JPH069622A - 2-alkoxyquinoxaline derivative, its production and its use - Google Patents

Abstract

PURPOSE:To obtain a new 2-alkoxyquinoxaline derivative exhibiting strong affinity for serotonin 1A receptor and useful as a therapeutic agent for serotonin nerve related diseases. CONSTITUTION:A compound of formula I (n is 2-4; R<1> is H or methyl; R<2> is 2-pyridyl or 2-pyrimidinyl) or its salt, e.g. 2-[2-{4-(2-pyridyl)-1- piperazinyl}ethoxy]-3-methylquinoxaline. The compound is obtained by reacting, e.g. a compound of formula II (X is eliminable group) with a compound of formula III in an inactive solvent. The compound is useful as a tranquilizer, an antidepressant, an antihypertensive agent or an antiemetic (including an anti-kinesia agent, an anti-space sickness agent or an anti-dizziness agent).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 2-alkoxyquinoxaline derivative, more specifically, an anxiolytic agent, antidepressant agent, blood pressure lowering agent, antiemetic agent (anti-sickness agent, anti-space sickness agent,
The present invention relates to a 2-alkoxyquinoxaline derivative useful as a medicine such as an anti-vertigo agent, etc., a method for producing the same, and its use.

[0002]

Compounds having an affinity for serotonin 1A receptors include anxiolytic agents, antidepressants, antihypertensive agents, antiemetic agents (including anti-motion sickness agents, anti-space sickness agents, anti-vertigo agents, etc.), etc. It is known that these compounds are useful as these, and many reports have already been made on these compounds (Japanese Clinical Practice Vol. 47, 19).
1989 special issue, pages 1241-1248, JP Feigh
nev, WFBoyer, Psychopathology, 22 , 21 (1989), PRSa
xenaC.M.Villalon, TiPS, 11 , 95 (1990), N. Matsuki et
al., Jpn. J. Pharmacol. Suppl., 58 , 313 (1992)).

[0003]

However, it has been desired to broadly search and find compounds having the above-mentioned pharmacological actions and to provide them.

[0004]

Means for Solving the Problems The present inventors have synthesized various compounds and investigated their pharmacological actions. As a result, 2-alkoxyquinoxaline derivatives represented by the following formula (I) have not been reported in the literature. Described and excellent serotonin 1
The present invention has been completed by finding that it has affinity for A receptor. Therefore, a first object of the present invention is to provide the following general formula (I)

[0005]

[Chemical 10] (In the formula, n is an integer of 2 to 4, R ₁ is a hydrogen atom or a methyl group, and R ₂ is a 2-pyridyl group or a 2-pyrimidinyl group) or a non-toxic poison thereof. It provides a natural salt. Also,
A second object of the present invention is to provide a method for producing a 2-alkoxyquinoxaline derivative represented by the above formula (I) or a non-toxic salt thereof. Still another object of the present invention is to provide a compound represented by the following general formula (VI) which is useful as an intermediate in the above production method.

[0006]

[Chemical 11] (Wherein X ′ represents a halogen atom or a hydroxyl group, and n and R ₁ have the same meanings as described above). Furthermore, another object of the present invention is to provide a therapeutic agent for serotonin nervous system-related diseases, which comprises a 2-alkoxyquinoxaline derivative represented by the general formula (I) or a non-toxic salt thereof as an active ingredient. .
The compound (I) of the present invention can be produced, for example, by the following general formula (II)

[0007]

[Chemical 12] (Wherein, n and R ₁ have the same meanings as described above, and X represents a leaving group), and a compound represented by the general formula (III)

[0008]

[Chemical 13] It is produced by reacting a compound represented by the formula (wherein R ₂ has the same meaning as described above) in an inert solvent.

The compound represented by the above general formula (II) (hereinafter referred to as compound (II)) is a novel compound which has not been described in the literature, and is a useful intermediate used in the production method of the present invention. In this compound (II), X represents a leaving group,
The leaving group means a group capable of increasing the reactivity with the compound (III) and leaving, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a methanesulfonyloxy group or a benzenesulfonyloxy group. Group, an alkyl or arylsulfonyloxy group such as a p-toluenesulfonyloxy group, and the like.

The compound represented by the general formula (III) (hereinafter referred to as compound (III)) is commercially available and can be obtained from, for example, Aldrich Co., Tokyo Kasei Co. and the like. The inert solvent used in the reaction of the compounds (II) and (III) is not particularly limited as long as it does not adversely affect the reaction, but preferable examples include, for example, benzene, toluene, xylene, Examples thereof include dimethylformamide, acetonitrile, acetone and the like.

In this reaction, it is preferable to allow a deoxidizing agent to be present. Examples of the deoxidizing agent include inorganic or organic bases. Specifically, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, Examples thereof include carbonates, bicarbonates or hydrides of alkali or alkaline earth metals such as sodium hydride, and tertiary amines such as triethylamine and pyridine.

Basically, the compound (II) and the compound (III) may be reacted in an equivalent amount.
5 equivalents, particularly preferably 1.2 to 2.0 equivalents, are used. The deoxidizing agent is usually preferably used in an amount equivalent to that of the compound (III).

Although the above reaction can proceed at room temperature, it is usually preferable to carry out it under heating conditions, for example under solvent reflux conditions. The reaction time may be appropriately selected depending on the combination of compounds, reaction temperature and the like, and may be completed after confirming that the reaction has proceeded sufficiently, but the reaction is usually completed in 1 hour to several days.
The amount of the solvent may be selected as appropriate and is, for example, 10 to 200 times the volume of the compound (II). The compound (II) which is a starting material has, for example, the general formula (IV)

[0014]

[Chemical 14] (Wherein R ₁ has the same meaning as described above) (hereinafter referred to as compound (IV)) and the general formula (V)

[0015]

[Chemical 15] (In the formula, n represents the same meaning as described above, Y represents a halogen atom, and X ′ represents a hydroxyl group or a halogen atom) and a compound (hereinafter, referred to as compound (V)) in an inert solvent. General reaction (VI)

[0016]

[Chemical 16] (Wherein n, R ₁ and X ′ have the same meanings as described above), and when X ′ is a hydroxyl group, it can be obtained by converting the hydroxyl group with a leaving group X. .

