WO2001034569A1 - Pancreatitis remedies - Google Patents

Abstract

Pancreatitis remedies containing as the active ingredient compounds of general formula (I) or pharmaceutically acceptable salts thereof wherein R1 and R2 are each independently hydrogen or lower alkyl, or alternatively R1 and R2 may together represent -(CH2)2-NH-(CH2)2-; R3 is hydrogen or lower alkyl; R4, R5 and R6 are each independently hydrogen, lower alkyl, lower alkoxy, halogeno, amino, or trifluoromethyl; and W1 and W2 are each independently nitrogen or carbon.

Description

 Specification

 Knee inflammation treatment

 Technical field

 The present invention relates to a piperazine derivative and a pharmaceutically acceptable salt thereof useful as a therapeutic agent for knee inflammatory disease, their use for the manufacture of a therapeutic agent for therapeutic inflammatory disease, a therapeutic agent for osteoarthritis containing them as an active ingredient, and The method used for treating inflammation. Background art

Knee inflammation is caused by injury to the acinar cells of the knee, extracellular extravasation of the knee fluid due to obstruction of the canal, etc., and autolysis of the knee parenchyma and interstitium by knee enzymes activated in the knee. It is mainly non-suppurative inflammation and is broadly divided into acute inflammation and chronic knee inflammation. The principle in treating acute knee inflammation is to keep the knees as restful as possible. For this purpose, it is necessary to suppress the secretion of acid in the stomach by fasting and to replenish electrolytes etc. with sufficient infusion to maintain circulatory dynamics. Moreover, H ₂ receptor antagonists to inhibit the secretion of knee enzymes, and protease inhibitors to inhibit the activity of spilled knee enzymes, their respective administered. Chronic knee inflammation is divided into acute relapse, intermittent, and decompensated periods. The pathology of acute relapse is similar to acute knee inflammation. In the treatment of chronic inflammation, anti-enzyme drugs and the like are similarly administered.

 Recently, serum levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid, increased in a mouse acute rhoutitis model fed choline-deficient etionine. The activation of serotonin (5-HT 2) receptor is involved in acute knee inflammation because the decrease and its effect correlated with the binding affinity to serotonin (5-HT 2) receptor [T. Yoshio et al., J. Pharmacol. Exp. Ther., 283: 1495-1502 (1997)].

On the other hand, Japanese Patent Application Laid-Open No. Hei 7-15757455, GB 1325 876, and Ind. m., 15B: 466-472 (1977) describes piperazine derivatives useful as antihypertensives and intraocular pressure lowering agents, and JP-A 8-325241 describes piperazine derivatives having an antiallergic effect. Have been.

 The present inventors have found that some of the piperazine derivatives have an anti-serotonin effect, and that they have a remarkable therapeutic effect on knee inflammation. Completed the invention. Disclosure of the invention

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

(Wherein 111 and 1¾2 are the same or different and each represent a hydrogen atom or a lower alkyl group, or R 1 and R 2 are taken together to form — (CH ₂ ) 2-NH— (CH ₂ ) ₂ Represents —

 R 3 represents hydrogen or a lower alkyl group,

 R4, 1¾5 and shaku 6 each represent a hydrogen atom, or two of R4, R5 and R6 represent a hydrogen atom and the others are lower alkyl, lower alkoxy, halogen, amino or trifluoro. Represents a methyl group, or one of R4, R5 and R6 is a hydrogen atom and the other is the same or different and is a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group Or R4, shaku 5 and! ^ 6 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 are the same or different and represent a nitrogen atom or a carbon atom. ) Or a pharmaceutically acceptable salt thereof (both are referred to as “the present compound”). The therapeutic agent for knee inflammation of the present invention is useful for treating acute symptoms of acute inflammation (acute knee inflammation including postoperative acute knee inflammation, acute tengitis after laparotomy, other traumatic knee inflammation), and acute knee inflammation. It is useful for remission of exacerbation.

 Accordingly, the present invention also provides a method for treating inflammation in mammals, including humans, comprising administering an effective amount of the present compound to a patient with inflammation, and the use of the present compound for the manufacture of a therapeutic agent for osteoarthritis. Also provide use.

 In this compound, 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 R 4, R 5, and R 6 each represent a lower alkoxy group, and R 4, R 5, and R 6 each represent a lower alkoxy group, wherein R 4, R 5, and R 6 Compounds or pharmaceutically acceptable salts thereof, one or two of which represent a lower alkoxy group and the other represent a hydrogen atom, are a group of compounds particularly suitable for use in the treatment of osteoarthritis. Is a compound of

 In the present compound, 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 Means that 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 Compounds or pharmaceutically acceptable salts thereof are another group of compounds that are particularly suitable for use in treating knee inflammation.

In this compound, in formula (I), 1 and! 12 each represent a lower alkyl group, or R 1 and R 2 together form one (CH ₂ ) 2 -NH- ( CH ₂ ) ₂ —, R 3 represents a hydrogen atom, W 1 and W 2 both represent a carbon atom, and R 4, 15 and 1 ^ 6 represent one of them being a lower alkoxy group Compounds or pharmaceutically acceptable salts thereof, the other two of which represent hydrogen atoms, are yet another group of compounds that are particularly suitable for use in treating spiritis.

In the present compound, in the general formula (I), R1, R2 and R3 all represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 Is it A compound or a pharmaceutically acceptable salt thereof, one of which represents a halogen and the other two represent a hydrogen atom, is still another group which is particularly suitable for use in the treatment of osteoarthritis. Is a compound of

 In this compound, in the general formula (I), R 1 and R 2 each represent a hydrogen atom, R 3 represents a lower alkyl group, W 1 and W 2 each represent a carbon atom, and R 4 and R 4 5 and R 6 are compounds in which one or two of them represent a lower alkoxy group and the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof is used for the treatment of osteoarthritis Yet another group of compounds which are particularly suitable for:

 In this compound, in the general formula (I), Rl, R2 and R3 each represent a hydrogen atom, and W1 and W2 represent whether one of them represents a carbon atom and the other represents a nitrogen atom. , Or both represent a nitrogen atom, and R4, shaku 5 and! ^ 6 each represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group A compound or a pharmaceutically usable salt thereof, which represents a hydrogen atom and the other represents a hydrogen atom, is yet another group of compounds which are particularly suitable for use in the treatment of osteoarthritis.

 Among the present compounds, a compound selected from the following (1) to (23) or a pharmaceutically acceptable salt thereof is particularly suitable for use in the treatment of osteoarthritis.

(1) 3-[4- (2-methoxyphenyl) piperazinyl] 1 1- (4-aminophenoxy) propan-1-ol

(2) 3- [4- (2-Methylphenyl) piperazinyl] 1-11 (4-aminophenoxy) propan-1-ol

 (3) 3- (4-1- (2-methoxyphenyl) piperazinyl) -1-1- (4-dimethylaminophenoxy) propan-2-ol

 (4) 3-[4--(2-Methoxyphenyl) piperazinyl] 1-1 (4-amino-3 -methylphenoxy) propane 1-2-ol

 (5) 3— [4- (2-Fluorophenyl) piperazinyl] 1-1— (4-aminophenoxy) propan-1-ol

(6) 3— [4— (3-methoxyphenyl) piperazinyl] 1 1— (4-amino Phenoxy) propane-1

 (7) 3— [4— (4-Methoxyphenyl) piperazinyl] ー 1-1 (4-aminophenoxy) propan-1-ol

 (8) 3- [4- (2,3-Dimethoxyphenyl) piperazinyl] 1-1- (4-aminophenoxy) propan-1--2-ol

 (9) 3- (4- (3,5-Dimethoxyphenyl) piperazinyl) 1-1- (4-Aminophenoxy) propan-2-ol

 (10) 3-[4- (2,3-dimethylphenyl) piperazinyl] 1 1- (4-aminophenoxy) propan-2-ol

(11) 3-[4- (2,5-dimethylphenyl) piperazinyl]-1- (4-aminophenoxy) propan-1-ol

 (12) 3-[4- (4,6-Dimethoxypyrimidin-2-yl) piperazinyl] — 1- (4-aminophenoxy) propan-1-ol

 (13) 3- (4- (2,3,4-trimethoxyphenyl) piperazinyl) 1-11 (4-aminophenoxy) propan-1-ol

 (14) 3— [4— (2-pyridyl) piperazinyl] 1 1— (4-aminophenol) propane 1 2-ol

 (15) 3- (4-1- (2-methoxyphenyl) piperazinyl) 1-1- (4-piperazinylphenoxy) propan-1--2-ol

(16) 3-[4-phenylbiperazinyl] 1-1 (4-aminophenoxy) propan-2-ol

 (17) 3-[4- (2-aminophenyl) piperazinyl]-1- (4-aminophenoxy) propan-1-ol

 (18) 3- [4- (3-Methylphenyl) piperazinyl] 1 1- (4-aminophenyl) propan-1-ol

 (19) 3- (4- (2-chlorophenyl) piperazinyl) 1-11 (4-aminophenoxy) propan-1-ol

(20) 3-[4- (2-ethoxyphenyl) piperazinyl] 1 1- (4-amino Phenoxy) propane-1

 (21) 3- (4-1- (2-methoxyphenyl) piperazinyl) -1-1 (2-aminophenoxy) propan-1--2-ol

 (22) 3— [4— (2-Methoxyphenyl) piperazinyl] 1 1— (3-aminophenoxy) propan 1—2-ol

 (23) 3- [4- (3-trifluoromethylphenyl) piperazinyl] -1-1 (4-aminophenoxy) propan-1-2-ol

 Further, the present invention provides a compound encompassed by the present compound, wherein the compound represented by the general formula (II):

(In the formula, 111 and 1 ^ 2 are the same or different and each represents a hydrogen atom or a lower alkyl group, or R 1 and R 2 together form one (CH ₂ ) 2-NH- (CH ₂ ) ₂ —

 R 3 represents hydrogen or a lower alkyl group,

 R4, scale 5 and! ¾6 each represent a hydrogen atom, or two of R4, R5 and R6 represent a hydrogen atom, and the others are lower alkyl, lower alkoxy, halogen, amino or trifyl. Represents a methyl group, or one of R4, R5 and R6 is a hydrogen atom and the other is the same or different and is a lower alkyl group, a lower alkoxy group, a halogen, an amino group or trifluoromethyl Or R 4, 5 and! ¾ 6 are all the same and represent 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 and represent a nitrogen atom or a carbon atom, However, when Rl, R2 and R3 are all hydrogen atoms and Wl and W2 are both carbon atoms:

 (1) R4, R5 and R6 do not all represent a hydrogen atom at the same time,

(2) R4, 1¾5 and 16 are such that when one of them represents a methoxy group, the other two do not simultaneously represent a hydrogen atom,

 (3) R4, 115 and 16 are such that when one of them represents a chlorine atom at position 4, the other two do not represent a hydrogen atom, and

 (4) When one of R4, 5, and! 6 represents an amino group, the other two do not represent a hydrogen atom. )

Or a pharmaceutically acceptable salt thereof (hereinafter, referred to as “the novel compound”).

 In the new compound, in the general formula (II), R1, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent A compound or a pharmaceutically acceptable salt thereof, in which two or three of them represent a lower alkoxy group and the other represents a hydrogen atom, is a group of compounds particularly suitable for use in the treatment of osteoarthritis. Is a compound of

 In the new compound, in the general formula (II), R1, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent , One, two or three of them represent a lower alkyl group, and when one or two of R4, R5 and R6 represent a lower alkyl group, the others represent a hydrogen atom Compounds or pharmaceutically acceptable salts thereof are another group of compounds that are particularly suitable for use in treating knee osteoarthritis.

