JPH07330769A - 2-(2-(substituted-amino)benzylthio)-5,6,7,8-tetrahydropyrido(3,4-d)pyrimidin-4(3h)-one derivative - Google Patents

Abstract

PURPOSE:To obtain a compound excellent in gastric inhibitory effect and gastrointestinal mucosa protecting effect on gastric ulcer and duodenal ulcer model and useful as an ahti-peptic ulcer agent excellent in safety. CONSTITUTION:A compound (salt) of formula I (R<1> is H, a lower alkyl, a hydroxyalkyl or a lower alkoxyalkyl; R<2> is H or a lower alkyl; R<3> and R<4> are each a lower alkyl), e.g. 2-[2-(N-n-butyl-Nmethylamino)benzylthio]-6- methyl-5,6,7,8-tetrahydropyrido[3,4-alpha]pyrimidin-4(3H)-one. This compound is obtained, e.g. by reacting a compound of formula II with a compound of formula III (X is Cl, Br, I or methanesulfonyloxy, etc.) in the presence of a base such as sodium hydroxide in a solvent such as methanol at -10 deg.C to the solvent reflux temperature for 10min to 24hr to conduct an S-benzylation reaction.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2- [2- (substituted amino) benzylthio] -5, which is useful as an anti-peptic ulcer drug.
The present invention relates to a 6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one derivative or a pharmaceutically acceptable salt thereof.

[0002]

As a 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one derivative, for example, 2-benzoylalkylthio-5,6 having antipyretic and analgesic effects. , 7,8-Tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one derivative (JP-A-53-28193) is disclosed, but it is a compound different from the compound of the present invention. , There is no description about anti-peptic ulcer action.

[0003]

The conventional anti-peptic ulcer drugs mainly suppress the attack factors such as gastric acid and pepsin, and enhance the defense factors such as mucosal resistance, cell protection, blood flow improvement and mucus secretion. They can be roughly divided into those that do and are used properly according to the condition. However, the attack factor inhibitors represented by cimetidine (histamine H2 receptor antagonist) and omeprazole (proton pump inhibitor) are
It has been reported that recurrence frequently occurs when the drug is stopped, which is a serious problem for the treatment of ulcer. Also,
Although various protective factor enhancers have been used, they are not always sufficient in terms of therapeutic effect. However, in recent years, for the treatment of peptic ulcer and the prevention of recurrence, combined maintenance therapy of the above-mentioned attack factor inhibitor and defense factor enhancer has been adopted. As a result, this combined maintenance therapy exerts superior therapeutic and prophylactic effects than each monotherapy. Therefore, from the above facts, the present invention aims to provide an effective and highly safe anti-peptic ulcer drug having both an attack factor suppressing action and a defense factor enhancing action with a single drug.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a novel 2- [2- (substituted amino) benzylthio compound different from conventional anti-peptic ulcer drugs is used. ] -5,6,7,8-Tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one derivative and its pharmacologically acceptable salt have a gastric acid secretion inhibitory action and a gastric mucosa protective action. The present invention has been completed by discovering that it has an excellent pharmacological effect on gastric ulcer and duodenal ulcer models.

That is, the present invention provides 2- [2- (substituted amino) benzylthio] -5,6,7,8-tetrahydropyrido [represented by the following general formula [I] which is extremely useful as an anti-peptic ulcer drug. It relates to a 4,3-d] pyrimidin-4 (3H) -one derivative or a pharmaceutically acceptable salt thereof.

[0006]

[Chemical 2]

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxyalkyl group or a lower alkoxyalkyl group. R ² represents a hydrogen atom or a lower alkyl group.
R ³ and R ⁴ are the same or different lower alkyl groups. ]

In the above general formula [I], R ¹ , R ² ,
Specific examples of R ³ , R ⁴ and pharmaceutically acceptable salts thereof can be shown as follows. As R ¹ ,
Examples thereof include hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, hydroxyethyl group and methoxyethyl group. Examples of R ² include a hydrogen atom and a methyl group. Examples of R ³ and R ⁴ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group.

