NL8003627A - BENZIMIDAZOLE DERIVATIVES, PHARMACEUTICAL PREPARATIONS AND METHOD FOR PREPARING THEREOF. - Google Patents

Description

te- Λ H.O. 29,170 X »r

Benzimidazole derivatives as well as pharmaceutical preparations and method for the preparation thereof.

The invention relates "to novel therapeutically" useful benzimidazole derivatives and to pharmaceutical compositions containing them, as well as to a process for their preparation.

The benzimidazole derivatives of the invention are

a

compounds of the formula 1, wherein R is a hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms (which may be optionally substituted by one or more of the same type of substituents belonging to the hydroxyl groups, alkenyl groups having 2 up to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms) 2 and E represent a straight or branched alkyl group, preferably a straight alkyl group, with 7 to 20 (preferably 10 to 18) carbon atoms as well as pharmaceutically permissible

a

15 salts thereof. Preferably B represents a hydrogen atom or a methyl group or an n-butyl, 2,3-dihydroxypropyl (1), allyl or pivaloyloxymethyl group.

a

The R OOC moiety is bound in position 4 or preferably in position 5 of the benzimidazole ring system.

It will be apparent to those skilled in the art that the compounds of the general formula 1 exhibit tautomerism, so that the hydrogen atom represented on one of the nitrogen atoms may also be present on the other nitrogen atom and both described hereinbefore. One can be present to a greater or lesser degree and be in a state of dynamic equilibrium with each other. At the tautomers places 4 and 5 become places 7 *

a

and 6. In addition, substituents E and 2 R in certain cases contribute to optical isomerism. All these forms are within the scope of the invention.

The term "pharmaceutically acceptable salt" is understood to mean a salt obtained by reaction with an acid or, if B represents a hydrogen atom, by reaction with a base, so that the anion (in the case of an acid addition salt) or the cation (in the case of a salt obtained from a compound of the formula 800 3 6 27 ¥

TL

S 'Λ le 1, where E represents a hydrogen atom) is relatively harmless to the animal organism when used in therapeutic doses, so that the beneficial pharmacological properties of the base compound of the general formula 1 are not offset by side effects, attributable to the anion or cation.

Suitable acid addition salts are salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulfates and nitrates, and organic salts, for example methanesulfonates, 2-hydroxyethanesulfonates, oxalates, lactates, tartrates, acetates, salicylates, citrates , propionates, succinates, fumarates, malelates, methylene bis-p-hydroxynaphthoates, gentisates and di-p-toluoyl tartrates.

Suitable salts formed by compounds Λ of the general formula 1, wherein E represents a hydrogen atom, are the alkali metal (eg sodium and potassium), alkaline earth metal (eg calcium and magnesium) and ammonium salts as well as salts of amines, 20 of which are known in the art to be pharmaceutically acceptable, ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2- (hydroxymethyl) propane-1,3-diol and 1 - (3, 4-di-hydroxyphenyl) -2-isopropylaminoethanol.

It should be noted that if mention is made in the description of compounds of the general formula 1, it is intended that this also includes the pharmaceutically acceptable salts, insofar as this is possible within the context.

The compounds of the general formula 1 have useful pharmacological properties, in particular hypolipidemic activity. For example, they cause a decrease in the concentrations of cholesterol and triglycerides in the blood. Furthermore, they inhibit or prevent the development of atheromatous lesions and, moreover, reduce proliferation of arterial smooth muscle cells, which is an important aspect of atheromatous accumulations. The compounds of the general formula 1 also lower the blood glucose level in mice suffering from diabetes 40 mellitus. Furthermore, the compounds of the general formula 1 suppress the transformation of lymphocytes, as it does Mg the treatment with anti-rheumatic drugs. Thus they are useful in preventing or treating diabetes mellitus, hyperlipoproteinic states, of atherosclerosis and related ailments, such as angina, myocardial infarction, vascular occlusion in the cerebrum, arterial aneurysm, peripheral vascular disease, chronic pancreatitis and xanthoma as well as arthritis, immunological disease, cancer and transplant rejection.

Compounds of general formula 1, which are described in the

of no interest are the following compounds, the optically active forms and their salts: methyl ester of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid A 2- (n-pentadecyl) benzimidazole-5-carboxylic acid B

15 methyl ester of 2- (n-undecyl) benzimidazole-5-carboxylic acid 0 2- (n-undecyl) b enzimidazo1-5-carbonic acid D

methyl ester of 2- (n-tridecyl) benzimidazole-5-carboxylic acid E 2-Cn-tridecyl) benzimidazole-5-carboxylic acid E

methyl ester of 2- (n-dodecyl) benzimidazole-5-carboxylic acid G 20 2- (n-dodecyl) benzimidazole-5-carboxylic acid H

methyl ester of 2- (n-decyl) benzimidazole-5-carboxylic acid I.

2- (n-decyl) benzimidazole-5-carboxylic acid J

methyl ester of 2- (n-heptadecyl) benzimidazole-5-carboxylic acid K 2- (n-heptadecyl) benzimidazole-5-carboxylic acid L

Methyl ester of / n-nonyl) benzimidazole-5-carboxylic acid M.

2- (n-nonyl) benzimidazole-5-carboxylic acid N

methyl ester of 2- (n-heptyl) benzimidazole-5-carboxylic acid 0 2- (n-heptyl) benzimidazole-5-carboxylic acid P

2- (n-tetradecyl) benzimidazole-5-carboxylic acid Q.

2- (n-octyl) benzimidazole-5-carboxylic acid R.

methyl ester of 2- (n-tetradecyl) benzimidazole-5-carboxylic acid S methyl ester of 2- (n-hexadecyl) benzimidazole-5-carboxylic acid T 2- (n-hexadecyl) benzimidazole-5-carboxylic acid U

methyl ester of 2- (n-eicosyl) benzimidazole-5-carboxylic acid V 55 2- (n-eicosyl) benzimidazole-5-carboxylic acid W

methyl ester of 2, (n-nonadecyl) benzimidazole-5-carboxylic acid X 2- (n-nonadecyl) benzimidazole-5-carboxylic acid X

2- (n-octadecyl) benzimidazole-5-carboxylic acid Z.

800 36 27 4

(ES) -2- (tetradec-2-yl) benzimidazole-5-carboxylic acid AA

(ES) -2- (tridec-3-yl) b enzimidazole-5-carboxylic acid BB

2- (tridec-7-yl) benzimidazole-5-carbomic acid OC

(ES) -2- (trideo-5-yl) bemzimidazole-5-carboxylic acid DB

5 ethyl ester Tan 2- (n-pemtadecyl) benzimidazole-5-

carboxylic acid EE

n-hexyl ester Tan 2- (m-pentadecyl) benzimidazole-5-acetic acid FF

n-butyl ester Tan 2- (n-pentadecyl) benzimidazole-5-carb0 carbonic acid GG

isopropyl ester Tan 2- (n-pentadecyl) benzimidazole-5-carboxylic acid HH

methyl ester Tan 2- (n-octadecyl) benzimidazole-5-carboxylic acid II

P5 pivaloyloxymethyl ester Tan 2- (n-pentadecyl) benz-

imidazole-5-carboxylic acid JJ

2,3-dihydrosyprop-1-ylester Tan 2- (n-pentadecyl) -benzimidazole-5-carboxylic acid KK

2- (n-tridecyl) benzimidazole-4-carboxylic acid LD

20 tert-butyl ester Tan 2- (n-pentadecyl) benzimidazole-

5-carboxylic acid MM

allyl ester Tan 2- (n-pentadecyl) benzimidazole-5-carboxylic acid NN

and

2- (n-pentadecyl) benzimidazole-4-carboxylic acid PP

The letters k to PP are assigned to the Terbindings for a simple reference in the description of the invention, in particular in the tables.

The properties of the Terbindings of the general formula 1 have been demonstrated in the Tolling tests: HTPolinidemisc activity in 1 rats.

Male Wistar rats, each weighing between 120 and 150 g, were caged in groups of Tan eight and fed a powdered diet for 10 days. During the last 7 days during this period, the compound to be tested was administered orally by mixing the compound with the diet and allowing the animals to feed normally. Feed consumption was measured on the ninth day for each group.

40 At the end of the morning of the tenth day, 800 3 6 27 animals were killed by breathing in carbon dioxide from carbon dioxide snow. A blood sample was taken by cardiac puncture and the serum cholesterol and serum triglycerides were analyzed using an automatic analyzer.

Control groups (who received only the normal diet without the test substance) were included in each trial.

The percentages of reductions in serum cholesterol and serum triglycerides concentrations were calculated by comparison to the concomitantly used control animals for each concentration of the test compound used.

The results achieved are shown in Table 15 below.

(gabel A

Yerbin- Yorm%% change in serum thing (w / w) compared to dose in control cholesterol triglycerides A HCl 0.2 +7 -1 salt B HCl 0.2 -50 -44 salt 0.2 - 50 -64 0.2 -39 -40 0.2 -22 -45 0.2 -21 -46 0.4 -61 -63 0.2 -55 -60 0.2 -42 -69 0.1 -31 -38 0.1 -14 -51 0.03 -2 -44 B mono- 0.2 +4 +19 hydrate 0.2 -10 -9 _Vl · _-63_-76 800 3 6 27 6 «

Table A (continued)

Compound-Form%% change in serum (w / w) compared to dose in control ^ 88 ^ cholesterol triglycerides B sodium- 0.2 -51 -64 salt- 0.1 -24 -44 mono- 0.4 -62 -79 hydrate 0.2 -55 -62 C basic compound 0.2 -30 -57 compound 0j2 _13 _54 B HCl 0.2 -34 -60 salt 0.2 -24 -50 0.2 - 40 -80 E HOI 0.2 -23 -58 salt F HOI 0.2 -34 -53 salt 0.2 -36 -47 0.03 -17 -10 G HOI 0.2 -18 -41 salt H HOI 0 , 2 -33 -52 salt 0.03 -4 -26 I HOI 0.2 -3 -36 salt J HOI 0.2 -13 -24 salt L HOI 0.2 -3 -36 salt 0.2 -20 - 26 N HOI 0.2 -14 -3 salt 0 HOI 0.2 -4 +24 salt P HOI 0.2 -18 -10 salt 800 3 6 27 7 (Dabei A (continued)

Verb In Form%% change in serum thing (w / w) compared to dose in control cholesterol triglycerides Q HOI 0.2 -41 -62 salt 0.2 -35 -69 0.03 -4 - 20 Η HOI 0.2 -2 -10 salt S HOI 0.2 +9 -28 salt T ÏC1 0.2 +6 -20 salt ÏÏ HOI 0.2 -20 -50 salt V HOI 0.2 +2 -12 salt W HC1 0.2 +5 -15 salt X HCl 0.2 -10 -3 salt X HCl 0.2 -17 -14 salt Z HOI 0.2 0 -20 salt AA HOI 0.2 -35 -75 salt BB HOI 0.2 -19 -46 salt OC HpSO ^ 0.2 -6 +9 half-salt ann fi 7 8

Table A (continued)

Verb In-Form%% change in serum thing (w / w) compared to dose in control diet; cholesterol triglycerides DD H2S04 0.2 +11 -15 half-salt EB HC1 0.2 -27 -47 salt FF HOI 0.2 -16 -51 salt GO HOI 0.2 -40 -54 salt 0.2 - 55 -60 HH HCl 0.2 -5 -52 salt II HOI 0.2 -1 -20 salt JJ basic compound 0.2 -40 -51 compound 0.1 -1 -53 KK HOI 0.2 -72 -75 salt 0.1 -28 -21 HH HOI 0.2 +4 -8 salt m HOI 0.2 -19 -54 salt EP HOI 0.2 -18 -11 salt 8003 627 9

Anti-atheroma activity bi.i koni.inen

Male New Zealand white rabbits each with a flawed Tan 2.2-2.8 kg were de-endothelialized Tan de aorta akdominalis and Tan one femoral artery using Tan balloon catheter. After recovery from Tan anesthesia, each Tan rabbit was administered a diet for 14 days, to which 1% (w / w) ch-cholesterol and the Terbinding to be tested were added at a given concentration. After the end of the said period, 10 animals were sacrificed and the concentration of Tan and serum cholesterol were determined. The aorta and femoral artery were removed, after which the intima layers of the adrentitia were separated and the cholesterol concentration was determined. Parts of the femoral artery were examined histologically.

A control group was included in each trial to which the Terbinding to be tested was not administered.

The percentage of Tan de Terlagingen Tan, the concentrations of Tan serum cholesterol and arterial cholesterol were calculated by comparing the concomitant controls.

The Terkregen results are shown in the Tolling Table B.

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Rypoglycemic activity in diabetic corn

Diabetic corn (strain 0 57, black, MRI obtained from Obese / Obese) of both sexes each weighing between 45 and 70 S were fed the test on a powdered diet for a period of one week before. The treated animals were then administered the compound to be tested for several days mixed with the diet at a given concentration. The animals were then weighed and anesthetized with carbon dioxide, after which blood was drawn by heart puncture.

The following serum parameters were determined: 1. Glucose - according to the glucose oxidase method of God-Perid 2. Cholesterol and triglycerides - these were measured by means of an automatic analyzer after removal of phospholipids by means of an activated zeolite and extraction with isopropanol.

Control groups were included in each trial (receiving only the normal diet without the compound to be tested).

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

The results achieved are shown in Table C below.

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Inhibitory activity on smooth muscle cell proliferation in the aorta

Smooth muscle cells were cultured in a culture of pig aortic thoracal explants using Dulbeceo's Modified Eagles (DME) medium containing 20% fetal calf serum (ECS) and antibiotics. The cells were incubated at a temperature of 37 ° C in an atmosphere of 95% air and 5% carbon dioxide. Upon confluence, the cells were routinely used for subcultures by trypsinization and replating at a density of about one third the density when confluent in DME medium containing 10% ECS and antibiotics.

The smooth muscle cells were plated in densities of 100,000 to 200,000 cells per 35x10 mm Ealcon dish in 2 ml DME medium containing 10% EOS and antibiotics. After 24 hours, when the cells had adhered to the dishes, the medium was replaced with 2 ml DME medium containing 1% ECS and antibiotics. The cultures were incubated for an additional three days to allow the cells to enter a resting state (ie, they no longer underwent cell division). The medium was then replaced with 2 ml of control or test medium. The test medium consisted of DME medium (containing 10% ECS and antibiotics) and the test compound at a concentration of 5 µg / ml of the medium.

