JPH0655740B2 - Pyridopyrimidine derivative - Google Patents

Description

Detailed Description of the Invention a. INDUSTRIAL APPLICABILITY The present invention relates to a novel pyridopyrimidine derivative having excellent antiulcer activity.

2. Description of the Related Art Conventionally, antiulcer agents have been actively developed in consideration of acid secretion inhibitory action and mucosal protective action. Above all,
Compounds showing anti-ulcer by mucosal protective action include sofalcon and carbenoxolon.
e): (US Pat. No. 3,070,623) and Japanese Patent Laid-Open No. 52-
Examples include FPL-52694 described in the specification of 83756.

Further, a compound having a pyridopyrimidine skeleton is disclosed in US Patent No.
No. 4,022,897, the compound of the present invention is not only different in structure from the compound of the present invention but also targets the action on the central nervous system. different.

Problems to be Solved by the Invention There is a demand for the development of a compound having an increased anti-ulcer action and reduced undesirable side effects.

B. Means for Solving Problems The present inventors have found that a compound represented by the following general formula (I) or a salt thereof exhibits an excellent anti-ulcer action,
The present invention has been completed.

General formula: [In the formula, n 0 or 1, R is ^formula: -COR 1, -CONR ⁴ R ⁵ or -CH ₂
Represents R ⁶ , wherein R ¹ is C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, allylthio, styryl, phenoxymethyl, thienylmethyl, substituted or unsubstituted C ₆ -C ₁₀ aryl (substituents: halogen, C ₁ -C _{3 alkoxy,} C 1 -C
₃ alkyl, C ₃ -C ₆ cycloalkyl, trifluoromethyl, nitro, cyano, acetyl, acetyloxy,
C ₂ -C ₄ alkoxycarbonyl, sulfamoyl, C
_1- C ₃ alkanesulfonyl, tetrazolyl, carbamoyl), substituted or unsubstituted benzyl (substituent: C
₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, halogen,
Nitro) or a substituted or unsubstituted heterocyclic residue (substituent: C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C
_3- C ₆ cycloalkyl), (heterocycle residue: furyl,
Thienyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl), R ² and R ³ are each hydrogen, C ₁ -C ₅ alkyl, carboxy, C ₂ -C ₅ alkoxycarbonyl or substituted or unsubstituted benzyloxycarbonyl (substituent: C
₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, halogen,
Nitro), R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₅ alkyl, C ₃
-C ₇ cycloalkyl or substituted or unsubstituted phenyl (substituent: _halogen, C 1 _{~ 3 alkyl, C} 1 ~
C ₃ alkoxy, alkoxycarbonyl, nitro, trifluoromethyl), R ⁶ is a substituted or unsubstituted phenyl (substituent: halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, alkoxycarbonyl, nitro, trifluoromethyl). ) Or pyridyl]] The terms used in the above definitions are explained below.

As alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t
Examples thereof include C ₁ -C ₅ alkyl such as ert-butyl, n-pentyl, isopentyl, sec-pentyl, neo-pentyl and the like.

Examples of cycloalkyl include C ₃ -C ₇ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.

Examples of aryl include phenyl and naphthyl.

Heterocyclic residues include furyl, thienyl, pyridyl,
Oxazolyl, thiazolyl, isoxazolyl and the like, and the substituents which may be present on the aryl include halogen (eg fluorine, chlorine, bromine, iodine etc.),
C ₁ -C _{3 alkoxy,} C 1 -C _{3 alkyl,} C 3 -C
₆ cycloalkyl, trifluoromethyl, nitro, cyano, acetyl, _acetyloxy, C 2 -C ₄ alkoxycarbonyl, _sulfamoyl, C 1 -C ₃ alkanesulfonyl, Tetorazoriru and carbamoyl are exemplified.

Substituents which may be present on the heterocycle include C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl and the like. Substituents which may be present on the benzyl group include C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy,
Examples include halogen and nitro.

Examples of the alkanesulfonyl include C ₁ -C ₃ alkanesulfonyl such as methanesulfonyl, ethanesulfonyl and propanesulfonyl.

In the substituted or unsubstituted phenyl, examples of the substituent include halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, alkoxycarbonyl, nitro, trifluoromethyl and the like.

The pyridopyrimidine derivative (I) of the present invention can be produced by the following production method A, production method B, production method C or production method D.

Manufacturing method A (when R is -CO-NHR ⁴ ) (In the formula, R ² , R ³ and R ⁴ have the same meanings as described above.) In the general formula (I), the compound in which R is —CO—NHR ⁴ can be produced according to the above process chart. That is, 9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine (II)
And the isocyanates (III) are reacted in a suitable solvent at a temperature of about 0 to about 80 ° C., preferably about room temperature (10 to 30 ° C., the same below) for about 1 to 10 hours to give the target compound (Ia ) Get.

Solvents that can be used in the reaction include dichloromethane, 1,2
-Halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride; cyclopentane, cyclohexane,
In addition to hydrocarbon solvents such as n-hexane, benzene,
Ethyl acetate, acetonitrile, tetrahydrofuran, or ketones such as acetone and methyl ethyl ketone are used.

Isocyanates (III) react with the corresponding amines and phosgene [RJ Slocombe et al., J. Am.chem. Soc., 72 , 1888 (1
950)] or the reaction of the corresponding amine with oxalyl chloride [H. Ulrich et al., J. Org. Chem., 34 , 3200 (1969)].

Manufacturing method B (R is When) (In the formula, R ² , R ³ , R ⁴ , and R ⁵ are as defined above.) In the general formula (I), R is The compound of 1 can be produced according to the above process chart.

Next, the first step and the second step will be described.

First Step 9-Mercapto-4-oxo-4H-pyrido [1,2-
a] The pyrimidine derivative (II) is reacted with 1,1′-carbonyldiimidazole to obtain the compound (IV).

However, a carbonylation reagent other than 1,1'-carbonyldiimidazole can also be used. As the solvent used in the reaction, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; benzene, tetrahydrofuran, acetonitrile,
Examples include ethyl acetate.

The reaction may be carried out at a temperature of about 0 to about 100 ° C., preferably around room temperature.

Step 2 The target compound (Ib) can be obtained by reacting the compound (IV) obtained with the compound (V).

As the solvent, the same solvent as that used in the first step can be used, and this reaction is carried out at room temperature to a temperature under heating (about 4 ° C).
If carried out at 0 to about 100 ° C., the process is completed in several hours to several tens of hours.

