JPH05320157A - 1-substituted alkylquinoxaline derivative and use thereof - Google Patents

Abstract

PURPOSE:To provide a new compound having high affinity for serotonin 1A receptor, thus useful as a medicine for serotonin neurally related diseases such as antianxiety agents, antidepressants, hypotensive agents, or antiemetic agents. CONSTITUTION:The compound of formula I (R1 is H or methyl; R2 is 2-pyridyl, 2-pyrimidinyl, or 1,2-benzo-3-isothiazolyl; n is 2-4), e.g. 1-[2-{-(2-pyridinyl)-1- piperazinyl}ethyl]-1,2-dihydro-2-oxoquinoxaline. The compound of the formula I can be obtained by reaction of a compound of formula II (X is eliminable group) with a compound of formula III in an inert solvent (e.g. benzene) pref. in the presence of a deacidifying agent (e.g. triethylamine) at room temperature to elevated temperatures (e.g. the solvent refluxing temperature). Among the present compounds, there are those with high affinity for adrenaline alpha-1 receptor and those with low affinity therefor; thus, appropriate compounds can be selected from the present compounds and used depending on causes and symptoms corresponding to the diseases to be cured.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 1-substituted alkylquinoxaline derivative, and more particularly to an anxiolytic agent, antidepressant agent, blood pressure reducing agent, antiemetic agent (anti-sickness agent, anti-space sickness agent, anti-sickness agent, anti-sickness agent). (Including dizziness agents, etc.)
The present invention relates to a substituted alkylquinoxaline derivative and its use.

[0002]

2. Description of the Related Art Compounds having an affinity for serotonin 1A receptors include anxiolytics, antidepressants, antihypertensives, antiemetics (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 Vol. 47, 1).
989 Special Issue, pp. 1241-1248; JP Feig
hnev, WF Boyer, Psychopathology, 22 , 21 (1989);
PR Saxena, CM Villalon, TiPS, 11 , 95 (1990), N. Ma
tsuki et al., Jpa.J.Pharmacol, Suppl., 58 , 313 (199
2) etc.).

[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, 1-substituted alkylquinoxaline derivatives represented by the following formula (I) The present invention was completed by discovering that it has not been described, and that it has excellent serotonin 1A receptor affinity.

Therefore, the first object of the present invention is to provide the following general formula (I):

[Chemical 3] (In the formula, n represents an integer of 2 to 4, R ₁ represents a hydrogen atom or a methyl group, and R ₂ represents a 2-pyridyl group, a 2-pyrimidinyl group, or a 1,2-benzo-3-isothiazolyl group)
The present invention provides a 1-substituted alkylquinoxaline derivative represented by or a non-toxic salt thereof. Another object of the present invention is to provide a therapeutic agent for a disease involving the serotonin nervous system, which comprises the 1-substituted alkylquinoxaline derivative represented by the general formula (I) or a non-toxic salt thereof as an active ingredient. It is a thing.

The compound (I) of the present invention can be prepared, for example, by the following general formula (II)

[Chemical 4] (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)

[Chemical 5] 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 general formula (II) (hereinafter referred to as compound (II)) is disclosed in JP-A-64-50868.
Known compounds described in No. 1 or compounds easily prepared according to the description. In the compound (II), X represents a leaving group, and the leaving group means a group capable of increasing the reactivity with the compound (III) and leaving, for example, a fluorine atom, a chlorine atom, a bromine atom. Halogen atom such as iodine atom, methanesulfonyloxy group, benzenesulfonyloxy group,
Examples thereof include alkyl- or aryl-sulfonyloxy groups such as p-toluenesulfonyloxy group.

The compound represented by the general formula (III) (hereinafter referred to as the compound (III)) is commercially available, and is available 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 is a solvent which does not adversely affect the reaction, and preferred examples include benzene. , Toluene, xylene, dimethylformamide, acetonitrile, acetone and the like. In this reaction, it is preferable to allow a deoxidizing agent to be present, and examples of the deoxidizing agent include an inorganic or organic base. Specific examples include alkali carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and sodium hydride. Examples thereof include alkaline earth metal carbonates, bicarbonates or hydrides, and tertiary amines such as triethylamine and pyridine.

