GB2053215A - Benzimidazole derivatives - Google Patents

Abstract

Benzimidazole derivatives of the formula: <IMAGE> [wherein R<1> represents a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), and R<2> represents an alkyl group containing from 7 to 20 carbon atoms], the group R<1>OOC- being attached to the 4- or 5-position of the benzimidazole ring system, which are new compounds possess useful pharmacological properties, for example hypolipidaemic activity.

Description

SPECIFICATION Benzimidazole derivatives This invention relates to new therapeutically useful benzimidazole derivatives, to processes for preparing them, and to pharmaceutical compositions containing them.

The benzimidazole derivatives of the present invention are those compounds of the general formula:

wherein R1 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of su bstituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), and R2 represents a straight- or branched-chain alkyl group, preferably a straight-chain alkyl group, containing from 7 to 20 (preferably from 10 to 18) carbon atoms, and pharmaceutically acceptable salts thereof. Preferably R1 represents a hydrogen atom, or a methyl group, or an n-butyl, 2,3-dihydroxyprop-1 -yl, allyl or pivaloyloxymethyl group.

The group R1OOC is attached to the 4 or, preferably, the 5-position of the benzimidazole ring system.

It will be understood by those skilled in the art that the compounds of general formula I exhibit tautomerism such that the hydrogen atom which is depicted as residing on one of the nitrogen atoms may reside on either nitrogen atom, and that both the forms thus described may be present to a greater or lesser degree and are in a state of dynamic equilibrium with each other. In the tautomers the 4-and 5-positions become the 7- and 6-positions respectively. Furthermore, in certain cases the substituents R' and R2 contribute to optical isomerism. All such forms are embraced by the present invention.

By the term "pharmaceutically acceptable salt" is meant a salt formed by reaction with an acid or, when R1 represents a hydrogen atom, by reaction with a base, so that the anion (in the case of an acid addition salt) or the cation (in the case of a salt formed by a compound of formula I wherein R1 represents a hydrogen atom) is relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the parent compound of general formula I are not vitiated by side-effects ascribable to the said anion or cation.

Suitable acid addition salts include salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic salts, for example methanesulphonates, 2-hydroxyethanesulphonates, oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-)3-hydroxynaphthoates, gentisates and di-p-toluoyltartrates.

Suitable salts formed by compounds of general formula I wherein R1 represents a hydrogen atom include the alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium) and ammonium salts, and salts of amines known in the art to be pharmaceutically acceptable, e.g.

ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2-(hydroxymethyl)propane-1 ,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

It is to be understood that, where in this specification reference is made to compounds of general formula I, it is intended to refer also to their pharmaceutically acceptable salts, where the context so permits.

The compounds of general formula I possess useful pharmacological properties, in particular, hypolipidaemic activity. For example, they lower the concentrations of cholesterol and of triglycerides in the blood. Furthermore, they hinder or prevent the development of atheromatous lesions, and in addition they reduce the proliferation of arterial smooth muscle cells which is a major feature of atheromatous plaques.

The compounds of general formula I also lower blood glucose levels in mice suffering from diabetes mellitus. The compounds of general formula I also suppress lymphocyte transformation as do antirheumatic drugs. Thus, they are of utility in the prevention or treatment of diabetes mellitus, hyperlipoproteinaemic states, of atherosclerosis, and of associated conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism, peripheral vascular disease, recurrent pancreatitis and xanthomas; as well as arthritis, immunological disease, cancer and graft rejection.

Compounds of general formula I which are of particular interest include the following compounds, their optically active forms and their salts: methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate A 2-(n-pentadecyl )benzim idazole-5-carboxylic acid B methyl 2-(n-undecyl)benzimidazole-5-carboxylate C 2-(n-undecyl)benzimidazole-5-carboxylic acid D methyl 2-(n-tridecyl)benzimidazole-5-carboxylate E 2-(n-tridecyl)benzimidazole-5-carboxylic acid F methyl 2-(n-dodecyl)benzimidazole-5-carboxylate G 2-(n-dodecyl)benzimidazole-5-carboxylic acid H methyl 2-(n-decyl)benzimidazole-5-carboxylate 2-(n-decyl Xbenzimidazole-5-carboxyl ic acid J methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate K 2-(n-heptadecyl)benzimidazole-5-carboxylic acid L methyl 2-(n-nonyl )benzim idazole-5-ca rboxylate M 2-(n-nonyl)benzimidazole-5-carboxylic acid N methyl 2-(n-heptyl)benzim idazole-5-carboxylate 0 2-(n-heptyl)benzimidazole-5-carboxylic acid P 2-(n-tetradecyl )benzimidazole-5-carboxyl ic acid Cl 2-(n-octyl)benzimidazole-5-carboxylic acid R methyl 2-(n-tetradecyl Xbenzim idazo le-5-ca rboxylate S methyl 2-(n-hexadecyl)benzimidazole-5-carboxylate T 2-(n-hexadecyl)benzimidazole-5-carboxylic acid U methyl 2-(n-eicosyl ) benzimidazole-5-ca rboxylate V 2-(n-eicosyl)benzimidazole-5-carboxylic acid w methyl 2-(n-nonadecyl)benzimidazole-5-carboxylate X 2-(n-nonadecyl)benzimidazole-5-carboxylic acid Y 2-(n-octadecyl)benzimidazole-5-carboxylic acid Z (RS)-2-(tetradec-2-yl )benzi midazol e-5-carboxylic acid AA (flS)-2-(tddec-3-yl)benzimidazole-5-carboxylic acid BB 2-(tridec-7-yl )benzimidazole-5-carboxyl ic acid CC (RS)-2-(tridec-5-yl)benzimidazole-5-carboxylic acid DD ethyl 2-(n-pentadecyl )benzim idazo le-5-carboxylate EE n-hexyl 2-(n-pentadecyl )benzimidazole-5-ca rboxylate FF n-butyl 2-(n-pentadecyl )benzimidazole-5-carboxylate GG isopropyl 2-(n-pentadecyl )benzimidazole-5-carboxylate HH methyl 2-(n-octadecyi)benzim idazole-5-ca rboxylate II pivaloyl oxymethyl 2- n-pentadecyl ) benzimidazole-5-carboxyl ate JJ 2,3-dihydroxyprop-1-yl 2-(n-pentadecyl) benzimidazole-5-carboxylate KK 2-(n-tridecyl)benzimidazole-4-carboxylic acid LL tert-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate MM allyl 2-(n-pentadecyl )benzim idazo le-5-ca rboxylate N N and 2-(n-pentadecyl)benzimidazoie-4-carboxylic acid PP The letters AtoPP are assigned to the compounds for easy reference later in the specification, for example in the Tables.

The properties of the compounds of general formula 1 were demonstrated in the following tests: Hypolipidaemic activity in rats Male Wistar rats each weighing between 120 and 150 g were caged in groups of eight and fed a powdered diet for 10 days. For the last 7 days of that period the test compound was administered orally by mixing the - compound in the diet and allowing the animals to feed normally. Food consumption was measured on day 9 for each group.

At noon on day 10 the animals were killed by inhalation of carbon dioxide from solid carbon dioxide. A sample of blood was removed by cardiac puncture and the serum cholesterol and serum triglycerides were analysed by means of an auto-analyser.

Control groups (receiving only the normal, unmedicated diet) were included with each test.

The percentage reductions in the concentrations of serum cholesterol and serum triglycerides were calculated by comparison with the simultaneous controls, for each concentration of the test compound used.

The results obtained are shown in following Table I.

TABLE Compound Form % w/w %change in serum dose compared with control in diet cholesterol triglycerides A HCI 0.2 +7 -1 salt B HCI 0.2 -50 -44 salt 0.2 -50 -64 0.2 -39 -40 0.2 -22 -45 0.2 -21 -46 0.4 -61 -63 0.2 -55 -60 0.2 -42 -69 0.1 -31 -38 0.1 -14 -51 0.03 -2 -44 B mono- 0.2 +4 +19 hydrate 0.2 -10 -9 0.4 -63 -76 B sodium 0.2 -51 -64 salt 0.1 -24 -44 mono- 0.4 -62 -79 hydrate 0.2 -55 -62 C parent 0.2 -30 -57 compound 0.2 -13 -54 d HCI 0.2 -34 -60 salt 0.2 -24 -50 0.2 -40 -80 E HCI 0.2 -23 -58 salt F HCI 0.2 -34 -53 salt 0.2 -36 -47 0.03 -17 -10 G HCI 0.2 -18 -41 salt H HCI 0.2 -33 -52 salt 0.03 -4 -26 HCI 0.2 -3 -36 salt J HCI 0.2 -13 -24 salt L HCI 0.2 -3 -36 salt 0.2 -20 -26 N HCI 0.2 -14 -3 salt O HCI 0.2 -4 +24 salt TABLE I (continued) Compound Form % wiz % change in serum dose compared with control in diet cholesterol triglycerides P HCI 0.2 -18 -10 salt Q HCI 0.2 -41 -62 salt 0.2 -35 -69 0.03 -4 -20 R HCI 0.2 -2 -10 salt S HCI 0.2 +9 -28 salt T HCl 0.2 +6 -20 salt U HCI 0.2 -20 -50 salt V HCI 0.2 +2 -12 salt W HCI 0.2 +5 -15 salt X HCI 0.2 -10 -3 salt Y HCI 0.2 -17 -14 salt Z HCI 0.2 0 -20 salt AA HCI 0.2 -35 -75 salt BB HCI 0.2 -19 -46 salt CC H2SO4 0.2 -6 +9 half salt DD H2S04 0.2 +11 -15 half salt EE HCI 0.2 -27 -47 salt FF HCI 0.2 -16 -51 salt GG HCI 0.2 -40 -54 salt 0.2 -33 -60 HH HCI 0.2 -5 -32 salt TABLE I (continued) Compound Form %w/w %change in serum dose compared with control in diet cholesterol triglycerides II HCI 0.2 -1 -20 salt JJ parent 0.2 -40 -51 compound 0.1 -1 -33 KK HCL 0.2 -72 -73 salt 0.1 -28 -21 MM HCI 0.2 +4 -8 salt NN HCI 0.2 -19 -54 salt PP HCI 0.2 -18 -11 salt Anti-atheroma activity in rabbits Male New Zealand White rabbits each weighing 2.2-2.8 kg were subjected to de-endothelialisation of the abdominal aorta and of one femoral artery by balloon catheter. After recovery from the anaesthetic, they were each administered a diet to which had been added 1% w/w cholesterol and a certain concentration of the test compound, for 14 days. At the end of that time the animals were killed and the concentration of the serum cholesterol was determined. The aorta and femoral arteries were removed, the intima-media were stripped from the adventitia, and the cholesterol concentrations were determined. Portions of the femoral arteries were examined histologically.

A control group, not receiving the test compound, was included with each test.

The percentage reductions in the concentrations of serum cholesterol and arterial cholesterol were calculated by comparison with the simultaneous controls.

The results obtained are shown in following Table II.

TABLE II

Compound Form % w/w % change in tissue cholesterol % change in serum dose concentrations compared with cholesterol compared with in diet controls controls "a (I, OF CDfl -3 = =CD ~ = V 0 0 0 O =.

rCU CD CD CD CD (Dg '0 ' ,, 0 0 cP 0 = = = B Sodium 0.2 -33 -53 -44 -39 salt mono hydrate D 0.4 -40 -73 -63 -34 Z Sodium 0.4 -25 -64 -30 -59 salt Hypoglycaemia activity in diabetic mice Diabetic mice (strain C 57, black, MRI derived Obese!Obese) of either sex each weighing between 45 and 70 g were fed a powdered diet for a period of 1 week preceding the test. Treated animals were then given the test compound mixed in the diet at a certain concentration for several days. The animals were then weighed, anaesthetised with carbon dioxide and blend by cardiac puncture.

The following serum parameters were assessed: 1. Glucose - by the glucose-oxidase method of God-Perid.

. 2. Cholesterol and triglycerides - these were measured by an auto-analyser after removal of phospholipids by means of activated zeolite and extraction by isopro panol.

Control groups (receiving only the normal, unmedicated diet) were included with each test.

The percentage reductions in the concentrations of serum glucose, and serum cholesterol and serum triglycerides were calculated by comparison with the simultaneous controls, for each concentration of the test compound used.

The results obtained are shown in following Table Ill.

