JPS63313784A - Novel pyrazole derivative, production thereof and antiulcer agent containing said derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound production formula I [R<1> and R<2> are H, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro, etc.; R<3> and R<5> are H, lower alkyl, lower alkoxy(carbonyl) or halogenated lower alkoxy; R<4> is H, alkyl, arylalkyl, lower alkoxy(methyl), nitro or halogen; X is S or S=O] and salt thereof. EXAMPLE:2-[1-(3,5-Dimethylpyrazolyl)]methylthiobenzimidazole. USE:An antiulcer agent. PREPARATION:A benzimidazole derivative expressed by formula II (e.g. 2- mercaptobenzimidazole) is reacted with a pyrazole derivative expressed by formula III (Y is halogen or activated ester residue) (e.g. 1-chloromethyl-3,5- dimethylpyrazole hydrochloride).

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a novel pyrazole derivative represented by the general formula (I) below and a salt thereof, which has an anti-ulcer effect and is useful as a medicine or an intermediate thereof. , and their production method, and also relates to an antiulcer agent containing at least one of them as an active ingredient.

[Prior Art] The mechanism of occurrence of peptic ulcer is complicated due to various factors, and it is said that peptic ulcer occurs due to an imbalance between attacking factors and protective factors for the gastric mucosa. Therefore, suppressing the secretion of gastric acid, which is an attack factor, is a useful method for preventing or treating ulcers.

Traditionally, it has been used as an effective drug to suppress gastric acid secretion.
A group of anticholinergic drugs and histamine H2 such as cimetidine
Receptor blockers are widely used clinically. Also recently,
Omebrazole (Japanese Patent Publication No. 60-34
956) is known.

Anticholinergic drugs have side effects such as suppression of gastric emptying, zero thirst, and suppression of mydriatic sweating.Also, even at doses that can almost suppress gastric acid secretion, they cannot be used to prevent ulcer aggravation or recurrence. has its limits. In addition, cimetidine exhibits side effects such as undesirable central effects and anti-androgenic effects, and a decrease in the protective factors of the gastric mucosa, which is particularly problematic during long-term treatment, is a major cause of recurrent ulcers after cimetidine use is discontinued. It is said that.

Therefore, it is strongly desired to provide an excellent anti-ulcer compound that strongly inhibits the secretion of gastric acid, which is an attack factor, and also has a protective factor-enhancing effect (cytoprotective effect).

[Disclosure of the Invention] The present inventors have conducted research and development in search of an excellent anti-ulcer compound that strongly suppresses gastric acid secretion and has a protective factor enhancing effect (cytoprotective effect), and as a result, the present invention has been developed. It has been discovered that a new compound according to the present invention meets that purpose. The present invention is based on this knowledge.

The compound according to the present invention is a novel compound created by the present inventors, and is characterized by having an N-substituted virazole ring in its structure.

That is, the present invention provides general formula (I) [wherein R1 and R2 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a nitro group, or a lower alkoxycarbonyl group] or acyl group, or together represent a 1,3-butadiene-1,4-diyl group, and R3 and R5 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, Represents a lower alkoxycarbonyl group or a halogenated lower alkoxy group, R4 represents a hydrogen atom, an alkyl group, an arylalkyl group, a lower narkoxy group, a lower alkoxymethyl group, a nitro group, or a halogen atom, and X represents S or S= The object of the present invention is to provide pyrazole derivatives and salts thereof represented by O and an anti-ulcer agent characterized by containing them as active ingredients.
II) A benzimidazole derivative represented by the formula (III) [wherein R1 and R2 have the above-mentioned meanings] [wherein Y represents a halogen atom or an activated ester residue, R3, In the general formula (Ia), characterized in that R4 and R5 have the above-mentioned meanings, a pyrazole derivative represented by the formula (Ia) [wherein R1, R2, R3, R4 and R5 have the above-mentioned meanings] is reacted. The present invention provides a method for producing the pyrazole derivatives and salts thereof. Furthermore, the present invention provides a compound represented by the general formula (Ib) [wherein R1, R2, R3, R4 and R5 have the above-mentioned meaning], characterized in that the compound of the general formula (Ia) is oxidized. The present invention also provides a method for producing pyrazole derivatives.

Specific examples of lower alkyl groups for R1 and R2 in the compound of formula (I) include methyl group, ethyl group, propyl group, butyl group, tert-butyl group, and the like. Specific examples of lower alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy groups.

Further, specific examples of the acyl group include a formyl group, an acetyl group, a propionyl group, a benzoyl group, and the like. Furthermore, specific examples of lower alkoxycarbonyl groups include:
Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert
-butoxycarbonyl group and the like. R3 and R
Specific examples of the lower alkyl group in 5 include a methyl group, an ethyl group, a propyl group, an isopropyl group, and the like. Further, specific examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and the like.

Specific examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like. Specific examples of the halogenated lower alkoxy group include 2,2,2-trifluoroethoxy group and the like. Further, specific examples of the alkyl group for R4 include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group, heptyl group, octyl group, and the like. Specific examples of lower alkoxy groups include methoxy, ethoxy, and propoxy groups. Specific examples of the lower alkoxymethyl group include a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, and the like. Specific examples of the arylalkyl group include benzyl group and phenethyl group. Examples of the halogen atom include a chloro atom and a bromo atom.

The novel compound according to the present invention represented by formula (I) has two types of tautomers due to the tautomerism of the benzimidazole ring, both of which are included within the scope of the compound according to the present invention. It is something.

Furthermore, in the general formula (I) representing the compound according to the present invention, when R3 and R5 are different, R
A mixture of isomers is obtained in which the positions of 3 and R5 are reversed, but they can be separated by suitable methods.

The following compounds are exemplified as typical compounds according to the present invention.

