LU82546A1 - BENZIMIDAZOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

"Y

The present invention relates to new benzimidazole derivatives useful in therapy, to processes for their preparation and to pharmaceutical compositions containing them.

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

H

in which R represents a hydrogen atom, a straight or branched chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of the same type chosen from the hydroxy group, the alkenyl groups containing from 2 to 5 carbon atoms and the alkanoyloxy groups containing from 2 to 7 carbon atoms) and R represents a straight chain or branched alkyl group, preferably a straight chain alkyl group, containing from 7 to 20 (preferably from 10 to 18) carbon atoms,,, 1 and their pharmaceutically acceptable salts. Preferably, R represents a hydrogen atom, or a methyl group, or an n-butyl, 2,3-dihydroxy-propyl-1, allyl or pivaloyloxymethyl group.

The group R 00C is attached to position 4 or, preferably, to position 5 of the benzimidazolic ring system.

It will be understood that the compounds of general formula (i)? have a tautomerism such that the hydrogen atom which is represented as located on one of the nitrogen atoms can be located on one or the other nitrogen atom and that both forms ·, * Thus described may be present in greater or lesser proportion, and are in a state of dynamic equilibrium with one another. In tautomers, positions 4 and 5 become positions 5 and 6 respectively. In addition, in some cases the / 12 r / substituents R and R contribute to optical isomerism. All of these forms are encompassed by the present invention. / J / ♦ a 2

By the term "pharmaceutically acceptable salt" is meant a salt formed by reaction with an acid or, when R represents a hydrogen atom, by reaction with a base, so that the anion (in the case of a salt acid addition) or cation 5 (in the case of a salt formed by a compound of formula (I) in which R represents a hydrogen atom) is relatively harmless> for the animal organism when using this salt at a therapeutic dose, so that the beneficial pharmacological properties of the initial compound of general formula (i) are not adversely affected by side effects attributable to said anion or cation.

Suitable acid addition salts include salts derived from mineral acids, for example hydrochlorides, hydrobromides. phosphates, sulfates and nitrates, and organic salts, for example methanesulfonates, 2-hydroxy-15 ethanesulfonates, oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, suecinates, the fumarates. maleates, methylene-bis-β-hydroxynaphtoates, gentisates and di-p-toluoyltartrates.

Among the salts formed by the compounds of general formula (I) 1 in which R represents a hydrogen atom, those which are suitable include the alkali metal salts (for example of sodium and potassium), the alkali metal salts earthy (e.g. calcium and magnesium), ammonium salts and amine salts known to be pharmaceutically acceptable, e.g. ethylenediamine, choline, diethanolamine, tri-thanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2-hydroxymethyl-1,3-propanediol and (3,4-dihydroxy phenyl) -1 isopropylamino-2 ethanol.

% It should be understood that, when in the present text 50 we are talking about the compounds of general formula (i), they are also their pharmaceutically acceptable salts, when the context allows.

The compounds of general formula (I) have useful pharmacological properties, in particular a hypolipidemic action.

35 For example, they lower the concentration of cholesterol and nj - ““ “- the development of atheromatous lesions, and in addition they reduce the proliferation of arterial smooth muscle cells which is a point of major importance for atheromatous plaques, The compounds of the general formula (I) also lower the blood glucose levels in mice suffering from diabetes mellitus. The compounds of general formula (I) also suppress lymphocyte transformation as do anti-rheumatic drugs. Thus, they are useful for the prevention or treatment of diabetes mellitus, hyperlipoproteinemic conditions, atherosclerosis, and associated conditions such as angina pectoris, myocardial infarction, cerebral vascular occlusion, aneurysm, peripheral vascular disease, recurrent pancreatitis and xanthomas, as well as arthritis, immunological diseases, cancer and transplant rejection.

I5 Among the compounds of general formula (I) which are of particular interest, mention may be made of the following compounds, their optically active forms and their salts: A. methyl 2-n-pentadecyl-5 benzimidazolecarboxylate B. acid “n- pentadecyl-2 benzimidazolecarboxylic-5 20 C, methyl n-undecyl-2 benzimidazoleearboxylate-5 D. acid n-undecyl-2 benzimidazolecarboxylic-5 methyl n-trldeeyl-2 benzimidazolecarboxylate-5, n-tridecyl-2 acid 5-methylbenzimidazolecarboxylic acid-2 methyl n-dodecyl-5 benzimidazolecarboxylate-25 H. 2-n-dodecylbenzimidazolecarboxylic acid-5 I. methyl 2-n-decylbenzimidazolecarboxylate-5 2-n-decylbenzimldazoleearboxylic acid K. methyl n-heptadecyl-2 benzimidazolecarboxylate-5 L. methyl n-heptadecyl-2 benzimidazolecarboxylic-5 30 M. methyl n-nonyl-2 benzimidazolecarboxylate-5 N. 2-n-nonyl-benzimidazolecarboxylic acid-5 O. n -methyl 2-benzimidazolecarboxylate-5 P. 2-n-heptyl-benzimidazolecarboxylic acid-5 Q. a cide n-2-tetradecyl benzimidazolecarboxylic-5 55 R. methyl n-octyl-2 benzimidazolecarboxylic-5 S. methyl n-tetradecyl-2 benzimidazolecarboxylate-5

T. methyl n-hexadecyl-2 benzimidazolecarboxylate-5 f \ L

U. 2-n-hexadecyl benzimidazolecarboxyic-5 jy * l 4 V. methyl n-eicosyl-2 benzimidazoleearboxylate-5 W. 5-n-eicosyl-2 benzimidazolecarboxylic acid 5-methyl n-nonadecyl-2 benzimidazolecarboxylate Y. 2-n-nonadecyl acid benz imidazole carboxylic-5 ,, 5 Z, 2-n-octadecyl acid benzimidazolecarboxylic-5 AA. (tetradecyl-2) -2 benzimidazolecarboxylic acid-5— (RS) EB. (tridecyl -?) - 2 benzimidazolecarboxylic acid-5—- (RS) CC. (7-tridecyl) -2 benzimidazolecarboxylic acid-5 DD. (5-tridecyl) -2 benzimidazolecarboxylic acid-5— (RS). 10 EE. methyl f-n-pentadecyl-2 benzimidazolecarboxylate-5 FF, 2-n-hexyl 6-n-pentadecyl-benzimidazolecarboxylate-5G. 2-n-butyl HH n-pentadecyl-2 benzimidazolecarboxylate-5. 2-isopropyl H-n-pentadecyl-2 benzimidazolecarboxylate-5, methyl-2-n-octadecyl benzimidazolecarboxylate-5 JJ 2-pivaloyloxymethyl-2-benzimidazolecarboxylate propyle-1 LL. 2-n-tridecyl benzimidazolecarboxylic acid-4MM, 2-tert-butyl benzimidazolecarboxylate-5-n-pentadecyl-NN. n-pentadecyl-2 benzimidazoleearboxylate-5 of allyl 20 and PP. n-pentadecyl-2 benzimidazolecarboxylic acid ^

The letters A to PP have been assigned to these compounds for easy reference in the following description, for example in the tables. The properties of the compounds of general formula (I) are demonstrated by the following tests:

Hypolipidemic action in rats

Male Wistar rats each weighing between 120 and 150 g are caged in groups of eight and fed with powdered food for 10 days. During the last 7 days of this period, the test compound is administered orally by mixing it with food and allowing the animals to eat normally. Food consumption is measured on day 9 for each group. y

55 At noon on day 10, the animals are sacrificed by inhalation D

carbon dioxide from carbon dioxide snow. We remove a éehart- /.

b% 5 tillon of blood per cardiac puncture and the serum cholesterol and the serum triglycerides are analyzed by means of a self-analyzer.

Control groups (receiving only the normal diet, without medication) are included in each test.

The percentage reduction in the concentration of serum cholesterol and serum triglycerides is calculated by comparison with the simultaneous controls, for each concentration of the compound to be tested.

The results obtained are shown in Table I below. 10 TABLE I

Composed! Form Dose% Change in% in the serum weight in compared to the controls Cholesterol diet Triglycerides A HCl salt 0.2 +7 -1 15 B HCl salt 0.2 -50 -44 0.2 -50 -64 0.2 -39 -40 0.2 -22 -45 0.2 -2l -46 20 0.4 -61 -63 0.2 -55 -60 0.2 -42 -69 0.1 -31 -38 0.1 -14 -51 25 0.03 "2 -44" B monohy- 0.2 +4 +19 -. drate 0.2 -10 -9 0.4 -63 -76 B monohy- 0.2 -51 -64 30 drate 0.1 -24 -44 0.4 d salt -62 -79 / sodium 0.2 d -55 -62_y 6

V

TABLE I (continued)

Compound Form Dose # in% change in serum weight in compared to controls the diet Cholesterol Triglycerides 5 C compound 0.2 -30 -57 original 0.2 -I3 -54 D HCl salt 0.2 -354 - 60 0.2 -24 -50 0.2 -40 -80 10 E HCl salt 0.2 -23 -58 F HCl salt 0.2 -34 -53 0.2 -36 -4γ 0.03 -17 -10 G HCl salt 0.2 -18 -41 3-5 H HCl salt 0.2 -33 -52 0.03 -4 -26 I HCl salt 0.2 -3 -36 J HCl salt 0.2 -I3 -24 L HCl salt 0.2 -3 -36 20 0.2 -20 -26 N HCl salt 0.2 -14 -3 0 HCl salt 0 , 2 -4 +24 P HCl salt 0.2 -18 -K) Q HCl salt 0.2 -41 -62 25 0.2 -35 -69 0.03 -4 -20 R salt HCl 0.2 -2 -lô S HCl salt 0.2 I +9 -28 * -— ---———-—-- / T HCl salt 0.2! +6 -20 / - #

V

% 7 TABLE I (continued)

Compound 'Form Dose $ in Change in $ in the serum weight in compared to the controls the Cholesterol diet Triglycerides * 5 U HCl salt 0.2 -20 -50 V HCl salt, 0.2 +2 -32 W HCl salt 0.2 +5 -I5 X HCl salt 0.2 -10 -5 Y HCl salt 0.2 -I7 -34 10 Z HCl salt 0.2 0 -20 AA salt d 'HCl 0.2 -35 -75 EB HCl salt 0.2 -I9 -46 CC acid salt 0.2 -6 +9 HgSOjj I5 DD acid salt 0.2 4-11 -I5 H2S0 ^ EE salt HCl 0.2 -27 -47

FF HCl salt 0.2 -36 -5I

GG HCl salt 0.2 -40 -54 20 0.2 -33 -60 HH HCl salt 0.2 -5 -32 II HCl salt 0.2 -1 -20

JJ compound 0.2 -40 -5I

original 0.1 -1 -33 25 KK HCl salt 0.2 -72 -73 0.1 -28 -21 d% w t 8 TABLE I (continued)

Compound Form Dose% in Change in% in the serum weight in compared to the controls the Cholesterol Triglycerides V - HMI ··· Μ - I | I I. Il 1 ............. | l ^ ——, I - 5 NN HCl salt 0.2 -¾ -54 PP HCl salt 0.2 -38 - 11

Anti-atheromatous action in rabbits

Male New Zealand white rabbits, each weighing 2.2 k 2.8 kg, were subjected to endothelialization of the abdominal aorta and a femoral artery using a catheter. At the end of the anesthesia, they are administered k each a diet to which was added 3. $ by weight of cholesterol and a certain concentration of the compound to be tested, for 14 days. At the end of this period the animals are sacrificed and the concentration of cholesterol in the serum is determined. The femoral and aortic arteries are removed, the intima and the media are separated from the weed, and cholesterol concentrations are determined. Portions of the femoral arteries are examined histologically.

