NL8301310A - BENZIMIDAZOLE DERIVATIVES, METHODS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS, CONTAINING THESE COMPOUNDS. - Google Patents

Description

* '* N.o. 31759

Benzimidazole derivatives, processes for their preparation and pharmaceutical compositions containing these compounds

The invention relates to novel therapeutically useful benzimidazole derivatives, to methods for. their preparation, to pharmaceutical compositions containing these compounds and to their use as medicaments.

The new benzimidazole derivatives are the compounds of the general formula 1, wherein R is a hydrogen atom, an mtro group or a hydrocarbon unit, such as a straight or branched chain alkyl group of 1-6 carbon atoms, for example a 3 methyl group, or a group -OR, wherein R represents a hydrocarbon unit such as an alkyl group of 1 to 20 carbon atoms with a straight or branched chain chain, for example an alkyl group of 1 to 6 or of 7 to 20 carbon atoms, in particular of 7 to 10 carbon atoms, or such as an unsubstituted or substituted 2 aryl group, for example a phenyl group, and R represents an alkyl group with 1 to 8, preferably 3 to 6, carbon atoms 2 or R in particular a halogen atom (for example a chlorine, fluorine or iodine atom or, in particular, a bromine atom).

When R 1 represents a substituted phenyl group, suitable substituents of this phenyl group include halogen atoms and alkyl, alkoxy, trifluoromethyl and nitro groups.

The compounds have valuable pharmacological properties, in particular properties, which have excellent utility in the treatment of arthritic conditions, such as joint rheumatism. In particular, compounds of the formula 1 have been shown to counteract the deterioration of joints in rabbit legs in laboratory tests. These results are particularly important when contrasted with the results of compounds commonly used in the treatment of arthritic conditions, which are primarily anti-inflammatory agents and do not have the said ability to combat joint deterioration. Furthermore, the compounds of the formula 1 are surprisingly considerably better in their pharmacological properties compared to closely related compounds.

Some of the compounds of formula 1 also have analgesic activity and this is advantageous when the 8301310 2 compounds are administered to arthritic patients.

Another useful property, which some of the compounds possess, is the ability to reduce proliferation of smooth muscle cells, indicating usefulness against atheroma.

The advantageous properties of the compounds of the formula I become more important due to the fact that they have only a very low toxicity to mammals.

Preferred classes of compounds of formula I are 10 such compounds, wherein R

a hydrogen atom, a nitro group, an alkoxy group, for example a methoxy, ethoxy, propoxy, isobutoxy or octyloxy group, or an alkyl group, eg a methyl or tert-butyl group, 2 and the like compounds, in which R is a halogen atom, a bromine atom, a chlorine atom or a fluorine atom, 2 in particular such compounds, wherein R represents a substituent at the para position.

Particularly important compounds of formula I include the following compounds:

2-p-bromobenzoylbenzimidazole A

2-p-bromobenzoyl-5-methoxybenzimidazole B

2-p-bromobenzoyl-5-nitrobenzimidazole C

2-p-tert-butylbenzoylbenzimidazole D

2-p-chlorobenzoyl benzimidazole E

2-p-fluorobenzoyl benzimidazole F.

2-p-methylbenzoylbenzimidazole G

2-p-propylbenzoylbenzimidazole H

2-m-bromobenzoylbenzimidazole I.

2-m-methylbenzoylbenzimidazole J

2-o-bromobenzoylbenzimidazole K

2-o-methylbenzoylbenzimidazole L.

2-p-bromobenzoyl-5-ethoxybenzimidazole M

2-p-bromobenzoyl-5-propoxybenzimidazole N

40 2-p-bromobenzoyl-5-isobutoxybenzimidazole 0 8301310 «3

2-p-bromobenzoyl-5-octyloxybenzimidazole P

2-p-bro ombenz oy1-5-methylethyl enzimidazole Q

2-p-bromo enzoyl-5-t ert.butylb enzimi dazole R

and

2-p-bromobenzoyl-5-phenoxybenzimidazole S

The compounds 3, C, Q and in particular A have a special meaning.

