CA1141765A - Benzimidazole derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

The invention is concerned with new benzimidazole derivatives of the general formula:

Description

This invention relates to new therapeutically useful benzimidazole derivatives and their pharmaceutically acceptable salts, as well as to processes for preparing them and pharma-ceutical compositions containing them.
The benzimidazole derivatives of the present invention are represented by the general ormula:

RlOOC ~ ¦ ~ R2 (I) H
wherein Rl 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 con-taining from 2 to 7 carbon atoms), and R2 represents a straight-or branched-chain alkyl group containing from 7 to 20 carbon atoms, the RlOOC- being attached to the 4- or 5-position of the benzimidazole ring system.
Preferably, Rl represents a hydrogen atom, or a methyl group, or a n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pival-oyloxymethyl group. Preferably also, R2 is a straight-chain alkyl group and contains from 10 to 18 carbon atoms.
The group RlOOC is preferably attached to 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 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 tauto~ers the 4- and 5~positions become the 7-and 6-positions respectively. Furthermore, in certain cases the substituents Rl and R contribute to optical isomerism. A11 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 Rl 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 Rl represents a hydrogen atom) is relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacolo-gical 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-~-hydroxy-naphthoates, gentisates and di-p-toluoyltartrates.
Suitable salts formed by compounds of general formula (I) wherein Rl 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 S

intended to refer also to their pharmaceutically acceptable salts, where the context so permits.
The new compounds of general ormula (I) are prepared in accordance with this invention by any of the following process (1) through (5).
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:

1 ~ ~NHCOR2 R OOC ~ ll (II) NHR

wherein R represents a hydrogen atom or a group -COR2, and and R are as hereinbefore defined, optionally prepared ln situ, for example as hereinafter described for the cyclisation of compounds of general formula (III) or (IV).
(i) Thus, when R is a group -COR2, a compound of the geneFal formula: ~ 2 NHCOR
RlOOC ~ (III~

wherein Rl and R2 are as hereinbefore defined, is cyclised, preferably at an elevated temperature, for example between 60 and 100C, e.g. at or near 8~C, by reaction wi.h 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 RO is a hydrogen atom (especially in respect of those compounds wherein Rl represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms), a compound of the geneLal formula:

NHCOR

R1OOC ~ (IV) \NH2 wherein Rl 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 10~C, e.g. at or near 80C, or (iii) (especially ;n respect of those compounds wherein Rl represents a straight- or branched-chain alkyl group containing from l to 6 carbon atoms) cyclisation usually without isolation of an acylated intermediate of formula (III) or (IV) either (a) in the absence of an organic solvent and at an elevated temperature, for example at between 150 and 250C, 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:

~NH2 RlOOC ~ ll ( V ) ~, wherein Rl is as hereinbefore defined, with a compound of general formula:
R CHO (VI) wherein R2 is as hereinbefore defined, and a copper (II) salt, fo~ example c~pric acetate~ in the presence of an a~ueous inert organic solvent medium, for example a mixture of water and methanol, at between ambient temperature and the reflux tem-perature of the reaction mixture, followed by converting the resulting copper salt into the corresponding compound of for~
mula (I).

3. According to another feature of the present inventionl carboxylic acids of genera~ formula (I) (wherein R2 is as here-inbefore defined and Rl represents a hydrogen atom) are pre-pared by hydrolysis o a corresponding ester of general formula (I) wherein R2 is a hereinbefore defined and Rl 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. 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 a~ueous ethanol and at the reflux temperature.

4. According to a still further feature of the present invention, esters of general formula (I) (wherein R is as hereinbefore defined and Rl 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 sub-stituent selected from the hydroxy groupt alkenyl groups con-taining from 2 to 5 carbon atoms or alkanoyloxy groups con-taining from 2 to 7 carbon atoms) are prepared by esterificationof a corresponding acid of general formula (I) wherein R2 is as hereinbefore deined and Rl represents a hydrogen atom. The esterification may be carried out by the application or adapta~
tion of known methods, or example by reaction of the acid with an excess of the appropriate alcohol of the general formula:
~ OH (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 groupl 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 pre-sence of an inorganic acid, e.g. hydrochloric acid, preferably at an elevated temperature, e.g. between 60 and 100C; or by reaction with the corresponding alkyl halide.
Acid chlorides formed by reaction with thionyl chloride, or salts of the acids may be used.

5. According to a further feature of the present invention, compounds of general formula (I) may be converted into pharma-ceutically acceptable salts, and vice versa, by the application or adaptation of known methods. As well as being useful in itself, this process is useful 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, 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.

\ - 6 -, .

(ii) On ~he othe~ 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 ~ general formula (I) wherein R represents a hydrogen atom (R2 being as hereinbefore defined) may be con-verted 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:
MloR4 (VIII) wherein Ml 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 ethylt or a hydrogen atom, in a suitable solvent, e.g. methanol or ethanol, or a mixture of water and acetone, followed if necessary by evaporation of part or all of the solvent, a~d 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).
By the term "known methods" as used in this specification is meant methods heretofore used or described in the literature.
It will be understoad by those skilled in the art that in the performance o 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 Rl depicted in general for-7f~5 mula (II) may have been converted into benzyloxy groups beforereaction as described with subsequent remo~al 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 tI).
Compounds of general formula (II) wherein R represents a hydrogen atom may be prepared from compounds of the general formula:

~
R ^~ W (IX) wherein Rl 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 formu~a IXI) depicted hereinafter.
Compounds of general formula (IX) may be prepared by the reaction of a compound of the general formula:

~\ '''-- (X) wherein Rl is as hereinbefore defined, with a compound of general formula XI, in a similar manner to that hereinafter described in method A (i).

,~

S

Compounds of general formula (Il) in which the substituent group -NHCOR2 is meta to the substituent group -COORl and in which R represents a hydrogen atom rnay be prepared by the reaction of a compound of general formula (V) with a compound of general formula (XI) as hereinaEter 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 herein-after described in method A (i).
Compounds of general formula (II) wherein Rl represents astraight- 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 substituen~ 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 o the corresponding compounds of general formula (II) wherein Rl 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.
Method A
The compounds of general formula (II) may be prepared by the reaction of a compound of the general formula:

,~IH2 RlOOC l ll (V) V~
~H2 wherein Rl is as hereinbefore defined, with an acylating agent of the general formula:

R COX (XI) wherein R2 is as hereinbefore defined and Xl represents a halogen, preferably chlorine, or a hydroxy group. (According to pro-cess (1) hereinbefore described, there follows cyclisation of the resulting product optionally in situ). Particularly suitable conditions are as follows:
(i) Compounds of general formula (V) wherein Rl is as hereinbeEore defined may be reacted with acyl halides of general formula (XI) wherein R2 is as hereinbefore defined and Xl represents a halogen, preferably chlorine, in an inert organic solvent, for example dichloromethane or dimethylformamide, pre-ferably under anhydrous conditions and preferably in the pre-sence of an acid binding agent, or 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 Rl represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, may be reacted with acyl halides ~f general formula (XI) wherein R2 is as herein-~0 before defined and Xl represents a halogen, preferably chlorine, under conditions similar to those described hereinbefore under (i) but using a lesser quantity of the acyl halide and con-trolling the temperature, preferably at between 0C and room temperature.
By using a set o conditions between those described here-inbefore under (i) and those described hereinbefore under (ii) there would be obtained a mixture of intermediates of general formula (III) and (IV)~ which would be cyclised under the con-ditions described hereinbefo~e under (1) (i) and (1) (ii).
(iii) Compounds of general formula (V), especially those wherein Rl represents a straight- or b~anched-chain alkyl group ~417fi~i containing fr~m 1 to 6 carbon atams, may be reacted with the com-pounds of general ormula (XI) wherein R2 is as hereinbefore defined and Xl represents a hydroxy group or a chlorine atom, to form compounds o general ormula (I), usually without isolation of acylated intermediates, either (a) in the absence of solvent at an elevated temperatures, for example at between 150 and 250C, or (b) in the presence o water and an inorganic acid, for examFle hydrochloric acid, and in a suitable solvent, for example diglyme~
The compounds of general formula (I) possess useful pharma-cological 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 o 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 anti-rheumatic 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-pentadecy~)benzimidazole~5-carboxylate A
2-(n-pentadecyl)benzimidazole-5-carboxylic acid B

