JP2551298B2 - Antidepressant - Google Patents

Description

Detailed Description of the Invention

[0001]

This invention relates to antidepressants.

[0002]

2. Description of the Related Art Monoamine oxidase (MAO) is an enzyme that catalyzes the oxidative deamination reaction of monoamines to produce aldehydes. Based on its substrate specificity, a neurotransmitter such as catecholamine or serotonin is used as a substrate. A type is distinguished from a B type using phenethylamine as a substrate. However, M, which is conventionally known as an antidepressant,
AO inhibitors do not have A / B type selectivity and exhibit an irreversible inhibitory action, and have a long duration of action, resulting in side effects [liver disorder, hypertension (cheese effect) after ingestion of tyramine-containing food, migraine headache. Etc.] has occurred.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a reversible, short-lasting and excellent, which does not show side effects as in the past.
It is intended to provide an antidepressant having a selective MAO-A inhibitory effect.

[0004]

The present invention has the general formula (I)

[0005]

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(Wherein R ¹ is a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a sulfo group, an aminosulfonyl group, a lower alkenyloxy group, a lower alkynyloxy group, a mono- or di-lower alkylaminocarbonyloxy group or a lower alkanoyloxy group. A group or an aryl group,
Cycloalkyl group, oxygen-containing heteromonocyclic group, hydroxyl group, lower alkoxy group, cyano group, di-lower alkylamino group, aminocarbonyl group, lower alkoxycarbonyl group, lower alkanoyloxy group, lower alkylthio group, lower alkylsulfinyl group and A lower alkoxy group which may be substituted with a group selected from a lower alkylsulfonyl group,
R ² represents a hydroxyl group, a lower alkoxy group, a lower alkylsulfonyloxy group, a triazo group, an amino group or a lower alkyl group or a lower alkanoyl group-substituted amino group. )
Relates to an antidepressant comprising a naphthyloxazolidone derivative or a pharmacologically acceptable salt thereof as an active ingredient.

The naphthyloxazolidone derivative (I) and its pharmaceutically acceptable salts, which are the active ingredients of the present invention, are:
It is a new compound and has excellent preventive and therapeutic effects on depressive symptoms.

As specific examples of the naphthyloxazolidone derivative (I), in the general formula (I), for example, the aryl group is a phenyl group, the cycloalkyl group is a cyclopropyl group, and the oxygen-containing heteromonocyclic group is a tetrahydrofuryl group. There are some.

Among these, compounds having excellent therapeutic effects are compounds of the general formula (I) in which R ¹ is a hydrogen atom, a hydroxyl group,
A lower alkenyloxy group, a lower alkynyloxy group, a mono-lower alkylaminocarbonyloxy group or a lower alkanoyloxy group, or a cyclopropyl group, a tetrahydrofuryl group, a hydroxyl group, a lower alkoxy group, a cyano group, a di-lower alkylamino group, A lower alkoxy group which may be substituted with a group selected from an aminocarbonyl group, a lower alkanoyloxy group and a lower alkylthio group, a compound wherein R ² is a hydroxyl group or a lower alkoxy group, and R ¹ is a hydrogen atom, a lower alkenyloxy group A group or a lower alkanoyloxy group, a lower alkoxy group which may be substituted with a group selected from a cyclopropyl group, a hydroxyl group and a cyano group, and a compound in which R ² is a lower alkoxy group are more preferable.

Furthermore, compounds wherein R ¹ is a cyclopropyl group and a lower alkoxy group optionally substituted by a group selected from cyano group, R ² is a lower alkoxy group are especially preferred. In addition, other compounds having excellent therapeutic effects are those in which R ¹ is substituted at the 6-position of the naphthalene ring, and 5-substituted-2
A compound in which an -oxazolidon-3-yl group is substituted at the 2-position of the naphthalene ring.

The naphthyloxazolidone derivative (I) is
It can be used for medicinal use either in the free form or in the form of its pharmacologically acceptable salt. Examples of the pharmaceutically acceptable salt include salts with inorganic or organic bases, for example, alkali metal salts such as sodium salt and potassium salt, calcium salt,
Examples thereof include alkaline earth metal salts such as magnesium salts, ammonium salts and the like, or inorganic or organic acid addition salts such as hydrochlorides, sulfates, acetates and benzenesulfonates.

The dose of the naphthyloxazolidone derivative (I) or a pharmacologically acceptable salt thereof varies depending on the age, weight, condition of the patient, the degree of disease, etc., but the daily dose is usually 0.01. ~ 250 mg / kg. Although the antidepressant of the present invention can be administered orally or parenterally, it is particularly preferably administered orally.

The dosage forms for oral administration are tablets, powders,
It may be a solid preparation such as capsule or granule, or a liquid preparation such as solution or suspension, and can be used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral administration. Examples of such pharmaceutical carriers include binders (syrup, acacia, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbit, glycine, etc., lubricants (magnesium stearate, talc,
Examples thereof include polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.).

On the other hand, the dosage form for parenteral administration is preferably an injection or drip injection, for example, using distilled water for injection, physiological saline, an aqueous glucose solution or the like. Naphthyloxazolidone derivative (I) which is an active ingredient of the present invention
Is (A) general formula (II)

[0015]

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(However, R ¹ has the same meaning as described above, and R ^1
3 represents lower alkyl. ) A lower alkyl ester compound of naphthylaminocarboxylic acid represented by the general formula (II)
I)

[0017]

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(Wherein R ² has the same meaning as described above) is reacted with an oxirane compound in the presence of a base [eg, tri (lower alkyl) amine], or (B) the general formula (IV)

[0019]

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(However, X ¹ represents a halogen atom, and R ¹
Has the same meaning as above. ) And a general formula (V)

[0021]

[Chemical 6]

(Wherein R ² has the same meaning as described above), reacted with a 2-oxazolidone compound in the presence of a deoxidizing agent (for example, alkali metal carbonate) and activated copper powder to produce can do. Further, the naphthyloxazolidone derivative (I) in which R ² is a hydroxyl group is represented by the general formula (VI)

[0023]

[Chemical 7]

It can also be produced by reacting a propanediol compound represented by (wherein R ¹ has the same meaning as described above) with carbonyldiimidazole in the presence of a base (for example, an alkali metal alkoxide).

