JPS634829B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel pyrimidoquinazoline derivatives. More specifically, the present invention relates to novel pyrimidoquinazoline derivatives and salts thereof having antiallergic effects, methods for producing the same, and antiallergic agents containing them as active ingredients. The pyrimidoquinazoline derivative of this invention is represented by the following general formula. (In the formula, R ¹ is an acyl group, R ² is a cyano group or N
Examples of the salts of the pyrimidoquinazoline derivative () include inorganic or organic bases such as sodium salt, potassium salt, calcium salt, triethylamine salt, dicyclohexylamine salt, imidazole salt, etc. Examples include salts such as The acyl group in R ¹ of the pyrimidoquinazoline derivative ( ) contains a residue of an organic carboxylic acid and an organic sulfonic acid, and preferable examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, 3,3-dimethylbutyryl, etc. Lil,
Lower alkanoyl groups such as valeryl, isovaleryl, pivaloyl, cycloalkanecarbonyl groups such as cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, lower cycloalkyl (lower) alkanoyl groups such as 3-cyclopentylpropionyl, e.g. methane Examples include lower alkanesulfonyl groups such as sulfonyl, ethanesulfonyl, and propanesulfonyl. In addition, R ² of pyrimidoquinazoline derivatives ()
Examples of the N-containing 5-membered aromatic heterocyclic carbamoyl group include pyrrolylcarbamoyl, imidazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, and tetrazolylcarbamoyl. The pyrimidoquinazoline derivative () and its salts of the present invention are produced by the method detailed below. Manufacturing method 1: Manufacturing method 2: (In the formula, R ¹ has the same meaning as before, R ² _a is an N-containing 5-membered aromatic heterocyclic carbamoyl group, and R ³ is an N-containing 5-membered aromatic heterocyclic carbamoyl group.
( ^R4 means an esterified carboxy group) Production method 1 The target compound (a) or its salt is a pyrimidoquinazoline carboxylic acid () or its salt, and an amine () or its salt. It can be produced by reacting with Examples of the salts of pyrimidoquinazolinecarboxylic acids () include salts with inorganic or organic bases such as sodium salts, potassium salts, calcium salts, magnesium salts, ethanolamine salts, dicyclohexylamine salts, and imidazole salts. Examples of the salts of amines () include salts with inorganic or organic acids such as hydrochloride, sulfate, nitrate, acetate, and p-toluenesulfonate. This reaction is usually carried out in an inert solvent such as N.N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, pyridine, or a mixture thereof at room temperature or with heating. Further, good results are often obtained when this reaction is carried out in the presence of a condensing agent such as N.N'-carbonyldiimidazole. Production method 2 The target compound (b) can be produced by heating the raw material compound (). This reaction is usually carried out by heating the compound (2) in an inert, high-boiling solvent such as N.N-dimethylformamide, diphenyl ether, biphenyl, paraffin, etc., preferably at about 160 to 270°C. The target compound produced by these reactions (
a), (b) and their salts can be isolated and purified from the reaction solution by conventional methods. The starting compounds () and () in the above production method are all new compounds, and are produced, for example, from known benzonitriles (XII) by the method illustrated below. (In the formula, R ¹ and R ⁴ have the same meanings as before, and R ⁵ means an alkoxy group.) The method for producing these raw material compounds is described in Example 1 below.
-(1) to (6) and Example 8-(1), or a method chemically equivalent thereto. Pyrimidoquinazoline derivatives () and their salts, which are the target compounds of this invention, have strong antiallergic activity, such as allergic asthma,
allergic rhinitis, hives, hay fever, allergic conjunctivitis, atopic dermatitis, ulcerative colitis,
dietary allergies (e.g. milk allergy);
It is effective as a preventive or therapeutic agent for symptoms associated with allergic diseases such as orniphilia and aphthous stomatitis. Next, the antiallergic effects of representative examples of the target compound () will be explained using test examples. Test example [PCA (passive cutaneous anaphylaxis) reaction inhibition effect] (1) Test compound N-(1H-tetrazol-5-yl)-4
-Oxo-10-(3,3-dimethylbutyramide)-4H-pyrimido[1,2-C]quinazoline-3-carboxamide N-(1H-tetrazol-5-yl)-4
-Oxo-10-pivalamide-4H-pyrimido[1,2-C]quinazoline-3-carboxamide imidazole salt N-(1H-tetrazol-5-yl)-4
-Oxo-10-isobutyramide-4H-pyrimide[1,2-C]quinazoline-3-carboxamide imidazole salt N-(1H-tetrazol-5-yl)-4
-Oxo-9-pivalamide-4H-pyrimide[1,2-C]quinazoline-3-carboxamide imidazole salt (2) Test method (a) Preparation of antiserum Ovalbumin (2 mg) pertussis-diphtheria-tetanus combination vaccine ( An emulsion was prepared by mixing the 1 ml solution with Freund's incomplete adjuvant (1 ml). This emulsion was added to an 8-week-old SD weighing approximately 300 g.