2-(I-pyrazolyl)methylthiobenzimidazole 2-(I-pyrazolyl)methylthio-5-trifluoromethylbenzimidazole 5-chloro-2-(I-pyrazolyl)methylthiobenzimidazole 5-methoxy-2-(I-pyrazolyl) ) Methylthiobenzimidazole 2-[1-(4-methylpyrazolyl)]comethylthiobenzimidazole-[1-(4-methylpyrazolyl)]]methylthio 5-trifluoromethylbenzimidazole 5chloro-
2-[1-(4-methylpyrazolyl)]comethylthiobenzimidazole-methoxy-2-[1-(4-methylpyrazolyl)]
Comethylthiobenzimidazole 56-dichloro-2-[1-(4-methylpyrazolyl)]comethylthiobenzimidazole 45-dimethyl-
2-[1-(4-methylpyrazolyl)]comethylthiobenzimidazole 5 Benzoyl-2-[1-(4-methylpyrazolyl)]comethylthiobenzimidazole 2
[1-(3,5-dimethylpyrazolyl)]comethylthiobenzimidazole-[1-(3,5-dimethylpyrazolyl)]]methylthio5-methylbenzimidazole 2 [1-(3,
5-dimethylpyrazolyl)]]methylthio5-nitrobenzimidazole15) 2-[1-(3,5-dimethylpyrazolyl)]]methylthio5-trifluoromethylbenzimidazole-chloro-2-[1-(3,5 -dimethylpyrazolyl)comethylthiobenzimidazole 2- [1-(3,
5-dimethylpyrazolyl)comethylthio-5-fluorobenzimidazole 2- [1-(3,5-dimethylpyrazolyl)]]methylthio 5-methoxybenzimidazole 2 [1-(3,5-dimethyl and lazolyl)]]
Methylthio 5,6-dimethylbenzimidazole 2[
1-(3,4,5-dimethyl and lazolyl)] comethylthiobenzimidazole-trifluoromethyl-2-[1-(3,4,5-trimethylpyrazolyl)comethylthiobenzimidazole 5-fluoro-2-[ 1-(3,4,5-)dimethylpyrazolyl)]comethylthiobenzimidazole 5methoxy-2-[1-<3.4.5-)dimethylvirazolyl)
] comethylthiobenzimidazole 5-ethoxy-2-[
1-(3,4,5-)dimethyl and lazolyl)]comethylthiobenzimidazole 5benzoyl-2-[1-(3
,4,5-)dimethylpyrazolyl)]comethylthiobenzimidazole-methoxycarbonyl-2-[1-(3,
4,5-trimethylpyrazolyl)]methylthiohenzimidazole 2-[1-(4-ethyl-3,5-dimethylpyrazolyl)comethylthiobenzimidazole 2-[1-(4-ethyl-3,5-dimethylpyrazolyl)comethylthio -5
-trifluoromethylbenzimidazole 2- [1-(4-butyl-3,5-dimethylpyrazolyl)comethylthiobenzimidazole 2-[1-(,!
1-butyl-3,5-dimethylpyrazolyl)]]methylthio5-trifluoromethylbenzimidazole-benzoyl-2-[1-(4-butyl-3,5-dimethylpyrazolyl)]comethylthiobenzimidazole-[1-' (4-hexyl-3,5-dimethylpyrazolyl)]comethylthiobenzimidazole 19) Nzimidazole 2-[1-(4-hexyl-3,5-dimethylpyrazolyl)]]methylthio 5-trifluoromethylbenzimidazole -[1-(4-hexyl-3,5-dimethylpyrazolyl)comethylthio-5-methoxybenzimidazole2-[1-(4-benzyl-3,5-dimethylpyrazolyl)]comethylthiobenzimidazole2 [1- (4
-benzyl-3,5-dimethylpyrazolyl)]]methylthio5-methoxybenzimidazole-['1-(4-bromo-3,5-dimethylpyrazolyl)]comethylthiobenzimidazole2 [1-(4
-bromo-3,5-dimethylpyrazolyl)]]methylthio 5-trifluoromethylbe20) rufinylbenzimidazole 2-[1-(4-bromo-3,5-dimethylpyrazolyl)]]methylthio 5-methoxybenzimidazole -Hensiru 2- [1-(4-bromo-3,5-
dimethylpyrazolyl)] comethylthiobenzimidazole-(I-pyrazolyl)methylsulfinylbenzimidazole 2-(I-pyrazolyl)methylsulfinyl-5-trifluoromethylbenzimidazole 5-chloro-2-(
I-pyrazolyl)methylsulfinylbenzimidazole 5-methoxy-2-(I-pyrazolyl)methyls 2-
(:1-(4-methylpyrazolyl)comethylsulfinylbenzimidazole2-[1-(4-methylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-chloro-2-[1-(4-methyl pyrazolyl)] methylsulfinylbenzimidazole 5-methoxy-2
-[1-(4-methylpyrazolyl)]methylsulfinylbenzimidazole5.6-dichloro-2-[1-(
4-Methylpyrazolyl)] Methylsulfinylbenzimidazole 4.5-dimethyl-2-[1-(4-methylpyrazolyl)]methylsulfinylbenzimidazole 5-benzoyl-2-[1-(4-methylpyrazolyl)
Comethylsulfinylbenzimidazole 2-[1-
(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 2- [1-(3,5-dimethylpyrazolyl)comethylsulfinyl-5-methylbenzimidazole 2- [
1-(3,5-dimethyl and lazolyl)]]methylsulfinyl-5-nitrobenzimidazole 2[1-(3,
5-dimethyl and lazolyl)]]methylsulfinyl-5
-Trifluoromethylbenzimidazole-chloro-2-[1-(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 2- [1
-(3,5-dimethylpyrazolyl)]]methylsulfinyl-5-fluorobenzimidazole-[1-(3,5
-dimethylpyrazolyl)comethylsulfinyl-5-methoxybenzimidazole 2- [1-(3,5-dimethylpyrazolyl)]]methylsulfinyl-5-ethoxybenzimidazole, 6-
Dichloro-2-[1-(3,5-dimethylpyrazolyl)
] Methylsulfinylbenzimidazole 2- [1-(3,5-dimethylpyrazolyl)comethylsulfinyl-5,6-dimethylbenzimidazole 2- [1-(3,5-dimethylpyrazolyl>]methylsulfinyl-4,5 -dimethylbenzimidazole 5-benzoyl-2-[1-(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 5-acetyl-2-[1-(3,5-dimethylpyrazolyl)comethylsulfinylbenzimidazole 2- [1-(3,5-dimethylpyrazolyl)]]methylsulfinyl-5-ethylbenzimidazole 5chloro-6-methyl-2-[1-(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 2- [1 -(3,5-dimethylpyrazolyl)]]methylsulfinyl-5-methoxycarbonyl6-methylbenzimidazole2-[1-(3,4,5-)dimethylpyrazolyl)]methylsulfinylbenzimidazole5-methyl-2-
[1-(3,4,5-)dimethylpyrazolyl)]methylsulfinylbenzimidazole 5-nitro-2-[1-(3,4,5-)dimethylpyrazolyl)]methylsulfinylbenzimidazole 5-trifluoromethyl- 2-[1-(3,4,5-trimethylpyrazolyl)]methylsulfinylbenzimidazole 5-chloro-2-[1-(3,4,5-trimethylpyrazolyl)comethylsulfinylbenzimidazole 5-fluoro- 2-[:1-(3,4,5-trimethylpyrazolyl)]comethylsulfinylbenzimidazole-methoxy-2-[1-(3,4,5-)dimethylpyrazolyl)]comethylsulfinylbenzimidazole-ethoxy- 2-[1-(3,4,5-)dimethylpyrazolyl)comethylsulfinylbenzimidazole 5.6-dichloro-2-[1-(3,4,5-)dimethylpyrazolyl)]comethylsulfinylbenzimidazole, 6-dimethyl-2-[1-(3,4,5-)dimethylpyrazolyl)comethylsulfinylbenzimidazole 4.5-dimethyl-2-[1-(3,4,5-trimethylpyrazolyl)]comethylsulfinylbenz Imidazole-benzoyl-2-[1-(3,4,5-trimethylpyrazolyl)comethylsulfinylbenzimidazole 5-acetyl-2-[1-(3,4,5-)dimethylpyrazolyl)]methylsulfinylhenzimidazole 5 -ethyl-2-[1-(3,4,5-)dimethylpyrazolyl)]comethylsulfinylbenzimidazole-propoxy-2-[1-(3,4,5-)dimethylpyrazolyl)]comethylsulfinylbenzimidazole 27) 5-methoxycarbonyl-2-[1-(3,4,5-trimethylpyrazolyl)]comethylsulfinylbenzimidazole-methoxycarbonyl-6-methyl-2-[1-(3
,4,5-)dimethylpyrazolyl)]comethylsulfinylbenzimidazole-[1-(4-ethyl-3,5-dimethylpyrazolyl)]comethylsulfinylbenzimidazole2[1-
(4-ethyl-3,5-dimethylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-chloro-2-[1=(4-ethyl-3,5-dimethylpyrazolyl)]comethylsulfinylbenzimidazole -[1-(4-ethyl-3,5-dimethylpyrazolyl)]]methylsulfinyl-5-fluorohenzimidazole-[1-(4-ethyl-3,5-dimethylpyrazolyl)]]methylsulfinyl-5 -Methoxyhenzimidazole-benzoyl-2-[1-(4-ethyl-3,5-dimethylpyrazolyl)comethylsulfinylbenzimidazole 2-[1-(4-butyl-3,5-dimethylpyrazolyl)comethylsulfinylbenz Imidazole 2-[1
-(4-Butyl-3,5-dimethyl and lazolyl)comethylsulfinyl-5-trifluoromethylbenzimidazole 5-benzoyl-2-[1-(4-butyl-3,5-dimethylpyrazolyl)]methylsulfinyl Nirhenzimidazole 2-[1-(4-hexyl-3,5-dimethylpyrazolyl)comethylsulfinylbenzimidazole 2-[1-(4-hexyl-3,5-dimethylpyrazolyl)]]methylsulfinyl-5- Trifluoromethylhenzimidazole-[1-(4-hexyl-3,5-dimethylpyrazolyl)comethylsulfinyl-5-methoxybenzimidazole 2-[1-(4-benzyl-3,5-dimethylpyrazolyl)comethyl Sulfinylbenzimidazole 2-[1-(4-benzyl-3,5-dimethylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-[1-(4-benzyl-3,5-dimethylpyrazolyl)]] Methylsulfinyl-5-methoxybenzimidazole-[1-(4-bromo-3,5-dimethylpyrazolyl)]comethylsulfinylbenzimidazole 2[1-
(4-bromo-3,5-dimethylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-[1-(4-bromo-3,5-dimethylpyrazolyl)comethylsulfinyl-5-methoxybenzimidazole 5 -benzoyl-2-[1-(4-bromo-3,5-dimethylpyrazolyl)]comethylsulfinylbenzimidazole31) 2-[1-(4-chloropyrazolyl)]comethylsulfinylbenzimidazole-[1-( 4-chloropyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-[1-(4-chloropyrazolyl)]]methylsulfinyl-5-ethoxybenzimidazole2 [1-(
4-benzylpyrazolyl)]comethylsulfinylbenzimidazole-[1-(4-benzylpyrazolyl)]]methylsulfinyl-5-methoxybenzimidazole 2[1-(
3,5-dimethyl-4-propylpyrazolyl)comethylsulfinylbenzimidazole 2-[1-(3,5-dimethyl-4-propylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-[1-( 4-chloro-3,5-dimethylpyrazolyl)]comethylsulfinylbenzimidazole 2['1
2- [1-(5-methoxy-3-methylpyrazolyl)
] Comethylthiobenzimidazole 2 [1-(5-methoxy-3-methylpyrazolyl)
]]Methylthio5-trifluoromethylbenzimidazole-fluoro-2-[1-(5-methoxy-3-methylpyrazolyl)]comethylthiobenzimidazole-methoxy-2-[1-(5-methoxy-3-methylpyrazolyl) ) comethylthiobenzimidazole 2-[1-(3-methoxy-5-methylpyrazolyl)
] Comethylthiobenzimidazole 2 [1-(3-methoxy-5-methylpyrazolyl)
]]Methylthio5-trifluoromethylbenzimidazole-fluoro-2-[1-(3-methoxy-5-methylpyrazolyl)]comethylthiobenzimidazole-methoxy-2-[1-(3-methoxy-5-methylpyrazolyl) ) comethylthiobenzimidazole 2-[1-(5-ethoxy-3-methylpyrazolyl)
Comethylthiobenzimidazole 2-[1-(5-ethoxy-3-methylpyrazolyl)