The compounds were previously dissolved in water, acetone or glyco-furol in such a way that the final concentration of the solvent in the medium reached 0.2% (v / v). The control medium consisted of DME medium 30 (containing 10% ECS and antibiotics) and suitable solvent at a concentration of 0.2% (vol./vol.). After incubation for three days in the test or control medium, the medium was replaced with fresh test or control medium and the cells incubated for an additional three or four days. At the end of the incubation period of six or seven days, the cell numbers were determined by trypsinizing the cells and counting the cell suspension in a Coulter counter.

All results listed in Table D below indicate the mean value for four dishes with cells. Onn 7 97 percent of the proliferation inhibition was calculated using the following formula:

Percentage inhibition of proliferation = 100 S x 100) V C - S '5 where S = mean cell count per dish piglet at the beginning of the assay (big addition of the control or test medium).

T = average cell count per dish in the test cultures after the end of the test.

10 C = average cell count per dish of big control cultures at the end of the experiment.

Compound Form Solvent% Inhibition L HCl II20 48 salt HgO 55 15 H20 31 H20 45 0 HOI acetone 35 salt acetone 38 glycofurol 54 20 acetone 23 A HCl acetone 21 salt acetone 16 acetone 41

Inhibitory activity on lymphocyte transformation in mitogen-stimulated lymph node cells, buttock guinea pigs

Guinea pigs were sensitized to Mycobacterium tuberculosum by injections in the footpad of Preund's complete adguvant (POA) (0.05 ml; 0.05 mg / ml of 50 percent (v / v) PCA solution in sterile saline). After 14 days, lymph node cells were resuspended in Eagles Minimal Essential (EME) medium containing 10% fetal calf serum (PCS) and buffered with Earle's salts at a concentration of 2.5 x 10 cells / ml.

For 24 hours, 0.1 ml of cell suspension big was incubated at 8003627 at a temperature of 37 ° C in an atmosphere of 95% air and 5% carbon dioxide big presence of 0.15 µm of mitogen or mitogen and the compound to be tested in ΕΜΕ medium (containing 10% ECS and buffered with Earle's 5 salts).

Eighteen hours before harvesting,% thymidine (1 µl of a 100 µCi / ml solution in 0.9% sterile saline) was added.

As an index of DNA synthesis, the rate of 10 H-thymidine uptake by the cells was measured compared to the mitogen-treated control.

The results achieved are summarized in Table E below.

Table E

Compound Dose in% Hemming of the H-thymidine incubation assay into cells DNA in media, Ug / ml comparison with the mitogen-treated control B 1 47 20 5 83 L 3 47 10 98 0 3 61 10 99 25 The utility of the compounds is favored by the fact that they have only a very low toxicity, as demonstrated by the following test:

Oral toxicity, mice. To groups of mice, orally graded doses of the test compound (in 0.5% (w / v) aqueous suspension of tragacanth mucus) were added and the mice were observed 3 days later. . The percentage of animals that died at each dose rate during this period was used to plot a graph showing the LD ^ q, i.e. the dose in mg / kg body weight of the animal, which was necessary to obtain 50% solids. kill mice was calculated.

Compounds of formula 1, which are included in the above list, were tested, and it was found that the LD 3 of each of these compounds was greater than 1000 mg / kg body weight of the animal.

Preferred compounds according to the invention are the compounds indicated by the letters 5 B, D, GG, EK, F, Ξ, JL &, U, Z, L and 0.

The compounds of the general formula 1 can be prepared in a manner known per se, that is to say by the application or adaptation of known methods, as explained in more detail below.

1. According to an embodiment of the invention, the compounds of the general formula 1 are prepared by cyclizing a compound of the general formula 2 waarin (wherein R 0 represents a hydrogen atom or a radical -COR 2 and S and E have the above meaning ), which compound is optionally prepared in situ, for example, as described in more detail below for the cyclization of compounds of the general formula 3 or 4. formula 3 o a compound with the / (i) Thus, if E is a residue - OOR represents / (where 1 2 E and B have the above meaning) subjected to a ring closure, preferably at elevated temperature, for example between 60 and 100 ° 0, for example at 80 ° 0 or about 80 ° 0, by conversion with an inorganic acid, for example hydrochloric acid, in the presence of water and in an organic solvent, for example an alcohol such as methanol or ethanol, or a ketone such as acetone or preferably methyl ethyl ketone, or (ii), if R 0 represents a hydrogen atom (especially with respect to the compounds wherein R 1 represents a straight or branched chain alkyl group of 1 to 6 carbon atoms) a compound of the general formula 4 1 2 (wherein R and R represents the above meaning) cyclized either under similar conditions as described above under (i) or by reaction with an organic acid, e.g. p-35 toluenesulfonic acid, in water or an organic solvent, e.g. toluene, preferably at elevated temperature e.g. between 60 and 100 ° C, for example at 80 ° C or about 80 ° C, or (iii) (especially with respect to compound

a

40 things in which R represents a straight or branched chain alkyl group with 800 3 6 27 17 1 to 6 carbon atoms) the cyclization is usually carried out without isolation of an acylated intermediate of the formula 3 or 4 either (a) in the absence of an organic solvent and an elevated temperature, eg between 150 and 250 ° C, or (b) in the presence of water and an inorganic acid, eg hydrochloric acid, and in a suitable organic solvent, eg diglyme.

2. According to a further embodiment of the invention, the compounds of the general formula 1 are prepared by reacting a compound of the general formula 5 (wherein R has the above meaning) with a compound

O

bond of the general formula 6 (wherein R has the above meaning) and a copper (II) salt, eg cupric acetate, in the presence of an aqueous inert organic solvent medium, for example a mixture of water and methanol, at a temperature between room temperature and the temperature at which the reaction mixture is refluxed, followed by conversion of the obtained copper salt into the corresponding compound of the formula 1.

3. According to a further embodiment of the invention, carboxylic acids of the general formula 1 (wherein R 1 has the above meaning and R represents a hydrogen atom) are prepared by hydrolysis of a corresponding pester of the general formula 1, wherein R the above meaning and R 1 represents a straight or branched chain alkyl group of 1 to 6 carbon atoms, which alkyl group may be optionally substituted by one or more of one of the same type of substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyl- oxy groups with 2 to 7 carbon atoms. Preferably, the hydrolysis is carried out under alkaline conditions, for example in the presence of an alkali metal hydroxide in an aqueous organic solvent system and at an elevated temperature, for example in the presence of sodium hydroxide in aqueous ethanol and at the reflux temperature of the system.

4. According to yet another embodiment of the invention, esters of the general formula 1 (in which R has the above-mentioned 80 0 3 6 27 18 en and R represents a straight or branched alkyl group with 1 to 6 carbon atoms which alkyl group may be optionally substituted by one or more than one of the same type of substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms or alkanoylexy groups of 2 to 7 carbon atoms) prepared by esterification of a corresponding carboxylic acid o with the general formula 1, wherein R has the above-mentioned meaning and R represents a hydrogen atom. The esterification can be carried out using or adapting known methods, for example, by reacting the acid with an excess of the required alcohol of the general formula 7 (wherein R 1 represents a straight or branched alkyl group having 1 to 6 carbon atoms, which alkyl group can be des-15 desirably substituted by one or more than one of the same type of substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms) optionally also as a solvent medium and in the presence of a inorganic acid, for example hydrochloric acid, preferably at an elevated temperature, for example between 60 and 100 ° C; or by reaction with the corresponding alkyl halide.

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

The term "known methods", as used in the description of the invention, means methods which have hitherto been used or which have been described in the literature.

5. According to a further embodiment of the invention, compounds of the general formula 1 can be converted into pharmaceutically acceptable salts and vice versa using or adapting known methods. While this conversion is useful as such, it is also useful for purifying compounds of formula 1 and salts thereof by taking advantage of differences in water solubility and various organic solvents of the compounds and their salts and of impurities possibly contained therein, using known methods such as crystallization.

40 (i) Compounds of the general formula (I) can be converted into pharmaceutically acceptable acid addition salts thereof, for example by reaction with the required acid in solution or suspension in a suitable solvent, for example acetone, methanol or ethanol, if necessary followed by evaporation of the solvent or part thereof and collection of the solid salt.

(ii) On the other hand, the acid addition salts can be converted to the basic compounds of the general formula 1, for example by reaction with aqueous ammonia in the presence of a suitable solvent, for example ethanol, followed by treatment with a weak acid, for example glacial acetic acid.

(Iii) Acids of the general formula 1, in which R represents a hydrogen atom and R has the above meaning, can be converted into salts of pharmaceutically acceptable bases, for example by reaction with the required base, for example the required amine or a compound of the general formula 8 (wherein M is an alkali metal, 1x.

for example sodium or potassium, and R represent an alkyl group having up to 4 carbon atoms, for example a methyl or ethyl group, or a hydrogen atom) in a suitable solvent, for example methanol or ethanol or a mixture of water and acetone, if necessary followed by evaporation of the solvent or part thereof and collecting the solid salt.

(Iv) These salts can be converted to the basic compounds of the formula 1, for example by reaction with a suitable acid, for example glacial acetic acid, as a solution in a suitable solvent, for example water or ethanol, if necessary followed by evaporation of the solution. 30 agent or a portion thereof and collecting the solid compound of the formula 1.

It will be appreciated by those skilled in the art that when carrying out the process of the invention it may be desirable to introduce chemical masking groups into the reactants to suppress the occurrence of secondary reactions; for example, in the above-described Embodiment Form 1.hydroxyl groups m, the substituent R in the compounds of the general formula II can be converted into benzyloxy groups before the described conversion, which is followed afterwards by 800 3 6 27 20 of the reaction by removal of the benzyl group. Furthermore, a particular preparation method may be preferentially chosen over others as a means of preparing certain intended compounds of general formula 1 in this manner.

Compounds of general formula 2, wherein R 0 represents a hydrogen atom, can be prepared from compounds of general formula 9 (wherein R and R have the above meaning) by reduction, for example, by catalytic hydrogenation, using for example palladium on carbon.

Compounds of the general formula 2, wherein R ° represents a 2 2 radical of the formula -COR (wherein R has the above meaning) can be prepared from compounds of the general formula 2, wherein R ° represents a hydrogen atom, by reaction with compounds of the formula 11 (wherein R has the above meaning and X represents a halogen atom, preferably a chlorine atom, or a hydroxyl group).

Compounds of the general formula 9 can be prepared by reacting a compound of the general formula 10 (wherein R has the above meaning) with a compound of the formula 11 in the same manner as described below for method A (i).

Compounds of the general formula 2, in which the substituent -NHCOR is in the m-position relative to the Λ Λ substituent -GOOR and wherein R represents a hydrogen atom, can be prepared by reacting a compound with the general formula 3 with a compound of general formula 11, as described further below for method A (ii).

Compounds of the general formula 2, wherein R 0 represents a 2 2 radical of the formula -COR (wherein R has the above meaning) can also be prepared by reacting a compound of the general formula 3 with a compound of the general Formula 11, as described further below for Method A (i).

Compounds of general formula 2, wherein R represents a straight or branched chain alkyl group of 1 to 6 carbon atoms (which alkyl group may be substituted by 800 3 6 27 21 one or more than one of the same type of substituent belonging to the hydroxyl groups, alkenyl groups having 2 up to 3 carbon atoms and alkanoyloxy groups with 2 to 7 carbon atoms) can be prepared by esterification of the corresponding

a

3 compounds of the general formula II, wherein R represents a hydrogen atom, by the application or adaptation of known methods, for example by reaction with the corresponding diazoalkane in the presence of an inert organic solvent.

10 Method A

The compounds of the general formula II can be prepared by reacting a compound of the general formula 3 (wherein R has the above meaning) with o

an acylating agent of the general formula 11, wherein H

a

15 has the above meaning and X represents a halogen atom, preferably a chlorine atom, or a hydroxyl group. (According to the method of the invention, the cyclization of the product obtained then follows optionally in situ). Particularly suitable conditions are the following: Λ 20 (i) Compounds of general formula 3 (in which R has the above meaning) can be used with acyl halides

O

of the general formula 11 (wherein R represents the above

a

and X represents a halogen atom, preferably a chlorine atom) are reacted in an inert organic solvent, for example dichloromethane or dimethylformamide, preferably under anhydrous conditions and preferably in the presence of an acid binding agent, for example a trialkylamine for example triethylamine, or an alkali metal carbonate or bicarbonate, for example anhydrous sodium or potassium carbonate.

(ii) Compounds of general formula 3 (in particular

a

the compounds in which R represents a straight or branched chain alkyl group of 1 to 6 carbon atoms) can be reacted with acyl halides of the general formula 11 (wherein R has the above meaning and

a

X represents a halogen atom, preferably a chlorine atom) under similar conditions as described above under (i), however, using a smaller amount of the acid halide and controlling the temperature, preferably between 0 ° C and room temperature.

800 3 6 27

Using a combination of conditions between the conditions described under (i) above and the conditions described under (ii), a mixture of intermediates of the general formulas 3 and 4 would be obtained, those under the above under 1 (i) and 1 (ii) described conditions would undergo ring closure.

(iii) Compounds of general formula 5 (especially of the compounds wherein R represents a straight or branched chain alkyl group of 1 to 6 carbon atoms) can be converted with the compounds of the general p formula 11 (wherein R has the above meaning and Λ X represents a hydroxyl group or a chlorine atom) to form compounds of the general formula 1, usually without isolation of acylated intermediates either (a) in the absence of solvent and at elevated temperatures , for example between 150 ° and 250 ° 0, or (b) in the presence of water and an inorganic acid, for example hydrochloric acid, and in a suitable solvent, for example diglyme.

The preparation of the compounds according to the invention is further elucidated by means of the following examples and reference examples.

Example I Compound A

A solution of 46 g of methyl ester of 4-amino-3- (n-hexadecanamido) benzoic acid and 15 g of p-toluenesulfonic acid in 1000 ml of toluene was stirred and refluxed for 2 hours, the water formed continuously with was removed using a Dean-and-Stark water separator. The solution was cooled to a temperature of 60 ° 0 and washed twice with 200 ml of a 2N sodium carbonate solution in water each time. The toluene layer was dried over magnesium sulfate and then concentrated in vacuo to give an oil. The oil was triturated with petroleum-35 ether (boiling range 40-60 ° C) to give a yellow-brown solid which, when recrystallized from petroleum ether (boiling range 40-60 ° C), gave 24.6 g of the methyl ester of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid in the form of a white solid with a melting point of 96 to 98 ° G.

