JPH0352459B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1,5-benzodioxepine derivatives and acid addition salts thereof having antihypertensive effects. The compound of the present invention is represented by the following general formula () In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ² is an alkyl group having 1 to 3 carbon atoms, and X is

[Formula] or

[Formula] Ar is

[Formula] (Y is a hydrogen atom, -OCH ₃ , a halogen atom) or

[Formula] and n represents an integer from 1 to 5. The method for producing the compound of the present invention will be explained. The compound of the present invention has the following general formula () (In the above general formula (), R ¹ , R ² and n have the same meanings as R ¹ , R ² and n in the general formula (),
Z represents a halogen atom. ) and the following general formula (): (In the above general formula, Ar is in the general formula ()
Synonymous with Ar. ) can be obtained by reaction with piperazines represented by: Although ω-halogenoalkanoyl-1,5-benzodioxepines and piperazines react in a ratio of 1:1, the reaction usually proceeds more smoothly when an excess of piperazine is used. Therefore, piperazines are ω-
It is used in an amount of 1 to 10 moles per mole of the halogenoalkanoyl-1,5-benzodioxepines. 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 if necessary, a strong aqueous base such as sodium hydroxide or potassium hydroxide is added, and then ethyl acetate, This 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. Also, among the ω-halogenoalkanoyl-1,5-benzodioxepines (), compounds in which n is 2 or more are ω-halogenoalkanoyl chloride () and the following formula () (In the above formula, R ¹ and R ² are in the general formula ()
It is synonymous with R ¹ and R ² . ) can be obtained by Friedel-Crafts reaction with 1,5-benzodioxepines represented by: (Org.Syn.Coll., Vol, 109
Page) When n is 1 in the general formula (), that is, halogenoacetyl-1,5-benzodioxepines are obtained by reacting the 1,5-benzodioxepines of the general formula () with acetyl chloride. It is produced by reacting the obtained acetyl-1,5-benzodioxepines with a halogen molecule.
(Org. Syn) Coll
(Collective). , Vol , 480
Page) Specific examples of the compounds of the present invention are shown below. 7-[4-(4-phenyl-1-piperazinyl)butyryl]-3-methyl-1,5-benzodioxepine 7-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyryl ]-3-methyl-1,5-
Benzodioxepine 7-[4-[4-(3-methoxyphenyl)-1-piperazinyl]butyryl]-3-methyl-1,5-
Benzodioxepin 7-[4-[4-4-methoxyphenyl)-1-piperazinyl]butyryl]-3-methyl-1,5-
Benzodioxepin 7-[4-[4-(2-fluorophenyl)-1-piperazinyl]butyryl]-3-methyl-1,5-
Benzodioxepine 7-[4-[4-(3-fluorophenyl)-1-piperazinyl]butyryl]-3-methyl-1,5-
Benzodioxepin 7-[4-[4-(4-fluorophenyl)-1-piperazinyl]butyryl]-3-methyl-1,5-
Benzodioxepine 7-[4-[4-(2-pyridyl)-1-piperazinyl]butyryl]-3-methyl-1,5-benzodioxepine In the above example, in the general formula (), R ¹ is This is a case where hydrogen atom, ^R2 is a methyl group, X is C=0, and n is 3, but compounds where n is 1, 2, 4, or 5 corresponding to each of the exemplified compounds are also exemplified as the present compound. Ru. 7-[4-(4-phenyl-1-piperazinyl)butyryl]-3,3-dimethyl-1,5-benzodioxepine 7-[4-[4-(2-methoxyphenyl)-1-piperazinyl] [Butyryl]-3,3-dimethyl-1,
5-Benzodioxepin 7-[4-[4-(3-methoxyphenyl)-1-piperazinyl]butyryl]-3,3-dimethyl-1,
5-Benzodioxepin 7-[4-[4-(4-methoxyphenyl)-1-piperazinyl]butyryl]-3,3-dimethyl-1,
5-Benzodioxepin 7-[4-[4-(2-fluorophenyl)-1-piperazinyl]butyryl]-3,3-dimethyl-1,
5-Benzodioxepin 7-[4-[4-(3-fluorophenyl)-1-piperazinyl]butyryl]-3,3-dimethyl-1,
5-Benzodioxepin 7-[4-[4-(4-fluorophenyl)-1-piperazinyl]butyryl]-3,3-dimethyl-1,
5-Benzodioxepine 7-[4-[4-(2-pyridyl)-1-piperazinyl]butyryl]-3,3-dimethyl-1,5-benzodioxepine The above examples are shown in the general formula (). In the case where R ¹ and R ² are methyl groups, X is C=0, and n is 3,
n corresponding to each of the exemplified compounds is 1,
Compounds 2, 4, and 5 are also all exemplified as the present compound. 7-[4-(4-phenyl-1-piperazinyl)-
1-hydroxybutyl]-3-methyl-1,5-
Benzodioxepine 7-[4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-hydroxybutyl]-3-methyl-1,5-benzodioxepine 7-[4-[4 -(3-methoxyphenyl)-1-piperazinyl]-1-hydroxybutyl]-3-methyl-1,5-benzodioxepine 7-[4-[4-(4-methoxyphenyl)-1- Piperazinyl]-1-hydroxybutyl]-3-methyl-1,5-benzodioxepine 7-[4-[4-(2-fluorophenyl)-1-piperazinyl]-1-hydroxybutyl]-3- Methyl-1,5-benzodioxepin 7-[4-[4-(3-fluorophenyl)-piperazinyl]-1-hydroxybutyl]-3-methyl-
1,5-Benzodioxepine 7-[4-[4-(4-fluorophenyl)-1-piperazinyl]-1-hydroxybutyl]-3-methyl-1,5-benzodioxepine 7-[ 4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-3-methyl-1,
5-Benzodioxepine The above examples are for the case where R ¹ is a hydrogen atom, R ² is a methyl group, X is CHOH, and n is 3 in the general formula (), but n corresponding to each of the exemplified compounds is Compounds 1, 2, 4, and 5 are also all exemplified as the present compound. 7-[4-(4-phenyl-1-piperazinyl)-
1-hydroxybutyl]-3,3-dimethyl-1,
5-Benzodioxepin 7-[4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-
Dimethyl-1,5-benzodioxepine 7-[4-[4-(3-methoxyphenyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-
Dimethyl-1,5-benzodioxepine 7-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-
Dimethyl-1,5-benzodioxepine 7-[4-[4-(2-fluorophenyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-
Dimethyl-1,5-benzodioxepine 7-[4-[4-(3-fluorophenyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-
Dimethyl-1,5-benzodioxepine 7-[4-[4-(4-fluorophenyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-
Dimethyl-1,5-benzodioxepine 7-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-3,3-dimethyl-1,5-benzodioxepine An example of this is in the general formula (), R ¹ , R ²
is a methyl group, X is CHOH, and n is 3, but compounds in which n is 1, 2, 4, or 5, which correspond to each of the exemplified compounds, are also exemplified as the present compound. Acid addition salts of the various compounds mentioned above 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. After measuring and determining the average blood pressure and heart rate before drug administration, the drug was orally administered at 13, 10, and 30 mg/Kg every hour, and the antihypertensive effect was determined and expressed as the rate of decrease from the pre-administration value. Ta. The results are shown in Table-1. As shown in Table 1, the compound of the present invention is 1 mg/Kg.
Shows sufficient blood pressure lowering effect when administered orally.

