JPS6140229B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel quinazoline derivative having the following properties, a pharmacologically acceptable acid addition salt thereof, and a method for producing the same. In the above formula, R represents an alkyl group or a phenyl group with or without a halogen atom as a substituent. In the preferred compound represented by the general formula (), R is a linear or branched alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl, or a straight chain alkyl group as a substituent. -O-CH ₂ R
Examples of the group include compounds occupying any of the 2, 3 and 4 positions on the benzene ring. Further, specific examples of preferred compound names represented by the general formula () include: (1) 4-amino-2-[4-2-benzyloxybenzoyl)-1-piperazinyl]-6,7-
Dimethoxyquinazoline and its hydrochloride (2) 4-amino-2-[4-(3-benzyloxybenzoyl)-1-piperazinyl]-6,7
-Dimethoxyquinazoline and its hydrochloride (3) 4-amino-2-[4-(4-benzyloxybenzoyl)-1-piperazinyl]-6,7
-Dimethoxyquinazoline and its hydrochloride (4) 4-Amino-2-[4-[4-(4-methylbenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline and its hydrochloride (5) 4-Amino-2-[4-[4-(4-fluorobenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline and hydrochloride (6) 4-amino-2-[4-[4] -(4-chlorobenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline and its hydrochloride (7) 4-amino-2-[4-[4-(2,4-dichlorobenzyloxy)] Benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline and its hydrochloride (8) 4-amino-2-[4-[4-(4-bromobenzyloxy)benzoyl]-1-piperazinyl]-6, Examples include 7-dimethoxyquinazoline and its hydrochloride. As a quinazoline antihypertensive agent, a drug of the following formula [A], commonly referred to as prazosin, described in US Pat. No. 3,511,836 is known. The present inventors conducted intensive research in search of quinazoline derivatives with even better antihypertensive effects, and as a result, a new compound represented by the above general formula () showed a rapid hypotensive effect similar to that seen in prazosin. First, they discovered that it is useful as an antihypertensive agent that has a slow antihypertensive effect and a sustained action, and completed the present invention. The quinazoline derivative () of the present invention can be produced by the following synthetic route. In the formula, X represents a halogen atom, and R has the same meaning 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 methanol, ethanol, and propanol. Alcohols; ethyl acetate; fatty acid dimethylamides such as dimethylformamide and dimethylacetamide, or dimethyl sulfoxide are suitable. 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, as the starting material, the compound having the general formula () is used in an amount equivalent to or more, preferably 1 to 2 moles, per mole of the compound having the general formula (). Furthermore, by adding an organic base such as triethylamine, 1,8-diazabicyclo[5.4.0]undecene-7, or an inorganic base such as alkali bicarbonate or alkali carbonate as a deoxidizing agent, the reaction can proceed smoothly. . Route (b) is 4-amino-6,7-dimethoxy-2
-(1-piperazinyl)quinazoline () is reacted with a benzoic acid derivative or its reactive derivative (). Reactive derivatives of benzoic acid derivatives include acid halides, acid anhydrides, and mixed acid anhydrides with carbonic acid monoalkyl esters, which are usually used in the 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. Alternatively, dimethyl sulfoxide and the like are preferred. Reaction temperature is -10°~150°C
The temperature is preferably -10° to 50°C, and the reaction time varies depending on the reaction temperature, but is 30 minutes to 24 hours. Further, as the starting material, the compound having the general formula () or a reactive derivative thereof is used in an equivalent mole or more, preferably 1 to 2 moles, relative to the compound having the general formula (). Additionally, triethylamine is used as a deoxidizing agent.
1,8-diazabicyclo[5.4.0]undecene-
The reaction can proceed smoothly by adding an organic base such as No. 7 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 () is collected by collecting crystals precipitated from the reaction mixture in accordance with 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. 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. 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, in the case of oral administration, it is 0.1 to 200 mg, preferably 1 to 100 mg, per day for adults. 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 and reference examples of the compounds of the present invention will be specifically explained, but these examples are not intended to limit the present invention. Example 1 4-amino-2-[4-(2-benzyloxybenzoyl)-1-piperazinyl]-6,7-
Dimethoxyquinazoline hydrochloride 0.848 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1.05 g of 1-(2-benzyloxybenzoyl)piperazine were added to 15 ml of isoamyl alcohol, and the mixture was heated under reflux for 2 hours. After cooling, the precipitated crystals were collected and recrystallized from methanol to obtain 1.09 g of colorless powdery crystals. Melting point 215-216℃ (decomposition)

