JPH07138238A - New quinazoline derivative and anti-tumor agent containing the derivative as active component - Google Patents

Abstract

PURPOSE:To provide a new quinazoline derivative or its pharmacologically permissible acid addition salt useful as a new anti-tumor agent having an action mechanism different from that of an agent to directly attack the cancer cells. CONSTITUTION:A quinazoline derivative expressed by formula I (R<1> is H, a halogen, methyl or methoxy; R<2> is H or F; R<3> is a 1-2C alkyl; R<4> is H, 2- hydroxyethyl or a 2-haloethyl; R<1> is H when R<2> is F) or its pharmacologically permissible acid addition salt, e.g. 2-[4-(2-hydroxyethyl) piperazin-1-yl]-4- methoxyquinazoline and 2-(1-piperazinyl)-4-methoxyquinazoline. A compound of formula I wherein R<4> is H or 2-hydroxyethyl can be produced by reacting a quinazoline derivative of formula II with a piperazine derivative of formula III (R<4>' is H or 2-hydroxyethyl) and as necessary converting to a pharmacologically permissible acid addition salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel quinazoline derivative and an antitumor agent containing the same as an active ingredient. More specifically, the following formula (I)

[0002]

[Chemical 3] (In the formula, R ¹ represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, R ² represents a hydrogen atom or a fluorine atom, R ³ represents an alkyl group having 1 to 2 carbon atoms, and R ⁴ represents Represents a hydrogen atom, a 2-hydroxyethyl group or a 2-haloethyl group, provided that when R ² is a fluorine atom, R ¹ represents a hydrogen atom) or a pharmaceutically acceptable acid thereof. The present invention relates to an addition salt and an antitumor agent containing it as an active ingredient.

[0003]

2. Description of the Related Art Research and development of antitumor agents have mainly been conducted on the search for agents that directly attack cancer cells. However, the type of anti-tumor agent developed by this damages not only cancer cells but also proliferation of normal cells, and thus has a drawback that serious side effects such as myelotoxicity are likely to occur. ing.

Japanese Patent Laid-Open No. 1-242472 discloses 2- (4
-Allylpiperazin-1-yl) -4-pentyloxyquinazoline or a pharmaceutically acceptable acid addition salt thereof,
The production method thereof and their use as an agent for improving brain dysfunction in senile dementia are disclosed. In addition, the present inventors, as described later, said 2- (4-allylpiperazine-
It was found that 1-yl) -4-pentyloxyquinazoline monofumarate (No.5666) is effective for solid tumors [Chemotherapy, page 447, Medical Research (199).
3)].

[0005]

DISCLOSURE OF THE INVENTION The present inventors have created a novel compound that exhibits an antitumor effect based on a mechanism of action different from the conventional type that directly attacks cancer cells, and use the compound as an active ingredient. Various studies were conducted for the purpose of developing antitumor agents.

[0006]

Means for Solving the Problems The present inventors have focused on the fact that it is essential for blood to flow into a tumor tissue in order to grow a solid tumor, and to suppress the inflow of blood. Based on this, various studies were conducted to find compounds that express antitumor activity.

[0007] In searching for such compounds, the present inventors focused on the fact that the dye (Evans blue) injected from the tail vein of tumor-bearing animals migrates into the tumor tissue by riding on the bloodstream. Compounds that inhibit the inflow of blood into the
It was also thought that the uptake of the dye into the tumor tissue was also suppressed.

[0008] Therefore, the inhibitory effect of the pigment on mouse solid tumor (colon 26) was examined as an index, and it was found that No. 5666 had such an effect and was effective for solid tumors.

However, No. 5666 had a hemolytic action, and as a result of further studies to find a new compound having a dye uptake inhibitory action without having a hemolytic action,
The present invention has been completed by confirming that the quinazoline derivative (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof satisfies such requirements and exhibits antitumor activity.

The present invention will be described in detail below.

Among the substituents in the quinazoline derivative (I) of the present invention, the halogen atom represents a chlorine atom, a fluorine atom and the like, and the 2-haloethyl group represents a 2-chloroethyl group, a 2-fluoroethyl group and the like. Further, as the pharmaceutically acceptable acid addition salts of the quinazoline derivative (I) of the present invention, hydrochlorides, inorganic acid salts such as sulfates and maleate salts, fumarate salts, succinate salts, tartrate salts, Organic acid salts such as acetates can be mentioned.

The quinazoline derivative (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof is prepared by the following method A or B.
It can be produced by any of the methods.

That is, among the quinazoline derivative (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof, the above formula
In (I), the compound in which R ⁴ is a hydrogen atom or a 2-hydroxyethyl group [hereinafter referred to as quinazoline derivative (Ia)] can be produced by the following Method A. [Method A] Method A is represented by the following formula (II)

[0014]

[Chemical 4] (In the formula, R ¹ , R ² and R ³ are the same as above. However, when R ² is a fluorine atom, R ¹ represents a hydrogen atom.) And a quinazoline derivative represented by the following formula (III)

[0015]

[Chemical 5] (In the formula, R ^{4 ′} represents a hydrogen atom or a 2-hydroxyethyl group.), And is reacted with a piperazine derivative,
Then, if necessary, it is carried out by a conventional method by introducing a pharmaceutically acceptable acid addition salt.

That is, the compound (II) and 2 to 10 equivalents of the piperazine derivative (III) with respect to the compound (II), preferably 1 to 5 equivalents of a tertiary amine such as triethylamine with respect to the compound (II). In the presence of amine, in an inert organic solvent such as toluene, dioxane, tetrahydrofuran, dichloroethane,
The quinazoline derivative (Ia) of the present invention can be obtained by reacting from room temperature to the boiling point of the solvent for 30 minutes to 50 hours, and the obtained quinazoline derivative (Ia) can be further used, if necessary, by a conventional method. It can lead to a physically acceptable acid addition salt.

The quinazoline derivative (II) used in the above-mentioned Method A can be produced according to a known method as shown in the reference example below, and is represented by the following formula (IV):

[0018]

[Chemical 6] (In the formula, R ¹ and R ² are the same as the above, provided that when R ² is a fluorine atom, R ¹ represents a hydrogen atom.), Methanol or ethanol, and sodium hydride It can be obtained by reacting in an inert solvent such as dioxane under ice cooling to room temperature for 1 to 5 hours.

Of the quinazoline derivative (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof, the above formula
In (I), the compound in which R ⁴ is a 2-haloethyl group [hereinafter referred to as quinazoline derivative (Ib)] can be produced by the following Method B. [Method B] Method B is represented by the following formula (Ia-1)

[0020]

[Chemical 7] (In the formula, R ¹ , R ² and R ³ are the same as the above, provided that when R ² is a fluorine atom, R ¹ represents a hydrogen atom.) And 1-bromo-2. -Reaction with haloethane, and then, if necessary, conversion to a pharmaceutically acceptable acid addition salt by a conventional method.

That is, the compound (Ia-1) and 2-3 equivalents of 1-bromo-2-haloethane to the compound (Ia-1)
Reaction in the presence of 1 to 5 equivalents of a tertiary amine such as triethylamine in (Ia-1) in an inert organic solvent such as toluene, dioxane, tetrahydrofuran or dichloroethane at room temperature to the boiling point of the solvent for 1 to 50 hours The quinazoline derivative (Ib) of the present invention can be obtained by the above, and the obtained quinazoline derivative (Ib) can be further converted into a pharmacologically acceptable acid addition salt by a conventional method, if necessary. it can.