]]Methylthio 5-trifluoromethylbenzimidazole-[1-(5-ethoxy-3-methylpyrazolyl)]
] Methylthio 5-fluorobenzimidazole35) 2-[1-(5-ethoxy-3-methylpyrazolyl)
]] Methylthio 5-methoxybenzimidazole-[1-(3-ethoxy-5-methylpyrazolyl)comethylthiobenzimidazole 2-[1-(3-ethoxy-5-methylpyrazolyl)
Comethylthio-5-trifluoromethylbenzimidazole 2-[1-(3-ethoxy-5-methylpyrazolyl)
]]Methylthio-5-fluorobenzimidazole-[1-(3-ethoxy-5-methylpyrazolyl)]
] Methylthio 5-methoxybenzimidazole-[1-(3-methylpyrazolyl)]methylthiobenzimidazole 2- [1-(5-methylpyrazolyl)comethylthiobenzimidazole 2-[1-(4-methoxypyrazolyl)comethylthiobenz Imidazole 2-[1-(4-propoxypyrazolyl)]comethylthiobenzimidazole-[1-(4-methoxy-3,5-dimethylpyrazolyl)]comethylthiobenzimidazole 2[1-(4
-methoxy-3,5-dimethyl and lazolyl)]]methylthio-5-methylbenzimidazole-[1-(4-methoxy-3,5-dimethylpyrazolyl)]methylthio-5-nitropenzimidazole 2-[1-( 4-methoxy-3,5-dimethyl and lazolyl)]comethylthio-5-trifluoromethylbenzimidazole-chloro-2-[1-(4-methoxy-3,5-dimethylpyrazolyl)comethylthiobenzimidazole 5-fluoro- 2-[1-(4-methoxy-3,5-dimethylpyrazolyl)comethylthiobenzimidazole 5-methoxy-2-[1-(4-methoxy-3,5-dimethyl and lazolyl)comethylthiobenzimidazole 5-ethoxy -2-[1-(4-methoxy-3,5-dimethylpyrazolyl)]comethylthiobenzimidazole, 6-dichloro-2-[1-(4-methoxy-3,5-dimethylpyrazolyl)]
-dimethylpyrazolyl)]comethylthiobenzimidazole-[1-(4-methoxy-3,5-dimethyl and lazolyl)]comethylthio-4,5-dimethylbenzimidazole-benzoyl-2-[1-(4-methoxy-3 ,5-
dimethylpyrazolyl)]comethylthiobenzimidazole-hydroxy-2-[1-(4-methoxy-3,5-
dimethylpyrazolyl)comethylthiobenzimidazole 2-[1-(3,δ-jethoxypyrazolyl)]comethylthiobenzimidazole38-2) 2-[1-(3,5-jethoxypyrazolyl)]comethylthio-5-methyl Benzimidazole 2 [1-(
3,5-jethoxypyrazolyl)]comethylthio-6-
Nidropenzimidazole 2 [1-(3,5-jethoxypyrazolyl)]comethylthio-5-trifluoromethylbenzimidazole-chloro-2-[1-(3,5-jethoxypyrazolyl)comethylthiobenzimidazole 2- [1-(3
, 5-jethoxypyrazolyl)] comethylthio-5-fluorobenzimidazole 2 [1-(3,5-jethoxypyrazolyl)comethylthio-5-methoxybenzimidazole 2-[1-(3,5-jethoxypyrazolyl)] Rice 38-3) Chilthio-5-ethoxybenzimidazole 2- [1
-(3,5-jethoxypyrazolyl)]comethylthio-
5,6-dimethylbenzimidazole 2[1-(3,5
-jethoxypyrazolyl)]comethylthio-4,5-dimethylbenzimidazole 2[1-(3,5-jethoxypyrazolyl)comethylthio-4,7-simethoxybenzimidazole 2-[1-(3,5-jethoxy pyrazolyl)] comethylthio-5-hydroxybenzimidazole 2 [1-(3,5-jethoxycarbonylpyrazolyl)] comethylthiobenzimidazole 2 [1-(
3-Methyl-5-(2,2,2-)trifluoroethoxy)pyrazolyl)comethylthiobenzimidazole 2- [1-(5-methyl-3-(2,2,2-trifluoroethoxy)pyrazolyl)] Comethylthiobenzimidazole-[1-(3,5-dimethyl-4-nitropyrazolyl)]comethylthiobenzimidazole 2 [1-(3,
5-dimethoxypyrazolyl)]comethylthiobenzimidazole-[1-(3,5-jethoxy-4-methylpyrazolyl)comethylthiobenzimidazole2-[1-(3
,5-dimethoxy-4-methylpyrazolyl)]comethylthiobenzimidazole-[1-(4-ethyl-3,5
-dimethoxypyrazolyl)]comethylthiobenzimidazole47-simethoxy2-[:1-(3,4,5
-)dimethylpyrazolyl)]comethylthiobenzimidazole, 7-simethoxy2-[1-(3,5-dimethylpyrazolyl)]comethylthiobenzimidazole 2[1
-(4-methoxymethyl-3,5-dimethylpyrazolyl)]]methylthio5-trifluoromethylbenzimidazole-methoxy-2-[1-(4-methoxymethyl-3,
5-dimethyl and lazolyl) comethylthiobenzimidazole 2-[1-(5-methoxy-3-methylpyrazolyl)
] Methylsulfinylbenzimidazole 2-[1-(
5-methoxy-3-methylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole 38-6) 5-fluoro-2-(I-(5-methoxy-3-methylpyrazolyl)]methylsulfinylbenzimidazole 5 -Methoxy-2-[1-(5-methoxy-3-methylpyrazolyl)]methylsulfinylbenzimidazole 2-[1-(3-methoxy-5-methylpyrazolyl)
] Methylsulfinylbenzimidazole 2- [1-
(3-methoxy-5-methylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-fluoro-2-[1-(3-methoxy-5-methylbirazolyl)comethylsulfinylbenzimidazole 5-methoxy-2- [1-(3-methoxy-5-methylpyrazolyl)]methylsulfinylbenzimidazole 2- [1-(5-ethoxy-3-methylpyrazolyl)
] Methylsulfinylbenzimidazole 2-[1-(
5-ethoxy-3-methylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-[1-(5-ethoxy-3-methylpyrazolyl)]
] Methylsulfinyl-5-fluorobenzimidazole-[1-(5-ethoxy-3-methylpyrazolyl)]
] Methylsulfinyl-5-methoxybenzimidazole-[1-(3-ethoxy-5-methylpyrazolyl)comethylsulfinylbenzimidazole 2-[1-(3
-ethoxy-5-methylpyrazolyl)]]methylsulfinyl-5-trifluoromethylbenzimidazole-[1-(3-ethoxy-5-methylpyrazolyl)]
] Methylsulfinyl-5-fluorobenzimidazole-[1-(3-ethoxy-5-methylpyrazolyl)]
] Methylsulfinyl-5-methoxybenzimidazole-[1-(3-methylpyrazolyl)]methylsulfinylbenzimidazole 2-[1-(5-methylpyrazolyl)]methylsulfinylbenzimidazole-comethylbenzimidazole 2-[1-( 4-methoxypyrazolyl)]methylsulfinylbenzimidazole 2-[1-(4-propoxypyrazolyl)]methylsulfinylbenzimidazole 2-[1-(4-methoxy-3,5-dimethyl and lazolyl)comethylsulfinylbenzimidazole 2 -[1-(4-methoxy-3,5-dimethylpyrazolyl)comethylsulfinyl-5-methylbenzimidazole2- [1-(4-methoxy-3,5-dimethyl and lazolyl)]]methylsulfinyl-5- Nitrobenzimidazole-[1-(4-methoxy-3,5-dimethyl and lazolyl)]]methylsulfinyl-5-trifluoro38-1
1) Benzimidazole 5-chloro-2-[1-(4-methoxy-3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 5-fluoro-2-[1-(4-methoxy-3,5-dimethyl) lazolyl)]methylsulfinylbenzimidazole 5-methoxy-2-[1-(4-methoxy-3,5-dimethyl and lazolyl)]methylsulfinylbenzimidazole 5-ethoxy-2-[1-(4-methoxy-3, 5-dimethyl and lazolyl)] methylsulfinylbenzimidazole 5,6-dichloro-2-[1-(4-methoxy-3,5
-dimethylpyrazolyl)]methylsulfinyl 2-[1
-(4-methoxy-3,5-dimethylpyrazolyl)]]
Methylsulfinyl-4,5-dimethylbenzimidazole-benzoyl-2-[1-(4-methoxy-3,5-
dimethylpyrazolyl)]methylsulfinylbenzimidazole 5-hydroxy-2-[1-(4-methoxy-3,5-
dimethylpyrazolyl) comethylsulfinylbenzimidazole 2-[1-(3,5-jethoxypyrazolyl)comethylsulfinylbenzimidazole 2-[1-(3,5-jethoxypyrazolyl)]methylsulfinyl-5-methylhenzimidazole 2-'['l -(3,5-jethoxypyrazolyl)comethylsulfinyl-5-nitrobenzimidazole 2-[1-(3,5-jethoxypyrazolyl)comethylsulfinyl-5-trifluoromethylbenzimidazole 5-chloro-2-[1-(3,5-jethoxypyrazolyl)comethylsulfinylbenzimidazole 2- [1-(3,5-jethoxypyrazolyl)comethylsulfinyl-5-fluorobenzimidazole 2- [1 -(3,5-jethoxypyrazolyl)]]methylsulfinyl-5-methoxybenzimidazole-[1-(3,5-jethoxypyrazolyl)]]methylsulfinyl-5-ethoxybenzimidazole-[1-(3, 5-jethoxypyrazolyl)]]methylsulfinyl-5,6-dimethylbenzimidazole-[1-(3,5-jethoxypyrazolyl)comethylsulfinyl-4,5-dimethylbenzimidazole2-[1-(3 ,5-jethoxypyrazolyl)]]methylsulfinyl-4,7-simethoxybenzimidazole-[1-(3,5-jethoxypyrazolyl)]]methylsulfinyl-5-hydroxybenzimidazole38-14) 2- [ 1-(3,5-jethoxycarbonylpyrazolyl)]methylsulfinylbenzimidazole 2-[
1-(3-Methyl-5-(2,2,2-trifluoroethoxy)pyrazolyl)]methylsulfinylbenzimidazole 2-[1-(5-methyl-3-(2,2,2-)trifluoroethoxy) ) pyrazolyl) comethylsulfinylbenzimidazole 2- [1-(3,5-dimethyl-4-nitropyrazolyl)]methylsulfinylbenzimidazole 2- [
1-(3,5-dimethoxypyrazolyl)]methylsulfinylbenzimidazole 2-[1-(3,5-jethoxy-4-methylpyrazolyl)]methylsulfinylbenzimidazole-2-[1
-(3,5-dimethoxy-4-methylpyrazolyl)]methylsulfinylbenzimidazole 2-[1-(4-ethyl-3,5-dimethoxypyrazolyl)]methylsulfinylbenzimidazole 4.7-Simethoxy2-[1- (3,4,5-trimethylpyrazolyl)]methylsulfinylbenzimidazole4.7-Simethoxy2-[1-(3,5-dimethylpyrazolyl)comethylsulfinylbenzimidazole2-[1-(4-methoxymethyl-3 ,5-dimethylpyrazolyl)]methylsulfinyl-5-trifluoromethylbenzimidazole 5-methoxy-2-[1-(4-methoxymethyl-3,
5-dimethylpyrazolyl)comethylsulfinylbenzimidazole (hereinafter referred to as blank space) The compound according to the present invention represented by formula (I) can be represented by examples [in the formula,
Y, R', R2, R3, R4 and R5 have the above-mentioned meanings] That is, when the benzimidazole derivative (I [>) is reacted with the pyrazole derivative (m), compound (Ia) is produced; If (Ia) is oxidized, the compound (Ib
) is obtained. The reaction between compound (II) and compound (III) is carried out in a suitable solvent in the presence of a base as a general rule, but the presence of a base may not be necessary depending on the type of compound. The above reaction solvents include protic solvents such as methanol, ethanol, and isopropanol, ether solvents such as dioxane, ethyl ether, and tetrahydrofuran, hydrocarbon solvents such as benzene and toluene, and basic solvents such as pyridine and triethylamine. , dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and other aprotic polar solvents. These solvents may be used alone or in combination of two or more.