The naphthyloxazolidone derivative (I) thus obtained can be appropriately interconverted by a conventional method. For example, in the target product (I), when R ¹ is a benzyloxy group, it is catalytically reduced to a hydroxyl group,
If desired, a lower alkoxy group (this group is an aryl group, a cycloalkyl group, an oxygen-containing heteromonocyclic group, a hydroxyl group,
Lower alkoxy group, cyano group, di-lower alkylamino group, aminocarbonyl group, lower alkoxycarbonyl group, lower alkanoyloxy group, lower alkylthio group,
It may be substituted with a group selected from a lower alkylsulfinyl group and a lower alkylsulfonyl group], a lower alkenyloxy group, a lower alkynyloxy group, a mono- or di-lower alkylaminocarbonyloxy group or a lower alkanoyloxy group. it can.

When R ¹ is a nitro group and / or R ² is a triazo group, it is catalytically reduced to an amino group and, if desired, a lower alkanoylamino group, or further diazotized and then subjected to a conventional method. It may also be a hydroxyl group or a lower alkoxy group. When R ¹ is a sulfo group, it can be aminated to give an aminosulfonyl group. Furthermore, when R ¹ is a lower alkylthio-substituted lower alkoxy group, it can be oxidized to the corresponding sulfinyl or sulfonyl body.

On the other hand, when R ² is a lower alkoxy group, it can be hydrolyzed to a hydroxyl group, and if desired, converted to a lower alkylsulfonyloxy group and further to an alkylamino group or a triazo group by a conventional method.

The naphthyloxazolidone derivative (I) has optical isomers, but the present invention includes any isomer and a mixture thereof. Further, since the above reaction proceeds without racemization, an optically active naphthyloxazolidone derivative can be obtained by using an optically active substance as a raw material compound. Furthermore, when the naphthyloxazolidone derivative (I) is a racemate based on the asymmetric carbon atom at the 5-position of the oxazolidine ring, the optically active substance is, for example, a product obtained by treating the naphthyloxazolidone derivative (I) with an alkali metal hydroxide. And optically active 1- (2-naphthylsulfonyl) -2-pyrrolidinylcarbonyl chloride are reacted, the resulting two diastereomers are separated by column chromatography, and then hydrolyzed and reacted with carbonyldiimidazole. Let's get it. The starting compound (II) has the general formula (VII)

[0029]

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(Wherein R ¹ has the same meaning as described above), and a naphthylamine compound represented by the general formula (V
III)

[0031]

[Chemical 9]

(Wherein X ³ represents a reactive residue) and a lower alkyl ester of a carboxylic acid compound,
It can be produced by reacting in a solvent (methylene chloride) in the presence of a deoxidizing agent (sodium hydrogen carbonate). The starting compound (V) has the general formula (IX)

[0033]

[Chemical 10]

(Wherein R ² has the same meaning as described above) and a benzyloxycarbonyl halide are reacted with each other in a solvent (tetrahydrofuran) in the presence of a deoxidizing agent (triethylamine). After that, the product can be produced by subjecting it to a ring closure reaction in the presence of a base (sodium hydride).

Experimental Example 1 Inhibitory Effect of Rat Brain Mitochondrial Fraction on MAO-A Activity (In Vitro) (Measurement of MAO-A Inhibitory Activity) Mitochondrial fraction (protein concentration) obtained from rat brain tissue by a conventional method. :
About 7 mg / ml) was used as the enzyme material. MAO
The -A activity was measured using serotonin as a substrate and using released ammonia (NH ₃ ) as an index. Each sample was dissolved in dimethyl sulfoxide (DMSO) and the final concentration was 10
^-7 M was added to the reaction system. The same amount of DMSO was added to the control system. Final concentration of each sample 10
The MAO-A activity inhibition rate at ⁻⁷ M was calculated according to the following formula. Inhibition rate (%) = [1- (sample addition system of the NH ₃ amount / NH ₃ amount of control system)] X100 (Results) The results are as follows in Table 1, wherein.

[0036]

[Table 1]

Experimental Example 2 Inhibitory effect on MAO-A and B activities of mouse brain (e
x vivo) 30 mg / kg specimen suspended in 0.5% carboxymethylcellulose (CMC) aqueous solution in 3 mice per group
Was orally administered, and 45 minutes later, brain tissue was extracted. In addition,
The same amount of 0.5% CMC aqueous solution was administered to the control group. MAO-A and B activities were measured using a homogenate prepared by adding 9 times the amount of ice-cold distilled water to the brain tissue as an enzyme material. The MAO-A activity was measured according to the method of Experimental Example 1, and the B activity was measured by using benzylamine as a substrate and the amount of benzaldehyde (BA) produced was used as an index [The Journal.
The Laboratory of Clinical Medicine (The Journal of Laboratories)
y and Clinical Medicine), Vol. 62, pp. 766-776, 1963].
In addition, as a comparative drug, purgulin (N-methyl-N-2
-Propynylbenzylamine, 30 mg / kg orally) was used.

The MAO-A and B activity inhibition rate of each sample was calculated by the following formula. Inhibition rate (%) = [1- (NH ₃ amount or BA of sample administration group
Amount / NH ₃ amount or BA amount of control group)] X100 (Result) The results are as shown in Table 2 below.

