GB2152036A - 4,5,6,7-Tetrahydrobenzimidazole derivatives - Google Patents

Abstract

4,5,6,7-tetrahydrobenzimidazole derivatives I <IMAGE> (n=0 or 1; R1=C1-C6 hydrocarbon, C3-C7 cycloalkyl, phenyl or substituted phenyl; each of R2 and R3 independently = H, any of the values of R1, benzyl or substituted benzyl, or NR2R3 = 5-7 membered heterocyclic ring) have anti-ulcerogenic activity.

Description

SPECIFICATION 4,5,6,7-Tetrahydrobenzimidazole derivatives The invention relates to 4,5,6,7-tetrahydrobenzimidazole derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

The invention provides 4,5,6,7-tetrahydrobenzimidazole derivatives of the general formula I

wherein n isO or 1, R1 represents a saturated or unsaturated, linear or branched hydrocarbon group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, a phenyl group, or a mono- or di-substituted phenyl group, the substituent(s) being selected from alkyl or alkoxy groups having from 1 to 4 carbon atoms, methylenedioxy or nitro groups, or fluorine, chlorine or bromine atoms, and either reach of R2 and R3 independently represents a hydrogen atom, any of the grops listed as values of R1, a benzyl group, or a mono- or di-substituted benzyl group, the substituents being selected from those listed as substituents for the phenyl group R1, or R2 and R3 together with the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring, which may contain other heteroatoms selected from oxygen and nitrogen any hydrogen bearing nitrogen ring atom may optionally be alkylated, and further provides pharmaceutically acceptable acid addition salts thereof.

The invention also provides a process for the preparation of 4,5,6,7-tetrahydrobenzimidazole derivatives of the general formula I wherein n isO and R1, R2 and R3 are as above defined. This process comprises a Birch-type reduction (see, e.g., E. M. Kaiser, synthesis 1972, 391 ) of a 5-alkoxy-benzimidazole of the general formula II wherein R1 is as above defined and R5 represents an alkyl group, mild acid treatment of the resultant 4,7-dihydro-5-alkoxy-benzimidazole of the general formula Ill wherein R1 and Rg are as above defined, and reductive amination (see, e.g. C. F. Lane, Synthesis 1975, 135) of the resultant 5-oxo-4,5,6,7tetrahydrobenzimidazole of the general formula IV wherein R1 is as above defined.

The process is illustrated by the following reaction scheme.

The invention also provides a process for the preparation of 4,5,6,7-tetrahydrobenzimidazole derivatives of the general formula I wherein n is 1 and R1, R2 and R3 are as above defined. This process comprises the first two steps of the previous process, followed by conversion of the 5-oxo-4,5,6,7-tetrahydrobenzimidazole IV to the corresponding 5-cyano-4,5,6,7-tetrnhydrnbenzimidazole of the general formula VI wherein Rq is as above defined via the hydrazone V, following known procedures (see, e.g. D.M. Orere and C.B. Reese, JCS Chemical Communication, 1977, 280).The intermediate VI is then reduced to the corresponding 5-aminomethyl-4,5,6,7-tetrahydrobenzimidazole (I: ni, R2=R3=H). The amino hydrogen atoms may subsequently be substituted to obtain other compounds I (n=l).

The process is illustrated by the following reaction scheme.

The 4,5,6,7-tetrahydrobenzimidazole derivatives according to the invention have proved to be well tolerated after oral or parenteral administration and to be active on the gastroenterical system. In particular they are endowed with anti-ulcerogenic activity and are therefore useful in therapy, for example in the prevention and treatment of peptic ulcers such as duodenal, gastric and oesophageal ulcers. The anti-ulcerogenic activity of the compounds of this invention is shown, for example by the fact that they are active in the test of the inhibition of restraint ulcers in rats, according to the method of Bonfils et al.

(Therapie, 1960,5,1096; Jap. J. Pharmac., 1968, 18, 9).

The tested compounds were administered per os one hour before the immobilization. Six Sprague-Dawley male rats (100-120 g body weight) fasted for 24 hours were used for each experimental group. A square flexible small-mesh wire netting was used for immobilization and 4 hours after imobilization the rats were sacrificed, their stomachs were removed and the lesions counted under a dissecting microscope.

