WO1993012792A1

WO1993012792A1 - Remedy for diseases related to serotonergic neuron system

Info

Publication number: WO1993012792A1
Application number: PCT/JP1992/001639
Authority: WO
Inventors: Masao Yaso; Yukio Suzuki; Tetsu Saito; Daisuke Mochizuki
Original assignee: Asahi Kasei Kogyo Kabushiki Kaisha
Priority date: 1991-12-20
Filing date: 1992-12-16
Publication date: 1993-07-08

Abstract

A remedy for diseases related to the serotonergic neuron system, such as antianxiety drug, antidepressant and antiemetic including antikinetotic, remedy for space sickness, antidinic, and the like, which contains a 2-alkoxyquinoxaline derivative, represented by general formula (I), or a nontoxic salt thereof as an active ingredient having a strong affinity for serotonin 1A receptor wherein n represents an integer of 2 to 4, R1 represents hydrogen or methyl, and R2 represents substituted phenyl.

Description

Specification

Serotonin treatment for nervous system related diseases

Industrial applications

The present invention relates to a serotonin nervous system such as an anti-anxiety agent, an antidepressant agent, an antiemetic agent (including an anti-motion sickness agent, an anti-sickness agent, an anti-vertigo agent) containing a 2-alkoxyquinoxaline derivative as an active ingredient. The present invention relates to a therapeutic agent for a related disease. Conventional technology

Compounds having affinity for serotonin 1A receptor are known to be useful as anxiolytics, antidepressants, and antiemetic drugs (including anti-sway agents, anti-sickness agents, anti-vertigo agents, etc.). Many reports have already been made on these compounds (Japanese clinical study, 47, 1989 extra edition, pp. 1241-128); JP Feighnev, WF Boyer , P syc "pathology, 22, 21 (1 89 9); PR S axena, CM Vi 1 1 a 1 on, Ti PS, 11, 95 (199 9); N. atsukieta 1., J pn. J. Parmaco 1. S upp 1., _5_8_, 3 1 3 (1992), etc.)

However, it is desired to search, find, and provide a compound having the above-mentioned pharmacological action that is more excellent than existing compounds. Means for solving the problem

The present inventors have synthesized various compounds and have searched extensively for their pharmacological actions. The 2-alkoxyquinoxaline derivative represented by the following formula (I) was found to be an excellent serotonin 1A receptor. The inventors have found that they have one affinity and completed the present invention. Accordingly, the present invention provides the following general formula (I)

(i)

(In the formula, n represents an integer of 2 to 4, R, represents a hydrogen atom or a methyl group, and _Rz represents a phenyl group having a substituent.)

It is intended to provide a therapeutic agent for a serotonin nervous system-related disease, comprising a 2-alkoxyquinoxaline derivative represented by the following formula or a non-toxic salt thereof as an active ingredient. In the present invention, the serotonergic nervous system-related disease means a disease which is treated by a drug having a high affinity for the serotonin 1A receptor. Examples include anxiolytics, antidepressants, and antiemetic agents (including anti-sway agents, anti-sickness agents, anti-vertigo, etc.).

Most of the 2-alkoxyquinoxaline derivative (I), which is an active ingredient of the therapeutic agent for serotonin nervous system-related disease II of the present invention, is a novel compound, but a part of the compound is a known compound. For example, in the above formula (I), the compound in which R is methyl, R ₂ is 0-tolyl and n is 2 is a known compound disclosed in JP-B-48-21949. However, despite the fact that Japanese Patent Publication No. 48-21999¾ "includes a large number of compounds, only the above compounds are disclosed as compounds of the formula (〖). In Japanese Patent Publication No. 48-21999, although there is a general disclosure that many of the compounds covered by the patent show or- -sympathetic blockade, they are supported by experiments, etc. Only one compound is described and it has not been determined whether such compounds have such an effect.

Therefore, not only the compound (II) of the present invention has excellent serotonin 1A resebuta monophilicity, but also these compounds have an anxiolytic action, an antidepressant action, It was not at all predictable to have an antiemetic effect (including anti-sway effect, anti-sickness effect, anti-dizziness effect, etc.). The compound (I) used in the wood invention is a compound which may be able to be synthesized according to the method disclosed in JP-B-48-21949 described above. The method is more convenient.

According to this method, compound (I) is represented by the following formula (II)

N 丫 CHCH ₂ ) n ~ X

(II)

(Wherein formulas Φ, η and R, have the same meanings as above, and X represents a leaving group) and a compound represented by the general formula (ΠΙ)

, J, "― \

(III)

(Wherein, R _z has the same meaning as described above)

It is produced by reacting a compound represented by the formula in an inert solvent.

The compound represented by the above general formula (II) (hereinafter referred to as compound (II)) is a novel compound not described in the literature and is a useful intermediate compound. This compound

In (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, and an iodine atom. Examples thereof include an halogen atom, an alkyl or arylsulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group and a p-toluenesulfonyloxy group. Also, the general formula The compound represented by (III) (hereinafter, referred to as compound (III)) is commercially available and can be obtained from, for example, Aldrich Co., Ltd., Tokyo Kasei Co., and the like. The inert solvent used in the reaction between the compounds (II) and (III) is not particularly limited as long as it does not adversely affect the reaction. Preferred examples include benzene and toluene. , Xylene, dimethylformamide, acetonitrile, aceton and the like. In this reaction, it is preferable to use a deoxidizing agent. As the deoxidizing agent, an inorganic or organic base can be used. Specifically, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like can be used. And alkaline earth metal carbonates, bicarbonates or hydrides, tertiary amines such as triethylamine and pyridine, and the like.