[0039]

[Table 2]

Experimental Example 3 Inhibitory effect on MAO-A and B activities of mouse brain (e
x vivo) 3 mg / kg of a sample suspended in a 0.5% carboxymethylcellulose (CMC) aqueous solution was orally administered to 3 mice per group, and MAO-A and B activities were performed thereafter in the same manner as in Experimental Example 2. Was measured. The MAO-A and B activity inhibition rate of each sample was calculated according to the formula of Experimental Example 2. (Results) The results are as shown in Table 3 below.

[0041]

[Table 3]

Production Example 1 (1) 20.0 g of 2-naphthylamine, 17.6 g of sodium hydrogen carbonate, 100 ml of water and 200 methylene chloride.
A mixture of 16.7 g of ethoxycarbonyl chloride and 20 ml of methylene chloride was added dropwise to the mixture of ml under ice-cooling, and the mixture was stirred at room temperature overnight. The organic layer was separated with chloroform, dried and treated with carbon powder, and the residue was washed with ethyl acetate-
Recrystallized from hexane to give N-ethoxycarbonyl-2
25.26 g of naphthylamine are obtained. m. P. 69.0-70.5 ° C

(2) 3.82 g of the product of (1) above, 2
A mixture of 3.13 g of-(methoxymethyl) oxirane and 0.4 g of triethylamine is refluxed for 3.5 hours. The reaction solution is extracted with ethyl acetate, washed with water, dried, and filtered. The filtrate was contracted and the residue was purified by a silica gel column [solvent; ethyl acetate-hexane (2: 3)] to give 3.75 g of crude 3- (2-naphthyl) -5-methoxymethyl-2-oxazolidone. obtain. Further, recrystallization from ethyl acetate-hexane gives 3.17 g of colorless needle crystals. m. p. 79.5-81.5 ° C

Crab Making Examples 2 to 4 (1) The corresponding raw material compounds are treated in the same manner as in Production Example 1- (1) to obtain the compounds shown in Table 4 below.

[0045]

[Table 4]

(2) The above product is treated in the same manner as in Production Example 1- (2) to obtain the desired product shown in Table 5 below.

[0047]

[Table 5]

Production Example 5 (I) 5.36 g of 2-amino-5-naphthol was treated in the same manner as in Production Example 1- (I) to obtain 4.65 g of N-ethoxycarbonyl-5-hydroxy-2-naphthylamine. obtain. m. p. 117-121 ° C (ethyl acetate-isopropyl ether-hexane)

(2) 4.14 g of the product of (1) above is dissolved in 45 ml of acetone, 12.4 g of potassium carbonate and 8.9 g of methyl iodide are added, and the mixture is stirred at room temperature for 4 hours.
Acetic acid is added to the reaction solution to dilute it, washed with water and saturated saline, dried, and filtered. The solvent was distilled off from the filtrate to obtain crude N
-Ethoxycarbonyl-5-methoxy-2-naphthylamine (oil) 4.31 g is obtained.

(3) The oily substance obtained in (2) above and 2.45 g of 2- (methoxymethyl) oxirane were prepared in Production Example 1-
Treated in the same manner as (2), 5-methoxymethyl-3-
4.27 g of (5-methoxy-2-naphthyl) -2-oxazolidone are obtained as an oil. IR ^Nujol ν _Max (cm ^-1 ): 1750

Production Example 6 N-ethoxycarbonyl-2-naphthylamine 4.63
g, a mixture of 4.2 g of 2- (t-butoxymethyl) oxirane and 0.22 g of triethylamine, 100-1
Heat and stir for 1.5 hours at 05 ° C. After allowing the reaction solution to cool, the precipitated crystals are collected by filtration. The crystals were treated with carbon powder and then recrystallized from ethyl acetate-isopropyl ether-hexane to give 3- (2-naphthyl) -5-t-butoxymethyl-.
4.7 g of 2-oxazolidone are obtained. m. p. 112.5-113.0 ° C

Production Example 7 (1) 1-Amino-3-methoxy-2-propanol 1
19.69 g of triethylamine is added to a solution of 0.23 g of tetrahydrofuran in 100 ml, and the mixture is ice-cooled. A solution of 16.60 g of benzyloxycarbonyl chloride in 50 ml of tetrahydrofuran was added dropwise to the solution over 30 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution is diluted with ethyl acetate, washed, and then 300 ml of the organic layer is dried. The residue is purified by silica gel column [solvent: ethyl acetate-hexane (2: 1)] to obtain 1-benzyloxycarbonylamino-3-methoxy-2-propanol (13.2 g) as a colorless oil. IR ^Neat ν _Max (cm ⁻¹ ): 3340 (b
r), 1700

(2) To a solution of 10.2 g of the product of (1) above in 200 ml of tetrahydrofuran was added 1.624 g of 63% sodium hydride, and the mixture was stirred at room temperature for 1 hour. Water is added to the reaction solution, extracted with chloroform, and concentrated. The residue is purified by silica gel column [solvent; ethyl acetate-hexane (3: 1)] to obtain 5.36 g of 5-methoxymethyl-2-oxazolidone as a colorless oil. IR ^Neat ν _Max (cm ⁻¹ ): 3320,165
0

(3) 130 ° C. in a mixture of 5.24 g of the product of (2) above and 4.14 g of 2-bromonaphthalene.
Under stirring at 6.10 g of activated copper powder and sodium carbonate 2.
After adding 76 g, the mixture is reacted at 200 ° C. for 3 hours. After cooling, ethyl acetate is added, and the insoluble matter is removed by filtration. The solvent was distilled off from the filtrate, and the residue was purified by silica gel column [solvent; ethyl acetate-hexane (2: 3)] to give 3- (2-naphthyl) -5-methoxymethyl-2-oxazolidone (2.36 g). As colorless needles. The physicochemical properties of this product were consistent with those of the product of Preparative Example 1.