The compound (IV) used here is a known compound and is commercially available, for example, from Aldrich.

In the compound (V), when the group Y and the group X ′ are both halogen atoms, the group Y and the group X ′ may be the same halogen atom or different. However, it is more preferable that the group Y is a more reactive group than the group X ′. Specific preferred compound (V) is a compound having a combination such that the group Y is bromine, the group X'is a hydroxyl group or a chlorine atom, the group Y is a chlorine atom, and the group X'is a hydroxyl group. Commercially available products of, for example, Tokyo Kasei Co., Ltd. can be advantageously used as these compounds.

The inert solvent used in the reaction of the compound (IV) and the compound (V) is not particularly limited as long as it does not adversely affect the reaction, but preferable examples include benzene, toluene and xylene. , Dimethylformamide, acetonitrile, acetone, t-butyl alcohol and the like. In this reaction, a deoxidizing agent is preferably present, and examples of the deoxidizing agent include alkali carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and potassium hydroxide, or alkaline earth metals. Examples thereof include metal carbonates, bicarbonates, hydrides or hydroxides, and inorganic or organic bases such as tertiary amines such as triethylamine and pyridine.

However, in this reaction, a substitution product of a carbonyl group as an objective product with an oxygen atom (referred to as an O-substitution product) and a substitution product with a nitrogen atom as a by-reaction product (referred to as an N-substitution product). ) And are produced in various ratios depending on the conditions, it is necessary to pay attention to the reaction conditions. Especially 1,8-diazabicyclo [5.4.0] -7-undecene (hereinafter DB
(Sometimes abbreviated as U) is preferable because the production rate of O-substitutes increases. On the other hand, if water is added to the solvent, the amount of N-substituted compound increases, which is not preferable.

[0021]

[Chemical 17]

The compound (IV) and the compound (V) may be basically reacted in an equivalent amount, but the compound (V) is usually used in an amount of 1 to 10 equivalents, particularly preferably 1 to 5 equivalents. Moreover, it is preferable to use an equivalent amount of the compound (V) as the deoxidizing agent.

The above reaction may be carried out under heating conditions from room temperature, for example, at 50 to 120 ° C. The reaction time may be appropriately selected depending on the combination of compounds, the reaction temperature and the like, and may be completed after confirming that the reaction has sufficiently proceeded, but the reaction is usually completed in 1 hour to 1 day. The amount of the solvent may be selected as appropriate and is, for example, 10 to 200 times the volume of the compound (IV).

Further, in the above compound (VI), the group X '
When is a hydroxyl group, a reaction for converting the hydroxyl group into the leaving group X is carried out. To convert the hydroxyl group into the leaving group X, a conventionally known method may be used. For example,
In order to convert a hydroxyl group into a halogen atom, it may be treated with a halogenating agent such as thionyl chloride or phosphorus pentachloride, and the hydroxyl group may be alkyl such as methanesulfonyloxy group, benzenesulfonyloxy group or p-toluenesulfonyloxy group or In order to convert into an arylsulfonyloxy group, a corresponding alkylsulfonyl chloride or arylsulfonyl chloride, such as methanesulfonyl chloride or p-toluenesulfonyl chloride, may be used.

These conversion reactions may be carried out in an inert solvent such as methylene chloride or chloroform, and the halogenating agent is 1 to 1.2 of the starting compound having a hydroxyl group.
The equivalent amount may be used. This conversion reaction may be carried out at room temperature or lower temperature, for example, under ice cooling, usually for 1 hour to overnight. The amount of the solvent may be selected as appropriate, but preferably 5 to 5 of the starting compound having a hydroxyl group.
A 100-fold solution amount is exemplified.

The compound (I), compound (II) and other compounds of the present invention may or may not be purified from each of the above reaction products, for example, column chromatography using a carrier such as silica gel. It is preferable to purify by a known purification method such as.

The compound (I) of the present invention can be converted into a pharmaceutically acceptable non-toxic salt thereof, if necessary. Examples of such salts include hydrochloric acid, sulfuric acid, salts with inorganic acids such as phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, malic acid, glutamic acid, aspartic acid, Examples thereof include salts with organic acids such as methanesulfonic acid.

These salts can be obtained from the compound (I) of the present invention by a known method of obtaining a salt from a free base. For example, an equivalent amount of a hydrochloric acid / methanol solution may be added to the compound (I) of the present invention to precipitate a hydrochloride, which may be recovered. When the salt is difficult to precipitate, an organic solvent such as diethyl ether may be added to this.

In the compound (I) of the present invention obtained as described above, n represents an integer of 2 to 4, among which 3 or 4 is preferable, and 4 is particularly preferable. The group R ₁ represents a hydrogen atom or a methyl group,
A hydrogen atom generally has a stronger affinity for the serotonin 1A receptor. On the other hand, regarding movement in the living body,
On the contrary, a methyl group may give preferable results.

Further, the group R ₂ is a 2-pyridyl group or 2
Represents a -pyrimidinyl group. If R ₂ is a 2-pyridyl group, not only exhibit a strong affinity for serotonin 1A receptor, show a strong affinity to adrenergic alpha ₁ receptor, serotonin 1A receptor and adrenergic alpha ₁ receptor is involved both It is particularly preferably used for the treatment of symptoms such as a blood pressure lowering agent. In addition, the group R ₂
Is a 2-pyrimidinyl group, serotonin 1A
Since it has a strong affinity for the receptor and a weak affinity for the adrenergic α ₁ receptor, a therapeutic agent for a condition selectively associated with the serotonin 1A receptor, such as an anxiolytic agent, an antidepressant, It is particularly preferably used as a blood pressure lowering agent, an antiemetic agent (including an anti-motion sickness agent, an anti-space sickness agent, an anti-vertigo agent, etc.) in which the serotonin 1A receptor is involved.

The compound (I) thus obtained and salts thereof have a high affinity for the serotonin 1A receptor as described below, and further, in animal experiments, a disease involving the serotonin nervous system such as anxiolytic action. Since it was confirmed to have an effect on the above, it can be used as a therapeutic agent for serotonin nervous system-related diseases. The disease involving the serotonin nervous system means a disease treated by a drug having a high affinity for the serotonin 1A receptor, and a serotonin nervous system-related disease therapeutic agent is a drug capable of treating the disease, for example, , Anxiolytics, antidepressants, antihypertensives, antiemetics (including anti-sickness agents, anti-space sickness agents, anti-vertigo agents, etc.) and the like.

