a rabbit thoracic aorta sample according to the method of Magnus, and pA was determined. expressed as a _binary. Table 1 below shows pA ₂ values of the above-mentioned moxicilto hydrochloride and prazosin hydrochloride used as the compound of the present invention and the control compound. 2) Experimental results

[0024]

[Table 1]

As a result, it was found that the compound of the present invention has a markedly potent blocking effect on the adrenergic α ₁ receptor. Some of them showed remarkably potent action even when compared with the control compounds moxicilito hydrochloride and prazosin hydrochloride.

[Experimental Example 2] Orthostatic hypotension effect 1) Experimental method Journal of Far-Macrological Method (J
individual ofPharmacological
Methods), Vol. 5, p. 53 (1981). The rabbit was fixed to an orthostatic hypotension measuring device in a dorsal position under anesthesia, a polyethylene catheter was inserted into each of the right femoral arteries and veins, and the catheter inserted into the artery was connected to a pressure transducer. Rabbits tilt their head at a 90 ° angle from the horizontal position with the heart position as the axis of rotation at 15 minute intervals.
After 1 minute, it was returned to the horizontal position again. Repeat Tilting 3 times,
After confirming that a certain reaction was obtained, the drug was administered through a polyethylene catheter inserted into a vein. The strength of the orthostatic hypotension effect of the drug is expressed by the following formula
The compound was evaluated by the hostatic Index (OI) and compared with the dose of the compound showing an OI value of 90%. The results are shown in Table 2 below. Orthostatic Responce (OR) = (blood pressure immediately before the end of Tilting) / (blood pressure immediately before the start of Tilting) OI (%) = {(OR after drug administration) / (O.
R.)} × 100 2) Experimental results

[0027]

[Table 2]

The compounds of the present invention showed the same OI value as the control compound prazosin hydrochloride, even though the pA ₂ value, which is a measure of the adrenergic α ₁ -blocking effect, showed the same or higher activity. It was confirmed that the compound is large and that it is a compound that hardly causes orthostatic hypotension.

From these results, it was confirmed that the compound of the present invention has an excellent adrenergic α ₁ -blocking action and a weak orthostatic hypotensive action.

One or two of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and a solvate thereof.
A pharmaceutical composition containing one or more kinds as active ingredients is prepared by using carriers, excipients and other additives which are usually used for formulation. Carriers and excipients for formulation include solid or liquid non-toxic pharmaceutical substances. Examples of these include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, and the like, and other commonly used ones can also be used.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder and liquid, or injection such as intravenous injection and intramuscular injection, suppository, transdermal administration and the like. The dose is appropriately determined according to each case in consideration of symptoms, age of the administration subject, sex, etc.,
Oral administration: 0.1 to 1000 m per day for adults
g, preferably about 1 to 500 mg, which is administered once or in 2 to 4 divided doses.

[0032]

EXAMPLES The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these. Example 1 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane hydrochloride] 4- (4-acetoxy-
2,3,5-Trimethylphenoxy) butyl chloride 2.
60 g, 4- (2-methoxyphenyl) piperazine hydrochloride 2.09 g, potassium carbonate 2.53 g, potassium iodide 1.52 g
And a mixture of 30 ml of N, N-dimethylformamide at 50 ° C.
It was stirred for 16 hours. After the reaction is completed, the reaction solution is poured into ice water,
It was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a pale brown oily substance. This oily substance was dissolved in ethanol, and 1 ml of concentrated hydrochloric acid was added. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to obtain 3.42 g of the title compound (colorless crystals). Melting point: 173-175 ° C (decomposition) IR (KBr) cm ^-1 : 3480,2940,2590,2430,1760,1635,1595,15
10,1455,1375,1335,1250,1210,1125,1080,1030,985,93
0,840,755 NMR (DMSO-d ₆ ) δ: 11.22 (1H, br), 6.95 (4H, m), 6.72 (1H, s),
3.97 (2H, t), 3.79 (3H, t), 3.50 (4H, m), 3.14 (6H, m), 2.31 (3
H, s), 2.09 (3H, s), 2.05 (3H, s), 1.97 (3H, s), 1.95 (2H, m),
1.80 (2H, m) Elemental analysis value (C ₂₆ H ₃₆ N ₂ O ₄・ HCl) Calculated value: C, 65.46; H, 7.82; N, 5.87; Cl, 7.43 Found value: C, 65.36; H, 7.79; N, 5.80; Cl, 7.78

Example 2 [Synthesis of 3- (4-hydroxy-2,3,5-trimethylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} propane dihydrochloride] 4- (4-acetoxy -2,3,5-Trimethylphenoxy) propyl chloride 5.42 g, 4- (2-methoxyphenyl) piperazine hydrochloride 4.23 g, potassium carbonate 3.00 g, potassium iodide
A mixture of 3.70 g and 50 ml of N, N-dimethylformamide was stirred at 50 ° C. for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a pale brown oily substance. This oil was added to methanol 50
It was dissolved in 4 ml of concentrated hydrochloric acid, 4 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 5 hours. After cooling, the solvent was evaporated under reduced pressure, the residue was recrystallized from ethanol / diethyl ether, and the title compound (colorless crystals) 4.60
got g. Melting point: 230 ° C (decomposition) IR (KBr) cm ^-1 : 3430,2930,2370,1760,1610,1460,1370,13
25,1270,1225,1205,1125,1080,1020,930,850,760 NMR (DMSO-d ₆ ) δ: 11.68 (1H, br), 7.03 (4H, m), 6.63 (1H, s),
6.60 (1H, s), 4.02 (2H, t), 3.82 (3H, s), 3.56 (4H, m), 3.28 (6
H, m), 2.26 (2H, m), 2.23 (3H, s), 2.17 (3H, s), 2.06 (3H, s) Elemental analysis value (C ₂₃ H ₃₂ N ₂ O ₃・ 2HCl) Calculated value: C, 60.39; H, 7.49; N, 6.12; Cl, 15.50 Found: C, 60.26; H, 7.55; N, 6.09; Cl, 15.25

Example 3 [4- (4-hydroxy-2-isopropyl-5-methylphenoxy) -1- {4- (2-methoxyphenyl)
Synthesis of piperazino} butane hydrochloride] 4- (4-acetylamino-2-isopropyl-5-
Methylphenoxy) butyl chloride 10.40 g, 4- (2-
A mixture of 6.92 g of methoxyphenyl) piperazine hydrochloride, 4.98 g of potassium carbonate, 5.98 g of potassium iodide and 100 ml of N, N-dimethylformamide was stirred at 50 ° C. for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a pale brown oily substance. This oil was dissolved in ethanol, 10 ml of concentrated hydrochloric acid was added, the solvent was evaporated under reduced pressure, the residue was recrystallized from ethanol / diethyl ether, and 3- (4-acetylamino-2-isopropyl-5- Methylphenoxy) -1-
{4- (2-Methoxyphenyl) piperazino} butane
12.5 g of dihydrochloride (colorless crystals) was obtained. NMR (DMSO-d ₆ ) δ: 11.28 (1H, br), 9.27 (1H, br), 7.05 (1H,
s), 6.98 (4H, m), 6.77 (1H, s), 3.99 (2H, t), 3.80 (3H, s), 3.5
1 (4H, m), 3.20 (7H, m), 2.13 (3H, s), 2.01 (3H, s), 1.95 (2H,
m), 1.82 (2H, m), 1.14 (6H, d) 3- (4-acetylamino-2-isopropyl-5-
5.0 g of methylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane dihydrochloride is heated to reflux with 40 ml of dilute hydrochloric acid for 1 hour. The reaction solution was cooled to room temperature, made alkaline with sodium hydroxide, and extracted with diethyl ether. The extract was washed with water, dried and concentrated, and the residue was diluted with sulfuric acid.
A solution of 0.9 g of sodium nitrite in 20 ml of water in 50 ml at -5 ° C was added. After stirring for 30 minutes, 0.1 g of copper sulfate was added,
The mixture was heated to reflux until no gas was generated. The reaction solution was cooled to room temperature, made alkaline with sodium hydroxide, and carbon dioxide was introduced to obtain a white solid. The solid collected by filtration was dissolved in ethanol, 3 ml of concentrated hydrochloric acid was added, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to obtain 1.3 g of the title compound (colorless crystal). Melting point: 259-261 ℃ (decomposition) IR (KBr) cm ^-1 : 3420,3210,2970,2460,1620,1590,1505,14
60,1415,1260,1211,1185,1120,1070,1025,985,930,885,
840,760 NMR (DMSO-d ₆ ) δ: 10.63 (1H, br), 8.64 (1H, s), 6.67 (4H, m),
6.66 (1H, s), 6.62 (1H, s), 3.88 (2H, t), 3.79 (3H, s), 3.49 (4
H, m), 3.14 (7H, m), 2.07 (3H, s), 1.87 (2H, m), 1.76 (2H, m),
1.12 (6H, dd) Elemental analysis value (C ₂₅ H ₃₆ N ₂ O ₃・ HCl ・ 1 / 4H ₂ O) Calculated value: C, 66.21; H, 8.33; N, 6.18; Cl, 7.82 Measured value: C, 66.04; H, 8.29; N, 6.48; Cl, 7.99