The salt of the compound represented by the general formula [I], that is, the compound of the present invention [I] is not particularly limited as long as it is a pharmacologically acceptable salt, but is preferably a sodium salt. Metal salts or hydrochlorides such as potassium salt and zinc salt, inorganic salts such as hydrobromide salt, sulfate salt and phosphate salt, and organic acid salts such as acetate salt, citrate salt and maleate salt. it can. Further, among the compounds included in the compound [I] of the present invention, those having a hydrate or tautomer,
Some of them have crystalline polymorphs, each of them or any of their mixtures are included in the present invention.

The compound [I] of the present invention can be produced by various methods. Typical methods are as follows.

The compound [I] of the present invention is obtained by reacting the compound [II] with the compound [III] in the presence of various bases to give S-
Obtained by benzylation.

[0012]

[Chemical 3]

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above, X is a chlorine atom, a bromine atom, an iodine atom,
A methanesulfonyloxy group or a p-toluenesulfonyloxy group is shown. ]

Examples of the solvent which can be used in this reaction include alcohols such as methanol, ethanol and propanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, chloroform and methylene chloride. Halogenated hydrocarbons such as these, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide,
Examples thereof include ketones such as acetone, organic solvents such as nitriles such as acetnitrile, water, or a mixed solvent thereof. Further, the base that can be used in this reaction is not particularly limited as long as it is used as a base in a normal reaction, but preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Sodium hydride, sodium methoxide, sodium ethoxide, potassium-t-butoxide, 1,8-diazabicyclo [5.6.0] -7-undecene and the like can be mentioned, and the used amount thereof is 1 to 5 Equivalent weights are preferred. When the reaction is carried out between the two phases of the aqueous layer and the organic layer, tetra-n-butylammonium bromide, tetra-n
-Butyl ammonium bisulfate, quaternary ammonium salts such as benzyl trimethyl ammonium chloride or 12-
Phase transfer catalysts typified by crown ethers such as crown-4-ether and 18-crown-6-ether can be used, and the amount used is preferably 0.01 to 1 equivalent. The reaction temperature is -10 ° C to the boiling temperature of the solvent, and the reaction time is usually 10 minutes to 24 hours, varying based on the reaction temperature, the starting compound or the kind of the solvent.

Further, as shown below, the compound [I] of the present invention is obtained by mixing the compound [Ia] of the present invention and the compound [IV] obtained above in a solvent in the presence or absence of various bases. It can be produced by reacting.

[0016]

[Chemical 4]

[In the formula, R ¹ represents a lower alkyl group, a hydroxyalkyl group or a lower alkoxyalkyl group. R
² , R ³ , R ⁴ and X are the same as above. The compound [Ia] is included in the compound [I] of the present invention, and is a compound in which R ¹ is a hydrogen atom. ] As a solvent that can be used in this reaction, for example, methanol,
Alcohols such as ethanol and propanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform and methylene chloride, N,
Examples thereof include amides such as N-dimethylformamide, sulfoxides such as dimethylsulfoxide, ketones such as acetone, organic solvents such as nitriles such as acetnitrile, water, or a mixed solvent thereof.
Further, the base that can be used in this reaction is not particularly limited as long as it can be used as a base in a normal reaction, but preferably triethylamine, pyridine, N,
N-dimethylaniline, 1,8-diazabicyclo [5.
6.0] -7-undecene and the like organic bases, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride and the like inorganic bases, and the amount thereof is 1 to 5 equivalents. When the reaction is carried out between the two phases of the aqueous layer and the organic layer, quaternary ammonium salts such as tetra-n-butylammonium bromide, tetra-n-butylammonium bisulfate, benzyltrimethylammonium chloride or 12-crown-4-ether. , 18-crown-6-ether and other crown ethers can be used, and the amount thereof is 0.01 to 1 equivalent. The reaction temperature is -10 ° C to the boiling temperature of the solvent, and the reaction time varies depending on the reaction temperature, the kind of the raw material compound or the solvent, but it is usually 1 hour to 96 hours.
It's time.

The compound represented by the general formula [II] used as the starting material can be produced, for example, by the following method.

[0019]

[Chemical 5] [In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group. ]

For compounds in which R ¹ is a methyl group:
The compound [V] was obtained from methylamine and acrylic acid ethyl ester, and then Dickman condensation reaction was carried out to react with thioureas to produce the compound. For compounds in which R ¹ is a hydrogen atom, see Journal of Heterocyclic Chemi
stry) Vol. 27, 1885 to 1892 (1990), and produced by reacting [VI] with thioureas.

