JPS61191678A - Antidepressant - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for depression comprising a piperidine derivative represented by the formula: or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. A compound of formula (I) is a compound represented by the formula: [Formula where 艮 represents a nitrogen protecting group, such as 4-nitrobenzoyl, other optionally substituted benzoyl, optionally substituted benzyl or optionally substituted alkyl. It can be produced by reacting with a compound represented by the formula: [wherein Y represents a reactive group, such as chlorine or bromine], and then removing the protective group.

When the piperidine derivatives of formula (I) and acid addition salts thereof according to the present invention were subjected to pharmacological experiments, it was found that these compounds have antidepressant effects.

Antidepressant activity is associated with reserpine-induced blepharoptosis (
RPS) was investigated in a culture anti-culture test (C0 Goure
[et al., J. Pharmacol, (Paris
) 3 333-350.1977). Mouse (male,
CD1 Charles River series, France, 18-22))
test compound (or solvent) and reserpine (4N/If
(body weight)) were administered simultaneously (the former was administered orally or intraperitoneally; the latter was administered subcutaneously). After 60 minutes, each mouse was graded for degree of ptosis (O-4).
. For each dose, the average grade and % deviation when compared to the control group were determined.

For each compound, the dose that would reduce the AD5o, ie, the average ptosis value by 50% compared to the control group, was determined by a graphical method.

Antidepressant activity is also associated with head twitches induced by L-5-hydroxytryptophan.
s) was investigated by the potentiation effect (PHT) of (V, V
anRiezen (1972) Arch, Int.
Pharmacology 198 256-269).

The procedure is as follows: Animals are placed in the operating room 24 hours before the experiment. On the day of the experiment, weigh the mice and let them sleep. 12 L5-HTP suspended in Tween
Test compounds are administered orally or injected intraperitoneally before subcutaneous injection at a rate of 5 capes/KP (body weight). L5-
Thirty minutes after injection of HTP, the number of cephalic constrictions is counted for 60 seconds. The mean curvature count and % deviation compared to the control group are calculated for each dose. Calculate the 50% effective dose from the curve.

On the other hand, the toxicity of the compound of formula (I) was investigated by administering it orally and intraperitoneally to mice.

The results of the above pharmacological experiments are shown in Table 1 of Water Temperature. As is clear from this table, the piperidine derivatives and acid addition salts thereof of the present invention were found to be useful for the treatment of depression.

Table 1 The compounds of the present invention can be administered in any dosage form suitable for oral or parenteral administration, such as tablets, sugar-coated tablets, capsules, oral or injectable solutions, etc., together with suitable excipients.

The daily dosage can be 5-200-v.

Examples of the production of the compound of formula (I) and of preparations containing the compound of formula (I) as an essential ingredient are listed below.

Production example 4-C(2-naphthyl)methoxycopiperidine (a) 4-hydroxy-1-methoxycarbonylpiperidine 4-hydroxypiperidine 202.30y (2 mol),
Mix and stir 185y (2.2 mol) of sodium hydrogen carbonate and 2.51 mol of chloroform, and heat at about 10°C on an ice/water bath.
Cool to Then methyl chloroformate 208 (170
-12.2 mol) is added.

If stirring is continued overnight, IJum will precipitate.

The mixture is filtered, the inorganic salts are washed several times with chloroform, the resulting organic phase is re-extracted with chloroform (the product is water soluble), the organic phase is collected, dried over magnesium sulfate and evaporated. let

A yellow oil remains which is purified by distillation under reduced pressure. 278.46 p of a clear oil is obtained.

(b) 1-Methoxycarbonyl-4-CC2-naphthyl)methoxycopiperidine A solution of carbamate 108y (0.68 mol) obtained in (a) above in dimethyl sulfoxide 11 was added to 15
Cool to 54°C and add 50.6% aqueous sodium hydroxide solution.
y (0.68 mol) is added dropwise over 20 minutes while stirring. 2
0.68 mol of -bromomethylnaphthalene 1509C) is slowly added and the mixture is stirred at 30° C. for 6.5 hours and then at room temperature overnight.

The reaction mixture was poured into 2.5 liters of cold water and extracted with 2.times.11 portions of [-butyl methyl ether. Collect the organic phase and add water 2
Wash with 0.71x, dry over magnesium sulfate and evaporate. An oil 166F remains and is crystallized by stirring in petroleum ether.

The melting point is 54.5°C.

(c) [(2-naphthyl)methoxy]piperidine above (
b) carbamate 124F (0,414 mol) and ION sodium hydroxide 260. /(2.6 mol) in 1.21 mol of ethanol is refluxed under stirring for 16 hours. The ethanol is evaporated under vacuum and the residual material is poured into a mixture of 0.5z of water and 11 of [-butyl methyl ether]. The organic phase was decanted and washed with 4x0.51 water until the pH was neutral, then with sulfuric acid)
Dry with IJum and distill. The remaining oil is purified by silica chromatography. A solid of 7B, 9f is obtained. The melting point is 46.8°C.

(d) Fumarate Free base of (C) above5. Of ethanol (95%)
30, / and add a solution of 1.22 d of fumaric acid in 40 d of ethanol (96%). The precipitate is pushed through and recrystallized with 50% of ethanol (95%) in the presence of activated carbon. The yield is 4.6f and the melting point is 170-171°C.

(e) Benzoate 6.5 g of the free base of (C) above was dissolved in ethanol (95%).
A solution of 3.17 f of benzoic acid in ethanol (95%) 75 is added. The mixture is concentrated and the precipitate is recrystallized from isopropyl alcohol. Yield: 6y, melting point: 126-128°C.

Formulation Example 1 Capsule ingredient Amount (gII) 4-
[2-Naphthyllamethyl] Piperidine benzoate 10.0 Microcrystalline cellulose 178.5 Sodium starch glycolate 6.0 Hydroxypropyl methylcellulose 4.0 Colloidal silica 0.5 Magnesium stearate 1.0 Total
200.0 The above ingredients were mixed and filled into a size O yellow capsule with a content of 200 cm.
Capsules containing 10 μ of active compound are obtained.

Formulation example 2 Capsule ingredients Amount (Cape) 4-CC
2-naphthyl) methyl] Piperidine benzoate 200.0 Microcrystalline cellulose 177.0 Sodium starch glycolate 12.0 Hydroxypropyl methylcellulose 8.O colloid silica 1.0 Magnesium stearate 2.0 Total
400.0 The above ingredients are mixed and filled into yellow capsules of size O with a content of 400"f to obtain capsules containing 200 caps of active compound.

Claims (1)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) A therapeutic agent for depression characterized by containing the compound represented by (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.