A control group, not receiving test compound k, is included in each test.

The percentage reduction in serum cholesterol and arterial cholesterol is calculated by comparison with the simultaneous controls.

The results obtained are shown in Table II below ^^ y ^ v.

"9 r-f Ο ^ W '3) β +3 * Η W Ο ο) ε ιΗ '01 Ο +3 £ = ° y

3 IS

ν · Ό '0) ^ ¾. β r a σ \ ^ σ>

Sc> Λ in ® | ,,, -ρ ο ε ε Ε 2 3) £ η - fcD '01 C m “ί £ 3 Ο £ g '. Femoral artery without de-endo-

c -J

£% prior knowledge <a p <

S * -e- KN O

g u ...

O 0.

C ai o a H O —--- M îq 3 Femoral artery with de-endr- d> o w <h ra thélialisation orealable

a § * Ώ PS

f »3 8 ...

vi Ό

rH

ç c _________ O £ -1 Ι.-.-- ΙΙΙΠ-. '—————

'G) CO

α n 5 Abdominal aorta with de-en-o o c | ^ „§ prior dothelialication

ύ £ £ ΙΛ Ο LO

5 ° ΙΛ CV) £ Φ ^ 1 1 - 1 0 ro ca

W 0% Γϋ B

· "%, · Γ4 · Μ oft '“ co. ^% G d ^ 000 Ω ai 3 £ Φ

-P

If O

g S- £ f = b

v p ί> 3 £ E Qi E

f- £ 01? £? P * O «· Η 1-.

C £ rH £

0 3 0 01 O

E £ w mm '% / 1 donation H, L--% * 10

Hypoglycemic aotion in diabetic mice

Diabetic mice (black strain C 57, Obese / Obese derived from MRI) of both sexes, were fed between 45 and 7 ° g with powdered food during the week preceding the test. The treated animals are then given the test compound k mixed with food, at a certain concentration, for several days. The animals are then weighed, anesthetized with carbon dioxide and bled by cardiac puncture.

The following serum parameters are evaluated: 10 1. Glucose - by the God-Perid glucose oxidase method.

2. Cholesterol and triglycerides - they are measured by an autoanalyzer after elimination of the phospholipids by means of activated zeolite and extraction with 1 * Isopropanol.

Each test has control groups (receiving only normal food, no medication).

The percentage reduction in the concentrations of glucose, cholesterol and triglycerides in the serum is calculated by comparison with the controls, for each concentration used of the compound k to be tested.

20 The results obtained are shown in Table III below s / f f il "

G

ρ ω O 0 E Ό

'0) -H

0 P P σ \ ΙΓ »Ή

H '0 CM - = t CM

KO 11 + ω g>,

G 0 rH

Gj bû Ό P * rl

U P

POP

C a ---------- 0 ft i E cd

0 G rH

- ^ ta o

CG G

<d cd su

£ * G * P cO

o w ca - = r o ir>

E t> I I CM

Φ P ΓΗ I

Ό G C

„£ ta o o

P

0

VS

this K)

• C G

• H

O o

tQ E

O '0 O P

r-f

rH X

U P

«Ri H -5 P LTi CM CD CTi Μ P ΚΛ p- LT \ K \ H P O I I I | G Ά CD 0O.

<E ß a s ^ m gg <0 0

Eh .C G.

ü

E

0 G

* C P

'0

> \ M

"w m io u) ^ h n ë & OP o o o o

o, m "dj ό · <-}" -J

P 0

PP C "- t— CM CM

Cl - ——--

P G

v ci i

-Ü * H

\ C H CM - =} · V} 0 C / J * "\. = 3- 0 TJ P O O ·> ·>

"-H W C O O

O G 0 0

Q H E

~ c B “

Tl E τί E TJ E

G P P

- O »ri Q) · Η 0) · Η

P TJ P Τί P TJ

0 0 G 0 O 0 G rH

E P «P W P W O

3 P y · 0 ό SC

C P5 0> 3 0> 1 0 -

fc Ä'dÄ'öil'ö'O

o c o q rH qp cpp C 0 O 0 O 0 0

_E B E B E W W

SEEN I

a / LJ- ï »12

Action to inhibit proliferation of aortic smooth muscle cells

Smooth muscle cells are grown in culture from pork thoracic aorta explants using Dulbecco modified Eagles 5 medium (DME) containing $ 20 fetal calf serum (SFV) and antibiotics. The cells are incubated at yjeC in an atmosphere of $ 95 of air and $ 5 of carbon dioxide. When the cells have reached confluence, they are submitted - in the usual way to a passage by trypsinization and reseeding - approximately 10% of their confluence density in a DME medium containing $ 30 of SFV and antibiotics.

Smooth muscle cells are seeded at. densities of 100,000 to 200,000 cells per Falcon box of 55 x ^ 0 mm in 2 ml of DME medium, containing $ 10 of SFV and antibiotics, 15 After 24 hours, when the cells became attached to the boxes , the medium is replaced by 2 ml of DME medium containing $ 1 of SFV and antibiotics. The cultures are incubated for a further three days to allow the cells to rest (i.e. no longer undergoing cell division). The medium is then replaced with 2 ml of control medium or of medium to be tested. The medium to be tested consists of K® medium (containing 10% of SFV and antibiotics) and of test compound at a concentration of 5 dg per ml of medium. The compounds are pre-dissolved in water, acetone or glycofurol so that the final concentration of the solvent in the medium is 0.2 $ by volume. The control medium consists of DME medium (containing 10 $ SFV and antibiotics) and a suitable solvent at a concentration of 0.2 $ by volume. After three days of incubation in test medium or in control medium, the medium is replaced by test medium or fresh control medium and the cells are incubated

for another three or four days. At the end of the 6 or 7 days of the incubation period, the number of cells is determined by tryp_ / sination thereof and counting of the cell suspension, J

- · (f

V

»13

All the results in Table 17 below represent the average value for four boxes of cells. The percentage of inhibition of proliferation is calculated using the following formula: Percentage of inhibition of proliferation: -100 - (§-r§ 1 * ") where S = average number of cells per dish at the start of l 'experiment (when adding the control medium or ^ the medium to be tested).

30 T »average number of cells per dish in the cultures tested at the end of the experiment.

C = average number of cells per dish in the control cultures at the end of the experiment.

TABLE IV

Compound Form Solvent% inhibition L HCl salt HgO 48 H20 55 H20 31

Hg0 45 20 0 HCl salt acetone 33 acetone 38 glycofurol 54 acetone 23 A HCl salt acetone 2l - 25 acetone 16 acetone _41 d

U

Action to inhibit the transformation into lymphocytes of the lymph node cells stimulated by the mitogen in guinea pigs

Guinea pigs are sensitized to Mycobacterium tuberculosum 5 by injections into the soles of the feet with complete Freund's adjuvant (FCA) (0.05 ml 0,0 0.05 mg / ml 50% solution by volume of FCA in sterile saline).

At the end of 14 days, lymph node cells are obtained, which are suspended in Eagle's minimum essential medium (ME) containing $ 10 of fetal calf serum (SFV) and buffered with salts of Earle, at a concentration of 2.5 x 10 cells per ml.

0.1 ml of cell suspension is incubated for 24 hours at JJ'C in an atmosphere of 95% air and 5 # carbon dioxide gas in the presence of 0.1-5 ml of mitogen or mitogen and of compound to be tested in EME medium (containing 10% of SFV and buffered with Earl salts).

Eighteen hours before harvesting,% -thymidine is added (1 μl of solution at. 100 jiCi / ml in sterile 0.9% saline solution).

As a DNA synthesis index, the rate of incorporation of H-thymidine by the cells is measured in comparison with the control mitogen.

/: / * 5?

TABLE V

Compound Dose in medium # of inhibition of incubation incubation pg / ml ration of ¾-thymidine in cellular DNA in comparison with the control mitogen B 1 47 3 83 L 3 47 10 98 10 0 3 61 10 99 The usefulness of these compounds is increased by the fact that they have very low toxicity, as demonstrated by the following test:

Oral toxicity in mice ^ 5 Groups of mice are treated orally with graded doses of the test compound (in an aqueous suspension at 0.5% w / v of tragacanth) and kept under observation for three days after. The percentages of animals that die during this period for each dose level are used to construct a graph from which the LDq, i.e. the dose, is calculated in mg per kg of body weight. animal, necessary to kill 50 ^ of mice.

The compounds of formula (I) designated in the above list were tested and the LD 50 of each compound is greater than 1000 mg per kg of body weight of the animal.

