NL8502384A - BENZIMIDAZOLE DERIVATIVES, PHARMACEUTICAL PREPARATIONS WITH AN ACTION AGAINST SILES CONTAINING THEM AND METHODS FOR PREPARING THESE DERIVATIVES - Google Patents

Description

- 1 - k

Benzimidazole derivatives, pharmaceutical preparations having an anti-ulcer activity containing them and methods for preparing these derivatives.

The invention relates to new benzimidazole derivatives and more particularly to benzimidazole derivatives of the general formula 1, wherein R 1 represents a hydrogen atom or an alkyl group with 1-8 carbon atoms or a cycloalkyl, phenyl or aralkyl group, R 1 represents a hydrogen atom or represents an alkyl group of 1-8 carbon atoms, or wherein R 1 and R 1? together with the adjacent nitrogen atom form a ring and R 1 and R 2 each represent a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy, lower alkoxycarbonyl or amino group. The invention further relates to a method of preparing such derivatives and to pharmaceutical preparations having an anti-ulcer activity containing such derivatives.

As is known from the prior art to which the present invention belongs, H ++ K + ATPase plays a fundamental role in the ultimate secretion mechanism of gastric acid in gastric cells. / Scand. J. Gastroenterol., 14, 131-135 (1979) /. Norinium bromide is known as a product with an H + K ATPase inhibitory activity / Proceeding of the Society 20 for Experimental Biology and Medicine, 1V2, 308-315 (1983), 7.

On the other hand, 2- / 2- (3,5-dimethyl-4-me thoxy) -pyridyme thy1s ulfinyl7- (5-me thoxy) -b etc imidazoo1 / 0meprazole7 has been developed as a compound having an anti-ulcer activity with an H + K + ATPase inhibitory activity / Am. J. or 25? "·» 'F Λ. V ·· 1 ** - * - 2 - * 4

Physiol., 245, G64-71 (1983) 7.

Therefore, there is a strong need for a new compound with a more potent action on the Η + K ATPase inhibition.

In view of the foregoing, after extensive studies it has been found that benzimidazole derivatives of the above formula given above due to their specific H + K ATPase inhibitory activity, coupled with a cytoprotective activity, have an excellent suppressive effect on the secretion of 10 exerts stomach acid.

Thus, an aspect of the present invention relates to the provision of novel benzimidazole derivatives of the above formula 1 which are useful for combating ulcers, especially gastric ulcers.

Another object of the invention is to provide a new method for preparing such benzimidazole derivatives.

Yet another aspect of the invention is directed to the preparation or manufacture of anti-ulcer active preparations containing such benzimidazole derivatives as active ingredient.

According to a first aspect of the invention, benzimidazole derivatives represented by the formula 1 are provided, wherein R 1 represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms or a cycloalkyl, phenyl or aralkyl group, R 2 represents a hydrogen atom or an alkyl group of 1 Represents 8 carbon atoms, or wherein R 4 and R 4 together with the adjacent nitrogen atom form a ring and R 4 and R 4 each represent a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy, lower alkoxycarbonyl or amino group introduce.

According to a second aspect of the invention there is provided a process for preparing a previously defined benzimidazole derivative, which comprises the reaction of a 2-mercaptobenzimidazole of formula 2, wherein R 1 is a previously -3 V λ3 ΐ "- 3 - "* Has defined meaning, with a 2-aminobenzyl compound of formula 3, wherein R 1, R 1, and R 1 have the previously defined meanings and X is a reactive group to form a compound of formula 4, wherein R 1, R 2 , R ^ and R ^ 5 have the meanings defined above, and then oxidation of the compound of formula IV.

According to a third aspect of the invention, a preparation with an action against (gastric) ulcers is provided, which preparation contains as active ingredient a previously specified benzimidazole derivative.

For example, a benzimidazole derivative of the formula 1 of the present invention can be prepared by reacting a 2-mercaptobenzimidazole of the formula 2 with a 2-aminobenzyl compound of the formula 3 to a compound of the formula 4 and then oxidation of this compound of the formula 4 according to the the formula sheet given under A reaction scheme, in which X is a reactive group and Rj to the previously defined meanings.

