JPS6237627B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to piperazinyl alkoxyindanes and acid addition salts thereof. More specifically, the present invention relates to piperazinyl alkoxyindanes which have anxiolytic effects and are effective as sedatives. The compound of the present invention has the following general formula () These are piperazinyl alkoxyindanes represented by In the general formula (), n represents an integer of 3 or 4,
R represents a phenyl group or a pyridyl group. In addition, the phenyl group and pyridyl group are one or more groups selected from a halogen atom, a trifluoromethyl group, an alkoxy group, an alkylcarbonyl group,
May be replaced. Examples of halogen atoms include fluorine atoms, chlorine atoms, sulfur atoms, etc.; examples of alkoxy groups include lower alkoxy groups having 1 to 5 carbon atoms such as methoxy, ethoxy, propoxy, and butoxy groups; and alkylcarbonyl groups. Examples include lower alkylcarbonyl groups having 1 to 5 carbon atoms such as an acetyl group, a propionyl group, a butyryl group, and an isobutyryl group. The position of the substituent on the phenyl group and the pyridyl group and the position of the pyridyl group bonded to the piperazinyl group are not particularly limited. The compound of the present invention is produced as follows.
i.e. expression () (In the above formula, n represents an integer of 3 or 4, and X represents a halogen atom.) and the halogenoalkoxyindanes represented by the formula () (In the above formula, R has the same meaning as R 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 and the type of reactive solvent used as the raw material, 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 the compounds of the present invention are illustrated below. 5-[3-(4-phenyl-1-piperazinyl)
Propoxy]indane 5-[4-(4-phenyl-1-piperazinyl)
butoxy]indane 4-[3-(4-phenyl-1-piperazinyl)
propoxy]indane 4-[4-(4-phenyl-1-piperazinyl)
Butoxy]indane 5-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{4-[4-(4-fluorophenyl)-1-
Piperazinyl]butoxy}indane 5-{4-[4-(3-fluorophenyl)-1-
Piperazinyl]butoxy}indane 5-{4-[4-(2-fluorophenyl)-1-
Piperazinyl]butoxy}indane 4-{4-[4-(4-fluorophenyl)-1-
Piperazinyl]butoxy}indane 5-{3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}indane 5-{ 3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(3- chlorophenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy}indane 5-{4-[4-(4-chlorophenyl)-1-piperazinyl]butoxy }Indane 5-{4-[4-(3-chlorophenyl)-1-piperazinyl]butoxy}Indane 5-{4-[4-(2-chlorophenyl)-1-piperazinyl]butoxy}Indane 4-{4-[ 4-(4-chlorophenyl)-1-piperazinyl]butoxy}indan 4-{4-[4-(3-chlorophenyl)-1-piperazinyl]butoxy}indan 5-{3-[4-(4-trifluoromethyl) phenyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(2-trifluoromethyl phenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(4-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(3-trifluoromethyl phenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(2-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 5-{4-[4-(4-trifluoromethyl phenyl)-1-piperazinyl]butoxy}indan 5-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]butoxy}indan 5-{4-[4-(2-trifluoromethyl phenyl)-1-piperazinyl]butoxy}indane 4-{4-[4-(4-trifluoromethylphenyl)-1-piperazinyl]butoxy}indane 4-{4-[4-(3-trifluoromethyl phenyl)-1-piperazinyl]butoxy}indane 4-{4-[4-(2-trifluoromethylphenyl)-1-piperazinyl]butoxy}indane 5-{3-[4-(4-methoxyphenyl) )-1-
Piperazinyl]propoxy}indane 5-{3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 5-{4-[4-(4-methoxyphenyl)-1-
Piperazinyl]butoxy}indane 4-{4-[4-(4-methoxyphenyl)-1-
piperazinyl]butoxy}indane 5-{3-[4-(4-ethoxyphenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(4-propoxyphenyl)-1
-piperazinyl]propoxy}indane 5-{3-[4-(4-acetoxyphenyl)-1
-piperazinyl]propoxy}indane 4-{3-[4-(4-acetoxyphenyl)-1
