JPH0249303B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to (ω-piperazinyl alkoxy) polyalkoxybenzene derivatives and acid addition salts thereof. More specifically, it is effective as a blood pressure lowering agent (ω-
This invention relates to (piperazinyl alkoxy) polyalkoxybenzene derivatives. The compound of the present invention is represented by the following general formula (). In the above general formula, m represents an integer of 2 or 3, and n
represents an integer of 3 or 4, and R ¹ is a carbon number of 1 to 3
represents an alkyl group, and R ² represents a phenyl group optionally substituted with one or more groups selected from a pyridyl group, pyrazinyl group, pyrimidyl group, or a halogen atom, a trifluoromethyl group, an alkoxy group, and an alkyl group. show. Halogen atoms include fluorine atoms, chlorine atoms,
Examples of the alkoxy group include lower alkoxy groups having 1 to 5 carbon atoms, such as a methoxy group and an ethoxy group. Examples of the alkyl group for R ² include lower alkyl groups having 1 to 5 carbon atoms such as a methyl group and an ethyl group. The position of the substituent (R ¹ O) on the phenyl group is not limited, but may include 2,6-, 2,3-, 3,4-, 3,
5-, 2,3,4- or 3,4,5- and the like. The method for producing the compound of the present invention will be explained below. The compound of the present invention has the following general formula () (In the above general formula, R ¹ , m, and n have the same meanings as R ¹ , m, and n in the general formula (), and X represents a halogen atom.) Halogenoalkoxypolyalkoxybenzene represented by the following general formula () (R ² in the above general formula has the same meaning as R ² in the general formula ()). Although the halogenoalkoxypolyalkoxybenzene and the piperazine derivative react in a ratio of 1:1, the reaction usually proceeds more smoothly when the piperazine derivative is used in excess. Therefore, the piperazine derivative is halogenoalkoxypolyalkoxybenzene 1
1 to 10 moles are used per mole. 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 in some cases, a strong aqueous base solution such as sodium hydroxide or potassium hydroxide is added to form free (ω -piperazinyl alkoxy) polyalkoxybenzene derivative, and then the compound is extracted 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. 1-[3-(4-phenyl-1-piperazinyl)
Propoxy]-3,4-dimethoxybenzene 1-[3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy]3,4-dimethoxybenzene 1-[3-[4-(3-chlorophenyl)-1 -Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(2-chlorophenyl)-1-piperazinyl)propoxy]-3,4-dimethoxybenzene 1-[3-[4-(4- fluorophenyl)-1-
Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(4-methylphenyl)-1-piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(3-methylphenyl) )-1-Piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4-(2-methylphenyl)-1-piperazinyl]propoxy]-3,4-dimethoxybenzene 1-[3-[4- (2-pyridyl)-1-piperazinyl]propoxy]-3,4-dimethoxybenzene In the above example, in the general formula (), m=2
The substitution positions of the methoxy group are the 3rd and 4th positions, and n=3, but all compounds where n is 4, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 1-[3-[4-phenyl-1-piperazinyl]
Propoxy]-2,6-dimethoxybenzene 1-[3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(3-chlorophenyl)- 1-Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(4 -fluorophenyl)-1-
Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(4-methylphenyl)-1-piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(3-methylphenyl) )-1-Piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4-(2-methylphenyl)-1-piperazinyl]propoxy]-2,6-dimethoxybenzene 1-[3-[4- (2-pyridyl)-1-piperazinyl]propoxy]-2,6-dimethoxybenzene In the above example, in the general formula (), m=2
The substitution positions of the methoxy group are the 2nd and 6th positions, and n=3, but all compounds in which n is 4, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 1-[3-(4-phenyl-1-piperazinyl)
Propoxy]-2,3-dimethoxybenzene 1-[3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(3-chlorophenyl)- 1-Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy-2,3-dimethoxybenzene 1-[3-[4-(4- fluorophenyl)-1-
Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(4-methylphenyl)-1-piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(3-methylphenyl) )-1-Piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4-(2-methylphenyl)-1-piperazinyl]propoxy]-2,3-dimethoxybenzene 1-[3-[4- (2-pyridyl)-1-piperazinyl]propoxy]-2,3-dimethoxybenzene In the above example, in the general formula (), m=2
The substitution positions of the methoxy group are the 2nd and 3rd positions, and n=3, but all compounds where n is 4, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 1-[3-(4-phenyl-1-piperazinyl)
Propoxy]-3,5-dimethoxybenzene 1-[3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(3-chlorophenyl)- 1-Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(4 -fluorophenyl)-1-
Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(4-methylphenyl)-1-piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(3-methylphenyl) )-1-Piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4-(2-methylphenyl)-1-piperazinyl]propoxy]-3,5-dimethoxybenzene 1-[3-[4- (2-pyridyl)-1-piperazinyl]propoxy]-3,5-dimethoxybenzene In the above example, in the general formula (), m=2
The substitution positions of the methoxy group are the 3rd and 5th positions, and n=3, but all the compounds where n is 4, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 1-[3-(4-phenyl-1-piperazinyl)
propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(4-chlorophenyl)-1-piperazinyl)propoxy]-3,4,5-trimethoxybenzene 1-[3-[4- (3-chlorophenyl)-1-piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy]-3,4,5-tri Methoxybenzene 1-[3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(4-methylphenyl)-1-piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[ 4-(3-methylphenyl)-1-piperazinyl]propoxy]-3,4,5-trimethoxybenzene 1-[3-[4-(2-methylphenyl)-1-piperazinyl]propoxy]-3,4,5 -Trimethoxybenzene 1-[3-[4-(2-pyridyl)-1-piperazinyl]propoxy]-3,4,5-trimethoxybenzene In the above example, in the general formula (), m=3 and methoxy group The substitution positions are the 3rd, 4th, and 5th positions, and n=3, but all compounds where n is 4, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 1-[3-(4-phenyl-1-piperazinyl)
propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4- (3-chlorophenyl)-1-piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy]-2,3,4-tri Methoxybenzene 1-[3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(4-methylphenyl)-1-piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[ 4-(3-methylphenyl)-1-piperazinyl]propoxy]-2,3,4-trimethoxybenzene 1-[3-[4-(2-methylphenyl)-1-piperazinyl]propoxy]-2,3,4 -Trimethoxybenzene 1-[3-[4-(2-pyridyl)-1-piperazinyl]propoxy]-2,3,4-trimethoxybenzene In the above example, in the general formula (), m=3 and methoxy group The substitution positions are the 2nd, 3rd, and 4th positions, and n=3, but all compounds where n is 4, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 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, and nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, and oxalic acid. , citric acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid, and other organic acids. The blood pressure lowering effect of the compound of the present invention will be explained below. The antihypertensive effect of the compounds of the present invention was examined using the following method. Specifically, the animals used were spontaneously hypertensive rats (SHR) (300-370 g, 5-7 months old), and blood pressure and heart rate were measured invasively under ether anesthesia with a catheter inserted through the tail artery. The average blood pressure and heart rate before drug administration were determined. The drug was orally administered at 1, 3, and 10 mg/Kg every hour, and the antihypertensive effect was determined and expressed as the rate of decrease from the pre-administration value. . The maximum blood pressure reduction rate indicates the maximum % reduction from the average blood pressure before administration, and the SDBP ₁₀ value indicates the dose (mg/Kg.PO) that maintains a 10% blood pressure reduction for 1 hour. The results are shown in Table-1. In addition, acute toxicity values (LD ₅₀ ) were determined using mice.
Litchfield Wilcoxon
-Calculated using the Wilcoxoh method, and the results are shown in the table-
Shown in 2. The compounds of the present invention are equal to 3 as shown in Table 1.
It exhibits a sufficient blood pressure lowering effect when administered mg/Kg orally, has a rapid onset of efficacy, and has a long-lasting effect. Also, table-
As shown in 2, the acute toxicity is weak, and considering the amount of medicinal efficacy expressed, it is estimated to be a very safe drug.