To prepare such a therapeutic agent for serotonin nervous system-related diseases, compound (I) or a salt thereof is combined with a pharmaceutically acceptable pharmaceutical carrier, and the compound is administered orally or parenterally by a known method. It should be formulated.

Examples of dosage forms for the above-mentioned formulation include injections, drops, tablets, pills, powders, granules, capsules, etc. Various pharmaceutically acceptable pharmaceutical carriers and the like can be used.

For example, when preparing oral preparations such as tablets, granules and capsules, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch,
Excipients such as inorganic salts, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinyl pyrrolidone, binders such as macrogol, starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, etc. Disintegrant, sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, surfactant such as polysorbate 80, talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, lubricant such as magnesium stearate, calcium stearate, flow A sex promoter, a corrigent, etc. can be used. Further, the drug of the present invention can be used as an emulsion, a syrup, and an elixir.

For preparation of parenteral preparations, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like can be generally used as a diluent. Further, a bactericidal agent, an antiseptic agent, a stabilizer, an isotonic agent, a soothing agent and the like may be added, if necessary.

The dose of the serotonin nervous system-related disease therapeutic agent of the present invention varies depending on the administration route, age, weight, symptoms of the recipient, etc., but is generally 0.1 mg as compound (I) per adult per day. It may be about 200 mg / kg.

[0037]

Next, the results of examining the pharmacological action of the compound of the present invention will be shown. 1. Affinity for Serotonin 1A (5HT1A) Receptor-Experimental Method- (A) Preparation of Rat Hippocampal Membrane Fraction SD male rats (7-week-old, Charles River) were decapitated, and the brain was quickly removed and iced. Under cold, 50 mM Tris / HCl buffer (pH 7.4) was added to suspend and homogenate. Centrifuge the homogenate (4800
0 g, 15 minutes), and the precipitate was resuspended in the above buffer solution. In order to decompose the endogenous serotonin, the suspension was incubated at 30 ° C. for 20 minutes and then centrifuged (48000).
g, 15 minutes), and the sediment was used as a hippocampal membrane fraction.

(B) Method for measuring ³ H-8-hydroxy-dipropylaminotetralin ( ³ H-8-OH-DPAT) binding ability The rat hippocampal membrane fraction (about 100 to 200 μm) prepared above
g protein) and ³ H-8-OH-DPAT (New England Nuclea, NEN) (final concentration 0.5 n
M) and pargyline (manufactured by Sigma) (final concentration 10 μM) were reacted at 30 ° C. for 30 minutes, and then the reaction solution was suction-filtered with Whatman GF / C filter to stop the reaction and adsorbed to the filter. The radioactivity was measured by a liquid scintillation counter, and the obtained measured value was defined as the total binding amount (TB). Serotonin (final concentration 10 μM) was added to the above composition and reacted in the same manner, and the measured value was defined as the non-specific binding amount (NB). Instead of serotonin, a sample of each compound at an appropriate concentration was added and reacted to obtain a measured value (DTB).

(C) Ki value calculation method The binding inhibition rate of a sample at a certain fixed concentration was calculated by the following formula.

[0040]

[Equation 1] Obtain the binding inhibition rate at an appropriate concentration (from high concentration to low concentration) for each sample, plot the logarithmic value of concentration on the horizontal axis and the binding inhibition rate on the vertical axis, and draw a curve by the nonlinear least squares method. The IC ₅₀ value (concentration that inhibits 50% binding) of each sample was determined. The Ki value was calculated by the following calculation formula.

[0041]

[Equation 2] [L]: Radioligand concentration used in the experiment (0.2n
M) Kd; concentration indicating the affinity of the radioligand for the receptor (0.7174 nM) IC ₅₀ ; 50% binding of the receptor to the radioligand
Inhibitory Drug Concentration In addition, each compound used as a sample was prepared in advance as a hydrochloride. -Measurement results-

[0042]

[Table 1]

* Reference 1: 2- {2- (4-methylpiperazin-1-yl) propoxy} quinoxaline (prepared in Reference Synthesis Example 1 below) ** Reference 2: 2- {2- (4-ethylpiperazin- 1
-Yl) propoxy} quinoxaline (Reference Synthesis Example 2 below)
Manufactured in)

2. Animal experiment (evaluation of antidepressant action) -Experimental method-ICR male mice (5-week-old) were used for measurement by a water wheel forced swimming method (reference; European Journal of Ph).
armacology 83 , (1982), 171-173). That is, there is a rotatable water wheel on the water surface of the tank, and even if you try to climb on the water wheel so that the mouse does not drown, you use the experimental device with the configuration that the water wheel rotates and you can not climb The number of rotations was measured. On the day before the test, mice were thrown into this experimental apparatus, and individuals with significantly low or high turbine speed were removed. The experiment was conducted with 6 animals per group. The compound to be evaluated is the hydrochloride salt of compound (I) (10 mg / kg)
Is suspended in 0.5% carboxymethylcellulose sodium salt (CMC-Na) and administered 30 minutes before the test in the case of intraperitoneal administration, and 60 minutes before the test in the case of oral administration. Was administered. -Results-

[0045]

[Table 2] As a result of this experiment, it was confirmed that the compound of the present invention has antidepressant action.

3. Animal Experiment (Evaluation of Anti-anxiety Effect) -Experimental Method-Using a group of 6 male Wistar rats, a water lick test (water lic) was performed.
k test) (references; Psychopharmacology 104,
432-438 (1991)). That is, it is a vogel type experimental apparatus equipped with a metal water supply tube, the floor surface of which is made of stainless steel grit, and an electrical stimulator is provided between the metal water supply tube and the grit. We used an experimental device with a structure that, when drinking water from a metal water supply tube, a pungent stimulus was given by applying a direct current. A rat that had been dewatered for 24 hours was placed in this experimental apparatus, and the number of punished stimuli per 10 minutes was measured. The rats to be used were preliminarily subjected to this test and divided into groups so that there was no difference in the number of times. The test compound to be evaluated is the hydrochloride (30 mg / kg)
0.5% carboxymethyl cellulose sodium salt (C
MC-Na) was used as a suspension and administered intraperitoneally 30 minutes before the test. -Results-

[0047]

[Table 3] As a result of this experiment, it was confirmed that the compound of the present invention has an anxiolytic effect.

