GB2119790A

GB2119790A - Benzimidazole derivatives

Info

Publication number: GB2119790A
Application number: GB08310146A
Authority: GB
Inventors: Barbara Joyce Broughton; Martin Arthur Heazell; Libert Clinton Saunders; Peter James Warne
Original assignee: May and Baker Ltd
Current assignee: May and Baker Ltd
Priority date: 1982-04-15
Filing date: 1983-04-14
Publication date: 1983-11-23
Also published as: ES523937A0; GB8310146D0; IT8320578A0; GR78209B; NL8301310A; DK164283A; KR840004407A; DE3313599A1; SE8302084L; AU1350883A; LU84747A1; FR2525218A1; ZA832638B; FI831258L; FI831258A0; ES521460A0; DK164283D0; BE896465A; IL68405A0; JPS58188865A

Abstract

Benzimidazole derivatives of the formula: <IMAGE> (wherein R<1> represents a hydrogen atom, a nitro group, a hydrocarbon moiety, or a group OR<3> wherein R<3> represents an unsubstituted or substituted hydrocarbon moiety, and R<2> represents a straight- or branched-chain alkyl group containing from 1 to 8 carbon atoms or a halogen atom) are useful in the treatment of arthritis.

Description

SPECIFICATION New benzimidazole derivatives This invention relates to new therapeutically useful benzimidazole derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.

The new benzimidazole derivatives are the compounds of the general formula shown in Figure I of the drawings assembled at the end of the present specification, wherein R' represents a hydrogen atom, a nitro group, or a hydrocarbon moiety such as a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, e.g. methyl, or a groupOR3 wherein R3 represents a hydrocarbon moiety such as straight- or branched-chain alkyl group containing from 1 to 20 carbon atoms, for example from 1 to 6 or from 7 to 20 carbon atoms, more especially from 7 to 10 carbon atoms, or such as a substituted or unsubstituted aryl, e.g. phenyl, group and R2 represents a straight- or branched-chain alkyl group containing from 1 to 8, preferably from 3 to 6 carbon atoms, or more especially R2 represents a halogen (e.g. chlorine, fluorine, iodine or, more particularly bromine) atom.

When R3 represents a substituted phenyl group, suitable substituents on the said phenyl group include halogen atoms and alkyl, alkoxy, trifluoromethyl and nitro groups.

The compounds have valuable pharmacological properties, in particular properties which are indicative of outstanding utility in the treatment of arthritic disorders such as rheumatoid arthritis. In particular, in laboratory tests, compounds of the formula shown in Figure I have been shown to inhibit the deterioration of joints in rabbits' limbs. These results are particularly important when contrasted with compounds currently employed in the treatment of arthritic disorders, which are primarily antiinflammatories and do not possess the said ability to inhibit joint deterioration. Furthermore, compounds of the formula shown in Figure I surprisingly are markedly superior in their pharmacological properties when compared with closely related compounds.

Some of the compounds of the formula shown in Figure I also possess analgesic activity, and this is of benefit when the compounds are administered to arthritic patients.

Another useful property possessed by some of the compounds is ability to reduce proliferation of smooth muscle cells, which is indicative of utility against atheroma.

The beneficial properties of the compounds of the formula shown in Figure I are enhanced by the fact that they have only very low mammalian toxicity.

Preferred classes of compounds of the formula shown in Figure I include those wherein R1 represents:- - a hydrogen atom; - a nitro group; - an alkoxy, eg methoxy, ethoxy, propoxy, isobutoxy or octyloxy, group; or - an alkyl, e.g. methyl or tert-butyl, group; and those wherein R2 represents: - a halogen atom; - a bromine atom; - a chlorine atom; or - a fluorine atom; especially those wherein R2 represents a substituent in the para-position.