Also, as bases, sodium hydroxide, potassium hydroxide,
Examples include inorganic bases such as sodium hydride and potassium carbonate, and organic bases such as sodium alkoxide, pyridine and triethylamine.

The reaction temperature does not require a particularly high temperature, and a temperature close to the boiling point of the solvent used, for example in the range of room temperature to 100°C, is sufficient. Reaction times range from about 5 minutes to 8 hours, usually 5 minutes to 3 hours.

Next, a method for producing the compound of general formula (Ib) of the present invention will be described. The compound of formula (Ib) is produced by oxidizing the compound of formula (Ia), and any oxidant commonly used for oxidizing sulfides can be used as the oxidizing agent. For example, m-chloroperbenzoic acid, peracetic acid,
3,5-dinitroperbenzoic acid, sodium periodate,
Examples include hydrogen peroxide. The reaction is carried out in a suitable solvent. For example, chloroform, methylene chloride, 1°2-
Halogenated solvents such as dichloroethane and carbon tetrachloride; ethereal solvents such as ethyl ether and tetrahydrofuran;
Alternatively, hydrocarbon solvents such as benzene and toluene may be used. These solvents may be used alone or in combination of two or more.

Although the reaction temperature varies depending on the type of oxidizing agent and the type of substituent of the compound, for example, when m-chloroperbenzoic acid is used, it is preferable to conduct the reaction at a low temperature of -60°C to 0°C to give preferable results. The reaction time also varies depending on the type of oxidizing agent and the reaction temperature, but for example, when m-chloroperbenzoic acid is used, a range of 5 minutes to 2 hours is usually sufficient.

The amount of oxidizing agent ranges from 1 to 2 equivalents, usually from 1 to 1.1 equivalents, to give preferable results.

In any of the above reactions, the target compound can be obtained and purified from the reaction product by various methods commonly used in organic synthetic chemistry, such as recrystallization, reprecipitation, column chromatography, and the like. The acid addition salt of the compound represented by the general formula (Ia) can be easily produced by neutralizing the free base produced by the method described above with an acid. In this case, preferred acids include hydrohalic acid, sulfonic acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, acetic acid, and the like.

The compounds according to the present invention differ somewhat depending on the types of substituents in their structures, but they are generally relatively stable compounds. For example, it is one of the compounds of the present invention. 2-[
Taking 1-(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole as an example, it dissolves in 1,2-dichloroethane, a halogenated solvent, even after several hours under heating or after a week at room temperature. However, almost no coloring or decomposition products are observed.

Compound (I[) which is a raw material for compound (I) according to the present invention
and (m) are known compounds or are produced according to known methods for producing similar compounds. That is, the compound of formula (If) has the general formula (IV) [wherein R1, R2
is produced by reacting a compound represented by the above meaning with carbon disulfide or potassium xanthate (Org, 5ynth, Vol. 30, 56
(see page).

Further, the compound of formula (m) is produced by subjecting it to the reaction represented by the following formula.

[Formula (m), (V), (Vl), middle, R3, R4,
R5 and Y have the meanings given above, i.e. the compound of formula (VI) is A, Michael
s method (Justus Liebig, 5Anna
len der Chemie, volume 338 282
Page 1904), and is produced by the reaction of the compound of formula (■) with formalin. In this reaction,
When R3 and R5 are different, the compound of formula (Vl) is 2
It is obtained as a mixture of two isomers (Vla) and (Vlb).

The compound of formula (III) is produced by rehalogenating the compound of formula (Vl) in a conventional manner or by reaction with an alcohol activating reagent such as tosyl chloride. Formula (I
Examples of Y in II) include a chloro atom, a bromo atom, or an R5-8O3 group (wherein R5 is a phenyl group, a substituted phenyl group, or a lower alkyl group).

Moreover, the compound of formula (■) is the compound of formula (■) [wherein,
R3, R4, R5 have the above-mentioned meanings, and Z represents an oxygen atom or a sulfur atom, and is produced by the reaction of hydrazine with the formula (■) [wherein R3, R5 has the above-mentioned meanings] ] by halogenation reaction or nitration reaction, or by Gunter Barniko
The method of W et al. (Chem, Ber, vol. 100, 1661~
1666 pages 1966) or H, Plump
(Arch, Pharm, Ber.

Dtsch, Pharm, Ges, vol. 300, 704~
708 pages, 1967) etc.

The compound represented by the general formula (I) and its pharmaceutically acceptable salt according to the present invention can be used as a medicine for the prevention and treatment of gastric ulcer, duodactyly 13j ulcer, gastritis, gastric hyperacidity, and Sollinger-Ellison syndrome. Compound (I) itself can be administered to mammals including humans as it is, but generally it can be administered orally or parenterally in the form of various pharmaceutically acceptable formulations. For formulation, the compounds of general formula (I) according to the invention can also be used in the form of pharmaceutically acceptable salts.

These compounds can be used alone or in an appropriate combination of two or more.

Moreover, these compounds may be used in combination with other pharmaceutically active ingredients.

For oral administration, the above compound may be combined with suitable excipients such as lactose, mannitol, corn starch,
By appropriately combining with excipients such as crystalline cellulose, binders such as cellulose derivatives, gum arabic, and gelatin, disintegrants such as carboxymethylcellulose calcium, and lubricants such as talc and magnesium stearate, tablets, powders, and capsules can be produced. It can be used as an agent.

Examples of parenteral administration include water, ethanol,
By combining with glycerin or the like, it can be made into an injectable solution.

The dosage varies depending on age, symptoms, therapeutic effects, administration method, and administration period, but usually 0.1 to 20 for oral administration.
It is preferable to administer the drug once to three times a day in the dosage range of mg/kg/day.

Next, regarding the anti-ulcer effect of each compound represented by the general formula (I) according to the present invention, the results of a water immersion stress ulcer test are as follows.
This will be explained by the results of a hydrochloric acid-ethanol ulcer test and the effect on gastric acid secretion induced by histamine stimulation in unanesthetized fistula rats. In addition, in the section of the test compound shown in the table, the example number in which the compound was shown is indicated.

1) Water immersion restraint stress ulcer test Male SD rats fasted for 24 hours (body weight 210-24
0g) was placed in a stress cage (Tokyo University Yakusaku type) and kept at 23°C.
The animals were immersed up to their chests in a water tank and subjected to stress. After 7 hours, the rat was taken out of the water tank and immediately beaten to death, and its stomach was removed. Inject 10 ml of 2% formalin solution into the stomach,
Further, it was fixed for 10 minutes using the same method. The stomach was opened along the large canal, and the length (mm') of the ulcer occurring in the glandular stomach was measured under a stereoscopic microscope (X 10), and the sum per animal was taken as the ulcer coefficient. The test compound was suspended in 1% sodium carboxymethyl cellulose (Na-CMC), and 0.5 ml/
It was orally administered by force at a rate of 100 g body weight 10 minutes before stress loading. In the control group, only 1% Na-CMC was administered in the same manner. The ulcer formation inhibition rate (%) was calculated using the following formula. The results are shown in Table-1.

Ulcer formation inhibition rate (%) Table 1 Effect on water immersion restraint stress ulcers ***p<0
．． 001 As shown in this table, the compounds according to the present invention are:
It has a strong anti-ulcer effect in the water immersion restraint stress ulcer model.

2) Hydrochloric acid-ethanol ulcer test After fasting for 24 hours, male SD rats (body weight 170-190 g) were orally administered 1 ml of 150 mM hydrochloric acid-60% ethanol. One hour later, the stomach of the rat was bludgeoned to death and removed. 10 ml of 2% Polmarin solution was injected into the stomach and fixed with the same wave for 10 minutes. Open the stomach along the large cap and examine the length of the ulcer that occurs in the glandular stomach area under a stereomicroscope (x10).
m m ) was measured, and the sum per animal was taken as the ulcer coefficient. The test compound was suspended in 0.5% sodium carboxymethylcellulose (Na-CMC), and 0.5ml/10
It was orally administered at a ratio of 0 g 30 minutes before administration of hydrochloric acid-ethanol. In the control group, 0.5% Na-CMC alone was similarly administered before hydrochloric acid-ethanol administration. The ulcer formation inhibition rate (%) was calculated using the following formula. Table 2 of the results
Shown below.

(Margins below) Table 2: Effect on ulcer formation induced by hydrochloric acid-ethanol ***p<0.001 As seen in this table, the compounds of the present invention showed no effect on ulcer formation induced by hydrochloric acid-ethanol. It exhibits an excellent rate of inhibiting ulcer formation and has a strong protective factor-enhancing effect.

3) Effect on gastric acid secretion induced by histamine stimulation in unanesthetized fistula rats After fasting for 24 hours, male SD rats (Japan Charles River) weighing 180 to 200 g were subjected to laparotomy under ether anesthesia, and the test drug was injected into the duodenum. A feeding tube (fr, 3.5) was inserted and the pylorus was ligated. A gastrofistula was performed on the forestomach using a polyethylene tube (inner diameter 7 mm), and after washing the inside of the stomach several times with warm physiological saline (37° C.), the abdomen was closed. A tube needle was inserted into the tail vein, fixed with tape, and then connected to an infusion pump (Barbard). The rat was placed in a KNN-type Pohlmann type cage (Natsume Seisakusho), and the gastric juice flowing out from the Feistra was collected in a test tube with a scalpel every hour. From 1 hour after surgery, histamine (8 mg/kg/hr) was continuously injected from the tail vein at a rate of 1.4 ml/hr, and the test compound was 0.
．． It was suspended in 5% Na-CMC and administered 1 hour after the start of histamine injection. Gastric juice was collected from 1 hour to 4 hours after drug administration, and after measuring the amount of gastric juice, it was titrated to pH 7 with 0.1N NaOH using an automatic titrator (Kyoto Denshi) to determine the total acid excretion.

Gastric acid secretion inhibition rate (%) was calculated using the following formula.