Then, when the compound of the present invention is used as an antitumor agent, the compound of the present invention is usually formulated into a dosage form such as an injection, and administered parenterally intravenously, subcutaneously, intramuscularly and the like.

Preparation of such a preparation such as an injection can be carried out by a conventional method, and isotonic agents such as mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose, sodium sulfite, etc. Stabilizers such as albumin and preservatives such as benzyl alcohol and methyl parahydroxybenzoate can be added to the preparation.

The dose of the compound of the present invention varies depending on the condition of the patient, age, body surface area, etc.
The compound (I) of the present invention has an amount of 1 to 1000 mg / m ² (body surface area), which is parenterally administered once or in 2 to 3 divided doses.

When the compound of the present invention is used in combination with another antitumor agent, an excellent antitumor effect can be obtained by administering the compound of the present invention after administration of the other antitumor agent.

[0026]

As shown below, the compound of the present invention suppresses the inflow of blood into the tumor tissue, which is essential for the growth of solid tumors (see Test Example 1), and is considered to be based on this action. The resulting antitumor effect [proliferative inhibitory effect of the compound of the present invention alone and the combined administration with doxorubicin hydrochloride on the solid tumor of colon 26, which is an experimental tumor of mouse] was shown (see Test Example 2). Further, the compound of the present invention did not show hemolytic action (see Test Example 3).

Therefore, the antitumor agent containing the compound of the present invention as an active ingredient is useful as a novel antitumor agent based on a mechanism of action different from the conventional type of directly attacking cancer cells.

Test Example 1 Suppression of dye uptake into solid tumors (suppression of blood influx into tumor tissue): a) Test material Test animal: BALB / c male mouse (21-27 g in weight, 1 group 6) Tumor : Colon 26 solid tumor Test compound: (1) 2- (1-piperazinyl) -4-methoxyquinazoline 1-fumarate (Compound of Example 2) (2) 4-methoxy-8-methyl-2- (1) -Piperazinyl) quinazoline diacetate (Compound of Example 5) (3) 4,8-dimethoxy-2- (1-piperazinyl) quinazoline diacetate (Compound of Example 7) (4) 5-Fluoro- 4-Methoxy-2- (1-piperazinyl) quinazoline monoacetate (Compound of Example 9) (5) 6-Fluoro-4-methoxy-2- (1-piperazinyl) quinazoline monoacetate (Example 11) Compound of (6) 8-chloro-4-methoxy-2 (1-Piperazinyl) quinazoline monoacetate (Compound of Example 13) (7) 4-Ethoxy-2- (1-piperazinyl) quinazoline monoacetate (Compound of Example 14) (8) 4-Ethoxy- 5-Fluoro-2- (1-piperazinyl) quinazoline monoacetate (Compound of Example 15) (9) 2- [4- (2-hydroxyethyl) piperazine-
1-yl] -4-methoxyquinazoline ・ 1 fumarate (Compound of Example 17) (10) 5-Fluoro-2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline * 1 fumarate (compound of Example 18) (11) 2- [4- (2-chloroethyl) piperazine-1
-Yl] -4-methoxyquinazoline monosulfate (compound of Example 20) (12) 2- [4- (2-fluoroethyl) piperazine-
1-yl] -4-methoxyquinazoline monofumarate (Compound of Example 22) (13) 5-Fluoro-2- [4- (2-chloroethyl)
Piperazin-1-yl] -4-methoxyquinazoline.1
Sulfate (Compound of Example 24) (14) 2- (4-allylpiperazin-1-yl) -4-
Pentyloxyquinazoline monofumarate (No.5666)

B) Test Method Colon 26 solid tumor was cut into pieces of about 1 mm square with a scalpel. This small piece was treated with a 0.25% collagenase solution at 37 ° C for 1 hour to remove Co
A cell suspension of lon 26 solid tumor was prepared. The suspension is
The concentration was adjusted to 3 × 10 ⁶ cells / ml, and 100 μl of the BALB / c male mouse was subcutaneously transplanted into the right dorsal region. The major axis of the tumor was measured 10 days after the transplantation, and when the major axis of the tumor reached about 10 mm, the mice were divided into groups, and the drug administration group was the compound of the present invention dissolved in physiological saline or No. 5666 10 mg / kg was administered intravenously. In addition, only physiological saline was intravenously administered to the control group.

1 hour after administration, 3% Evans blue physiological saline was intravenously administered through the tail vein of the mouse at a rate of 0.1 ml per 10 g of mouse body weight, and 5 minutes later, the mouse was sacrificed by cervical dislocation.

The tumor was excised and the tumor weight was weighed. A 0.5% aqueous sodium sulfate solution was added at a ratio of 1.5 ml to a tumor weight of 1 g, and the mixture was homogenized. Then, acetone was added at a ratio of 3.5 ml to 1 g of tumor weight, and the mixture was left at room temperature overnight, and
Evans blue was extracted by centrifugation at 00 rpm for 10 minutes. The absorbance of the obtained supernatant at 630 nm was measured, and the inhibition rate of dye uptake into the solid tumor by the test compound was calculated by the following formula.

[0032]

[Equation 1] Dye uptake inhibition rate (%) = [1- (average value of absorbance of drug administration group / average value of absorbance of control group)] × 10
0 c) Test results The results are shown in Table 1.

[0033]

[Table 1]

Test Example 2 Antitumor effect of the compound of the present invention alone and the combined use of the compound of the present invention and doxorubicin hydrochloride on Colon 26 solid tumors: a) Test materials Test animals: BALB / c male mice (6 weeks old, 1 group 6) Tumor: Colon 26 solid tumor Test compound: (1) 2- (1-piperazinyl) -4-methoxyquinazoline monofumarate (compound of Example 2) (2) 2- [4- (2-hydroxy) Ethyl) piperazine
1-yl] -4-methoxyquinazoline monofumarate (Compound of Example 17)

B) Test Method A colon 26 solid tumor cell suspension prepared by the same method as in Test Example 1 was subcutaneously injected into the right dorsal region of BALB / c male mice in an amount of 100 μl.
Transplanted. The major axis of the tumor was measured from the 7th day after the transplantation, and when the major axis of the tumor reached about 4 to 8 mm, the mice were divided into groups, and the group to which the compound of the present invention was administered was dissolved in physiological saline from the next day. 20 mg / kg of the compound of the present invention was intravenously administered once a day for 10 consecutive days. Doxorubicin hydrochloride alone was administered intravenously 7 mg / kg of doxorubicin hydrochloride dissolved in physiological saline, and 24 hours after that, physiological saline was administered 10 times a day.
It was administered intravenously for consecutive days. To the combination group, doxorubicin hydrochloride 7 mg / kg was intravenously administered, and 24 hours after that, 20 mg / kg of the compound of the present invention dissolved in physiological saline was intravenously administered once a day for 10 consecutive days. In the control group, physiological saline was intravenously administered once a day for 11 consecutive days.

On the day after the end of administration, the tumor was excised, the tumor weight was weighed, and the tumor growth inhibitory rate by the test compound was calculated by the following formula.

[0037]

[Equation 2] Tumor growth inhibition rate (%) = [1- (average tumor weight of drug administration group / average tumor weight of control group)] × 100

C) Test results (1) The results of the antitumor effect of the compound of the present invention alone are shown in Table 2. Further, necrosis of the tumor center was observed in the group administered with the compound of the present invention.

[0039]

[Table 2] (2) The antitumor effect of the combined use of the compound of the present invention and doxorubicin hydrochloride is shown in Table 3. As shown in Table 3, in the group in which the compound of the present invention was used in combination with doxorubicin hydrochloride, the antitumor effect of doxorubicin hydrochloride was remarkably enhanced.