TABLE Ill Compound Form Dose Duration % change in serum % change in serum compared % wiw of test glucose compared with control in diet with control cholesterol triglycerides B Sodium 0.2 7 days -35 -9 salt mono hydrate Sodium 04 7 days -42 -46 -29 salt mono hydrate Sodium 0.4 2 days -56 0 -45 salt mono hydrate HCI 0.4 2 days -39 -25 +21 salt Aortic smooth muscle cell proliferation inhibiting activity Smooth muscle cells were grown in culture from explants of pig thoracic aorta, using Dulbecco's Modified Eagles (DME) Medium containing 20% foetal calf serum (FCs) and antibiotics. The cells were incubated at 37"C in an atmosphere of 95% air and 5% carbon dioxide.At confluency the cells were routinely subcultured by trypsinising and replating at approximately one third of their confluent density in DME Medium containing 10% FCS and antibiotics.

The smooth muscle cells were plated out at densities of 100,000 - 200,000 cells per 35 x 10 mm Falcon dish in 2 ml DME Medium, containing 10% FCS and antibiotics. After 24 hours, when the cells had attached to the dishes, the medium was replaced with 2 ml DME Medium containing 1% FCS and antibiotics. The cultures were incubated for a further three days to allow the cells to become quiescent (i.e. no longer undergoing cell division). The medium was then replaced by 2 ml control or test medium. The test medium consisted of DME Medium (containing 10% FCS and antibiotics) and the compound to be tested at a concentration of 5 ltgimi medium. The compounds were pre-dissolved in water, acetone or glycofuroi such that the final concentration of solvent in the medium was 0.2% (vv). The control medium consisted of DME Medium (containing 10% FCS and antibiotics) and appropriate solvent at 0.2% (v v) concentration. After three days incubation in test or control medium, the medium was replaced with fresh test or control medium and the cells incubated for a further three or four days. At the end of the six or seven day incubation period cell numbers were determined by trypsinising the cells and counting the cell suspension in a Coulter counter.

All results in Table IV hereafter represent the mean value for four dishes of cells. Percentage inhibition of proliferation was calculated using the following formula: Percentage inhibition of proliferation =1 0 - ( C- too) Where S = Mean cell number per dish at start of experiment (upon addition of control or test medium).

T = Mean cell number per dish in test cultures at completion of experiment.

C = Mean cell number per dish in control cultures at completion of experiment.

Compound Form Solvent % inhibition L HCI M2O 48 salt H20 55 M2O . 31 M2O 45 O HCI acetone 33 salt acetone 38 glycofurol 54 acetone 23 A HCI acetone 21 salt acetone 16 acetone 41 Mitogen-stimulated lymph node cell lymphocyte transformation inhibiting activity in Guinea Pigs Guinea pigs were sensitised to Mycobacterium tuberculosum by footpad injections of Freund's Complete Adjuvant (FCA) (0.05 ml; 0.05 mgSml of 50% v/v FCA solution in-sterite.physiological saline).

After 14 days lymph node cells were obtained and suspended in Eagles Minimal Essential (EME) Medium, containing 10% foetal calf serum (FCS) and buffered with Earle's salts, at a concentration of 2.5 x 106 cells/ml.

For 24 hours, 0.1 ml of cell suspension was incubated at 370C in an atmosphere of 95% air and 5% carbon dioxide in the presence of 0.15 ml of mitogen or mitogen and the compound to be tested in EME Medium (containing 10% FCS and buffered with Earle's salts).

Eighteen hours before harvesting, 3H-thymidine(l yl of 100 XttCi/ml solution in 0.9% sterile saline) was added.

As an index of DNA synthesis, the level of 3H-thymidine incorporation by the cells was measured, with comparison with the mitogen control.

The results are given below in Table V.

TABLE V Compound Dose in % inhibition of incubation 3H-thymidine incorporation medium into cell DNA compared tig/ml with mitogen control B 1 47 3 83 L 3 47 10 98 0 3 61 10 99 The utility of the compounds is enhanced by the fact that they are of only very low toxicity, as demonstrated in the following test: Oral toxicity in mice Groups of mice were dosed orally with graded doses of the test compound (in a 0.5% wlV aqueous suspension of tragacanth mucilage) and observed for 3 days thereafter. The percentages of animals which died during that period at each dose level were used to construct a graph, from which the LD50, that is to say the dose in mglkg animal body weight, necessary to kill 50% of the mice; was calculated.

Compounds of formula I specified in the list above were tested and the LD50 of each compound was greaterthan 1000 mg/kg animal body weight.

Preferred compounds of the invention are those hereinbefore identified bytheletters B, D, GG, KK, F, H, AA, U, Z, Land 0.

The compounds of general formula I can be prepared by application or adaptation of known methods, for example as hereinafter identified.

1. According to a feature of the present invention, the compounds of general formula I are prepared by the cyclisation of a compound of the general formula:

(wherein RO represents a hydrogen atom or a group -COR2, and R1 and R2 are as hereinbefore defined), optionally prepared in situ, for example as hereinafter described for the cyclisation of compounds of general formula Ill or IV.

(i) Thus, when R" is a group -COR2, a compound of the general formula:

(wherein R1 and R2 are as hereinbefore defined) is cyclised, preferably at an elevated temperature, for example between 60 and 104 C, e.g. at or near 80"C, by reaction with an inorganic acid, for example hydrochloric acid, in the presence of water and in an organic solvent, for example an alcohol such as methanol or ethanol, or a ketone such as acetone or, preferably, methyl ethyl ketone, or (ii) when Re is a hydrogen atom (especially in respect of those compounds wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms), a compound of the general formula::

(wherein R1 and R2 are as hereinbefore defined) is cyclised, either under conditions similar to those described hereinbefore under (i) or, alternatively, by reaction with an organic acid, e.g. p-toluenesulphonic acid, in water or an organic solvent, e.g. toluene, preferably at an elevated temperature, for example between 60 and 100"C, e.g. at or near 80"C, or (iii) (especially in respect of those compounds wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms) cyclisation usually without isolation of an acylated intermediate of formula Ill or IV either (a) in the absence of an organic solvent and at an elevated temperature, for example at between 1500 and 2500C, or (b) in the presence of water and an inorganic acid, for example hydrochloric acid, and in a suitable organic solvent, for example diglyme.

2. According to a further feature of the present invention, the compounds of general formula I are prepared by the reaction of a compound of the general formula:

(wherein R1 is as hereinbefore defined) with a compound of general formula: R2CHO VI (wherein R2 is as hereinbefore defined) and a copper (II) salt, for example cupric acetate, in the presence of an aqueous inert organic solvent medium, for example a mixture of water and methanol, at between ambient temperature and the reflux temperature of the reaction mixture, followed by converting the resulting copper salt into the corresponding compound of formula 3. According to another feature of the present invention, carboxylic acids of general formula I (wherein R2 is as hereinbefore defined and R1 represents a hydrogen atom) are prepared by hydrolysis of a corresponding ester of general formula I wherein R2 is as herein before defined and R1 represents a straightor branched-chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms. Preferably the hydrolysis is carried out under alkaline conditions, for example in the presence of an alkali metal hydroxide in an aqueous organic solvent system and at an elevated temperature, e.g. in the presence of sodium hydroxide, in aqueous ethanol and at the reflux temperature.

4. According to a still further feature of the present invention, esters of general formula I (wherein R2is as hereinbefore- defined and R1 represents a straight- or branched-chain alkyl group containing from 1 -to 6 carbon atoms, which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group; alkenyl groups containing from 2to-5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms) are prepared by esterification of a corresponding carboxylic acid of general formula I wherein R2 is as hereinbefore defined and R1 represents a hydrogen atom.The esterification may be carried out by the application or adaptation of known methods, for example by reaction of the acid with an excess of the appropriate alcohol of the general formula: R30H VII (wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms) optionally as the solvent medium, and-in the presence of an inorganic acid, e.g. hydrochloric acid, preferably at an elevated temperature, e.g. between 60 and 100 C; or by reaction with the corresponding alkyl-halide.

Acid chlorides formed by reaction with thionyl chloride, or salts of the acids may be used.

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

5. According to a further feature of the present invention, compounds of general formula I may be converted into pharmaceutically acceptable'salts, and viceyersa, by the application or adaption of known methods. As well as being useful in itself, this process isuseful for the purification of compounds of general formula I and their salts by taking advantage of differences in solubility in water and various organic solvents of the compounds and their salts and of any impurities present, by means of known methods such as crystallisation.

(i) Compounds of general formula I may be converted to their pharmaceutically acceptable acid addition salts, for example, by reaction with the appropriate acid in solution or suspension in a suitable solvent, e.g.

acetone, methanol or ethanol, followed if necessary by evaporation of part or all of the solvent, and collection of the solid salt.

(ii) On the other hand, the acid addition salts may be converted to the parent compounds of general formula I, for example by reaction with aqueous ammonia in the presence of a suitable solvent, e.g. ethanol, followed by treatment with a weak acid, for example glacial acetic acid.

(iii) Acids of general formula I wherein R1 represents a hydrogen atom (R2 being as hereinbefore defined) may be converted to salts of pharmaceutically acceptable bases, for example, by reaction with the appropriate base, for example the appropriate amine or a compound of the general formula: M1OR4 VIII (wherein M1 represents an alkali metal, e.g. sodium or potassium, and R4 represents an alkyl group containing up to 4 carbon atoms, e.g. methyl or ethyl, or a hydrogen atom) in a suitable solvent, e.g.

methanol or ethanol, our a mixture of water and acetone, followed if necessary by evaporation of part or all of the solvent, and collection of the solid salt.

(iv) These salts may be converted to the parent compounds of formula I, for example by reaction with a suitable acid, e.g. glacial acetic acid, in solution in a suitable solvent, e.g. water or ethanol, followed if necessary by evaporation of part or all of the solvent, and collection of the solid compound of formula I.

It will be understood by those skilled in the art that in the performance of the processes of the present invention it may be desirable to introduce chemical protecting groups into the reactants in order to avoid secondary reactions taking place; for example in process 1 hereinbefore described, hydroxy groups in the substituent R1 depicted in general formula II may have been converted into benzyloxy groups before reaction as described with subsequent removal of the benzyl group. Furthermore, one process of preparation may be selected in preference to others as a means of making certain envisaged compounds of general formula 1.

Compounds of general formula II wherein F represents a hydrogen atom may be prepared from compounds of the general formula;

(wherein R' and R2 are as hereinbefore defined) by reduction, for example by catalytic hydrogenation, using for example palladium on charcoal.

Compounds of general formula II wherein R represents a group of the formula -COR2 (R2 being as hereinbefore defined) may be prepared from compounds of general formula II wherein R" represents a hydrogen atom by reaction with compounds of general formula Xl depicted hereinafter.

Compounds of general formula IX may be prepared by the reaction of a compound of the general formula:

(wherein R1 is as hereinbefore defined) with a compoundofgeneral formula XI, in a similar manner to that hereinafter described in method A(i).

Compounds of general formula II in which the substituent group -NHCOR2 is meta to the substituent group -COOR1 and in which R" represents a hydrogen atom may be prepared by the reaction of a compound of general formula V with a compound of general formula Xl as hereinafter described in method A(ii).

Compounds of general formula II wherein R" represents a group of the formula -COR2 (R2 being as hereinbefore described) may also be prepared by the reaction of a compound of general formula V with a compound of general formula Xi as hereinafter described in method A(i).

Compounds of general formula II wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms) may be prepared by esterification of the corresponding compounds of general formula II wherein R1 represents a hydrogen atom by the application or adaptation of known methods, for example by reaction with the corresponding diazoalkane in the presence of an inert organic solvent.

MethodA The compounds of general formula II may be prepared by the reaction of a compound of the general formula:

(wherein R1 is as hereinbefore defined) with an acylating agent of the general formula: R2COX1 Xl wherein R2 is as hereinbefore defined and X1 represents a halogen, preferably chlorine, atom or a hydroxy group. (According to a process of the present invention there follows cyclisation of the resulting product optionally in situ).Particularly suitable conditions are as follows: (i) Compounds of general formula V (wherein R1 is as herein before defined) may be reacted with acyl halides of general formula XI (wherein R2 is as hereinbefore defined and X represents a halogen, preferably chlorine, atom) in an inert organic solvent, for example dichloromethane or dimethylformamide, preferably under anhydrous conditions and preferably in the presence of an acid binding agent, for example a trialkylamine, e.g. triethylamine, or an alkali metal carbonate or bicarbonate, e.g. anhydrous sodium or potassium carbonate.