The preferred compounds of the invention are those listed above by the letters B, D, GG, KK, P, H, AA, U, * Z * L and 0 #

The compounds of formula (I) can be prepared by / 50 application or adaptation of known methods, for example as described below. / If t "16 1 - According to a characteristic of the present invention, the compounds of general formula (l) are prepared by cyclization of a compound of general formula: aNHCOR2 (II) NHR ° 2 5 (in which R ° represents a hydrogen atom or a group -COR, and Rx and R are as defined above), optionally prepared in situ, for example as described below for the cyclization of the compounds of general formula (III) or (IV), pa) Thus, when R ° is a -COR group, a compound of general formula is cyelized: aNHCOR2 (III) NIICOR2 λ 2 (in which R1 and R are as defined above), preferably at high temperature, for example between oG and 100 ° C, for example at or around 80 ° C, by reaction with a mineral acid, for example hydrochloric acid, in the presence of water and within an organic solvent, for example an alcohol such as me-thanol or ethanol, or me ketone like acetone or, preferably, methyl ethyl ketone, or: b) When R ° is a hydrogen atom (especially in this

20 which concerns the compounds in which R represents a straight or branched chain adL-coyl group containing from 1 to 6 carbon atoms), a compound of general formula is cyclized: f L

V

* * 17 C / NHGOR2 |] Civ)

^ \ NHU

d. Λ (in which R1 and K sor.t as defined above), either under conditions similar to those described above in a), or again by reaction with an organic acid, for example p-toluenesulfonic acid, in water or in an organic solvent, for example toluene, preferably at elevated temperature, for example between 60 and 100 ° G, for example at or around G ° C, or else: e) (especially with regard to relates to the compounds in which represents a straight or branched alkyl group containing from 1 to 6 carbon atoms) the cyclization is usually carried out without isolating an acylated intermediate of formula (ill) or (IV), ie (i) in l absence of an organic solvent and at elevated temperature, for example between 150 and 250 ° C., ie (2) 15 in the presence of water and a mineral acid, for example hydrochloric acid, and within a suitable organic solvent, for example diglyme.

vs. _ another feature of the present invention, the compounds of general formula (l) are prepared by reaction / 20 of a compound of general formula: / y 18 Λ (in which Rx is as defined above) with a compound of general formula: R2CH0 (VI) (in which ΓΓ is as defined above), and a copper II salt, for example cupric acetate, in the presence of a. inert aqueous organic solvent, for example a mixture of water and methanol, between room temperature and the reflux temperature of the reaction mixture, then transformation of the resulting copper salt into the corresponding compound of formula (l).

According to another characteristic of the present invention, the carboxylic acids of formula (i) are prepared (in which R is as defined above and R represents a hydrogen atom) by hydrolysis of a corresponding ester of formula general (i) in which R is as defined above and R represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more substituents of the same type chosen from hydroxy group, alkenyl groups containing 2 to 5 carbon atoms and alkanoyloxy groups containing 2 to 7 carbon atoms. Preferably, the hydrolysis is carried out in an alkaline medium, for example in the presence of an alkali metal hydroxide within an inert hydro-organic solvent system and at elevated temperature, for example in the presence of sodium hydroxide in aqueous ethanol and at reflux temperature.

If - According to another characteristic of the present invention, it is possible to prepare the esters of general formula (i) (in which R is as defined above and R represents a straight or branched chain alkyl group containing from i to 6 atoms carbon, which may be substituted by one or more · 30 substituents of the same type chosen from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms) by Prté - / Rification of a corresponding earboxylic acid of the general formula ^ / 2,, 1 / / line (i) in which R is as defined above and R j ji t 19 represents a hydrogen atom. Esterification can be carried out by application or adaptation of known methods, for example by reaction of the acid with an excess of the appropriate alcohol of general formula: 5 1¾½ (VII) (in which fP represents a straight chain alkyl group or branched containing from 1 to 6 carbon atoms, which may be substituted by one or more substituents of the same type chosen from the hydroxy group, the alkenyl groups containing 2 to 5 to 5 carbon atoms and the alkanoyloxy groups containing from 2 to 7 atoms carbon) optionally constituting the solvent medium, and in the presence of a mineral acid, for example hydrochloric acid, preferably at elevated temperature, for example between 60 and 100 ° C; or by reaction with the corresponding cores-15 alkyl halide.

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

By the term "known methods" as used in the present text is meant methods previously used or described in the literature.

5 - According to another characteristic of the present invention, the compounds of general formula (I) can be transformed into their pharmaceutically acceptable salts, and vice versa, by application or adaptation of known methods. This process is useful not only in itself but also for the purification o of the compounds of general formula (i) and their salts by taking advantage of the differences in solubility, in water and in various organic solvents, compounds and their salts and any impurities present, using known methods such as crystallization.

a) The compounds of general formula (i) can be transformed into their pharmaceutically acceptable acid addition salts, for example by reaction with the appropriate acid, in solution or in /

suspension in a suitable solvent such as acetone, methanol / V

i 20 or ethanol, followed, if necessary, by evaporation of all or part of the solvent and recovery of the solid salt.

b) On the other hand, the acid addition salts can be transformed into the original compound of general formula (i), for example by reaction with ammonia in the presence of a suitable solvent, such as ethanol, followed by treatment with a weak acid, for example glacial acetic acid.

c) The compounds of general formula (i) 1 2 in which R1 represents a hydrogen atom (R being as defined above) can be transformed into their pharmaceutically acceptable base salts, for example by reaction with the appropriate base, such as the appropriate amine or a compound of general formula: mW (VIII) (in which M represents an alkali metal, for example sodium or potassium, and represents an aleoyl group containing up to 4 carbon atoms, by example methyl or ethyl, or a hydrogen atom), in a suitable solvent, for example methane or ethanol, or a mixture of water and acetone, followed, if necessary, by evaporation of all or part of the solvent and recovery of the solid salt.

d) These salts can be transformed into the original compounds of formula (I), for example by reaction with a suitable acid, such as glacial acetic acid, in solution in a suitable solvent, for example water or ethanol , followed, if necessary, by evaporation of any part of the solvent and recovery of the solid compound of formula (i).

* It will be understood that in carrying out the methods of the present invention, it may be desirable to introduce protective chemical groups into the reagents to prevent side reactions from occurring; for example, in process 1 described above, the hydroxy groups of the substituent R listed in the general formula (II) may have been converted to benzyloxy groups before the reaction as described , with subsequent removal of the benzyl group. In addition, /, / 21 one can choose a method of preparation in preference to the others, as a means of making certain envisaged compounds of general formula (1).

The compounds of general formula (II) in which 5 R ° represents a hydrogen atom can be prepared from compounds of general formula:> Vv ^^^, NHC0R2 R ^ OOC-- | (IX) NO 2 1 p (in which R and R are as defined above) by reduction, for example by catalytic hydrogenation, using for example palladium on black.

The compounds of general formula (II) in which R ° 2 g * represents a group of formula -COR (R being as defined above) can be prepared from compounds of general formula (II) in which R ° represents an atom of hydro-gene by reaction with compounds of the general formula (XI) shown below.

The compounds of general formula (IX) can be prepared by reaction of a compound of general formula:, B100C-- | (X) - j_

(In which R is as defined above) with a compound r of general formula (xi), in a similar manner to that described below / below in method A (1). NOT

<22

The compounds of general formula (II) in which the substituent group -NHCOR is in meta with respect to the substituent group -COOK1 "and in which R ° represents a hydrogen atom can be prepared by reaction of a compound of general formula 5 (V) with a compound of general formula (XI) as described below in method A (2).

The compounds of general formula (II) in which R 2 22 represents a group of formula -COR (R being as defined above) can also be prepared by reaction of a compound of general formula (V) with a compound of general formula (Xi) as described below in method A (1).

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

Method A

The compounds of general formula (II) can be prepared by reaction of a compound of general formula: [R100C - j (v) nh2

(in which R1 is as defined above) with an acylating agent of general formula: f L

R2C0X1 (XI) 23 in which R is as defined above and X represents a halogen atom, preferably chlorine, or a hy-droxy group. (According to a process of the present invention, the process continues with the cyclization of the resulting product, possibly in situ).

Particularly suitable conditions are as follows: (1) The compounds of general formula (v) (in which R ^ · is as defined above) can be reacted with acyl halides of general formula (XI) (in la-; which R is as defined above and X represents a halogen atom (preferably chlorine) in an inert organic solvent, for example chloromethane or dimethylformamide, preferably in an anhydrous medium and preferably in the presence of an acid scavenger, for example a trialkylamine such as triethylamine, or an alkali metal carbonate or bi-carbonate, such as anhydrous sodium carbonate.

(2) The compounds of general formula (V) (V) (especially those in which R represents a straight or branched alkyl group containing from 1 to 6 carbon atoms) can be reacted with acyl halides. of general formula (XI) 20 (in which R is as defined above and X represents a halogen atom, preferably chlorine) under conditions similar to those described above in (l) but using a lesser amount acyl halide and adjusting the temperature, preferably between 0 ° C and ambient temperature-25 te.

Using a set of conditions between those described above in (l) and those described above in (2), v we would obtain a mixture of intermediaries of general formulas (III) -> and (Γ /) that 'we would cyclize under the conditions described above * 30 in (l) and (2).

(3) The compounds of general formula can be reacted

AT

(V) (especially those in which R represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms) with the compounds of general formula (XI) (in which / 4-,. 4 24 or a chlorine atom to obtain compounds of general formula (i), usually without isolating the acylated intermediates, either (a) in the absence of solvent and at elevated temperature, for example between 150 and 250 ° C, or (b) presence of water and a mineral acid, for example hydrochloric acid, and within a suitable solvent, for example diglyme.

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

EXAMPLE 1

- Compound A

5 A solution of 4-amino-3-hexadecanamido-3 benzoate (46 g) and p-toluenesulfonic acid (15 g) in 1000 ml of toluene is stirred and refluxed for 2 hours, continuously removing the produced using a Dean and Stark device. The solution is cooled to 60 ° C. and washed with twice 200 ml of a 2N aqueous solution of sodium carbonate. The toluene layer is dried over magnesium sulfate and then concentrated in vacuo to give an oil. This oil is triturated with petroleum ether (P.E.

40-60 ° C), which gives a buff-colored solid which, by recrystallization from petroleum ether (PE 40-60 ° C), gives 24.6 g of 15 2-pentadecyl-2 benzimidazolecarboxylate-5 methyl in the form of a white solid, mp 96-98 ° C.