[0040]

[Table 3]

Test Example 3 Hemolytic action: a) Test material Test compound: Same as Test Example 1.

B) Test method About 6 ml of blood was collected from the abdominal aorta of a male Donryu rat in a test tube containing 10 mg of dipotassium ethylenediaminetetraacetate dissolved in 0.1 ml of physiological saline. Whole blood was divided into 2 ml portions, and each was centrifuged at 3000 rpm for 5 minutes, and the supernatant was removed to obtain blood cells. Phosphate buffer at pH 7.4 for blood cells
(PB) (10 ml) was added and gently mixed, followed by centrifugation at 3000 rpm for 5 minutes to remove the supernatant. After repeating this washing operation twice more, 10 ml of PB was added to obtain a blood cell preparation.

The test compound was dissolved in physiological saline or dimethylsulfoxide at a concentration of 10 mg / ml or 20 mg / ml, and finally with PB so that the concentration in 3 ml was 200 μg / ml.
Diluted to 7 ml (note that the compounds of Example 2 and Example 17 were also tested at a concentration of 400 μg / ml). However, No.5666 was dissolved in physiological saline at a concentration of 2 mg / ml, and the final concentration in 3 ml was 20 μg / ml.
diluted to ml. Next, add 0.3 ml of blood cell preparation to PB diluted solution.
And gently mixed and incubated at 37 ° C. for 60 minutes. After the incubation, the mixture was immediately centrifuged at 3000 rpm for 5 minutes, 200 μl of the supernatant was transferred to a 96-well microplate (flat bottom immunoassay plate), and the absorbance at 550 nm was measured with a microplate reader.

As a control (spontaneous hemolysis), 30 μL of physiological saline solution
A solution prepared by adding 0.3 ml of the blood cell preparation to a solution prepared by diluting 1 with PB to 2.7 ml was used. For complete hemolysis, 2.7 ml of distilled water plus 0.3 ml of the blood cell preparation was used.

The hemolysis rate by the test compound was calculated by the following formula.

[0046]

[Equation 3] Hemolysis rate (%) = [(absorbance of test compound-added group-absorbance by spontaneous hemolysis group) / (absorbance of complete hemolysis group-
Absorbance due to spontaneous hemolysis group)] × 100

C) Test results No. 5666 causes 38% hemolysis at a concentration of 20 μg / ml, whereas Example 2, Example 5, Example 7, Example 9, Example 11, Example 13 None of the compounds of Example 14, Example 15, Example 17, Example 18, Example 20, Example 22, and Example 24 exhibited hemolytic activity at a concentration of 200 μg / ml. The compounds of Example 2 and Example 17 did not show hemolytic action even at a concentration of 400 μg / ml.

Test Example 4 Acute toxicity: a) Test material Test animal: ICR male mice (weight 26-35 g, 5 animals per group) Test compound: Same as Test Example 2. b) Test method The test compound dissolved in physiological saline was intravenously administered to ICR male mice, and the LD ₅₀ value was calculated by the Weil method from the number of deaths after 1 week. c) Test results The results are shown in Table 4.

[0049]

[Table 4]

[0050]

EXAMPLES The present invention will be described in more detail below with reference to Reference Examples and Examples. Reference Example 1 2-chloro-4-methoxy-8-methylquinazoline : 2,4-dichloro-8-methylquinazoline (see Published Patent Publication No. 1-502462) 3.8 g and methanol 0.58 g in dioxane 50 ml solution,
Under water cooling, 0.71 g of 60% sodium hydride (oil) was gradually added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and then dried under reduced pressure to give 2-chloro-4-
3.7 g of methoxy-8-methylquinazoline was obtained.

NMR (CDCl ₃ , δppm): 2.67 (3H, s), 4.19 (3H,
s), 7.41 (1H, dd, J = 7.5,8Hz), 7.65 (1H, m), 7.93 (1H, m).

Reference Example 2 2-chloro-4,8-dimethoxyquinazoline : 2,4-dichloro-8
-Methoxyquinazoline (see Published Patent Publication No. 1-502462)
To a solution of 2.3 g of methanol and 0.32 g of methanol in 30 ml of dioxane, 0.4 g of 60% sodium hydride (oil) was gradually added under water cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and then dried under reduced pressure to give 2-chloro-4,8-dimethoxyquinazoline (2.2 g).

NMR (CDCl ₃ , δppm): 4.04 (3H, s), 4.21 (3H,
s), 7.20 (1H, dd, J = 1,8Hz), 7.47 (1H, dd, J = 8,8.5Hz), 7.66
(1H, dd, J = 1,8.5Hz).

Reference Example 3 2-Chloro-5-fluoro-4-methoxyquinazoline : 2,4-
Dichloro-5-fluoroquinazoline (Chem.Abs., 99 , 175790
2.0 g and 0.44 g of methanol in 10 ml of dioxane.
To the solution was gradually added 0.388 g of 60% sodium hydride (oil-based) under water cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue
It was washed with n-hexane to obtain 1.52 g of 2-chloro-5-fluoro-4-methoxyquinazoline. A product obtained by recrystallizing a part of this from isopropyl ether exhibited the following physical properties.

Mp 140-142 ° C. NMR (CDCl ₃ , δppm): 4.23 (3H, s), 7.22 (1H, ddd, J = 1,8,10.5)
. Hz), 7.67 (1H, d, J = 8.5Hz), 7.78 (1H, dt, J = 5.5,8Hz) Elemental analysis (C ₉ H ₆ ClFN ₂ O) Calculated value (%) C, 50.84; H , 2.84; N, 13.18 Analytical value (%) C, 50.70; H, 2.94; N, 13.18

[0056] Reference Example 4 2-Chloro-6-fluoro-4-methoxyquinazoline:. 2,4-dichloro-6-fluoro quinazoline (Chem.Abs, 115, 92284q
To a solution of 1.30 g of methanol and 0.192 g of methanol in 7 ml of dioxane, 0.312 g of 60% sodium hydride (oil) was gradually added under water cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform, dried over anhydrous magnesium sulfate, and then dried under reduced pressure to give 2-chloro-6-fluoro-4-methoxyquinazoline (1.19 g).

NMR (CDCl ₃ , δppm): 4.23 (3H, s), 7.60 (1H, d
t, J = 3,9Hz), 7.72 (1H, dd, J = 3,7Hz), 7.87 (1H, dd, 4.5,9H
z).

Reference Example 5 2,8-Dichloro-4- methoxyquinazoline: 2,4,8-trichloroquinazoline (see JP-A-52-10297) 2.20 g and 0.453 g of methanol in 22 ml of dioxane were cooled with water. Bottom 60
% Sodium hydride (oil-based) 0.397 g was added, and the mixture was kept at room temperature for 2 hours.
Stir for 40 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue was washed with isopropyl ether to give 2,8-dichloro-4-methoxyquinazoline 1.85.
got g.

NMR (CDCl ₃ , δppm): 4.24 (3H, s), 7.48 (1H, t,
J = 8Hz), 7.92 (1H, dd, J = 1.5,7.5Hz), 8.05 (1H, dd, J = 1.5,8H
z).

Reference Example 6 2-Chloro-4-ethoxyquinazoline : 2,4-dichloroquinazoline [See J. Am. Chem. Soc., 53 , 3867 (1931)] 3.00 g and ethanol 0.715 g in dioxane. To the above, 0.785 g of 60% sodium hydride (oil-based) was gradually added under water cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform, dried over anhydrous magnesium sulfate, and then dried under reduced pressure to give 2.76 g of 2-chloro-4-ethoxyquinazoline as colorless crystals. A product obtained by recrystallizing a part of this from isopropyl ether exhibited the following physical properties.