A

1141~7~S

methyl 2-(n-undecyl)benzimidazole-5-carboxylate C
2-(n-undecyl)benzimidazole-S-carboxylic acid D
methyl 2-(n-tridecy])benzimidazole-5-carboxylate E
2-(n-tridecyl)benzimidazole-5-carboxylic acid F
methyl 2-(n-dodec~l)benzimidazole-5-carboxylate G
2-(n-dodecyl)benzimidazole-5-carboxylic acid H
methyl 2-(n-decyl)benzimidazole-5-carboxylate 2-(n-decyl)benzimidazole-5-carboxylic acid J
methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate 1~
2-(n-heptadecyl)benzimidazole-5-carboxylic acid L
methyl 2-(n-nonyl)benzimidazole-5-carboxylate M
2-(n-nonyl)benzimidazole-5-carboxylic acid N
methyl 2-(n-heptyl)benzi.midazole-5-carboxylate O
2-(n-heptyl)benzimidazole-5-carboxylic acid P
2-(n-tetradecyl)benzimidazole-5-carboxylic acid Q
2-(n-octyl)benzimidazole-5-carboxylic acid R
methyl 2-(n-tetradecyl.)benzimidazole-5-carboxylate S
methyl 2-(n-hexadecyl)benzimidazole-5-carboxylate T
2-(n-hexadecyl)benzimidazole-5-carboxylic acid U
methyl 2-(n-eicosyl)benzimidazole-5-carboxylate 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)benzimidazole-5-carboxylic acid AA
(RS)-2-(tridec-3-yl)benzimidazole-5-carboxylic acid BB
2-(tridec-7-yl)benzimidazole-5-carboxylic acid CC
(RS)-2-(tridec-5-yl)benzimidazole-5-carboxylic acid DD
ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate EE
n-hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate FF
n-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate GG

Ii~s'i isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxylate HH
methyl 2-(n-octadecyl)benzimidazole-5-carboxylate II
pivaloyloxymethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate 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)benzimidazole-5-carboxylate NN
and 2-(n-pentadecyl)benzimidazole-4-carboxylic acid PP
The letters A to PP 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 (I) -were demonstrated in the following tests:
Hypolipidaemic Activity in Rats Male Wistar rats each weighing between 120 and 150 g were caged in groups af eight and fed a powdered diet for 10 days.
For the last 7 days cf that period the test compound was administered orally by mixing the compound in the diet and allowing the animals to feed no~mally. 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 sc-rum cholestero]
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 com-~1765 parison with the simultaneous controls, for each concentra-tion of the test compound used.
The results obtained are shown in following Table I.
TABI,E I
. .
ompound Form ~ w/w % change in serum dose compared witl I control . in diet cholesterol triglycerides ~ . _ A HCl 0.2 +7 -1 salt B HCl a . 2 -50 -44 salt 0.2 -50 -64 0.2 -39 -40 a . 2 -22 -45 0.2 -21 -46 . 0.4 -61 -63 0.2 _ -55 -60 0.2 -42 -69 0.1 -3~ -3~
0.1 -14 -51 B mono- 0.2 +4 +19 hydrate 0.2 -10 _9 . 0.4 -63 -76 s 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 ~1~17fi5 TABLE I (continued) ~ompound Form % w/w % change in serum dose compared with control in diet cholesterol triglyceridec D HCl 0.2 -34 -60 salt 0.2 -24 -50 0.2 -40 -~0 E HCl 0.2 -23 -58 _ _ salt ~ __ . _ F HCl 0.2 _ ___ .
salt 0.2 -36 -47 0.03 -17 -10 G salt 0.2 -18 -41 H HCl 0.2~ -33 -52 salt 0.03 -4 -26 I HCl 0.2 -3 -36 . salt J HCl -1~ .~

L HCl 0.2 -3 -36 salt 0.2 -20 -26 N HCl 0.2 -14 -3 _ salt . .
. O HCl 0.2 -4 +24 salt .

P 5 alt -18 -10 11'~1~6S

TABLE I (continued) -~ompound Form ~ w/w % change in serum dose compared with control in diet cholesterol triglycerldes Q HCl 0.2 -41 -62 salt 0.2 -35 -69 . 0.03 -4 -20 R HCl 0.2 -2 -10 sal t S HCl 0.2 ~9 -28 sal t T HCl 0.2 +6 -20 salt U HCl 0.2 -20 -50 salt . .
V HCl 0~2 +2 -12 salt W HCl 0.2 +5 -15 salt .
X HC1 0.2 -10 -3 salt _ Y HCl 0.2 -17 -14 sal t Z HC1 0.2 0 -20 sal t _ AA HG1 0.2 -35 -75 sal t 11~17t~5 TABLE I (continued) ~ompound Form ~ w/w % change in serum dose compared wit~ control in diet cholesterol triglycerides .
BB HCl 0 . 2 -lg -46 salt . _ CC H2SO4 0.2 -6 +9 half salt .
DD H2SO4 0.2 +11 -15 half salt _ EE HCl 0 . 2 -27 -47 salt .
FF HCl 0 . 2 -16 -51 salt GG HCl 0 . 2 -40 -54 salt 0.2 -33 -60 . .
HH HCl 0 . 2 -5 -32 salt l II HCl 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 TABLE I (continued~
_ Compound Form % w/w % change in serum dose compared wit ~ control in diet cholesterol I triglycerides MV HCl +4 I -8 ~U salt 0.2 -19 ~. u5Clt L

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 concen-tration 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 yroup, 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 com-parison with the simultaneous controls.
The results obtained are shown in following Table II.

~ _ a E~
~ o a~ ~r a~
~ . l i tJ ~'~I
~
O o o o~ O O
.
Femoral artery ~ ~ o aJ ~ ~ ~D r~
without prior de-endothelialisation o ~ .
~ ~ Femoral artery ~ ~ ~
H ~ 8 wi th prior de- l l .~ endothelialisation o .~ Abdo.~inal aorta c ~ o with prior de- ~ o o o endotheliallsation 0~o~ __ ~ ~ , ~r 3 0 ~ o o o o\ ~ ,~
.. .,, ,~, o r~d~ .,~ ~

O '~ ~ C ~ r O 1~ 0 :>~ O
u~ ~ ~
.~ _ .
o a:
~) __ _ -- lg --~141i7~5 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 than 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 bled by cardiac puncture.
The following serum parameters were assessed:
1. Glucose - by the glucose-oxidase method of God-Perid 2. Cholesterol and trigl~cerides - these were measured by an auto-analyser after removal of phospholipids by means of activated zeolite and extraction by isopropanol, 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 III.
_ . /

;5 ,~, .
o C ~
o ~ ~ Ln c ;) a~ ~ o ~ S: o O~o 3 ~
. .
~s ~a a tn Q~ ,~
.,~ O ~ Ln ~ ~D
H ~ tlJ O
H ~ t) 5 ~ O ~
m O~o ~ 3 o ~ u~
.,~ ~ ~ ~ ~ :~
,~
~o l~

J~
3 .a) ~
a) 3 ~ o o o o C: o\'' ,~
___.
a ~ ~ E L) E
Li rl ~J O ~ ~ ~ OS~ ~ ~ O
o ~ ~1 C ~ro ~ I c O ~ O ~ O ~ O ~ O ~ O
u~ ~n E Su~
_ ._ ~C
O
m .
E
_. __ 7~
Aortic smooth muscle cell proliferation inhibiting activity.
Smooth muscle cells were grown in culture from explants of pig thoracic aorta, using Dulbeccc's Modified Eagles (DME) Medium containing 2G ~ foetal calf serum (ECS) and antibiotics.
The cells were incubated at 37C ln 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 ,ug/ml medium. The com-pounds were pre-dissolved in water, acetone or glycofurol such that the final concentration of solvent in the medium was 0.2 (v/v). The controlmedium 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. ~t 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 ~'able IV hereafter represent the mean value for our dishes of cells. Percentage inhibition of pro-liferation was calcu]ated using the following formula:
Percentage inhibition of proliferat;on = 100 - (C S)x 100 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 HCl H2O 48 salt 2 31 . -O HClacetone 33 saltacetone 38 glycofurol 54 acetone 23 A HClacetone 21 saltacetone 16 acetone 41 Mitoqen-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 mg/ml of 50 ~ v/v FCA solution in sterile physiological saline).

1~17~5 After L4 days lymph node cells were obtained and suspended in Eagles Minimal Essential (EME) Medium~ containing 10 %
foetal cal serum (FCS) and bufered with Earle's salts~ at a concentration of 2.5 x 10~ ~ells/ml.
For 24 hours, 0.1 ml o cell suspension was incubated at 37C in an atmosphere of 95 % air and 5 % carbon dioxide in the presence o 0.15 ml o mitogen or of mitogen plus the compound to be tested in E~ Medium (containing 10% FCS and buffered with Earle's salts).
Eighteen hours befo~e harvestingr 3H-th~midine (l ul of lO0 ~Ci/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 ~g/ml with mitogen control O Cl The utility of the compounds is enhanced by the fact that they are of only very low toxicity, as demonstrated in the following test:

11~1 1~65 Oral Toxicity in ~lice Groups of mice were dosed orally with graded doses o~ the test compound (in a 0.5 % w/v aqueous suspension of tragacanth mucilage) and observed or 3 days thereafter. The percentages of animals which died during that period at each dose ]evel were used to construct a graph, from which the LD50, that is to say the dose in mg/kg 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 f each compound was greater than 1000 mg/kg animal body weight.
Preferred compounds of the invention are those hereinbefore identified by the letters B, D, GG, KK, F, H, AA, U, Z, L and O.
The present invention therefore 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 com-pounds of the present invention may be administered parenterally, but are preferably administered rectally or, more preferably, orally.
Solid compositions for oral administration include com-pressed 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 s~bstances other than inert di]uents, e.g.
lub~icating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharma-ceutically acceptable emulsions, solutionsr suspensions,syrups and elixirs containing inert diluents commonly used in 7~5 the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting, and suspending agents, and sweeteniny, 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 administation include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, poly-ethylene 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 sup-positories formulated in accordance with known methods and con-taining one or more o the compounds of formula I or a pharma-ceutically acceptable salt thereo.
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 adminis-tered at about the same time. The dose employed will be 11~17t~S

determined by the physician, and depends upon the desirecl therapeutic effect, the route of administration and the dura-tion o 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 anti-atheroma agents and in associated car-diovascular 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 bod~ weight per day by oral administration and in the treatment of arthritis and associated diseases, bet-- ween 0.1 and 10 mg/kg body weight per day by oral administration.
The following Examples and Reference Examples illustrate the preparation of the compounds of the present invention.