The letters A to S denote the compounds in the present description.

In experiments, the compounds of formula 1, when administered orally to mice twice, each time giving the dose indicated in Table A, decreased by 50% inhibiting the displacement of incubated mouse macrophage cells. This is a measure of the antagonism or reduction of lymphokinesis levels and is indicative of the utility and treatment of arthritic patients.

In 3 tests, the compounds were compared with compound A, which gives an indication of the relative activity.

Table A

Test Oral dose (mg / kg body weight of the binding animal)

Test 1 Test 2 Test 3 A less than 3 5 10 B k C less than 2 E about 10 F about 10 K about 10 M about 10 Q less than 2

In acute oral toxicity tests, 20 mice received an oral dose of the test compound and were observed for 3 days. The mice did not die when compound A or compound B was administered at doses up to 8301310 1000 mg / kg body weight of the animal, giving TF LD50 values much greater than 1000 mg / kg.

The compounds of the formula I can be prepared using or adapting known methods.

For example, compounds of the formula I of the invention are prepared by oxidation of compounds of the general formula-12 (wherein R and R are as defined above) or a salt thereof, preferably an acid addition salt, for example a hydrohalide, for example the hydrochloride.

The oxidation can be carried out by treatment with a solution prepared from chromium trioxide, sulfuric acid and water, preferably in the presence of acetone and at room temperature or at a lower temperature. The oxidation is preferably carried out by treatment with a mixture of an alkali metal dichromate, eg sodium dichromate, and an acid, eg glacial acetic acid, preferably at an elevated temperature, eg 80-120 ° C.

Compounds of the formula II can be obtained by the application or adaptation of known methods, for example, by Sinnur et al., Monatsh. Chem. (1966), 97, p. ^ 17.

Thus, the compounds of formula 2 can be prepared by converting compounds of general formula 3 (wherein R has the above defined meaning) and compounds of the general formula if (wherein R has the above defined meaning) into acidic water. environment, for example dilute hydrochloric acid, for example 2N to 6 N.

Furthermore, the compounds of the formula I according to the invention can be obtained by reacting compounds of the general formula 3 (wherein R has the above-defined meaning) with compounds of the general formula 6 (wherein 2 R has the above-defined meaning and X represents a halogen atom, for example a chlorine atom) in the presence of a base such as a mixture of pyridine and triethylamine, preferably under anhydrous conditions under an inert atmosphere and at room temperature or at a lower temperature, preferably at a temperature between 0 ° C and 15 ° C, followed by heating with an aqueous alkali solution, for example sodium hydroxide solution.

ifO Compounds of formulas 3, if, 5 and 6 can be obtained by applying or adapting known methods.

By the term "known methods" used in this description is meant methods which have hitherto been employed or have been described in the literature.

Examples I - IV below illustrate the preparation of the compounds of formula I and Example V illustrates the preparation of intermediates.

