JPS63208579A - Benzimidazole derivative, its production and antiulcer agent containing said derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R2 are H or lower alkyl; R3 is H, lower alkyl or lower alkoxy; R4 is lower alkyl or lower alkoxy). EXAMPLE:2(2-Dimethylamino-5-methylbenzylsulfinyl)-5-methoxybenzimidazole. USE:An antiulcer agent. PREPARATION:The compound of formula I can be produced by reacting 2- mercaptobenzimidazole of formula II with a 2-aminobenzyl compound of formula III (X is reactive group) in an inert solvent (e.g. benzene) preferably in the presence of an alkaline agent as an acid acceptor at a temperature between room temperature and refluxing temperature for 30min-24hr under agitation and reacting the resultant compound of formula IV with an oxidizing agent (e.g. H2O2, m-chloroperbenzoic acid, etc.) in an inert solvent (e.g. chloroform) at -15-+5 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a benzimidazole derivative useful as an anti-ulcer agent, a method for producing the same, and an anti-ulcer agent containing the same.

[Prior Art] Benzimidazole derivatives exhibiting anti-ulcer effects have already been disclosed in Japanese Patent Application Laid-open Nos. 61-60660 and 61-221.
It is disclosed in Japanese Patent No. 175 and Japanese Patent No. 61-221176.

[Summary of the Invention] The present invention is directed to the following general formula () useful as an antiulcer agent: (wherein R1 and R2 are a hydrogen atom or a lower alkyl group, and R3 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group) , R4 represents a lower alkyl group or a lower alkoxy group), a method for producing the same, and an antiulcer agent containing the same.

The benzimidazole derivative (I) of the present invention is, for example, 1
According to the following reaction formula, 2-mercaptobenzimidazole (11) is reacted with 2-aminobenzyl compound (III) to form compound e! (IV) and then oxidizing it.

(II) (III) (IV) (I) (In the formula, X represents a reactive group, and Rt to R4 are the same as above) The raw material (II) of the production method of the present invention is an already known compound. 1 For example, Org, 5ynth, Volume 30, No. 56
Manufactured by the method described on p.

Examples of the reactive group represented by X in the raw material (III) include halogen atoms such as chlorine and bromine, methylsulfonyloxy groups, and toluenesulfonyloxy groups. ,Chem,S.
oc, 98-102 (1942). These can also be used in the reaction in the form of salts.

The reaction between compound (II) and compound (III) or a salt thereof is carried out by stirring in an inert solvent such as toluene, benzene, ethanol, acetone, etc. at room temperature to reflux temperature for 30 minutes to 24 hours. . At this time, it is preferable to make an alkaline agent such as sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium bicarbonate present to receive the generated acid.

Oxylation of compound (IV) can be carried out by a conventional method, for example, using hydrogen peroxide, an organic peracid such as m-chloroperbenzoic acid, or an oxidizing agent such as sodium metaperiodate.
Compound (tv) may be oxidized.

The reaction involves chloroform, dichloromethane, methanol,
It is carried out in an inert solvent such as ethyl acetate at a temperature of -30°C to 50°C, preferably -15°C to 5°C.

The pharmacological effects of the representative compound of the present invention compound (1) obtained in this manner were tested and the results are as follows.

(1) Conventional method for suppressing gastric acid secretion (Shay H, et al, Gastr
oenterology.

・Body weight 200 according to Dan, 43-61 (1945))
After administering ~250 g of Donryu male rats for 24 hours (with free access to water), the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was administered into the duodenum. After 4 hours, the animals were sacrificed, the stomachs were removed, and gastric fluid was collected. Acidity (acidoutput) was measured using an automatic titration device. pH 7.0 with IN sodium hydroxide
and the values obtained were compared with those of similarly treated control animals but not receiving the test compound. The results are shown in Table 1.

Margin below Table 1 Dose Gastric juice secretion suppressing effect (Kasumi g/Kg) (%) Compound 1 30 88.010 32.
9 Compound 2 30 96.310
37, 4 Cimetidine 30 59.110
25.3 Compound 1 and Compound 2 are compounds obtained in Synthesis Example 1 and Synthesis Example 2 described below, and cimetidine is a known anti-ulcer agent.

(2) Effect on stress ulcers Tonryu rats weighing 240 to 260 g were fed for 24 hours and Takagi et al.
.

18 (9) 9-18, 1968) and was placed in a 21"C water tank with water up to the xiphoid process to apply stress. After 7 hours, the animal was removed from the tank, immediately killed, and its stomach was removed. 1% formalin solution 10mj
At the same time as injecting L into the stomach.

After being immersed in 1% formalin solution for 10 minutes, the stomach was incised along the diameter, and the length (mm) of the mucosal ulcer occurring in the glandular stomach was measured and compared with that without drug administration. The suppression rate was determined. The drug was orally administered 10 minutes before stress loading. The results are shown in Table 2.