Production Examples 8 and 9 The corresponding starting material compounds were treated in the same manner as in Production Example 7- (3),
The target product shown in Table 6 below is obtained.

[0056]

[Table 6]

Production Example 10 (1) In 500 ml of concentrated ammonia water under ice cooling, 2-
After dropping 100 g of (t-butoxymethyl) oxirane,
Stir at room temperature for 20 hours. Ammonia water is distilled off from the reaction solution under reduced pressure, chloroform is added to the residue, dried over potassium carbonate and filtered, and then the solvent is distilled off. The residue is subjected to vacuum distillation and purified to give 49.3 g of 1-amino-3-t-butoxy-2-propanol. b. p. 109-110 ° C / 8 mmHg m.p. p. 41-43 ° C

(2) 49.3 g of the product of (1) above, 49.1 g of diethyl carbonate and 0.1 parts of sodium methoxide.
8 g of the mixture are heated at about 150 ° C. for 3 hours (during which time about 40 ml of the ethanol formed is distilled off). After the reaction, excess diethyl carbonate is distilled off under reduced pressure. The residue is allowed to cool, and the precipitated crystals are washed with hexane to obtain 55.4 g of 5-t-butoxymethyl-2-oxazolidone as colorless crystals. m. p. 57-65 ° C

(3) 1.1 g of the product of (2) above and 2-
1.0 g of benzyloxy-6-bromonaphthalene was treated in the same manner as in Production Example 7- (3) to give 3- (6-benzyloxy-2-naphthyl) -5-t-butoxymethyl-2.
-0.73 g of oxazolidone are obtained as colorless crystals. m. p. 151.5-152 ° C (ethyl acetate-isopropyl ether)

Production Example 11 (1) A mixture of (R) -α, β-isopropylideneglycerol (14.4 g) and pyridine (60 ml) was cooled with ice.
Add 21.0 g of tosyl chloride and stir for 4 hours.
50 ml of water is added to the mixture under ice cooling, and the mixture is stirred at room temperature for 10 minutes. The reaction solution was extracted with diethyl ether, the extract was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain (4S) -2,
29.5 g of 2-dimethyl-4-tosyloxymethyl-1,3-dioxolane are obtained as a brown oil. IR ^Liquid ν _Max (cm ⁻¹ ): 1365,1
260,1210 Mass (m / z): 276 (M ⁺ -15), 155,
101, 91 (base), 43

(2) 9.51 g of the product of (1) above, 6
-(Cyclopropylmethoxy) naphthylamine 5.25
g, sodium iodide 5.54 g, sodium hydrogen carbonate 6.2 g and hexamethylphosphoric triamide 42
The ml mixture is stirred at 120 ° C. for 11 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the extract was washed with water, dried,
Distill off. The residue was purified by silica gel column chromatography [solvent: ethyl acetate-hexane (1: 5)] and then recrystallized from ethyl acetate-hexane to give (4R)-
5.88 g of 4 [6- (cyclopropylmethoxy) -2-naphthylaminomethyl] -2,2-dimethyl-1,3-dioxolane are obtained as pale yellow scaly crystals. m. p. 108.5-109.0 ° C [α] _D ²⁰ -12.9 ° (c = 1.089, chloroform)

(3) 8.09 g of the product of (2) above, 1
A mixture of 35 ml of N hydrochloric acid and 80 ml of tetrahydrofuran is stirred at 60 ° C. for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After the extract is washed with water and dried, the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to obtain (2R) -3- (6-cyclopropylmethoxy-2-naphthylamino) -1,2-propanediol (6.93 g) as pale yellow scaly crystals. m. p. 138.0 to 138.5 ° C. [α] _D ²⁰ + 8.0 ° (c = 0.898, tetrahydrofuran)

(4) A mixture of 1.36 g of the product of (3) above, 670 mg of diethyl carbonate, 1 ml of toluene and 50 mg of sodium methoxide is stirred at 150 ° C. for 1 hour. After distilling off the solvent from the reaction solution under reduced pressure, acetic acid 1 was added to the residue.
After the addition, the product was purified by silica gel column chromatography [solvent: chloroform-ethyl acetate (1: 1 to 1: 3)] and then recrystallized from ethyl acetate-hexane to give (5
R) -3- (6-Cyclopropylmethoxy-2-naphthyl) -5-hydroxymethyl-2-oxazolidone 1.
06 g are obtained as colorless needles. m. p. 181.5-182.5 ° C [α] _D ²⁰ -61.4 ° (c = 1.031, chloroform)

Production Example 12 6.99 g of 3- (7-nitro-2-naphthyl) -5-methoxymethyl-2-oxazolidone was suspended in 140 ml of acetic acid, 2.1 g of 10% palladium-carbon was added, and the mixture was kept at room temperature at room temperature. Subject to catalytic reduction with pressure. The reaction solution is filtered through celite, and the filtrate is distilled off under reduced pressure. Ethyl acetate was added to the residue, and the ethyl acetate layer was washed, dried and concentrated, and then concentrated on a silica gel column [solvent; ethyl acetate-hexane (2: 1 to 3: I)].
Purify with. The residue was recrystallized from ethyl acetate-isopropyl ether to give 3- (7-amino-2-naphthyl)-
4.96 g of 5-methoxymethyl-2-oxazolidone are obtained. m. p. 98-99 ° C