(ii) Compounds of general formula V (especially those wherein R1 represents a straight- or branchedchain alkyl group containing from 1 to 6 carbon atoms) may be reacted with acyl halides of general formula XI (wherein R2 is as hereinbefore defined and X1 represents a halogen, preferably chlorine, atom) under conditions similar to those described hereinbefore under (i) but using a lesser quantity of the acyl halide and controlling the temperature, preferably at between 0-C and room temperature.

By using a set of conditions between those described hereinbefore under (i) and those described hereinbefore under (ii) there would be obtained a mixture of intermediates af general formulae lil and IV, which would be cyclised under the conditions described hereinbefore under 1 (i) and 1 (ii).

(iii) Compounds of general formula V (especially those wherein R1 represents a straight- or branchedchain alkyl group containing from 1 to 6 carbon atoms) may be reacted with the compounds of general formula XI (wherein R2 is as herein before defined and X1 represents a hydroxy group or a chlorine atom) to form compounds of general formula I, usually without isolation of acylated intermediates, either (a) in the absence of solvent and at elevated temperatures, for example at between 150 and 250we, or (b) in the presence of water and an inorganic acid, for example hydrochloric acid, and in a suitable solvent, for example diglyme.

The following Examples and Reference Examples illustrate the preparation of the compounds of the present invention.

EXAMPLE 1 Compound A A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate (46 g) and p-toluenesulphonic acid (15 g) in toluene (1000 ml) was stirred and heated at reflux for 2 hours, with the water produced being removed continuously by means of a Dean and Stark apparatus. The solution was cooled to 600C and was washed with aqueous sodium carbonate solution (2N; 2 x 200 ml). The toluene layer was dried over magnesium sulphate and was then concentrated in vacuo, to give an oil. The oil was triturated with petroleum ether (b.p.

40 - 60"C) to yield a buff solid which, on recrystallisation from petroleum ether(b.p. 400 - 60"C), gave methyl 2-(n-pentadecyl )benzimidazole-5-carboxylate (24.6 g) in the form of a white solid, m.p. 96" -98 C.

The methyl 4-amino-3-(n-hexadecanamido)-benzoate, used as starting material, was prepared by eithe: of the following methods: (i) A stirred solution of methyl 3,4-diaminobenzoate (35 g) in dry dimethylformamide (1200 my), containing anhydrous sodium carbonate (11.8 g), was treated dropwise with n-hexadecanoyl chloride (58 g) during one hour. The rate of addition of the n-hexadecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from an initial value of 1 00C to room temperature. The mixture was then stirred at room temperature for a further period of 3 hours and was then poured into water (5 litres). The resulting solid was collected and was boiled in acetone (1000 ml) and the boiling mixture was then filtered.The filtrate was cooled to 0 C and the resulting buff solid was filtered off, to give methyl 4-amino-3-(nhexadecanamido)benzoate (48.2 g), m.p. 112 - 114 C.

(ii) A stirred solution of methyl 3,4-diaminobenzoate (16.6 g) in dry dichloromethane (270 ml), containing triethylamine (10.3 g), was treated dropwise with a solution of n-hexadecanoyl chloride (27.5 g) in dry dichloromethane (30 ml) during 45 minutes. The temperature during the addition was maintained between 16 and 20"C. The mixture was stirred for a further period of 2 hours. The resulting solid was then collected and boiled in a mixture of acetone (1000 ml) and methanol (150 ml) and the insoluble material was removed by filtration. The filtrate was cooled to 25"C and treated with water (800 ml) to give methyl 4-amino-3-(nhexadecanamido)-benzoate in the form of a buff solid, m.p. 112" - 114 C.

EXAMPLE 2 Compound A A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate (34 g; prepared as described hereinbefore in Example 1) in a mixture of ethanol and water (200 ml; 9:1 v/v) was treated with an excess of a saturated solution of hydrogen chloride in ethanol. The mixture was heated at reflux for 2 hours and was then cooled.

The resulting solid was collected and recrystallised from a mixture of ethanol and water (9:1 viv) to give methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (24.2 g) in the form of a white solid, m.p.

230 - 232"C (with decomposition).

EXAMPLE 3 Compound A Methyl 3,4-diaminobenzoate (8.8 g) and hexadecanoic acid (12.8 g) were ground together to form an intimate mixture. The mixture was heated at 2000C for 150 minutes. The mixture was then cooled to 60"C and was extracted with boiling petroleum ether (b.p. 60" - 80"C; 200 ml). The extract was concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (100 ml) and the solution was treated with a solution of potassium hydroxide in ethanol (10% w w) until the pH of the mixture was 7. The mixture was then cooled to 0 C and filtered and the filtrate was concentrated in vacuo to give a brown oil (10.2 g). The oil was dissolved in chloroform (15 ml) and chromatographed on silica gel (275 g).Elution with chloroform gave an off-white solid (6.0 g), which was recrystallised from petroleum ether (b.p. 40" 60-C), to give methyl 2-(n- pentadecyl)benzimidazole-5-carboxylate (5.3 g) in the form of a white solid, m.p. 96 - 984C.

EXAMPLE 4 Compound B A stirred solution of methyl 2-(n-pentadecyl)-benzimidazole-5-carboxylate (36 g; prepared as described hereinbefore in Example 1 or 3) in a mixture of ethanol and water (500 ml; 4:1 v,v) containing sodium hydroxide (8 g) was heated at reflux for 90 minutes. The mixture was cooled to 0 C and was acidified by treatment with concentrated hydrochloric acid. The resulting off-white solid was collected and was recrystallised (with treatment with charcoal) from a mixture of ethanol and water (800 ml; 4:1 viv) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (32 g) in the form of a white solid, m.p. 289" 291"C (with decomposition).

EXAMPLE 5 Compound B A solution of methyl 2-(n-pentadecyl)-benzimidazole-5-carboxylate hydrochloride (24.2 g; prepared as described hereinbefore in Example 2) in a mixture of ethanol and water (250 ml; 4:1 vtv), containing sodium hydroxide (7 g) was treated in a manner similar to that described hereinbefore in Example 4 to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (22.4 g), m.p. 289" - 291"C (with decomposition).

EXAMPLE 6 Compound C A solution of methyl 4-amino-3-(n-dodecanamido)benzoate (41.0 g) in toluene (1000 ml) containing p-toluenesulphonic acid (25 g) was treated in a manner similar to that described hereinbefore in Example 1 to give methyl 2-(n-undecyl)-benzimidazole-5-carboxylate (27.0 g) in the form of a white solid, m.p. 93" - 95"C.

The methyl 4-amino-3-(n-dodecanamido)-benzoate, used as starting material, was prepared as follows: A solution of methyl 3,4-diaminobenzoate (25.0 g) in dry dimethylformamide (1120 ml), containing anhydrous sodium carbonate (7.7 g), was treated with n-dodecanoyl chloride (30.5 g) in a manner similar to that hereinbefore described in Example 1 (i) to give crude methyl 4-amino-3-(n-dodecanamido)benzoate (41 g) in the form of a buffsolid.

EXAMPLE 7 Compound C Methyl 3,4-diaminobenzoate (33 g) and dodecanoic acid (40 g) were ground together to form an intimate mixture and the mixture was heated at 200"C for 3 hours. The mixture was then treated in a manner similar to that described hereinbefore in Example 3 to give methyl 2-(n-undecyl)benzimidazole-5-carboxylate (19 g) in the form of a white solid, m.p. 92" - 94"C.

EXAMPLE 8 Compound D A solution of methyl 2-(n-undecyi)-benzimidazole-5-carboxylate (28.6 g; prepared as described hereinbefore in Example 7) in a mixture of ethanol and water (350 ml; 4:1 vZv) containing sodium hydroxide (6.93 g) was treated in a manner similar to that described hereinbefore in Example 4 to give 2-(n- undecyl)benzimidazole-5-carboxylic acid hydrochloride (22.3 g) in the form of a white solid, m.p. 289" - 294cm (with decomposition).

EXAMPLE 9 Compound E Methyl 3,4-diaminobenzoate (33.0 g) and n-tetradecanoic acid (45.6 g) were ground together to form an intimate mixture and the mixture was heated at 2000C for 6 hours. The mixture was cooled to 60"C and was then extracted with petroleum ether (b.p. 60" - 80 C), and the petroleum ether extracts were concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (500 ml) and the solution was treated with a solution of potassium hydroxide in ethanol (10% w/v) until the pH of the mixture was 7. The mixture was cooled to 0 C and filtered and the filtrate was concentrated in vacuo to give a brown oil.The oil was partitioned between a hot mixture of petroleum ether (b.p. 60" - 80Cl and toluene (300 ml; 4:1 viz), and water (300 ml). The organic layer was concentrated in vacuo to give an oil which was then dissolved in hot toluene (100 ml) and treated with an excess of a saturated solution of hydrogen chloride in ethanol. The resulting solid was collected and recrystallised from ethanol (with treatment with charcoal) to give methyl 2-(n-tridecyl)benzimidazole-5-carboxylate hydrochloride (16 g) in the form of a white solid, m.p. 2282 - 236"C (with decomposition).

EXAMPLE 10 Compound Methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) was treated in a manner similar to that described hereinbefore in Example 2 to give methyl 2-(n-tridecyi)benzimidazole-5-carboxylate hydrochloride (33 g) in the form of a white solid, m.p. 228- - 234no (with decomposition).

The methyl 4-amino-3-(n-tetradecanamido)benzoate, used as starting material, was prepared as follows: A stirred solution of methyl 3,4-diaminobenzoate (25.0 g) in dry dichloromethane (500 ml), containing triethylamine (15.5 g), was treated dropwise with a solution of n-tetradecanoyl chloride (37.12 g) in dry dichloromethane (50 ml) in a manner similar to that described hereinbefore in Example 1 (ii) to give crude methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) in the form of a buff solid.

EXAMPLE 11 Compound F A solution of methyl 2-(n-tridecyl)-benzimidazole-5-carboxylate (7.9 g) in a mixture of ethanol and water (200 ml; 4:1 viv) containing sodium hydroxide (2.4 g) was treated in a manner similar to that described hereinbefore in Example 4 to give 2-(n-tridecyl)benzimidazole-5-carboxylic acid hydrochloride (5.7 g) in the form of a white solid, m.p. 299" - 306"C (with decomposition).

EXAMPLE 12 Compound B 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (15.0 g; prepared as described hereinbefore in Example 4) was dissolved in a hot mixture of ethanol and water (1 000.ml; 6:1 v/v). The hot solution was treated with aqueous ammonia solution (2N) until the solution was alkaline. Glacial acetic acid was then added to the mixture until the solution was acidic, and the solution was cooled to 0 C to give a white solid (12.3 g). This solid was recrystallised from a mixture of ethanol and water (4:1 v/v) to give 2-(n- pentadecyl)benzimidazole-5-carboxylic acid (12.0 g) in the form of a white solid, m.p. 113" - 115"C, thought to be the monohydrate.

EXAMPLE 13 Compound G Methyl 4-amino-3-(n-tridecanamido)benzoate (prepared as described hereinafter from 17.8 g of methyl 3,4-diaminobenzoate and used without further purification) was dissolved in hot ethanol (500 ml) containing an excess of hydrochloric acid, and was treated in a manner similar to that described hereinbefore in Example 2 to give methyl 2-(n-dodecyl)-benzimidazole-5-carboxylate hydrochloride (25.5 g) in the form of a white solid, m.p. 221" - 2250C (with decomposition).

The methyl 4-amino-3-(n-tridecanamido)benzoate, used as starting material, was prepared as follows: A solution of methyl 3,4-diaminobenzoate (17.8 in dichloromethane-(350 ml) containing triethylamine (10.8 g) was treated with n-tridecanoyl chloride (25 g) in a manner similar to that described hereinbefore in Example 1 (ii) to give crude methyl 4-amino-3-(n-tridecanamido)benzoate (40 g).

EXAMPLE 14 Compound H A solution of methyl 2-(n-dodecyl-benzimidazole-5-carboxylate (15.5 g) in a mixture of ethanol and water (100 ml; 4:1 v/v) containing sodium hydroxide (50 g) was treated in a manner similar to that described hereinbefore in Example 4to give 2-(n-dodecyl)benzimidazole-5-carboxylic acid hydrochloride (11.7 g) in the form of a white solid, m.p. 276" - 290"C (with decomposition).

EXAMPLE 15 Compound B A solution of 3,4-bis(n-hexadecanamido)benzoic acid (20 g) in methyl ethyl ketone (460 ml) was treated with concentrated hydrochloric acid (35 ml of strength 36.5% wiv). The mixture was heated at reflux for 5 hours and was then cooled. The resulting solid was collected and washed with boiling petroleum ether (b.p.