Table 2 Test drug Dose Inhibition rate (g/Kg
p, o) (%) Compound 1
30 45100 8B Compound 2 30 62 (3) Gastrointestinal cytoprotective effect After fasting male Tonryu rats (240-270 g) for 24 hours, prepare a hydrochloric acid/ethanol solution (150 mM hydrochloric acid in 60% ethanol) l ml 7200
g body weight was administered orally. One hour later, the rats were sacrificed with ether, the stomach was removed, and the length of the damage (mm) occurring in the glandular stomach area was measured. The total length was taken as the damage factor.

The test drug was suspended in a 1% carboxymethyl cellulose solution immediately before use, at a dose of 0.5 mJl/100 g body weight,
It was orally administered 30 minutes before the administration of hydrochloric acid and ethanol. The same dose of vehicle alone was administered to the control group. Note that the suppression rate was determined using a linear equation, and the results are shown in Table 3.

Inhibition rate (%) = [1-damage coefficient (f) when administering the drug
mlm) / damage coefficient without drug administration (mm)
]x100 Table 3 Test drug Dose Inhibition rate Administration time (-g
/Kg) (%) Compound 1 10 68 30 minutes ago 30
85 30 minutes ago Compound 2 10 71 30 minutes ago 30
95 30 minutes before (4) Acute toxicity test Compounds 1 and 2 of the present invention were orally administered to ICR male mice weighing 23 to 26 g and observed for 3 days.
D was found to be 1000 mg/Kg or more.

The compounds of the present invention can be administered either orally or parenterally. Examples of dosage forms for oral administration include tablets, capsules, R&D preparations, granules, syrups, etc., and dosage forms for parenteral administration include injections. For their preparation, conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used. Excipients include glucose, lactose, etc. Disintegrants include starch, carboxymethylcellulose calcium, etc. Lubricants include magnesium stearate, talc, etc. Binders include hydroxypropyl cellulose, gelatin, Polyvinylpyrrolidone and the like are used.

The dosage is usually about 1 m/day for adults as an injection.
g ~50 mg g, orally administered approximately lomg ~50
The dose is 0 mg, but it can be increased or decreased depending on age, symptoms, etc.

Next, a synthesis example of the compound of the present invention will be explained by giving a synthesis example.

[Synthesis Example 11 (1) Synthesis of 2-(2-dimethylamino-5-methylbenzylthio)-5-methoxybenzimidazole 16.4 g (138 mmol) of thionyl chloride was dissolved in 90 g (111 mmol) of methylene chloride, and the mixture was cooled on ice. 2-dimethylamino-5-methylbenzyl alcohol 19.0g (1
15 mmol) of methychloride was added dropwise. After further stirring for 30 minutes at room temperature. The solvent was distilled off under reduced pressure at 40"C or below, and 27 g (150 mmol) of 2-mercapto-5-methoxybenzimidazole and 9 mL of ethanol were added to the resulting residue.
0 ml was added and stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and added with 50 mjL of ethanol. and ether 5
The solution was washed twice with 0ml to obtain 47g of dihydrochloride as a gray powder. This was mixed with 100nnjL of water and 1l of methylene chloride.
oOmJl mixture, plus 41g (29g) of potassium carbonate
7 mmol) was added little by little.

Insoluble materials were filtered off, and the organic layer was separated and dried over anhydrous sodium sulfate. After carefully separating out the sodium sulfate and distilling off the solvent under reduced pressure, 100 m of ether was added to the brown oil obtained.
jL, the precipitated crystals were collected by filtration, and 50 m of ether was added.
24.4 g (64.9%) of the above compound was obtained as a light brown powder. Furthermore, 2.3 g of second crystals were recovered from the mother liquor.

'HNMR (CDC!L3) δ=2.28 (s, 3H) 2.88 (s, 6H) 3.82 (s, 3H) 4.32 (s, 2H) 6.6~7.5 (m , 6H) (2) Synthesis of 2-(2-dimethylamino-5-methylbenzylsulfinyl)-5-methoxybenzimidazole 2-(2-dimethylamino-5-methylbenzylthio)
-5-methoxybenzimidazole 2.5g (7,6
mmol) in 12.5 mJL of methylene chloride,
1,69 g of m-chloroperbenzoic acid (purity 7) under water cooling.
0%, 6.8 mmol) was added dropwise over 15 minutes at below 10°C. The mixture was further stirred at this temperature for 15 minutes, saturated sodium bicarbonate solution was added, and the JR layer was washed with 10% sodium thiosulfate and saturated brine, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, and 5 rn l of methylene chloride was added to the residue.
．． Washed twice with 3.7ml of IN sodium hydroxide, then 13.4ml of 0.5N sodium hydroxide (6,7
After neutralizing the aqueous layer with 10 ml of a 20% aqueous ammonium chloride solution, the oily substance that separated was extracted with 20 ml of methylene chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residual liquid was purified by silica gel column chromatography and crystallized from ether/hexane to obtain 680 mg of the above compound as a white crystalline powder.