Production Examples 13 and 14 0.97 g of sodium nitrite was added to a mixture of 3- (7-amino-2-naphthyl) -5-methoxymethyl-2-oxazolidone (3.47 g), water (6 ml) and agricultural hydrochloric acid (3.3 ml).
6 ml of water solution of was added dropwise at 0-5 ° C., stirred for a while, 100 ml of methanol was added all at once, and the mixture was stirred at room temperature for 7 hours.
After stirring for an hour, leave it in the refrigerator overnight. The reaction solution is extracted with ethyl acetate, washed and dried, and the aqueous layer is further extracted with chloroform and dried. The obtained residue (1.88 g) is purified by silica gel column [solvent; ethyl acetate-hexane (1: 1)] to give 3- (7-methoxy-2-naphthyl) -5-.
Methoxymethyl-2-oxazolidone [Production Example 13,
m. p. 95.5-96.5 ° C. (ethyl acetate-hexane)] and 3- (7-hydroxy-2-naphthyl) -5
-Methoxymethyl-2-oxazolidone [Production Example 14,
m. p. 155 to 157 ° C (ethyl acetate-hexane)]
Get.

Production Example 15 6- (5-methoxymethyl-2-oxazolidone-3-
To a suspension of 3.0 g of sodium) -2-ylnaphthylsulfonate in 24 ml of dimethylformamide, 1.0 ml of thionyl chloride is added under ice cooling, and the mixture is stirred at room temperature for 1 hour. After ice cooling, extract with ethyl acetate, wash, dry,
2.91 g of a light brown foam are obtained. To a solution of the product in 50 ml of tetrahydrofuran was added 10 ml of a concentrated aqueous solution of ammonium hydroxide under ice cooling, and the mixture was stirred at room temperature for 2 hours.
200 ml of water is added, and after stirring for a while, the mixture is left overnight at room temperature. The precipitated crystals were collected by filtration, washed, and recrystallized from ethanol to give 3- (6-aminosulfonyl-2-naphthyl) -5.
1.97 g of -methoxymethyl-2-oxazolidone are obtained as a colorless powder. m. p. 166-168 ° C

Production Example 16 3- (6-benzyloxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone 18.9 g, 10% palladium-carbon 10.0 g tetrahydrofuran 700
In addition to ml, it is subjected to catalytic reduction for 10 hours at room temperature and atmospheric pressure.
After the catalyst was filtered off from the reaction solution, the solvent was distilled off, and the residue was recrystallized from ethanol-tetrahydrofuran-isopropyl ether to give 3- (6-hydroxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone. 11.
2 g are obtained as colorless needles. m. p. 192-193 ° C

Production Example 17 3- (6-benzyloxy-2-naphthyl) -5-t-
30.6 g of butoxymethyl-2-oxazolidone was treated in the same manner as in Production Example 15 to give 3- (6-hydroxy-2-
22.7 g of naphthyl) -5-t-butoxymethyl-2-oxazolidone are obtained as colorless crystals. m. p. 177 to 178 ° C (tetrahydrofuran-isopropyl ether-hexane)

Production Example 18 5.06 g of potassium carbonate and 2 ml of ethyl iodide were added to a solution of 2.0 g of 3- (6-hydroxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone in 25 ml of dimethylformamide, and the mixture was stirred at room temperature. Stir for 4 hours. The reaction mixture was diluted with ethyl acetate, washed and dried, and the obtained residue was recrystallized from ethyl acetate-isopropyl ether to give 3
1.89 g of-(6-ethoxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone are obtained as colorless mica. m. p. 129.5-130.5 ° C

Production Examples 19 to 45 The corresponding starting material compounds were treated in the same manner as in Production Example 18 to obtain the target compounds shown in Table 7 below. [In the table, Me and tB
u represents a methyl group and a tert-butyl group, respectively (the same applies hereinafter). ]

[0071]

[Table 7]

[0072]

[Table 8]

Production Example 46 720 mg of 3- (6-hydroxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone, 5 ml of acrylonitrile, 5 ml of tetrahydrofuran and 0.1 ml of a methanol solution of 40% benzyltrimethylammonium hydroxide were added and added. Reflux for days. The reaction solution is dried under reduced pressure, extracted with ethyl acetate, washed with water, dried, and further dried under reduced pressure. The residue was purified by silica gel column [solvent: chloroform-methanol (20: 1)], and then ethyl acetate-
Recrystallized from hexane to give 3- (6-cyanoethoxy-
410 mg of 2-naphthyl) -5-methoxymethyl-2-oxazolidone are obtained as colorless scaly crystals. m. p. 110-112 ℃

Production Examples 47-49 The corresponding starting compounds were treated in the same manner as in Production Example 46 to obtain the compounds shown in Table 8 below.

[0075]

[Table 9]

Production Example 50 A mixture of 3- (6-hydroxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone (950 mg), ethylisocyanate (310 mg), methylene chloride (15 ml), tetrahydrofuran (10 ml) and triethylamine (1 drop) was stirred at room temperature for 4 hours. After that, ethyl isocyanate 1.
Add 5 ml and reflux for 3 hours. The reaction solution is dried under reduced pressure, ethyl acetate is added, washed, treated with carbon powder, dried, filtered, and further dried under reduced pressure. The residue is recrystallized from ethyl acetate-isopropyl ether to give 3- (6-ethylaminocarbonyloxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone 800 mg as colorless prism crystals. m. p. 126.5-127.5 ° C

Production Example 51 3- (6-hydroxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone 2.0 g and acetic anhydride 10
Heat ml to reflux for 1 hour. Excess acetic anhydride was distilled off from the reaction solution, and the residue was recrystallized from ethyl acetate-isopropyl ether and washed with isopropyl ether to give 3
2.25 g of-(6-acetyloxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone are obtained as colorless crystals. m. p. 110-112.5 ° C

