SU1098521A3 - Process for preparing derivatives of quinozaline or their salts - Google Patents

Abstract

The method of obtaining quinazoline derivatives of the general formula of a carbon atom, an alkoxy group containing 1-4 carbon atoms, an alkanoyl group containing 2-4 carbon atoms, halogen, or their salts, characterized in that the quinazoline of the formula Ing, where the shooting range has the indicated values, § subject interaction with a compound (L is Formula R - hydrogen or methyl, XSI., -, - (CHj) -, - or -СЖСНр-, R and R- each independently of one another is a hydrogen atom, an alkyl group containing 1-4 o CO 00 El CfO-CJH; o X, R and R have the indicated values, followed by isolation of the target product in free form or in salt form.

Description

310985 Thus, the invention further provides a pharmaceutical composition comprising a compound of the formula 1) or a pharmaceutically acceptable acid addition salt thereof, acceptable with a pharmaceutical point of view, together with a diluent or carrier acceptable from the pharmaceutical point of view. The proposed compound can be applied to a human for the purpose of treating hypertonia either by oral or intravenous methods, and for oral use, the dose is about 1-20 mg / day for a patient with an average weight (70 kg) this (5 dose is taken either at one time, or divided into three separate doses. For intravenous administration, it is expected that the dose should be about 1 / 5-1 / 10 daily dose for 20 dental applications. Thus, for a patient with an average weight for dental use, individualOses in tablets or capsules soy "vJlei A solution of 6-methoxy-1, D-benzodioxan-2-carbonyl chloride (2.17 g), which is prepared from acid and TIONES1 chloride in dichloromethane (25 ml) is added dropwise to the stirred suspension 4 -amino-2-piperazin-1-yl-6, 7-dimethoxy-quinazoline (2.48 g) in methylene chloride (50 ml) at room temperature. After the addition is complete, the mixture is stirred at room temperature for 4 h, then filtered, and the solid material is suspended in an aqueous solution of potassium carbonate and extracted with chloroform. The combined extracts are washed with water, dried over sodium sulfate and evaporated in vacuo to give a solid residue 4 (15 g), which is chromatographed on silica gel (160 g) and eluted with chloroform, followed by chloroform-methanol. The same fraction (TLC) is combined, evaporated under vacuum, then the residue is dissolved in an ethyl acetate mixture and approximately 1-50 mg of the active compound is evaporated. Of course, various variations are possible depending on the weight of the patient and the conditions of use of the drug, as well as the specific method of use of the drug that is selected, all these variations and variations are known to every expert in this field. In addition, in accordance with the inventive method, a method of treating animals, including a person suffering from hypertension, is provided, which comprises applying to the animal an anti-hypertonic amount of a compound of formula I or a pharmaceutically acceptable acid addition or pharmaceutical composition as defined above, Example 1. 4-amino-2- 4- (6-methoxy-1,4-benzodioxan-2-carbonyl) piperazin-1-yl-6,7-dimethoxyquinazoline rvW tat-methanol and treated with ethereal hydrogen chloride. Ether is then added again, the mixture is cooled, and a solid is formed, which is collected and recrystallized from methanol to yield 4-amino-2-4- (6-methoxy-1, 4-benzodioxane -2-carbonyl) piperazin-1-yl 3-6,7-dimethoxyquinazoline hydrochloride (0.95 g) with so pl. 220-222 ° C. Data analysis,%. Found: C 53.5, H 5.5, N 13.4. С24К tН5Оь HCl-HjO. Calculated: C 53.8, H 5.6, N 13.1, Examples 2-20. The following compounds were prepared according to Example 5, starting from 4-amino-2-piperazine-1-yl or .2- (3-methyl-piperazin-1-yl) -6,7-dimethoxy-quinazoline and the corresponding carbonyl chloride. Example 21. 4-Amino-6,7-dimethoxy-2-A- (mixture-6 and 7-carbonyl-1,4-benzo-dioxane-2-carbonyl) piperizin j quinazoline hydrochloride. $ 10 Dicyclohexylcarbodiimide (2.06 g) and N-oxysuccinimide (1.15 g) add. There is a mixed solution of a mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2-carboxylic acid (2.23 g) in dimethylformamide (70 ml) at. The mixture was stirred for 1 hour, then 4-amino-6, -dimethoxy-2-piperazine-quinazoline (2.8 g) was added to it and the resulting mixture was stirred at room temperature for 12 hours. Next the reaction mixture is filtered, the filtrate is taken up with ether (500 ml) and the resulting oily residue is collected. The resulting product is then divided between a solution of chloroform (isopropanol) sodium bicarbonate, the chloroform layer is separated, washed with water and evaporated under vacuum. The residue is chromatographed on silica gel and eluted with chloroform-methanol to form a crude product, which, after treatment with ether (ether) with a solution of hydrogen chloride and recrystallized from methanol (water), is dimethyl formamide and then from methanol (water ) dimethylformamide gives 4-amino-6,7-dimethoxy-2-G4- (b- and 7- (mixture) -carbamoyl-1,4-benzodioxan-2-carbonyl | piperazine quinazoline hydrochloride hydrate with mp 228- 235 ° C (decomposition.) (Table 1). T a b l and c a 1 T1,