Example I Compounds At B and C

A stirred solution of (i) -2- (p-bromo-α-hydroxybenzyl) -benzimidazole (52.5 g, prepared according to the method described by Sinnur et al., Above liter control site) in acetone (250 ml), which is was kept at a temperature between 10 and 15 ° C by means of an ice bath, was treated dropwise with a solution prepared from chromium trioxide, sulfuric acid and water [by adding concentrated sulfuric acid (94 ml), dropwise and with external cooling by means of a ice bath, to a stirred solution of chromium trioxide (106 g) in water (200 ml), then dilute to a volume of 400 ml by adding a further amount of water]. This mixture was stirred at a temperature between 10 and 15 ° C for a further period of 30 minutes after the addition and then for 3 hours at ambient temperature. It was then added to water (700 ml). The separated solid material was filtered off, washed with water, dried and recrystallized from acetone to give 2-p-bromobenzoylbenzimidazole (24 g) in the form of cream-colored crystals, mp 224-226 ° C [Elemental analysis: found: C 56.0; H 3.0; N 9.4 #? calculated: C 55.8; H 3.0; N 9.3% · IR spectrum: 1655, 30 1583 »838, 740 cm, NMS in deuterodimethyl sulfoxide: broad singlet at 13.5 ppm (exchangeable with D2O), doublet at 8.55 ppm (J = 8 revolutions / second ), doublet at 7.85 ppm (J = 8 revolutions / second) and multiplet at 7.2-8.0 ppm; mass spectrum: m / e 300/302, 272/274, 221, 193, 183/185, 155/157, 35 110.5, 96.5; UV spectrum: 327 nm (19300), 277 nm (12500)].

According to the same procedure, but replacing the (+) - 2- (p-bromo-a-hydroxy-benzyl) -benzimidazole used as starting material with the appropriate amounts of (+) - 2- (p-bromo-a- hydroxybenzyl) -5-methoxybenzimidazole and 40 (+) - 2- (p-bromo-a-hydroxybenzyl) -5 ** nitrobenzimidazole, respectively (both prepared by Sinnur et al., cited above) were prepared: 2-p-bromobenzoyl-5-methoxyberizimidazole, mp 204-205 ° C (with decomposition) (Elemental analysis: 5 found: C 54.0; H 3.2; N 8.3%. calculated: C 54.4, H 3.35, N 8.3%, IR spectrum: 3290, 1623, 1580, 1260, 835, 760 cm -1); and 2-p-bromobenzoyl-5-nitrobenzimidazole, mp 296-297 ° C (with decomposition) (Elemental analysis: TO found: C 48.5, H 2.2, N 12.1 calculated: C 48.6; H 2.3; N 12.1 IR spectrum: 3280, 1630, 1618, 1580, 1325, 833, 770, 730 cm -1).

Example II Compounds A and D

15 p-Bromobenzoyl chloride (9 * 6 g) was added in portions to a stirred suspension of benzimidazole (2.6 g) in anhydrous pyridine (35 ml), containing anhydrous triethylamine (6.12 ml), in an atmosphere of nitrogen, keeping this suspension at 5-10 ° C by means of an ice bath. This temperature was maintained for 30 minutes after the addition and then the mixture was stirred at ambient temperature for 3 hours. The mixture was then treated with a solution of sodium hydroxide in water (4.4 ml; 7 * 5 N) and then heated (2X) and heated under reflux for 1 hour. It was then cooled and poured onto a mixture of ice and water (50 ml). The brownish-yellow precipitate formed was filtered off, washed with water, dried and recrystallized from ethyl acetate to give 2-p-bromobenzoylbenzimida sole (0.3 g) in the form of cream needles, mp 223-225 ° C .

(Elemental analysis: found: C 55 * 8; H 2.9; N 9 * 5 calculated: C 55.8; H 3.0; N 9.3%)

By acting in a similar manner, but replacing the p-bromobenzoyl chloride used as starting material with p-tert-butylbenzoyl chloride, 2-p-tert-butylbenzoyl-benzimidazole was prepared, mp 298-299 ° C (with decomposition) (Elemental analysis: found: C 77.6; H 6.6; N 10.2 40 calculated: C 77.7; H 6.5; N 10.1 #; 8301310% 7

I.R. spectrum: 2970, 1640, 1600, 1265, 1170, 855, 740 cm -1) Example III Compounds A and D

