JPH05262763A - 2-(@(3754/24)1h-benzimidazol-2-yl)sulfinylmethyl)-4-substituted amino-5-phrimidinecarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To provide the subject low toxic new compound having a combination of gastric acid secretion-inhibitory activity and digestive tract mucous membrane-protective activity, thus useful as an anti-digestive ulcerous agent. CONSTITUTION:The objective compound of formula I (R<1> is N,N-dimethylammno, N-ethyl-N-methylammno or morpholmno; R<2> is lower alkyl), e.g. 2-[(IH-benz imidazolk-2-yl)sulfinylmethyl]-4-dimethylamino-5-pyrimidinecarboxylic ethyl ester. The compound of the formula I can be obtained by oxidizing a compound of formula II with an oxidizing agent such as hydrogen peroxide, peracetic acid, or m-chloroperbenzoic acid.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2-[(1H-benzimidazol-2-yl) useful as an anti-peptic ulcer drug.
The present invention relates to a sulfinylmethyl] -4-substituted amino-5-pyrimidinecarboxylic acid derivative.

[0002]

As a compound having an anti-peptic ulcer action and having a benzimidazole ring and a pyrimidine ring bonded by a methylsulfinyl group, JP-A-61-85384 is disclosed.
JP-A-61-205276 and JP-A-1-13325
The compounds described in JP-A-81 are known.

[0003]

DISCLOSURE OF THE INVENTION In recent years, the treatment of peptic ulcer has progressed dramatically since a histamine H2 receptor antagonist (eg, cimetidine) that strongly suppresses gastric acid secretion has been put to clinical use. , Even ulcers that had previously required surgery were cured by medical treatment. In addition, the recently developed H + / K + ATPase inhibitor (for example, omeprazole) is also effective against intractable ulcers such as histamine H2 receptor antagonists which do not show the expected effect, and Solinga-Ellison syndrome, It has been reported to show a high cure rate. However, it has been reported that an ulcer once cured by these drugs frequently recurs when the drug is stopped, which is a serious problem.

Therefore, it is an object of the present invention to provide an anti-peptic ulcer drug which exhibits an excellent therapeutic effect and is free from the problem of recurrence due to discontinuation of medication.

[0005]

Means for Solving the Problems Recurrence after treatment with a histamine H2 receptor antagonist or H + / K + ATPase inhibitor is considered to be due to fragile fibrosis of scar tissue. From this, it is considered that protection of the gastrointestinal mucosa from any irritation in the course of treatment with these drugs promotes more complete repair of scar tissue and leads to prevention of recurrence. In fact, there are many reports that the recurrence rate is lower in the combination therapy with the gastrointestinal mucosa protective factor enhancer than in the treatment with the histamine H2 receptor antagonist alone. From such a viewpoint, the present inventors have found that H + / K + ATPa
We aimed to develop an anti-peptic ulcer agent that has both a strong gastric acid secretion inhibitory action based on se inhibitory action and a gastrointestinal mucosal protective action.

In searching for the target compound, the present inventors have proposed the following compound [A] described in JP-A-62-267229 as a compound having both gastric acid secretion inhibitory action and gastrointestinal mucosal protective action. I paid attention.

[0007]

[Chemical 2]

The present inventors have examined in detail both of the above-mentioned actions of this compound [A]. Its gastric acid secretion inhibitory action is weaker than that of cimetidine or omeprazole, but its gastrointestinal mucosal protective action is extremely strong. I confirmed that.

Therefore, it was considered that the compound [A] could be chemically modified without weakening the gastrointestinal mucosa-protecting action to enhance the gastric acid secretion inhibiting action. However, in general, it is often experienced that the pharmacological activity possessed by even a minimal modification of a compound is lost. Therefore, first, the following compound [B], which can be easily derived from the compound [A], and the following compound [C], which is an isomer of the compound [A], were synthesized, and their gastrointestinal mucosa protective action was investigated. As a result, it was found that the activity of the compound [B] was almost the same as that of the original compound [A] and that of the compound [C] was weakened.

[0010]

[Chemical 3]

From these facts, the gastrointestinal mucosa-protecting action of the compound [A] was not affected even if the 1,6-dihydro-6-oxopyrimidine ring was changed to a pyrimidine ring. It was estimated to be the relative positions of the nitrogen atom and each substituent and their electronic effects.