Compound A
A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate (46 g) and p-toluenesulphonic acid (lS 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 60C and was washed with aqueous sodium carbonate solution (2N; 2 x 200 ml).
The toluene layer was dried over magnesium sulpha~e and was then concentrated in vacuo, to give an oil. The oil was tri-turated with petroleum ether (b.p. 40 - 60C) to yield a buff solid which, on recrystailisation rom petroleum ether (b.p. 40 - 60C), gave methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate (24.6 g) in the form of a white solid, m.p. 96 -98C.
The methyl 4-amino-3-(n-hexadecanamido)-benzoate, used as starting material, was prepared by either of the following methods:

i5 (i) A stirred solution o~ methyl 3,4-diaminobenzoate (35 g) in dry dimethylormami~e (12aO ml)f containing anhydrous sodium carbonate (11.~ 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 10C to room temperature. The mixture was then stirred at room tem-perature 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 mixt~re was then filtered. The filtrate was cooled to 0C and the resulting buff solid was filtered off, to give methyl 4-amino-3-(n-hexa-decanamido)benzoate (48.2 g), m.p. 112 - 114C.
(ii) A stirred solution o methyl 3,4-diaminobenzoate (16.6 g) in dry dichloromethane (270 ml), containing triethylamine (10.3 g) t 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 o acetone (1000 ml) and methanol (150 ml) and the insoluble material was removed by filtration. The filtrate was cooled to 25C and treated with water (800 ml) to give methyl 4-amino-3-(n-hexadecanamido)-benzoate in the form of a buff solid, m.p. 112~ - 114C.

Compound A
A solution of meth~l 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 o a saturated solution of hydrogen chloride in ethanol. The mixture was heated at ref]ux for 2 hours and was then cooled. The resulting solid was collected and recrystallised from a mixture of ethanol and water (9:1 v/v) to give methyl 2-~n-pentadecyl)benzimidazole-S-carboxylate hydrochloYide (24.2 g) in the form of a white solid, m.p. 230 - 232C (with decomposition).

Compound A
Methyl 3r4-diaminobenzoate (8.8 g) and hexadecanoic acid (12.8 g) were ground together to form an intimate mixture.
The mixture was heated at 200C for 150 minutes. The mixture was then cooled to 60C and was extracted with boiling petroleum ether (b.p. 60 - 80C; 2~ ml). The extract was concentrated n 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 OOC and filtered and the filtrate was concentrated _ vacuo to give a brown oil (ln.2 g). The oi] was dissolved in chlorofo~m (15 ml) and chromatographed on silica gel (275 g). Elution with ¢hlorofo~m gave an of-white solid (6.0 g), which was recrystallised from petroleum ether (b.p. 40~ - 60C), to give meth~l 2-(n-penta-decyl)benzimidazole-5-carboxylate (5.3 g) in the form of a white solid, m.p. 96 - 98C.

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 0C and was acidified by il~l7~iS

treatment with concentrated hydrochloric acid. The resulting off-white so]id was collected and was recrystallised (with treat-ment with charcoal) from a mixture o ethanol and water (800 ml;
4:1 v/v) to give 2-(n-pelltadecyl)benzimidazole-5-carboxylic acid hydrochloride (32 g) in the form of a white solid, m.p.
289 - 291C (with decomposition).

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

Compound C
A solution o 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)-ben-zimidazole-5-carboxylate (27.0 g) in the form of a white solid, m.p. 93 - 95C
~he 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 car-bonate (7.7 g), was treated with n-dodecanoyl chloride (30.5 g) in a manner similar to that hereinbefore described in Example l(i) to give crude methyl 4-amino-3-(n-dodecanamido)benzoate (41 g) in the form o~ a buf solid.

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 200C for 3 hours. The mixture was then treated in a manner similar ta that described hereinbefore in Example 3 to give methyl 2-(n-undecyl)benzimidazole-5-car-boxylate (19 g) in the form of a white~solid, m.p. 92 - 94C.

Compound D
A solution of methyl 2-(n-undecyl)-benzimidazole-5-carboxy-late (28.6 g; prepared as described hereinbefore in Example 7) in a mixture of ethanol and water (350 ml; 4:1 v/v) 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 - 294C (with decomposition).

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 200C for 6 hours. The mixture was cooled to 60C and was then extracted with petroleum ether (b.p. 60 - ~0C), and the petroleum ether extracts were com-centrated ln vacuo to give a brown oil. The oi] was dissolved in ethanol (500 m]) 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 0C
and filtered and the filtrate was concentrated in vacuo to give a brown oil. The oil was partitioned between a hot mix-~1~17~5 ture of petroleum ether (b.p. 60 - 80C) and toluene (300 ml;
4:1 v/v~, and water (3~0 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 charcoa') to give methyl 2-(n-tridec~l)benzimidazole-5-carboxylate hydro-chloride (16 g) in the form of a white solid, m.p. 228 - 236 C
(with decomposition).

_ Compound E
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-tridecyl)benzimidazole-5-car-boxylate hydrochloride (33 g) in the form of a white solid, m.p. 228 - 234C (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 (5aO 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 l(ii) to give crude methyl 4-amino-3-(n-tetradecanamido)-benzoate (40 g) in the form of a buff solid.

Compound F
A solution of methyl 2-(n-tridecyl)-benzimidazole-5-car-boxylate (7.9 g) in a mixture of ethanol and water (200 ml;
4:1 v/v) containing sodium hydroxide (2.4 g) was treated in a manner similar to that described hereinbefore in Example 4 to 11~1765 give 2-(n-tridecyl)benzimidazole-5-carboxylic acid hydrochloride (5.7 g) in the form of a white solidt m.p. 299 - 305C
(with decomposition).
EXAMPLE ]2 Compound B
2-(n-Pentadecyl)benzimidazole-5-carboxylic acid hydro-chloride ( 15~0 g; prepared as described hereinbefore in ~xample 4) was dissolved in a hot mixture of ethanol and water (1000 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 0C 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)benzimida-zole-5-carboxy]ic acid ~12.0 g) in the form of a white solid, m.p. 113 - 115C, thought to be the monohydrate.
EXAMPL~ 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 - 225 C (with decomposition).
The methyl 4-amino-3-(n-tridecanamido)benzoate, used as starting material, was prepared as follows:
A solution of methyl 3,4-diaminoben20ate (17.8 g) in dichloromethane (350 ml) containing triethylamine (10.8 g) was treated with n-tridecanoyl chloride (25 g) in a manner 11417f~5 similar to that described hereinbefore in Example l(ii) to give crude methyl 4-amino-3-(n-tridecanamido)benzoate (40 g).

Compound H
A solution of methyl 2-(n-dodecyl)-benzimidazole-5-car-boxylate (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 4 to give 2-(n-dodecyl)benzimidazole-5-carboxylic acid hydrochloride (11.7 g) in the form of a white solid, m.p. 276 - 290C (with decomposition).
EXAMPLE lS
Compound B
A solution of 3,4-bis(n-hexadecanamido)-benzoic acid (20 g) in methyl ethyl ketone (400 ml) was treated with concentrated hydrochloric acid (35 ml of strength 36.5 % w/v). The mixture was heated at reflux far 5 hours and was then cooled. The resulting solid-was collected and washed with boiling petro-leum ether (b.p. 60 - 80C), and recrystallised from ethanol to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydro-chloride (15 g) in the form of a white solid, m.p. 289 - 291C
(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 dichloro-methane (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 l(ii). A solid was collected and was recrystallised from glacial acetic acid and was then recrystallised from methyl ethyl ketone (with filtra-tion o the hot solution) to give 3,4-bis(n-hexadecanamido)ben-. i ... ..,~

zoic acid (20 g) in the orm of a buf solid/ m.p. 198-202C.
EXAMPLE ]6 Compound A
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. 230-232C (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 l(ii) (the temperature of the reaction mixture during the addition being allowed to rise from 20C to 30C). A solid was collected and recrystallised from chloroform to give methyl 3,4-bis(n-hexa-decanamido)benzoate (14.9 g) in the form of a white solid, m.p. 129-132C.