Compounds of the formula shown in Figure I which are particularly important include the following: 2-p-bromobenzoylbenzimidazole; A 2-p-bromobenzoyl-5-methoxybenzimidazole; B 2-p-bromobenzoyl-5-nitrobenzimidazole; C 2-p-tert-butylbenzoylbenzimidazole; D 2-p-chlorobenzoylbenzimidazole; E 2-p-fluorobenzoylbenzimidazole; F 2-p-methyibenzoylbenzimidazole; G 2-p-propylbenzoylbenzimidazole; H 2-m-bromobenzoylbenzimidazole; 2-m-methylbenzoylbenzimidazole; J 2-o-bromobenzoylbenzimidazole; K 2-o-methylbenzoylbenzimidazole; L 2-p-bromobenzoyl-5-ethoxybenzimidazole; M 2-p-bromobenzoyl-5-propoxybenzimidazole; N 2-p-bromobenzoyl-5-isobutoxybenzimidazole; 0 2-p-bromobenzoyl-5-octyloxybenzimidazole; P 2-p-bromobenzoyl-5-methylbenzimidazole;Q 2-p-bromobenzoyl-5-tert-butylbenzimidazole; and R 2-p-bromobenzoyl-5-phenoxybenzimidazole. S Compounds B, C, Q and, more especially A, are of outstanding importance.

The letters A to S are assigned to the compounds for easy reference later in the specification.

In tests, compunds of the formula shown in Figure I when twice administered orally to mice, each time at the dose shown in the following Table I, reduced by 50% the inhibition of migration of incubated mouse macrophage cells. This is a measure of antagonism or reduction of the levels of lymphokines and is indicative of utility in the treatment of arthritic patients. In 3 tests the compounds were compared with compound A to give an indication of relative activity.

TABLE 1

Oral dose (mg/kg animal body weight) Test Compound Test 1 Test 2 Test 3 A less than 3 5 10 B 4 C less than 2 E about 10 F about 10 K about 10 M about 10 0 , less than 2 In acute oral toxicity tests mice were dosed orally with test compound and observed for 3 days. No deaths occurred when compound A or compound B was administered at doses up to 1000 mg/kg animal body weight inclusive, giving LD50 figures much greater than 1000 mg/kg.

The compounds of the formula shown in Figure I may be prepared by the application or adaptation of known methods.

Thus, as a feature of the present invention, compounds of the formula shown in Figure I are prepared by the oxidation of compounds of the general formula shown in Figure II (wherein R' and R2 are as hereinbefore defined) or a salt, preferably an acid addition salt, thereof, for example a hydrohalide, e.g. the hydrochloride. Oxidation may be carried out by treatment with a solution prepared from chromium trioxide, sulphuric acid and water, preferably in the presence of acetone and at or below room temperature. Oxidation is preferably carried out by treatment with a mixture of an alkali metal dichromate, e.g. sodium dichromate, and an acid, e.g. glacial acetic acid, preferably at an elevated temperature, e.g. 80-1 200C.

Compounds of the formula shown in Figure II may be obtained by the application or adaptation of known methods, for example methods described by Sinnur et a/., Monatsh. Chem. (1966), 97, p41 7.

Thus, compounds of the formula shown in Figure li may be prepared by the reaction together of compounds of the general formula shown in Figure III (wherein R2 is as hereinbefore defined) and compounds of the general formula shown in Figure IV (wherein R1 is as hereinbefore defined) in an acidic aqueous medium, e.g. dilute hydrochloric acid, e.g. 2N to 6N.

According to a further feature of the invention, compounds of the formula shown in Figure I may be obtained by the reaction of compounds of the general formula shown in Figure V (wherein R1 is as hereinbefore defined) with compounds of the general formula shown in Figure VI (wherein R2 is as hereinbefore defined and X represents a halogen, e.g. chlorine, atom) in the presence of a base such as a mixture of pyridine and triethylamine, preferably in anhydrous conditions under an inert atmosphere and at or below room temperature, preferably at between 0 and 1 50C, followed by heating with aqueous alkali, e.g. sodium hydroxide, solution.

