NO801875L - PROCEDURE FOR PREPARING BENZIMIDAZOLD DERIVATIVES - Google Patents

Description

The present invention relates to new therapeutically effective benzimidazole derivatives, methods for their production and pharmaceutical mixtures containing them.

The benzimidazole derivatives according to the present invention are compounds with the general formula:

wherein R means a hydrogen atom, a straight or branched alkyl group of 1 to 6 carbon atoms (which may be substituted-with one or more substituents of the same type selected from the hydroxy group, alkenyl groups of 2 to 5 carbon atoms and

2 alkanoyloxy groups of 2 to 7 carbon atoms), and R means a straight or branched alkyl group, preferably a straight-chain alkyl group of 7 to 20 (preferably 10 to 18) carbon atoms, and pharmaceutically acceptable salts thereof. Preferably, R"*" means a hydrogen atom or a methyl group or an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group.

The group R^OOC is linked to the 4- or preferably the 5-position in the benzimidazole ring system.

It will be clear to a person skilled in the art that the compound of the general formula I exhibits tautomerism so that the hydrogen atom which is placed on one of the nitrogen atoms can sit on the other nitrogen atom, and that both forms thus described can exist to a greater or lesser degree and be - are in a dynamic state of equilibrium with each other. In the tautomers, the 4 and 5 positions are respectively 6 and 7 positions. Furthermore, in certain cases the substituents R 1 and R<2> contribute. to optical isomerism. All such forms are covered by the present invention.

By the term "pharmaceutically acceptable salt" is meant a salt formed by reaction with an acid or, when R"^ means, a hydrogen atom, by reaction with a base, such that the anions (in the case of an acid addition salt) or the cation (in the case of ;

trap of a salt formed by a compound of formula I where ' means a hydrogen atom) is relatively harmless to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the starting compound of the general formula I are not destroyed by side effects attributed to this anion or cation. •

Suitable acid addition salts include salts of inorganic bases, eg hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic salts, eg methanesulfonates,

2-hydroxyethanesulfonates, oxalates, lactates, tartrates,

acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-|3-hydroxynaphthoates, gentisates and di-p-toluene tartrates..

Suitable salts formed with compounds of general formula I wherein R"^ represents a hydrogen atom include alkali metal (e.g. sodium and potassium), alkaline metal (e.g. calcium and magnesium) and ammonium salts, and salts of amines which are known to be pharmaceutically acceptable, eg ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2-(hydroxymethyl)-propane-1,3-diene and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

It must be clear that when in this description reference is made to compounds of the general formula I, their pharmaceutically tolerable salts are also meant where comparison allows this.

The compounds of the general formula I have useful pharmacological properties, especially hypolipidemic activity. E.g. reduces the cholesterol concentrations and the concentrations of triglycerides in the blood. Furthermore, they prevent or prevent the development of atheromatous lesions, and in addition, they reduce the vegetative proliferation of arterial smooth muscle cells which is a main feature of atheromatous "plaques". The compounds of the general formula I also lower blood sugar levels in mice suffering from diabetes mellitus. Compounds of the general formula I also reduce lympho-<:>cyte transformation similarly to antirheumatic drugs. They can also be used to prevent or treat diabetes, mellitus, hyperlipoproteinemic conditions, atherosclerosis<:> and accompanying conditions such as angina, myocardial infarction,; cerebral vascular occlusion, arterial aneury, peripheral.; vascular diseases, including pancreatitis and xanthomas as well as arthritis, immunological diseases, cancer and transplant rejection.

Compounds of the general formula I of particular interest are the following compounds, their optically active forms and their salts:

The letters A to PP denote the compounds to make it easier to refer to them later in the description, e.g. in the ta-bells.

The properties of the compounds of the general formula I were demonstrated through the following experiments:

. Hypolipidemic activity in rats

Wistar. male rats all weighing between 120 and 150 g were caged in groups of 8 and fed a powdered diet for 10 days.

In the last 7 days of this period, the test compounds were given orally by mixing the compounds into the diet and the animals were fed normally. FSr consumption was measured on the 9th day in each group.

In the middle of the 10th day, the animals were euthanized by inhalation of carbon dioxide from solid carbon dioxide. A blood sample was removed by cardiac puncture and serum cholesterol and serum triglycerides were taken. ier was "■ analyzed using an autoanalyser.

Control groups (which only received a normal, unmedicated diet) were included in each experiment.

in r

RéI d.uxition shares in concentrations of serum cholesterolbg

I serum triglycerides were calculated by comparison with simultaneous controls for each concentration of the test compound used. in |

i ■ - 1

in

The results obtained are shown in the following table I. I

Anti-atheroma activity in rabbits.. New Zealand white male rabbits all weighing 2.2-2.8 kg were subjected to de-endothelialization of the main artery and a femoral artery by balloon catheter. After recovering from anaesthesia, they were all given a diet to which was added 1% by weight of cholesterol and a certain concentration of test compound. .one for 14 days. At the end of this period, the animals were sacrificed and the concentration of serum cholesterol was determined. The aorta and femoral arteries were removed, the "intima-media" was removed from the adventitia and the cholesterol concentrations were determined. Parts of the femoral arteries were examined histologically.

- A control group that did not receive the experimental compound was included

in each attempt.

The percentages of reduction in the concentrations of serum cholesterol and arterial cholesterol were calculated with comparison with concurrent controls.

The results obtained are shown in the following table II:

Hypoglycemic activity in diabetic mice

Diabetic mice (strain C 57, black, MRI-derived Obese/Obese) of both sexes, all weighing between 45 and 70 g, were fed powdered diet for a period of one week prior to the experiment. Treated animals were then given the test compound mixed into the diet at a specific concentration for several days. The animals . were weighed, anesthetized with carbon dioxide and euthanized by cardiac puncture.

The following serum parameters were measured:

1. Glucose - by the glucose-oxidase method of God-Perid

2. Cholesterol and triglycerides - these were measured with an auto-analyser after removing phospholipids using activated zeolite and extraction with iso-. propanol.

Control groups (which only received a normal, unmedicated diet) were included in each experiment.

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

The results obtained are shown in the following table III.

Inhibitory effect on vegetative growth of aortic smooth muscle cells Smooth muscle cells were grown in culture from explants

of pig thoracic aorta using Dulbecco's Modified Eagles (DME) Medium containing 20% fetal calf serum (FCS.) and antibiotics. The cells were incubated at 37°C in an atmosphere •

of 95% air and 5% carbon dioxide. At confluence, the cells were routinely cultured by trypsinization and repletting to approximately 1/3 of their confluent density in DME Medium containing 10% FCS and antibiotics.

The smooth muscle cells were plated at densities of

100,000 to 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 of DME Medium containing 1% FCS and antibiotics. The cultures were incubated for a further 3 days for the cells to become static, i.e. no longer.during-running_ cell division). The medium was then replaced with 2 ml of control or experimental medium. The test medium consisted of DME Medium (containing 10% FCS bg antibiotics) and the compound to be investigated in a concentration of 5 µg/ml medium. The compounds were previously dissolved in water, acetone or glycofurol so that the final concentration of the solvent in the medium was 0.2% (v/v). The control medium consisted of DME Medium (containing 10% FCS and antibiotics) and the correct solvent at 0.2% (v/v) concentration. After three days of incubation in the experimental or control medium, the medium was replaced with fresh experimental or control medium and the cells incubated for a further 3 or 4 days. At the end of the 6 or 7 day incubation periods, cell numbers were determined by •

trypsinizing cells and counting the cell suspension in a Coulter counter.

All the results in Table IV below represent the average value for 4 dishes of cells. Percent inhibition of vegetative growth was calculated using the following formula:

Percentage inhibition of vegetative growth

where S = average cell number per bowl at the start of the experiment (after addition of control or test medium).

T = Average number of cells per bowl.in experimental cultures

at the end of the experiment.

C = Average number of cells per bowl in control,

cultures at the end of the experiment.

Mitogen- stimulated lymph node cell- lymphocyte- transformation-. inhibitory activity in guinea pigs

Guinea pigs were sensitized 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).

After 14 days, lymph node cells were obtained and suspended in Eagle's Minimal Essential (EME) Medium containing 10% fetal calf serum' (FCS) and buffered with Earle's salts in a

concentration of 2.5 x 10^ cells/ml.

For 24 hours, 0.1 ml of cell suspension was incubated at 37°C in an atmosphere of 95% air and 5% carbon dioxide in the presence of 0.15

ml mitogen or mitogen and the compound to be investigated in EME medium (containing 10% FCS and buffered with Earle's salts)

Eighteen hours before harvest, 3 H-thymidine (1 µl of 10 uCi/ml solution in 0.9% sterile saline) was added.

As an index of DNA synthesis, the degree of 3 H■-thymidine- . incorporation of the cells measured in comparison with the mitogen control.

The results are set out below in Table V.

The applicability of the compounds is increased by the fact that they are only mildly toxic, as shown in the following experiment:

Oral toxicity in mice

Groups of mice were orally given graded doses of the test compound (in a 0.5% w/v aqueous suspension of tragacanth porridge) and observed for three consecutive days. The percentage of animals that died during this period at each dose level was used to construct a curve from which LD,-q, i.e. the dose in mg/kg animal body weight that was necessary to kill. 50% of the mice, was calculated.

Compounds of formula I as set forth in the above list

T

was investigated and the LD^q for all compounds was greater than 1000 mg/kg animal body weight

Preferred compounds according to the invention are those which are indicated in the following with the letters B, D, GG, KK, F, H, AA, U, Z, L and. 0.

The compounds of the general formula I can be prepared

by applying or adapting known methods, e.g.

as indicated below.