60 - 80"C), and recrystallised from ethanol to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (15 g) in the form of a white solid, m.p. 2899 - 291"C (with decomposition).

The 3,4-bis(n-hexadecanamido)benzoic acid, used as starting material, was prepared as follows: A solution of 3,4-diaminobenzoic acid (7.5 g) in dichloromethane (100 ml) containing triethylamine (15 g) was treated with n-hexadecanoyl chloride (27.5 g) in a manner similar to that described hereinbefore in Example 1 (ii). A solid was collected and was recrystallised from glacial acetic acid and was then recrystallised from methyl ethyl ketone (with filtration of the hot solution) to give 3,4-bis(nhexadecanamido)benzoic acid (20 g) in the form of a buff solid, m.p. 198 - 202"C.

EXAMPLE 16 Compound A solution of methyl 3,4-bis(n-hexadecanamido)benzoate (10.0 g) in methyl ethyl ketone (100 ml)was treated in a manner similar to that described hereinbefore in Example 15 to give methyl 2-(n- pentadecyl)benzimidazole-5-carboxylate hydrochloride (5.7 g) in the form of a white solid, m.p. 2300 - 232"C (with decomposition).

The methyl 3,4-bis(n-hexadecanamido)benzoate, used as starting material, was prepared as follows: A solution of methyl 3,4-diaminobenzoate (5.0 g) in dichloromethane (50 ml), containing triethylamine (6.2 g), was treated with n-hexadecanoyl chloride (16.5 g) in a manner similar to that described hereinbefore in Example 1(ii) (the temperature of the reaction mixture during the addition being allowed to rise from 20"C to 30"C). A solid was collected and recrystallised from chloroform to give methyl 3,4-bis(nhexadecanamido)benzoate (14.9 g) in the form of a white solid, m.p. 129; - 132-C.

EXAMPLE 17 Compound I A stirred solution of methyl 3,4-bis(n-undecanamido)benzoate (33.0 g) in methanol (400 ml) containing concentrated hydrochloric acid (50 ml of strength 36.5% wiv) was heated at reflux for 3 hours. The mixture was then cooled to 0 C and filtered, and the solid obtained was combined with the residue resulting from evaporation of the filtrate in vacuo. The combined solids were washed with hot petroleum ether (b.p. 60" 80"C; 200 ml) and recrystallised from ethanol (with filtration of the hot solution) to give methyl 2-(n-decyl)benzimidazole-5-carboxylate hydrochloride in the form of a white solid (13.7 g), m.p. 230" - 240"C (with decomposition).

The methyl 3,4-bis(n-undecanamido)benzoate, used as starting material, was prepared as follows: A solution of methyl 3,4-diaminobenzoate (17.9 g) in dichloromethane (300 ml) containing triethylamine (21.8 g) was treated with n-undecanoyl chloride (44.3 g) in a manner similar to that described herein before in Example 16. A solid was collected and recrystallised twice from ethanol (with filtration of the hot solution) to give methyl 3,4-bis(n-undecanamido)benzoate (40.2 g) in the form of a white solid, m.p. 139" - 141"C.

EXAMPLE 18 Compounds A solution of methyl 2-(n-decyl)-benzimidazole-5-carboxylate hydrochioride (13.7 g; prepared as described hereinbefore in Example 17) in a mixture of ethanol and water (250 ml; 4:1 viv) containing sodium hydroxide (4.6 g) was treated in a manner similar to that described hereinbefore in Example 4 to give 2-(n-decyl)benzimidazole-5-carboxylic acid hydrochloride (9.4 g) in the form of a white solid, m.p. 270"-282"C (with decomposition).

EXAMPLE 19 Compound B A solution of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (11.16 g: prepared as described hereinbefore in Example 12) in methanol (150 ml) was heated to 60"C and treated with a solution of sodium methoxide [prepared by carefully dissolving sodium (0.69 g) in anhydrous methanol (40 ml)] and the mixture was then cooled. The solvent was evaporated in vacuo and the residue was recrystallised from water to give sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate monohydrate (9.7 g) in the form of a white solid, which darkens at 2500C and decomposes at above 300"C.

EXAMPLE 20 Compound B A stirred suspension of 2-(n-pentadecyl)-benzimidazole-5-carboxylic acid monohydrate (1.00 g; prepared as described herein before in Example 12) in acetone (30 ml) was treated dropwise with a solution of methanesulphonic acid (0.25 g) in methanol (15 ml) at room temperature. The mixture was heated to 40"C to obtain a solution, and then the solvent was evaporated in vacuo. The white solid residue was triturated with acetone (30 ml) and the resulting solid was collected and washed with acetone (10 ml) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid methanesulphonate (1.19 g) in the form of a white solid, m.p. 115"-117"C.

EXAMPLE 21 Compound B A stirred suspension of 2-(n-pentadecyl )-benzimidazole-5-carboxyl ic acid monohydrate (1.00 g; prepared as described hereinbefore in Example 12) in acetone (30 ml) was treated with an excess of a solution of 2-hydroxyethylsulphonic acid (10% w-v) in a mixture of methanol and water (19:1 viv). The solution was evaporated in vacuo and the residue was triturated with acetone (30 ml). The resulting solid was collected and washed with acetone (10 ml) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid 2hydroxyethylsulphonate (1.24 g) in the form of a white solid, m.p. 93"-95'C.

EXAMPLE 22 Compound A 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (10.0 g; prepared as described hereinbefore in Example 4) was dissolved in boiling methanol (250 ml) in a reflux apparatus and then was treated with concentrated hydrochloric acid (20 ml of strength 36.5% w.v). The mixture was heated at reflux for 3 hours and was then cooled to 0WC. The resulting white solid was collected, washed with water, and recrystallised from ethanol to give methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (9.2 g) in the form of a white solid, m.p. 230-232-C (with decomposition).

EXAMPLE 23 Compound K Methyl 3,4-diaminobenzoate (33.0 g) and n-octadecanoic acid (56.8 g) were ground together to form an intimate mixture and the mixture was heated at 2000C for 210 minutes. The mixture was then treated in a manner similar to that described hereinbefore in Example 9. The brown oil obtained after partition between the hot mixture of petroleum ether, toluene and water was dissolved in chloroform (25 ml) and subjected to chromatography on a column of silica gel (750 g). Elution with a mixture of chloroform and methanol (19:1 v/v) gave a light brown solid (40 g). This solid was dissolved in hottoluene (200 ml) and treated with an excess of a saturated solution of hydrogen chloride in ethanol. The resulting solid was collected and recrystallised (with treatment with charcoal) from a mixture of ethanol and water (9:1 viva, to give methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate hydrochloride (19.9 g) in the form of a white solid, m.p.

229"-234"C (with decomposition).

EXAMPLE 24 Compound L A solution of methyl 2-(n-heptadecyl)-benzimidazole-5-carboxylate hydrochloride (11.5 g; prepared as described hereinbefore in Example 23) in a mixture of ethanol and water (200 ml; 1:1 v/v) containing sodium hydroxide (14.35 g)was treated in a manner similar to that described hereinbefore in Example 4 to give 2-(n-heptadecyl)benzimidazole-5-carboxylic acid hydrochloride (8.8 g) in the form of a white solid, m.p.

279"-284"C (with decomposition).

EXAMPLE 25 Compound M A mixture of methyl 4-amino-3-(n-decanamido)benzoate (16.7 g) and toluene (600 ml) containing p-toluenesulphonic acid (5.0 g) was treated in a manner similar to that described hereinbefore in Example 1 to give methyl 2-(n-nonyl)-benzim idazole-5-carboxylate (14.0 g) in the form of a white solid, m.p. 101"-103"e.

The methyl 4-amino-3-(n-decanamido)-benzoate, used as starting material, was prepared as follows: A stirred solution of methyl 3,4-diaminobenzoate (16.6 g) in dry dimethylformamide (600 ml) containing anhydrous sodium carbonate (5.3 g) was treated dropwise with n-decanoyl chloride (19.1 g) in a manner similar to that described hereinbefore in Example 1 (i) to give methyl 4-amino-3-(n-decanamido)-benzoate (18.8 g) in the form of a buff solid, m.p. 96"-98"C.

EXAMPLE 26 Compound N A solution of methyl 2-(n-nonyl)benzimidazole-5-carboxylate (13.5 g; prepared as described hereinbefore in Example 25) in a mixture ofethanol and water (400 ml; 4:1 v/v) containing sodium hydroxide (3.6 g) was treated in a manner similar to that described hereinbefore in Example 4 to give 2-(n--nonyl)benzimidazole-5- carboxylic acid hydrochloride (8.6 g) in the form of a white solid, m.p. 275-280"C.

EXAMPLE 27 Compound O A stirred solution of methyl 3,4-bis(n-octanamido)benzoate (81.8 g) in methanol (800 rnI) containing concentrated hydrochloric acid (100 ml of strength 36.5% w/v) was heated at reflux for 4 hours. The mixture was then cooled and treated in a manner similar to that described hereinbefore in Example 17 to give methyl 2-(n-heptyl)benzimidazole-5-carboxylate hydrochloride (33.8 g) in the form of a white solid, m.p. 140-142"C (with decomposition).

The methyl 3,4-bis(n-octanamido)benzoate, used as starting material, was prepared as follows: A solution of methyl 3,4-diaminobenzoate (41.2 g) in dichloromethane (412 ml) containing triethylamine (51.0 g) was treated with a solution of n-octanoyl chloride (80.6 g) in dichloromethane (330 ml) in a manner similar to that described hereinbefore in Example 16, recrystallisingfrom methanol (with treatment with charcoal), to give methyl 3,4-bis(n-octanamido)benzoate (81.8 g) in the form of a white solid, m.p. 138-140"C.

EXAMPLE 28 Compound P A stirred solution of methyl 2-(n-heptyl)-benzimidazole-5-carboxylate hydrochloride (23.0 g; prepared as described hereinbefore in Example 27) in a mixture of ethanol and water (200 ml; 12:1 vivl containing sodium hydroxide (8.9 g) was heated at reflux for 5 hours. The mixture was treated in a manner similar to that described herein before in Example 4 to give 2-(n-heptyl )-benzimidazole-5-carboxylic acid hydrochloride (14.4 g) in the form of a white solid, m.p. 310"-313"C (with decomposition).

EXAMPLE 29 Compounds A stirred solution of 3,4-bis(n-pentadecanamido)benzoic acid (49.3 g) in a mixture of methyl ethyl ketone and concentrated hydrochloric acid (560 ml; 10:1 viv) was heated at reflux for 3 hours. The mixture was then cooled. The resulting solid was collected and washed with methyl ethyl ketone (200 ml) and then washed with boiling petroleum ether (200 ml; b.p. 60"-80"C. It was recrystallised from a mixture of ethanol and water (4:1 v/v) (with treatment with charcoal and with filtration of the hot solution) to give 2-(n- tetradecyl )benzimidazole-5-carboxylic acid hydrochloride (15.7 g), m.p. above 300"C (with decomposition).

The 3,4-bis(n-pentadecanamido)benzoic acid, used as starting material, was prepared as follows: A solution of 3,4-diaminobenzoic acid (13.85 g) in dimethylformamide (180 ml) containing triethylamine (27.6 g) was treated with n-pentadecanoyl chloride (47.4 g) in a manner similar to-that described hereinbefore in Example 1(i). The resulting solid was collected and recrystallised from methyl ethyl ketone (with treatment with charcoal and with filtration of the hot solution) to give 3,4-bis(npentadecanamido)benzoic acid (49.3 g), m.p. 178"-180"C.

EXAMPLE 30 Compound R (a) A stirred solution of methyl 3,4-bis(n-nonanamido)benzoate (23.3 g) in methanol (300 ml) was treated with concentrated hydrochloric acid (40 ml of strength 36.5% w/v). The mixture was heated at reflux for 3 hours and the solvent was removed in vacuo to give a white solid. The solid was washed with hot petroleum ether (100 ml; b.p. 40"-60"C) and was recrystallised from water (700 ml) with hot filtration to give methyl 2-n-octylbenzimidazole-5-carboxylate hydrochloride in the form of a white solid, m.p. 238-243"C (12.0 g).

(b) A stirred solution of methyl 2-n-octylbenzimidazole-5-carboxylate hydrochloride (11 g; prepared as described above) in a mixture of ethanol and water (240 ml; 12:1 v/v) containing sodium hydroxide (4.0 g) was heated at reflux for 4 hours. The mixture was treated in a manner similar to that described herein before in Example 4 to give 2-(n-octyl)benzimidazole-5-carboxylic acid hydrochloride (7.8 g) in the form of a white solid, m.p. 280"-300"C (with decomposition).

