CH665417A5 - BENZIMIDAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND ANTI-ULCER AGENTS CONTAINING THESE DERIVATIVES. - Google Patents

Description

DESCRIPTION

The present invention relates to new benzimidazole derivatives, more particularly to benzimidazole derivatives represented by the general formula (I)

r s-ch

2

h in which Rj is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms, or a cycloalkyl, phenyl or aralkyl group, R2 is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms carbon, or Ri and R2 taken together form a ring with the adjacent nitrogen atom, and R3 and R4 each represent a hydrogen atom, a halogen or a trifluoromethyl group, - lower alkyl, lower alkoxy, al-coxycarbonyl lower or amino. The invention also relates to a process for the preparation of these derivatives and to antiulcer agents containing these derivatives.

It is known in the prior art to which the present invention relates that H + + K + ATPase plays a decisive role in the mechanism of the final secretion of gastric acid in the cells of the stomach [Scand. J. Gastroenterol., 14, 131-135 (1979)].

Norinium bromide is known to be a substance with H ++ K + ATPase inhibitory activity [Proceeding of the Society for Experimental Biology and Medicine, 172, 308-315 (1983)].

On the other hand, 2- [2- (3,5-dimethyl-4-methoxy) -pyridylmethylsul-finyl] - (5-methoxy) -benzimidazole [Omeprazole] has been proposed as an antiulcer agent having an inhibitory activity on H ++ K + ATPase [Am. J. of Physiol., 245, G64-71 (1983)].

There is therefore an acute need for compounds which can exert an even more marked inhibitory activity of H + + K + ATPase.

In the context of the present invention, the inventors have carried out in-depth research and have found that the benzimidazole derivatives of formula (I) exhibit excellent suppressive effects with respect to gastric secretions, given their specific inhibitory action on H ++ K + ATPase combined with a cytoprotective action.

This is why one of the objects of the present invention is to provide benzimidazole derivatives of formula (I) useful for purposes

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therapeutic treatment of ulcers. Another object of the invention is to propose a new process for the preparation of these benzimidazole derivatives. Another object of the invention is to provide antiulcer agents containing such benzimidazole derivatives as a therapeutically active component.

According to the first implementation of the invention, there is provided a benzimidazole derivative represented by the formula (I)

R

S-CH

2

H

in which R! is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms, or a cycloalkyl, phenyl or aralkyl group, R2 is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms, or alternatively R 1 and R 2 taken together form a ring with the adjacent nitrogen atom, and R 3 and R 4 each represent a hydrogen atom, a halogen or a trifluoromethyl, lower alkyl, lower alkoxy, lower al-coxycarbonyl or amino group.

According to a second implementation of the invention, there is provided a process for the preparation of the benzimidazole derivatives defined above, characterized in that a 2-mercaptobenzimid-azole represented by the formula (II) is reacted

R

S H

H

wherein R3 is defined as above, with a 2-ami-nobenzyl compound represented by the formula (III)

XH-.C

in which R1; R2 and R4 are defined as above and X is a reactive group, to form a compound represented by formula (IV)

R

3

H

^ -S-CH

in which R1 (R2, R3 and R4 are defined above, and in that the compound of formula (IV) is then oxidized.

According to a third implementation of the invention, an antiulcer agent is proposed comprising, as a therapeutically active component, a benzimidazole derivative as defined below.

A benzimidazole derivative of formula (I) can be prepared, for example, by reacting a 2-mercaptobenzimidazole of formula (II) with a 2-aminobenzyl of formula (III) to form a compound of formula (IV) and then oxidize the compound of formula (IV), according to the following reaction scheme

R

s h

H

(III)

R

H

(IV)

at)

In the diagram above, X represents a reactive group and R! to R4 are defined as indicated above.

The starting compounds (II) used in the process of the invention are known compounds. Compound (II) can be prepared, for example, by the method described in Org. Synth., 30, 56. The reactive group X in the other starting compound (III) can be a halogen atom such as chlorine or bromine, or a sulfon-yloxy group such as methylsulfonyloxy or toluenesulfonyloxy. Compound (III) having a chlorine atom as a reactive group X can be prepared, for example, by the method described in J. Chem. Soc., 98-102 (1942). These two starting compounds can also be in the form of salts.

The reaction between the compounds (II) and (III) or between their respective salts can be carried out by mixing them in an inert solvent such as toluene, benzene, ethanol or acetone, at a temperature ranging from from room temperature to reflux temperature, for a period ranging from 30 minutes to 24 hours. In such cases, it is preferable to conduct the reaction in the presence of an alkaline compound such as NaOH, KOH, K2CO3 or NaHCO3 so that the resulting acid is neutralized.

Compound (IV) can be converted to the corresponding oxo compound by any method known in the art. This conversion can be, for example, carried out by oxidizing the compound (IV) using an oxidizing agent such as, for example, an organic peracid such as m-chlorperbenzoic acid, hydrogen peroxide, l 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 of -30 to + 50 ° C, preferably of - 15 to + 5 ° vs.

The pharmacological effects have been determined for certain characteristic compounds of the invention. The results of the tests carried out are given below.

1) Inhibiting effects of "H + + K + A TPase"

Following the method of Forte et al. [J. Applied Physiol., 32, 714-717 (1972)] gastric acid secreting cells were isolated from the gastric mucosa of rabbits and the vesicles containing "H + + K + ATPase" were obtained by centrifugation of the cells in a Ficoll with discontinuous density gradient. After incubating the enzyme at room temperature for 25 minutes in 0.5 ml of a solution containing 5 mmol of imidazole buffer (pH 6.0) and 2 x 10 -4 mole of the test compound, the mixture was heated to 37 ° C and

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maintained for 5 minutes at this temperature. To this mixture was then added 0.5 ml of a solution containing 4 mmol of magnesium chloride, 80 mmol of imidazole buffer (pH 7.4), 20 mmol of potassium chloride and 4 mmol of adenosine triphosphate (ATP ). The resulting mixture was then reacted for 15 minutes at 37 ° C, 1 ml of a 24% solution of trichloroacetic acid was then added to terminate the reaction. The released inorganic phosphorus was measured by the method of Taussky and Shorr [J. Biol. Chem., 202, 675-685 (1953)]. The activity of K + dependent adenosinetriphos phatase was determined by subtracting the activity measured in the absence of potassium chloride in the mixture.