[Table] Example 2 4-amino-2-[4-(3-benzyloxybenzoyl)-1-piperazinyl]-6,7-
Dimethoxyquinazoline hydrochloride 3.48 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 3.93 g of 1-(3-benzyloxybenzoyl)piperazine were added to 70 ml of isoamyl alcohol, and the mixture was heated under reflux for 4 hours. After cooling, the precipitated crystals were collected and recrystallized from ethanol to obtain 6.59 g of pale yellow columnar crystals. Melting point 180-182℃ (decomposed) Elemental analysis value (%) C ₂₈ H ₂₉ N ₅ O ₄・HCl・H ₂ O Calculated value: C, 60.69; H, 5.83; N, 12.63;
Cl, 6.40 Actual value: C, 60.87; H, 5.63; N, 12.62;
Cl, 6.24 Example 3 4-amino-2-[4-(4-benzyloxybenzoyl)-1-piperazinyl]-6,7-
Dimethoxyquinazoline/hydrochloride route (a) Add 0.77 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1.04 g of 1-(4-benzyloxybenzoyl)piperazine to 15 ml of isoamyl alcohol and mix for 2 hours and 30 minutes. The mixture was heated to reflux. After cooling, the precipitated crystals were collected and recrystallized from methanol to obtain 1.63 g of pale yellow powdery crystals. Melting point 251-253℃ (decomposition)

[Table] Route (b) 4-amino-2-(1-piperazinyl)-6,
Add 1.16 g of 7-dimethoxyquinazoline and 1.16 g of triethylamine to 20 ml of tetrahydrofuran,
After stirring for 30 minutes, 1.0 g of 4-benzyloxybenzoyl chloride was added, and the mixture was stirred at room temperature for 15 hours. Collect the precipitated crystals, wash with water, dissolve in methanol, and dilute to 10%.
Hydrogen chloride-methanol was added to obtain 1.9 g of the hydrochloride of the target compound. Example 4 4-amino-2-[4-[4-(4-chlorobenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride 4-amino-2-chloro-6,7 0.75 g of -dimethoxyquinazoline and 1.14 g of 1-[4-(4-chlorobenzyloxy)benzoyl]piperazine were added to 20 ml of isoamyl alcohol, and the mixture was heated under reflux for 2 hours. After cooling, the precipitated crystals were collected and recrystallized from methanol to obtain 1.35 g of pale yellow needle crystals.
Melting point 269-270℃ (decomposition)

[Table] Example 5 4-amino-2-[4-[4-(4-methylbenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride 4-amino-2-chloro- 0.56 g of 6,7-dimethoxyquinazoline and 0.80 g of 1-[4-(4-methylbenzyloxy)benzoyl]piperazine were added to 15 ml of isoamyl alcohol, and the mixture was heated under reflux for 4 hours. After cooling, the precipitated crystals were collected and recrystallized from ethanol to obtain 0.26 g of pale yellow powdery crystals.
Melting point 235-237℃ (decomposition)

[Table] Example 6 4-Amino-2-[4-[4-(2,4-dichlorobenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline.
Hydrochloride 1.0 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1-[4-(2,4-dichlorobenzyloxy)benzoyl]-1-piperazine
Add 1.68g to 27ml of isoamyl alcohol,
The mixture was heated to reflux for an hour. After cooling, the precipitated crystals were collected and recrystallized from 50% water-ethanol to obtain 2.32 g of pale yellow powdery crystals.