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 % w/v) was heated at . . .
reflux for 3 hours. The mixture was then cooled to 0C and filtered, and the solid obtained was combined with the residue resulting from evaporation of the filtrate in vacuo. The com-bined solids were washed with hot petroleum ether (b.p. 60-80C; 200 ml) and recrystallised from ethanol (with filtration of the hot solution) to give methyl 2-(n-decyl)benzimidazole-5-carboxylate hydrochloride in ~he form o a white solid (13.7 g), m.p. 230-240C (with decomposition).
The methyl 3~4-bis(n-undecanamido)-benzoate, used as starting material, was prepared as follows:
A solution of methyl 3,4-diamin~benzoate (17.9 g) in dichloromethane (300 ml) containing triethylamine (21.8 g) was treated with n-undecano~l chloride (44.3 g) in a manner similar to that described hereinbefore in Example 16. A solid was collected and recrystallised twice from ethanol (with filtra-tion of the hot so]ution) to give methyl 3,4-bis(n-undecanamido) benzoate (40.2 g) in the form of a white solid, m.p. 139-141C.

Compound J
- A solution of methyl 2-(n-decyl)-benzimidazole-5-carboxy-late hydrochloride (13.7 g; prepared as described hereinbefore in Example 17) in a mixture o~ ethanol and water (250 ml; 4:1 v/v) 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-carboxy]ic acid hydrochloride (9.4 g) in the form of a white solid, m.p. 270-282C (with decomposition).

Compound B
A solution of 2-(n-pentadecyl)benzimidazole-5-carboxy]ic acid monohydrate (11.16 g; prepared as described hereinbefore in Example 12) in methanol (150 ml) was heated to 60C and treated with a solution of sodium methoxide ~prepared by carefully dissolving sodium (0.6~ g) in anhydrous methanol (40 mll7 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-calboxy-late monohydrate (9.7 g) in the form of a white solid, which _ - 36 -114~765 darkens at 250C and decomposes at above 300C.

Compound B
A stirred suspension of 2-(n-pentadecyl)-benzimidazole-5-carboxylic acid monohydrate (1.00 g; prepared as described hereinbefore 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 40C 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-pentadecy])benzimidazole-5-car-boxylic acid methanesulphonate (1.19 g) in the form of a white solid~ m.p. 115-117C.

Compound B
A stirred suspension of 2-(n-pentadecyl)-benzimidazole-~-carboxylic acid monohydrate (1.00 g; prepared as described here-inbefore 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 v/v). 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 2-hydroxyethylsulphonate (1.24 g) in the form of a white solid, m,p. 93-95C.

Com~ound A
2-(n-Pentadecyl)benzimidazole-5-carboxylic acid hydro-chloride (10.0 g, prepared as described hereinbefore in Example4) was dissolved in boiling methanol (250 ml) in a reflux -~41765 apparatus and then was treated with concentrated hydrochloric acid (2G ml of strength 3G.5 % w/v). The mixture was heated at reflux for 3 hours and was then cooled to 0C. The resulting white solid was collectedl washed with water, and recrystallised from ethanol to give methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (3.2 g) in the form oE a white solid, m.p. 230-232C (with decomposition).

Compound K
Methyl 3t4-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 200C for 210 minutes. The mixture was then treated in a manner similar to that described here-inbefore 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 chromato-graphy on a column of silica gel (750 g). Elution with a mix-ture of chloroform and methanol (19:1 v/v) gave a light brown solid (40 g)~ This solid was dissolved in hot toluene (200 ml) and treated with an excess o~ a saturated solution of hydrogen chloride in ethanol. The resulting solid was collected and recrystallised (with treatment with charcoal) Erom a mix-ture of ethanol and water (9:1 v/v), to give methyl 2-(n-hepta-decyl)benzimidazole-5-carboxylate hydrochloride (19.9 g) in the form of a white solid~ m.p. 22g-234C (with decomposition).

Compound L
A solution of methyl 2-(n-heptadecyl) benzimidazole-5-carboxylate hydrochloride (11.5 g; prepared as described herein-before 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 - 3~ -7~5 manner similar to that described hereinbefore in Example 4 to give 2-(n-heptadecyl)benzimidazole-5-carboxylic acid hydro-chloride (8.8 g) in the form of a white solid, m.p. 279-284C (with decomposition).

Compound M
A mixture of methyl 4-amino-3-(n-decanamido)benzoate (16.7 g) and toluene ~60G ml) containing p-toluenesulphonic acid (5.0 g) was treated in a manner similar to that described here-inbefore in Example 1 to give methyl 2-(n-nony]) benzimidazole-5-carboxylate (14.0 g) in the form of a white solid, m.p 101-103C.
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 l(i) to give methyl 4-amino-3-(n-decanamido) benzoate (18.8 g) in the form of a buff solid, m.p. 96-98C.

Compound N
A solution of methyl 2-(n-nonyl)benzimidazo]e-5-carboxylate (13.5 g; prepared as described hereinbefore in Example 25) in a mixture of ethanol 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~ 275-280C.

Compound O

1~41~7~i$

A stirred solution of methyl 3,4-bis(n-octanamido)benzoate (81.8 g) in methanol (~0~ ml) containing concentrated hydro-chloric acid (100 ml of strength 36.5 ~ w/v) was heated at reflux for 4 hours. The mixture was then c~oled and treated in a manner similar to that described hereinbeore in Example 17 to give methyl 2~(n-hepty])benzimidazole-5-carboxylate hydrochloride (33.8 g) in the form of a white solid, m.p. 140-142C (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, recrystallising from methanol (with treatment with charcoal), to give methyl 3,4-bis(n-octan-amido)benzoate (81.8 g) in the form of a white solid, m.p. 138-140C.

-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 v/v) containing sodium hydroxide (8.9 g) was heated at reflux for 5 hours. The mixture was treated in a manner similar to that described hereinbefore 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. 310-313C (with decomposition).

-Compound Q

A stirred sol~tion o 3,4-bis~n-pentadeeanamido)benzoie aeid (49.3 g) in a mixture ~ methy] ethyl ketone and eoncen-trated hydroehlorie acid (560 ml 10:1 v/v) was heated at reflux for 3 hours. The mixture was then cooled. The resulting solid was eolleeted and washed with methyl ethyl ketone (200 ml) and then washed with boiling petroleum ether (200 ml; b.p. 60-80C). It was recrystallised rom a mixture of ethanol and water (4 1 v/v) (with treatment with charcoal and with filtra-tion of the hot solution) to give 2-(n-tetradecyl)benzimidazole-5-earboxylic aeid hydrochloride (15.7 g), m.p. above 300C
(with decomposition).
The 3,4-bis(n-pentadeeanamido)benzoie aeid, used as starting material, was prepared as follows:
A solution of 3,4-diaminobenzoie acid (13.85 g) in dimethylformamide (180 ml) containing triethylamine (27.6 g) was treated with n-pentadeeanoyl chloride (47.4 g) in a manner similar to that deseribed hereinbefore in Example l(i). The resulting solid was colleeted and reerystallised from methyl ethyl ketone (with treatment with ehareoal and with filtra-tion of the hot solution) to give 3,4-bis(n-pentadeeanamido) benzoie aeid (49.3 g), m.p. 178- 180C.

Compound R
(a) A stirred solution of methyl 3,4-bis(n-nonanamido)ben-zoate (23.3 g) in methanol (300 ml) was treated with eoneen-trated 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. 40-60C) and was recrystallised from water (700 ml) with hot filtration to give methyl 2-n-octy].benzimidazo]e-5-carboxylate hydrochloride in 7~;5 the form of a white so~id, m.~. 238-243C (12.0 g).
lb) A stirred solution o~ 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 hereinbefore 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. 280-300C (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-diamino-benzoate (2G g) in dry dichloromethane 1250 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 l(ii). The resulting pink solid was recrystallised from methanol, with treatment with charcoal, to give methyl 3,4-bis-(n-nonanamido)benzoate (30.3 g) in the form of a white solid, m.p. 142-145C.

Compound S
2-(n-Tetradecyl)benzimidazole-5-carboxylic acid hydro-chloride ~8.5 g; prepared as described hereinbefore 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-tetra-decyl)benzimidazole-5-carboxylate hydrochloride (6.2 g) in the form of a white solid, m.p. 233-235C.

11~1765 Compound T
2-(n-Hexadec~l)benzimidazole-5-carboxylic acid hydro-chloride (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 solidj m.p. 225-230C (with decompo-sition).

Compound U
A solution of 3,4-bis(n-heptadecanamido)-benzoic acid (250 g) in methyl ethyl ketone (1500 ml) was treated with con-centrated hydrochloric acid (180 ml, of strength 36.5 ~ w/v).
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 hydro-chloride (44.9 g) in the form of an off-white solid, m.p. 296-306C (with decomposition).
The 3,4-bis(n-heptadecanamido)benzoic acid, used as starting material, was prepared as follows:
A stirred solution o 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 1~1'7~5 hours and was then poured in~o hot water (3500 ml kept at 70C~
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.

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. 220-226C.

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 3~.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) to give 2-(n-eicosyl)benzimidazole-5-carboxylic acid hydrochloride (45.1 g) in the form of a white solid, m.p. 294-298C (with decomposition).
The 3,4-bis(n-heneicosanamido)benzoic acid, used as starting material, was prepared as follows:
A stirred solution of 3,~-diaminobenzoic acid (21.9 g) in 7f~5 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 crude 3,4-bis(n-heneicosanamido)-benzoic acid (126.5 g) in the form of a light brown solid.