The first step and the second step can be performed continuously,
Further, the intermediate (IV) can be isolated if necessary.

Production method C (when R is -CH ₂ -R ⁶ ) (In the formula, R ² , R ³ and R ⁶ have the same meanings as described above, and Hal represents halogen (chlorine, bromine, iodine, etc.).) In the general formula (I), R is —CH ₂ —R ⁶ The compound of 1 can be produced according to the above process chart.

Next, each of the first step and the second step will be described.

First Step 9-Mercapto-4-oxo-4H-pyrido [1,2-
a] The compound (Ic) is obtained by reacting the pyrimidine derivative (II) with the compound (VI) in the presence of a base in a suitable solvent at about 10 to about 100 ° C.

Examples of the base that can be used in the reaction include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydride, and triethylamine,
Organic bases such as N-methylpyrrolidine, N-ethylpiperidine, morpholine, pyridine, picoline and the like can be mentioned. Examples of the solvent include alkanols such as methanol, ethanol and isopropanol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as ether and tetrahydrofuran; dimethylformamide, dimethylacetamide and dimethyl sulfoxide.

Second Step Further, the compound (Ic) obtained is added with a peroxide in a suitable solvent at a temperature under cooling (eg, about −50 to about 10 ° C., the same below), and then the temperature under cooling or room temperature. The target compound (Id) can be obtained by reacting for several hours. As the solvent that can be used in the reaction, chloroform, dichloromethyl,
Halogenated hydrocarbon solvents such as 1,2-dichloroethane and carbon tetrachloride; alkanols such as ethanol and isopropanol; aprotic solvents such as dioxane, benzene, toluene, etc., depending on the nature of the peroxide used. It may be selected as appropriate. As a peroxide,
Hydrogen peroxide, ethyl hydroperoxide, hydroperoxide tert-
Hydroperoxides such as butyl; or peracids such as peracetic acid, perbenzoic acid, and halogenated perbenzoic acid (eg, 3-chloroperbenzoic acid) may be used. When a hydroperoxide is used, the reaction may be accelerated by adding a mineral acid such as hydrochloric acid or sulfuric acid; a sulfonic acid such as p-toluenesulfonic acid or methanesulfonic acid; or an acid catalyst such as a Lewis acid.

Manufacturing method D (when R is -COR ¹ ) (In the formula, X represents a halogen, a hydroxyl group or an active ester group, and R ¹ , R ² and R ³ have the same meanings as described above.) That is, 9-mercapto-4-oxo-4H-pyrido [1,2] -A] pyrimidine (II) and acylating agent (VII)
In a suitable solvent, optionally in the presence of a base, from about 0 to about 8
When the reaction is carried out at 0 ° C., preferably at a temperature near room temperature (10 to 30 ° C.) for 1 to 10 hours, the target substance (Ie) is obtained. As the solvent used in the reaction, dichloromethane, 1,
Examples thereof include halogenated hydrocarbons such as 2-dichloroethane and chloroform, hydrocarbon solvents such as cyclopentane, cyclohexane, n-hexane and benzene, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile and tetrahydrofuran.

As the base used in the reaction, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydride, triethylamine, N-methylpyrrolidine, N-ethylpiperidine, morpholine,
Examples include organic bases such as pyridine and picoline, sodium methoxide, sodium ethoxide, and basic ion exchange resins.

The organic acid halogenide (VII) can be obtained by reacting the corresponding organic acid with a halogenating agent such as thionyl chloride by a conventional method.

Alternatively, acylation with carboxylic acid (VII) can be accomplished by carrying out the reaction in a solvent in the presence of a dehydrating agent such as DCC. Further, the acylation with carboxylic acid (VII) -lower carbonic acid chloroester-triethylamine is carried out in a solvent at 0-100 ° C. These reactions are carried out by a conventional method of acylation.

As an alternative method for producing the compound (Ie) of the present invention, a 9-mercapto compound (II) and an activated ester of an organic acid derived from an organic acid (R ¹ CO ₂ H) in a suitable solvent are used. -1
0 to about 80 ° C., preferably around room temperature (10 to 30 ° C.
It is a method of reacting at (C) for 1 to 10 hours. In addition to the above, examples of the solvent used in the reaction include dimethylformamide, dimethylacetamide, and dimethylsulfoxide.

As another method for producing the compound (Ie) of the present invention,
As shown in the reaction formula below (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.) The presence of a Lewis acid such as zinc iodide, zinc chloride or aluminum chloride causes the presence of a carbamoyl compound (Ib). There is a method of reacting a carboxylic acid halide (VII). This reaction is 1,2-
It may be carried out by heating under reflux in a suitable solvent such as dichloroethane, methylene chloride or toluene to about the boiling point of the solvent.

The method for producing the raw material (II) will be described below.

Production Method of Raw Material Compound (II) The introduction of the thiol group into the raw material compound (II) is described in “
Chemistry of the Thiol Group (The Chemi
stry of the thilol group ", Saul Ptai
atai), Inter Science Publishing (An Interscience Pu
blication), any of the methods described in p163 to 269 (1974) may be used, but the method of deriving a thiol group from a hydroxy group is illustrated below.

Raw material synthesis (1) (In the formula, R ² and R ³ are as defined above, and X is halogen (chlorine, bromine, iodine, etc.), methoxy, ethoxy,
A leaving group such as tosyloxy, mesyloxy, dimethylamino, alkylthio (methylthio, ethylthio, propylthio, butylthio, etc.); A ¹ and A ² represent lower alkyl. ) Step 1 The compound (X) is obtained by reacting with the thiocarbamoyl chloride compound (IX) in the presence of a suitable base in a solvent suitable for the compound (VIII). As the base used in the reaction, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, inorganic salts such as sodium hydride, triethylamine,
Examples thereof include organic bases such as N-methylpyrrolidine, N-ethylpiperidine, morpholine, pyridine, 4-dimethylaminopyridine and 4-pyrrolidylpyridine, sodium methoxide, sodium ethoxide, and basic ion exchange resins. This reaction may be carried out at 0 to 80 ° C, preferably room temperature. Examples of the solvent include acetone, toluene, ether, dioxane, dimethyl sulfoxide, methyl ethyl ketone, ethyl acetate, tetrahydrofuran and the like.

Step 2 The aminopyridine compound (X) and the compound (XI) are heated in the presence or absence of a solvent at a temperature from room temperature to heating (for example,
Enamine (XII) by reacting at about 40 to about 100 ℃
Is a step of obtaining.