The compound (III) and the compound (III) may basically be reacted in an equivalent amount. Usually, the compound (III) is used in an amount of 1 to 5 equivalents, particularly preferably 1 () to 2.0 equivalents]. In addition, if it is a deoxidizing agent, it is usually equivalent to compound (化合物)! It is preferable to use?:. The above-mentioned reaction is preferably carried out under heating conditions, for example, under reflux conditions of a solvent, for example, a force that can proceed even at room temperature. The reaction time may be appropriately selected depending on the combination of the compounds, the reaction temperature, and the like, and may be terminated after confirming that the reaction has sufficiently proceeded, but the reaction is usually completed in 1 hour to several hours. The amount of the solvent may be appropriately selected, and examples thereof include a volume of 1 to 2 times () times that of the compound (!).

The compound (II) as a starting material is represented by, for example, the general formula (iV)

(IV) (Wherein has the same meaning as described above)

(Hereinafter referred to as compound (IV)) and the general formula (V) 丫 '(V)

(In the formula, n represents the same meaning as described above, Y represents halogen (child, X ′ represents a hydroxyl group or a halogen atom.)

(Hereinafter referred to as compound (V)) in an inert solvent to give a compound of the general formula (VI)

'Ν R,

(VI)

(Wherein, 11, R, and) ('has the same meaning as described above)

When X ′ is a hydroxyl group, the compound is obtained by converting the hydroxyl group to a leaving group X.

The compound (IV) used here is a known compound and is commercially available from, for example, Aldrich. In the compound ((V)), when the group Y and the group X ′ are both halogen atoms, and ¾Χ ′ may be the same halogen atom or may be different from each other. Is more preferably a more reactive group than ¾Χ ′. Specific preferred examples of the compound (V) include compounds having a combination of a group 臭 with bromine and a group X, with a hydroxyl group or a chlorine atom, a group 原 with a chlorine atom and a group X 'with a hydroxyl group or the like. As these compounds, commercially available products such as Tokyo Kasei can be advantageously used.

As an inert solvent used in the reaction between compound (IV) and compound (V) Is not particularly limited as long as it does not adversely affect the reaction. Preferred examples include benzene, tonolene, xylene, dimethylformamide, acetonitrile, aceton, t-butyl alcohol and the like. In this reaction, it is preferable to use a deoxidizing agent. The deoxidizing agents include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide, and hydroxide. Alkali or alkaline earth metal carbonates, bicarbonates, hydrides or hydroxides, or inorganic or organic such as tertiary amines such as triethylamine and viridine Bases.

However, in this reaction, the substitution product of carbonyl S, which is the target product, with an oxygen atom (referred to as a 0-substituted product) and the substitution product for a nitrogen atom, which is a by-product, (referred to as an N-substituted product) Is generated in various ratios depending on the conditions, so care must be taken in the reaction conditions. In particular, it is preferable to use 1,8-diazabicyclo [5.4.0] -7-indene (hereinafter sometimes abbreviated as DBU) because the generation rate of 0-substituted product is increased. Conversely, when water is added to the solvent in a negative manner, the N-substituted product increases, which is not preferable.

N people R,

o-substitution

N-substitute The compound (IV) and the compound (V) may basically be reacted in an equivalent amount, but usually, the compound (V) is preferably used in an amount of 1 to 10 equivalents, particularly preferably 1 to 5 equivalents. The deoxidizing agent is preferably used in an equivalent amount to the compound (V). The above reaction may be carried out under heating conditions from room temperature, for example, 50 to 12 O'C. The reaction time may be appropriately selected depending on the combination of compounds, the reaction temperature, and the like, and may be determined to be sufficient after completion of the reaction. The amount of the solvent may be appropriately selected, and an example of the amount is 10 to 200 times the volume of the compound (IV). Further, in the above compound (VI), when the group X ′ is a hydroxyl group, a reaction for converting the hydroxyl group to a leaving group X is performed. To convert the hydroxyl group to the above-mentioned leaving group X, A conventionally known method may be used. For example, a hydroxyl group can be converted to a halogen atom by treating it with a halogenating agent such as thiol-lucide or phosphorus pentachloride. In order to convert to an alkyl such as a xy group or an arylsulfonyloxy group, a corresponding alkylsulfurylc or an arylsulfyroxylide, for example, a methanesulfurylc or a p-toluene Sulfonyl chloride or the like may be used.

These conversion reactions may be performed in an inert solvent, for example, methylene chloride, chloroform, or the like, and the halogenating agent may be used in an amount of about 1 to 1.2 equivalents of the starting compound having a hydroxyl group. This conversion reaction may be carried out at room temperature or lower, for example, under ice-cooling conditions, usually for 1 hour to overnight. The amount of the solvent may be appropriately selected, but preferably the capacity is 5 to 100 times the capacity of the starting compound having a hydroxyl group. The compound (I) of the present invention may or may not be purified from the reaction product of the compound (II) and the compound (II), but a carrier such as silica gel is used. It is preferable to purify by a known purification method such as column chromatography. In the present invention, if necessary, compound (I) can be used as a pharmaceutically acceptable non-toxic salt thereof. Examples of such salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, dalconic acid, succinic acid, malic acid, glutamic acid, and aspartic acid. And 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 for obtaining a salt from a free base. For example, an equivalent amount of methanol solution of hydrochloric acid Z may be added to the compound (I) of the present invention to elute hydrochloride, which may be recovered. If it is difficult to produce salt, an organic solvent such as getyl ether may be added to this.

As described later, the compound (I) thus obtained and the salt thereof have a high affinity for the mouth tonin 1A receptor, and furthermore, a disease involving the serotonin nervous system such as an anxiolytic effect by animal experiments. Can be used as a therapeutic agent for serotonin-related nervous system-related diseases. However, to prepare such a therapeutic agent, compound (I) or a salt thereof is pharmaceutically acceptable. What is necessary is just to combine with an acceptable pharmaceutical carrier and formulate it by a well-known method.