The starting compound of formula II which is useful in the method according to the invention is known in the art. This compound of formula 2 can be prepared, for example, according to the method described in Org. Synth., 30, 56. Among the reactive group X in the other starting compound of formula 3, a halogen atom, such as a chlorine or bromine atom, or a sulfonyloxy group such as the methylsulfonyloxy or toluenesulfonyloxy group. for example, a chlorine atom is bonded as X can be prepared according to the method described in J. Chem. Soc., 98-102 (1942). Both starting compounds 30 can also be in the form of salts.

The reaction of the compound of formula 2 and the compound of formula 3 or of their respective salts can be carried out by placing them in an inert solvent, such as toluene, benzene, ethanol or acetone, at a temperature between room temperature and reflux temperature, for C Stir for 4 - 30 minutes to 24 hours. In such a case, it is recommended that an alkaline compound such as NaOH, KOH, K 2 CO 2 or NaHCO 2 be present in the reaction system in this reaction so that the acid formed can be neutralized. The compound of formula 4 may be in its corresponding oxo compound by any method known per se in the art. be converted. This conversion can be effected, for example, by oxidizing the compound of formula 4 with an oxidizing agent, for example an organic peracid, such as m-chloroperperbenzoic acid, hydrogen peroxide, sodium hypochlorite or sodium metaperiodate. The reaction can be carried out in an inert solvent, such as chloroform, dichloromethane, methanol or ethyl acetate, at a temperature between -30 and + 50 ° C, preferably at a temperature between -15 and + 5 ° C, 15.

The pharmacological effects of some compounds characteristic of the invention were investigated.

The results obtained in the tests are stated below.

(1) The Η + K ATPase inhibitory effects: 20 According to the method of Forte and med. (J.

Applied Physiol., 32, 714-771 (1972)), cells secreting gastric acid were isolated from the rabbit gastric mucosa * + + and vesicles containing Η + K ATPase were obtained by centrifuging the cells in Ficoll with a discontinuous density. gradient. After the enzyme was incubated for 25 min at room temperature in 0.5 ml of a solution containing -5mM, of an imidazole buffer -4 '' (pH 6.0) and 2 x 10 M of each test compound, the mixture is heated to 37 ° C, at which temperature the mixture is left to stand for an additional 5 minutes.

Then 0.5 ml of a solution containing 4 mM magnesium chloride, 80 mM of an imidazole buffer (pH 7.4), 20 mM potassium chloride and 4 mM ATP was added to the mixture. The resulting mixture was allowed to react at 37 ° C for 15 min and then 1 ml of a 24% solution of trichloroacetic acid 35 was added to stop the reaction. The released 8532 38 4 * - 5 - inorganic phosphorus was quantitatively analyzed according to the method proposed by Taussky and Shorr (J. Biol. Chem., 202, 675-685 (1953)). The K + dependent activity of the ATPase was determined by subtracting its activity obtained when no potassium chloride was present. The results are summarized in Table 1, wherein the compounds 1-19 of the invention are the compounds obtained in some of Examples I-XXVI and comparative compound I is the compound obtained according to Reference Example I.

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i 'll 1! ι! "I I 1 85000?" : - 8 - (2) inhibitory effects against gastric acid secretion:

Male Donryu rats of body weight between 200 and 250 g were used, which had fasted for 24 hours according to the usual method of (Shay, H. and med., Gastroenterology, 5, 43-61 (1945)). had free access to water). The pylorus was ligated under ether anesthesia and each compound tested was administered through the duodenum. Four hours later, each rat was killed and the stomach removed to collect the gastric juice. The inhibitory effect was determined by comparing the acid production * obtained by titration with an automatic titrator to pH 7.0 with a 0.1 N sodium hydroxide solution with the corresponding value of a control rat which was in the same manner except that only a vehicle was administered. The results are shown in Table 2 below.

850 9 3 8 OP 'ON S & / -V at h? t * - 9 -

Table 2_ compound tested dose suppressive effect against (mg / kg) secretion of gastric _______________ acid (%) ______ comparative compound 1 100 44 100 80.3

Cimetidine 30 59.1 10 25.3 100 99.3 Compound according to the invention 3 __________ 10 62.9 Compound according to the invention 7 100 77.5 Compound according to the invention 9 100 95.7 Compound according to the invention 10 300 98.7 compound according to the invention 11 100 72.8 compound according to the invention 13 100 97.9 100 91.5 compound according to 'n 71 7 the invention 15' ____ 10 48.8 830 2 3 3 4

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CS) inhibitory effects against four gastric disorder models.