When the reaction is carried out in the presence of a solvent, the same aprotic solvent as that which can be used in the second step of the production method C is used. In this reaction, a base that can be used in the first step of production method C may be used, if necessary.

Raw compound (XI) is RM Carlson et al., Tetrahedron Lette
rs, 4819 (1973), and GH Posner et al., Chem. Commun. 907.
(1973) or the methods cited therein.

Step 3 The enamine compound (XII) is subjected to a ring closure reaction to give the desired compound (I
This is the step of obtaining b).

The reaction can be accomplished in a few minutes to a few hours if the reaction is carried out while heating the solvent under reflux.

As the solvent, toluene, xylene, or diphenyl ether has a boiling point of about 100 ° C. or higher, preferably about 20.
A solvent at 0 ° C or higher may be used.

Fourth Step In this step, compound (Ib) is reacted with sodium propylmercapto in a suitable solvent to give compound (II). This reaction may be carried out in a nitrogen stream at 0 to 80 ° C, preferably 0 ° C to room temperature. Examples of the solvent include THF, dioxane, ethanol, toluene, dimethyl sulfoxide and the like.

Raw material synthesis (2) (In the formula, R ² , R ³ , A ¹ , A ² and X have the same meanings as described above. A ³ represents lower alkyl.) Step 1 Aminopyridines (VIII) and β-oxocarboxylic acid In this step, the ester (XIV) is reacted in the presence of an acidic condensing agent in a suitable solvent to obtain the target compound (XV).

As the acidic condensing agent, polyphosphoric acid, alkanoic acids such as acetic acid and propionic acid, and the like may be used, and the solvent may be water; alkanols such as methanol, ethanol, isopropanol, butanol, and the like, and a mixture thereof. A solvent is used.

Raw material β-oxocarboxylic acid ester (XIV) is CRHau
It can be produced according to the method described in ser et al., Organic Reactions 1 , 266 (1942).

Alternatively, the β-oxocarboxylic acid esters (XI
Compound (XV) using compound (XI) instead of V)
You may lead to. This reaction may be carried out in the presence of a base, as in the second step of production method (1).

Second Step This step can be performed in the same manner as the first step of the production method (1).

Third Step This step can be performed at a lower temperature than the third step of the production method (1).

As the solvent, the boiling point of toluene, xylene, anisole, diethylene glycol, tetrachloroethane, etc. is 10
It can be carried out using a solvent at 0 ° C to 170 ° C.

Fourth Step This step can be performed in the same manner as the fourth step of the production method (1).

When R ² and / or R ³ in the target compound obtained by each of the production methods A to D above is an alkoxycarbonyl group, it can be hydrolyzed to a carboxyl group by a conventional method.

The compound (I) of the present invention can be converted into a salt, and can be converted into an alkali metal salt (such as a lithium, sodium or potassium salt) or an alkaline earth metal salt (such as a calcium or magnesium salt) depending on the kind of substituents and the like. . In some cases, the target compound (I) can be converted into an acid addition salt. In this case, as an acid that may be used, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, maleic acid, Examples thereof include organic acids such as fumaric acid, citric acid, malic acid, adipic acid and succinic acid.

The compound (I) of the present invention and / or a salt thereof can be orally or parenterally administered to humans or animals. For example,
Compound (I) is orally administered as tablets, granules, powders, capsules, solutions and the like, and parenterally as injections, suppositories and the like. These formulations are prepared by well-known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, suspending agents, dispersants, solubilizers and preservatives. Manufactured accordingly. Excipients include lactose, sucrose, starch, cellulose, sorbit, etc .; binders, gum arabic, gelatin, polyvinylpyrrolidone, etc .; lubricants, magnesium stearate,
Examples are talc and silica gel.

When the compound (I) of the present invention is used for treating adult peptic ulcer disease, it may be administered orally or parenterally at a dose of about 1 to 100 mg / kg daily in one or several divided doses.

Hereinafter, the embodiments of the present invention will be clarified by showing Examples, Reference Examples, and Formulation Examples.

However, the abbreviations used in Examples, Reference Examples, and Tables have the following meanings.

Me: methyl; Et: ethyl; n-Pr: n-propyl; t-Bu:
t- butyl; CH ₂ Cl _2: dichloromethane; CHCl _3: chloroform; AcOEt: ethyl acetate; THF: tetrahydrofuran; K ₂ CO _3: potassium carbonate; DMF: dimethylformamide; NaH: Sodium hydride (60% oily suspension ); MC
PBA: 3-chloroperbenzoic acid; (d): decomposition point.

Example 1 3-Ethoxycarbonyl-9- (4-methylphenylcarbamoylthio) -4-oxo-4H-pyrido [1,2
-A] Preparation of pyrimidine Ia-1: 3-Ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine II-10.
4 g was suspended in 10 ml of dry CH ₂ Cl ₂ , 0.35 g of 4-methylphenyl isocyanate III-1 was added, and the mixture was stirred at room temperature for 4 hours. At this time, the reaction mixture once dissolved and then crystallized again, so this was collected by filtration, washed with AcOEt, and recrystallized from AcOEt to give the title compound Ia-1 0.4
41 g was obtained.

Yield: 72% mp: 170-172 ° C Elemental analysis (as C ₁₉ H ₁₇ O ₄ N ₃ S): Calculated value (%): C, 59.52: H, 4.47; N, 10.96; S. 8.36 Measured value ( %): C, 59.52: H, 4.55; N, 10.84; S. 8.47 Examples 2 to 19 (In the formula, R ² , R ³ , and R ⁴ have the same meanings as described above.) 9-mercapto-4-oxo-4H-pyrido [1,2-
a] The pyrimidine derivative (II) was suspended in an appropriate solvent, the isocyanates (III) were added, and the mixture was stirred at room temperature for about 1 to 5 hours. The precipitated crystals are collected by filtration and washed with AcOEt, then AcOEt
The crystals were recrystallized from to obtain the target compound (Ia).

Table 1 shows the details of reaction conditions for the production of compound (Ia) (structure of reactant and charged amount thereof, solvent, reaction time, etc.) and structure and physical constants (melting point, melting point, etc.) of the obtained target compound (Ia). Elemental analysis value) is shown.