In the novel compound, in formula (II), 1¾1 and 1¾2 each represent a lower alkyl group, or R 1 and R 2 together form — (CH ₂ ) 2-NH— (CH ₂ ) ₂ —, R 3 represents a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 each represent a lower alkoxy group. Compounds wherein the other two represent a hydrogen atom or pharmaceutically acceptable salts thereof are yet another group of compounds which are particularly suitable for use in the treatment of osteoarthritis. In the present novel compound, in the general formula (II), R1, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent A compound or a pharmaceutically acceptable salt thereof, in which one of them represents a halogen bonded to the 2- or 3-position of the phenyl group and the other two represent a hydrogen atom, or a pharmaceutically acceptable salt thereof, is used for treating knee inflammation Yet another group of compounds that are particularly suitable for

 In the new compound, in the general formula (II), R 1 and R 2 each represent a hydrogen atom, R 3 represents a lower alkyl group, W 1 and W 2 each represent a carbon atom, and R 4 , R 5 and R 6 are compounds in which one or two of them represent a lower alkoxy group and the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof is used for the treatment of osteoarthritis Yet another group of compounds which are particularly suitable for:

 In this new compound, Rl, R2, and R3 in Formula (II) each represent a hydrogen atom, and W1 and W2 represent whether 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 each represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group A compound or a pharmaceutically acceptable salt thereof, which represents a hydrogen atom and the other represents a hydrogen atom, is yet another group of compounds which are particularly suitable for use in treating osteoarthritis.

 Among the novel compounds, the following compounds (1) to (16) or pharmaceutically acceptable salts thereof are particularly suitable for use in treating knee osteoarthritis.

 (1) 3- (4- (2-Methylphenyl) piperazinyl) -1- (4-aminophenyl) propan-1-ol

 (2) 3- (4-1- (2-methoxyphenyl) piperazinyl) -1-1- (4-dimethylaminophenoxy) propan-1--2-ol

 (3) 3— [4— (2-methoxyphenyl) piperazinyl] 1-1-1 (4-amino 3-methylphenoxy) propan-1-ol

 (4) 3- (4- (2-Fluorophenyl) piperazinyl) — 1- (4-aminophosphenoxy) propan-2-ol

(5) 3— [4- (2,3-Dimethoxyphenyl) piperazinyl] 1 1— (4 1-aminophenoxy) propane-1-ol

 (6) 3— [4- (3,5-dimethoxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-1-ol

 (7) 3- [4-1 (2,3-dimethylphenyl) piperazinyl] 1 1- (4-1aminophenoxy) propan-2-ol

 (8) 3- (4- (2,5-dimethylphenyl) piperazinyl) 1 1- (4-1 aminophenoxy) propan-1-ol

 (9) 3- (4- (4,6-Dimethoxypyrimidine-1-yl) piperazinyl)-1- (4-aminophenoxy) propan-1-ol

 (10) 3- [4- (2,3,4-trimethoxyphenyl) piperazinyl] 1-1- (4-aminophenoxy) propan-1-ol

 (11) 3- [4- (2-pyridyl) piperazinyl] 1 1- (4-aminophenoxy) propan-2-ol

 (12) 3— [4— (2-Methoxyphenyl) piperazinyl] 1 1— (4-Pipazinylphenoxy) propane 1 2-ol

 (13) 3- [4- (3-Methylphenyl) piperazinyl] 1 1- (4-aminophenyl) propan-1-ol

 (14) 3- (4- (2-chlorophenyl) piperazinyl) 1- (1-aminophenoxy) propan-1-ol

 (15) 3-[4- (2-ethoxyphenyl) piperazinyl]-1- (4-aminophenol) propan-1-ol

 (16) 3— [4— (3-trifluoromethylphenyl) piperazinyl] 1-11- (4-aminophenoxy) propan-1-ol.

 In the present specification, the term "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 an alkyl group having 1 or 2 carbon atoms, that is, methyl. Group or ethyl group.

Further, in the present specification, the “lower alkoxy group” refers to an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and particularly preferably an alkoxy group having 1 to 3 carbon atoms. Refers to an alkoxy group of Formula 1 or 2, that is, a methoxy group or an ethoxy group.

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

 The production of the present compound is carried out by referring to Ind. J. Chem., 15B: 466-472 (1977) or JP-A No. A person skilled in the art can easily carry out the reaction by appropriately selecting the corresponding starting materials. The outline is as follows.

 Referring to the synthesis scheme below, one of the starting materials, 2,3-epoxypropanol derivative, can be prepared according to a known method (a method described in JP-A-8-325241), for example, It can be obtained by heating a phenol having a nitro group and a substituent R 3 and a halogenated methyloxysilane in a solvent such as acetone or methyl ethyl ketone in the presence of an alkyl carbonate. R 4, R 5, R 6 -substituted phenylbiperazine and R 4, R 5, R 6 -substituted pyridylpiperazine R 4, R 5, R 6 -substituted pyrimidylpi Perazine is commercially available or can be N-monobenzylpiperazine substituted with R 4, R 5, R 6 -substituted according to a known method (method described in JP-A-9-290570). A halogenated benzene having a group is heated in an organic solvent or in the absence of a solvent to obtain [1-benzyl 4- (R4, R5, R6, substituted) phenyl] piperazine. Thereafter, it can be synthesized by catalytic reduction with palladium carbon (Pd-C) or the like. R 4, R 5, R 6 -substituted pyridylpiperazine and R 4, R 5, R 6 -substituted pyrimidylpiperazine can also be synthesized in the same manner.

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 the nitro group with a metal such as zinc or Pd-C and adding 2N hydrochloric acid to form a hydrochloride, the alcohol (methanol, ethanol, propanol, etc.) noacetone, or alcohol (methanol, ethanol, The desired compound can be obtained by recrystallization from ethyl acetate or the like. Further, the amino group of the target compound was replaced with 丄 Ora. Chem., 37: 1 67 By dimethylation according to the method of 3 (1972), a dimethyl compound as another target compound can also be obtained.

 (III) (IV)

(V)

In addition, the present compound having a piperazylphenoxy group can be synthesized, for example, as follows. That is, commercially available 4-hydroxyphenylpyrazine (VI) is dissolved in ethanol or the like, and di-t-butyl dicarbonate or benzyloxycarbonyl chloride is added thereto to introduce a urethane-type protecting group to form an N-protected product. (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 methyloxysilane is added to a solvent such as acetone or methylethylketone in the presence of alkali carbonate. By heating in the solution, the formula (VIII) can be obtained. The compound of formula (IX), which is obtained by heating and stirring for about 5 to 20 hours in a solvent such as dioxane or methanol, evaporates the solvent and extracts with ethyl acetate, etc. Is obtained. 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.

(I)

 (ΛΙ)

 81

Z.iO/00 <If / IDt [OM. The present compounds can be used in free form or in the form of a pharmaceutically acceptable salt as a therapeutic agent for osteoarthritis. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloride, lead sulfate, and nitrate or salts of organic acids such as acetate, maleate, and tartrate. Not done.

 The compound of the present invention can be formulated into a form for oral administration or for injection as a therapeutic agent for knee inflammation. Here, the “agent for oral administration” means various forms to be taken, and examples thereof include appropriate solid preparations such as tablets, granules, powders, and capsules. “Injection preparations” also include those in the form of injection preparations for normal intravenous injection, intramuscular injection, subcutaneous injection, and infusion for intravenous drip infusion. These preparations include commonly used excipients, binders, disintegrants, dispersants, lubricants, diluents, absorption enhancers, buffers, surfactants, solubilizing agents, preservatives, Various additives such as an emulsifier, an isotonic agent, a stabilizing agent, a dissolving agent for injection, and a pH adjuster may be appropriately used.

 The dosage of the therapeutic agent for knee inflammation of the present invention varies depending on the age, body weight, symptoms, and dosage form of the patient.For example, in the case of an injection, an adult is usually administered at a dose of about 1 to 200 mg once daily, orally In the case of preparations, the dosage is usually about 10 to 1000 mg per adult, several times a day. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows the IR spectrum of the compound of Example 10. BEST MODE FOR CARRYING OUT THE INVENTION

 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]

 1- (4-nitrophenoxy) 1,2,3-epoxypropane

Dissolve 3.5 g (0.025 mol) of 4-nitrophenol and 7 mL of chloromethyloxylan in 40 mL of methyl ethyl ketone, and add 2.4 g of potassium hydroxide to 10 m of water. An aqueous solution dissolved in L was added. After heating under reflux for 5 hours, the inorganic salts were separated 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 the ethyl acetate was distilled off. The obtained residue was recrystallized from ethanol to give 3.5 g of pale yellow crystals, 1- (4-nitrophenoxy) -2,3-epoxypropane having a melting point of 64 to 66.

 [Example 1]

 3- [4- (2-Methoxyphenyl) piperazinyl] — 1- (4-aminophenoxy) propan-1-ol hydrochloride

 2.9 g of 11- (4-nitrophenoxy) -12,3-epoxypropane obtained in Reference Example 1 and 3.) g of (2-methoxyphenyl) piperazine were heated to 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) with a melting point of 164 to 166—1— (4-nitrophenoxy) 4.0 g of all was obtained. This compound was dissolved in methanol (80 mL), 2N hydrochloric acid (20 mL) was added, and the mixture was catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off, and the obtained crystals were recrystallized from ethanol-isopropyl ether to obtain 3.0 g of the target compound as white crystals, melting point: 252 to 253 °: (decomposition).

 [Example 2]

 3- [4- (2-Methylphenyl) piperazinyl] 1-11- (4-aminophenoxy) propan-1-ol hydrochloride

1.9 g of 1- (4-trophenoxy) 1-2,3-epoxypropane obtained in Reference Example 1, 2.2 g of (2-methylphenyl) piperazine hydrochloride and 1.5 mL of triethylamine were dissolved in 100 mL of methanol. The mixture was 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 obtained residue was recrystallized from ethanol to give white crystals, melting point 1

 One 16—

3.9 g of 3— [4- (2-methylphenyl) piperazinyl] 1-11- (4-nitrophenoxy) propan-2-ol hydrochloride at 184-18 ° were obtained. 3.5 g of the compound thus obtained was dissolved in 100 mL of 70% ethanol, and catalytically reduced using palladium carbon (Pd-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 white crystal, melting point of 220 to 222, (decomposed).

As _{C 22 H 27 N 3 0 2} · HC 1 · 0.5H 2 ○: Elemental analysis

Theoretical value (%): C, 62.08 H, 7.55 N, 10.86

Observed value (%): C, 62.03 H, 7.55 N, 10.88

 [Example 3]

 3-[4- (2-Methoxyphenyl) piperazinyl] — 1 — (4-Dimethylaminophenoxy) propan-2-ol trihydrochloride

 5.0 g of 3- [4- (2-methoxyphenyl) piperazinyl] 111- (4-aminophenoxy) propan-2-ol obtained in Example 1 was dissolved in 100 mL of acetonitrile, and 5.2 mL of formaldehyde was added thereto. After the dropwise addition, 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 to the hydrochloride with 2N hydrochloric acid, and recrystallized from methanol-ethyl acetate to give white crystals, melting point 209 Through ~ 212, 2.9 g of the target compound (decomposition) was obtained.

Elemental analysis: C _{2 2} H _{3 1} N ₃ 〇 ₃ · 3 As HC 1 · 0.5H ₂ 〇

Theoretical value (%): C, 52.44 H, 7.00 N, 8.34

Observed value (%): C, 52.47 H, 7.12 N, 8.23

 [Example 4]

 3- [4- (2-Methoxyphenyl) piperazinyl] 1-11 (4-amino-3-methylphenoxy) propan-2-ol hydrochloride

4 12 g 3-methylphenol 3.1 g and chloromethyloxylan 5 m L was dissolved in 50 mL of dioxane, 2.8 g of carbon dioxide lime was added thereto, and the mixture was heated under reflux for 10 hours. After that, inorganic salts were separated 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) 1-1_ (4- Nitro-3-methylphenoxy) propane-2-ol 4.4 g was obtained. 3.2 g of this compound was dissolved in 80 mL of dioxane, 20 mL of 2N hydrochloric acid was added thereto, and the mixture was subjected to catalytic reduction using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off, neutralized with 1 N 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), converted to the hydrochloride with 2 N hydrochloric acid, and recrystallized from methanol-acetone to give white crystals, melting point 210 By ~ 212, 2.2 g of the target compound (decomposition) was obtained.

