JPH0375549B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a pyrido[1,2-a]pyrimidine derivative or a physiologically acceptable salt thereof, a method for producing the same, and a medicament containing the same as an active ingredient. The pyrido[1,2-a]pyrimidine derivative or physiologically acceptable salt thereof of the present invention is a slow reacting substance for anaphylaxis.
of anaphylaxis; hereinafter abbreviated as SRS-A. ) and can be used as a therapeutic agent for type I allergic diseases caused by SRS-A. Prior Art SRS-A has a strong smooth muscle contraction effect and is a causative agent in type I allergic diseases, especially bronchial asthma and allergic rhinitis [Quarterly Journal of Experimental Physiology] of
Experimental Physiology) vol. 30, p. 121, 1940].
The main active ingredient of this substance is leukotriene
This leukotriene was found to be _D4 .
The presence or absence of a drug's inhibitory effect on the in vivo activity of _D4 is considered an indicator for a therapeutic drug for type I allergic disease caused by SRS-A [Nature, Vol. 288]
484 pages 1980]. Treatment drugs for type I allergic diseases caused by SRS-A are:
SRS-A that blocks the release of SRS-A from mast cells or basophils and indirectly inhibits the activity of the substance.
A release-inhibiting drug and SRS-A that competes with released SRS-A in vivo and directly inhibits its activity.
They are broadly classified into antagonistic drugs. However, SRS-A release inhibiting drugs are used for the purpose of preventing allergic attacks caused by SRS-A, and generally tend to lack effectiveness immediately after an attack, so-called immediate effect. Therefore, in recent years, there has been a strong desire for the emergence of a good SRS-A antagonist type drug from the viewpoint of immediate efficacy against allergic attacks. As a conventional pyridopyrimidine compound, 9
-Methyl-3-(1H-tetrazol-5-yl)
-4H-pyrido[1,2-a]pyrimidine-4-
Potassium salt (hereinafter abbreviated as compound TBX) is known and has been reported to be useful as a blocker of type I allergic reactions (Japanese Patent Application Laid-Open No. 1983-1972).
-36294). Problems to be Solved by the Invention However, subsequent research has reported that this compound TBX belongs to SRS-A release inhibiting drugs (Allergy Vol. 33, No. 9, p. 728, 1984).
Further experiments conducted by the present inventors revealed that it does not exhibit an antagonistic effect on SRS-A represented by leukotriene _D4 . Therefore, the inventors
After extensive research into compounds that antagonize the in vivo activity of SRS-A, especially leukotriene _D4 , we found that
Surprisingly, pyrido[1,2-
a] Among compounds having a pyrimidine ring, a novel compound having remarkable leukotriene D ₄ antagonistic activity was discovered, and the present invention was achieved. Means for Solving the Problems According to the present invention, the following general formula [] (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group,
R ² represents a hydrogen atom or an alkanoyl group having 1 to 4 carbon atoms, R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an allyl group, and n is 0 to 5
represents an integer. However, n is an integer of 0 to 2, R ¹ is a hydroxyl group, R ² is an acetyl group, and R ³ is n-
Except when it is a propyl group. ) A pyrido[1,2-a]pyrimidine derivative or a physiologically acceptable salt thereof is provided. Further, according to the present invention, there is provided a method for producing the pyrido[1,2-a]pyrimidine derivative represented by the general formula [] or a physiologically acceptable salt thereof. Furthermore, according to the present invention, this general formula []
Provided is a therapeutic agent for allergic diseases containing a pyrido[1,2-a]pyrimidine derivative represented by the formula or a physiologically acceptable salt thereof as an active ingredient. Pyrido [1,2-a] represented by the general formula []
Pyrimidine derivatives (hereinafter simply referred to as compounds of the present invention []