(Sprague Dawly) A four-legged family of male rats,
A single dose of 1 ml was divided into 4 equal parts (0.25 ml each) and each was administered subcutaneously. Ten days after the immunization, blood was collected from the femoral artery of the rat and left on ice for 5 hours. The separated supernatant was centrifuged at 4°C (10,000 revolutions x 1 hour). −80% until use of the antiserum thus obtained.
Stored at °C. (b) PCA reaction inhibitory effect A PCA reaction was carried out using SD male rats, 8 weeks old and weighing 290 to 330 g, using the allogeneic sensitized antibody antiserum prepared as described above.
0.1 ml of each 32-fold diluted antiserum was injected intradermally into separate posterior parts of the back of fully shaved rats, and after 48 hours was injected with ovalbumin and Evans blue to elicit a PCA reaction. 1 ml of an aqueous solution containing 5 mg of each was injected intravenously. Test compound (dose: 1 mg/Kg) was injected intravenously 5 minutes before antigen challenge. The control group received vehicle. There were 5 animals in each administration group. Animals were sacrificed and skinned 1 hour after antigen challenge. The size of spots stained on the back side of the skin with the antiserum was examined. The results were expressed as a ratio of the inhibition value calculated from the average value of the longest and shortest diameters of each spot compared to the control group. (3) Test results The test results are shown in the table below.

[Table] Pyrimidoquinazoline derivatives of this invention ()
can be used as an antiallergic agent both in free form and in the form of pharmaceutically acceptable salts, such as salts with inorganic or organic bases or salts with amino acids. The target compound () or a pharmaceutically acceptable salt thereof is usually administered to mammals including humans, such as capsules, microcapsules, tablets, granules, powders, troches, syrups, aerosols, inhalants, etc. It can be administered in the form of solutions, injections, suspensions, emulsions, suppositories, ointments, and the like. The pharmaceutical composition of the present invention uses various organic or inorganic carrier materials commonly used in pharmaceutical applications, such as excipients (e.g., sucrose,
Starch, mannite, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate,
calcium carbonate, etc.), binders (e.g., cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin,
gum arabic, polyethylene glycol, sucrose, starch, etc.), disintegrants (e.g. starch,
carboxymethylcellulose, calcium salts of carboxymethylcellulose, hydroxypropyl starch, sodium glycol-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricants (e.g., magnesium stearate, aerosil, talc, sodium lauryl sulfate, etc.), flavoring agents (e.g. citric acid,
Menthol, ammonium salt of glycyrrhizine,
glycine, orange powder, etc.), preservatives, (e.g. sodium benzoate, sodium bisulfite,
methylparaben, propylparaben, etc.), stabilizers (e.g., citric acid, sodium citrate, acetic acid, etc.), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersants (e.g., polysorbate 80, emulgen), 408, Emazol (both surfactants)
], aqueous diluents (eg, water), and wax bases (eg, cocoa butter, polyethylene glycol, Huitepsol, white petrolatum, etc.). The dose of the active compound () of this invention varies depending on various factors such as the patient's weight, age, symptoms, administration route, etc., but the effective dose is usually about 20 to 2000 mg/day for oral administration. , approximately 2.5-250 mg/day for intramuscular or intravenous injection, approximately 10-250 mg/day for subcutaneous injection