The results are collated in Table 1 in which the compounds according to the invention 1 to 19 were prepared according to examples 1 to 26. The control compound was prepared according to reference example No. 1.

Table 1

E

Compound tested

r r3

r4

h ++ k + ATPase inhibitory effect (%)

Control compound h

h h

0

Compound 1

nh2

h h

88.2 -

nhch3

h h

100

N (CH3) 2

h h

100

N (CHj) 2

5-OCH3

h

100

N (CH3) 2

5-COOCH3

h

97.9

N (CH3) 2

5-CH3

h

100

N (CH3) 2

5-C1

h

100

N (CH3) 2

5-CF3

h

100

Compound 9

N (CH3) 2

4-CH3

h

100

Compound 10

N (CH3) 2

h

6-CH3

100

Compound 11

N (CH3) 2

h

4-C1

100

Compound 12

N (CH3) 2

h

5-OCH3

100

Compound 13

N (CH3) 2

h

5-CH3

100

Compound 14

1

Ö

h

H

82.3

Compound 15

-nh- (h)

H

H

100

Compound 16

h h

100

Compound 17

-N <®

ch3

H

H

66.7

Compound 18

ch3

h h

77.9

Compound 19

ch ^ ch (ch.) 0

-n (2 d 2

ch3

h h

100

5

665417

2) Inhibitory effect vis-à-vis the secretion of gastric acid

Male Donryu rats weighing 200 to 250 g were put on the diet for 24 hours, although having free access to water, according to the usual methods [Shay, H. et al., Gastroentorologie, J , 43-61 (1945)]. Under anesthesia, the pylorus was ligated and the test compound was administered intraduodenally. Four hours after administration, the rats were killed and their stomachs were removed in order to extract the gastric juice therefrom. The inhibitory effect was determined by measuring the acid released by titration (up to pH 7.0) with a 0.1N NaOH solution and comparing this value with the corresponding value obtained in a rat which was administered only the vehicle of the active component. The results obtained are shown in Table 2.

Table 2

Compound tested

Dose (mg / kg)

Suppressive effect on gastric secretion (%)

Control compound

100

44

Cimetidine

100

80.3

30

59.1

10

25.3

Compound 3

100

99.3

30

94.3

10

62.9

Compound 7

100

77.5

Compound 9

100

95.7

Compound 10

100

98.7

Compound 11

100

72.8

Compound 13

100

97.9

Compound 15

100

91.5

30

71.7

10

48.8

3) Inhibitory effect vis-à-vis four typical lesions

Four different models of gastric lesions were caused in male Donryu rats weighing from 180 to 240 g, deprived of food for 24 to 48 hours preceding the experiment, but having free access to water.

a) Shay's ulcers

Under ether anesthesia, the abdomen of each rat subjected to the diet for 48 hours was incised, and the pylorus ligated. 14 hours after the operation, the animal was killed and the stomach examined for the presence of ulcers in its anterior part. Each test compound, or the vehicle alone, was administered intraduodenally at the rate of 0.2 ml of solution per 100 g of body weight, immediately after ligation of the pylorus.

b) Erosions induced by stress under immersion in water

Rats subjected to the diet for 24 hours beforehand were restrained in cramped cages. The animals were then immersed vertically up to the height of the xiphoid appendix, for 7 hours in water at 21 ° C and finally killed. The stomach of each rat was then excised and then inflated by injection of 10 ml of a 1% formalin solution, in order to fix the internal and external layers of the gastric walls. Treatment with formalin was performed for all subsequent experiments. Subsequently, the stomach was incised along its greatest line of curvature and examined for the presence of erosions in its glandular part. Each compound tested was administered orally, 10 minutes before stress.

3) Indomethacin-induced erosions

Indomethacin suspended in a 0.2% CMC solution was administered subcutaneously at a rate of 25 mg per kg of body weight, to rats subjected to a diet for 24 hours prior to the experiment. . 7 hours after administration, each animal was killed and the stomach examined for the presence of erosions in its glandular portion. Each of the compounds tested, or the vehicle alone, was administered orally 10 minutes before treatment with indomethacin.

d) Erosions induced by HCl-EtOH

A solution of hydrochloric acid in ethyl alcohol (150 mmol 60% HCl) was administered orally, at the rate of 1 ml per 200 g of body weight, to rats previously subjected to the diet for 24 hours. An hour later, each animal was killed and the stomach examined for erosions in its glandular portion. Each of the compounds tested, or the vehicle alone, was administered orally 30 minutes before treatment with acid ethanol.

The results obtained are collated in Tables 3-A to 3-D.

Table 3-A

a) Shay's ulcers

Compound tested

mg / kg id

Inhibition (%)

Compound 3

3

28

10

68

30

69

Cimetidine

100

-29

300

44

Table 3-B b) Erosions induced by stress under immersion

Compound tested

mg / kg po

Inhibition (%)

Compound 3

30

69

100

97

Compound 4

30

27

100

95

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Compound tested

mg / kg po

Inhibition (%)

Compound 10

30

39

100

91

Compound 12

30

41

100

74

Compound 13

30

64

100

88

Cimetidine

60

49

200

87

Table 3-C

c) Indomethacin-induced erosions

Compound tested

mg / kg po

Inhibition (%)

Compound 3

30

7.0

100

88

Cimetidine

30

39

100

76

Table 3-D d) Erosions induced by HCl-EtOH

Compound tested

mg / kg po

Inhibition (%)

Compound 3

10

89

30

100

30

4) Acute toxicity

To male Wistar rats weighing 80 to 90 g, suspensions of some of the compounds of the invention were administered intraperitoneally (suspension in 0.2% CMC saline). The rats were observed for 7 days and the results obtained are collated in Table 4.