The pharmaceutically acceptable salt of the compound [I] of the present invention obtained as described above can be easily produced according to a conventional method.

[0022]

The compound [I] of the present invention and a pharmaceutically acceptable salt thereof have excellent gastric acid secretion inhibitory action and gastrointestinal mucosa protective action, and are highly safe, and therefore have a human or animal peptic ulcer. It is useful as a therapeutic or preventive drug for. The peptic ulcer includes gastric ulcer, duodenal ulcer, Zolinger-Ellison syndrome, anastomotic ulcer, reflux esophagitis and the like.

When the compound [I] of the present invention and a pharmacologically acceptable salt thereof are used as the above-mentioned medicaments, pharmaceutically acceptable excipients, carriers, diluents and other formulation auxiliaries are appropriately mixed, Tablets, coated tablets, capsules, granules,
It can be administered orally or parenterally in the form of powder or injection. The dose of the compound of the present invention varies depending on the degree of symptoms, the type of ulcer, the age, the body weight, etc., but is usually 5 to 1500 mg, preferably 20 to 800 mg per day for an adult.
The dose can be appropriately adjusted within the range of 1 to several times per day, and can be administered in divided doses.

The preparation of the compound [I] of the present invention and a pharmacologically acceptable salt thereof may be carried out according to a known method. That is, the oral solid preparations as exemplified above include an excipient as a main ingredient, a binder as required, a disintegrating agent, a lubricant, a coloring agent,
It can be produced by a conventional method using a flavoring agent and the like. As the excipient, lactose, corn starch, sucrose, glucose, crystalline cellulose, silicon dioxide, sorbit, non-pareil and the like can be used. As the binder, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like can be used. As a disintegrant,
Starch, agar, gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, carboxymethyl cellulose calcium, dextrin and the like can be used. As the lubricant, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like can be used. In addition, as the coloring agent and the flavoring agent, any of those permitted as pharmaceutical additives can be used. Tablets, granules and the like may be coated with sugar coating, gelatin coating and the like. When preparing an injection,
If necessary, a pH adjusting agent, a buffering agent, a stabilizer, a solubilizing agent and the like may be added to the main drug to produce the active ingredient by a conventional method.

[0025]

The present invention will be described in more detail based on the following examples, reference examples, formulation examples and test examples, but the present invention is not limited to these examples. In addition, in the reference example,
The production of raw material compounds in producing the compound of the present invention is shown.

Example 1 2- [2- (N-n-butyl-N-methylamino) benzylthio] -6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] Synthesis of Pyrimidin-4 (3H) -one 2-Mercapto-6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H)-
Dissolve 5.92 g of ON in a mixed solution of 20.0 ml of 4N sodium hydroxide aqueous solution and 60 ml of methanol, and then 2-
A solution prepared by dissolving 4.96 g of (Nn-butyl-N-methylamino) benzyl chloride · hydrochloride in 20 ml of methanol was added dropwise. After stirring at room temperature for 2 hours, water was added. After further adding 1N hydrochloric acid to make the mixture acidic, the pH was adjusted to 8 with an aqueous sodium hydrogen carbonate solution. It was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and column chromatography [Wakogel C
-200 (200 g) and a developing solvent (chloroform: methanol = 50: 1 V / V → 10: 1 V / V)]. Recrystallization from isopropyl ether gave 4.7 g (63%) of the desired product.

Melting point: 98 to 101 ° C. IR (nujol method) ν _max cm ⁻¹ : 2800-2200 (NH), 1640 (C =
O) MS m / z: 372 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (3H, t, J = 7.2Hz, CH ₂ CH
₂ CH ₂ C H ₃ ), 1.23-1.49 (4H, m, CH ₂ C H ₂ C H ₂ CH ₃ ), 2.34 (3H,
s, NCH ₃ ), 2.58−2.60 (7H, m, NCH ₂ CH ₂ and NCH ₃ ), 2.
79−2.85 (2H, m, C H ₂ CH ₂ CH ₂ CH ₃ ), 3.14 (2H, s, NCH ₂ ),
4.44 (2H, s, SCH ₂ ), 7.00−7.06 (1H, m, Ar-H), 7.17−
7.29 (2H, m, Ar-H), 7.37-7.41 (1H, m, Ar-H) Elemental analysis (C ₂₀ H ₂₈ N ₄ OS) Theoretical value (%): C, 64.48; H, 7.58; N, 15.04 Found (%): C, 64.51; H, 7.52; N, 14.96