Four different types of gastric anomaly models were induced in Donryo male rats (180 to 240 g) 5 that were fasted for 24 to 48 hours before the experiments, but given free access to water.

a) "Shay" stomach ulcers:

Under ether anesthesia, an incision was made in the lower body of each rat that had fasted for 48 hours and the pylorus ligated. The animal was then sacrificed 14 hours later and the stomach was examined for any ulcers in the front part of the stomach. Each test compound or carrier alone was administered via the duodenum in a volume of 0.2 ml / 100 g body weight immediately after ligation of the pylorus.

b) Stress-induced erosions by immersion in water.

Rats that had fasted 24 hours before the experiments were placed in a closed cage. The animals were immersed vertically in a water bath (21 ° C) for 7 hours to the level of the sword-shaped appendage and then killed. The stomach of each rat was removed and expanded by injecting 10 ml of 1% formalin to fix the internal and external layers of the stomach walls. This formalin treatment was performed in all subsequent experiments. An incision along the major curve was then made in the stomach and examined for possible erosion in its jlier area. Each test compound or carrier alone was administered orally 10 min before stress onset.

c) Indomethacin-induced erosions:

Rats were administered indomethacin suspended in a 0.2% CMC solution at a dose of 25 mg / kg subcutaneously, which rats fasted 24 hours before the 35 experiments. 7 hours later, each animal was sacrificed and each stomach was examined for possible erosion in the gland portion. Each test compound or vehicle alone was administered orally 10 min before indomethacin treatment.

d) The HCl-EtOH-induced erosions: 5 Rats were administered at a dose of 1 mg / 200 g orally with a solution of hydrogen chloride in ethanol (150 mM HCl in 60% ethanol), which rats had 24 hours before the experiments fasted. One hour later each animal was sacrificed and its stomach examined for possible erosion in the gland-10 portion. Each compound tested or a carrier alone was administered orally 30 min before ethanol treatment.

The results are shown in Table 3 - A

to table 3D.

Table 3-A

A) "Shay" gastric ulcer compound tested mg / kg id inhibition (%) 3 28 compound of the invention 3 10 68 30 69 100 -29 20 Cimetidine - 300 44 / :. '238 4

- 12 -Table 3-B

b) stress-induced erosions induced by water immersion compound tested mg / kg po inhibition (%) compound of the invention 3 100 9? compound according to the invention 4 100 95 30 39 compound according to the invention 10 1Q0 gi compound according to the invention 12 100 74 compound according to the invention 13 100 38 60 49

Cimetidine - 200 87

Table 3-C

c) compound tested by indomethacin-induced erosions mg / kg po inhibition (%) compound according to the invention 100 88 30 39

Cimetidine - 100 76 «30 2 3 8 4« * - 13 -

Table 3-D

d) compound tested by HCl-EtOH-induced erosions mg / kg po inhibition (%) compound according to the invention 3 30 100 4) Acute toxicity test:

Male rats weighing 80-90 g of intraperitoneal suspensions of certain compounds of the invention suspended in 0.2% 10 CMC physiological saline were administered to male Wistar. The rats were observed for 7 days and the results are shown in Table 4.

Table 4 Compound according to the invention LD ^ q 15 10 600 mg / kg or more 12 500 - 600 mg / kg 13 600 mg / kg or more 18 300 mg / kg or more 19 300 mg / kg or more 20 In addition, ICR males were rats with a body weight of 23 to 26 g orally administered the compound 3 according to the invention. The mice were then observed for 3 days. The MLD was found to be 1000 mg / kg or more.

The compounds of formula I of the present invention can be administered both orally and parenterally. Preparation forms for oral administration include, for example, tablets, capsules, powders, granules, syrups, etc.