1. According to a feature of the present invention, compounds of the general formula I are prepared by cyclization of a compound of the general formula: 0 2 1 (where R means a hydrogen atom or eh group -COR , and R and R 2 are as previously described ), possibly produced in situ, e.g. ••as described below for the cyclization of compounds of the general formula III or IV. (i) Thus, when R 0 is a group -COR 2, a compound of the general formula 12 is cyclized ■ (in which R and R are as previously indicated), preferably at a higher temperature, e.g. between 60° and .100°C, e.g. at or near 80°C, by reaction with an inorganic acid, e.g. hydrochloric acid, in the presence of water and. in an organic solvent, e.g. an alcohol such as methanol or ethanol, or a ketone such as acetone or, preferably methyl ethyl ketone, or . (ii) when R 0 is a hydrogen atom (especially with respect to such compounds where R"*" means a linear or branched alkyl group of 1 to 6 carbon atoms) a compound is cyclized else with the general formula

■ 1 2 (in which R and R are as previously indicated), either under similar conditions to those previously described under (i), or optionally by reaction with an organic acid, e.g. p-toluenesulfonic acid in water or an organic solvent, e.g. toluene, preferably at a higher temperature, f-, e.g. between 60° and 100°C, e.g. at or near 80°C,. or (iii) (in particular with respect to such compounds where R"<*>" means a linear or branched alkyl group of 1 to 6 carbon atoms) cyclization normally without isolation of an acylated intermediate of formula III or IV either (a) without a organic solvent and at a higher temperature, e.g. between...150° and 250°C, or (b) in the presence of water and "an inorganic acid, e.g. hydrochloric acid, and in a suitable organic solvent, e.g. diglyme. 2. According to a further features of the present invention - compounds with the general formula I are prepared by reacting a compound with the general formula:

(in which R is as previously indicated) with a compound of the general formula: 2 (in which R is as previously indicated) and a copper(II) salt, for for example copper acetate in the presence of an aqueous inert organic solvent medium, e.g. a mixture of water and methanol at between room temperature and the reflux temperature of the reaction mixture followed by transfer of the resulting copper salt into the corresponding compound of formula I. 3. According to another feature of the present invention, carboxylic acids of the general formula I (where R<2 >is as previously indicated and R"*" means a hydrogen atom) by hydro- . lysis of a corresponding ester with the general formula I 2 1 where R is as previously indicated and R means a linear or branched alkyl group with 1 to 6 carbon atoms which can be substituted with one or more of the same type of substituents selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms. atoms or alkanoyloxy groups of 2 to 7 carbon atoms. Preferably, the hydrolysis is carried out under alkaline conditions, e.g. with an alkali metal hydroxide in an aqueous organic solution.agent system and at a higher temperature, e.g. in the presence of sodium hydroxide in aqueous ethanol and at reflux temperature.. 4. According to a further feature of the present invention 2, esters of the general formula I are prepared (where R is as previously indicated and R"'" means a linear or branched alkyl group with 1 to 6 carbon atoms, which may be substituted with one or more substituents of the same type chosen from

the hydroxy group, alkenyl groups with 2 to 5 carbon atoms or alkanoyloxy groups with 2 to 7 carbon atoms) by esterification of a corresponding carboxylic acid with general formula

In where R is as previously indicated and R" means a hydrogen atom. The esterification can be carried out by using or adapting known methods, for example by reacting the acid with an excess of the important alcohol with the general formula:

T

(where R 3 means a straight or branched alkyl group with 1 to 6 carbon atoms (which may be substituted with one or more of the same type of substituents selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms or alkanoyloxy groups with 2 to 7 carbon atoms) optionally as solvent medium, and in the presence of an inorganic acid, eg hydrochloric acid, preferably at a higher temperature, eg between 60° and 100°C, or by reaction with the corresponding alkyl halide.

The acid chloride formed by reaction with thionyl chloride, or salts of the acids can be used.

The term "known methods" used in the present description means methods that have previously been used or described in the literature.

5. According to a further feature of the present invention

compounds of the general formula I can be converted into pharmaceutically acceptable salts, and vice versa, using or adapting known methods. This method can both be applicable in itself and can be used for purification of compounds of the general formula I and their salts by exploiting differences in solubility in water and different organic solvents for the compounds and. their salts and for any impurities present using known methods such as crystallization.

(i) Compounds of general formula I may be transferred in their pharmaceutically acceptable acid addition salts, e.g. by reaction with the appropriate acid in solution or suspension in a suitable solvent, e.g. acetone, methanol or ethanol, if necessary followed by evaporation of some or all of the solvent and collection of the solid salt. (ii) On the other hand, the acid addition salts can be transferred to the parent compounds of the general formula I, e.g. by reaction with aqueous ammonia in the presence of a suitable solvent, e.g. ethanol, followed by treatment with a weak acid, e.g. glacial acetic acid.-(iii) Acids with the general formula I where R means a . hydrogen atom (R 2 is as previously stated) can be transferred to salts of pharmaceutically acceptable bases, e.g. by turnover with the correct base, e.g. by the appropriate amine or a compound of the general formula:

(where M"*" means an alkali metal, e.g. sodium or potassium, and R 4 means an alkyl group with up to .4 carbon atoms, e.g. methyl or ethyl, or a hydrogen atom) in a suitable solvent, e.g. .ex. methanol or ethanol, or a mixture of water and acetone, if necessary followed by evaporation of some or all of the solvent, and collection of. the solid salt.

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

It will be clear to a person skilled in the art that during the implementation of the method according to the present invention it may be desirable to introduce chemical protective groups into the reaction

the aunts to avoid secondary reactions, e.g. in method 1 previously described, it may have been necessary to transfer hydroxy groups in the substituent R"<*>" in the general formula II to benzyloxy groups before the described reaction with subsequent removal of the benzyl group. Furthermore, one manufacturing process may be chosen over others as a means of manufacturing certain indicated compounds of general formula I.

Compounds of general formula II where R^ denotes a hydrogen atom can be prepared from compounds of the general formula:

12

(where R and R are as previously indicated) by reduction, e.g. by catalytic hydrogenation, by using e.g. palladium-on-carbon.

Compounds of the general formula II where R 2 means a group of the formula -COR 2 (R 2 is as previously indicated) can be prepared from compounds of the general formula II where R means a hydrogen atom by reaction with compounds of the general formula XI which is indicated in the following.

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

(wherein R"<*>" is as previously indicated) with a compound of general formula XI in a similar manner as described in method A(i). Compounds of general formula II in which the substituent group 2 1 0 -NHCOR is meta to the substituent group -COOR' and in which R represents a hydrogen atom can be prepared by reacting a compound of general formula V with a compound of general formula XI as described in method A (ii).

Compounds of general formula II where means a group of formula -COR 2 (R 2 is as previously described) can also be prepared by reacting a compound of general formula V with a compound of general formula XI as described in method A (i) .

Compounds of general formula II in which R means a straight or branched alkyl group with 1 to 6 carbon atoms (which may be substituted by one or more of the same type of substituent selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms. and alkanoyloxy groups with 2 to 7 carbon atoms )' can be produced by esterification of the. corresponding compounds of general formula II where R means a hydrogen atom by using or adapting known methods, e.g. by reacting the corresponding diazoalkane in the presence of an inert organic solvent.

Method A

The compounds of general formula II can be prepared by reacting a compound of the general formula:

(where R"*" is as previously indicated) with an acylating agent of the general formula: ■ . in which R 2 is as previously indicated and X 1' means a halogen, preferably chlorine, atom) or a hydroxy group. (According to a method of the present invention follows the cyclization of the resulting product possibly in situ). Spe particularly suitable conditions are as follows: (i) Compounds of the general formula V (wherein R"<*>" is as previously indicated) can be reacted with acyl halides of general formula XI (where R is as previously indicated and X means a halogen, preferably chlorine, atom) in an inert organic solvent, e.g. dichloromethane or dimethylformamide, preferably under aqueous conditions and preferably in the presence of an acid-binding agent, e.g. 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 where R"'" means a linear or branched alkyl group of 1 to 6 carbon atoms) can be reacted with acyl halides of 1 general formula XI (where R is as previously indicated and X means a halogen , preferably chlorine, atom) under conditions similar to those described under (i), but using a smaller amount of the acyl halide and controlling the temperature, preferably at between 0°C and room temperature.

■ By using experimental conditions between those previously described under (i) and those previously described under (ii), a mixture of intermediates of general formula III and IV would be obtained, which could be cyclized under the conditions previously described described under l(i) and l(ii).

(iii). Compounds of general formula V (especially those . where R"*" means a straight or branched alkyl group with 1 to 6 carbon atoms) can be reacted with compounds of general

formula XI (where R is as previously indicated and X means a hydroxy group or a chlorine atom) to form compounds of general formula I, normally without isolation of acylated intermediates, either (a) without solvent and at elevated temperature, e.g. at between 150° and 250°C, or (b) in the presence of water and an inorganic acid, e.g. hydrochloric acid, and in a pass-' .

end solvent, e.g. diglym.

The following examples and reference examples illustrate the preparation of the compounds according to the present invention.

EXAMPLE 1

Compound A

A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate (46

g) and p-toluenesulfonic acid (15 g) in toluene (1000 ml) were stirred and heated at reflux for 2 hours while the water which became

formed was removed continuously using a Dean and Stark apparatus. The solution was cooled to 60°C<p>g was washed with aqueous sodium carbonate solution (2N; 2 x 200 ml). The toluene layer was dried over magnesium sulfate and then concentrated in vacuo to give an oil. The oil was triturated with petroleum ether (b.p. 40° to 60°C) and gave a tan solid which, after recrystallization from petroleum ether (b.p. 40°

to 60°C), gave methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate (24.6 g) as a white solid, mp 96° to 98°C.

The methyl 4-amino-3-(n-hexadecanamido)benzoate used as starting material was prepared by one of the following methods: (i) A stirred solution of methyl 3,4-diaminobenzoate (35 g) in dry dimethylformamide (1200 ml) containing anhydrous sodium carbonate (11.8 g) was treated dropwise with n-hexadecanoyl chloride (5-8 g) for 1 hour. The rate of addition of the n-hexadecanoyl chloride was such that the temperature of the reaction mixture rose from an initial temperature of 10°C to room temperature. The mixture was then stirred at room temperature for a further 3 hours and then poured into water (5 litres). The resulting solid was collected and boiled in acetone

(1000 mL) and the boiling mixture was then filtered. The filtrate was cooled to 0°C and the resulting tan solid filtered off to give methyl 4-amino-3-(n-hexadecanamido)benzoate (48.2 g), m.p. 112° to 114°C.

(ii) A stirred solution of methyl 3,4-diamino-benzoate (16.6 g)

in dry dichloromethane (270 ml) containing triethylamine (10.3 g) was treated dropwise with a solution of n-hexadecanoyl chloride (27.5 g) in dry dichloromethane (30 ml) for 45 min. The temperature during the addition was kept between 16° and 20°C. The mixture was stirred for an additional 2 hours. The resulting solid was then collected and boiled in a mixture of ace-

ton (1000 ml) and methanol (150 ml)' and the insoluble material was removed by filtration. The filtrate was cooled to 25°C and treated with water (800 mL) to give methyl 4-amino-3-(n-hexadecanamido)benzoate as a tan solid, m.p. 112° to 114°C.

EXAMPLE 2

Compound A

A solution of methyl 4-amino-3-(n-hexadecanamido)benzoate

(34 g; prepared as previously described in Example 1) in a mixture of ethanol and water (200 ml; 9:1 v/v) was treated with an excess of a saturated solution of hydrogen chloride in ethanol. The mixture was heated at reflux for 2 hours and then cooled. The resulting solid was collected and recrystallized from a mixture of ethanol and water (9:1 v/v) to give methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (24.2 g) as a white solid substance, m.p. 230°-232°C (during decomposition).

EXAMPLE 3

Compound A

Methyl 3,4-diaminobenzoate (8.8 g) and hexadecanoic acid (12.8 g) were ground together to a thorough mixture. The mixture was heated at 200°C for 150 min. The mixture was then cooled to 60°C and extracted with boiling petroleum ether (boiling point 60°-80°C; 200 ml). The extract was concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (100 ml) and the solution was treated with a solution of potassium hydroxide in ethanol (10% by weight) until the pH of the mixture was 7. The mixture was then cooled to 0 °C and filtered and the filtrate was concentrated in vacuo to give a brown oil (10.2 g). The oil was dissolved in chloroform (15 ml) and chromatographed on silica gel (275

g). Eluting with chloroform gave an off-white solid (6.0 g) which was recrystallized from petroleum ether (bp 40°-60°C)

and gave methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate (5,3

g)' in the form of a white solid, m.p. 96°-98°C.