The dose is appropriately selected from the range of 1000 mg/day, or about 120 to 2000 mg/day for the rectal route. The above total daily dosage may be administered to the patient in divided doses at intervals of 6 to 12 hours per day. A single dose of the active compound () of this invention is preferably, for example, about 10 to 500 mg as a tablet or capsule, about 1.25 to 250 mg as a vial or ampoule, about 60 to 500 mg as a suppository, etc. The dosage form for external use is, for example, about 1 to 10% in the form of an ointment, solution, or emulsion. Next, the present invention will be explained using examples. Example 1 [Manufacture of raw material compounds] (1) Mixture of 2-amino-5-nitrobenzonitrile (48.9 g), anhydrous potassium carbonate (45.6 g), formamide (240 ml) and N.N-dimethylformamide (200 ml) The mixture was stirred at 150°C for 50 minutes and then cooled to room temperature. A small amount of water was added to this reaction solution while stirring. The precipitated crystals were collected, washed with water three times, and dried under reduced pressure to give 4-amino-
6-nitroquinazoline (50.1 g) was obtained. mp: ＞360℃ IR (nujiol) νmax: 3350, 3200, 1680,
1620cm ^-1 N・MRδppm (DMSO−d ₆ ): 7.76 (1H, d,
J=9.0Hz), 8.43(1H, dd, J=3.0 and
9.0Hz), 9.26 (1H, d, J = 3.0Hz), 8.30
(2H, m) (2) A mixture of iron (113.9g), concentrated hydrochloric acid (57ml) and water (2.3ml) was stirred at 95°C for 20 minutes. To this mixture was added 4-amino-6-nitroquinazoline (114.1 g) over 10 minutes. The reaction mixture was stirred at 95° C. for 1.5 hours and then filtered.
The excess residue was washed with hot water. The liquid and washing liquid were combined and concentrated under reduced pressure, and a small amount of ethanol was added to the residue to form a precipitate. The precipitate was removed and dried to give 4,6-diaminoquinazoline hydrochloride (94.8
g) was obtained. The same compound (4.3 g) was recovered from the mother liquor in the same manner as above. IR (nujiol) νmax: 3310, 1665, 1610,
1560cm ^-1 (3) 4,6-diaminoquinazoline hydrochloride (10.0
g), 3,3-dimethylbutyryl chloride (10.34 g) was added to a mixture of tripropylamine (17.61 g) and dry pyridine (100 ml) under ice cooling.
It was added dropwise over 35 minutes. The reaction mixture was stirred at the same temperature for 2 hours. Ice water was added to this mixture, stirred for 5 minutes, and then concentrated under reduced pressure. Water and sodium hydrogen carbonate (13.0 g) were added little by little to the residue to form a precipitate, and the precipitate was collected, washed with water, and then dried. The crude crystals thus obtained were heated and dissolved in a mixed solvent of chloroform and methanol. Insoluble matters were separated, and the liquid was concentrated under reduced pressure, and the resulting residue was suspended in a 5% methanol/chloroform solution (70 ml). After heating and stirring, the suspension was filtered to obtain crystals of 4-amino-6-(3,3-dimethylbutyramide)quinazoline (8.5 g). mp: 273−274℃ IR (nujiol) νmax: 3330, 3220, 1685,
1650cm ^-1 NMRδppm (DMSO-d ₆ ): 1.06 (9H, s),
2.26 (2H, s), 7.6 (2H, s) 7.63 (1H, d,
J=8.0Hz), 7.83(1H, dd, J=2.0 and
8.0Hz), 8.4 (1H, s), 8.4 (1H, d, J=2.0
Hz), 10.03 (1H, s) (4) 4-amino-6-(3,3-dimethylbutyramide)quinazoline (8.5g), dimethyl methoxymethylenepropanedioate (12.75g)
and N/N-dimethylformamide (34g)
The mixture was stirred at 100°C for 1 hour. After cooling to room temperature, water was added to the mixture to collect the formed precipitate, washed with water, dried, and dimethyl [{6
Crystals of -(3,3-dimethylbutyramide)-4-quinazolinylamino}methylene]propanedioate (10.9 g) were obtained. mp: 196-198℃ IR (nujiol) νmax: 3540, 3350, 3250,
1705, 1680, 1660, 1650, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.10 (9H, s), 2.3
(2H, s), 4.83 (3H, s), 4.9 (3H, s),
7.93 (2H, s), 8.3 (2H, m), 8.8 (1H, s),
9.3 (1H, d, J = 12.0Hz), 11.9 (1H, d,
J=12.0Hz) (5) Dimethyl [{6-(3,3-dimethylbutyramide)-4-quinazolinylamino}methylene]
A mixture of propanedioate (7.30 g) and diphenyl ether (44 ml) was stirred at 260°C for 10 minutes and cooled to room temperature. Hexane was added to this mixture to precipitate crystals, which were collected and washed with hexane to give methyl 4-oxo-10-(3.