The methyl amino-n-hexadecanamido-3 benzoate used as starting material is prepared by one or other of the following methods: a) A stirred solution of 3,4-diamino benzoate is treated dropwise methyl (55 g) in 1200 ml of anhydrous dimethylformamide, containing 11.8 g of anhydrous sodium carbonate, per 58 g of n-hexadecanoyl chloride for one hour. The rate of addition of n-hexadecanoyl chloride is such that it allows the temperature of the reaction mixture to rise from an initial value of 10cC to room temperature. The mixture is then stirred at room temperature for a further 3 hours, then poured into 5 liters of water. The resulting solid is collected and boiled in 1000 ml of acetone and then the boiling mixture is filtered. The filtrate is cooled to 0 ° C and the resulting buff-colored solid is filtered off, giving 48.2 g of methyl amino-4 n-hexadecanamido-3 benzoate, m.p. 112.-11 ° C.

b) A stirred solution of 3,4-diamino methyl benzoate (166.6 g) in 270 ml of anhydrous diehloromethane, / 35 containing 10.3 g of triethylamine, is treated dropwise with a solution of / t chloride. / r 26 n-hexadecanoyl (27.5 g) in 30 ml of anhydrous dichloromethane for 45 minutes. During the addition, the temperature is maintained between 16 and 20 ° C. The mixture is stirred for a further 2 hours. The resulting solid is then collected and boiled in a mixture of acetone (100 ml) and methanol (15 ml) and the insoluble matter is removed by filtration. The filtrate is cooled to 25 ° C. and treated with 800 ml of water, which gives 4-amino-n-hexadecanamido-3 benzoate in the form of a buff-colored solid, PF 112-114 ° C.

10 EXAMPLE 2

Compound A

A solution of methyl amino-4-hexadecanamidobenzoate (34 g; prepared as described above in Example i) is treated in 200 μl of a mixture of ethanol and water (9/1 by volume ) with an excess of a saturated solution of HCl in ethanol. The mixture is heated to reflux for 2 hours, then cooled. The resulting solid is collected and recrystallized from a mixture of ethanol and water (9/1 by volume), which gives 24.2 g of methyl n-pentadecyl-2 benzimidazolecarboxylate-5. as a white solid, mp 230-232 ° C (with decomposition).

EXAMPLE 3

Compound A

8.8 g of methyl diamino-3,4 benzoate and 12.8 g of hexadeanic acid are milled together to form an intimate mixture. The mixture is heated at 200 ° C for 150 minutes. Then this mixture is cooled to 60 ° C and extracted with 200 ml of petroleum ether (P.E.

60-80 ° C) boiling. The extract is concentrated in vacuo, which gives. a brown oil. This oil is dissolved in 100 ml of ethanol and the solution is treated with a solution of potassium hydroxide in ethanol (10% by weight) until the pH of the mixture is 7.

Then the mixture is cooled to 0 ° C and filtered; the filtrate is concentrated in vacuo, which gives 10.2 g of a brown oil. This oil is dissolved in 15 ml of chloroform and subjected to chromatography on 275 g of silica gel. By elution ion using chloroy "/ 35 form, 6.0 g of a whitish solid is obtained which is recrystallized 7 f / ¥ 27 from petroleum ether (PE 40-60 ° C) which sleeps 5.3 g of 2-n-pentadecyl-benzimidazolecarboxylate-5 in the form of a white solid, mp 96-98 ° C.

EXAMPLE 4

5 Corcposd B

A stirred solution of methyl n-pentadecyl-2-benzimidazolecarboxylate-5 (36 g; prepared as described above in example 1 or 3) in 500 ml of an ethanol mixture is heated at reflux for 90 minutes. of water (4 / l by volume), containing 8 g of sodium hydroxide. The mixture is cooled to 0 ° C and acidified with concentrated hydrochloric acid. The resulting whitish solid is collected and recrystallized (with black treatment) from 800 ml of a mixture of ethanol and water (4 µl by volume), which gives 32 g of the hydrochloride of the n-pentadecyl-2 benzimidazole-15 carboxylic-5 acid as a white solid, mp 289-291 ° C (with decomposition).

EXAMPLE 5

Compound B

A solution of methyl 2-pentadecyl-2-benzimidazolecarboxylate-5 hydrochloride (24.2 g; prepared as described above in Example 2) in 250 ml of a mixture of ethanol and water (4/1 by volume), containing 7 g of sodium hydroxide, in a manner similar to that described above in Example 4, which gives 22.4 g of the hydrochloride of the acid n- pentadecyl-2 benzimidazole-25 carboxylic-5> mp 289-291 ° C (with decomposition).

EXAMPLE 6

Compound C

A solution of methyl amino-3-dodecanamido-3 benzoate (4l, 0 g) in 1000 ml of toluene, containing 25 g of p-toluenesulfonic acid, is treated in a similar manner to that described above in Example 1, which gives 27.0 g of 2-n-undecyl benzimidazolecarboxylate-5 in the form of a white solid, mp 9j5-95 ° C · f 4-amino-n-3-dodecanamido benzoate methyl used comfitei starting material is prepared as follows! / 'J / t 26

A solution of 3,4-diamino methyl benzoate (25.0 g) in 1120 ml of anhydrous dimethylformamide, containing 7.7 g of anhydrous sodium carbonate, is treated with 30.5 g of n-dodecanoyl chloride, similar to that described above in Example 1 (a), which gives 4 g of 4-amino-n-dodecanamido-3 benzoate, in the form of a buff-colored solid.

/ 7

Compound C

33 g of methyl diamino-3,4 benzoate 10 and 40 g of dodecanoic acid are ground together to form an intimate mixture and this mixture is heated at 200 ° C. for 3 hours. The mixture is then treated in a similar manner to that described above in Example 3 *, which gives 19 g of 2-n-undecyl benzimidazolecarboxylate-5 in the form of a white solid, mp 92-94 ° C. .

15 EXAMPLE 8

Compound D

A solution of methyl n-undecyl-2-benzimidazolecarboxy-late-5 (28.6 g; prepared as described above in Example 7) is treated in 350 ml of a mixture of ethanol and water ( 4/1 in 20 volumes), containing 6.93 pounds of sodium hydroxide, similar to that described above in Example 4, which gives 22.3 pounds of n-undecyl acid hydrochloride -2 benzimidazolecarboxylic-5 in the form of a white solid, mp 289-294 ° C (with decomposition).

EXAMPLE 9

25 Compound E

33.0 g of methyl diamino-3,4 benzoate and 45.0 g of n-tetradecanol acid are milled together to form an intimate mixture and this mixture is heated at 200 ° C. for 6 hours. The mixture was cooled to 60 ° C, then extracted with petroleum ether (m.p. 60-50 ° C) and the petroleum ether extracts concentrated in vacuo to give a brown oil. This oil is dissolved in 500 ml of ethanol / and the solution is treated with a solution of potassium hydroxide ^ / in ethanol (10% w / v) until the pH of the / ί

U

The mixture is 7. The mixture is cooled to 0 ° C, filtered and the filtrate is concentrated in vacuo to give a brown oil. This oil is partitioned between a hot mixture of petroleum ether (P.E.

60-80 ° C) and toluene (300 ml; 4/1 by volume) and water (300 ml).

The organic layer is concentrated under vacuum, which gives an oil which is then dissolved in 100 ml of hot toluene and which is treated with an excess of a saturated solution of HCl in ethanol. The resulting solid is collected and recrystallized from ethanol (with black treatment), which gives 16 g of methyl 10 n-tridecyl-2-foenzimidazoleearboxylate-5 hydrochloride in the form of a white solid, PF 228 -236 ° C (with decomposition).

EXAMPLE 10

Compound E

4q g of 4-amino-n-tetradecanamido-3 benzoate are treated in a similar manner to that described above in Example 2, which gives 33% of 2-n-tridecyl-benzimidazole-carboxylate hydrochloride. 5 of methyl in the form of a white solid, mp 228-234 ° c (with decomposition).

The methyl amino-4 n-tetradecanamido-3 benzoate used as starting material is prepared as follows:

A solution of 3,4-diamino methyl benzoate (25.0 g) in 500 ml of anhydrous dichloromethane, containing 15.5 2 of triethylamine, is treated dropwise with a solution of n-tetradeoanoyl chloride (37.12 g) in 50 ml of anhydrous dichloromethane 25 in a manner similar to that described above in example l (b), which gives 40 g of methyl amino-4 n-tetradecanamido-3 benzoate crude under form of a buff-colored solid.

EXAMPLE 11 s

Compound F

v jq On. treats a solution of methyl 2-n-tridecyl benzimidazolecarboxylate-5 (7.9 g) in 200 ml of a mixture of ethanol and water (4/1 by volume), containing 2.4 g of sodium hydroxide, in a similar manner to that described above in Example 4, which gives 5.7 g of the hydrochloride of 2-n-tridecyl-benzimidazole / 50-5-carboxylic acid 'a white solid, mp 299 ~ 506 ° C (with decomposition).

EXAMPLE 12

- Compound B

5.0.0 g of 2-pentadecyl-2-benzimidazolecarboxylic acid-5 hydrochloride (dissolved as described above in Example 4) are dissolved in 1000 ml of a hot mixture of ethanol and water ( 6/1 by volume) c The hot solution is treated with 2N ammonia until the solution is alkaline. Glacial acetic acid is then added to the mixture until the solution is acidic, and cooled to 0 ° C to give 12.3 g of a white solid. This solid is recrystallized from a mixture of ethanol and water (4/1 by volume), which gives 12.0 g of 2-n-pentadecyl-benzimidazolecarboxylic-5 in the form of a white solid , Mp 113-115 ° C, 15 which is estimated to be the monohydrate, EXAMPLE 13

Compound G

It is dissolved in 500 ml of hot ethanol containing an excess of hydrochloric acid of 4-amino-n-tridecanamido-3 benzoate (prepared, as described below, from 17.8 g of diamino- 3,4 methyl benzoate and used without further purification) and the solution is treated in a similar manner to that described above in Example 2, which gives 25.5 G of 2-n-dodeayl benzimidazolecarboxyiate hydrochloride -5 methyl as a white solid, mp 221-225 ° C (with decomposition).