Compounds of the formulae shown in Figures III, IV, V and VI may be obtained by the application or adaptation of known methods.

By the term "known methods" as used in this specification is meant methods heretofore used or described in the literature.

The following Examples illustrate the preparation of the compounds of the formula shown in Figure I and the Reference Example illustrates the preparation of intermediates.

EXAMPLE 1 Compounds A, B and C A stirred solution of (#)-2-(p-bromo-α-hydroxybenzyl) benzimidazole (52.5 g; prepared as described by Sinnur et at., op. cit) in acetone (250 ml), maintained at between 100 and 1 50C by means of an ice bath, was treated dropwise with a solution prepared from chromium trioxide, sulphuric acid and water [by adding concentrated sulphuric acid (94 ml), dropwise and with external cooling by means of an ice bath, to a stirred solution of chromium trioxide (106 g) in water (200 ml), and then diluting to 400 ml volume by the addition of a further quantity of water]. This mixture was stirred at between 100 and 1 50C for a further period of 30 minutes after the addition, and then at ambient temperature for 3 hours. It was then added to water (700 ml).The solid which separated was filtered off, washed with water, dried, and recrystallised from acetone, to give 2-p-bromobenzoylbenzimidazole (24 g), in the form of cream needles, m.p. 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% I.R. spectrum : 1655, 1583, 838 740 cm-1, NMR in deuterodimethylsulphoxide: broad singlet at 13.5 ppm (exchangable with D2O), doublet at 8.55 ppm (J = 8 cycles/second), doublet at 7.85 ppm (J = 8 cycles/second) and multiplet at 7.2-8.0 ppm; Mass spectrum: m/e 300/302, 272/274, 221, 193, 183/185, 155/157, 110.5, 96.5; U.V. spectrum: 327 nm (19300), 277 nm (12500)].

By proceeding in a similar manner, but replacing the (+)-2-(p-bromo-ahydroxybenzyl)benzimidazole, used as starting material, by the appropriate quantities of (+)-2-(p bromo-α-hydroxybenzyl)-5-methoxybenzimidazole and (#)-2-(p-bromo-α-hydroxybenzyl)-5- nitrobenzimidazole, respectively (both prepared as described by Sinnur et al., op. cit.), there were prepared 2-p-bromobenzoyl-5-methoxybenzimidazole m.p. 204-2050C (with decomposition) (Elemental analysis : Found : C, 54.0 ; H, 3.2 ; N, 8.3% ; Calculated : c, 54.4 ; H, 3.35 ; N, 8.5% ; I.R. spectrum : 3290, 1623, 1580, 1260, 835, 760 cm-1) ; and 2-p-bromobenzoyl-5-nitrobenzimidazole, m.p. 296-2970C (with decomposition) (Elemental analysis: Found:C, 48.5; H, 2.2; N, 12.1%; Calculated: C, 48.6; H, 2.3; N, 12.1%; I.R. spectrum: 3280, 1630, 1618, 1580, 1325, 835, 770, 730 cm~').

EXAMPLE 2 Compounds A andD p-Bromobenzoyl chloride (9.6 g) was added, portionwise, to a stirred suspension of benzimidazole (2.6 g) in anhydrous pyridine (35 ml) containing anhydroustriethylamine (6.12 ml) in an atmosphere of nitrogen, maintained 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 aqueous sodium hydroxide solution (4.4 ml; 7.5 N) and then it was stirred and heated at reflux for 1 hour. It was then cooled and poured onto a mixture of ice and water (50 ml).

The resulting bluff precip7tate was filtered off, washed with water, dried, and recrystallised from ethyl acetate, to give 2-p-bromobenzoylbenzimidazole (0.3 g), in the form of cream needles, m.p.

223-2250C. (Elemental analysis: Found, C, 55.8; H, 2.9; N, 9.5% ; Calculated: C, 55.8; H, 3.0; N, 9.3%).