Table 4

Compound

ld50

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

In addition to this, compound 3 according to the invention was administered to male ICR mice weighing 23 to 26 g, orally, and the mice observed for 3 days. The minimum lethal dose (MLD) determined was 1000 mg or more per kg of body weight.

The compounds (I) of the present invention can be administered either orally or parenterally. Preparations for oral administration may include, for example, tablets, capsules, powders, granules, syrups and the like. Preparations for parenteral administration may include injections and the like. For the preparation of such preparations, excipients, disintegrants, binders, lubricants, pigments, diluents and similar products commonly used in the art can be used. Excipients may include dextrose, lactose and the like. Starch, carboxymetylcellulose and the like can be used as disintegrants. Magnesium stearate, talc and the like can be used as lubricants. The binders can be hydroxypropylcellulose, gelatin, polyvi-nylpyrrolidone and others.

The usual effective dose may be between approximately 1 and 50 mg per day in the case of an injectable preparation and between approximately 10 and 500 mg per day in the case of oral administration, the dose being intended for one person adult. This dose can either be increased or decreased depending on age or other conditions.

The examples below are intended to illustrate the present invention, without however limiting it.

Reference example

1. 2-Benzylthiobenzimidazole

To 1.47 g of NaOH dissolved in a mixture of 5 ml of water and 50 ml of ethanol, 5 g of 2-mercaptobenzimidazole and 4.2 g of benzyl chloride were added, and the resulting solution was heated for 1 hour at reflux. The reaction mixture was then poured onto ice and the crystals thus precipitated collected by filtration (7.7 g of crude crystals; yield 96%). The product obtained was recrystallized from ethanol to give 5.9 g of 2-benzylthiobenzimidazole in the form of colorless needles, mp 184 ° C.

2. Control compound: 2-benzylsulfinylbenzimidazole

4.5 g of 2-benzylthiobenzimidazole were dissolved in 30 ml of chloroform, then 4.6 g of m-chloroperbenzoic acid (70% purity) were gradually added to it, at a temperature below 0 ° C. The mixture was stirred for 20 minutes and the crystals obtained collected by filtration. The filtrate was successively washed with a saturated NaHCO3 solution, a sodium thiosulfate solution then with saturated brine, and finally dried over Na2SO4. The solvent was removed by distillation under reduced pressure to give 4.3 g of crude crystals. These were recrystallized from ethanol to give 2.0 g of 2-benzylsulfinylbenzimidazole in the form of colorless crystals, mp 169-170 ° C.

Example 1

1) 2- (2- Aminobenzylthio) benzimidazole

In 40 ml of ethanol were dissolved 1.8 g of 2-aminobenzyl hydrochloride and 1.5 g of 2-mercaptobenzimidazole. Under shelter from light, the resulting solution was stirred for 23 hours at room temperature and the precipitate obtained was collected by filtration. After having been successively washed with ethanol 60 and with ether, the powder obtained was recrystallized from a mixture of methanol and ether to give 1.8 g of 2- (2-friend-nobenzylthio) benzimidazole hydrochloride in the form of colorless crystalline granules, m.p. 207 ° C (decomposition).

65 2) 2- (2-Aminobenzylsulfinyl) benzimidazole (= compound 1)

1 g of 2- (2-aminobenzylthio) benzimidazole hydrochloride was dissolved in ice water, then the solution neutralized with 512 mg of NaHCO3 and finally extracted with chloroform. The organic extract

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that was washed with saturated brine, dried over anhydrous Na2SO4 and the solvent removed by distillation under reduced pressure at room temperature. 0.5 g of the 2- (2-aminobenzylthio) benzimidazole thus obtained was dissolved in a mixture of 30 ml of CHCl3 and 3 ml of methanol and the resulting solution cooled to -10 ° C before being gradually added to 0, 4 g m-chloroperben-zoic acid (purity 70%). The reaction mixture was stirred for 10 minutes at this temperature and the precipitated pale yellow powder collected by filtration. After washing with ether, the powder obtained was recrystallized from a mixture of methanol and ether to give 0.33 g of 2- (2-aminobenzylsulfinyl) benzimidazole in the form of a white crystalline powder, F. 150 ° C (decomposition).

ICRr

IRv cm "1: 3200,1440,1400,1260, 1035 max

O

1H-NMR (DMSO-d6) S: d

4.40 and 4.64 (each d, 2H, J = 14 Hz, -SCH2-),

6.24 - 7.80 (m, 8H, aromatic protons)

Example 2

1) 2- (2-Methylaminobenzylthio) benzimidazole

2-Mercaptobenzimidazole (1.8 g) and chloride hydrochloride (2.5 g) in 10 ml of ethanol were stirred for 30 minutes at room temperature. 10 ml of ether were then added and the precipitated crystals collected by filtration, then washed with ether to give 3.5 g of 2- (2-methylaminobenzylthio) benzimidazole hydrochloride (yield 85%). The crystals obtained were suspended in ethyl acetate and neutralized using a solution of NaHCO3. After washing with brine, the organic extract was dried over anhydrous Na2SO4. After distilling off the solvent under reduced pressure, the residue obtained was recrystallized from acetonitrile to give 1.87 g of 2- (2-methylaminobenzylthio) benzimidazole in the form of colorless crystals, mp 107-108 ° C.