The amino-4 n-tridecanamido-3 methyl benzoate used as starting material is prepared as follows:

A solution of 3,4-diamino methyl benzoate (17.8 g) in 350 ml of adorned chlorine thane, containing 10.8 g of triethyl-30 amine, is treated with 25 g of n-tridecanoyl chloride, similar to that described above in Example 1 (b), which gives 40 g rj of amino-4 n-tridecanaœido-3 crude methyl benzoate.

Compound H

EXAMPLE 14 51

A solution of methyl 2-n-dodecyl benzimidazolecarboxy-late-5 (15.5 g) is treated in 100 ml of a mixture of ethanol and water 5 (4 / l by volume), containing 50 K d sodium hydroxide, similar to that described above in Example 4, which gives 11.7 g of 2-n-dodecyl benzimidazolecarboxy-5-acid hydrochloride in the form of a solid white, PF 276-290¾ (with decomposition).

10 EXAMPLE 15

Compound B

A solution of bis (n-hexadecanamido) -3.4 benzoic acid (20 g) in 400 ml of methyl ethyl ketone is treated with 35 ml of concentrated hydrochloric acid (at 36.5% by weight / volume). The mixture is heated to reflux for 5 hours and then cooled. The resulting solid is collected, washed with boiling petroleum ether (PE 60-80 ° C) and recrystallized from ethanol, which gives 15 g of hydrochloride and n-pentadecyl acid. 2 benzimidazole-carboxylic-5 in the form of a white solid, PF 289-291¾ 20 (with decomposition).

The benzoic bis (n-hexadecanamido) -3.4 acid used as starting material is prepared as follows:

A solution of 3,4-diamino benzoic acid (7.5 g) in 100 ml of diehloromethane, containing 15 g of triethylamine, is treated with 27 * 5 g of n-hexadecanoyl chloride in a similar manner to that * described above in Example 1 (b). A solid is collected which is recrystallized from glacial acetic acid and then from methyl ethyl ketone (with filtration of the hot solution), which gives 20 g of bis (n-hexadeaneanido) -3.4 benzoic acid under form of solid 30 in buff color, PF 198-202¾. ^? 2

Compound A

EXAMPLE 16

A solution of methyl bis (n-hexadeaneandido) -3.4 benzoate (10.0 g) in 100 ml of methyl ethyl ketone is treated in a similar manner to that described above in Example 15, which gives 5 * 7 S of methyl n-pentadecyl-2-benzimidazolecarboxylate-5 hydrochloride in the form of a white solid, mp 230-232 ° C (with decomposition).

The methyl bis (n-hexadecanamido) -3.4 benzoate used as starting material is prepared as follows: A solution of methyl diamino-3,4 benzoate (5.0 g) in 50 ml of dichloromethane is treated, containing 6.2 g of triethylamine, per 16.5 S of n-hexadecanoyl chloride in a similar manner to that described above in Example 1 (b) (the temperature of the reaction mixture is left during the addition rise from 20 to 15 30 ° C). A solid is collected which is recrystallized from chloroform, which gives 1.9 g of methyl bis (n-hexadecanamido) -3.4 benzoate in the form of a white solid, m.p. 129-132 ° C.

EXAMPLE 17

Compound I

A stirred solution of methyl bis (n-undecanaraidc) -3.4 benzoate (33.0 g) in 400 ml of mechanol, containing 50 ml of concentrated hydrochloric acid (36.5) is heated to reflux for 3 hours. % w / v). The mixture is then cooled to 0 ° C, filtered and the solid obtained is combined with the residue resulting from the evaporation of the filtrate in vacuo. The combined solids are washed with 200 ml of petroleum ether (PE 60-80 ° C) and recrystallized from ethanol * · * (with filtration of the hot solution), which gives £ 13.7 methyl 2-n-deyl benzimidazolecarboxylate-5 chlorohydrate in the form of a white solid, mp 230-240 ° C (with decomposition). y 30 Methyl bis (n-undecanamido) -3.4 benzoate used as starting material is prepared as follows: /// \ 33

A solution of 3,4-methyl diaraino benzoate (17.9 g) in 300 ml of dichloromethane, containing 21.8 E of triethylamine, is treated with 44.3 g of n-undecanoyl chloride in a similar manner to that described above in Example 16. A solid is collected which is recrystallized twice from ethanol (with filtration of the hot solution), which gives 40.2 g of bis (n-undecanamido) -3.4 methyl benzoate in the form of a white solid, mp 139-144 ° C.

EXAMPLE 18

Compound J

j_0 A solution of methyl n-2-decyl-benzimidazoleearboxylate-5 hydrochloride (13.7 g; prepared as described above in Example 17) is treated in 250 ml of a mixture of ethanol and d water (4/1 by volume), containing 4.6 g of sodium hydroxide, in a similar manner to that described above in Example 4, which gives 9 * 4 g of chlo-15 hydrate n-2-decyl-benzimidazoleearboxylic-5 acid as a white solid, P, F. 270-282 ° C (with decomposition).

EXAMPLE 19

Compound B

A solution of n-pentadecyl-2-henziradazolecarboxylic acid-5 monohydrate (11.66 g; prepared as described above in Example 12) in 150 ml of methanol is heated to 10 ° C. treated with a solution of scdium methoxide (prepared by carefully dissolving 0.69 S of sodium in 40 ml of anhydrous methanol), then the mixture is cooled. The solvent is evaporated in vacuo and the residue is recrystallized from water, which gives 9.7 E as sodium n-pentadecyl-2 bensimidazoleearboxylate-5 as mono-hydrate in the form of a white solid. which darkens at 230 ° C and decomposes above „300 ° c.

EXAMPLE 20

30 Compound B

A stirred suspension of morihydrate, 2-pentadecyl-2-benzimidazolecarboxylic acid-5 (1.00 g; prepared / as described above in Example 12) is treated dropwise in 30 ml of acetone with / L a solution of methanesulfonic acid (0.25 e) in 15 ml of methanol ^ 34 at room temperature. The mixture is heated to 40 ° C to obtain a solution, then the solvent is evaporated in vacuo. The white solid residue is triturated with 30 ml of acetone and the resulting solid is collected, which is washed with 10 ml of acetone, which gives 1.19 6 of the 5-methanesulfonate of n-pentadecyl-2-benzimidazolecarboxylic acid -5 IN THE FORM OF A WHITE SOLID, P, F, 115-117 ° C. EXAMPLE 21

Compound B

A stirred suspension of 2 n-pentadecyl-2 benzimidazolecarboxylic acid-5 monohydrate (1000 g; prepared as described above in Example 12) is treated in ~ $ Q ml of acetone with an excess of a solution. (at 10% by weight / volume) of 2-hydroxyethylsulfonic acid in a mixture of methanol and water (19 / i by volume). The solution is evaporated in vacuo and the residue is triturated with 50 ml of acetone.

The resulting solid is collected and washed with 10 ml of acetone to give 1.24 g of 2-hydroxy-2-ethyl-2-benzylidazolecarboxylic acid 5-hydroxyethylsulfonate. white solid, FF 93-95 ° C.

EXAMPLE 22

20 Compound A

10.0 g of n-pentadecyl-2 benzimi-dazolecarbcxylic acid-5 hydrochloride (prepared as described above in example 4) are dissolved in 2 × 0 ml of boiling methanol, in a reflux apparatus. treated with 20 ml of concentrated hydrochloric acid (at 56.5 / 25 in weight / volume). The mixture is heated at reflux for 3 hours and then cooled to 0 ° C. The resulting white solid is collected, washed with water and recrystallized from ethanol to give 9.2 g of methyl 2-n-pentadecyl benzimidazclecarboxy-5-late-5 hydrochloride. '' a white solid, mp 230-232 ° C (with / 30 decomposition). /! /

T

i

Compound K

35 EXAMPLE 25

33 * 0 g of methyl diamino-3,4 benzoate and 56.8 g of n-octadecanolic acid are ground together to form an intimate mixture and this mixture is heated at 200 ° C. for 210 minutes. The mixture is then treated in a similar manner to that described above in Example 9. The brown oil obtained after separation between the hot mixture of petroleum ether and toluene and water is dissolved in 25 ml of chloroform and subjected to chromatography on a column of silica gel (750 g). By elution with a mixture (l9 / l by volume) of chloroform and methanol, 40 g of a light brown solid are obtained. This solid is dissolved in 200 ml of hot toluene and treated with an excess of a saturated solution of HCl in ethanol. The resulting solid is collected and re-recrystallized (with black treatment) from a mixture of ethanol and water (9/1 by volume), which gives 19.9 g of n-heptadecyl hydrochloride -2 methyl benzimidazolecarboxylate-5 in the form of a white solid, mp 229-234 ° C (with decomposition).

EXEMFITED 24

20 Compound L

A solution of methyl n-heptadecyl-2-benzimidazolecarboxylate-5 hydrochloride (11.5 g; prepared as described above in Example 23) is treated in 200 ml of a mixture of ethanol and water ( l / l by volume), containing 14.35 g of sodium hydroxide, similar to that described above in Example 4, which gives 8.8 g of the hydrochloride of n-heptadecyl acid -2 benzimidazole-carboxylic-5 in the form of a white solid, mp 279-284 ° C (with decomposition).

EXAMPLE 25

30 Compound M

A mixture of 16.7 g of 4-araino-3-decanamido-3 methyl benzoate and 600 ml of toluene, containing 5.0 g of p-toluenesulfonic acid, is treated in a similar manner to that described above. in Example 1, which gives 14.0 g ce n-nonyl-2 benzimidazolecar ^ / 35 methyl boxylate-5 as a white solid, mp 101-103 ° C4 // "36 Amino- 4 n-deeanamido-3 methyl benzoate used as starting material is prepared as follows î

A stirred solution of methyl diamino-3,4 benzoate (166.6 g) in 600 ml of anhydrous dimethylformamide, containing 5.3 g of anhydrous sodium carbonate, is treated dropwise with 19.1 g of sodium chloride. n-decanoyl, in a manner similar to that described above in example l (a), which gives 16.8 6 of amino-4 n-decanamido-3 benzoate under firm a solid buff color, FF 96-96 ° C.

