JPH0118073B2 - - 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 ¹ is a halogen atom, an alkyl group, an alkoxy group,
Indicates a hydroxy group, phenyl group or nitro group, halogen atoms include fluorine atom, chlorine atom, sulfur atom, etc., and alkyl groups include methyl, ethyl, propyl, isopropyl, and butyl groups having 1 carbon number. ~5 lower alkyl groups are mentioned. Alkoxy groups include methoxy, ethoxy, propoxy, butoxy groups with a carbon number of 1
-5 lower alkoxy groups are mentioned. R ² represents a phenyl group, and this phenyl group may be substituted with a halogen atom or a trifluoromethyl group. Examples of the halogen atom include the same ones as in the case of R ¹ . The positions of R ¹ and the piperazinyl alkoxy group and the position of the substituent R ² on the indane ring 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 R ¹
has the same meaning as R ¹ in general formula (1), 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 ()). Halogenoalkoxyindane and piperazine 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 the 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 alkoxyindan. , 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. 6-fluoro-5-[3-(4-phenyl-1
-piperazinyl)propoxy]indane 6-fluoro-5-[4-(4-phenyl-1
-piperazinyl)butoxy]indane 6-methyl-5-[3-(4-phenyl-1-
piperazinyl)propoxy]indane 6-chloro-5-[3-(4-phenyl-1-
Piperazinyl) propoxy] indane 6-fluoro-5-{3-[4-(4-fluorophenyl)-1-piperazinyl] propoxy}
Indane 6-fluoro-5-{3-[4-(3-fluorophenyl)-1-piperazinyl]propoxy}
Indane 6-chloro-5-{3-[4-(2-fluorophenyl)-1-piperazinyl]propoxy}Indane 6-methoxy-5-{3-[4-(4-fluorophenyl)-1- Piperazinyl [propoxy]
Indane 6-ethoxy-5-{3-[4-(3-fluorophenyl)-1-piperazinyl]propoxy}
Indane 1-Ethyl-5-{3-[4-(2-fluorophenyl)-1-piperazinyl]propoxy}Indane 6-fluoro-5-{4-[4-(4-fluorophenyl)-1- Piperazinyl]butoxy}indane 6-chloro-5-{4-[4-(3-fluorophenyl)-1-piperazinyl]butoxy}indane 6-propoxy-5-{4-[4-(2-fluorophenyl) )-1-piperazinyl]butoxy}
Indane 1-phenyl-5-{3-[4-(4-fluorophenyl)-1-piperazinyl]propoxy}
Indane 6-fluoro-5-{3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy} Indane 6-fluoro-5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy} Indane 6-hydroxy-5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}
Indane 6-nitro-4-{3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy} Indane 6-nitro-5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy} Indane 6-methoxy-5-{3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy} Indane 6-methoxy-5-{4-[4-(4-chlorophenyl)-1-piperazinyl]butoxy} Indane 6-chloro-5-{4-[4-(3-chlorophenyl)-1-piperazinyl]butoxy} Indane 6-chloro-5-{4-[4-(2-chlorophenyl)-1-piperazinyl]butoxy} Indane 6-ethyl-5-{4-[4-(4-chlorophenyl)-1-piperazinyl]butoxy} Indane 6-chloro-4-{4-[4-(3-chlorophenyl)-1-piperazinyl]butoxy} Indane 6-chloro-5-{3-[4-(4-trifluoromethylphenyl)-1-piperazinyl]propoxy}Indane 6-fluoro-5-{3-[4-(3-trifluoromethylphenyl) )-1-piperazinyl]propoxy}indane 6-methyl-5-{3-[4-(2-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 6-methoxy-5-{3-[4- (4-Trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 1-ethyl-5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 6-methyl- 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 6-fluoro-5-{4-[4-(4-trifluoromethylphenyl)-1-piperazinyl ]butoxy}indane 6-chloro-5-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]butoxy}indane 6-nitro-5-{4-[4-(2-trifluoro methylphenyl)-1-piperazinyl]butoxy}indane 6-methoxy-4-{4-[4-(4-trifluoromethylphenyl)-1-piperazinyl]butoxy}indane 6-methyl-5-{3- [4-(4-fluorophenyl)-1-piperazinyl]propoxy}indane 6-chloro-5-{3-[4-(4-fluorophenyl)-1-piperazinyl]propoxy}indane 6-chloro-5 -{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}indane 6-methoxy-5-[3-(4-phenyl-1
-piperazinyl)propoxy]indane 6-methoxy-5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}indane 6-hydroxy-5-[3-(4-phenyl-
1-piperazinyl)propoxy]indane 6-hydroxy-5-{3-[4-(4-fluorophenyl)-1-piperazinyl]propoxy}indane 6-nitro-5-[3-(4-phenyl-1-
Piperazinyl) propoxy] indane 6-nitro-5-{3-[4-(4-fluorophenyl)-1-piperazinyl] propoxy} indane 1-ethyl-5-{3-[4-(4-fluorophenyl) )-1-piperazinyl]propoxy}indane 1-phenyl-5-[3-(4-phenyl-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. Chlorodiazeboxide, a well-known anxiolytic drug or minor translizer, was used as a control drug. The results are 50% effective dose (ED ₅₀ , mg/Kg
PO). The animals used were ddy male mice (20-22 g).
Anti-fighting effect and anti-morphine as indicators of anxiolytic effect
The effect was investigated. In other words, the anti-fighting effect is 28V.
Developed by applying DC, 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 20 mg/Kgi.p of morphine according to the method of Takagi et al. , 66 , 107 (1970)) The muscle relaxant effect was determined by the traction of Courvoisier et al.
Examined using the traction test method (S.
Courvoisier, R. Ducrot, L. Julou. “Psychotropic drugs”
Ed, by S. Gar attini, V. Ghetti, p313 (Elsevier 1957). LD ₅₀ 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, 2, and 7 were found to have anxiolytic effects superior to the control drug chlorodiazepoxide; It is thought to be a highly safe drug, with lower toxicity and weaker muscle relaxant effect than poxide.