2) 2- (2-Methylaminobenzylsulfinyl) benzimidazole (= compound 2)

2- (2-methylbenzylthio) benzimidazole (1.0 g) was dissolved in 20 ml of chloroform. After the solution has cooled to -10 ° C, 0.87 g of m-chloroperbenzoic acid (70% purity) is gradually added thereto. After being stirred at this temperature for 10 minutes, the reaction mixture was successively washed with saturated NaHCO3 solution, saturated brine and finally dried over anhydrous Na2SO4.

After removing the solvent under reduced pressure, the residue obtained was recrystallized from acetonitrile to give 0.43 g of 2- (2-methylaminobenzylsulfinyl) benzimidazole in the form of a white crystalline powder, m.p. 122.5-124 ° C.

T7 "Dr

IRv cm "1: 3220,1600,1500,1435,1400,1305,1265,1045 max

* H-NMR (CDC13) S:

2.52 (s, 3H, -NCH3), 4.36 and 4.60 (each d, 2H, J = 16 Hz,

O î

-SCH2-),

6.30 - 7.80 (m, 8H, aromatic protons)

Example 3

1) 2- (2-Dimethylaminobenzylthio) benzimidazole

4.73 g of 2-mercaptobenzimidazole were dissolved in 150 ml of ethanol, then added with 6.18 g of 2-dimethylami-nobenzyl chloride. The mixture was stirred for 30 minutes and the precipitated crystals collected by filtration. After adding a saturated solution of NaHCO3 to the collected crystals, the aqueous phase was extracted with chloroform, the organic layer washed with saturated brine and finally dried over anhydrous Na2SO4. The solvent was distilled under reduced pressure and the residue obtained recrystallized from a CHCl 3 and acetonitrile mixture to give 5.39 g of 2- (2-dimethylaminobenzylthio) benzimidazole in the form of colorless crystals, mp 164 ° C.

2) 2- (2-Dimethylaminobenzylsulfinyl) benzimidazole (= compound 3)

a) 4.8 g of 2- (2-dimethylaminobenzylthio) benzimidazole were dissolved in a mixture of 40 ml of CHCl3 and 5 ml of methanol. After cooling to 0 ° C, 3.86 g of m-chloroperbenzoic acid (70% purity) was gradually added thereto. 10 minutes after addition, a saturated NaHCO3 solution was added to the reaction mixture and it was extracted with chloroform. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4 and the solvent distilled under reduced pressure. The residue obtained was recrystallized from a mixture of CHCl3 and ether to give 2.97 g of 2- (2-dimethylaminobenzylsulfinyl) benzimidazole in the form of colorless crystals, mp 112 ° C (decomposition).

T / D-

IRv cm "1: 3170,1485, 1435, 1400,1260,1040 max

'H-NMR (CDC13) 5:

2.62 (s, 6H,> N (CH3) 2), 4.47 and 4.87 (each d, 2H, J = 14 Hz,

O

t

- SCH2—),

6.70-7.90 (m, 8H, aromatic protons), 12.16 (br., 1H,> NH)

b) 400 g of 2- (2-dimethylaminobenzylthio) benzimidazole were dissolved in a mixture of 1.06 l of CH2Cl2 and 1.061 of methanol. 212 ml of acetic acid were added to the solution and the mixture stirred until the solid had completely dissolved. After cooling the solution to 2 to 5 ° C, 182 ml of hydrogen peroxide, 123 ml of water and 8.83 g of ammonium metavanadate were added thereto and the mixture stirred at 2 to 5 ° C for 9 hours. The reaction was stopped by adding a 20% NaHCO3 solution and the organic phase washed with an aqueous solution of Na2SO2, then saturated brine and finally dried over anhydrous Na2SO4. After evaporation of the solvent under reduced pressure and recrystallization of the residue from acetonitrile, 317 g of 2- (2-dimethylaminobenzylsulfinyl) -benzimidazole were obtained in the form of colorless crystals.

c) 10 g of 2- (2-dimethylaminobenzylthio) benzimidazole were dissolved in 30 ml of 20% NaOH in water and 120 ml of ethyl acetate. After the solution had cooled in ice water, a mixture of 70 ml of 12% NaCIO was added dropwise and

30 ml of 20% NaOH, at a temperature of 3 to 5 ° C, over a period of 80 minutes, and the reaction mixture was stirred for 1 hour at this temperature. The reaction was stopped by adding a 10% Na2S203 solution, then the organic phase washed with saturated brine and finally dried over anhydrous Na2SO4. After evaporation of the solvent under reduced pressure and recrystallization of the residue from acetonitrile, 7.9 g of 2- (2-dimethylaminobenzylsulfinyl) benzimidazole were obtained in the form of colorless crystals.

Example 4

1) 2- (2-Dimethylaminobenzylthio) benzimidazole

2.70 g of 2-mercapo-5-methoxybenzimidazole were dissolved in 60 ml of ethanol, then added with 3.09 g of 2-dimethylaminobenzyl chloride hydrochloride and the resulting mixture was stirred for 30 minutes at room temperature . The precipitated crystals were collected by filtration, added with a saturated NaHCO3 solution and then extracted with chloroform. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4 and then the chloroform was distilled under reduced pressure. 3.85 g of 2- (2-dimethylaminobenzylthio) -5-methoxy-benzimidazole were thus collected in the form of a colorless oil.

