JP2786695B2 - Antidepressants containing benzoisoxazolin-3-one derivatives - Google Patents

Description

The present invention relates to an antidepressant comprising a benzoisoxazolin-3-one derivative represented by the following general formula (I) as an active ingredient.

[Conventional technology]

In recent years, senile diseases associated with aging of the population are rapidly increasing, and senile depression is one of them. Therefore, development of therapeutic agents for these diseases is desired.

[Problems to be solved by the invention]

The inventors of the present invention have found that a benzoisoxazolin-3-one derivative having the general formula (I) has an antidepressant effect in the course of searching for a chemical substance for such purpose, and The present invention has been completed after confirming that it is useful as a depressant.

[Configuration of the invention]

The novel antidepressant of the present invention has the general formula (Wherein, R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group or a lower aliphatic acylamino group, and R ¹ and R ² represent a hydrogen atom, a lower alkyl group, a substituent Represents a benzyl group which may have a substituent or an aryl group which may have a substituent, or R ¹ and R ² together represent an alicyclic amino group formed together with a nitrogen atom to which they are bonded. The present invention relates to a benzoisoxazolin-3-one derivative represented by the formula (1) or an acid addition salt thereof.

Preferred compounds used in the present invention include, in the general formula (I), R ³ is a hydrogen atom; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Alkyl group having 1 to 4 carbon atoms; methoxy, ethoxy, n-
An alkoxy group having 1 to 3 carbon atoms such as propoxy and isopropoxy; a halogen atom such as fluorine, chlorine and bromine; a nitro group; an amino group or acetylamino;
Shows a lower aliphatic acylamino group such as propionylamino.

R ¹ and R ² are a hydrogen atom; substitutions as defined for the R ^3, an alkyl group having 4 or 1 to carbon atoms straight chain or branched chain showing the example as defined above in the alkyl group R ³ An aryl group such as benzyl or phenyl, with or without a group, or morpholino, 1-piperazinyl, formed by R ₁ and R ² together with the nitrogen atom to which they are attached.
It may represent a 5- or 6-membered alicyclic amino group such as piperidino.

Specific compounds represented by the general formula (I) in the present invention include, for example, the following compounds.

Benzoisoxazoline having the general formula (I)
The pharmacologically acceptable acid addition salts of the 3-one derivatives include
Like mineral salts such as hydrochloride, hydrobromide, sulfate, oxalate, lactate, citrate, tartrate, succinate, maleate, fumarate, methanesulfonate Organic acid salts.

In the compound having the general formula (I),
Includes optical isomers due to the presence of asymmetric carbon atoms.

Compound (I) of the present invention can be produced by the following method.

Manufacturing process In the above formula, R ¹ , R ² and R ³ have the same meaning as described above.

1) Step This reaction is carried out by adding phosgene or a halocarbonate and then a tertiary amine to the diol compound (II) in the presence of an organic solvent. Examples of the organic solvent used include ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene and toluene. As the halocarbonate of the reaction reagent, trichloromethyl chloroformate, and as the tertiary amine, triethylamine, dimethylaniline,
Pyridine and the like can be mentioned. The reaction temperature is around room temperature, and the reaction time is 1 to 6 hours. After completion of the reaction, the insolubles are removed from the reaction mixture, and the resulting solution is used in the next step of the reaction.

2) Step This reaction is carried out by adding amines (III) to the carbonate reaction solution obtained in the previous step. Examples of the amines (III) to be used include ammonia having a substituent described above, an aliphatic primary or secondary amine, and a cyclic amine. The reaction is carried out at a reaction temperature and time of about 1 to 5 hours at about room temperature and then for 1 to 5 hours under reflux of the reaction solvent. If necessary, the reaction solution is concentrated under reduced pressure in order to complete the reaction, and then the amine (III) and an alcohol such as methanol or ethanol are added again to the residue, followed by heating under reflux for 1 to 5 hours. It is also done.

After completion of the reaction, the target compound (I) of this step is collected from the reaction mixture according to a conventional method. For example, if the target compound precipitates from the reaction system, take it off.If it is in the form of a solution, distill off the solvent, dissolve the residue in a solvent that is difficult to mix with water, wash with acid and water, and evaporate the solvent. The compound can be purified by a conventional method, for example, a recrystallization method, a vacuum distillation method, chromatography or the like, if necessary.

Diol compound (II) which is a raw material compound for the above reaction
Can be produced from a 3-hydroxyisoxazole compound and epihalohydrin according to the method described in JP-A-55-83766.

〔The invention's effect〕

The benzisoxazolin-3-one compound having the general formula (I) of the present invention exhibits excellent antidepressant activity and low toxicity according to pharmacological tests and toxicity tests. Tests such as are described specifically.