Formulations for parenteral administration include injectable preparations, etc. Excipients, 302 3, can be used to prepare or manufacture these preparations. Disintegrants, binders, lubricants, pigments, diluents, etc. commonly used in the art. The excipients may include dextrose, lactose, etc. Starch, carboxymethyl-5 cellulose, etc. may be used as disintegrants. As the lubricants, magnesium stearate, talc, etc. can be used. The binders can be hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, etc.

The dose will usually be between about 1 mg / day 10 to 50 mg / day in the case of an injectable preparation and about 10 mg / day to 500 mg / day in the case of oral administration, in both cases for an adult. . Depending on age and other circumstances, the dose may be increased or decreased.

15 Reference example I

(1) 2-benzylthiobenzimidazole.

To a solution containing 1.47 g of sodium hydroxide dissolved in a mixed solvent, 5 ml of water and 50 ml of ethanol, 5 g of 2-mercaptobenzimidazole and 4.2 g of benzyl chloride were added. The resulting solution was then heated under reflux for one hour. The reaction mixture was then poured onto ice water and the precipitated crystals were filtered off, yielding 7.7 g of crude crystals (96%). The crystals were recrystallized from ethanol to give 5.9 g of 2-benzylthiobenzimidazole as colorless needles. Melting point: 184 ° C.

(2) 2-benzylsulfinylbenzimidazole (comparative compound 1): _

4.5 g of 2-benzylthio-30 benzimidazole were dissolved in 30 ml of chloroform, and 4.6 g of m-chloroperbenzoic acid (purity: 70%) were gradually added at temperatures below 0 ° C. The mixture was then stirred for 20 minutes and the separated crystals were filtered off. The filtrate was washed successively with a saturated sodium hydrogen carbonate solution, sodium thiosulfate and a saturated sodium 8502334 chloride solution, and the filtrate thus washed was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.3 g of crude crystals. The crystals were recrystallized from ethanol to give 2.0 g of 2-benzylsulfinylbenzimidazole as colorless crystals. Melting point; 169-170 ° C.

Example I

(1) 2- (2-aminobenzylthio) benzimidazole:

1.8 g of 2-amino-benzyl chloride hydrochloride and 1.5 g of 2-mercaptobenzimidazole were dissolved in 40 ml of ethanol.

The resulting solution was stirred at room temperature for 23 hours under protection from light. The precipitated powder was filtered off and, after successively washing with ethanol and ether, the powder was recrystallized from a mixed solvent of methanol and ether to give 1.8 g of 2- (2-aminobenzylthio) benzimidazole hydrochloride as colorless granular crystals obtained. Melting point: 207 ° C (dec.).

(2) 2- (2-aminobenzylsulfinyl) benzimidazole (the compound 1 of the invention; 1 g of 2- (2-aminobenzylthio) benzimidazole was dissolved.

hydrochloride in ice water. The solution was then neutralized with 512 mg of sodium bicarbonate, followed by extraction with chloroform. The resulting chloroform solution was washed with a saturated sodium chloride solution. After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off at room temperature under reduced pressure. Then 0.5 g of the 2- (2-aminobenzylthio) benzimidazole thus obtained were dissolved in a mixed solvent consisting of 30 ml of chloroform and 3 ml of methanol. The resulting solution was cooled to -10 ° C and a little 0.4 g of m-chloroperbenzoic acid (purity: 70%) was added thereto. The mixture was then stirred at the same temperature for 10 minutes. A light, yellowish powder precipitated which was filtered off. After washing with ether, the powder was recrystallized from a mixed solvent of methanol and ether, 32: 2 3 8 4 - 16 - to give 0.33 g of 2- (2-aminobenzylsulfinyl) benzimidazole as a white crystalline powder.

M.p .: 150 ° C (dec.). .....

V "Dr _ 1 1 3 IRV sm: 3200, 1440, 1260, 1035 max 5 ^ -NMR (DMSO-dg) £: 4.40 and 4.64 (each d, 2H, J = 14Hz, 0 ♦ -SCI ^ -), 6.24-7.80 (m, 8H, aromatic protons)

Example II

(1) 2- (2-methylaminobenzylthio) benzimidazole:

1.8 g of 2-mercaptobenzimidazole and 2.5 g of 2-methyl-aminobenzyl chloride hydrochloride were stirred in 10 ml of ethanol at room temperature for 30 min. Then 10 ml of ether were added and the precipitated crystals were filtered off. These crystals were washed with ether to give 3.5 g (85%) of 2- (2-methylaminobenzylthio) benzimidazole hydrochloride. The crystals were suspended in ethyl acetate and then neutralized by adding a saturated sodium hydrogen carbonate solution. After washing with a sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from acetonitrile, whereby 1.87 g of 2- (2-methylaminobenzylthio) -25 benzimidazole were obtained as colorless crystals.