2) 2.43 g of the compound obtained above were dissolved in a mixture of 25 ml of CHCl 3 and 2 ml of methanol, then cooled to

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0e C. 3.86 g of m-chloroperbenzoic acid (70% purity) was then added thereto, gradually, of a saturated solution of NaHCO 3 being added to the reaction mixture 10 minutes after addition. After extraction with CHCl 3, washing of the organic phase with saturated brine and removal of the solvent by distillation under reduced pressure, the residue obtained was purified by chromatography on silica gel (eluent: CHCl 3 / methanol 50: 1). After recrystallization from a mixture of ether and hexane, 1.50 g of 2- (2-dimethylaminobenzylsulfinyl) -5-methoxybenzimidazole was obtained in the form of pale yellow crystals, m.p. 105 ° C (decomposition).

IRv cm'1: 3270, 1625, 1485,1390,1205, 1175, 1030 max

'H-MNR (CDC13) 5:

2.63 (s, 6H, -N (CH3) 2), 3.81 (s, 3H, -OCH3), 4.48 and 4.85 (each d, 2H, J = 15 Hz, ^

t

-SCH2-),

6.60 - 7.80 (m, 7H, aromatic protons), 12.16 (br., 1H,> NH) Example 5

1) 2- (2-Diethylaminobenzylthio) benzimidazole

50.0 g of 2-mercaptobenzimidazole suspended in 500 ml of ethanol were added to 77.9 g of 2-diethylaminobenzyl chloride hydrochloride, and the reaction mixture stirred for 30 minutes at room temperature. The precipitated crystals were collected by filtration, added with a saturated NaHCO3 solution and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4 and the solvent removed by distillation under reduced pressure. After dissolving in ethanol, the residue was treated with activated carbon, the latter then being filtered and the solvent removed by distillation under reduced pressure. After recrystallization from a mixture of ethyl acetate and hexane, 88.7 g of 2- (2-diethylaminobenzylthio) benz-imidazole were obtained in the form of slightly brownish crystals, mp 134-135 ° C.

2) 2- (2-Dithylaminobenzylsulfinyl) benzimidazole

84.0 g of the compound obtained above were dissolved in a mixture of 600 ml of ch2c12 and 150 ml of methanol. After cooling to 0 ° C., 79.8 g of m-chloroperbenzoic acid (60% purity) were gradually added thereto, then, 10 minutes later, a saturated NaHCO3 solution was added and the reaction mixture was added. was extracted with CH2C12. The organic phase was dried over anhydrous Na2SO4, the solvent removed by distillation under reduced pressure and the residue obtained subjected to chromatography on silica gel (280 g; eluent: acetone / hexane 1: 2 by volume). The eluate was dissolved in a 1: 8 mixture (volumes) of ethanol and hexane and the precipitated crystals collected by filtration. After concentrating the filtrate under reduced pressure and recrystallization twice from isopropyl ether, 32.3 g of 2- (2-diethylaminobenzylsulfinyl) benz-imidazole were obtained in the form of colorless crystals, F. 110.5-112 ° C (decomposition).

\ C Rr

IRv cm "': 3200, 2980, 1490, 1400, 1270,1015, 765, 750 max

1H-NMR (CDC13) 5:

1.01 (t, 6H, J = 7 Hz, -CH2CH3 x 2), 3.00 (q, 4H, J = 7 Hz, -CH2CH3 x 2), 4.46 and 4.97 (each d, 2H , J = 13 Hz,

O t

-SCH2-),

6.80-7.90 (m, 8H, aromatic protons), 12.41 (br., 1H,> NH) Example 6

1) 2- (2-Dimethylaminobenzylthio) -4-methylbenzimidazole:

1.26 g of 2-dimethylaminobenzyl chloride hydrochloride a

was added to 1.0 g of 2-mercapto-4-methylbenzimidazole suspended in 10 ml of ethanol and the resulting mixture was stirred for 2 hours at room temperature. The precipitated crystals were collected by filtration, successively washed with ethanol and water and finally dissolved in CHCl3. The CHCl3 solution was neutralized with a saturated NaHCO3 solution, washed with saturated brine, dried over anhydrous Na2SO4 and the solvent finally removed by distillation under reduced pressure. After adding ether to the residue obtained, the precipitated crystals were collected by filtration to give 13.8 g of 2- (2-dimethylaminobenzylthio) -4-methylbenzimidazole in the form of white crystalline powder.

! H-NMR (CDC13) 5: 2.52 (s, 3H), 2.84 (s, 6H), 4.36 (2.2H), 6.8-7.6 (m, 7H)

2) 2- (2-Dimethylaminobenzylsulfinyl) -4-methylbenzimidazole (= compound 9)

1.1 g of the compound obtained above was dissolved in 15 ml of CHCl3 and then gradually added with 0.8 g of m-chloroperbenzoic acid (80% purity), under cooling to 0 ° C. After stirring at this temperature for 10 minutes, the resulting mixture was successively washed with a saturated NaHCO3 solution and then saturated brine and finally dried over anhydrous Na2SO4. The solvent was removed by distillation under reduced pressure and the residue obtained recrystallized from acetonitrile to give 0.81 g of 2- (2-di-methylaminobenzylsulfinyl) -4-methylbenzimidazole in the form of pale yellow crystals, F. 112- 114 ° C (decomposition).

IRvKBrcm- ': 3200, 1480, 1440,1420, 1290,1040, 750 max

XH-NMR (CDC13) 5:

2.2-2.8 (br., 3H), 2.60 (s, 6H), 4.52 and 4.84 (each d, J = 13 Hz, 2H), 6.7-7.6 ( m, 7H)

Example 7

1) 2- (2-Dimethylamino-6-methylbenzylthio) benzimidazole:

4.41 g of 2-dimethylamino-6-methylbenzyl chloride hydrochloride were dissolved in 40 ml of acetone and then added with 3.64 g of 2-mercaptobenzimidazole, 10 g of K2CO3 and 4 ml of water and the mixture resulting stirred for 1 hour at room temperature. After adding CHCl 3 and water to the reaction mixture, the organic phase was separated, washed with saturated brine and dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the crude residue was recrystallized from a mixture of ethanol and hexane and the crystals collected by filtration to give 4.68 g of 2- (2-dimethylamino-6-methylbenzylthio) benzimidazole under the shape of a slightly brownish powder.

