JPH032863B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula The present invention relates to an aminoquinazoline derivative having the following formula, a pharmaceutically acceptable acid addition salt thereof, and a method for producing the same. In addition, in the compound having the above formula (), there are optical isomers and stereoisomers based on the asymmetric carbon atom, and all of these isomers are shown by a single formula. The scope of the description of the present invention is not limited. As a quinazoline antihypertensive agent, a drug called prazosin (generic name) described in US Pat. No. 3,511,836 is known. The present inventors conducted extensive research in search of quinazoline derivatives with even better antihypertensive effects, and found that the novel compound represented by () above did not exhibit the rapid hypotensive effect seen in prazosin. The present invention was completed based on the discovery that it is useful as an antihypertensive agent that has a slow antihypertensive effect and a sustained action. The aminoquinazoline derivative () of the present invention can be produced by the following synthetic route. In the formula, Y represents a halogen atom. Route (a) is a 2-halogenoquinazoline derivative ()
This is a production method in which the compound is reacted with a cyclic diamine derivative (). In carrying out this reaction, the reaction is achieved by bringing the compound having the general formula () into contact with the compound having the formula (). The solvent used is not particularly limited as long as it does not participate in this reaction, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as ethyl ether, tetrahydrofuran, and dioxane; and alcohols such as methanol, ethanol, and propanol. ethyl acetate; fatty acid dimethylamides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide; and the like are preferred. The reaction temperature is 40 to 200°C, preferably 60 to 150°C, and the reaction time varies depending on the reaction temperature, but is 1 to 24 hours. Further, the starting material is used in an amount of at least 1 mole, preferably 1 to 2 moles, of the compound having the formula () relative to the compound having the general formula (). Furthermore, the reaction can be made to proceed smoothly by adding an organic base such as triethylamine or 1,8-diazabicyclo[5,4,0]undecene-7 or an inorganic base such as alkali bicarbonate or alkali carbonate as a deoxidizing agent. Can be done. After completing the reaction according to route (a), the target compound ()
is collected by collecting crystals precipitated from the reaction mixture according to a conventional method. After completion of the reaction, the reaction mixture is concentrated, and the solvent is distilled off from the solution extracted with an organic solvent such as chloroform or ethyl acetate. The target compound thus obtained can be further purified, if necessary, by a conventional method, such as a recrystallization method. Aminoquinazoline derivatives having the formula () synthesized by the above manufacturing method can be obtained as a free base or a pharmaceutically acceptable salt depending on the manufacturing method. Conversion to can be performed using conventional methods. Pharmaceutically acceptable acid addition salts mean salts that do not substantially increase the toxicity of the basic compound, and include hydrochloric acid,
salts of mineral acids such as phosphoric acid, sulfuric acid, nitric acid, tartaric acid,
Includes salts of organic acids such as citric acid, malic acid, lactic acid, ascorbic acid, and maleic acid. The compound of the present invention has excellent antihypertensive effects in pharmacological tests and is an effective compound for the prevention and treatment of various types of hypertension, such as essential hypertension, renal hypertension, and adrenal hypertension. In the case of oral administration, the dosage forms of this compound include tablets, capsules, powders, fine granules, granules,
Examples include solutions, suspensions, and the like. In the case of parenteral administration, examples include injections and suppositories. The dosage of the present compound varies depending on the type of hypertension and the severity of symptoms, but generally speaking, when administered orally, it is 0.05 to 200 mg per day for adults, preferably 0.1 to 50 mg per day. In the case of parenteral administration, the dose is 1/3 to 1/10 of the oral dose. Although the present compound is effective in preventing and treating various types of hypertension even when administered alone, it can also be used in combination with other antihypertensive agents such as diuretics and β-adrenergic receptor blockers. Next, examples of the compounds of the present invention will be specifically explained with reference to examples, but these examples are not intended to limit the present invention. Example 1 4-amino-6,7-dimethoxy-2-[4-
(trans-2-phenylcyclopropyl-carbonyl)-1-piperazinyl]quinazoline.
Hydrochloride/Dihydrate 1.2 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1.4 g of 1-(trans-2-phenylcyclopropylcarbonyl)piperazine were added to 25 ml of isoamyl alcohol and refluxed for 4 hours. The precipitated crystals were collected, neutralized with 20% sodium hydroxide, and extracted with chloroform. Subjected to silica gel chromatography and eluted with chloroform, 10%
Hydrogen chloride-ethanol was added and the precipitated crystals were collected to obtain 1.22 g of colorless powdery crystals of the title target compound. Melting point 195-198℃ (decomposition) Elemental analysis value (%) C ₂₄ H ₂₇ N ₂ O ₃・HC・2H ₂ O
Calculated value: C, 56.97; H, 6.37; N, 13.84; C, 7.01 Actual value: C, 56.97; H, 6.47; N, 13.96; C, 6.97 Antihypertensive effect test In spontaneously hypertensive rats (hereinafter referred to as SHR) The antihypertensive effect was tested by orally administering the specimen. A 15-week-old male SHR was anesthetized with sodium pentobarbital (50 mg/Kg intraperitoneal administration).
Weeks and Jones Law (Weeks JRand Jones JA,
A polyethylene cannula was inserted into the abdominal aorta according to Proc. Soc. One week after the surgery, when the animal had recovered from the trauma of the surgery, the other end of the animal's cannula was connected to a blood pressure measuring device, and blood pressure and heart rate were measured by the direct method in an unanesthetized and unrestrained state. Blood pressure measuring device Laffan PJ, Peterson A.
Hitch SWand Jeunelot C., Cardiovascular
Res., Vol. 6, pp. 319-324 (1972)] was used. The specimen was suspended in 0.3% carboxymethylcellulose and administered orally. The blood pressure and heart rate of the control subjects were observed for 1 hour before administration of the sample, and administration was carried out when they became stable. After administration of the sample, blood pressure and heart rate were measured every 15 minutes for 24 hours. 【table】

Claims (1)

[Claims] 1 formula Aminoquinazoline derivatives and pharmaceutically acceptable acid addition salts thereof represented by General formula 2 (In the formula, Y represents a halogen atom.) A 2-halogenoquinazoline derivative represented by the formula It is characterized by being condensed by a dehydrohalogenation reaction with a cyclic diamine derivative represented by the formula A method for producing an aminoquinazoline derivative and an acid addition salt thereof.