Example 2 6-Methyl-2- [2- [N-methyl-N- (2-methylpropyl) amino] benzylthio] -5,6,7,8
-Tetrahydropyrido [4,3-d] pyrimidine-4
Synthesis of (3H) -one 2-mercapto-6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H)-
3.00 g of ON was dissolved in a mixed solution of 10.0 ml of 4N sodium hydroxide aqueous solution and 30 ml of methanol, and 2-
[N-methyl-N- (2-methylpropyl) amino) benzyl chloride / hydrochloride 2.48 g was added to methanol 10 ml.
The solution dissolved in was added dropwise. After stirring at room temperature for 2 hours,
Water was added. Next, 1N hydrochloric acid was added to make the mixture acidic, and the pH was adjusted to 8 with an aqueous sodium hydrogen carbonate solution. It was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, column chromatography [Wakogel C-200 (100 g), developing solvent (chloroform:
Methanol = 50: 1 V / V → 10: 1 V / V)]. Recrystallize from isopropyl ether to give 2.5
g (67%) were obtained.

Melting point: 146-148 ° C. IR (nujol method) ν _max cm ⁻¹ : 1640 (C═O) MS m / z: 372 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 ( 6H, d, J = 6.6Hz, CH ₂ CH
(C H ₃ ) ₂ ), 1.77 (1H, m, CH ₂ C H (CH ₃ ) ₂ ), 2.34 (3H, s, NC
H ₃ ), 2.58−2.62 (9H, m, NCH ₂ CH ₂ and NCH ₃ and C H ₂ C
H (CH ₃ ) ₂ ), 3.14 (2H, s, NCH ₂ ), 4.49 (2H, s, SCH ₂ ), 7.
01-7.07 (1H, m, Ar-H), 7.18-7.29 (2H, m, Ar-H), 7.3
9-7.42 (1H, m, Ar-H) Elemental analysis (C ₂₀ H ₂₈ N ₄ OS) Theoretical value (%): C, 64.48; H, 7.58; N, 15.04 Actual value (%): C, 64.18; H, 7.56; N, 15.27

[Examples 3 to 12] The compounds obtained in the same manner as in Example 1 are shown in Table 1 collectively.

[0031]

[Table 1]

Example 13 2- [2- (N, N-dimethylamino) benzylthio]
Synthesis of 6-ethyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one 2- [2- (N, N-dimethylamino) benzylthio]
-5,6,7,8-Tetrahydropyrido [4,3-d]
Pyrimidin-4 (3H) -one (2.00 g) in chloroform
The mixture was suspended in 50 ml, 1.97 g of ethyl iodide and 1.8 ml of triethylamine were added, and the mixture was stirred under reflux for 24 hours. The reaction solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography [Wakogel C
-200 (100 g) and a developing solvent (chloroform: methanol = 50: 1 V / V → 10: 1 V / V)]. Recrystallize from a mixture of ethanol and diethyl ether to give the desired compound 1.3.
g (60%) was obtained.

Melting point: 174 to 175 ° C. IR (nujol method) ν _max cm ⁻¹ : 2800-2500 (NH), 1645 (C =
O) MS m / z: 344 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (3H, t, J = 7.1Hz, CH ₂ C H
₃ ), 2.47−2.64 (12H, m, N (CH ₃ ) ₂ and C H ₂ CH ₃ and NCH
₂ CH ₂ ), 3.18 (2H, s, NCH ₂ ), 4.45 (2H, s, SCH ₂ ), 6.99
−7.06 (1H, m, Ar-H), 7.17−7.29 (2H, m, Ar-H), 7.3
7-7.40 (1H, m, Ar- H) Elemental analysis _{(C 18 H 24 N 4 OS} ) theory (%): C, 62.76; H, 7.02; N, 16.26 Found (%): C, 62.68; H, 7.23; N, 16.09

[Examples 14 to 23] The compounds obtained in the same manner as in Example 13 are collectively shown in Table 2.