Example 4 [3- (4-hydroxy-2-isopropyl-5-methylphenoxy) -1- {4- (2-methoxyphenyl)
Synthesis of Piperazino} propane Hydrochloride] 4- (4-Acetylamino-2-isopropyl-5-
Methylphenoxy) propyl chloride 10 g, 4- (2-
A mixture of 6.92 g of methoxyphenyl) piperazine hydrochloride, 4.98 g of potassium carbonate, 5.98 g of potassium iodide and 100 ml of N, N-dimethylformamide was stirred at 50 ° C. for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a pale brown oily substance. This oily substance was dissolved in ethanol, 8 ml of concentrated hydrochloric acid was added, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to give 3- (4-acetylamino-2-isopropyl-5- Methylphenoxy) -1-
11.8 g of {4- (2-methoxyphenyl) piperazino} propane dihydrochloride (colorless crystals) was obtained. NMR (DMSO-d ₆ ) δ: 11.64 (1H, br), 9.33 (1H, br), 7.07 (1H,
s), 6.99 (4H, m), 6.80 (1H, s), 4.05 (2H, m), 3.81 (3H, s), 3.5
5 (4H, m), 3.25 (7H, m), 2.28 (2H, m), 2.14 (3H, s), 2.02 (3H,
s), 1.14 (6H, d) 3- (4-acetylamino-2-isopropyl-5-
8 g of methylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} propane dihydrochloride are heated to reflux with 50 ml of dilute hydrochloric acid for 1 hour. The reaction solution was cooled to room temperature, made alkaline with sodium hydroxide, and extracted with diethyl ether. The extract was washed with water, dried and concentrated, and the residue was diluted with sulfuric acid.
A solution of 1.3 g of sodium nitrite in 30 ml of water in 50 ml at -5 ° C was added. After stirring for 30 minutes, 0.1 g of copper sulfate was added,
The mixture was heated to reflux until no gas was generated. The reaction solution was cooled to room temperature, made alkaline with sodium hydroxide, and carbon dioxide was introduced to obtain a white solid. The solid collected by filtration was dissolved in ethanol, 3 ml of concentrated hydrochloric acid was added, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to obtain 1.5 g of the title compound (colorless crystal). Melting point: 180 ° C (decomposition) IR (KBr) cm ^-1 : 3440,2970,2430,1615,1505,1455,1415,12
70,1200,1125,1065,1025,970,880,840,765 NMR (DMSO-d ₆ ) δ: 11.03 (1H, br), 8.70 (1H, s), 6.97 (4H, m),
6.68 (1H, s), 6.64 (1H, s), 3.94 (2H, t), 3.80 (3H, s), 3.53 (4
H, m), 3.05-3.30 (7H, m), 2.21 (2H, m), 2.07 (3H, s), 1.12 (6
H, dd) Elemental analysis (C ₂₄ H ₃₄ N ₂ O ₃・ HCl) Calculated: C, 66.27; H, 8.11; N, 6.44; Cl, 8.15 Found: C, 65.96; H, 8.15; N, 6.35; Cl, 8.30

Example 5 [Synthesis of 4- (4-hydroxy-2,3,5-trimethylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane dihydrochloride] 4- (4-acetoxy -2,3,5-Trimethylphenoxy) -1- {4-
(2-Methoxyphenyl) piperazino} butane hydrochloride
2 g was dissolved in 50 ml of methanol, 10 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to obtain 1.25 g of the title compound (colorless crystals). Melting point: 208-210 ℃ (decomposition) IR (KBr) cm ^-1 : 3420,2940,2420,1615,1490,1475,1300,12
75,1260,1210,1130,1095,1025,965,855,770 NMR (DMSO-d ₆ ) δ: 11.07 (1H, br), 6.97 (4H, m), 6.55 (1H, s),
3.87 (2H, t), 3.80 (3H, s), 3.51 (4H, m), 3.16 (6H, m), 2.13 (3
H, s), 2.08 (3H, s), 2.05 (3H, s), 1.92 (2H, m), 1.73 (2H, m) Elemental analysis value (C ₂₄ H ₃₃ N ₂ O ₃・ 2HCl ・ 1 / 4H ₂ O) Calculated: C, 60.69; H, 7.53; N, 5.90; Cl, 14.93 Found: C, 60.42; H, 7.75; N, 5.95; Cl, 14.60

Example 6 [Synthesis of 1- {4- (5-chloro-2-methylphenyl) piperazino} -3- (4-hydroxy-2,3,5-trimethylphenoxy) propane hydrochloride] 4- ( 4-
Acetoxy-2,3,5-trimethylphenoxy) propyl chloride 5.42 g, 4- (5-chloro-2-methylphenyl) piperazine 4.21 g, potassium carbonate 2.76 g, potassium iodide 3.3 g and N, N-dimethylformamide 30 ml.
The mixture was stirred at 50 ° C. for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. Wash the extract with water,
Dry and concentrate to give a pale brown oil. This oily substance was dissolved in 50 ml of methanol, 10 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to obtain 7.8 g of the title compound (colorless crystals). Melting point: 233-235 ° C (decomposition) IR (KBr) cm ^-1 : 3420,320,2930,2600,1600,1490,1475,144
5,1415,1335,1300,1250,1210,1130,1095,1040,1005,98
5,960,865 NMR (DMSO-d ₆ ) δ: 11.23 (1H, br), 7.67 (1H, br), 7.23 (1H,
d), 7.07 (1H, dd), 7.05 (1H, d), 6.57 (1H, br), 3.93 (2H, t),
3.56 (4H, m), 3.17-3.36 (6H, m), 2.24 (3H, s), 2.20 (2H, m),
2.14 (3H, s), 2.08 (3H, s), 2.07 (3H, s) Elemental analysis value (C ₂₃ H ₃₁ N ₂ O ₂ Cl ・ HCl) Calculated value: C, 62.87; H, 7.34; N, 6.38 ; Cl, 16.14 Found: C, 63.20; H, 7.37; N, 6.43; Cl, 16.45

Example 7 [Synthesis of 1- {4- (5-chloro-2-methylphenyl) piperazino} -4- (4-hydroxy-2,3,5-trimethylphenoxy) butane hydrochloride] 4- ( 4-acetoxy-2,3,5-trimethylphenoxy) butyl chloride 2.85 g, 4- (5-chloro-2-methylphenyl) piperazine 2.11 g, potassium carbonate 1.39 g, potassium iodide 1.66 g and N, N-dimethyl. A mixture of 30 ml of formamide was stirred at 50 ° C for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a pale brown oily substance. This oily substance was dissolved in 50 ml of methanol, 10 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was ethanol /
Recrystallization from diethyl ether gave 3.33 g of the title compound (colorless crystals). Melting point: 235 ~ 236 ℃ (decomposition) IR (KBr) cm ^-1 : 3300,2920,2550,2460,1590,1490,1475,14
10,1330,1300,1250,1130,1090,960,870,835 NMR (DMSO-d ₆ ) δ: 8.92 (1H, br), 7.22 (1H, d), 7.07 (1H, dd),
7.03 (1H, d), 6.54 (1H, s), 3.87 (2H, t), 3.52 (2H, m), 3.19 (6
H, m), 2.50 (2H, m), 2.23 (3H, s), 2.14 (3H, s), 2.08 (3H, s),
2.06 (3H, s), 1.93 (2H, m), 1.76 (2H, m) Elemental analysis value (C ₂₄ H ₃₃ N ₂ O ₂ Cl ・ HCl) Calculated value: C, 63.57; H, 7.56; N, 6.18 ; Cl, 15.64 Found: C, 63.43; H, 7.62; N, 6.17; Cl, 15.57

Example 8 [4- (2-formyl-4-hydroxyphenoxy)-
Synthesis of 1- {4- (2-methoxyphenyl) piperazino} butane hydrochloride] 4- {4-benzyloxy-2- (2,5-dioxolyl) phenoxy} butyl chloride 10.88 g, 4- (2-
A mixture of 6.86 g of methoxyphenyl) piperazine hydrochloride, 8.45 g of potassium carbonate, 4.98 g of potassium iodide and 30 ml of N, N-dimethylformamide was stirred at 50 ° C. for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a light brown oily product of 4- {4-benzyloxy-2- (2,5-dioxolyl) phenoxy} -1- {4- (2-methoxyphenyl) piperazino} butane 12.35. got g. NMR (DMSO-d ₆ ) δ: 7.38 (5H, m), 6.92 (7H, m), 5.98 (1H, s), 5.
03 (2H, s), 3.96 (6H, m), 3.76 (3H, s), 2.93 (4H, m), 2.50 (4H,
m), 2.36 (2H, t), 1.71 (2H, m), 1.11 (2H, m) 4- {4-benzyloxy-2- (2,5-dioxolyl) phenoxy} -1- {4- (2 To a solution prepared by dissolving 11.5 g of -methoxyphenyl) piperazino} butane in 40 ml of ethanol was added 1 g of 10% palladium / carbon, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure to give 4- {2- (2,5-dioxolyl) -4.
8.3 g of a light brown oily substance of -hydroxyphenoxy} -1- {4- (2-methoxyphenyl) piperazino} butane was obtained. NMR (DMSO-d ₆ ) δ: 8.98 (1H, s), 6.87 (6H, m), 6.69 (1H, dd),
5.93 (1H, s), 3.97 (6H, m), 3.76 (3H, s), 2.94 (4H, m), 2.50 (4
H, m), 2.33 (2H, t), 1.63 (4H, m) 4- {2- (2,5-dioxolyl) -4-hydroxyphenoxy} -1- {4- (2-methoxyphenyl)
To a solution of 7.5 g of piperazino} butane dissolved in 40 ml of ethanol was added 10 ml of concentrated hydrochloric acid, and the mixture was stirred under a nitrogen stream at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the residue was recrystallized from ethanol / diethyl ether to give the title compound (colorless crystals) 4.
79g was obtained. Melting point: 210 ° C (decomposition) IR (KBr) cm ^-1 : 3450,3140,2950,2700,2620,1675,1595,15
00,1455,1400,1275,1255,1225,1160,1120,1070,1030,98
0,935,895,830,750 NMR (DMSO-d ₆ ) δ: 11.03 (1H, br), 10.36 (1H, s), 9.52 (1H, b
r), 7.09 (3H, s), 6.96 (4H, m), 4.08 (2H, t), 3.79 (3H, s), 3.5
2 (4H, m), 3.14 (6H, m), 1.95 (2H, m), 1.82 (2H, m) Elemental analysis value (C ₂₂ H ₂₈ N ₂ O ₄・ HCl) Calculated value: C, 62.77; H , 6.94; N, 6.66; Cl, 8.42 Found: C, 62.46; H, 6.99; N, 6.57; Cl, 8.53