Crystals of 3-dimethylbutyramide)-4H-pyrimide[1.2-c]quinazoline-3-carboxylate (6.28 g) were obtained. mp: 247−249℃ IR (nujiol) νmax: 3350, 1740, 1720,
1685, 1610 cm ^-1 NMR δppm (DMSO-d ₆ ): 1.1 (9H, s),
2.33 (2H, s), 3.9 (3H, s), 7.96 (1H, d,
J=9.0Hz), 8.23(1H, dd, J=2.0 and
9.0Hz), 9.00 (1H, s), 9.22 (1H, s), 9.46
(1H, s), 10.43 (1H, s) (6) Methyl 4-oxo-10-(3,3-dimethylbutyramide)-4H-pyrimide [1,2-
c] Quinazoline-3-carboxylate (6.0
g), anhydrous lithium iodide (15.0 g) and dry pyridine (60 ml) were stirred at 120°C for 2 hours. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The crystals obtained by filtering the mixture were mixed with water (100
ml) and adjusted the pH to 1-2 with concentrated hydrochloric acid to obtain crystals, dry them, and give 4-oxo-10-
Crystals of (3,3-dimethylbutyramide)-4H-pyrimide[1,2-c]quinazoline-3-carboxylic acid (2.5 g) were obtained. mp: 304-306℃ IR (nujiol) νmax: 3330, 1730, 1690,
1660, 1610 cm ^-1 NMR δppm (DMSO-d ₆ ): 1.00 (9H, s),
2.26 (2H, s), 7.93 (1H, d, J = 9.0Hz),
8.16 (1H, dd, J=2.0 and 9.0Hz), 8.96
(1H, s), 9.20 (1H, d, J=2.0Hz), 9.43
(1H, s), 10.40 (1H, s) [Production of target compound] (7) 4-oxo-10-(3,3-dimethylbutyramide)-4H-pyrimide[1,2-c]quinazoline-3 -carboxylic acid (2.1 g) and N.N'-carbonyldiimidazole (1.25 g) with dry N.
Add N-dimethylformamide (21 ml) to 50
Stirred at ℃ for 4 hours. In this, 5-amino-1H
-Tetrazole (0.66g) was added and the mixture was further stirred at 50°C for 5 hours. After cooling the reaction solution to room temperature, the precipitated crystals were collected by filtration, washed with water, and washed with N
-(1H-tetrazol-5-yl)-4-oxo-10-(3,3-dimethylbutyramide)-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxamide (1.42g) was obtained. mp: 285℃ (decomposition) IR (nujiol) νmax: 3420, 3250−3050,
1690, 1670, 1610, 1570 cm ^-1 Elemental analysis: Experimental value: C 53.01; H 4.95; N 29.42 Calculated value as C ₁₉ H ₁₉ N ₉ O ₃・0.5H ₂ O: C 53.02; H 4.68; N 29.29 Conducted Example 2 4-oxo-10-pivalamide-4H-pyrimide[1,2-c]quinazoline-3-carboxylic acid (1.85 g) and N·N'-carbonyldiimidazole (1.23 g) were mixed with dry N·N-dimethyl Formamide (9.2 ml) was added and stirred at 50°C for 2 hours. 5-amino-1H-tetrazole (0.6 g) was added to this, and the mixture was further stirred at 50°C for 5 hours. After cooling the reaction solution to room temperature, the precipitated crystals were collected by filtration.
g target product was obtained. The crude crystals were recrystallized from N.N-dimethylformamide (50 ml) to give N-(1H-tetrazol-5-yl)-4-oxo-10-pivalamide-4H-pyrimide[1.2-c]quinazoline-3. -Imidazole salt of carboxamide (0.62g) was obtained. mp: 319−320℃ IR (nujiol) νmax: 3220, 3050, 1695,
1665, 1650, 1600 cm ^-1 Example 3 4-oxo-10-isobutyramide-4H-pyrimide [1,2-c]quinazoline-3-carboxylic acid (1.80 g) and N/N'-carbonyldiimidazole (1.43 Dry N·N-dimethylformamide (18 ml) was added to g), and the mixture was stirred at 50°C for 1:30.