By proceeding in a similar manner, but replacing the p-bromobenzoyl chloride, used as a starting material, by p-tert-butylbenzoyl chloride, there was prepared 2-p-tert-butylbenzoylbenzimidazole, m.p.

298-2990C (with decomposition) (Elemental analysis: Found: C, 77.6; H, 6.6; N, 10.2%; Calculated.

C,77.7: H, 6.5; N,10.1 l.R. spectrum: 2970, 1640, 1600, 1265, 1170, 855, 740 cm-1).

EXAMPLE 3 Compounds A andD A solution of sodium dichromate dihydrate (105 g) in glacial acetic acid (610 ml) at 95-1 000C was added in one portion to a stirred solution of (#)-2-(p-bromo-α-hydroxybenzyl) benzimidazole (132 g) in glacial acetic acid (610 ml) at 95-1 000C. The mixture was stirred and heated on the steam-bath for 10 minutes and was then poured into ice and water (3000 ml).The resulting precipitate was filtered off, washed successively with water, with aqueous sodium carbonate solution (2 N), and with water, and then was recrystallised from a mixture of water and dimethylformamide, to give 2-pbromobenzoylbenzimidazole (88 g), in the form of cream needles, m.p. 224-2260C. (Elemental analysis : Found : c, 56.1 ; H, 2.9 ; N, 9.2% ; Calculated : C, 55.8 ; H, 3.0 ; N, 9.3%).

By proceeding in a similar manner, but replacing the (#) -2-(p-bromo-α- hydroxybenzyl)benzimidazole, used as starting material, by the appropriate quantity of (i)-2-(p-tert- butyl-α-hydroxybenzyl) benzimidazole, there was prepared 2-p-tert-butylbenzoylbenzimidazole, m.p.

298-2990C (with decomposition) (recrystallised from aqueous dimethylformamide) (Elemental analysis: Found: C, 78.1; H, 6.4; N, 10.1% ; Calculated: C, 77.7; H, 6.5; N, 10.1 %).