It is abbreviated as ) is the following general formula [] (In the formula, R ¹ , R ² , R ³ and n have the same meanings as above.) It can be produced by reacting the nitrile derivative represented by the following with hydrazoic acid or a salt thereof. Examples of the hydroazide salts used include alkali metal salts such as sodium azide or potassium azide, alkaline earth metal salts such as calcium azide or magnesium azide, aluminum azide, tin azide, or titanium azide. salts with other metals or with organic bases such as ammonium azide or aniline azide. Hydroazide may be used alone, but
In the case of an alkali metal salt of hydrazoic acid, aluminum azide,
It is preferable to use it after converting it into tin azide, ammonium azide, aniline azide, or the like. Here, the most desirable combination is one consisting of sodium azide and aluminum chloride or ammonium chloride. Examples of the reaction solvent include ethers such as tetrahydrofuran or dioxane, or polar solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide or hexamethylphosphorotriamide. Reaction at 50-150℃
This is done by heating for 1 minute to 72 hours. The compound of the present invention [] produced as described above can be separated from the reaction solution by acid treatment, recrystallization, silica gel column chromatography, or a combination thereof. The recrystallization solvent in the recrystallization method includes water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, hexamethylphosphorotriamide, acetic acid, acetonitrile, trifluoroacetic acid, or tetrahydrofuran, or two of these. A mixed liquid consisting of the above may be mentioned. Examples of the developing solvent in silica gel column chromatography include a mixture of a halogenated hydrocarbon such as chloroform or dichloromethane and an alcohol such as methanol or ethanol. Physiologically acceptable salts of the compounds of the present invention [] include the corresponding compounds [] in water, alcohols, or mixtures thereof, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc. alkali metal or alkaline earth metal hydroxides, sodium carbonate,
alkali metal or alkaline earth metal carbonates such as potassium carbonate, calcium carbonate or magnesium carbonate; alkali metal or alkaline earth metal alcoholates such as sodium, potassium or magnesium; organic amines such as ethanolamine or methyl ephedrin; or ammonia. It can be produced by reacting with. Examples of the alcohols used include methanol, ethanol, isopropyl alcohol, and n-butyl alcohol. The amount of the hydroxide, carbonate, alcoholate, organic amine or ammonia to be used is 0.5 to 6 times, preferably 0.5 to 2 times, the amount of the compound of the present invention []. The salt produced as described above can be purified by recrystallization, if necessary. Examples of the recrystallization solvent include water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, hexamethylphosphorotriamide, acetonitrile, or tetrahydrofuran, or a mixture of two or more thereof. The obtained compound of the present invention [] or a physiologically acceptable salt thereof can be dried using a conventional method such as heat drying, ventilation drying, or freeze drying. The nitrile derivative represented by the general formula [] is represented by the following general formula [] (In the formula, n has the same meaning as above.) A compound represented by the following general formula [] in a molar amount of 1 to 6 times (In the formula, R ¹ , R ² and R ³ have the same meanings as above.) It can be produced by condensing a compound represented by the following in the presence of an acid acceptor. Acid acceptors used include alkali metal carbonates such as sodium or potassium carbonate or alkali metal hydroxides such as sodium or potassium hydroxide. Note that potassium iodide may be present as a reaction accelerator. As a reaction solvent, methanol, ethanol,
Examples include isopropyl alcohol, n-butyl alcohol, acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, dimethyl formamide, dimethyl sulfoxide, a mixture of two or more thereof, or a mixture of these and water. The reaction takes place at 50-110℃ for 1 minute.