Based on this estimation, the design of the compound,
Through repeated synthesis and pharmacological tests, the present invention that achieves the intended purpose was completed. That is, the present invention provides a 2-[(1H-benzimidazol-2-yl) sulfinylmethyl] -4-substituted amino-5-pyrimidine represented by the following general formula [I], which is extremely useful as an anti-peptic ulcer drug. A carboxylic acid derivative or a pharmaceutically acceptable salt thereof is provided.

[0013]

[Chemical 4]

[In the formula, R1 represents an N, N-dimethylamino group, N-ethyl-N-methylamino group or morpholino group, and R2 represents a lower alkyl group. ]

Specific examples of R 2 in the above general formula [I] include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group and an isobutyl group, which are pharmacologically acceptable. Examples of the salt include alkali metal salts such as sodium salt and potassium salt.

The compound [I] of the present invention can be produced by various methods. Typical methods are as follows. That is, as shown in the following Chemical formula 5, the compound [II] of the present invention can be obtained by oxidizing the compound [II] by a conventional method.

[0017]

[Chemical 5]

[In the formula, R 1 and R 2 are the same as defined above. ]

Examples of the oxidizing agent that can be used in this reaction include hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite, sodium bromate and sodium metaperiodate. The amount used is preferably 1 to 5 equivalents. Examples of the solvent used in this reaction include methylene chloride, chloroform, toluene,
Examples thereof include organic solvents such as methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran and dioxane, and mixed solvents thereof. Reaction temperature is -4
The reaction time is preferably 0 ° C. to 0 ° C., and the reaction time is preferably about 10 minutes to 3 hours.

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

The compound [II] used as a starting material in the above reaction can be produced by the following method.

[0022]

[Chemical 6]

[In the formula, R 1 and R 2 are the same as described above. ]

First, the starting compound [III]
Jornal of Organi
C Chemistry), Vol. 26, 412 (1961).

Step A The compound [V] can be produced by reacting the starting compound [III] with the compound [IV] in the presence of a base, without solvent or in a solvent. Examples of the base that can be used in this reaction include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydride, sodium hydride, sodium methoxide, sodium ethoxide and the like. The use ratio thereof is usually 1 to 4 times mol of the compound [III]. Further, as the solvent, methanol, ethanol, propanol, dioxane, tetrahydrofuran,
Organic solvents such as toluene, N, N-dimethylformamide and dimethylsulfoxide, water, or a mixed solvent thereof can be preferably used. The reaction temperature may be from 0 ° C. to the boiling point of the solvent, and the reaction time is usually 2 to 24 hours.

Step B Compound [VII] can be produced by reacting compound [V] with compound [VI] in the same manner as described above.

Step C Compound [VIII] can be obtained by reacting compound [VII] with phosphorus oxychloride. The reaction is usually carried out in an organic solvent such as tetrahydrofuran, dioxane, acetonitrile, toluene, methylene chloride, chloroform, carbon tetrachloride and the like, and an organic base such as triethylamine, N-methylpiperidine, pyridine and N, N-dimethylaniline is added. Good. The reaction temperature is preferably room temperature to the boiling point of the solvent, and the reaction time is usually 0.5 to 24 hours.

Step D Compound [II] is a compound [VIII] and an amine represented by the formula R1 -H [wherein R1 is the same as above], usually
It can be produced by reacting in a solvent. The solvent used in the reaction may be used as a solvent by using excess amines to be reacted, but diethyl ether, tetrahydrofuran, dioxane, toluene, acetone, methylene chloride,
Organic solvents such as chloroform, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof with water are preferable. In order to capture the hydrochloric acid generated in this reaction, a base such as triethylamine, pyridine, 1,8-azabicyclo [5.6.0] -7-undecene, sodium hydrogen carbonate, sodium carbonate, potassium carbonate may be present. .. The reaction temperature is preferably 0 ° C. to room temperature, and the reaction time is usually within the range of 10 minutes to 3 hours.