In the above reaction, the compound (II) and the compound (III) may be basically reacted in an equivalent amount, but the compound (III) is usually 1 to 5 equivalents, particularly preferably 1.2 to 2
It is good to use an equivalent amount. The deoxidizing agent is usually the compound (III)
Is preferably used.

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, the reaction temperature and the like, and may be completed after confirming that the reaction has sufficiently proceeded, but it is usually 1 hour to several days. The amount of the solvent may be selected as appropriate, but the amount of the compound (II) is 10
A capacity of up to 200 times is exemplified.

The compound (I) of the present invention obtained by the above reaction may or may not be purified from the reaction product. For example, known purification methods such as column chromatography using a carrier such as silica gel. It is preferable to purify by.

The obtained compound (I) of the present invention can be converted into a pharmaceutically acceptable non-toxic salt thereof, if necessary. Examples of such salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, tartaric acid,
Examples thereof include salts with organic acids such as citric acid, glycolic acid, gluconic acid, succinic acid, malic acid, glutamic acid, aspartic acid and 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, with 3 or 4 being preferred. Further, the group R ₁ represents a hydrogen atom or a methyl group, but a hydrogen atom generally exhibits a strong affinity for the serotonin 1A receptor. On the other hand, in terms of migration in a living body, a methyl group may give preferable results on the contrary. Further, the group R ₂ is a 2-pyridyl group, a 2-pyrimidinyl group or a 1,2-benzo-3 group.
An isothiazolyl group, wherein R ₂ is a 2-pyridyl group,
In the case of a 2-pyrimidinyl group, it has a strong affinity for the serotonin 1A receptor, whereas it has a weak affinity for the adrenergic α ₁ receptor, so that it is associated with a condition selectively associated with the serotonin 1A receptor. It is particularly preferably used as a therapeutic agent such as an anxiolytic agent, antidepressant agent, a hypotensive agent associated with serotonin 1A receptor, an antiemetic agent (including an anti-motion sickness agent, an anti-space sickness agent, an anti-vertigo agent, etc.). Further, when R ₂ is a 1,2-benzo-3-isothiazolyl group, it not only has a strong affinity for the serotonin 1A receptor, but also a relatively strong affinity for the adrenergic α ₁ receptor. It is particularly preferably used for treatment of a condition in which both the receptor and the adrenergic α ₁ receptor are involved, such as a hypotensive agent.

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 that it has an effect on, 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 serotonin nervous system-related disease therapeutic agent, compound (I) or a salt thereof is combined with a pharmaceutically acceptable pharmaceutical carrier, and the compound is administered by oral administration or parenteral administration 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, in the preparation of 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, soybean 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 agent of the present invention can be used as an emulsion agent, a syrup agent, and an elixir agent.

To prepare a parenteral preparation, generally, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like can be used as a diluent. Further, if necessary, a bactericide, an antiseptic, a stabilizer, an isotonicity agent, a soothing agent, etc. may be added.

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 day per adult. It may be about 200 mg / kg.

Action 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 Fractions SD male rats (7-week-old, Charles River) were decapitated, and the brain was quickly removed and iced. Under cold conditions, 50 mM Tris / HCl buffer (pH 7.4) was added to suspend and homogenate. Centrifuge this 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 precipitate 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 adsorb to the filter. Radioactivity was measured with a liquid scintillation counter, and the obtained measurement value was used 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.

[0025]

[Equation 1]

The binding inhibition rate at an appropriate concentration (from high concentration to low concentration) is determined for each sample, the horizontal axis is the logarithmic value of the concentration, and the vertical axis is the binding inhibition rate, which is plotted by the nonlinear least squares method. A curve was drawn to determine the IC ₅₀ value (concentration that inhibits 50% binding) of each sample.