This is done by heating for 72 hours. The compound represented by the general formula [] is represented by the following general formula [] (In the formula, n has the same meaning as above.) The compound represented by the formula is brominated using a brominating agent such as phosphorus tribromide or phosphoryl bromide, or the following general formula [] (In the formula, n has the same meaning as above.) The compound represented by the formula can be produced by simultaneously dehydrating the compound using phosphoryl bromide and brominating it. In addition, in the general formula [], a compound in which n is 0 is a compound in which 3-cyano-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is replaced by N
- It can also be produced by bromination using bromosuccinimide. Action and Effects of the Invention The SRS-A antagonistic action of the compound of the present invention [] or a physiologically acceptable salt thereof was investigated by the following experimental method using leukotriene _D4 , a representative active ingredient thereof. As test compounds, the compounds listed below, which are representative examples of the compounds of the present invention [] or physiologically acceptable salts thereof, were used. Note that the display in parentheses after each compound name means the respective tentative names of those compounds in this specification, and corresponds to the examples described later. 9-[(4-acetyl-2-allyl-3-hydroxyphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidine-4-4- on (Example 1), 9-[(4
-acetyl-3-hydroxyphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H
-pyrido[1,2-a]pyrimidin-4-one (Example 2), 9-[(4-n-propylphenoxy)methyl]
-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 3), 9-[(2-n-propylphenoxy)methyl]
-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 4), 9-[(4-acetyl-2-allyl-3-hydroxyphenyl) enoxy)methyl]-3-[3-(1H-tetrazol-5-yl)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (Example 5), 9-[(4- Acetyl-3-hydroxyphenoxy)methyl]-3-[4-(1H-tetrazole-5
-yl)butyl]-4H-pyrido[1,2-a]pyrimidin-4-one (Example 6), 9-[(4-n-propylphenoxy)methyl]
-3-[5-(1H-tetrazol-5-yl)pentyl]-4H-pyrido[1,2-a]pyrimidin-4-one (Example 7), 9-[(4-acetyl-3-hydroxy -2-n
-propylphenoxy)methyl]-3-[3-(1H
-tetrazol-5-yl)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (Example 8), 9-[(4-acetyl-3-hydroxy-2-n
-propylphenoxy)methyl]-3-[5-(1H
-tetrazol-5-yl)pentyl]-4H-pyrido[1,2-a]pyrimidin-4-one (Example 9), 9-[(4-butyrylphenoxy)methyl]-3
-[(1H-tetrazol-5-yl)methyl]-
4H-pyrido[1,2-a]pyrimidin-4-one (Example 10), 9-[(4-acetyl-2-allyl-3-hydroxyphenoxy)methyl]-3-(1H-tetrazole- 5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (Example 11). (i) In vitro test Using the end of the ileum removed from a male Hartley guinea pig, the compound of the present invention []
and its physiologically acceptable salts were tested for leukotriene _D4 antagonism. The test was carried out by first suspending the end of the ileum under ventilation in 10 ml of Tyrode's solution containing 5 × 10 ^-7 molar concentrations of atropine and 1 × 10 ^-6 molar concentrations of mepyramine, and then suspending the suspension for 30 seconds. Test compound and leukotriene D ₄
(manufactured by Wako Pure Chemical Industries, Ltd.) were added one after another, and the degree of contraction of the ileum was measured after 4 to 6 minutes using an isotonic transducer TD-112S (manufactured by Nihon Kohden). The amount of test compound added is
10 ^-9 to 10 ^-3 g/ml, the amount of leukotriene _D4 added is
Each was set to 0.3ng/ml. Leukotriene D ₄ antagonism was evaluated by the concentration of the test compound that suppresses the ileal contractile response induced by leukotriene D ₄ by 50% (hereinafter abbreviated as IC ₅₀ ). This IC ₅₀ is calculated by first calculating the contraction inhibition rate from the measured ileal contraction degree using the following formula: Contraction inhibition rate (%) = (Contraction degree when no test compound is added - Contraction degree when the test compound is added) / Test compound It was calculated according to the degree of contraction in the absence of additives x 100, and then it was determined from a dose-response curve drawn on a graph based on this. The results are shown in Table 1. The same table also shows the leukotriene D ₄ antagonistic effect of compound TBX, which was tested in the same manner as above, for comparison.

[Table] As is clear from Table 1, the compound of the present invention [ ] and its physiologically acceptable salts are found to exhibit significant leukotriene D ₄ antagonism that cannot be predicted from compound TBX. (ii) In vivo test Using male Hartley guinea pigs weighing approximately 400 g in groups of 6 animals, the compound of the present invention [] and its physiological effects on type I allergic reactions induced by leukotriene _D4 were tested. The inhibitory effect of salt tolerable in the salt was determined by the Konzett-Roßssler method (Naunyn Schmiederbergs Archiv, fu¨). r
Experimentelle Pathologie und
PharmaKologie, Vol. 195, p. 71, 1940]. Each guinea pig was anesthetized by intraperitoneal administration of 1.5 g/kg of urethane, and the trachea exposed through neck incision was ventilated via a cannula (inflated air volume 5 to 7 ml, number of air inflows 70 times/min, lung Load pressure 10cm
H ₂ O (manufactured by Ugobasil Biological Research Apparatus) was connected. The amount of air overflowing from the side branches of the cannula was recorded on a Polygraph RM-6000 (manufactured by Nihon Kohden) via a Bronchospassum transducer model 7020 (manufactured by Ugobasil Biological Research Apparatus). The test involved administering 5 mg/Kg of the test compound and 0.5 μg/Kg of leukotriene D ₄ to each guinea pig treated with 1 mg/Kg of garamin trithiodide intravenously.