The agent for treating a nervous system-related disease of the oral nervous system according to the present invention may be administered orally or parenterally, such as by injection with intravenous infusion, depending on the administration route, age, body weight, It varies according to the symptoms and the like, generally or Ah 1 day adult to 0. may be set to Lmg～2 0 0 m Roh k _g about as compound (I). Dosage forms for the above formulation include injections, drops, tablets, pills, powders, granules, capsules, etc. Various kinds of medical carriers that are acceptable are used.

For example, in preparing oral preparations such as tablets, granules, capsules, etc., excipients such as powder killing, lactose, sucrose, mannite, carboxymethylcellulose, corn starch, inorganic salts, methylcellulose, carboxymethyl Binders such as sodium cellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, starch, hydroxypropylstarch, carboxymethylcellulose, carboxymethylcellulose Disintegrators such as sodium and hydroxypropylcellulose; surfactants such as sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, polysorbate 80, talc, mouth water, hydrogenated vegetable oil Lubricants such as sucrose fatty acid ester, magnesium stearate, calcium stearate and the like, fluidity promoters, flavoring agents and the like can be used. The drug of the present invention can also be used as an emulsion, syrup or elixir.

In order 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. If necessary, bactericides, preservatives, stabilizers, tonicity agents, soothing agents and the like may be added. Action

Next, the results of examining the pharmacological effects of the compound of the present invention will be described. 1. Affinity for serotonin 1A (5HT1A) receptor

-Experimental method-(A) Preparation of rat hippocampus membrane fraction

After decapitation of an SD male rat (7-week-old, Charl'Riva-1), the brain was quickly removed, to which 5 OmM Tris'HCl buffer (PH 7.4) was added under ice-cooling. Suspended and homogenized. The homogenate was centrifuged (480,000 g, 15 minutes), and the precipitate was resuspended in the above buffer. In order to degrade endogenous serotonin, this suspension was incubated at 30 ° C for 20 minutes, centrifuged (480 g, 15 minutes), and the sediment was collected in the hippocampus. The membrane fraction was used.

(B) ³ H- 8- arsenide Dorokishi one dipropyl § Minote Torari emissions ⁽³ H- 8 -OH-D PAT) Method for measuring binding ability

Rat hippocampal membrane fraction prepared above (approximately 100-200 ^ & protein) and 3H-8-0H-DPAT (New England 'Nuclea, NBN) (final concentration 0.5 nM ) and pargyline (par _g Yline, after reacting for 30 minutes at 3 ϋ ΐ a sigma) (final concentration 1 0 / M), the reaction is stopped by suction filtration the reaction solution Wa Tsu Toman GFZC filter The radioactivity adsorbed on the filter was measured with a liquid resting scintillation force counter, and the measured value was defined as the total binding amount (ΤΒ). Serotonin (final concentration 10 / Μ) was added to the above composition and reacted in the same manner, and the measured value was taken as the nonspecific binding amount (ΝΝ). 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 meter

The binding inhibition rate of the sample at a certain concentration was calculated by the following formula.

DTB-NB

Binding inhibition rate (%) = 100 XI 00

TB-NB Calculate the binding skin damage rate at an appropriate concentration (from high concentration to low concentration) for each sample, plot the logarithmic value of the concentration on the horizontal axis and the binding inhibition rate on the vertical axis, and use the nonlinear least squares method. pull the curve at, C ₅ of each specimen. The value (concentration of 131% at 50%) was determined.

Ί ί value was calculated by the following formula.

I 60

K i =

1 + [shi] / K d

CD: concentration of radioligand used in the experiment (0.2 nM)

K d; Degree of affinity of radioligand for receptor (0.7.1 7 4 n)

IC _s . A drug concentration that inhibits binding of the receptor to the radioligand by 50%

In addition, each compound used as a specimen was prepared in advance as a hydrochloride. Table 1 shows the measurement results.

Table 1 Compound No. 5 HT 1 A K i Compound No. 5 H T 1 A K i

(_ n M) (n M)

26 8 8. 0 9 1 9 6 1 2. 7 9

27 2 8.4 8 1 9 7 1 3.1.8

1 丄 9 9 ^ 6. 2 9 2 4 7 1

丄 * 9 Q

19 0 1 0.8 8 24 24 5.18

240 8.1 1 24 9 1.6 1

24 5 1 1.5 1 2 5 0 2.4.4

24 6 5.3 9 25 4 8. 4 7

1 5 5 0. 2 1 2 5 0 1 9. 3 4

1 5 6 1.4 2 2 5 6 7. 1 4

1 9 3 2. 0 0 25 7 8. 2 9

1 9 4 2. 0 7 2 8 3 5. 2 4

1 9 5 0. 9 7 28 5 1 9. 1 1

2. Animal experiment (Antidepressant action evaluation)

-Experimental method 1

ICR strain male mice (5-week-old) were measured by the waterwheel forced swimming method (Sanr 文献 literature; European Journalof Phar). ma cology _8_3_, (1 9 8 2), 1 7 1— 1 73). In other words, there is a water wheel that can be turned on the water surface of the tank, so that even if the mouse tries to climb the water wheel so that it does not drown, the water wheel of the water wheel is used. The number of mouse rotations was measured. The day before the test, a mouse was thrown into the experimental device to remove individuals with significantly lower or higher turbine speeds. The experiment was performed with one group consisting of six animals.

The compound to be evaluated is the compound (I) hydrochloride (10 m & _kg ) suspended in 0.5% carboxymethylcellulose sodium salt (CMC-Na). Was administered 30 minutes before the test, and in the case of oral administration, 60 minutes before the test. The results are as shown in Table 2.