Production Example 52 3- [6- (Methylthioethyloxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone 1.8
To a solution of 8 g of methylene chloride in 100 ml, 1.07 g of 87% m-chloroperbenzoic acid is added little by little at room temperature. After stirring at room temperature for 1 hour, the mixture is washed with 10% aqueous sodium hydroxide solution and water, dried, filtered, and the solvent is distilled off. The residue was purified by silica gel column [solvent: chloroform-methanol (30: 1)] and then recrystallized from ethyl acetate-tetrahydrofuran-isopropyl ether to give 3-
[6- (Methylsulfinylethyloxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone 1.
21 g are obtained as colorless prism crystals. m. p. 133-141 ° C

Production Example 53 3- [6- (Methylthioethyloxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone 1.2
To 0 g of 40 ml of methylene chloride, 1.65 g of 87% m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution is washed with a 10% aqueous sodium hydroxide solution, dried and then filtered, and the solvent is distilled off. The residue was purified by silica gel column [solvent: chloroform-ethyl acetate (1: 1)] and then recrystallized from ethanol-tetrahydrofuran-isopropyl ether to give 3- [6- (methylsulfonylethyloxy) -2-naphthyl]. 0.73 g of -5-methoxymethyl-2-oxazolidone is obtained as colorless needle crystals. m. p. 128-129 ° C

Production Example 54 3- (2-naphthyl) -5-t-butoxymethyl-2-
Under cooling, 10 ml of trifluoroacetic acid is added to 3.36 g of oxazolidone, and the mixture is stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, and the residue was recrystallized from ethanol-dimethylformamide-isopropyl ether to give 3- (2-
2.16 g of naphthyl) -5-hydroxymethyl-2-oxazolidone are obtained as colorless crystals. m. p. 174-14.5 ° C

Production Examples 55 to 57 The corresponding starting compound was treated in the same manner as in Production Example 54 to obtain the compounds shown in Table 9 below.

[0082]

[Table 10]

Production Example 58 To a suspension mixture of 3- (2-naphthyl) -5-hydroxymethyl-2-oxazolidone (12.0 g), methylene chloride (240 ml) and triethylamine (10.0 g) was added methylsulfonyl chloride (8) under ice cooling. A solution of 5 g of methylene chloride in 120 ml is added dropwise, and the mixture is stirred at room temperature for 3 hours. A solution of 1.0 g of methylsulfonyl chloride in 50 ml of tetrahydrofuran was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. After washing the reaction solution, it is extracted with methylene chloride and dried. The residue was recrystallized from isopropyl ether to give 3-
14.7 g of (2-naphthyl) -5-methylsulfonyloxymethyl-2-oxazolidone are obtained as colorless crystals. m. p. 169-172 ° C

Production Example 59 3- (2-naphthyl) -5-methylsulfonyloxymethyl-2-oxazolidone 3.0 g, 40% monomethylamine aqueous solution 120 ml, tetrahydrofuran 100
ml and 50 ml of dimethylformamide are sealed and stirred at room temperature for 2 days. After distilling off excess monomethylamine and tetrahydrofuran from the reaction solution, it is extracted with ethyl acetate, washed and dried. The residue was purified by silica gel column [solvent: chloroform-methanol (20: 1)], recrystallized from ethyl acetate-hexane, and washed with hexane to give 3- (2-naphthyl) -5-monomethylaminomethyl-. 1.12 g of 2-oxazolidone are obtained as colorless crystals. m. p. 76.5 to 78.0 ° C

Preparation Example 60 A mixture of 11.6 g of 3- (2-naphthyl) -5-methylsulfonyloxymethyl-2-oxazolidone, 230 ml of dimethylformamide and 4.84 g of sodium azide in 23 ml of water at 80 ° C. for 9 hours. Stir. The reaction solution was extracted with ethyl acetate, washed, dried, and recrystallized from ethyl acetate-hexane to obtain 3- (2-naphthyl) -5-triazomethyl-2-oxazolidone (8.62 g) as colorless crystals. m. p. 115.0-116.5 ° C

Preparation Example 61 3- (2-naphthyl) -5-triazomethyl-2-oxazolidone 8.53 g was added to tetrahydrofuran 100 ml.
-Dissolved in a mixed solution of 100 ml of acetic acid and 10% palladium-
2.0 g of carbon is added and catalytic reduction is performed at room temperature and atmospheric pressure. After removing the palladium-carbon, it is washed and the solvent is distilled off. The mixture is made alkaline with an aqueous sodium hydrogen carbonate solution, the precipitated crystals are collected by filtration, washed, and then dissolved in heated methanol. 50 g of silicon dioxide was added to the solution, and a silica gel column [solvent;
Chloroform-methanol (40: 1 to 8: 1)], recrystallized from ethanol-isopropyl ether-hexane, washed with isopropyl ether and washed with 3
4.90 g of-(2-naphthyl) -5-aminomethyl-2-oxazolidone are obtained as colorless crystals. m. p. 112-114 ° C

Production Example 62 A mixture of 1.8 g of 3- (2-naphthyl) -5-aminomethyl-2-oxazolidone, 36 ml of chloroform, 1.5 ml of acetic anhydride and 1.5 ml of pyridine is stirred at room temperature for 1 hour. After washing and drying the reaction solution, ethyl acetate-
Recrystallization from isopropyl ether and washing with isopropyl ether give 1.56 g of 3- (2-naphthyl) -5-acetylaminomethyl-2-oxazolidone as colorless crystals. m. p. 152-154 ° C