Mp88-90 ° C NMR (CDCl ₃ , δppm): 1.53 (3H, t, J = 7Hz), 4.67 (2H, q, J = 7H)
z), 7.56 (1H, ddd, J = 1.5,5.5,8Hz), 7.8-7.9 (2H, m), 8.15 (1
H, dt, J = 1,8Hz). Elemental analysis (as C ₁₀ H ₉ ClN ₂ O) Calculated value (%) C, 57.57; H, 4.35; N, 13.43 Analytical value (%) C, 57.55; H, 4.43; N, 13.43

[0062] Reference Example 7 2-Chloro-4-ethoxy-5-fluoroquinazoline:. 2,4-dichloro-5-fluoro-quinazoline (Chem.Abs, 99, 175790d
Seed) 1.30 g and ethanol 0.289 g in dioxane 8 ml solution, while stirring at room temperature, 60% sodium hydride (oil-based) 0.311 g
Was added, and the mixture was stirred at room temperature for 1 hour and 42 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and then dried under reduced pressure. The obtained crystals
It was washed with n-hexane to obtain 0.927 g of 2-chloro-4-ethoxy-5-fluoroquinazoline. A product obtained by recrystallizing a part of this from n-hexane exhibited the following physical properties.

Decomposition NMR around mp98 ° C. (CDCl ₃ , δppm): 1.53 (3H, t, J = 7Hz), 4.68 (2H, q, J = 7H)
z), 7.20 (1H, ddd, J = 1,8,10.5Hz), 7.65 (1H, dd, J = 1,8.5H
z), 7.76 (1H, dt, J = 5.5,8Hz). Elemental analysis (as C ₁₀ H ₈ ClFN ₂ O) Calculated value (%) C, 53.00; H, 3.56; N, 12.36 Analytical value (%) C , 52.81; H, 3.61; N, 12.37

Example 1 2- (1-Piperazinyl) -4-methoxyquinazoline : 2-chloro
-4-Methoxyquinazoline [J.Am.Chem.Soc., 53 , 3867 (193
1) Reference] To a solution of 16.0 g of dioxane in 110 ml, a solution of piperazine 70.8 g in dioxane 50 ml was gradually added dropwise at 70 ° C. with stirring. After stirring at 70 ° C. for 3 hours, the reaction mixture was poured into 800 g of ice, and the precipitated crystals were collected by filtration. The obtained crystals were washed twice with water, dissolved in chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained crystals were dissolved in 160 ml of ethanol, and filtered using Celite. The filtrate was dried under reduced pressure to give 2- (1-piperazinyl) -4-methoxyquinazoline (13.7 g) as colorless crystals. A product obtained by recrystallizing a part of this from a mixed solvent of water and dioxane exhibited the following physical properties.

Mp86-89 ° C. NMR (CDCl ₃ , δppm): 1.83 (1H, s), 2.96 (4H, m), 3.90 (4H, m),
4.08 (3H, s), 7.12 (1H, ddd, J = 1,7,8Hz), 7.49 (1H, dt, J = 1,
8.5Hz), 7.58 (1H, ddd, J = 1.5,7,8.5Hz), 7.90 (1H, ddd, J = 1,
_. 1.5, 8 Hz) as elemental analysis _{(C 13 H 16 N 4 O} ): Calculated (%) C, 63.92; H , 6.60; N, 22.93 analytical value (%) C, 64.09; H , 6.64; N, 23.06

Example 2 2- (1-Piperazinyl) -4-methoxyquinazoline-1 fumaric acid
Salt : To a solution of 4.76 g of fumaric acid in 60 ml of ethanol, 10.0 g of 2- (1-piperazinyl) -4-methoxyquinazoline (see Example 1) was added with stirring at 70 ° C., and the mixture was further stirred for 20 minutes. The precipitated crystals were collected by filtration, the obtained crystals were dissolved in water and then filtered again. The residue obtained by drying the filtrate under reduced pressure was recrystallized from a mixed solvent of water and ethanol to give 2- (1-piperazinyl)-
4.12 g of 4-methoxyquinazoline monofumarate was obtained.

Decomposition NMR (DMSO-d ₆ , δppm) near mp 190 ° C .: 3.09 (4H, m), 4.00 (4H, m), 4.08 (3H,
s), 4.54 (3H, br), 6.49 (2H, s), 7.23 (1H, ddd, J = 1,7,8Hz),
7.46 (1H, d, J = 8.5Hz), 7.69 (1H, ddd, J = 1.5,7,8.5Hz), 7.89
. (1H, dd, J = 1.5,8Hz) Elemental analysis (as _{C 17 H 20 N 4 O 5} · 1 / 4H 2 O): Calculated (%) C, 55.96; H , 5.66; N, 15.36 analytical value (%) C, 55.91; H, 5.65; N, 15.36

Example 3 2- (1-Piperazinyl) -4-methoxyquinazoline monoacetate salt :
2- (1-piperazinyl) -4-methoxyquinazoline (Example 1
Reference) 2.50 g of ethyl acetate in 15 ml of solution under stirring at room temperature,
0.62 ml of acetic acid was added. After stirring for 10 minutes, n-hexane 15
ml was added, the mixture was further stirred for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 2.0 g of 2- (1-piperazinyl) -4-methoxyquinazoline monoacetate.

Mp129-132 ° C. NMR (DMSO-d ₆ , δppm): 1.88 (3H, s), 2.81 (4H, m), 3.80 (4H,
m), 4.06 (3H, s), 6.45 (2H, br), 7.17 (1H, ddd, J = 1,7,8Hz),
7.42 (1H, dt, J = 1,8.5Hz), 7.65 (1H, ddd, J = 1.5,7,8.5Hz),
7.86 (1H, dt, J = 1.5,8Hz) Elemental analysis (as _{C 15 H 20 N 4 O 3} ):. Calculated (%) C, 59.20; H , 6.62; N, 18.41 analytical value (%) C, 59.20; H, 6.52; N, 18.37

Example 4 4-Methoxy-8-methyl-2- (1-piperazinyl) quinazoli
N : To a solution of 6.7 g of piperazine in 50 ml of dioxane, at 50 ° C., a solution of 3.5 g of 2-chloro-4-methoxy-8-methylquinazoline (see Reference Example 1) in 50 ml of dioxane was gradually added dropwise. After heating and stirring at 70 ° C. for 1 hour, the reaction mixture was poured into ice water and extracted with chloroform. Wash the extract with water,
After drying over anhydrous sodium sulfate, the mixture was dried under reduced pressure. The obtained residue is subjected to medium pressure liquid column chromatography [elution solvent:
Chloroform-methanol (20: 1, v / v)] and purified, 4-methoxy-8-methyl-2- (1-piperazinyl) quinazoline 4.0 g
Got

NMR (CDCl ₃ , δppm): 2.05 (1H, s), 2.53 (3H,
s), 2.95 (4H, m), 3.91 (4H, m), 4.05 (3H, s) 7.01 (1H, dd, J = 7,
8Hz), 7.43 (1H, m), 7.75 (1H, m).

Example 5 4-Methoxy-8-methyl-2- (1-piperazinyl) quinazoline
・ Diacetate: 4-methoxy-8-methyl-2- (1-piperazinyl)
To a solution of 0.39 g of quinazoline (see Example 4) in 20 ml of acetone, 0.11 g of acetic acid was added, and the mixture was dried under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 4-methoxy-8-methyl-2- (1-
0.25 g of piperazinyl) quinazoline diacetate was obtained.