4. Animal experiment (evaluation of anti-motion sickness action) -Experimental method- (1) Sunx was used as an experimental animal. Sunkus is a small animal of the shrew family and is known to cause motion sickness and vomiting (Biological Sciences, 42 , 538).
(1990)). When Sunkus is given a simple acceleration stimulus, it exhibits symptoms equivalent to motion sickness in humans (motion sickness) and eventually causes vomiting. It is also known that administration of drugs such as cisplatin causes vomiting. Therefore, if this vomiting can be suppressed, it is useful as an antiemetic agent, and also an anti-motion sickness agent, an anti-space sickness agent,
It is also useful as an anti-vertigo agent. The test compound was intraperitoneally administered to the suncus, and 30 minutes after that, the amplitude was 4 cm and the frequency was 1H.
The z acceleration stimulus was given and the presence or absence of vomiting was observed. (2) Measurement result

[0049]

[Table 4] According to the above measurement results, the physiological saline administration group is 100%
He presented with motion sickness and caused vomiting within 5 minutes after the start of stimulation. However, when the compound (I) of the present invention is previously administered,
Since the expression of vomiting is suppressed, the compound (I) of the present invention is useful as an antiemetic agent (including an anti-motion sickness agent, an anti-space sickness agent, an anti-vertigo agent, etc.).

5. Affinity for Adrenergic α ₁ Receptor-Experimental Method- (A) Preparation of Rat Hippocampal Membrane Fraction SD male rats (7-week-old, Charles River) were decapitated, and the brain was rapidly taken out. The cerebral cortex was separated under ice cooling. The extracted cerebral cortex was frozen at -80 ° C for one day or longer. This frozen tissue was thawed slowly under ice-cooling, 50 mM Tris / HCl buffer (pH 7.4) was added and suspended, and homogenized. The homogenate was centrifuged (48,000 g, 15 minutes), the precipitate was washed twice with the above buffer solution, and the obtained precipitate was resuspended in the above buffer solution to give a membrane sample of the adrenergic α1 receptor.

(B) Method for measuring ³ H-prazosin binding ability Membrane preparations of α ₁ receptor prepared as described above, ³ H-prazosin (manufactured by New England Nuclea) (final concentration 0.2 nM) and Ascorbic acid (final concentration 0.
005%) and the total volume was 1 ml, and the mixture was incubated at 25 ° C for 30 minutes. Then, the reaction solution was mixed with glass fiber filter paper (W
Hatman GF / C) is suction filtered, and the filter paper is 50 m.
It was washed 3 times with 4 ml of M Tris / hydrochloric acid buffer (pH 7.4), transferred to a vial bottle, and a scintillator was added to measure the radioactivity. The measured value was taken as the total binding amount (TB).
A non-specific binding amount (NB) was obtained by adding prazosin (final concentration 0.1 μM) to the above composition and reacting in the same manner. Instead of prazosin, a sample of each compound at an appropriate concentration was added and reacted to obtain a measured value (DTB).

(C) Ki value calculation method The binding inhibition rate of a sample at a certain fixed concentration was calculated by the following formula.

[0053]

[Equation 3] Obtain the binding inhibition rate at an appropriate concentration (from high concentration to low concentration) for each sample, plot the logarithmic value of concentration on the horizontal axis and the binding inhibition rate on the vertical axis, and draw a curve by the nonlinear least squares method. , IC ₅₀ value (concentration that inhibits 50% binding) was determined.

The Ki value was calculated by the following formula.

[Equation 4] [L]: Radioligand concentration used in the experiment (0.2n
M) Kd; concentration (0.133 nM) representing the affinity of the radioligand for the receptor IC ₅₀ ; 50% binding between the receptor and the radioligand
Inhibitory Drug Concentration In addition, each compound used as a sample was prepared in advance as a hydrochloride. -Results-

[0055]

[Table 5] In addition, any compound (I) was administered to three mice at 50 mg /
It was confirmed that the intraperitoneal administration of kg did not result in death and that the safety was high.

[0056]

INDUSTRIAL APPLICABILITY As described above, the compound (I) of the present invention and a salt thereof have a strong affinity for the serotonin 1A receptor, and are anxiolytics, antidepressants, antihypertensives, antiemetics ( It is useful as a therapeutic agent for serotonin nervous system-related diseases such as anti-motion sickness agents, anti-space sickness agents, and anti-vertigo agents).
Further, some of the compounds of the present invention have strong affinity for the adrenergic α ₁ receptor and some have weak affinity for them, and an appropriate compound can be selected and used depending on the cause and the symptom to be treated.

[0057]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Production Examples concerning the object compound (I) of the present invention, its hydrochloride, its production examples and intermediates thereof. In addition, representative examples of the object compound (I) of the present invention and its hydrochloride are described in Examples 1 to 4, and production examples of other compounds are summarized in Example 5.

Production Example 1 Production of 2- (2-hydroxyethoxy) quinoxaline:
2-hydroxyquinoxaline 14.6 g (100 mm
2, Aldrich), 1,8-diazabicyclo [5.4.0] -7-undecene (abbreviated as DBU, Aldrich) 29.9 ml (200 mmol) and ethylene chlorohydrin (Tokyo Kasei) 13 .4 ml
(200 mmol) of dimethylformamide (DMF
It was dissolved in 240 ml and heated and stirred at 60 ° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with an aqueous potassium carbonate solution. The chloroform solution was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Wakogel C200, 300 g, elution solvent: chloroform: methanol = 300: 1) and fractionated. Rf = 0.4 (silica gel T
LC, developing solvent; chloroform: methanol = 20:
The fractions of 1) were collected to obtain the title compound (O-substituted product).

Further, the above column was eluted with chloroform: methanol = 300: 1 to give a flush cushion, and a fraction around Rf = 0.3 (silica gel TLC, developing solvent: chloroform: methanol = 20: 1). Were collected to obtain 1- (2-hydroxyethyl) -1,2-dihydro-2-oxoquinoxaline which is an N-substituted product as a by-product.