The Ki value was calculated by the following formula.

[0028]

[Equation 2]

[L]: Radioligand concentration used in the experiment (0.2n
M) Kd; the concentration showing 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-

[0031]

[Table 1]

* Reference 1: 1- [4- (4-methyl-1
-Piperazinyl) butyl] -1,2-dihiro-2-oxoquinoxaline (prepared in Reference Synthesis Example 1 below) ** Reference 2: 1- [4- (4-ethyl-1-piperazinyl) butyl] -1,2 -Dihiro-2-oxoquinoxaline (produced in Reference Synthesis Example 2 below)

2. Animal Experiment (Evaluation of Antidepressant Effect) -Experimental Method-Measurement was carried out by a water wheel type forced swimming method using male ICR mice (5 weeks old) (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 onto 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 of compound (I) (10 mg / kg)
Is suspended in 0.5% carboxymethylcellulose sodium salt (CMC-Na) and used 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. The results are shown in Table 2.

[0034]

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

3. Animal Experiment (Evaluation of Anti-anxiety Effect) -Experimental Method-Using a group of 6 Wistar male rats, a water lick test (water lic)
k test) (references; Psychopharmacology 104,
432-438, (1991)). That is, it is a vogel type experimental device 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 in which drinking water from a metal water supply tube gave a punitive stimulus by applying a direct current. A rat that had been dewatered for 24 hours was placed in this experimental device, and the number of punished stimuli per 10 minutes was measured. The rats to be used were subjected to this test in advance and divided into groups so that the number of times was not different. The test compound to be evaluated is the hydrochloride (10 mg / kg)
0.5% carboxymethyl cellulose sodium salt (C
MC-Na) was used as a suspension and administered intraperitoneally 30 minutes before the test. The results are shown in Table 3.

[0036]

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

4. Animal Experiment (Evaluation of Antiemetic Effect) (1) Experimental Method Sunx was used as an experimental animal. Sunkus is a small animal of the shrew family, and is known as an animal causing motion sickness and vomiting (Biological Sciences, 42 , 538 (19).
90)). 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 as an anti-motion sickness agent, an anti-space sickness agent, an anti-vertigo agent, etc. 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 results Table 4 shows the results of the measurement of the effect on vomiting of Sunkus motion sickness disease.
Is the street.

[0039]

[Table 4]

According to the above measurement results, the physiological saline-administered group exhibited 100% motion sickness and vomiting within 5 minutes after the start of stimulation. However, the compound (I) of the present invention was previously prepared.
Since the expression of vomiting is suppressed by the administration of the compound, 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 weeks 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 more. The frozen tissue was slowly thawed under ice-cooling, 50 mM Tris / hydrochloric acid 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 obtain a membrane sample of the adrenergic α ₁ receptor.

(B) Method for measuring ³ H-prazosin binding ability Membrane preparation of α ₁ receptor prepared above, ³ H-prazosin (manufactured by New England Nuclea Co.) (final concentration 0.2 nM) and ascorbin A total volume of 1 ml with acid (final concentration 0.005%) was added and incubated at 25 ° C. for 30 minutes. Then, the reaction solution was suction-filtered with a glass fiber filter paper (Whatman GF / C), and the filter paper was filtered to 5
It was washed 3 times with 4 ml of 0 mM 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). In addition to the above composition, prazosin (final concentration 0.1μ
M) The value obtained by adding and reacting in the same manner was defined as the nonspecific binding amount (NB). Measured value (DTB) by adding specimens of each compound at appropriate concentrations instead of prazosin and reacting
Got

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

[0044]

[Equation 3]

The binding inhibition rate at an appropriate concentration (from high concentration to low concentration) was obtained for each sample, and the logarithmic value of the concentration was plotted on the horizontal axis and the binding inhibition rate was plotted on the vertical axis, using the nonlinear least squares method. A curve is drawn and an IC ₅₀ value (concentration that inhibits 50% binding)
I asked. The Ki value was calculated by the following calculation formula.