Elemental analysis: as C ₂₁ H ₂₉ N ₃ 〇 ₃ · 2 HC 1

Theoretical value (%): C, 56.76 H, 7.03 N, 9.46

Observed value (%): C, 50.52 H, 7.09 N, 9.37

 [Example 5]

 3- [4- (2-fluorophenyl) piperazinyl] 1-1-1 (4-aminophenoxy) propan-1-ol dihydrochloride

3.9 g of 11- (4-nitrophenoxy) 1-2,3-epoxypropane obtained in Reference Example 1, 4.8 g of (2-fluorophenyl) pidazine hydrochloride and 2.2 g of triethylamine were added to 20 mL of methanol and dioxane. The mixture was heated and refluxed in 80 mL 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 resulting residue was recrystallized from ethyl ethyl acetate to give 3- [4- (2-fluorophenyl) piperazinyl] -111 (4-nitrophenoxy) at a pale yellow crystal, mp 138-] 42. 4.5 g of bread-2-ol was obtained. Dissolve 3.4 g of this compound in 70 mL of methanol Then, 20 mL of 2N hydrochloric acid was added thereto, and catalytic reduction was performed using palladium on carbon (Pd-C). Next, after filtering off Pd-C, 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, black mouth form: methyl alcohol = 50: 1), and hydrochloride was added thereto by adding hydrochloric acid. To give 1.9 g of the desired compound (decomposed) with white crystals, mp 280-285.

Elemental analysis: as C, ₉ H ₂₄ N ₃ 〇 ₂ F · 2 HC 1

Theoretical value (%): C, 54.55 H, 6.26 N, 10.04

Observed value (%): C, 54.29 H, 6.35 N, 10.24

 [Example 6]

 3- [4- (3-methoxyphenyl) piperazinyl] — 1- (4-aminophenoxy) propan-2-ol dihydrochloride

 3.9 g of 1- (4-trophenoxy) -2,3-epoxypropane obtained in Reference Example 1, 6.4 g of (3-methoxyphenyl) piperazine dihydrochloride, 4.9 g of triethylamine were added to dioxane. The mixture was heated and refluxed in 100 mL 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, 3- (4- (3-methoxyphenyl) piperazinyl having a melting point of 167 to 170. ] — 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, after filtering off Pd-C, 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 resulting residue was purified by column chromatography (silica gel, chloroform: methanol = 20: 1), and 2N hydrochloric acid was added thereto to form a hydrochloride, which was then recrystallized from methanol-ethyl acetate to give white. 1.1 g of the desired compound as crystals was obtained. Ot: foaming, 245-250 disassembly.

Elemental analysis: C _2. H ₂₇ N ₃ 〇 ₃ '2HC 1' As H ₂₀

Theoretical value (%): C, 53.57 H, 6.96 N, 9.37 Observed value (%): C, 53.51 H, 6.88 N, 8.89

 [Example 7]

 3— [4— (4-Methoxyphenyl) piperazinyl] — 1— (4-Aminophenoxy) propan-2-ol trihydrochloride

2.9 g of 1- (4-2-trophenoxy) 1-2,3-epoxypropane obtained in Reference Example 1, 4.8 g of (4-methoxyphenyl) pidazine dihydrochloride and 3.6 g of triethylamine were added to dioxane lOOmL. The mixture was heated under reflux for 15 hours. After the reaction, the solvent was distilled off, the obtained residue was washed with water, and recrystallized from ethyl acetate to give yellow crystals, 3- [4- (4-methoxyphenyl) piperazinyl having a melting point of 180 to 183. ] — 1— (4-Nitrophenoxy) propane-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). 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, and extracted with ethyl acetate, and the solvent was distilled off. The resulting residue was purified by column chromatography (silica gel, chloroform: methanol = 30: 1), to which 2N hydrochloric acid was added to form a hydrochloride, and then recrystallized from methanol-ethyl acetate to give a white color. 1.3 g of the desired compound (decomposed) with crystals, mp 257-259. Elemental analysis: C _2. H ₂₇ N ₃ 〇 ₃ - as 3 HC 1

Theoretical value (%): C, 51.46 H, 6.47 N, 9.00

Observed value (%): C, 51.43 H, 6.49 N, 8.97

 [Example 8]

 3- [4- (2,3-Dimethoxyphenyl) piperazinyl] — 1— (4-Aminophenoxy) propane-2-ol Hydrochloride

1.6 g of 1,1- (2-trophenoxy) -2,3-epoxypropane obtained in Reference Example 1, 2.4 g of (2,3-dimethoxyphenyl) pidazine dihydrochloride and 1.8 g of triethylamine The mixture was 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 hydrochloric acid, and the solvent was distilled off. The obtained residue was recrystallized from water to give white crystals, mp 196 ~ ] ^-3-[4- (2,3-Dimethoxyphenyl) piperazinyl]-1- (4-12-Trophenoxy) propan-1-ol hydrochloride 3.1 g was obtained. 2.9 g of this compound was dissolved in 80 mL of methanol, and subjected to catalytic reduction using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the obtained residue was recrystallized from isopropanol to obtain 0.4 g of a white crystal, melting point 240 to 245 (decomposed).

As Elemental Analysis C ₂₁ H ₂₉ N ₃ 〇 ₄ · HC 1 · 0.25H ₂ O

Theoretical value (%): C, 58.87 H, 7.17 N, 9.81

Observed value (%): C, 58.74 H, 7.21 N, 9.57

 [Example 9]

 3-[4- (3,5-Dimethoxyphenyl) piperazinyl] — 1— (4-Aminophenoxy) propan-1-ol trihydrochloride

 2.0 g of 1- (4-nitrophenoxy) 1-2,3-epoxypropane obtained in Reference Example 1, 3.0 g of (3,5-dimethoxyphenyl) pidazine dihydrochloride and 1.5 g of triethylamine were added to The mixture was 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 was purified by column chromatography (silica gel, ethyl acetate: hexane = 2: 1) and recrystallized from ethyl acetate to give pale yellow crystals, 3- [4-] having a melting point of 143 to 145. (3,5-Dimethoxyphenyl) piperazinyl] —1- (4-nitrophenoxy) propan-1-ol 3.1 g was obtained. 2.9 g of this compound was dissolved in 100 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Next, the 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 isopropyl alcohol to give white crystals. 1.1 g of the target compound which foams and decomposes in 217 to 219 was obtained.

As _{C 2, Η 29 Ν 3 0} 4 · 3 HC 1 · 0.5H 2 ○: Elemental analysis

Theoretical value (%): C, 49.86 H, 6.57 N, 8.31

Observed value (%): C, 49.73 H, 6.83 N, 8.23

[Example 10] 3- [4- (2,3-dimethylphenyl) piperazinyl] 1- (4-aminophenyl) propan-1-ol dihydrochloride

 3.9 g of 1- (4-2-trophenoxy) 1-2,3-epoxypropane and 4.9 g of (2,3-dimethylphenyl) pidazine obtained in Reference Example 1 were heated and refluxed in 100 mL of methanol for 5 hours. . 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 give 3- [4-1-1 (2) , 3-Dimethylphenyl) piperazinyl] -1-1 (4-nitrophenoxy) propan-1-ol 6.5 g was obtained. 5.8 g of this compound was dissolved in 100 mL of methanol and subjected to catalytic reduction 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 isopropyl alcohol to give white crystals, melting point 28 to 289289. 5.8 g of the target compound of (decomposition) was obtained. Figure 1 shows the IR spectrum of this compound.

Elemental analysis: as C ₂₁ H ₂₉ N ₃ 0 ₂ '2HC 1

Theoretical value (%): C, 58.88 H, 7.29 N, 9.81

Observed value (%): C, 58.78 H, 7.42 N, 9.79

 [Example 11]

 3-[4- (2,5-dimethylphenyl) piperazinyl] — 1— (4-aminophenyl) propan-1-ol hydrochloride

3.9 g of 111- (412-trophenoxy) -2,3-epoxypropane and 4.6 g of (2,5-dimethylphenyl) piperazine obtained in Reference Example 1 were heated and refluxed 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— as a yellow oil. 0.8 g of (4-nitrophenoxy) propan-2-ol was obtained. This compound was converted into a hydrochloride with 2 N hydrochloric acid and then recrystallized from methanol-ethyl acetate to obtain a hydrochloride having a melting point of 177 to 79 (decomposition). 0.3 g of this compound in methanol It was dissolved in 100 mL and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off PdC, the solvent was distilled off, and the obtained residue was recrystallized from isopropyl alcohol to obtain 4.1 g of the target compound (decomposed) as pale red crystals, melting point 260-263. Elemental analysis: C ₂ ! H NsOz · HC 1 · 1.75H ₂₀

Theoretical value (%): C, 59.56 H, 7.97 N, 9.92

Observed value (%): C, 59.40 H, 7.61 N, 9.79

 [Example 12]

 3- [4- (4,6-Dimethoxypyrimidin-2-yl) piperazinyl] — 1- (4-aminophenoxy) propan-1-ol hydrochloride

 2.3 g of 1- (4-nitrophenoxy) 1-2,3-epoxypropane obtained in Reference Example 1, 4.3 g of (4,6-dimethoxypyrimidine-12-yl) pidazine dihydrochloride and triethylamine 2.9 g was heated to reflux in 50 mL of methanol for 6 hours. After the reaction, the solvent was distilled off. 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 obtained residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1), and yellow crystals of 3- (4- (4,6-dimethoxypyrimidine) having a melting point of 126 to 129 were obtained. 21-yl) Piperazinyl-1--1- (4-nitrophenoxy) propan-2-ol 3.8 g 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, the residue obtained by evaporating the solvent after Pd-C filtration was recrystallized from ethyl alcohol to obtain 2.0 g of the target compound (decomposed) as white crystals having a melting point of 171-174.

As _{C, 9 Η 27 Ν 5 0} 4 · HC 1 · 0.75H 2 ○: Elemental analysis

Theoretical value (%): C, 51.93 H, 6.76 N,】 5.94

Observed value (%): C, 52.18 H, 6.87 N, 16.01

 [Example 13]

 3-[4— (2,3,4-trimethoxyphenyl) piperazinyl] — 1— (4—aminophenoxy) propan-1-ol dihydrochloride

1_ (4-nitrophenoxy) 1-2,3-epoxypropane obtained in Reference Example 1 1.6 g, (2,3,4-trimethoxyphenyl) pidazine hydrochloride (2.8 g) and triethylamine (1.9 g) were heated and refluxed 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 was purified by column chromatography (silica gel, ethyl acetate: hexane = 2: 1) to give 3- [4- (2,3,4-trimethoxyphene) as yellow crystals having a melting point of 159 to 163. 2.5g of piperazinyl] -1- (4-nitrophenoxy) propan-2-ol 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). Next, after filtering off Pd-C, the solvent was distilled off, and the obtained residue was recrystallized from isopropyl alcohol to obtain 1.8 g of the desired compound (decomposed) as pale red crystals having a melting point of 231 to 233.