~ .
2-(n-Nonadecyl)benzimidazole-5-carboxylic acid hydro-chloride (14.6 9; prepared as described hereinafter in Example 37) was suspended in thionyl chloride (350 ml) and the mix-ture was stirred and refluxed for 6 hours. The excess thionyl chloride was removed _ 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-carboxy-late hydrochloride (12.2 g) in the form of a white solid, m p 219 227C

ComPound Y
A suspension of 3~4-bis(n-eicosanamido)-benzoic acid (89.1 g) in methyl ethyl ketone (1200 ml) was heated with con-centrated 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. 290-300C (with decompo-sition).

The 3,4-bis(n-eicosanamido)benzoic acid, used as starting k~
~ .

material~ was prepared as ollows:
A stirred solution o 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~ 16a-170C.

Compound Z
A suspension of 4-amino-3-(n-nonadecanamido)-benzoic acid (107 g) in methyl ethyl ketone (1500 ml) was treated with con-centrated hydrochloric acid (100 ml, of strength 36~5 % w/v).
The mixture was stirred and refluxed for 3 hours. The mixture was cooled to 10C and the solid was collected, washed with methyl ethyl ketone (2 x S00 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 60C 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 ethanol, with treatment with charcoal, to give a white solid which was care-fully dried and then suspended in methyl ethyl ketone (500 ml) containing concentrated hydrochloric acid (100 ml, of strength 36.5 % w/v). The mixture was stirred and refluxed for 1 hour and then cooled to give 2-~n-octadecy])ben~imidazole-5-carboxylic acid hydrochloride (33.8 g) in the fo~m of a white solid, m.p. 292-297C (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 114~7~;5 dimethylormamide (500 ml), containi~g triethylamine (50.5 g), was treated dropwise with n-nonadecano~l chloride (79.1 g) in a similar manner to that described hereinbeore in Example 33 to give an orange solution, which was poured into water (3000 ml), containing concentrated h~drochloric ac d (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-;13C.
EXAMPLE 3g Compound II
2-(n-Octadecyl)benzimidazole-5-carboxylic acid hydro-chloride (12 g; prepared as described hereinbefore in Example 38) in thionyl chloride (L00 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)ben-zimidazole-5-carboxylate hydrochloride (11.6 g) in the form of a white solid, m.p 224-230C.
~XAMPLE 40 Compound AA
A suspension of 3,4-bis~2-methyltetradecanamido7benzoic 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 0C and the solid was collected (11.17 g) and washed with methyl ethyl ~etone (2 x 25 ml). The solid was suspended in water (50 ml), and sodium hydroxide solution ~20 g in water (50 ml)7 was added to the suspension. The mixture was stirred and warmed to 60C 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 '~

ll~i7~5 with charcoal, and then treated'in a similar manner to that described hereinbeore in Example 38 to give (RS)-2-(tetradec-2-yl)-benzimidazole-5-carb~xylic acid hydrochloride (11 g) in the form of a white solid, m,p. 214-21~C.
The 3,4-bis~2-methyltetradecanamido7-benzoic acid, used as starting material, was prepared as follows:
A stirred solution of 3,4-diaminobenzoic acid (17.5 g) in dimethylformamide (1~0 ml), containing triethylamine (34.8 g), was treated dropwise with pentadecan-2-oyl chloride (59.7 g) in a similar manner to that described hereinbefore in ~xample 33 to give crude 3,4-bis~2-methyltetradecanamido7-benzoic acid (68 g).

Compound CC
A solution of 4-amino-3-~2-hexyloctanamido7-benzoic acid (15.2 g) in methyl ketone (78 ml) was treated with concentrated hydrochloric acid (18.2 ml~ of strength 36.5 % w/v). The mix-ture 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 mix-ture was heated to 90C 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-carboxylic acid (8.89 g), m.p.
157-158C.
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 ~1417fi5 recrystallised rom 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. 202-205C.
The 4-amino-3-~2-hexyloctanamido7benzoic acid, used as starting material, was prepared as ollows:
A stirred solution of 3t4-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-~2-hexyloctan-amido7benzoic acid (15.2 g) in the form of a white solid, m.p.
219-222C.

Compound BB
A solution of 4-amino-3-(2-ethyldodecanamido)-benzoic acid (24.7 g) in methyl ethyl ketone (125 ml) was treated with con-centrated 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 (20a 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. 185-187C.
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 7~5 dimethylormamide (2~0 ml), containing triethylamine (22.7 g), was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in a similar manner to that described hereinbefore in Exanlple 41 to give a solid, which was recrystallised from ethyl acetate with treatment with charcoal to give 4-amino-3-(2-ethyldodecan-amido)benzoic acid (22.2 g) in the form of a white solid, m.p.
188- 191C.

Compound DD
A solution of 4-amino-3-~2-butyldecanamido7-benzoic acid (9.8 g) in methyl ethyl ketone (50 ml) was treated with con-centrated hydrochloric acid (11.5 ml, 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 hemisulphate (4.7 g) in the orm of a white solid m.p. 161-164C.
The 4-amino-3-~2-butyldecanamido7benzoic 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-butyldecanoyl chloride (51.4 g) in a similar manner to that described hereinbefore in Example 41 to give 4-amino-3-~2-butyldecanamido7benzoic acid (9.8 g) in the form of a white solid~ m.p. 178-182C.

Compound EE
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g) in ethanol (250 ml) was stirred and refluxed for 2 hours. The mixture was cooled to room tem-perature and the solid was collected and washed with ethanol (50 ml) and then with diethyl ether (2 x 50 ml). The solid ~l~lt7~;5 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 t~ 0C and the resulting solid was collected to give ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (7.8 g) in the form of a white solid, m.p. 207-213C.
The 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride, used as starting material, was prepared as follows:
2-(n-Pentadecyl)benzimidazole-5-carboxylic acid mono-hydrate (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 theh 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. 286-288C (with decomposition).

Compound FF
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as described herein-before 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 hydrochloride (9.3 g) in the orm of a white solid m.p.
166-170C.

Compound GG
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as described herein-before 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 i765 hydrochloride (8.9 g) in the form of a white solid, m.p, 170-Compound HH
A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as described herein-before in Example 44) in isopropyl alcohol (300 ml) was treated in a similar manner to that described hereinbefore ln Example 44 to give isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxy-late hydrochloride (6.4 g) in the form of a white solid,m p 184 186C
EXA~PLE 48 ComPound JJ
A stirred mixture o sodium 2-(n-pentadecyl)-benzimidazole-5-carboxylate (13.7 g; prepared as described hereinbefore in Example 19) and chloromethyl pivalate (5 g) in hexamethyl-phosphoramide (35 ml) was heated to 50C or 3 hours. After coolingl 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 silica gel (400 g) using chloroform as the eluent. Fractions (100 ml) were collected and fractions 14 to 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 pll of the mixture was pll 1. The white solid was collected and washed with diethyl ether (3 x 100 ml) to give pivaloyloxymethyl 2-n-pentadecylbenzimidazole-5-carboxylate hydrochloride (1~ g) in the form of a white solidm p. 165-175C.

,, ~

11~17~

Compound KK
Sodium hydride (12 g o~ a 50 ~ oil dispersion) was added during 15 minutes to a stirred mixture of glycerol (100 g) and dry tetrahydrofuran (100 ml). ~hen the addition was complete, the mixture was stirred vigorously for a further 30 minutes and then 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydro-chloride (20 g; prepared as described hereinbefore in Example 4) was added to the mixture during 5 minutes. The mixture was stirred vigorously for 2 hours and was then allowed to stand overnight. The brown mixture was poured into water (800 ml) containing glacial acetic acid (g.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 1n 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 -30C, a white solid precipitated out and was collected and washed with diethyl ether (2 x 100 ml) to give 2,3-dihydroxyprop-l-yl 2-(n-pentadecyl)-benzimidazole-5-carboxylate (6.6 g) in the form of a white solid, m.p. 109-112C.

Compound B
3,4-Diamillobenzoic acid (10 g) and palmitic acid (168 g) in diglyme containing concentra-ted 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 11~176S

ether (4 x lOa ml, b.p. 40-60C). The solid was recrystallised from ethanol, with treatment with charcoal, to give 2-(n-penta-decyl)benzimidazole-5-carboxylic acid hydrochloride (50 mg), m.p. 295-300C (with decomp~sition).

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 130C or 2 hours. The mixture was then cooled to room temperature and was triturated with water (100 ml) to give 2-~n-pentadecyl)benzimidazole-5-car-boxylic acid hydrochloride (0.1 g), m.p. 29~-300C (with decomposition).

_ompound B
A stirred solution o 3,4-diaminobenzoic acid (9 g) in dimethylformamide (19a 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-5-carboxylic acid hydrochloride (3 g), m.p. 295-300C (with decomposition).
EXA~IPLE 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 60C and then treated with an aqueous solution of sodium hydroxide (40 g, in water 50 ml). The 7~5 mixture was stirred fo~ ~ hour with refluxing and was then cooled to 0C. 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 monoh~drate (345 g), m.p. above 300C with decomposition.