Example 9 [Synthesis of 4- (5-hydroxy-2-methoxycarbonylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane dihydrochloride] 4-benzyloxy-2-hydroxybenzoic acid Methyl acid
25.8 g, 17.3 ml of 1-bromo-4-chlorobutane and 27.6 g of anhydrous potassium carbonate were added to 100 m of N, N-dimethylformamide.
It was dissolved in 1 l and stirred at 50 ° C. for 10 hours under a nitrogen stream.
After the reaction, N, N-dimethylformamide was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution and then with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane), and 4-benzyloxy-2-
36.6 g of methyl (4-chlorobutoxy) benzoate was obtained. IR (KBr) cm ^-1 : 2950,1720,1610,1575,1505,1445,1380,12
80,1260,1190,1140,1095,1030,840,775,740,700 NMR (DMSO-d ₆ ) δ: 7.71 (d, 1H), 7.50-7.29 (5H), 6.74 (d, 1
H), 6.67 (dd, 1H), 5.17 (s, 2H), 4.06 (t, 2H), 3.74 (s, 3H), 3.
73 (t, 2H), 2.05-1.72 (4H) methyl 4-benzyloxy-2- (4-chlorobutoxy) benzoate 36.6 g, 1- (2-methoxyphenyl) piperazine hydrochloride 31.2 g and anhydrous potassium carbonate 34.5 g was dissolved in N, N-dimethylformamide, and under a nitrogen stream,
The mixture was heated and stirred at 50 ° C. for 10 hours. After the reaction, N, N-dimethylformamide was distilled off, water was added, and the mixture was acidified with dilute hydrochloric acid. The aqueous layer was washed with ethyl acetate and then neutralized with sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, the organic layer was water,
It was washed successively with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give oily 4- (5-benzyloxy-2-methoxycarbonylphenoxy) -1- {4- (2-methoxyphenyl). 25.0 g of piperazino} butane was obtained. Then
25.0 g of this oily substance was dissolved in methanol and subjected to hydrogenolysis for 15 hours at room temperature and atmospheric pressure using 10% palladium / carbon (1.5 g) as a catalyst. After the reaction, the catalyst was filtered and the solvent was distilled off.
The obtained oil was purified by silica gel column chromatography (ethyl acetate / n-hexane), the obtained oil was dissolved in methanol, hydrochloric acid was added, and the solvent was evaporated. The obtained solid was recrystallized from methanol / ethyl acetate / diethyl ether to give the title compound (14.5 g). Melting point: 190 ℃ (decomposition) IR (KBr) cm ^-1 : 3480,2950,2450,1720,1610,1520,1440,12
70,1230,1130,1090,840,755 NMR (DMSO-d ₆ ) δ: 11.15 (br, 1H), 7.62 (d, 1H), 7.11-6.85 (4
H), 6.54 (d, 1H), 6.44 (dd, 1H), 6.20 (bs, 2H), 4.00 (t, 2H),
3.80 (s, 3H), 3.75 (s, 1H), 3.65-3.35 (4H), 3.30-3.02 (4H),
2.06-1.69 (4H) Elemental analysis _{(C 23 H 30 N 2 O} 5 · 2HCl) theory: C, 56.68; H, 6.62 ; N, 5.75 Found: C, 56.39; H, 6.67 ; N, 5.99

Example 10 [4- (2-carboxy-5-hydroxyphenoxy)
Synthesis of -1- {4- (2-methoxyphenyl) piperazino} butane hydrochloride] 4-{(5-hydroxy-2-methoxycarbonyl) phenoxy} -1- {4- (2-methoxyphenyl) piperazino} butane 2.38 g was dissolved in 20 ml of methanol, 10 ml of 1N sodium hydroxide aqueous solution was added, and the mixture was heated under reflux for 5 hours. After the reaction, the solvent was distilled off, and hydrochloric acid was added to adjust the pH to 1. After standing overnight, the precipitated crystals were filtered off and dried. The crystals were recrystallized from a mixed solvent of methanol / ethyl acetate / diethyl ether to obtain 1.65 g of the title compound. Melting point: 189-190 ℃ IR (KBr) cm ^-1 : 3320,3220,2950,2740,1740,1620,1590,15
00,1475,1420,1250,1190,1130,1035,1020,1005,860,775 NMR (DMSO-d ₆ ) δ: 12.03 (br, 1H), 10.88 (br, 1H), 10.35 (s, 1
H), 7.63 (d, 1H), 7.10-6.85 (4H), 6.51 (d, 1H), 6.44 (dd, 1
H), 4.01 (t, 2H), 3.79 (s, 3H), 3.65-2.81 (8H), 2.08-1.64 (4
H) Elemental analysis value (C ₂₂ H ₂₈ N ₂ O ₅ .HCl ・ 1 / 4H ₂ O) Theoretical value: C, 59.86; H, 6.74; N, 6.35 Actual value: C, 59.84; H, 6.80; N, 6.34

Example 11 [Synthesis of 4- (4-hydroxy-2-methoxycarbonylphenoxy) -1- {4- (2-methoxyphenyl) piperazino} butane hydrochloride] 4- (4-benzyloxy-2-) Methoxycarbonylphenoxy) -1- {4
8 g of-(2-methoxyphenyl) piperazino} butane was dissolved in methanol and subjected to hydrogenolysis for 15 hours at room temperature and atmospheric pressure using 0.8% of 10% palladium / carbon as a catalyst. After the reaction,
The catalyst was filtered off and the solvent was distilled off. The obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane). The obtained oily substance was dissolved in methanol, hydrochloric acid was added, and the solvent was evaporated. The obtained solid was recrystallized from methanol / ethyl acetate / diethyl ether to give the title compound (5.9 g). Melting point: 155 ℃ (decomposition) IR (KBr) cm ^-1 : 3450,3170,2950,2640,1715,1610,1590,15
00,1445,1305,1275,1250,1220,1080,1035,1025,815,760 NMR (DMSO-d ₆ ) δ: 11.02 (br, 1H), 7.14-6.85 (m, 7H), 3.96
(t, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.67-3.32 (4H), 3.29-3.
00 (6H), 2.03-1.67 (4H) Elemental analysis value (C ₂₃ H ₃₀ N ₂ O ₅・ HCl ・ 5 / 4H ₂ O) Theoretical value: C, 58.35; H, 7.13; N, 5.92 Actual value: C , 58.33; H, 6.81; N, 6.05

Example 12 [4- (2-t-butyl-4-hydroxyphenoxy)-
Synthesis of 1- {4- (2-methoxyphenyl) piperazino} butane hydrochloride] 16.6 g of t-butylhydroquinone was added to 200 ml of methylene chloride.
The solution was dissolved in, and 13.9 ml of triethylamine was added. This solution was cooled to 0 ° C., and 11.6 ml of benzoyl chloride was added dropwise under a nitrogen stream. Then, it stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was recrystallized from a mixed solvent of ethyl acetate / n-hexane to obtain 23.1 g of 4-benzoyloxy-2-t-butylphenol. Melting point: 119-120 ℃ IR (KBr) cm ^-1 : 3450,2970,2920,1710,1605,1600,1590,15
20,1500,1460,1430,1395,1375,1325,1285,1265,1210,11
80,1130,1100,1080,1070,1030,930,900,820,790,720 NMR (DMSO-d ₆ ) δ: 9.50 (s, 1H), 8.18-8.08 (2H), 7.80-7.54
(3H), 7.02-6.81 (3H), 1.36 (s, 9H) 4-benzoyloxy-2-t-butylphenol 13.5
g was dissolved in 200 ml of acetone, 7.6 g of anhydrous potassium carbonate and 8.1 ml of 1-bromo-4-chlorobutane were added, and the mixture was heated under reflux for 20 hours under a nitrogen stream. After the reaction, the solvent was distilled off, diluted hydrochloric acid was added for neutralization, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained solid was recrystallized from benzene / n-hexane to give 4- (4
15.1 g of -benzoyloxy-2-t-butylphenoxy) butyl chloride was obtained. Melting point: 105-106 ℃ IR (KBr) cm ^-1 : 3480,2960,1740,1605,1500,1480,1460,14
20,1320,1275,1255,1195,1180,1085,1070,1030,900,81
5,745,715 NMR (DMSO-d ₆ ) δ: 8.23-8.07 (2H), 7.82-7.52 (3H), 7.17-6.
96 (3H), 4.06 (t, 2H), 3.75 (t, 2H), 2.08-1.84 (4H), 1.36 (s,
9H) 4- (4-benzoyloxy-2-t-butylphenoxy) butyl chloride (14.4 g) and 1- (2-methoxyphenyl) piperazine (16.2 g) were dissolved in 100 ml of toluene and heated under reflux for 20 hours under a nitrogen stream. After the reaction, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The obtained oily substance was dissolved in 50 ml of methanol, 20 ml of a 1N sodium hydroxide aqueous solution was added, and the mixture was heated under reflux for 2 hours. After the reaction, the solvent was distilled off, water was added, and the mixture was neutralized with dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate and washed with water and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. This was purified by silica gel column chromatography (ethyl acetate / n-hexane), the obtained oily substance was dissolved in methanol, hydrochloric acid was added, and the solvent was evaporated. The obtained solid was recrystallized from a mixed solvent of methanol / ethyl acetate / diethyl ether to obtain 14.9 g of the title compound. Melting point: 265-266 ℃ IR (KBr) cm ^-1 : 3450,3270,2940,2680,2610,1610,1595,15
10,1445,1410,1300,1260,1225,1120,1095,1025,980,93
5,880,790,760 NMR (DMSO-d ₆ ) δ: 8.79 (s, 1H), 7.03-6.83 (4H), 6.79 (d, 1
H), 6.64 (d, 1H), 6.46 (dd, 1H), 3.92 (t, 2H), 3.79 (s, 3H), 3.
62-3.39 (4H), 3.30-2.97 (6H), 2.00-1.71 (4H), 1.32 (s, 9H) Elemental analysis value (C ₂₅ H ₃₆ N ₂ O ₃ · HCl) Theoretical value: C, 66.87; H , 8.31; N, 6.24 Found: C, 66.55; H, 8.28; N, 6.20

Example 13 [4- (4-hydroxyphenoxy) -1- {4- (2
Synthesis of -methoxyphenyl) piperazino} butane dihydrochloride] 4- (4-benzyloxyphenoxy) -1-
{4- (2-Methoxyphenyl) piperazino} butane
5.2 g of dihydrochloride was dissolved in 100 ml of methanol, and hydrogenolysis was carried out for 3 hours at room temperature and normal pressure using 10% palladium / carbon 0.5 g as a catalyst. After the reaction, the catalyst was filtered off and the solvent was distilled off. The obtained solid was recrystallized from a mixed solvent of methanol / ethyl acetate / diethyl ether to obtain 2.9 g of the title compound. Melting point: 224 to 225 ℃ IR (KBr) cm ^-1 : 3220,2940,2620,2560,2430,1605,1505,14
75,1440,1355,1295,1265,1255,1245,1215,1030,1010,95
5,830,760,755 NMR (DMSO-d ₆ ) δ: 11.04 (br, 1H), 7.10-6.83 (4H), 6.77 (d, 2
H), 6.69 (d, 2H), 3.89 (t, 2H), 3.80 (s, 3H), 3.61-3.34 (4H),
3.29-3.30 (6H), 2.00-1.62 (4H ) Elemental analysis _{(C 21 H 28 N 2 O} 3 · 2HCl) theory: C, 58.74; H, 7.04 ; N, 6.52; Cl, 16.51 Found: C , 58.94; H, 7.07; N, 6.58; Cl, 16.42