M.p .: 107-108 ° C.

(2) 2- (2-methylaminobenzylsulfinyl) benzimidazole (compound of the invention 2). 1.0 g of 2- (2-methylaminobenzylthio) benzimidazole were dissolved in 20 ml of chloroform. After cooling the solution to -10 ° C, 0.87 g m-chloroperbenzoic acid (purity: 70%) was added little by little / After stirring for 10 min at the same temperature, the mixture was washed successively with a saturated sodium hydrogen carbonate solution $ Λ 0 1 Λ ii ii m m m m m f f - - - - - - - - - en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en of at by bye bye at least anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from acetonitrile to give 0.43 g of 2- (2-methylamino-5-benzylsulfinyl) benzimidazole as a white crystalline powder.

M.p .: 122.5-124 ° C.

IR-p rar cm-1: 3220, 1600, 1500, 1435, 1400, 1305, 1265, "max * '1045 10 1 H-NMR (CDC13) S: 2.52 (s, 3H, -NQEg), 4 , 36 and 4.60 (d, 2H, J = 16Hz, 0 f · -SCH--), 6.30-7.80 (m, 8H, aromatic protons) i J ^

Example III

(1) 2- (2-dimethylaminobenzylthio) benzimidazole:

4.73 g of 2-mercaptobenzimidazole were dissolved in 150 ml of ethanol and 6.18 g of 2-dimethylaminobenzyl chloride hydrochloride were added. The mixture was then stirred at room temperature for 30 minutes. The precipitated crystals were filtered off. A saturated solution of sodium hydrogen carbonate was then added to the crystals and extracted with chloroform. The chloroform layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of chloroform and acetonitrile to give 5.39 g of 2- (2-dimethylaminobenzylthio) benzimidazole 3q as colorless crystals. Mp. 164 ° C.

(2) 2- (2-dimethylaminobenzylsulfinyl) benzimidazole (compound 3 of the invention).

(a) 4.8 g of 2- (2-dimethylaminobenzyl-22 thio) benzimidazole were dissolved in a mixed solvent consisting of 40 ml of chloroform and 5 ml of methanol. After cooling the 8502534-18 solution to 0 ° C, 3.86 g m-chloroperbenzoic acid (purity: 70%) was added little by little. Ten minutes later, a saturated sodium hydrogen carbonate solution was added to the reaction mixture and extracted with chloroform. The chloroform solution was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of chloroform and ether to give 2.97 g of 2- (2-dimethylaminobenzylsulfinyl) benzimidazole as colorless crystals: mp: 112 ° C (dec. .).

IRtf cm 1: 3170, 1485, 1435, 1400, 1260, 1040 15 H NMR (CDCl 3) £ 2.62 (s, 6H,> N (CH 3) 2), 4.47 and 4, 87 (each d, 2H, J = 14Hz, 0 r -SCIhj-), 6.70-7.90 (m, 8H, aromatic protons), 20 12.16 (br., 1H,> NH) (b) 400 g of 2- (2-dimethylaminobenzyl-thio) benzimidazole are dissolved in 1.06 l of methylene chloride - 1.06 l of methanol, then 212 ml of acetic acid are added to the solution and the mixture is stirred until the solid compound is 25 After cooling the resulting solution to a temperature between 2 and 5 ° C, 182 ml of 35% hydrogen peroxide, 123 ml of water and 8.83 g of ammonium metavanadate were added and the reaction mixture was stirred at a temperature for 9 hours. between 2 and 5 ° C. The reaction mixture was quenched with a 20% sodium hydrogen carbonate solution, the organic layer was separated, washed with an aqueous Na 2 S 2 O 3 solution and with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. evaporated under reduced pressure and the residue was recrystallized from acetonitrile to give 317 g of 2- (2-dimethylaminobenzyl-3502384-sulfyl) benzimidazole as colorless crystals.