As Elemental Analysis C ₂₂ H ₃₁ N ₃ 〇 _{5 · 2HC 1 · 0 · 75Η} 2 〇

Theoretical value (%): C, 52.44Η, 6.90Ν, 8.34

Observed value (%): C, 52.69Η, 7.16Ν, 8.19

 [Example 14]

 3- [4- (2-Pyridyl) piperazinyl] — 1- (4-Aminophenoxy) propan-2-ol trihydrochloride

2.1 g of 1- (4-2trophenoxy) -2,3-epoxypropane and 2.2 g of (2-pyridyl) pidazine obtained in Reference Example 1 were heated to 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- (2-pyridyl) piperazinyl] with a melting point of 140 to 142—1- (4-nitrophenoxy) 2.5 g of propane-2-ol were obtained. 3.5 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 was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, 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 recrystallized from methanol-ethyl acetate to give pale red crystals, melting point of 210-200. In 215, 1.2 g of the target compound (decomposition) was obtained. Elemental _{analysis:! C 8 H 24 N 4} 0 2 · 3 HC 1 · 0.25H 2 〇 theoretically (%): C, 48.88 H , 6.26 N, 12.67

Observed value (%): C, 48.89 H, 6.66, 12.43

 [Example 15]

 3— [4— (2-Methoxyphenyl) piperazinyl] — 1— (4-Piperazinyl phenoxy) propan-1-ol tetrahydrochloride

 Dissolve 4.2 g of 4- (4-hydroxyphenyl) piperazine-tert-butyl ester rubrate and 4.2 g of chloromethyloxysilane in 100 mL of methyl ethyl ketone, and add 2.1 g of potassium carbonate to this. In addition, after heating under reflux for 12 hours, the 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 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 purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1), and 3- [4- (2-methoxyphenyl) piperazinyl] having a melting point of 123 to 125 of white crystals was used. 4.8 g of 1- [4- (4-tert-butoxycarbonyl) piperazinylphenoxy] propan-2-ol was obtained. 4.5 g of this compound was dissolved in 50 mL of methanol, 20 mL of 2N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off, and the obtained residue was recrystallized from water / acetone to obtain 4.7 g of the desired compound (decomposed) as white crystals, melting point 240-245.

As Elemental Analysis C ₂₄ H ₃₄ N ₄ 〇 ₃ · 4HC 1 .2.5H ₂ 〇

Theoretical value (%): C, 46.69 H, 7.02 N, 9.07

Observed value (%): C, 46.63 H, 7.00 N, 8.99

 [Example 16]

 3-[4-Fenrubiperazinyl] — 1- (4-aminophenoxy) propan-1-ol dihydrochloride

1- (4-nitrophenoxy) -2,3-epoxypropane obtained in Reference Example 1 3.9 g and 3.9 g of phenylbiperazine were 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, 3- (4-phenylubiperazinyl) 1-11- (4) having a melting point of 150-153. (12-trophenoxy) 4.5 g of propan-2-ol was obtained. 3.0 g of this compound was dissolved in 80 mL of dioxane and catalytically reduced 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 sodium hydrogen carbonate solution, and extracted with ethyl acetate, and the solvent was distilled off. The residue obtained was purified by column chromatography (silica gel, chloroform: methanol = 20: 1), to which 2N hydrochloric acid was added to form the hydrochloride, which was recrystallized from ethanol-ethyl acetate to give white crystals. Mp 275-278, yielding 1.1 g of the (decomposed) target compound.

Elemental analysis: C ₁₉ H ₂₅ N _{30 2} '2 HC 1' H ₂と し て

Theoretical value (%): C, 54.55 H, 6.98 N, 10.04

Observed value (%): C, 54.67 H, 6.88 N, 9.85

 [Example 17]

 3— [4— (2-Aminophenyl) piperazinyl] — 1— (4-Aminophenoxy) propan-1-ol dihydrochloride

 1- (4-nitrophenoxy) -2,3-epoxypropane obtained in Reference Example 1

2.9 g and 3.4 g of 11- (2-nitrophenyl) pidazine were 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 yield yellow crystals, melting point of 136 to 139: 3- [4- (2-ditrophenyl) piperazinyl] — 1 — (4-Nitrophenoxy) propane-1-ol

3.1 g were obtained. 2.9 g of this compound was dissolved in 80 mL of ethanol, 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. In the obtained residue,

After adding 2N hydrochloric acid to make a hydrochloride, recrystallization from isopropanol gave 2.4 g of the target compound as pale red crystals, melting point 209-271 (decomposed).

Elemental analysis: C ₁₉ H ₂₆ N ₃ 〇 ₂ '2 HC 1'. As H ₂₀ Theoretical value (%): C, 52.66 H, 6.97 N, 12.93

Observed value (%): C, 53.06 H, 7.04 N, 12.81

 [Example 18]

 3— [4- (3-Methylphenyl) piperazinyl] — 1— (4-Aminophenoxy) propan-1-ol dihydrochloride

 2.9 g of 1- (4-212-trophenoxy) -2,3-epoxypropane obtained in Reference Example 1 and 4.1 g of 1- (3-methylphenyl) pidazine dihydrochloride and 3.3 g of triethylamine in 80 mL of methanol And refluxed 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- [4- (3-methylphenyl) piperazinyl having a melting point of 117 to 120. One-one-one (412-trophenoxy) propane-2-ol 3.0 g was obtained. 3.0 g of this compound was dissolved in 80 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Next, the Pd-C was filtered off, and 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 2 N hydrochloric acid to form a hydrochloride, and then recrystallized from ethanol-isopropanol-ethyl acetate to obtain 2.7 g of the target compound as white crystals, melting point 245 to 249 ^ (decomposition). .

Elemental analysis: C _2. As _{H 27 N 3 0 2 · 2} HC 1 · 0.25H 2 〇

Theoretical value (%): C, 57.35 H, 7.09 N, 10.03

Observed value (%): C, 57.57 H, 7.16 N, 9.72

 [Example 19]

 3- [4- (2-chlorophenyl) piperazinyl] 1 1- (4-aminophenoxy) propan-2-ol dihydrochloride

4.9 g of 1- (4-nitrophenoxy) -2,3-epoxypropane and 5.4 g of 1- (2-cyclopentenyl) pidazine obtained in Reference Example 1 were heated and refluxed 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 having a melting point of 9 to 123 ", 3- [4-1-1 (2-chloro). Methyl phenyl) piperazinyl] — 1- (4-nitrophenoxy) propane-2-ol 7.0 g was obtained 3.3 g of this compound was dissolved in methanol 80 mL. It was dissolved 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 methanol-isopropanol to give 3.1 g of the target compound (decomposed) as white crystals, melting point 280-284.

Elemental analysis: C, H ₂₄ N ₃ 0 ₂ · 2 As HC 1

Theoretical value (%): C, 52.49 H, 6.02 N, 9.66

Found (%): C, 52.44 H, 6.16 N, 9.58

 [Example 20]

 3- [4- (2-Ethoxyphenyl) piperazinyl] 1- (4-Aminophenoxy) propan-1-ol

 In 1 mL of 80 mL of methanol, 4.9 g of 1- (4-12-trophenoxy) 1-23-epoxypropane obtained in Reference Example 1, 5.3 g of 11- (2-ethoxyphenyl) pidazine hydrochloride and 2.2 g of triethylamine were added. 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 ethyl acetate-isopropyl ether to give pale yellow crystals, 3- [4- (2-ethoxyphenyl) having a melting point of 126 to 128. 3.4 g of (piradizinyl) —1— (412-trophenoxy) propan-1-ol were obtained. 3.2 g of this compound was dissolved in 80 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Next, 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 isopropyl ether to give 2.6 g of the desired compound as pale red crystals, melting point 126-129 (decomposition).

Elemental analysis: C ₂₁ H ₂₉ N ₃ 〇 ₃

Theoretical value (%): C, 67.90 H, 7.87 N, 11.3]

Observed value (%): C, 67.97 H, 8.00 N, 11.27

 [Example 21]

3— [4— (2-Methoxyphenyl) piperazinyl] — 1— (2-Aminophenoxy) propan-1-ol Triol After dissolving 7.0 g of 2-ditrophenol and 13.88 g of chloromethyloxysilane in 100 mL of methyl ethyl ketone, an aqueous solution of 3.1 g of potassium hydroxide dissolved in 10 mL of water was added.After heating under reflux for 15 hours, the inorganic salt was removed. The mixture was filtered 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 the ethyl acetate was distilled off. The obtained residue was dissolved in 100 mL of methanol, and thereto was added 5.8 g of 11- (2-methoxyphenyl) piperazine, and the mixture was refluxed 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, melting point of 110 to 114: 3- [4- (2-methoxyphenyl) Piperazinyl] —1— (2-nitrophenoxy) propan-1-ol (9.1 g) was obtained. 5.0 g of this compound was dissolved in 100 mL of methanol and catalytically reduced using palladium on carbon (Pd-C). Then, the Pd-C was filtered off, the solvent was distilled off, and the obtained residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 1), and 2N hydrochloric acid was added thereto to add hydrochloric acid. After salting, the product was recrystallized from methanol-acetone to obtain 4.2 g of the target compound (decomposed) as white crystals, mp 235-240.

Elemental analysis: C _2. As _{H 27 N 3 0 3 · 3} HC 1 · 0.25H 2 O

Theoretical value (%): C, 50.97 H, 6.52 N, 8.92

Observed value (%): C, 50.96 H, 6.53 N, 8.69

 [Example 22]

 3- [4- (2-Methoxyphenyl) piperazinyl] — 1- (3-Aminophenoxy) propan-2-ol Trihydrochloride

Dissolve 7.0 g of 3-ditrophenol and 13.88 g of chloromethyloxysilane in 100 mL of methyl ethyl ketone, add an aqueous solution of 3.1 g of potassium hydroxide dissolved in 10 mL of water, and heat to reflux for 15 hours. The mixture was filtered and the filtrate was concentrated. The residual oily substance was extracted with ethyl acetate, washed with a 1% aqueous sodium hydroxide solution and water in that order, and then ethyl nitrate was distilled off. The obtained residue was dissolved in 100 mL of methanol, 5.8 g of 1- (2-methoxyphenyl) piperazine was added thereto, 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. By crystallization, yellow crystals were obtained at a melting point of 115 to Π8, yielding 7.0 g of 3- [4- (2-methoxyphenyl) pirazinyl] 111- (3-nitrophenoxy) propan-1-ol. 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 2 N hydrochloric acid to form a hydrochloride, and then recrystallized from methanol-acetone to obtain 3.5 g of the target compound as white crystals. Was. Foamed at 125, decomposed at 225-230.

Elemental analysis: C _2. H ₂₇ N ₃ 〇 ₃ · 3 HC 1 · 1.25H ₂と し て

Theoretical value (%): C, 49.09 H, 6.69 N, 8.59

Observed value (%): C, 49.36 H, 6.98 N, 8.73

 [Example 23]

 3— [4- (3-trifluoromethylphenyl) piperazinyl] —1— (4-aminophenoxy) propan-2-ol trihydrochloride

 2.9 g of 1- (412-trophenoxy) -2,3-epoxypropane obtained in Reference Example 1 and 4.〗 g of 1- (3-trifluorophenyl) piperazine were heated under reflux in methanol (100 mL) for 15 hours. did. After the reaction, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed successively with 1% aqueous sodium hydroxide solution and water, and the ethyl acetate was distilled off. The obtained residue was subjected to column chromatography (silica gel). Purified with ethyl acetate: hexane = 1: 1) to give 3- [4- (3-trifluorophenyl) piperazinyl] yellow oily substance 1- (4-nitrophenoxy) propane-2-ol 3.6 g was obtained. 3.4 g of this compound was dissolved in 150 mL of methanol, and catalytically reduced using palladium 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. To the resulting residue is added 2N hydrochloric acid to form a hydrochloride, which is then recrystallized from methanol monoethyl acetate to obtain 2.8 g of the target compound (decomposed) as white crystals, melting point 218-222.

Elemental analysis: C _2. As _{3 HC 1 · H 2 0 -} H 24 N 3 〇 ₃

Theoretical value (%): C, 45.95 H, 5.59 N, 8.04

Observed value (%): C, 46.13 H, 5.40 N, 7.80

[Test Example 1] Effect of this compound on serotonin 5-HT! _A receptor

The effect of this compound on serotonin 5-HT _{1 A} receptor was examined as follows.