8003627 23

The methyl ester of 4-amino-3 - (n.hexadecaanamido) benzoic acid used as starting material was prepared by one of two methods: (i) A solution of 35 S methyl ester of 3, 4-diamino-5 benzoic acid in 1200 ml dry dimethylformamide, containing 11.8 g of anhydrous sodium carbonate, was treated dropwise with 58 g of n-hexadecanoyl chloride over one hour with stirring. 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 an additional 3 hours and poured into 5 liters of water. The solid obtained was collected and boiled in 1000 ml of acetone, after which the boiling mixture was filtered off. The filtrate was cooled to a temperature of 0 ° C, then the resulting tan-colored solid was filtered off, removing 48.2 g of the methyl ester of 4-amino-3- (n-hexadeaneamido) benzoic acid, mp 112-114 ° 0 was obtained.

(Ii) A solution of 16.6 g of methyl ester of 3,4-diamino-benzoic acid in 270 ml of dry dichloromethane containing 10.3 S triethylamine was treated dropwise with a solution of 45 minutes with stirring. 27.5 S n-hexadecanoyl chloride in 30 ml of dry dichloromethane. During the addition, the temperature was kept between 16 and 20 ° G. The mixture was then stirred for an additional 2 hours. The solid obtained was then collected and boiled in a mixture of 1000 ml of acetone and 150 ml of methanol, after which the insoluble material was removed by filtration.

The filtrate was cooled to a temperature of 25 ° C and treated with 800 ml of water, the methyl ester of 4-amino-3- (n-hexadecanamido) benzoic acid as a yellow-brown solid, m.p. 112-114 ° C was obtained.

Example II Compound A

A solution of 34 g of methyl ester of 4-amino-3- (n-he-xadecanamido) benzoic acid (prepared according to the procedure described in Example I) in 200 ml of a mixture of ethanol 40 and water in a ratio of 9: 1 ( vol./vol.) was treated with 8003627 with an excess of a saturated solution of hydrogen chloride in ethanol. The mixture was refluxed for 2 hours and then cooled. The solid obtained was collected and recrystallized from a mixture of ethanol and water in a ratio of 9: 1 (v / v) to give 24.2 g of the hydrochloride salt of the methyl ester of 2- (n-pentadecyl) Benzimidazole-5-carboxylic acid in the form of a white solid was obtained, which melted at decomposition at a temperature of 230 to 232 ° C.

Example III Compound A

An intimate mixture was prepared by triturating 8.8 g of methyl ester of 3,4-diaminobenzoic acid and 12.8 g of hexadecanoic acid together. The mixture was heated at a temperature of 200 ° C for 150 minutes. The mixture was then cooled to a temperature of 60 ° G and extracted with 200 ml of boiling petroleum ether (boiling range 60 - 80 ° C). The extract was concentrated in vacuo to give a brown oil. The oil was dissolved in 100 ml of ethanol and the solution was treated with a solution of potassium hydroxide in ethanol (10% w / w) until the mixture reached pH 7. The mixture was then cooled to a temperature of 0 ° C and filtered, then the filtrate was concentrated in vacuo to give 10.2 g of a brown oil. The oil was dissolved in 15 ml of chloroform and chromatographed on 275 g of silica gel. Elution with chloroform gave 6.0 g of an off-white solid, which was recrystallized from petroleum ether (boiling range 40 DEG-60 DEG C.), yielding 5.5 g methyl ester of 2- (n-pentadecyl) benzimidazole-5- carboxylic acid in the form of a white solid was obtained, which melted at a temperature of 96-98 ° C.

Example IV 35 Compound 3

A solution of 36 g of methyl ester of 2- (n-pentadecyl) -benzimidazole-5-carboxylic acid (prepared according to the procedure of example I or III) in 500 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 (vol / vol.), containing 8 g of sodium hydroxide, was stirred and refluxed for 800 minutes for 90 minutes. The mixture was cooled to a temperature of 0 ° 0 and acidified by treatment with concentrated hydrochloric acid. The resulting off-white solid was collected and recrystallized (under charcoal treatment) from 800 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 (vol./vol.) To 52 g of 2- (n-pentadecyl) benzimidazole-5-earbon-HCl acid / m in the form of a white solid, which melted at a temperature of 289-291 ° C with decomposition.

Example V Connection B

A solution of 24.2 g of the hydrochloride of the methyl ester of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid 15 (prepared according to the procedure of Example II) in 250 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 (v / v) containing 7 δ sodium hydroxide was treated in the same manner as described in Example IV to obtain 22.4 g of 2- (n-pentadecyl) benzimidazole-5-20 carboxylic acid hydrochloride which melted under decomposition at a temperature of 289-291 ° C.

Example VI Compound C

A solution of 41.0 g of methyl ester of 4-amino-3-25 (n.dodeaneamido) benzoic acid in 1000 ml of toluene, containing 25 δ p-toluenesulfonic acid, was treated in the same manner as described in Example I, whereby 27.0 g of 2- (n-undecyl) benzimidazole-5-carboxylic acid methyl ester was obtained in the form of a white solid with a melting point of 93 DEG-95 DEG.

The methyl ester of--amino-3- (n-dodecanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 25.0 g of methyl ester of 3,4-diamino-35 benzoic acid in 1120 ml of dry dimethylformamide containing 7 * 7 δ anhydrous sodium carbonate was treated with 30 * 5 δ in the same manner as described in Example I (i). n-de-deeanoyl chloride to give 41 g of crude methyl ester of 4-amino-3- (n-dodecanamido) benzoic acid as a yellow-brown solid.

800 3 6 27 26

Example VII Compound 0

An intimate mixture was prepared by triturating 33 δ methyl ester Tan 3,4-diaminobenzoic acid and 40 g dodecanoic acid together, after which the mixture was heated at a temperature of 200 ° C for 3 hours. The mixture was then treated in the same manner as described in Example III to obtain 19 g of the methyl ester of 2- (n.undecyl) benzimidazole-5-carboxylic acid as a white solid, m.p. 92-94 ° C.

Example VIII Compound 33

A solution of 28.6 g of methyl ester of 2- (n.undecyl) -benzimidazole-5-carboxylic acid (prepared according to the procedure 15 of Example VII) in 350 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 ( vol./vol.), containing 6.95 S sodium hydroxide, was treated in the same manner as described in Example IV, with 22.3 S 2- (n.undecyl) benzimidazole-5-carboxylic acid hydrochloride in the form of a white solid was obtained, which melted under decomposition at a temperature of 289-294 ° C. Example IX Compound E

An intimate mixture was prepared by triturating together 33.0 g of methyl ester of 3> 4-diaminobenzoic acid and 45.6 g of n-tetradecanoic acid, after which the resulting mixture was heated at a temperature of 200 ° for 6 hours. The mixture was cooled to a temperature of 60 ° C and then extracted with petroleum ether (boiling range 60 - 80 ° C), after which the petroleum ether extracts were concentrated in vacuo to form a brown oil. The oil was dissolved in 500 ml of ethanol and this solution was treated with a solution of potassium hydroxide in ethanol (10% w / v) until the mixture reached a pH of 7. The mixture was cooled to a temperature of 0 ° C and filtered and the filtrate was concentrated in vacuo to give a brown oil. The oil was partitioned between 300 ml of a hot mixture of petroleum ether (boiling range 60 - 80 ° C) and 40 toluene in a mixing ratio of 4: 1 (v / v) and 800 3 6 27 27

300 ml of water. The organic layer was concentrated in vacuo to give an oil, which was then dissolved in 100 ml of hot toluene and treated with an excess of a saturated solution of hydrogen chloride in ethanol. The resulting solid material was collected and recrystallized from ethanol (charcoal treatment) to give 16 g of the hydrochloride of the methyl ester of 2- (n.tridecyl) benzimidazole-5-carboxylic acid as a white solid substance which melted under decomposition at a temperature of 228-236 ° C. Example X Connection E

40 g of methyl ester of 4-amino-3- (n.tetradeaneamido) -15 benzoic acid were treated in the same manner as described in example II, with 33 g of the hydrochloride of the methyl ester of 2- (n.tridecyl) benzimidazole-5- carboxylic acid was obtained in the form of a white solid, which melted under decomposition at a temperature of 228 DEG-234 DEG.

The methyl ester of 4-amino-3- (n.tetradecanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 25.0 g of methyl ester of 3,4-diamino-benzoic acid in 500 ml of dichloromethane containing 15.5 g of triethyl-25 amine was treated dropwise with stirring in a manner similar to that described in Example I (ii). solution of 37 * 12 g of n-tetradecanoyl chloride in 50 ml of dry dichloromethane to give 40 g of the crude methyl ester of 4-amino-3- (n-tetradecanamido) benzoic acid as a yellow-brown solid.

Example ΣΙ Connection ff

A solution of 7-9 g methyl ester of 2- (n.tridecyl) -benzimidazole-5-carboxylic acid in 200 ml of a mixture of 35 ethanol and water in a mixing ratio of 4: 1 (vol./vol.), 2 Containing 4 g of sodium hydroxide was treated in the same manner as described in Example IV to obtain 5 * 7 g of 2- (n, tridecyl) benzimidazole-5-carboxylic acid hydrochloride in the form of a white solid, which was The temperature of 299-306 ° C melted under decomposition.

800 3 6 27 28

Example XII Compound B

In 1000 ml of a bite mixture of ethanol and water in a mixing ratio of 6: 1 (vol./vol.), 15.0 g of 5 2- (n.pentadecyl) benzimidazo © 1-5-carboxylic acid hydrochloride (prepared according to solved the requirement of example IV). The hot solution was treated with 2N aqueous ammonia until the solution reacted alkaline. Then, ice vinegar was added to the mixture until the solution reacted acid 10, then the solution was cooled to a temperature of 0 ° C to obtain 12.3 g of a white solid. This solid was recrystallized from a mixture of ethanol and water at a mixing ratio of 4: 1 (v / v) to give 12.0 g of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid in the form of a white solid with a melting point of 113-115 ° C, which is believed to be the monohydrate.

Example XIII Compound G · 20 In 300 ml of hot ethanol, containing an excess of hydrogen chloride, 4-amino-3- (n.tridecanamido) benzoic acid methyl ester (prepared as described below from 17.8 g of methyl ester of 3 4-diaminobenzoic acid, which was used without further purification) was dissolved, after which the resulting solution was treated in the same manner as described in Example II, whereby 25.5 g of the hydrochloride of the methyl ester of 2- (n.dodecyl Benzimidazole-5-carboxylic acid was obtained in the form of a white solid, which melted under decomposition at a temperature of 221-225 ° C.

The 4-amino-3- (n-triadeaamido) benzoic acid methyl ester used as starting material was prepared in the following manner:

A solution of 17 * 8 g of methyl ester of 3 * 4-diamino-35 benzoic acid in 350 ml of dichloromethane, containing 10.8 g of triethyl amine, was mixed with 25 g of n-tridecanoyl chloride in the same manner as described in Example I (ii). treated to give 40 g of crude methyl ester of 4-amino-3- (n-tridecane-amido) benzoic acid.

8003627 29

Example XIV Compound 5

A solution of 15 * 5 g of methyl ester of 2- (n.dodecyl) -benzimidazole-5-carboxylic acid in 100 ml of a mixture of 5 ethanol and water in a mixing ratio of 4: 1 (v / v), which is 50 g of sodium hydroxide was treated in the same manner as described in Example IV, whereby 11.7 g of 2- (n.dodecyl) benzimidazole-5-carboxylic acid hydrochloride were obtained in the form of a white solid, which was melted at 276-290 ° C under decomposition.

Example XV Connection B

A solution of 20 g of 3 »4-bis (n.hexadecanamido) benzoic acid in 400 ml of methyl ethyl ketone was treated with 15 µl of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was refluxed for 5 hours and then cooled. The resulting solid was collected and washed with boiling petroleum ether (boiling range 60 - 80 ° C) and recrystallized from ethanol to give 15 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid hydrochloride in the form of a white solid, which melted under decomposition at a temperature of 289-291 ° C.

The 3,4-bis (n.hexa-25deanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 7.5 g of 3,4-diaminobenzoic acid in 100 ml of dichloromethane containing 15 g of triethylamine was treated with 27.5 g of n-hexadecanoyl chloride in the same manner as described in Example I (ii). A solid was collected, which was recrystallized from glacial acetic acid and then from methyl ethyl ketone (under filtration of the hot solution), whereby 20 g of 3,4-bis (n-hexadecane-amido) benzoic acid were obtained in the form of a yellow-brown solid, which melted at a temperature of 198 - 202 ° C.

Example XVI Compound A

A solution of 10.0 g of methyl ester of 3,4-bis (n.he-xadecanamido) benzoic acid in 100 ml of methyl ethyl ketone was treated in the same manner as described in Example XV, 8003627, whereby 5.7 g of the hydrochloride of methyl ester of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid was obtained as a white solid, which melted under decomposition at a temperature of 250-232 ° C.

The methyl ester ran 3,4-bis (n.hexadecaanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 5.0 g of methyl ester of 3,4-diamino-benzoic acid in 50 ml of dichloromethane containing 6.2 g of triethyl-10 amine was treated with 16.5 g of n-hexadecanoyl chloride in the same manner as described in Example I (ii) (raising the temperature of the reaction mixture to 20 ° C during addition from 20 ° C). A solid was collected, which was recrystallized from chloroform to give 14.9 g of methyl ester of 3,4-bis (n-hexadecanamido) benzoic acid as a white solid, m.p. 129 - 132 ° C. 7Example Σ7ΙΙ Connection I

A solution of 33.0 g of methyl ester of 3,4-bis (n.undecaanamido) benzoic acid in 400 ml of methanol, containing 50 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v), was Stirred and refluxed for 3 hours. The mixture was then cooled to a temperature of 0 ° and filtered and the resulting solid was combined with the residue obtained by evaporation of the filtrate in vacuo. The combined solid material was washed with 200 ml of hot petroleum ether (boiling range of 60 DEG-80 DEG C.) and recrystallized from ethanol (filtering off the hot solution) to give 13.7 g of the hydrochloride of the methyl ester of 2- (n. decyl) benzimidazole-5-carboxylic acid was obtained in the form of a white solid, which melted under decomposition at a temperature of 230-240 ° C.

The methyl ester of 3,4-bis (n.undecaanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 17.9 g of methyl ester of 3,4-diamino-benzoic acid in 300 ml of dichloromethane containing 21.8 g of triethyl-40 amine was prepared in the same manner as described in 8003627 31 Example XVI with 44.3 g of n-unanoyl chloride treated. A solid was obtained, which was recrystallized twice from ethanol (with the hot solution being filtered) with 40.2 g of methyl ester of 3,4-bis (n.un-5 decanamido) benzoic acid as a white solid with a melting point of 139 DEG-14 DEG C. was obtained.