[0035]

[Table 2]

Example 24 2- [2- (N, N-dimethylamino) benzylthio]
-6- (2-Methoxyethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H)
Synthesis of 1-one 2- [2- (N, N-dimethylamino) benzylthio]
-5,6,7,8-Tetrahydropyrido [4,3-d]
Pyrimidin-4 (3H) -one (1.59 g) was dissolved in a mixture of 1.3 ml of 4N aqueous sodium hydroxide solution and 20 ml of methanol. 2-chloroethyl methyl ether 0.9 m
l was added, the mixture was stirred under reflux for 24 hours, 0.9 ml of 2-chloroethyl methyl ether was further added, and the mixture was stirred under reflux for 2 days. Water was added to this, and the mixture was acidified with 1N hydrochloric acid, adjusted to pH 8 with an aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. After washing with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [Wakogel C-200 (50 g), developing solvent (chloroform: methanol = 50: 1 V / V → 10: 1 V / V)]. Recrystallize from diethyl ether to give 0.8
g (43%) was obtained.

Melting point: 126 to 129 ° C. IR (nujol method) ν _max cm ⁻¹ : 2800-2300 (NH), 1640 (C =
O) MS m / z: 374 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 2.60-2.69 (12H, m, N (CH ₃ ) ₂
And C H ₂ CH ₂ OCH ₃ and NCH ₂ CH ₂ ), 3.25−3.26 (5H, m,
NCH ₂ and OCH ₃ ), 3.49 (2H, t, J = 5.8Hz, CH ₂ C H ₂ OCH ₃ ),
4.45 (2H, s, SCH ₂ ), 6.990−7.06 (1H, m, Ar-H), 7.16
−7.29 (2H, m, Ar-H), 7.37−7.40 (1H, m, Ar-H), 12.6
(1H, brs, NH) Elemental analysis (C ₁₉ H ₂₆ N ₄ O ₂ S) Theoretical value (%): C, 60.94; H, 7.00; N, 14.96 Actual value (%): C, 60.79; H, 7.22 ; N, 14.73

Example 25 2- [2- (N, N-dimethylamino) benzylthio]
-6- (2-hydroxyethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3
Synthesis of H) -one The procedure of Example 24 was repeated to obtain 33% of the product.

Melting point: 198 to 200 ° C. IR (nujol method) ν _max cm ⁻¹ : 3340-3100 (OH), 2750-22
00 (NH), 1650 (C = O) MS m / z: 360 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 2.54-2.69 (12H, m, N (CH ₃ ) ₂
And C H ₂ CH ₂ OH and NCH ₂ CH ₂ ), 3.24 (2H, m, NCH ₂ ), 3.
56 (2H, t, J = 5.8Hz, CH ₂ C H ₂ OH), 4.45 (2H, s, SCH ₂ ), 6.
99-7.06 (1H, m, Ar-H), 7.16-7.29 (2H, m, Ar-H), 7.3
7−7.40 (1H, m, Ar-H), 12.6 (1H, brs, NH) Elemental analysis (C ₁₈ H ₂₄ N ₄ O ₂ S) Theoretical value (%): C, 59.98; H, 6.71; N, 15.54 Found (%): C, 59.72; H, 6.96; N, 15.64.

[Reference Example 1] Synthesis of 3- [N- (2-ethoxycarbonylethyl) -N-methyl] aminopropionic acid ethyl ester Acrylic acid ethyl ester 120 ml under ice-cooling, 30% methylamine ethanol solution 51.8 g in 1 hour,
The mixture was stirred under reflux for an hour. After the solvent was distilled off under reduced pressure, the residue was purified by distillation under reduced pressure to obtain 103.2 g (89%) of the desired product.

Boiling point: 108-109 ° C./0.5 mmHg IR (liquid film method) ν _max cm ⁻¹ : 2990, 2800 (CH2), 1735 (C =
O) MS m / z: 231 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, t, J = 7.1Hz, CH ₂ C H ₃
× 2), 2.25 (3H, s, NCH ₃ ), 2.46 (4H, t, J = 7.4Hz, NC H ₂
CH ₂ × 2), 2.71 (4H, t, J = 7.4Hz, NCH ₂ C H ₂ × 2), 4.13 (4H,
q, J = 7.1Hz, C H ₂ CH ₃ × 2) Elemental analysis (C ₁₁ H ₂₁ NO ₄ ) Theoretical value (%): C, 57.12; H, 9.15; N, 6.06 Actual value (%): C, 56.95; H, 9.44; N, 6.10