[0046]

[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 of the receptor to the radioligand
Inhibitory Drug Concentration In addition, each compound used as a sample was prepared in advance as a hydrochloride.

[0048]

[Table 5]

It was confirmed that none of the compounds (I) died by intraperitoneal administration of 50 mg / kg to 3 mice, and the compound (I) was highly safe.

[0050]

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 anxiolytic agents, antidepressants, antihypertensive agents, and antiemetic agents ( (Including anti-sickness drug, anti-space sickness drug, anti-vertigo drug, etc.)
And the like are useful as therapeutic agents for serotonin nervous system-related diseases. In addition, 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 of the treatment target.

[0051]

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 salt, examples of its production and intermediates thereof. Representative examples of the objective compound (I) of the present invention and its hydrochloride are described in Examples 1 to 3, and Production Examples of other compounds are summarized in Example 4.

Production Example 1 1- (2-hydroxyethyl) -1,2-dihydro-2
-Manufacture of oxoquinoxaline: 7.30 g of 2-hydroxyquinoxaline (manufactured by 50 mM Aldrich) and 50 ml of 5N aqueous sodium hydroxide solution and 150 t-butanol.
Dissolve in a mixed solution of ml, ethylene chlorohydrin 16.
8 ml (0.25 M) was added, and the mixture was heated with stirring at 60 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and 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 was purified by silica gel column chromatography (carrier: Wakogel C200, 300 g, elution solvent: chloroform: methanol = 500-200: 1) to give Rf = 0.
Around 3 (silica gel TLC, developing solvent; chloroform:
A fraction of methanol = 20: 1) was collected to obtain the title compound.

Yield 7.13 g (75.1%) 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

Production Example 2 1- (3-chloropropyl) -1,2-dihydro-2-
Production of oxoquinoxaline: 7.30 g (50 mM) of 2-hydroxyquinoxaline was dissolved in a mixed solution of 50 ml of 5N sodium hydroxide aqueous solution and 150 ml of t-butanol, and 24.7 ml of 1-bromo-3-chloropropane (2
50 mM manufactured by Tokyo Kasei Co., Ltd.) was added, and the mixture was heated and stirred at 60 ° C. for 9 hours. The reaction mixture 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 was subjected to silica gel column chromatography (carrier: Wakogel C200, 1 Kg, elution solvent: chloroform:
Methanol = 500: 1) was performed and a fraction around Rf = 0.85 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1) was collected to obtain the title compound.

Yield 6.68 g (60.0%) 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

Example 1 Preparation of 1- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethyl] -1,2-dihydro-2-oxoquinoxaline (Compound No. 077): Obtained in Preparation Example 1. 1- (2-hydroxyethyl) -1,2-dihydro-
2-oxoquinoxaline 0.95g (5.0m mo
l) was dissolved in 15 ml of methylene chloride, 0.70 ml (5.0 mmol) of triethylamine was added, and 0.39 ml (5.0 m) of methanesulfonyl chloride under ice cooling.
(mol) was added dropwise and the mixture was stirred overnight. After concentration under reduced pressure, this was dissolved in 25 ml of benzene, 1.64 g (10 mmol) of 2-pyrimidinylpiperazine and 1.4 ml (10 mmol) of triethylamine were added, and the mixture was heated under reflux for 31 hours. After the reaction, chloroform was added and washed with an 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 purified by silica gel column chromatography (Wako Gel C-200, 100 g, elution solvent; chloroform: methanol = 200: 1) to obtain the title compound.