Example 14 [3- (4-hydroxyphenoxy) -1- {4- (2
Synthesis of -methoxyphenyl) piperazino} propane hydrochloride] 3- (4-benzyloxyphenoxy) -1-
Dissolve 4.0 g of {4- (2-methoxyphenyl) piperazino} propane dihydrochloride in methanol / ethyl acetate,
Hydrogenolysis was carried out at room temperature and atmospheric pressure using 0% palladium / carbon (0.5 g) as a catalyst. After stirring for 2 hours, the catalyst was filtered off,
The solvent was distilled off. The obtained solid was recrystallized from methanol / ethyl acetate / diethyl ether to obtain 2.6 g of the title compound. Melting point: 216-218 ℃ IR (KBr) cm ^-1 : 3440,3350,3275,3025,2700,2660,2600,24
80,2420,1615,1600,1520,1475,1460,1445,1275,1260,12
45,1230,1130,1075,1065,1030,1020,980,955,935,835,8
15,775,760,755 NMR (DMSO-d ₆ ) δ: 11.39 (br, 1H), 7.15-6.66 (4H), 6.72 (dd,
4H), 3.96 (t, 2H), 3.80 (s, 3H), 3.70-3.35 (4H), 3.35-3.06
(6H), 2.21 (tt, 2H) Elemental analysis value (C ₂₀ H ₂₆ N ₂ O ₃ .HCl ・ 5 / 4H ₂ O) Theoretical value: C, 59.84; H, 7.41; N, 6.98 Actual value: C, 59.87; H, 7.03; N, 7.04

Example 15 [3- (2-carboxy-5-hydroxyphenoxy)]
Synthesis of -1- {4- (2-methoxyphenyl) piperazino} propane hydrochloride] 3-{(5-benzyloxy-
2-carboxy) phenoxy} -1- {4- (2-methoxyphenyl) piperazino} propane hydrochloride 6.1 g was dissolved in methanol 150 ml and 10% palladium / carbon 0.6 g
Was used as a catalyst, and hydrogenolysis was performed for 3 hours at room temperature and atmospheric pressure. After the reaction, the catalyst was filtered off and the solvent was distilled off. The obtained solid was recrystallized from a mixed solvent of methanol / ethyl acetate / n-hexane to give the title compound (2.8 g). Melting point: 208-209 ℃ IR (KBr) cm ^-1 : 3460,3330,3180,2930,2700,2620,1730,16
05,1590,1500,1475,1455,1420,1400,1390,1365,1325,12
70,1250,1225,1190,1115,1090,1055,1020,990,970,930,
890,765,760,735 NMR (DMSO-d ₆ ) δ: 12.25 (br, 1H), 11.80 (br, 1H), 10.48 (br,
1H), 7.66 (d, 1H), 7.10-6.85 (4H), 6.56 (d, 1H), 4.48 (dd, 1
H), 4.10 (2H), 3.80 (s, 3H), 3.75-3.00 (10H), 2.23 (dd, 2H) Elemental analysis value (C ₂₁ H ₂₆ N ₂ O ₅・ HCl) Theoretical value: C, 59.64; H, 6.44; N, 6.62 Found: C, 59.39; H, 6.51; N, 6.59

Example 16 [1- {4- (2-ethoxycarbonylphenyl) piperazino} -4- (4-hydroxyphenoxy) butane
Synthesis of Hydrochloride] A solution of 5.82 g of 4- (4-benzyloxyphenoxy) butyl chloride and 4.69 g of 1- (2-ethoxycarbonylphenyl) piperazine in N, N-dimethylformamide was added to anhydrous sodium carbonate 2.00 g and potassium iodide. 1.00 g was added, and the mixture was stirred under a nitrogen stream at room temperature for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate to obtain a crude product.
This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 7.70 g of a slightly yellow oily substance. NMR (CDCl ₃ ) δ: 7.70 (1H, dd) 7.38 (6H, m) 6.95 (6H, m) 5.0
1 (2H, s) 4.34 (2H, q) 3.94 (2H, t) 3.10 (4H, t) 2.63 (4H,
t) 2.46 (2H, t) 1.78 (4H, m) 1.39 (3H, t) 1.94 g of this oily substance was converted into a hydrochloride using concentrated hydrochloric acid according to a conventional method, and recrystallized from a mixed solvent of ethyl acetate / methanol. 4- (4-benzyloxyphenoxy) -1- {4-
There were obtained 1.41 g of (2-ethoxycarbonylphenyl) piperazino} butane hydrochloride (colorless crystals). Melting point: 110 ° C (decomposition) IR (KBr) cm ^-1 : 2930,2380,1700,1605,1500,1445,1295,12
75,1230,1070,1015,820,750,735,690 NMR (DMSO-d ₆ ) δ: 11.40 (1H, br), 7.70 (1H, dd), 7.45 (6H,
m), 7.18 (1H, t), 7.11 (1H, t), 6.91 (4H, d), 5.04 (2H, s), 4.2
8 (2H, q), 3.93 (2H, t), 3.60 (2H, br), 3.40-3.00 (8H, br), 1.
91 (2H, m), 1.76 (2H, m), 1.31 (3H, t) Elemental analysis value (C ₃₀ H ₃₆ N ₂ O ₄・ 2HCl ・ 1 / 2H ₂ O) Theoretical value: C, 63.15; H, 6.89; N, 4.91; Cl, 12.43 Found: C, 62.98; H, 6.87; N, 4.99; Cl, 12.34 4- (4-benzyloxyphenoxy) -1- {4-
0.5 g of 10% palladium / carbon was added to 130 ml of a methanol solution of 5.76 g of (2-ethoxycarbonylphenyl) piperazino} butane, and the mixture was reduced in a hydrogen atmosphere for 5 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain 4.03 g of a colorless oily substance. NMR (CDCl ₃ ) δ: 7.72 (1H, dd), 7.41 (1H, td), 7.03 (2H, m), 6.
72 (4H, s), 4.35 (2H, q), 3.88 (2H, t), 3.11 (4H, t), 2.67 (4H,
t), 2.50 (2H, t), 1.75 (4H, m), 1.39 (3H, t) 1.68 g of this oily substance was converted into a hydrochloride using concentrated hydrochloric acid according to a conventional method, and re-converted from an ethanol / ether mixed solvent. The crystals were crystallized to obtain 1.73 g of the title compound (colorless crystals). Melting point: 196-198 ℃ IR (KBr) cm ^-1 : 3220,2925,2675,2590,2450,1720,1690,15
95,1505,1440,1295,1270,1225,1110,925 830,765 NMR (DMSO-d ₆ ) δ: 11.20 (1H, br), 9.00 (1H, br), 7.71 (1H, d
d), 7.52 (1H, td), 7.14 (1H, t), 7.11 (1H, t), 6.73 (4H, m), 4.
29 (2H, q), 3.89 (2H, t), 3.60-3.00 (10H, m), 2.00-1.60 (4H,
m), 1.31 (3H, t) Elemental analysis value (C ₂₃ H ₃₀ N ₂ O ₄ · HCl) Theoretical value: C, 63.51; H, 7.18; N, 6.44; Cl, 8.15 Found value: C, 63.36; H , 7.27; N, 6.73; Cl, 8.35

Example 17 [4- (4-acetoxyphenoxy) -1- {4- (2
-Ethoxycarbonylphenyl) piperazino} butane
Synthesis of hydrochloride] 1- {4- (2-ethoxycarbonylphenyl) piperazino} -4- (4-hydroxyphenoxy) butane 2.35 g of methylene chloride solution 50 ml of pyridine 1.
0 ml and acetic anhydride 1.0 ml were added, and the mixture was stirred at room temperature for 16 hours. The solution was washed with water and the solvent was distilled off to obtain 2.69 g of a brown oily substance. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 2.52 g of a slightly yellow oily substance. NMR (CDCl ₃ ) δ: 7.73 (1H, dd), 7.41 (1H, dt), 7.00 (4H, m), 6.
88 (2H, m), 4.35 (2H, q), 3.96 (2H, t), 3.13 (4H, t), 2.73 (4H,
t), 2.58 (2H, t), 2.27 (3H, s), 1.95-1.65 (4H, m), 1.39 (3H,
t) This oily substance, 1.94 g, was converted into a hydrochloride using concentrated hydrochloric acid by a conventional method, and this was recrystallized from a mixed solvent of ethyl acetate / methanol to obtain 2.35 g of the title compound (colorless crystals). Melting point: 126-128 ℃ IR (KBr) cm ^-1 : 2945,2650,2570,2425,1740,1695,1590,15
00,1475,1440,1365,1290,1270,1220 1185,1085,1020,93
0,765 NMR (DMSO-d ₆ ) δ: 11.40 (1H, br), 7.72 (1H, dd), 7.53 (1H, d)
t), 7.25-6.95 (6H, m), 4.29 (2H, q), 4.01 (2H, t), 3.63-2.97
(10H, m), 2.24 (3H, s), 2.05-1.70 (4H, m), 1.32 (3H, t) Elemental analysis value (C ₂₅ H ₃₂ N ₂ O ₅ · HCl) Theoretical value: C, 62.95; H, 6.97; N, 5.87; Cl, 7.43 Found: C, 62.97; H, 7.09; N, 5.94; Cl, 7.64

Example 18 [4- (4-benzoyloxy-2-t-butylphenoxy) -1- {4- (2-ethoxycarbonylphenyl)
Synthesis of piperazino} butane hydrochloride] 4- (4-benzoyloxy-2-t-butylphenoxy) butyl chloride
40 ml of a solution of 5.05 g and 3.30 g of 1- (2-ethoxycarbonylphenyl) piperazine in N, N-dimethylformamide
To this, 1.93 g of anhydrous potassium carbonate and 1.66 g of potassium iodide were added, and the mixture was stirred at 60 ° C. for 16 hours under a nitrogen stream. The reaction solution was poured into ice water and extracted with ethyl acetate to obtain a crude product.
This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 6.46 g of a slightly yellow oily substance. NMR (CDCl ₃ ) δ: 8.20 (2H, d), 7.75-7.35 (5H, m), 7.10-6.83
(5H, m), 4.37 (2H, q), 4.02 (2H, t), 3.13 (4H, t), 2.64 (4H,
t), 2.50 (2H, t), 2.05-1.67 (4H, m), 1.40 (9H, s), 1.39 (3H,
t) 1.71 g of this oily substance was converted into a hydrochloride using concentrated hydrochloric acid according to a conventional method, and this was recrystallized from a mixed solvent of ethyl acetate / ether to obtain 1.53 g of the title compound (colorless crystals). Melting point: 111 ° C (decomposition) IR (KBr) cm ^-1 : 3430,2950,1720,1590,1480,1440,1260,12
30,1180,1075,1060,1020,710 NMR (DMSO-d ₆ ) δ: 1130 (1H, br), 8.12 (2H, d), 7.80-7.45 (5
H, m), 7.23-7.00 (5H, m), 4.29 (2H, q), 4.08 (2H, t), 3.65-2.
95 (10H, m), 2.10-1.80 (4H, m), 1.38 (9H, s), 1.32 (3H, t) Elemental analysis _{(C 34 H 42 N 2 O} 5 · HCl · H 2 O) theory : C, 66.60; H, 7.40; N, 4.57 Actual value: C, 66.53; H, 7.37; N, 4.63