The methyl 3,4-bis(n-nonanamido)benzoate, used as starting material, was prepared as follows: (c) A stirred solution of methyl 3,4-diaminobenzoate (20 g) in dry dichloromethane (250 ml), containing triethylamine (24.2 g), was treated dropwise with a solution of nonanoyl chloride (44.12 g) in dry dichloromethane (50 ml) in a manner similar to that hereinbefore described in Example 1 (it). The resulting pink solid was recrystallised from methanol, with treatment with charcoal, to give methyl 3,4-bis-(nnonanamido)benzoate (30.3 g) in the form of a white solid, m.p. 142"-145"C.

EXAMPLE 31 Compound S 2-(n-Tetradecyl)benzimidazole-5-carboxylic acid hydrochloride (8.5 g; prepared as described herein before in Example 29) was dissolved in boiling methanol (96 ml) in a reflux apparatus and was then treated with concentrated hydrochloric acid (22 ml, of strength 36.5% w/v). The mixture was refluxed for 3 hours, and was then treated in a manner similar to that described hereinbefore in Example 22 to give methyl 2-(n-tetradecyl)benzimidazole-5-carboxylate hydrochloride (6.2 g) in the form of a white solid, m.p.

233"-235"C.

EXAMPLE 32 Compound T 2-(n-Hexadecyl)benzimidazole-5-carboxylic acid hydrochloride (9.0 g; prepared as described hereinafter in Example 33) was dissolved in boiling methanol (400 ml) in a reflux apparatus and then was treated with concentrated hydrochloric acid (100 ml of strength 36.5% w/v). The mixture was heated at reflux for 8 hours and was then treated in a similar manner to that described hereinbefore in Example 22 to give methyl 2-(n-hexadecyl)benzimidazole-5-carboxylate hydrochloride (7.4 g) in the form of a white solid, m.p.

225"-230"C (with decomposition).

EXAMPLE 33 Compound U A solution of 3,4-bis(n-heptadecanamido)-benzoic acid (250 g) in methyl ethyl ketone (1500 ml) was treated with concentrated hydrochloric acid (180 ml, of strength 36.5% wiz). The mixture was refluxed for 8 hours and was treated in a similar manner to that described hereinbefore in Example 15 to give 2-(n hexadecyl)benzimidazole-5-carboxylic acid hydrochloride (44.9 g) in the form of an off-white solid, m.p.

296 -306 C (with decomposition).

The 3,4-bis(n-heptadecanamido)benzoic acid, used as starting material, was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (45.6 g) in dimethylformamide (400 ml), containing triethylamine (75.8 g), was treated dropwise with n-heptadecanoyl chloride (130 g) during 1.5 hours. The rate of addition of n-heptadecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from room temperature to 35"-40"C. The mixture was then stirred at room temperature for a further period of 2 hours and was then poured into hot water (3500 ml kept at 70"C) containing concentrated hydrochloric acid (50 ml of strength 36.5% w v) to give crude 3,4-bis(n-heptadecanamido)-benzoic acid (140 g) in the form of a pink solid.

EXAMPLE 34 Compound V 2-n-Eicosylbenzimidazole-5-carboxylic acid hydrochloride (12 g; prepared as described hereinafter in Example 35) in chloroform (300 ml) was treated dropwise with stirring with thionyl chloride (100 ml). The mixture was refluxed for 4 hours and was then cooled and the excess thionyl chloride and the solvent was removed in vacuo to give a white solid. The solid was suspended in anhydrous methanol (300 ml) and the mixture was stirred and refluxed for 8 hours and then cooled. The solid was collected and washed with methanol to give methyl 2-(n-eicosyl)benzimidazole-5-carboxylate hydrochloride (9.2 g) in the form of a white solid, m.p. 220"-226"C.

EXAMPLE 35 Compound W A solution of 3,4-bis(n-heneicosanamido)-benzoic acid (126.5 g) in methyl ethyl ketone (1000 ml) was treated with concentrated hydrochloric acid (100 ml, of strength 36.5% w/v). The mixture was refluxed for 10 hours and was then treated in a similar manner to that described hereinbefore in Example 15 to give a white solid which was recrystallised from n-butanol~(1200 ml) td give 2-(n-eicosyl)benzimidazole-5-carboxylic acid hydrochloride-(45.1 g);n the form of a white solid, m.p. 294-298"C (with decomposition).

The 3,4-bis(n-heneicosanamido)benzoic acid, used as starting material, was prepared as follows A stirred solution of 3,4-diaminobenzoic acid (21.9 9) !n dimethylformamide (175 ml), containing triethylamine (43.6 g), was treated dropwise with n-heneicosanoyl chloride (99.2 g) in a manner similar to that described hereinbefore in Example 33 to give crdde 3,4-bis(n-heneicosanamido)-benzoic acid (126.5 g) in the form of a light brown solid.

EXAMPLE 36 Compound X 2-(n-Nonadecyl)benzimidazole-5-carboxylic acid hydrochloride (14.6 g; prepared as described hereinafter in Example 37) was suspended in thionyl chloride (350 ml) and the mixture was stirred and refluxed for 6 hours. The excess thionyl chloride was removed in vacuo to give a yellow-brown solid. The solid was suspended in anhydrous methanol (500 ml) and the mixture was stirred and refluxed for 3 hours. The mixture was then treated in a similar manner to that described in Example 34 to give methyl 2-(n-nonadecyl)benzimidazole-5-carboxylate hydrochloride (12.2 g) in the form of a white solid, m.p.

219"-227"C.

EXAMPLE 37 Compound Y A suspension of 3,4-bis(n-eicosanamido)-benzoic acid (89.1 g) in methyl ethyl ketone (1200 ml) was heated with concentrated hydrochloric acid (120 ml, of strength 36.5% w/v). The mixture was stirred and refluxed for 8 hours and then treated in a similar manner to that described-hereinbefore in Example 15 to give a white solid. The solid was boiled with n-butanol (100 ml) and the mixture was cooled to give 2-(n- nonadecyl)benzimidazole-5-carboxylic acid hydrochloride (36.5 g) in the form of a white solid, m.p.

290 -300 C (with decompositon).

The 3,4-bis(n-eicosanamido)benzoic acid, used as starting material, was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (18.3 g) in dimethylformamide (200 ml), containing triethylamine (36.5 g), was treated dropwise with n-eicosanoyl chloride (79.4 g) in a manner similar to that described hereinbefore in Example 33 to give crude 3,4-bis(n-eicosanamido)benzoic acid (93 g) in the form of a pale brown solid, m.p. 1600-1700C.

EXAMPLE 38 CompoundZ A suspension of 4-amino-3-(n-nonadecanamido)-benzoic acid (107 g) in methyl ethyl ketone (1500 ml) was treated with concentrated hydrochloric acid (100 ml, of strength 36.5% w/v). The mixture was stirred and refluxed for 3 hours. The mixture was cooled to 100C and the solid was collected, washed with methyl ethyl ketone (2 x 500 ml) and suspended in water (500 ml). Sodium hydroxide solution (50 g in water (150 ml)) was added to the mixture and the mixture was stirred and warmed to 60"C to effect solution. Glacial acetic acid was added to the stirred mixture until the mixture was pH 5, and the resultant solid was collected, washed with water (2 x 500 ml) and dried.The solid was recrystallised from methanol, with treatment with charcoal, to give a white solid which was carefully dried and then suspended in methyl ethyl ketone (500 ml) containing concentrated hydmohioric acid (100 ml, of strength 36.5% wlv). The mixture was stirred and refluxed for 1 hour and then cooled to give 2-(n-octadecyl)benzimidazole-5-carboxylic acid hydrochloride (33.8 g) in the form of a white solid, m.p. -297cC (with decomposition).

The 4-amino-3-(n-nonadecanamido)benzoic acid, used as starting material, was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (38 g) in dimethylformamide (500 ml), containing triethylamine (50.5 g), was treated dropwise with n-nonadecanoyl chloride (79.1 g) in a similar manner to that described hereinbefore in Example 33 to give an orange solution, which was poured into water (3000 ml), containing concentrated hydrochloric acid (100 ml, of strength 36.5% w,v). The solid was collected, washed with water (2 x 100 ml) and then dried to give crude 4-amino-3-(n-nonadecanamido)-benzoic acid (107 g), m.p. 103"-113"C.

EXAMPLE 39 Compound 11 2-(n-Octadecyl)benzimidazole-5-carboxylic acid hydrochloride (12 g; prepared as described hereinbefore in Example 38) in thionyl chloride (100 ml) was stirred and refluxed for 3 hours and then treated in a manner similar to that described hereinbefore in Example 36 to give methyl 2-(n-octadecyl)benzimidazole-5carboxylate hydrochloride (11.6 g) in the form of a white solid, m.p. 2240-2300C.

EXAMPLE 40 Compound A suspension of 3,4-bis[2-methyltetradecanamido]-benzoic acid (53.1 g) in methyl ethyl ketone (250 ml) was treated with concentrated hydrochloric acid (37.6 ml, of strength 36.5% w/v). The mixture was stirred and refluxed for 16 hours. The mixture was cooled to 0 C and the solid was collected (11.17 g) and washed with methyl ethyl ketone (2 x 25 ml). The solid was suspended in water (50 ml), and sodium hydroxide solution [20 g in water (50 ml)] was added to the suspension. The mixture was stirred and warmed to 60"C to effect solution, and then glacial acetic acid was added to the stirred mixture until the mixture was pH 5.The resulting solid was collected, washed with water and recrystallised from ethanol with treatment with charcoal, and then treated in a similar manner to that described hereinbefore in Example 38 to give (RS)-2-(tetradec-2-yl)-benzimidazole-5-carboxylic acid hydrochloride (11 g) in the form of a white solid, m.p.

214"-218"C.

The 3,4-bis[2-methyltetradecanamido]-benzoic acid, used as starting material, was prepared as follows A stirred solution of 3,4-diaminobenzoic acid (17.5 g) in dimethylformamide (140 mi), containing triethylamine (34.8 g), was treated dropwise with pentadecan-2-oyi chloride (59.7 g) in a similar manner to that described hereinbefore in Example 33 to give crude 3,4-bis[2-methyltetradecanamido]-benzoic acid (68 9).

EXAMPLE 41 Compound CC A solution of 4-amino-3-[2-hexyloctanamido]-benzoic acid (1-5.2 g) in methyl ethyl ketone (78 ml) was treated with concentrated hydrochloric acid (18.2 ml, of strength 36.5% wiv). The mixture was stirred and refluxed for 12 hours and the methyl ethyl ketone was then removed in vacuo. The residue was suspended in water (200 ml) and sodium hydroxide solution (50% w/v in water) was added to the mixture until it was pH 11. The mixture was heated to 90"C and then diluted with water to a total volume of 1500 ml. The solution was treated with charcoal and then treated with an excess of acetic acid (25% w/v in water) to give an off-white solid.The solid was collected, washed with water and recrystallised from ethyl acetate to give 2-(tridec-7-yl)benzimidazole-5-carboxyiic acid (8.89 g), m.p. 1 57"-1 58"C.

The solid was dissolved in acetone (350 ml) and the solution treated with concentrated sulphuric acid (1.55 ml, of strength 98% w'w). On cooling, a white solid was obtained, which was recrystallised from methyl ethyl ketone to give 2-(tridec-7-yl)-benzimidazole-5-carboxylic acid hemisulphate (6.8 g), in the form of a white solid, m.p. 202 -2055C.

The 4-amino-3-[2-hexyloctanamido]benzoic acid, used as starting material, was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (20.7 g) in dimethylformamide (165 ml), containing triethylamine (56.5 ml), was treated dropwise with 2-hexyloctanoyl chloride (67 g) in a similar manner to that described in Example 33. The waxy solid was collected and dissolved in diethyl ether (500 ml), and the ether solution was dried and evaporated to give a red brown oil. This oil was extracted with hot methanol, using a continuous extraction apparatus, for 5 hours. The methanol solution was evaporated on a rotary evaporator to give a brown solid, which was recrystallised from acetone to give 4-amino-3-12-hexyloctanamidolbenzoic acid (15.2 g) in the form of a white solid, m.p. 2195-225C.

EXAMPLE 42 Compound BB A solution of 4-amino-3-(2-ethyldodecanamido)-benzoic acid (24.7 g) in methyl ethyl ketone (125 ml) was treated with concentrated hydrochloric acid (29 ml, of strength 36.5% w v). The mixture was stirred and refluxed for 12 hours and was then treated in a similar manner to that described hereinbefore in Example 41 to give a white solid, which was recrystallised from a mixture of acetone (200 ml) and water (200 ml) to give (RS)-2-(tridec-3-yl)benzimidazole-5-carboxylic acid hemisulphate (14.2 g) in the form of a white solid, m.p.

