JPS6332787B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel aminoquinazoline derivative having a carbon atom (derivatives having an inactive carbon atom include optically active derivatives), a pharmacologically acceptable acid addition salt thereof, and a method for producing the same. In the above formula, R represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a halogen atom, or an amino group with or without an alkyl group or acyl group as a substituent, A represents a lower alkylene group, and Y represents a lower alkylene group. It represents an oxygen atom, a sulfur atom or a single bond, m represents an integer of 1 to 3, and n represents an integer of 2 or 3. Preferred compounds represented by the above general formula () include R being a hydrogen atom, methyl, ethyl, propyl,
A linear or branched alkyl group having 1 to 3 carbon atoms such as isopropyl, a hydroxyl group,
A linear or branched alkoxy group having 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy, and isopropoxy, a halogen atom such as fluorine, chlorine, and bromine, or methyl or ethyl as a substituent. , propyl, and isopropyl, or have a straight or branched alkyl group having 1 to 3 carbon atoms, such as formyl, acetyl, and propionyl. A is methylene, ethylene, trimethylene, tetramethylene, ethylidene, propylidene, butylidene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1,2-diethylethylene, 1-n-propylethylene, 2-n-propylethylene, 1-methyl-2-ethylethylene, 1-methyltrimethylene, 1-ethyltrimethylene, 1-methyltetramethylene, 1- It represents a linear or branched alkylene group having 1 to 6 carbon atoms such as ethyltetramethylene, Y represents an oxygen atom, a sulfur atom, or a single bond, and m represents an integer of 1 to 3. , n is 2 or 3
Compounds that exhibit an integer of . Incidentally, in the compound having the above general formula (), there may be optical isomers based on non-satile carbon atoms, and all of these isomers are expressed by a single formula, but this does not mean that the present invention The scope of the description is not limited. As a quinazoline antihypertensive agent, a drug called prazosin (generic name) described in US Pat. No. 3,511,836 is known. As a result of intensive research in search of a quinazoline derivative with even better antihypertensive effects, the present inventor found that
The present invention was completed based on the discovery that the novel aminoquinazoline derivative represented by the above general formula () is useful as a medicine having antihypertensive effects. The aminoquinazoline derivative of the present invention can be produced by the following synthetic route. In the formula, X represents a halogen atom, R, A, Y,
m and n have the same meanings as described above. 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 general 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 dimethylformamides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide; and the like are preferred. The reaction is carried out at 40-200℃, preferably 60-150℃,
The reaction time varies depending on the reaction temperature, but ranges from 1 to 24
It's time. The compound having the general formula () is used in an amount equal to or more than the equivalent mole, preferably 1 to 2 moles, 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-5 or an inorganic base such as alkali bicarbonate or alkali carbonate as a deoxidizing agent. Can be done. Route (b) is 4-amino-6,7-dimethoxy-2
-(1-piperazinyl)quinazoline or 4-
Amino-2-(1-homopiperazinyl)-6,7-
This is a production method in which dimethoxyquinazoline () is reacted with a carboxylic acid or its reactive derivative ().
Examples of reactive derivatives of carboxylic acids include acid halides, acid anhydrides, and mixed acid anhydrides with carbonic acid monoalkyl esters, which are usually used for acylation of amines. In carrying out this reaction, the reaction is achieved by bringing the compound having the general formula () into contact with the compound having the general formula () or a reactive derivative thereof. The solvent used is not particularly limited as long as it does not participate in this reaction, such as benzene,
Aromatic hydrocarbons such as toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; 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 is carried out at -10° to 150°C, preferably -10° to 50°C, and the reaction time varies depending on the reaction temperature, but is 30 minutes to 24 hours. General formula ()
The compound having the formula (2) or its reactive derivative is used in an amount equivalent to or more, preferably 1 to 2 moles, relative to the compound having the general formula (). Furthermore, triethylamine, 1,8-diazabicyclo[5,
The reaction can proceed smoothly by adding an organic base such as 4,0]undecene-5 or an inorganic base such as alkali bicarbonate or alkali carbonate. After completing the reaction according to route (a) or route (b), the target compound can be recovered by crystallizing the reaction mixture in a conventional manner. 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 by conventional methods, such as recrystallization, if necessary. The quinazoline derivatives having the general formula () synthesized by the above manufacturing method can be obtained as a free base or a pharmaceutically acceptable salt depending on the manufacturing method. The conversion to can be done in the usual way. 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 organic acids such as citric acid, malic acid, lactic acid, ascorbic acid, fumaric acid, maleic acid, and the like. 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 this compound varies depending on the type of hypertension and the severity of symptoms, but generally speaking, oral administration is 0.01 to 200 mg per day, preferably 0.1 to 50 mg per day.