Suppression rate of gastric acid secretion (%) Table 3: Effect on gastric acid secretion induced by histamine stimulation in unanesthetized Fistra rats As seen in this table, the compound of the present invention suppresses gastric acid secretion induced by histamine stimulation in unanesthetized Fistra rats. strongly suppresses the secretion of

Furthermore, the safety of each compound represented by the general formula (I) according to the present invention will be explained using a two-week continuous oral administration toxicity test and a hepatocellular toxicity test.

1) Toxicity test The compound obtained in Example 4 was suspended in a 3% gum arabic solution and administered to three 5-week-old ICR:Crj male mice at a dose of 500
As a result of continuous forced oral administration at a dose of mg/kg/day for 14 days, no deaths or decreases in body weight were observed.

2) Hepatocellular toxicity test a) Preparation of test compound solution The compound obtained in Example 4, the compound obtained in Example 48, and omebrazole were each added to OXlo-2M.
After dissolving in 100% dimethyl sulfoxide, the final concentration is 1.0X10-3.1.0X in culture medium.
10-' and 1. It was diluted to OXIO-5M and exposed to cells.

b) Exposure to test compound Primary cultured rat hepatocytes were precultured for 20 hours and cultured in a culture solution containing the test compound at various concentrations.

After 6 hours, 24 hours, and 48 hours of culture, intracellular lactate dehydrogenase (LD) was released into the culture medium.
The activity of H) was measured using an LDH assay kit to determine hepatotoxicity.

As a result of the experiment, no increase in LDH was observed for the compound of Example 4 and the compound of Example 48 after 24 hours and 48 hours of exposure. The compound according to the present invention has extremely low hepatotoxicity.

On the other hand, with omebrazole, an increase in cell necrosis was observed after 24 and 48 hours of exposure, suggesting strong hepatotoxicity. As described above, the compound of the present invention exhibits a strong anti-ulcer effect in the water immersion restraint stress ulcer test, strongly suppresses the secretion of gastric acid induced by histamine stimulation in unanesthetized fistula rats, and furthermore, the compound according to the present invention exhibits a strong anti-ulcer effect in the water immersion restraint stress ulcer test, strongly inhibits the secretion of gastric acid induced by histamine stimulation in unanesthetized fistula rats, and furthermore, in the hydrochloric acid-ethanol ulcer test, the compound of the present invention exhibits a strong anti-ulcer effect. It was recognized that it is an excellent anti-ulcer substance that has both an aggressive factor suppressing effect and a defensive factor enhancing effect (cytoprotective effect). Moreover, the compound according to the present invention is
It is an extremely safe compound as confirmed in toxicity tests and hepatotoxicity tests, and anti-ulcer agents containing it are effective in preventing acute and chronic gastric ulcers, duodenal ulcers, gastritis, gastric hyperacidity, and Solinger-Ellison syndrome. It is also useful as a therapeutic drug.

The present invention will be explained in more detail below using Examples and Reference Examples, but the present invention is not limited to these Examples.

(Left below) Example 1 2-[1-(3,5-dimethylpyrazolyl)]methylthiobenzimidazole 85% sodium hydroxide 590 mg was added to methanol 1
600 mg of 2-mercaptobenzimidazole and 920 mg of 1-chloromethyl-3,5-dimethylpyrazole hydrochloride were added to a solution dissolved in
Stirred for 0 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

This residue was purified by silica gel column chromatography (Merck, Kieselgel 60) to obtain colorless crystals.
-[1-(3,5-dimethylpyrazolyl)]methylthiobenzimidazole 311 mg was obtained.

Melting point 155-157°C NMR spectrum δ (CDC13): 2.26 (6
H,s), 5.54 (2H,s).

5.81 (IH, s).

6.85-7.67 (4H, m) KBr-IR spectrum ν −+, 1410. 1265°1
225, 795. 740 Example 2 5-methoxy-2-[1-(3,4,5-)dimethylbirazolyl)]methylthiobenzimidazole 2-mercapto-5-methoxybenzimidazole 50
0 mg of methylene chloride-acetonitrile (I:1)
Suspend in 40 ml and add 1.0% triethylamine under stirring at room temperature.
After adding 5 ml, 1-chloromethyl-3,4,5-)
Dimethyl and 650 mg of lazole hydrochloride were added slowly. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, Kieselgel 60) to obtain 411 mg of colorless crystals of 5-methoxy-2-[1-(3,4,5-trimethylpyrazolyl)]methylthiobenzimidazole.
I got it.

Melting point 105-106°C NMR spectrum δ (CDC13): 1.84
(3H,S), 2.15 (3H,S).

2.1 7 (3H,s), 3.78 (3
H,s).

5.87 (2H, S), 6.78 (IH
, bs), 8.6 5-7.80 (3H, m
)KBr.

IR spectrum ν-, 1640, 1410°IW 1290, 1160. 1035. 860° Example 3 2-[1-(4-hexyl-3,5-dimethylpyrazolyl)]methylthiobenzimidazole 480 mg of 2-mercaptobenzimidazole + 1-chloromethyl-
4-hexyl-3,5-dimethylpyrazole hydrochloride 1.
12 g was dissolved in 5 ml of dimethylformamide under water cooling. After vigorously stirring the reaction solution for several minutes, 30 ml of saturated sodium hydrogen carbonate solution was added, and the aqueous layer was removed by decantation. The obtained residue was dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily product of 2-[1-(4-hexyl-3,5
-dimethylpyrazolyl)] 980 mg of methylthiobenzimidazole was obtained.

NMR spectrum δ (CDC13): 0.55-1.
85 (I1H, m).

1.85-2.78 (2H, m).

2.18 (3H, s), 2.22 (3H, s).

5.58 ('2H,s).

8.85-7.85 (4H, m).

11.25 (IH, bs) (Hereafter the margin) Example 4 2-[1-(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 2-[1-(3,5-dimethylpyrazolyl)]methylthiobenzimidazole 2
Dissolve 58 mg in 10 ml of methylene chloride, -60
Cooled to ~-70°C. To this solution, 10 ml of a methylene chloride solution containing 237 mg of 80% m-chloroperbenzoic acid was added dropwise, and after the dropwise addition was completed, the mixture was further stirred for 10 minutes. This reaction solution was washed with saturated sodium hydrogen carbonate solution, and the methylene chloride layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, Kieselgel 60),
Colorless crystals of 2-[1-(3,5-dimethylpyrazolyl)
128 mg of comethylsulfinylbenzimidazole was obtained.

Melting point 155-157°C (decomposition) NMR spectrum δ(DMsO-d6) = 2.04
(3H,s), 2.22 (3H,s).

5.58 (2H,s), 5.82 (I
H,s).

7.02-7.8 1 (4H, m) 13B0.
1050. 745 Example 5 2-(I-pyrazolyl)methylsulfinyl-5-trifluoromethylbenzimidazole 298 mg of 2-(I-pyrazolyl)methylthio-5-trifluoromethylbenzimidazole was dissolved in 60 ml of methylene chloride, and -10 A solution of 216 mg m-chloroperbenzoic acid in 20 ml methylene chloride was added to 15 ml at a temperature range of ~0°C.
It was added dropwise over a period of minutes. After the dropwise addition was completed, the mixture was stirred for 30 minutes at the same temperature, and then washed with a saturated sodium bicarbonate solution. After drying the methylene chloride layer over anhydrous magnesium sulfate, the methylene chloride was distilled off under reduced pressure, and the resulting residue was washed with ethyl ether to obtain colorless crystals of 2-(I-pyrazolyl)methylsulfinyl-5-trifluoromethylbenz. 138 mg of imidazole was obtained.

Melting point 169-170℃ (decomposition) NMR spectrum k & (DMSO-de
): 5.92 (IH, d), 5.97 (IH, d)
6.33 (IH, t).

7.33-8.20 (6H, m) 1175, 1040 Compound of general formula (II) having substituents R1 and R2 and substituents Y, R3, R4 and R5 listed in Table-10
Using the compound of general formula (III) having A compound of general formula (Ia) was prepared.

(Left below) A compound of general formula (II) having substituents R1 and R2 and 1-chloromethyl-3,4,5-)dimethylpyrazole hydrochloride or 1-chloromethyl-4-hexyl-
Compounds of general formula (Ia) listed in Table 5 were produced by the method according to Example 2 using 3,5-dimethylpyrazole hydrochloride.

(Blank below) In place of 2-[1-(3,5-dimethylpyrazolyl)]methylthiobenzimidazole in Example 4, the general formula (
Using the compound Ia) and m-chloroperbenzoic acid, the general formula (
Compound Ib) was prepared.

(Left below) In place of 2-(I-pyrazolyl)methylthiobenzimidazole in Example 5, substituents R1゜R2, R3,
A compound of general formula (Ia) having R4 and R5, and m
-Chloroperbenzoic acid and the method according to Example 5, the compounds of general formula (Ib) listed in Table 7 were produced.

Interosseous IJH6J-JIJ784 (37); Compound of general formula (If) having Tomoe substituents R1 and R2 and substituents Y, R3, R' and R5 listed in Table-10
Using the compound of the general formula (III) having the formula or 1-chloromethyl-3,4,5-trimethylpyrazole hydrochloride prepared in Reference Example 1, the general formula listed in Table 8 was prepared by the method according to Example 1. Compound (Ia) was prepared.

(Left below) Example 88 2-[1-(4-methoxypyrazolyl)comethylthiobenzimidazole l-hydroxymethyl-4-methoxypyrazole 1.6
8 g was dissolved in 10 ml of methylene chloride, and 1.9 ml of thionyl chloride was added dropwise while stirring while cooling with water.

After completion of the upstream flow, the mixture was refluxed at 60° C. for 1 hour, and methylene chloride was distilled off under reduced pressure to obtain 1.6 g of oily 1-chloromethyl-4-methoxypyrazole hydrochloride.

A solution of 1.6 g of 1-chloromethyl-4-methoxypyrazole hydrochloride obtained here in 10 ml of acetonitrile was added to 2-
Mercaptobenzimidazole 300 mg, )
Suspension of 607 mg of ethylamine in acetonitrile 10
ml under stirring under water cooling, and then stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer over anhydrous magnesium sulfate, the oily substance obtained by distilling it off under reduced pressure was purified by alumina column chromatography (Merck & Co., aluminum oxide 90: basic) to obtain an oily 2-[:1
10 mg of -(4-methoxypyrazolyl)]comethylthiobenzimidazole was obtained.