Table 2 '

As a result of this experiment, it was confirmed that the target compound has an anti-adhesive effect. '

3. Animal experiments (Anxiolytic effects evaluation)

One experimental method—

Water 1 ricktest (reference: P sycopha rmacology 1004, 432-438 (1991)) was performed using 6 male rats of the wistar strain. went. In other words, Borge with a metal water supply tube (Voge 1) type experimental device, the floor surface of which is made of stainless steel grit, the space between the metal water supply tube and the dalit communicates with the electric stimulator, We used an experimental device that was configured to be able to stimulate punishment by applying direct current when drinking water from a water supply tube. A rat dewatered for 24 hours was placed in this experimental apparatus, and the number of punishment stimulations per 10 minutes was measured. The rats used were subjected to this test in advance, and the rats were grouped so that there was no difference in the number of times.

The test compound to be evaluated was used by suspending its hydrochloride (1 O mg / kg) in 0.5% carboxymethylcellular sodium salt (CM C-Na) for 30 minutes. Administered intraperitoneally before. The results are shown in Table 3.

^> 0 ^.

As a result of the experiment, it was confirmed that the target compound had an anxiolytic effect.

In addition, none of the compounds (I) was intraperitoneally administered to S O mgZkg in three mice, and no death was observed, confirming that the safety was high.

4. Animal experiment (evaluation of antiemetic effect)

One experimental method one

Sunks were used as experimental animals. Sunks are small animals of the shrew family, known to cause sickness and vomiting. Science, 42, 538 (1990)). Sunks, when subjected to simple acceleration stimuli, exhibit symptoms (motion sickness) corresponding to motion sickness in humans, eventually causing vomiting. It is also known that administration of drugs such as cisplatin causes vomiting. Therefore, if this vomiting can be suppressed, it is effective as an antiemetic and is also useful as an anti-motion sickness agent, an anti-sickness agent, an anti-vertigo agent and the like.

The test compound was intraperitoneally administered to Sunks, and 30 minutes later, an acceleration stimulus having an amplitude of 4 cm ♦ and a frequency of 1 Hz was applied to observe whether or not vomiting had occurred. The results are as shown in Table 4.

Table 4

According to the above measurement results, the saline administration group exhibited 100% motion sickness and caused vomiting within 5 minutes after the start of stimulation. However, when the compound (I) of the present invention is administered in advance, the onset of vomiting is completely suppressed. It is useful as a chemical agent. The invention's effect

As described above, the compound (I) of the present invention and a salt thereof exhibit strong affinity for the serotonin 1A receptor, and have an anxiolytic, an antidepressant, an antiemetic (an anti-sway agent, an anti-universe). It is useful as a therapeutic agent for serotonin nervous system related diseases such as sickness medicine and anti-vertigo. Example

Next, the present invention will be described in more detail with reference to examples and production examples of the target compound (I) of the present invention, its hydrochloride, examples of its production and intermediates thereof. Production Example 1

Production of 2- (2-hydroxyethoxy) quinoxaline:

2-hydroxyquinoxaline 14.6 g (100 mmo 1 manufactured by Aldrich), 1,8-diazabicyclo [5.4.0] — 7-ndecene (abbreviated as DBU, manufactured by Adritic) 29.9 ml (200 mmo 1) and ethylene chlorohydrin (Tokyo Kasei Co., Ltd.) 13.4 m 1 (200 mmo 1) were combined with dimethylformamide (abbreviated as DMF) 24 The solution was dissolved in 0 ml, and heated and stirred at 60 ° C. for 22 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with aqueous potassium carbonate solution. The black-mouthed form solution was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Picogel C 200, 300 g, elution solvent: chloroform: methanol = 300: 1), and fractionated. Fractions near = 0.4 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1) were collected to give the title compound (0-substituted).

The column was eluted with an elution solvent; chloroform: methanol = 300: 1, fractionated, and R f was around 0.3 (silica gel TL C. developing solvent; chloroform: methanol = 20) The fractions of 1) were collected to obtain 1_ (2-hydroxyethyl) 1-1,2-dihydro-12-oxoquinoxaline which is an N-substituted by-product. 0 monosubstitution:

Yield: 8.34 g (43.9%)

— NMR (CD C 13); 4 1—4.2 (2 H, m), 4.6

One 4.7 (2 H, m), 7.4-8.1 (4 H, m), 8.54 (1 H, s)

F a b— Ma s s; 9 1 1 47

N—substituted:

Yield; 55 g (34.5%)

'H-NMR (CD C 1 3); 2 25 (1 H, t, J = 5), 4.

0 -4. 2 (2 H, m), 4.49 (2 H, t, J = 6), 7.3-8.0 (4 H, m), 8.33 (1 H, s)

F a-M a s s; 19 1, 154, 1 36 Production Example 2

2- (2-Hydroxychetoxy) 1-Methylquinoxaline

8.00 g of 2-hydroxy-1-methylquinoxaline (50 mmo1, manufactured by Adricz), 5.0 m1 (100 mmol) of DBU and 6.70 ml of ethylene clohydrin (100 mMol) ) To DM F l

The mixture was dissolved in 20 ml, and the mixture was heated and stirred for 20 hours at 60. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform and washed with aqueous potassium carbonate solution. This black-mouthed form solution was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier: Picogel C20 (1 Kg, elution solvent; chloroform: methanol-

Purification and fractionation with 300: 1), fractions near Rί = 0.4 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1) were collected, and the title compound (0- Substituted product) was obtained. The column was eluted with an elution solvent; chloroform: methanol-300: 1, and fractionation was carried out. R f = around 0.3 (silica gel TLC, developing solvent; pore form: methanol = 20: The fraction of 1) was collected to obtain 1- (2-hydroxyethyl) -13-methyl-1,2-dihydro-2-oxoquinoxaline which is an N-substituted by-product.