Production Example 63 (1) 3- (6-benzyloxy-2-naphthyl) -5
-Methoxymethyl-2-oxazolidone 2.0 g, ethanol 20 ml, water 4 ml and potassium hydroxide 1.08
The g mixture is stirred at 100 ° C. for 1 hour. After ethanol was distilled off under reduced pressure from the reaction solution, the residue was extracted with ethyl acetate. After the extract is washed with water and dried, the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to obtain 1.64 g of N- (3-methoxy-2-hydroxypropyl) -6-benzyloxy-2-naphthylamine as colorless needle crystals. m. p. 103 ~ 104 ℃

(2) In a mixture of 10.0 g of the product of (1) above, 70 ml of methylene chloride, 70 ml of water and 4.98 g of sodium hydrogencarbonate, a mixture of 3.53 g of ethyl chloroformate and 5 ml of methylene chloride was added. Then, the mixture is added dropwise under ice cooling and stirred at room temperature for 1.5 hours. After further adding a mixture of 0.35 g of ethyl chloroformate and 2 ml of methylene chloride, the mixture is stirred at room temperature for 4 hours. After separating the organic layer from the reaction solution, the aqueous layer is extracted with methylene chloride, and the extract and the organic layer are mixed. After drying the mixed solution, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [solvent: ethyl acetate-hexane (1: 1)] to give N-ethoxycarbonyl-N- (3-methoxy-). Two
12.66 g of -hydroxypropyl) -6-benzyloxy-2-naphthylamine is obtained as a colorless oil. IR ^Neat ν _Max (cm ⁻¹ ): 3450 (b
r), 1700, 1605 Mass (m / z): 409 (M ⁺ ), 318, 91
(Base)

(3) 12.12 g of the product of (2) above,
Tetrahydrofuran 120 ml and (2S) -1- (2
To a mixture of 11.5 g of -naphthylsulfonyl) -2-pyrrolidinylcarbonyl chloride, a mixture of 4.68 g of pyridine and 10 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution is ethyl acetate 5
Dilute with 00 ml, wash with 5% hydrochloric acid and water, dry, and evaporate the solvent. The residue was purified by silica gel column chromatography [solvent: ethyl acetate-hexane (2: 3)], and N-ethoxycarbonyl-N-{(2R) -3-methoxy-2-[(2S) -1- (2 -Naphthylsulfonyl) -2-pyrrolidinylcarbonyloxy] propyl}
-9-Benzyloxy-2-naphthylamine (Product A) 9.48 g and N-ethoxycarbonyl-N-
{(2S) -3-methoxy-2-[(2S) -1- (2
9.28 g of -naphthylsulfonyl) -2-pyrrolidinylcarbonyloxy] propyl} -6-benzyloxy-2-naphthylamine (product B) is obtained as a colorless oil. Product A: IR ^Chloroform ν _Max (cm ⁻¹ ): 17
50 (br), 1695 (br), 1605 [α] _D ²⁰ −35.50 ° (c = 0.569, chloroform) Product B: IR ^Chlorophorm ν _Max (cm ⁻¹ ): 17
50 (br), 1695, 1605 [α] _D ²⁰ −56.42 ° (c = 0.677, chloroform)

(4) Product A 8.95 obtained in the above (3)
g, sodium hydroxide 2.57g, ethanol 100m
A mixture of 1 and 20 ml of water is stirred at 100 ° C. for 1 hour. After distilling off the solvent under reduced pressure from the reaction solution, water is added to the residue. The mixture is extracted with ethyl acetate, the extract is washed with water, dried and concentrated. Hexane is added to the residue, and the precipitated crystals are collected by filtration to obtain 3.76 g of N-[(2R) -3-methoxy-2-hydroxypropyl] -6-benzyloxy-2-naphthylamine as colorless crystals. m. p. 105 to 106 ° C. [α] _D ²⁰ −8.2 ° (c = 0.533, chloroform)

(5) 3.65 g of the product of (4) above, 70 ml of anhydrous methylene chloride, 3.51 g of carbonyldiimidazole and 0.14 g of diisopropylethylamine.
The mixture is stirred at room temperature for 2 hours. The reaction solution is washed with 5% hydrochloric acid, the organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The extract is mixed with the organic layer, the mixture is dried, and the solvent is evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give (5
R) -3- (6-Benzyloxy-2-naphthyl) -5
3.60 g of -methoxymethyl-2-oxazolidone are obtained as colorless scaly crystals. m. p. 150 to 150.5 ° C [α] _D ²⁰ -51.1 ° (c = 0.305, chloroform)

Production Example 64 (1) N-ethoxycarbonyl-N-{(2S) -3-
Methoxy-2-[(2S) -1- (2-naphthylsulfonyl) -2-pyrrolidinylcarbonyloxy] propyl} -6-benzyloxy-2-naphthylamine 9.2
g was treated in the same manner as in Production Example 63- (4) to give N-[(2
S) -3-Methoxy-2-hydroxypropyl] -6-
3.76 g of benzyloxy-2-naphthylamine are obtained as colorless needles. m. p. 105 to 106 ° C. [α] _D ²⁰ + 7.90 ° (c = 0.354, chloroform)

(2) 3.62 g of the product of (1) above was treated in the same manner as in Production Example 63- (5) to give (5S) -3-
3.55 g of (6-benzyloxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone are obtained as colorless needle crystals. m. p. 149.5-150.5 ° C. [α] _D ²⁰ + 49.9 ° (c = 0.305, chloroform)

Production Example 65 (5R) -3- (6-benzyloxy-2-naphthyl)
-5-methoxymethyl-2-oxazolidone 16.9
g, 10% palladium-carbon 8.50 g and a mixture of tetrahydrofuran 400 ml are subjected to catalytic reduction under atmospheric pressure at 45 to 50 ° C. for 2 hours. After the insoluble matter is filtered off, the solvent is distilled off under reduced pressure from the filtrate. The residue was recrystallized from tetrahydrofuran-isopropyl ether to give (5R) -3- (6
-Hydroxy-2-naphthyl) -5-methoxymethyl-
11.5 g of 2-oxazolidone is obtained as colorless prism crystals. m. p. 190 to 191 ° C. [α] ^{_{D 20 -74.0 ° (c = 0.396}} , tetrahydrofuran)