Example 2 1- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethyl] -1,2-dihydro-3-methyl-2-
Preparation of oxoquinoxaline (Compound No. 83): 1-
(2-hydroxyethyl) -1,2-dihydro-3-methyl-2-oxoquinoxaline 1.02 g (5.0 m
(mol) was dissolved in 10 ml of methylene chloride, 0.42 ml of thionyl chloride was added dropwise under ice cooling, and the mixture was stirred overnight. Concentrated under reduced pressure and crude 1- (2-chloroethyl)-
3-Methyl-1,2-dihydro-2-oxoquinoxaline was obtained. Then, this 1- (2-chloroethyl) -3
-Methyl-1,2-dihydroquinoxaline with benzene 2
Dissolve in 5 ml, 2-pyrimidinylpiperazine 1.64
g (10 mmol) and triethylamine 1.4 m
1 (10 mmol) was added, and the mixture was heated under reflux for 23 hours.
After the reaction, chloroform was added and washed with an 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 purified by silica gel column chromatography (Wako Gel C-200, 100 g, elution solvent; chloroform: methanol = 200: 1) to obtain the title compound.

Example 3 Preparation of 1- [3- {4- (2-pyridyl) -1-piperazinyl} propyl] -1,2-dihydro-2-oxoquinoxaline (Compound No. 121): Obtained in Preparation Example 2. 1- (3-chloropropyl) -1,2-dihydro-2
-Oxoquinoxaline 0.67 g (5.0 mmol)
Was dissolved in 25 ml of acetonitrile, 1.92 g (7.5 mmol) of potassium carbonate and 0.77 g (5 mmol) of 2-pyridylpiperazine were added, and the mixture was heated under reflux for 27 hours. After the reaction, chloroform was added and washed with an aqueous potassium carbonate solution, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over sodium sulfate, and the resulting residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g, elution solvent; chloroform:
Purification with methanol = 200: 1) gave the title compound.

Example 4 According to the method described in Examples 1 to 3, the compounds shown in Table 6 were obtained. Table 7 shows the physical properties of these compounds (free base).
It was shown to.

[0060]

[Table 6]

In the table, the following symbols have the following meanings. OMs: methanesulfonyloxy group Pdyl: 2-pyridine group Pmi: 2-pyrimidinyl group Bzis: 1,2-benzo-3-isothiazolyl group

[0062]

[Table 7]

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

1- [2- {4- (2-pyrimidinyl)-
1-Piperazinyl} ethyl] -1,2-dihydro-2-
Oxoquinoxaline (Compound No. 077) .1- [2-
{4- (2-Pyrimidinyl) -1-piperazinyl} ethyl] -1,2-dihydro-3-methyl-2-oxoquinoxaline (Compound No. 083). 1- [2- {4- (2
-Pyridyl) -1-piperazinyl} ethyl] -1,2-
Hydro-2-oxoquinoxaline (Compound No. 22
7). 1- [2- {4- (2-pyridyl) -1-piperazinyl} ethyl] -1,2-hydro-3-methyl-2-
Oxoquinoxaline (Compound No. 230) .1- [3-
{4- (2-Pyrimidinyl) -1-piperazinyl} propyl] -1,2-dihydro-2-oxoquinoxaline (Compound No. 102) .1- [3- {4- (2-pyridyl) -1-piperazinyl} Propyl] -1,2-dihydro-2-oxoquinoxaline (Compound No. 121).

1- [3- {4- (2-pyrimidinyl)-
1-piperazinyl} propyl] -1,2-dihydro-3
-Methyl-2-oxoquinoxaline (Compound No. 1
0). 1- [3- {4- (2-pyridyl) -1-piperazinyl} propyl] -1,2-dihydro-3-methyl-
2-oxoquinoxaline (Compound No. 131). 1-
[3- {4- (1,2-benzo-3-isothiazolyl)]
-1-Piperazinyl} propyl] -1,2-dihydro-
2-oxoquinoxaline (Compound No. 215) .1-
[3- {4- (1,2-benzo-3-isothiazolyl)]
-1-Piperazinyl} propyl] -1,2-dihydro-
3-methyl-2-oxoquinoxaline (Compound No. 21
6).