EXAMPLE 4 Compounds B, andE to S By proceeding in a manner similar to that hereinbefore described in Example 3, but replacing the (#)-2-(p-bromo-α-hydroxybenzyl) benzimidazole, used as starting material, by the appropriate quantities of: ( +)-2-(p-bromo--hydroxybenzyl)-5-methoxybenzimidazole, (#)-2-(p-chloro-α-hydroxybenzyl)benzimidazole, (#)-2-(p-fluoro-α-hydroxybenzyl)benzimidazole, (#)-2-(p-methyl-α-hydroxybenzyl)benzimidazole, (#)-2-(p-propyl-α-hydroxybenzyl)benzimidazole, (#)-2-(m-bromo-α-hydroxybenzyl)benzimidazole, (#)-2-(m-methyl-α-hydroxybenzyl)benzimidazole, (#)-2-(o-bromo-α-hydroxybenzyl)benzimidazole, (#)-2-(o-methyl-α-hydroxybenzyl)benzimidazole, (#)-2-(p-bromo-α;-hydroxybenzyl)-5-ethoxybenzimidazole, (+)-2-(p-bromo--hydroxybenzyl)-5-propoxybenzimidazole, (#)-2-(p-bromo-α-hydroxybenzyl)-5-isobutoxybenzimidazole, (#)-2-(p-bromo-α-hydroxybenzyl)-5-octyloxybenzimidazole, (+)-2-(p-bromo--hydroxybenzyl)-5-methylbenzimidazole, (+)-2-(p-bromo--hydroxybenzyl)-5-tert-butylbenzimidazole, and (i)-2-(p-bromo-a-hydrnxybenzyl)-5-phenoxybenzimidazole, optionally in the form of their hydrochlorides, there were prepared 2-p-bromobenzoyl-5-methoxybenzimidazole, m.p. 205-207 C (Elemental analysis : Found : C, 54.3 ; H, 3.3; N, 8.4% ; Calculated : C, 54.4 ; H, 3.35 ; N, 8.5% ; I.R. spectrum: 3290, 1623, 1580, 1260, 835, 760 cm-1) ; 2-p-chlorobenzoylbenzimidazole, m.p. 223-224 C (Elemental analysis : Found : C, 65.5 ; H, 3.4; N, 10.9 % ; Calculated :C, 65.5 ; H, 3.5 ; N, 10.9 % ; I.R. spectrum : 1655, 1585, 840, 740 cm-1); 2-p-fluorobenzoylbenzimidazole, m.p. 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%; .R. spectrum: 1658, 1595, 845, 740 cm-1); 2-p-methylbenzoylbenzimidazole, m.p. 252-2530C (Elemental analysis: Found: C, 76.5; H, 4.95; N, 11.7%; Calculated: C, 76.25; H, 5.1; N, 11.9%; I.R. spectrum: 1650, 1605, 840, 750 cm-1); 2-p-propylbenzoylbenzimidazole, m.p. 176-1 780C (Elemental analysis: Found: C, 77.4; H, 6.1; N, 10.6%; Calculated: C, 77.2; H, 6.1; N, 10.6%; I.R. spectrum: 1640, 1600, 850, 740 cm-1); 2-m-bromobenzoylbenzimidazole, m.p. 194-195 C (Elemental analysis : Found : C, 56.0; H, 2.95 ; N, 9.3%; calculated:C, 55.8; H, 3.0; N, 9.3%; I.R. spectrum: 1655, 930, 740, 730 cm-1); 2-m-methylbenzoylbenzimidazole, m.p. 164-165 C (Elemental analysis: FOund : C, 76.3 ; H, 5.0; N, 11.8%; Calculated: C, 76.25; H, 5.1; N, 11.9; I.R. spectrum: 1625, 1575, 845, 740 cm-1); 2-o-bromobenzoylbenzimidazole, m.p. 222-224 C (Elemental analysis: Found: C, 56.0; N, 2.9; N, 9.2%; Calculated: C, 55.8; H, 3.0; N, 9.3%; I.R. spectrum: 1680, 1590, 758, 740 cm~'); 2-o-methylbenzoylbenzimidazole, m.p. 229-231 C (with decomposition) (Elemental analysis: Found: C, 76.5; H, 5.0; N, 11.9%; Calculated: C, 76.25; H, 5.1; N, 11.9%; I.R. spectrum: 1660, 770, 745 cm-1); 2-p-bromobenzoyl-5-ethoxybenzimidazole, m.p. 188-1 890C (Elemental analysis: Found:C, 55.7; H, 3.7; N, 8.1%; Calculated: C, 55.7; H, 3.8; N, 8.1%; I.R. spectrum: 3220, 1620, 1585, 1270, 805, 765 cm-1); 2-p-bromobenzoyl-5-propoxybenzimidazole, m.p. 178-1 790C (Elemental analysis: Found: C, 57.1; H, 4.2; N, 7.8%; Calculated: C, 56.8; H, 4.2; N, 7.8%; I.R. spectrum: 3320, 1620, 1585, 1265, 810, 765 cm-1); 2-p-bromobenzoyl-5-isobutoxybenzimidazole, m.p. 194-196 C (Elemental analysis: Found : C, 58.1; H, 4.6; N, 7.5%; Calculated: C, 57.9; H, 4.6; N, 7.5%; I.R. spectrum: 3320, 1620, 1585, 1270, 810, 765 cm-1); 2-p-bromobenzoyl-5-octyloxybenzimidazole, m.p. 132-133 C (Elemental analysis: Found: C, 61.5; H, 5.8; N, 6.5%; Calculated: C, 61.5; H, 5.9; N, 6.5%; l.R. spectrum: 3310, 1630, 1585, 1275, 800, 770 cm-1); 2-p-bromobenzoyl-5-methylbenzimidazole, m.p. 204-205 C (with decomposition) (Elemental analysis: Found: C, 57.1; H, 3.3; N, 8.6%; Calculated: C, 57.2; H, 3.5; N, 8.9%; I.R. spectrum: 1630, 1585, 840, 760 cm-1); 2-p-bromobenzoyl-5-tert-butylbenzimidazole, m.p. 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-1); and 2-p-bromobenzoyl-5-phenoxybenzimidazole, m.p. 189-190 C (Elemental analysis : Found : C, 61.0; H, 3.3; N, 7.0%; Calculated: C, 61.1; H, 3.3; N, 7.1%; I.R. spectrum: 3310, 1620, 1585, 1260, 820, 770 cm-1); respectively.