Example XVIII Compound J

A solution of 13.7 g of the hydrochloride of the 2- (n-decyl) benzimidazole-5-carboxylic acid methyl ester (prepared according to the procedure of Example XVII) in 250 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 (v / v) containing 4.6 g of sodium hydroxide was treated in the same manner as described in Example IV, whereby 9.4 g of 2- (n.decyl) benzimidazole-5-carbon -acid hydrochloride was obtained in the form of a white solid which melted at a temperature of 270 DEG-282 DEG C. with decomposition.

Example XIX 20 Compound B

A solution of 11.16 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid monohydrate (prepared according to the procedure of Example XII) in 150 ml of methanol was heated to a temperature of 60 ° C and with a solution of sodium Methanolate (prepared by carefully dissolving 0.69 g of sodium in 40 ml of anhydrous methanol) was treated and the mixture was cooled. The solvent was evaporated in vacuo and the residue was recrystallized from water to give 9.7 g of sodium salt of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid as the monohydrate as a white solid which takes on a dark color at a temperature of 250 ° C and decomposes at a temperature above 300 ° C.

Example XX 35 Compound B

A suspension of 1.00 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid monohydrate (prepared according to the procedure of Example XII) in 30 ml of acetone was treated dropwise with a solution of 40 0.25 g at room temperature with stirring. methanesulfonic acid in 15 ml of methanol. The mixture 8003627 4 30 whereby 5 7 S of the hydrochloride of the methyl ester of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid was obtained in the form of a white solid, which was at a temperature of 230-232 ° C. melted under decomposition.

The methyl ester of 3.4-bis (n.hexadecanamido) benzoic acid used as starting material was prepared in the following manner

A solution of 5 0 g of methyl ester of 3,4-diamino-benzoic acid in 30 ml of dichloromethane containing 6.2 g of triethyl-10 amine was treated with 16.5 g of n-hexadecanoyl chloride in the same manner as described in Example I (ii) (raising the temperature of the reaction mixture from 20 ° to 30 ° 0 during the addition). A solid was collected, which was recrystallized from chloroform to give 14.9 g of methyl ester of 3,4-bis (n-hexadecanamido) benzoic acid as a white solid, m.p. 129 - 132 ° C. Example Σ7ΙΙ Connection I

A solution of 33 ° g of methyl ester of 3 »4-bis (n.undecaanamido) benzoic acid in 400 ml of methanol containing 50 ml of concentrated hydrochloric acid at a concentration of 36.3% (w / v) was Stirred and refluxed for 3 hours. The mixture was then cooled to a temperature of 0 ° and filtered and the resulting solid was combined with the residue obtained by evaporation of the filtrate in vacuo. The combined solid material was washed with 200 ml of hot petroleum ether (boiling range 60-80 ° C) and recrystallized from ethanol (filtering off the hot solution) to give 13.7 g of the hydrochloride of the methyl ester of 2- (n. decyl) benzimidazole-5-carboxylic acid was obtained in the form of a white solid, which melted under decomposition at a temperature of 230-240 ° C.

The methyl ester of 3,4-bis (n.undecaanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 17.9 g of methyl ester of 3,4-diamino-benzoic acid in 300 ml of dichloromethane containing 21.8 g of triethyl-40 amine was prepared in the same manner as described in 8003627 31 Example XVI with 44.3 g of n-unanoyl chloride treated. A solid was obtained, which was recrystallized twice from ethanol (with the hot solution being filtered off), giving 40.2 g of methyl ester of 1,4-bis (n.un-5 decanamido) benzoic acid in the form of a white solid substance with a melting point of 139-141 ° C was obtained.

Example XVIII Connection J

A solution of 13.7 g of the hydrochloride of the 2- (n-decyl) benzimidazole-5-carboxylic acid methyl ester (prepared according to the procedure of Example XVII) in 250 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 (v / v) containing 4.6 g of sodium hydroxide was treated in the same manner as described in Example IV, whereby 9.4 g of 2- (n.decyl) benzimidazole-5-carbon Acid hydrochloride was obtained in the form of a white solid melting at a temperature of 270-282 ° C with decomposition.

Example XIX 20 Compound B

A solution of 11.16 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid monohydrate (prepared according to the procedure of Example XII) in 150 ml of methanol was heated to a temperature of 60 ° C and with a solution of sodium Methanolate (prepared by carefully dissolving 0.69 g of sodium in 40 ml of anhydrous methanol) was treated and the mixture was cooled. The solvent was evaporated in vacuo and the residue was recrystallized from water to give 9.7 g of sodium salt of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid as the monohydrate as a white solid which takes on a dark color at a temperature of 250 ° C and decomposes at a temperature above 300 ° C.

Example XX 35 Compound B

A suspension of 1.00 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid monohydrate (prepared according to the procedure of Example XII) in 30 ml of acetone was treated dropwise with a solution of 40 0.25 g at room temperature with stirring. methanesulfonic acid in 15 ml of methanol. The mixture 8003627 32 was heated to a temperature of 40 ° C, whereby a solution was obtained, after which the solvent was evaporated in vacuo. The white solid residue was triturated with 30 ml of acetone, then the resulting solid was collected and washed with 10 ml of acetone, adding 1.19 S of 2- (n-p-tadecyl) benzimidazole-5-carboxylic acid ethylene sulfonate a white solid with a melting point of 115-117 ° C was obtained.

Example XXI 10 Compound B

A suspension of 1.00 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid monohydrate (prepared according to the procedure of Example XII) in 30 ml of acetone was treated with an excess of 10% solution (wt. / vol.) 15 2-hydroxyethylsulfonic acid in a mixture of methanol and water in a mixing ratio of 19: 1 (v / v). The solution was evaporated in vacuo and the residue was triturated with 30 ml of acetone. The resulting solid was collected and washed with 10 ml of acetone to give 1.24 g of 2- (n.pen-20 tadecyl) benzimidazole-5-carboxylic acid 2-hydroxyethyl sulfonate as a white solid, m.p. 93 DEG-95 DEG C. was obtained.

Example XXII Compound A

In a reflux apparatus, 10.0 g of 2- (n-pentadecyl) -benzimidazole-5-carboxylic acid hydrochloride (prepared according to the procedure of Example IV) were dissolved in 250 ml of boiling methanol the solution was treated with 20 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was refluxed for 3 hours and then cooled to a temperature of 0 ° C. The white solid obtained was collected, washed with water and recrystallized from ethanol to obtain 9 g of the hydrochloride of the methyl ester of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid in the form of a white solid, which melted under decomposition at a temperature of 230-232 ° C.

Example XXIII 40 Compound K

800 3 6 27 33

An intimate mixture was prepared by triturating together 33.0 g of methyl ester of 3-4-diaminobenzoic acid and 56.8 g of n-octadecanoic acid, after which the mixture was heated at 200 ° C for 210 minutes. The mixture 5 was then treated in the same manner as described in Example IX. The brown oil, which was obtained after partition between the hot mixture of petroleum ether, toluene and water, was dissolved in 25 ml of chloroform and chromatographed on a column with 750 g of silica gel. 40 g of a light brown solid was obtained by eluting with a mixture of chloroform and methanol in a mixing ratio of 19: 1 (v / v). This solid was dissolved in 200 ml of hot toluene and treated with an excess of a saturated hydrogen chloride solution in ethanol. The solid obtained was collected and recrystallized from a mixture of ethanol and water in a mixing ratio of 9 * 1 (v / v) (using carbon treatment) to give 19.9 g of the hydrochloride of the methyl ester of 2 - (n.hep-tadecyl) benzimidazole-5-carboxylic acid was obtained in the form of a white solid, which melted under decomposition at a temperature of 229-234 ° C.

Example XXIV Connection L

A solution of 11.5 g of the hydrochloride of the methyl ester of 2- (n.heptadecyl) benzimidazole-5-carboxylic acid (prepared according to the procedure of Example XXIII) in 200 ml of a mixture of ethanol and water in a mixing ratio of 1: 1 (v / v) containing 14.35 g of sodium hydroxide was treated in the same manner as described in Example IV, with 8.8 g of 2- (n.heptadecyl) benzimidazole-5 -carboxylic acid hydrochloride was obtained in the form of a white solid, which melted under decomposition at a temperature of 279-284 ° C.

Example XXV 35 Connection M

A mixture of 16.7 g of methyl ester of 4-amino-3- (n.de-caanamldo) benzoic acid and 600 ml of toluene containing 5 0 g of p-toluene sulfonic acid was treated in the same manner as described in Example I to give 14.0 g of methyl ester of 40 2- (n.nonyl) benzimidazole-5-carboxylic acid in the form of an 800 3 6 27 white solid, mp 101-103 ° C.

The methyl ester of 4-amino-3- (n-decanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 16.6 g of methyl ester of 3,4-diamino-benzoic acid in 600 ml of dry dimethylformamide containing 5-3 g of anhydrous sodium carbonate was stirred in the same manner as described in Example I (i) in Example I (i). Treated dropwise with 19.1 g of n-decanoyl chloride, with 18.8 g of methyl ester of 4-amino-3- (n-decanamido) benzoic acid in the form of a yellow-brown solid, m.p. 96-98 ° C was obtained.

Example XXVI 15 Compound N

A solution of 13.5 g of methyl ester of 2- (n.nonyl) -benzimidazole-5-carboxylic acid (prepared according to the procedure of Example XXV) in 400 ml of a mixture of ethanol and water in a mixing ratio of 4: 1 (vol ./vol.) containing 3.6 g of sodium hydroxide was treated in the same manner as described in Example IV to obtain 8.6 g of 2- (n-no-nyl) benzimidazole-5-carboxylic acid hydrochloride in in the form of a white solid, which melted at a temperature of from 275 to 280 ° C.

Example XXVII Connection 0

A solution of 81.8 g of methyl ester of 3,4-bis (n.octaanamido) benzoic acid in 800 ml of methanol, containing 100 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v), was Stirred and refluxed for 4 hours. The mixture was then cooled and treated in the same manner as described in Example XVII, whereby 33.8 g of the hydrochloride of the methyl ester of 2- (n.heptyl) benzimidazole-5-carboxylic acid 35 were obtained in the form of a white solid substance which melted under decomposition at a temperature of 140 to 142 ° C.

The methyl ester of 3,4-bis (n.utanamido) benzoic acid used as starting material was prepared in the following manner: 40 A solution of 41.2 g of methyl ester of 3,4-diamino-8003627 35 benzoic acid in 412 ml of dichloromethane containing 5 Containing 0 g of triethyl amine, it was treated in the same manner as described in Example XVI with a solution of 80.6 g of n.oc-tanoyl chloride in 330 ml of dichloromethane, followed by recrystallization from methanol (under treatment with charcoal), whereby 81.8 g of methyl ester of 3, 4-bis (n.octaanami-do) benzoic acid as a white solid, mp 138-140 ° C, were obtained.

Example XXVIII 10 Compound P

A solution of 23.0 g of the hydrochloride of the methyl ester of 2- (n.heptyl) benzimidazole-5-carboxylic acid (prepared according to the procedure of Example XXVII) in 200 ml of a mixture of ethanol and water in a mixing mixture. 12: 1 (vol./vol.) attitude, which contained 8.9 g of sodium hydroxide, was stirred and refluxed for 5 hours. The mixture was treated in the same manner as described in Example IV to obtain 14.4 g of 2- (n.heptyl) benzimidazole-5-carbonic acid hydrochloride in the form of a white solid, which was heated at a temperature melted from 310 to 313 ° C under decomposition. Example XXIX Connection Q

A solution of 49.3 S 3,4-bis (n.pentadecanamido) -25 benzoic acid in 560 ml of a mixture of methyl ethyl ketone and concentrated hydrochloric acid in a mixing ratio of 10: 1 (v / v) was stirred for 3 hours and refluxed. The mixture was then cooled. The solid material obtained was collected and washed with 200 ml of methyl ethyl ketone and then with 200 ml of boiling petroleum ether (boiling range 60-80 ° C). The material was then recrystallized from a mixture of ethanol and water in a mixing ratio of 4: 1 (v / v) (with carbon treatment and the hot solution being filtered off) whereby 15.7 g of 2- (n tetra-decyl) benzimidazole-5-carboxylic acid hydrochloride was obtained, which melted under decomposition at a temperature above 300 ° C.

The 3,4-bis (n.penta-40 decanamido) benzoic acid used as starting material was prepared in the following manner: 8003627 36

A solution of 13 * 85 g of 3,4-diaminobenzoic acid in 180 ml of dimethylformamide containing 27.6 g of triethylamine was treated with 4-7.4 g of n-pentadecanoyl chloride in the same manner as described in Example I (i). The resulting solid material was collected and recrystallized from methyl ethyl ketone (charcoal treated and the hot solution filtered), 49.3 g of 3,4-bis (n.pentadecanamido) benzoic acid, m.p. 178-180 ° C was obtained.

10 Example ΣΣΣ Connection R

(a) A solution of 23.3 g of methyl ester of 3,4-bis Cn.no-naanamido) benzoic acid in 300 ml of methanol was treated with stirring with 40 ml of concentrated hydrochloric acid at a concentration of 36.5% (wt ./full.). The mixture was refluxed for 3 hours, then the solvent was removed in vacuo to give a white solid. The solid material was washed with 100 ml of hot petroleum ether (boiling range of 40 DEG-60 DEG) and then recrystallized from 700 ml of water and filtered while hot, yielding 12.0 g of the hydrochloride of the 2-n methyl ester. octylbenzimidazole-5-carboxylic acid was obtained as a white solid, which melted at a temperature of 238-243 ° C.

(B) A solution of 11 g of the hydrochloride of the methyl ester of 2-n-octylbenzimidazole-5-carboxylic acid prepared in the manner described above in 240 ml of a mixture of ethanol and water in a mixing ratio of 12: 1 (vol./vol.) containing 4.0 g of sodium hydroxide was stirred and refluxed for 4 hours. The mixture was treated in the same manner as described in Example IV to obtain 7.8 g of 2- (n-octyl) benzimidazole-5-carboxylic acid hydrochloride in the form of a white solid, which was at a temperature of 280-300 ° C melted under decomposition.