Example 19 [4- (2-t-Butyl-4-hydroxyphenoxy)-
Synthesis of 1- {4- (2-ethoxycarbonylphenyl) piperazino} butane hydrochloride] 4- (4-benzoyloxy-2-t-butylphenoxy) -1- {4- (2-ethoxycarbonylphenyl) piperazino} Butane 4.55g
2.0 ml of 25% aqueous ammonia was added to 30 ml of the methanol solution of and the mixture was stirred at room temperature for 4 days. After distilling off methanol and extracting with ethyl acetate, the solvent was distilled off under reduced pressure to obtain a crude product 4.20.
got g. This was purified by silica gel column chromatography (benzene / ethyl acetate) to give a colorless oil 3.14.
got g. NMR (CDCl ₃ ) δ: 7.72 (1H, dd), 7.38 (1H, dt), 7.00 (2H, m), 6.
78 (1H, d), 6.66 (1H, d), 6.55 (1H, dd), 4.35 (2H, q), 3.89 (2
H, t), 3.13 (4H, t), 2.71 (4H, t), 2.53 (2H, t), 1.95-1.65 (4
(H, m), 1.39 (3H, t), 1.32 (9H, s) 3.14 g of this oily substance was converted into a hydrochloride using concentrated hydrochloric acid according to a conventional method, and recrystallized from an ethanol / ether mixed solvent to give the title compound ( 2.87 g of colorless crystals were obtained. Melting point: 145 ° C (decomposition) IR (KBr) cm ^-1 : 3120,2945,2560,1705,1585,1485,1430,12
15,1080,930 NMR (DMSO-d ₆ ) δ: 11.00 (1H, br), 8.80 (1H, s), 7.71 (1H, d
d), 7.52 (1H, dt), 7.16 (1H, t), 7.12 (1H, t), 6.78 (1H, d), 6.
69 (1H, d), 6.54 (1H, dd), 4.28 (2H, q), 3.92 (2H, t), 3.65-2.
95 (10H, m), 2.05-1.70 (4H, m), 1.32 (12H, m) Elemental analysis value (C ₂₇ H ₃₈ N ₂ O ₄・ HCl ・ 1 / 2H ₂ O) Theoretical value: C, 64.85; H, 8.06; N, 5.60; Cl, 7.09 Found: C, 64.94; H, 8.23; N, 5.64; Cl, 7.22

Example 20 [4- (4-acetoxy-2-t-butylphenoxy)-
Synthesis of 1- {4- (2-ethoxycarbonylphenyl) piperazino} butane dihydrochloride] 4- (2-t-butyl-
4-hydroxyphenoxy) -1- {4- (2-ethoxycarbonylphenyl) piperazino} butane hydrochloride 1.
A mixed solution of 00 g, 1.0 ml of pyridine and 1.0 ml of acetic anhydride was stirred at room temperature for 3 days. After adding water to this solution and extracting with ethyl acetate, the solvent was distilled off to obtain a brown oily substance. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 0.38 g of a colorless oily substance. NMR (CDCl ₃ ) δ: 7.70 (1H, dd), 7.43 (1H, m), 7.10-6.78 (5H,
m), 4.35 (2H, q), 3.99 (2H, t), 3.10 (4H, t), 2.63 (4H, t), 2.5
1 (2H, t), 2.27 (3H, s), 2.05-1.65 (4H, m), 1.39 (3H, t), 1.38
(9H, s) 0.38 g of this oily substance was dissolved in ether, and the hydrochloride was converted to the hydrochloride using 20% ethanolic hydrochloric acid. The title compound (colorless crystals) 0.40
got g. Melting point: 108 ° C (decomposition) IR (KBr) cm ^-1 : 2950,2500,1755,1695,1485,1440,1360,12
80,1210,1180,1080,1000,755,690 NMR (DMSO-d ₆ ) δ: 11.30 (1H, br), 7.65 (1H, dd), 7.47 (1H, d
t), 7.16 (1H, t), 7.12 (1H, t), 7.04-6.88 (3H, m), 4.28 (2H,
q), 4.04 (2H, t), 3.62-2.95 (10H, m), 2.23 (3H, s), 2.10-1.7
5 (4H, m), 1.35 (9H, s), 1.31 (3H, t) Elemental analysis value (C ₂₉ H ₄₀ N ₂ O ₅・ 2HCl ・ H ₂ O) Theoretical value: C, 59.28; H, 7.55; N, 4.77; Cl, 12.07 Found: C, 59.53; H, 7.57; N, 4.86; Cl, 11.76

Example 21 [Synthesis of 4- (4-hydroxyphenoxy) -1- (4-phenylpiperazino) butane hydrochloride] 2.91 g of 4- (4-benzyloxyphenoxy) butyl chloride and 1-phenylpiperazine 20 ml of 1.62 g of N, N-dimethylformamide solution was added with 1.38 g of anhydrous potassium carbonate.
g and 1.66 g of potassium iodide were added, and the mixture was stirred under a nitrogen stream at 50 ° C. for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate to obtain a crude product. This was purified by silica gel column chromatography (benzene / ethyl acetate),
Obtained 3.67 g of 4- (4-benzyloxyphenoxy) -1- (4-phenylpiperazino) butane (light yellow solid). IR (KBr) cm ^-1 : 3025,2950,2905,1590,1502,1230,1000,82
0,760,745,690 NMR (CDCl ₃ ) δ: 7.50-7.20 (7H, m), 7.00-6.75 (7H, m), 5.00
(2H, s), 3.93 (2H, t), 3.20 (4H, t), 2.61 (4H, t), 2.45 (2H,
t), 1.90-1.60 (4H, m) 4- (4-benzyloxyphenoxy) -1- (4-
Phenylpiperazino) butane 3.50g in methanol 50
Add 10% palladium / carbon 0.3g to ml and under hydrogen atmosphere 1
Reduced for 6 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethanol to obtain 1.75 g of the title compound (colorless needle crystals). IR (KBr) cm ^-1 : 2950,2825,2580,1600,1500,1460,1440,13
75,1230,990,915,815,755,680,515 NMR (DMSO-d ₆ ) δ: 8.88 (1H, s), 7.20 (2H, t), 6.90 (2H, d), 6.
83-6.65 (5H, m), 3.87 (2H, t), 3.10 (4H, t), 2.50 (4H, t), 2.3
7 (2H, t), 1.80-1.50 (4H, m) 1.68g of this crystal was converted into hydrochloride using concentrated hydrochloric acid according to the usual method, and recrystallized from ethanol / ether mixed solvent to give 0.65g of colorless needle crystal. Obtained. Melting point: 237-238 ° C (decomposition) IR (KBr) cm ^-1 : 3125,2910,2660,2575,2450,1600,1505,14
40,1230,1210,1020,820,765,760,690 NMR (DMSO-d ₆ ) δ: 11.10 (1H, br), 8.99 (1H, s), 7.26 (2H, t),
7.00 (2H, d), 6.93-6.65 (5H, m), 4.00-3.00 (12H, m), 2.05-
1.65 (4H, m) Elemental analysis value (C ₂₀ H ₂₆ N ₂ O ₂ · HCl) Theoretical value: C, 66.19; H, 7.50; N, 7.72 Actual value: C, 65.13; H, 7.50; N, 7.71

Example 22 [Synthesis of 4- (4-acetoxyphenoxy) -1- (4-phenylpiperazino) butane hydrochloride] 4- (4-hydroxyphenoxy) -1- (4-phenylpiperazino) )
A mixed solution of 0.79 g of butane, 1.0 ml of pyridine and 1.0 ml of acetic anhydride was stirred at room temperature for 16 hours. After adding water to this solution and extracting with ethyl acetate, the solvent was distilled off to obtain a brown oily substance. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 0.80 g of colorless needle crystals. IR (KBr) cm ^-1 : 3060,2940,2810,1745,1590,1495,1460,13
70,1215,1195,1180,760,690 NMR (DMSO-d ₆ ) δ: 7.20 (2H, t), 7.10-6.85 (6H, m), 6.76 (1H,
t), 3.99 (2H, t), 3.11 (4H, t), 2.50 (4H, t), 2.38 (2H, t), 2.2
3 (3H, s), 1.85-1.50 (4H, m) 0.80 g of this needle crystal was converted to a hydrochloride by a conventional method using concentrated hydrochloric acid, and recrystallized from a mixed solvent of ether / ethanol to give the title compound (colorless needle). C.) 0.76 g was obtained. Melting point: 184-187 ℃ IR (KBr) cm ^-1 : 2940,2580,1740,1600,1500,1220,1195,75
5,685 NMR (DMSO-d ₆ ) δ; 11.00 (1H, br), 7.28 (2H, t), 7.10-6.80 (7
H, m), 4.00 (2H, t), 3.90-3.00 (10H, m), 2.24 (3H, s), 2.05-
1.70 (4H, m) Elemental analysis _{(C 22 H 28 N 2 O} 3 · HCl) theory: C, 66.19; H, 7.50 ; N, 7.72; Cl, 9.77 Found: C, 66.13; H, 7.52 ; N, 7.74; Cl, 9.96