0-substitution:

Yield: 3.28 g (32.2%)

_{Ή-NMR (CD C1 3)} ;. 2. 67 (3 H, s), 3. 1 8 (1 H, t, J = 6), 4. 0 -4 1 (2 H, m), 4. 6—4.7 (2 H, m), 7.4-8.0 (4 H, m)

F ab -Ma s s; 205, 1 54, 1 36

N—substituted:

Yield; 3.46 g (33.9%)

'Η—NMR (CDC13) 2.34 (1H, t, J = 5), 2.

60 (3H, s), 4.0 to 4.2 (2H, m), .51 (2H, t, J = 6), 7.3--7.9 (4H, m)

F ab -Ma s s; 2005 Production Example 3

Production of 2- (3-chloropropoxy) quinoxaline:

2-Hydroxyquinoxaline 14.60 g (100 mmol), DBUI 7.9 ml (120 mm 01) and 1-Promo 3-Cropropane 11.8 ml (1 20 mm 01 (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 240 ml of DMF, and the mixture was heated and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform and washed with an aqueous solution of carbon dioxide. After drying this black-mouthed form solution with sodium sulfate, the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel gel chromatography (carrier: Cogel C 200, 1 Kg, elution solvent: black form: methanol = 300: 1), fractionated, and R f = A fraction of about 0.93 to 0.96 (silica gel TLC, developing solvent; chloroform: methanol = 20: 1) was collected to obtain the title compound (0-substituted product).

In addition, the column was eluted with a solvent: chloroform: methanol = 500: 1 to give a cushion, and R ί = 0.84 to 0.88 (Sili-force gel TLC, developing solvent; A fraction of chloroform: methanol = 20: 1) was collected to obtain an N-substituted by-product, 11- (3-chloropropyl) -1,1,2-dihydro-12-oxoquinoxaline. Was.

0—Substitution:

Yield: 6.04 g (27.1%)

^ -NMR (CD C I a); 2.34 (2 H, u int, J = 6),

3.75 (2 H, t, J = 6), 4.65 (2 H, t, J = 6) .7.5-8.1 (4 E, m), 8.47 (1 H, s)

F ab -Ma s s; 2 2 5, 2 2 3, 1 8 7

N—substituted:

Yield: 6.57 g (29.5%)

^ -NMR (CD C 13); 2.2-2.4 "(2H, m), 3.7

0 (2 H, t, J = 6), 4.43 (2 H, t, J = 6), 7.3 -8. 0 (4 H, m), 8.34 (1 H, s ) F ab-Ma ss; 225, 2 2 3, 1 8 7, 1 5 4 Production Example 4

Production of 2- (4-chlorobutoxy) quinoxaline:

7.30 g (50 mmol) of 2-hydroxyquinoxaline, 8.97 ml (60 mmo 1) of DBU and 6.9 ml (60 mmo 1 of 1-bromo-4-chlorobutane, manufactured by Tokyo Chemical Industry Co., Ltd. ) Was dissolved in 120 ml of DMF, and the mixture was heated and stirred at 60 ° C for 3 B. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform and washed with an aqueous potassium carbonate solution. The black-mouthed form solution was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel gel chromatography (carrier: Co-gel C200, 450 g, elution solvent: black form), fractionated, and R f = 0.9 Fractions around 0 to 0.95 (silica gel TLC, developing solvent; black form: methanol-20: 1) were collected to obtain the title compound (0-substituted product).

Further, the column described above was eluted with an eluting solvent; chloroform: methanol = 500: 1, and fractionation was performed. R f = around 0.83 to 88 (silica gel TLC, developing solvent; Fractions of chloroform: methanol = 20: 1) were collected to obtain N-substituted 1_ (4-chlorobutyl) 1-1,2-dihydro-2-oxoquinoxaline as a by-product. .

0—Conversion:

Yield; 4.45 g (37.6%)

JH-NMR (CD Cl s); 1.9-2.3 (4H, m), 3.6

5 (2 H, t, J = 6), 4.5 3 (2 H, t, J = 6), 7.4-8.1 (4 H, m), 8.46 (1 H, s ) Ma ss (E i); 238, 2 36, 20 1

N—substituted:

Yield; 5.44 g (46.0%)

lH-NMR (CD C ls); 1.8—2.1 (4H, m), 3.6 3 (2 H, t, J = 6), 4.30 (

2 H, t, J = 6), 7.3 -8.0 (4 H, m), 8.3 1 (1 H, s)

20

Mass (E I); 238, 236, 146 Example 1

Preparation of 2- [2- [4- {2,3-dimethylphenyl) 1-1-piperazinyl] ethoxy] quinoxaline:

0.96 g (5.0 mMol) of 2- (2-hydroxy) quinoxaline obtained in Production Example 1 was dissolved in 10 ml of chloroform and dissolved in 0.1 ml of thionyl chloride under ice-cooling. 42 ml was added dropwise and stirred overnight. The reaction solution was concentrated under reduced pressure to obtain a crudely purified 1- (2-chloroethoxy) quinoxaline. Then, the 2- (2-chloroethoxy) quinoxaline was dissolved in 25 ml of benzene, and 1.90 g (10.0 mmo 1) of 2,3-dimerfenerubiperazine (manufactured by Aldrich) was added thereto Triethylamine (2.80 ml, 20 mMol) was added, and the mixture was heated under reflux for 24 hours. Chloroform was added, and the mixture was washed with dilute aqueous potassium carbonate solution. The aqueous layer was further extracted with chloroform. The black-mouthed form layer thus obtained was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Picogel C 200, 100 g, elution solvent: chloroform: methanol = 200: 1) to obtain the title compound.

