JPH0129772B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to piperazinyl alkoxyindan anxiolytics. More specifically, the present invention relates to an anxiolytic drug with low toxicity and weak muscle relaxing effect, which is considered a side effect. The anxiolytic drug of the present invention contains a compound represented by the following formula () as an active ingredient. In the general formula (), n represents an integer of 3 or 4,
R ¹ represents a hydrogen atom, a lower alkyl group or a halogen atom. Examples of the lower alkyl group include C ₁ -C ₅ alkyl groups, with C ₁ -C ₂ alkyl groups being particularly preferred. Examples of the halogen atom include a fluorine atom, a chlorine atom, a fluorine atom, and the like, with a fluorine atom being particularly preferred. R ² represents a phenyl group that may have a halogen atom, and the halogen atom is
Examples include the same halogen atoms as R ¹ , and among them, fluorine atoms are preferred. The substitution position of R ¹ and the substitution position of the halogen atom on R ² are not particularly limited. The indanes represented by the general formula () are produced as follows. i.e. expression () (In the above formula, n and R ¹ are n and R ¹ of the general formula ()
, and X represents a halogen atom. ) and the formula () (In the above formula, R ² has the same meaning as R ² in the general formula ()). Halogenoalkoxyindanes and piperazines react in a ratio of 1:1, but the reaction usually proceeds more smoothly when piperazine is used in excess. Therefore, 1 to 10 moles of piperazine are used per mole of halogenoalkoxyindan. Although the reaction proceeds satisfactorily even without a solvent, an inert solvent may be used to facilitate the reaction. As the solvent, water, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, lower alcohol, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but is usually from room temperature.
The temperature is 150℃. The reaction time varies depending on the reaction temperature, reactivity of the raw materials, and type of solvent, but is usually in the range of 10 minutes to 20 hours. Furthermore, bases may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. Examples of the bases include inorganic salts such as potassium hydroxide, potassium carbonate, sodium hydroxide, sodium bicarbonate, and sodium carbonate, and tertiary organic amines such as pyridine and triethylamine. The amount used is usually 1 to 5 mol per mol of piperazine. In order to obtain a desired acid addition salt, after the reaction is complete, excess amines and solvent are removed by distillation or washing with water, and a strong aqueous base solution such as sodium hydroxide or potassium hydroxide is added to form the free piperazinyl alkoxyindanes. , and then extract the compound with a solvent such as ether, chloroform, benzene, or toluene. Further, by neutralizing by adding a desired acid, the desired acid addition salt can be obtained. Specific examples of indanes represented by the general formula () are illustrated below. 5-[3-(4-phenyl-1-piperazinyl)
Propoxy]indane 5-[4-(4-phenyl-1-piperazinyl)
Butoxy]indane 5-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{4-[4-(4-fluorophenyl)-1-
piperazinyl]butoxy}indane 6-fluoro-5-[3-(4-phenyl-1-
piperazinyl)propoxy]indane 6-methyl-5-[3-(4-phenyl-1-piperazinyl)propoxy]indane 4-fluoro-5-{3-[4-(4-fluorophenyl)-1-piperazinyl] propoxy}indane 6-fluoro-5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}indane 6-fluoro-5-{4-[4-(4-fluorophenyl)-1- Piperazinyl]butoxy}indane 6-chloro-5-[3-(4-phenyl-1-piperazinyl)propoxy]indane 6-chloro-5-{3-[4-(4-fluorophenyl)-1-piperazinyl] Acid addition salts of the above compounds are also included within the scope of the present invention. Acids used as addition salts include:
Inorganic acids such as hydrochloric acid, hydrooxalic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfone Examples include organic acids such as acid and methanesulfonic acid. The anxiolytic effect of the present invention will be explained below. The anxiolytic effect of the compound represented by the general formula () was examined by the following method. Chlorodiazepoxide, known compound A, which is a known anxiolytic drug or minor tranquilizer, was used as a control drug. The results are shown in the table as 50% effective dose (ED ₅₀ , mg/KgPO). The animals used were ddy male mice (20-22 g).
Anti-fighting effect and anti-morphine as an indicator of anxiolytic effect
The effect was investigated. In other words, the anti-fighting effect is
Developed by applying a 28VDC.4-5mA, 3min electric shock to the foot via the grid.
The suppressive effect on fighting (taming effect) was investigated (RETedeschi,
DHTedeschi, A. Mucha, L. Cook, P.A.
Mattis, EJFellows. Journal of Pharmacology and Experimental Therapy. , (J.pharmacol.exp.TheraP.,
125, 28 (1959)). The anti-morphine effect was measured by the inhibitory effect on the tail-raising reaction caused by administering morphine 20mg/Kgi.p according to the method of Takagi et al. , 66 , 107 (1970)) The muscle relaxing effect was examined using the traction test method of Courvoisier et al. (S.
Courvoisier, R. Ducrot, L. Julou. “Psychotropic drugs” Ed.
by S. Gar attini, V. Ghetti, p313 (Elsevier) 1957). _LD50 was calculated by the Litchfield-Wilcoxon method. (JTLitchfield and F.Wilcoxon, J.
Pharmacol.exp.Therap., 96 , 99 (1949)) Table 1 shows the anxiolytic effects of the compounds represented by the general formula (). [Table] [Table] *All compounds are dihydrochlorides.
As shown in Table 1, Compounds 1 to 7 are control drug No.
Compound No. 2 was found to have an anti-anxiety effect superior to that of chlorodiazepoxide and chlorodiazepoxide, but the No. 2 compound was found to be less toxic than chlorodiazepoxide and have a weaker muscle relaxant effect, making it a highly safe drug. It is. Although the drug of the present invention can be administered by any method, the following method is preferably carried out. 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, 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 drug of the present invention is administered orally, it is 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 to
Contains 95% by weight of active ingredient, preferably 25-90%. That is, these dosage forms should contain 5 to 500 mg, preferably 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, usually 0.5
~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. As explained above, according to the present invention, an excellent anxiolytic drug can be provided. Production example 5-(3-bromopropoxy)indane 25.5g
(0.1 mol) and N-phenylpiperazine 17.8 g
(0.11 mol) and 15 g of triethylamine are dissolved in 300 ml of dimethylformamide and heated at 80°C for 2 hours. The reaction solution was added to 500 ml of 1N NaOH aqueous solution and extracted twice with 400 ml of ethyl ether. After washing the ethyl ether with saturated brine and drying over anhydrous sodium sulfate, the ethyl ether is distilled off. When 50 ml of 20% HCl-ethyl alcohol solution is added to the residual oily substance, crystals will precipitate. After cooling and recrystallizing from ethyl alcohol, 5-[3-(4
35 g (85.6%) of -phenyl-1-piperazinyl)propoxy]indane are obtained. Compounds were produced in the same manner below, and the results are shown in Table 2 together with the above compounds. 【table】

Claims (1)

[Claims] 1. The following formula (In the above formula, n represents an integer of 3 or 4, R ¹ represents a hydrogen atom, a lower alkyl group, or a halogen atom, and R ² represents a phenyl group which may have a halogen atom.) An anti-anxiety drug containing a piperazinyl alkoxyindan and/or its acid addition salt as an active ingredient.