The compound [I] of the present invention and a pharmacologically acceptable salt thereof exhibit excellent gastric acid secretion inhibitory action, gastrointestinal mucosa protective action, H + / K + ATPase inhibitory action and high safety. It is useful as a therapeutic or preventive agent for peptic ulcer in humans or animals. The peptic ulcer includes a gastric ulcer,
It includes duodenal ulcer, Solinga-Ellison syndrome, anastomotic ulcer, reflux esophagitis and the like.

When the compound [I] of the present invention or a pharmaceutically acceptable salt thereof is used as the above-mentioned medicine, it is orally administered in the form of tablets, powders, granules, capsules, syrups, suppositories, injections and the like. Can be administered parenterally or parenterally.
The dose varies depending on the patient's condition, age, body weight, administration route, etc., but is usually 5 to 1500 mg per day for an adult, preferably within the range of 20 to 800┼, and may be adjusted once a day or 2-3 times. It can be administered in divided doses.

There is no particular difficulty in formulating the compound [I] of the present invention or a pharmacologically acceptable salt thereof, and any known method may be used. That is, the oral solid preparations as exemplified above can be produced according to a conventional method by using an excipient, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent and the like, if necessary. 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 the disintegrant, starch, agar, gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, carboxymethyl cellulose calcium, dextrin and the like can be used. For tablets, granules, etc., sugar coating,
A coating such as gelatin coating may be applied. Injectables can also be easily produced by conventional methods using appropriately distilled water, pH adjusters, buffers, stabilizers, solubilizers and the like.

[0032]

In order to investigate the essential gastrointestinal mucosa-protecting effect of the compound of the present invention, the compound of the present invention was administered to rats parenterally, that is, intraperitoneally, and the inhibitory effect on the acute gastric mucosal damage by ethanol was measured. As a result, it was found that it showed excellent activity.

Incidentally, 2-[(1H-benzimidazol-2-yl) sulfinyl, which is an isomer of a compound in which a dimethylamino group is substituted at the 4- to 6-positions of the pyrimidine ring, that is, an isomer of the compound of the present invention (Example 1). Methyl] -6-
Dimethylamino-4-pyrimidinecarboxylic acid ethyl ester, 2-[(4-dimethylamino-5-methylpyrimidin-6-yl) methylsulfinyl] -1H described in the examples of JP-A-61-85384. -Benzimidazole and 2-[(4-dimethylamino-2-) disclosed in JP-A-61-205276.
Pyrimidinyl) methylsulfinyl] -1H-benzimidazole was synthesized and examined for its gastric mucosal protective action in the same manner as the compound of the present invention, but no significant activity was observed at a dose of 100 mg / ╂.

Furthermore, as a result of examining the gastric acid secretion inhibitory action and the H + / K + ATPase inhibitory action of the compound of the present invention, strong activity was observed for both of these actions.

Therefore, the compounds of the present invention are H + / K + A
It was clarified that it has both a strong gastric acid secretion inhibitory action based on the TPase inhibitory action and an excellent gastrointestinal mucosa protective action.

Next, a reference example will be described. [Reference Example 1] 2-[(1H-benzimidazol-2-yl) thiomethyl] -6-dimethylamino-4-pyrimidinecarboxylic acid ethyl ester 1.97 obtained by a conventional method
g was dissolved in 50 ml of methylene chloride and 1.19 g of m-chloroperbenzoic acid was added to 2 ml of methylene chloride under stirring at -20 ° C.
A solution dissolved in 0 ml was added dropwise over 1 hour. After continuously stirring for 1 hour, the reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and further washed with water. After drying, the solvent was distilled off under reduced pressure,
The residue was recrystallized from ethyl acetate to give 2-[(1H-benzimidazol-2-yl) sulfinylmethyl] -6-.
1.3 g (yield 64%) of dimethylamino-4-pyrimidinecarboxylic acid ethyl ester was obtained. Melting point: 162-1
63 ° C.

[Reference Example 2] 2-[(4-dimethylamino-5-methylpyrimidin-6-yl) methylthio] -1H-benzimidazole 7 obtained according to the method described in JP-A-61-85384. 0.78 g of Reference Example 1
Oxidation in the same manner as in 2-[(4-dimethylamino-5
-Methylpyrimidin-6-yl) methylsulfinyl]
-1H-benzimidazole (6.4 g, yield 78%) was obtained. Melting point: 176-178 [deg.] C.