-piperazinyl]propoxy}indane 5-{4-[4-(4-acetoxyphenyl)-1
-piperazinyl]butoxy}indane 5-{3-[4-(2-pyridyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(3-pyridyl)-1-piperazinyl]propoxy}indane 5- {3-[4-(4-pyridyl)-1-piperazinyl]propoxy}indane 5-{4-[4-(2-pyridyl)-1-piperazinyl]butoxy}indane 4-{3-[4-(2 -pyridyl)-1-piperazinyl]propoxy}indane 4-{4-[4-(2-pyridyl)-1-piperazinyl]butoxy}indane 5-{3-[4-(4-chloro-2-pyridyl)-
1-Piperazinyl]propoxy}indane 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 effects of the compounds of the present invention will be explained below. The anxiolytic effects of the compounds of the present invention were examined using the following method. Chlorodiazepoxide, known compound 17, as an anxiolytic or minor tranquilizer was used as a control drug. The results are shown in the table as the 50% effective dose (ED ₅₀ , mg/KgPO). The animals used were ddy male mice (20-22 g).
Anti-fighting and anti-morphine effects were investigated as indicators of anxiolytic effects. That is, the anti-fighting effect was investigated from the suppressive effect (taming effect) on fighting that occurs by applying an electric shock of 28 V DC, 4-5 mA, 3 minutes to the foot via the grid (RETedeschi, DHTedeschi, A.
Mucha, L.Cook, PAMattis, EJFellows., J.
Pharmacol.exp.Therap., 125 , 28 (1959)). The anti-morphine effect was determined according to the method of Takagi et al.
Measured by the inhibitory effect on the tail-raising reaction caused by administering morphine 20 mg/Kgi.p (Hiroshi Takagi, Toshiharu Kamioka, Shinsaku Kobayashi, Yoshio Suzuki, Furuji Tachikawa, Japanese Pharmacological Journal, 66 , 107 (1970)) Muscle relaxant effect was investigated using the traction test method of Courvoisier et al. (S. Courvoisier, R. Ducrot, L.
Julou.，“Psychotropic druge”Ed.by S.Gar
attini, V. Ghetti, p313 (Elsevier) 1957). _LD50 was calculated by the Litchfield-Wilcoxon method. (JTLitchfield and F.Wilcoxon, J.Phar
macol.exp.Therap., 96 , 99 (1949)) As shown in Table 1, compounds 1, 4, and 5 were found to have anxiolytic effects superior to the control drugs, chlorodiazepoxide or 17. Among them, Compound 4 has lower toxicity and weaker muscle relaxant effect than chlorodiazepoxide, and is presumed to be a highly safe drug.

[Table] Particularly effective range as a compound having anxiolytic effect is a compound represented by the general formula () where n is 3.
or an integer of 4, R is a phenyl group or a pyridyl group, and when this phenyl group or pyridyl group has a substituent, the substituent is a halogen atom, especially a fluorine atom, a chlorine atom, a carbon number of 1 to
3 alkoxy group, an alkylcarbonyl group having 1 to 3 carbon atoms, and a trifluoromethyl group.
The substitution position of the piperazinyl alkoxy group on the indane ring is particularly preferably the 4th or 5th position. A compound with particularly effective anxiolytic effects is 5-[3-(4-phenyl-1-piperazinyl)
propoxy]indane 4-[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 4-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propoxy}indan and the like. Although the compound 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 compound 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, the compounds of the present invention can be effectively used as sedatives having anxiolytic effects. 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. 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】

【table】

Claims (1)

[Claims] 1. The following general formula (In the above formula, n represents an integer of 3 or 4, and R is 1 selected from a halogen atom, a trifluoromethyl group, an alkoxy group, and an alkylcarbonyl group.
Indicates a phenyl group or a pyridyl group which may be substituted with more than one type of group. ) Piperazinyl alkoxyindanes and their acid addition salts.