In addition, the hydrochloride of the title compound was obtained by dissolving the title compound in a 5 N hydrochloric acid-methanol solution, adding ether thereto, and depositing crystals. Example 2

Preparation of 2- [2- {4- (2,3-dimethylphenyl) -1-biperazinyl] ethoxy] —3-methylquinoxaline: 1.02 g (5.0 mmo 1) of 2- (2-hydroxyethoxy) -13-methylquinoxaline obtained in Production Example 2 was dissolved in 15 ml of ethylene chloride, and 0.7 ml of triethylamine was dissolved. To the mixture was added 0 ml (5.0 mmo 1), and 0.39 ml (5.0 mmo 1) of methanesulfoyluc mouth was added dropwise under ice cooling, followed by stirring overnight. The residue obtained by decompression and concentration was dissolved in 25 ml of benzene, and 1.90 g (10.0 mmo 1) of 2,3-dimethylphenylbiperan and 1.4 ml of triethylamine (10. Ommol) was added, and the mixture was heated under reflux for 39 hours. After addition of black-mouthed form, the mixture was washed with dilute potassium carbonate aqueous solution, and the aqueous layer was further extracted with black-mouthed form. Combine the chromatographic form layers, dry with sodium sulfate, and concentrate under reduced pressure. The resulting residue is subjected to silica gel ram chromatography (carrier: Picogel C 200, 100 g, elution solvent: chloroform). Purification by methanol = 0: 1) gave the title compound. Example 3

2— [3- {4- (3-Chlorophenyl) -11-pirazuryl] propoxy] Quinoxaline Production:

0.67 g (3.0 mmo 1) of 2- (3-cyclopropoxy) quinoxaline obtained in Production Example 3 was dissolved in 20 ml of benzene, and 0.4 ml of triethylamine (0.4 ml) was dissolved. 3.0 mmol) and 0.59 g (3.0 mmol) of 3-cyclomouth phenylpiperazine, and the mixture was refluxed for 120 hours. After the reaction, chloroform was added, and the mixture was washed with dilute aqueous potassium carbonate solution. The aqueous layer was further extracted with chloroform. Combine the chromatographic form layers, dry with sodium sulfate, and concentrate under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier: Picogel C200, 100 g, elution solvent: chloroform). : Methanol-200: 1) to give the title compound. Example 4

2-C4- {4- (2-Methoxyphenyl) -1-piperazinyl} butoxy] Production of quinoxaline:

2.37 g (10.0 mmo 1) of 2- (4-chlorobutoxy) quinoxaline obtained in Production Example 4 was dissolved in 50 ml of acetonitrile, and 2.07 g (15. 0 mmo 1) and 3.85 g (20.0 mmo 1) of 2-methoxyethoxybiperazine were added, and the mixture was heated and refluxed for 21 hours. After the reaction, the insoluble material was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (carrier: coco-gel C 200, 100 g, elution solvent; Purification by 200: 1) afforded the title compound. Example 5

According to the methods described in Examples 1 to 4, the compounds shown in Table 5 were obtained. Table 6 shows the physical properties of those compounds (free base).

It it * A stand ϊ¾ Ri n according to ひ hikari 间 ¾ half

Example number K η T) 7 No A u

Δ Ό On 0

丄 0 t — — · 羊 '1 "" 《7 7 1 し ο ο クリリ 7 ゥ n 0 IV IVL S £ "7 ザ丄メ丄 II II II q q AA 7 * 1 丄 ion rr

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Oshi-no-Nori-no-nore 4 44. f

246 C H3 3 C 丄 3— Tricle Chrome Techrefle 4 2 2 21.0

1 55 H 4 C on 2-metkinfern 4 96 60.1

156 C Ha 4 C 1 2—Methoxyquin 4 120 46.9

193 H 4 C 12-Black phenyl 4 144 26.1

194 H 4 C 1 3 phenyl phenyl 4 1 4 1 8.0

.195 H 4 C 12 2-Fluorophenyl 4 9 6 24.8

196 CH ₃ 4 c 1 2—Chlorophenyl 4 1 4 20.7

197 CH ₃ 4 c 1 3 -Black phenyl 4 144 16.9

247 H c 13 -Methoxyphenyl 4 18 34.9

248 H 4 c 1 2 -Methylphenyl 3 17 38.1

249 H 4 c 13 3-Methylphenyl 3 1 8 23.1

250 H 4 c 13 3—Trifluoromethylphenyl 4 45 13.1

254 CH ₃ 4 c 1 3-methoxy ethoxy 4 52 24.7

255 CH ₃ 4 c 12 2-Methylphenyl 4 41 22.5

256 CH ₃ 4 c 13 3-Methylphenyl 4 22 40.7

257 CHa 4 c 12 2-Fluorophenyl 4 46 26.3

283 H c 1 2,3-Dimethylphenyl 4 18 41.8

285 CH ₃ 4 c 1 2,3-Dimethylphenyl 4 27 37.0

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(Continuation of Table 6)

3.2 (4H, m), 4.53C2H, t, J = 7), 6.9-8.0 (8H, m)

1 9 7 1.75 (2H, quint, J = 7), 1.91 (2H, quint, J = 7), 2.50 (2H, 413,411 t, J = 7), 2.64 (3H, s), 2, 6-2.7 ( 4H, m), 3.1- 3.3 (4H, m) 307, 251 4.53 C2H, t, J = 7), 6.7-7.2 (2H, m), 7.4-8.0 (6H, m)