Reference Example 2 2-Mercapto-6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H)-
On-synthesis 3.49 g of sodium metal was dissolved in 150 ml of dry ethanol, and 23.1 g of 3- [N- (2-ethoxycarbonylethyl) -N-methyl] aminopropionic acid ethyl ester was added thereto, and the mixture was stirred under reflux for 3 hours. . The mixture was allowed to cool to room temperature, 9.14 g of thiourea was added, and the mixture was stirred under reflux for 1 hr. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, and adjusted to pH 8 with sodium hydrogen carbonate. The precipitated crystals were melted by heating and then cooled. The precipitated crystals were collected by filtration, washed with ethanol, and dried to obtain 11.5 g (58%) of the desired product.

Melting point: 250-254 ° C. IR (nujol method) ν _max cm ⁻¹ : 3190 (NH), 1660 (C═O) MS m / z: 197 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 2.80 (5H, m, NCH ₃ and NC H ₂
CH ₂ ), 3.30 (2H, m, NCH ₂ C H ₂ ), 3.77 (2H, s, NCH ₂ ), (2
H, brs, NH and SH) Elemental analysis (C ₈ H ₁₁ N ₃ OS ・ H ₂ O) Theoretical value (%): C, 44.63; H, 6.09; N, 19.52 Actual value (%): C, 44.29; H, 6.21; N, 19.22

Reference Example 3 Synthesis of 2-mercapto-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one 2.53 g of sodium metal was added to 150 ml of dry ethanol. After dissolution, it was mixed with 4-oxo-3-piperidinecarboxylic acid ethyl ester / hydrochloride 8.56 g and thiourea 5.33.
g was added and the mixture was stirred under reflux for 2 hours. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, and pH adjusted with sodium hydrogen carbonate.
Adjusted to 8. The precipitated crystals are collected by filtration, washed with water and dried,
7.4 g (98%) of the desired product was obtained.

Melting point: 300 ° C. or higher IR (nujol method) ν _max cm ⁻¹ : 2800-2200 (NH), 1700, 1
685 (C = O) MS m / z: 183 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ: 2.46 (2H, t, J = 5.6Hz, NC H ₂ CH
₂ ), 3.00 (2H, t, J = 5.8Hz, NCH ₂ C H ₂ ), 3.48 (2H, s, NC
H ₂ ) Elemental analysis (C ₇ H ₉ N ₃ OS ・ H ₂ O) Theoretical value (%): C, 41.78; H, 5.51; N, 20.88 Actual value (%): C, 41.22; H, 5.32; N , 20.48

Formulation Example 1 The compound of Example 1, lactose, corn starch, microcrystalline cellulose and hydroxypropyl cellulose were mixed with a universal stirrer (manufactured by Shinagawa Kogyo Co., Ltd.), and then a wetting liquid (30% ethanol) was added. Grained. The granulated product is dried and sieved (20 mesh), then carboxymethylcellulose calcium, magnesium stearate and talc are added and mixed, and 200 mg tablets per tablet are produced with a rotary tableting machine (Kikusui Seisakusho). did. Composition in 1 tablet (200 mg) Compound of Example 1 50 mg Lactose 60 mg Corn starch 40 mg Crystalline cellulose 30 mg Hydroxypropylcellulose 8 mg Carboxymethylcellulose calcium 10 mg Magnesium stearate 1 mg Talc 1 mg

[Formulation Example 2] The tablets obtained in Formulation Example 1 were coated with an enteric solution having the following composition under the conditions of tablets 45 ° C and air supply temperature 55 ° C in a fluid coating device (manufactured by Freund Corporation), An enteric-coated preparation of 230 mg per tablet was produced. Composition of enteric solution Eudragit L-30D 69.0 mg (solid component 20.7 mg) Polyethylene glycol 6.2 mg Talc 2.1 mg Tween 80 1.0 mg Water 0.28 ml

Formulation Example 3 After thoroughly mixing the following compositions, a wetting liquid (30% ethanol) was added and kneaded, and granulated by an extrusion granulator (manufactured by Fuji Paudal Co., screen diameter 0.9 mm). Then, it was immediately sized with a Marumerizer (Fuji Paudal Co., Ltd.), dried and sieved to produce 12-42 mesh columnar granules. Composition of columnar granules 200 mg Compound of Example 1 50 mg Lactose 50 mg Corn starch 40 mg Microcrystalline cellulose 30 mg Hydroxypropylcellulose 10 mg Carboxymethylcellulose 20 mg