The Table shows the approximate ED50 value o the anti-ulcerogenic activity in the rats obtained for some of the compounds of the invention after oral administration. The approximate acute toxicity (LD50) of the compounds of the invention was determined in the mouse by single administration of increasing doses and measured on the seventh day after treatment. Results are reported in the Table.

Considering that some anti-ulcer agents display, as does atropine, a remarkable but undesired anti-cholinergic activity, some of the compounds of the invention were also assessed for their antagonism against the syndrome induced by intraperitoneally (i.p.) administered oxotremorine in mice, according to the method described by Leszkovszky G.P. and Tardos L. (Eur. J. Pharmac., 1971, 15,310). The tested compounds were administered to groups of 5 male mice, 20-25 g body weight, at the screening dose of 100 mg/kg per os. The degree of peripheral cholinergic activation induced by oxotremorine was measured by salivation and lachrymation, and the degree of central cholinergic activation by the severity of tremors and hypothermia. Atropine sulphate suppressed both peripheral and central effects induced by oxotremorine.

The results are reported in the Table.

Accordingly, the invention further comprises a pharmaceutical composition comprising a 4,5,6,7tetrahydrobenzimidazole derivative of the general formula I as above defined or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. TABLE Acute toxicity, anti-ulcer activity and anti-cholinergic activity of selected compounds* (see general formula (I) Anti-cholinergic Example R1 R2 R3 n LD50 Anti-ulcer activity activity mg/kg ED50 mg/kg screening dose: per os per os 100 mg/kg per os 3 C2H5 H i-C3H7 0 > 400 9 inactive 5 C2H5 H CH2-CH(CH3)2 0 > 400 10 inactive 7 C2H5 H 0 > 200 < 400 3 inactive 8 C2H5 -(CH2)4- 0 > 200 < 400 6.5 inactive 11 C2H5 -(CH2)2-O-(CH2)2- 0 > 400 < 800 6 inactive *) All the biological activity data are referred to the free bases.

The invention is illustrated by the following Examples.

Example 1 1-Eth yl-5-m ethoxy-4, 7-dihydrobenzimidazole A solution of 47 g (0.267 mol) of 1-ethyl-5-methoxybenzimidazole (K. Tanaka, M. Ino, Y. Murakami, Chem.

Pharm. Bull. 29, 1876 (1981)) in a mixture of 330 m I ml oftetrahydrofuran and 220 ml of methanol was added dropwise to 1.8 litres of liquid ammonia under vigorous stirring. 12.9 g (1.86 mol) of lithium was added portionwise to the solution over 6 hours. After evaporation off the ammonia and solvents, the solid residue was taken up in 400 ml of water and the aqueous phase was extracted four timers with 350 ml aliquots of toluene. The combined extracts were dried over anhydrous sodium sulphate filtered and evaporated to dryness under reduced pressure. The residue was crystallized from 250 ml of diethyl ether at 0 -4tC, to give 17.1 g of the title compound. Concentration of the mother liquor gave a second crop (3 g).

Yield: 42.3%- m.p. 106 -108 C.

Example 2 1-Ethyl-5-oxo-4,5,6, 7-tetrahydrobenzimidazole To a solution of 5 g (0.028 mol) of 1-ethyl-5-methoxy-4,7-dihydrobenzimidazole, prepared as described in Example 1, in 100 ml of 95% ethanol, 56 ml of 1 N hydrochloric acid was added dropwise at 0 C. The reaction solution was allowed to stand at room temperature for 2 hours, and evaporated to dryness under reduced pressure at room temperature.The residue was redissolved in 30 ml of water and 50 ml of methylene dichloride: methanol (9:1 by volume) and the mixture was neutralized with 2N sodium hydroxide at 0 C. The phases were separated, and the aqueous phase was exhaustively extracted with methylene dichloride:methanol (9:1 by volume) while its pH was carefully kept neutral The combined organic extracts were dried over anhydrous sodium sulphate, treated with charcoal, filtered and evaporated to dryness under reduced pressure at room temperature. 4.6 g of the title compound was obtained as a white solid.

Yield: 100%-m.p. p.108 -112 C.