Example 20 Preparation of 3-ethoxycarbonyl-9- (N-ethyl-N-phenylcarbamoylthio) -4-oxo-4H-pyrido [1,2-a] pyrimidine Ib-20: 3-Ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine II-10.
413 g was suspended in 10 ml of dry CH ₂ Cl ₂ and stirred under 1,
0.3 g of 1'-carbonyldiimidazole was added and stirred for 1 hour. N-ethylaniline V-1 0.2 was added to the mixture.
g was added and the mixture was stirred for 16 hours. After completion of the reaction, the solvent was distilled off and the residue was subjected to silica gel chromatography to obtain 0.33 g of the title compound Ib-20 as a viscous oily substance.

NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7Hz), 1.27 (3H, d, J = 7Hz),
3.22 (2H, q, J = 7Hz), 4.15 (2H, q, J = 7Hz), 6.80 ~ 7.80 (8H,
m), 7.96 (1H, s) mass spectrum M ⁺ (m / e): 397 Example 21 (1) 3-ethoxycarbonyl-9-benzylthio-4
-Oxo-4H-pyrido [1,2-a] pyrimidine Ic-2
Manufacture of 1: 3-Ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine II-10.
3 g was suspended in 4 ml of anhydrous DMF, and benzyl bromide VI-1
0.3 g and K ₂ CO ₃ 0.5 g were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water, the precipitated crystals were collected by filtration and then dissolved in CHCl ₃ . It was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 0.389 g of the title compound Ic-21. Yield: 95.3% mp: 173~174 ℃ elemental analysis (recrystallized from AcOEt) (as _{C 18 H 16 O 3 N 2} S): Calculated (%): C, 63.51; H, 4.74; N, 8.23; S.9.42 Found (%): C, 63.48: H, 4.63; N, 8.17; S, 9.30 (2) 3-Ethoxycarbonyl-9-benzylsulfinyl-4-oxo-4H-pyrido [1 , 2-a] Pyrimidine Id-22: 3-Ethoxycarbonyl-9-benzylmercapto-4-oxo-4H-pyrido [1,2-a] obtained in (1) above
Pyrimidine Ic-21 was dissolved in 25 ml CHCl ₃ and cooled to 0 ° C. While stirring, 0.5 g of m-CPBA was added as a solid, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed successively with a 5% aqueous sodium thionitrate solution and a 5% aqueous sodium hydrogen carbonate solution, and further washed with water. After drying this over anhydrous sodium sulfate, the solvent was distilled off, and the residue (1 g) was subjected to flash chromatography and eluted with AcOEt. The solid obtained from the eluate was recrystallized from AcOEt to give the title compound Id-22
0.6 g was obtained. Yield: 81.9% mp: 175~176 ℃ Elemental analysis (as _{C 18 H 16 O 4 N 2} S): Calculated (%) C, 60.66; H , 4.53; N, 7.86; S, 9.00 Found (%) C, 60.72; H, 4.64; N, 7.75; S, 8.80 Examples 22-23 (In the formula, R ⁶ has the same meaning as described above.) (1) 3-ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine II-1 is suspended in anhydrous DMF. It became cloudy, compound (VI) and K ₂ CO ₃ were added, and the mixture was stirred at room temperature for several hours. The reaction mixture was diluted with water, the precipitated crystals were collected by filtration and then dissolved in CHCl ₃ . It was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a compound (Ic).

Table 2 shows the details of reaction conditions for the production of compound (Ic) (structure of reactant and charged amount thereof, amount of solvent used, reaction time, etc.), and structure and physical constant of the obtained compound (Ic) ( Melting point, elemental analysis value).

(2) Dissolve compound (Ic) in CHCl ₃ and cool m-CP with stirring.
BA was added and the mixture was stirred at the same temperature for several hours. 5% of reaction mixture
It was washed successively with a sodium thiosulfate aqueous solution and a 5% sodium hydrogen carbonate aqueous solution, and further washed with water. After drying this over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to flash chromatography and eluted with AcOEt. The solid obtained from the eluate was recrystallized from AcOEt to give the compound (I
got d).

Table 3 shows the details of the reaction conditions for the production of the compound (Id) (the structure of the reaction product and the charged amount thereof, the solvent, the reaction time, etc.), and the structure and physical constants (melting point, melting point, etc.) of the obtained target compound (Id). Elemental analysis value) is shown.

Example 24 3-Ethoxycarbonyl-9-[(4-n-butoxybenzoyl) thio] -4-oxo-4H-pyrido [1,2
Preparation of -a] pyrimidine Ie-27: 3-ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine II-10.
8 g, finely powdered potassium carbonate 0.5 g, acetone 25
With stirring, 0.7 g of 4-n-butoxybenzoyl chloride is added to the mixture of ml and stirred at room temperature for 2 hours. The precipitate obtained is filtered off and distributed between water and chloroform. The chloroform layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue, 1.1 g, was subjected to column chromatography using silica gel and eluted with ethyl acetate to obtain 0.7 g of the title compound Ie-27. Yield 51%.
Melting point 148-149 [deg.] C.

Elemental analysis _{(as C 22 H 22 O 5 N 2} S): Calculated (%): C, 61.96; H, 5.20; N, 6.57; S, 7.52 Found (%): C, 61.73; H, 5.22; N, 6.47; S, 7.65 Examples 25-50 9-mercapto-4-oxo-4H-pyrido [1,2-
a] The pyrimidine derivative (II) is suspended or dissolved in an appropriate solvent, an appropriate base and then the acid chlorides (III) are added,
Stir at room temperature for about 1-5 hours. The reaction mixture was dried under reduced pressure, the residue was partitioned into water-chloroform, the organic layer was washed with water, the solvent was distilled off after drying, and the residue was recrystallized with an appropriate solvent or chromatographed. Then, the compound of interest (Ie) is obtained.

Table 1 shows the details of reaction conditions for the production of compound (Ie) (structure of reactant and charged amount thereof, solvent, reaction time, etc.) and structure and physical constants (melting point, melting point, etc.) of the obtained target compound (Ie). Elemental analysis value) is shown.