Compound LL
A solution of 2,3-bis(n-tetradecanamido)-benzoic acid (17.6 g) in methyl ethyl ketone (250 ml) was treated with con-centrated hydrochloric acid (25 ml, strength 36.5 % w/v). The mixture was refluxed for 5 hours, then coo]ed and treated in a similar manner to that described hereinbe-fore in Example 15 to give 2-(n-tridecyl)benzimidazole-4-carboxylic acid hydro-chloride (6.5 g) in the form of a buff solid, m.p. 192-200C.
The 2,3~bis(n-tetradecanamico)benzoic acid, used as starting material, was prepared as follows:
A solution of 2,3-diaminobenzoic acid (20 g) in dimethyl-formamide (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 45-50C. The mixture was then stirred foL a further 2 hours and allowed to stand at room temperature over-night. Methanol (20 ml) was added to the mixture, and the - resulting mixture was stirred for 20 minutes and afterwards treated with concentrated hydrochloric acid (strength 36.5 %
w/v) until the pE~ was 2. The resultant mixture was poured into water (1000 ml) and the black solid was collected, washed with water (2 x 500 ml) and then with hot light petroleum (b.p. 60-80C; 500 ml), and was finally recrystallised from ethanol, with treatment with charcoal, to give 2,3-bis(n-tetra-11~176S

decanamido)benzoic acid (17.7 g) in the form of a buff solid, m p 150 158C
EX~MPIE 55 Compound B
A suspension of 3-amina-4-(hexadecanamido)-benzoic acid (2.0 g) in methyl ethyl ketone (60 ml) containing hydrochloric acid (1.5 ml, of strength 36.S ~ w/v) was refluxed for 5 hours.
The resul'ing solid was collected, washed with boiling petro-leum ether (b.p. 60-80C) and recrystallised from ethanol to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydro-chloride (2.0 g) in the form of a white solid m.p. 288-290C
(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 ~ w/w palladium on charcoal (2.5 g) at 70C 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. 160-162C.
The 3-nitro-4-(n-hexadecanamido)benzoic acidr 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 97C. 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 recrystal-lised from a mixture of acetone and water (5:1) (with treat-ment with charcoal~ to give 3-nitro-4-(n-hexadecanamido)benzoic 7i5 acid (31.7 g) in the ~rm of a pale yellow solidt m.p. 153-15~C.

Compound ~lM
A suspension of 2-(n-pe~tadecyl)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 dis-tillation 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 ln vacuo and the residue was suspended in ethyl acetate (150 ml). The suspension was refluxed for 1~ minutes and was filtered hot.
The filtrate was cooled and the resulting solid was collected.
The solid was washed with ethanol (2 x S0 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. 16$-lG8C.
EXA~lPLE 57 ComPound NN
A mixture of 2-(n-pentadec~l)benzimidazole-5-carbonyl chloride (lS 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. 198-200C.

Compound ~l To a stirred solution o~ methyl 3,4-diaminobenzoate (9.8 g) 11~1765 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 sul-phide 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 Gooling the greyish-green solid was collected and was dissolved in tetra-hydrofuran (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 o 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 ml) yielding methyl 2-(n-nonyl)-benzimidazole-5-carboxylate hydro-chlori~e (5.3 g) in the form of white solid, m.p. 234-237C
(with decomposition).

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 1~1765 with water (2000 ml), the granular solid was collected and washed with hot petroleum ether (b.p. 60-~0C; 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 evapo-rated ln vacuo leaving a buff solid. The solid was chromato-graphed on silica with a mixt~re of chloroform and methanol (9:1 v/v) 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. 160-166C.
The 2,3-bis(n-hexadecanamido)benzoic acid, used as starting material, was prepared as follows:
A solution of 2t3-diaminobenzoic acid (40 g) in dimethyl-formamide (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 45-50C. The mix-ture 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 % w/v), and the resulting solid was collected and washed with water (1200 ml). The solid was stirred with hot water (4000 ml; 65C) for 30 minutes and was collected and dried at 70C in vacuo. The resulting product 2,3-bis(n-hexadecanamido)benzoic acid was used without further purification in the above preparation.

REFERE;NCE EXA~IPLE~ 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 11~176S

chloride was such as to allow the temperature of the reaction mixture to rise rom r~om 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 (10 litres kept at 70C) 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 Eorm of a buff solid, m.p. 180-190C, suitable for use in the preparation hereinbefore described in Example 15.

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-octan-amido)benzoic acid in the form of an off-white solid, m.p.
202-203C after recrystallisation from methanol.

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.

By proceeding in a similar manner to that hereinbefore des-cribed in Example 38 for the preparation of 4-amino-3-(n-nona-- decanamido)benzoic acid but replacing n-nonadecano~l 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. 185-187C after recrystallisation from methyl ethyl ketone.

il9~1765 A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry dimethylfo~mamide (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 8C.
The mixture was stirred for a further period of 2 hours. The solid was removed by filtration and the filtrate was poured into water (800~ ml). The resulting solid was collected and was recrystallised twice from methanol to give methyl 4-amino-3-(n-octanamido)-benzoate (65.S g) in the form of a white solid, m.p. 120C.

By proceeding in a similar manner to-that hereinbefore des-cribed 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. 102-105C after recrystallisation from methanol.

By proceeding in a similar manner to that hereinbefore described in Reference Example 5 for the prepa~ation 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. 101-104C after recrystallisation from metharol.

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 1141~7~i5 4-amino-3-(n-tetradecanamido)benzoate in the form o~ a light brown solid, m.p. 108-lOgC after recrystallisation from methanol.

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 prepaLed methyl 4-amino-3-(n-hexadecanamido)benzoate in the form of a white solid, m.p. 109-110C after recrystallisation from methanol.

A stirred solution of methyl 3,4-diaminobenzoate (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 20C to 50C.
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. 129-132C, which is identical to the starting material used in Example 16.
REFERENCE EXA~PLE 11 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-octanoyl chloride, there was prepared methyl 3,4-bis(n-octanamido)benzoate in the form of a white solid, m.p. 145-147C after recrystallisation from acetone.

6~

RE~ERENCE EXAMPLE 12 By proceeding in a similar manner to that hereinbefore des-cribed in Reference Example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-dodecanoyl chloridel there was prepared methyl 3,4-bis(n-dodecanamido)benzoate in the form of an off-white solid, m.p. 129-131C after recrystallisation from acetone.

By proceeding in a similar manner to that hereinbefore described in Reference Example 10 for the preparation of ;nethyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride by n-tridecanoyl chloride, there was prepared methyl 3,4-bis(n-tridecanamidojbenzoate in the form of a white solid, m.p. 132-134C after recrystallisation from acetone.

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 chloridel there was prepared methyl 3t4-bis(n-tetradecanamido)benzoate in the form of a white solid, m.p. 132-133C after recrystallisation from acetone.
REFERENCE EXArfilPLE 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. 120C after recrystallisation from a mixture of acetone and methanol (1:1).

3-Amino-4-(n-octanamido)bellzoic acid (12.1 g) in methanol 1~4~65 (200 ml) was treated with ethereal diazomethane until the reaction had gone to completion (as shown by thin layer chromato-graphy on silica, using methanol: chloroform: glacial acetic acid; 10:90:0.5). Acetic acid (~.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. 128-131C.
REEERENCE EXA~PLE 17 -3-Nitro-4-(n-octanamido)benzoic acid (25 g) dissolved in ethanol (500 ml) at 50C was hydrogenated by shaking in the presence of 5 % w/w palladium on charcoal (2.5 g) at 50C 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-amino-4-(n-octanamido)benzoic acid (8 g) in the form of a yellow solid, m.p. 155-156C.
The 3-nitro-4-(n-octanamido)benzoic acid, used as starting material, was prepared as follows:
A solution of 4-amino-3-nitrobenzoic acid (l8.2 g) and n-octanoyl chloride (19.4 g) in dry dimethylformamide (100 ml) was treated for 90 minutes at 97C. 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 gi~e 3-nitro-4-(n-octanamido)benzoic acid (22 g) in the form of a pale yellow solid, m.p. 153C-154C.

3-Nitro-4-(n-dodecanamido)benzoic acid (21 g) dissolved in ethyl acetate (500 ml) was hydrogenated by shaking in the pre~ence of 5 % w/w palladium on charcoal (2.5 g) at 50C and atmospheric 1~1765 pressure. The resulting mixture was iltered hot to yield a cream solid on cooling. This product was ~ecrystallised from methanol to give 3-amino-4-(n-dodecanamido)benzoic acid (7.4 g) as a beige solid m.p. 158-16a~C.

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.
96-100C.

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.
139-141C after recrystallisation from ethanol.

A stirred solution of 3,4-diaminobenzoic acid (10 g) in dry dimethylformamide (laO 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 20 to 50C.
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 recrysta]lised 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 1'765 solidI m.p. 195-197C.

By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation oi 3,4-bis~n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by n-hexadecanoyl 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. 198-202 C
after successive recrystallisation from glacial acetic acid and methyl ethyl ketone. .-By proceeding in a similar manner to that hereinbefore described in Reference Example 21 for the preparation of 3r4~
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.
195-197C after successive recrystallisation from glacial acetic acid and methyl ethyl Icetone.