■ H-NMR (CDC13): 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 10)

2.97 g of the compound obtained above were dissolved in a mixture of 30 ml of CHCl 3 and 3 ml of methanol, then cooled to 0 ° C. 2.18 g of m-chloroperbenzoic acid (purity 80%) y were added gradually and the resulting mixture stirred at this temperature for 10 minutes. After washing with a saturated NaHCO3 solution, saturated brine and then drying over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure. The residue obtained was recrystallized from a mixture of CHCl3 and ethanol to give 0.75 g of 2- (2-dimethyl-6-methylbenzylsulfinyl) -benzimidazole in the form of a white crystalline powder, m.p. 141-142 ° C ( decomposition).

T7D-

IRv cm "1: 3230, 1435, 1400, 1270,1040, 740 max

^ -NMR (CDCI3) 5:

2.31 (s, 3H), 2.61 (s, 6H), 4.68 and 4.92 (each d, J = 13 Hz, 2H), 6.8-7.8 (m, 7H)

5

10

15

20

25

30

35

40

45

50

55

60

65

9

665,417

Examples 8 to 19

In an identical manner to that described in Examples 6 and 7.12 compounds according to the present invention were prepared. The characteristics of the compounds obtained are given in Table 5.

Table 5

Example No.

ri r2

r3

r4

Intermediate (X = S)

Final compound (X = SO)

8

Compound 5

ch3

ch3

5-COOCH3

H

NMR (CDC13) 8 ppm: 2.88 (s, 6H) 3.88 (s, 3H) 4.36 (s, 2H) 6.9-8.1 (m, 7H)

m.p. 147-148 ° C (dec.) (Acetonitrile)

T £ T3r

IRv cm "': 3175,1725,1490,1425,1290,

maX 1080, 1040 NMR (CDC13) 8 ppm:

2.62 (s, 6H)

3.94 (s, 3H)

4.48 and 4.88 (each d,

J = 13 Hz, 2H)

6.8-8.0 (m, 7H)

9

Compound 6

ch3

ch3

5-CH3

H

NMR (CDCI3) 5 ppm: 2.38 (s, 3H) 2.80 (s, 6H) 4.34 (s, 2H) 6.7-7.5 (m, 7H)

m.p. 94-95 ° C (dec.) (Acetonitrile)

ktlr

IRv cm "': 3200, 1480,1440, 1065, 1040,

maX 935,750 NMR (CDC13) 8 ppm:

2.46 (s, 3H)

2.60 (s, 6H)

4.45 and 4.84 (each d,

J = 13Hz, 2H)

6.7-7.6 (m, 7H)

10

Compound 7

ch3

ch3

5-C1

H

NMR (CDC13) 5 ppm: 2.88 (s, 6H) 4.36 (s, 2H) 6.9-7.5 (m, 7H)

m.p. 130.5-131.5 ° C (dec.) (Ethanol-hexane) krr

IRv cm- ': 3200, 1490, 1400, 1045, 1040,

maX 760 NMR (CDC13) 8 ppm:

2.66 (s, 6H)

4.49 and 4.83 (each d, J = 13 Hz, 2H)

6.7-7.8 (m, 7H)

11

Compound 8

ch3

ch3

5-CF3

h

NMR (CDC13) 6 ppm: 2.92 (s, 6H) 4.38 (s, 2H) 7.0-7.7 (m, 7H)

m.p. 148 ° C (dec.) (Acetonitrile) NMR (CDC13) 8 ppm:

2.66 (s, 6H)

4.50 and 4.88 (each d, J = 13 Hz, 2H)

6.8-8.1 (m, 7H)

12

ch3

ch3

5-NH2

h

NMR (CDC13) 8 ppm: 2.86 (s, 6H) 4.34 (s, 2H) 6.4-7.5 (m, 7H)

m.p. 146-148 ° C (dec.) (Ethanol-ether)

IRv cm "': 3200, 1620,1490,1400, 1205,

MAX 1050,760 NMR (CD3OD) 5 ppm:

2.57 (s, 6H)

4.54 and 4.79 (each d, J = 13 Hz, 2H)

6.6-7.4 (m, 7H)

13

Compound 11

ch3

ch3

h

4-C1

NMR (CDC13) 8 ppm: 2.80 (s, 6H) 4.40 (s, 2H) 6.8-7.6 (m, 7H)

m.p. 139-140 ° C (dec.) (Acetonitrile)

T / tJ-

IRv cm- ': 1585,1425,1400,1260,1060,

maX 950,740 NMR (CDCI3) 8 ppm:

2.58 (s, 6H)

4.42 and 4.78 (each d, J = 13 Hz, 2H)

6.7-7.8 (m, 7H)

665,417

10

Table 5 (continued)

ȧX> -xc "2 ^ '

, miR2

Example No.

R.