Example 51 3-Ethoxycarbonyl-9- (5-methylisoxazol-3-yl) carbonylthio-4-oxo-4H-
Preparation of pyrido [1,2-a] pyrimidine Ie-54: 3-carboxy-5-methylisoxazole VII 0.
23 g was dissolved in 5 ml of dry benzene and thionyl chloride of 0.1.
39 g are added, then 3 drops of dry N, N-dimethylformamide are added, and the mixture is heated under reflux on an oil bath for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 10 ml of acetone, and 1.1 g of finely powdered potassium carbonate and 0.4 g of thiol (II) were obtained.
And stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography and eluted with ethyl acetate to obtain 0.2 g of the title compound.
Melting point 147-150 [deg.] C. 33.8 percent yield elemental analysis (recrystallized from chloroform -n- hexane) _{(as C 16 H 13 O 5 N 3} S · 1 / 2H 2 O): Calculated (%): C, 52.17; H, 3.93 N, 11.41; S, 8.71 Found (%): C, 52.42; H, 3.69; N, 11.32; S, 8.87 Example 52 3-Ethoxycarbonyl-9-[[(5-cyclopropylisoxazole- 3-yl) carbonyl] thio] -4
-Oxo-4H-pyrido [1,2-a] pyrimidine Ie-5
Preparation of 5: 0.28 g of 3-carboxy-5-cyclopropylisoxazole was dissolved in 5 ml of dry benzene, 0.39 g of thionyl chloride was added, and then 3 drops of dry N, N-dimethylformamide were added to the oil bath. Heat to reflux for 5 hours. After distilling off the solvent under reduced pressure and dissolving the residue in 10 ml of acetone, 1.1 g of finely powdered potassium carbonate and thiol derivative (I
I) Add 0.4 g and stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, the insoluble matter was removed, the chloroform solution was dried under reduced pressure, and the residue was recrystallized from chloroform-n-hexane to give 0.32.
g of the title compound Ie-55 is obtained. Yield 52%, melting point 189-
191 ° C. (decomposition) Elemental analysis _{(as C 16 H 15 O 5 N 3} S · 1 / 5H 2 O): Calculated (%); C, 55.57; H, 3.99; N, 10.80; S, 8.24 Found ( %); C, 55.53; H, 3.99; N, 10.72; S, 8.17 Example 53 3-Ethoxycarbonyl-9- (4-ethoxycarbonylbenzoyl) thio-4-oxo-4H-pyrido [1,
Preparation of 2-a] pyrimidine Ie-56: 4-ethoxycarbonylbenzoic acid (VII) 1.47 g
To a mixture of (2.4 mmol), 3 drops of DMF and 10 ml of benzene, 0.52 g (4.4 mmol) of thionyl chloride was added, and the mixture was heated under reflux with stirring for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in 10 ml of acetone, 1.4 g of solid potassium carbonate was added, and then 3-ethoxycarbonyl-9.
-Mercapto-4-oxo-4H-pyrido [1,2-
a] 0.5 g (2 mmol) of pyrimidine (II-1) is added and vigorously stirred at room temperature for 20 minutes. The reaction mixture is dried under reduced pressure and the residue is partitioned between chloroform and water. The organic layer is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel chromatography and eluted with ethyl acetate to obtain 0.9 g of the title compound Ie-56.

Yield: about 100% Melting point: 146-148 ° C (chloroform-n-hexane) Elemental analysis As C ₂₁ H ₁₈ N ₂ O ₆ S: Calculated value (%): C, 59.14; H, 4.25; N, 6.57; S, 7.52 Found (%): C, 58.92; H, 4.23; N, 6.55; S, 7.44 Examples 54-57 The substituted aryl carboxylic acid (VII) is suspended or dissolved in a suitable solvent (solvent a), a catalytic amount of DMF and then thionyl chloride are added, and the mixture is refluxed under heating for about 1 to 5 hours (reaction time h
₁ ) Do. The reaction mixture is dried under reduced pressure and the residue is dissolved in a suitable solvent (solvent b). Suitable bases, and 9-mercapto-4-oxo -4H- pyrido [1,2-a] pyrimidine II-1 was added, about 0.5 to 3 hours at room temperature (reaction time _{h 2)} and stirred. The reaction mixture was dried under reduced pressure,
Partition the residue between chloroform and water. Wash the organic layer with water,
After drying, the solvent is distilled off. Recrystallize the residue in a suitable solvent,
Alternatively, it is purified by silica gel chromatography to obtain the target compound (Ie).

Table 5 shows the details of the reaction conditions for the production of compound (Ie) (structure of reactant and charged amount thereof, solvent, reaction time, etc.),
And the structure and physical constants (melting point, elemental analysis value) of the obtained target compound (Ie) are shown.

Example 58 3-Ethoxycarbonyl-9- (4-sulfamoylbenzoyl) thio-4-oxo-4H-pyrido [1,2-
a] Preparation of pyrimidine Ie-61: 0.48 g (2.4 mmol) of 4-sulfamoylbenzoic acid was dissolved in 10 ml of DMF, 0.29 g of Et ₃ N was added, 0.28 g of ethyl chlorocarbonate was added at room temperature, and the mixture was stirred for 1 hour. 9-mercapto-4-oxo-4
H-pyrido [1,2-a] pyrimidine (II-1) 0.5
g is added as a solid form and stirred for 2 hours. Reaction mixture with water 1
Dilute with 00 ml and extract with ethyl acetate. The organic layer is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue is washed with ethyl acetate to give 0.68 g of the title compound Ie-61. yield:
78.5%. Recrystallize from ethyl acetate-tetrahydrofuran to obtain crystals. Mp: 214-217 ° C. (decomposition) as elemental analysis _{C 18 H 15 N 3 O 6} S 2: Calculated (%); C, 49.87; H, 3.49; N, 9.70; S, 14.80 Found (%); C, 49.86; H, 3.57; N, 9.49; S, 14.64 Example 59-62 The substituted aryl carboxylic acid (VII) is suspended or dissolved in a suitable solvent, and a suitable base and then ethyl chlorocarbonate are added to give 0. About 0.5 to 2 hours (reaction time h ₁ ) at ℃ to room temperature
Stir. 9-Mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidine II-1 was added as a solid or dissolved in a suitable solvent and added at 0 to 100 ° C. to about 0.5.
5 hours (reaction time _{h 2)}攪拌Ru. The reaction mixture is partitioned between water and a suitable organic solvent, the organic layer is washed with water, dried and dried under reduced pressure. The residue is recrystallized or purified by silica gel chromatography to obtain the target compound (Ie).

Table 6 shows the details of reaction conditions for the production of compound (Ie) (structure of reactant and charged amount, solvent, reaction time, etc.),
And the structure and physical constants (melting point, elemental analysis value) of the obtained target compound (Ie) are shown.