[Table] * Compound structures correspond to Table 3.
It is the same as the compound in the No. column.
Ru.

[Table] *The structure of the compound is the same as the compound in the corresponding No. column of Table 3.
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 active ingredient is 0.1-100mg/
Kg body weight, usually 1-3 mg/Kg body weight, administered in one or more doses. When the compound of the present invention is administered orally, it is used in the form of a tablet, capsule, solution, solution, or elixir, and when administered parenterally, it is used in a sterile 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 vegetable 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 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 antihypertensive agents. Example 1 1-[3-(4-phenyl-1-piperazinyl)
Propoxy]-3,4-dimethoxybenzene 20 ml of N,N-dimethylformamide, 3.5 g of phenylpiperazine, and 3.8 ml of triethylamine were added to 5.0 g of 1-(3-bromopropoxy)-3,4-dimethoxybenzene, and the mixture was heated at room temperature. Stir for 5-6 hours. The reaction solvent was distilled off under reduced pressure, and ethyl ether was added to the residue.
Add 70ml and 10ml of 2N sodium hydroxide solution,
Separate the aqueous layer and wash sequentially with water and saturated saline,
After drying the ethyl ether layer over anhydrous sodium sulfate, 8.3 ml of 20% hydrochloric acid-ethyl acetate was added while stirring under ice cooling. The precipitated crystals were collected and recrystallized from ethanol to obtain 6.6 g of 1-[3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dimethoxybenzene dihydrochloride. (Yield 85%) The physical properties of the above compound are listed in the No. 1 column of Table 3. Other compounds may be prepared by similar methods.
The physical properties are shown in Table 3.

【table】

【table】

Claims (1)

[Claims] 1. The following general formula (In the above general formula, m represents an integer of 2 or 3, and n
represents an integer of 3 or 4, and R ¹ is a carbon number of 1 to 3
represents an alkyl group, and R ² represents a phenyl group optionally substituted with one or more groups selected from a pyridyl group, pyrazinyl group, pyrimidyl group, or a halogen atom, a trifluoromethyl group, an alkoxy group, and an alkyl group. (ω-piperazinylalkoxy)polyalkoxybenzene derivatives represented by (shown) and acid addition salts thereof.