 (Test substance)

 The compounds of Examples 1 and 2 were dissolved in DMS〇 at a concentration of 0.4% and used. (Test method)

The test was performed according to the method of Martin GR, Humphrey PPA: Neuropharmacol., 33: 261-273 (1993). That using human recombinant CHO-K1 cells, 50mM Tris-H C 1, 10mM Mg S_〇 _4, 0.5 mM EDTA, 0.1% acetic acid, in a buffer of pH 7.4, at 25, at incubation conditions of 60 minutes, The effect of ⁵ nM of 3H-8-OH-DPAT on the specific binding was determined. The effect was judged by IC ₅₀ , K _t , and n _H. IC _5. Represents the concentration of the gonist which inhibits the reaction of the agonist alone by 50%, and represents the dissociation constant of the inhibitor. _η Η represents the ΗΠΙ counting. (Test results)

 The results are shown in the following table.

 table 1

As seen in the table above, none of the compounds of Examples 1 and 2 have a en evening agonist action on the serotonin 5-HT _{1 A} receptions evening one was found.

 [Test Example 2]

 Effect of this compound on etionine acute knee inflammation in mice. 1

 The effects of this compound on the mouse etionine acute acute inflammation model were examined as follows.

 (Test substance)

The compounds of Examples 1 and 2 and the mesilate power moststat as a positive control were It was used by dissolving in distilled water to a concentration of mg / lOm1.

 (Test method)

 Test II: Lombard! B., Estes L.W., Longnecker D.S., Am. J. Pathol., 79: 465-480 (1975), was performed as follows. That is, 9-week-old female BALB / c mice purchased from Japan SLC were used. Mice fasted for 48 hours before were fed a choline-deficient 0.5% DL-ethionine-supplemented diet (prepared by CLEA Japan) to induce severe etionine knee inflammation. The normal group received normal feeding. Blood was collected 54 hours after the start of feeding with a choline-deficient 0.5% DL-ethionine supplemented diet, and serum amylase levels were measured. The test substances of the compounds of Examples 1 and 2 were orally administered at a total of three times (30 mgZl0m1 / kg) at 0, 24, and 48 hours after the start of feeding with a choline-deficient 0.5% DL-ethionine-supplemented diet. As a positive control, a mesylate-powered maststat was orally administered 5 times at 0, 12, 24, 36, and 48 hours after the start of feeding with a choline-deficient 0.5% DL-ethionine supplemented diet (30 m 10 m 1 Zk g).

 (Test results)

 The results are shown in the following table.

 Table 2

Values indicate mean SD (n = 8): p <0.001, significant difference from control group As shown in the above table, choline-deficient 0.5% DL-ethionine supplemented serum in control group Amylase level was 42391 ± 6974 IU / L, which was significantly higher than that of the normal group of 10407 persons, 385 IU / L. On the other hand, the compound of Example 1 and the compound of Example 2 Amylase levels in the serum-treated amylase group and in the group receiving mesylate-powered stats were 112 114 ± 2038 IU / m 22001 ± 61 96 IU / m and 19573 ± 8446 IU / L, respectively. It was significantly lower than that. In particular, the serum amylase level in the group to which the compound of Example 1 was administered was lower than that of the positive control, mesylic acid moss, and the compound of Example 1 was less effective in suppressing knee inflammation. It turned out to be stronger than the acid power statistics. The serum amylase level in the group to which the compound of Example 2 was administered was equivalent to that in the group to which mesylate-powered statat was administered. Considering that the number of administrations of the compound of Example 2 is smaller than that of the mesylate-powered mosquito, it is presumed that the compound of Example 2 also has a stronger inhibitory action on phlegmitis than the mesylate-based mosquito.

 [Test Example 3]

 The effect of this compound on rat model of acute coleinitis in rats

 The effects of the present compound on the rat model of acute cerebral acute inflammation were studied as follows.

 (Test substance)

 The compounds of Examples 1 and 2 and mesylic acid moss were dissolved in distilled water so as to have a concentration of 30 mg Z 5 ml, respectively.

 (Test method)

 The test was performed on Tani S. e.a. in accordance with the method described in International Journal of Pancreatology, 2: 337-348 (1987), as follows. That is, Wistar rats weighing about 200 g were fasted for 12 hours, and then cellulane (20 g / m 1 kg) was injected subcutaneously four times every hour to induce acute edema inflammation. Blood was collected 6 hours after the first injection of caerulein, and the amylase and lipase levels in the serum were measured. The test substance was orally administered 1 hour before the first injection of caerulein.

 (Result)

Table 3 shows the results. Table 3

 The value indicates mean soil SD, (n = 8): p <0.001, significant difference from control group As can be seen in the above table, the amylase value of the control group was 56593 ± 7404 IU / L by injection of caerulein, The level significantly increased from 623 IU / L in the normal group. On the other hand, in the group to which the compound of Example 1 or 2 was administered, the amylase value was 31529 ± 10019 IU / L and 34528 ± 1281 ό IU / L, respectively, which was lower than that in the control group. It was significantly lower. On the other hand, in the mesylate-powered statut administration group, it was 54,331 soil, 8825 IU / L, which was not significantly different from the control group. As described above, the compounds of Examples 1 and 2 exhibited a significant inhibitory effect on knee inflammation induced by injection of caerulein, and were clearly superior to mesylate power Mostat.

 The lipase level was significantly increased to 2884 ± 418 IU / L in the control group, compared to 5.7 ± 5.〗 IU / L in the normal group. On the other hand, in the group to which the compound of Example 1 or 2 was administered, the lipase value was 1150 ± 382 IU / L and 1440 ± 708 IU / L, respectively, which were significantly lower than the values in the control group. . On the other hand, the mesylate-powered monstat-administered group showed a slight suppression tendency of 2506 ± 530 IU / L, but no significant difference from the control group.

 As described above, the compounds of Examples 1 and 2 exhibited a significant inhibitory effect on knee inflammation induced by injection of caerulein, and were clearly superior to mesylate power statistics.

[Test Example 4] Closed Duodenal Loop (hereinafter abbreviated as "CDLj") in rats. Effect of this compound on acute knee inflammation model.

 The effect of the present compound on the CDL acute knee inflammatory model in rats was studied as follows.

 (Test substance)

 The compounds of Examples 1 and 2 and the mesylate-based power state were each dissolved in distilled water so as to have a concentration of 30 mg / 5 ml.

 (Test method)

 Ferrie M.M.e.a. was performed as follows according to the method described in Digestion, 18: 280-285 (1978). That is, using a male SD rat weighing about 200 g, after fasting for 12 hours, laparotomy was performed under anesthesia with chloral hydrate SSOmgZSm 1 / kg, and both sides of the duodenum were ligated around the opening of the common bile duct. After creating a 1 cm blind loop, the abdomen was closed. Blood was collected 6 hours after the blind loop was prepared, and the amylase and lipase levels in the serum were measured. The test substance was orally administered one hour before the preparation of the bride loop.

 (Test results)

 The results are shown in the following table.

 Table 4

Values represent mean SD (n = 8) p <0.001, significant difference from control group As shown in the table above, by creating a blind loop, The serum amylase level was 9784 ± 3] 70 IU / L, which was significantly higher than that of the normal group at 131818187 IU / L. On the other hand, in the group to which the compound of Example 1 or 2 was administered, the serum amylase value was 7747 ± 1590 IU / L and 8088 ± 2590 IU / L, respectively, which were slightly suppressed compared to the control group. ing. On the other hand, the mesylate-power moststat administration group showed a tendency to further increase from the control group to 11,292,3079 IU / L. The lipase value was 477 ± 169 IU / L and 483 ± 164 IU / L in the group to which the compound of Example 1 or 2 was administered, compared to 630 ± 231 IU / L in the control group. And the tendency to suppress slightly compared to the control group. On the other hand, the group receiving mesilate-powered statat showed a tendency to further increase to 801 ± 2851 l / l compared to the control group.

 As described above, in the present knee inflammation model, the mesylate power test showed no effect and showed a tendency to worsen, whereas the compounds of Examples 1 and 2 showed a tendency to suppress the rhoutitis. Was done.

 [Test Example 5]

 Effect of this compound on endotoxin acute acute inflammation model in rat

 The effect of this compound on rat endotoxin acute knee inflammation model was examined as follows.

 (Test substance)

 The compounds of Examples 1 and 2, and the mesylate-based power state were each dissolved in distilled water so as to have a concentration of 30 mg / 5 ml.

 (Test method)

Mizama et al., Modified the method described in Nikkei Gaijikai, 11: 822-828 (1978) as follows. That is, male SD rats weighing about 200 g were used, and after fasting for 12 hours, the abdomen was opened under anesthesia with hydrochloride hydrochloride 300 m 2 m 1 / kg, and the liver side of the common bile duct was closed with a temporary clip. 0.1 ml of an endotoxin solution (10 / z gZml) was retrogradely injected with a continuous syringe through a polyethylene tube (1 minute: at a flow rate of 6 ml), and after ligation of the common bile duct, the abdomen was sutured. . Blood was collected 7 hours after ligation of the common bile duct, and the amylase and lipase levels in the serum were measured. The test substance was administered 1 hour before ligation of the common bile duct. (Test results)

 The results are shown in the following table.

 Table 5

 Values indicate mean SD (n = 5): p <0.05, p <0.001, vs. control group As shown in the above table, injection of endotoxin into the common bile duct of rats resulted in control group The amylase level significantly increased from 2107 IU / L in 77 soils to 36980 ± 15795 IU / L in the normal group. On the other hand, in the group to which the compound of Example 1 was administered, the serum amylase value was 22844 ± 4080 IU / L, which was significantly suppressed as compared with the control group. In the group to which the compound of Example 2 was administered, the value was 28715 ± 13143 IU / L, which was also smaller than that in the control group. In contrast, the serum amylase value of the mesylate-powered monstat administration group was 32572 ± 13814 IU / L, indicating only a tendency of suppression compared to the control group.

In the control group, the serum lipase level was remarkably increased from 58.7 ± 35.3 IU / L in the normal group to 1430 ± 797 IU / L, whereas in the group to which the compound of Example 1 was administered, 701 ± 240 IU / L L and the magnitude of the rise were significantly less. In the group to which the compound of Example 2 was administered, the value was 914 ± 601 IU / L, which was also smaller than that in the control group. In contrast, the lipase level in the serum of the mesylate-powered monstat administration group was 1105 ± 647 IU / L, indicating a tendency toward suppression compared to the control group. As described above, in the present model, the compounds of Examples 1 and 2 have a stronger inhibitory effect on osteoarthritis than the mesilic acid power test Rukoto has been shown.

 [Test Example 6]

 Effect of this compound on acute etionine inflammation model in mice. 1

 Examples of the effects of this compound on mouse etionine acute knee inflammation model

The compound of No. 3 was added, and further studied by the same method as in Test Example 2. The results are shown in the following table.

 Table 6

 The value indicates the mean person SD (η == 8) ρ <0.001, significant difference from the control group As can be seen from the above table, the compound of Example 3 is similar to the compounds of Examples 1 and 2 in serum. It showed a significant inhibitory effect on the increase in amylase level.

 [Test Example 7]

 Effect of this compound on mouse etionine acute acute inflammation model 1

 The effect of this compound on the ethonin acute knee inflammation model in mice was investigated (test substance)

 The compounds of the examples used in the test were dissolved in physiological saline to make each lOmgZlOmL. Their dose was lOmgZkg.