247 1.75 (2H ₅ quint, J = 7), 1.92 (2H, quint, J = 7), 2.49 (2H, 393,247 t, J = 7), 2.6-2.7 (4H, m), 3.1-3.3 (4H, m), 3.79 (3H, s) 154 4.52C2H, t, J = 7), 6.3-6.7 (3H, m), 7.1-8.1 (5H, m)

8.46QH, s)

2 48 1.76C2H, quint, J = 7), 1.89 (2H, quint, J = 7), 2.30

(3H, s), 2.52 (2H, t, J = 7), 2.6-2.7 (4H, m), 2.9-3.0 (4H, m), 4.53 (2H, t, J = 7), 6.9-8.1 ( 8H, m), 8.46

(lH, s)

24 9 1.76 (2H, quint, J = 7), 1.92 (2H, quint, J = 7), 2.31 377,231

(3H, s), 2,50 (2H, t, J = 7), 2.6-2,7 (4H, m), 3.1- 3.3 154 (4H, m), 4.52 (2H, t, J = 7) , 6.6-6.8 (3H, m), 7.1-8.1

(5H, m), 8.46 (lH, s)

250 1.75 (2H, quint, J = 7), 1.93 (2H, quint, J = 7) 431,285

2.51 (2H, t, J = 7), 2.6-2.7 (4H, m), 3.2-3.3 (4H, m) 154 4.53 (2H, t 5 J = 7), 7.0-8.1C8H, m), 8.46 ( lH, s) 5 4 1.6-2.0 (4H, m), 2.50C2H, t, J = 7), 2.64C3H, s) 407,247

, 3.1-3.3 (4H, m), 3.79 (3H, s), 4.53 154 (Surroundings in Table 6)

(2H, t, J = 7), 6.3-6.6 (3H, m), 7.1-8.0 (5H, m)

2 5 5 1.76 (2H, quint, J = 7), 1.91 (2H, quint, J = 7), 2.30 391,307

(3H ₎ s), 2.52 (2H, t ₎ J = 7) ₎ 2.6-2.7 (4H, m), 2.65 (3H ₎ s) 289,154 2.9-3.0 (4H, m), 4.53 (2H, t, J = 7), 6.9-8.0 (8H, m)

2 5 6 1.76 (2H, quint ₎ J = 7), 1.90 (2H, quint, J = 7), 2.31 391,231

(3H, s) ₎ 2.51 (2H, t, J = 7), 2.64 (3H, s), 2.6-2.7 (4H, m)

3.1-3.3 (4H, m), 4.53 (2H, t, J = 7), 6.4-8.0 (8H, m)

2 5 7 1.76 (2H, quint, J = 7), 1.91 (2H, quint, J = 7), 2.52 395,235

(2H, t ₎ J = 7), 2.64 (3H, s) ₎ 2.6-2.7 (4H, m), 3.0-3.2 (4H _> 154 m), 4.53 (2H, t, J = 7), 6.8-7.1 (4H, m), 7.4-8.0 (4H, m)

2 8 3 1.76 (2H, quint , J = 7)) 1.92 (2H) quint) J = 7), 2.22 (3H, s) 390,245

2.26 (3H, s), 2.52

, 2.8-3.0 154 (4H ₎ m) ₎ 4.53 (2H ₎ t, J = 7) ₎ 6.8-8.1 (7H ₎ m), 8.46 (lH, s)

2 8 5 1.77 (2H, quint, J = 7), 1.9 (2H, quint, J = 7), 2,22 (3H, s) 405,245

2.26 (3H, s), 2.53 (2H, t, J = 7), 2.64 (3H, s), 2.5-2.7 (4H, m), 2, 8-3.0 (4H, m), 4.53 (2H, t , J = 7), 6.8-8.0 (7H, m) The compound names and compound numbers of the compounds used in the above Examples are as follows.

2-[2-{4-(2,3-dimethylphenyl) 1-1-biperazinyl} ethoxy] quinoxaline (Compound No.

2- [2- {4- (2,3-dimethylphenyl) -1-piperazinyl} Ethoxy] 1-3-methylquinoxaline (Compound No. 272).

2- [3- {4- (2-Methoxyphenyl) 1-1-pirazur} propoxy] quinoxaline (Compound No. 122).

2- [3- {4- (3-chlorophenyl) 1-1-piperazinyl} propoxy] quinoxaline (Compound No. 190).

2- [3- {4- (3-Methylphenyl) -11-piperazinyl} propoxy] -13-methylquinoxaline (Compound No. 240).

2- [3- {4- (3-Trifluoromethylphenyl) -1-piperazinyl} propoxy] quinoxaline (Compound No. 245).

2- [3- {4- (3-trifluoromethylphenyl) -11-biperazinyl} propoxy] -13-methylquinoxaline (Compound No. 246).

2 -— [4- {2- (2-Methoxyethoxy) 1-1-biradil} butoxy] quinoxaline (Compound No. 155).

2- [4- {4- (2-Methoxyphenyl) 1-1-biperazinyl} butoxy] -13-methylquinoxaline (Compound No. 156).

2— [4 {4- (2-chlorophenyl) 1-1-pidazur} butoxy] quinoxaline (Compound No. 193)

2- [4- (4- (3-chlorophenyl) 1-1-piperazinyl] butoxy] quinoxaline (Compound No. 194).

2- [4- {4- (2-Fluorophenyl) 1-1-piperazinyl} butoxy] quinoxaline (Compound No. 195).

2 -— {-(2-Chlorophenyl) -11-biperazinyl} butoxy] -13-methylquinoxaline (Compound No. 196).

2- [4- {4- (3-Chlorophenyl) -11-biperazinyl} butoxy] -1-methylquinoxaline (Compound No. 197).

2- (4- {4- (3-Methoxyphenyl) 1-1-piperazinyl) butoxy] quinoxaline (Compound No. 247).