REFERENCE EXAMPLE 1 The following alcohols of the formula shown in Figure II were prepaced by the reaction together of the appropriate substituted or unsubstituted mandelic acid of the formula shown in Figure III and the appropriate substituted or unsubstituted o-phenylenediamine of the formula shown in Figure IV in dilute aqueous hydrochloric acidl ( +)-2-(p-tert-butyl--hydroxybenzyl)benzimidazole hydrochloride, m.p. 234-236 0C; (+)-2-(p-propyl--hydroxybenzyl)benzimidazole, m.p. 100--1020C; (+)-2-(m-brnmo-a-hydrnxybenzyl)benzimidazole hydrochloride, m.p. 247-2480C (with decomposition); (+)-2-(m-methyl-a-hydroxybenzyl)benzimidazole hydrochloride, m.p. 223-225 0C (with decomposition);; (+)-2-(o-methyl-g-hydroxybenzyl)benzimidazole hydrochloride, m.p. 204-205 0C (with decomposition); (+)-2-(p-bromo-cg-hydroxybenzyl)-5-ethoxybenzimidazole hydrochloride, m.p. 218-219 0C (with decomposition); (+)-2-(p-brnmo-a-hydrnxybenzyl)-5-prnpoxybenzimidazole hydrochloride, m.p. 216--2180C (with decomposition); (+)-2-(p-bromo-c-hydroxybenzyl)-5-isobutoxybenzimidazole hydrochloride, m.p. 227--2290C (with decomposition); (*)-2-(p-brnmo-a-hydrnxybenzyl)-5-octyloxybenzimidazole hydrochloride, m.p. 215-217 0C (with decomposition);; ( +)-2-(p-bromo-a-hydroxybenzyl)-5-methylbenzimidazole hydrochloride, m.p. 225-227 0C (with decomposition); (+)-2-(p-bromo-a-hydroxybenzyl)-5-tert-butylbenzimidazole hydrochloride, m.p. 232-233 0C; and (+)-2-(p-bromo-cg-hydroxybenzyl)-5-phenoxybenzimidazole hydrochloride, m.p. 221--223 OC (with decomposition), respectively.

The present invention includes within its scope pharmaceutical compositions which comprise at least one compound of the formula shown in Figure I in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compositions of the present invention will normally be administered orally or rectally, or parenterally, for example topically or intraarticularly.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granuies. 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 comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing the active compounds with or without the addition of diluents or excipients.

Solid compositions for rectal administration include suppositories formulated in manner known perse and containing the active compound or compounds.

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or suspending media are propylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions,-by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in a sterile injectable medium immediately before use. As well as the more customary intravenous and intramuscular routes, the compositions may be administered by intraarticular injection.

Compositions in the form of solutions or suspensions, if desired together with additives as described above, in vegetable or other greases, paraffin or other waxes or lacquers or creams, to be applied topically, for example to the skin area around an affected joint to relieve arthritis, are also included in the invention.

The percentage of active ingredients in the compositions of the invention may be varied, it being necessary that they should constitute a proportion such that a suitable dosage for the desired antiarthritic effect shall be obtained. Obviously several unit dosage forms may be administered at about the same time. Generally the compositions should contain 0.1% to 80% by weight of active ingredient, especially when in tablet form.