Add to this 5-amino-1H-tetrazole (0.66g)
was added, and the mixture was further stirred at 50°C for 4 hours and 30 minutes.
After cooling the reaction mixture to room temperature, the precipitated crystals were collected by filtration, washed with water and then with ethanol, and purified with N-
(1H-tetrazol-5-yl)-4-oxo-
10-isobutyramide-4H-pyrimide [1・2
-c] An imidazole salt (2.3 g) of xazoline-3-carboxamide was obtained. mp: 287℃ (decomposition) IR (nujiol) νmax: 3150, 1690, 1640,
1610, 1570cm ^-1 NMRδppm (DMSO-d ₆ ): 1.15 (6H, d, J=
7Hz), 2.2-2.9 (1H, m), 7.1 (2H, s), 7.6
−8.3 (2H, m), 7.85 (1H, s), 9.2 (1H, s),
9.23 (1H, d, J=2Hz), 9.55 (1H, s),
10.43 (1H, s) Example 4 4-oxo-9-pivalamide-4H-pyrimide[1,2-c]quinazoline-3-carboxylic acid (1.45g) and N·N'-carbonyldiimidazole (1.11g) Dry N·N-dimethylformamide (14.5 ml) was added to the mixture, and the mixture was stirred at 50°C for 1 hour and 30 minutes.
Add to this 5-amino-1H-tetrazole (0.54g)
was added, and the mixture was further stirred at 50°C for 5 hours. After cooling the reaction mixture to room temperature, the precipitated crystals were collected by filtration,
Once with N・N-dimethylformamide, twice with water
The plate was washed twice with ethanol and once with ethanol. The crystals are dried at 50°C under reduced pressure to give N-(1H-tetrazol-5-yl)-4-oxo-9-pivalamide-
4H-pyrimido[1,2-c]quinazoline-3-
An imidazole salt of carboxamide (0.9 g) was obtained. mp: 288℃ (decomposition) IR (nujiol) νmax: 3150, 1695, 1600,
1590, 1570, 1500cm ^-1 NMRδppm (CF ₃ COOH): 1.53 (9H, s), 7.6
(2H, s), 8.4 (1H, dd, J=2.8Hz), 8.72
(2H, m), 8.85-9.30 (3H, m), 9.60 (1H,
s) Elemental analysis: Experimental value: C 50.23; H 4.65; N 30.78 C ₁₈ H ₁₇ N ₉ O ₃・C ₃ H ₄ N ₂・3/2 Calculated value as H ₂ O: C 50.19; H 4.81; N 30.66 Example 5 (1) 4-oxo-10-(3-cyclopentylpropionamide)-4H-pyrimide [1.2-c]
Quinazoline-3-carboxylic acid (2.57g) and N.
Dry N·N-dimethylformamide (25 ml) was added to N'-carbonyldiimidazole (1.75 g), and the mixture was stirred at 50°C for 1 hour and 30 minutes. Add 5-amino-1H-tetrazole (0.86g) to this,
The mixture was further stirred at 50°C for 5 hours. The reaction solution was cooled to room temperature, and the precipitated result was collected by filtration. The crystals were washed once with N・N-dimethylformamide and twice with water.