185C-187-C.

The 4-amino-3-(2-ethyldodecanamido)benzoic acid, used as starting material, was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (22.8 g) in dimethylformamide (200 ml), containing triethylamine (22.7 g), was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in a similar manner to that described hereinbefore in Example 41 to give a solid, which was recrystaliised from ethyl acetate with treatment with charcoal to give 4-amino-3-(2-ethyldodecanamido)benzoic acid (22.2 g) in the form of a white solid, 188'-191:C.

EXAMPLE 43 Compound DD A solution of 4-amino-3-[2-butyldecanamido]-benzoic acid (9.8 g) in methyl ethyl ketone (50 ml) was treated with concentrated hydrochloric acid (11.5 ml, of strength 36.5% w v) in a manner similar to that described hereinbefore in Example 41 to give (RS)-2-(tridec-5-yl)benzimidazole-5-carboxylic acid hemisu phate (4.7 g) in the form of a white solid m.p. 1 61164C.

The 4-amino-3-[2-butyidecanamido jbenzoic acid, used as starting material, was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (15.8 g) in dimethylformamide (130 ml), containing triethylamine (43.4 g), was treated dropwise with 2-butyidecanoyl chloride (51;4 g) in a similar manner to that described hereinbefore in Example 41 to give 4-amino-3-[2-butyidecanamido]kenzoic acid (9.8 g) in the form of a white solid, m.p. 178"-182"C.

EXAMPLE 44 Compound EE A mixture of 2-(n-pentadecyl)benzimidazole-5-carb6nyl chloride hydrochloride (10 g) in ethanol (250 ml) was stirred and refluxed for 2 hours. The mixture was cooled to room temperature and the solid was collected and washed with ethanol (50 ml) and then with diethyl ether (2 x 50 ml). The solid was dissolved in boiling ethanol (25 ml) and the solution treated with concentrated hydrochloric acid (0.5 ml of strength 36.5%w/v). The solution was cooled to 00and the resulting solid ways collected to give ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (7.8 g) in the form of a white solid, m.p.

207-213"C.

The 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride, used as starting material, was prepared as follows: 2-(n-PentadecVl)benzimidazole-5-carboxylic acid monohydrate (32 g) was added portionwise to a stirred solution of thionyl chloride (250 ml) at room temperature. The mixture was stirred and refluxed for 2 hours and theri the thionyl chloride was removed in vacuo to give 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (33 g) in the form of a cream solid, m.p. 286"-288"C (with decomposition).

EXAMPLE 45 Compound FF A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as described hereinbefore in Example 44) in n-hexyl alcohol (300 ml) was treated in a similar manner to that described hereinbefore in Example 44 to give hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydroch bride (9.8 g) in the form of a white solid m.p. 166-170"C.

EXAMPLE 46 Compound GG A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as described hereinbefore in Example 44) in n-butyl alcohol (300 ml) was treated in a similar manner to that described hereinbefore in Example 44 to give butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (8.9g) in the form of a white solid, m.p.170 -174 C.

EXAMPLE 47 Compound HH A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as described hereinbefore in Example 44) in isopropyl alcohol (300 ml) was treated in a similar manner to that described hereinbefore in Example 44 to give isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (6.4 g) in the form of a white solid, m.p.184 -186 C.

EXAMPLE 48 Compound A stirred mixture of sodium 2-(n-pentadecyl)-benzimidazole-5-carboxylate (13.7 g; prepared as described hereinbefore in Example 19) and chloromethyl pivalate (5 gin hexamethylphosphoramide (35 ml) was heated to 50"C for 3 hours. After cooling, the mixture was poured into water (250 ml) and extracted with diethyl ether (3 x 75 ml). The organic layer was washed with water (3 x 100 ml) and dried over magnesium sulphate. The organic solvent was removed in vacuo to give a brown oil, which was chromatographed on silical gel (400 g) using chloroform as the eluent. Fractions (100 ml) were collected and fractions 14to 22 on evaporation of the solvent gave a colourless oil.The oil was dissolved in diethyl ether and was treated with a saturated solution of hydrochloric acid in ethanol until the pH ofthe mixture was pH 1. The white solid was colleced and washed with diethyl ether (3 x 100 ml) to give pivaloyloxymethyl 2-n-pentadecylbenzimidazole5-carboxylate hydrochloride (10 g) in the form of a white solid, m.p. 165"-175"C.

EXAMPLE 49 Compound KK Sodium hydride (12 g of a 50% oil dispersion) was added during 15 minutes to a stirred mixture of glycerol (100 g) and dry tetrahydrofuran (100 ml). When the addition was complete, the mixture was stirred vigorously for a further 30 minutes and then 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (20 g; prepared as described hereinbefore in Example 4) was added to the mixture during 5 minutes. The mixture was stirred v.igorously for 2 hours and was then allowed to stand overnight. The brown mixture was poured into water (800 ml) containing glacial acetic acid (9.4 g) and the oily product was extracted into chloroform (2 x 400 ml). The combined extracts were washed with water (2 x 500 ml) and dried over sodium sulphate.The solvent was evaporated in vacuo, the residual oil was dissolved in toluene (300 ml)-and the solution was filtered and cooled to give a brown gum. The toluene was decanted, diethyl ether (100 ml) was added and the mixture was warmed until the gum dissolved. On rapid cooling to -30 C, a white solid precipitated out and was collected and washed with diethyl ether (2 x 100 ml) to give 2,3-dihydroxyprop-1-yl 2-(n-pentadecyl)-benzimidazole-5-carboxylate (6.6 g) in the form of a white solid, m.p. 109"-1 12"C.

EXAMPLE 50 Compound B 3,4-Diaminobenzoic acid (10 g) and palmitic acid (168 g) in diglyme containing concentrated hydrochloric acid (10 ml, of strength 36.5% w/v) (100 ml) were heated at reflux for 10 hours. The cooled mixture was poured into water (300 ml) and the solid was collected. The solid was washed with dilute hydrochloric acid (2 x 100 ml, of strength 2N) and then boiling petroleum ether (4 x 100 ml, b.p. 40"-60"C). The solid was recrystallised from ethanol, with treatment with charcoal, to give 2-(n-pentadecyl)benzimidazole-5- carboxylic acid hydrochloride (50 mg), m.p. 295"-300"C (with decomposition).

EXAMPLE 51 Compound B 3,4-Diaminobenzoic acid monohydrochloride (1.88 g) and n-hexadecanoyl chloride (2.74 g) were mixed together intimately and the mixture was heated at 1 300C for 2 hours. The mixture was then cooled to room temperature and was triturated with water (100 ml) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (0.1 g), m.p. 298"-300"C (with decomposition).

EXAMPLE 52 Compound B Astirred solution of 3,4-diaminobenzoic acid (9 g) in dimethylformamide (190 ml) was treated with n-hexadecanoyl chloride (16.3 g) during 30 minutes. The mixture was then refluxed for 6 hours and was poured into water (100 ml). The solid was collected and suspended in dilute hydrochloric acid (100 ml, of strength 2N). The solid was again collected and washed with water to give 2-(n-pentadecyl)benzimidazole-5carboxylic acid hydrochloride (3 g), m.p. 295"-300"C (with decomposition).

EXAMPLE 53 Compound B A solution of 2-(n-pentadecyl )benzimidazole-5-carboxylic acid monohydrate (390 g; prepared as described hereinbefore in Example 12) in a mixture of acetone (2000 ml) and water (1000 ml) was heated to 60"C and then treated with an aqueous solution of sodium hydroxide (40 g, in water 50 ml). The mixture was stirred for 1 hour with refluxing and was then cooled to 0 C. The solid was collected and recrystallised from a mixture of acetone (1000 ml) and water (500 ml) to give sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate monohydrate (345 g), m.p. above 300"C with decompositon.

EXAMPLE 54 Compound LL A solution of 2,3-bis(n-tetradecanamido)-benzoic acid (17.6 g) in methyl ethyl ketone (250 ml) was treated with concentrated hydrochloric acid (25 ml, of strength 36.5% w/v). The mixture was refluxed for 5 hours, then cooled and treated in a similar manner to that described hereinbefore in Example 15 to give 2-(n-tridecyl)benzimidazole-4-carboxylic acid hydrochloride (6.5 g) in the form of a buff solid, m.p.

192"-200"C.

The 2,3-bis(n-tetradecanamido)benzoic acid, used as starting material, was prepared as follows: A solution of 2,3-diaminobenzoic acid (20 g) in dimethylformamide (200 ml), containing triethylamine (39.9 g), was treated with n-tetradecanoyl chloride (65.0 g). The rate of addition of the n-tetradecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from room temperature to 45 -50 C. The mixture was then stirred for a further 2 hours and allowed to stand at room temperature overnight. Methanol (20 ml) was added to the mixture, and the resulting mixture was stirred for 20 minutes and afterwards treated with concentrated hydrochloric acid (stength 36.5% w/v) until-the pH was 2.The resultant mixture was poured into water (1000 ml) and the black solid was collected, washed with water (2x500 ml) and then with hot light petroleum (b.p. 60"-80'C; 500 ml), and was finally recrystallised from ethanol, with treatment with charcoal, to give 2,3-bis(n-tetra-decanamido)benzoic acid (17.7 g) in the form of a buff solid, m.p.

150 -158 C.

EXAMPLE 55 Compound B A suspension of 3-amino-4-(hexadecanamido)-benzoic acid (2.0 g) in methyl ethyl ketone (60 ml) containing hydrochloric acid (1.5 ml, of strength 36.5% w/v) was refluxed for 5 hours. The resulting solid was collected, washed with boiling petroleum ether (b.p. 60"-80"C) and recrystallised from ethanol to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (2.0 g) in the form of a white solid m.p.

288"-290"C (with decomposition).

The 3-amino-4-(n-hexadecanamido)benzoic acid, used as starting material, was prepared as follows A solution of 3-nitro-4-(n-hexadecanamido)-benzoic acid (22 g) in n-butanol (500 ml) was hydrogenated by shaking in the presence of 5% wlw palladium on charcoal (2.5 g) at 70"C and atmospheric pressure for 6 hours. The mixture was filtered hot and the filtrate allowed to cool. The resulting solid was collected and washed with ethanol (100 ml) to give 3-amino-4-(hexadecanamido)benzoic acid (11.6 g) in the form of a cream solid m.p.160 -162 C.

The 3-nitro-4(n-hexadecanamido)benzoic acid, used as starting material, was prepared as follows: A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and hexadecanoyl chloride (33.0 g) in dry dimethylformamide (100 ml) was heated for 90 minutes at 97 C. The solution was cooled and then poured onto crushed ice (300 g). The resulting solid was collected, washed with water (3 x 100 ml), dried and recrystallised from a mixture of acetone and water (5:1) (with treatment with charcoal) to give 3-nitro-4-(nhexadecanamido)benzoic acid (31.7 g) in the form of a pale yellow solid, m.p. 153"-154"C.

EXAMPLE 56 Compound MM A suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (9.6 g; prepared as described hereinbefore in Example 4) in thionyl chloride (75 ml) was refluxed for 2 hours. The excess thionyl chloride was removed by vacuum distillation leaving a brown solid. The solid was triturated with toluene (200 ml) and the toluene was evaporated in vacuo. The residue was added to a solution of triethylamine (3.64 ml) in tert-butanol (250 ml) and the mixture was refluxed for 3 hours. After cooling, the excess tert-butanol was evaporated in vacuo and the residue was suspended in ethyl acetate (150 ml). The suspension was refluxed for 10 minutes and was filtered hot. The filtrate was cooled and the resulting solid was collected.

The solid was washed with ethanol (2 x 50 ml) and then with diethyl ether (2 x 50 ml), and dried to give tert-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (5.5 g) as an off-white solid, m.p.

165"-1 68"C.

EXAMPLE 57 Compound A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride (15 g; prepared as described hereinbefore in Example 44) in allyl alcohol (300 ml) was treated in a similar manner to that described hereinbefore in Example 44 to give allyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (10.4 g) in the form of a white solid, m.p. 198"-200"C.