EXAMPLE 26

10 Compound N

A solution of methyl n-nonyl-2-benzimidazolecarboxyla-te-5 (13.3 g, prepared as described above in Example 25) is treated in 400 ml of a mixture of ethanol and water (4/1 by volume), containing 3 * 6 6 sodium hydroxide, in a manner similar to that described above in Example 4, which gives 8 * 6 g of hydrochloride do n-nonyl-2 bensimidazoccarboxylic acid-S only as a white solid, PF 275-260o0 „EXAMPLE 27

Compose O

2® 6n c'nauffo at reflux for 4 hours one lut 3 stirred with bss (n-oc „anami ^ o) -3.4 methyl benzoate (81 * 8 g) in 800 ml of methanol, containing 100 ml concentrated hydrochloric acid (at 36.5 Γ in POts / tfolu ™;, gn r-then cools the mixture and it is treated in a way that seemed bit- - the one shown below in example 17, which crj gives 33 * 6 G of methyl n-heptyl-2 bonzimidazolecarboxylate-5 hydrochloride in the form of a white solid, m.p., M. 140-142 ° C (with decomposition).

^ s (n-octanamido) -3.4 methyl benzoate used as starting material. <30 prepares as follows: 50 A solution of diamin ^ -3 * il methyl benzoate (41.2 g) in 4j_g nî] _ of dcnlorométhane, containing 51 * GG of triethylamine, is treated with a chloride solution. n-octanoyl (80.6 g) in 330 ml of di chloromsuhan ", similarly to that described above in"

1 example 16, er. resistallizing from raethanol (with black treatment 1 35, which gives 81.6 E of bis (n-octanamido) -3.4 / / methyl benzoate under fer-n., of a white solid, PF iX -l40eC. j H

Compound P

37 EXAMPLE 28

A stirred solution of methyl n-heptyl-2-benzimidazolecarboxylate-5 hydrochloride 5 (2 ^ 0.0 g; prepared as described above in Example 27) in 200 ml of a mixture is heated at reflux for 5 hours. ethanol and water (12 / l by volume), containing 8.9 pounds of sodium hydroxide. The mixture is treated similarly to that described above in Example 4, which gives 14.4 g of 2-n-heptyl-2-benzimidazolecarboxylic acid hydrochloride in the form of a white solid, FF 310-313 ° C (with decomposition).

EXAMPLE 29

Compound Q,

A stirred solution of bis (n-pentadecanamido) -3.4 benzoic acid (49.3 ß) in 560 ml of a mixture (10 / l by volume) of methyl ethyl etone and concentrated hydrochloric acid. Then the mixture is cooled. The resulting solid is collected and washed with 200 ml of this methyl ethyl etone, then with 200 ml of boiling petroleum ether (m.p. 60-80 ° C). It is recrystallized from a mixture (4 / i by volume) of ethanol and water (with black treatment and filtration of the hot solution), which gives 15.7 E of the hydrochloride of l n-tetradecyl-2-benzimidazolecarboxylic acid-5, PF above 3r-'0 ° C 4 & with decomposition).

The benzoic bis (n-pentadecanamido) -3.4 acid used as starting material is prepared as cooked: 25 One trone solution of 3,4-diamino benzoic acid (13.85 ε) in 180 ml of imethylformamide , containing 27.6 g of triethylamine, per 47.4 g of n-pentadecanoyl chloride, similar to that described above in Example 1 (a). The resulting solid is collected and recrystallized from methylethyletone (with black treatment and filtration of the hot solution), which gives 49.3 g of benzoic acid (n-pentadecanamido) -3.4, PF /

178-180 ° C. NOT

3S

"

Compose .

EXAMPLE 30 a) A stirred solution of methyl bis (n-nonanamido) -3.4 benzoate (23.3 g) in 300 ml of methanol is treated with 40 ml of concentrated hydrochloric acid (at $ 36.5 weight / volume). The mixture is heated to reflux for 3 hours and the solvent is removed in vacuo to give a white solid. The solid is washed with 100 ml of warm petroleum ether (PE 40-60oC) and recrystallized from 700 ml of water with hot filtration, which gives 12.0 g of n-octyl hydrochloride -2 methyl benzimidazolecarboxylate-5 in the form of a white solid, PF 238-243cC.

b) A stirred solution of 2-n-octyl-2-benzimidazolecarboxylate-5 hydrochloride (11 gj prepared as described above) is refluxed for 4 hours in 240 ml of a mixture of etha-15 nol and d water (12/1 by volume), containing 4.0 g of sodium hydroxide.

The mixture is treated in a similar manner to that described above in Example 4, which gives 7.8 g of n-octyl-2-benzimidazolecarboxylic-5 hydrochloride in the form of a white solid, Mp 280-300 ° C (with decomposition).

The methyl bis (n-nonanamido) -3.4 benzoate used as starting material is prepared as follows: C) A solution of 20 g of methyl diamino-3,4 benzoate in 250 ml of is treated dropwise anhydrous dichloromethane, containing 24.2 g of triethylamine, with a solution of nonanoyl chloride (44.12 g) in 50 ml of anhydrous dichloromethane, in a manner similar to that described above in Example 1 (b ). The resulting pink solid is recrystallized from methanol, with black treatment, which gives 30.3 g of methyl bis (n-nonanamido) -3.4 benzoate in the form of a white solid, PF, 142-245 ° C.

30 ΕΧΞΜΡΙΕ 31

Compound S

N-tetradecyl-2-benzimida-zoleearboxylic-5 (3.5 Si prepared as described above in Example 29) hydrochloride is dissolved in 96 ml of boiling methanol in a reflux apparatus, then 35 it is treated with 22 ml of concentrated hydrochloric acid (36.5% I w / v). The mixture is heated at reflux for 3 hours, / day / 39 then it is treated in a manner similar to that described above in Example 22, which gives 6.2 g of n-tetradecyl hydrochloride. 2 methyl benzlmidazolecarboxylate-5 in the form of a white solid, mp 233-235 ° C.

5 EXAMPLE 32

Compound T

N-hexadecyl-2-benzimidazole G arboxylic acid-5 hydrochloride (5 * 0 g; prepared as described below in Example 33) is dissolved in 400 ml of boiling methanol in a reflux apparatus, then 10 it is treated with 100 ml of concentrated hydrochloric acid (36.5% w / v). The mixture is heated to reflux for δ hours, then it is treated in a similar manner to that described above in Example 22, which gives 7.4 g of methyl n-hexadecyl-2 benzimidazoleearboxylate-5 under form of a white solid, 15 PF 225-230oC (with decomposition).

EXAMPLE 33

Compound U

A solution of 250 g of bis (n-heptadecanamido) -3.4 benzoic acid in 1500 ml of methyl ethyl ketone is treated with 180 ml of concentrated hydrochloric acid (36.5% w / v). The mixture is heated at reflux for P hours and treated in a similar manner to that described above in Example 15, which gives 44.9 g of 2-n-hexacecyl benzimidazolecarboxylic acid hydrochloride under 5 form of a whitish solid, PF 296-306¾ (with decomposition).

The bis (n-heptadecanamido) -3.4 benzoic acid used as starting material is prepared as follows:

A stirred solution of diami-110-3, benzoic acid (4p, 6 g) in 4C0 ml of dimethylformamide, containing 75 * 8 g of tviethy 1 amine, is treated dropwise with 13Ο g of n-heptadecanoyl chloride for 1 hour 1/2. The rate of addition of the n-heptadeca-30 chloride nucleus is such that it allows the temperature of the reaction mixture to rise from room temperature to 35-40¾. The mixture is then stirred at room temperature for a further 2 hours, then poured into 3500 ml of hot water, maintained at 70 ° C., containing 50 ml of concentrated hydrochloric acid (36.5% by weight / volume), which a / 35 gives 140 g of crude bis (n-heptadecanamido) -3.4 benzoic acid / J / rf EXAMPLE 34 * 40 in the form of a pink solid.

Compound V

N-eicosyl-2-benzimidazolecarboxylic acid-5 hydrochloride (12 g; prepared as described below in Example 35) is treated dropwise with stirring, 5 n-eicosyl-2-hydrochloride in 300 ml of chloroform per 100 ml of chloride chloride thionyle. The mixture is heated to reflux for 4 hours, then cooled and the excess thionyl chloride and the solvent are removed in vacuo to give a white solid.

This solid is suspended in 300 ml of anhydrous methanol and the mixture is stirred and heated to reflux for 8 hours, then cooled. The solid is collected and washed with methanol, which gives 9.2 g of methyl n-eicosyl-2-benzimidazolecarbo-xylate-5 hydrochloride in the form of a white solid, m.p. 220-226 ° C.

15 EXAMPLE 35

Compound W

We have a solution of bis (n ~ heneicosanamido) -3.4 benzoic acid (l26.5 g) in 1000 ml of methyl ethyl ketone per 100 ml of concentrated hydrochloric acid (at 36.5 / by weight / volume). Ch 20 heats the mixture at reflux for 10 hours, then it is treated in a similar manner to that described above in Example 15, which gives a white solid which is recrystallized from 1200 ml of n-butancl on obtains 45.1 g of the hydrochloride of n-eicosyl-2-benzimidazolecarbcxylic-5 as a white solid, mp 294-25 298 ° C (with decomposition).

Benzoic bis (n-hene.lcosanamido) -3 * 4 acid used as starting material is prepared as follows: a

A stirred solution of 21.9 6 of 3,4-diamino benzoic acid in 175 ml of diroethylforraamide, containing 43.6 g of triethylamine, is treated dropwise with 33.2 g of n-heneicosa chloride. - nucleus, similar to that described above in Example 33, y which gives 126.5 g of bis (n-heneieosanamido} -3 * 4 benzoic acid / in the form of a light brown solid . / JL · EXAMPLE 56

Compound X

H

Suspended in 350 ml of thionyl chloride 3.4.6 g of n-nonadecyl-2-benzimidazolecarboxyli-5-that-5 acid hydrochloride (prepared as described below in Example 37) and the mixture is stirred and the reflux heater for 6 hours. Excess thionyl chloride is removed in vacuo to give a brown-yellow solid. This solid is suspended in 500 ml of anhydrous methanol and the mixture is stirred and heated to reflux for 3 hours. The mixture is then treated in a similar manner to that described in Example 3 ^, which gives 12.2 g of methyl n-nonadecyl-2-benzimidazolecarboxylate-5 hydrochloride in the form of a white solid, PF 219- 227 ° C.