Reference Example 3 2 g of 2-[(4-dimethylamino-2-pyrimidinyl) methylthio] -1H-benzimidazole obtained according to the method described in JP-A No. 61-205276 was used as Reference Example 1. Oxidize in the same way,
2-[(4-Dimethylamino-2-pyrimidinyl) methylsulfinyl] -1H-benzimidazole (1 g, yield 48%) was obtained. Melting point: 158-168 [deg.] C.

Reference Example 4 83 g of chloroacetamidine hydrochloride and ethoxymethylenemalonic acid diethyl ester 1
39.2 g of ethanol (1300 ml) was added dropwise over 1 hour. After stirring for 4 hours at room temperature, add 70 ml of concentrated hydrochloric acid to 1
It was dripped in 0 minutes. Then, the solvent was distilled off under reduced pressure, and water was added to the residue.
000 ml was added, and the mixture was stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol to give 2-chloromethyl-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester 104 g (yield 75
%) Was obtained. Melting point: 169-170C.

Reference Example 5 To 200 ml of ethanol was added 6.6 ml of a 40% aqueous solution of sodium hydroxide, and then 2-
9.83 g of mercaptobenzimidazole was added and dissolved. To this solution, 11.81 g of 2-chloromethyl-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester was added and stirred for 15 hours. Continue 60
After stirring at 0 ° C for 2 hours, the mixture was cooled to room temperature, 200 ml of water was added, and the mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration, washed with water, and recrystallized from a mixed solution of N, N-dimethylformamide and ethanol to give 2-[(1H-benzimidazole-2.
-Yl) thiomethyl] -1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester 16.8 g
(Yield 93%) was obtained. Melting point: 205-206 ° C.

Reference Example 6 2 to 200 ml of acetonitrile
26 g of [[(1H-benzimidazol-2-yl) thiomethyl] -1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester was suspended, 14.4 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 30 minutes. did. Next, acetonitrile was distilled off under reduced pressure, methylene chloride and ice water were added to the residue, and the mixture was neutralized with a 40% aqueous solution of sodium hydroxide. The organic layer was separated, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized from a mixed solution of tetrahydrofuran and isopropyl ether to give 2-[(1H-benzimidazole-2.
24.5 g (yield 89%) of ethyl ester of -yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid was obtained. Melting point: 133-135 [deg.] C.

[Reference Example 7] 2.48 g of 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved in 30 ml of tetrahydrofuran and stirred under ice cooling. 3 ml of a 50% aqueous solution of dimethylamine was added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue to dissolve it. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After evaporating methylene chloride under reduced pressure, the residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester. 2.0 g (79%) of ester were obtained. Melting point:
128-130 ° C.

Reference Examples 8 to 21 The compounds shown in Table 1 were obtained in the same manner as in Reference Examples 4 to 7.

[0044]

[Table 1]

[0045]

【Example】

[Example 1] 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester (9.1 g) was dissolved in 100 ml of methylene chloride and stirred at -40 ° C. Below, a solution prepared by dissolving 6.04 g of 80% m-chloroperbenzoic acid in 120 ml of methylene chloride was added dropwise over 1 hour. Then, 20 ml of a 5% aqueous solution of sodium thiosulfate and 100 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred. Separate the organic layer, wash with water,
After drying, the solvent was distilled off. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazol-2-yl) sulfinylmethyl] -4.
8.3 g (yield 88%) of ethyl ester of -dimethylamino-5-pyrimidinecarboxylic acid was obtained.

Melting point: 134 to 135 ° C. IR (nujol method) ν max cm −1: 3160 (NH), 1720
(C = O) Mass m / z: 373 (M +) NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7Hz, OCH2CH3),
2.85 [6H, s, N (CH3) 2], 4.82 (2H, q, J = 7Hz, OCH2CH3),
4.64 and 4.75 (2H, d and d, J = 13.5Hz, SOCH2), 7.20
~ 7.45 (2H, m, benzen-H), 7.50 ~ 7.80 (2H, m, benzen-H)
H), 8.47 (1H, s, pyrimizine-H), 13.61 (1H, bs, NH). Elemental analysis (C17H19N5O3S) Theoretical value (%): C, 54.68; H, 5.13; N, 18.75 Measured value ( %): C, 54.51; H, 5.22; N, 19.09

Examples 2 to 6 The compounds obtained in the same manner as in Example 1 are collectively shown in Table 2.