EXAMPLE - 4

Compound B A stirred solution of methyl 2-(n-pentadecyl.) benzimidazole-5-carboxylate (3&g; prepared as previously described 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 under reflux for 90 min. ■ The mixture was cooled to Q°C and acidified by treatment with concentrated hydrochloric acid. The resulting off-white solid was collected and recrystallized (under treatment with activated carbon) from a mixture of ethanol and water (800 mL; 4:1 v/v) to give 2-(n-pentadecyl)benzimidazol-5- carboxylic acid hydrochloride (32 g) as a white solid, m.p. 289°-291°C (under decomposition).

EXAMPLE 5.

Compound B

A solution of methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (24.2 g; prepared as previously described 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 similar manner as previously described in Example 4 and gave 2-(n-pentadecyl) benzimidazole-5-carboxylic acid hydrochloride (22.4 g) m.p. 289<0>;-291<0>C (under cleavage) .

EXAMPLE 6

Compound C

A solution of methyl 4-amino-3-(n-dodecanamido)benzoate (41.0 g) in toluene (1000 ml) containing p-toluenesulfonic acid (25 g) was treated. similar way as described'before in example. 1 and' gave methyl 2-(n-undecyl)-benzimidazole-5-carboxylate (27.0 g.) in the form of a white solid, m.p. 9-3°-95°C.

The methyl 4-amino-3-(n-dodecanamido)benzoate used as starting material was prepared as follows: A solution of methyl 3,4-diaminobenzoate (25.0 g) in dry dimethylformamide (1120 mL) containing anhydrous sodium carbonate (7 .7 g) was treated with n-dodecanoyl chloride (30.5 g) on;. similar way as previously described in example l(i.) and ga. crude methyl 4-amino-3-(n-dodecaneamido)benzoate (41 g) as a tan solid.

"EXAMPLE" 7

Compound C

Methyl 3,4-diaminobenzoate (33 g) and dodecanoic acid (40 g) were ground together to give a thorough mixture and the mixture was heated at 200°C for 3 hours. The mixture was then treated in a similar manner as previously described in Example 3 and gave methyl 2-(n-undecyl)benzimidazole-5-carboxylate (19 g) as a white solid, m.p. 92°-94°C.

EXAMPLE 8

Compound D A solution of methyl 2-(n-undecyl)benzimidazole-5-carboxylate (28.6 g; prepared as previously described 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 similar manner as previously described in Example 4 and gave 2-(n-undecyl)benzimidazole-5-carboxylic acid hydrochloride (22.3 g) in the form of a white solid, m.p. 289°-294°C (under decomposition).

EXAMPLE 9

Connection E

Methyl 3,4-diaminobenzoate (33.0 g) and n-tetradecanoic acid (45.6 g) were ground together to a thorough mixture and the mixture was heated at 200°C for 6 hours. The mixture was cooled to

60°C and then extracted with petroleum ether (b.p. 60°-80°C), and the petroleum ether extracts were concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (500 ml) and the solution was treated with a solution of potassium hydroxide in . ethanol (10% w/v) until the pH of the mixture was 7. The mixture was cooled to 0°C and filtered and the filtrate was concentrated in vacuo to give a brown oil. The oil was partitioned between a hot mixture of petroleum ether (boiling point 60° -80°C). and toluene (300 ml; .4:1 v/v), and water (300 ml). The organic layer was concentrated in vacuo to give an oil which was then dissolved in hot toluene (100 ml) and treated with an excess of a saturated solution of hydrogen chloride in ethanol.

The precipitated solid was collected and recrystallized from ethanol (under treatment with activated carbon) to give methyl 2-(n-tridecyl)benzimidazole-5-carboxylate hydrochloride (16 g) in form; of a white solid, mp; 228°-236°C (under decomposition). !•

EXAMPLE 10..

■ Connection E

Methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) was treated in a similar manner as previously described in Example 2 to give methyl 2-(n-tridecyl)benzimidazole-5-carboxylate hydrochloride (33 g) in the form of a white solid, m.p. 228°-234°C (below, cleavage).

The methyl 4-amino-3-(n-tetradecanamido)benzoate variety used as starting material was prepared as follows:

A stirred solution of methyl 3,4-diaminobenzoate (25.0 g) i

dry dichloromethane (500 ml) containing triethylamine (15.5 g) was treated dropwise with a solution of n-tetradecanoyl chloride (37.12 g) in dry dichloromethane (50 ml) in a similar manner as previously described in example 1(ii) ) and gave crude methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) as a tan solid.

EXAMPLE 11

Connection F

A solution of methyl 2-(n-tridecyl)benzimidazole-5-carboxylate (7.9 g) in a mixture of ethanol and water (200 ml; 4:1 v/v) containing sodium hydroxide (2.4 g) was treated in a similar manner as previously described in Example 4 and gave 2-(n-tride-cyl)benzimidazole-5-carboxylic acid hydrochloride (5.7 g) in the form of a white solid, m.p. 299°- 306°C (under decomposition).

EXAMPLE 12 Compound B

2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride

(15.0 g; prepared as previously described in Example 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 0°C to give a white solid (12.3 g.). This solid was recrystallized from a mixture of ethanol and water (4:1 v/v) to give 2-(n-pentadecyl)benzimidazol-,5-carboxylic acid (12.0 g) as a white solid, m.p. 113°-115°C which was assumed to be the monohydrate.

E KS: EMPEL 13

■ Connection G

Methyl 4-amino-3-(n-tridecanamido)benzoate (prepared as in

(the following described 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 treated in a similar manner as previously described in Example 2 to give 2-(n-dodecyl)benzimidazole-5-carboxylate hydrochloride (25.5 g) as a white solid, m.p. 221°-225°C (under decomposition)'.

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

EXAMPLE 14 Compound H A solution of methyl 2-(n-dodecyl)benzimidazole-5-carboxylate (15.5 g) in a mixture of ethanol and water (100 ml; 4:1 v/v), containing sodium hydroxide (50 g ) was treated in a similar manner as previously described in example 4 oa to give 2-(n-dodecyl)-benzimidazole-5-carboxylic acid hydrochloride (11.7 g) in the form of a white solid. substance, m.p. 276°-290°C (under decomposition) . EXAMPLE 15 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 at strength 36.5% w/v) . The mixture was heated at reflux for 5 hours and then cooled. The resulting solid was collected and washed with boiling petrol;

ether (boiling point 60°-80°C) and recrystallized from ethanol and

gave 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (15 g) as a white solid, m.p. 298°-291°C (under 1 cleavage).

The 3,4-bis(n-hexadecanamido)benzoic acid used as. starting material was prepared as follows:

A solution of 3,4-diaminobenzoic acid (7.5 g) in dichloromethane (100 ml) containing triethylamine (15 g) was treated with n-hexadecanoyl chloride (27.5 g) in a similar manner as previously described in, example 1(ii). A solid was collected and recrystallized from glacial acetic acid and then recrystallized from methyl ethyl ketone (filtering the hot solution) to give 3,4-bis(n-hexadecanamido)benzoate (20 g) as a tan solid, m.p. 198-202°C. EXAMPLE 16 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 similar manner as previously described in Example 15... and gave methyl 2- (n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (5.7 g) as a white solid, m.p. 230°-232°C (during decomposition).

The methyl 3,4-bis(n-hexadecanamido)benzoate which was 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 similar manner as previously described in example 1(ii) (the temperature of the reaction mixture during the addition was allowed to rise from 20°C to 30°C). A solid was collected and recrystallized from chloroform to give methyl 3,4-bis(n-hexadecanamido)benzoate (14.9 g). in the form of a white solid, m.p. 129°-132°C.

EXAMPLE 17 Compound I

A stirred solution of methyl 3,4-bis(n-undecanamido)benzoate (33.0 g) in methanol (400 mL) containing concentrated hydrochloric acid (50 mL strength '3 6.5% v//v) was heated at back-run for 3 timfers. The mixture was then cooled to 0°C and filtered, and solid material was obtained combined with the evaporation residue from the filtrate in vacuo. The collected solids were washed with hot petroleum ether (boiling point 60°-80°C;

200 ml) and recrystallized from ethanol (while filtering the hot solution) to give methyl 2-(n-decyl)benzimidazole-5-carboxylate hydrochloride as a white solid (13.7 g), m.p. 230°-240°C (during decomposition).

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

EXAMPLE 18

Connection J

A solution of methyl 2-(n-decyl)benzimidazole-5-carboxylate hydrochloride (13.7 g; prepared as previously described in Example 17) in a mixture of ethanol and water (250 ml; 4:1 v/v) containing sodium hydroxide (4.6 g) was treated in a similar manner as described in Example 4 and gave 2-(n-decyl)benzimidazole-5-carboxylic acid hydrochloride (9.4 g) in the form of a white solid, m.p. . 270°-282°C (under decomposition).

EXAMPLE 19

Compound B

A solution of 2-(n-pentadecyl) benzimidazole-5-carboxylic acid monohydrate (11.16 g; prepared as previously described in Example 12) in methanol (150 ml) was heated to 60°C and treated.

was treated with a solution of sodium methoxide [prepared by carefully dissolving sodium (0.69 g) in anhydrous methanol (40 ml)] and the mixture was then cooled. The solvent was evaporated in vacuo and the residue was recrystallized from water to give sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate monohydrate (9.7 g) as a white solid which darkens at 250°C and decomposes. 'at over 300°C.

. EXAMPLE 20 Compound B A stirred suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (1.00 g; prepared as previously described in Example 12) in acetone (30 ml) was treated dropwise with

a solution of methanesulfonic acid (0.25 g) in methanol (15 ml)

at room temperature. The mixture was heated to 40°C to give •'. a solution, and then the solvent was evaporated in vacuo. The white solid residue was triturated with acetone (30 mL) and the resulting solid was collected and washed with acetone (10 mL) to give 2-(n-pentadecyl)benzimidazol-5-carboxylic acid methanesulfonate (1.19 g) in' the form of a white solid, .. •m.p. 115°-1170C.

EXAMPLE 21

Compound B

A stirred suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (1.00 g; prepared as previously described;

in Example 12) in acetone (30 ml) was treated with an excess of a solution of 2-hydroxyethylsulfonic 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-hydroxyethyl sulfonate (1.24 g) as a white solid, m.p. 93°- 95°C.

EXAMPLE 2, 2

Compound A. 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride i (10.0 g; prepared as previously described in Example 4) was dissolved in boiling methanol (250 mL) in a reflux apparatus and then treated with concentrated hydrochloric acid (20 ml at strength 36.5% w/v) The mixture was heated at reflux

for 3 hours and then cooled to 0°C. The resulting white solid was collected, washed with water and recrystallized from ethanol and methyl 2-(n-pentadecyl)benzimidazol-5-carboxylate hydrochloride (9.2 g) as a white solid m.p. 230°-232°C (during decomposition).