' HN M R (CD Cl s ) δ=2.06
(s, 3H) 2.60 (S, 6H) 3.80 (br, 3H) 4.44.4.80 (both d, 2H)

J=14Hz) 6.7-7.8 (m, 6H) 12.3 (br, IH) Br IRymax cm-' 3200, l 620, l 495, l 400
．． 1200, 1140, l 040 Melting point: 9B, 5-100°C [Synthesis Example 2] (1) Synthesis of 2-(2-dimethylamino-5-methoxybenzylthio)-5-methoxybenzimidazole 14.1 g of thionyl chloride ( A solution of 54 ml of dry benzene (119 mmol) was cooled with water, and while stirring, 17.9 g of 2-dimethylamino-5-methoxybenzyl alcohol (9
A solution of 8.9 mmol) in 18 ml of dry benzene was added dropwise over about 15 minutes. After stirring for an additional 30 minutes at room temperature, the solvent was distilled off under reduced pressure at below 40°C, and 72 ml of ethanol and 17.8 g (98.9 mmol) of 2-mercapto-5-methoxybenzimidazole were immediately added to the resulting dark brown oil. The reaction mixture was stirred at room temperature for 1.5 hours, poured into 100 ml of cooled 10% potassium carbonate solution, extracted with 100 ml of methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. . After filtering off sodium sulfate, the solvent was distilled off under reduced pressure, and ether was added to the residue.
By adding oOmJl and stirring at room temperature for 30 minutes, removing the precipitated crystals and washing with ether, 18.8
g (55.4%) of the above compound were obtained as a light brown powder. Furthermore, 1.8 g of second crystals were recovered from the mother liquor.

' HN M R (CD Cl z ) δ=2.84
(s, 6H) 3.72, 3.80 (both s, 6H) 4.32 (s
, 2H) 6.6~? , 4 (m, 6) 1) (2) Synthesis of 2-(2-dimethylamino-5-methoxybenzylsulfinyl)-5-methoxybenzimidazole 2-(2-dimethylamino-5-methoxybenzylthio)-5 -Methoxybenzimidazole 1.85g (5
, 4 mmol) was dissolved in 30 ml of methylene chloride, and 1.33 g of m-chloroperbenzoic acid (purity 70%) was dissolved under water cooling.
, 5.4 mmol) was added over about 15 minutes at below 10°C. After further stirring at this temperature for 30 minutes, saturated sodium bicarbonate solution was added. The 41st layer was separated, washed with 20% sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in 15 mJl of methylene chloride. After washing with 2,000ml of sodium hydroxide, it was extracted with 1011141 (5 mmol) of 0.5N sodium hydroxide. To the aqueous layer, add 1 part of a 20% ammonium chloride aqueous solution and separate the oily substance with 20 parts of methylene chloride.
After extraction with mJl, the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the remaining liquid was purified by column chromatography.The resulting solution was crystallized from chloroform/methanol (100/l) and ether/hexane to give 70.5 mg of the above compound as a white product. Obtained as a crystalline powder.

Otori HN M R (CD Cl x ) δ=2.61
(s, 6H) 3, 51 (s, 3H) 3, 82 (br, 3H) 4.49.4.87 (both d, 2H1J-13Hz) 6, 6-7. 8 (m, 6H) IRSBii
ax cm-' 3200, 1620. 1490. 1400.12
00, 1040. 1020 Melting point: 95-96.5℃

Claims (1)

[Claims] 1. The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are hydrogen atoms or lower alkyl groups, and R_3 is hydrogen atoms, lower alkyl groups, or lower alkoxy groups. , and R_4 represents a lower alkyl group or a lower alkoxy group). 2. General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R_3 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group.) The general formula for 2-mercaptobenzimidazoles represented by (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1 and R_2 are hydrogen atoms or lower alkyl groups, R_4 is lower alkyl groups or lower alkoxy groups, and X is a reactive group. ) is reacted with a 2-aminobenzyl compound represented by the general formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (wherein R_1 to R_4 are the same as above) A benzyl compound represented by the general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (wherein R_1 to R_4 are the same as above) Method for producing imidazole derivatives. 3. The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are hydrogen atoms or lower alkyl groups, and R_3 is hydrogen atoms, lower alkyl groups, or lower alkoxy and R_4 represents a lower alkyl group or a lower alkoxy group) as an active ingredient.