Hydrochloride, 56.2 5.4 13.9

hemihydrate

238-240 (56.4 5.7 13.7)

eight

. Continuation of the table.1 Subsequent recrystallization gives an analytical sample with m, pl.245248 ° C. The results of the analysis,%. Found: C 52.6, H 5.5, N 14.6. C AHzfcNfcO HClH O. Calculated: C 52.5, H 5.3, N 15.3. Liquid chromatography under high IMM pressure indicates that the product is a mixture of 6- and 7-isomers in a 7: 3 ratio. The closest to the proposed are compounds that correspond to the desired formula V ..

Continued table. 1 pressure, i.e. their systological blood pressure was 170 mm (blood pressure - control value) compared with 130 mm for rats with normal blood pressure. Assuming that the maximum drop in pressure is 40 mm, then the activity of the substance as an anti-pressure agent can be calculated using the following formula 40: 100% T70-130 In medical practice, there are compounds to combat elevated pressure, which are less similar. proposed compounds than the compounds noted above. This compound, known collectively as Prazosin, corresponds to the following formula

These compounds have activity as anti-povishin pressure agents, corresponding to only 33% at 5 mg / kg body weight when tested in C23 rats.

The proposed compounds are superior to those of prior art.

Table 2 shows the activity of the compounds. The rats used for the experiments had

This compound is a good means of lowering blood pressure and has a 100% activity at 5 mg / kg body weight. However, it has the disadvantage that it should be consumed 1 or 3 times a day. This disadvantage does not extend to at least one proposed compound for which X represents CH, m is 1, and each of the radicals R, R and R is a hydrogen atom. However, it should be noted that compounds for the treatment of elevated pressure are compounds that should be taken for extended periods of time. However, it is always possible that different patients have different reactions to long-term medication, and it is particularly important that such effects become apparent only after a long period of time using the drug. Thus, in dealing with an overpressure, it is desirable to have a significant amount of drugs for treating patients in case a negative reaction is observed to the compound that initially seemed well-chosen for the given case. From the above data it is clear that all the compounds included in the subject matter of the present invention are very effective means for dealing with pressure that is superior to the compounds of the current state of the art. Test method. The compounds were administered orally in an amount of 5.0 mg / kg body weight in groups of 6 rats with elevated pressure. The recording of the systological pressure and the rate of contractions of the heart was carried out by means of an inflated cuff, which is put on the tail and a multi-diagonal transducer connected to the oscilloscope. The rats are placed in a crate with an artificial climate, the temperature in which is maintained at 33 ° C, for 20-30 minutes before measuring blood pressure, in order to allow accurate measurement of the pulse in the tail artery. Blood pressure and the rate of contractions of the heart are measured prior to dosing and then 1, 2, 4, and 6 hours after the oral administration of the test compound. The control value of the systological pressure for all used animals exceeds 160 mm Hg. Art. 109 13, 1098521

Continued table. 2

14

Continued table. 2

67

116

58

ns OY

72

0

Claims (1)

The method of obtaining quinazoline derivatives of General formula where t is 1 or 2, .K ¹ - hydrogen or methyl, X - -CH ₂ -, - (CH ₂ ) _g - or-CH (CH ₃ ) -, КЛи К ³ - each independently of each other from a friend a hydrogen atom, an alkyl group containing 1-4 * carbon atom, alkoxy group containing 1-4 carbon atoms, alkanoyl group containing 2-4 carbon atoms, halogen, or their salts, characterized in that the quinazoline formula where (Feast ¹ have the indicated meanings, are reacted with a compound of the formula where Y is chlorine or the group 's? o-CH ₂ X, K ² and K ³ have the indicated meanings, followed by isolation of the target product in free form or in the form of a salt. 5 and 1098521 1 1098521