1- [4- {4- (2-pyrimidinyl)-
1-Piperazinyl} butyl] -1,2-dihydro-2-
Oxoquinoxaline (Compound No. 133). 1- [4-
{4- (2-Pyridyl) -1-piperazinyl} butyl]
-1,2-hydro-2-oxoquinoxaline (Compound No. 134). 1- [4- {4- (2-pyrimidinyl)-
1-Piperazinyl} butyl] -1,2-dihydro-3-
Methyl-2-oxoquinoxaline (Compound No. 14
2). 1- [4- {4- (2-pyridyl) -1-piperazinyl} butyl] -1,2-hydro-3-methyl-2-
Oxoquinoxaline (Compound No. 153). 1- [4-
{4- (1,2-benzo-3-isothiazolyl) -1-
Piperazinyl} butyl] -1,2-dihydro-2-oxoquinoxaline (Compound No. 18). 1- [4- {4-
(1,2-Benzo-3-isothiazolyl) -1-piperazinyl} butyl] -1,2-dihydro-3-methyl-2
-Oxoquinoxaline (Compound No. 219).

Production Reference Example 1 1- [4- (4-Methyl-1-piperazinyl) butyl]
Preparation of -1,2-dihydro-2-oxoquinoxaline:
7.30 g of 2-hydroxyquinoxaline (50 m mo
l) was dissolved in a mixed solution of 50 ml of a 5N aqueous solution of sodium hydroxide and 150 ml of t-butanol, and 15.5 ml (135 mmol) of 1-bromo-4-chlorobutane was added,
The mixture was heated and stirred at 60 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform and washed with water.
This chloroform solution was dried over sodium sulfate, and the obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 500: 1) to a value near Rf = 0.85 (silica gel TLC, development). Solvent; chloroform: methanol = 20: 1) gave 1- (4-chlorobutyl) -1,2-dihydro-2-oxoquinoxaline.

Yield: 8.03 g (67.9%) 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

This 1- (4-chlorobutyl) -1,2-
1.19 g of dihydro-2-oxoquinoxaline (5.0
(mol mol) is dissolved in 25 ml of benzene, and 1.00 g (10.0 m) of methylpyrazine (manufactured by Tokyo Kasei)
mol) and 1.4 ml of triethylan (10.0 m
mol) was added and the mixture was heated under reflux for 120 hours. After the reaction
Chloroform was added, washed with dilute aqueous potassium carbonate solution,
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;
Wako gel C200, 100 g, elution solvent; chloroform: methanol = 200: 1) was purified to obtain 1.01 g of the title compound.

¹ H-NMR (CDCl ₃ ); 1.6-1.9 (4H, m), 2.29 (3H, s), 2.
4-2.6 (10H, m), 4.2-4.4 (2H, m), 7.3-7.9 (4H, m), 8.30
(1H, s) Fab-Mass; 301, 154 The hydrochloride of the compound of Reference 1 was obtained by dissolving the above compound in a 5N hydrochloric acid-methanol solution and adding ether to the solution to precipitate crystals.

Synthesis Reference Example 2 1- [4- (4-Ethyl-1-piperazinyl) butyl]
Production of -1,2-dihydro-2-oxoquinoxaline:
The same treatment was carried out using 1.14 g (10.0 mmol) of ethylpiperazine (manufactured by Tokyo Chemical Industry Co., Ltd.) instead of the methylpiperazine of Reference 1, to obtain 0.7 g of the title compound.

¹ H-NMR (CDCl ₃ ); 1.01 (3H, t, J = 7), 1.6-1.9 (4H,
m), 2.4-2.7 (12H, m), 4.28 (2H, t, J = 7), 7.3-8.0 (4H, m),
8.30 (1H, s) Fab-Mass; 315, 201 The hydrochloride of the compound of Reference 2 was obtained by dissolving the above compound in a 5N hydrochloric acid-methanol solution and adding ether to the solution to precipitate crystals.