(c) 10 g of 2- (2-dimethylaminobenzyl-thio) benzimidazole were dissolved in 30 ml of a 20% sodium hydroxide solution and 120 ml of ethyl acetate. After cooling the solution with ice water, it was dripped for 80 min.

at a temperature between 3 and 5 ° G add a mixture of 70 ml of 12% NaOCl and 30 ml of a 20% sodium hydroxide solution. The reaction mixture was then stirred for an hour at the same temperature mentioned above. The reaction mixture was quenched with a 10% 2820 solution and the organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from acetonitrile to obtain 7.9 g of 2- (2-dimethylaminobenzylsulfinyl) benzimidazole as colorless crystals.

Example IV

(1) 2- (2-dimethylamino-benzylthio) -5-methoxy-benzimidazole; 2.70 g of 2-mercapto-5-methoxybenzimidazole were dissolved in 60 ml of ethanol, followed by 3.09 g of 2-dimethyl- aminobenzyl chloride.hydrochloride. The resulting mixture was then stirred at room temperature for 30 minutes.

The precipitated crystals were filtered off. A saturated sodium hydrogen carbonate solution was added to the crystals and extracted with chloroform. The chloroform solution was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure to give 3.85 g of 2- (2-dimethylaminobenzylthio) -5-methoxybenzimidazole as a colorless oily product.

(2) 2.4 3 g of 2- (2-dimethylamino-benzylthio) -5-methoxybenzimidazole were dissolved in a mixed solvent consisting of 25 ml of chloroform and 2 ml of methanol.

«502384» \ - 20 -

After cooling the solution to 0 ° C, 3.86 g of m-chloroperbenzoic acid (purity: 70%) were added little by little.

Then, a saturated sodium hydrogen carbonate solution was added to the reaction mixture 10 minutes later and extracted with chloroform. The chloroform solution was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the chloroform was removed by distillation under reduced pressure.

The residue was purified by chromatography on a silica gel column (a mixture of chloroform and methanol: 50: 1) and then recrystallized from a mixed solvent of ether and hexane to give 1.50 g of 2- (2-dimethylaminobenzylsulfinyl) -5-methoxybenzimidazole as light yellowish crystals were obtained. Mp: 105 ° C (dec.).

15 IR1 '* ^ cm "1: 3270, 1625, 1485, 1390, 1205, 1175, 1030 max" 1 H-NMR (CDCl3) 2,6: 2.63 (s, 6H, -N (CH3) 2) , 3.81 (s, 3H, -0Cg3), 4.48 and 4.85 (each d, 2H, J = 15Hz?

20 T

-SCE ^ -), 6.60-7.80 (m, 7H, aromatic protons) 12.16 (br., 1H,> ΝΉ) (1) 2- (2-diethylaminobenzylthio) benzimidazole.

50.0 g of 2-mercaptobenzimidazole were suspended in 50 ml of ethanol and 77.9 g of 2-diethylaminobenzyl-25-chloride hydrochloride were added. The resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were then filtered and a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in ethanol. The resulting solution was treated with activated carbon.

The activated carbon was filtered off and the ethanol was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 88.7 g of 2- (2-diethylaminobenzylthio) benzimidazole as a light brownish crystalline powder.

Mp .; 134-135 ° C.

5 (2) 2- (2-diethylaminobenzylsulfinyl) benzimidazole____

84.0 g of 2- (2-diethylaminobenzylthio) -benzimidazole were dissolved in a mixed solvent consisting of 600 ml of methylene chloride and 150 ml of methanol. After cooling the solution to 0 ° C, little by little 79.8 g of m-chloroperbenzoic acid (purity: 60%) were added. Then, a saturated solution of sodium hydrogen carbonate was added to the reaction mixture 10 minutes later and extracted with methylene chloride. The resulting methylene chloride solution was dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure and the residue was chromatographed on a silica gel column (silica gel, 280 g; eluent: a mixture of acetone and hexane 1: 2 (v / v)). The eluate was dissolved in a mixed solvent of ethanol and hexane (1: 8, v / v) and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure. The residue was recrystallized 2x from isopropyl ether to give 32.3 g of 2- (2-diethylaminobenzylsulfinyl) benzimidazole as colorless crystals. Mp .: 110.5-112 ° C (dec.).