[Table] Example 7 4-Amino-2-[4-[4-(4-fluorobenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride route (a) 4-amino- 1.2 g of 2-chloro-6,7-dimethoxyquinazoline and 1-[4-4-fluoro-benzyloxy)benzoyl]piperazine (melting point 102
~103°C) was added to 25 ml of isoamyl alcohol and heated under reflux for 4 hours. Take the precipitated crystals and 10
% NaOH was added and extracted with chloroform, and the concentrated residue was subjected to silica gel chromatography, eluted with chloroform, and a 10% hydrogen chloride-ethanol solution was added. The precipitated crystals were collected to obtain 1.27 g of colorless powdery crystals. Melting point 276-277℃ (decomposition) Elemental analysis value (%) C ₂₈ H ₂₈ N ₅ O ₄ F. As HCl Calculated value: C, 60.70;; H, 5.28; N, 12.64;
Cl, 6.40; F, 3.43 Actual value: C, 60.45; H, 5.24; N, 12.59;
Cl, 6.60; F, 3.18 Route (b) 4-amino-2-(1-piperazinyl)-6,
Dissolve 1.45 g of 7-dimethoxyquinazoline and 1.3 g of triethylamine in 10 ml of dimethylformamide,
While cooling, a solution of 1.32 g of 4-(4-fluorobenzyloxy)benzoyl chloride in 3 ml of dimethylformamide was added. After stirring for 15 hours, methanol was added to collect the precipitated crystals. It was dissolved in a chloroform solution, subjected to silica gel chromatography, and treated in the same manner as in (a) above to obtain 2.6 g of the hydrochloride of the target compound. Example 8 4-amino-2-[4-[4-(4-bromobenzyloxy)benzoyl]-1-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride 4-amino-2-chloro-6,7 -Dimethoxyquinazoline 0.35g and 1-[4-(4-bromobenzyloxy)-benzoyl]piperazine (melting point 91
~92°C) was added to 10 ml of isoamyl alcohol and heated under reflux for 4 hours. Remove precipitated crystals and 50%
Recrystallization from ethanol gave 0.55 g of colorless powdery crystals. Melting point 262-263℃ (decomposition) Elemental analysis value (%) C ₂₈ H ₂₈ N ₅ O ₄ Br.HCl.1/2H ₂ O
Calculated value: C, 53.90; H, 4.85; N, 11.22;
Cl, 5.68; Br, 12.81 Actual value: C, 53.80; H4.91; N, 11.16; Cl,
5.43; Br, 12.24 Reference Example 1--Production of (4-benzyloxybenzoyl)piperazine 0.35 g of piperazine was added to 6 ml of acetic acid at 65°C and 4-
After adding a solution of 1.0 g of benzyloxybenzoyl chloride in 7 ml of chloroform, the mixture was stirred at 65°C for 4 hours. The precipitated crystals were filtered and washed with chloroform to obtain 0.7 g of colorless powder. It was dissolved in a 10N aqueous sodium hydroxide solution and extracted with chloroform. After dehydration and distillation of the solvent, ether was added and the precipitated crystals were filtered and washed to obtain 0.45 g of colorless powder. Recrystallization from isopropyl ether gave the target compound as colorless needles. Substituted benzoylpiperazine was obtained by reacting in the same manner as in Reference Example.

[Table] 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 , and the other end of the cannula was guided outside the body and fixed to the neck. . 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. The blood pressure measuring device uses the Laffan et al. method [Laffan PJ,
Peterson A., Hitch SWand Jeunelot C.,
Cardiovascular Res., vol. 6 , pp. 319-324 (1972
An improved version of 2003 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 phenyl group with or without an alkyl group or a halogen atom as a substituent.) A quinazoline derivative and a pharmaceutically acceptable acid addition salt 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 an alkyl group or a phenyl group having or not having a halogen atom as a substituent.) A general formula characterized by condensation with a cyclic diamine represented by the following by a dehydrohalogenation reaction. (In the formula, R has the same meaning as described above.)
A method for producing a quinazoline derivative and an acid addition salt thereof. 3 formulas The compound represented by the general formula (In the formula, R represents an alkyl group or a phenyl group with or without a halogen atom as a substituent.) General formula characterized by condensation with benzoic acid or a reactive derivative thereof represented by (In the formula, R has the same meaning as described above.)
A method for producing a quinazoline derivative and an acid addition salt thereof.