Example 23 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-carbamoylphenyl) piperazino} butane hydrochloride] 4- (4-acetoxy- 2,3,5-trimethylphenoxy) butyl chloride 2.85 g and 1- (2-carbamoylphenyl) piperazine 2.05 g in an N, N-dimethylformamide solution 30 ml,
Anhydrous potassium carbonate (1.38 g) and potassium iodide (1.66 g) were added, and the mixture was stirred under a nitrogen stream at 50 ° C for 16 hours. The reaction solution
It was poured into ice water and extracted with ethyl acetate to obtain a crude product. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 2.09 g of a slightly yellow solid. IR (KBr) cm ^-1 : 3395,3160,2950,2815,1750,1660,1585,14
50,1370,1220,1190,1120 NMR (DMSO-d ₆ ) δ: 8.58 (1H, br), 7.75 (1H, dd), 7.53 (1H, b
r), 7.42 (1H, dt), 7.20 (1H, d), 7.14 (1H, t), 6.71 (1H, s), 3.
96 (2H, t), 2.93 (4H, t), 2.65-2.25 (6H, m), 2.30 (3H, s), 2.0
6 (3H, s), 2.04 (3H, s), 1.96 (3H, s), 1.85-1.50 (4H, m) 2.09 g of this solid was converted to hydrochloric acid salt using concentrated hydrochloric acid according to a conventional method, and ethanol / The crystals were recrystallized from an ether mixed solvent to obtain 2.13 g of the title compound (colorless crystals). Melting point: 201-202 ℃ IR (KBr) cm ^-1 : 3400,2950,2510,2450,1740,1650,1580,14
80,1445,1370,1210,1190,1105 NMR (DMSO-d ₆ ) δ: 11.20 (1H, br), 8.05 (1H, br), 7.65 (1H,
d), 7.60-7.37 (2H, m), 7.22-7.08 (2H, m), 6.72 (1H, s), 3.98
(2H, t), 3.65-3.10 (10H, m), 2.31 (3H, s), 2.09 (3H, s), 2.05
(3H, s), 1.97 ( 3H, s), 2.10-1.70 (4H, m) Elemental analysis _{(C 26 H 35 N 3 O} 4 · HCl · H 2 O) theory: C, 61.47; H, 7.54 ; N, 8.27; Cl, 6.98 Found: C, 61.62; H, 7.55; N, 8.29; Cl, 7.12

Example 24 [4- (2-t-butyl-4-hydroxyphenoxy)-
Synthesis of 1- {4- (2-chlorophenyl) piperazino} butane hydrochloride] 4- (4-benzoyloxy-2-t-butylphenoxy) butyl chloride 7.22 g and 1- (2-chlorophenyl) piperazine hydrochloride 4.66 g 2.76 g of anhydrous potassium carbonate and 3.32 g of potassium iodide were added to 60 ml of the N, N-dimethylformamide solution of, and the mixture was stirred at 60 ° C. for 16 hours under a nitrogen stream. The reaction solution was poured into ice water and extracted with ethyl acetate to obtain a crude product. This was purified by silica gel column chromatography (benzene / ethyl acetate), and 1- (4-
Benzoyloxy-2-t-butylphenoxy) -4-
8.06 g of {4- (2-chlorophenyl) piperazino)} butane (light yellow oil) was obtained. NMR (CDCl ₃ ) δ: 8.21 (2H, d), 7.70-6.85 (10H, m), 4.06 (2H,
t), 3.12 (4H, t), 2.68 (4H, t), 2.52 (2H, t), 2.03-1.68 (4H,
m), 1.40 (9H, s) 1- (4-benzoyloxy-2-t-butylphenoxy) -4- {4- (2-chlorophenyl) piperazino}
Potassium hydroxide was added to 130 ml of methanol solution containing 8.00 g of butane.
3.00 g was added, and the mixture was stirred at 60 ° C for 2 hours. Methanol was distilled off, water was added, the mixture was extracted with ethyl acetate, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 4.09 g of a colorless solid. NMR (CDCl ₃ ) δ: 7.36 (1H, dd), 7.20 (1H, dt), 7.10-6.90 (2H,
m), 6.78 (1H, d), 6.70-6.50 (2H, m), 3.90 (2H, t), 3.12 (4H,
t), 2.71 (4H, t), 2.54 (2H, t), 2.00-1.65 (4H, m), 1.34 (9H,
s) 4.09 g of this solid was converted into a hydrochloride using concentrated hydrochloric acid according to a conventional method, and this was recrystallized from a mixed solvent of ethanol / ether to obtain 3.64 g of the title compound (colorless needle crystals). Melting point: 228-229 ℃ (decomposition) IR (KBr) cm ^-1 : 3190,2950,2660,2580,2440,1580,1475,14
35,1210,1080,1035 NMR (DMSO-d ₆ ) δ: 11.10 (1H, br), 8.80 (1H, br), 7.50-7.05
(4H, m), 6.85-6.50 (3H, m), 3.92 (2H, t), 3.70-3.00 (10H,
m), 2.05-1.70 (4H, m), 1.32 (9H, s) Elemental analysis value (C ₂₄ H ₃₃ N ₂ O ₂ Cl ・ HCl) Theoretical value: C, 63.57; H, 7.56; N, 6.18; Cl , 15.64 Found: C, 63.75; H, 7.49; N, 6.24; Cl, 15.68

Example 25 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-ethoxycarbonylphenyl) piperazino} butane dihydrochloride] 4- (4-
0.69 g of anhydrous potassium carbonate was added to 30 ml of a solution of 2.85 g of acetoxy-2,3,5-trimethylphenoxy) butyl chloride and 2.50 g of 1- (2-ethylcarbonylphenyl) piperazine in N, N-dimethylformamide. The mixture was stirred at 50 ° C for 24 hours. The reaction solution was poured into ice water and extracted with ethyl acetate to obtain a crude product. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 2.47 g of a pale yellow oily substance. This oil 2.47
g was converted to a hydrochloride using concentrated hydrochloric acid by a conventional method, and recrystallized from an ethanol / ether mixed solvent to obtain 1.35 g of the title compound (colorless crystals). Melting point: 142 ° C (decomposition) IR (KBr) cm ^-1 : 2930,2650,2500,2425,1745,1705,1610,14
40,1365,1300,1210,1195,1110,1070,995,750 NMR (DMSO-d ₆ ) δ: 11.10 (1H, br), 7.70 (1H, dd), 7.52 (1H, t
d), 7.18 (1H, td), 7.11 (1H, dd), 6.73 (1H, s), 4.28 (2H, q),
3.97 (2H, t), 3.56 (2H, m), 3.50-3.00 (8H, m), 2.31 (3H, s),
2.09 (3H, s), 2.05 (3H, s), 1.97 (3H, s), 2.10-1.70 (4H, m),
1.31 (3H, t) Elemental analysis value (C ₂₈ H ₃₈ N ₂ O ₅・ 2HCl ・ 3 / 2H ₂ O) Theoretical value: C, 57.73; H, 7.44; N, 4.81 Actual value: C, 57.81; H, 7.12; N, 4.98

Example 26 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-nitrophenyl) piperazino} butane hydrochloride] 4- (4-acetoxy- 2,3,5-Trimethylphenoxy) butyl chloride (34.1 g) and benzylpiperazine (42.3 g) were mixed and stirred at 100 ° C. for 13 hours. After the reaction,
Ethyl acetate and water were added for extraction, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The crude product was purified by silica gel chromatography (ethyl acetate / benzene) to give 1- {4-
45.8 g of (4-acetoxyphenoxy-2,3,5-trimethylphenoxy) butyl} -4-benzylpiperazine (colorless oil) was obtained. 1- {4- (4-acetoxy-2,3,5-trimethylphenoxy) butyl} -4-benzylpiperazine 45.8
g was dissolved in 200 ml of methanol and 10% palladium / carbon was added.
4.0 g was added and the reaction was carried out in a hydrogen atmosphere for 14 hours. After the reaction, the catalyst was filtered and the solvent was distilled off to obtain 36.4 g of 1- (4-acetoxy-2,3,5-trimethylphenoxy) -4-piperazinobutane. 36.4 g of 1- (4-acetoxy-2,3,5-trimethylphenoxy) -4-piperazinobutane and 17.7 g of 2-nitrochlorobenzene were dissolved in 150 ml of toluene and refluxed for 3 hours. Water was added to the reaction solution and neutralized with anhydrous potassium carbonate, followed by extraction with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The crude product was purified by silica gel chromatography (ethyl acetate / benzene) to give a yellow oil (9.74 g). 1.
37 g was taken, dissolved in methanol, 0.25 ml of concentrated hydrochloric acid was added, and the mixture was dried under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound (1.07 g). Melting point; 174 ° C or higher (decomposition) IR (KBr) cm ^-1 : 3450,3025,2940,2580,1760,1605,1530,14
70,1875,1230,1205,1125,1085,855 NMR (DMSO-d ₆ ) δ: 11.30 (1H, br), 7.91 (1H, dd), 7.67 (1H, d
t), 7.40 (1H, dd), 7.25 (1H, dt), 6.72 (1H, s), 3.97 (2H, t),
3.15-3.00 (10H, m), 2.31 (3H, s), 2.09 (3H, s), 2.05 (3H, s),
1.97 (3H, s), 2.10-1.70 (4H, m) Elemental analysis value (C ₂₅ H ₃₃ N ₃ O ₅ · HCl) Theoretical value: C, 61.03; H, 6.97; N, 8.54; Cl, 7.21 Measured value : C, 60.75; H, 6.88; N, 8.60; Cl, 7.49

Example 27 [4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-acetylaminophenyl))
Synthesis of piperazino} butane hydrochloride] 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-nitrophenyl) piperazino} butane 9.20 g was dissolved in 100 ml of methanol to obtain 10%. Add 1.0 g of palladium / carbon and add 4 at room temperature under hydrogen atmosphere.
Allowed to react for hours. After the reaction, the catalyst was filtered and the solvent was distilled off under reduced pressure to give 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-aminophenyl).
8.11 g of piperazino} butane (colorless oily substance) was obtained. 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2-aminophenyl) piperazino} butane (6.78 g) was dissolved in 100 ml of methylene chloride and stirred at 0 ° C. 2.55 g acetic acid and 1.
98 g was added dropwise and stirring was continued for 2 hours. After the reaction, add water,
It was extracted with methylene chloride. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained product was purified by silica gel chromatography (ethyl acetate / methylene chloride) to obtain 3.54 g of a colorless oil. Dissolve this in methanol and add concentrated hydrochloric acid 0.
63 ml was added, dried under reduced pressure and recrystallized from methanol / ethanol to obtain the title compound. Melting point: 236.6-238.4 ℃ IR (KBr) cm ^-1 : 3400,2960,2570,2475,2360,1750,1690,15
90,1510,1445,1210,1195,1125,770 NMR (DMSO-d ₆ ) δ: 11.35 (1H, br), 8.92 (1H, s), 7.95 (1H, m),
7.11 (3H, m), 6.73 (1H, s), 3.99 (2H, t), 3.55 (2H, br), 3.50-
3.05 (8H, m), 2.31 (3H, s), 2.15 (3H, s), 2.10 (3H, s), 2.05 (3
H, s), 1.97 (3H, s), 2.10-1.75 (4H, m) Elemental analysis value (C ₂₇ H ₃₇ N ₃ O ₄・ HCl) Theoretical value: C, 64.34; H, 7.60; N, 8.34; Cl, 7.03 Found: C, 64.06; H, 7.85; N, 8.20; Cl, 6.94