IR ^ rar cm "1; 3200, 2980, 1490, 1400, 1270, 1015, 765, 750 ^ -NMR (CDC13) S: 1.01 (t, 6H, J = 7Hz, -CH2CH3 x 2) 3.00 (q, 4H, J * 7Hz, -CH-CH., x 2) 30-4.46 and 4.97 (each d, 2H, J = 13Hz, 0 t -SCILj-), 6.80-7 90 (m, 8H, aromatic protons), 12.41 (br., 1H,> NH) (1) 2- (2-dimethylaminobenzylthio) -4-methylbenzimidazole: 8502334 t-22 -

1.26 g of 2-dimethylaminobenzyl chloride hydrochloride were added to a suspension of 1.0 g of 2-mercapto-4-methylbenzimidazole in 10 ml of ethanol. The resulting mixture was then stirred at room temperature for 2 hours.

The precipitated crystals were filtered off and, after successively washing with ethanol and ether, were dissolved in chloroform. The chloroform solution was neutralized with a saturated sodium hydrogen carbonate solution, washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and ether was added to the residue. The precipitated crystals were filtered to yield 13.8 g of 2- (2-dimethylaminobenzylthio) -4-methylbenzimidazole as a white crystalline powder.

^ -NMR (CDCLi): £ 2.52 (s, 3H), 2.84 (s, 6H), 4.36 (s, 2H), 6.8-7.6 (m, 7H) (2) 2- (2-dimethylaminobenzylsulfinyl) -4-20 methylbenzimidazole (compound 9 of the invention):

1.1 g of 2- (2-dimethylaminobenzylthio) -4-methylbenzimidazole were dissolved in 15 ml of chloroform and 0.8 g (purity: 80%) of m-CPBA were gradually added with ice-cooling. After stirring for 10 min at the same temperature, the resulting mixture was washed successively with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from acetonitrile to give 0.81 g of 2- (2-dimethylamino-benzylsulfinyl) -4-methylbenzimidazole as yellowish crystals. Mp .: 112-114 ° C (dec.) Cm -1: 3200, 1480, 1440, 1420, 1290, 1040, 750 35 H-NMR (CDCl 3) δ: 8502 38 4 - 23 - 2.2-2, 8 (br. 3H), 2.60 (s, 6H), 4.52 and 4.84 (each d, J-13Hz, 2H), 6.7-7.6 (m, 7H)

Example VII

(1) 2- (2-dimethylamino-6-methylbenzyIthio) benz-5 imidazole_

4.41 g of 2-dimethylamino-6-methyl-benzyl chloride hydrochloride were dissolved in 40 ml of acetone, and 3.64 g of 2-mercaptobenzimidazole, 10 g of potassium carbonate and 4 ml of water were added. The resulting mixture was stirred for an hour at room temperature. Chloroform and water were then added to the reaction mixture, the chloroform layer was separated and washed with a saturated sodium chloride solution. After drying the chloroform layer over anhydrous sodium sulfate, the solvents were distilled off under reduced pressure. The residue was crystallized from a mixed solvent of ethanol and hexane and the crystals were filtered to give 4.68 g of 2- (2-dimethylamino-6-methylbenzylthio) benzimidazole as a light brownish powder.

] H-NMR (CDCl 3) S: 2.42 (s, 3H), 2.84 (s, 6H), 4.42 (s, 2H), 6.8-7.6 (m, 7H) ( 2) 2- (2-dimethylamino-6-methylbenzylsulfinyl) benzimidazole (compound No. 10 of the invention);

2.97 g of 2- (2-dimethylamino-6-methyl-25) were dissolved.

benzylthio) benzimidazole on m a mixed solvent consisting of 30 ml chloroform and 3 ml methanol. 2.18 g of m-CPBA (purity: 80%) were then added little by little under ice-cooling. The resulting mixture was stirred at the same temperature for 10 min, after which it was first washed with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, the residue obtained was recrystallized from a mixed solvent 8502 334-24 of chloroform and ethanol, yielding 0.75 g of 2- (2-6-dimethylamino-methylbenzylsulfinyl) benzimidazole as obtained white crystalline powder. M.p .: 141-142 ° C (dec.).