EXAMPLE 23

Connection K

Methyl 3,4-diaminobenzoate (33.0 g) and n-octadecanoic acid (56.8 g). was ground together to a thorough mixture and the mixture was heated at 200°C for 210 min. The mixture was then treated in a similar way as described previously in example 9. The brown oil obtained was, after distribution between a warm mixture of petroleum ether, toluene and water, dissolved in chloroform (25 ml) and chromatographed on a column of silica gel. (750g) . Elution with a mixture of chloroform and methanol (19:1 v/v) gave a light brown solid. fabric (40 g). This solid was dissolved in hot toluene (200 mL) and treated with an excess of a saturated solution of hydrogen chloride in ethanol. The resulting solid was collected and recrystallized (under treatment with activated carbon) from a mixture of ethanol and water (9:1 v/v) to give methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate hydrochloride (19.9 g) as a white solid, m.p. 229°-234°C (under decomposition).

EXAMPLE 2 4

Connection L

A solution of methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate hydrochloride (11.5 g; prepared as previously described in Example 23) in a mixture of ethanol and water (2.00 ml; 1:1 v/v) containing sodium hydroxide (14.35 g) was treated in a similar manner as previously described in Example 4 and gave

2-(-n-heptadecyl) benzimidazole-5-carboxylic acid hydrochloride

(8.8 g) as a white solid, m.p. 279°-284°C

(under cleavage).

EXAMPLE 2 5 Compound M

A mixture of methyl 4-amino-3-(n-decanamido)-benzoate (16.7 g)

r

and toluene (600 ml) containing p-toluenesulfonic acid (5.0 g) was treated in a similar manner as previously described in Example 1 to give methyl 2-(n-nonyl)benzimidazole-5-carboxylate (14.0 g ) in the form of a white solid, m.p. 101°-103°C..

The methyl 4-amino-3-(n-decanamido)benzoate which was 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 a decanyl chloride (19.1 g) in a similar manner as previously described in Example 1(i) and gave methyl 4-amino-3-(n-decanamido)benzoate (18.8 g) as a tan solid, m.p. 96°-98°C.

EXAMPLE 2 6

Connection N

A solution of methyl 2-(n-nonyl)benzimidazole-5-carboxylate

(13.5 g; prepared as previously described 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 similar manner as described previously in Example 4 and gave 2-(n-nonyl)benzimidazole-5-carboxylic acid hydrochloride (8.6 g) as a white solid, m.p. 275°-280°C.

EXAMPLE 27

Connection 0

A stirred solution of methyl 3,4-bis(n-octanamido)benzoate

.(81.8 g) in methanol (800 ml) containing concentrated hydrochloric acid (100 ml with a strength of 36.5% w/v) was heated at reflux for 4 hours. The mixture was then cooled and treated in a similar manner as previously described in Example 17 and gave

methyl 2-(.n-heptyl) benzimidazole-5-carboxylate hydrochloride (33.8 g) as a white solid, m.p. 140°-142°C (during cleavage).

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 similar manner as previously described in example-16 by recrystallization from methanol (under treatment with activated carbon) and gave methyl 3,4-bis(n-octanamido)benzoate (81.8 g) in form of a white solid, m.p. 138°-140°C.

EXAMPLE 2 8 Compound P

A stirred solution of methyl 2-(n-heptyl)benzimidazol-5-car-. boxylate hydrochloride (23.0 g; prepared as previously described 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 similar manner as described previously in Example 4 and gave 2-(n-heptyl) benzimidazole-5-carboxylic acid hydrochloride (14.4 g) in the form of a white solid, m.p. 310°-313°C. (under cleavage) .

EXAMPLE 2 9

Connection Q

A stirred solution of 3,4-bis(n-pentadecahamido)benzoic acid (49.3 g) in a mixture of methyl ethyl ketone and concentrated hydrochloric acid (560 ml; 10.:.1 v/v) was heated at reflux for 3 hours. The mixture was then cooled. The resulting solid was collected and dried with methyl ethyl ketone (200 mL) and then washed with boiling petroleum ether (-200 mL; b.p. 60°-80°C). It was recrystallized from a mixture of ethanol and water (4:1 v/v) (treating with activated carbon and filtering the hot solution) to give 2-(n-tetradecyl)benzimidazole-5-carboxylic acid hydrochloride (15 .7 g), m.p.J

• above 300°C (during decomposition) . 3,4-bis(n-pentadecanamido)benzoic acid, which is used as starting material, was prepared as follows: A solution of 3,4-diaminobenzoic acid (13.85 g) in dimethylformamide (180 ml) containing triethylamine (27.6 g) was treated with pentadecanoyl chloride (47.4 g) in a similar manner as previously described in Example 1(i). The resulting solid was collected and recrystallized from methyl ethyl ketone (under, treatment with activated carbon and filtration of the hot solution) to give 3,4-bis(n-pentadecanamido)benzoic acid (49.3 g) m.p. 178°-180°C.

EXAMPLE 3 0

Compound R

(a) A stirred solution of methyl 3,4-bis(n-nonatamido)benzoate

(23.3 g) in methanol (300 ml) was treated with concentrated hydrochloric acid (40 ml with strength 36.5% v//v). The mixture was heated at reflux for 3 hours and the solvent removed in vacuo to give a white solid. The solid became

washed with hot petroleum ether (100 ml; b.p. 40°-60°C) and recrystallized from water (700 ml) under hot filtration to give methyl'2^n-octylbenzimidazole-5-carboxylate hydrochloride as a white solid, m.p. 238°-243°C (12.Og).

.(b) One. stirred solution of methyl 2-n-octyl-benzimidazole-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 on return run for 4 hours. The mixture was treated in a similar manner

as described above in Example 4 and gave 2-(n-octyl)benzimidazole-5-carboxylic acid hydrochloride (7.8 g) as a white solid, m.p. 280°-300°C (during 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 (20 g) in

dry. dichloromethane (250 ml), containing triethylamine (24.2' g) was treated dropwise with a solution of nonanoyl chloride'

(44.12 g) in dry dichloromethane (50 ml) in a similar manner as previously described in example 1(ii). The resulting bright red substance was recrystallized from methanol under treatment with activated carbon to give methyl 3,4-bis-(n-nonanamido)benzoate

(30.3 g) as a white solid, m.p. 142°-145°C.

EXAMPLE 31 Compound S

2-(n-tetradecyl)benzimidazole-5-carboxylic acid hydrochloride

(8.5 g; prepared as previously described in example.29) was dissolved in boiling methanol (96 ml) in a reflux apparatus and was then treated with concentrated hydrochloric acid (22 ml) at a strength of 36.5% w/y). The mixture was refluxed for 3 hours

and then treated in a similar manner as previously described in Example 22 to give methyl 2-(n-tetradecyl)benzimidazole-5-carboxylate hydrochloride (6.2 g) in the form of a white solid, m.p. 233°-235°C.

EXAMPLE 3 2

Connection T

2-(n-hexadecyl)benzimidazole-5-carboxylic acid hydrochloride

(9.6 g; prepared as described below in Example

33) was dissolved in boiling methanol (400 ml) in a reflux apparatus and then treated with concentrated hydrochloric acid (100 ml at strength 36.5% w/v). The mixture was heated at reflux for 8 hours, and then treated in a similar manner as previously described in Example 22 to give methyl 2-(n-hexadecyl)-benzimidazole-5-carboxylate hydrochloride (7.4 g) as a white solid, m.p. 225°-230°C (during cleavage).

EXAMPLE 33

Connection U

A solution of 3,4-bis(n-heptadecanamido)benzoic acid (250 g) in methyl ethyl ketone (1500 ml) was treated with concentrated hydrochloric acid (180 ml, strength 36.5% w/v). The mixture was refluxed for 8 hours and then treated in a similar manner as previously described in the example. 15 and gave 2-(n-hexadecyl)benzimidazole-5-carboxylic acid hydrochloride. (44.9 g) in the form of an off-white solid, m.p. 296°-306°C (under decomposition).

The 3,4-bis(h-heptadecanamido)benzoic acid used as starting! material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (45.6 g) in dimethylformamide (400 ml), containing triethylamine (75.8 g) was treated dropwise with n-heptadecanoyl chloride (130 g) in 1 .5 hours. The rate of addition of the n-heptadecanoyl chloride was such that the temperature of the reaction mixture was allowed to rise from room temperature to 35°-40°C. The mixture was then stirred at this temperature for a further 2 hours and then poured into hot water (3500 ml at 70°C) containing concentrated hydrochloric acid (50 ml at strength 36.5%) which gave crude 3,4-bis-(n- heptadecanamido)benzoic acid (140 g) as a pink solid.

EXAMPLE 3 4.

Connection V

2-n-Eicosylbenzimidazole-5-carboxylic acid hydrochloride (12 g.;

prepared as described in the following example 35) in chloroform (300 ml) was treated dropwise with stirring with thionyl chloride (100 ml). The mixture was refluxed for 4 hours and then cooled and the excess thionyl chloride and solvent removed in vacuo to give a white solid. The solid was slurried 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) as a white solid, m.p. 220°-226°C.

EXAMPLE 3 5

Connection 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, 36.5% w/v). The mixture was refluxed for 10 hours and then treated in a manner similar to that previously described in Example 15 to give a white solid which was recrystallized from n-butanol (1200 mL) to give 2-(n-eico-syl )benzimidazole-5-carboxylic acid hydrochloride (45.1 g) in the form of a white solid, m.p. 294°-298°C (under decomposition).

The 3,4-bis(n-heneicosanamido)benzoic acid used as starting material was prepared as follows: .

A stirred solution of 3,4-diaminobenzoic acid (21.9g) in dimethylformamide (175ml) containing triethylamine (43.6g) was treated dropwise with n-heneicosanoyl chloride (99.2g). in a similar manner to that previously described in Example 33 which gave crude 3,4-bis(n-hene.icosanamido)benzoic acid (126.5 g) in the form of a light brown solid.

EXAMPLE 3 6 Compound X

2-(n-nonadecyl)benzimidazole-5-carboxylic acid hydrochloride (14.6 g; prepared as described in the following Example 37) was slurried in thionyl chloride (350 ml) and the mixture was refluxed for 6 hours. The excess thionyl chloride was removed in vacuo to give a tan solid. The solid was slurried in anhydrous methanol (500 mL) and the mixture was stirred and refluxed for 3 hours. The mixture was then treated in a similar manner as described in Example 34 and gave methyl 2-(n-nonadecyl)benzimidazole-5-carboxylate hydrochloride (12.2 g) as a white solid, m.p. 219°-227°C.

EXAMPLE<3>7

Compound Y A suspension of 3,4-bis(n-eicosanamido)benzoic acid (89.1 g) in methyl ethyl ketone (1200 ml) was heated with concentrated brine. acid (120 ml, 36.5%). The mixture was stirred and refluxed for 8 hours and then treated in a similar manner as previously described 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-carboxylate hydrochloride (36.5 g) as a white solid, m.p. 290- 300°C (during decomposition).