Decomposition NMR (CDCl ₃ , δppm) near mp 148 ° C .: 1.89 (6H, s), 2.46 (3H, s), 2.85 (4H, m),
3.83 (4H, m), 4.05 (3H, s), 6.8 (3H, br), 7.08 (1H, dd, J = 7,8H
. z), 7.51 (1H, m), 7.70 (1H, m) as the element analysis _{(C 18 H 26 N 4 O} 5): Calculated (%) C, 57.13; H , 6.93; N, 14.81 analytical value ( %) C, 57.09; H, 6.96; N, 14.90

Example 6 4,8-Dimethoxy-2- (1-piperazinyl) quinazoline : Piperazine (2.7 g ) in dioxane (20 ml) solution was stirred at 70 ° C. to give 2-
Chloro-4,8-dimethoxyquinazoline (see Reference Example 2) 1.
A solution of 5 g of dioxane in 10 ml was gradually added dropwise. After heating and stirring at 70 ° C. for 1 hour, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and then dried under reduced pressure. The obtained residue was purified by medium pressure liquid column chromatography [elution solvent: chloroform-methanol (10: 1, v / v)], and 4,8-dimethoxy-2- (1-
1.2 g of piperazinyl) quinazoline was obtained. A product obtained by recrystallizing a part of this from acetonitrile showed the following physical properties.

Decomposition NMR (CDCl ₃ , δppm) near mp211 ° C .: 1.81 (1H, s), 2.96 (4H, m), 3.92 (4H, m),
3.97 (3H, s), 4.07 (3H, s), 6.99 (1H, dd, J = 1.5,8Hz), 7.05 (1
. H, t, J = 8Hz ), 7.50 (1H, dd, J = 1.5,8Hz) Elemental analysis (C ₁₄ H ₁₈ N ₄ as O ₂₎ Calculated (%) C, 61.30; H , 6.61; N, 20.42 Analytical value (%) C, 61.02; H, 6.53; N, 20.41

Example 7 4,8-Dimethoxy-2- (1-piperazinyl) quinazoline diacetic acid
Salt : 0.28 g of 4,8-dimethoxy-2- (1-piperazinyl) quinazoline (see Example 6) with 30 ml of acetone and methanol 3
It was dissolved in a mixed solvent with ml and the insoluble material was filtered off. Acetic acid (0.63 g) was added to the filtrate and the mixture was dried under reduced pressure.
Dissolve it in a mixed solvent of 0.6 ml and 30 ml of acetone and add 0.0
5 ml drops were added and left at room temperature. The precipitated crystals are collected by filtration,
The obtained crystals were recrystallized from ethyl acetate to obtain 0.13 g of 4,8-dimethoxy-2- (1-piperazinyl) quinazoline diacetate.

NMR (DMSO-d ₆ , δppm): 1.89 (6H, s), 2.80 (4H,
m), 3.78 (4H, m), 3.88 (3H, s), 4.04 (3H, s), 7.08 (1H, t, J = 8H
z), 7.14 (1H, dd, J = 1.5,8Hz), 7.42 (1H, dd, J = 1.5,8Hz).

Example 8 5-Fluoro-4-methoxy-2- (1-piperazinyl) quinazoli
Down: dioxane 3ml solution of piperazine 1.49 g, under stirring at 70 ° C., was added dropwise over 2-chloro-5-fluoro-4-methoxyquinazoline (Reference Example 3 reference) 0.734 g 2 hours dioxane 5ml solution, then Stir for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue was purified by medium-pressure liquid column chromatography [elution solvent: chloroform-methanol (10: 1, v / v)] to give 5-fluoro-4-methoxy-2- (1-piperazinyl) quinazoline 0.795. g
Got

NMR (CDCl ₃ , δppm): 1.75 (1H.s), 2.96 (4H,
m), 3.90 (4H, m), 4.10 (3H, s), 6.75 (1H, ddd, J = 1,8,11Hz),
7.26 (1H, d, J = 8.5Hz), 7.47 (1H, dt, J = 6,8Hz).

Example 9 5-Fluoro-4-methoxy-2- (1-piperazinyl) quinazoli
1-acetate salt : 5-fluoro-4-methoxy-2- (1-piperazinyl) quinazoline (see Example 8) (0.65 g) in ether (65 ml)
The mixture was dissolved in, the insoluble matter was filtered off, 0.144 ml of acetic acid was added to the filtrate, and the mixture was left at room temperature. The precipitated crystals are collected by filtration and 5-fluoro-4
-Methoxy-2- (1-piperazinyl) quinazoline monoacetate salt
I got 318g.

Mp 134-136 ° C. NMR (DMSO-d ₆ , δppm): 1.90 (3H, s), 2.78 (4H, m), 3.77 (4H,
m), 4.04 (3H, s), 4.51 (2H, br), 6.88 (1H, ddd, J = 1,8,11Hz),
7.21 (1H, dd, J = 1,8.5Hz), 7.59 (1H, dt, J = 6,8Hz). Elemental analysis _{(C 15 H 19 FN 4 O} 3 · 1 / 2H 2 O ) Calculated value (% ) C, 54.37; H, 6.08; N, 16.91 Analytical value (%) C, 54.30; H, 6.03; N, 16.98

Example 10 6-Fluoro-4-methoxy-2- (1-piperazinyl) quinazoli
Down: dioxane 6ml solution of piperazine 2.21 g, under stirring at 70 ° C., was added dropwise over 2-chloro-6-fluoro-4-methoxyquinazoline (Reference Example 4 reference) 1.09 g 1 hour dioxane 6ml solution, then Stir for 30 minutes. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The obtained residue was subjected to medium pressure liquid column chromatography [elution solvent: chloroform-methanol].
(10: 1, v / v)] and 6-fluoro-4-methoxy-2- (1-
0.888 g of piperazinyl) quinazoline was obtained. A product obtained by recrystallizing a part of this from a mixed solvent of dioxane and n-hexane exhibited the following physical properties.

Mp 116-118 ° C. NMR (CDCl ₃ , δppm): 2.21 (1H, s), 2.97 (4H, m), 3.89 (4H, m),
4.07 (3H, s), 7.35 (1H, dt, J = 3,8.5Hz), 7.47 (1H, dd, J = 5,9H
z), 7.87 (1H, dd, 3,8.5Hz). Elemental analysis (as C ₁₃ H ₁₅ FN ₄ O) Calculated value (%) C, 59.53; H, 5.76; N, 21.36 Analytical value (%) C, 59.65; H, 5.65; N, 21.13

Example 11 6-Fluoro-4-methoxy-2- (1-piperazinyl) quinazoli
1-acetate salt : 6-fluoro-4-methoxy-2- (1-piperazinyl) quinazoline (see Example 10) 0.788 g in ethyl acetate 13
It was dissolved in ml, the insoluble matter was filtered off, 0.18 ml of acetic acid was added to the filtrate, and the mixture was left at room temperature. The precipitated crystals are collected by filtration, and 6-fluoro-4
-Methoxy-2- (1-piperazinyl) quinazoline monoacetate salt
773 g was obtained.