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-tetradecanoyl chloride, there was prepared 3,4-bis(n-tetradecanamido)benzoic acid in the form of a white solid, m.p. 201-206C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

Methyl 4-(n-dodecanamido)-3-nitrobenzoate (21 g) dissolved in warm ethyl acetate (500 ml) (50-55C) was hydrogenated by shaking in the presence of 5 % w/w palladium on charcoal (2.0 g) at 60C and atmospheric pressure for 2 hours. The mixture was 11~1765 filtered hot and the ~iltrate was allowed to cool. The solid was collected to give methyl 3-amina-4-(n-dodecanamido)benzoate (14.1 g) in the form o a white solidf m.p. 134-137C.
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 g) in dimethylformamide (100 ml) were heated for 2 1/2 hours at 97C with occasional shaking. 'rhe resulting solution was poured onto crushed ice (30a g) and the solid collected and recrystallised from a mixture of methanol and chloroform (5:1) to give methyl 4-(n-dodecanamido)-3-nitroben-zoate (31 g) in the form of a yellow solid, m.p. 78 -80C.
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 ml~7. The resulting mix-ture 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. 193-195C.

By proceeding in a similar manner to that hereinbefore described in Reference Example 25 for the preparation of methy]
3-amino-4-(n-dodecanamido)-benzoate but replacing methyl 4-(n-dodecanamido)-3-nitrobenzoate by methyl 4-(n-hexadecanamido)-3-nitrobenzoate, there was prepared methyl 3-amino-4-(n-hexade-canamido)benzoate in the Eorm of a white slolid, m.p. 135-137C.
REFERE~ICE EXAMPLE 27 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)-3-nitrobenzoate by methyl 4-(n-decanamido)-3-nitrobenzoate~ there was prepared methyl 3-amino-4-(n-decan-amido)benzoate in the form of a white solidr m.p. 131-133C.

A stirred solution of 3,4-diaminobenzoic acid (8.4 g) in dry dimethylformamide (1~0 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 0-5C. The mixture was stirred for a further 2 hours at 0-5C 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 50C, 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. 197-199C.

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. 194-196C after successive recrystallisation from glacial acetic acid and methyl ethyl ~etone.

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. 192-194C after successive recrystallisation . ,,. ~

. .

from glacial acetlc acid and methyl ethyl ketone.

By proceeding in a similar manner to that hereinbefore described in Reference Example 21 f~r 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-octade-canamido)benzoic acid in the form of a white solid, m.p~ 193-196C after successive recrystallisation from glacial acetic acid and methyl ethyl kctone.
The following Example illustrates a pharmaceutical com-position according to the present invention.
EXAMPLE 60 .
No. 2 size gelatin capsules each containing:
sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate 20 mg lactose , 100 mg starch 60 mg dextrin -' 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

_ ., , 69 .

Claims (88)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of benzimidazole deri-vatives having the general formula:

(I) wherein R1 represents a hyarogen 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 con-taining 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 of the pharmaceutically acceptable salts thereof, which comprises:
a) cyclising a compound of the general formula:

(II) wherein R0 represents a hydrogen atom or a group -COR2, and R1 and R2 are as hereinbefore defined; or b) reacting a compound of the general formula:

(V) 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 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 general formula (I); or c) for preparing benzimidazole derivatives of general formula (I) wherein R1 represents a hydrogen atom and R2 is as hereinbefore defined, hydrolysing a corresponding ester of general formula (I) 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 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms, and R2 is as hereinbefore defined; or d) for preparing benzimidazole derivatives of general formula (I) wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, which may by substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups con-taining from 2 to 5 carbon atoms or alkanoyloxy groups con-taining from 2 to 7 carbon atoms and R2 is as hereinbefore defined, esterifying a corresponding carboxylic acid of general formula (I) wherein R1 represents a hydrogen atom, and R2 is as hereinbefore defined; and e) where desired, converting the benzimidazole derivative of general formula (I) thus obtained into a pharmaceutically acceptable salt.

2. A process according to claim 1, wherein a compound of the general formula:

(II) wherein R0 represents a hydrogen atom or a group -COR2, and R1 and R2 are as hereinbefore defined, is cyclised.

3. A process according to claim 2, wherein the compound is cyclised by reaction with an inorganic acid in the presence of water and in an organic solvent.

4. A process according to claim 3, wherein the cyclisation is carried out at an elevated temperature.

5. A process according to claim 2, wherein R0 represents a hydrogen atom and the compound is cyclised by reaction with an organic acid in water or an organic solvent.

6. A process according to claim 5, wherein the compound is cyclised at an elevated temperature.

7. A process according to claim 2, wherein 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.

8. A process according to claim 2, wherein R1 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms,

9. A process according to claim 2, wherein R1 represents a hydrogen atom.

10. A process according to claim 2, wherein R1 represents the methyl group.

11. A process according to claim 2, wherein R1 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.

12. A process according to claim 2, wherein R2 represents a straight-chain alky] group containing from 7 to 20 carbon atoms.

13. A process according to claim 2, wherein R2 represents an alkyl group containing from 10 to 18 carbon atoms.

14. A process according to claim 2, wherein the group R1OOC-is attached to the 5-position of the benzimidazole ring system.

15. A process according to claim 1, wherein a compound of the general formula:

(V) wherein R1 is as hereinbefore defined, is reacted with a com-pound of general formula:
R2CHO (VI) wherein R2 is as hereinbefore defined, 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, and the resulting copper salt is converted into the corresponding compound of general formula (I).

16. A process according to claim 15, wherein R1 represents a hydrogen atom or a straight- or branched-chain alkyl group con-taining from 1 to 6 carbon atoms.

17. A process according to claim 15, wherein R1 represents a hydrogen atom.

18. A process according to claim 15, wherein R1 represents the methyl group.

19. A process according to claim 15, wherein R1 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.

20. A process according to claim 15, wherein R2 represents a straight-chain alkyl group containing from 7 to 20 carbon atoms.

21. A process according to claim 15, wherein R2 represents an alkyl group containing from 10 to 18 carbon atoms.

22. A process according to claim 15, wherein the group R1OOC- is attached to the 5-position of the benzimidazole ring system.

23. A process according to claim 1, which comprises:
a) cyclising a compound of the general formula:

(II) wherein R0 represents a hydrogen atom or a group -COR2, 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 hereinbefore defined; or b) reacting a compound of the general formula:

(V) wherein R1 represents a straight- or branched- chain alkyl group containing from 1 to 6 carbon atoms, which may be sub-stituted by one or more than one of the same type of substi-tuent selected from the hydroxy group, alkenyl groups con-taining from 2 to 5 carbon atoms or alkanoyloxy groups con-taining from 2 to 7 carbon atoms, with a compound of the general formula:

R2CHO (VI) wherein R2 is as hereinbefore defined, 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 general formula (I);
and c) hydrolysing the resulting ester of general formula (I) to provide a benzimidazole derivative of general formula (I) wherein R1 represents a hydrogen atom.

24. A process according to claim 23, wherein R2 represents a straight-chain alkyl group containing from 7 to 20 carbon atoms.

25. A process according to claim 23, wherein R2 represents an alkyl group containing from 10 to 18 carbon atoms.

26. A process according to claim 23, wherein the group RlOOC- is attached to the 5-position of the benzimidazole ring system.

27. A process according to claim 1, which comprises:
a) cyclising a compound of the general formula:

(II) wherein R° represents a hydrogen atom or a group -COR2, R1 represents a hydrogen atom and R2 is as hereinbefore defined; or b) reacting a compound of the general formula;

(V) wherein R1 represents a hydrogen atom, with a compound of general formula:

R2CHO (VI) wherein R2 is as hereinbefore defined and 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 general formula (I);
and c) esterifying the resulting carboxylic acid of general formula (I) by reaction of the acid, or an acyl chloride or salt thereof, with an excess of an alcohol of the general for-mula:

R3OH (VII) wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, which may be substi-tuted 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 or by reaction with the corresponding alkyl halide.

28. A process according to claim 27, wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms.

29. A process according to claim 27, wherein R3 represents the methyl group.

30. A process according to claim 27, wherein R3 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.

31. A process according to claim 27, wherein R2 represents a straight-chain alkyl group containing from 7 to 20 carbon atoms.

32. A process according to claim 27, wherein R2 represents an alkyl group containing from 10 to 18 carbon atoms.

33. A process according to claim 27, wherein the group RlOOC- is attached to the 5-position of the benzimidazole ring system.

34. Benzimidazole derivatives of the general formula:

(I) 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 RlOOC- being attached to the 4-or 5-position of the benzimidazole ring system, and pharma-ceutically acceptable salts thereof, whenever prepared by a process according to claim 1 or its obvious chemical equivalents.

35. Benzimidazole derivatives according to claim 34, when-ever prepared by a process according to claims 2 or 7, or their obvious chemical equivalents.

36. Benzimidazole derivatives according to claim 34, wherein R1 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, whenever prepared by a process according to claim 8 or its obvious chemical equivalents.

37. Benzimidazole derivatives according to claim 34, wherein R1 represents a hydrogen atom, whenever prepared by a process according to claim 9 or its obvious chemical equivalents.

38. Benzimidazole derivatives according to claim 34, wherein R1 represents the methyl group, whenever prepared by a process according to claim 10 or its obvious chemical equivalents.

39. Benzimidazole derivatives according to claim 34, wherein R1 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxy-methyl group, whenever prepared by a process according to claim 11 or its obvious chemical equivalents.