mg. For parenteral administration, 1/3 of the oral dose
It is 1/10 to 1/10. 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-
(2-Phenoxypropionyl)-1-piperazinyl]quinazoline, hydrochloride, hemihydrate 4-amino-2-(1-piperazinyl)-6,7
- Add 1.16 g of dimethoxyquinazoline and 1.5 g of triethylamine to 23 ml of tetrahydrofuran, then 0.72 g of 2-phenoxypropionyl chloride.
was added and stirred at room temperature for 15 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel chromatography and eluted with chloroform to obtain 1.48 g of a yellow oil. This product was dissolved in ethanol, and a 10% hydrogen chloride-ethanol solution was added. The precipitated crystals were taken and dried to give pale yellow powder crystals of 0.88 g.
I got g. Melting point 211-213℃ (decomposed) Elemental analysis value (%) C ₂₃ H ₂₇ N ₅ O ₄・HCl・1/2H ₂ O Calculated value; C, 57.20; H, 6.05; N, 14.50; Cl, 7.34 Actual measurement Value; C, 57.44; H, 6.01; N, 14.66; Cl, 7.40 Example 2 4-Amino-6,7-dimethoxy-2-[4-
(3-Phenoxypropionyl)-1-piperazine] quinazoline, hydrochloride, hemihydrate 4-amino-2-chloro-6,7-dimethoxyquinazoline 4.55g and 1-(3-phenoxypropionyl)piperazine 4.50g was added to 80 ml of isoamyl alcohol, and the mixture was heated under reflux for 4 hours. After the reaction was completed, the hot filtrate was cooled. The precipitated crystals were collected and recrystallized from ethanol to obtain 4.02 g of yellow powdery crystals. Melting point 189-191°C (decomposition). Elemental analysis value (%) As C ₂₃ H ₂₇ N ₅ O ₄・HCl・1/2H ₂ O Calculated value: C, 57.20; H, 6.05; N, 14.50; Cl, 7.34 Actual value: C, 57.42; H, 6.41; N, 14.58; Cl, 6.95 Example 3 4-Amino-6,7-dimethoxy-2-[4-
(Phenoxyacetyl)-1-piperazinyl]quinazoline, hydrochloride, hydrate 4-amino-2-(1-piperazinyl)-6,7
- Add 1.16 g of dimethoxyquinazoline and 1.5 g of triethylamine to 20 ml of tetrahydrofuran, then add 0.7 g of phenoxyacetyl chloride,
Stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water. The solvent was distilled off from the extract under reduced pressure, the residue was dissolved in ethanol, and a 10% hydrogen chloride-ethanol solution was added. The precipitated crystals were collected and dried to obtain 1.04 g of pale yellow powdery crystals. Melting point 238-240℃ (decomposition). Elemental analysis value (%) as C ₂₂ H ₂₅ N ₅ O ₄・HCl・H ₂ O Calculated value: C, 55.29; H, 5.91; N, 14.65; Cl, 7.42 Actual value: C, 55.64; H, 5.94; N, 14.69; Cl, 7.50 Example 4 4-amino-6,7-dimethoxy-2-[4-
(phenylacetyl)-1-piperazinyl]-quinazoline hydrochloride hydrate 4-amino-2-(1-piperazinyl)-6,7
-1.16 g of dimethoxyquinazoline and 1.5 g of triethylamine were added to 20 ml of tetrahydrofuran, then 0.58 g of phenylacetyl chloride was added and stirred at room temperature for 15 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel chromatography and eluted with 4% ethanol-chloroform to obtain 0.5 g of an oil.