Example 28 [4- (4-acetoxy-2-t-butylphenoxy)-
Synthesis of 1- {4- (2-chlorophenyl) piperazino} butane hydrochloride] 4- (2-t-butyl-4-hydroxyphenoxy) -1- {4- (2-chlorophenyl) piperazino} butane 1.71 g, pyridine 30.0 ml, acetic anhydride 10.0
The mixed solution of ml was stirred at 60 ° C. for 16 hours. After adding water to this solution and extracting with ethyl acetate, the solvent was distilled off to obtain a brown oily substance. This was purified by silica gel column chromatography (benzene / ethyl acetate) to give a colorless oil.
Obtained 1.52 g. NMR (CDCl ₃ ) δ: 7.40-6.80 (7H, m), 4.03 (2H, t), 3.10 (4H,
t), 2.65 (4H, t), 2.52 (2H, t), 2.27 (3H, s), 2.00-1.65 (4H,
m), 1.38 (9H, s) 1.52 g of this oily substance was converted into a hydrochloride using concentrated hydrochloric acid according to a conventional method, and this was recrystallized from an ethanol / ether mixed solvent to obtain 1.35 g of the title compound (colorless crystal). Melting point: 214 ~ 216 ℃ IR (KBr) cm ^-1 : 2950,2870,2660,2435,1755,1580,1480,12
10,1180,1030,940,760 NMR (DMSO-d ₆ ) δ: 11.05 (1H, br), 7.50-6.85 (7H, m), 4.03 (2
H, t), 3.70-3.10 (10H, m), 2.23 (3H, s), 2.10-1.75 (4H, m),
1.35 (9H, s) Elemental analysis _{(C 26 H 35 N 2 O} 3 Cl · HCl) theory: C, 63.03; H, 7.32 ; N, 5.65; Cl, 14.31 Found: C, 62.82; H, 7.24 ; N, 5.70; Cl, 14.34

Example 29 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (4-fluorophenyl) piperazino} butane dihydrochloride] 4- (4-acetoxy -2,3,5-Trimethylphenoxy) butyl chloride
2.00 g and 1- (4-fluorophenyl) piperazine 1.27
0.96 g of anhydrous potassium carbonate and 1.16 g of potassium iodide were added to 30 ml of a g solution of N, N-dimethylformamide, and the mixture was stirred at 50 ° C. for 16 hours under a nitrogen stream. The reaction solution was poured into ice water and extracted with ethyl acetate to obtain a crude product. This was purified by silica gel column chromatography (benzene / ethyl acetate) to obtain 2.09 g of a slightly yellow solid. NMR (CDCl ₃ ) δ: 7.03-6.80 (4H, m), 6.55 (1H, s), 3.96 (2H,
t), 3.15 (4H, t), 2.63 (4H, t), 2.48 (2H, t), 2.32 (3H, s), 2.1
3 (3H, s), 2.11 (3H, s), 2.05 (3H, s), 1.95-1.65 (4H, m) 2.09 g of this solid was converted to a hydrochloride using concentrated hydrochloric acid according to a conventional method, and this was converted from methanol. The crystals were recrystallized to obtain 1.47 g of the title compound (colorless crystals). Melting point: 207 to 208 ℃ (decomposition) IR (KBr) cm ^-1 : 2930,2375,1750,1510,1230,1195,1120,84
5 NMR (DMSO-d ₆ ) δ: 11.20 (1H, br), 7.20-6.97 (4H, m), 6.72 (1
H, s), 3.96 (2H, t), 3.80-3.50 (4H, m), 3.30-3.05 (6H, m), 2.
31 (3H, s), 2.09 (3H, s), 2.05 (3H, s), 1.97 (3H, s), 2.10-1.7
0 (4H, m) Elemental analysis value (C ₂₅ H ₃₃ N ₂ O ₃ F ・ 2HCl ・ 1 / 2H ₂ O) Theoretical value: C, 58.82; H, 7.11; N, 5.49; Cl, 13.89; F, 3.72 Found: C, 58.65; H, 7.21; N, 5.78; Cl, 13.52; F, 3.83.

Example 30 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (2,4-dimethylphenyl) piperazino} butane hydrochloride] 4-acetoxy-
[1- (4-chlorobutoxy)]-2,3,5-trimethylbenzene 5.7 g and 1- (2,4-dimethylphenyl)
Piperazine (4.8 g) and anhydrous potassium carbonate (3.5 g) were dissolved in N, N-dimethylformamide (50 ml), and the mixture was stirred at 50 ° C for 15 hr under a nitrogen stream. After the reaction, N, N-dimethylformamide was distilled off and the residue was dissolved in ethyl acetate. Water was added, and the organic layer was washed, further washed with 0.1N sodium hydroxide aqueous solution and then with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain an oily substance. This oily substance was dissolved in methanol, and 20% ethanolic hydrochloric acid was added. Evaporate the solvent,
The solid obtained was methanol / ethyl acetate / diethyl ether.
Recrystallization from a tellur mixed solvent gave 4.8 g of the title compound. Melting point: 210 ° C (decomposition) IR (KBr) cm ^-1 : 3470,2940,2520,1760,1620,1500,1475,14
45,1380,1330,1225,1200,1120,1080,1010,900 NMR (DMSO-d ₆ ) δ: 11.34 (br, 1H), 7.04-6.90 (3H), 6.74 (s, 1
H), 3.98 (t, 2H), 3.32-3.05 (8H), 3.44 (t, 2H), 2.32 (s, 3H),
2.24 (s, 6H), 2.10 (s, 3H), 2.06 (s, 3H), 1.98 (s, 3H) 1.96-1.
71 (4H) Elemental analysis value (C ₂₇ H ₃₈ N ₂ O ₃・ HCl ・ 3 / 4H ₂ O) Theoretical value: C, 66.38; H, 8.36; N, 5.73 Actual value: C, 66.55; H, 8.28; N, 5.80

Example 31 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (4-nitrophenyl) piperazino} butane] 4-acetoxy-1- (4- Chlorobutoxy) -2,3,5-trimethylbenzene 71.2g, 1- (4-nitrophenyl) piperazine 64.8g and anhydrous potassium carbonate 41.4g were added to N, N-dimethylformamide 500m.
It was dissolved in 1 l and stirred under a nitrogen stream at 50 ° C. for 15 hours.
After the reaction, N, N-dimethylformamide was distilled off and the residue was dissolved in ethyl acetate. Water was added, the organic layer was washed, and then washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain a solid. The obtained solid is ethyl acetate / n
Recrystallization from a mixed solvent of hexane gave 85.9 g of the title compound. Melting point: 120-123 ℃ IR (KBr) cm ^-1 : 3470,2950,2870,2830,1750,1600,1510,14
90,1485,1325,1240,1230,1200,1115, 995, 925, 840 NMR (DMSO-d ₆ ) δ: 8.04 (d, 2H), 7.02 (d, 2H), 6.70 (s, 1H), 3 .
95 (t, 2H), 3.50-3.41 (4H), 2.55-2.38 (6H), 2.30 (s, 3H), 2.
07 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.87-1.56 (4H) Elemental analysis value (C ₂₅ H ₃₃ N ₃ O ₅ ) Theoretical value: C, 65.91; H, 7.30 ; N, 9.22 Found: C, 65.83; H, 7.22; N, 9.23

Example 32 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (4-aminophenyl) piperazino} butane hydrochloride] 4- (4-acetoxy-
2,3,5-Trimethylphenoxy) -1- {4- (4
2nitrog of -nitrophenyl) piperazino} butane was suspended in 250 ml of methanol and 10% palladium / catalyst was added as a catalyst.
Carbon (1.0 g) was added, and the mixture was reacted under a hydrogen atmosphere at room temperature and atmospheric pressure for 2 hours. After the reaction, the catalyst was filtered off from the reaction solution which became a homogeneous solution, and the solvent was distilled off. The obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane). The solvent was distilled off, the obtained oily substance was dissolved in methanol, 20% ethanolic hydrochloric acid was added, and the solvent was distilled off. The solid obtained was methanol / ethyl acetate /
Recrystallized with a mixed solvent of diethyl ether to give the title compound 1
4.8 g was obtained. Melting point: 222-223 ℃ IR (KBr) cm ^-1 : 3430,2935,2590,1760,1520,1365,1320,12
20,1195,1115,1080, 810NMR (DMSO-d ₆ ) δ: 6.76 (d, 2H), 6.
72 (S, 1H), 6.57 (d, 2H), 3.97 (t, 3H), 3.58-3.03 (10H), 2.30
(s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H), 2.00-1.69
(4H) Elemental analysis value (C ₂₅ H ₃₅ N ₃ O ₃ · HCl) Theoretical value: C, 64.99; H, 7.85; N, 9.09; Cl, 7.67 Actual value: C, 64.98; H, 7.86; N, 9.16 ; Cl, 7.85

Example 33 [Synthesis of 4- (4-hydroxy-2,3,5-trimethylphenoxy) -1- {4- (4-nitrophenyl) piperazino} butane hydrochloride] 4- (4-acetoxy-
2,3,5-Trimethylphenoxy) -1- {4- (4
-Nitrophenyl) piperazino} butane (4.5 g) was added to methano-
10 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 8 hours. After the reaction, the solvent was distilled off, and the obtained solid was washed with water and dried. Then, this solid was recrystallized with a mixed solvent of methanol / ethyl acetate to obtain 3.1 g of the title compound. Melting point: 231 ℃ (decomposition) IR (KBr) cm ^-1 : 3450,3350,2600,1600,1520,1485,1415,13
35,1250,1205,1130,1120,1090,1000, 975, 940, 840, 7
55 NMR (DMSO-d ₆ ) δ: 11.26 (br, 1H), 8.11 (d, 2H), 7.60 (br, 1)
H), 7.13 (d, 2H), 6.54 (s, 1H), 3.87 (t, 2H), 3.72-3.52 (6H),
3.45-2.98 (4H), 2.13 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.
00-1.63 (4H) Elemental analysis value (C ₂₃ H ₃₁ N ₃ O ₄・ HCl ・ 1 / 4H ₂ O) Theoretical value: C, 60.78; H, 7.21; N, 9.25; Cl, 7.80 Actual value: C, 60.94; H, 7.13; N, 9.27; Cl, 7.99