Example 3 1-Ethyl-5-isopropylamino-4,5,6, 7-tetrahydrobenzimidazole 8.52 ml (42.6 mmol) of 5N hydrogen chloride in methanol was added dropwise to a solution of 10.9 ml (128 mmol) of isopropylamine in 60 ml of methanol cooled with an ice-water bath. 3.5 g (21.3 mmol) of 1-ethyl-5-oxo-4,5,6,7-tetrahydrobenzimidazole, prepared as described in Example 2 dissolved in 20 ml of methanol, and 0.412 g (9.5 mmol) of sodium cyanoborohydride were successively added to the solution. The reaction mixture was stirred for an hour. The pH was adjusted to pH 2 with 6N hydrochloric acid, and the reaction mixture was then evaporated in vacuo. The residue was dissolved in 50 ml of water and the solution was basified with 2N sodium hydroxide and extracted five times with 50 ml aliquots of chloroform.The chloroform extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. A brownish oil was obtained (about 4.3 g). To this oily residue, dissolved in 50 ml of ethanol, a solution of 3.73 g of oxalic acid in 50 ml of ethanol was added. The solution was allowed to stand overnight and the dioxalate of the title compound was collected (about 4 g). The dioxalate was dissolved in 40 ml of water, the pH of the solution was adjusted to pH 10 with 2N sodium hydroxide, and the solution was then extracted five times with 50 ml aliquots of chloroform. The chloroform extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. To the yellow oily residue (about 2 g), dissolved in 30 ml of ethanol, a solution of 2.28 g of fumaric acid in 100 ml of ethanol was added.The solution was allowed to stand overnight and the title compound, crystallized with 1.5 mole offumaric acid, was collected (3.5 g, m.p. 215 C).

Example 4 l-EthyA5-hutylamino-4, 5, 6, 7-tetrah ydrob enzimidazole Following the procedure of Example 3, but employing n-butylamine in place of isopropylamine the title compound, crystallized with 1.5 mole of fumaric acid, was obtained in 40% overall yield (m.p. 178 C), Example 5 1-Ethyl-5-isobutylamino-4,5, 6, 7-tetrahydrobenzimidazole Following the procedure of Example 3, but employing isobutylamine in place of isopropylamine, the title compound, crystallized with 1.5 mole offumaric acid, was obtained in 55 overall yield (m.p. 205 C).

Example 6 1-Ethyl-5-cyclopentylamino-4,5,6,7-tetrahydrobenzimidazole Following the procedure of Example 3, but employing cyclopentylamine in place of isopropylamine, the title compound, crystallized with 1.5 mole of fumaric acid, was obtained in 40% overall yield (m.p. 210"C).

Example 7 1-Ethyl-5-cyclohexylamino-4,5,6, 7-tetrahydrobenzimidaxole Following the procedure of Example 3, but employing cyclohexylamine in place of isopropylamine, the difumarate of the title compound (m.p. 200C) was obtained in 40% overall yield.

Example 8 i-Ethyl-5-( i-p yrrolidinylj-4, 6,6, 7-tetrahydrobenzimidazole Following the procedure of Example 3, but employing pyrrolidine in place of isopropylamine, the trifumarate of the title compound (m.p. 173"C) was obtained in 51% overall yield.

Example 9 1-Eth yl-5-piperidino-4,5, 6, 7-tetrahydrobenzimidazole Following the procedure of Example 3, but employing piperidine in place of isopropylamine, the trifumarate of the title compound (m.p. 156"C) was obtained in 45% overall yield.

Example 10 1-Eth yl-5-( 1-hexahydroazepinyl)-4, 5,6, 7-tetrahydrobenzimidazole Following the procedure of Example 3, but employing hexamethyleneimine in place of isopropylamine, the title compound, crystallized with 2.5 mole of fumaric acid, was obtained in 40% overall yield (m.p. 1 65"C).

Example 11 l-Ethyl-5-m orpholino-4,5, 5,6, 7-tetrahydrobenzimidazole Following the procedure of Example 3, but employing morpholine in place of isopropylamine, the trifumarate of the title compound (m.p. 180"C) was obtained in 45% overall yield.

Example 12 1-Eth yl-5-(4-methyl- 1-piperazin ylJ-4,5, 6, 7-tetrah ydrobenzimidazole Following the procedure of Example 3, but employing N-methylpiperazine in place of isopropylamine, the difumarate of the title compound (m.p. 1 55C) was obtained in 50% overall yield.

Example 13 1-Eth yl-5-anilin o-4, 5, 6, 7-tetrahdrobenzimidazole Following the procedure of Example 3, but employing aniline in place of isopropylamine, the title compound (m.p. 145"C) was obtained in 70% overall yield.