The methyl ester of 3,4-bis (n.nonanamido) benzoic acid used as starting material was prepared in the following manner: (c) A solution of 20 g methyl ester of 3,4-diamino-40 benzoic acid in 250 ml dry dichloromethane containing 24 2 g of tri-800 3 6 27 37 ethylamine was treated dropwise with a solution of 44.12 g of nonanoyl chloride in 50 ml of dry dichloromethane with stirring in the same manner as described in example I (ii). The pink solid obtained was recrystallized from methanol and treated with charcoal, whereby 50.3 g of the methyl ester of 3 * 4-bis (n. Nonanamido) benzoic acid as a white solid, m.p. 142-145 ° C was obtained.

Example UZI 10 Connection S

In a reflux apparatus, 8.5 g of 2- (n.tetradecyl) benzimidazole-5-carboxylic acid hydrochloride prepared according to the procedure of Example XXIX were dissolved in 96 ml of boiling methanol and then treated with 22 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was refluxed for 3 hours and then treated in the same manner as described in Example XXII to obtain 6.2 g of the hydrochloride of the methyl ester of 2- (n-tetradecyl) benzimidazole-5-carboxylic acid in the form of a white solid with a melting point of 233 - 235 ° C.

Example XXXII Compound T

In a reflux apparatus, 9.0 g of 2- (n.hexadecyl) benzimidazole-5-carboxylic acid hydrochloride prepared in accordance with Example XXXIII below were dissolved in 400 ml of boiling methanol treated with 100 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was refluxed for 8 hours and then treated in the same manner as described in Example XXII, whereby 7.4 g of the hydrochloride of the methyl ester of 2- (n-hexadecyl) benzimida-35-sole-5-carboxylic acid were obtained in in the form of a white solid which melted under decomposition at a temperature of 225-230 ° C.

Example XXXIII Compound U

40 A solution of 250 g of 3,4-bis (n.heptadecanamido) - 8003627 38 benzoic acid in 1500 ml of methyl ethyl ketone was treated with 180 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was refluxed for 8 hours and then treated in the same manner as described in Example XV to yield 44.9 g of 2- (n-hexadecyl) benzimidazole-5-carboxylic acid hydrochloride in the form of an off-white solid, which melted under decomposition at a temperature of 296-306 ° C.

The 3,4-bis (n.hepta-decanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 45.6 g of 3,4-diaminobenzoic acid in 400 ml of dimethylformamide containing 75-8 g of trietbylamine was treated dropwise with 130 g of heptadecanoyl chloride over 1.5 hours with stirring. The n-hepta-decanoyl chloride was added at such a rate that the temperature of the reaction mixture rose from room temperature to 35-40 ° C. The mixture was then stirred at room temperature for 2 hours and then poured into 3500 ml of hot water at a temperature of 70 ° C containing 50 µl of concentrated hydrochloric acid at a concentration of 36.5% (w / v), whereby 140 g of crude 3,4-Ms (n.heptadecaanamido) benzoic acid in the form of a pink solid were obtained.

Example XXX1T ^ Compound V

A solution of 12 g of the 2-n-eicosylbenzimidazole-5-carboxylic acid hydrochloride prepared according to the procedure of Example XXXV in 300 ml of chloroform was treated dropwise with 100 ml of thionyl chloride under stirring.

The mixture was refluxed for 4 hours then cooled and the excess thionyl chloride and solvent removed in vacuo to give a white solid. The solid 35 was suspended in 300 ml anhydrous methanol, the mixture was stirred and refluxed for 8 hours and then cooled. The solid was collected and washed with methanol to give 9.2 g of the hydrochloride of the methyl ester of 2- (n.eicosyl) benzimida-40 sole-5-carboxylic acid as a white 8003627 39

Taste material, which melted at a temperature of Tan 220 - 226 ° C. Example XXXV Connection ¥

A solution of Tan 126.5 g of 3 * 4-bis (n-heneicosanamido) -5 benzoic acid in 1000 ml of methyl ethyl ketone was treated with 100 ml of concentrated hydrochloric acid at a concentration of Tan 36 * 5% (w / w). The mixture was refluxed for 10 hours and then treated in the same manner as described in Example XV, yielding a white solid, which was recrystallized from 1200 ml of n-butanol to yield 45.1 g of 2- (n.eicosyl ) benzimi-dazole-5-carboxylic acid hydrochloride was obtained in the form of Tan and a white solid, which melted at a temperature of Tan 294 - 298 ° C with decomposition.

The 3,4-bis (n-heneicosanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 21.9 g of 3,4-diaminobenzoic acid in 175 ml of dimethylformamide containing 43.6 g of triethylamine was treated dropwise with 99.2 g of n-heneico-sanoyl chloride in the same manner as described in Example XXXIII, yielding 126.5 g of crude 3,4-bis (n-heneicosan-amido) benzoic acid in the form of a light brown solid.

Example XXXVI 25 Compound X

14.6 g of 2- (n.nonodeeyl) benzimidazole-5-carboxylic acid hydrochloride prepared according to the procedure of Example XXXVII below were suspended in 350 ml of thionyl chloride, and the mixture was stirred and refluxed for 6 hours. The excess thionyl chloride was removed in vacuo to yield a tan solid. This solid material was suspended in 500 ml of anhydrous methanol, then the mixture was stirred and refluxed for 3 hours. The mixture was then treated in the same manner as described in Example XXXIV to give 12.2 g of the hydrochloride of the methyl ester of 2- (n.no-nadecyl) benzimidazole-5-carboxylic acid as a white solid which melted at a temperature of 40-219-227 ° 0.

003627 40

Example XXXYII Compound T

A suspension of 89.1 g of 3'-4-bis (n.eicosanamido) -benzoic acid in 1200 ml of fayletfayl ketone was heated with 120 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was stirred and refluxed for 8 hours and then treated in the same manner as described in Example XV to give a white solid. The solid 10 was mixed with 100 ml of n. butanol, then the mixture was cooled to give 36.5 g of 2- (n.nonadeeyl) benzimidazole-5-carboxylic acid hydrochloride as a white solid, which was heated at a temperature of 290-300 ° C under decomposition melted.

The 3 »4-bis (n.eicosaneamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 18.3 g of 3 »4-diaminobenzoic acid in 200 ml of dimethylformamide containing 36.5 g of triethylamine was treated dropwise with stirring with 79.4 g of n.eicosanoyl chloride in the same manner as described in

Example XXXI.II, whereby 93 g of crude 3 * 4-bis (n.eicosan amido) -benzoic acid were obtained as a pale brown solid, melting at a temperature of 160-170 ° C. Example XXXVIII Compound Z

A suspension of 107 g of 4-amino-3- (n-nonadecane) benzoic acid in 1500 ml of methyl ethyl ketone was treated with 100 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was stirred and refluxed for 3 hours. The mixture was then cooled to 10 ° 0, the solid material collected, washed twice with 500 ml of methyl ethyl ketone each time and suspended in 500 ml of water. A solution of 50 g of sodium hydroxide in 150 ml of water was added to the mixture, the mixture was stirred and heated to a temperature of 60 ° 0 to obtain a solution. Glacial acetic acid was added to the mixture with stirring until the pH of the mixture was 5, after which the solid obtained was collected, washed twice with 500 ml of water and dried. The solid was recrystallized 8003627 4-1 from ethanol under charcoal treatment to give a white solid which was carefully dried and then slurried in 500 mL of methyl ethyl ketone to give 100 mL of concentrated hydrochloric acid with a concentration of 36.5% (w / v). The mixture was stirred and refluxed for one hour and then cooled to give 33.8 g of 2- (n.octadecyl) benzimidazole-5-acetic acid hydrochloride as a white solid, which was at 10 a temperature of 292-297 ° M melted under decomposition.

The 4-amino-3- (n.nona-decanamido) benzozaur used as starting material was prepared in the following manner:

A solution of 38 g of 3,4-diaminobenzoic acid in 500 ml of dimethylformamide containing 50.5 g of triethylamine was treated dropwise, with stirring, in the same manner as described in Example XXXTII, with 79 µg of nonadecanoyl chloride, whereby a an orange solution was obtained, which was poured into 3000 ml of water containing 100 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v) -20%. The solid material was collected, washed twice with 100 ml of water each time and then dried, yielding 107 S of crude 4-amino-3- (n-nonadecanamido) benzoic acid, which melted at a temperature of from 103 DEG-113 DEG. Example ΧΣΣΙΣ 25 Connection II

For 3 hours, 12 g of 2- (n-octadecyl) benzimidazole-5-carboxylic acid hydrochloride prepared according to the procedure of Example 7ΧΣΣ were stirred in 100 ml of thionyl chloride and refluxed, then in the same manner as described in Example XXXVI, whereby 11.6 g of the hydrochloride of the methyl ester of 2- (n. octadecyl) benzimidazole-5-carboxylic acid are obtained in the form of a white solid, which is at a temperature of 224 DEG C. 230 ° C melted.

35 Example XL Connection AA

A suspension of 53 * 1 g of 3? 4-bis (2-methyltetradecan-amido) benzoic acid in 250 ml of methyl ethyl ketone was added with 37.6 ml of concentrated hydrochloric acid at a concentration of 4-0 36.5% (w / v). treated. The mixture was stirred and refluxed for 8003627 42 hours. The mixture was then cooled to a temperature of 0 ° G, after which the solid material was collected in an amount of 11.17 g and washed twice with 25 ml of methyl ethyl ketone each time. The solid material was suspended in 50 ml of water, after which a solution of 20 g of sodium hydroxide in 50 al of water was added to the suspension. The mixture was stirred and heated to a temperature of 60 ° G to obtain a solution, then glacial acetic acid was added to the mixture with stirring until the pH of the mixture was 5. The resulting solid was collected, washed with water, and recrystallized from ethanol under charcoal treatment and then treated in the same manner as described in Example XXXVIII, yielding 11 g (BS) -2- (tetradee-2- yl) benzimidazole-5-carboxylic acid hydrochloride was obtained in the form of a white solid, which melted at a temperature of 214-218 ° G.

«

The 3,4-bis (2-methyl-20-tetradecanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 17.5 g of 3,4-diaminobenzoic acid in 140 ml of dimethylformamide containing 34.8 g of triethylamine was treated dropwise with stirring in the same manner as described in Example XXXIII with 59.7 g of penta-decan-2- oyl chloride, yielding 68 g of crude 3,4-bis (2-methyl-tetradecanamido) benzoic acid.

Example XLI Compound 00 30 A solution of 15.2 g of 4-amino-3- (2-hexyloctanamide) benzoic acid in 78 ml of methyl ethyl ketone was added with 18.2 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). vol.). The mixture was stirred and refluxed for 12 hours, after which time the methyl ethyl ketone was removed in vacuo. The residue was suspended in 200 ml of water and a 50% (w / v) aqueous sodium hydroxide solution was added to the mixture until its pH was 11. The mixture was heated to a temperature of 90 ° G and then diluted with water 40 to a total volume of 1500 ml. The solution 800 3 6 27 43 was treated with charcoal and then treated with an excess of a 25% (w / v) acetic acid solution in water to give an off-white solid. The solid was collected, washed with water and recrystallized from ethyl acetate to yield 8.89 g of 2- (tri-dec-7-yl) benzimidazole-5-carboxylic acid, mp 157-158 ° G.

The solid material was dissolved in 350 µl acetone and the resulting solution was treated with 1.55 ml of concentrated sulfuric acid at a concentration of 98% (w / w). On cooling, a white solid was obtained, which was recrystallized from methyl ethyl ketone, with 6.8 g of 2- (tridec-7-yl) benzimidazole-5-carboxylic acid hemisulfate as a white solid, m.p. 202 - 205 ° 0 was obtained.

The 4-amino-3- (2-hexyloetanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 20.7 g of 5'-hiaminobenzoic acid in 165 ml of dimethylformamide containing 56.5 ml of triethylamine was treated dropwise with 67 g of 2-hexyl-octanoyl chloride while stirring in the same manner as described in Example XXXIII. A waxy solid was collected, which was dissolved in 500 ml of diethyl ether, the ether solution was dried and evaporated to give a reddish brown oil. This oil was extracted with hot methanol for 5 hours using a continuously operating extractor. The methanol solution was evaporated on a rotary evaporator to give a brown solid, which was recrystallized from acetone to obtain 15.2 g of 4-amino-3- (2-hexyloctanamido) benzoic acid in the form of a white solid, which melted at a temperature of 219-222 ° C.

Example XIII Compound BB

A solution of 24.7 g of 4-amino-3- (2-ethyl-dodecane-amido) benzoic acid in 125 ml of methyl ethyl ketone was treated with 29 g of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was stirred and refluxed for 12 hours at 800 3 6 27 44 and then treated in the same manner as described in Example XLI to give a white solid which was recrystallized from a mixture of 200 ml of acetone and 200 ml of water. -5, yielding 14.2 g of (HS) -2- (tridec-3-yl) benzimidazole 5-earboxylic acid hemisulfate in the form of a white solid, mp 185-187 ° C.

The 4-amino-3- (2-ethyldodecanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 22.8 g of 3,4-diaminobenzoic acid in 200 ml of dimethylformamide containing 22.7 g of triethylamine was treated dropwise with stirring with 37 g of 2-ethyldode-15-canoyl chloride in a manner similar to that described in Example XLI, whereby a solid, which was recrystallized from ethyl acetate under charcoal treatment to yield 22.2 g of 4-amino-3- (2-etbyldodecane-amido) benzoic acid as a white solid, which was obtained at a temperature of 188-191 ° C melted.

Example XLIII Compound PD

A solution of 9.8 g of 4-amino-3- (2-butyl-decanamido) -benzoic acid in 50 µl of methyl ethyl ketone was treated in the same manner as described in Example XLI with 11.5 µl of concentrated hydrochloric acid at a concentration of 36.5% (w / v) to give 4.7 g of (HS) -2- (tridec-5-yl) benzimidazole-5-carboxylic acid hemisulfate in the form of a white solid, which is kept at a temperature mp 161-164 ° C.

The 4-amino-3- (2-butyl decanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 15.8 g of 3,4-diaminobenzoic acid in 130 ml of dimethylformamide containing 43.4 g of triethylamine was treated dropwise with stirring in the same manner as described in Example XLI with 5.4 g of 2-butyl decanoyl chloride to obtain 9.8 g of 4-amino-3- (2-butyldecan-amido) benzoic acid as a white solid, which melted at a temperature of 178-182 ° C. Example XLIV 40 Connection EE

8003627 45

A mixture of 10 g of 2- (n.pentadecyl) benzimidazole-5-carbonyl chloride hydrochloride in 250 ml of ethanol was stirred and refluxed for 2 hours.

The mixture was cooled to room temperature, then the solid was collected and washed with 50 ml of ethanol and then twice with 50 ml of diethyl ether each time.