[0048]

[Table 2]

[Example 7] 2-to 30 ml of methylene chloride
Dissolve 4 g of [(1H-benzimidazol-2-yl) thiomethyl] -4- (N-ethyl-N-methylamino) -5-pyrimidinecarboxylic acid ethyl ester, -3
80% m-chloroperbenzoic acid 2.44 under stirring at 0 ° C.
A solution prepared by dissolving g in 30 ml of methylene chloride was added dropwise over 1 hour. Then, 10 ml of a 5% aqueous solution of sodium thiosulfate and 50 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazol-2-yl) sulfinylmethyl] -4- (N-ethyl-N-methylamino) -5-pyrimidinecarboxylic acid. 3.0 g (yield 72%) of ethyl ester was obtained.

Melting point: 116 to 118 ° C. IR (nujol method) νmax cm −1: 1720 (C═O) Mass m / z: 387 (M +) NMR (DMSO-d6) δ: 0.99 (3H, t, J) = 7.1Hz, NCH2CH
3), 1.29 (3H, t, J = 7Hz, OCH2CH3), 2.78 (3H, s, NCH3
], 3.41 (2H, q, J = 7.1Hz, NCH2CH3), 4.28 (2H, q, J = 7
Hz, OCH2CH3), 4.64 and 4.79 (2H, d and d, J = 13.6Hz,
SOCH2), 7.25 ~ 7.30 (2H, m, benzen-H), 7.60 ~ 7.75 (2
H, m, benzen-H), 8.46 (1H, s, pyrimizine-H), 13.65 (1H,
bs, NH). Elemental analysis (C18H21N5O3S) Theoretical value (%): C, 55.80; H, 5.46; N, 18.08 Actual value (%): C, 55.76; H, 5.33; N, 17.99

[Examples 8 and 9] Table 3 collectively shows the compounds obtained in the same manner as in Example 7.

[0052]

[Table 3]

Example 10 2 to 100 ml of methylene chloride
-[(1H-Benzimidazol-2-yl) thiomethyl] -4-morpholino-5-pyrimidinecarboxylic acid ethyl ester 9 g was dissolved and stirred at -20 ° C under 80%.
m-Chloroperbenzoic acid (5.34 g) was added to methylene chloride (100).
The liquid dissolved in ml was added dropwise over 1 hour. After stirring for 20 minutes, 100 ml of a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was stirred. Then, the organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate, washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solution of methylene chloride and ethyl acetate to give 2-[(1H-benzimidazole-2-
Yl) sulfinylmethyl] -4-morpholino-5-pyrimidinecarboxylic acid ethyl ester 7.7 g (yield 83
%) Was obtained.

Melting point: 167 to 168 ° C. IR (nujol method) νmax cm −1: 1715 (C═O) Mass m / z: 415 (M +) NMR (DMSO-d6) δ: 1.29 (3H, t, J) = 7Hz, OCH2CH3),
3.29 (4H, m, morpholin-H), 3.45 (4H, m, morpholin-H),
4.27 (2H, q, J = 7Hz, OCH2CH3), 4.65 and 4.81 (2H, d and d, J = 13.4Hz, SOCH2), 7.25 ~ 7.35 (2H, m, benzen-
H), 7.55 ~ 7.65 (2H, m, benzen-H), 8.55 (1H, s, pyrimiz
ine-H), 13.61 (1H, bs, NH). Elemental analysis (C19H21N5O4S) Theoretical value (%): C, 54.93; H, 5.05; N, 16.86 Measured value (%): C, 54.93; H, 4.91; N, 16.95

[Examples 11 to 15] The compounds obtained in the same manner as in Example 10 are collectively shown in Table 4.