EXAMPLE 58 Compound M To a stirred solution of methyl 3,4-diaminobenzoate (9.8 g) in methanol (200 ml) was added a solution of cupric acetate (23.6 g) in water (300 ml) followed by a solution of n-decanal (10 g) in methanol (40 ml). The mixture was refluxed for one hour and allowed to cool, and the purple solid was collected. The solid was dissolved in 75% v/v aqueous methanol (600 ml) and hydrogen sulphide gas was passed into the solution until the precipitation of copper sulphide ceased. The copper sulphide was collected and the filtrate was concentrated to give a red oil. The oil was dissolved in methanol (100 ml) containing concentrated hydrochloric acid (15 ml, of strength 36.5% w/v) and the solution was refluxed for 4 hours. After cooling the greyish-green solid was collected and was dissolved in tetrahydrofuran (100 ml) containing aqueous ammonia (5 ml, of strength 33% w,w).The solution was diluted with water (400 ml) and the pink solid was collected. The solid was chromatographed on silica with a mixture of chloroform and methanol (25:1 v/v) as eluent. The isolated material was dissolved in methyl ethyl ketone (25 ml) and concentrated hydrochloric acid (2.3 ml, of strength 36.5% w/v) was added with stirring. The resulting solid was collected and washed with diethyl ether (2 x 50 m I) yielding methyl 2-(n-nonyi)-benzimidazole-5-carboxylate hydrochloride (5.3 g) in the form of white solid, m.p. 234"-237"C (with decomposition).

EXAMPLE 59 Compound PP Concentrated hydrochloric acid (120 ml, of strength 36.5% w!v) was added during 20 minutes to a refluxing solution of crude 2,3-bis(n-hexadecanamido)-benzoic acid (165.3 g) in methyl ethyl ketone (1200 ml), and the mixture was refluxed for 6 hours. The resulting solution was cooled and the solvent was removed by vacuum distillation. After triturating the residue with water (2000 ml), the granular solid was collected and washed with hot petroleum ether (b.p. 60'-80"C; 2 x 500 ml) and then with diethyl ether (500 ml). The solid was dissolved in boiling methyl ethyl ketone (250 ml), and the solution was treated with charcoal and filtered hot. The filtrate was evaporated in vacuo leaving a buff solid. The solid was chromatographed on silica with a mixture of chloroform and methanol (9:1 viv) as eluent.The resulting product was recrystallised from ethyl acetate to give 2-(n-pentadecyl )benzimidazole-4-carboxylic acid (5.4 g) as a buff solid, m.p. 160"-166"C.

The 2,3-bis(n-hexadecanamido)benzoic acid, used as starting material, was prepared as follows: A solution of 2,3-diaminobenzoic acid (40 g) in dimethylformamide (600 ml), containing triethylamine (79.7 g, 109.5 ml), was treated with n-hexadecanoyl chloride (144.5 g). The rate of addition was such as to allow the temperature of the reaction mixture to rise from room temperature to 45"-50"C. The mixture was then stirred for a further 3 hours and was allowed to stand at room temperature overnight. The mixture was added to water (1200 ml) containing concentrated hydrochloric acid (50 ml, of strength 36.5% wiv), and the resulting solid was collected and washed with water (1200 ml).The solid was stirred with hot water (4000 ml; 65"C) for 30 minutes and was collected and dried at 70"C in vacuo. The resulting product 2,3-bis(nhexadecanamido)benzoic acid was used without further purification in the above preparation.

Reference example 1 A stirred solution of 3,4-diaminobenzoic acid (152 g) in dimethylformamide (1500 ml), containing triethylamine (303 g), was treated dropwise with n-hexadecanoyl chloride (549.0 g) during 1.5 hours. The rate of addition of n-hexadecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from room temperature to 350-400C. The mixture was then stirred at room temperature for a further period of 2 hours and was then poured into hot water (10 litres kept at 70"C) containing concentrated hydrochloric acid (150 ml of strength 36.5% w/v).The resulting solid was collected and gave crude 3,4-bis(n-hexadecanamido)benzoic acid (600 g) in the form of a buff solid, m.p. 180"-190"C, suitable for use in the preparation hereinbefore described in Example 15.

Referance example 2 By proceeding in a similar manner to that hereinbefore described in Example 38 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride by n-octanoyl chloride, there was prepared 4-amino-3-(n-octanamido)benzoic acid in the form of an off-white solid, m.p.202 -203 C after recrystallisation from methanol.

Reference example 3 By proceeding in a similar manner to that hereinbefore described in Example 38 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride by n-dodecanoyl chloride, there was prepared 4-amino-3-(n-dodecanamido)benzoic acid in the form of a white solid, m.p.

183"-185"C.

Reference example 4 By proceeding in a similar manner to that hereinbefore described in Example 38 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride by n-octadecanoyl chloride, there was prepared 4-amino-3-(n-octadecanamido)benzoic acid in the form of a light brown solid, m.p. 1 85"-187"C after recrystallisation from methyl ethyl ketone.

Reference example 5 A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry dimethylformamide (900 ml) containing triethylamine (50.8 g) was treated dropwise with n-octanoyl chloride (81.3 g) during 30 minutes at a temperature maintained between 5 and 8"C. The mixture was stirred for a further period of 2 hours. The solid was removed by filtration and the filtrate was poured into water (8000 mull. The resulting solid was collected and was recrystallised twice from methanol to give methyl 4-amino-3-(n-octanamido)-benzoate (65.5 g) in the form of a white solid, m.p. 120"C.

Reference example 6 By proceeding in a similar manner to that herein before described in Reference Example 5 for the preparation of methyl 4-amino-3-(n-octanamido)-benzoate but replacing n-octanoyl chloride by n dodecanoyl chloride, there was prepared methyl 4-amino-3-(n-dodecanamido)benzoate in the form of an off-white solid, m.p. 102"-105;C after recrystallisation from methanol.

Reference example 7 By proceeding in a similar manner to that hereinbefore described in Reference Example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by n-tridecanoyl chloride, there was prepared methyl 4-amino-3-(n-tridecanamido)benzoate in the form of a light brown solid, m.p. 101"-104"C after recrystallisation from methanol.

Reference example S By proceeding in a similar manner to that hereinbefore described in Reference Example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by n tetradecanoyl chloride, there was prepared methyl 4-amino-3-(n-tetradecanamido)benzoate in the form of a light brown solid, m.p. 108"-109'C after recrystallisation from methanol.

Reference example 9 By proceeding in a similar manner to that hereinbefore described in Reference Example 5 for the preparation of methyl 4-amino-3-(n-octanamido)-benzoate but replacing n-octanoyl chloride by n hexadecanoyl chloride, there was prepared methyl 4-amino-3-(n-hexadecanamido)benzoate in the form of a white solid, m.p. 109"-110jC after recrystallisation from methanol.

Reference example 10 A stirred solution of methyl 3,4-diamino-benzoate (5 g) in dry dimethylformamide (50 ml), containing triethylamine (6.1 g), was treated dropwise with a solution of hexadecanoyl chloride (16.54 g) in dry dimethylformamide (40 ml) during 5 minutes. The temperature was-allowed to rise from 20"C to 500C. The mixture was stirred for a further period of 3 hours. The resulting suspension was poured into water (800 ml) containing hydrochloric acid (10 ml,36.5% w/v).The resulting solid was collected and recrystallised from a mixture of chloroform and acetone (1:1) to give methyl 3,4-bis(n-hexadecanamido)benzoate (12. 1 g) in the form of a white solid, m.p. 129"-132"C, which is identical to the starting material used in Example 16.

Reference example 11 By proceeding in a similar manner to that hereinbefore described in Reference Example i 0 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-octanoyl chloride, there was prepared methyl 3,4-bis(n-octanamido)benzoate in the form of a white solid, m.p. 145"-147"C after recrystallisation from acetone.

Reference example 12 By proceeding in a similar manner to that hereinbefore described in Reference Example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-dodecanoyl chloride, there was prepared methyl 3,4-bis(n-dodecanamido)benzoate in the form of an off-white solid, m.p. 129s131"C after recrystallisation from acetone.

Reference example 13 By proceeding in a similar manner to that hereinbefore described in Reference Example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-tridecanoyl chloride, there was prepared methyl 3,4-bis(n-tridecanamido)benzoate in the form of a white solid, m.p. 1329134"Cafter recrystallisation from acetone.

Reference example 14 By proceeding in a similar manner to that hereinbefore described in Reference Example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-tetradecanoyl chloride, there was prepared methyl 3,4-bis(n-tetradecanamido)benzoate in the form of a white solid, m-.p. 132"-133"C after recrystallisation from acetone.

Reference example 15 By proceeding in a similar manner to that hereinbefore described in Reference Example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-octadecanoyl chloride, there was prepared methyl 3,4-bis(n-octadecanamido)benzoate in the form of a white solid, m.p. 120"C after recrystallisation from a mixture of acetone and methanol (1:1).

Reference example 16 3-Amino-4-(n-octanamido)benzoic acid (12.1 g) in methanol (200 ml) was treated with ethereal diazomethane until the reaction had gone to completion (as shown by thin layer chromatography on silica, using methanol: chloroform:glacial acetic acid; 10:90:0.5). Acetic acid (0.2 ml) was then added and the reaction mixture concentrated under reduced pressure. The resulting solid was recrystallised from ethyl acetate to give methyl 3-amino-4-(n-octanamido)benzoate (9.2 g) in the.form of a cream solid, m.p.

128 -131'C.

Reference example 17 3-Nitro-4-(n-octanamido)benzoic acid (25 g) dissolved in ethanol (500 ml) at 50iC was hydrogenated by shaking in the presence of 5% w w palladium on charcoal (2.5 g) at 50"C and atmospheric pressure for 3 hours. The mixture was filtered hot and the filtrate was evaporated in vacuo. The residue was recrystallised from a mixture of ethanol and water (1:1) to give 3-amino4-(n-octanamido)benzoic acid (8 g) in the form of a yellow solid, m.p. 155-156-C.

The 3-nitro-4-(n-octanamido)benzoic acid, used as starting material, was prepared as follows: A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-octanoyl chloride (19.4 gin dry dimethylformamide (100 ml) was treated for 90 minutes at 97-C. The solution was cooled and poured onto ice (300 g). The resulting solid was collected and washed with water (3 x 100 ml), dried and recrystallised from a mixture of methanol and water (8:1) with treatment with charcoal) to give 3-nitro-4-(n-octanamido)benzoic acid (22 g) in the form of a pale yellow solid, m.p. 153-1 54-C.

Reference example 18 3-Nitro-4-(n-dodecanamido)benzoic acid (21 g) dissolved in ethyl acetate (500 ml) was hydrogenated by shaking in the presence of 5% wlw palladium on charcoal (2.5 g) at 50"C and atmospheric pressure. The resulting mixture was filtered hot to yield a cream solid on cooling. This product was recrystallised from methanol to give 3-amino-4-(n-dodecanamido)benzoic acid (7.4 g) as a beige solid m.p. 158"-160"C. Reference example 19 By proceeding in a similar manner to that hereinbefore described in Reference Example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by n-decanoyl chloride, there was prepared methyl 4-amino-3-(n-decanamido)benzoate in the form of a white solid, m.p.

96 -100 C.

Reference example 20 By proceeding in a similar manner to that hereinbefore described in Reference Example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-decanoyl chloride, there was prepared methyl 3,4-bis(n-decanamido)benzoate in the form of a white solid, m.p. 1 39"-1 410C after recrystallisation from ethanol.

Reference example 21 A stirred solution of 3,4-diaminobenzoic acid (10 g) in dry dimethylformamide (100 ml) containing potassium carbonate (28 g) was treated dropwise with a solution of n-dodecanoyl chloride (33.1 g) in dry dimethylformamide (30 ml) during 5 minutes. The temperature was allowed to rise from 200 to 500C. The mixture was stirred for a further period of 3 hours. The resulting suspension was filtered and the filtrate poured into water (700 ml) containing hydrochloric acid (10 ml, 36.5% w/v). The resulting solid was collected and recrystallised from glacial acetic acid; the product was then washed with water and recrystallised from methyl ethyl ketone to give 3,4-bis(n-dodecanamido)-benzoic acid (12.5 g) in the form of a white solid, m.p.

195"-1 97"C.