O-Substitute: Yield: 8.34 g (43.9%) ¹ H-NMR (CDCl ₃ ); 4.1-4.2 (2H, m), 4.6-4.7 (2H, m),
7.4-8.1 (4H, m), 8.54 (1H, s) Fab-Mass; 191,147 N-Substitute: Yield; 6.55 g (34.5%) ¹ H-NMR (CDCl ₃ ); 2.25 (1H, t , J = 5), 4.0-4.2 (2H,
m), 4.49 (2H, t, J = 6), 7.3-8.0 (4H, m), 8.33 (1H, s) Fab-Mass; 191,154,136

Comparative Example 1 7.30 g (50 m mo) of 2-hydroxyquinoxaline
1N Aldrich) 5N sodium hydroxide aqueous solution 5
Dissolved in a mixed solution of 0 ml and 150 ml of t-butanol,
Ethylene chlorohydrin 16.8ml (0.25mo
1) was added, and the mixture was heated with stirring at 60 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with water. The chloroform solution was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier; Wakogel C200, 30
0 g, elution solvent; chloroform: methanol = 500-
200: 1), Rf = around 0.3 (silica gel TLC, developing solvent; chloroform: methanol = 2)
The 0: 1) fraction was collected and production of only the N-substituted product of Production Example 1 was observed.

N-Substitute: Yield 7.13 g (75.1%) ¹ H-NMR (CDCl ₃ ) and Fab-Mass were as described in Preparation Example 1.

Production Example 2 Production of 2- (2-hydroxyethoxy) -3-methylquinoxaline: 8.00 g (50 mmol, Aldrich) of 2-hydroxy-3-methylquinoxaline, D
BU 15.0 ml (100 mmol) and ethylene chlorohydrin 6.70 ml (100 mmol) D
It was dissolved in 120 ml of MF and heated and stirred at 60 ° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with an aqueous potassium carbonate solution. The chloroform solution was dried over Glauber's salt and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (carrier: Wakogel C200, 1 Kg, elution solvent;
Chloroform: methanol = 300: 1) was purified and fractionated. Rf = 0.4 (silica gel TLC,
Fractions of developing solvent: chloroform: methanol = 20: 1) were collected to obtain the title compound (O-substituted product).

Further, the above column was eluted with chloroform: methanol = 300: 1 to make a flush cushion, and a fraction around Rf = 0.3 (silica gel TLC, developing solvent: chloroform: methanol = 20: 1). Was collected to obtain 1- (2
-Hydroxyethyl) -3-methyl-1,2-dihydro-2-oxoquinoxaline was obtained.

O-Substitute: Yield: 3.28 g (32.2%) ¹ H-NMR (CDCl ₃ ); 2.67 (3H, s), 3.18 (1H, t, J = 6),
4.0-4.1 (2H, m), 4.6-4.7 (2H, m), 7.4-8.0 (4H, m) Fab-Mass; 205,154,136 N-Substitute: Yield; 3.46 g (33.9%) ¹ H- NMR (CDCl ₃ ); 2.34 (1H, t, J = 5), 2.60 (3H, s),
4.0-4.2 (2H, m), 4.51 (2H, t, J = 6), 7.3-7.9 (4H, m) Fab-Mass; 205

Comparative Example 2 3-Methyl-2-hydroxyquinoxaline 8.00 g
(50 mmol) of 5N sodium hydroxide aqueous solution 50
dissolved in a mixed solution of 150 ml of t-butanol and 16.8 ml (0.25 mol) of ethylenechlorohydrin
Was added and the mixture was heated with stirring at 60 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with water. After drying this chloroform solution with Glauber's salt,
It was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier: Wakogel C200, 300
g, elution solvent; chloroform: methanol = 500-2
00: 1), Rf = around 0.3 (silica gel TLC, developing solvent; chloroform: methanol = 20:
The fraction 1) was collected, and production of only the N-substituted product of Production Example 2 was observed.

N-Substitute: Yield: 9.44 g (92.5%) ¹ H-NMR (CDCl ₃ ) and Fab-Mass were as described in Preparation Example 2.

Preparation Example 3 Preparation of 2- (3-chloropropoxy) quinoxaline: 2
-Hydroxyquinoxaline 14.60 g (100 mm
ol), 17.9 ml of DBU (120 mmol) and 11.81 ml of 1-bromo-3-chloropropane (1
20 mmol of Tokyo Kasei) was dissolved in 240 ml of DMF, and the mixture was heated with stirring at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with an aqueous potassium carbonate solution. The chloroform solution was dried over Glauber's salt and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier; Wakogel C200, 1 Kg, elution solvent; chloroform: methanol = 300: 1) and fractionated to obtain Rf.
= 0.93 to 0.96 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1) was collected to obtain the title compound (O-substituted product).

Further, the above column was eluted with chloroform: methanol = 500: 1 to give a flush cushion, and the column was closed with Rf = 0.84 to 0.88 (silica gel T).
LC developing solvent; chloroform: methanol = 20: 1)
Was collected to collect 1- (3-chloropropyl) -1,2-dihydro-2 which is an N-substituted product of a by-product.
-Oxoquinoxaline was obtained.

O-Substitute: Yield: 6.04 g (27.1%) ¹ H-NMR (CDCl ₃ ); 2.34 (2H, quint, J = 7), 3.75 (2H,
t, J = 7), 4.65 (2H, t, J = 7), 7.5-8.1 (4H, m), 8.47 (1H, s) Fab-Mass; 225,223,187 N-substitute: Yield: 6.57 g (29 .5%) ¹ H-NMR (CDCl ₃ ); 2.2-2.4 (2H, m), 3.70 (2H, t, J =
6), 4.43 (2H, t, J = 6), 7.3-8.0 (4H, m), 8.34 (1H, s) Fab-Mass; 225,223,187,154

Preparation Example 4 Preparation of 2- (3-chloropropoxy) quinoxaline: 2
-Hydroxyquinoxaline 7.30g (50m mo
1) was dissolved in a mixed solution of 50 ml of 5N sodium hydroxide aqueous solution and 150 ml of t-butanol, and 1-bromo-
2-chloropropane 24.7 ml (250 mmol)
Was added and the mixture was heated with stirring at 60 ° C. for 9 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with water. The chloroform solution was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography in the same manner as in Production Example 3,
-Substituted product and N-substituted product were obtained.