A solution of sodium dichromate-5 dihydrate (105 g) in glacial acetic acid (610 ml) kept at 95-100 ° C was added in one portion to a stirred solution of (+ -2- (p-) held at 95-100 ° C. bromo-α-hydroxybenzyl) benzimidazole (132 g) in glacial acetic acid (610 ml) The mixture was stirred and heated on a steam bath for 10 minutes then poured into ice and water (3000 ml) The precipitate formed was filtered, successively washed with water, with aqueous sodium carbonate solution (2N), and with water, then recrystallized from a mixture of water and dimethylformamide to give 2-p-bromobenzoylbenzimidazole (88 g) in the form of cream crystals, melting point 15 224-226 ° C. (Elemental analysis: found: C 56.1? H 2.9; N 9.2 #; calculated: C 55.8; H 3.0; N 9.3%)

By acting in a similar manner, but replacing the (+) .- 2- (p-bromo-a-hydroxybenzyl) benzimidazole 20 as the starting material with the appropriate amount of (+) - 2- (p-tert-butyl- a -hydroxybenzyl) benzimidazole, 2-p-tert-butylbenzoylbenzimidazole was prepared, mp 298-299 ° C (with decomposition) (recrystallized from a mixture of dimethylformamide and water) (elemental analysis: found: C 78.1 H 6.4, N 10.1 #, calculated: C 77.7, H 6.5, N 10.1 #).

Example IV

Compounds B, and E to 5

By working in a similar manner as described in Example 3 above, but replacing the (+) - 2- (p-bromo-α-hydroxybenzyl) benzimidazole used as starting material with the appropriate amounts of : (-) - 2- (p-bromo-a-hydroxybenzyl) -5-methoxybenzimidazole, (+) - 2- (p-chloro-a-hydroxybenzyl) benzimidazole, (+) - 2- (p-fluoro-a -hydroxybenzyl) benzimidazole, 35 (-) - 2- (p-methyl-oc-hydroxybenzyl) benzimidazcol, (+) - 2- (p-pr opyΙ-α-hydr oxyb enzyl) b and zimidaz o1, (+) -2- (m-bromo-a-hydroxyb enzyl) b enzimi dazole, (+) - 2- (m-methyl-α-hydr oxyb enzyl) b enzimi dazole, (+) - 2- (o-bromo-a -hydroxybenzyl) benzimidazole, 40 (+) - 2- (p'-methyl-a-hydroxybenzyl) benzimidazole, 8301310 '"8 * (+) - 2- (p-bromo-a-hydroxybenzyl) -5-ethoxyb enzimi dazo ol, (+) -2- (p-bromo-a-hydroxybenzyl) -5-propoxybenzimidazc> ol, (+) -2- (p-brom-α-hydr oxyb enzyl) -5-isobut oxyb enzimi dazo ol , (+) - 2- (p-bromo-a-hydroxyb enzyl) -5-oc tyloxyb enzimidazol, 5 (+) -2- (p-bromo-a-hydroxyb enzyl) -5-methyl benz imidazole, (+) -2- (p-bro om-a-hydroxyb enzyl) -5-tert-butylb enzimidazole and '(+) - 2- (p-bromo-a-hydroxybenzyl) -5-phenoxybenzimidazole, optionally in the form of their hydrochlorides, 2-p-bromobenzoyl-5-methoxybenzimidazole were prepared. melting point 205-207 ° C 10 (elemental analysis: found: C 54.3; H 3.3 »N 8.4 calculated: C 34.4; H 3.35» N 8.5 IR spectrum: 3290, -1623, 1500, 1260, 835, 760 cm-1); 2-p-chlorobenzoylbenzimidazole, mp 223-224 ° C (elemental analysis: found: C 65.5; H 3.4; N 10.9%; 15 calculated: C 65.5, H 3.5, N 10.9%, IR spectrum: 1655, 1585, 840, 740 cm -1); 2-p-fluorobenzoyl benzimidazole, mp 215-216 ° C (elemental analysis: found: C 70.0; H 3.7; N 11.7%; calculated: C 70.0; H 3.8; N 11, 7%; 20 IR spectrum: 1658, 1595, 845, 740 cm 1); 2-p-methylbenzoylbenzimidazole, mp 252-253 C (elemental analysis: found: C 76.5; H 4.95; N 11.7%; calculated: C 76.25; H 5.1; N 11.9 %; IR spectrum: 1650, 1605, 840, 750 cm);