NMR spectrum &(CDC1a): 3.52 (
3H,s), 5.53 (2H,s).

6.67-7.27 (6H, m).

8.70 (IH, bs) 1400, 1380. 1340. 1270°10
40.745 (Hereafter blank) Example 89 2-[1-(3,5-jethoxycarbonylpyrazolyl)]comethylthiobenzimidazole, 5-jethoxycarbonyl-1-hydroxymethylpyrazole 1.25
g and 2-mercaptohenzimidazole 205 m
According to the method of Example 88, oily 2-[1
61 mg of -(3°5-jethoxycarbonylpyrazolyl)]comethylthiobenzimidazole was obtained.

NMR spectrum δ(CDCl2): 1.35 (
3H,t), 1.42 (3H,t).

4.30 (2H, (I), 4.43 (2H, q)
.

6.25 (2H, s).

6.92-7.98 (4H, m) 11.9 (IH, bs) KBr.

IR spectrum ν −, 1720, 1260゜ff
1 1215.1090. 1020.765,745 (blank below) General formula (
Using the compound of Ia) and m-chloroperbenzoic acid, the general formula (
Compound Ib) was prepared.

Example 99 2-[1-(3,5-jethoxypyrazolyl)comethylthiobenzimidazole 335 mg of 3.5-jethoxy-1-hydroxymethylpyrazole was suspended in 10 ml of benzene, and thionyl chloride was added under stirring at room temperature. 257 mg of benzene solution 1
0 ml was added dropwise. After further stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure to obtain colorless columnar crystals of 1-chloromethyl-3,5-jethoxypyrazole hydrochloride. The crystals were dissolved in 10 ml of tetrahydrofuran, and 10 ml of a tetrahydrofuran solution containing 180 mg of 2-mercaptobenzimidazole and 360 mg of triethylamine was added dropwise under stirring at room temperature. After the reaction solution was left to stand for 5 minutes, the solvent was distilled off under reduced pressure, cold water was added to the residue, and the mixture was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was crystallized from n-hexane to give 340 m
I got g.

Melting point: 74-77℃ (decomposition) NMR spectrum δ (CDC13): 1.40 (3H, t), 1.46 (3H, t).

4.08 (2H, q), 4.28 (2H, q).

4.98 (IH, s), 5.35 (2H, s).

6.80-7.80 (5H, m) 1265.740 Example 100 2-[1-(3,5-jethoxypyrazolyl)]methylsulfinylbenzimidazole 2-[1-(3,5-
200 mg of comethylthiobenzimidazole was dissolved in 50 ml of methylene chloride,
At a temperature of -40 °C, m-chloroperbenzoic acid 136 m
10 ml of methylene chloride solution was added dropwise over 10 minutes. After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour, and then washed with saturated sodium hydrogen carbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Merck & Co., Ltd.) as a solvent.

2-[1-
95 mg of (3,5-jethoxypyrazolyl)]methylsulfinylbenzimidazole was obtained.

Melting point 79-81.5°C (decomposition) NMR spectrum δ (CDC13): 1.07 (3
H,t), 1.20 (3H,t).

3.76 (2H, q), 3.87 (2H, (I).

4.88 (IH, s), 5.40 (IH, d).

5.43 (IH, d).

7.00-8.03 (4H, m).

11.50-13.03 (IH, bs) 1055.75
0 Example 101 2-[1-(3-methoxy-5-methylvirazolyl)comethylthiobenzimidazole and 2-[1-(5-
35% in 2g of methoxy-3-methylpyrazolyl)]comethylthiobenzimidazole)3-methoxy-5-methylpyrazole
3 ml of formalin was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. After the reaction solution was distilled off, water was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.3 g of colorless crystals.

NMR spectrum δ(CDCl2): 2.27 (b
s), 3.75 (b s).

5.30 (bs), 5.43 (bs) From the NMR results, the obtained crystals were 1-hydroxymethyl-3-methoxy-5-methylpyrazole, 1-hydroxymethyl-5-methoxy-3-methyl It was determined to be a mixture of pyrazole isomers.

b) 2.5 ml of thionyl chloride was added dropwise to 1 g of the isomer mixture, and the mixture was continuously stirred for 4 hours. Excess thionyl chloride was distilled off under reduced pressure to obtain 1.30 g of a pale brown oil.

C) 1.30 g of the oil obtained here and 1.00 g of 2-mercaptobenzimidazole were dissolved in 20 ml of ethanol, and an ethanol solution of 0.88 g of 85% potassium hydroxide was added dropwise. After stirring for 2 hours, ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer over anhydrous sodium sulfate, chloroform was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Merck & Co., Kieselgel 60) to obtain 0.62 g of an oily substance.

NMR spectrum δ (CD CI's): 2.20
(s), 2.23 (s).

3.81 (bS), 5.23 (S).

5.33 (s), 5.46 (s).

7.40-7.73 (m) From the NMR results, the obtained oil was 2-[1-(3
-methoxy-5-methylpyrazolyl)comethylthiobenzimidazole and 2-[1-(5-methoxy-3-
It was determined to be an isomer mixture of methylthiobenzimidazole (methylpyrazolyl)].

Example 102 2-[1-(3-methoxy-5-methylpyrazolyl)]
Methylsulfinylbenzimidazole or 2- [
1-(5-methoxy-3-methylpyrazolyl)]methylsulfinylbenzimidazole Oily isomer mixture obtained in C) of Example 101 620
mlg was oxidized according to the method of Example 4, and the resulting oil was subjected to silica gel column chromatography (Merck & Co., Ltd.,
Colorless crystals were obtained by applying Kieselgel 60). Further, it was recrystallized with isopropyl ether-acetone and 200 m
g colorless crystals were obtained. The obtained crystals were determined by instrumental analysis.
-[1-(3-methoxy-5-methylpyrazolyl)]methylsulfinylbenzimidazole or 2-[1-
It was determined to be (5-methoxy-3-methylpyrazolyl)]methylsulfinylbenzimidazole.

Melting point 145°C (decomposition) NMR spectrum δ (CD Cl 3D MS Oda): 2
．． 13 (3H, s), 3.50 (3H, s).

5.25 (I H,s), 5.40 (2
H,s).

7.11-7.45 (2H, m).

7.45-7.82 (2H, m) 1440, 1400. 1050 (S=0).

Example 103 2-[1-(3-ethoxy-5-methylpyrazolyl)]
] Methylthio 5-fluorobenzimidazole and 2
-[1-(5-ethoxy-3-methylpyrazolyl)]]
3 to 1.8 g of methylthio-5-fluorobenzimidazole) 3-ethoxy-5-methylpyrazole
8.2 ml of 5% formalin was added and stirred at room temperature for 15 minutes. After the reaction solution was distilled off, water was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.5 g of colorless crystals.

NMR spectrum δ (CDCIs): 1.27 (t
), 2.22 (s), 3.97 (q).

5.18 (b s) 5.33 (s) From the NMR results, the obtained crystals are 3-ethoxy-1-hydroxymethyl-5-methylpyrazole, 5-ethoxy-1-hydroxymethyl-3-methyl It was determined to be a mixture of pyrazole isomers.

b) An oily substance was obtained according to b) and c) of Example 101 using the isomer mixture and 5-fluoro-2-mercaptobenzimidazole.

NMR spectrum δ (CDC13): 1.33 (t
), 2.20 (s), 4.00 (q).

5.23 (S), 5.40 (S).

6.56-7. According to the results of 50(m) NMR, the obtained oil was 2-[1-(3
-ethoxy-5-methylpyrazolyl)comethylthio-5
-fluorobenzimidazole and 2-[1-(5
-ethoxy-3-methylpyrazolyl)comethylthio-5
- It was determined to be an isomer mixture of fluorobenzimidazole.

Example 104 2-[1-(3-ethoxy-5-methylpyrazolyl)comethylsulfinyl-5-fluorobenzimidazole or 2-[1-(5-ethoxy-3-methylpyrazolyl)]]methylsulfinyl-5- The oily isomer mixture obtained in fluorobenzimidazole Example 10 b) was oxidized according to the method of Example 4, and the obtained oil was purified by silica gel column chromatography (Merck & Co., Kieselgel 60). Colorless crystals were obtained. The obtained crystals were determined to be 2-[1-(3-ethoxy-5-methylpyrazolyl)]]methylsulfinyl-5-fluorobenzimidazole or 2-,[1-(5-ethoxy-3-methyl)] by instrumental analysis. pyrazolyl)]] was determined to be methylsulfinyl-5-fluorobenzimidazole.

Melting point 119-120°C (decomposition) NMR spectrum δ (CD Cl3): 1.06
(3H, t), 2.00 (3H, s).

3.73 (2H,q), 5.13 (I H,s
).

5.43 (2H, S).

6.73-7.73 (3H, m) 1'060 (s=o) Example 105 2-[1-(3-ethoxy-5-methylpyrazolyl)
comethylthiobenzimidazole and 2-[1-(
5-Ethoxy-1-hydroxymethyl-5-methylpyrazole obtained in Example 103 a), 5-ethoxy-1-hydroxymethyl-3-methyl Using an isomer mixture of pyrazole and 2-mercaptobenzimidazole,
An oily substance was obtained according to b) and c) of Example 101.

NMR spectrum δ (CD Cl3): 1.33
(t), 2.23 (s).

4.06 (q), 5.03 (S).

5.43 (S), 7.00-7.70 (m) NMR
From the results, the obtained oils were 2-[1-(3-ethoxy-5-methylpyrazolyl)]methylthiobenzimidazole and 2-[1-(5-ethoxy-3-methylpyrazolyl)]methylthiobenzimidazole. It was judged to be a mixture of isomers.

Example 106 2-[1-(3-ethoxy-5-methylpyrazolyl)comethylsulfinylbenzimidazole or 2-[1
-(5-Ethoxy-3-methylpyrazolyl)]methylsulfinylbenzimidazole The oily isomer mixture obtained in Example 105 was oxidized according to the method of Example 4, and the obtained oil was subjected to silica gel column chromatography ( After purification using Kieselgel 60 (manufactured by Merlisha), the product was recrystallized from ethyl acetate to obtain colorless crystals. The obtained crystals were determined by instrumental analysis to be 2-[1-(3-ethoxy-5-methylpyrazolyl)]methylsulfinylbenzimidazole or 2-[1-(5-ethoxy-3-methylpyrazolyl)comethylsulfinylbenzimidazole. I decided that.