O-Substitute: Yield: 1.57 g (14.1%) N-Substitute: Yield: 6.68 g (60.0%)

Preparation Example 5 Preparation of 2- (3-chloropropoxy) -3-methylquinoxaline: 2-hydroxy-3-methylquinoxaline 1
6.00 g (100 mmol was dissolved in a mixed solution of 100 ml of 5N sodium hydroxide aqueous solution and 300 ml of t-butanol, and 1-bromo-3-chloropropane 29.67 was added.
ml (300 ml) was added, and the mixture was heated with stirring at 60 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, an aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier;
Wakogel C200, 850 g, elution solvent; chloroform) was purified, and a fraction around Rf = 0.90-0.93 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1) was collected to give the title compound. (O-substituted product) was obtained.

Further, the column was eluted with chloroform: methanol = 500: 1 as an elution solvent to make a flush cushion, and then Rf = 0.80 to 0.86 (silica gel T).
LC developing solvent; chloroform: methanol = 20: 1)
Was collected, and N-substituted product 1- (3-chloropropyl) -3-methyl-1,2 as a by-product was collected.
-Dihydro-2-oxoquinoxaline was obtained.

O-Substitute: Yield; 1.51 g (6.4%) ¹ H-NMR (CDCl ₃ ); 2.3-2.5 (2H, m), 2.64 (3H, s), 4.
66 (2H, t, J = 7), 7.4-8.0 (4H, m) Mass (EI); 238,236,132 N-Substitute: Yield; 17.3 g (73.0%) ¹ H-NMR (CDCl ₃ ); 2.2-2.4 (2H, m), 2.60 (3H, s), 3.
70 (2H, t, J = 7), 4.43 (2H, t, J = 7), 7.3-7.9 (4H, m) Mass (EI); 238,236,201,145

Production Example 6 Production of 2- (4-chlorobutoxy) quinoxaline: 2-
Hydroxyquinoxaline 7.30g (50m mo
l), DBU 8.97 ml (60 mmol) and 1
-Bromo-4-chlorobutane 6.9 ml (60 mMo
1 Tokyo Kasei Co., Ltd.) is dissolved in 120 ml of DMF at 60 ° C.
The mixture was heated and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with an aqueous potassium carbonate solution. The chloroform solution was dried over Glauber's salt and then concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier: Wako Gel C200,
Purification and fractionation with 450 g, eluting solvent: chloroform), and fractionation near Rf = 0.90-0.95 (silica gel TLC, developing solvent; chloroform: methanol = 2)
0: 1) fractions were collected and the title compound (O-
Substituted product) was obtained.

Further, the above column was eluted with chloroform: methanol = 500: 1 to make a flush cushion, and Rf = 0.83 to 0.88 (silica gel TL).
C developing solvent; chloroform: methanol = 20: 1) was collected to obtain 1- (4-chlorobutyl) -1,2-dihydro-2 which is an N-substituted product as a by-product.
-Oxoquinoxaline was obtained.

O-Substitute: Yield; 4.45 g (37.6%) ¹ H-NMR (CDCl ₃ ); 1.9-2.3 (4H, m), 3.65 (2H, t, J =
6), 4.53 (2H, t, J = 6), 7.4-8.1 (4H, m), 8.46 (1H, s) Mass (EI); 238,236,201 N-Substitute: Yield; 5.44 g (46.0%) ) ¹ H-NMR (CDCl ₃ ); 1.8-2.1 (4H, m), 3.63 (2H, t, J =
6), 4.30 (2H, t, J = 6), 7.3-8.0 (4H, m), 8.31 (1H, s) Mass (EI); 238,236,201,146

Production Example 7 Production of 2- (4-chlorobutoxy) quinoxaline: 2-
7.30 g (50 mmol) of hydroxyquinoxaline
Was dissolved in a mixed solution of 50 ml of a 5N sodium hydroxide aqueous solution and 150 ml of t-butanol, 15.5 ml (135 mmol) of 1-bromo-4-chlorobutane was added, and 6
The mixture was heated and stirred at 0 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The chloroform solution was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography in the same manner as in Production Example 6 to obtain an O-substituted product and an N-substituted product.

O-Substitute: Yield: 2.82 g (23.8%) N-Substitute: Yield: 8.03 g (67.9%)

Production Example 8 Production of 2- (4-chlorobutoxy) -3-methylquinoxaline: 2-hydroxy-3-methylquinoxaline 1
6.00 g (100 mmol) was dissolved in a mixed solution of 100 ml of 5N sodium hydroxide aqueous solution and 300 ml of t-butanol, and 34.6 ml of 1-bromo-4-chlorobutane.
(300 mmol) was added, and the mixture was heated with stirring at 60 ° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The chloroform solution was dried over Glauber's salt and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Wakogel C200, 850 g, elution solvent: chloroform), and around Rf = 0.92 to 0.96 (silica gel TLC, developing solvent: chloroform: methanol = 20). The fraction (1) was collected to obtain the title compound (O-substituted product).

Further, the column was eluted with chloroform: methanol = 500: 1 as an elution solvent to give a flush cushion, and Rf = 0.85 to 0.90 (silica gel T).
LC, developing solvent; chloroform: methanol = 20:
The fraction of 1) was collected and 1- (4-chlorobutyl) -3-methyl-1,2- which is an N-substituted product of a by-product.
Dihydro-2-oxoquinoxaline was obtained.

