JPH0545586B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel quinazoline derivatives having antihypertensive action and acid addition salts thereof. Disclosure of the Invention The compound of the present invention is represented by the following general formula (). In the above general formula (), R ¹ , R ² and R ³ represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (methyl, ethyl, propyl, i-propyl),
R ¹ and R ² may be combined to form an alkylene group having 1 to 3 carbon atoms. n represents an integer of 2, 3 or 4. 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 () (In the above general formula (), R ¹ , R ² and n are as defined in the above general formula (), and X represents a halogen atom.) and the following general formula () (In the above general formula (), R ³ is the above general formula ()
As defined in ) with 4-(o-alkoxyphenyl)piperazine in an inert solvent such as dimethylformamide or dimethyl sulfoxide at a temperature usually 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-alkoxyphenyl)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 of the present invention can be expressed by the following general formula () (In the above general formula (), R ¹ and R ² are as defined in the above general formula ().) and the following general formula () (In the above general formula (), R ³ and n are as defined in the above general formula (), and X represents a halogen atom.) . In this case, the quinazoline derivative () is made into a sodium salt by using caustic soda, caustic potash, a metal alkoxide such as sodium methoxide, or a metal hydride such as sodium hydride, and the sodium salt is prepared in various inert solvents, such as dimethylformamide, dimethylsulfoxide, etc. It can be obtained by reacting with a piperazine derivative () in water, alcohol, etc. at a temperature within the range of room temperature to 100°C. Compound of the present invention obtained by the above method ()
can be purified, for example, by recrystallizing the crystals produced by adding water with alcohol or the like, or by concentrating the reaction solution and then using 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-
1,2,3,4-tetrahydroquinazoline-2,
4-dione 3-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propyl]-6,7-dimethoxy-1,2,3,4-tetrahydroquinazoline-
2,4-dione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-methylenedioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 3-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethylenedioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 3-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propyl]-6,7-dimethylenedioxy-1,2,3,4-tetrahydroxynazoline-2,4-dione 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylene dioxane-1,2,3,4-tetrahydroquinazoline-2,4-dione 3-[3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propyl]-6,7-trimethylenedioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 3-[4-[4-(2-methoxyphenyl)-1-
Piperazinyl]butyl]-6,7-trimethylenedioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione Acid addition salts of the various compounds described above are also encompassed by 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 by 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 injections 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 further explained in detail using Examples and Test Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded. Example 1 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroquinazoline-
2,4-dione 6,7-dimethoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione (2 g) was dissolved in dimethylformamide (30 ml), and sodium hydride (1230 mg) was added under cooling. After that, stir for 10 minutes. Then, 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride (2.3
g) and stirred at 70°C for 6 hours. After the reaction was completed, water was added and extracted with chloroform. After concentration, the resulting residue was purified by silica gel chromatography and crystallized from methanol to give 3-[2-[4-(2- methoxyphenyl)-1
-Piperazinyl]ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroquinazoline-
2,4-dione (1.4 g) (35% yield) was obtained. The physical properties of this compound are shown in the No. 1 column of Table 1. Example 2 3-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 3-(2-chloroethyl)-6,7-trimethylenedioxy-1,2 , 3,4-tetrahydroquinazoline-2,4-dione (6.0 g), 4-(2-methoxyphenyl)piperazine (5.8 g) and dimethylformamide (60 ml) were added with triethylamine (4.2 ml) at 90°C for 26 hours. Time reacts. The resulting reaction solution was concentrated and crystallized from methanol to yield 7.4 g of 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6,7-
Trimethylene dioxy-1,2,3,4-tetrahydroquinazoline-2,4-dione was obtained (81% yield). The physical properties of this compound are shown in the No. 2 column of Table 1.
Compounds Nos. 3 to 8 were also obtained in the same manner.

[Table] *Comparative 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 orally administered, and the blood pressure and heart rate are then measured until 6 hours after administration.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
Oral administration of 1 mg/Kg or 3 mg/Kg exhibits a sufficient blood pressure lowering effect, and the onset of drug efficacy is rapid and the action is sustained. In addition, it has low acute toxicity, and considering the amount of medicinal efficacy expressed, it is presumed to be a very safe drug.

[Table] *1 Corresponds to No. in Table-1.
*2 Comparative example

Claims (1)

[Claims] 1 General formula () [In the above formula, R ¹ , R ² and R ³ represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ¹ and R ² combine to form an alkylene group having 1 to 3 carbon atoms. Good too. n represents an integer of 2, 3 or 4. ] Quinazoline derivatives and acid addition salts thereof.