EXAMPLE 37

15 Compound Y

Heating a suspension of 89 * 1 G of bis (n-eicosana-mido) 3, i »benzoic acid in 1200 ml of methyl ethyl ketone with 120 ml of concentrated hydrochloric acid (36.5% w / v). The mixture was stirred and heated to reflux for 8 hours, then treated in a similar manner to that described above in Example 15, to give a white solid. This solid is boiled with 100 ml of n-butanol and the mixture is cooled, which gives 36.5 g of n-nonadecyl-2 benzimidazolecarboxylic-5 hydrochloride in the form of a white solid, F, F . 290-300 ° C (with decomposition).

25 The benzoic bis (n-eicosanamido) -Ζ> Λ acid used as starting material is prepared as follows:

A stirred solution of diami-no-p, benzoic acid (18 * 3 g) in 200 ml of dimethylformamide, containing 36.5 g of triethylamine, is treated dropwise with 30 g of n-eicosanoyl chloride, 30 similar to that described above in Example 33 *, which gives 93 E of crude ben (n-eicosanamido) -3.4 benzoic acid in the form / of a pale brown solid, mp 160-170 ° vs. //

Compound 2 EXAMPLE 38 h2

A suspension of 107 g of 4-amino-n-nonadé-canamido-3 benzoic acid in 1500 ml of methyl ethyl ketone is treated with 100 ml of concentrated hydrochloric acid (at 36.5 / w / v). the mixture is stirred and heated to reflux for 3 hours. It is cooled to 10 ° C. and the solid is collected which is washed with methyl ethyl ketone (2 times 500 ml) and which is suspended in 500 ml of water. To the mixture is added a solution of 50 G of sodium hydroxide in 150 ml of water and cr. stir the mixture and heat it to 60 ° C to dissolve.

Glacial acetic acid is added to the stirred mixture until it is at pH 5 and the resulting solid is collected which is washed with water (2 times 500 ml) and dried. This solid is recrystallized from ethanol, with black treatment, which gives a white solid which is dried thoroughly and then suspended in 50 ml of methyl ethyl ketone containing 100 ml of concentrated hydrochloric acid (at 36 , $ 5 in weight / volume). The mixture is stirred and refluxed for 1 hour, then cooled to give 33.8 g of 2-octadecyl-2-benzimidazolecarboxylic acid hydrochloride-5 as a white solid, PF 252-297eC (with decomposition).

The 4-amino-n-nonadecanamido-3 benzoic acid used as starting material is prepared as follows:

A stirred solution of 38 g of diamino-p, "benzoic acid in ^ 00 ml of dimethylformamide, containing 50.5 g of triethylamine, is treated dropwise with 79 * 1 C of n-nonadeaneanl chloride, similar to that described above in Example 33 * which gives an orange solution which is poured into JOOO ml of water containing 100 ml of concentrated hydrochloric acid (at 36 * 5 λ by weight / volume).

The solid is collected, washed with water (2 times 100 ml) and then dried, which gives 107 g of crude benzoic acid 4 n-3-nonadecanamido-3, PF IO3-II3 ° vs.

EXAMPLE 39

Compound U

Cn stirred and heated to reflux for 3 hours 12 g of. / 35 2-n-octadylyl benzimidazolecarboxylic acid hydrochloride / 5 / hi 43 (prepared as described above in Example 38) in 100 ml of thionyl chloride, then treated in a similar manner to that described above above in Example 36 ”which gives 11.6 g of 2-n-octadecyl hydrochloride methyl benzimidazolecarboxylate in the form of a white solid, mp 224-230 ° C.

EXAMPLE 4θ

Compound AA

A suspension of 53 * 1 E of bis (2-methyl tetradecanamido) -3.4 benzoic acid in 250 ml of methyl ethyl ketone is treated with 10 37.6 ml of concentrated hydrochloric acid (at $ 36.5 w / v ).

The mixture is stirred and heated to reflux for 16 hours. It is cooled to 0 ° C. and 11.17 g of solid are collected which are washed with methyl ethyl ketone (2 times 25 ml). This solid is suspended in 50 ml of water, and to this suspension is added a solution of 20 g of sodium hydroxide in 50 ml of water. The mixture is stirred and heated to 60 ° C to dissolve, then glacial acetic acid is added to the stirred mixture until it is at pH 5 · The resulting solid is collected, washed with water and recrystallized from ethanol, with black treatment, then treated similarly to that described above in Example 36 * which gives H g of the hydrochloride of the acid ( tetradecyl-2) -2 benzimidazolecarboxylic-5- (RO) in the form of a white solid, mp 2l4-2lS ° C.

The benzoic acid bis (msthyl-2 tétradécanamido) -3,4 used as starting material is prepared as follows: A solution of 17 * 5 S of 3,4-diamino benzoic acid in 140 ml is treated dropwise of dimethylformamide, containing 34.8 S of triethylamine, per 59 * 7 g of pentadecanoyl-2 chloride in a similar manner to. that described above in Example 33 * which gives 66 g of crude bis (2-methyl-tetradecanamido) -3 * 4 acid.

50 EXAMPLE 4l

CC compound

A solution of 15.2 g of 4-amino acid (hexyl-2 s octanamido 5-3 benzoic in 78 ml of methyl ethyl ketone is treated with 18.2 ml / of concentrated hydrochloric acid (36.5% by weight / The mixture is stirred // 44 and heated under reflux for 12 hours and the methyl ethyl kione is removed in vacuo, the residue is suspended in 200 ml of water and an aqueous solution of hydroxide is added to the mixture. sodium (50% w / v) until the mixture is at pH 5 It is heated to 90 ° C and then diluted with water to a total volume of 1500 ml This solution is treated with black and then with an excess of acetic acid (at 25% w / v in water), which gives a whitish solid. This solid is collected and washed with water. and recrystallized from ethyl acetate, which gives 8.89 g (7-tridecyl) -2 benzimidazolecarboxylic-5, mp 157-158 ° C.

The solid is dissolved in 350 ml of acetone and the solution is treated with 1.55 ml of concentrated sulfuric acid (98% by weight / volume). A white solid is obtained by cooling, which is recrystallized from methyl ethyl ketone, which gives 6.8 g of the acid hemi-sulfate (tridey1-7) -2 benzimidazoleearboxylic-5 as a solid. white, mp 202-205 ° C.

Arnino-4 (2-hexyl-octanamido) -3 benzoic acid used as starting material is prepared as follows: stirred 20 A solution / of 20.7 F. of diamino-5,4 benzoic acid is treated dropwise in 165 ml of dimethylformamide, containing 56.5 ml of triethylamine, per 67 g of 2-hexyl octanoyl chloride, in a similar manner to that described in example 33 · The waxy solid is collected and dissolved in 500 ral diethyl ether; the ethereal solution is dried and evaporated to give a reddish-brown oil.

This oil is extracted with hot methanol, using a continuous extractor, for 5 hours. The metha - = - nolic solution is evaporated on a rotary evaporator, which gives a brown solid which is

recrystallizes from acetone to obtain 15 * 2 g of amino-4/30 (2-hexyl octanamido) ~ 3 benzoic acid, in the form of a white solid, m.p.J. 219-221 ° C. W

BB compound

45 EXAMPLE 42

A solution of benzoic 4-amino (2-ethyl-dodecanamido) -3 (24.7s) in 125 ml of methylethyletone is treated with 29 ml of concentrated hydrochloric acid (56.5% w / v). The mixture is stirred and heated to reflux for 12 hours, then it is treated in a similar manner to that described above in Example 4l, which gives a white solid which is recrystallized from a mixture of 200 ml of acetone and 200 ml of water to obtain 14.2 g of the acid hemisulfate (tridecy1-3) -2 benzimidazolecarboxylic ~ 5- (RS) in the form of a white solid, PP 185 ~ 187 ° C.

Arnino-4 (2-ethyl dodecanamido) -3 benzoic acid used as starting material is prepared as follows:

A stirred solution of 22.8 g of 3,4-benzoic diamide aid in 200 ml of dimethylformamide, containing 22.7 g of triethylamine, is treated dropwise with 37 E of 2-ethyl dodeca- chloride. core, similar to that described above in Example 4l, which gives a solid which is recrystallized from ethyl acetate, with black treatment, to obtain 22.2 g of amino acid -4 (2-ethyl-dodecanamido) -3 benzoic as a white solid, mp, 188-191 ° C.

EXAMPLE 43

DD compound

A solution of 9 * 8 S of 4-amino (2-butyl decanamido) -3 benzoic acid in 50 ml of methylethyletone is treated with 11.5 ml of concentrated hydrochloric acid (at 36 * 5 $ by weight / volume ), similarly to that described above in Example 4l, which gives 4.7 g of the hemi-sulphate of (tridecy1-5) -2 benzimidazoleearbo-xylic-5 - {? sS) acid. as a white solid, P.B '. 166-164 ° C. , f The amino-4 (2-butyl-decanamido) -3 benzoic acid used / 30 as a starting material is prepared as follows: // 46

A stirred solution of 15 * 8 g of 3,4-diamino benzoic acid in 130 ml of imethylfmamide, containing 43.4 g of triethylamine, is treated dropwise with 51 * 4 g of 2-butyl decanoyl chloride, similarly to that described above in Example 5 4l, which gives 9.8 g of 4-amino (2-butyl decanamido) -3 benzoic acid in the form of a white solid, PF 17B-182 ° C.

EXAMPLE 44

EE compound

Stirred and heated at reflux for 2 hours a mixture of 10 10 g of 2-n-pentadecyl chloride hydrochloride benzimidazolecarbo-nyle-5 and 250 ml of ethanol. The mixture is cooled to room temperature, the solid is collected and washed with 50 ml of ethanol then with 2 times 50 ml of diethyl ether. This solid is dissolved in 25 ml of boiling ethanol and the solution is treated with 0.5 ml of concentrated hydrochloric acid (at 56.5 / w / v). The solution is cooled to 0 ° C. and the resulting solid is collected, which gives 7.6 C of ethyl n-pentadecyl-2 benzimidazclecarbcxylate-5 in the form of a white solid, FF 2C7- £ 13 ° C · n-pentadecyl-2 bensimidasole-20 carbonyl-5 chloride hydrochloride used as starting material is prepared as follows:

32 Z of 2-n-pentadecyl-2-benzimidazolecarboxylic acid-5 monohydrate are added in portions to 250 ml of a stirred thionyl chloride solution at room temperature. The mixture is stirred and heated under reflux for 2 hours, then the thionyl chloride is removed in vacuo, which gives 33 g of 2-n-pentadecyl benzimidazoleearbonyl-5 hydrochloride as a solid * cream-colored, mp 286-238 ° C (with decomposition).