Melting point 147°C (decomposition) NMR spectrum δ (CD Cla): 0.96
(3H, t), 1.96 (3H, s).

3.63 (2H, q), 5.13 (IH, s).

5.43 (2H, s).

7.06-7.83 (4H, m) 1400, 1300, 1100°1070 (s=o), 755 Example 107 2-[1-(3-methylpyrazolyl)]methylthiobenzimidazole or 2-[1- (5-Methylpyrazolyl)comethylthiobenzimidazole a) 2.31 g of 3-methylpyrazole and 10 ml of water
, and 2.41 g of 35% formalin were added and stirred at room temperature for 16 hours. After concentrating the reaction solution, pale yellow oil 2
．． 96g was obtained.

NMR spectrum δ(CDC13)'2.22 (S
), 2.25 (S), 5.37 (S).

5.42 (S), 5.93 (S), 7.33 (S
) Based on the NMR results, the obtained oil was judged to be an isomer mixture of 1-hydroxymethyl-3-methylpyrazole and 1-hydroxymethyl-5-methylpyrazole.

b) 2.9 g of the oily isomer mixture obtained in a) above.
was dissolved in 20 ml of methylene chloride, and 3.75 ml of thionyl chloride was added dropwise while stirring while cooling with water.

After the dropwise addition was completed, the mixture was refluxed at 60° C. for 1 hour, and methylene chloride was distilled off under reduced pressure to obtain 2.36 g of an oily substance.

C) 852 mg of the oil obtained in b) above and 451 mg of 2-mercaptobenzimidazole were mixed with 10 ml of methanol.
To this was added a solution of 420 mg of potassium hydroxide in 5 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 741
mg of colorless crystals were obtained.

Melting point 159-163°C NMR spectrum δ (CDC13+DMso-da): 2.22 (3H,S), 5.95 (2H,
S).

5.95 (IH, S).

6.85-7.85 (5H, m), 1270. 1055.980,765,745
From the results of instrumental analysis, the obtained crystals were 2-[1-(3
-methylpyrazolyl)] methylthiobenzimidazole or 2-[1-(5-methylpyrazolyl)]methylthiobenzimidazole.

Example 108 2-[1-(3-methylpyrazolyl)]methylsulfinylbenzimidazole or 2-[1-(5-methylpyrazolyl)]methylsulfinylbenzimidazole 366 mg of the crystals obtained in C) of Example 107 were Oxidation was performed according to the method of Example 4 to obtain 319 mg of colorless crystals. The obtained crystals were found to be 2-[1-(3-
methylpyrazolyl)]methylsulfinylbenzimidazole or 2-[1-(5-methylpyrazolyl)comethylsulfinylbenzimidazole.

Melting point 152-154°C NMR spectrum δ(DMSO-d6): 2.15(
3H, S), 5.77 (2H, bS).

6.10 (IH, d).

7.10~8.17 (5H, m) 1410, 1065 (s=o), 760
° Example 109 2-[1-[3-methyl-5-(2-,2-.

2-[1-[5-methyl-3-(2-,2-,2--)trifluoroethoxy)]pyrazolyl]methylthiobenzimidazole or 2-[1-[5-methyl-3-(2-,2-,2--)trifluoroethoxy)]
Pyrazolylcomethylthiobenzimidazole IL) 8.35 g of 3-methyl-5-(2-,2-,2--)lifluoroethoxy)pyrazole was added to 15 g of methanol.
ml, 15 ml of 35% formalin was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was distilled off, water was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer with magnesium sulfate, the solvent was distilled off under reduced pressure to give 9.6 g.
crystals were obtained. Recrystallize the crystals from benzene, 6.8g
Colorless crystals were obtained.

Melting point 73-74°C NMR spectrum δ (CDCI3+D,,O): 2.
28 (3H, s), 4.38 (2H, q)
5.27 (2H, S), 5.55 (I H, 5)K
Br.

IR spectrum v −+, 1560, 1490rl1
1 1280, 1175. 1155. According to the results of 960°2O NMR, the obtained crystals were 1-hydroxymethyl-3-methyl-5-(2-,2-.

2-trifluoroethoxy)pyrazole or 1-hydroxymethyl-5-methyl-3-(2-.

2-. It was determined to be 2-trifluoroethoxy) pyrazole.

b) Using 3.8 g of the crystals obtained here and 676 mg of 2-mercaptobenzimidazole, Example 1.7 b)
, 2.0 g of crystals were obtained according to step c).

Recrystallization from chloroform petroleum ether gave 1.3 g of pale yellow crystals.

NMR spectrum δ(CDCl2): 2.18 (3
H,s), 4.47 (2H,q).

5.55 (3H, S).

9.88 (IH, bs) 1410, 1270. 1160. 1065°9
From the results of 55.75O NMR, the obtained crystal was 2-[1-[3-
Methyl-5-(2-,2-,2--)lifluoroethoxy)]pyrazolyl]methylthiobenzimidazole or 2-[1-[5-methyl-3-(2-,2-,2--
) pyrazolylcomethylthiobenzimidazole.

Example 110 2-[1-[3-methyl-5-(2-,2-.

2-trifluoroethoxy)]pyrazolyl]methylsulfinylbenzimidazole or 2-[1-[5
-Methyl-3-(2-,2-,2-trifluoroethoxy)cobyrazolylcomethylsulfinylbenzimidazole 755 mg g obtained in Example 109 was oxidized according to the method of Example 4 to give a colorless 700 mg of crystals were obtained. Instrumental analysis revealed that the obtained crystals were 2-[1-[3-methyl-5
-(2",2-.2--)lifluoroethoxy)]pyrazolyl]methylsulfinylhenzimidazole or 2-[1-[5-methyl-3-(2-,2-,2"-
) Lifluoroethoxy)copyrazolyl]methylsulfinylbenzimidazole.

Melting point 176-177°C NMR spectrum δ (DMSOda): 2.27 (3
H,s).

3.85-4.52 (2H, m).

5.43 (IH, d), 5.6.8 (IH, s).

5.75 (IH, d).

7.02~7.95 (4,H,m)KBr
.

IR spectrum ν -, 1580, 1490°C ■ 1290, 1170. 1070. 1055
゜980, 880. 750 Example 111 2-[1-(4-methoxymethyl-3,5-dimethylpyrazolyl)]thiobenzimidazole a) 1.40 g of 4-methoxymethyl-3,5-dimethylpyrazole was dissolved in 3
1.8 ml of 5% formalin was added and stirred at room temperature for 2.5 hours. After distilling off the reaction solution, water was added to the residue and the mixture was heated to r:1
Extracted with 0 form. After drying the chloroform layer over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.5 g of colorless crystals.

Melting point 75-76°C NMR spectrum δ (CDCl2): 2.18 (3H
, s), 2.32 (3H, s) 3.27 (3H, s)
, 4.22 (2H, s) 5.35 (2H, 5) KBr.

IR spectrum ν −, , 1580, 1480°0
m 1300, 1100. 1070,935°840,
740 b) Using 1.4 g of the crystals obtained here and 1.2 g of 2-mercaptobenzimidazole, b) and c) of Example 101 were prepared.
0.8 g of colorless crystals were obtained.

Melting point 162°C NMR spectrum δ (CDC13): 2.22 (6
H, s), 3.22 (3H, s) 4.12 (2H,
s), 5.65 (2H, s) 6.85-7.65 (
4H, m) KBr.

IR spectrum ν -, 1555, 1430°0m 1405, 1260. 1080.730 Example 11
2 2-[1-(4-methoxymethyl-3,5-dimethyl and lazolyl)]sulfinylbenzimidazole 303 mg of the crystals obtained in C) of Example 111 was oxidized according to the method of Example 4. The crystals were recrystallized from methanol-ethyl acetate to obtain 140 mg of colorless crystals.

Melting point 153°C NMR spectrum δ (DMSO-d6): 2.05
(3H,s), 2.20 (3H,s).

3.1 5 (3H,s), 4.1 0 (
2H,s).

5.53 (2H, s).

6.93-7.77 (4H, m) KBr.

IR spectrum ν-,,15B0. 1430゜0
m 1400, 1090. 1050 (S=O)
.

Formulation Example 1 5-benzoyl-2-[:1- (4-methylpyrazolyl)]methylsulfinylbenzimidazole 0g Lactose 315g Corn starch 125g Crystalline cellulose
Mix 25g of the above components uniformly and prepare 7.5% hydroxypropylcellulose aqueous solution 200g.
Add ml and use an extrusion granulator to make a diameter of 0.5 mm.
The mixture was made into granules using a screen, immediately rounded using a marmerizer, and then dried. The dried granules were coated with 1.9 kg of a film coating liquid having the following composition using a fluidized bed granulator to obtain enteric granules.

Coating liquid composition: Hydroxypropyl methyl cellulose phthalate 5. 0 (w/w)%
Stearin 0.25 (w/w)% Methylene chloride 50.0 (w/w)% Ethanol
44.4 (w/w)% Formulation Example 2 2-[1-(3,5-dimethylpyrazolyl)]methylsulfinylbenzimidazole 0g Lactose 100g Corn starch 36g Crystalline cellulose
30 g Carboxymethyl cellulose calcium 0 g Magnesium stearate 4 g The components of the above composition were mixed uniformly and made into tablets each weighing 200 mg using a punch with a diameter of 7.5 mm in a single-shot tablet machine. Next, the tablets were spray-coated with a coating liquid having the composition shown below to provide a coating of 10 mg per tablet to obtain enteric film-coated tablets.

Coating liquid composition: Hydroxypropyl methyl cellulose phthalate 8. 0 (w/w)% Mybaset 0. 4 (w/w)% methylene chloride 50. O (w/w)% white beeswax O-1 (w/w)% isopropanol
41. 5 (w/w)% Formulation Example 3 5-trifluoromethyl-2-[:1-(3°4.5-
) Dimethylpyrazolyl)] Methylsulfinylbenzimidazole 0g Lactose 232g Corn starch 108g Polyvinylpyrrolidone
Mix 20g of the above ingredients uniformly and mix 70 (v/
v) add 180 ml of % isopropyl alcohol;
The mixture was made into granules using an extrusion granulator using a 0.8 mm screen, immediately rolled into balls using a marmerizer, and then dried. These dry granules were coated with 1.5 kg of the film coating liquid used in Formulation Example 1 using a fluidized bed granulator to form enteric-coated granules. Furthermore, the present enteric-coated granules are filled into No. 2 hard gelatin capsules, and the contents of one capsule are ff.
i 240 mg capsules.