 (Test method)

The test was performed according to the method of Lombardi II, Estes LW, Longnecker DS, Am. J. Pathol., 79: 465-480 (1975). As a test animal, a 3 week-old female R strain mouse purchased from Nippon Chars River Co., Ltd. was used. Choline deficiency in mice 0.5% Feeding a diet supplemented with DL-ethionine (prepared by CLEA Japan) induced severe knee inflammation of etionine. The normal group was given a normal diet (MF: Oriental yeast) ad libitum. Blood was collected 72 hours after the start of the choline-deficient 0.5% DL-ethionine supplemented diet, and the amylase level in the serum was measured.

 The test substance was administered intravenously a total of 6 times 0, 6, 24, 30, 48, and 54 hours after the start of the choline-deficient 0.5% DL-ethionine supplementation diet.

 (Test results)

The results are shown in the following Tables 7-1 to 7-3.

W

 • 39-

Table 7 — 1. Effects of this compound on etyonine acute tengitis model in mice

 Dose Amylase (IU / L) Inhibition rate (%) Control lOmL / kg 539122.9 ± 326119.0

Compound of Example 10 10 mg / kg 179502.8 ± 101766.4 ** 66.7

Nafamostat mesilate 10mg / kg 352562.7 ± 117857.8 34.6

Normal 1 10077.9 ± 1362.1 ***

 丄 Shi / Kg

Compound of Example 5 lOmg / kg 230847.3 ± 149416.6 * 57.7

Compound of Example 8 lOmg / kg 339300.0 ± 114368.4 37.9

Compound of Example 10 lOmg / kg 233109.3 ± 229395.5 57.3

Compound of Example 16 lOmg / kg 44657L0 ± 175273.2 18.2

Nafamostat mesilate lOmg / kg 372674.9 ± 14 2017.7 31.7

Normal 12779.8 ± 1463.6 ***

Values represent mean soil SD (n = 4-9) _c ρ <0.001, **: ρ <0 · 0], *: ρ <0.05, thought for control group

Table 7-2. Effect of this compound on etionine acute knee inflammation model in mice

 Dose Amylase (IU / L) Inhibition rate control lOmL / kg 433794.9 ± 202036.8 ―

Compound of Example 1 10 mg / kg 196736.0 ± 118942.6 ** 54.6

Compound of Example 2 lOmg / kg 170569.7 ± 38078.4 ** 60.7

Compound of Example 6 10 mg / kg 158390.8 ± 91171.1 ** 63.5

Compound of Example 7 lOmg / kg 253153.4 ± 100594.3 * 41.6

Compound of Example 10 lOmg / kg 170790.7 ± 52352.6 ** 60.6

Compound of Example 17 lOmg / kg 332847.5 ± 115047.7 23.3

Compound of Example 18 lOmg / kg 208700.6 ± 70260.8 * 51.9

Compound of Example 19 lOmg / kg 271796.3 ± 154623.7 37.3 Compound of Example 21 lOmg / kg 194300.0 ± 55307.1 ** 55.2

Compound of Example 22 lOmg / kg 345288.5 ± 205022.5 20.4

Compound of Example 23 lOmg / kg 379276.5 ± 179934.4 12.6

Nafamostat mesinolate lOmg / kg 277868.3 ± 82179.6 35.9

Normal 10052.3 ± 1016.7 ***

Values represent mean soil SD (π = 4-9). ρ <0 · 00〗, **: ρ <0.01, *: ρ <0.05, relative to control group

Table 7—3. Effects of this compound on mouse etionine acute knee inflammation model

 Dose Amylase (IU / L) inhibition rate

Control 10mL / kg 334071.7 ± 177298.7 I

Compound of Example 3 10 mg / kg 233696.5 ± 131894.1 30.0

Compound of Example 4 10 mg / kg 290915.1 ± 164996.9 12.9

Compound of Example 9 10 mg / kg 273682.7 ± 170160.1 18.1

Compound of Example 12 lOmg / kg 294780.9 ± 162216.8 11.8

Compound of Example 13 lOmg / kg 286329.4 ± 93875.3 14.3

Compound of Example 14 lOmg / kg 322559.8 ± 144214.7 3.4

Nafamostat mesilate lOmg / kg 279241.0 ± 81302.2 16.4

Normal 8870.4 ± 731.3

The value represents the average person SD (π = ^ 9 ρ <0.001 **: ρ <0.01 * ρ <0.05, relative to the control group

As shown in Table 7-1, when mice were fed a choline-deficient 0.5% DL-ethionine supplemented diet, serum amylase levels in the control group were significantly higher than in the normal group. In contrast, the amylase levels of each compound administration group and the nafamosate mesilate evening administration group in the examples increased in Table 7- :! As shown in Fig. 7-3, it was suppressed. From these results, it can be seen that the compounds of Examples 2, 3, 5, 6, 7, 8, 9, 10, 18, 19 and 21 have a stronger inhibitory effect on fleas than nafamosyl mesylate. it seems to do.

 [Test Example 8] Effect of the present compound on rat model of acute colitis in rats The effect of this compound on rat model of acute acute knee veinitis was examined. (Test substance)

 The compounds of the examples used in the test were dissolved in physiological saline to make 0.3 mL, 1, 3, 10, or 30 mg Z5 mL, and their doses were 0.3, 1, 3, 10, or 30 mg / kg, respectively. did.

 Nafamostat mesilate was dissolved in physiological saline to a concentration of 10 mg and 5 mL, and the dose was 10 mg / kg.

 (Test method)

 The test was performed according to the method of Ταηί S., Otsuki M., Ke oh H., Fujii I., Nakamura I., Oka I., Baba S., International Journal of Pancreatology, 2: 337-348 (1987).

 As test animals, male Wistar rats (body weight: about 200 g) purchased from SLC Japan were used. Acute edematous knee inflammation was induced by subcutaneously injecting cerulein (20 gZlmL / kg) four times every 2 hours into rats that had been fasted for 2 hours. Blood was collected 6 hours after the initial administration of caerulein, and the amylase, lipase, and trypsin-like activities in serum were measured. In addition, the wet weight of the knee was measured. The test substance was administered intravenously 0, 1, and 2 hours after the initial administration of caerulein.

 (Test results)

The results are shown in Tables 8-1 and 8-2. Table 8.Effects of this compound on rat serlene acute knee inflammation model

 Dosage Amylase (IU / L) Lipase (IU / L)

Control 5mL / kg 125959.4 ± 24624.1 5083.7 ± 2249.3 Compound of Example 10 0.3mg / kg 132795.8 ± 6828.2 4035.2 ± 555.4 Compound of Example 10 lmg / kg 110214.5 ± 28428.3 2985.6 ± 575.5 Shading Example 10 / 79657.2 ± 9804.3 ** 2430.5 ± 632.1 * Compound of Example 10 10 mg / kg 69536.2 ± 18233.6 ** 5583.7 ± 3511.4 Compound of Example 10 30 mg / kg 47328.0 ± 16879.3 *** 873.2 ± 190.5 ** Nafamostat mesinolate lOmg / kg 43606.3 ± 13057.4 *** 854.0 ± 116.7 **

Normal 5224.0 ± 333.4 *** 23.2 ± 9.4 *** The value represents the average soil S.D. (n = 5 to 8). ***: p <0.001, **: p <0.01, *: p <0.05, significant difference from control group Table 8-2. Effect of this compound on rat celerin acute knee inflammation model

 Dosage Trypsin-like activity Wet weight of the knee

(nmol / min / mL) (mg wet weight / 100g rat body weight) Control 5mL / kg 3.77 ± 0.35 927.5 ± 134.1 Compound of Example 10 0.3mg / kg 3.42 ± 0.66 923.6 ± 137.0 Compound of Example 10 lmg / kg 3.50 ± 0.39 1005.3 ± 81.7 Compound of Example 10 3mg / kg 3.53 ± 0.56 1104.8 ± 96.6 * Compound of Example 10 lOmg / kg 3.95 ± 1.82 943.8 ± 158.2 Compound of Example 10 30mg / kg 2.36 ± 0.28 *** 704.2 ± 95.2 ** Nafamostat mesilate lOmg / kg 3.38 ± 0.14 * 579.3 ± 161.3 ** Normal 2.14 ± 0.50 *** 404.0 ± 15.2 * Ne * The value represents the average soil SD (n = 5-8). ***: p <0.001, **: p <0.01, *: p <0.05, significant difference from control group As shown in Tables 8-1 and 8-2, subcutaneous administration of caerulein to rats significantly increased serum amylase, lipase, and trypsin-like activities in the control group compared to the normal group. And the wet weight of the tunnel increased significantly.

 On the other hand, in the compound administration group of Example 10, the increase in amylase level was significantly suppressed in a dose-dependent manner. Similar results were obtained in the nafamos mesylate evening group.

 In the compound-administered group of Example 10, the increase in lipase value was also significantly suppressed in a dose-dependent manner. In addition, results equivalent to those of the nafamostat mesilate administration group were obtained.

 The increase in trypsin-like activity was also significantly suppressed in a dose-dependent manner by administration of the compound of Example 10, and the effect was stronger than in the nafamostat mesilate administration group. The increase in the wet weight of the kidney was also significantly suppressed in a dose-dependent manner by the administration of the compound of Example 10. In the nafamostat mesilate administration group, even stronger suppression was observed. Taken together, these results indicate that the compound of Example 10 has almost the same knee-suppressing activity as nafamostat mesilate.

 [Test Example 9]

 Effect of this compound on rat CDL acute knee inflammation model

 The effects of the present compound on rat CDL acute knee inflammation model were examined.

 (Test substance)

 The compounds of the examples used in the test were dissolved in physiological saline to give a concentration of 3, 10 or SOmg / ZSmL, and the dose was 3, 10, or SOmg / kg.

 Nafamostat mesilate was dissolved in physiological saline to a concentration of 10 mg / 5 mL, and the dose was 10 mg / kg.

 (Test method)

 Ferrie M.M., O'Hare R., Joff S.N., Digestion, 8: 280-285 (1 978).

Approximately 220 g of a Wistar male rat purchased from S.L.I.C. was used as a test animal. Rats fasted for 2 hours were converted to pentobarbital Na 40 mg / 1 The abdomen was opened under anesthesia with m LZ kg, and a 1-cm long blind loop was created by ligating both sides of the duodenum around the opening of the common bile duct. Blood was collected 6 hours after the creation of the blind loop, and the serum amylase, lipase, and trypsin-like activities were measured. In addition, the wet weight of the knee was measured. The test substance was administered intravenously 0, 1, and 2 hours after the blind loop was created.

 (Test results)

Table 9 shows the results.

Table 9. Effect of this compound on rat CDL acute knee inflammation model

 Dose Amylase (IU / L) Lipase (IU / L) Control 5 mL / kg 51150.2 ± 16925.2 1282.4 ± 742.2 Compound of Example 10 3 mg / kg 30195.0 ± 7129.7 * 680.6 ± 155.3 Compound of Example 10 10 mg / kg 29134.3 ± 2728.3 ** 1080.6 ± 314.1 Compound of Example 10 30 mg / kg 27695.4 ± 3507.2 * 781.0 ± 84.1 Nafamostat mesinolate lOmg / kg 56784.1 ± 26349.6 1199.0 ± 858.9 Sham operation-8828.8 ± 2677.8 *** 48.7 ± 13.9 *** Dose Trypsin Like activity 湿 wet weight

(nmol / min / mL) (mg wet weight / 100g rat body weight) Control 5mL / kg 27.56 ± 5.36 753.5 ± 88.6 Compound of Example 10 3mg / kg 21.06 ± 7.87 * 697.0 ± 76.2 Compound of Example 10 lOmg / kg 22.45 ± 6.77 706.6 ± 65.1 Compound of Example 10 lOmg / kg 17.91 ± 2.70 *** 667.1 ± 20.7 Nafamostat mesinolate lOmg / kg 15.32 ± 5.23 *** 818.5 ± 138.5 Sham operation 4.41 ± 2.68 *** 361.9 ± 32.2 ** * Value represents mean soil SD (n = 4-20) <p <0.001, **: p <0.01 p <0.05, vs control group

As shown in Table 9, by creating a blind loop in rats, the amylase, lipase, and trypsin-like activities in serum were significantly increased in the control group compared to the sham-operated group, and in the knee. The wet weight of the offal increased significantly. On the other hand, in the compound administration group of Example 10, the increase in amylase level was significantly suppressed in a dose-dependent manner. On the other hand, in the nafamostat mesilate administration group, the amylase level tended to be further enhanced rather than increased. In addition, the increase in the lipase level was suppressed in both the group administered with the compound of Example 10 and the group administered with nafamostat mesilate. The increase in trypsin-like activity was significantly suppressed in a dose-dependent manner by administration of the compound of Example 10. Also, in the nafamos mesylate evening administration group, the increase in tribcine-like activity was significantly suppressed. The increase in wet weight of the knee tended to be suppressed in a dose-dependent manner by the compound of Example 10. In contrast, in the nafamostat mesilate group, the increase in the wet weight of the knee tended to be further enhanced.