Example 63 3-Ethoxycarbonyl-9- (4-methoxycarbonylbenzoyl) thio-4-oxo-4H-pyrido [1,
Preparation of 2-a] pyrimidine Ie-66 3-ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2-a] pyrimidiun (II-1)
To a mixture of 30 g, pulverized potassium carbonate 2.49 g, and acetone 500 ml, 23.8 g of 4-methoxycarbonylbenzoyl chloride was added with stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture is dried under reduced pressure and the residue is partitioned between water and chloroform. The chloroform layer is washed with saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate to obtain 43 g of the title compound Ie-66.

Yield: 86.9% mp: 174-176 (° C.) Elemental analysis C ₂₀ H ₁₆ N ₂ O ₆ Calculated S (%): C, 58.24 ; H, 3.91; N, 6.79; S, 7.78 Found (%): C, 57.88; H, 3.83; N, 6.62; S, 7.57 Examples 64-74 9-mercapto-4-oxo-4H-pyrido [1,2-
a] Pyrimidine (II) is suspended or dissolved in a suitable solvent, a suitable base and then the acid chloride (VII) are added, and the mixture is stirred at room temperature for about 1 to 5 hours. The reaction mixture is dried under reduced pressure, the residue is partitioned into water-chloroform, the organic layer is washed with water and dried, and the solvent is distilled off. The residue is recrystallized with an appropriate solvent or purified by silica gel chromatography to obtain the target compound (Ie). Table 7 shows the details of the reaction conditions for the production of the compound (the structure of the reaction product, the charged amount thereof, the solvent, the reaction time, etc.) and the structure and physical constants (melting point, elemental analysis) of the obtained target compound (Ie). Value).

Example 75 9- (Dimethylcarbamoyl) thio-4-oxo-4H
-Preparation of pyrido [1,2-a] pyrimidine Ib-78: (1) 2,2-dimethyl-1,3-dioxane-4,6-
A mixture of 6.0 g of dione and 30 ml of ethyl orthoformate was heated under reflux on an oil bath for 2 hours, and then 8.0 g of 2-amino-3-dimethylthiocarbamoyloxy-pyridine was added,
Further, the mixture is heated and stirred under reflux for 2 hours. After cooling, the precipitated crystals were collected by filtration and washed with ether to give 6.4 g of 2-
(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemethyl) amino-3-dimethylthiocarbamoyloxypyridine is obtained. Recrystallize from ethyl acetate to obtain crystals. Melting point: 223-225 ° C. (decomposition) Elemental analysis Calculated as C ₁₅ H ₁₇ O ₅ N ₃ S (%): C, 51.27; H, 4.88; N, 11.96; S, 9.12 Measured value (%); C, 51.29; H, 4.78; N, 11.84; S, 8.99 (2) 2.5 g of the above purified product is dissolved in 100 ml of Dowtherm (Dowtherm A Dow Chemical Co.) and heated under reflux for 5 minutes.

After cooling, the reaction mixture was chromatographed on silica gel, first eluting with n-hexane to remove Dowtherm and then with ethyl acetate to obtain 1.4 g of the title compound Ib-78. .

Melting point: 151-152 ° C (ethyl acetate) Elemental analysis Calculated as C ₁₁ H ₁₁ O ₂ N ₃ S (%): C, 53.00; H, 4.45; N, 16.86; S, 12.86 Measured value (%): C , 52.89; H, 4.36; N, 16.74; S, 12.83 Example 76 9- (benzylcarbonyl) thio-3-carboxy-4
-Oxo-4H-pyrido [1,2-a] pyrimidine Ie-8
Manufacturing 0: 0.87 g of 9- (benzylcarbonyl) thio-3- (4-methoxybenzyloxycarbonyl) -4-oxo-4H-pyrido [1,2-a] pyrimidine Ie-79, 2.5 g of anisole, 10 ml of dry methylene chloride. The mixture was cooled with ice water, 5 ml of trifluoroacetic acid was added, and the mixture was stirred for 3 hours while cooling with ice water. The reaction mixture was evaporated to dryness under reduced pressure and the residue (0.494 g) was recrystallized from ethyl acetate,
The title compound Ie-80 is obtained.

Melting point: 143-144 ° C Elemental analysis Calculated as C ₁₇ H ₁₂ O ₄ N ₂ S (%): C, 59.99; H, 3.55; N, 8.23; S, 9.42 Measured value (%): C, 60.00; H , 3.68; N, 8.20; S.9.27 Example 77 3-carboxy-9- (dimethylcarbamoyl) thio-
4-oxo-4H-pyrido [1,2-a] pyrimidine Ib
Preparation of -82: 9- (dimethylcarbamoyl) thio-3- (4-methoxybenzyloxycarbonyl) -4-oxo-4H-pyrido [1,2-a] pyrimidine Ib-81 0.508 g,
A mixture of 2.5 g of anisole and 5 ml of dry methylene chloride is cooled with ice water, 5 ml of trifluoroacetic acid is added, and the mixture is stirred for 3 hours while cooling with ice water. The reaction mixture was evaporated to dryness under reduced pressure and the residue was washed with ether to give a crude product (0.32
g) was recrystallized from 95% ethanol to give the title compound Ib
You get -82.

Melting point 223 to 224 ° C Elemental analysis Calculated as C ₁₂ H ₁₁ O ₄ N ₃ S (%): C, 49.14; H, 3.78; N, 14.33; S, 10.93 Measured value (%): C, 49.08; H, 3.80; N, 14.24; S, 10.98 Example 78 Preparation of 3- (4-methoxybenzyloxy) -9-mercapult-4-oxo-4H-pyrido [1,2-a] pyrimidine II-2: (1) 4-methoxybenzyloxymethylene malonic acid di-
A mixture of 14.4 g of (4-methoxybenzyl) ester and 5.9 g of 2-amino-3- (dimethylthiocarbamoyloxy) pyridine XI is heated on an oil bath at 120 ° C. for 1 hour with stirring. Silica gel chromatography, purification with a mixture of n-hexane-ethyl acetate (1: 1), 3-dimethylthiocarbamoyloxy-2
13.3 g of [2,2-bis (4-methoxybenzdioxycarbonyl) ethenylamino] pyridine XIII are obtained.