Production Example 66 (5S) -3- (6-benzyloxy-2-naphthyl)
-5-methoxymethyl-2-oxazolidone 15.0 g
Was treated in the same manner as in Production Example 65 to give (5S) -3- (6-
Hydroxy-2-naphthyl) -5-methoxymethyl-2
-Oxazolidone 10.3 g is obtained as colorless prism crystals. m. p. 190 to 191 ° C. [α] _D ²⁰ + 77.1 ° (c = 0.358, tetrahydrofuran)

Production Example 67 (5R) -3- (6-hydroxy-2-naphthyl) -5
A mixture of 2.38 g of methoxymethyl-2-oxazolidone, 1.83 g of cyclopropylmethyl bromide, 3.55 g of potassium carbonate and 30 ml of dimethylformamide is stirred at 50 ° C. for 7 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the extract is washed with water, dried and the solvent is evaporated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: ethyl acetate-chloroform (1:10)] and then recrystallized from ethyl acetate-hexane to give (5R).
-3- (6-cyclopropylmethoxy-2-naphthyl)
-5-methoxymethyl-2-oxazolidone 2.51 g
Is obtained as colorless scaly crystals. m. p. 120.5 to 121 ° C. [α] _D ²⁰ -54.4 ° (c = 1.08, chloroform)

Production Example 68 (5S) -3- (6-hydroxy-2-naphthyl) -5
-Methoxymethyl-2-oxazolidone (3.69 g) and cyclopropylmethyl bromide (2.84 g)
Is treated in the same manner as in (5S) -3- (6-cyclopropylmethoxy-2-naphthyl) -5-methoxymethyl-2.
-4.07 g of oxazolidone are obtained as colorless scaly crystals. m. p. 119 to 119.5 ° C. [α] _D ²⁰ + 54.4 ° (c = 1.05, chloroform)

[0099]

The naphthyloxazolidone derivative (I), which is the active ingredient of the present invention, has a short duration and is reversible,
Since it has a selective MAO-A inhibitory action, it is used as an antidepressant for the treatment / prevention of depression, senile depressive symptoms, depression of mood, depression of motivation, anxiety and accompanying depression symptoms such as insomnia and anorexia. Can be used for. Further, the naphthyloxazolidone derivative (I) has an excellent feature that it has few side effects (liver disorder, cheese effect, migraine, etc.) as shown by conventional MAO inhibitors. Further, the object (I) of the present invention has low toxicity and high safety. For example, mouse (Slc; ddY strain, male, 5-6 weeks old)
, 3- (6-cyanoethoxy-2-naphthyl) -5-
When methoxymethyl-2-oxazolidone 2 g / kg was orally administered, no deaths were observed even after 2 weeks.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Hiroshi Iwata 7-6-3-504 Suzuya, Yono City, Saitama Prefecture

Claims (7)

(57) [Claims] 1. A compound of the general formula (I) (However, R ¹ is a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a sulfo group, an aminosulfonyl group, a lower alkenyloxy group, a lower alkynyloxy group, a mono- or di-lower alkylaminocarbonyloxy group or a lower alkanoyloxy group. Alternatively, an aryl group, a cycloalkyl group, an oxygen-containing heteromonocyclic group, a hydroxyl group, a lower alkoxy group, a cyano group, a di-lower alkylamino group, an aminocarbonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkylthio group. A lower alkoxy group which may be substituted with a group selected from a lower alkylsulfinyl group and a lower alkylsulfonyl group, R ² represents a hydroxyl group, a lower alkoxy group, a lower alkylsulfonyloxy group, a triazo group, an amino group or a lower alkyl group, or Lower alkanoyl Naphthyl oxazolidone derivative or antidepressant agent comprising a a pharmaceutically acceptable salt thereof as an active ingredient represented by the representative.) The substituted amino group. 2. The antidepressant according to claim 1, wherein the aryl group is a phenyl group, the cycloalkyl group is a cyclopropyl group, and the oxygen-containing heteromonocyclic group is a tetrahydrofuryl group. 3. R ¹ is a hydrogen atom, a hydroxyl group, a lower alkenyloxy group, a lower alkynyloxy group, a mono-lower alkylaminocarbonyloxy group or a lower alkanoyloxy group, or a cyclopropyl group, a tetrahydrofuryl group, a hydroxyl group, A lower alkoxy group which may be substituted with a group selected from a lower alkoxy group, a cyano group, a di-lower alkylamino group, an aminocarbonyl group, a lower alkanoyloxy group and a lower alkylthio group, and R ² is a hydroxyl group or a lower alkoxy group The antidepressant according to claim 2. 4. R ¹ is a hydrogen atom, a lower alkenyloxy group or a lower alkanoyloxy group, or a lower alkoxy group optionally substituted with a group selected from a cyclopropyl group, a hydroxyl group and a cyano group, R ² The antidepressant according to claim 3, wherein is a lower alkoxy group. 5. The antidepressant according to claim 4, wherein R ¹ is a lower alkoxy group which may be substituted with a group selected from a cyclopropyl group and a cyano group. 6. R ¹ is substituted at the 6-position of the naphthalene ring, and 5
The antidepressant according to claims 1 to 5, wherein a -substituted-2-oxazolidon-3-yl group is substituted at the 2-position of the naphthalene ring. 7. The antidepressant according to claim 1, which is a prophylactic / therapeutic agent for depression, senile depressive symptoms, mood depression, decreased motivation, anxiety and accompanying insomnia and anorexia.