2— [4— {4 -— (2-methylphenyl) -1-piperazinyl} Xy] quinoxaline (compound number 248).

2-[4-{4-(3-Methylphenyl) 1-1-piperazinyl} butoxy] quinoxaline (Compound No.

2- [4- (4- (3-trifluoromethylphenyl) -11-piperazinyl] butoxy] quinoxaline (Compound No. 250).

2- [4- {4- (3-methoxyphenyl) -1-piperazul} butoxy] -3-methylquinoxaline (Compound No. 25 4)

2 -— [4- {4- (2-methylphenyl) -1-1-piperazinyl} butoxy] —3-methylquinoxaline (Compound No. 255).

2-[4-{4-(3-Methylphenyl) 1-1-pirazuryl] butoxy]-1-Methylquinoxaline (Compound No. 256).

2— [4- {4- (2-Fluorophenyl) -11-piperazul} butoxy] -13-methylquinoxaline (Compound No.257).

2-[2-{4-(2,3-dimethylphenyl) 1-1-pirazul} butoxy] quinoxaline (Compound No. 283).

2- (2- {4- (2,3-dimethylphenyl) -11-piperazul} butoxy) -13-methylquinoxaline (Compound No. 285). Formulation Example 1

Force capsules:

The following ingredients were filled into No. 1 capsule to prepare a capsule.

Compound 195 (dihydrochloride) 20 mg Lactose 90 mg Microcrystalline cellulose 70 mg Magnesium stearate 10 mg Total 190 mg Formulation Example 2

Tablets:

The following components were tableted by a conventional method to give tablets.

Compound 122 (dihydrochloride) 25 mg Lactose 135 mg Microcrystalline cellulose 30 mg Magnesium stearate 10 mg

1 † 20 0 mg Production 3

Injection:

1 g of Compound 245 (dihydrochloride) is dissolved in 5 Om 1 of distilled water for injection, passed through a filter of 0.22 m or less, dispensed into vials in a quantity of 500 1 and freeze-dried to give an injection. I got

Claims

The scope of the claims

1. General formula (I)

(I)

(In the formula, n represents an integer of 2 to 4, R, represents a hydrogen atom or a methyl group, and R ₂ represents a funyl group having a substituent.)

A method for treating a serotonin nervous system-related disease, which comprises a 2-alkoxyquinoxaline derivative represented by the following formula or a non-toxic salt thereof as an active ingredient.

2. The therapeutic agent for semen nervous system related diseases according to claim 1, which is an anxiolytic.

3. The therapeutic agent for serotonin nervous system-related diseases according to claim 1, which is an antidepressant.

4. The therapeutic agent for serotonin nervous system conjunctival disease according to claim 1, which is an antiemetic.

5. The 2-alkoxyquinoxaline derivative is 2- (2- {4- (2,3-dimethylphenyl) -11-biradiul} ethoxy] quinoxaline, 2- -2- (4-) (2,3-Dimethylphenyl) 1-1-piperazinyl} ethoxy] -1-methylquinoxaline, 2- [3- {4— (2-methoxyphenyl) 1-1-biperazinyl} propoxy] quinoxaline, 2- [ 3- {4-(3-chlorophenyl) 1-1-piperazinyl} propoxy] quinoxaline, 2- [3- {4- (3-methylphenyl) -11-piperazinyl} propoxy] -13-methylquinoxaline ゝ 2 — [3— {4— (

3-trifluoromethylphenyl) 1-biperazul} propoxy] quinoxaline, 2- [3- {4- (3-trifluoromethylphenyl)-1-piperazinyl} propoxy] 1-3-methylquinoxali , 2— 〔

4- {4-(2-Methoxyphenyl) 1-1-piperazinyl} butoxy] quinoxaline, 2- [4- {4-(2-Methoxyphenyl) 1-1-pirazuryl} butoxy] -13-Methylquinoxaline , 2- [4- {4- (2-chlorophenyl) -1-1-piperazinyl} butoxy] quinoxaline, 2- [4- (4- {4-(3-chlorophenyl) -1-1-piperazinyl] butoxy) quinoxaline , 2- [4- {4- (2-fluorophenyl) -11-piperazinyl) butoxy] quinoxaline, 2- [4- {4- (2-chlorophenyl) 1-1-biperazinyl} butoxy] 13- Methylquinoxaline, 2- [4- {4- (3-chlorophenyl) -11-piperazul} butoxy] -13-Methylquinoxaline, 2- [4- {4- (3-methoxyphenyl) 1-1-1 [Virazur} butoxy] quinoxaline, twenty four-

{4- (2-Methylphenyl) 1-1-piperazinyl} butoxy] quinoxaline, 2-C4- {4- (3-methylphenyl) 1-1-piperazinyl} butoxy] quinoxaline, 2- [4- {4-- 3—Trifluoromethylphenyl) 1-1-pirazuryl butoxy] quinoxaline, 2-—4-4- (3-Methoxyphenyl) -11-virazur} butoxy-13-methylquinoxaline, 2-— 4- {4-(2-Methylphenyl) -1-1-pirazuryl-butoxy] -1-3-Methylquinoxaline, 2- [4-1

{4- (3-Methylphenyl) -11-pidazul} butoxy] -13-methylquinoxaline, 2- [4- {4- (2-fluorophenyl) -11-biperazinyl} butoxy] -13-methylquinoxaline, 2—C 2-{4- (2,3-dimethylphenyl) -1- (piperazul) butoxy] Noxalin, 2- [2- (4- (2,3-dimethylphenyl) -11-biperazinyl} butoxy] -13-methylquinoxaline and their non-toxic salts selected from claim 1 5. The therapeutic agent for a sip-tonin nervous system-related disease according to any of 4.