Example 14 1-Ethyl-5-(2,4, 6-triiso prop ylphenylsulphonyl-hydrazono)-4,5, 6, 7-tetrahydrobenzimidazole To a solution of 4 g (0.024 mol) of 1-ethyl-5-oxo-4,5,6,7-tetrahydrobenzimidazole, prepared as described in Example 2, in 40 ml of methanol,9.09 g (0.03 mol) of 2,4,6-triisopropyl-1-hydrazinesulphonyl-benzene was added under stirring. After 3 hours at room temperature, the resultant white precipitate was recovered by filtration, washed with a small amount of cold methanol and dried (7.65 g). The filtrate was concentrated to about 20 ml under reduced pressure at room temperature, and added dropwise to 600 ml of water.The resultant suspension was filtered to recover the precipitate, which was dried over phosphorus pentoxide for 24 hours, thus giving a second crop of the title compound (2.8 g). Yield: 96%- m.p. 155'C (with decomposition).

Example 15 1-Eth yl-5-cyano-4, 5,6, 7-tetrahydrobenzimidazole 3.3 g (0.051 mol) of potassium cyanide and 7.5 g (0.017 mol) of 1-ethyl-5-(2,4,6 triisopropylphenylsulphonyl-hydrazono)-4,5,6,7-tetrahydro-benzimidazole, prepared as described in Example 14, were heated in 40 ml of methanol under reflux. over 36 hours 3.3 g (0.051 mol) of potassium cyanide was added portionwise to the reaction mixture to obtain full conversion. The suspension was evaporated to dryness under reduced pressure, the residue was taken up with 10 ml of water and the aqueous phase was extracted four times with 30 ml aliquots of methylene dichloride. The combined extracts were washed with 15 ml of a saturated aqueous solution of sodim bicarbonate and with water, and dried over anhydrous sodium sulphate.The methylene dichloride was evaporated off under reduced pressure and the residue was purified by column chromatography (120 g silica, ethyl acetate graduating to ethyl acetate : methanol 96:4 by volume) to obtain 2.8 g of the title compound as a low-melting white solid.

'H-NMR spectrum (200 MHz, CDC13): 1.343 (t,3H, CH3-CH2-N)

3.803 (q, 2H, CH3-CH2-N) 7.343 (s, 1 H, H-2) Example 16 1-Ethyl-5-aminomethyl-4,5, 6, 7-tetrahydrobenzimidazole To a suspension of 667 mg (0.018 mol) of lithium aluminium hydride in 20 ml of diethyl ether, a solution of 2.34 g (0.018 mol) of aluminium chloride in 30 ml of diethyl ether was added rapidly under nitrogen at 0 C with vigorous stirring.Five minutes after the last addition of halide, a solution of 2.8 g (0.016 mol) of 1-ethyl-5-cyano-4,5,6,7-tetrahydrobenzimidazole, prepared as described in Example 15, in 20 ml of tetrahydrofuran was added dropwise under the same conditions. After stirring the mixture for 4 hours at room temperature, the reaction was quenched at 0 C with 1 ml of ethyl acetate and then 8 ml of water; the mixture was alkalinized with 2N sodium hydroxide and filtered; the cake was thoroughly washed with 2N sodium hydroxide, and the filtrate was extracted exhaustively with methylene dichloride: methanol (9:1 by volume). The combined extracts were dried over an hydros sodium sulphate and evaporated to dryness under reduced pressure.The residue was purified by column chromatography (75 g silica, ethyl acetate: methanol 5:1 by volume graduating to ethyl acetate: methanol : 30% aqueous ammonium hydroxide 5:1:0.35 by volume) to obtain 2.3 g of the title compound as a colourless oil.

Yield: 80%.

For analytical purposes the dihydrochloride of the title compound (m.p. 265"C) can be prepared by treatment of the free base in methanol solution with methanolic hydrochloric acid.