【table】

[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, and R ¹ is a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms, or an integer having 1 carbon number.
-3 alkoxy group, ^R2 is a phenyl group, and if this phenyl group has a substituent, the substituent is a halogen atom, especially a fluorine atom, a chlorine atom, or a trifluoromethyl group. It is. 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 6-fluoro-5-[3-(4-phenyl-1
-piperazinyl)propoxy]indane 6-methyl-5-[3-(4-phenyl-1-
Piperazinyl) propoxy] indane 6-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-methoxy-5-{3-[4-(4-fluorophenyl)-1-piperazinyl]propoxy}
Indane 6-chloro-5-[3-(4-phenyl-1-
Piperazinyl) propoxy] indane 6-chloro-5-{3-[4-(4-fluorophenyl)-1-piperazinyl] propoxy} indane 6-methoxy-5-[3-(4-phenyl-1
-piperazinyl)propoxy]indane 6-methoxy-5-{3-[4-(4-fluorophenyl)-1-piperazinyl]propoxy}
Indane 1-ethyl-5-{3-[4-fluorophenyl)-1-piperazinyl]propoxy}indane 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 27.3 g (0.1 mol) of 5-(3-bromopropoxy)-6-fluoro-indan, 17.8 g (0.11 mol) of N-phenylpiperazine, and triethylamine
Dissolve 15 g in 300 ml of dimethylformamide and add 80
Heat at ℃ for 2 hours. The reaction solution was diluted with 1N NaOH aqueous solution.
Extract twice with 500 ml and 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. Melting point: 212-3°C, recrystallized from ethyl alcohol after cooling.
6-Fluoro-5-[3-(4-phenyl-1
36.5 g (85.6%) of indane 2HCl salt (piperazinyl)propoxy] 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】

【table】

Claims (1)

[Claims] 1. The following general formula (In the above formula, n represents an integer of 3 or 4, and R ¹
represents a halogen atom, an alkyl group, an alkoxy group, a hydroxy group, a phenyl group or a nitro group,
R ² represents a phenyl group which may be substituted with a halogen atom or a trifluoromethyl group. )
Piperazinyl alkoxyindanes represented by and acid addition salts thereof.