JPH0345070B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to (ω-aminoalkyl)alkylenedioxybenzene derivatives and acid addition salts thereof having hypotensive action. The compound of the present invention is represented by the following general formula (). In the above general formula, m represents an integer of 1 to 3, and n represents 3
Indicates an integer between ~5. 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, m and n have the same meanings as m and n in the general formula (), and Y represents a halogen atom.)
Halogenoalkylalkylenedioxybenzene derivative represented by and the following formula () It can be obtained by reaction with an amine represented by: The halogenoalkylalkylene dioxybenzene derivative and the amine react in a ratio of 1:1, but the reaction usually proceeds more smoothly when the amine is used in excess. Therefore, the amount of amine is 1 per mole of halogenoalkylalkylenedioxybenzene derivative.
~10 mol is used. 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 moles per mole of the amine of formula (). In order to obtain the desired acid addition salt, after the reaction is complete, remove the excess amine and solvent by distillation or washing with water, add a strong aqueous base such as sodium hydroxide or potassium hydroxide, and remove the free (ω-aminoalkyl)alkylene dichloride. Oxybenzene derivative, then ether, chloroform, benzene,
Extract this compound with a solvent such as 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-[(1,4-benzodioxan-2-ylmethyl)amino]propyl]-1,3-benzodioxole 5-[4-[(1,4-benzodioxane-2-
ylmethyl)amino]butyl]-1,3-benzodioxole 5-[5-[(1,4-benzodioxane-2-
ylmethyl)amino]pentyl]-1,3-benzodioxole 6-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propyl]-1,4-benzodioxane 6-[4-[ (1,4-benzodioxane-2-
ylmethyl)amino]butyl]-1,4-benzodioxane 6-[5-[(1,4-benzodioxane-2-
ylmethyl)amino]pentyl]-1,4-benzodioxane 1-[3-[(1,4-benzodioxane-2-
ylmethyl)amino]propyl]-3,4-trimethylenedioxybenzene 1-[4-[(1,4-benzodioxane-2-
ylmethyl)amino]butyl]-3,4-trimethylenedioxybenzene 1-[5-[(1,4-benzodioxane-2-
ylmethyl)amino]pentyl]-3,4-trimethylenedioxybenzene Acid addition salts of the various compounds described above are also included within the scope of the present invention. Acids used as addition salts include hydrochloric acid, hydrooxalic acid, sulfuric acid,
Examples include inorganic acids such as phosphoric acid and nitric acid, and organic acids such as acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, and methanesulfonic acid. It will be done. 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. After measuring and determining the average blood pressure and heart rate before drug administration, the drug was orally administered at 1, 3, or 10 mg/Kg every hour, and the antihypertensive effect was determined and expressed as the rate of decrease from the pre-administration value. Ta. 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/KgP.O.) 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 Wilcoxon 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 also weak, and considering the amount of medicinal efficacy expressed, it is presumed to be a very safe drug.

[Table] *1 The structure of the compound is the same as the compound in the corresponding No. column of Table-3.
*2 Comparison data

Compounds in the corresponding No. column of [Table]
It is the same as a thing.
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 1-30 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 preferably contain 5 to 500 mg, preferably 25 to 250 mg, of the 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 antihypertensive agents. Example 1 1-[4-[(1,4-benzodioxane-2-
ylmethyl)amino]butyl]-3,4-trimethylenedioxybenzene hydrochloride 1-(4-chlorobutyl)-3,4-trimethylenedioxybenzene (9.8g), (1,4-benzodioxane-2- ylmethyl)amine (9.1 g) and triethylamine (8 g) were dissolved in dimethylformamide (50 ml) and heated and stirred at 80°C for 45 hours. After the reaction, the solvent was distilled off under reduced pressure,
Add 2NNaOH and extract with ether. The ether layer was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , the solvent was distilled off, the resulting residue was dissolved in ether, and 20% HCl/ethyl acetate was added under ice cooling. By collecting the crystals and recrystallizing them from ethanol, 1-[4-[(1,4-benzodioxan-2-ylmethyl)amino]butyl]-3,
4-trimethylenedioxybenzene hydrochloride (10.9 g, 61% yield) is obtained. The physical properties of this compound are as listed in No. 5 of Table 3. In addition, other compounds were obtained in the same manner, Table 3
As stated in

[Table] * Comparative example

Claims (1)

[Claims] 1. The following general formula (In the above formula, m represents an integer of 1 to 3, and n represents 3 to 3.
Indicates an integer of 5. )(ω-Aminoalkyl)alkylenedioxybenzene derivatives and their acid addition salts