Melting point: 117 to 118 ° C. (ethyl acetate-ether) Elemental analysis Calculated as C ₂₈ H ₂₉ O ₇ N ₃ S (%): C, 60.97; H, 5.30; N, 7.62; S, 5.81 Measured value (%) : C, 60.91: H, 5.31, N, 7.55; S, 5.80 (2) 11 g of the above purified product XIII was added to diphenyl ether 1
Dissolve in 00 ml and heat at reflux for 30 minutes. After cooling, this is chromatographed on a silica gel column packed with n-hexane. First, the diphenyl ether was removed by elution with n-hexane and then eluted with ethyl acetate to obtain 9-dimethylcarbamoylthio-3- (4-methoxybenzyloxycarbonyl) -4-oxo-4H-pyrido [1,2]. -A] 4.3 g of pyrimidine Ib-81 are obtained.

Melting point: 153-154 ° C. (ethyl acetate) Elemental analysis Calculated as C ₂₀ H ₁₉ O ₅ N ₃ S (%): C, 58.10; H, 4.63; N, 10.16; S, 7.75 Measured value (%): C , 57.98; H, 4.75; N, 10.07; S, 7.64 (3) 0.5 g of sodium hydride (60% oily) is dried and suspended in 50 ml of tetrahydrofuran. 1.13 ml of n-propyl mercaptan was added dropwise at room temperature in a nitrogen stream, and the mixture was stirred for 1 hour. Then, the purified product Ib-81
Dissolve 4.3 g in 300 ml tetrahydrofuran and add all at once. The reaction mixture is stirred at room temperature for 24 hours, 0.9 g of acetic acid is added, and the mixture is dried under reduced pressure. The residue is partitioned between chloroform and water, the organic layers are collected, washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was washed with ether-ethyl acetate to give 1.8 g of the reddish brown title compound II-2.
To get

Melting point: 230 ° C or higher.

Example 79 Preparation of 9- (benzylcarbonyl) thio-3-ethoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine Ie-84 0.129 g of 9- (dimethylcarbamoyl) thio-3-ethoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine Ib-83 was dissolved in 5 ml of 1,2-dichloroethane, and 65 μl of phenylacetyl chloride was obtained.
Zinc iodide (0.13 g) is added, and the mixture is heated under a nitrogen stream for 45 minutes under reflux. After cooling the reaction mixture, N-HCl aqueous solution is shaken, and the organic layer is washed with saturated sodium bicarbonate water and then saturated saline. After drying, the solvent is distilled off under reduced pressure. The residue is subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound Ie-84 (0.118 g).

Yield: 58% Melting point: 126-128 ° C Elemental analysis As C ₁₉ H ₁₆ N ₂ O ₄ S: Calculated value (%): C, 61.94; H, 4.38; N, 7.60; S, 8.70 Measured value (%) : C, 62.09; H, 4.29; N, 7.48; S, 8.64 Reference Example 1 (1) 2-amino-3-dimethylthiocarbamoyl pyridine c-1 of the production of 2-amino-3-hydroxypyridine VIII45g was dissolved in acetone 700 ml, was added and stirred K ₂ CO ₃ 58g. After adding 49 g of dimethylcarbamoyl chloride thereto, the mixture was stirred at room temperature for 48 hours. The insoluble material was filtered off, washed with acetone, the filtrates were combined and the solvent was distilled off. The residue was subjected to silica gel chromatography, and from the fraction eluted with AcOEt, 44.2 g of the title compound X-1 (yield:
54.8%).

mp: 134-136 ° C. Analysis Calculated (recrystallized from AcOEt) (%) (as _{C 8 H 11 ON 3 S)} : C, 48.71; H, 5.62; N, 21.30; S, 16.25 Found (%) : C, 48.43; H, 5.59; N, 20.77; S, 16.29 (2) 2- {2 ', 2'-bis (ethoxycarbonyl) ethyleneamino} -3- (N, N'-dimethylthiocarbamoyloxy) Production of Pyridine VII-1 13.7 g of Compound X-1 obtained in (1) and 14 g of diethyl ethoxymethylene malonate XI-1 were heated at 100 ° C. for 1 hour. The reaction mixture was subjected to silica gel chromatography, and 19.3 g of the title compound XII-1 was obtained from the fraction eluted with benzene / AcOEt = 4/1 (V / V).

mp: 91 to 92.5 ° C. (recrystallized from ether) Elemental analysis (as C ₁₆ H ₂₁ O ₅ N ₃ S): Calculated value (%): C, 52.30; H, 5.76; N, 11.44; S, 8.73 Found (%): C, 52.37; H, 5.82; N, 11.48; S, 8.50 (3) 3-Ethoxycarbonyl-9-dimethylcarbamoylthio-4-oxo-4H-pyrido [1,2-a] pyrimidine. Preparation of Ib-83 8.0 g of the compound XII-1 obtained in (2) was dissolved in 20 ml of diphenyl ether and heated under reflux on an oil bath for 30 minutes. The reaction mixture was added to 1 liter of n-hexane, and the precipitated crystals were collected by filtration and subjected to silica gel chromatography.
From the fraction eluted with AcOEt, 4.0 g of the title compound Ib-83
Got (Yield: 53%) mp: 133 to 134 ° C. (recrystallized from AcOEt) Elemental analysis (as C ₁₄ H ₁₅ O ₄ N ₃ S): Calculated value (%): C, 52.33; H, 4.71; N, 13.08; S, 9.98 Found (%): C, 52.13; H, 4.66; N, 12.99; S, 9.75 (4) 3-Ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido [1,2- a] Preparation of Pyrimidine II-1 0.3 g of NaH was suspended in 30 ml of anhydrous THF, and the suspension was cooled to 0 in a nitrogen stream.
0.6 ml of n-propyl mercaptan was added dropwise at ℃, 1
Stir for 5 minutes. The compound Ib-83 2.0 obtained in (3) was added to the mixed solution.
A solution of 100 g of anhydrous THF was added, the mixture was returned to room temperature, stirred for 8 hours, and allowed to stand overnight. Acetic acid 0.5 in the reaction mixture
g, and dried under reduced pressure, about 150 ml of water was added to the residue, and the mixture was stirred to give 1.3 g of the title compound II-1 (yield: 81
%) Was obtained.

mp: 151 to 152 ° C. (recrystallized from AcOEt) Elemental analysis (as C ₁₁ H ₁₀ O ₃ N ₂ S): Calculated value (%): C, 52.79; H, 4.03; N, 11.19; S, 12.81 Measured value (%): C, 52.88; H, 3.97; N, 11.24; S, 12.66 Reference example 2 (1) 9-hydroxy-2-methyl-4-oxo-4H-
Preparation of pyrido [1,2-a] pyrimidine XV-1 1.1 g of 2-amino-3-hydroxypyridine VIII and 1.3 g of ethyl acetoacetate were added to a mixed solution of 4 ml of acetic acid and 4 ml of polyphosphoric acid, and the mixture was placed on an oil bath at 100 ° C. The mixture was heated and stirred for 4 hours. The reaction mixture was added to ice water, adjusted to pH 4 with a 2N aqueous sodium hydroxide solution, and further adjusted to pH 7 with sodium carbonate. It was extracted with CHCl ₃ , the organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 0.9 g of the title compound XV-1 (yield: 55.5%).