The solid was dissolved in 25 ml of boiling ethanol and the solution was treated with 0.5 ml of concentrated hydrochloric acid at a concentration of 56.5% (w / v). The solution was cooled to a temperature of 0 ° C, after which the resulting solid was collected, whereby 7 * 8 g of the hydrochloride of the ethyl ester of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid hydrochloride in the form of a white solid, which melted at a temperature of 207 * 213 ° C.

The 2- (n.pentadeeyl) -benzimidazole-5-carbonyl chloride used as starting material was prepared in the following manner:

To a solution of 250 ml of thionyl chloride, 32 g of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid monohydrate were added in portions under stirring at room temperature. The mixture was stirred and refluxed for 2 hours, then the thionyl chloride was removed in vacuo to give 33 g of 2- (n-pentadecyl) benzimidazole-5-25 carboxylic acid hydrochloride as a cream solid which melted under decomposition at a temperature of 286-288 ° C.

Example XLV Connection UT

A mixture of 10 g according to the procedure of 2- (n.pentadecyl) benzimidazole-5-carbonyl chloride hydrochloride prepared in example ΣΕΐν in 300 ml n.hexanol was treated in the same manner as described in example XLIV, whereby 9 * 8 g of the hydrochloride of the hexyl ester of 2-35 (n.pentadeeyl) benzimidazole-5-carboxylic acid in the form of a white solid were obtained, which melted at a temperature of 166-170 ° C.

Example XLVI Connection; GO

A mixture of 10 g of 2- (n.pentadecyl) benzimidazole-5-carbonyl chloride hydrochloride prepared in accordance with the procedure 800 3 6 27 46 of Example XLIV in 300 ml of n-butanol was treated in the same manner as described in Example XLTV to give 8.9 g of the hydrochloride of the butyl ester of 5 2- (n.pentadeeyl) benzimidazole-5-earbon salt in the form of a white solid, which melted at a temperature of 170-174 ° C.

Example ZLYII Connection BH

A mixture of 10 g of 2- (n.pentadecyl) benzimidazole-5-carbonyl chloride hydrochloride prepared according to the procedure of Example XLIV in 300 ml of isopropanol was treated in the same manner as described in Example XLIY, whereby 6.4 g of the hydrochloride of the isopropyl-15 ester of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid as a white solid, mp 184-186 ° C.

Example ZLVIII Compound JJ

A mixture of 13.7 g of the sodium salt of 2- (n-pentadecyl) -benzimidazole-5-carboxylic acid and 5 g of chloromethyl ester of pivalic acid prepared in 35 ml of heramethylphosphoramide was prepared for 3 hours at a temperature of Heated at 50 ° C. After cooling, the mixture was poured into 250 ml of water and extracted three times with 75 ml of diethyl ether each time. The organic phase was washed three times with 100 ml of water each time and dried over magnesium sulfate. The organic solvent was removed in vacuo to give a brown oil, which was chromatographed on 400g of Kelsel gel using chloroform as the eluent. 100 ml fractions were collected, with fractions 14 to 22 yielding a colorless oil on evaporation of the solvent. The oil was dissolved in diethyl ether and treated with a saturated hydrochloric acid solution in ethanol until the pH of the mixture was 1. The white solid was collected and washed three times with 100 ml of diethyl ether each time to give 10 g of the hydrochloride of the pivaloyloxymethyl ester of 2-n-pentadecylbenzimida-40 sole-5-carboxylic acid as a white 8003627 47

dust, which melted at a temperature of 165 - 175 ° C. Yoorbeeld XIIX Connection KK

Over the course of 15 minutes, 12 g of a 50% sodium hydride dispersion in oil was added with stirring to a mixture of 100 g of glycerol and 100 ml of dry tetrahydrofuran.

After the addition was complete, the mixture was stirred vigorously for a further 50 minutes, after which 20 g of the 10 2- (n.pentadecyl) benzimidazole-5-carboxylic acid hydrochloride prepared in the course of 5 I became a mixture over the course of 5 minutes. added * The mixture was stirred vigorously for 2 hours and then left overnight. The brown mixture was poured into 800 ml of water containing 9.4 g of glacial acetic acid, after which the oily product was extracted twice with 400 ml of chloroform. The combined extracts were washed twice with 500 ml of water each time and dried over sodium sulfate. The solvent was evaporated in vacuo, the residual oil was dissolved in 500 ml of toluene, and the solution was filtered and cooled to form a brown gummy material. The toluene was removed by decantation, 100 ml of diethyl ether were added and the mixture was heated until the gummy material was dissolved. By rapidly cooling to a temperature of -50 ° 0, a white solid precipitated, which was collected and washed twice with 100 ml of diethyl ether each time, yielding 6.6 g of 2.5- <3.ihydroxyprop ~ 1 ethyl ester of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid in the form of a white solid was obtained, which melted at a temperature of from 109 to 112 ° C.

Yoorbeeld L Yerbinding B

In 100 ml of diglyme containing 10 ml of concentrated hydrochloric acid at a concentration of 56.5% (w / v), 10 g of 5 ml of aminobthoic acid and 9 g of palmitic acid were refluxed for 10 hours. The cooled mixture was poured into 500 ml of water and the resulting solid material was collected. The solid material was washed twice with 100 ml of 2N hydrochloric acid each time and then 40 times with 100 ml of boiling petroleum-800 3 6 27 48 ether each time (boiling range of 4G - 60 ° G). The solid was recrystallized from ethanol under charcoal treatment to give 50 mg of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid hydrochloride, which melted under decomposition at a temperature of 295-300 ° C. .

Example LI Connection B

A mixture was prepared by mixing 1.88 g of 3 »4-diaminobenzoic acid monohydrochloride and 2.74 g of n-hexadecanoyl chloride in-nig, after which the resulting mixture was heated at 130 ° C for 2 hours. heated. The mixture was then cooled to room temperature and triturated with 100 ml of water to give 0.1 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid hydrochloride, which was at a temperature of 298-300 ° C under decomposition melted.

Example Lil Connection B

A solution of 9 g of 3 »4- <diaminobenzoic acid in 190 ml of dimethylformamide was treated with 16.3 S n-hexadecanoyl chloride over 30 minutes with stirring. The mixture was then refluxed for 6 hours and poured into 100 ml of water. The solid material was collected and suspended in 100 ml of 2 n hydrochloric acid. The solid material was collected again and washed with water to give 3 g of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid hydrochloride, which melted under decomposition at a temperature of 295-300 ° C.

Example LUI 30 Connection B

A solution of 390 g of the 2- (n-pentadecyl) benzimidazole-5-carboxylic acid monohydrate prepared according to the procedure of Example XII was mixed in a mixture of 2000 ml of acetone and 1000 ml of water to a temperature of 60 ° C. heated and then treated with a solution of 40 g of sodium hydroxide in 50 ml of water. The mixture was stirred and refluxed for one hour and then cooled to a temperature of 0 ° C. The solid material was collected and recrystallized from a mixture of 1000 ml ace-40 ton and 500 ml water to give 345 g of the 8003627 49 sodium salt Tan 2- (n.pentadecyl) benzimidazole-5-carboxylic acid in the form of the monohydrate which melted under decomposition at a temperature above 300 ° C.

Example LIT 5 Connection LL

A solution of 17.6 g of 2,3-bis (n-tetradeaneamido) -benzoic acid in 250 ml of methyl ethyl ketone was treated with 25 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The mixture was refluxed for 5 hours, then cooled and treated in the same manner as described in Example ZV, yielding 6.5 g of 2- (n-tridecyl) benzimidazole-4-carboxylic acid hydrochloride in the form of a yellow-brown solid, which melted at a temperature of 192 DEG-200 DEG.

The 2,3-bis (n-tetradecanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 20 g of 2,3-diaminobenzoic acid in 200 ml of dimethylformamide containing 39.9 g of triethylamine was treated with 65.0 g of n-tetradecanoyl chloride. The n-tetra-deeanoyl chloride was added at such a rate that the temperature of the reaction mixture rose from room temperature to 45-50 ° C. The mixture was then stirred for an additional 2 hours, then left to stand at room temperature overnight. 20 ml of methanol were added to the mixture, the resulting mixture was stirred for 20 minutes and then treated with concentrated hydrochloric acid at a concentration of 36.5% (w / v) until a pH of 2 was reached . The resulting mixture was poured into 1000 ml of water, the resulting black solid was collected, which was washed twice with 500 ml of water each and then with 500 ml of hot light petroleum (boiling range 60 - 80 ° C) and finally from ethanol recrystallized under charcoal treatment to give 17.7 g of 2,3-bis (n-tetradecanamido) benzoic acid as a yellow-brown solid, which melted at a temperature of 150-158 ° C.

Example LV Connection B

A suspension of 2.0 g of 3-amino-4- (hexadecanamido) -40 benzoic acid in 60 ml of methyl ethyl ketone containing 1.5 ml of hydrochloric acid 8003627 50 at a concentration of 36.5% (w / v) was added refluxed for 5 hours. The resulting solid was collected, washed with boiling petroleum ether (boiling range 60 - 80 ° C) and recrystallized from ethanol 5 to give 2.0 g of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid hydrochloride obtained in the form of a white solid which melted a temperature of 288-290 ° C with decomposition.

The 3- & miuo-4 ~ (n.hexa-10 decanamido) benzoic acid used as starting material was prepared on the following wedge:

A solution of 22 g of 3-nitro-4- (n.hexadecanamido) -benzoic acid in 500 ml of n-butanol was hydrogenated by the presence of 2.5 g of 5% (w / w) palladium over 6 hours shake charcoal at a temperature of 70 ° C under atmospheric pressure. The mixture was filtered while hot and the filtrate was allowed to cool. The solid obtained was collected and washed with 100 ml of ethanol to obtain 11.6 g of 3-amino-4- (hexadecanamino-do) benzoic acid in the form of a cream-colored solid 20, m.p. 160-162 °. .

The 3-nitro-4- (n.hexa-decane amido) benzoic acid used as starting material was prepared in the following manner:

A solution of 18.2 g of 4-amino-3-nitrobenzoic acid and 33.0 g of hexadecanoyl chloride in 100 ml of dry dimethylformamide was heated to a temperature of 97 ° C for 90 minutes. The solution was cooled and then poured onto 300 g of crushed ice. The solid obtained was collected, washed three times with 100 ml of water each time, dried and recrystallized from a mixture of acetone and water in a mixing ratio of 5 · 1 and under charcoal treatment, whereby 3 7,7 g of 3- nitro-4- (n-hexadecane-amido) benzoic acid in the form of a light yellow solid, mp 153 DEG-154 DEG.

Example LVI 35 Connection MM

A suspension of 9> 6 g of the 2- (n-pentadecyl) benzimidazole-5-carboxylic acid hydrochloride prepared according to the procedure of Example IV in 75 ml of thionyl chloride was refluxed for 2 hours. The excess thionyl chloride was removed by distillation in vacuo 8003627 51 to leave a brown solid. The solid material was triturated with 200 ml of toluene and the toluene was evaporated in vacuo. The residue was added to a solution of 3 * 64 ml triethylamine in 250 ml tert-bu-5-tanol and the mixture was refluxed for hours. After cooling, the excess tert.-butanol was evaporated in vacuo and the residue was suspended in 150 ml of ethyl acetate. The suspension was refluxed for 10 minutes and then filtered for 10 bites. The filtrate was cooled and the solid material obtained was collected. The solid material was washed twice with 50 ml of ethanol each and then twice with 50 ml of dietbylether each time and dried, taking 5 * 5 S of the hydrochloride of the tertiary butyl ester of 2- (n-pentadecyl) Benzimidazole-5-carboxylic acid as an off-white solid was obtained, which melted at a temperature of 165-168 ° C.

Example LVII Connection NN

A mixture of 15 g of 2- (n.pentadecyl) benzimidazole-5-carbonyl chloride prepared in accordance with the procedure of Example X1IV in 300 ml of allyl alcohol was treated in the same manner as described in Example XLIV, with 10.4 g of the hydrochloride of the allyl ester of 2- (n.pen-25 tadecyl) benzimidazole-5-carboxylic acid in the form of a white solid, which melted at a temperature of 198 DEG-200 DEG.

Example LVIII Compound M

To a solution of 9 * 8 g of 3 * 4-diaminobenzoic acid methyl ester in 200 ml of methanol was added a solution of 23 * 6 g of eupriacetate in 300 ml of water, followed by a solution of 10 g of n.decanal in 40 ml methanol. The mixture was refluxed for one hour, then allowed to cool and the purple solid collected. The solid was dissolved in 600 ml of 75% (v / v) aqueous methanol and gaseous hydrogen sulfide was introduced into the solution until no more copper sulfide precipitated. The copper sulfide was collected, after which 40 after the filtrate was concentrated, a red oil 8003627 52 was obtained. The oil was dissolved in 100 ml of ethanol containing 15 ml of concentrated hydrochloric acid at a concentration of 36.5% w / v), which solution was refluxed for 4 hours. After cooling, the gray-green solid was collected and dissolved in 100 ml of tetrahydrofuran containing 5 ml of aqueous ammonia at a concentration of 33% (w / w). The solution was diluted with 400 ml of water and the pink solid collected. The solid material was chromatographed on silica using a mixture of chloroform and methanol at a mixing ratio of 25 * 1 (v / v) as the eluent. The isolated material was dissolved in 25 ml of methyl ethyl ketone, after which 2.3 ml of concentrated hydrochloric acid with a concentration of 36.5% (Cw / v) was added with stirring. The solid obtained was collected and washed twice with 50 ml of diethyl ether to obtain 5-3 g of the hydrochloride of the methyl ester of 2- (n.nonyl) benzimidazole-5-carboxylic acid as a white solid, which melted under decomposition at a temperature of 234 - 237 ° C.

Example LIX Connection PP

Over a period of 20 minutes, 120 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v) were added to a reflux solution of 165> 3 g of crude 2,3-bis (n-hexadecanamido) benzoic acid in 1200 ml of methyl ethyl ketone were added and the mixture was refluxed for an additional 6 hours. The resulting solution was cooled and the solvent was removed by distillation in vacuo. After the residue was triturated with 200 ml of water, the granular solid was collected and washed twice with 500 ml of hot petroleum ether each time (boiling range 60-80 ° C) and then with 500 ml diethyl ether. The solid was dissolved in 250 ml of boiling methyl ethyl-35 ketone, the solution was treated with charcoal and filtered off hot. The filtrate was evaporated in vacuo to leave a yellow-brown solid. The solid material was chromatographed on silica using a mixture of chloroform 40 and methanol in a mixing ratio of 9 µl (v / v) as 8003627 53 eluent. The product obtained was recrystallized from ethyl acetate to give 5 * 4 g of 2- (n-pentadecyl) benzimidazole-4-carboxylic acid as a yellow-brown solid, which melted at a temperature of 160-166 ° G.