Mp 144-146 ° C NMR (DMSO-d ₆ , δppm): 1.89 (3H, s), 2.81 (4H, m), 3.78 (4H,
m), 4.06 (3H, s), 6.13 (2H, br), 7.46 (1H, ddd, J = 0.5,5,9H
z), 7.5-7.6 (1H, m), 7.58 (1H, dd, J = 3,9Hz). Elemental analysis (as C ₁₅ H ₁₉ FN ₄ O ₃ ) Calculated value (%) C, 55.89; H, 5.94 ; N, 17.38 Analytical value (%) C, 55.92; H, 5.96; N, 17.28

Example 12 8-Chloro-4-methoxy-2- (1-piperazinyl) quinazoli
Down: dioxane 6ml solution of piperazine 1.70 g, stirring, 2,8-dichloro-4-methoxyquinazoline was gradually added dropwise a mixed solution of dioxane 20ml and 15ml chloroform (Reference Example 5 refer) 0.9 g at 70 ° C. Then, the mixture was heated and stirred for 1 hour.
The reaction mixture was diluted with chloroform and washed with water. The chloroform solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue was subjected to medium pressure liquid column chromatography [elution solvent: chloroform-methanol (30: 1, v / v)].
Purified with 8-chloro-4-methoxy-2- (1-piperazinyl)
0.979 g of quinazoline was obtained.

NMR (CDCl ₃ , δppm): 1.79 (1H, s), 2.97 (4H,
m), 3.96 (4H, m), 4.08 (3H, s), 7.00 (1H, t, J = 8Hz), 7.67 (1H,
dd, J = 1.5,7.5Hz), 7.81 (1H, dd, J = 1.5,8Hz).

Example 13 8-Chloro-4-methoxy-2- (1-piperazinyl) quinazoline
・ 1 Acetate : 8-chloro-4-methoxy-2- (1-piperazinyl)
0.85 g of quinazoline (see Example 12) was dissolved in 30 ml of ether, 0.20 ml of acetic acid was added, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to obtain 0.6 g of 8-chloro-4-methoxy-2- (1-piperazinyl) quinazoline monoacetate.

Mp 158-161 ° C NMR (DMSO-d ₆ , δppm): 1.90 (3H, s), 2.81 (4H, m), 3.84 (4H,
m), 4.07 (3H, s), 5.28 (2H, br), 7.11 (1H, t, J = 8Hz), 7.80 (2
. H, dd, J = 1.5,7.5Hz ), 7.81 (2H, dd, J = 1.5,8Hz) Elemental analysis (C ₁₅ H ₁₉ as ClN ₄ O ₃₎ Calculated (%) C, 53.18; H , 5.65 ; N, 16.54 Analytical value (%) C, 53.06; H, 5.67; N, 16.35

Example 14 4-Ethoxy-2- (1-piperazinyl) quinazoline monoacetate salt :
2-chloro-4-ethoxyquinazoline (see Reference Example 6) was added to a solution of piperazine (4.23 g) in dioxane (10 ml) at 70 ° C with stirring.
A solution of 2.00 g of dioxane in 10 ml was added dropwise. The mixture was heated and stirred at 70 ° C for 45 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue was subjected to medium pressure liquid column chromatography [elution solvent: chloroform-methanol].
(20: 1-10: 1, v / v)] to obtain 4-ethoxy-2- (1-piperazinyl) quinazoline (1.61 g). Next, 1.61 g of the obtained 4-ethoxy-2- (1-piperazinyl) quinazoline was dissolved in 16 ml of acetone, the insoluble matter was filtered off, and the filtrate was stirred at room temperature,
0.38 ml of acetic acid was added and left at room temperature. The precipitated crystals were collected by filtration to give 1.32 g of 4-ethoxy-2- (1-piperazinyl) quinazoline monoacetate as colorless crystals.

Mp 130-132 ° C. NMR (DMSO-d ₆ , δppm): 1.43 (3H, t, J = 7Hz), 1.89 (3H, s), 2.8
0 (4H, m), 3.78 (4H, m), 4.53 (2H, q, J = 7Hz), 6.25 (2H, br), 7.
17 (1H, ddd, J = 1,7,8Hz), 7.40 (1H, dd, J = 1,8.5Hz), 7.64 (1
H, ddd, J = 1.5,7,8.5Hz) , 7.85 (1H, ddd, J = 0.5,1.5,8Hz). Elemental analysis (as _{C 16 H 22 N 4 O 3} ) Calculated (%) C, 60.36 ; H, 6.96; N, 17.60 Analytical value (%) C, 60.44; H, 6.93; N, 17.80

Example 15 4-Ethoxy-5-fluoro-2- (1-piperazinyl) quinazoli
N- monoacetate salt : To a solution of 1.60 g of piperazine in 9 ml of dioxane, 0.9 g of 2-chloro-4-ethoxy-5-fluoroquinazoline (see Reference Example 7) was added with stirring at 80 ° C, and heated at 80 ° C for 1.5 hours. It was stirred. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and then dried under reduced pressure. The obtained residue was purified by medium pressure liquid column chromatography [elution solvent: chloroform-methanol (20: 1-10: 1, v / v)], and 4-ethoxy-5-fluoro-2- ( 0.833 g of 1-piperazinyl) quinazoline was obtained. Next, 0.833 g of the obtained 4-ethoxy-5-fluoro-2- (1-piperazinyl) quinazoline was dissolved in 10 ml of ethyl acetate, and 12 ml of acetic acid was added with stirring at room temperature. Ethyl acetate was added to the precipitated crystals to dissolve them under heating, and then the crystals were allowed to stand at room temperature. The precipitated crystals were collected by filtration to obtain 0.780 g of 4-ethoxy-5-fluoro-2- (1-piperazinyl) quinazoline monoacetate.

Mp 134-136 ° C. NMR (DMSO-d ₆ , δppm): 1.40 (3H, t, J = 7Hz), 1.90 (3H, s), 2.7
8 (4H, m), 3.76 (4H, m), 4.52 (2H, q, J = 7Hz), 4.91 (2H, br), 6.
87 (1H, ddd, J = 1,8,11Hz), 7.20 (1H, dd, J = 1,8.5Hz), 7.57 (1
H, dt, J = 6,8.5Hz). Elemental analysis (as C ₁₆ H ₂₁ FN ₄ O ₃ ) Calculated value (%) C, 57.13; H, 6.29; N, 16.66 Analytical value (%) C, 57.27; H, 6.29; N, 16.89

Example 16 2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-meth
Xyquinazoline : 2-chloro-4-methoxyquinazoline [J.
Am.Chem.Soc., 53 , 3867 (1931)] 3.0 g dioxane
1- (2-hydroxyethyl) piperazine 2.2 in 30 ml solution
1 g and triethylamine 2.34 g were added and stirred at 60 ° C. for 42 hours. After cooling, the reaction mixture was evaporated to dryness under reduced pressure, chloroform was added to the residue, and the mixture was washed with aqueous sodium bicarbonate solution and saturated brine. After drying over anhydrous sodium sulfate, it was evaporated to dryness under reduced pressure, and the residue was purified by medium pressure liquid column chromatography [elution solvent: chloroform-methanol (50: 1-20: 1, v / v)], and 2- [4 4.38 g of-(2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline was obtained as pale yellow crystals. A part of this was recrystallized from a mixed solvent of chloroform and isopropyl ether, and exhibited the following physical properties.