3,4-bis(n-eicosanamido)benzos<y>rene' used as starting material was prepared as follows:

A stirred solution of 3,4-diaminobenzoic acid (1.8.3 g) in ■dimethyl-. formamide (200 ml) containing triethylamine (36.5 g) was added. treated dropwise with n-eicosanoyl chloride (79.4 g) in a similar manner as previously described in Example 33 and gave crude 3,4-bis-(n-eicosanamido)benzoic acid (93 g) in the form of a light brown solid, m.p. 160O-'170°C.' EXAMPLE PEL 3 8 Compound Z A slurry of 4-amino-3-(n-nonadecanamido)benzoic acid (107g) in methyl ethyl ketone (1500ml) was treated with concentrated hydrochloric acid (100ml, 36.5%). The mixture was stirred and refluxed for 3 hours. The mixture was cooled to 10°C and the solid collected, washed with methyl ethyl ketone (2 x 500 mL) and slurried in water (500 mL). The sodium hydroxide solution (50 g in water (150 ml)) was added to the mixture and the mixture was stirred and heated to 60°C for dissolution. Glacial acetic acid was added to the stirred mixture until the mixture was pH 5, and the resulting solid was collected, washed with water (2 x 500 mL) and dried. The solid was recrystallized from ethanol under treatment with activated carbon to give a white solid which was carefully dried and then slurried in methyl ethyl ketone (500 mL) containing concentrated hydrochloric acid (100 mL, 36.5%). The mixture was stirred and refluxed for one hour and then cooled to give 2-(n-octadecyl)benzimidazole-5-carboxylic acid hydrochloride (33.8 g) as a white solid, m.p. 292°-297°C (under decomposition) . The 4-amino-3-(n-npnadecanamido)benzoic acid used as starting material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (38 g) in dimethylformamide (500 ml) containing triethylamine (50.5 .g) was treated dropwise with n-nonadecanoyl chloride (79.1 g) in a similar manner to that previously described in Example 33 and gave an orange solution which was poured into water (300.0 ml) containing concentrated hydrochloric acid (100 ml, strength 36, 5%). The solid was: collected, washed with water (2 x 100 ml) and then dried to give crude 4-amino-3-(n-nonadecanamido)benzoic acid (107 g), m.p. 103°-113°C.

EXAMPLE- 3 9 Compound II 2-(n-octadecyl)benzimidazole-5-carboxylic acid hydrochloride (12

g; prepared as previously described in Example 38) in thionyl chloride (100 ml) was stirred and refluxed for 3 hours and

.then treated in a similar manner as previously described in Example 36, which gave methyl 2-(n-octadecyl)benzimidazole-5-carboxylate hydrochloride (11.6 g) as a white solid, m.p. 224° - 230°C. EXAMPLE 40 Compound AA A slurry of 3,4-bis[2-methyltetradecanamido]benzoic acid (53.1 g) in methyl ethyl ketone (250 ml) was treated with concentrated hydrochloric acid (37.6 ml, strength 36.5%). The mixture was stirred and refluxed for 16 hours. The mixture was cooled to 0°C and the solid collected (11.17 g) and washed with methyl ethyl ketone (2 x 25 mL). The solid was slurried in water (50 mL) and sodium hydroxide solution [20 g in water (50 mL)] was added to the slurry. The mixture was stirred and heated to 60°C for dissolution, and then glacial acetic acid was added to the stirred mixture until the mixture reached pH 5. The resulting solid was collected, washed with water and recrystallized from ethanol under treatment with activated carbon, and then treated in a similar manner as previously described in examples 3-8 and gave (RS)-2-(tetradec-2-yl)-benzimidazole-5-carboxylic acid hydrochloride (11 g) in the form of a white solid, m.p. 214°-218°C. The 3,4-bis[2-methyltetradecanamido]benzoic acid used as starting material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (17.5 g) in dimethylformamide (140 ml) containing triethylamine (34.8 g) was treated dropwise with pentadecan-2-oyl chloride (59.7 g) in a similar manner as previously described in Example 33 and gave crude 3,4-bis[2-methyltetradecanamido]benzoic acid (68 g).

EXAMPLE' 41

Compound CC A solution of 4-amino-3-['2-hexyloctanamido]benzoic acid (15.2

g) in methyl ethyl ketone (78 ml) was treated with concentrated hydrochloric acid (18.2 ml, strength 36.5%). The mixture was stirred and

refluxed 12 hours and the methyl ethyl ketone was then removed in vacuo. The residue was slurried in water (200 mL) and sodium hydroxide solution (50% in water) was added to the mixture until

The pH was 11. The mixture was heated to 90°C and then diluted with water to a total volume of 1500 ml. The solution was treated with activated carbon and then treated with an excess of acetic acid (25% in water) which gave an off-white solid. The solid was collected, washed with water and recrystallized from ethyl acetate to give 2-(tridec-7-yl)benzimidazole-5-carboxylic acid (8.89 g), m.p. 157°-1580c.

The solid was dissolved in acetone (350 ml) and. the solution was treated with concentrated sulfuric acid (1.55 ml, strength 98%). After cooling, a white solid was obtained which was recrystallized from methyl ethyl ketone to give 2-(tridec-7-yl)-benzimidazol-5-carboxylic acid hemisulfate (6.8 g) as a white solid, m.p. 202°-205°C.

4-amxnd-3-[2-hexyloctanamido]benzoic acid used as starting material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (20.7 g) in dimethylformamide (165 ml) containing triethylamine (56.5 ml) was treated dropwise with 2-hexyloctanoyl chloride (67 g) in a similar manner to that described in example 33. The waxy solid was collected and dissolved in diethyl ether (500 ml), and

the ether solution was dried and evaporated. -which produced a reddish-brown oil. This oil was extracted with hot methanol in use

of a continuous extraction apparatus for 5 hours. The methanol solution was evaporated on a rotary evaporator to give a brown solid which was recrystallized from acetone to give 4-amino-3-[2-hexyloctanamido]benzoic acid (15.2 g) as a white solid, m.p. 219°-22°C.

EXAMPLE 4 2 Compound BB

A solution of 4-amino-3-(2-ethyldodecanamido)benzoic acid (24.7 1

g) in methyl ethyl ketone (125 ml) was treated with concentrated hydrochloric acid (29 ml, strength 36.5%). The mixture was stirred and refluxed for 12 hours and then treated in a similar manner as previously described in Example; 41, which gave a white solid which was recrystallized from a mixture of acetone (200 mL) and water (200 mL) to give (RS)-2-(tridec-3-yl)benzimidazole-5-carboxylic acid hemis' sulfate (14.2 g) in the form of a white solid, m.p. 185°-18'7°C. The 4-amino-3-(2-ethyldodecanamido)benzoic acid used as a starting material was prepared as follows: A stirred solution of 3,4-diaminobenzoic acid (22.8 g) in dimethylformamide (200 ml) containing triethylamine (22.7 g) was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in a similar manner to that previously described in Example 41 and gave a solid which was recrystallized from ethyl acetate under treatment with activated carbon to give 4-amino-3-(2- ethyldodecanamido)-benzoic acid (22.2 g) as a white solid, m.p. - 188°-191°C.

EXAMPLE 4 3

Connection DD

A solution of 4-amino-3-[2^-butyl decanamido]benzoic acid (9.8 g)

in methyl ethyl ketone (50 ml) was treated with concentrated brine; acid (11.5 ml, strength 36.5%) in a similar manner as previously described in Example 41 to give (RS)-2-(tri.dec-5-yl) benzimidazole-5-carboxylic acid hemisulphate (4 .7 g) in the form of a white solid, m.p. 161°-164°C.

The 4-amino-3-[2-butyldecanamido]benzoic 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 ) became

treated dropwise with 2-b'butyldecanoyl chloride (51.4 g) in a similar manner as previously described in Example 41, which gave 4-amino-3-'<[>2-but<y>ldecanamido]benzoic acid ( 9.8 g) in the form of a white solid, m.p. 178°-182°C.

EXAMPLE 44

Compound EE A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g) in ethanol (25.0 mL) was stirred and refluxed for 2 h. The mixture was cooled to room temperature

and the solid collected and washed with ethanol (50 mL)

and then with diethyl ether (2 x 50 ml). The solid was dissolved in boiling ethanol (25 ml) and the solution treated with concentrated hydrochloric acid (0.5 ml at strength 36.5%). The solution was cooled to 0°C and the resulting solid was collected to give ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (7.8 g) as a white solid, m.p. 207°-213°C.

The 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride used as starting material was prepared as follows: 2-(n-pentadecyl)benzimidazole-5-carboxylic acid monohydrate (32 g) was added portionwise to a stirred solution of thionyl chloride

(250 ml) 'at room temperature. The mixture was stirred and refluxed for 2 hours and then the thionyl chloride was removed in vacuo to give 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (33 g) as a cream solid, m.p. 286°-288°C (during decomposition)..

EXAMPLE 4 5

Connection FF

A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as previously described in Example

44) in n-hexyl alcohol (300 ml) was treated similarly

manner as previously described in Example 44 and gave hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (9.8 g) in ;

form of a white solid, m.p. 166°- 170°C.

EXAMPLE 4 6 Compound GG A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride hydrochloride (10 g; prepared as previously described in Example 44) in n-butyl alcohol (300 ml) was treated in a manner similar to previously described in Example 44 and gave butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (8.9 g) as a white solid, m.p. 170°-174°C.

EXAMPLE 4 7 Compound HH A mixture of 2-(n-pentadecyl)benzimidazole-5-carbonyl chloride-hydrochloride (10 g; prepared as previously described in Example 44) in isopropyl alcohol (300 ml) was treated in a similar manner

manner as described above in Example 44 and gave isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxylate hydrochloride (6.4 g)

in the form of a white solid, m.p. 184°-186°C.

EXAMPLE 4 8 Connection JJ

A stirred mixture of sodium 2-(n-pentadecyl)behzimidazole-5-carboxylate (13.7 g; prepared as previously described in Example 19)' and chloromethyl pivalate (5 g) in hexamethylphosphoramide (35 ml) was heated to 50°C for 3 hours. After cooling, the mixture was poured into water (250 mL) and extracted with diethyl ether. ether (3 x 75 ml). The organic layer was washed with water (3 x 100 ml) and dried over magnesium sulfate. The organic solvent was removed in vacuo to give a brown oil, which was chromatographed on silica gel (400 g) using chloroform as eluent. Fractions (100 ml) were collected and fractions 14 to 22 gave, after evaporation of the solvent, a colorless oil. The oil was dissolved in diethyl ether and treated with a saturated solution of hydrochloric acid in ethanol until the pH of the mixture was 1. The white solid was collected and washed with diethyl ether (3 x 100 mL) to give pivaloyloxymethyl 2-n-pentadecylbenzimidazole-5-carboxylate hydrochloride (10 g)

in the form of a white solid, m.p. 165°-175°C.