O-Substitute: Yield; 4.48 g (17.9%) ¹ H-NMR (CDCl ₃ ); 1.9-2.1 (4H, m), 2.64 (3H, s), 3.
64 (2H, t, J = 6), 4.54 (2H, t, J = 6), 7.4-8.0 (4H, m) Mass (EI); 252,250,215,160 N-Substitute: Yield; 18.7 g (74.7) %) ¹ H-NMR (CDCl ₃ ); 1.8-2.1 (4H, m), 2.60 (3H, s), 3.
63 (2H, t, J = 6), 4.30 (2H, t, J = 6), 7.2-7.9 (4H, m) Mass (EI); 252,250,215,132

Example 1 Preparation of 2- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethoxy] quinoxaline (Compound No. 270): 2- (2-hydroxyethoxy) obtained in Preparation Example 1. Quinoxaline 0.95 g (5.0 mmol),
It was dissolved in 15 ml of methylene chloride and triethylamine of 0.1.
7 ml (5.0 mmol) was added, and under ice-cooling, 0.39 ml (5.0 mmol) of methanesulfonyl chloride.
1) was added dropwise and the mixture was stirred overnight. The residue obtained by concentration under reduced pressure was dissolved in 25 ml of benzene, and 1.64 g of 2-pyrimidinylpiperazine (produced by Tokyo Kasei) and 2.8 ml (20.0 mmol) of triethylamine were heated under reflux for 72 hours. After the reaction, chloroform was added and the mixture was washed with a dilute potassium carbonate aqueous solution, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wakogel C-200, 100 g, elution solvent; chloroform: methanol = 200: 1) to give the title compound. Got The hydrochloride of the title compound was prepared by dissolving the title compound in a 5N hydrochloric acid-methanol solution,
Ether was added to this to obtain crystals which were precipitated.

Example 2 Preparation of 2- [3- {4- (2-pyridyl) -1-piperazinyl} propoxy] quinoxaline (Compound No. 191): 2- (3-chloropropoxy) obtained in Preparation Example 4. 0.67 g (3.0 mmol) of quinoxaline,
It was dissolved in 20 ml of benzene, 0.84 ml (6 mmol) of triethylamine and 0.87 ml (6.0 mol) of 2-pyridylpiperazine were added thereto, and the mixture was heated under reflux for 144 hours. After the reaction, chloroform was added and the mixture was washed with dilute aqueous potassium carbonate solution, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (carrier; Wakogel C200, 100).
g, elution solvent; chloroform: methanol = 200:
Purification in 1) gave the title compound. Also, in the same manner as in Example 1, the hydrochloride of the title compound was obtained.

Example 3 2- [4- {4- (2-pyrimidinyl) -1-piperazinyl} butoxy] quinoxaline (Compound No. 252):
2.37 g (10.0 mmol) of 2- (4-chlorobutoxy) quinoxaline obtained in Preparation Example 6 was dissolved in 50 ml of acetonitrile, and 2.07 g of potassium carbonate was added thereto.
(15.0 mmol) and 2-pyrimidinylpiperazine (3.28 g, 20.0 mmol) were added, and the mixture was heated under reflux for 21 hours. After the reaction, the insoluble matter was filtered off, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (carrier; Wakogel C200, 100 g, elution solvent; chloroform: methanol = 200: 1) to give the title compound. The compound was obtained. Also, in the same manner as in Example 1, the hydrochloride of the title compound was obtained.

Example 4 Preparation of 2- [4- {4- (2-pyridyl) -1-piperazinyl} ethoxy] quinoxaline (Compound No. 269): (1) 2- (2-obtained in Preparation Example 2) Hydroxyethoxy) quinoxaline 0.95 g (5.0 mmol),
It was dissolved in 10 ml of chloroform, 0.42 ml of thionyl chloride was added dropwise under ice cooling, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to obtain crude 2- (2-chloroethoxy) quinoxaline [Rf = about 0.90 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1)].

(2) Next, this 2- (2-chloroethoxy) quinoxaline was dissolved in 25 ml of benzene, 0.82 g (5.0 mmol) of 2-pyridylpiperazine and 1.40 ml of triethylamine were added, and the mixture was heated under reflux for 48 hours. . After the reaction, chloroform was added and the mixture was washed with an aqueous potassium carbonate solution, and the aqueous layer was further extracted with chloroform.
The chloroform layer thus obtained was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (carrier: Wakogel C200, 50 g, elution solvent;
Purification with chloroform: methanol = 200: 1) gave the title compound. Also, in the same manner as in Example 1, the hydrochloride of the title compound was obtained.

Example 5 According to the methods described in Examples 1 to 4, the compounds shown in Table 6 were obtained. The physical properties of these compounds (free base) are shown in Table 7.

[0090]

[Table 6] The meaning of each symbol in the table is as follows. OMs: methanesulfonyloxy group Pdyl: 2-pyridyl group Pmi: 2-pyrimidinyl group

[0091]

[Table 7]

The compound names and the compound numbers of the compounds contained in each of the above Examples are as follows.

2- [2- {4- (2-pyridyl) -1-
Piperazinyl} ethoxy] -3-methylquinoxaline (Compound No. 236). 2- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethoxy] -3-methylquinoxaline (Compound No. 237). 2- [2- {4-
(2-Pyridyl) -1-piperazinyl} ethoxy] quinoxaline (Compound No. 269). 2- [2- {4- (2
-Pyrimidinyl) -1-piperazinyl} ethoxy] quinoxaline (Compound No. 270). 2- [3- {4- (2
-Pyridyl) -1-piperazinyl} propoxy] quinoxaline (Compound No. 191). 2- [3- {4- (2-
Pyrimidinyl) -1-piperazinyl} propoxy] quinoxaline (Compound No. 192).

2- [3- {4- (2-pyrimidinyl)-
1-Piperazinyl} propoxy] -3-methylquinoxaline (Compound No. 241). 2- [3- {4- (2-pyridyl) -1-piperazinyl} propoxy] -3-methylquinoxaline (Compound No. 242). 2- [4- {4
-(2-Pyridyl) -1-piperazinyl} butoxy] quinoxaline (Compound No. 251). 2- [4- {4-
(2-Pyrimidinyl) -1-piperazinyl} butoxy]
Quinoxaline (Compound No. 252). 2- [4- {4-
(2-Pyridyl) -1-piperazinyl} butoxy] -3
-Methylquinoxaline (Compound No. 258). 2- [4
-{4- (2-pyrimidinyl) -1-piperazinyl} butoxy] -3-methylquinoxaline (Compound No. 25
9).