In addition, the general formula (
An example of the production of the compound represented by m) is listed below.

Production Example 1 1-Chloromethyl-3,4,5-trimethylpyrazole hydrochloride a) 28.8 g of 3-methyl-2,4-pentanedione was dissolved in 300 ml of ethanol, and 80% hydrazine monohydrate was dissolved. 26.15 g was slowly added dropwise. After continued stirring for 1 hour, ethanol was distilled off under reduced pressure to obtain colorless crystals. The crystals were dissolved in chloroform, thoroughly washed with water, dried over anhydrous sodium sulfate, and the chloroform was distilled off under reduced pressure to obtain 24.3 g of 3.4.5-)limethylvirazole as colorless crystals.

b) Add 40 ml of 35% formalin aqueous solution to 24.0 g of 3,4.5-)limethylpyrazole prepared in a) above.
After leaving the mixture at room temperature for 6 hours, the mixture was extracted with chloroform, and the chloroform layer was washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain 29.10 g of colorless crystals of 1-hydroxymethyl-3,4,5-)limethyl and lazole.

NMR spectrum δ (CDCl2): 1.90 (3H
, s), 2.13 (3H, s).

2.33 (3H, s), 5.36 (2H, bs).

7.53 (IH, bs) C) 1-hydroxy-3°4.5 produced in b) above
- Suspend 28.50 g of trimethylpyrazole in 40 ml of methylene chloride, stir with water cooling, and add 32 ml of thionyl chloride.
1 was slowly added dropwise. After refluxing for 1 hour after the dropwise addition, excess thionyl chloride was distilled off under reduced pressure and washed with isopropyl ether to give colorless crystals of 1-chloromethyl-3,4,5-
) 43.1 g of lymethylvirazole hydrochloride was obtained.

NMR spectrum δ (CD Cl3): 2.06
(3H,s), 2.63 (6H,sL6.37(2
H, s) Production Examples 2 to 12 Based on the method of Production Example 1, the general formula (
Compound m) was prepared.

Production Examples 13-14 Based on the method of Production Example 1b), the formula (V
Compound 1) was prepared.

(The following is a blank space)': 41Open I'l 3-313784 (54) Production Example 15 1-Chloromethyl-4-methoxy-3,5-dimethylpyrazole a) 3-methoxy-2,4-pentanedione 2. 428
Dissolve g in 20 ml of ethanol, add hydrazine.
Hydrate 1. Added OOg all at once. After 10 minutes, ethanol was distilled off under reduced pressure, and 10 ml of saturated brine was added to the residue, followed by extraction with 30 ml of chloroform. After drying the chloroform layer over anhydrous sodium sulfate, chloroform was distilled off under reduced pressure, and the resulting yellow oil was subjected to silica gel column chromatography (Merck & Co., Kieselgel 60) to extract 4-methoxy-3, 1.504 g of 5-dimethyl and lazole were obtained. This is a new compound that has not been published in any literature.

NMR spectrum δ(CD Cl3): 2.21
(6H,S), 3.70 (3H,5)b) a) above
While vigorously stirring, 1.270 g of a 35% formalin aqueous solution was added dropwise to 1.504 g of 4-methoxy-3,5-dimethylpyrazole prepared above, followed by stirring for 10 minutes. The reaction solution was extracted with chloroform, dried over anhydrous sodium sulfate, and then chloroform was distilled off under reduced pressure to obtain 1.906 g of a yellow oil. This oil was crystallized from n-hexane to obtain 1.193 g of 1-hydroxymethyl-4-methoxy-3,5-dimethylpyrazole as colorless needle crystals. This compound is a new compound that has not been described in any literature.

NMR spectrum δ(CD C, 13): 2.15
(3H, s), 2.25 (3H, s).

3.66 (3H, s), 5.2f3 (2H, s).

6.33 (IH, bs) C) 1-hydroxymethyl-4- produced in b) above
Methoxy-3,5-dimethylpyrazole 548 mg
was dissolved in 5 ml of methylene chloride, and while stirring under water cooling, a solution of 461 mg of thionyl chloride in methylene chloride was added to 1 ml.
was added dropwise over 10 minutes. After continued stirring at the same temperature for 1 hour, excess thionyl chloride and methylene chloride were distilled off under reduced pressure to obtain 1-chloromethyl-4-methoxy-3.5-dimethylpyrazole hydrochloride as a brown oil. This compound is a new compound that has not been described in any literature.

NMR spectrum δ(CDCl2): 2.43 (6
H,S), 3.8(I(3H,S).

6.20 (2H,S) Production Example 16 To 37.8 g of 3-methyl-5-(2-,2-,2--)lifluoroethoxy)pyrazolehydrazine dihydrochloride was added 100 ml of water, and 80 heated to ℃. Next, 2', 2-.

2'-trifluoroethyl-3-oxobutanoate 5
5.2 g was added dropwise over 30 minutes and heated for an additional 30 minutes. After neutralizing the reaction solution with 3N NaOH, insoluble matter was filtered off, and the filtrate was extracted with ethyl ether. After drying the ethyl ether layer over anhydrous magnesium sulfate, it was distilled off under reduced pressure to obtain colorless needle-like crystals of 3-methyl-5-(2-,2-,2--).
2.5 g of (lifluoroethoxy)pyrazole was obtained. This compound is a new compound that has not been described in any literature.

Melting point 83-84°C NMR spectrum δ(CD Cl3): 2.22
(3H, s), 4.48 (2H, (I)
.

5.53 (IH,s), 10.1 (IH
, bs) KBr.

IR spectrum ν -, 1580, 1490゜0m 1275, 1185. 1170. 1145
゜1080, 970. 860. 775 Production Example 17 4-Methoxymethyl-3,5-dimethylpyrazole a) 4-chloromethyl-3,5-dimethylpyrazole hydrochloride = 1.0 g of 4-hydroxymethyl-3,5-dimethylpyrazole was added to 30 ml of methylene chloride. Dissolve 3 ml of thionyl chloride in 5 ml of methylene chloride while cooling with water and stirring.
A solution dissolved in 1 ml was added dropwise. After continued stirring at room temperature for 5 hours, excess thionyl chloride and methylene chloride were distilled off under reduced pressure, and the resulting residual crystalline material was dissolved in a small amount of ethanol and crystallized by gradually adding ethyl ether. -Chloromethyl-3,5 dimethylpyrazole hydrochloride was obtained.

Melting point: 114°C b) 4-Methoxymethyl-3,5-dimethyl and Razol: 750 ml of sodium metal in 60 ml of absolute methanol
1.7 g of 4-chloromethyl-3.5-dimethylpyrazole was gradually added to the solution containing 1.7 g of 4-chloromethyl-3.5-dimethylpyrazole while stirring at room temperature. After stirring for 3 hours, the reaction solution was neutralized with 5% hydrochloric acid, methanol was distilled off under reduced pressure, the resulting residue was dissolved in 5 ml of water, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. , chloroform was distilled off under reduced pressure, 4
-methoxymethyl-3,δ-dimethylpyrazole 1.2
I got g.

Melting point 66-67℃ NMR spectrum & (CDC13): 2.27 (
6H,s), 3.28 (3H,q).

4.25 (2H, 5) 1380, 1310. 1190. 10B0
゜945, 840

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 and R^2 are the same or different, and each represents a hydrogen atom, a halogen atom, Represents a lower alkyl group, lower alkoxy group, trifluoromethyl group, nitro group, lower alkoxycarbonyl group or acyl group, or together represents a 1,3-butadiene-1,4-diyl group, R^3 and R^5 are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group,
Represents a lower alkoxycarbonyl group or a halogenated lower alkoxy group, R^4 represents a hydrogen atom, an alkyl group, an arylalkyl group, a lower alkoxy group, a lower alkoxymethyl group, a nitro group or a halogen atom, and X represents S
or S=O] and salts thereof. 2. General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R^1 and R^2 are the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy benzimidazole derivatives and general Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R^3 and R^5 are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group,
Represents a lower alkoxycarbonyl group or a halogenated lower alkoxy group, R^4 represents a hydrogen atom, an alkyl group, an arylalkyl group, a lower alkoxy group, a lower alkoxymethyl group, a nitro group, or a halogen atom, and Y represents a halogen atom or an activated General formula (I a) ▲There are numerical formulas, chemical formulas, tables, etc.▼ (I a) [In the formula, R^1 , R^2, R^3, R^4 and R^5
is the manufacturing method of the salt mentioned above. 3. General formula (Ia) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Ia) [In the formula, R^1 and R^2 are the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, Represents a lower alkoxy group, trifluoromethyl group, nitro group, lower alkoxycarbonyl group or acyl group, or together represents a 1,3-butadiene-1,4-diyl group, R^3 and R^5 are the same or different,
Each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, or a halogenated lower alkoxy group, and R^4 represents a hydrogen atom, an alkyl group, an arylalkyl group, a lower alkoxy group, a lower alkoxymethyl group, a nitro General formula (I b) ▲There are numerical formulas, chemical formulas, tables, etc.▼ (I b) [In the formula, R^1, R ^2, R^3, R^4 and R^5
has the above-mentioned meaning] and a method for producing a pyrazole derivative and a salt thereof. 4. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R^1 and R^2 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, trifluoromethyl group, nitro group, lower alkoxycarbonyl group or acyl group, or together represent a 1,3-butadiene-1,4-diyl group, and R^3 and R^5 are the same or differently,
Each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, or a halogenated lower alkoxy group, and R^4 is a hydrogen atom, an alkyl group,
an arylalkyl group, a lower alkoxy group, a lower alkoxymethyl group, a nitro group, or a halogen atom, and X represents S or S=O] or a pharmaceutically acceptable salt thereof as an active ingredient. An anti-ulcer agent characterized by containing.