Example 34 [4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (4-acetylaminophenyl)
Synthesis of piperazino} butane hydrochloride] 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4
4.3 g of-(4-aminophenyl) piperazino} butane was dissolved in 40 ml of anhydrous pyridine, and 0.85 ml of acetyl chloride was added dropwise at 0 ° C. Then, the mixture was stirred at room temperature for 1 hour, and pyridine was distilled off. Ethyl acetate and water were added to the obtained oily substance, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane). The obtained oily substance was dissolved in methanol, hydrochloric acid was added, and the solvent was evaporated. The obtained solid was recrystallized from a mixed solvent of methanol / ethyl acetate / diethyl ether to give 3.8 g of the title compound.
I got Melting point: 240 ° C (decomposition) IR (KBr) cm ^-1 : 3450,3350,2930,2380,1745,1685,1590,15
30,1510,1410, 1370,1320,1255,1230,1200,1120,1080,
925, 835 NMR (DMSO-d ₆ ) δ: 9.81 (s, 1H), 7.46 (d, 2H), 6.92 (d, 2H), 6.
72 (s, 1H), 3.97 (t, 2H), 3.70-2.96 (10H), 2.31 (s, 3H), 2.09
(s, 3H), 2.04 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 2.00-1.70
(4H) Elemental analysis value (C ₂₇ H ₃₇ N ₃ O ₄・ HCl) Theoretical value: C, 64.33; H, 7.60; N, 8.34 Actual value: C, 64.04; H, 7.79; N, 8.23

Example 35 [4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (4-dimethylaminophenyl)]
Synthesis of piperazino} butane dihydrochloride] 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1-
1.9 g of {4- (4-aminophenyl) piperazino} butane
And 5% 37% aqueous formaldehyde solution in acetonitrile
It was dissolved in 40 ml, cooled to 0 ° C., 1.26 g of sodium cyanoborohydride was added, and the mixture was stirred for 30 minutes. Then, the mixture was stirred at room temperature for 2 hours, 2 ml of acetic acid was added, and the mixture was further stirred for 1 hour.
After the reaction, dilute hydrochloric acid was added to acidify and the mixture was allowed to stand. Sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, the obtained solid was dissolved in methanol, hydrochloric acid was added, and the solvent was distilled off. The obtained solid was recrystallized from a mixed solvent of methanol / ethyl acetate / diethyl ether to obtain 1.3 g of the title compound. Melting point: 172 ° C (decomposition) IR (KBr) cm ^-1 : 3450,2930,2690,2600,1755,1610,1520,14
70,1230,1200,1120,1080, 815 NMR (DMSO-d ₆ ) δ: 11.22 (br, 1H), 7.66 (d, 2H), 7.13 (d, 2H),
6.72 (s, 1H), 3.97 (t, 2H), 3.96-3.05 (16H), 2.31 (s, 3H), 2.
09 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H), 1.97-1.68 (4H) Elemental analysis value (C ₂₇ H ₃₉ N ₃ O ₃・ 2HCl ・ 1 / 2H ₂ O) Theoretical value : C, 60.55; H, 7.90; N, 7.85; Cl, 13.24 Actual value: C, 60.20; H, 7.90; N, 7.99; Cl, 13.20

Example 36 [Synthesis of 4- (4-acetoxy-2,3,5-trimethylphenoxy) -1- {4- (3-trifluoromethylphenyl) piperazino} butane dihydrochloride] 4-acetoxy- 1- (4-chlorobutoxy) -2,3,5-trimethylbenzene 11.4 g, 1- (3-trifluoromethylphenyl) piperazine hydrochloride 12.0 g and anhydrous potassium carbonate
8.4 g was dissolved in 80 ml of N, N-dimethylformamide, and heated and stirred at 50 ° C. for 12 hours under a nitrogen stream. After the reaction, the solvent was distilled off, and ethyl acetate and then water were added for extraction. The organic layer was washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the obtained oily substance was purified by silica gel column chromatography (ethyl acetate / n-hexane), and the solvent was evaporated. The obtained oily substance was dissolved in methanol, fumaric acid was added, and the solvent was evaporated. The obtained solid was recrystallized from a mixed solvent of methanol / ethyl acetate / diethyl ether to obtain 16.8 g of the title compound. Melting point: 124-125 ℃ IR (KBr) cm ^-1 : 3480,2950,1755,1620,1590,1500,1460,13
70,1320,1240,1210,1170,1125,1095, 995, 960, 800,70
5 NMR (DMSO-d ₆ ) δ: 7.48-7.36 (t, 1H), 7.27-7.14 (m, 2H), 7.1
0-7.03 (d, 1H), 6.70 (s, 1H), 6.61 (s, 1H), 3.96 (t, 2H), 3.33
-3.18 (m, 4H), 2.67-2.52 (m, 4H), 2.48 (m, 2H), 2.30 (s, 3H),
2.07 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H), 1.88-1.57 (m, 4H) Elemental analysis value (C ₂₆ H ₃₃ N ₂ O ₃ F ₃・ 1 / 2C ₄ H ₄ O ₄・ H ₂ O) Theoretical value: C, 60.64; H, 6.72; N, 5.05; F, 10.28 Actual value: C, 60.83; H, 6.41; N, 4.81; F, 9.93

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location A61K 31/495 ABQ ABU ACJ ACN ACV ADN ADP AED (72) Inventor Hiroaki Taguchi Jitsu Katata, Otsu City, Shiga Prefecture 1-1-1, Toyobo Co., Ltd., Pharmaceutical Research Center (72) Inventor, Mitsuru Takahashi 2-1-1, Katata, Otsu City, Shiga Prefecture Toyobo Co., Ltd., Pharmaceutical Research Center (72) Inventor, Takeo Katsushima, Nii Katata, Otsu, Shiga Prefecture 1-1-1 Toyobo Co., Ltd. Pharmaceutical Research Center

Claims (8)

[Claims] 1. A novel ferrite represented by the following general formula (I):
Nylpiperazine derivatives, salts thereof and solvates thereof. General formula (I):[Wherein, R¹Is a hydrogen atom or (CO) R⁷Indicated by
Group (R⁷Is a lower alkyl group or a phenyl group); R²Is
Hydrogen atom, lower alkyl group, (CO) R⁸Group represented by
Or (CO) OR⁹A group represented by (R⁸, R⁹Is hydrogen
Atom or lower alkyl group); R³, R^FourEach is German
Vertically hydrogen atom or lower alkyl group; R^FiveIs a hydrogen atom,
Lower alkyl group, (CO) NR^TenR¹¹A group represented by
(CO) OR ¹²A group represented by, a trifluoromethyl group,
NR¹³R¹⁴A group represented by NH (CO) R^FifteenIndicated by
Group, nitro group, OR¹⁶Group or halogen atom
(R^Ten, R¹¹Are each independently a hydrogen atom or a lower
Kill group, R¹²Is a hydrogen atom or a lower alkyl group, R¹³,
R¹⁴Are each independently a hydrogen atom or a lower alkyl group,
R^Fifteen, R¹⁶Is a lower alkyl group); R⁶Is a hydrogen atom, lower
Alkyl group or halogen atom; n is an integer of 3 to 5
Represent. ] 2. A novel ferrite represented by the following general formula (II):
Nylpiperazine derivatives, salts thereof and solvates thereof. General formula (II):[Wherein, R¹Is a hydrogen atom or (CO) R⁷Indicated by
Group (R⁷Is a lower alkyl group or a phenyl group); R²,
R³, R^FourAre each independently a hydrogen atom or a lower alkyl
R group; R^FiveIs a hydrogen atom, (CO) NR^TenR¹¹Indicated by
Group, (CO) OR ¹²Group represented by, NR¹³R¹⁴Indicated by
Group, NH (CO) R^FifteenGroup represented by, nitro group, OR
¹⁶Or a halogen atom (R^Ten, R¹¹Is it
Each independently a hydrogen atom or a lower alkyl group, R¹²Is hydrogen
Atom or lower alkyl group, R¹³, R¹⁴Are independent
A hydrogen atom or a lower alkyl group, R^Fifteen, R¹⁶Is a lower class
Rukyi group); n represents an integer of 3 to 5. ] 3. A novel phenylpiperazine derivative represented by the following general formula (I), a salt thereof and a solvate thereof. General formula (I): [In the formula, R ¹ is a hydrogen atom or a group represented by (CO) R ⁷ (R ⁷ is a lower alkyl group or a phenyl group); R ² ,
R ³ and R ⁴ are each independently a hydrogen atom or a lower alkyl group; R ⁵ is a hydrogen atom, a lower alkyl group, a group represented by OR ¹⁶ or a halogen atom (R ¹⁶ is a lower alkyl group);
R ⁶ is a hydrogen atom or a lower alkyl group; n is an integer of 3 to 5. ] 4. A novel compound represented by the following general formula (III):
Nylpiperazine derivatives, salts thereof and solvates thereof. General formula (III):[Wherein, R¹Is a hydrogen atom or (CO) R⁷Indicated by
Group (R⁷Is a lower alkyl group or a phenyl group); R²,
R³, R^FourAre each independently a hydrogen atom or a lower alkyl
R group; R^FiveIs a hydrogen atom, (CO) NR^TenR¹¹Indicated by
Group, (CO) OR ¹²Group represented by, NR¹³R¹⁴Indicated by
Group, NH (CO) R^FifteenGroup represented by, nitro group, OR
¹⁶Or a halogen atom (R^Ten, R¹¹Is it
Each independently a hydrogen atom or a lower alkyl group, R¹²Is hydrogen
Atom or lower alkyl group, R¹³, R¹⁴Are independent
A hydrogen atom or a lower alkyl group, R^Fifteen, R¹⁶Is a lower class
Rukyi group); n represents an integer of 3 to 5. ] 5. A pharmaceutical composition comprising the compound represented by the general formula (I) according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof. 6. A pharmaceutical composition comprising the compound represented by the general formula (II) according to claim 2, a pharmaceutically acceptable salt thereof or a solvate thereof. 7. A pharmaceutical composition comprising the compound represented by the general formula (I) according to claim 3, a pharmaceutically acceptable salt thereof or a solvate thereof. 8. A pharmaceutical composition comprising the compound represented by the general formula (III) according to claim 4, a pharmaceutically acceptable salt thereof or a solvate thereof.