[0056]

[Table 4]

Example 16 2-to 15 ml of ethanol
[(1H-Benzimidazol-2-yl) sulfinylmethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester (1.87 g) was dissolved, and 1N aqueous sodium hydroxide solution 5 was added to the mixture at 60 ° C. Stir for 1 hour. Next, the reaction solution was evaporated to dryness under reduced pressure, dry ethanol was added, and the reaction solution was dried again under reduced pressure. The residue was recrystallized from a mixed solution of dry ethanol and dry diethyl ether to give 2-[(1
1.7 g (yield 86%) of sodium salt of H-benzimidazol-2-yl) sulfinylmethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester
Got

Melting point: 173-176 ° C. IR (nujol method) νmax cm −1: 1720 (C═O) Mass m / z: 396 (M ++ 1), 418 (M +)
+ Na) NMR (DMF-d7) δ: 1.35 (3H, t, J = 7Hz, OCH2CH3), 3.
06 (6H, s, N (CH3) 2], 4.35 (2H, q, J = 7Hz, OCH2CH3), 4.
49 and 4.60 (2H, d and d, J = 13.4Hz, SOCH2), 6.90
~ 6.95 (2H, m, benzen-H), 7.50 ~ 7.56 (2H, m, benzen-
H), 8.57 (1H, s, pyrimizine-H). Elemental analysis (C17H18N5NaO3S.1 / 2H2O) Theoretical value (%): C, 50.49; H, 4.74; N, 17.32 Actual value (%): C, 50.53; H, 4.65; N, 17.43

[Embodiment 17] Same as Embodiment 16 except that
-[(1H-benzimidazol-2-yl) sulfinylmethyl] -4- (N-ethyl-N-methylamino)
A sodium salt of ethyl 5-pyrimidinecarboxylic acid was obtained.

Melting point: 160 to 163 ° C. IR (nujol method) νmax cm −1: 1720 (C═O) Mass m / z: 410 (M ++ 1), 432 (M +)
+ Na) NMR (DMSO-d6) δ: 1.20 (3H, t, J = 7.1Hz, NCH2CH
3), 1.35 (3H, t, J = 7Hz, OCH2CH3), 2.92 (3H, s, NCH3
], 3.72 (2H, q, J = 7.1Hz, NCH2CH3), 4.35 (2H, q, J = 7
Hz, OCH2CH3), 4.46 and 4.59 (2H, d and d, J = 13.4Hz,
SOCH2), 6.85 ~ 6.95 (2H, m, benzen-H), 7.45 ~ 7.55 (2
H, m, benzen-H), 8.55 (1H, s, pyrimizine-H). Elemental analysis (C18H20N5NaO3S.1 / 2H2O) Theoretical value (%): C, 51.67; H, 5.06; N, 16.74 Measured value (%): C, 51.67; H, 4.98; N, 16.90

[Embodiment 18] As in Embodiment 16, 2
A sodium salt of-[(1H-benzimidazol-2-yl) sulfinylmethyl] -4-morpholino-5-pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 184-187 ° C. IR (nujol method) νmax cm −1: 1720 (C═O) Mass m / z: 438 (M ++ 1), 460 (M +)
+ Na) NMR (DMSO-d6) δ: 1.35 (3H, t, J = 7Hz, OCH2CH3),
3.50 to 3.70 (8H, m, morpholin-H), 4.34 (2H, q, J ＝ 7Hz, O
CH2CH3), 4.51 and 4.63 (2H, d and d, J = 13.2Hz, SO
CH2), 6.80 ~ 6.90 (2H, m, benzen-H), 7.40 ~ 7.50 (2H,
m, benzen-H), 8.64 (1H, s, pyrimizine-H). Elemental analysis (C19H20N5NaO4S ・ 1 / 2H2O) Theoretical value (%): C, 51.11; H, 4.74; N, 15.69 Measured value (%): C, 51.35; H, 4.64; N, 15.69

Next, formulation examples of the compound of the present invention will be described. [Formulation Example 1] The compound of Example 1, lactose, corn starch, microcrystalline cellulose and hydroxypropyl cellulose were mixed by a universal stirrer (manufactured by Shinagawa Kogyo Co., Ltd.), and then a wetting liquid (30% ethanol) was added for granulation. .. The granulated product was dried and sieved (20 mesh), then carboxymethyl cellulose calcium, magnesium stearate and talc were added and mixed, and 200 mg per tablet was obtained with a rotary tableting machine (Kikusui Seisakusho). .. Composition in 1 tablet (200 mg) Compound of Example 1 50 mg Lactose 60 mg Corn starch 40 mg Microcrystalline cellulose 30 mg Hydroxypropyl cellulose 8 mg Carboxymethyl cellulose calcium 10 mg Magnesium stearate 1 mg Talc 1 mg