2-p-propylbenzoylbenzimidazole, mp 176-178 ° C

(elemental analysis: found: C 77.4; H 6.1; N 10.6 #; calculated: C 77.2; H 6.1; N 10.6%; IR spectrum: 1640, 1600, 850, 740 cm); 2-m-bromobenzoylbenzimidazole, melting point 194-195 ° C 30 (elemental analysis: found: C 56.0; H 2.95; N 9.3 calculated: C 55.8; H 3.0; N 9.3 % IR spectrum: 1665, 930, 740, 730 cm); 2-m-methylbenzoylbenzimidazole, melting point 16 / f-165 ° C (elemental analysis: found: C 76.3; H 5.0; N 11.8 35 calculated: C 76.25; H 5.1; N 11 1.9%; IR spectrum: 1625, 1575, 845, 740 cm); 2-o-bromobenzoylbenzimidazole, mp 222-224 ° C; (elemental analysis: found: C 5 ^ .0; H 2.9; N 9.2% calculated: C 55.8; H 3.0; N 9.3%; 40 IR spectrum: 1680, 1590, 758, 740 cm); 8301310 9 '' 2-o-methylbenzoylbenzimidazole, melting point 229-231 ° C (with decomposition) (elemental analysis: found: C 76 * 5; H 5 * 0; N 11.9 Jé; calculated: C 76.25 » »5.1 N N 11.9-4 IR spectrum: 1660, 770, 745 cm); 5 2-p-bromobenzoyl-5-ethoxybenzimidazole, melting point 188-189 ° C (elemental analysis: found: C 55 »7» Η 3.7; N 8.1%, calculated: C 55 * 7 »H 3 , 8; N 8.1 Jé; IR spectrum: 3220, 1620 * 1585, 1270, 805, 765 cm -1); 2-p-bromobenzoyl-5-propoxybenzimidazole, mp 178-179 ° C (elemental analysis : found: C 57, H »H 4.2; N 7.8 #; calculated: C 56.8; H 4.2; N 7.8%; IR spectrum: 3320, 1620, 1585, 1265, 810 , 765 cm -1); 2-p-bromobenzoyl-5-isobutoxybenzimidazole, mp 194-196 ° C (elemental analysis: found: C 58.1; H 4.6; N 7.5 5é; Ί5 calculated: C 57.9; H 4, 6; N 7.5 IR spectrum: 3320, 1620, 1585, 1270, 810, 765 cm-1); 2-p-bromobenzoyl-5-octyloxybenzimidazole, melting point 132-133 ° C (elemental analysis: found: C 61.5; H 5.8; N 6.5 #; calculated: C 61.5; Η 5.9i N 6.5 20 IR spectrum: 3310, 1630, 1585 * 1275, 800, 770 cm -1); 2-p-bromobenzoyl-5-methylbenzimidazole, mp 204-205 ° C (with decomposition) (Elemenatir analysis: found: c 57.1; H 3.3; N 8.6 calculated: C 57.2; H 3.5 »N 8.9% .25 IR spectrum: 1630, 1585» 840, 76 cm-1 2-p-bromobenzoyl-5-tert-butylbenzimidazole, melting point 193-194 ° C (elemental analysis: found: C 60.9; H 4.8; N 7.8 $; calculated: C 60.5] H 4.8, N 7.8

I.R. spectrum: 3310, 1630, 1585, 870, 845 cm); 30-p-bromobenzoyl-5-phenoxybenzimidazole, mp 189-190 ° C, respectively

(elemental analysis: found: C 61.0; H 3.3; N 7.0 # »calculated: C 61.1; H 3.3; N 7.1 _ IR spectrum: 3310, 1620, 1585, 1260, 820, 770 cm).