The dose employed depends upon the desired antiarthritic effect, the route of administration and the duration of the treatment. In the adult, the doses are generally between 0.01 and 100 mg (preferably between 0.1 and 10 mg, more especially between 1 and 10 mg) of compound of the formula shown in Figure I per kg body weight per day.

The compounds of the formula shown in Figure I may be administered each day or, according to the wishes of the medical practitioner, less often, e.g. weekly.

The present invention provides a method of treating arthritic disorders in man which comprises administering to the patient an amount of a compound or compounds of the formula shown in Figure I sufficient to combat an arthritic disorder.

The following Composition Example illustrates pharmaceutical compositions according to the present invention.

COMPOSITION EXAMPLE 1 Capsules for oral administration were made up in the usual manner by filling No. 2 size gelatin capsules each 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 Similar compositions can be prepared by the use of any of the other compounds of the formula shown in Figure I instead of compound A, for example compounds B to S hereinbefore identified.

Claims

1. Benzimidazole derivatives of the general formula shown in Figure l of the accompanying drawings wherein R1 represents a hydrogen atom, a nitro group, a hydrocarbon moiety, or a group -OR3 wherein R3 represents a hydrocarbon moiety, and R2 represents a straight- or branched-chain alkyl group containing from 1 to 8 carbon atoms or a halogen atom.

2. Benzimidazole derivatives according to claim 1 wherein R' as a hydrocarbon moiety represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms.

3. Benzimidazole derivatives according to claim 1 wherein R' represents a groupOR3 in which R3 represents a straight- or branched-chain alkyl group containing from 1 to 20 carbon atoms.

4. Benzimidazole derivatives according to claim 1 wherein R1 represents a groupOR3 in which R3 represents a straight- or branched-chain alkyl group containing 1 to 6 carbon atoms.

5. Benzimidazole derivatives according to claim 1 wherein R' represents a groupOR3 in which R3 represents a straight- or branched-chain alkyl group containing 7 to 10 carbon atoms.

6. Benzimidazole derivatives according to claim 1 wherein R1 represents a groupOR3 in which R3 represents a substituted or unsubstituted aryl group.

7. Benzimidazole derivatives according to claim 1 wherein R1 represents a groupOR3 in which R3 represents an unsubstituted phenyl group or a phenyl group substituted by one or more atoms or groups selected from halogen atoms and alkyl, alkoxy, trifluoromethyl and nitro groups.

8. Benzimidazole derivatives according to any one of claims 1 to 7 wherein R2 represents a halogen atom.

9. Benzimidazole derivatives according to any one of claims 1 to 7 wherein R2 represents a bromine atom.

1 0. Benzimidazole derivatives according to any one of claims 1 to 7 wherein R2 represents a straight- or branched-chain alkyl group containing from 3 to 6 carbon atoms.

11. Benzimidazole derivatives according to any one of claims 1 to 10 wherein the substituent R2 is attached to the para-position of the phenyl radical depicted in the general formula shown in Figure

12. Benzimidazole derivatives according to any claim 1 wherein R1 represents a hydrogen atom, a nitro group, or a groupOR3 wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, and the substituent R2 is in the para-position of the phenyl radical depicted in the general formula shown in Figure I and represents a straight- or branched-chain alkyl group containing from 1 to 8 carbon atoms, or a halogen atom.

1 3. Benzimidazole derivatives according to claim 1 wherein R' represents a hydrogen atom, a nitro group, a groupOR3 wherein R3 represents an alkyl group, or R1 represents an alkyl group.

14. Benzimidazole derivatives according to claim 1 3 wherein R1 represents a methoxy, ethoxy, propoxy, isobutoxy or octyloxy group, or a methyl or tert-butyl group.

1 5. Benzimidazole derivatives according to claim 1 3 or 14 wherein R2 represents a halogen atom.

1 6. Benzimidazole derivatives according to claim 1 3 or 14 wherein R2 represents a bromine atom.