TR.V *** cm "1: 3230, 1435, 1400, 1270, 1040, 740 max '5 5] Hm (CDC13) S: 2.31 (s, 3H), 2.61 (s, 6H), 4.68 and 4.92 (each d, J = 13Hz, 2H), 6.8-7.8 (m, 7H)

Examples VIII-XIX

In the same manner as described in Example VI or VII, the following 12 compounds were prepared, details of which are given in Table 5.

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Example XX

(2) 2- (2-piperidinobenzylthio) benzimidazole To a solution of 1.42 g of 2-piperidinobenzyl chloride hydrochloride in 35 ml of ethanol was added 0.87 g of 2-mercaptobenzimidazole and 0.5 g of NaOH. The mixture was then stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure. Water was then added to the residue and extracted with ethyl acetate.

The ethyl acetate solution was washed successively with a 10% sodium hydroxide solution and a saturated sodium chloride solution. After drying the resulting solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was washed with ether to give 1.0 g of 2- (2-piperidinobenzylthio) benzimidazole as a yellow powder. M.p .: 165 ° C.

NMR (CDCl3) &: 1.4-2.1 (m, 6H), 2.8-3.1 (m, 4H), 4.34 (s, 2H), 6.9-7.6 (m 8H) (2) 2- (2-piperidinobenzylsulfinyl) benzimidazole 20 (compound of the invention 14).

0.70 g of 2- (2-piperidinobenzylthio) -benzimidazole were dissolved in a mixed solvent, which consisted of 50 ml of chloroform and 2 ml of methanol, and 1.3 g of m-CPBA (purity) were gradually added with ice-cooling : 80%) 25. The resulting mixture was then stirred at the same temperature for 10 minutes. Then the mixture was successively washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvents were distilled off under reduced pressure and the residue was recrystallized from ether to give 0.45 g of 2- (2-piperidinobenzyl-sulfinyl) benzimidazole as a white powder was obtained.

M.p .: 158 ° C (dec.).

83 02 m

Si - 30 -, νηΟγ. _ 1 IR'y cm: 3160, 1435, 1325, 1215, 1030, 920, 740 max -NMR (DMSO-dg) b: 1.3-1.8 (m, 6H), 2.6- 2.8 (m, 4H), 4.41-4.74 (each d, J = 12Hz, 2H), 6.8-7.8 (m, 8H)

5 Examples XXI -XXVI

In the same manner as described in Example XX, six more compounds were prepared, details of which are listed in Table 6.

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Preparation (tablets):

Each tablet (220 mg) contained the following ingredients: 5 active ingredient 50 mg lactose 103 mg starch 50 mg magnesium stearate 2 mg hydroxypropyl cellulose 15 mg

Example XXVIII

Preparation (capsules):

Each hard gelatin capsule (350 mg) contained the following ingredients: active ingredient 40 mg 15 lactose 200 mg starch 70 mg polyvinylpyrrolidone 5 mg crystalline cellulose 35 mg

Example XXIX

20 Preparation (granules):

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Example XXX

Preparation (coated tablets): Each coated tablet contained the ingredients of Example XXVII.

2384

Claims (3)

1. Benzimidazole derivatives of the formula 1, wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms or a cycloalkyl, phenyl or aralkyl group, R 2 represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms, or wherein R 1 and R 2 form a ring together with the adjacent nitrogen atom and R 1 and R 2 each represent a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy -, lower alkoxycarbonyl or amino group. 2. Process for the preparation of a benzimidazole derivative, characterized in that a benzimidazole derivative of the formula 1, wherein R 1, R 2, R 1 and R 1 have the meanings given in claim 1, is prepared by a 2-mercaptobenzimidazole of formula 2, wherein R 2 has a meaning defined above, with a 2-aminobenzyl compound of formula 3, wherein R 1, R 2 and R 2. have the previously defined meanings and X represents a reactive group to react to form a compound of formula 4 wherein R 1, R 2 J and R 2 have the previously defined meanings and then oxidize the compound of formula 4. Anti-ulcer preparation containing as active ingredient one or more benzimidazole derivatives as defined in claim 1. 8532384