1. Anti-reserpine action Method: Three ddy mice of male maturity (4 weeks old, weighing 22 to 27 g) were used per group. Subcutaneously administered reserpine 2 mg / kg,
Ninety minutes after that, the degree of ptosis was observed and displayed as a score according to the following criteria. That is, 0 point when the shape of the eye immediately after the mouse is taken out of the cage and placed on the table is a circle like a normal animal, 1 point when 1/3 ptosis is observed, 2/3 2 points, and 3 points when the eyelids did not open. The test compound is dissolved in a suitable solvent (saline or 0.5% CMC).
Solution), orally administered immediately before reserpine administration. On the other hand, each solvent was similarly administered to the control group. The indication of the bottle containing the test drug solution was symbolized, and the administration was performed in a random order, and the scorer was careful not to know which drug was administered to which animal. With respect to the above scores, the inhibition rate at each dose was calculated according to the following formula.

Inhibition rate (%) = (1-Total score of sample administration group / Total score of solvent administration group) x 100 Inhibition rate is 71% or more (+), 41% to 70% (±), 40% or less Was determined as (-).

Results: As summarized in Table 2, the results for Compound 2 were 30 and 10
At a dose of 0 mg / kg, it exhibited an anti-reserpine effect in a dose-dependent manner.

2. Acute toxicity Compound 2 was suspended in a 0.5% CMC solution, orally administered at 300 mg / kg to mice, and observed for 5 days. As a result, all the animals survived without any noticeable symptoms. .

As described above, the compound having the general formula (I) has extremely low toxicity and has a so-called antidepressant action. It can be clinically administered orally and is useful as an antidepressant as a therapeutic agent for depression patients and anxiety patients.

As the administration form, for example, tablets, capsules,
Oral administration methods such as granules, powders and syrups, and parenteral administration methods such as injections, suppositories and the like can be mentioned. These various preparations are prepared by adding known auxiliaries which can be usually used in the technical field of pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, and flavoring agents to the main drug according to the purpose according to the usual method. Can be used to formulate. The amount used depends on the condition, age, body weight, etc., but in the case of oral administration, usually 5 to 50 mg once a day can be administered to an adult once to three times a day.

Next, the formulation examples and production examples will be described more specifically.

Formulation Example 1. Capsule 2- (3-carbamoyloxy-2-hydroxypropyl) -5-chloro-benzoisoxazolin-3-one (Compound No. 2) 25.0 mg Lactose 153.6 mg Corn starch 100.0 mg Magnesium stearate 1.4 mg 280.0 mg in total The above starch powder was mixed and passed through a 60-mesh sieve, and 280 mg of this powder was placed in a No. 3 gelatin capsule to prepare a capsule.

Production Example 1. Synthesis of 2- (3-carbamoyloxy-2-hydroxypropyl) -5-chloro-benzisoxazolin-3-one 5-chloro-2- (2,3-dihydroxypropyl)-
1.00 g of 1,2-benzisoxazolin-3-one in dry TH
F (20 ml) solution in trichloromethylchloroformate 0.4
After adding 0 g and stirring at room temperature for 30 minutes, 0.42 g of triethylamine was added dropwise while cooling to 5 ° C., and the mixture was stirred at the same temperature for 30 minutes. Then, 5.0 ml of 28% NH ₄ OH was added, and further stirred at room temperature for 2 hours Then, heat and reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in ethyl acetate (100 ml).
Wash with aqueous NaCl and dry the organic layer over anhydrous magnesium sulfate. The desiccant was removed, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (developing agent: ethyl acetate) to give a melting point of 161.
0.75 g (64.1%) of a colorless powdery target substance having a temperature of 162? 162 ° C. was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3420, 3320, 3260 (OH, NH ₂ ), 1683, 1662 (C = 0).

Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ ppm; 3.86 to 4.46 (5H, b), 5.31 (1H, d, J = 4.5), 6.50 (2
H, s), 7.46-7.90 (3H, m)

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-3-86823 (JP, A) JP-A-1-301669 (JP, A) JP-A-1-249759 (JP, A) (58) Field (Int.Cl. ⁶ , DB name) CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula (Wherein, R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group or a lower aliphatic acylamino group, and R ¹ and R ² represent a hydrogen atom, a lower alkyl group, a substituent A benzyl group which may have a substituent or an aryl group which may have a substituent, or R ¹ and R ² may together form a cycloaliphatic amino group together with the nitrogen atom to which they are attached. An antidepressant comprising a benzoisoxazolin-3-one derivative represented by the formula (1) or an acid addition salt thereof.