(2) 2-Methyl-9-dimethylthiocarbamoyloxy-4-oxo-4H-pyrido [1,2-a] pyrimidine
Preparation of XVI-1 0.3 g of the compound XV-1 obtained in the above (1) and 15 m of acetone
0.3 g of K ₂ CO _{3 and} 0.3 g of dimethylthiocarbamoyl chloride were added to the mixed solution of 1 and stirred at room temperature for 8 hours.
The solid matter was filtered off, washed with acetone, the filtrates were combined and the solvent was distilled off. The residue is washed with water and dried to give the title compound XV
0.3 g (yield: 66.9%) of I-1 was obtained.

mp: 186-187 ° C. (recrystallized from AcOEt) Elemental analysis (as C ₁₂ H ₁₃ O ₂ N ₃ S): Calculated value (%): C, 54.79; H, 4.88; N, 15.94; S, 12.O7 Found (%): C, 54.74; H, 4.98; N, 15.96; S, 12.18 NMR (CDCl 3) δ: 2.37 (3H, s), 3.46 (6H, s) (3) 2- methyl-9 Dimethylcarbamoylthio-4-
Oxo-4H-pyrido [1.2-a] pyrimidine Ib-85
Preparation of Compound XVI-1 (5.2 g) obtained in the above (2) was suspended in 40 ml of Dowtherm A (manufactured by Dow Chemical Co.) and heated under reflux for 20 minutes. The reaction mixture is cooled and then added to 800 ml of n-hexane to precipitate the title compound Ib-85.
5.0 g was collected by filtration.

mp: 165 to 167 ° C. (recrystallized from AcOEt) Elemental analysis (as C ₁₂ H ₁₃ O ₂ N ₃ S) Calculated value (%): C, 54.74; H, 4.98; N, 15.96; S, 12.18 Measured value ( %): C, 54.78; H, 4.90, N, 15.94; S, 12.10 NMR (CDCl ₃ ) δ; 2.43 (3H, s), 3.10 (6H, s) (4) 9-mercapto-2-methyl-4. -Oxo-4H-
Preparation of pyrido [1,2-a] pyrimidine II-3 0.4 g of NaH was suspended in 20 ml of anhydrous THF, cooled to 0 ° C., 1.4 ml of n-propylmercaptan was added dropwise, and the mixture was stirred for 20 minutes. A solution of the compound Ib-854.1 g obtained in (3) above in 130 ml of anhydrous THF was added to the mixed solution, and the mixture was returned to room temperature and stirred for 24 hours. The reaction mixture is evaporated to dryness under reduced pressure and 100
ml was added and dissolved, 2 g of acetic acid was added, and the precipitated crystals were collected by filtration. This was dried to obtain 3.0 g of the title compound II-3.

mp: 240 to 241 ° C. (recrystallized from CHCl ₃ ) Elemental analysis (as C ₉ H ₈ ON ₂ S): Calculated value (%): C, 56.23; H, 4.19; N, 14.57; S, 16.59 Measured value ( %): C, 56.11; H, 4.11; N, 14.52; S, 16.59 Formulation example The above is filled to make a capsule.

C. Effect of the invention Experimental Example 1 (effect on stress ulcer) Test method SD male rat fasted for 24 hours (body weight: 260-2
90 g) was placed in a wire mesh restraint stress cage and immersed in water at 23 ° C. up to the chest. After 7 hours, the animals were killed, the stomach was excised, the incision was made, the total length of the ulcers generated in the glandular stomach was calculated, and the ulcer generation suppression rate was calculated in comparison with the control group. The test compound was orally administered as a 5% gum arabic suspension 30 minutes before stress loading.

The compound numbers shown in the table of test compound results correspond to the compound numbers used in the examples.

As a control drug, cimetidine was used.

Indication method When suppressing ulcer development due to stress load by 70% or more ++ When suppressing 50 to 70% ＋ Test results are shown in Table 8. From the above results, it is clear that the compound (I) of the present invention exhibits an excellent antiulcer action. Therefore, the compound (I) of the present invention is effective for treating and preventing gastrointestinal ulcer, preventing recurrence after discontinuation of administration, and the like.

Claims (1)

[Claims] 1. A general formula: [In the formula, n 0 or 1, R is ^formula: -COR 1, -CONR ⁴ R ⁵ or -CH ₂
Represents R ⁶ , wherein R ¹ is C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, allylthio, styryl, phenoxymethyl, thienylmethyl, substituted or unsubstituted C ₆ -C ₁₀ aryl (substituents: halogen, C ₁ -C _{3 alkoxy,} C 1 -C
₃ alkyl, C ₃ -C ₆ cycloalkyl, trifluoromethyl, nitro, cyano, acetyl, acetyloxy,
C ₂ -C ₄ alkoxycarbonyl, sulfamoyl, C
_1- C ₃ alkanesulfonyl, tetrazolyl, carbamoyl), substituted or unsubstituted benzyl (substituent: C
₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, halogen,
Nitro) or a substituted or unsubstituted heterocyclic residue (substituent: C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C
_3- C ₆ cycloalkyl), (heterocycle residue: furyl,
Thienyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl), R ² and R ³ are each hydrogen, C ₁ -C ₅ alkyl, carboxy, C ₂ -C ₅ alkoxycarbonyl or substituted or unsubstituted benzyloxycarbonyl (substituent: C
₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, halogen,
Nitro), R ⁴ and R ⁵ are each hydrogen, C ₁ -C ₅ alkyl, C ₃
-C ₇ cycloalkyl, or substituted or unsubstituted phenyl (substituent: halogen, C ₁ -C ₃ alkyl, C ₁
To C ₃ alkoxy, alkoxycarbonyl, nitro, trifluoromethyl), R ⁶ is a substituted or unsubstituted phenyl (substituent: halogen, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ alkoxy, alkoxycarbonyl, nitro, trifluoro). Methyl) or pyridyl]] or a salt thereof.