1 7. Benzimidazole derivatives according to claim 1 3 or 14 wherein R2 represents a chlorine atom.

1 8. Benzimidazole derivatives according to claim 1 3 or 14 wherein R2 represents a fluorine atom.

1 9. Benzimidazole derivatives according to any one of claims 13 to 1 8 wherein the substituent R2 is attached to the para-position of the phenyl radical depicted in the general formula shown in Figure I.

20. 2-p-Bromobenzoylbenzimidazole.

21. 2-p-Bromobenzoyl-5-methoxybenzimidazole.

22. 2-p-Bromobenzoyl-5-nitrobenzimidazole.

23. 2-p-tert-Butylbenzoylbenzimidazole.

24. 2-p-Chlorobenzoylbenzimidazole.

25. 2-p-Fluorobenzoylbenzimidazole.

26. 2-p-Methylbenzoylbenzimidazole.

27. 2-p-Propylbenzoylbenzimidazole.

28. 2-m-Bromobenzoylbenzimidazole.

29. 2-m-Methylbenzoylbenzimidazole.

30. 2-o-Bromobenzoylbenzimidazole.

31. 2-o-Methylbenzoylbenzimidazole.

32. 2-p-Bromobenzoyl-5-ethoxybenzimidazole.

33. 2-p-Bromobenzoyl-5-propoxybenzimidazole.

34. 2-p-Bromobenzoyl-5-isobutoxybenzimidazole.

35. 2-p-Bromobenzoyl-5-octyloxybenzimidazole

36. 2-p-Bromobenzoyl-5-methylbenzimidazole.

37. 2-p-Bromobenzoyl-5-tert-butylbenzimidazole.

38. 2-p-Bromobenzoyl-5-phenoxybenzimidazole.

39. A process for the preparation of a benzimidazole derivative of the general formula depicted in Figure I of the accompanying drawings wherein R1 and R2 are as defined in claim 1 which comprises the oxidation of a compound of the general formula shown in Figure II (wherein R1 and R2 are as defined in claim 1) or a salt thereof, preferably an acid addition salt, to convert the hydroxymethylene group -CH(OH)- of such a compound to a carbonyl

radical.

40. A process for the preparation of a benzimidazole derivative of the general formula depicted in Figure I of the accompanying drawings wherein R1 and R2 are as defined in claim 1 which comprises reacting a compound of the general formula shown in Figure V (wherein R1 is as defined in claim 1) with a compound of the general formula shown in Figure VI, wherein R2 is as defined in claim 1 and X represents a halogen, preferably chlorine, atom.

41. A process for the preparation of a benzimidazole derivative of the general formula depicted in Figure l of the accompanying drawings wherein R1 and R2 are as defined in claim1 substantially as hereinbefore described with especial reference to Example 1, 2, 3 or 4.

42. A pharmaceutical composition which comprises, as active ingredient, at least one benzimidazole derivative as claimed in any one of claims 1 to 38 in association with a pharmaceutically acceptable carrier.

43. A pharmaceutical composition according to claim 42 in a form suitable for administration to a patient suffering from arthritis.

44. A pharmaceutical composition according to claim 42 substantially as hereinbefore described with especial reference to Composition Example I.

45. Benzimidazole derivatives as claimed in any one of claims 1 to 38 for use in the treatment of a patient with an arthritic disorder.

46. A method for the treatment of an arthritic disorder in man which comprises administering to the patient an amount of a benzimidazole derivative as claimed in any one of claims 1 to 38 sufficient to combat the arthritic disorder.

47. A method according to claim 46 in which a dose of between 0.01 and 100 mg of the benzimidazole derivative is administered to an adult per kg body weight per day.

48. A method according to claim 46 in which a dose of between 0.1 and 10 mg of the benzimidazole derivative is administered to an adult per kg body weight per day.

49. A method according to claim 46 in which a dose of between 1 and 10 mg of the benzimidazole derivative is administered to an adult per kg body weight per day.