Example 17 1-Eth yl-5-cyclop en tylaminometh yl-4, 5,6, 7-tetrahydrobenzimidazole To a solution of 0.72 g (4 mmol) of 1-ethyl-5-aminomethyl-4,5,6,7-tetrahydrobenzimidazole, prepared as described in Example 16, in 10 ml of methanol, cooled in an ice-bath, there was added 0.8 ml (4 mmol) of methanolic 5N hydrogen chloride, followed by 0.39 ml (4.4 mmol) of cyclopentanone and 0.11 g (1.74 mmol) of sodium cyanoborohydride. The ice-bath was removed and the mixture was stirred for 1 hour at room temperature. After adjusting the pH to about 2 with 6N hydrochloric acid, the reaction solution was evaporated to dryness under reduced pressure.The residue was taken up in 10 ml of water and the aqueous solution was washed twice with diethyl ether, basified with 2N sodium hydroxide and extracted three times with 30 ml aliquots of methylene dichloride: methanol 9:1 by volume. After treatment with anhydrous sodium sulphate, the combined organic extracts were evaporated to dryness, thus affording 0.9 g of the title compound as a colourless oil. The oily compound was dissolved in 10 ml of ethanol, and 0.85 g of fumaric acid dissolved in 50 ml of ethanol was added. The solution was concentrated and treated with 80 ml of diethyl ether to obtain 1.01 g of the title compound crystallized with 1.5 mole of fumaric acid (Yield 60%, m.p.

184"C).

Example 18 1-Ethyl-5-amlno-4,5 6, 7-tetrahydrobenzimidazole To a stirred solution of 2.1 g (12.8 mmol) of 1-ethyl-5-oxo-4,5,6,7-tetrahydrobenzimidazole, prepared as described in Example 2, in 40 ml of methanol, 9.8 g (127 mmol) of ammonium acetate and 540 mg (8.7 mmol) of sodium borohydride were successively added over a period of 30 minutes. The reaction mixture was acidified with 6N hydrochloric acid, and then evaporated in vacuo to distill off most of the methanol.

The residue was taken up in 40 ml of water and the solution was basified with 2N sodium hydroxide and throughly extracted with methylene dichloride: methanol 9:1 by volume. The extracts were evaporated to dryness, the residue was redissolved in 45 ml of methylene chloride and the solution was exhaustively extracted with water. The aqueous extracts were evaporated to dryness and the dark oily residue was redissolved in 20 ml of anhydrous ethanol. To this solution 0.84 g of fumaric acid dissolved in 100 ml of anhydrous ethanol was added. 1.0 g of the pure title compound crystallized with 1.5 mole offumaric acid were collected (m.p. 183"C).

Claims (28)

1. A 4,5,6,7-tetrahydrobenzimidazole derivative of the general formula I

wherein n is O or 1.

R1 represents a saturated or unsaturated, linear or branched hydrocarbon group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, a phenyl group, or a mono- or di-substituted phenyl group, the substituent(s) being selected from alkyl or alkoxy groups having from 1 to 4 carbon atoms, methylenedioxy or nitro groups, or fluorine, chlorine or bromine atoms, and either each of R2 and R2 independently represents a hydrogen atom, any of the groups listed as values of R1, a benzyl group, or a mono- or di-substituted benzyl group, the substituents being selected from those listed as substituents for the phenyl group R1, or R2 and R3 together with the nitrogen atom to which they are attached form a 6-, or 7-membered heterocyclic ring, which may contain other heteroatoms selected from oxygen and nitrogen, any hydrogen bearing nitrogen ring atom may optionally be alkylated; or a pharmaceutically acceptable acid addition salt thereof.

2. 1 -Ethyl-5-isopropylamino-4,5,6,7-tetrahydrobenzimidazole.

3. 1 -Ethyl-5-butylamino-4,5,6,7-tetrahydrobenzimidazole.

4. 1-Ethyl-5-isobutylamino-4,5,6,7-tetrahydrobenzimidazole.

5. 1 -Ethyl-5-cyclopentylam ino-4,5,6,7-tetra hydrobenzimidazole.

6. 1 -Ethyl-5-cyclo hexylamino-4,5,6,7-tetrahydrobenzimidazole.

7. 1-Ethyl-5-(1-pyrrolidinyl)-4,5,6,7-tetrahydrobenzimidazole.

8. 1 -Ethyl-5-piperidino-4,5,6,7-tetrahydrobenzimidazole.

9. 1-Ethyl-5-(1-hexahydroazepinyl)-4,5,6,7-tetrahydrobenzimidazole.

10. 1 -Ethyl-5-morpholino-4,5,6,7-tetrahydrobenzimidazole.