Formulation Example 1 Capsule: Capsule No. 1 was filled with the following ingredients to prepare a capsule. Compound 134 (dihydrochloride) 20 mg Lactose 90 mg Microcrystalline cellulose 70 mg Magnesium stearate 10 mg ──────────────────────── Total 190 mg

Formulation Example 2 Tablets: The following ingredients were tableted by a conventional method to give tablets. Compound 134 (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 134 (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 code Internal reference number FI Technical display location A61K 31/505 AEN 9360-4C C07D 403/12 239 8829-4C 417/12 241 9051-4C (72 ) Inventor Daisuke Mochizuki 1 Asahi Kasei Kogyo Co., Ltd. 1 632, Mifuku Mitsufuku, Ohi Town, Takata-gun, Shizuoka

Claims (14)

[Claims] 1. A compound represented by the general formula (I): (In the formula, n represents an integer of 2 to 4, R ₁ represents a hydrogen atom or a methyl group, and R ₂ represents a 2-pyridyl group, a 2-pyrimidinyl group, or a 1,2-benzo-3-isothiazolyl group)
The 1-substituted alkylquinoxaline derivative represented by or a non-toxic salt thereof. 2. The 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof according to claim 1, wherein n is 3 or 4 in the general formula (I). 3. The 1-substituted alkylquinoxaline derivative according to claim ₁ , wherein R ₁ is a hydrogen atom in the general formula (I), or a non-toxic salt thereof. 4. The 1-substituted alkylquinoxaline derivative according to claim ₁ , wherein R ₁ in the general formula (I) is a methyl group, or a non-toxic salt thereof. 5. The 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof according to claim 1, wherein R ₂ in the general formula (I) is a 2-pyridyl group or a 2-pyrimidinyl group. 6. The 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof according to claim 1, wherein R ₂ in the general formula (I) is a 1,2-benzo-3-isothiazolyl group. 7. A 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof is 1- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethyl] -1,2-dihydro-2-oxoquinoxaline, 1. -[2- {4- (2-pyrimidinyl) -1-piperazinyl} ethyl] -1,2-
Dihydro-3-methyl-2-oxoquinoxaline, 1-
[2- {4- (2-pyridyl) -1-piperazinyl} ethyl] -1,2-dihydro-2-oxoquinoxaline,
1- [2- {4- (2-pyridyl) -1-piperazinyl} ethyl] -1,2-dihydro-3-methyl-2-oxoquinoxaline, 1- [3- {4- (2-pyrimidinyl)- 1-piperazinyl} propyl] -1,2-dihydro-2-oxoquinoxaline, 1- [3- {4- (2-
Pyridyl) -1-piperazinyl} propyl] -1,2-
Dihydro-2-oxoquinoxaline, 1- [3- {4-
(2-Pyrimidinyl) -1-piperazinyl} propyl]
-1,2-Dihydro-3-methyl-2-oxoquinoxaline, 1- [3- {4- (2-pyridyl) -1-piperazinyl} propyl] -1,2-dihydro-3-methyl-
2-oxoquinoxaline, 1- [3- {4- (1,2-
Benzo-3-isothiazolyl) -1-piperazinyl} propyl] -1,2-dihydro-2-oxoquinoxaline, 1- [3- {4- (1,2-benzo-3-isothiazolyl) -1-piperazinyl} propyl ] -1,2-Dihydro-3-methyl-2-oxoquinoxaline, 1-
[4- {4- (2-Pyrimidinyl) -1-piperazinyl} butyl] -1,2-dihydro-2-oxoquinoxaline, 1- [4- {4- (2-pyridyl) -1-piperazinyl} butyl] -1,2-dihydro-2-oxoquinoxaline, 1- [4- {4- (2-pyrimidinyl) -1
-Piperazinyl} butyl] -1,2-dihydro-3-methyl-2-oxoquinoxaline, 1- [4- {4- (2
-Pyridyl) -1-piperazinyl} butyl] -1,2-
