JPH0582386B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel phenylpiperazine derivative having a blood pressure lowering effect and an acid addition salt thereof. (Structure of the Invention) The compound of the present invention is represented by the following general formula ().

[Chemical Formula] In the above general formula (), R ¹ , R ² and R ³ each independently represent an alkyl group having 1 to 3 carbon atoms (methyl, ethyl, n-propyl, isopropyl), and R ¹ and R ² may be combined to form an alkylene group having 1 to 3 carbon atoms. X is

[expression] or

[Formula] is shown. Next, a method for producing the compound of the present invention will be explained. The compound of the present invention () has the following general formula ()

[Chemical formula] (In the above general formula (), R ¹ , R ² and X are as defined in the above general formula ().) The phenylpiperazine derivative represented by In a solvent, form a metal salt such as sodium with a metal hydride such as sodium hydride, usually at room temperature to 150°C.
It is obtained by reacting with an alkyl halide to a certain extent. The phenylpiperazine derivative represented by the above general formula () is, for example, the following general formula ()

[Chemical formula] (In the above general formula (), R ¹ , R ² and X are as defined in the above general formula (), and Y represents a halogen atom.) Quinazoline derivative represented by the following formula ()

It can be obtained by reacting 4-(o-methoxyphenyl)piperazine represented by the following formula in an inert solvent such as dimethylformamide or dimethyl sulfoxide, usually within a temperature range from room temperature to about 150°C. In addition, in order to collect hydrogen halide generated by the reaction and accelerate the reaction, excess 4-(o-methoxyphenyl)piperazine may be added, inert organic amines such as triethylamine, sodium carbonate, potassium carbonate, etc. An inorganic base such as the like may also be added. Alternatively, the compound represented by the above general formula () can be expressed by the following general formula ()

[Chemical formula] (In the above general formula (), R ¹ , R ² and X are as defined in the above general formula ().) Quinazoline derivative represented by the following general formula ()

It can also be obtained by reacting with a piperazine derivative represented by the formula (in the above general formula (), Y represents a halogen atom). In this case, the quinazoline derivative () is converted into a sodium salt with a metal alkoxide such as caustic soda, caustic potash, sodium methoxide, or a metal hydride such as sodium hydride, and is dissolved in various inert solvents such as dimethylformamide, dimethyl sulfoxide, etc.
It can be obtained by reacting it with a piperazine derivative () in water, alcohol, etc. at a temperature within the range of room temperature to about 100°C. Compound of the present invention obtained by the above method ()
can be purified, for example, by adding water and recrystallizing the resulting crystals with alcohol or the like, or by concentrating the reaction solution and then silica gel chromatography. Further, the compound () of the present invention forms an acid addition salt with an organic acid or an inorganic acid. Such acids include, for example, 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. Specific examples of the compounds according to the present invention are as follows. 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethoxy-
1-Methyl-2,4-(1H,3H)quinazolinedione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-methylenedioxy-1-methyl-2,4-(1H,3H)quinazolinedione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethylenedioxy-1-methyl-2,4-(1H,3H)quinazolinedione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-1-methyl-2,4-(1H,3H)quinazolinedione 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethoxy-
4-Methyl-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-methylenedioxy-4-methyl-3,4-dihydro-1,2,
4-Benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethylenedioxy-4-methyl-3,4-dihydro-1,
2,4-Benzothiadiazin-3-one 1,1-
Dioxide 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-4-methyl-3,4-dihydro-1,
2,4-Benzothiadiazin-3-one 1,1-
Dioxide The above examples are cases in which R ³ is a methyl group in the general formula (), but compounds in which R ³ is an ethyl, n-propyl, or isopropyl group are also included in the present invention. Acid addition salts of the various compounds described above are also included in the present invention. (Effects of the Invention) The compounds of the present invention are useful as antihypertensive agents. Although any method of administration may be used, the following method is preferably carried out. i.e. subcutaneous injection, intravenous injection, intramuscular injection,
Parenteral administration, such as intraperitoneal injection, and oral administration are also 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. For oral administration, tablets, capsules, powders,
It is used in the form of solutions, elixirs, etc., and in the case of parenteral administration, it is used in the form of sterile liquids such as liquids or suspensions. 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%. i.e., 5 to 500 mg for these modes of administration;
Preferably, it contains 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. Also commonly used are physiological saline, dextrose or similar sucrose solutions, propylene glycol,
Glycols such as polyethylene glycol are preferred as liquid carriers, and especially in the case of injection solutions using physiological saline, the amount is usually 0.5 to 20%, preferably 1%.
Contain ~10% active ingredient by weight. 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. (Examples) Hereinafter, the present invention will be explained in further detail with reference to Examples and Test Examples. Example 1 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-1-methyl-2,4(1H,3H)quinazolinedione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl[ethyl]-6,7-trimethylenedioxy-2,4(1H,3H)quinazolinedione
Dissolve 830 mg in 15 ml of dimethylformamide,
Add 100mg of NaH50% oil and stir for 30 minutes. Then, warm it to 60℃, add 0.13ml of methyl iodide,
Stir for 1 hour. The reaction solution was extracted with ethyl acetate,
Wash with water and saturated brine, dry over anhydrous Na ₂ SO ₄ and evaporate the solvent. The resulting residue was purified by silica gel chromatography and crystallized from ethanol to give 640 mg of 3-[2-
[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-6,7-trimethylenedioxy-1
-Methyl-2,4(1H,3H)quinazolinedione is obtained (74.8% yield). The physical properties of this compound are shown in the No. 1 column of Table 1. Other compounds were synthesized by similar methods. The results are shown in columns No. 2 to 5 of Table 1. Test Example The antihypertensive effect of the compound of the present invention was investigated 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 determining the average blood pressure and heart rate before drug administration, the drug is administered orally, and the blood pressure and heart rate are then measured until 6 hours after administration, and the maximum hypotensive response from the pre-administration value is determined and the rate of change is calculated. It was expressed as The results are shown in Table-2. As is clear from Table 2, the compound of the present invention is
It exhibits a sufficient blood pressure lowering effect with a small amount of oral administration, has a rapid onset of drug efficacy, and has a long-lasting effect. In addition, it has low acute toxicity, and considering the amount of medicinal efficacy expressed, it is presumed to be a very safe drug.

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Claims (1)

[Claims] 1 The following general formula () [In the above formula, R ¹ , R ² and R ³ each independently represent an alkyl group having 1 to 3 carbon atoms, and R ¹ and
R ² may be combined to form an alkylene group having 1 to 3 carbon atoms. X represents [Formula] or [Formula]. ] A phenylpiperazine derivative or an acid addition salt thereof.