Example V

The following alcohols of Formula 2 were prepared by reacting the suitably substituted or unsubstituted hydroxyphenylacetic acid of Formula 3 and the suitably substituted or unsubstituted o-phenylenediamine of Formula 4 in water-dilute hydrochloric acid: 8301310 1 ° (+ -2- (p-tert-butyl-α-hydroxybenzyl) benzimidazole hydrochloride, mp 234-236 ° C; (+) - 2- (p-propyl-α-hydroxybenzyl) benzimidazole, mp 100-102 ° C; 5 (+) - 2- (m-bromo-α-hydroxybenzyl) benzimidazole hydrochloride, mp 2 ^ 7-225 ° C (with decomposition); (+) - 2- (m-methyl-α-hydroxybenzyl) benzimidazole hydroshloride, mp 223-225 ° C (with decomposition); (+) - 2- (o-methyl-α-hydroxybenzyl) benzimidazole hydrochloride, mp 204-205 ° C (with decomposition); (+) - 2- (p-bromo-α-hydroxybenzyl) -5-ethoxybenzimidazole hydrochloride, mp 218-219 ° C (with decomposition); (+) _ 2- (p-bromo-α-hydroxybenzyl) -5-propoxybenzimidazole hydrochloride, mp 216-218 ° C (with decomposition); 15 (+) - 2- (p-bromo-α-hydroxybenzyl) -5-isobutoxybenzimidazole hydrochloride, mp 227-229 ° C (with decomposition); (+) - 2- (p-bromo-α-hydroxybenzyl) -5-octyloxybenzimidazole hydrochloride, mp 213-217 ° C (with decomposition); (+) - 2- (p-bromo-α-hydroxybenzyl) -5-methylbenzimidazole hydrochloride, mp 223-227 ° C (with decomposition); (+) - 2- (p-bromo-α-hydroxybenzyl) -5-tert-butylbenzimidazole hydrochloride, mp 232-233 ° C; (+) - 2- (p-bromo-α-hydroxyb enzyl) -5-phenoxyb enzimidazole hydrochloride, m.p. 221-223 ° C (with decomposition), respectively.

The field of the present invention includes pharmaceutical compositions comprising at least one compound of formula 1 with a pharmaceutically acceptable carrier or coating. In clinical practice, the compositions of the invention will normally be administered orally or rectally, or parenterally, for example, topically or intra-articularly.

Compositions for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid compositions, the active compound or compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose. The compositions may also contain, as usual, various additional substances of inert diluents, for example lubricants such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and elixirs, 8301310 11 containing the inert diluents customary in the art, such as water and liquid paraffin. In addition to inert diluents, such compositions may also contain additives, such as wetting and suspending agents, and sweeteners, flavors, fragrances and preservatives. The compositions of the invention suitable for oral administration also include capsules of absorbable material, such as gelatin, which contain the active compounds, whether or not in combination with diluents or excipients.

Solid compositions for rectal administration include suppositories formulated in a manner known per se, containing the active compound or compounds.

Compositions of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending agents are propylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain additives such as preservatives, wetting, emulsifying and dispersing agents. For example, they can be sterilized by filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved in a sterile injectable immediately before use. Like the more common intravenous and intramuscular routes of administration, the compositions can be administered by intra-articular injection.

Compositions in the form of solutions or suspensions, optionally together with additives as described above, in vegetable or other fats, paraffin or other waxes or lacquers or creams to be applied topically, for example, on the skin in the area of an affected joint for the relief of joint inflammation are also included in the present invention.

The percentage of active ingredients in the compositions of the invention may be varied, it being necessary that they must be such a part of the compositions that an appropriate dosage for the desired 2 * 0 anti-arthritic effect is obtained. Of course, various unit dosage forms can be administered at about the same time. In general, the compositions should contain from 0.1 to 80% by weight of active ingredient, especially when in tablet form.

