JPS6344727B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has a strong anti-reserpine effect.
The present invention relates to an antidepressant containing (3-aminopropoxy)diphenyl ethers or acid addition salts thereof as an active ingredient. The inventors previously filed Japanese Patent Application No. 50-74741;
-108336, Patent Application 1972-108337 and Patent Application 1972-
130178, etc., we discovered ω-aminoalkoxydiphenyls that have a strong antireserpine effect and are useful as antidepressants.As a result of further exploration, we found the following 2-(3-aminopropoxy)diphenyl ether. The present invention was completed based on the discovery that a compound of the same name has a strong anti-reserpine effect. That is, the present invention is based on the following general formula () (A in the above general formula () is

[Formula] (wherein R ¹ and R ² each independently represent a hydrogen atom, a methyl group, or an ethyl group) and a 1-pyrrolidinyl group. )
The antidepressant contains 2-(3-propoxy)diphenyl ethers and/or its acid addition salts as an active ingredient. The present invention will be explained in detail below. A in the general formula () is

[Formula] or 1-pyrrolidinyl group, R ¹ and R ² each represent a hydrogen atom, a methyl group, or an ethyl group, and R ¹ and R ² may be the same or different. Good too.

Specific examples of the group represented by the formula include a methylamino group, a dimethylamino group, an ethylamino group, and a diethylamino group. Specific compounds are 2-(3-aminopropoxy)-2'-methyldiphenyl ether 2-(3-methylaminopropoxy)-2'-methyldiphenyl ether 2-(3-dimethylaminopropoxy)-2' ―
Methyl diphenyl ether 2-(3-ethylaminopropoxy)-2'-methyldiphenyl ether 2-(3-diethylaminopropoxy)-2'-
Methyl diphenyl ether 2-{3-(1-pyrrolidinyl)propoxy}
-2'-Methyl diphenyl ether The antidepressant of the present invention also includes pharmaceutically acceptable acid addition salts of the above-mentioned 2-(3-aminopropoxy) diphenyl ethers. The above acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, and toluenesulfonic acid. ,
Examples include addition salts of acids such as methanesulfonic acid. Next, a method for producing 2-(3-aminopropoxy)diphenyl ethers represented by the general formula () used in the present invention will be explained. 2-(3-aminopropoxy)diphenyl ethers () have the following general formula () (In the formula, Y represents a halogen atom.) 2-(3-halogenopropoxy) diphenyl ethers represented by the following general formula () A-H ... () (wherein A is the general formula ()) (synonymous with A)
It is produced by reacting with amines represented by: The amines () consumed in the above reaction are 2-
The amount is 1 mole per mole of (3-halogenopropoxy)diphenyl ether. The reaction rate can be further increased by using an excess of amines. Usually, 1 to 100 moles of amines are used per mole of 2-(3-halogenopropoxy)diphenyl. Although the reaction proceeds satisfactorily even in the absence of a solvent, an inert solvent may be used to carry out the reaction in a homogeneous system. As the solvent, water, dioxane, tetrahydrofuran, dimethylfuran, dimethyl sulfoxide, lower alcohol, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but usually ranges from room temperature to
The temperature is 150℃. The reaction time varies depending on the reaction temperature and the reactivity of the raw materials, but is usually 40 hours or less. Furthermore, bases may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. As the bases, inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, and tertiary amines such as pyridine and triethylamine are used. The amount of bases used is 2
-(3-halogenopropoxy)diphenyl ether is usually 1 to 5 mol per mol of diphenyl ether. If the above-mentioned bases are not added, 2-
(3-Aminopropoxy)diphenyl ethers further react with hydrogen halide produced in the reaction and are converted into acid addition salts thereof. To obtain the desired acid addition salt, excess amines and solvent are distilled off, and a strong base aqueous solution such as sodium hydroxide or potassium hydroxide is added to form 2-(3-aminopropoxy).
Acid addition salts of diphenyl ethers are converted into free 2-