Mp93-95 ° C. NMR (CDCl ₃ , δppm): 2.60 (6H, m), 2.5-2.8 (1H, br), 3.68 (2
H, m), 3.95 (4H, m), 4.08 (3H, s), 7.13 (1H, ddd, J = 1,6.5,8H
z), 7.50 (1H, dd, J = 1,8.5Hz), 7.59 (1H, ddd, J = 1.5,6.5,8.5
. Hz), 7.90 (1H, dd, as J = 1.5, 8 Hz) Elementary analysis _{(C 15 H 20 N 4 O} 2): Calculated (%) C, 62.48; H , 6.99; N, 19.43 analysis (% ) C, 62.59; H, 7.04; N, 19.55

Example 17 2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-meth
Xyquinazoline monofumarate : 2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline (Example
(Refer to 16) 2.38 g ethanol 30 ml solution, fumaric acid 0.958 g
Was added and the mixture was stirred at room temperature for 15 minutes. An appropriate amount of ethanol was added, and the precipitated crystals were dissolved by heating, filtered while hot, and the filtrate was left at room temperature. The precipitated crystals were collected by filtration to give 2.44 g of 2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline monofumarate as colorless crystals.

Mp152-157 ° C. NMR (DMSO-d ₆ , δppm): 2.59 (2H, t, J = 6Hz), 2.67 (4H, m), 3.6
0 (2H, t, J = 6Hz), 3.88 (4H, m), 4.07 (3H, s), 6.61 (2H, s), 7.2
0 (1H, ddd, J = 1,7,8Hz), 7.43 (1H, dd, J = 1,8.5Hz), 7.66 (1H,
. ddd, J = 1.5,7,8.5Hz), 7.87 (1H, dd, as J = 1.5, 8 Hz) Elementary analysis _{(C 19 H 24 N 4 O} 6): Calculated (%) C, 56.43; H , 5.98; N, 13.85 Measured value (%) C, 56.39; H, 5.95; N, 13.91

Example 18 5-Fluoro-2- [4- (2-hydroxyethyl) piperazine-1
-Yl] -4-methoxyquinazoline monofumarate : 2-chloro-5-fluoro-4-methoxyquinazoline (see Reference Example 3)
A solution of 0.70 g, triethylamine 0.93 ml and 1- (2-hydroxyethyl) piperazine 0.65 g in dioxane 7 ml was added.
The mixture was stirred at 60 ° C for 10 hours and at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue is subjected to medium pressure liquid column chromatography [elution solvent:
Chloroform-methanol (100: 1, v / v)] to obtain 5-fluoro-2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline (0.878 g) . Then, 0.878 g of the obtained 5-fluoro-2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline was added to methanol.
Dissolve in 15 ml, filter off insoluble matter, and add 0.348 g of fumaric acid to the filtrate.
Was added, and the mixture was stirred at room temperature for 15 minutes. After the methanol was evaporated to dryness under reduced pressure, the residue was dissolved in 15 ml of ethyl acetate, left to stand and the precipitated crystals were collected by filtration to give 5-fluoro-2- [4- (2-hydroxyethyl) piperazin-1-yl. ] -4-Methoxyquinazoline monofumarate 0.967 g was obtained.

Decomposition NMR (DMSO-d ₆ , δppm) near mp 187 ° C .: 2.62 (2H, t, J = 6Hz), 2.70 (4H, m), 3.6
1 (2H, t, J = 6Hz), 3.89 (4H, m), 4.05 (3H, s), 6.61 (2H, s), 6.9
2 (1H, dd, J = 8,11Hz), 7.23 (1H, d, J = 8.5Hz), 7.61 (1H, dt, J =
Elemental analysis (as C ₁₉ H ₂₃ FN ₄ O ₆ ) Calculated value (%) C, 54.03; H, 5.49; N, 13.26 Analytical value (%) C, 53.94; H, 5.51; N, 13.36

Example 19 2- [4- (2-chloroethyl) piperazin-1-yl] -4-methoxy
Cyquinazoline : 4-methoxy-2- (1-piperazinyl) quinazoline (see Example 1) 2.00 g, triethylamine 2.3 ml
And 1-bromo-2-chloroethane 3.53 g of dioxane 20
The ml solution was heated and stirred at 60 ° C. for 46 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue was purified by medium-pressure liquid column chromatography [elution solvent: chloroform, chloroform-methanol (100: 1, v / v)] and 2- [4- (2-chloroethyl) piperazine-1. -Yl] -4-methoxyquinazoline (1.67 g) was obtained.

NMR (CDCl ₃ , δppm): 2.60 (4H, m), 2.78 (2H, t,
J = 7Hz), 3.64 (2H, t, J = 7Hz), 3.96 (4H, m), 4.08 (3H, s), 7.13
(1H, ddd, J = 1.5,7,8Hz), 7.49 (1H, d, J = 8.5Hz), 7.58 (1H, dd
d, J = 1.5,7,8.5Hz), 7.90 (1H, dd, J = 1.5,8Hz).

Example 20 2- [4- (2-chloroethyl) piperazin-1-yl] -4-methoxy
Siquinazoline monosulfate : 2- [4- (2-chloroethyl) piperazine was added to a solution of 0.239 g of concentrated sulfuric acid in 15 ml of acetone under stirring at room temperature.
-1-yl] -4-methoxyquinazoline (see Example 19) 0.70
A solution of 0 g of acetone in 8 ml was added, and the mixture was stirred at room temperature for 15 minutes, and the precipitated crystals were collected by filtration, and 2- [4- (2-chloroethyl) piperazin-1-yl] -4-methoxyquinazoline monosulfate 0.89
2g was obtained.

Decomposition NMR (D ₂ O, δppm) near mp 234 ° C .: 3.73 (4H, br), 3.79 (2H, m), 4.10 (2H, m),
4.28 (3H, s), 4.44 (4H, br), 7.58 (1H, ddd, J = 1,7.5,8Hz), 7.
77 (1H, dd, J = 8.5Hz), 7.97 (1H, ddd, J = 1.5,7.5,8.5Hz), 8.0
7 (1H, dd, J = 1.5,8Hz). Elemental analysis (as C ₁₅ H ₂₁ ClN ₄ O ₅ S ・ H ₂ O) Calculated value (%) C, 42.60; H, 5.48; N, 13.25 Analytical value ( %) C, 42.69; H, 5.19; N, 13.29

Example 21 2- [4- (2-Fluoroethyl) piperazin-1-yl] -4-meth
Xyquinazoline : 4-methoxy-2- (1-piperazinyl) quinazoline (see Example 1) 1.50 g, triethylamine 1.73
ml and 1-bromo-2-fluoroethane (2.34 g) in dioxane (15 ml) were heated and stirred at 60 ° C. for 22 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and dried under reduced pressure. The obtained residue was purified by medium pressure liquid column chromatography [elution solvent: chloroform] to obtain 1.70 g of 2- [4- (2-fluoroethyl) piperazin-1-yl] -4-methoxyquinazoline.
A product obtained by recrystallizing a part of this from ethanol exhibited the following physical properties.

Mp 73-75 ° C. NMR (CDCl ₃ , δppm): 2.64 (4H, m), 2.77 (2H, dt, J = 5,28Hz),
3.98 (4H, m), 4.09 (3H, s), 4.63 (2H, dt, J = 5,47.5Hz), 7.13
(1H, ddd, J = 1,7,8Hz), 7.49 (1H, dt, J = 1,8.5Hz), 7.58 (1H, d
. dd, J = 1.5,7,8.5Hz), 7.91 (1H, ddd, J = 0.5,1.5,8Hz) Elemental analysis (C ₁₅ H ₁₉ FN ₄ O) Calculated value (%) C, 62.05; H , 6.60; N, 19.30 Analytical value (%) C, 62.18; H, 6.58; N, 19.48

Example 22 2- [4- (2-Fluoroethyl) piperazin-1-yl] -4-meth
Xyquinazoline monofumarate : 2- [4- (2-fluoroethyl) piperazin-1-yl] -4-methoxyquinazoline (see Example 21) (1.00 g) was dissolved in ethanol (10 ml) to prepare fumaric acid.
0.465 g was added and dissolved, followed by filtration. The filtrate was left at room temperature, and the precipitated crystals were collected by filtration to give 2- [4- (2-fluoroethyl)
0.943 g of piperazin-1-yl] -4-methoxyquinazoline monofumarate was obtained.