 As described above, the compound of Example 10 is considered to have a stronger inhibitory effect on osteoarthritis than nafamosid mesylate.

 [Formulation Example 1] Oral tablet

Compound of any of Examples 1 to 23

Lactose 75mg

Starch 20mg

Polyethylene glycol 6000 5mg

 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 '

Mannitol 5.0g

 IN Sodium hydroxide suitable amount (pH 5)

Distilled water 100% 1

The above components were mixed by a conventional method to form a solution, and then sterile-filtered. Fill the pull aseptically and seal the ampoule. Industrial applicability

 The present invention is intended for remission of acute symptoms of knee inflammation (acute knee inflammation after surgery, acute knee inflammation after angiography, other acute inflammation including traumatic knee inflammation, and acute exacerbation of chronic knee inflammation). It enables the manufacture of useful, therapeutic agents for knee inflammation.

Claims

The scope of the claims

1. As an active ingredient, general formula (I)

(Wherein, shaku 1 and! ¾2 are the same or different and each represents a hydrogen atom or a lower alkyl group, or R 1 and R 2 are taken together to form-(CH ₂ ) ₂ --NH-(CH ₂ ) _2—

 R 3 represents hydrogen or a lower alkyl group,

 R4, R5 and R6 each represent a hydrogen atom, or two of R4, R5 and R6 represent a hydrogen atom and the others represent a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoro group. Represents a methyl group, or one of R4, R5 and R6 is a hydrogen atom and the other is the same or different and is a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group Or R4, scales 5 and 1-6 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 are the same or different and represent a nitrogen atom or a carbon atom. Or a pharmaceutically acceptable salt thereof.

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, 15 and 1 ^ 6 each represent a hydrogen atom. Represents an atom, or R4, 1 ^ 5 and 1¾6 are one, two or three of them 2. The anti-inflammatory agent according to claim 1, wherein the agent represents 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.

 3. In the general formula (I), Rl, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent Claim 1 wherein one, two or three of them represent a lower alkyl group, and when one or two of R4, R5 and R6 represent a lower alkyl group, the others represent a hydrogen atom. The therapeutic agent for inflammation according to claim.

4. In the general formula (I), each of 11 and 1¾2 represents a lower alkyl group, or R 1 and R 2 are taken together and — (CH ₂ ) —NH— (CH ₂ ) ₂ , R 3 represents a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent one of them being a lower alkoxy group and the other two being hydrogen The therapeutic agent for knee inflammation according to claim 1, which represents an atom.

 5. In the general formula (I), Rl, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent 2. The anti-inflammatory agent according to claim 1, wherein one represents a halogen and the other two represent a hydrogen atom.

 6. In the general formula (I), R 1 and R 2 each represent a hydrogen atom, R 3 represents a lower alkyl group, W 1 and W 2 each represent a carbon atom, and R 4 and R 5 2. The therapeutic agent for treating inflammation according to claim 1, wherein one or two of R 6 and R 6 represent a lower alkoxy group and the other represents a hydrogen atom.

 7. —In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, and W 1 and W 2 each represent a carbon atom and the other represents a nitrogen atom, or Both of them represent a nitrogen atom and R4, 5 and! ¾6 each represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group. 2. The therapeutic agent for knee inflammation according to claim 1, wherein the other represents a hydrogen atom.

 8. The active ingredient is

(1) 3— [4-1 (2-methoxyphenyl) piperazinyl] 1 1 1 (4-amino Phenoxy) 2-propane

 (2) 3- (4- (2-Methylphenyl) piperazinyl) 1-1-1 (4-aminophenyl) propan-1-ol

 (3) 3-[4- (2-methoxyphenyl) piperazinyl]-1- (4-dimethylaminophenoxy) propane 1- 2-ol

 (4) 3 — [4- (2-methoxyphenyl) piperazinyl] 1-11 (4-amino-3-methylphenoxy) propane

 (5) 3 — [4- (2-Fluorophenyl) piperazinyl] -1- (4-aminophenoxy) propan-1-ol

 (6) 3— [4- (3-methoxyphenyl) piperazinyl] 1 1— (4-aminophenoxy) propan-2-ol

 (7) 3— [4- (4-methoxyphenyl) piperazinyl] 1 1 — (4-aminophenoxy) propan-1-ol

 (8) 3— [4— (2,3-Dimethoxyphenyl) piperazinyl] 1 1— (4—Aminophenoxy) propan-1-2

 (9) 3— [4- (3,5-dimethoxyphenyl) piperazinyl] 1 1— (4-1 aminophenoxy) propane 1 2—ol

 (10) 3— [4- (2,3-dimethylphenyl) piperazinyl] 1 1 — (4-aminophenoxy) propan-1-ol

 (11) 3— [4- (2,5-dimethylphenyl) piperazinyl] — 1 — (4-aminopynoxy) propan-1-ol

 (12) 3— [4- (4,6-Dimethoxypyrimidine-1-yl) piperazinyl] -1- (4-aminophenoxy) propan-1-ol

 (13) 3— [4— (2.3, 4-trimethoxyphenyl) piperazinyl] 1 1 — (4-aminophenoxy) propane 1 2—ol

 (14) 3— [4 _ (2-pyridyl) piperazinyl] 1 1 — (4-aminophenol) propane 1 2-ol

(15) 3— [4-1 (2-methoxyphenyl) piperazinyl] 1 1 — (4-pipera Dinylphenoxy) propane-1-ol

 (16) 3-([4-phenylpiperazinyl])-1- (4-aminophenoxy) propan-1--2-ol

 (17) 3- [4- (2-aminophenyl) piperazinyl] 1- (4-aminophenoxy) propan-2-ol

 (18) 3- (4- (3-methylphenyl) piperazinyl) — 1- (4-aminophenoxy) propan-1-ol

 (19) 3-[4- (2-chlorophenyl) piperazinyl] 1 1-(4-aminophenyl) propan-1-ol

 (20) 3- (4- (2-ethoxyphenyl) piperazinyl)-1- (4-aminophenyl) propan-l-ol

 (21) 3— [4— (2-Methoxyphenyl) piperazinyl] 1 1— (2-Aminophenoxy) propan 1—2-ol

 (22) 3- [4- (2-methoxyphenyl) piperazinyl] 1-1- (3-aminophenoxy) propan-2-ol, and

 (23) 3- [4- (3-trifluoromethylphenyl) piperazinyl] 1 1 1- (4-aminophenoxy) propan-1-2-ol

The remedy for tengitis according to claim 1, which is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

 9. General formula (Π)

(II)

(Wherein 111 and 12 are the same or different and each represent a hydrogen atom or a lower alkyl group, or R 1 and R 2 together form one (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ — represents

 R 3 represents hydrogen or a lower alkyl group,

 R 4, shaku 5 and! ¾ 6 each represent a hydrogen atom, or two of R 4, R 5 and R 6 represent a hydrogen atom and the others represent lower alkyl, lower alkoxy, halogen, amino or Represents a trifluoromethyl group, or one of R4, R5 and R6 is a hydrogen atom and the other is the same or different and is a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl Represents a methyl group, or R4, 1¾5 and 1 全 て 6 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 are the same or different from each other and represent a nitrogen atom or a carbon atom, provided that when R1, R2 and R3 are all hydrogen atoms and W1 and W2 are both carbon atoms, :

 (1) R4, R5 and R6 do not all represent a hydrogen atom at the same time,

 (2) R4, 115 and 116 are such that when one of them represents a methoxy group, the other two do not simultaneously represent a hydrogen atom,

 (3) R4, 1¾5 and 116 are such that when one of them represents a chlorine atom at position 4, the other two do not represent a hydrogen atom, and

 (4) In R4, 1、5 and scale 6, when one of them represents an amino group, the other two do not represent a hydrogen atom. )

Or a pharmaceutically acceptable salt thereof.

 10. In the general formula (II), Rl, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent 10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein two or three of them represent a lower alkoxy group and the other represents a hydrogen atom.

1 1. In the general formula (Π), R 1, R 2 and R 3 each represent a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent U Wherein one, two or three 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. Item 10. The compound according to item 9, or a pharmaceutically acceptable salt thereof.

1 2. —In the general formula (Π), 111 and 1¾2 each represent a lower alkyl group, or R 1 and R 2 together form one (CH ₂ ) ₂ — NH— (CH ₂ ) ₂ —

R 3 represents a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent one of them representing a lower alkoxy group and the other two representing a hydrogen atom. 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

 1 3. In the general formula (II), Rl, R2 and R3 each represent a hydrogen atom, W1 and W2 each represent a carbon atom, and R4, R5 and R6 represent 10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein one of them represents a halogen bonded to the 2- or 3-position of the phenyl group and the other two represent a hydrogen atom.

 14. In the general formula (II), R 1 and R 2 each represent a hydrogen atom, R 3 represents a lower alkyl group, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and 10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein one or two of R 6 represent a lower alkoxy group and the other represents a hydrogen atom.

 1 5. In the general formula (II), R 1, R 2 and R 3 each represent a hydrogen atom, and W 1 and W 2 represent whether one of them represents a carbon atom and the other represents a nitrogen atom, or Represents both nitrogen atoms, and R4, R5, and R6 each represent a hydrogen atom, or one or two of R4, R5, and R6 represent a lower alkoxy group. 10. The compound according to claim 9, wherein the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof.

 1 6. (1) 3— [4- (2-methylphenyl) piperazinyl] -1-1 (4-aminophenoxy) propan-1-ol

 (2) 3- (4-1- (2-methoxyphenyl) piperazinyl) 1-1-1 (4-dimethylaminophenoxy) propane-1-2-ol

(3) 3- (4-1- (2-methoxyphenyl) piperazinyl) -1 1- (4-amino-3-methylphenoxy) propan-2-ol (4) 3- (4- (2-fluorophenyl) piperazinyl) 1-1-1 (4-aminophenoxy) propan-1-ol

 (5) 3- (4- (2,3-Dimethoxyphenyl) piperazinyl)-1- (4-aminophenoxy) propan-1-ol

 (6) 3— [4-1 (3,5-dimethoxyphenyl) piperazinyl] 1 1 1 (4 1-aminophenoxy) propane 1 2—ol

 (7) 3- (4- (2,3-dimethylphenyl) piperazinyl) 1-1-1 (4-aminophenyl) propan-1-ol

 (8) 3-[4- (2,5-dimethylphenyl) piperazinyl] 1 1-(4-aminophenoxy) propan-2-ol

 (9) 3- [4- (4,6-Dimethoxypyrimidin-2-yl) piperazinyl] 1 1 1 (4-Aminophenoxy) propan-1-ol

 (10) 3— [4— (2,3,4-trimethoxyphenyl) piperazinyl] 1 1 1 (4 1-aminophenoxy) propane 1 2—ol

 (11) 3- (4-1- (2-pyridyl) piperazinyl) 1-1-1 (4-aminophenol) 2-propane

 (12) 3- [4- (2-Methoxyphenyl) piperazinyl] 1-11 (4-piperazinylphenoxy) propan-1-ol

 (13) 3- (4-1- (3-methylphenyl) piperazinyl) 1-1-1 (4-aminophenyl) propan-1-ol

 (14) 3- [4- (2-chlorophenyl) piperazinyl] 1- (4-aminophenoxy) propan-1-ol

 (15) 3- [4- (2-ethoxyphenyl) piperazinyl] 1 1-(4-aminophenoxy) propan-1-ol, and

 (16) 3- (4- (3-trifluoromethylphenyl) piperazinyl) 1 1 — (4-aminophenoxy) propan-1- 2-ol

10. The compound according to claim 9, which is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

7. General formula (I)

(Where 1 and 2 are the same or different and each represent a hydrogen atom or a lower alkyl group, or R 1 and R 2 together form one (CH ₂ ) 2-NH- (CH ₂ ) ₂ — represents

 R 3 represents hydrogen or a lower alkyl group,

 R4, shaku 5 and! ^ 6 represents a hydrogen atom, or two of R4, 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. At least one of R4, R5 and R6 is a hydrogen atom and the other is the same or different and represents a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group; or , R4, 5 and! ¾6 are all the same and represent 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 and represent a nitrogen atom or a carbon atom. A method for treating human inflammation in mammals including humans, which comprises administering an effective amount of the compound represented by the formula or a pharmaceutically acceptable salt thereof to a patient with knee inflammation.