The test was performed by sequentially administering the drug through the jugular vein at intervals of minutes, and measuring the amount of air that overflowed due to the induced airway constriction reaction. The test compound was dissolved in physiological saline containing sodium bicarbonate or potassium carbonate, and the leukotriene _D4 was dissolved in physiological saline. Five compounds of Examples 1, 5, 8, 9 and 11 were selected as test compounds. These five compounds are
against leukotriene _D4 -induced airway constriction reaction.
Each dose of 5 mg showed an inhibition rate of 50% or more. (iii) Toxicity test The acute toxicity (LD ₅₀ ) of the compound of the present invention and representative examples of physiologically acceptable salts thereof was tested using 5-week-old male ddY mice and male SD rats. Three compounds of Examples 1, 9 and 11 were selected as representative examples. The LD ₅₀ values of all three compounds were 4.0 g/Kg or more for oral administration and 100 mg/Kg or more for intravenous administration in mice. Similarly,
In rats, 4.0 g/Kg or more, 200 g/Kg or more intravenously.
It was more than mg/Kg. From the in vitro, in vivo, and toxicity test results described above, the compound of the present invention [ ] and its physiologically acceptable salts are effective against type I allergic diseases caused by SRS-A, especially bronchial asthma or allergic diseases. It is useful as a therapeutic agent for rhinitis, etc. Further, it can also be applied as an anti-ulcer drug, an anti-inflammatory drug, or a therapeutic drug for ischemic heart disease. Furthermore, the compound of the present invention [] and its physiologically acceptable salt can be made into a pharmaceutical composition by blending it with a physiologically harmless solid or liquid pharmaceutical carrier. This composition can be used in injections, tablets, capsules, powders, fine granules, granules,
It can take the form of syrup, solution, suspension or emulsion. The pharmaceutical carrier may be any carrier commonly used in such formulations, including, for example, corn starch, dextrin, α, β
or γ-cyclodextrin, glucose, lactose, sucrose, methylcellulose, carboxymethylcellulose calcium, crystalline cellulose, magnesium stearate, sodium alginate,
Uitepsol W35, Uitepsol E85, excipients, binders or disintegrants such as polyvinyl alcohol or light silicic anhydride; lubricants such as talc, stearic acid, waxes, hydroxypropylcellulose or boric acid; shellac, cellulose acetate phthalate or coating agents such as polyvinyl acetal diethylamino acetate; solubilizing agents such as glycerin, propylene glycol or mannitol; emulsifying or suspending agents such as polyoxyethylene stearate, polyoxyethylene cetyl alcohol ether, gum arabic or polyvinylpyrrolidone; Stabilizers such as sorbitol, Tween 80, Span 60 or fats and oils; various solvents; or suitable flavorings or syrups may be included. In the above-mentioned pharmaceutical composition, the content of the compound of the present invention [] or a physiologically acceptable salt thereof is such that the daily dose of the active ingredient is
0.002-60mg/Kg, preferably 0.02-10mg/Kg,
For intravenous injection, 1-1000 μg/Kg, preferably 10-200 μg
Set it so that it is g/Kg. The present invention will be further explained with reference examples, examples, and formulation examples. Reference example 9-bromomethyl-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one 6.00g
(22.72 mmol), 4.40 g (22.89 mmol) of 3'-allyl-2',4'-dihydroxyacetophenone, and 1.86 g of anhydrous potassium carbonate were heated under reflux for 2 hours in 160 ml of methyl ethyl ketone. After cooling, the reaction solution was diluted with water and neutralized with dilute hydrochloric acid, and the precipitate was collected by filtration, washed with water, and dried. This precipitate was recrystallized from acetonitrile and 9-[(4-acetyl-2-allyl-3-hydroxyphenoxy)methyl]-3-cyano-4H-pyrido[1,2-a]pyrimidine-4- 6.20 g (yield 73%) of ion was obtained.