Dihydro-3-methyl-2-oxoquinoxaline, 1-
[4- {4- (1,2-benzo-3-isothiazolyl)
-1-Piperazinyl} butyl] -1,2-dihydro-2
-Oxoquinoxaline, 1- [4- {4- (1,2-benzo-3-isothiazolyl) -1-piperazinyl} butyl] -1,2-dihydro-3-methyl-2-oxoquinoxaline and their non-toxicity The 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof according to claim 1, which is a compound selected from the group consisting of salts. 8. A compound represented by the general formula (I): (In the formula, n represents an integer of 2 to 4, R ₁ represents a hydrogen atom or a methyl group, and R ₂ represents a 2-pyridyl group, a 2-pyrimidinyl group, or a 1,2-benzo-3-isothiazolyl group)
A therapeutic agent for serotonin nervous system-related diseases, which comprises a 1-substituted alkylquinoxaline derivative represented by the following formula or a non-toxic salt thereof as an active ingredient. 9. The therapeutic agent according to claim 6, wherein n is 3 or 4 in the general formula (I). 10. The therapeutic agent according to claim 6, wherein in the general formula (I), R ₁ is a hydrogen atom. 11. The therapeutic agent according to claim 6, wherein in the general formula (I), R ₁ is a methyl group. 12. The compound according to claim 1, wherein in the general formula (I), R ₂ is a 2-pyridyl group or a 2-pyrimidinyl group.
A substituted alkylquinoxaline derivative or a non-toxic salt thereof. 13. A 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof according to claim 1, wherein R ₂ in the general formula (I) is a 1,2-benzo-3-isothiazolyl group. 14. A 1-substituted alkylquinoxaline derivative or a non-toxic salt thereof is 1- [2- {4- (2-pyrimidinyl) -1-piperazinyl} ethyl] -1,2-dihydro-2-oxoquinoxaline, 1- [2- {4- (2
-Pyrimidinyl) -1-piperazinyl} ethyl] -1,
2-dihydro-3-methyl-2-oxoquinoxaline,
1- [2- {4- (2-pyridyl) -1-piperazinyl} ethyl] -1,2-dihydro-2-oxoquinoxaline, 1- [2- {4- (2-pyridyl) -1-piperazinyl} Ethyl] -1,2-dihydro-3-methyl-2
-Oxoquinoxaline, 1- [3- {4- (2-pyrimidinyl) -1-piperazinyl} propyl] -1,2-dihydro-2-oxoquinoxaline, 1- [3- {4-
(2-Pyridyl) -1-piperazinyl} propyl]-
1,2-dihydro-2-oxoquinoxaline, 1- [3
-{4- (2-Pyrimidinyl) -1-piperazinyl} propyl] -1,2-dihydro-3-methyl-2-oxoquinoxaline, 1- [3- {4- (2-pyridyl) -1
-Piperazinyl} propyl] -1,2-dihydro-3-
Methyl-2-oxoquinoxaline, 1- [3- {4-
(1,2-benzo-3-isothiazolyl) -1-piperazinyl} propyl] -1,2-dihydro-2-oxoquinoxaline, 1- [3- {4- (1,2-benzo-3-
Isothiazolyl) -1-piperazinyl} propyl]-
1,2-dihydro-3-methyl-2-oxoquinoxaline, 1- [4- {4- (2-pyrimidinyl) -1-piperazinyl} butyl] -1,2-dihydro-2-oxoquinoxaline, 1- [ 4- {4- (2-pyridyl) -1-
Piperazinyl} butyl] -1,2-dihydro-2-oxoquinoxaline, 1- [4- {4- (2-pyrimidinyl) -1-piperazinyl} butyl] -1,2-dihydro-3-methyl-2-oxo Quinoxaline, 1- [4-
{4- (2-Pyridyl) -1-piperazinyl} butyl]
-1,2-Dihydro-3-methyl-2-oxoquinoxaline, 1- [4- {4- (1,2-benzo-3-isothiazolyl) -1-piperazinyl} butyl] -1,2-dihydro-2 -Oxoquinoxaline, 1- [4- {4-
(1,2-Benz-3-isothiazolyl) -1-piperazinyl} butyl] -1,2-dihydro-3-methyl-2
The therapeutic agent according to claim 6, which is a compound selected from the group consisting of -oxoquinoxaline and non-toxic salts thereof.