After washing twice and once with ethanol and drying, N-(1H-tetrazol-5-yl)
-4-oxo-10-(3-cyclopentylpropionamide)-4H-pyrimide [1,2-c]
The imidazole salt of quinazoline-3-carboxamide (2.6 g) was obtained. mp: 284℃ (decomposition) IR (nujiol) νmax: 3090, 1690, 1670,
1610, 1580cm ^-1 NMRδppm (CF ₃ COOH): 0.7−2.3 (11H,
m), 2.5−3.0 (2H, m), 7.55 (2H, s),
8.43 (2H, s), 8.70 (1H, s), 9.4 (1H,
s), 9.5 (1H, s), 9.86 (1H, s), 10.06
(1H, s), 10.2 (1H, s) Elemental analysis: Experimental values: C 55.38; H 5.00; N 28.82 C ₂₁ H ₂₁ N ₉ O ₃・C ₃ H ₄ N ₂・1/2HCON (CH ₃ ) ₂
Calculated value as: C 55.48; H 5.20; N 29.18 (2) N-(1H-tetrazol-5-yl)-4-
Add N·N-dimethylformamide (1.5 ml) to the imidazole salt of oxo-10-(3-cyclopentylpropionamide)-4H-pyrimide [1,2-c]quinazoline-3-carboxamide (103 mg) and stir at room temperature. did. A 1N aqueous sodium hydroxide solution (0.3 ml) was added dropwise, and the mixture was stirred at room temperature for 5 minutes. The solution was neutralized with 1N hydrochloric acid, the precipitated crystals were collected by filtration, and washed twice each with water, ethanol, and ether, resulting in N-
(1H-tetrazol-5-yl)-4-oxo-10-(3-cyclopentylpropionamide)
-4H-pyrimido[1,2-c]quinazoline-
3-carboxamide (65 mg) was obtained. mp: 265-275℃ (decomposition) IR (nujiol): 1685, 1630, 1610, 1575cm
^-1 Example 6 4-oxo-10-(cyclohexanecarboxamide)-4H-pyrimide[1,2-c]quinazoline-3-carboxylic acid (1.5g) and N・N'-carbonyldiimidazole (1.06g) Add dry N・N-dimethylformamide (15 ml) and incubate at 50℃ for 1 hour.
Stirred for 30 minutes. 5-amino-1H-tetrazole (0.52 g) was added to this, and the mixture was further stirred at 50°C for 5 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals were washed with water and then with ethanol, and dried to give N-(1H-tetrazol-5-yl)-4-oxo-10-(cyclohexanecarboxamide)-4H-pyrimide[1,2-c]quinazoline-3. - imidazole salt of carboxamide (1.56
g) was obtained. mp: 270℃ (decomposition) IR (nujiol) νmax: 1695, 1660, 1610,
1570, 1480cm ^-1 NMRδppm (CF ₃ COOH): 1.0−2.5 (10H, m),
2.5−3.0 (1H, m), 7.56 (2H, s), 8.5 (2H,
s), 8.76 (1H, s), 9.36 (1H, s), 9.53 (1H,
s), 10.05 (1H, s), 10.13 (1H, s), 10.4
(1H, s) Elemental analysis: Experimental value: C 55.12; H 4.50; N 30.35 C ₂₀ H ₁₉ Calculated value as N ₂ O ₃・C ₃ H ₄ N ₂ : C 55.08; H 4.62; N 30.72 Example 7 4-oxo-10-methanesulfonamide-4H
-Pyrimide[1,2-c]quinazoline-3-carboxylic acid (1.9 g) and N·N'-carbonyldiimidazole (1.2 g) were added with dry N·N-dimethylformamide (48 ml) and heated at 50°C for 3 hours. Stir for hours.
Add to this 5-amino-1H-tetrazole (0.63g)
was added, and the mixture was further stirred at 50°C for 6 hours. After cooling the reaction solution to room temperature, the precipitated crystals were collected by filtration.
Washed once with N·N-dimethylformamide and once with methanol, dried to obtain N-(1H-tetrazol-5-yl)-4-oxo-10-(methanesulfonamide)-4H-pyrimide [1. 2-c] An imidazole salt (1.7 g) of quinazoline-3-carboxamide was obtained. mp: 283−285℃ IR (nujiol) νmax: 3250, 3140, 3050,
1695, 1660, 1620, 1595cm ^-1 NMRδppm (DMSO-d ₆ ): 3.13 (3H, s), 7.0
−7.3 (2H, m), 7.8−8.3 (3H, m), 8.65 (1H,
d, J=2Hz), 9.2 (1H, s), 9.6 (1H, s) Example 8 [Production of raw material compound] (1) 4-amino-6-pivalamide quinazoline (5.2 g) and ethyl ethoxymethylene N.N-dimethylformamide (21 ml) was added to cyanoacetate (4.32 g) and stirred at 70°C for 3 hours.