EXAMPLE 4 9 Compound KK Sodium hydride (12 g of a 50% oil dispersion) was added

within 15 min. to a stirred mixture of glycerol (100 g) and dry tetrahydrofuran (10.0 ml). After finished. addition, the mixture was stirred vigorously for a further 30 min. and then 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (.20 g; prepared as previously described in Example 4) was added to the mixture during 5 min. The mixture was stirred vigorously for 2 hours and then allowed to stand overnight. The brown mixture was poured into water (800 ml) containing glacial acetic acid (9.4 g) and the oily product was extracted into chloroform (2 x 400 ml). . The combined extracts were washed with water (2 x 500 ml) and dried over sodium sulfate. The solvent was evaporated in vacuo, the remaining oil was dissolved in toluene (300 ml) and the solution was filtered to give a brown gum. The toluene was decanted, diethyl ether (100 ml) added and the mixture heated until the gum was dissolved. After rapid cooling to -30°, a white solid was collected and washed with diethyl ether (2 x 100 ml) to give 2,'3- dihydroxyprop-1-yl 2-(n-pentadecyl) benzimidazole-5-carboxylate (6.6 g) as a white solid, mp 10 9°-112°C.

EXAMPLE 5 0

Compound B

3,4-diaminobenzoic acid (10 g) and palmitic acid (168 g) in diglym• containing concentrated hydrochloric acid (10 ml of strength 3 6.5%)

(100 ml) was heated at reflux for 10 hrs. The cooled mixture was poured into water (300 mL) and the solid collected. The solid was washed with "dilute hydrochloric acid (2 x 100 ml of strength 2N) and then boiling petroleum ether (4 x 100 ml, boiling point 40°-60°C). The solid was recrystallized from ethanol under treatment with activated carbon which gave 2-(n-pentadecyl)benzimidazole-5-carboxylic acid-

hydrochloride (50 g), m.p., 295°-300°C (with decomposition).

EXAMPLE 51 Compound B 3,4-diaminobenzoic acid monohydrochloride (1.88 g) and n-hexadecanoyl chloride (2.74 g) were mixed well and the mixture was heated at 130° G for 2 hours. The mixture was then cooled to room temperature and triturated with water (100 mL) to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (0.1 g), m.p. 298°-300°C (under decomposition).

EXAMPLE 52

Compound B

A stirred solution of 3,4-diaminobenzoic acid (9 g) in dimethylformamide (190 ml) was treated with n-hexadecanoyl chloride (16.3 g) for 30 min. The mixture was then refluxed for 6 hours and poured into water (100 ml). The solid was collected and slurried in dilute hydrochloric acid (100 ml, 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°-300°C (under decomposition).

EXAMPLE 5 3 Compound B

A solution of 2-(n-pentadecyl) benzimidazole-.5-carboxylic acid mono<p>hydrate (390 g; prepared as previously described in Example 12) in a mixture of acetone (2000 ml) and water (1000 ml) was

heated to 60°C and then treated with an aqueous solution of sodium hydroxide (40 g in 50 ml of water). The mixture was stirred for one hour, refluxed and then cooled to 0°C. The solid was collected and recrystallized from a mixture of acetone (1000 mL) and water (500 mL) to give sodium 2-(n-pentadecyl)benzimidazole-5-carboxylate monohydrate (345 g), m.p. above 3 00°C during decomposition.

EXAMPLE 5 4

Connection LL

A solution of 2,3-bis(n-tetradecanamido)benzoic acid (17.6 g) in methyl ethyl ketone (250 ml) was treated with concentrated hydrochloric acid (25 ml at strength 36.5%). The mixture was refluxed for 5 hours, then cooled and treated in a manner similar to that previously described in Example 15 to give 2-(n-tridecyl)-benzimidazole-4-carboxylic acid hydrochloride (6.5 g) as a tan solid , m.p. 192°-200°C..

The 2,3-bis(n-tetradecanamido)benzoic acid used as starting material was prepared * as follows:

A solution of 2,3-diaminobenzoic acid (20 g) in dimethylformamide (200 ml) containing triethylamine (39.9 g) was treated with tritetradecanoyl chloride (65.0 g). The rate of addition of the n-tetradecanoyl chloride was such that the temperature of the reaction mixture was allowed to rise from room temperature to 45°-50°C. , The mixture was then stirred for a further 2 hours and allowed to stand overnight at room temperature. Methanol (20 mL) was added to the mixture and the resulting mixture was stirred for 20 min. and then treated with concentrated hydrochloric acid (strength 36.5%) until the pH was 2. The resulting mixture was poured into water (1000 mL) and the black solid collected, washed with water (2 x 500 mL) and then with hot petroleum ether (boiling point 60°-80°C;: 500 ml), and was finally recrystallized from ethanol under treatment with activated carbon, which gave 2,3-bis(n-tetradecanamido)benzoic acid (17.7 g) in the form of a yellowish-brown solid, m.p. 150°-158°C. EXAMPLE' 55 Compound B A slurry of 3-amino-4-(hexadecanamido)benzoic acid (2.0 g) 1 methyl ethyl ketone (60 ml) containing hydrochloric acid (1.5 ml. of strength 3 6.5%) was refluxed for 5 hours. The resulting solid was collected, washed with boiling petroleum ether (b.p. 60°-80°C) and recrystallized from ethanol to give 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (2.0 g) as a white solid with m.p. 288°-290°C (under decomposition). The 3-amino-4-(n-hexadecanamido)benzoic acid used, as ut-. 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% palladium-on-carbon (2.5 g) at 70°C and atmospheric pressure for 6 hours. The mixture was filtered hot and the filtrate allowed to cool. The resulting solid was collected and washed with ethanol (100 mL) to give 3-amino-4-(hexadecanamido)benzoic acid (11.6 g) as a cream solid, m.p. 160 -162 C.. The 3-nitro-4-(n-hexadecanamido)benzoic acid used as starting material was prepared as follows: A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and hexadecanoyl chloride (33.0 g) in dry dimethylformamide (100 ml) was . heated 90 min. at 97°C. The solution was cooled and poured onto crushed ice (300 g). The resulting solid was collected, washed with water (3 x 10 0 ml), dried and recrystallized from a mixture of acetone and water (5:1)-(under treatment with activated carbon) to give 3-nitro-4-(n -hexadecanamido) benzoic acid (31.7 g) in the form of a pale yellow solid, m.p. 153°-154°C.

EXAMPLE 5 6 Connection MM

A suspension of 2-(n-pentadecyl)benzimidazole-5-carboxylic acid hydrochloride (9.6 g; prepared as previously described in

example 4) in thionyl chloride (75 ml) was refluxed for 2 hours. The excess thionyl chloride was removed by vacuum distillation, giving a brown solid residue. The solid was triturated with toluene (200 mL) and the toluene evaporated in vacuo. The residue -was added to a solution of triethylamine .(3.64 ml) 1 '

tert-butanol (250 ml) and the mixture was refluxed for 3 hours. After cooling, the excess of tert-butanol was evaporated in vacuo and the residue was slurried in ethyl acetate (150 ml). The slurry was refluxed for 10 min. and filtered hot. The filtrate was cooled and the resulting solid was collected. The solid was washed with ethanol (2 x 50 mL) and then with diethyl ether (2 x 50 mL), and dried to give tert-butyl 2-(n-pentadecyl)benzimidazole-5-

carboxylate hydrochloride (5.5 g) as an off-white solid,

m.p. 165°-168°G.

EXAMPLE' 57 Compound NN A mixture of 2-(n-pentadecyl)benzimidazo.1-5-carbonyl chloride..

(15 g; prepared as previously described in Example 44) in allyl alcohol (300 ml) was treated in a similar manner as previously described' in Example 44 to give 'ally 1 2-(n-pentadecyl) benzimidazole-5- carboxylate hydrochloride (10.4 g) as a white solid, m.p. 198°-200°C.

EXAMPLE 58 Compound M

To a stirred solution of methyl 3,4-diaminobenzoate (9.8 g) in methanol (200 mL) was added a solution of copper(II) 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 1 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 through the solution until precipitation of copper sulphide ceased. The copper sulfide was collected and the filtrate was concentrated

and yielded a red oil. The oil was dissolved in methanol (100 ml) containing concentrated hydrochloric acid (15 ml at strength 36.5%)

and the solution was refluxed for 4 hours. After cooling, the grey-green solid was filtered off and dissolved in tetrahydrofuran (100 ml) containing aqueous ammonia (5 ml at strength 33%). The solution was diluted with water (400 ml) and the pink solid filtered off... The solid was chromatographed on silica gel with a mixture of chloroform and

methanol (25:1 v/v) as eluent. The isolated material was dissolved in methyl ethyl ketone (25 mL) and concentrated hydrochloric acid (2.3 mL at strength 36.5%) was added with stirring. The resulting solid was filtered off and washed with diethyl ether (2 x 50 mL). which gave methyl 2-■

zol-5-carboxylate hydrochloride (5.3 g) as a white solid, m.p. 234°-237°C (under decomposition) .

EXAMPLE 5 9

Compound PP Concentrated hydrochloric acid (120 ml•at strength 36.5%) was added

within 20 min. 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 trituration of the residue with water (2000 ml), the granular solid was collected and

washed with hot petroleum ether (boiling point 60°-80°C; 2 x 500 ml) . and then . with' diethyl ether (500 ml). The solid was dissolved

in boiling methyl ethyl ketone (2 50 ml) and the solution was treated with activated carbon' and filtered hot. The filtrate was evaporated in vacuo to give a tan solid. The solid was chromatographed on silica gel with a mixture of chloroform and methanol (9:1 v/v) as eluent. The resulting product was recrystallized from ethyl acetate to give 2-(n-pentadecyl)benzimidazole-4-carboxylic acid (5.4 g) as a tan solid, m.p. 160°-166°C.

. The 2,3-bis(n-hexadecanamido)benzoic acid used as starting material was prepared as follows: A solution of .2,3-diaminobenzoic acid (40 g) in dimethylformamide (600 ml) containing triethylamine (79.7 g, 109.5 ml) was treated with n-hexadecanoyl chloride (144.5 g). The rate of addition was such that the temperature of the reaction mixture was allowed to rise from room temperature to 45°-50°C. The mixture was then stirred for a further 3 hours and gave stand at room temperature, overnight. The mixture was added to water (1200 ml) containing concentrated hydrochloric acid (50 ml, strength 3 6.5%) and the resulting solid collected and washed with water (1200 ml). The solid was stirred with hot water (4000 mL; 65°C) for .30 min. and was collected and dried at 70°C in vacuum.

The resulting product 2,3-bis(n-hexadecanamido)benzoic acid was used without further purification in the above preparation.

REFERENCE EXAMPLE 1

A stirred solution of 3,4-diaminobenzoic acid (152 g) in dimethyl-'

formamide (1500 ml) containing triethylamine (303 g) was treated dropwise with n-hexadecanoyl chloride (549.0 g) for 1.5 hours. The rate of addition of the n-hexadecanoyl chloride was such that the temperature of the reaction mixture rose from room temperature to 35°-40°C. The mixture was then stirred at room temperature for a further 2 hours and then poured into hot water (10 -f held at 70°C) containing concentrated hydrochloric acid (150 ml,

with strength 36.5%). The resulting solid was collected to give crude 3,4-bis(n-hexadecanamido)benzoic acid (600 g)

in the form of a yellowish-brown solid, m.p. 180°-190°C, suitable for use in the preparation previously described in example 15.