Reference Synthesis Example 1 Preparation of 2- {2- (4-methylpiperazin-1-yl) propoxy} quinoxaline: 2 obtained in Preparation Example 4
(3-chloropropoxy) quinoxaline 0.67 g
(3.0 mmol) was dissolved in 20 ml of benzene, 0.84 ml (6.0 mmol) of triethylamine and 0.60 g (6.0 mmol, manufactured by Tokyo Kasei) of methylpiperazine were added, and the mixture was heated under reflux for 120 hours. After the reaction, chloroform was added and the mixture was washed with a dilute potassium carbonate aqueous solution, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Wakogel C200, 100 g, elution solvent: chloroform: methanol = 200: 1) to prepare Reference 1 0.72 g of the compound of

Reference Synthesis Example 2 Preparation of 2- {2- (4-ethylpiperazin-1-yl) propoxy} quinoxaline: 0.69 g of ethylpiperazine (manufactured by Tokyo Kasei) was used in place of the methylpiperazine of Reference 1, Compound 2 of Reference 2 was treated in the same manner.
8 g was obtained.

Formulation Example 1 Capsule: Capsule No. 1 was filled with the following ingredients to prepare a capsule. Compound 251 (dihydrochloride) 20 mg Lactose 90 mg Microcrystalline cellulose 70 mg Magnesium stearate 10 mg ───────────────────────────── Total 190 mg

Formulation Example 2 Tablet: The following ingredients were tableted by a conventional method to give tablets. Compound 251 (dihydrochloride) 25 mg Lactose 135 mg Crystalline cellulose 30 mg Magnesium stearate 10 mg ───────────────────────────── Total 200 mg

Formulation Example 3 Injection: 1 g of Compound 251 (dihydrochloride) was dissolved in 50 ml of distilled water for injection, passed through a filter of 0.22 μm or less, dispensed in 500 μl aliquots, and freeze-dried. An injection was obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location C07D 241/44 8615-4C 403/12 237 8829-4C (72) Inventor Daisuke Mochizuki Takata-gun, Shizuoka Prefecture 1 Asahi Kasei Kogyo Co., Ltd., No.632, Mifuku, Ohi Town

Claims (11)

[Claims] 1. A compound represented by the general formula (I): (In the formula, n is an integer of 2 to 4, R ₁ is a hydrogen atom or a methyl group, and R ₂ is a 2-pyridyl group or a 2-pyrimidinyl group) or a non-toxic poison thereof. Sex salt. 2. The 2-alkoxyquinoxaline derivative or the non-toxic salt thereof according to claim 1, wherein n is 3 or 4 in the general formula (I). 3. A 2-alkoxyquinoxaline derivative or a non-toxic salt thereof according to claim ₁ , wherein in the general formula (I), R ₁ is a hydrogen atom. 4. A 2-alkoxyquinoxaline derivative or a non-toxic salt thereof according to claim ₁ , wherein in the general formula (I), R ₁ is a methyl group. 5. The 2-alkoxyquinoxaline derivative or the non-toxic salt thereof according to claim 1, wherein R ₂ in the general formula (I) is a 2-pyridyl group. 6. The 2-alkoxyquinoxaline derivative or the non-toxic salt thereof according to claim 1, wherein R ₂ in the general formula (I) is a 2-pyrimidinyl group. 7. A 2-alkoxyquinoxaline derivative or a non-toxic salt thereof is 2- [2- {4- (2-pyridyl)-
1-piperazinyl} ethoxy] -3-methylquinoxaline, 2- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethoxy] -3-methylquinoxaline, 2-
[2- {4- (2-pyridyl) -1-piperazinyl} ethoxy] quinoxaline, 2- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethoxy] quinoxaline, 2- [3- {4- (2-Pyridyl) -1-piperazinyl} propoxy] quinoxaline, 2- [3- {4-
(2-Pyrimidinyl) -1-piperazinyl} propoxy] quinoxaline, 2- [3- {4- (2-pyrimidinyl) -1-piperazinyl} propoxy] -3-methylquinoxaline, 2- [3- {4- (2 -Pyridyl) -1-
Piperazinyl} propoxy] -3-methylquinoxaline, 2- [4- {4- (2-pyridyl) -1-piperazinyl} butoxy] quinoxaline, 2- [4- {4- (2
-Pyrimidinyl) -1-piperazinyl} butoxy] quinoxaline, 2- [4- {4- (2-pyridyl) -1-piperazinyl} butoxy] -3-methylquinoxaline, 2
The 2-alkoxyquinoxaline derivative according to claim 1, which is a compound selected from the group consisting of-[4- {4- (2-pyrimidinyl) -1-piperazinyl} butoxy] -3-methylquinoxaline and non-toxic salts thereof. Its non-toxic salt. 8. A compound represented by the general formula (II): (In the formula, n is an integer of 2 to 4, R ₁ is a hydrogen atom or a methyl group, and X is a leaving group) and a compound represented by the general formula (III): (Wherein R ₂ represents a 2-pyridyl group or a 2-pyrimidinyl group) is reacted in an inert solvent, and the compound represented by the general formula (I): (In the formula, n, R ₁ and R ₂ have the same meanings as described above.)
A method for producing a 2-alkoxyquinoxaline derivative represented by or a non-toxic salt thereof. 9. A compound represented by the general formula (II) is a compound represented by the general formula (IV): (Wherein R ₁ represents a hydrogen atom or a methyl group) and a compound represented by the general formula (V): (Wherein n represents the same meaning as described above, Y represents a halogen atom, X ′ represents a hydroxyl group or a halogen atom), and the compound represented by the general formula (V
I) [Chemical 7] (In the formula, n, R ₁ and X ′ have the same meanings as described above)
9. The method according to claim 8, which is a compound represented by the formula (1), wherein when X ′ is a hydroxyl group, the compound is produced by converting the hydroxyl group into a leaving group X. 10. A compound represented by the general formula (VI): (In the formula, n is an integer of 2 to 4, R ₁ is a hydrogen atom or a methyl group, and X ′ is a hydroxyl group or a halogen atom, respectively). 11. A compound represented by the general formula (I): (In the formula, n is an integer of 2 to 4, R ₁ is a hydrogen atom or a methyl group, and R ₂ is a 2-pyridyl group or a 2-pyrimidinyl group) or a non-toxic poison thereof. A therapeutic agent for serotonin nervous system-related diseases, which comprises a soluble salt as an active ingredient.