11. 1 -Ethyl-5-(4-methyl-1 -piperazinyl )-4,5,6,7-tetrahydrobenzimidazole.

12. 1-Ethyl-5-anilino-4,5,6,7-tetrahydrobenzimidazole.

13. 1-Ethyl-5-aminomethyl-4,5,6,7-tetrahydrobenzimidazole.

14. 1 -Ethyl-5-cyclopentylami nomethyl-4,5,6,7-tetrahydrobenzimidazole.

15. 1 -Ethyl-5-ami no-4,5,6,7-tetra hydrobenzimidazole.

16. A process for the preparation of a 4,5,6,7-tetrahydrobenzimidazole of the general formula I wherein n isO and R1, R2 and R3 are as defined in claim 1,the process comprising reducing a 5-alkoxy-benzimidazole of the general formula II as herein defined by reaction with lithium and liquid ammonia, treating the resultant 5-alkoxy-4,7-dihydrobenzimidazole of the general formula Ill as herein defined with an acid, and reductively aminating the resultant 5-oxo-4,5,6,7-tetrahydmvenzimidazole of the general formula IV as herein defind by reaction with sodium cyanobornhydride and an amine of the general formula R2R3NH wherein R2 and R3 are as defined in claim 1.

17. A process for the preparation of a 4,5,6,7-tetrahydrobenzimidazole of the general formula I wherein n is 1 and R1, R2 and R3 are as defined in claim 1, the process comprising reducing a 5-alkoxy-benzimidazole of the general formula II as herein defind by reaction with lithium and liquid ammonia, treating the resultant 5-alkoxyA,7-dihydrobenzimidazole of the general formula Ill as herein defined with an acid, reacting the resultant 5-oxo-4,5,6,7-tetrahydrnbenzimidazole of the general formula IV as herein defined with 2,4,6 triisopropyl-1 -hydrazinosulphonyl-benzene, reacting the resultant 5-(2,4,6,-triisopropylphenylsulphonyl hydrazono)-4,5,6,7-tetrahydrobenzimidazole of the general formula V as herein defined with potassium cyanide, reducing the resultant 5-cyano-4,5,6,7-tetrahydrobenzimidazole of the general formula VI as herein defined with a hydride ion donor, and optionally alkylating the resultant 5-methylamino-4,5,6,7 tetrahydrobenzimidazole of the general Formula I wherein n is 1, R1 is as defined in claim 1 and R2 and R2 represent hydrogen atoms.

18. A process according to claim 16 or claim 17 in which the reduction of the 5-alkoxy-benzimidazole II is carried out in a solvent.

19. A process according to claim 18 in which the solvent is a mixture of methanol and tetrahydrofuran.

20. A process according to any of claims 16 to 19 in which the 5-alkoxy-4,7-dihydrobenzimidazole Ill is treated with 1 N hydrochloric acid at 0 C in ethanol.

21. A process according to claim 16 in which the reductive amination is carried out in an ice cooled methanolic acidic solution.

22. A process accordng to claim 17 in which the reaction of the 5-oxo-4,5,6,7-tetrahydrobenzimidazole IV with 2,4,6-triisopropyl-i-hydrazinosulphonyl-benzene is carried out in methanolic solution at ambient temperature.

23. A process according to claim 17 or claim 22 in which the reaction of the 5-(2,4,6 triisopropylphenylsulphonyl-hydrazono)-4,5,6,7-tetrahydrobenzimidazole V with potassium cyanide is carried out in boiling methanol.

24. A process according to any of claims 17, 22 and 23 in which the hydride ion donor is lithium aluminium hydride and the reaction is carried out in suspension in a mixture of tetrahydrofuran and diethyl ether in the presence of aluminium chloride first at OOC an d subsequently at ambient temperature.

25. A process according to any of claims 17,22 and 23 in which the hydride ion donor is sodium cyanoborohydride and the reaction is carried out in the presence of ammonium acetate.

26. A process according to claim 16, the process being substantially as described herein with reference to Examples 1 and 2 and any of Examples 3 to 13 or 18.

27. A process according to claim 17, the process being substantially as described herein with reference to Examples 1,2 and 14to 16 or Examples 1,2 and 14to 17.

28. A pharmaceutical composition comprising a 4,5,6,7-tetrahydrobenzimidazole derivative according to any of claims 1 to 15 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.