The dose used depends on the desired anti-arthritic effect, the mode of administration and the duration of the treatment. In adults, the doses are generally between 0.01 and 100 mg (preferably between 0.1 and 10 mg, especially between 1 and 10 mg) of the compound of the formula 1 per 10 kg of body weight per day.

The compounds of the formula 1 can be administered daily or, in accordance with the instructions of the attending physician, less often, for example weekly.

According to the present invention, there is provided a method of treating arthritic conditions in humans, which administer an amount of a compound or compounds of the formula 1 sufficient to control an arthritic condition. includes a patient.

In the following example, a pharmaceutical composition according to the present invention is illustrated.

Example VI

Capsules for oral administration were prepared in the usual manner by each filling gelatin capsules (size no. 2) with 155 mg of the following composition: 2-p-bromobenzoylbenzimidazole 50 mg potato starch 100 mg magnesium stearate 2.5 mg

Aerosil 2.5 mg 30 Similar compositions can be prepared using any of the other compounds of formula 1 in place of compound A, for example compounds B - S indicated above.

8301310

Claims (6)

Benzimidazole derivative, characterized in that it corresponds to the general formula 1, in which a hydrogen atom, a nitro group, a hydrocarbon radical or a radical -OR ^ 5, wherein R ^ represents a hydrocarbon radical, and R. an alkyl radical with a straight or branched chain with 1-8 carbon atoms or a halogen atom. 2- (4-Bromobenzoyl) -b enzimidazole, 2- (4-bromobenzoyl) -5-methoxybenzimidazole, 2- (4-bromobenzoyl) -5-nitrobenzimidazole, 2- (4-tert-butylb enzoyl) - benzimidazole, 2- (4-chlorobenzoyl) -benzimidazole, 2- (4-fluorobenzoyl) -benzimidazole, 2- (4-methylbenzoyl) -b enzimi dazole, 2- (4-propylb enzoyl) -benzimi dazole, 2- ( 3-br o omb etc oyl) -b enzi mi daz oo 1, 2- (J-methylbenzoyl) -benzimidazole, 2- (2-bromobenzoyl) -benzimidazole, 2- (2-methylbenzoyl) -benzimidazole, 20 2- ( 4-bromobenzoyl) -5-ethoxyb enzimidazole, 2- (4-bromobenzoyl) -5-propoxyb enzimidazole, 2- (if-br oomb etc oyl) -5-isobutoxyb enzimidazole, 2- (4 "bromobenzoyl) -5- octyloxybenzimidazole, 2- (4-bromobenzoyl) -5-methylbenzimidazole, 2- (4-bromobenzoyl) -5-tert-butylb enzimi dazole, 2- (4-bromobenzoyl) -5-phenoxybenzimidazole. 3. A process for the preparation of a benzimidazole derivative according to claim 1, characterized in that a compound of the general formula 2 in which R 1 and R 2 have the meaning defined in claim 1 or is oxidized is one of its salts, wherein the hydroxymethylene group of this compound is converted into a carbonyl group, and then isolates the product obtained. 4- Process for the preparation of a benzimidazole derivative according to claim 1, characterized in that a compound of the general formula 5 wherein R 1 has the meaning defined in claim 1 is reacted with a compound of the general formula 6, wherein R2 has the meaning defined in claim 1 and X represents a halogen atom, and then isolates the product obtained. 8301310 ^ V v 5 * Process according to claim if, characterized in that in the compound of the general formula 6 X represents a chlorine atom. Pharmaceutical composition, characterized in that it contains as active ingredient at least one benzimidazole derivative according to claim 1 or 2 or obtained according to the method of claims 3-5 with a pharmaceutically acceptable carrier or coating. ****** 8301310 xx-h-a, ^ * L OH: 4.2 E1 1., Xr> i_ciHGL 8301310