REFERENCE EXAMPLE 2

By proceeding in a similar manner to that previously described in example 38 for the preparation of 4-amino-3-(n-nonadecanamido)-benzoic acid, but replacing the n-nonadecanoyl chloride with n-octanoyl chloride, 4^amino-3-(n -octanamido)benzoic acid in the form of a grey-white solid, m.p. 202°-203°C after orn crystallization from methanol.

REFERENCE EXAMPLE 3

By proceeding in a similar way to that previously described in example 38 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid, but replacing n-nonadecanoyl chloride with n-dodecanoyl chloride, 4-amino-3 -(n-dodecanamido)benzoic acid in the form of a white solid, m.p. 183°-185°C.

REFERENCE EXAMPLE 4

By proceeding in a similar manner to that previously described in example 38 for the preparation of -4-amino-3-(n-nonadecanamido)ben-. zosyre, - but replacing n-nonadecanoyl chloride with n-octadecanoyl chloride produced 4-amino-3-(n-octadecanamido)benzoic acid in the form of a light brown solid, m.p. 185°-187°C after recrystallization from methyl ethyl ketone.

REFERENCE EXAMPLE 5

A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry dimethylformamide (900 nil) containing triethylamine (50.8 g) was treated dropwise with n-octanoyl chloride (81.3 g). for 30 min. at a temperature between 5° and 8°C. The mixture was stirred for an additional 2 hours. The solid was removed by filtration and the filtrate dissolved in water (8000 ml). The resulting solid was collected and crystallized twice from methanol to give methyl 4-amino-3-(n-octanamido)benzoate (65.5 g) as a white solid, m.p. l20°C.......

REFERENCE EXAMPLE 6

By proceeding in a similar manner as previously described in reference example 5 for the preparation of methyl 4-amiho-3-(n-octane-amido) benzoate, but replacing n-octanoyl chloride with n-dodecanoyl chloride, methyl 4-amino-3 -(n-dodecanamido)-benzoate in the form of an off-white solid, m.p. 102°-105°C after recrystallization from methanol.

REFERENCE EXAMPLE 7

. By proceeding in a similar manner as previously described in reference example 5 for the production of methyl 4-amino-3-(n-octanamido)benzoate, but replacing n-octanoyl chloride with n-tridecanoyl chloride, methyl 4- amino-3-(n-tridecane-amido) benzoate in the form of a light brown solid, m.p. 101°-104°C after recrystallization from methanol.

REFERENCE EXAMPLE 8

By proceeding in a similar way as previously described in reference example 5 for the preparation of methyl-4-amino-3-(n-octanamido)benzoate, but replacing the n-octanoyl chloride with n-tetradecanoyl chloride, methyl 4-amino- The 3-(n-tetradecanamido)benzoate as a light brown solid, m.p. 108°-109°C after recrystallization from methanol.

REFERENCE EXAMPLE 9

By proceeding in a similar manner as previously described in reference example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate, but replacing the n-octanoyl chloride with n-hexadecanoyl chloride, methyl 4-amino-3- (n-hexadecanamido)benzoate as a white solid, m.p. 109°-110°C after recrystallization f r .7; methanol.

REFERENCE EXAMPLE. IO

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 hexadecatroyl chloride

(16.54 g) in dry dimethylformamide (40 ml) for 5 min. The temperature was allowed to rise from 20°-50°C. The mixture was stirred for a further 3 hours. The resulting slurry was poured into water (800 mL) containing hydrochloric acid (10 mL, 36.5%) The resulting solid was collected and recrystallized from a mixture of chloroform and acetone (1:1) to give methyl 3,4 -bis-(n-hexadecanamido)benzoate (12.1 g) as a white solid, m.p. 129°-132°C, which is identical to the starting materials used in Example 16.

REFERENCE EXAMPLE 11

By proceeding in a similar manner as previously described in reference example 10 for the production of methyl 3,4-bis(n-hexadecanamido) benzoate, but replacing the n-hexadecanoyl chloride with n-octanoyl chloride, methyl 3,4-bis(n- octanamido)-.benzoate in the form of a white solid, m.p. 145°-147°C after recrystallization from acetone.

REFERENCE EXAMPLE 12

By proceeding in a similar manner as previously described in reference example 10 for the preparation of methyl 3,4-bis(n-hexadecanamido) benzoate, but replacing the n-hexadecanoyl chloride with n-dodecanoyl chloride, methyl 3,4-bis(n- dodecane-amido)benzoate in the form of an off-white solid, m.p. 129°-131°C after recrystallization from acetone.

REFERENCE EXAMPLE 13

By proceeding in a similar manner as previously described in reference example 10 for the production of methyl 3,4-bis-(n-hexadecanamido)benzoate, but replacing the n-hexadecanoyl chloride with n-tridecanoyl chloride, methyl 3,4-bis(n -tridecane-amino)benzoate.in the form of a white solid, m.p. 132°-134°C after recrystallization from acetone.

REFERENCE EXAMPLE 14

By proceeding in a similar manner as previously described in example 10 for the preparation of methyl 3,4-bis-(n-hexadecanamido)benzoate, but replacing the n-hexadecanoyl chloride with n-tetradecanoyl chloride, methyl 3,4-bis was prepared (n-tetra-'decanamido)benzoate as a white solid, m.p. 132°-. 133°C after recrystallization from acetone.

REFERENCE EXAMPLE 15

By proceeding in a similar manner to that previously described in reference example 10 for the production of methyl 3,4-bis-(n-hexa-decanamido)benzoate, but replacing the n-hexadecanoyl chloride with n-octadecanoyl chloride, methyl 3 was produced, ■ 4-bis-(n-octadecanamido)benzoate. in the form of a white solid, m.p. 120°C. after recrystallization from a mixture of acetone and methanol, (1:1),

REFERENCE EXAMPLE 16

3-Amino-4-(n-octanamido)benzoic acid (12.1 g) in methanol (200 mL) was treated with diazomethane solution in ether until the reaction was complete (as shown by thin layer chromatography on silica gel using methanol:chloroform:glacial acetic acid; 10:90:0.5). Acetic acid (0.2 mL) was then added and the reaction mixture concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate to give methyl 3-amino-4-(n-octanamido)benzoate (9.2 g) as a cream solid, m.p. 128°-131°C.

REFERENCE EXAMPLE 17

3-nitro-4-(n-octanamido)benzoic acid (25 g) dissolved in ethanol. (500 ml) at 50°C was hydrogenated with shaking in the presence of 5% palladium-on-carbon (2.5 g) at 50°C and atmosphere for 3 hours. The mixture was filtered hot and the filtrate was evaporated in vacuo. The residue was recrystallized 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°-156°C.

The 3-nitro-4-(n-octanamido)benzoic acid used as starting

material', was produced as follows:

A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-octanoyl chloride (19.4 g) in dry dimethylformamide (100 ml) was treated for 90 min. at 97°C. The solution was cooled and poured into ice (300 g). The resulting solid was collected and. washed with water, (3 x 100 ml), dried and recrystallized from a mixture of methanol and. water (8:1) (under treatment with activated carbon) which gave 3-nitro-4-(n-octanamido)benzoic acid (22 g) as a pale yellow solid, m.p. 153°-154°C.

REFERENCE EXAMPLE 18

3-nitro-4-(n-dodecanamido)benzoic acid (21 g) dissolved in ethyl acetate (500 ml) was hydrogenated with shaking in the presence of 5% w/w palladium on activated carbon (2.5 g) at 50° C and atmospheric pressure. The resulting mixture was filtered hot and gave a cream colored solid after cooling. This product was recrystallized from methanol to give 3-amino-4-(n-dodecane-amido)benzoic acid (7.4 g) as a beige solid, m.p. 158°-160°C.

' REFERENCE EXAMPLE 19

By proceeding in a similar manner as previously described in reference example 5 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate, but replacing the n-octanoyl chloride with n-decanoyl chloride, methyl 4-amino-3-( n-decahamido)-benzoate in the form of a white solid, m.p. 96°-100°C.

REFERENCE EXAMPLE 2 0

By proceeding in a similar manner as previously described in reference example 10 in the production of methyl 3,4-bis(n-hexadecanamido)benzoate, but replacing the n-hexanoyl chloride with n-decanoyl chloride, methyl 3,4-bis-( n-decane-amido) benzoate in the form of a white solid, m.p. 139°-141°C' after recrystallization from ethanol.

REFERENCE EXAMPLE 21

A stirred solution of 3,4-diaminobenzoic acid (10 g) in dry dimethylformamide (100 ml) containing potassium carbonate (28 g) was treated dropwise with a solution of n-dodecanoyl chloride ■

(33.1 g) in dry dimethylformamide (30 ml) for 5 min.' The temperature was allowed to rise from 20°-50°C. The mixture was stirred for an additional 3 hours. The resulting slurry was filtered.

and the filtrate entirely in water (700 ml) containing hydrochloric acid (10 ml, 36.5%). The resulting solid was collected and recrystallized from glacial acetic acid, the product was then washed with water and recrystallized from methyl ethyl ketone to give 3,4-bis(n-dodecanamido)benzoic acid (12.5 g) as a white solid substance, m.p. 195°-197°C.

REFERENCE EXAMPLE 2 2

By proceeding in a similar manner as previously described in reference example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing the n-dodecanoyl chloride with n-hexadecanoyl chloride and. the potassium carbonate with sodium carbonate, 3,4-bis(n-hexadecanamido)benzoic acid was prepared in the form of a white solid, m.p. 198°-202°C after successive ■recrystallizations from glacial acetic acid and methyl ethyl ketone.

REFERENCE EXAMPLE 2 3

By proceeding in a similar manner as previously described in reference example 21 for the preparation of 3,4-bis-(n-dodecane-amido)benzoic acid, but replacing the n-dodecanoyl chloride with n-octanoyl chloride, 3,4-bis was prepared (n-octanamido)benzoic acid as a white solid, m.p. 195°-197°C after subsequent recrystallizations. from glacial acetic acid and methyl ethyl ketone.

REFERENCE EXAMPLE 2 4

By proceeding in a similar manner as described in reference example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing the n-dodecanoyl chloride with n-tetradecanoyl chloride, 3,4-bis(n-tetradecanamido )benzoic acid in the form of a white solid, m.p. 201°-206°C after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone.

REFERENCE EXAMPLE 2 5

Methyl 4-(n-dodecanamido)-3-nitrobenzoate (21 g) dissolved in hot ethyl acetate (500 ml) (50°-55°C) was hydrogenated with shaking in the presence of 5% w/w palladium on -carbon (2.0 g) at 60°C and atmospheric pressure for 2 hours. The mixture was filtered hot and the filtrate allowed to cool. The solid was collected to give methyl 3-amino-4-(n-dodecanamido)benzoate (14.1 g) in

form of a white solid, m.p. 134°-137°C.