R2

Ra r4

Intermediate (X = S)

Final compound (X = SO)

14

Compound 12

ch3

ch3

H

5-OCH3

NMR (CDC13) S ppm: 2.84 (s, 6H) 3.72 (s, 3H) 4.32 (s, 2H) 6.6-7.6 (m, 7H)

m.p. 115-116 ° C (dec.) (Ethyl acetate)

IRvKBrcm_I: 3200,1495,1400,1280,1245,

maX 1150.1020 NMR (CDC13) S ppm:

2.60 (s, 6H)

3.50 (s, 3H)

4.47 and 4.87 (each d,

J = 13 Hz, 2H)

6.6-7.8 (m, 7H)

15

Compound 13

ch3

ch3

H

5-Me

NMR (CDC13) 5 ppm: 2.24 (s, 3H) 2.32 (s, 6H) 4.30 (s, 2H) 6.8-7.5 (m, 7H)

m.p. 141.5-142.5 ° C (ethanol-hexane) KTVr

IRv cm "1: 3220, 1500, 1410,1270,1045,

maX 820,740 NMR (CDC13) 8 ppm:

2.09 (s, 3H)

2.62 (s, 6H)

4.45 and 4.84 (each d,

J = 13 Hz, 2H)

6.9-7.8 (m, 7H)

16

ch3

ch3

H

3-Me

NMR (CDC13) 5 ppm: 2.80 (s, 3H) 2.84 (s, 6H) 4.52 (s, 2H) 6.8-7.7 (m, 7H)

m.p. 155-156 ° C (dec.) (Acetone-hexane) tctvr

IRv cm "1: 3160, 1430,1400,1260, 1075,

maX 1035, 860, 830 NMR (CDC13) 8 ppm:

2.35 (s, 3H)

2.86 (s, 6H)

4.38 and 4.85 (each d,

J = 13 Hz, 2H)

6.8-8.0 (m, 7H)

17

ch3

ch3

H

4-F

NMR (CDC13) s ppm: 2.76 (s, 6H) 4.38 (s, 2H) 6.5-7.6 (m, 7H)

m.p. 118-119 ° C (dec.) (Methylenechloride-

acetonitrile)

krr

IRv cm "1: 3170,1605,1580,1490,1210,

m o v '7 3' 7

1035.980, 760 NMR (CDC13) 5 ppm:

2.60 (s, 6H)

4.44 and 4.88 (each d, J = 13 Hz, 2H)

6.4-7.7 (m, 7H)

18

ch3

ch3

5-OCH3

6-CH3

NMR (CDC13) 5 ppm: 2.44 (s, 3H) 2.88 (s, 6H) 3.80 (s, 3H) 4.40 (s, 2H) 6.6-7.4 (m, 6H )

m.p. 143-144 ° C (dec.) (Acetone-ether)

r / p-

IRv cm "1: 3220, 1440, 1190,1140,1035, max 790

NMR (CDC13) 5 ppm:

2.34 (s, 3H)

2.63 (s, 6H)

3.84 (s, 3H)

4.38 and 4.86 (each d,

J = 13 Hz, 2H)

6.8-7.7 (m, 6H)

11 665417

Table 5 (continued)

tmi R2

Example No.

ri r2

ra r4

Intermediate (X = S)

Final compound (X = SO)

19

CH3

ch3

5-C1

5-OCH3

NMR (CDC13) 8 ppm: 2.88 (s, 6H) 3.74 (s, 3H) 4.28 (s, 2H) 6.6-7.5 (m, 6H)

m.p. 161-162 ° C (dec.) (Acetone)

IRvKBrcm- ': 3210,1495,1395,1285,1250,

max 1040.1025, 810 NMR (CDC13) 8 ppm:

2.61 (s, 6H)

3.58 (s, 3H)

4.40 and 4.82 (each d,

J = 13 Hz, 2H)

6.6-7.8 (m, 6H)

Example 20

1) 2- (2-Piperidinobenzylthio) benzimidazole

To 1.42 g of 2-piperidinobenzyl hydrochloride in 35 ml of ethanol was added 0.87 g of 2-mercaptobenzimidazole and 0.5 g of NaOH and the resulting mixture stirred for 5 hours at room temperature. After distilling off the solvent under reduced pressure and adding water to the residue, the mixture was extracted with ethyl acetate. The organic phase was successively washed with a 10% NaOH solution, saturated brine, dried over anhydrous Na2SO4 and the solvent removed by distillation under reduced pressure. After washing the residue with ether, 1.0 g of 2- (2-piperidinobenzylthio) benzimidazole was obtained in the form of a yellow powder, mp 165 ° C.

NMR (CDCI3) 8: 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 (= compound 14)

0.70 g of the product obtained above was dissolved in a mixture of 50 ml of CHCl3 and 2 ml of methanol, then gradually added with 1.3 g of m-chloroperbenzoic acid (purity 80%), after cooling to 0 ° C, and the resulting mixture was then successively washed with saturated NaHCO3 solution, saturated brine and dried over Na2SO4. After removal of the solvent under reduced pressure and recrystallization of the residue from ether, 0.45 g of 2- (2-piperidinobenzylsulfinyl) benzimidazole was obtained in the form of a white powder. Mp 158 ° C (decomposition).

KBr

IRvmax cm "': 3160> 1435,1325,1215,1030, 920, 740

JH-NMR (DMSO-d6) 8: 1.3-1.8 (m, 6H), 2.6-2.8 (m, 4H), 4.41-4.74 (each d, J = 12 Hz, 2H), 6.8-7.8 (m, 8H)

Examples 21 to 26

Analogously to that described in Example 20, the following six compounds were prepared and their characteristics given in Table 6.

(See next page)

Example 27

Preparation of tablets

Each of the prepared tablets (220 mg) contains the following ingredients:

Active compound according to the invention 50 mg

Lactose 103 mg

30 Starch 50 mg

Magnesium stearate 2 mg

Hydroxypropylcellulose 15 mg

Example 28

Preparation of capsules

Each of the prepared gelatin capsules (350 mg) contains the following ingredients:

Active compound according to the invention 40 mg

40 Lactose 200 mg

Starch 70 mg

Polyvinylpyrrolidone 5 mg

Crystallized cellulose 35 mg

45 Example 29

Preparation of granules

Each of the prepared granules (1 g) contains the following ingredients:

50 Active compound according to the invention 200 mg

Lactose '450 mg

Corn starch 300 mg

Hydroxypropylcellulose 50 mg

55 Example 30

Preparation of coated coated shelves

Each of the coated tablets contains the ingredients shown in Example 27.