Test Example 1 Effect on Histamine-stimulated Gastric Acid Secretion Male SD rats (6-7 weeks old, 1 group 5) fasted for 24 hours
To 7 animals), the test compound 30 mg / kg suspended in a 0.5% sodium carboxymethylcellulose aqueous solution was orally administered. The control group was administered with 0.5% sodium carboxymethyl cellulose aqueous solution only. One hour later, the abdomen was opened under anesthesia with diethyl ether, the pylorus was ligated, the incision was immediately sutured, and then histamine dihydrochloride 30 mg / kg was subcutaneously administered. Two hours later, the animals were killed and the gastric juice stored in the stomach was collected. After measuring the gastric juice volume, the acid concentration was measured by the neutralization titration method to calculate the gastric acidity. Next, the inhibition rate (%) from the gastric acidity of the control group and the gastric acidity of the test compound group
Was obtained and the results are shown in Table 3.

[0050]

[Table 3]

[Test Example 2] Inhibitory activity against indomethacin gastric ulcer SD male male rats (6 to 7 weeks old, 1 group 5) fasted for 24 hours
(About 7 animals), 15 mg / kg of the test compound suspended in a 0.5% sodium carboxymethylcellulose aqueous solution was orally administered. The control group was administered with 0.5% sodium carboxymethyl cellulose aqueous solution only. One hour later, after emulsification with a small amount of Tween 80, 25 mg / kg of indomethacin suspended in physiological saline was subcutaneously administered. After 7 hours, the animals were killed by exsanguination, and the stomach was removed and fixed with 1% formalin. After fixation, an incision was made along the greater curvature, the length of gastric mucosal damage was measured under a stereoscopic microscope, and the total sum per animal was taken as the ulcer index (mm). The inhibition rate (%) was determined from the ulcer index of the control group and the ulcer index of the test compound group, and the results are shown in Table 4.

[0052]

[Table 4]

[Test Example 3] Inhibitory effect of ethanol on acute gastric mucosal damage SD male rats (6 to 7 weeks old, 1 group 5) fasted for 24 hours
(About 7 animals), 100 mg / kg of the test compound suspended in a 0.5% sodium carboxymethylcellulose aqueous solution was orally administered. The control group was administered with 0.5% sodium carboxymethyl cellulose aqueous solution only. Weight after 30 minutes
Oral administration of 0.5 ml of ethanol per 100 g caused gastric mucosal damage. One hour after that, the rat was killed by exsanguination, and the inhibition rate (%) was determined by the same method as in Test Example 2 below.
The results are shown in Table 5.

[0054]

[Table 5]

Test Example 4 Acute Toxicity Test Male ddY mice fasted for 18 hours (5 weeks old, 5 in 1 group)
In the case of oral administration, 1000 mg / kg of the test compound (Examples 1 and 2) suspended in a 0.5% sodium carboxymethylcellulose aqueous solution was administered to each mouse. In the case of intraperitoneal administration, test compound 500 mg / kg suspended in 0.5% sodium carboxymethylcellulose sodium chloride solution.
Was administered. As a result of observation for 7 days, no death was observed in any of the groups.

[0056]

As is apparent from the above test examples, the compound [I] of the present invention and a pharmacologically acceptable salt thereof have an excellent gastric acid secretion inhibitory action and gastric mucosa against gastric ulcer and duodenal ulcer models. It had a protective effect and low toxicity. Therefore, according to the present invention, it is possible to provide an anti-peptic ulcer agent having both an inhibitory action on an attacking factor and an enhancing action on a protective factor, and since it is also highly safe, the treatment of gastric ulcer or duodenal ulcer of a human or animal or Useful for prevention.

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxyalkyl group or a lower alkoxyalkyl group. R ²
Represents a hydrogen atom or a lower alkyl group. R ³ and R ⁴ are the same or different lower alkyl groups. ] 2- [2- (substituted amino) benzylthio] -5,6 represented by
A 7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one derivative or a pharmaceutically acceptable salt thereof. 2. In the general formula [I], R ¹ , R ³
Is a methyl group, R ² is a hydrogen atom, and R ⁴ is an n-butyl group or an isobutyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 1.