This product was dissolved in ethanol, and a 10% hydrogen chloride-ethanol solution was added. The precipitated crystals were collected and dried to obtain 0.30 g of colorless powdery crystals. Melting point 173-175℃ Elemental analysis value (%) C ₂₂ H ₂₅ N ₅ O ₃ · HCl · H ₂ O Calculated value: C, 57.20; H, 6.11; N, 15.16; Cl, 7.67 Actual value: C, 57.25 ;H, 6.43;N, 15.18;Cl, 7.51 Example 5 4-Amino-6,7-dimethoxy-2-[4-
(3-phenylpropionyl)-1-piperazinyl]-quinazoline hydrochloride hydrate 4-amino-2-(1-piperazinyl)-6,7
- Add 1.16 g of dimethoxyquinazoline and 1.5 g of triethylamine to 25 ml of tetrahydrofuran, then add 0.6 g of 3-phenylpropionyl chloride.
was added and stirred at room temperature for 12 hours. The reaction mixture was concentrated, the residue was extracted with chloroform, and the extract was washed with water. Evaporate the solvent and dissolve the residue in ethanol.
A 10% hydrogen chloride-ethanol solution was added. The precipitated crystals were collected to obtain 0.75 g of colorless powdery crystals. Melting point 212~
215℃ (decomposition) Elemental analysis value (%) C ₂₃ H ₂₇ N ₅ O ₃・HCl・H ₂ O Calculated value: C, 58.04; H, 6.35; N, 14.71; Cl, 7.45 Actual value: C, 57.60 ; H, 6.31; N, 14.69; Cl, 7.41 Example 6 4-Amino-6,7-dimethoxy-2-(4-
Phenylthioacetyl-1-piperazinyl)quinazoline hydrochloride 1.20 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1-(phenylthioacetyl)
1.30 g of piperazine and 25 ml of isoamyl alcohol
and heated under reflux for 4 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from ethanol to give colorless needle-shaped crystals.
1.04g was obtained. Melting point 254-255℃ (decomposition) Elemental analysis value (%) C ₂₂ H ₂₅ N ₅ O ₃ As S・HCl Calculated value: C, 55.51; H, 5.51; N, 14.71; Cl, 7.45; S, 6.74 Actual value : C, 55.43; H, 5.50; N, 14.58; Cl7.28; S, 6.84 Antihypertensive effect test The antihypertensive effect was tested by orally administering the sample to spontaneously hypertensive rats (SHR). 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 the blood pressure and heart rate were measured by the direct method in an unanesthetized and unrestrained state. Blood pressure measuring device is Laffan et al. method [Laffan PJ
Peterson A., Hitch SWand Jeunelot C.
Cardiovascular Res., vol. 6, pp. 319-324 (1972)
An improved version of 2010 was used. The specimen was suspended in 0.3% carboxymethyl cellulose 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.

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Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a halogen atom, or an amino group with or without an alkyl group or acyl group as a substituent, A represents a lower alkylene group, and Y represents a (represents an oxygen atom, a sulfur atom or a single bond, m represents an integer of 1 to 3, and n represents an integer of 2 or 3) and pharmaceutically acceptable acid addition salts thereof. 2 General formula (In the formula, X represents a halogen atom.) A 2-halogenoquinazoline derivative represented by the general formula (In the formula, R represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a halogen atom, or an amino group with or without an alkyl group or acyl group as a substituent, A represents a lower alkylene group, and Y represents a represents an oxygen atom, a sulfur atom, or a single bond, m represents an integer of 1 to 3, and n represents an integer of 2 or 3. General formula for (In the formula, R, A, Y, m and n have the same meanings as described above.) A method for producing an aminoquinazoline derivative and an acid addition salt thereof. 3 General formula (In the formula, n represents an integer of 2 or 3.) A quinazoline derivative represented by the general formula (In the formula, R represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a halogen atom, or an amino group with or without an alkyl group or acyl group as a substituent, A represents a lower alkylene group, and Y represents a (representing an oxygen atom, a sulfur atom, or a single bond, m is an integer of 1 to 3), or a reactive derivative thereof. (In the formula, R, A, Y, m and n have the same meanings as described above.) A method for producing an aminoquinazoline derivative and an acid addition salt thereof.