(3-Aminopropoxy)diphenyl ethers are extracted with a solvent such as ether, chloroform, or benzene. Further, by neutralizing by adding a desired acid, the desired acid addition salt of 2-(3-aminopropoxy)diphenyl ethers can be obtained. The 2-(3-aminopropoxy)diphenyl ethers and acid addition salts thereof obtained by the above reaction are purified by recrystallization using a suitable solvent such as alcohol-ether. Next, the pharmacological effects of the compounds of the present invention, 2-(3-aminopropoxy)diphenyl ethers and their acid addition salts, will be explained. 2-(3-aminopropoxy)diphenyl ethers and their acid addition salts have antireserpine effects in the central nervous system that are characteristic of antidepressants. Pharmacological tests were conducted using ddY male mice regarding the following various effects. Anti-reserpine action is reserpine (10mg/Kgi.p.)
Judgment was made from the antagonism to the decrease in body temperature caused by PSJSpencer in Antidepresant Drax S Galateini and MNG Deugees Examer Medica Foundation Amsterdam (PSJ Spencer in
“Antidepressant Drugs” S. Garattini and M.
NGDuhes, ed., Excerpta Medica
Foundation, Amsterdam, P.194-204 (1967)) LD ₅₀ is Richfield Wilcoxon
(Litchfield-Wilcoxon) method. The results are shown in Table-1. Compounds of the invention that are effective in alleviating depression in warm-blooded animals can be administered in any manner. That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection, as well as oral administration are possible. The dosage is determined depending on the patient's age, health condition, weight, degree of depression, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc. Generally, the daily dose of the active ingredient is 0.5-50mg/
Kg body weight, usually 1-30 mg/Kg body weight, administered in one or more doses. When the compound of the present invention is administered orally, it can be administered in the form of tablets, capsules, powders, liquids, elixirs, etc.
In the case of parenteral administration, it is used in a sterilized liquid form such as a liquid or suspension. When used in such forms, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. As an example of a solid carrier, conventional gelatin type capsules are used. The active ingredient may also be packaged as a tablet or powder, with or without adjuvants. These capsules, tablets, and powders generally contain 5
Contains ~95% by weight of active ingredient, preferably 25-90%. i.e., 5 to 500 mg for these modes of administration;
Preferably, it contains 25 to 250 mg of active ingredient. As the liquid carrier, water or oils of animal or plant origin or synthetic oils such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. are used. In general, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers, and in particular, in the case of injections using physiological saline, the concentration is usually 0.5 to
20%, preferably 1-10% by weight of active ingredient. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the active ingredient are preferred. In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers. Examples of the production of 2-(3-propoxy)diphenyl ethers used in the present invention are described below. Production example: 5.0 g of 2-(3-bromopropoxy)-2'-methyldiphenyl ether and 100 ml of ethanol.
Dissolve in 30 ml of 40% methylamine aqueous solution at room temperature for 10
Leave it for a while. The solvent and excess methylamine are distilled off under reduced pressure. A 2N aqueous sodium hydroxide solution is added to the obtained oil and extracted with ether. The ether layer is washed with saturated saline and the ether is distilled off to obtain a viscous oily substance. Add 20ml of 2N hydrochloric acid to this
After addition, evaporation under reduced pressure yields 2-(3-methylaminopropoxy)-2'-methyldiphenyl ether, hydrochloride. This was recrystallized from ethanol-ether. Yield 4g (85%), melting point 128℃ Elemental analysis C ₁₇ H ₂₁ O ₂ As N・HCl C H N Calculated value (%) 66.30 7.21 4.56 Experimental value (%) 66.21 7.18 4.49 Other 2-(3-aminopropoxy ) Diphenyl ethers were produced in the same manner and are listed in Table 1 along with pharmacological data.

【table】

Claims (1)

[Claims] 1. The following general formula (In the above general formula, A is one group selected from the group consisting of [Formula] (wherein R ¹ and R ² each independently represent a hydrogen atom, a methyl group, or an ethyl group) and a 1-pyrrolidinyl group. An antidepressant containing 2-(3-aminopropoxy)diphenyl ethers and/or acid addition salts thereof as an active ingredient. 2. The antidepressant according to claim 1, wherein A is methylamino, dimethylamino, ethylamino, diethylamino, or 1-pyrrolidinyl group.