The melting point was 244-246°C. 9-bromomethyl-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one to the corresponding compound [] and/or 3'-allyl-2',
4′-dihydroxyacetophenone was changed to the corresponding compound [], and the reaction molar ratio, reaction solvent,
The following 16 nitrile derivatives [ ] were produced in yields of 47 to 71% by operating in substantially the same manner as described above, except for slightly changing reaction conditions such as temperature and time. 9-[(4-acetyl-3-hydroxyphenoxy)methyl]-3-cyano-4H-pyrido[1,2
-a] pyrimidin-4-one. 3-Cyano-9-[(4-n-propylphenoxy)methyl]-4H-pyrido[1,2-a]pyrimidin-4-one. 3-Cyano-9-[(2-n-propylphenoxy)methyl]-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-acetyl-2-allyl-3-hydroxyphenoxy)methyl]-3-(3-cyanopropyl)-4H-pyrido[1,2-a]pyrimidine-
4-on. 9-[(4-acetyl-3-hydroxyphenoxy)methyl]-3-(4-cyanobutyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 3-(5-cyanopentyl)-9-[(4-n-propylphenoxy)methyl]-4H-pyrido[1,
2-a] pyrimidin-4-one. 9-[(4-acetyl-3-hydroxy-2-n
-propylphenoxy)methyl]-3-(3-cyanopropyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-acetyl-3-hydroxy-2-n
-propylphenoxy)methyl]-3-(5-cyanopentyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-butyrylphenoxy)methyl]-3
-Cyanomethyl-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-acetyl-3-hydroxy-2-methylphenoxy)methyl]-3-cyanomethyl-
4H-pyrido[1,2-a]pyrimidin-4-one. 3-(2-cyanoethyl)-9-[(4-n-propylphenoxy)methyl]-4H-pyrido[1,2
-a] pyrimidin-4-one. 9-[(4-acetyl-2-allylphenoxy)
methyl]-3-(5-cyanopentyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 3-(4-cyanobutyl)-9-[(4-propionylphenoxy)methyl]-4H-pyrido[1,2
-a] pyrimidin-4-one. 9-[(4-acetyl-3-hydroxyphenoxy)methyl]-3-(2-cyanoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-n-butylphenoxy)methyl]-
3-cyanomethyl-4H-pyrido[1,2-a]
Pyrimidin-4-one. 3-Cyano-9-phenoxymethyl-4H-pyrido[1,2-a]pyrimidin-4-one. Example 1 9-[(4-acetyl-2-allyl-3-hydroxyphenoxy)methyl]-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one 2.00 g
(5.33 mmol), aluminum chloride 2.10 g (15.75
3.10 g (47.68 mmol) of sodium azide and 60 ml of tetrahydrofuran.
The mixture was heated to reflux for an hour. After cooling, the reaction solution was diluted with ice water, made acidic with dilute hydrochloric acid, and the precipitate was collected by filtration.
This precipitate was recrystallized from a dimethylformamide-ethanol mixture, and 9-[(4-acetyl-2-
Allyl-3-hydroxyphenoxy)methyl]-
1.63 g (yield 73%) of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one was obtained as white crystals. The melting point of this crystal was 267-270°C (decomposition). Infrared absorption spectrum (KBr, cm ^-1 ): 3270, 1690, 1635, 1270 Elemental analysis value (as C ₂₁ H ₁₈ N ₆ O ₄ ): Theoretical value (%); C, 60.28H, 4.34N, 20.09 Actual value (%); C, 60.10H, 4.45N, 19.92 In the above Example 1, 9-[(4-acetyl-
2-allyl-3-hydroxyphenoxy)methyl]-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one (5.33 mmol) was replaced with the corresponding nitrile derivative [] (5.33 mmol) The following Examples 2 to 10 were carried out in almost the same manner except that
The compound was prepared. Example 2 9-[(4-acetyl-3-hydroxyphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidine-4