665,417

12

Table 6

<ì

Example No.

ri r2

r3

r *

Intermediate (X = S)

Final compound (X = SO)

21

Compound 15

H

H

H

NMR (CDCI3) 5 ppm: 0.8-2.1 (m, 10H) 3.0-3.4 (br, 1H) 4.48 (s, 2H) 6.4-7.6 (m, 8H )

m.p. 89-92 ° C (dec.) (Acetonitrile) KRr

IRv cm-1: 2940, 1605, 1510, 1430,1310,

maX 1270, 1050, 750 NMR (CDCI3) 5 ppm:

0.7-2.1 (m, 10H)

2.9-3.3 (m, 1H)

4.35 and 4.64 (each d, J = 14 Hz, 2H)

6.3-7.9 (m, 8H)

22

Compound 16

H

H

H

NMR (CDCI3) 8 ppm: 4.48 (s, 2H) 6.6-7.5 (m, 13H)

m.p. 89-92 ° C (dec.) (Chloroform-ether)

ir-pr

IRv cm "1: 3360, 1600,1495, 1410, 1305,

maX 1050,750 NMR (CDCI3) 5 ppm:

4.47 and 4.78 (each d, J = 14 Hz, 2H)

6.5-8.0 (m, 13H)

23

Compose 17

CH3

H

H

NMR (CDC13) S ppm: 3.18 (s, 3H) 4.40 (s, 2H) 6.4-7.6 (m, 13H)

m.p. 168-169 ° C (dec.)

(chloroform-acetonitrile)

KRr

IRv cm "': 3050,1590, 1485, 1400,1260,

maX 1055,740 NMR (CDCI3) 8 ppm:

3.18 (s, 3H)

4.32 and 4.62 (each d, J = 13 Hz, 2H)

6.3-7.8 (m, 13H)

24

Compound 18

-c "2- <5>

ch3

H

H

NMR (CDCI3) 8 ppm: 2.66 (s, 3H) 4.04 (s, 2H) 4.56 (s, 2H) 6.9-7.5 (m, 13H)

m.p. 137 ° C (dec.) (Acetonitrile)

IRvKBrcm- ': 3170,1440, 1400,1260,1025,

maX 940,740 NMR (CDC13) 8 ppm:

2.52 (s, 3H)

4.00 (s, 2H)

4.52 and 4.92 (each d,

J = 12 Hz, 2H)

6.7-7.9 (m, 13H)

25

- (CH2) sCH3

ch3

H

H

NMR (CDCI3) 8 ppm: 0.90 (d, J = 7 Hz, 6H)

1.8-2.2 (m, 1H)

2.68 (d, J = 8 Hz, 2H) 2.80 (s, 3H) 4.40 (s, 2H)

6.9-7.8 (m, 8H)

m.p. 121 ° C (dec.) (Chloroform-hexane) NMR (CDC13) 8 ppm:

0.92 (d, J = 7 Hz, 6H) 1.5-2.0 (m, 1H)

2.62 (d, J = 8 Hz, 2H) 2.64 (s, 3H)

4.52 and 4.90 (each d, J = 14 Hz, 2H)

6.8-7.9 (m, 8H)

26

Compound 19

- CH2CH (CH3) 2

ch3

H

H

NMR (CDC13) 8 ppm: 0.6-2.0 (m, 11 H)

2.7-3.1 (m, 2H) 2.80 (s, 3H) 4.42 (s, 2H)

6.8-7.7 (m, 8H)

m.p. 90-92.5 ° C (dec.) (Chloroform-hexane) NMR (CDCI3) 8 ppm:

0.7-1.7 (m, 11H)

2.64 (s, 3H)

2.7-3.0 (m, 2H)

4.48 and 4.89 (each d, J = 12 Hz, 2H)

6.7-8.0 (m, 8H)

Claims (2)

665,417 claims 1. Benzimidazole derivative represented by formula (I) R s-ch 2 k in which R, is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms, or a cycloalkyl, phenyl or aralkyl group, R2 is a hydrogen atom or an alkyl group containing from 1 to 8 atoms carbon, or even R! and R2 taken together form a ring with the adjacent nitrogen atom, and R3 and R4 each represents a hydrogen atom, a halogen or a trifluoromethyl, lower alkyl, lower alkoxy, lower al-coxycarbonyl or amino group. 2. Process for the preparation of a benzimidazole derivative represented by formula (I) R not ^ .- s-ch n * k in which R, is a hydrogen atom, or an alkyl group containing from 1 to 8 carbon atoms, or a cycloalkyl, phenyl or aralkyl group, R2 is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms, or Rj and R2 taken together form a ring with the adjacent nitrogen atom, and R3 and R4 each represent a hydrogen atom, a halogen or a trifluoromethyl, lower alkyl, lower alkoxy, al- lower coxycarbonyl or amino, characterized in that a 2-mercaptobenzimidazole represented by the formula (II) is reacted r s h a wherein R3 is defined as above, with a 2-ami-nobenzyl compound represented by the formula (III) (III) in which R ,, R2 and R4 are defined as above and X is a reactive group, to form a compound represented by the form (IV) R 3 in which Rj, R2, R3 and R4 are defined above, and in that the compound of formula (IV) is then oxidized. 3. Antiulcer agent comprising, as a therapeutically active component, a benzimidazole derivative represented by formula (I) r k "2 in which R 1 is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms, or a cycloalkyl, phenyl or aralkyl group, R 2 is a hydrogen atom or an alkyl group containing from 1 to 8 carbon atoms , or alternatively Rx and R2 taken together form a ring with the adjacent nitrogen atom, and R3 and R4 each represent a hydrogen atom, a halogen or a trifluoromethyl, lower alkyl, lower alkoxy, lower al-coxycarbonyl or amino.