[Table] 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 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, 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 7-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-3-methyl-
1,5-benzodioxepine 7-(4-chlorobutyryl)-3-methyl-1,
After dissolving 3.0 g of 5-benzodioxepine in 15 ml of N,N-dimethylformamide, 2.2 g of 1-(2-pyridyl)piperazine and 5 ml of triethylamine were added, and the mixture was stirred at 80° C. for 15 hours under a nitrogen atmosphere. After cooling, water is added, and the precipitated oil is extracted with ethyl acetate. After separation, the mixture is washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate, 20% hydrogen chloride-ethyl acetate was added to the liquid under ice cooling. The precipitated crystals were collected and recrystallized from ethanol to give 7-[4-[4-(2-pyridyl)]
-1-piperazinyl]butyryl]-3-methyl-
4.1 g of 1,5-benzodioxepine trihydrochloride is obtained. (Yield 72.8%). Next, suspend 2.0 g of this substance in 20 ml of methanol, add 7 ml of 2N aqueous sodium hydroxide solution, dissolve, and add sodium borohydride.
Add 0.2g. After stirring at room temperature for 2 hours, under ice cooling,
Add water. The precipitated crystals were collected, washed with water, and recrystallized from ethanol to give 7-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-3-methyl-1,5-benzo 1.4 g of dioxepin is obtained (yield 88.9%). The physical properties of these compounds are shown in Table 2 (Nos. 3 and 5). Similarly, the compounds (Nos. 1, 2, 4 and 6) listed in Table 2 can be produced.
Its physical properties are also shown in Table 2.

【table】

【table】

Claims (1)

[Claims] 1 General formula () [In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ² is an alkyl group having 1 to 3 carbon atoms,
is [Formula] or [Formula] Ar is [Formula] (Y is a hydrogen atom, -OCH ₃ , a halogen atom) or [Formula], and n is an integer from 1 to 5] 1,5- Benzodioxepine derivatives and their acid addition salts.