-On. White crystals: yield 0.93g (yield 46%) Melting point: 290-295℃ (decomposition; recrystallized from dimethylformamide) Infrared absorption spectrum (KBr, cm ^-1 ): 3230, 1680, 1625, 1270 Elemental analysis value (C ₁₈ H ₁₄ N ₆ O ₄ ): Theoretical value (%); C, 57.14H, 3.73N, 22.21 Actual value (%); C, 57.01H, 3.95N, 22.09 Example 3 9-[(4-n -propylphenoxy)methyl]
-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one. White crystals: Yield 0.51g (yield 26%) Melting point: 270-273℃ (decomposition; recrystallized from acetic acid) Infrared absorption spectrum (KBr, cm ^-1 ): 3220, 1675, 1270 Elemental analysis value (C ₁₉ H ₁₈ As N ₆ O ₂ ): Theoretical value (%); C, 62.97H, 5.01N, 23,19 Actual value (%); C, 62.80H, 5.11N, 22.97 Example 4 9-[(2-n- propylphenoxy)methyl]
-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one. White crystals: yield 1.19g (yield 61%) Melting point: 255-260℃ (decomposition; recrystallized from dimethylformamide) Infrared absorption spectrum (KBr, cm ^-1 ): 3250, 1670, 1270 Elemental analysis value (C ₁₉ H ₁₈ N ₆ O ₂ ): Theoretical value (%); C, 62.97H, 5.01N, 23.19 Actual value (%); C, 62.93H, 4.91N, 23.01 Example 5 9-[(4-acetyl-2 -allyl-3-hydroxyphenoxy)methyl]-3-[3-(1H-tetrazol-5-yl)propyl]-4H-pyrido[1,2-a]pyridin-4-one. White powder: Yield 0.74g (yield 30%) Infrared absorption spectrum (KBr, cm ^-1 ): 1680, 1630, 1275 Elemental analysis value (as C ₂₄ N ₂₄ N ₆ O ₄ ): Theoretical value (%); C , 62.59H, 5.25N, 18.25 Actual value (%); C, 62.85H, 5.36N, 18.21 Example 6 9-[(4-acetyl-3-hydroxyphenoxy)methyl]-3-[4-( 1H-tetrazole-5
-yl)butyl]-4H-pyrido[1,2-a]pyrimidin-4-one. White powder: Yield 1.48g (yield 64%) Infrared absorption spectrum (KBr, cm ^-1 ): 3240, 1680, 1620, 1275 Elemental analysis value (as C ₂₂ H ₂₂ N ₆ O ₄ ): Theoretical value (%) ; C, 60.82H, 5.10N, 19.34 Actual value (%); C, 60.44H, 5.32N, 19.23 Example 7 9-[(4-n-propylphenoxy)methyl]
-3-[5-(1H-tetrazol-5-yl)pentyl]-4H-pyrido[1,2-a]pyrimidin-4-one. White powder: Yield 1.13g (yield 49%) Infrared absorption spectrum (KBr, cm ^-1 ): 3225, 1675, 1275 Elemental analysis value (as C ₂₄ H ₂₈ N ₆ O ₂ ): Theoretical value (%); C , 66.65H, 6.53N, 19.43 Actual value (%); C, 66.37H, 6.78N, 19.24 Example 8 9-[(4-acetyl-3-hydroxy-2-n
-propylphenoxy)methyl]-3-[3-(1H
-tetrazol-5-yl)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one. Pale yellow powder: Yield 1.25g (yield 51%) Infrared absorption spectrum (KBr, cm ^-1 ): 1675, 1630, 1270 Elemental analysis value (as C ₂₄ H ₂₆ N ₆ O ₄ ): Theoretical value (%); C, 26.34H, 5.67N, 18.17 Actual value (%); C, 62.69H, 5.72N, 17.82 Example 9 9-[(4-acetyl-3-hydroxy-2-n
-propylphenoxy)methyl]-3-[5-(1H
-tetrazol-5-yl)pentyl]-4H-pyrido[1,2-a]pyrimidin-4-one. Pale yellow powder: 1.12g (yield 43%) Infrared absorption spectrum (KBr, cm ^-1 ): 1680, 1630, 1270 Elemental analysis value (as C ₂₆ H ₃₀ N ₆ O ₄ ): Theoretical value (%); C , 63.66H, 6.16N, 17.13 Actual value (%); C, 63.40H, 6.52N, 17.00 Example 10 9-[(4-butyrylphenoxy)methyl]-3
-[(1H-tetrazol-5-yl)methyl]-
4H-pyrido[1,2-a]pyrimidin-4-one. White crystals: yield 0.43g (yield 20%) Melting point: 226-230℃ (decomposition; recrystallized from dimethylformamide) Infrared absorption spectrum (KBr, cm ^-1 ): 1675, 1620, 1265 Elemental analysis value (C ₂₁ H ₂₀ N ₆ O ₃ ): Theoretical value (%); C, 62.37H, 4.98N, 20.78 Actual value (%); C, 62.06H, 4.83N, 20.72 Example 11 9-[(4-acetyl-2 -allyl-3-hydroxyphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 1.00 g (2.39 mmol) in 50 ml of methanol. 2.75 ml (2.33 mmol) of 5.6% potassium hydroxide in ethanol was added to the suspension, and the mixture was heated to reflux to dissolve. Insoluble matter in this solution was filtered off, and the filtrate was cooled. The precipitate was then collected by filtration to give 9-[(4-acetyl-2-allyl-3-hydroxyphexy)methyl]-3-(1H