The methyl 4-(n-dodecanamido]-3-nitrobenzoate which was 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 97°C with occasional shaking. The resulting solution was poured onto crushed ice (300 g) and the solid collected and recrystallized from a mixture of methanol and chloroform (5:1) to give 4-(n-dodecanamido)-3-nitrobenzoate

(31 g) as a yellow solid, m.p. 78°-80°C.

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 [prepared from acetyl chloride (78 g) and dry methanol (300 ml )]. The resulting mixture was refluxed 10 hours, cooled in ice, and the solid filtered off, yielding methyl 4-amino-3-nitrobenzoate (62 g) as a yellow solid, m.p. 193°-195°C.

REFERENCE EXAMPLE 2 6

By presenting in a similar way as previously described in reference,

■ considered example 25 for the preparation of methyl 3-amino-4-(n-dodecanamido)benzoate, but replacing methyl 4-(n-dodecanamido)-3-nitrobenzoate with methyl 4-(n-hexadecanamido)-3-nitrobenzoate, methyl 3-amino-4-(n-hexadecanamido)benzoate was prepared in the form of a white solid, m.p. 135°-137°C.

REFERENCE EXAMPLE 27

By proceeding in a similar manner as previously described in reference example 25 for the preparation of methyl 3-amino-4-(n-dodecanamido)benzoate, but replacing methyl 4-(n-dodecanamido)-3-nitrobenzoate with methyl 4- (n-decanamido)-3-nitrobenzoate,

• methyl 3-amino-4-(n-decanamido)benzoate was produced in the form

of a white solid, m.p. 131°-133°C..

REFERENCE EXAMPLE 28

A stirred solution of 3,4-diaminobenzoic acid (8.4 g) in dry dimethylformamide (100 mL) containing potassium carbonate (15.27 g) was treated dropwise with a solution of n-hexadecanoyl chloride (15.17 g) in dry dimethylformamide' (30 ml) for 30 min.

at 0°-5°C. The mixture was stirred for an additional 2 hours at 0°-5°C and allowed to warm to room temperature over 30 min.

The solution was then poured into water (700 ml) containing hydrochloric acid (10 ml, -36.5%). The solid was collected, heated with acetone (300 mL) at 50°C and recrystallized from methyl ethyl ketone to give 4-amino-3-(n-hexadecanamido)benzoic acid (9.4 g) as a white solid fabric, - m.p. 197°-199°C.

REFERENCE EXAMPLE 2 9

By proceeding in a similar manner as previously described in reference example 21 for the preparation of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing n-dodecanoyl chloride with n-decanoyl chloride, 3,4- bis(n-decanamido)benzoic acid■in the form of a white solid, m.p. 194°-196°C after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone.

REFERENCE EXAMPLE 3 0

By proceeding in a similar manner as previously described in reference example 21 for the production of 3,4-bis(n-dodecanamido)-benzoic acid, but replacing the n-dodecanoyl chloride with n-tridecanoyl chloride, 3,4-bis(n- tridecanamido)benzoic acid in the form of a grey-white solid, m.p. 192°-194°C after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone.

REFERENCE EXAMPLE 31

Proceeding in a similar manner to that previously described in Reference Example 21 for the preparation of 3,4-bis(n-dodecane-amido)benzoic acid, but replacing the n-dodecanoyl chloride with n-

octadecanoyl chloride, 3, 4-bis (n-octadecanamido,)-benzoic acid was prepared in the form of a white solid, m.p. 193°-196°C

after subsequent recrystallizations from glacial acetic acid and methyl ethyl ketone..

The present invention also encompasses pharmaceutical mixtures containing at least one compound: with the general formula I or a pharmaceutically acceptable salt thereof in connection with a pharmaceutically acceptable carrier or coating agent. In clinical practice, the compounds according to the present invention can be given parenterally, but in stages they are given rectally or preferably orally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid mixtures, one or more of the active compounds are mixed with at least one effective diluent such as starch, sucrose or lactose. The mixtures can also include, which is normal in practice, further substances apart from inert diluents, e.g. lubricants such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the field such as water and liquid paraffin. In addition to inert diluents, such mixtures may include auxiliaries such as wetting and suspending agents, and sweeteners, flavourings, perfuming or preserving agents. The mixtures according to the invention for oral administration also comprise capsules of absorbable materials such as gelatin, which contain one or more of the active substances with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile, aqueous, aqueous-organic. and organic solutions, suspensions and emulsions. Examples of organic solvents or suspension media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and

injectable organic esters such as ethyl oleate. These mixtures can also contain auxiliaries such as stabilising-preserving, wetting-emulsifying and dispersing agents.... They can be sterilized by e.g. filtration through a bacteria-proof filter, by introducing sterilizing agents into the mixtures, by irradiation or heating. They can also be produced in the form of sterile solid mixtures that can be dissolved in sterile water or other sterile injectable medium.

divisible before. use.

Solid mixtures for rectal administration comprise suppositories formulated in accordance with known methods and which contain one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof.

The proportion of active ingredient in the mixtures according to the invention can be varied, but it is necessary that it constitutes such a proportion that an appropriate dosage is achieved. Of course, multiple unit dosage forms may be administered approximately simultaneously. The dose used will be determined by the doctor, and depends on the desired therapeutic effect, route of administration and duration of treatment, and on the patient's condition. In adults, the doses are generally between 0.1 and 50 mg/kg body weight per day oral administration, e.g. as hypolipidemic and anti-atheromic agents and in related cardiovascular diseases between 10 and 50 mg/kg body weight per day by oral administration; in the treatment of diabetes between 5 and 40 mg/kg body weight per day oral administration, and in the treatment of arthritis' and related diseases between. 0.1 and 10 mg/kg body weight per day by oral administration.

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

EXAMPLE 6 0

Gelatin capsules size No. 2 each containing:

was prepared according to the usual method.

Claims (8)

1. Benzimidazole derivatives of the general formula characterized in that R means a hydrogen atom, a straight or branched alkyl group with 1 to 6 carbon atoms (which may be substituted with one or more of the same type of substituent selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms and alkanoyloxy groups with 2 to 7 carbon atoms) . 2. Benzimidazole derivatives according to claim 1, characterized in that R means a hydrogen atom or a linear or branched alkyl group with 1 to 6 carbon atoms. 3. 2-(n-pentadecyl)benzimidazole-5-carboxylic acid, 2-(n-unde-cyl )benzimidazole-5-^carboxylic acid, n-butyl 2-(n-pentadecyl)-benzimidazole-5-carboxylate, 2, 3-dihydroxyprop-l-yl 2-(n-pentadecyl )benzimidazole-5-carboxylate, 2-(n-tridecyl)benzimidazole-5-carboxylic acid, 2-(n-dodecyl)benzimidazole.-5-carboxylic acid, ( RS)-2-(tetradec-2-yl)benzimidazole-5-carboxylic acid, 2-(n-hexadecyl)benzimidazole-5-carboxylic acid, 2-(n-octadecyl)-benzimidazole-5-carboxylic acid, 2-(n- heptadecyl)benzimidazole-5-carboxylic acid and methyl 2-(n-heptyl)benzimidazole-5-carboxylate and pharmaceutically acceptable salts thereof. 4. - Methyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, methyl 2-(n-undecyl)benzimldazole-5-carboxylate, methyl. 2-(n-tridecyl)-benzimidazole-5-carboxylate, methyl 2-(n-dodecyl)benzimidazole-; 5-carboxylate, methyl 2-(n-decyl)benzimidazole-5-carboxylate, 2-(n-decyl)benzimidazole-5-carboxylic acid, methyl 2-(n-heptadecyl)benzimidazole-5-carboxylate, methyl 2-(n -nonyl)benzimi- . dazole 5-carboxylate, 2-(n-nonyl) benzimidazole-5-carboxylic acid, 2-(n-heptyl)benzimidazole-5-carboxylic acid and 2-(n-tetradecyl)-benzimidazole-5-carboxylic acid and pharmaceutically acceptable salts thereof. 5. 2-(n-octyl)'benzimidazol-5-carboxylic acid, methyl 2-(n-tetradecyl)benzimidazole-5-carboxylate, methyl 2-(n-hexadecyl)benzimidazole-5-carboxylate, methyl 2-(n-eicosyl)benzimi- dazole-5-^carboxylate, 2-(n-eicosyl)benzimidazole-5-carboxylic acid, methyl 2-(n-nonadecyl)benzimidazole-5-carboxylate, 2-(n-nonadecyl)benzimidazole-5-carboxylic acid, (RS) -2-(tridec-3-yl)benzimidazol-5-carboxylic acid, 2-(tridec-7-yl)benzimidazole-5-carboxylic acid, (RS)-2-(tridec-5-yl)benzimidazol-5- carboxylic acid, ethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, n-hexyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, isopropyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, methyl 2-( n-octadecyl)benzimidazole-5-carboxylate, pivaloyloxymethyl 2-(n-pentadecyl)benzimidazole-5-carboxylate and 2-(n-tridecyl)-benzimidazole-4-carboxylic acid and pharmaceutically acceptable salts thereof. 6. tert-butyl 2-(n-pentadecyl)benzimidazole-5-carboxylate, allyl 2-(n-pentadecyl)benzimidazole-5-carboxylate and 2-(n-pentade'cy'l)benzimidazole-4-carboxylic acid and pharmaceutically acceptable salts thereof. 7. Process for the preparation of a ben-imidazole derivative as set forth in claim 1, characterized in that (A) cyclizes a compound with the general formula 0 2 where R • means a hydrogen atom or a group -COR , and R and R 2 are as stated in claim 1, (B) reacts a compound with the general formula: (where R" <*> " is as defined in claim 10 with a compound of the general formula: (where R 2 is as stated in claim 1) and a copper(II) salt in the presence of an aqueous inert organic solvent medium at between room temperature and the reflux temperature of the reaction mixture, followed by transfer of the resulting copper salt into the corresponding compound with the general formula stated in claim 1, (C) in the case of a benzimidazpl derivative of the general formula I set forth in claim 1 wherein R 1 represents a hydrogen atom, hydrolyzes a corresponding ester of the general formula set forth, in claim 1 wherein R 1 represents a linear or branched alkyl group of 1 to 6 carbon atoms, which may be substituted with one or more of the same type of substituent selected from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms or alkanoyloxy groups. with 2 to 7 carbon atoms, and R 2 is as stated in claim 1, (D) in the case of a benzimidazole derivative of the general formula I~ as set forth in claim 1 where R"*" means a linear or branched, alkyl group of 1 to 6 carbon atoms, which may be substituted by one or more of the same type of substituent chosen from the hydroxy group, alkenyl groups with 2 to 5 carbon atoms or alkanoyloxy groups with 2 to 7 carbon atoms and R 2 is as stated in claim 1, -esters a corresponding carboxylic acid with the general formula I stated in claim. 1 in which R 1 means a hydrogen atom, and R 2 is as stated in claim after which, if desired, by known methods, a benzimidazole derivative thus obtained with the general formula, stated in claim 1, is transferred into a pharmaceutically acceptable salt. 8. Pharmaceutical mixtures characterized in that they comprise at least one benzimidazole derivative as stated in claim 1, or a pharmaceutically acceptable salt thereof in connection with a pharmaceutical carrier or coating agent.