The 2,3-bis (n-hexadeeamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 40 g of 2,3-disminobenzoic acid in 600 ml of dimethylformamide containing 79.7 S (109.5 ml) of trietbylamine was treated with 144.5 g of n-hexadecanoyl chloride.

The n-hexadecanoyl chloride was added at such a rate that the temperature of the reaction mixture rose from room temperature to 45-50 ° C. The mixture was then stirred for an additional 3 hours and then left to stand at room temperature overnight. The mixture was added to 1200 ml of water containing 50 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v), the resulting solid material was collected and washed with 1200 ml of water. The solid material was stirred with 4000 ml hot water at 65 ° 0 for 30 minutes and collected and then dried in vacuo at a temperature of 70 ° C. The product obtained: the 2,3-bis (n-hexadecanamido) benzoic acid was used in the above procedure without further purification.

Reference Example 1 A solution of 152 g of 3-diamino-benzoic acid in 1500 ml of dimethylformamide containing 303 g of triethylamine was treated dropwise with 549.0 g of n-hexadecanoyl chloride over 1.5 hours with stirring. The n-hexa-decanoyl chloride was added at a rate such that the temperature of the reaction mixture rose from initial room temperature to 35-40 ° C. The mixture was then stirred for an additional 2 hours at room temperature and then poured into 10 liters of hot water at a temperature of 70 ° C containing 150 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The solid material formed was collected to yield 600 g of crude 3 »4-bis (n.hexadecanamido) benzoic acid in the form of a yellow-brown solid, which melted at a temperature of 180-190 ° C and was suitable for use in the rule of 40 example XV.

800 36 27

Reference example 2

By essentially following the procedure of Example ΧΧΧΥΙΙΙ for the preparation of 4-amino-3- (n.nonadecanamido) benzoic acid but replacing the n.nonadecanoyl chloride with n-octanoyl chloride, the 4-amino-3- ( n.oc-taanamido) benzoic acid prepared in the form of an off-white solid, which melted at a temperature of 202 DEG-203 DEG C. after recrystallization from methanol.

Reference example 5

By essentially the prescription of Example XXXVIII

to follow the preparation of 4-amino-3- (n.nonadecanamido) benzoic acid but replacing the n.nonadecanoyl chloride with n.dodecanoyl chloride, the 4-amino-3- (n.dodecanamido) benzoic acid was prepared in the form of a white solid with a melting point of 183-185 ° 0. Reference example 4

By essentially following the procedure of Example XXXVIII for the preparation of 4-amino-3- (n.nonadecaanajaido) benzoic acid but thereby replacing the n.nonadecanoyl chloride with n-octadecanoyl chloride, the 4-amino-3- (n.octadecaanamido) benzoic acid prepared in the form of a light brown solid, which melted at 185-187 ° C after recrystallization from methyl ethyl ketone.

Reference Example 5 A solution of 83.1 g of methyl ester of 3,4-diaminobenzoic acid in 900 ml of dry dimethylformamide containing 50.8 g of triethylamine was treated dropwise with 81.3 g of n-octanoyl chloride over 30 minutes, while keeping the temperature between 5 and 8 ° C. The mixture was stirred for an additional 2 hours. The solid material was removed by filtration and the filtrate was poured into 8000 ml of water. The solid formed was collected and recrystallized twice from methanol to give 65.5 S methyl ester of ^-amino-3- (n-octanamido) benzoic acid 35 - as a white solid, m.p. 120 ° C. obtained.

Reference example 6

By essentially following the procedure of Reference Example 5 for the preparation of the methyl ester of 4-amino-40 3- (n.utanamido) benzoic acid but replacing the 800 3 8 27 55 n-octanoyl chloride with n-dodecanoyl chloride, the methyl ester Tan 4-amino-3 (n.dodecanamido) benzoic acid in the form of Tan, produced a Taalwitte Taste substance, which melted at a temperature of Tan 102 -5 1: 5 ° 0 after recrystallization from methanol.

Reference example 7

By Tolging substantially the same procedure as described in Reference Example 5 for the preparation of the methyl ester of 4-amino-3 - (- U.octaanamido) benzoic acid, but replacing the n-octanoyl chloride with n.tri- decanoyl chloride, the methyl ester of 4-amino-3- (n.tri-decanamido) benzoic acid was prepared in the Torm Tan a light brown solid, which melted at 101 DEG-104 DEG after recrystallization from methanol.

15 Reference example 8

By Tolgen essentially the same procedure as described in Reference Example 5 for the preparation of the methyl ester Tan 4-amino-3- (n.octaanamido) benzoic acid but replacing the n.octanoyl chloride with n.te-20 tradecanoyl chloride, the methyl ester of 4-amino-3- (n-te-tradecanamido) benzoic acid in the form of a light brown solid, which melted at 108-109 ° C after recrystallization from methanol.

Reference Example 9 By essentially following the procedure described in Example 5 for the preparation of the methyl ester of 4-amino-3- (n.octaanamido) benzoic acid but replacing the n-octanoyl chloride with n-hexadecanoyl chloride, the methyl ester of 4-amino-3- (n, hexadecanamido) benzoic acid in the form of a white solid, which melted at a temperature of 109-110 ° C after recrystallization from methanol,

Reference example 10

A solution of 5 g of methyl ester of 3,4-diamino-35 benzoic acid in 50 ml of dry dimethylformamide containing 6.1 g of triethylamine was treated dropwise over 5 minutes with stirring with a solution of 16.54 g of hexadecanoyl chloride in 40 ml of dry dimethylformamide. The temperature was allowed to rise from 20 ° C to 50 ° C. The mixture 40 was stirred for an additional 3 hours. The suspension obtained ft Ω Ω 3? 7 56 was poured into 800 ml of water containing 10 ml of hydrochloric acid with a concentration of Tan 36.5% (w / v). The solid formed was collected and recrystallized from a mixture of chloroform and acetone in a mixing ratio of 1: 1, whereby 12.1 g of the methyl ester of 3'-4-bis (n.hes: adecaanamido) benzoic acid in the a white solid with a melting point of 129-132 ° 0 was obtained, which material was identical to the starting material used in Example XVI.

10 Lifting example 11

Following essentially the same procedure as described in Reference Example 10 for the preparation of the methyl ester of 3 * 4-bis (n.hexadecaanamido) benzoic acid but replacing the n.hexadecanoyl chloride with 15 n.octanoyl chloride, the methyl ester of 3j4- bis (n.oc-taanamido) benzoic acid in the form of a white solid, which melted at a temperature of 145-147 ° C after recrystallization from acetone.

Reference Example 12 Following substantially the same procedure as described in Reference Example 10 for the preparation of the methyl ester of 3,4-bis (n.hexadecaanamido) benzoic acid but replacing the n.hexadecanoyl chloride with n.dodecanoyl chloride, the methyl ester of 3> 4-bis (n.do-25 decanamido) benzoic acid in the form of an off-white solid, which melted at a temperature of 129-131 ° C after recrystallization from acetone.

Reference example 13

By substantially the same prescription as described 30 ia. Reference Example 10 for the preparation of the methyl ester of 3> 4-bis (n.hexadecanamido) benzoic acid but replacing the n.hexadecanoyl chloride with n.tridecanoyl chloride, the methyl ester of 3 »4-bis (n.tri-decane amido) benzoic acid in the form of a white solid, which melted at a temperature of 132-134 ° C after recrystallization from acetone.

Reference example 14

By following essentially the same procedure as described in Reference Example 10 for the preparation of the methyl 40-ester of 3,4-bis (n.hexadecaanamido) benzoic acid 800 36 27 57 but replacing the n-hexadecanoyl chloride with n-tetradecanoyl chloride. the methyl ester of 3,4-bis (n-tetradeaneamido) benzoic acid in the form of a white solid, which melted at 132-133 ° C after recrystallization from acetone.

Reference example 15

By following essentially the same procedure as described in Reference Example 10 for the preparation of the methyl ester of 3 * 4 ™ bis (n.hexadecaanamido) benzoic acid 10 but replacing the n.hexadecanoyl chloride with n.octadecanoyl chloride, the methyl ester of 3 > 4-bis (n.octadecaanamido) benzoic acid in the form of a white solid, which, after recrystallization from a mixture of acetone and methanol in a mixing ratio of 1: 1, had an H5 melting point of 120 ° C.

Reference example 16

According to this procedure, 12.1 g of 3-amiao-4- (n.oc-taanamido) benzoic acid in 200 ml of methanol were treated with ether diazomethane until conversion was complete (as shown by thin layer chromatography on silica under use of methanol: chloroform: glacial acetic acid: 10: 90: 0.5 as an eluent). Then 0.2 ml acetic acid was added and the reaction mixture was concentrated under reduced pressure. The resulting solid material was recrystallized from ethyl acetate to give 9 µg of methyl ester of 3-amino-4- (n-octanamido) benzoic acid as a cream-colored solid, which was at a temperature of 128-131 ° C melted.

Reference Example 17 According to this protocol, 25 g of 3-nitro-4- (n.ocotaanamido) benzoic acid as a solution in 500 ml of ethanol at a temperature of 50 ° C were hydrogenated for 3 hours in the presence of 2.5 g of 5 shake percentages (w / w) palladium-on-charcoal at a temperature of 50 ° C and under atmospheric pressure. The mixture was filtered while hot, and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and water at a mixing ratio of 1: 1, whereby 8 g of 3-amino-4- (n.octaanamido) benzoic acid as a yellow solid 40, mp 155-156 °. 0 was obtained.

8003627

The 3-nitro-4- (n.oc-taanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 18.2 g of 4-amino-4-nitrobenzoic acid and 19.4 g of n-octanoyl chloride in 100 ml of dry dimethylformamide 5 was heated to a temperature of 97 ° C for 90 minutes. The solution was cooled and poured onto 300 g of ice. The solid material formed was collected and washed three times with 100 ml of water each time, dried and recrystallized from a mixture of methanol and water in a mixture ratio of 10: 8: 1 with charcoal treatment, whereby 22 g of 3-nitro-4- (n acetanamido) benzoic acid in the form of a pale yellow solid with a melting point of 153 DEG-154 DEG.

Reference Example 18 15 According to this procedure, 21 g of 3-nitro-4- (n.dodecaneamido) benzoic acid as a solution in 500 ml of ethyl acetate hydrogenated by palladium-op in the presence of 2.5 g of 5% w / w. - shake hot coal at a temperature of 50 ° C and under atmospheric pressure. The resulting mixture was filtered off hot, yielding a cream-colored solid after cooling. This product was recrystallized from methanol, yielding 7 * 4 g of 3-smiao-4- (n.dodeanamido) benzoic acid as a beige solid, mp 158-160 ° G.

25 Reference Example 19

By following essentially the same procedure as described in Reference Example 5 for the preparation of the methyl ester of 4-amino-3- (n.octanamido) benzoic acid but replacing the n-octanoyl chloride with n.de-30 canoyl chloride, the methyl ester of 4-amino-3- (n-decano-amido) benzoic acid in the form of a white solid, which melted at a temperature of 96-100 ° C. Reference example 20

Following substantially the same procedure as described in Reference Example 10 for the preparation of the methyl ester of 3> 4-bis- (n.hexadecaanamido) benzoic acid but replacing the n.hexadecanoyl chloride with n.decanoyl chloride, the methyl ester of 3 * 4-bis (n.de-caanamido) benzoic acid in the form of a white solid 40 which, after recrystallization from ethanol, melted at a temperature of 139-141 ° G,

Reference example 21

A solution of 10 g of 3,4-diaminobenzoic acid in 100 ml of dry dimethylformamide, containing 28 g of potassium carbonate, was treated dropwise with stirring over a period of 5 minutes with a solution of 33 µg of n.dodecanoyl chloride in 30 ml of dry dimethylformamide. The temperature was then allowed to rise from 20 ° C to 50 ° C. The mixture was stirred for an additional 3 hours. The suspension obtained was filtered, and the filtrate was poured into 700 ml of water containing 10 ml of hydrochloric acid at a concentration of 36.5% (w / v). The solid formed was collected and recrystallized from ice-vinegar, then the product was washed with water and methyl ethyl ketone was recrystallized to yield 12.5 g of 3,4-bis (n-dodecanamido) benzoic acid in the form of a white solid. a melting point of 195 - 197 ° C was obtained.

Reference example 22

By following essentially the same procedure as described in Reference Example 21 for the preparation of 3,4-bis (n.dodecaanamido) benzoic acid but replacing the n.dodecanoyl chloride with n.hexadeeanoyl chloride and the potassium carbonate with sodium carbonate, 4-bis (n-hexadecanamido) benzoic acid in the form of a white solid, which melted at a temperature of from 198 to 202 ° C after successive recrystallization from glacial acetic acid and methyl ethyl ketone.

Reference example 25

By following essentially the same procedure as described in Reference Example 21 for the preparation of 3,4-bis (n-dodecanamido) benzoic acid, but thereby replacing the n-dodecanoyl chloride with n-octanoyl chloride, the 3,4-bis (n. octane amido) benzoic acid in the form of a white solid, which melted at a temperature of 195 DEG-197 DEG C. after successive recrystallization from glacial acetic acid and methyl ethyl ketone.

Reference example 24

By following essentially the same procedure as described in Reference Example 21 for the preparation of 3,4-bis 40 (n.dodecaanamido) benzoic acid, but with 800 3 6 27

bU

Replacing n.dodecanoyl chloride with n.tetradecanoyl chloride, the 3,4-bis (n.tetradecanamido) benzoic acid was prepared in the form of a white solid, which after successive recrystallization from glacial acetic acid and methyl ethyl ketone at a temperature of 201 - 206 ° C melted. Reference example 25

According to this protocol, 21 g of methyl ester of 3-nitro-4- (n.dodecanamido) benzoic acid as a solution in 500 ml of warm ethyl acetate (50-55 ° C) were hydrogenated for 2 hours in the presence of 2.0 g Shake 5-parts (w / w) palladium-on-charcoal at a temperature of 60 ° C and under atmospheric pressure. The mixture was filtered while hot and the filtrate was allowed to cool. The solid was collected to give 14.1 g of methyl 15-ester of 3-amino-4- (n.dodecanamido) benzoic acid as a white solid, which melted at a temperature of 134-137 ° G .