-tetrazol-5-yl)-4H-pyrido[1,
2-a] Pyrimidin-4-one potassium salt was obtained as a pale yellow powder in an amount of 0.76 g (yield: 70%). Infrared absorption spectrum (KBr, cm ^-1 ): 1695, 1635, 1280 Elemental analysis value (as C ₂₁ H ₁₇ KN ₆ O ₄ ): Theoretical value (%); C, 55.25H, 3.75N, 18.41 Actual value (% ); C, 54.88H, 3.56N, 18.10 In addition, seven compounds listed below were also produced according to Example 1 above. 9-[(4-acetyl-3-hydroxy-2-methylphenoxy)methyl]-3-[(1H-tetrazol-5-yl)methyl]-4H-pyrido[1,2
-a] pyrimidin-4-one. 9-[(4-n-propylphenoxy)methyl]
-3-[2-(1H-tetrazol-5-yl)
ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-acetyl-2-allylphenoxy)
methyl]-3-[5-(1H-tetrazol-5-yl)pentyl]-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-propionylphenoxy)methyl]
-3-[4-(1H-tetrazol-5-yl)butyl]-pyrido[1,2-a]pyrimidine-4-
on. 9-[(4-acetyl-3-hydroxyphenoxy)methyl]-3-[2-(1H-tetrazole-5
-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one. 9-[(4-n-butylphenoxy)methyl]-
3-[(1H-tetrazol-5-yl)methyl]-
4H-pyrido[1,2-a]pyrimidin-4-one. 9-Phenoxymethyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one. Formulation example (tablet) Weight (%) (1) Example 1 10.0 (2) Lactose 56.0 (3) Corn starch 15.0 (4) Crystalline cellulose 15.0 (5) Hydroxypropylcellulose 3.0 (6) Magnesium stearate 1.0 100.0 Above-mentioned Mix (1) to (5), add water and granulate,
Then it was dried. After sizing the obtained granules,
Add (6) and mix, compression mold this and make 1 tablet 100.
mg tablets were prepared.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group,
R ² represents a hydrogen atom or an alkanoyl group having 1 to 4 carbon atoms, R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an allyl group, and n is 0 to 5
represents an integer. However, n is an integer of 0 to 2, R ¹ is a hydroxyl group, R ² is an acetyl group, and R ³ is n-
Except when it is a propyl group. ) A pyrido[1,2-a]pyrimidine derivative or a physiologically acceptable salt thereof. 2 General formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group,
R ² represents a hydrogen atom or an alkanoyl group having 1 to 4 carbon atoms, R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an allyl group, and n is 0 to 5
represents an integer. However, n is an integer of 0 to 2, R ¹ is a hydroxyl group, R ² is an acetyl group, and R ³ is n-
Except when it is a propyl group. ) A general formula characterized by reacting the nitrile derivative shown in (In the formula, R ¹ , R ² , R ³ and n have the same meanings as above.) A method for producing a pyrido[1,2-a]pyrimidine derivative or a physiologically acceptable salt thereof. 3 General formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group,
R ² represents a hydrogen atom or an alkanoyl group having 1 to 4 carbon atoms, R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an allyl group, and n is 0 to 5
represents an integer. However, n is an integer of 0 to 2, R ¹ is a hydroxyl group, R ² is an acetyl group, and R ³ is n-
Except when it is a propyl group. 1. A therapeutic agent for allergic diseases characterized by containing a pyrido[1,2-a]pyrimidine derivative represented by the following formula or a physiologically acceptable salt thereof as an active ingredient.