1 8. —In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, 5 and! ¾ 6 represent R 4, R 5 and R 6 each represent a hydrogen atom, or one, two or three of them represent a lower alkoxy group, wherein one of R 4, R 5 and R 6 represents One or two 18. The method for treating knee inflammation according to claim 17, wherein when represents a lower alkoxy group, the others represent a hydrogen atom.

 1 9. In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent One, two or three of them represent a lower alkyl group, and when one or two of R4, R5 and R6 represent a lower alkyl group, the other represents a hydrogen atom; The method for treating knee injuries according to claim 17.

20. —In the general formula (I), 1 and! ^ 2 each represent a lower alkyl group, or R 1 and R 2 are taken together— (CH ₂ ) 2-NH— (CH ₂ ) ₂ —, R 3 represents a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent one of them representing a lower alkoxy group and the other two representing The method for treating knee inflammation according to claim 17, which represents a hydrogen atom.

 2 1. In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent 18. The method for treating knee inflammation according to claim 17, wherein one of them represents halogen and the other two represent hydrogen atoms.

 22. In the general formula (I), R 1 and R 2 each represent a hydrogen atom, R 3 represents a lower alkyl group, W 1 and W 2 each represent a carbon atom, and R 4 and R 4 The method for treating knee inflammation according to claim 17, wherein one or two of 5 and R6 represent a lower alkoxy group and the other represents a hydrogen atom.

 23. —In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, and W 1 and W 2 each represent one carbon atom and the other represents a nitrogen atom, or Both represent a nitrogen atom and R4, 1-5 and 1-6 all represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group and 18. The method for treating knee inflammation according to claim 17, wherein represents a hydrogen atom.

 24. The compound or a pharmaceutically acceptable salt thereof,

(1) 3— [4- (2-methoxyphenyl) piperazinyl] 1 1- (4-aminophenoxy) propan-1-ol (2) 3- (4- (2-methylphenyl) piperazinyl) 1- (4-aminophenyl) propan-2-ol

 (3) 3- (4- (2-methoxyphenyl) piperazinyl) 1-1-1 (4-dimethylaminophenoxy) propan-1-ol

 (4) 3— [4— (2-Methoxyphenyl) piperazinyl] 1 1— (4-amino-13-methylphenoxy) propan-2-ol

 (5) 3- (4- (2-fluorophenyl) piperazinyl) 1-1- (4-aminophenoxy) propan-1-ol

 (6) 3— [4- (3-methoxyphenyl) piperazinyl] 1-1-1 (4-amino phenoxy) propane 1-2-ol

 (7) 3- (4-1- (4-methoxyphenyl) piperazinyl) 1-1-1 (4-aminophenoxy) propan-1-ol

 (8) 3- [4-1 (2,3-dimethoxyphenyl) piperazinyl] 1 1 1 (4 1-aminophenoxy) propan-1-ol

 (9) 3- (4- (3,5-dimethoxyphenyl) piperazinyl)-1- (4-aminophenoxy) propan-1--2-ol

 (10) 3- (4- (2,3-dimethylphenyl) piperazinyl) 1-11 (4-amino phenoxy) propan-1-ol

 (11) 3— [4- (2,5-dimethylphenyl) piperazinyl] — 1— (4-aminophenyl) propan-1-ol

 (12) 3- (4- (4,6-Dimethoxypyrimidine-1-yl) piperazinyl) 1-1- (4-aminophenoxy) propan-1-ol

 (13) 3- (4- (2,3,4-trimethoxyphenyl) piperazinyl)-1- (4-aminophenoxy) propan-2-ol

 (14) 3- (4-1- (2-pyridyl) piperazinyl) 1-1- (4-aminophenol) propane-1-ol

(15) 3- [4- (2-Methoxyphenyl) piperazinyl] 1- (4-piperazinylphenoxy) propan-2-ol (16) 3— [4-Phenylpiperazinyl] 1-1— (4-aminophenoxy) propan-1--2-ol

 (17) 3- (4- (2-aminophenyl) piperazinyl) 1 1 — (4-aminophenyl) propan-1-ol

 (18) 3- [4- (3-methylphenyl) piperazinyl] -1-1 (4-aminophenyl) propan-2-ol

 (19) 3- (4- (2-chlorophenyl) piperazinyl) 1- (4-aminophenyl) propan-1-ol

 (20) 3— [4- (2-ethoxyphenyl) piperazinyl] 1-11 (4-aminophenoxy) propan-2-ol

 (21) 3— [4- (2-methoxyphenyl) piperazinyl] 1-11 (2-aminophenoxy) propan-1-ol

 (22) 3- [4- (2-Methoxyphenyl) piperazinyl] -1- (3-aminophenoxy) propan-2-ol, and

 (23) 3- (4- (3-trifluoromethylphenyl) piperazinyl) 1 1 1 (4-aminophenoxy) propan-1 2-ol

The method for treating knee inflammation according to claim 17, wherein the method is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

 2 5. General formula (I) for the manufacture of Teng flame treatment agent

(I)

(Wherein, Shaku 1 and! 12 are the same or different and each represent a hydrogen atom or a lower alkyl group, or R 1 and R 2 are taken together to form-(CH ₂ ) 2-NH- (CH ₂ ) ₂ —

 R 3 represents hydrogen or a lower alkyl group,

 R4, 5 and 1-6 each represent a hydrogen atom, or two of R4, R5 and R6 represent a hydrogen atom and the others are lower alkyl, lower alkoxy, halogen, amino or trifluoro. Represents a methyl group, or one of R4, R5 and R6 is a hydrogen atom and the other is the same or different and is a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group. Or R4, 15 and 1-6 are all the same and represent 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 and represent a nitrogen atom or a carbon atom. ) Use of the compound of the formula or a pharmaceutically acceptable salt thereof.

 26. —In general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, 1¾5 and 6 each represent a hydrogen atom Represents an atom, or R4, R5 and R6 represent one, two or three of them representing a lower alkoxy group, wherein one or two of R4, R5 and R6 represent 26. Use according to claim 25, wherein one represents a lower alkoxy group and the other represents a hydrogen atom.

 27. 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 Wherein one, two or three 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. Use of clause 25.

28. —In formula (I), 1 and! 12 each represent a lower alkyl group, or R 1 and R 2 together form one (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ —, R 3 represents a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent one of them being a lower alkoxy group and the other two being hydrogen atom 26. Use according to claim 25, which represents

 2 9. —In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 represent 26. Use according to claim 25, wherein one of them represents halogen and the other two represent hydrogen atoms.

 30. —In the general formula (I), R 1 and R 2 both represent a hydrogen atom, R 3 represents a lower alkyl group, W 1 and W 2 both represent a carbon atom, and R 4 and 26. The use according to claim 25, wherein one or two of R5 and R6 represent a lower alkoxy group and the other represents a hydrogen atom.

 3 1. In the general formula (I), R 1, R 2 and R 3 each represent a hydrogen atom, and W 1 and W 2 each represent a carbon atom and the other represents a nitrogen atom. Represents both nitrogen atoms, and R4, 5 and 1-6 each represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group. 26. Use according to claim 25, wherein the other represents a hydrogen atom.

 3 2. The compound or a pharmaceutically acceptable salt thereof,

 (1) 3— [4— (2-Methoxyphenyl) piperazinyl] 1 1— (4-Aminophenoxy) propan-1-ol

 (2) 3- (4- (2-Methylphenyl) piperazinyl) 1 1 — (4-aminophenyl) propan-1-ol

 (3) 3- (4- (2-Methoxyphenyl) piperazinyl) 1-1-1 (4-dimethylaminophenoxy) propan-1-ol

 (4) 3— [4- (2-methoxyphenyl) piperazinyl] 1 1 — (4-amino-1-3-methylphenoxy) propan-2-ol

 (5) 3— [4- (2-fluorophenyl) piperazinyl] 1 1 — (4-aminophenoxy) propan-1-ol

 (6) 3— (4— (3-Methoxyphen) piperazinyl) 1 1— (4—amino phenoxy) propane 1—2-ol

(7) 3— [4- (4-methoxyphenyl) piperazinyl] 1 1 — (4-amino Phenoxy) 2-propane

 (8) 3— [4— (2,3-Dimethoxyphenyl) piperazinyl] 1 1— (4—Aminophenoxy) propane 1—2-ol

 (9) 3— [4- (3,5-Dimethoxyphenyl) piperazinyl] 1 1— (4-1Aminophenoxy) propan-1-2-ol

 (10) 3-[4- (2,3-dimethylphenyl) piperazinyl] 1-1 (4-aminophenoxy) propane 1-2-ol

 (11) 3- (4- (2,5-dimethylphenyl) piperazinyl) -1-1 (4-aminophenoxy) propan-2-ol

 (12) 3— [4- (4,6-dimethoxypyrimidine-1-yl) piperazinyl] — 1— (4-aminophenoxy) propan-1-ol

 (13) 3-[4-1 (2,3,4-trimethoxyphenyl) piperazinyl] 1-1 (4-aminophenoxy) propane 1-2-ol

 (14) 3- [4- (2-pyridyl) piperazinyl] 1-1-1 (4-aminophenoxy) propan-2-ol

 (15) 3- (4- (2-Methoxyphenyl) piperazinyl) 1-1-1 (4-piperazinylphenoxy) propan-1-2-ol

 (16) 3-([4-phenylbiperazinyl])-1-1 (4-aminophenoxy) propan-2-ol

 (17) 3- (4- (2-aminophenyl) piperazinyl) 1-1-1 (4-aminophenyl) propan-1-ol

 (18) 3- [4- (3-methylphenyl) piperazinyl] 1- (4-aminophenyl) propan-2-ol

 (19) 3- (4- (2-chlorophenyl) piperazinyl) 1- (4-aminophenoxy) propan-1-ol

 (20) 3— [4- (2-ethoxyphenyl) piperazinyl] 1 1— (4-aminophenoxy) propan-1-ol

(21) 3-[4-1 (2-methoxyphenyl) piperazinyl] 1 1-(2-amino Phenoxy) 2-propane

 (22) 3- [4- (2-methoxyphenyl) piperazinyl] 1 1- (3-aminophenoxy) propan-2-ol, and

 (23) 3 — [4-1 (3-trifluoromethylphenyl) piperazinyl] 1 1 1 (4 -aminophenoxy) propane 1-2-ol

26. The use according to claim 25, which is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.