Mp 137-139 ° C. NMR (DMSO-d ₆ , δppm): 2.59 (4H, m), 2.72 (2H, dt, J = 5,28.5H)
z), 3.86 (4H, m), 4.07 (3H, s), 4.61 (2H, dt, J = 5,48Hz), 6.64
(2H, s), 7.19 (1H, ddd, J = 1,7,8Hz), 7.43 (1H, dt, J = 1,8.5H
z), 7.65 (1H, ddd, J = 1.5,7,8.5Hz), 7.87 (1H, d, J = 8Hz). Elemental analysis (as C ₁₉ H ₂₃ FN ₄ O ₅ ) Calculated value (%) C, 56.15; H, 5.70; N, 13.79 Analytical value (%) C, 56.12; H, 5.73; N, 13.82

Example 23 5-Fluoro-2- [4- (2-chloroethyl) piperazine-1-i
] -4-Methoxyquinazoline : 5-fluoro-4-methoxy-2
-(1-Piperazinyl) quinazoline (see Example 8) 1.00 g
A solution of triethylamine 1.1 ml and 1-bromo-2-chloroethane 1.64 g in dioxane 10 ml was heated with stirring at 60 ° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate,
It was dried under reduced pressure. The obtained residue was subjected to medium pressure liquid column chromatography [elution solvent: chloroform-methanol (20
0: 1, v / v)], 5-fluoro-2- [4- (2-chloroethyl) piperazin-1-yl] -4-methoxyquinazoline 1.09 g
Got

NMR (CDCl ₃ , δppm): 2.60 (4H, m), 2.78 (2H, t,
J = 7Hz), 3.64 (2H, t, J = 7Hz), 3.95 (4H, m), 4.09 (3H, s), 6.76
(1H, ddd, J = 1,8,11Hz), 7.26 (1H, d, J = 8.5Hz), 7.47 (1H, dt,
J = 6,8Hz).

Example 24 5-Fluoro-2- [4- (2-chloroethyl) piperazine-1-i
] -Methoxyquinazoline monosulfate : 5-fluoro-2- [4-
0.500 g of (2-chloroethyl) piperazin-1-yl] -4-methoxyquinazoline (see Example 23) was dissolved in 12 ml of acetone, and while stirring at room temperature, a solution of 0.145 g of concentrated sulfuric acid in 3 ml of acetone was added to dryness under reduced pressure. The obtained residue was dissolved by heating in 3 ml of methanol, the insoluble matter was filtered off, 10 ml of ethanol was added to the filtrate, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration to obtain 0.412 g of 5-fluoro-2- [4- (2-chloroethyl) piperazin-1-yl] -4-methoxyquinazoline monosulfate.

Decomposed at around mp142 ° C., and foamed at around 232 ° C. NMR (D ₂ O, δ ppm): 3.6-3.7 (4H, br), 3.75 (2H, m), 4.06 (2H,
m), 4.25 (3H, s), 4.39 (4H, br), 7.25 (1H, ddd, J = 1,8.5,11H
z), 7.54 (1H, d, J = 8.5Hz), 7.89 (1H, dt, J = 5.5,8.5Hz). Elemental analysis (as C ₁₅ H ₂₀ ClFN ₄ O ₅ S ・ 1 / 4H ₂ O) calculation Value (%) C, 42.16; H, 4.83; N, 13.11 Analytical value (%) C, 42.20; H, 4.78; N, 13.00

Example 25 5-Fluoro-2- [4- (2-fluoroethyl) piperazine-1-
Il] -4-methoxyquinazoline : 5-fluoro-4-methoxy
-2- (1-Piperazinyl) quinazoline (see Example 8) 1.00
A solution of g, 1.1 ml of triethylamine and 1.38 g of 1-bromo-2-fluoroethane in 10 ml of dioxane was heated and stirred at 60 ° C. for 28 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was dried over anhydrous magnesium sulfate,
It was dried under reduced pressure. The obtained residue was subjected to medium pressure liquid column chromatography [elution solvent: chloroform-methanol (20
0: 1, v / v)], 5-fluoro-2- [4- (2-fluoroethyl) piperazin-1-yl] -4-methoxyquinazoline 1.0
I got 9g. A product obtained by recrystallizing a part of this from ethanol exhibited the following physical properties.

Mp 78-79 ° C. NMR (CDCl ₃ , δppm): 2.63 (4H, m), 2.76 (2H, dt, J = 5,28.5H)
z), 3.99 (4H, m), 4.10 (3H, s), 4.63 (2H, dt, J = 5,47.5Hz), 6.
75 (1H, ddd, J = 1,8,11Hz), 7.26 (1H, dd, J = 1,8.5Hz), 7.47 (1
H, ddd, J = 6,8,8.5Hz). Elemental analysis (as C ₁₅ H ₁₈ F ₂ N ₄ O) Calculated value (%) C, 58.43; H, 5.88; N, 18.17 Analytical value (%) C , 58.51; H, 5.91; N, 18.22

Example 26 Injection : 2- (1-piperazinyl) -4-methoxyquinazoline-1
5 g of fumarate (see Example 2) and 25 g of mannitol
Is dissolved in purified water for injection to make 1000 ml, and this is sterilized and filtered, and 5 ml each is dispensed into ampoules. After freeze-drying, it is sealed to obtain an injection for dissolution at the time of use.

Examples 27-38 Injectables : Examples 5, 7 instead of 2- (1-piperazinyl) -4-methoxyquinazoline monofumarate in Example 26.
Injectable preparations are prepared in the same manner as in Example 26, except that the compounds of 9, 11, 13, 14, 15, 17, 18, 20, 22, or 24 are used. An injectable solution for occasional dissolution is obtained.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takashi Sekita 4-2-20 Kuwazu, Higashisumiyoshi-ku, Osaka-shi, Osaka (72) Inventor Naruse Qi 8-19 Tonomachi, Takatsuki-shi, Osaka (72) Inventor Shigeru Iwaki Osaka Prefecture, Osaka City, Joto-ku, Emission West 1-2-59-701

Claims (6)

[Claims] 1. Formula (I): (In the formula, R ¹ represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, R ² represents a hydrogen atom or a fluorine atom, R ³ represents an alkyl group having 1 to 2 carbon atoms, and R ⁴ represents Represents a hydrogen atom, a 2-hydroxyethyl group or a 2-haloethyl group, provided that when R ² is a fluorine atom, R ¹ represents a hydrogen atom) or a pharmaceutically acceptable acid thereof. Addition salt. 2. 2- [4- (2-Hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof. 3. 2- (1-Piperazinyl) -4-methoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof. 4. Formula (I): (In the formula, R ¹ represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, R ² represents a hydrogen atom or a fluorine atom, R ³ represents an alkyl group having 1 to 2 carbon atoms, and R ⁴ represents Represents a hydrogen atom, a 2-hydroxyethyl group or a 2-haloethyl group, provided that when R ² is a fluorine atom, R ¹ represents a hydrogen atom) or a pharmaceutically acceptable acid thereof. An antitumor agent containing an addition salt as an active ingredient. 5. An antitumor agent comprising 2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 6. An antitumor agent comprising 2- (1-piperazinyl) -4-methoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.