[Formulation Example 2] Tablets 45 ° C, air supply temperature 55 ° C in a fluidized granulation coating apparatus (manufactured by Freund Sangyo)
Under the conditions of, the tablets obtained in Formulation Example 1 were coated with an enteric solution having the following composition to produce 230 mg of enteric coated tablets per tablet. Composition of enteric solution Eudragit L-30D 69.0 mg (solid component 20.7 mg) Polyethylene glycol 6000 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 the mixture was granulated with an extrusion granulator (manufactured by Fuji Paudal Co., screen diameter 0.9 mg). The granules were granulated and immediately sized with a Marumerizer (manufactured by Fuji Paudal), dried and sieved to produce 12-42 mesh columnar granules. Composition in 200 mg of columnar granules Compound of Example 1 50 mg Lactose 50 mg Corn starch 40 mg Microcrystalline cellulose 30 mg Hydroxypropyl cellulose 10 mg Carboxymethyl cellulose 20 mg

[Formulation Example 4] In the same manner as in Preparation Example 2, the columnar granules obtained in Preparation Example 3 were coated with an enteric solution having the following composition to obtain enteric-coated granules. 260 mg of this granule is 1
No. gelatin hard capsules were filled. Composition of enteric solution Eudragit L-30D 138.0 mg (solid component 41.4 mg) Polyethylene glycol 6000 12.4 mg Talc 4.1 mg Tween 80 2.1 mg Water 0.28 ml Enteric coated granules 260 mg Composition of Preparation Example 3 Columnar granules 200 mg Enteric film 60 mg Capsule formulation composition Enteric columnar granules 260 mg No. 1 gelatin hard capsule 76 mg

[Formulation Example 5] The compound of Example 1, lactose and corn starch were mixed to give a dusting agent. Further, the above-mentioned spraying agent and non-parel were put into a centrifugal fluidized coating granulator (manufactured by Freund Sangyo), and coating was performed while spraying a 4% aqueous solution of hydroxypropyl cellulose to obtain spherical granules. After drying this spherical granule, it is sieved to 12-32
A granule of mesh was obtained. Composition in 190 mg of spherical granules Compound of Example 1 50 mg Nonpareil 100 mg Lactose 20 mg Corn starch 18 mg Hydroxypropylcellulose 2 mg

[Formulation Example 6] In the same manner as in Preparation Example 2, the spherical granules obtained in Preparation Example 5 were coated with an enteric solution having the following composition to obtain enteric-coated spherical granules. This granule 240
No. 2 gelatin hard capsules were filled with mg. Composition of enteric solution Eudragit L-30D 104.7 mg (solid component 31.4 mg) Polyethylene glycol 6000 5.4 mg Talc 11.6 mg Tween 80 1.6 mg Water 0.22 ml Composition in 240 mg enteric coated granules Spherical granules 190 mg Enteric coating 50 mg Capsule formulation composition Enteric coated spherical granules 240 mg No. 2 gelatin hard capsule 65 mg

[Formulation Example 7] 6 g of the compound of Example 1 was dispersed in distilled water for injection to prepare a 1N sodium hydroxide aqueous solution 16
After dissolving by adding ml, distilled water for injection was added so that the total amount was 300 ml, and the bacteria was removed by filtration in the usual way. Each 1 ml of the obtained filtrate was dispensed into a sterilized bottle, freeze-dried, and sealed. As described above, the lyophilized powder in a bottle containing 20 mg of the compound of Example 1 was dissolved in an appropriate amount of physiological saline at the time of administration and used as an injection.

[Formulation Example 8] An injection containing the following components containing 5 mg of the compound of Example 1 per ml was prepared by a conventional method. Compound of Example 1 50 mg Polyethylene glycol 400 for injection 5 ml Sodium dihydrogen phosphate 20 mg Distilled water for injection is added to make a total volume of 10 ml.