The reaction solution was cooled to room temperature, water was added, and the resulting precipitate was collected by filtration and washed with water. The obtained crude crystals were dissolved in a mixture of 10% methanol and chloroform, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (210 g of silica gel) using 1.4% methanol-chloroform as an eluent to obtain 9.0 g of crude crystals. The crystals were dissolved in a mixed solvent of chloroform and methanol, treated with activated carbon, and then recrystallized to obtain 1.4 g of crude crystals. The crystals were recrystallized from ethyl acetate to obtain ethyl [(6-pivalamido-4-quinazolinylamino)methylene]cyanoacetate (1.05 g). mp: 204-205℃ IR (nujiol): 3320, 2210, 1710, 1630,
1620cm ^-1 NMR (DMSO-d ₆ ) δppm: 1.1-1.6 (12H,
m), 4.1-4.7 (2H, m), 7.93 (1H, d, J
= 10.0Hz), 8.26 (1H, dd, J = 10.0, 2.0
Hz), 8.55 (1H, d, J = 2.0Hz), 8.86 (1H,
s), 8.65-9.1 (1H, m), 9.80 (1H, s),
11.33 (1H, d, J = 12.0 Hz) The above crystal mother liquor was subjected to silica gel column chromatography (100 g of silica gel) using 1.6% methanol-chloroform as an elution solvent. The eluate was concentrated, ethyl acetate was added to the obtained crystals, the mixture was stirred, and the crude crystals were filtered. Further, hexane was added to the filtrate and the resulting crude crystals (1.15 g) were filtered. These crude crystals were combined and recrystallized from chloroform-hexane to obtain ethyl 2-[(6-pivalamido-4-quinazolinylamino)methylene]carbamoyl acetate (0.64 g). mp: 228-229℃ IR (nujiol): 3420, 3260, 1695, 1670,
1645, 1620cm ^-1 NMR (DMSO-d ₆ ) δppm: 1.2 (9H, s),
1.3 (3H, t, J = 7.0Hz), 4.33 (2H, q, J
=7.0Hz), 7.6-7.9 (2H, m), 8.3-8.8 (4H,
m), 8.86 (1H, s), 9.33 (1H, s), 12.5
(1H, s) [Production of target compound] (2) Ethyl (6-pivalamido-4-quinazolinylamino)methylene cyanoacetate (1.7 g)
in diphenyl ether (10 ml) at 255 °C for 15 min.
Stir for a minute. The reaction solution was cooled, hexane was added, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from chloroform-methanol to give N-(3-
Cyano-4-oxo-4H-pyrimide [1,2
-c]quinazolin-10-yl)pivalamide (0.4 g) was obtained. This was further mixed with chloroform.
It was dissolved in methanol, treated with activated carbon, and then recrystallized to obtain a purified product (0.26 g). mp273−276℃ IR (nujiol): 3340, 2220, 1725, 1690,
1610cm ^-1 NMR (DMSO-d ₆ ) δppm: 1.26 (9H, s),
7.93 (1H, d, J=9.0Hz), 8.33 (1H, dd,
J=9.0, 2.0Hz), 8.95 (1H, s), 9.13 (1H,
d, J=2.0Hz), 9.33 (1H, s), 9.76 (1H,
s)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is an acyl group, R ² is a cyano group or N
Pyrimidoquinazoline derivatives and salts thereof, each of which represents a 5-membered aromatic heterocyclic substituted carbamoyl group. 2 General formula (In the formula, R ¹ is an acyl group, R ² is a cyano group or N
5-membered aromatic heterocyclic substituted carbamoyl group) and its salts, (a) general formula (In the formula, R ¹ has the same meaning as above) or a salt thereof, and an amine represented by the general formula R ³ -NH ₂ (In the formula, R ³ means an N-containing 5-membered aromatic heterocyclic group) or its salts to form the general formula (In the formula, R ¹ has the same meaning as before, and R ² _a means an N-containing 5-membered aromatic heterocyclic substituted carbamoyl group) or a salt thereof, or (b) the general formula (In the formula, R ¹ has the same meaning as before, and R ⁴ means an esterified carboxy group) by heating the compound represented by the general formula (In the formula, R ¹ has the same meaning as above.) A method for producing pyrimidoquinazoline derivatives and salts thereof, which is characterized by obtaining a compound represented by the following. 3 General formula (In the formula, R ¹ is an acyl group, R ² is a cyano group or N
An anti-allergic agent comprising a pyrimidoquinazoline derivative or a salt thereof as an active ingredient.