Reference example 22 By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by nehexadecanoyl chloride and potassium carbonate by sodium carbonate, there was prepared 3,4-bis(n-hexadecanamido)benzoic acid in the form of a white solid, m.p. 1 980-2020C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

Reference example 23 By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid but replacing n-dodecanoyl chloride by n-octanoyl chloride there was prepared 3,4-bis(n-octanamido)benzoic acid in the form of a white solid, m.p. 195"-197"C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

Reference example 24 By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid but replacing n-dodecanoyi chloride by ntetradecanoyl chloride, there was prepared 3,4-bis(n-tetradecanamido)benzoic acid in the form of a white solid, m.p. 2010-2060C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

Reference example 25 Methyl 4-(n-dodecanamido)-3-nitrobenzoate (21 9) dissolved in warm ethyl acetate (500 ml) (50C-55'C) was hydrogenated by shaking in the presence of 5"iso w w palladium on charcoal (2.0 g) at 60"C and atmospheric pressure for 2 hours. The mixture was filtered hot and the filtrate was allowed to cool. The solid was collected to give methyl 3-amino-4-(n-dodecanamido)benzoate (14.1 g) in the form of a white solid, m.p.

134 -137 C.

The methyl 4-(n-dodecanamido)-3-nitrobenzoate, used as starting material, was prepared as follows: Methyl 4-amino-3-nitrobenzoate (19.6 g) and n-dodecanoyl chloride (23 gin dimethylformamide (100 ml) were heated for 2 12 hours at 97"C with occasional shaking. The resulting solution was poured onto crushed ice (300 g) and the solid collected and recrystallised from a mixture of methanol and chloroform (5:1) to give methyl 4-(n-dodecanamido)-3-nitrobenzoate (31 g) in the form of a yellow solid, m.p.78G-80CC.

The methyl 4-amino-3-nitrobenzoate was prepared as follows: 4-Amino-3-nitrobenzoic acid (70 g) was added to a solution of anhydrous hydrogen chloride in methanol [made from acetyl chloride (78 g) and dry methanol (300 ml11. The resulting mixture was refluxed for 10 hours, cooled in ice and the solid collected to give methyl 4-amino-3-nitrobenzoate (62 g) in the form of a yellow solid, m.p. 1930-195-C.

Reference example 26 By proceeding in a similar manner to that hereinbefore described in Reference Example 25 for the preparation of methyl 3-amino-4-(n-dodecanamido)-benzoate but replacing methyl 4-(n-dodecanamido)-3nitrobenzoate by methyl 4-(n-hexadecanamido)-3-nitrobenzoate, there was prepared methyl 3-amino-4-(nhexadecanamido)benzoate in the form of a white solid, m.p.135O-137GC.

Reference example 27 O By proceeding in a similar manner to that herein before described in Reference Example 25 for the preparation of methyl 3-amino-4-(n-dodecanamido)-benzoate but replacing methyl 4-(n-dodecanamido)-3nitrobenzoate by methyl 4-(n-aecan8mido)-3-nitrobenzoate, there was prepared methyl 3-amino-4-(ndecanamido)benzoate in the form of a white solid, m.p. -133 C.

Reference example 28 A stirred solution of 3,4-diamino-benzoic acid (8.4 g) in dry dimethylformamide (100 ml) containing potassium carbonate (15.27 g) was treated dropwise with a solution of n-hexadecanoyl chloride (15.17 g) in dry dimethylformamide (30 ml) during 30 minutes at 00-5"C. The mixture was stirred for a further 2 hours at 0"-5"C and allowed to warm to room temperature in 30 minutes.

The solution was then poured into water (700 ml) containing hydrochloric acid (10 ml, 36.5% w/v). The solid was collected, heated with acetone (300 ml) at 500C, and recrystallised from methyl ethyl ketone giving 4-amino-3-(n-hexadecanamido)benzoic acid (9.4 g) in the form of a white solid, m.p. 197"-199"C.

Reference example 29 By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by n-decanoyl chloride, there was prepared 3,4-bis(n-decanamido)-benzoic acid, in the form of a white solid, m.p.

194"-196"C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

Reference example 30 By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by n-tridecanoyl chloride there was prepared 3,4-bis(n-tridecanamido)-benzoic acid in the form of an off-white solid, m.p.

192"-194"C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

Reference example 31 By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by n-octadecanoyl chloride there was prepared 3,4-bis(n-octadecanamido)benzoic acid in the form of a white solid, m.p.

193 -196 C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

The present invention includes within its scope pharmaceutical compositions which comprise at least one of the compounds of general formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compounds of the present invention may be administered parenterally, but are preferably administered rectally or, more preferably, orally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose 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, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may 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 one or more of the active substances with or without the addition of diluents or excipients.

Preparation according to the invention for parenteral administration include sterile aqueous, aqueousorganic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilizing agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Solid compositions for rectal administration include suppbsitories formulated in accordance with known methods and containing one or more of the compounds of formula i or a pharmaceutically acceptable salt thereof.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally between 0.1 and 50 mg/kg body weight per day by oral administration, for example as hypolipidaemic and antiatheroma agents and in associated cardiovascular diseases, between 10 and 50 mg/kg body weight per day by oral administration; in the treatment of diabetes, between 5 and 40 mg/kg body weight per day by oral administration and in the treatment of arthritis and associated diseases, between 0.1 and 10 mglkg body weight per day by oral administration.

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

Example 60 No.2 size gelatin capsules each containing:sodium 2-(n-pentadecyl)benzimidazole-5carboxylate 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

Claims (39)

1. Benzimidazole derivatives of the general formula:

wherein R1 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), and R2 represents a straight- or branched-chain alkyl group containing from 7 to 20 carbon atoms, the group R1OOC- being attached to the 4-or 5-position of the benzimidazole ring system, and pharmaceutically acceptable salts thereof.

2. Benzimidazole derivatives according to claim 1 wherein R1 represents a hydrogen atom or a straightor branched-chain alkyl group containing from 1 to 6 carbon atoms.

3. Benzimidazole derivatives according to claim 1 wherein R1 represents a hydrogen atom.

4. Benzimidazole derivatives according to claim 1 wherein R1 represents the methyl group.

5. Benzimidazole derivatives according to claim 1 wherein R1 is an n-butyl, 2,3-dihydroxy-prop-1-yl, allyl or pivaloyloxymethyl group.

6. Benzimidazole derivatives according to any one of claims 1 to 5 wherein RZ represents a straight-chain alkyl group containing from 7 to 20 carbon atoms.

7. Benzimidazole derivatives according to any one of claims 1 to 6 wherein R2 represents an alkyl group containing from 10 to 18 carbon atoms.

8. Benzimidazole derivatives according to any one of claims 1 to 7 in which the group R1OOC- is attached to the 5-position of the benzimidazole ring system.

9. 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid.

10. 2-(n-Undecyl)benzimidazole-5-carboxylic acid.

11. n-Butyl 2-(n-pentadecyl-benzimidazole-5-carboxylate.

12. 2,3-Dihydroxyprop-1 -yl 2-(n-pentadecyl)-benzimidazole-5-carboxylate.

13. 2-(n-Tridecyl lbenzimidazole-5-carboxylic acid.

14. 2-(n-Dodecyl)benzimidazole)-5-carboxylic acid.

15. (RS)-2-(Tetradec-2-yl )benzimidazole-5-carboxylic acid.

16. 2-(n-Hexadecyl)benzimidazole-5-carboxylic acid.

17. 2-(n-Octadecyl)benzimidazole-5-carboxylic acid.

18. 2-(n-Heptadecyl)benzimidazole-5-carboxyiic acid.

19. Methyl 2-(n-heptyl ) benzim idazole-5-ca rboxylate.

20. Pharmaceutically acceptable salts of the compound claimed in each of claims 9 to 19.

21. Methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, methyl 2-(n-undecyl)benzimidazole-5carboxylate, methyl 2-(n-tridecyl)benzimidazole-5-carboxylate, methyl 2-(n-dodecyl)benzimidazole-5carboxylate, methyl 2-(n-decyl)benzimidazole-5-carboxylate, 2-(n-decyl)benzimidazole-5-carboxylic acid, methyl 2-(n-heptadecyl )benzimidazole-5-carboxylate, methyl 2-(n-nonyllbenzimidazole-5-carboxylate, 2-(nnonyl)benzimidazole-5-carboxylic acid, 2-(n-heptyl)benzimidazole-5-carboxylic acid and 2-(ntetradecyl)benzimidazole-5-carboxylic acid.

22. Pharmaceutically acceptable salts of each compound claimed in claim 21.

23. 2-( n-Octyl )benzim idazole-5-carboxyl ic acid, methyl 2-(n-tetradecyl )benzimidazole-5-ca rboxylate, methyl 2-(n-hexadecyl )benzimidazole-5-carboxylate, methyl 2-(n-eicosyl )benzi midazole-5-ca rboxylate, 2-(n- eicosyl)benzimidazole-5-carboxylic acid, methyl 2-(n-nonadecyl)benzimidazole-5- carboxylate, 2-(n nonadecyi )benzim idazole-5-carboxyl ic acid, (RS)-2-(tridec-3-yl )benzimidazole-5-carboxylic acid, 2-(tridec-7yl)benzimidazole-5-carboxylic acid, (RS)-2-(tridec-5-yl)benzimidazole-5-carboxylic acid, ethyl 2-(npentadecyl)benzimidazole-5-carboxylate, n-hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, isopropyl 2-(n-pentadecyl)benziinidazole-5-carboxylate, methyl 2-(n-octadecyl)benzimidazole-5-carboxylate, pivaloyloxymethyl 2-(n-pentadecyl)-benzimidazole-5-carboxylate and 2-(n-tridecyl)-benzimidazole-4-carboxylic acid.

24. Pharmaceutically acceptable salts of each compound claimed in claim 23.

25. tert-Butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, allyl 2-(n-pentadecyl)benzimidazole-6 carboxylate and 2-(n-pentadecyl)benzimidazole-4-carboxylic acid, and pharmaceutically acceptable salts of each such compound.

26. A process for the preparation of a benzimidazole derivative as claimed in claim 1 which comprises the cyclisation of a compound of the general formula:

wherein R represents a hydrogen atom or a group -COR2, and R1 and R2 are as defined as claim 1.

27. A process according to claim 26 in which the compound is cyclised, preferably at an elevated temperature, by reaction with an inorganic acid in the presence of water and in an organic solvent.

28. A process according to claim 26 in which R" represents a hydrogen atom and the compound is cyclised by reaction with an organic acid in water or an organic solvent, preferably at an elevated temperature.

29. A process according to claim 26 in which the compound is cyclised either (a) in the absence of an organic solvent and at an elevated temperature, or (b) in the presence of water and an inorganic acid and in a suitable organic solvent.

30. A process for the preparation of a benzimidazole derivative as claimed in claim 1 which comprises reacting a compound of the general formula:

(wherein Ri is as defined in claim 1) with a compound of general formula: R2CHO VI (wherein R2 is as defined in claim 1) and a copper (II) salt in the presence of an aqueous inert organic solvent medium at between ambient temperature and the reflux temperature of the reaction mixture, followed by converting the resulting copper salt into the corresponding compound of the general formula depicted in claim 1.

31. A process for the preparation of a benzimidazole derivative as claimed in claim 1 wherein R1 represents a hydrogen atom which comprises the hydrolysis of a corresponding ester of the general formula depicted in claim 1 wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms, and R2 is as defined in claim 1.

32. A process for the preparation of a benzimidazole derivative as claimed in claim 1, wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms and R2 is as defined in claim 1, which comprises the esterification of a corresponding carboxylic acid of the general formula depicted in claim 1 wherein R1 represents a hydrogen atom, and R2 is as defined in claim 1.

33. A process according to any one of claims 26 to 32 followed by the step of converting by known methods a benzimidazole derivative of the general formula depicted in claim 1 thus obtained into a pharmaceutically acceptable salt.

34. A process for the preparation of a benzimidazole derivative of the general formula depicted in claim 1 or a pharmaceutically acceptable salt thereof substantially as herein before described with esDecial refernnr.n to any one of Examples 1 to 29.

35. A process for the preparation of a benzimidazole derivative of the general formula depicted in claim 1 or a pharmaceutically acceptable salt thereof as hereinbefore described in any one of Examples 30 to 55.

36. A process for the preparation of a benzimidazole derivative of the general formula depicted in claim 1 or a pharmaceutically acceptable salt thereof as hereinbefore described in any one of Examples 56 to 59.

37. Pharmaceutical compositions which comprise at least one benzimidazole derivative as claimed in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutical carrier or coating.

38. Pharmaceutical compositions according to claim 37 substantially as hereinbefore described with especial reference to Example 60.

39. A benzimidazole derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 25 for use as a medicament and, more particularly, for the prevention or treatment of diabetes mellitus, hyperlipoproteinaemic states, of atherosclerosis, and of associated conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism, peripheral vascular disease, recurrent pancreatitis and xanthomas; as well as arthritis, immunological disease, cancer and graft rejection.