40. Benzimidazole derivatives according to claim 34, wherein R2 represents a straight-chain alkyl group containing from 7 to 20 carbon atoms, whenever prepared by a process according to claim 12 or its obvious chemical equivalents.

41. Benzimidazole derivatives according to claim 34, wherein R2 represents an alkyl group containing from 10 to 18 carbon atoms, whenever prepared by a process according to claim 13 or its obvious chemical equivalents:

42. Benzimidazole derivatives according to claim 34, wherein the group R1OOC- is attached to the 5-position of the benzimi-dazole ring system, whenever prepared by a process according to claim 14 or its obvious chemical equivalents.

43. Benzimidazole derivatives according to claim 34, whenever prepared by a process according to claim 15 or its obvious chemical equivalents.

44. Benzimidazole derivatives according to claim 34, wherein R1 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, whenever pre-pared by a process according to claim 16 or its obvious chemical equivalents.

45. Benzimidazole derivatives according to claim 34, wherein R1 represents a hydrogen atom, whenever prepared by a process according to claim 17 or its obvious chemical equivalents.

46. Benzimidazole derivatives according to claim 34, wherein R1 represents the methyl group, whenever prepared by a process according to claim 18 or its obvious chemical equivalents.

47. Benzimidazole derivatives according to claim 34, wherein R1 is an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxy-methyl group, whenever prepared by a process according to claim 19 or its obvious chemical equivalents.

48. Benzimidazole derivatives according to claim 34, wherein R2 represents a straight-chain alkyl group containing from 7 to 20 carbon atoms, whenever prepared by a process according to claim 20 or its obvious chemical equivalents.

49. Benzimidazole derivatives according to claim 34, wherein R2 represents an alkyl group containing from 10 to 13 carbon atoms, whenever prepared by a process according to claim 21 or its obvious chemical equivalents.

50. Benzimidazole derivatives according to claim 34, wherein the group RlOOC- is attached to the 5-position of the benzimi-dazole ring system, whenever prepared by a process according to claim 22 or its obvious chemical equivalents.

51. Benzimidazole derivatives according to claim 34, wherein R1 represents a hydrogen atom, whenever prepared by a process according to claim 23 or its-obvious chemical equivalents.

52. Benzimidazole derivatives according to claim 34 r wherein R1 represents a hydrogen atom and R2 represents a straight-chain alkyl group containing from 7 to 20 carbon atoms, whenever pre-pared by a process according to claim 24 or its obvious chemical equivalents.

53. Benzimidazole derivatives according to claim 34, wherein R1 represents a hydrogen atom and R2 represents an alkyl group containing from 10 to 18 carbon atoms, whenever prepared by a process according to claim 25 or its obvious chemical equivalents.

54. Benzimidazole derivatives according to claim 34, wherein the group R1OOC- is attached to the 5-position of the benzimi-dazole ring system and R1 represents a hydrogen atom, whenever prepared by a process according to claim 26 or its obvious chemical equivalents.

55. Benzimidazole derivatives according to claim 34, wherein R1 represents a straight- or branched-chain alkyl group con-taining 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 car-bon atoms, whenever prepared by a process according to claim 27 or its obvious chemical equivalents.

56. Benzimidazole derivatives according to claim 34, wherein R1 represents a straight- or branched-chain alkyl group con-taining from 1 to 6 carbon atoms, whenever prepared by a process according to claim 28 or its obvious chemical equivalents.

57. Benzimidazole derivatives according to claim 34, wherein R represents the methyl group, whenever prepared by a process according to claim 29 or its obvious chemical equivalent.

58. Benzimidazole derivatives according to claim 34, wherein R1 is an n-butyl, 2,3-dihydroxyprop-l-yl, allyl or pivaloyloxy-methyl group, whenever prepared by a process according to claim 30 or its obvious chemical equivalents.

59. Benzimidazole derivatives according to claim 34, wherein R1 represents a straight- or branched-chain alkyl group con-taining 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 represents a straight-chain alkyl group containing from 1 to 20 carbon atoms, whenever prepared by a process according to claim 31 or its obvious chemical equivalents.

60. Benzimidazole derivatives according to claim 34, 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 represents an alkyl group containing from 10 to 18 carbon atoms, whenever prepared by a process according to claim 32 or its obvious chemical equivalents.

61. Benzimidazole derivatives according to claim 34, wherein the group RlOOC- is attached to the 5-position of the benzimidazole ring system 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 2 to 5 carbon atoms or alka-noyloxy groups containing from 2 to 7 carbon atoms, whenever prepared by a process according to claim 33 or its obvious chemical equivalents.

62. A process according to claim 1 for the prepara-tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising hydrolysing methyl 2-(n-pentadecyl )-benzimidazole-5-carboxylate or an acid addition salt thereof under alkaline conditions and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

63. A process according to claim 3 for the prepara-tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising cyclising 3,4-bis(n-hexadecanamido)-benzoic acid with an inorganic acid in the presence of water in an organic solvent, and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

64. A process according to claim 2 for the prepara-tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising reacting 3,4-diaminobenzoic acid with palmitic acid in the presence of water and an inorganic acid and in a suitable solvent, allowing the resulting product to cyclise in situ and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

65. A process according to claim 2 for the prepara-tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising treating 3,4-diaminobenzoic acid or a salt thereof with n-hexadecanoyl chloride, cyclising to resulting product in situ and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

66. A process according to claim 3 for the prepara-tion of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising cyclising 3-amino-4-(hexadecanamido)-benzoic acid with an inorganic acid in the presence of water in an organic solvent and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

67. 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever prepared by a process according to claim 62, 63 or 64 or its obvious chemical equivalents.

68. 2-(n-Pentadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever prepared by a process according to claim 65 or 66 or its obvious chemical equivalents.

69. A process according to claim l for the preparation of 2-(n-undecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising hydrolysing methyl 2-(n-undecyl)-benzimidazole-5-carboxylate and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

70. 2-(n-Undecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 69 or its obvious chemical equivalents.

71. A process according to claim l for the prepara-tion of n-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate and its pharmaceutically acceptable salts, comprising esterifying 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride or a salt thereof with n-butanol and when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

72. n-Butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 71 or its obvious chemical equivalents.

73. A process according to claim 1 for the prepara-tion of 2,3-dihydroxyprop-1-yl 2-(n-pentadecyl)-benzimidazole-5-carboxylate and its pharmaceutically acceptable salts, comprising esterifying 2-(n-pentadecyl)benzimidazole-5-carboxylic acid or a salt thereof with glycerol in the presence of sodium hydroxide and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

74. 2,3-Dihydroxyprop-l-yl 2-(n-pentadecyl)-benzimi-dazole-5-carboxylate and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 73 or its obvious chemical equivalents.

75. A process according to claim 3 for the prepara-tion of 2-(n-tridecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising cyclising 2,3-bis(n-tetradecanamido)-benzoic acid with an inorganic acid in the presence of water in an organic solvent, and, when desired, converting the so obtained derivative into a pharmaceutically salt.

76. 2-(n-Tridecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 75 and its obvious chemical equivalents.

77. A process according to claim 1 for the prepara-tion of 2-(n-dodecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising hydrolysing methyl 2-(n-dodecyl)-benzimidazole-5-carboxylate or a salt thereof and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

78. 2-(n-Dodecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 77 or its obvious chemical equivalents.

79. A process according to claim 3 for the prepara-tion of (RS)-2-(tetradec-2-yl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising cyclising 3,4-bis [2-methyltetradecanamido] benzoic acid with an inorganic acid in the presence of water and an organic solvent and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

80. (RS)-2-(tetradec-2-yl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 79 or its obvious chemical equivalents.

81. A process according to claim 3 for the prepara-tion of 2-(n-hexadecyl)benzimida]ole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising cyclising 3,4-bis(n-heptadecanamido)-benzoic acid with an inorganic acid in the presence of water and an organic solvent, and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

82. 2-(n-Hexadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 81 and its obvious chemical equivalents.

83. A process according to claim 3 for the prepara-tion of 2-(n-octadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising cyclising 4-amino-3-(n-nonadecanamido)-benzoic acid with an inorganic acid in the presence of water and an organic solvent, and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

84. 2-(n-Octadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 83 or its obvious chemical equivalents.

85. A process according to claim 1 for the prepara-tion of 2-(n-heptadecyl)benzimidazole-5-carboxylic acid and its pharmaceutically acceptable salts, comprising hydrolysing methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate or a salt thereof and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

86. 2-(n-Heptadecyl)benzimidazole-5-carkoxylic acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 85 or its obvious chemical equivalents.

87. A process according to claim 3 for the prepara-tion of methyl 2-(n-heptyl)benzimidazole-5-carboxylate acid and its pharmaceutically acceptable salts, comprising cyclising methl 3,4-bis(n-octanamido)benzoate with an inorganic acid in the presence of water and an organic solvent, and, when desired, converting the so obtained derivative into a pharmaceutically acceptable salt.

88. Methyl 2-(n-heptyl)benzimidazole-5-carboxylate acid and its pharmaceutically acceptable salts, whenever obtained by a process according to claim 87 or its obvious chemical equivalents.