Next, test examples relating to the pharmacological action and acute toxicity of the compound of the present invention will be described. [Test Example 1] Inhibitory effect on acute gastric mucosal damage by ethanol SD male rats (7-week-old, 1 group 5) fasted for 24 hours
The test compound suspended in a 0.5% aqueous solution of sodium carboxymethyl cellulose was intraperitoneally administered to each mouse. The control group received only a 0.5% aqueous solution of sodium carboxymethyl cellulose. Weight 1 after 30 minutes
Oral administration of 0.5 ml of ethanol per 00 g caused gastric mucosal damage. One hour later, the rat was killed by exsanguination,
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 gastric mucosal damage inhibition rate (%) of the test compound was determined by the following formula, and the ED50 value (mg / ╂) was calculated according to a conventional method. The results are shown in Table 5. [1- (ulcer index of test compound administration group / ulcer index of control group)] × 100

[0072]

[Table 5]

Test Example 2 Suppressive Effect on Gastric Acid Secretion Male SD rats (7 weeks old, 1 group 5) fasted for 24 hours
100 mg / ╂ of the test compound suspended in 0.5% aqueous solution of sodium carboxymethylcellulose immediately after laparotomy under diethyl ether anesthesia, ligation of the pylorus
Was administered intraduodenally. The control group received only a 0.5% aqueous solution of sodium carboxymethyl cellulose. Then, the abdomen was sutured and left under fasting and dewatering for 4 hours, and then the rat was killed with an excessive amount of diethyl ether, 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 determine the gastric acid secretion amount.
Next, the gastric acid secretion inhibitory rate (%) of the test compound was calculated by the following formula, and the results are shown in Table 6. [1- (gastric acid secretion amount of test compound administration group / control gastric acid secretion amount)] × 100

[0074]

[Table 6]

[Test Example 3] H + / K + -ATPase activity inhibitory action (1) Preparation of H + / K + -ATPase Saccoma (Saccoma) was prepared from fresh fundic glands of dogs.
ni) et al. [Biochem. and Bioph
ys. Acta, 464, 313 (1977)]. (2) Measurement of H + / K + -ATPase activity Test compound dissolved in dimethyl sulfoxide, H + /
K + -ATPase, 20 μg protein / ml, 70 mM T
ris HCl (pH 8.6), 10 mM KCl and 5
mM MgCl2 was incubated at 37 ° C for 60 minutes. Next, the ATPase reaction was started with ATP, the reaction was stopped after 20 minutes, and the released phosphoric acid was treated with the method of Fiske and Sbbarow [J. Biol. Chem., 66, 375 (192
5)] was measured. The inhibitory effect of the test compound was determined by the following formula, and 50% inhibitory concentration (IC5
0) was calculated. The results are shown in Table 7. [1- (measured value of test compound administration group / measured value of control group)] × 100

[0076]

[Table 7]

Test Example 4 Acute Toxicity Test Male ddY mice weighing 5 to 30 g (5 mice per group) and SD male rats weighing 220 to 250 g (5 rats per group)
500 mg / ╂ each of the compounds of Examples 1, 7 and 10 suspended in a 5% aqueous solution of carboxymethyl cellulose.
Was intraperitoneally administered and observed for 7 days. as a result,
No deaths were observed in any of the groups.

[0078]

The compound [I] of the present invention and the pharmacologically acceptable salt thereof according to the above-mentioned test examples show excellent gastrointestinal mucosal protective action, gastric acid secretion inhibitory action and H + / K + -ATPas.
It has been revealed that it has an e activity inhibitory action and has low toxicity. Therefore, according to the present invention, it is possible to provide a highly useful anti-peptic ulcer drug that has both an inhibitory action on an attacking factor and an enhancing action on a protective factor.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Isami Kimura, No. 35-334, Yamanoura, Ryuo-cho, Gamo-gun, Shiga (72) Inventor Akemi Kamiya, Osuhara, Yasu-cho, Yasu-gun, Shiga Prefecture 1823 No. 1 (72) Inventor Mikiko Kataoka 1060-6-403, Babacho, Kusatsu City, Shiga Prefecture (72) Makoto Sato 166-40 Harimatacho, Moriyama City, Shiga Prefecture

Claims (1)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R1 represents an N, N-dimethylamino group, N-ethyl-N-methylamino group or morpholino group, and R2 represents a lower alkyl group. ] 2-[(1H-benzimidazol-2-yl) sulfinylmethyl]-
4-Substituted amino-5-pyrimidinecarboxylic acid derivative or a pharmaceutically acceptable salt thereof.