The methyl ester of 3-nitro-4- (n.dodecanamido) benzoic acid used as starting material was prepared in the following manner:

For 21/2 hours, 19.6 g of methyl ester of 3-nitro-4-aminobenzoic acid and 23 g of n-dodecanoyl chloride in 100 ml of dimethylformamide were heated to a temperature of 97 ° 0 and shaken occasionally. The resulting solution was poured onto 300 g of crushed ice, the solid material was collected and recrystallized from a mixture of methanol and chloroform in a mixing ratio of 5: 1, whereby 31 g of methyl ester of 3-nitro-4- (n. dodecanamido) benzoic acid in the form of a yellow solid with a melting point of 78-80 ° C.

The methyl ester of 3-Qitro-4-aminobenzoic acid was prepared in the following manner:

70 g of 3-aitro-4-aminobenzoic acid were added to a solution of anhydrous hydrogen chloride in methanol prepared from 78 g of acetyl chloride and 300 ml of dry methanol. The resulting mixture was refluxed for 10 hours and cooled in ice, after which the solid was collected, melting 62 g of methyl ester of 3-nitro-4-aminobenzoic acid as a yellow solid with 40 ^ i ^ v ^ n ^ 3-195 ° 0 was obtained.

61

Reference example 26

By following essentially the same procedure as described in Reference Example 25 for the preparation of the methyl ester of 3-amino-4- (n.dodecanamido) benzoic acid 5 but thereby the methyl ester of 3-nitro-4- (n.dodecanamido) replacing benzoic acid with the methyl ester of 3-nitro-4- (n.hexadecanamido) benzoic acid became the methyl ester of 3-amino-4- (n.hexadecanamido) benzoic acid in the form of a white solid, melting point 155 - 137 ° C.

10 Reference example 27

By following essentially the same procedure as described in Reference Example 25 for the preparation of the methyl ester of 3-amino-4- (n.dodecanamido) benzoic acid but thereby the methyl ester of 3-nitro-4- (n.dodecanamido) -15 benzoic acid replaced by the methyl ester of 3-nitro-4- (n-decanamido) benzoic acid, the methyl ester of 3-amino-4- (n-decanamido) benzoic acid as a white solid, melting point 131-133 ° C prepared. Reference Example 28 To a solution of 8.4 g of 3,4-diaminobenzoic acid in 100 ml of dry dimethylformamide containing 15-27 g of potassium carbonate, a solution was added dropwise with stirring at a temperature of 0 - 5 ° C over 30 minutes. of 15.17 g of n-hexadecanoyl chloride in 30 ml of dry dimethylformamide-25 mide. The mixture was stirred for a further 2 hours at a temperature of 0-5 ° C, after which it was allowed to warm to room temperature over a period of 30 minutes.

The solution was then poured into 700 ml of water containing 10 ml of hydrochloric acid at a concentration of 36.5 ° / w (w / 30 vol). The solid material was collected, heated to a temperature of 50 ° C with 300 ml of acetone and recrystallized from methyl ethyl ketone, yielding 9.4 g of 3- (n-hexadecane-amido) -4-aminobenzoic acid as a white solid substance with a melting point of 197-1990 was obtained.

35 Reference example 29

By following essentially the same procedure 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.decanoyl chloride 40, the 3,4-bis (n. decanamido) benzoic acid in the form of 8003627 a white solid which, after successive recrystallization from glacial acetic acid and methyl ethyl ketone, had a melting point of 194 DEG-196 DEG.

Reference Example 50 5 Following substantially the same procedure 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.tridecanoyl chloride, the 3,4- bis (n.tridecanamido) benzoic acid in the form of an off-white solid which, after successive recrystallization from glacial acetic acid and methyl ethyl ketone, had a melting point of 192-194 ° C.

Reference example 31

By following essentially the same procedure as described in Reference Example 21 for the preparation of 3 »4-bis (n.dodecaanamido) benzoic acid, but thereby replacing the n.dodecanoyl chloride with n.octadecanoyl chloride the 3 * 4-bis (n.octadecaanamido) benzoic acid in the form of a white solid, which melted at a temperature of 193 DEG-196 DEG C. after recrystallization from glacial acetic acid and methyl ethyl ketone.

The invention also includes within its scope pharmaceutical preparations containing at least one of the compounds of the general formula 1 and / or pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier and / or coating. In clinical use, the compounds of the invention can be administered parenterally, although they are preferably administered rectally or especially orally.

Solid preparations for oral administration include pressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds are mixed with at least one inert extenders such as starch, sucrose or lactose. The compositions may also, as is customary in practice, contain further materials other than the inert excipients, for example lubricants, such as magnesium stearate.

Liquid preparations for oral administration include 8003627 63 pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in this field, such as water and liquid paraffin. In addition to inert diluents, these compositions may contain adjuvants such as wetting and suspending agents, sweeteners, flavors, perfumes and preservatives. The compositions of the invention for oral administration also include capsules of absorbable material, such as gelatin, which contain one of the 10 active substances, whether or not in combination with extenders and / or excipients.

The compositions of the invention for parenteral administration include sterile aqueous, aqueous organic and organic solutions, suspensions and emulsions.

Examples of organic solvents or suspending media are propyle englycol, polyethylene glycol, vegetable oils, such as olive oil, injectable organic esters, such as ethyl oleate. These preparations may also contain adjuvants, such as stabilizers, preservatives, wetting, emulsifying and dispersing agents. They can be sterilized, for example, by filtration through a Baeteria filter, by incorporation of sterilizing agents into the preparations, by irradiation or by heating. They can also be prepared in the form of sterile solid preparations, which can be dissolved in sterile water or any other sterile injectable medium immediately before use.

Solid compositions for rectal administration include suppositories, which are prepared by known methods and contain one of the compounds of the formula 1 or pharmaceutically acceptable salts thereof.

The percentage of active ingredient in the compositions according to the invention can vary, however it is necessary that this percentage is such that a suitable dosage will be obtained. Of course, several unit dosage forms can be administered at about the same time. The dosage used will be determined by the treating physician and depends on the desired therapeutic effect, the mode of administration and duration of treatment, as well as the general condition of the patient. In the adult, the doses are generally between 0.1 and 50 mg / kg body weight per day when administered orally, for example as hypolipidemics and anti-atheroma agents and associated cardiovascular ailments, between 10 and 50 mg / kg body weight. per day for oral administration, in the treatment of diabetes between 5 and 40 mg / kg body weight per day for oral administration and for the treatment of arthritis and related ailments between 0.1 and 10 mg / kg body weight for oral administration.

The following example illustrates the pharmaceutical preparations of the invention.

Example LZ

Gelatin capsules of size no. 2, each containing sodium salt of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg, were prepared by the usual method.

800 3 6 27

Claims (23)

65 1. Benzimidazole derivative characterized by A the general formula 1, wherein R represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, which may be optionally substituted by one or more of the same type of substituents belonging to the hydroxyl groups , alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, o and R represent a straight or branched alkyl group of 7 to 20 carbon A 10 atoms, the radical R 00 Cr being bonded at position 4 or 5 of the benzimidazole ring system which benzimidazole derivative may optionally be in the form of a salt, in particular a pharmaceutically acceptable salt. Benzimidazole derivative according to claim 1, g e - A characterized by the formula 1, wherein R represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. Benzimidazole derivative according to claim 1, g e - A 20, characterized by the formula 1, wherein R represents a hydrogen atom, Benzimidazole derivative according to claim 1, g e - A characterized by the formula 1, wherein R represents a methyl group. Benzimidazole derivative according to claim 1, characterized by the formula 1, wherein R represents an n-butyl, 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxy-methyl group. 6. Benzimidazole derivative according to one or more of claims 1 to 5, characterized by the formula 1, 2 in which R represents a straight alkyl group with 7 to 20 carbon atoms. Benzimidazole derivative according to one or more of claims 1 to 6, characterized by the formula 1, 35 in which R represents an alkyl group with 10 to 18 carbon atoms. Benzimidazole derivative according to one or more of claims 1 to 7, characterized by the formula 1, A in which the residue R 00C- is bound in the position 5 of the benzimidazole-40 ring system. 8003627 66 9. 2- (n.Pentadecyl) benzimidazole-5-carboxylic acid. 10. 2- (n.Undecyl) benzimidazole-5-carboxylic acid. 11. n.Butyl ester Tan 2- (n.pentadecyl) benzimidazole-5-carboxylic acid. 12, 2,3-Pibydroxyprop-1-ylester Tan 2- (n.pentadecyl) -benzimidazole-5-carboxylic acid. 13. 2- (n. Tridecyl) benzimidazole-5-carboxylic acid. 14. 2- (n.Dodecyl) benzimidazole-5-carboxylic acid. 15. (BS) -2- (Tetradec-2-yl) benzimidazole-5-carboxylic acid. 16. 2- (n.Hexadecyl) benzimidazole-5-carboxylic acid. 17. 2- (n.Octadecyl) benzimidazole-5-carboxylic acid. 18. 2- (n.H € pbadecyl) benzimidazole-5-carboxylic acid. 19. Methyl ester Tan 2- (n.heptyl) benzimidazole-5-carboxylic acid. 20. Pharmaceutically acceptable salt Tan de Terbinding According to one or more of claims 9 to 19. 21. Ethyl ester Tan 2- (n.pentadecyl) benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.undecyl) benzimidazole-5-carboxylic acid , methyl ester Tan 2- (n.tridecyl) benzimidazole-5-20 carboxylic acid, methyl ester Tan 2- (n.dodecyl) benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.decyl) benzimidazole-5-carboxylic acid, 2- ( n.decyl) benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.heptadecyl) benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.nonyl) benzimidazole-5-carboxylic acid, 25 2- (n.nonyl) benzimidazole- 5-carboxylic acid, 2- (n.heptyl) benzimidazole-5-carboxylic acid and 2- (n.tetradecyl) benzimidazole-5-carboxylic acid. 22. Pharmaceutically acceptable salt Tan a Terbinding according to claim 21, 23. 2- (n.Octyl) benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.tetradecyl) benzimidazole-5-acetic acid, methyl ester Tan 2- (n. hexadecyl) benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.eicosyl) benzimidazole-5-carboxylic acid, 2- (n.eicosyl) -benzimidazole-5-carboxylic acid, methyl ester Tan 2- (n.nonadecyl) -benzimidazole- 5-carboxylic acid, 2- (n.nonadecyl) benzimidazole-5-carboxylic acid, (BS) -2- (tridec-3-yl) benzimidazole-5-carboxylic acid, 2- (tridec-7-yl) benzimidazole-5 -carboxylic acid, (BS) -2- (tridec-5-yl) benzimidazole-5-carboxylic acid, ethyl ester Tan 2- (n.pentadecyl) benzimidazole-5-carboxylic acid, n.hexyl ester 40 Tan 2- (n.pentadecyl) hienzimidazole-5-carboxylic acid, isopropyl- 800 3 6 27 67 ester of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid, methyl ester of 2- (n.octadecyl) benzimidazole-5- carboxylic acid, pivaloyloxymethyl ester of 2- (n-pentadecyl) benzimidazole-5-carboxylic acid and 2- (n-tridecyl) benzimidazole-4-carboxylic acid. Pharmaceutical, permissible salt of a compound according to claim 23. 23. t-Butyl ester of 2- (n.pentadecyl) benzimidazole-5-carboxylic acid, allyl ester of 2- (n.pentadeeyl) benzimidazole-5-carboxylic acid, and 2- (n.pentadecyl) benzimidazole-4-carboxylic acid 10 as well as pharmaceutically acceptable salt of each of these compounds. 26. Process for preparing a benzimidazole derivative, characterized in that a benzimidazole derivative or salt thereof, as defined in claim 1, is prepared in a manner known per se. 27. Process according to claim 26, characterized in that a compound of the general formula 2, wherein R ° represents a hydrogen atom or a residue -COR 1 2 and R and R have the meaning as defined in claim 1 , subject to a ring closure. 28. A process according to claim 27, characterized in that the compound is preferably cyclized at an elevated temperature by treatment with an inorganic acid in the presence of water and an organic solvent. 29. Process according to claim 27, characterized in that a compound of the formula 2 is started from, in which R ° represents a hydrogen atom and subject the compound to the cyclization by treatment with an organic acid in water or an organic solvent, at preferably at elevated temperature. 30. Process according to claim 27, characterized in that the compound is cyclized either (a) in the absence of an organic solvent and at an elevated temperature or (b) in the presence of water and an inorganic acid and in a suitable organic solvent. 31. Process according to claim 26, characterized in that a compound of the general formula A in which R is as defined in claim 1 is reacted with a compound of the alga 2, formula 6, wherein H has the meaning defined in claim 1, and a copper (II) salt in the presence of an aqueous inert organic solvent medium at a temperature between room temperature and the temperature at which the reaction mixture is refluxed, and converts the copper salt obtained in this way into the corresponding compound of the general formula 1. 32. Process according to claim 26, characterized in that a compound of the general formula 1 is prepared in which E represents a hydrogen atom by hydrolysis of a corresponding ester of the general formula 1, in which E represents a straight or represents branched alkyl group of 1 to 6 carbon atoms, which may be optionally substituted by one or more of the same type of substituents belonging to the group of the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms or 2 alkanoyloxy groups of 2 to 2 7 carbon atoms, and E has the meaning defined in claim 1. 33. Process according to claim 26, characterized in that a compound of the general formula 1 is prepared, in which E represents a straight or branched alkyl group having 1 to 6 carbon atoms, which may be optionally substituted by one or more than one of the same type of substituents belonging to the group of the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, and E has the meaning referred to in claim 1, by esterification of a corresponding carboxylic acid of the general formula 1 , 1 2 30 wherein E represents a hydrogen atom and E has the meaning defined in claim 1. Process according to one or more of claims 26 to 33, characterized in that a benzimidazole derivative of the general formula 1 obtained according to the process is converted into a salt by known methods, in particular a pharmaceutically permissible salt thereof. Pharmaceutical composition characterized by at least one benzimidazole derivative according to one or more of claims 1 to 25 or pharmaceutically acceptable salt thereof in combination with a pharmaceutical carrier or 800 3 6 27, '69 coating. 36. Benzimidazole derivative or pharmaceutically acceptable salt thereof, characterized by the form of a dosage unit suitable for use in preventing or treating diabetes mellitus, hyperlipoproteinemic conditions, atherosclerosis and related ailments, such as angina, myocardial infarction, vascular occlusion in the cerebrum , arterial aneurysm, peripheral vascular disease, chronic pancreatitis and xanthomas as well as arthritis, immunological disease, cancer and implant rejection reactions. ** ** * 80036 27