-. EXAMPLE 45

Compound FF

A mixture of 10 g of 2-pentadecyl-2-benzimidazolecarbonyl-5 chloride hydrochloride (prepared as described above in Example 44) and 300 ml of n-hexyl alcohol is treated in a manner similar to that described above in Example 44, which gives / 9 gg of 2-n-pentadecyl-2-benzimidazoleearboxylate-5 il / 35 hydrochloride in the form of a white solid, PF 166-170eC. Uf EXAMPLE 46

GG compound

4?

V

r

A mixture of 10 g of 2-pentadecyl-2-benzimidazolecarbonyl-5 hydrochloride (prepared as described above in Example 44 above) and 300 ml of n-butyl alcohol is treated in a similar manner. to that described above in Example 44, which gives 8.9 g of butyl-2-pentadecyl-benzimidazolecarboxylate-5 hydrochloride in the form of a white solid, P.?, 170-174¾.

EXAMPLE 47

10 HH compound

A mixture of 10 g of 2-pentadecyl-2-benzimidazolecarbonyl-5 chloride hydrochloride (prepared as described above in Example 44) and 300 ml of isopropyl alcohol is treated in a similar manner to that described above. in Example 44, which gives 6.4 g of isopropyl 2-n-pentadecyl-2 benzimidazolecarbo-xylate-5 hydrochloride in the form of a white solid, PF 184-186¾.

EXAMPLE 48

Compose JJ

Heated at 50¾ for 3 hours a stirred mixture of 20 13.7 S of n-pentadéeyl-2 benzimidazolecarboxylate-3 (prepared as described above in Example 19) and 5 G of chloromethyl pivalate in 35 ml of 'hexamethylphosphotriamide. After cooling, the mixture is poured into 250 ml of water and extracted with diethyl ether (3 times 73 ml). The organic layer is washed with water (3 times 100 ml) and is washed. dry over magnesium sulfate. The organic solvent is removed in vacuo to give a brown oil which is chromatographed on silica gel (400 g) using chloroform as eluent. Cn collects fractions of 100 ml; the fractions, 14 to 22 giving, by evaporation of the solvent, a colorless oil. This oil is dissolved in diethyl ether and treated with a saturated solution of hydrochloric acid in ethanol until the mixture is less than 1%. The white solid is collected and collected. washed with diethyl ether (3 times 100 ml), which gives 10 g / / of pivaloyloxymethyl-2-pentadéeyl-2 henzimidazolecarboxylate-5 hydrochloride in the form of a white solid, mp 165-175 ° C.

EXAMPLE 49

KK compound

12 g of a 50% dispersion of sodium hydride in oil is added over 15 minutes to a stirred mixture of 100 g of glycerol and 100 ml of anhydrous tetrahydrofuran. When the addition is complete, the mixture is vigorously stirred for a further 30 minutes, then 20 g of n-penta-2-deyl-benzimidazolecarboxylic acid-5 hydrochloride (prepared as described above in Example 4). The mixture is vigorously stirred for 2 hours, then left to stand overnight. The brown mixture is poured into 800 ml of water containing 9.4 g of glacial acetic acid and the oily product is extracted with chloroform (2 times 400 ml). The combined extracts are washed with water (twice 500 ml) and dried over sodium sulfate. The empty solvent is evaporated off, the residual oil is dissolved in 500 ml of toluene, the solution is filtered and cooled, which gives a brown gum. The toluene is decanted, 100 ml of diethyl ether are added and the mixture is heated until the gum dissolves, by cooling, rapid to −50 ° C., a white solid preci-20 pite; it is collected and washed with diethyl ether (2 times 100 ml), which gives 6.6 g of n-pentadecyl-2-benzimidazolecarboxy-late-5 of 2,3-dihydroxy-propyl-1 in the form of 'a white solid, PF

109-112 ° C.

ΕΧΕΜΡΣΞ 50

25 Compound B

10 g of diamino-3,4 τ benzoic acid and 168 E of palmitic acid in 100 ml of diglyme containing 10 ml of concentrated hydrochloric acid (at 56.5% w / v) are heated at reflux for 10 hours. . The cooled mixture is poured into 300 ml of water and the solid is collected.

This solid is washed with 2N dilute hydrochloric acid (2 times 100 ml) then with boiling petroleum ether (m.p. 40-60 ° C) (4 times 100 ml). The solid is recrystallized from ethanol, with treatment with black, which gives 50 μg of the hydrochloride of n-pentadecyl-2r j benziEidaaoloearbûxylique-5, mp 295-300 ° C (with decomposition). // '

* K

EXAMPLE 51

Compound B

49

1.88 g of 3,4-diamino benzoic acid hydrochloride and 2.74 g of n-hexadecanoyl chloride 5 are intimately mixed together and the mixture is heated at 130 ° C. for 2 hours. The mixture is then cooled to room temperature and triturated with 100 ml of water, which gives 0.1 g of the 2-n-penta-decyl-benzirnidazoleca.rboxylic acid-5 hydrochloride, PP 295- 300 ° C (with decomposition).

EXAMPLE 52

10 Compound B

A stirred solution of 9 S of 3,4-diamino benzoic acid in 190 ml of dimethylformamide is treated with 16.3 g of n-hexadecanoyl chloride for 30 minutes. The mixture is then heated to reflux for 6 hours and poured into 100 ml of water. The solid is collected and suspended in 100 ml of 2IJ dilute hydrochloric acid. The solid is collected again and washed with water to give 3 g of 2-n-pentadecyl-benzimida-zolecarboxylic acid-5 hydrochloride, m.p. 295-300 ° C (with decomposition).

EXAMPLE 53

20 Compound B

A solution of 390 g of pentadecyl-2-benzimidazolecarboxylic-5-acid monohydrate (prepared as described above in example 12) in a mixture of 2000 ml of acetone and 1000 ml of is heated to 60 ° C. water, then treated with a solution of 40 g of sodium hydroxide in 50 ml of water. The mixture is stirred for 1 hour while * heating at reflux, then cooled to 0 ° C. The solid is collected and recrystallized from a mixture of 1000 ml of acetone and 500 ml of water, which gives 3 ^ 5 g of n-pentadecyl-2 / monohydrate. , sodium bensimidasolecarboxylate-5, m.p. above 300 ° C with //

30 decomposition. f / J

Compound IL

ff ff EXAMPLE 54 50

A solution of 17.6 g of bis (n-tetradecana-mido) -2.3 benzoic acid in 250 ml of methyl ethyl ketone is treated with 25 ml of concentrated hydrochloric acid (at $ 36.5 by weight / volurae) . The mixture is heated to reflux: for 5 hours, then cooled and treated in a similar manner to that described above in Example 15, which gives 6.5 g of the hydrochloride of n-tridecyl acid. 2 benzimidazole-carboxylic-1) in the form of a buff-colored solid, mp 192-10 200 ° C.

Benzo (n-tetradeaneandido) -2.5 acid used as starting material is prepared as follows:

A solution of 20 g of 2,3-diamino benzoic acid in 200 ml of dimethylformamide, containing 39 * 9 g of triethylamine, is treated with 65.0 g of n-tetradecanoyl chloride. The speed of addition of n-tetradecanoyl chloride is such that it allows the temperature of the reaction mixture to rise from room temperature to 45-50 ° C. The mixture is then stirred for a further 2 hours and allowed to stand at room temperature overnight.

20 ml of methanol are added to the mixture, the resulting mixture is stirred for 20 minutes and then treated with concentrated hydrochloric acid (at $ 36.5 w / v) until it is pH 2. The resulting mixture is poured into 1000 μl of water, the black solid is collected, washed with water (twice 500 ml) and then with 500 ml of petroleum ether (PE 60-30 ° C) hot and finally recrystallized from ethanol, with black treatment, which gives 17.7 g of bis (n-tetradecanamido) -2.3 benzoic acid in the form of a buff-colored solid, Mp 150-158 ° C.

EXAMPLE 55

30 Compound S

A suspension of 2.0 g of 3-amino acid :: 4-amino-benzoic acid in 60 ml of methyl ethyl ketcene, containing 1.5 ml of hydrochloric acid (concentration 36.5) is heated at reflux for 5 hours. % // by weight / volume). The resulting solid is collected and washed with / Jf

Y

i 51 boiling petroleum ether (PE 60-80 ° C) and recrystallized from ethanol, which gives 2.0 g of n-pentadecyl-2-benzimidazolecarboxylic acid-5 hydrochloride in the form of a white solid, mp 288-290 ° C (with decomposition).

5 The amino-3 n-hexadecanamido-4 benzoic acid used as starting material is prepared as follows:

A solution of 22 g of 3-nitro-n-hexadecanamido-4 benzoic acid in 500 ml of n-butanol is hydrogenated by shaking in the presence of 2.5 g of palladium on black at 5% by weight, at 70 ° C. and at atmospheric pressure for 6 hours, the mixture is filtered hot and the filtrate is allowed to cool. The resulting solid is collected and washed with 100 ml of ethanol, which gives 11.6 g of 3-amino-4-hexadecanamida benzoic acid in the form of a cream-colored solid, m.p. 160 ~ 162 ° C.

The 3-nitro-n-hexadecanamido-4 benzoic acid used as starting material is prepared as follows:

Gn heats for 90 minutes at 97 ° C a solution of 18.2 g of 4-amino-3-nitro benzoic acid and 33.0 g of hexa-decanoyl chloride in 100 ml of dimethylformamide. The solution is cooled and then poured onto 3CO g of crushed ice. The resulting solid is collected, washed with water (3 times 100 ml), dried and recrystallized from a mixture of acetone and water (5 / l), with treatment with black, which gives 31. ”7 pounds of 3-nitro-n-hexadecanamido-4 benzoic acid form a pale yellow solid, mp 153-25 154 ° c.

EXAMPLE 56

Compound MM

A suspension of 9.6 g of 2-n-pentadecyl-2-benzimidazolecarboxylic acid hydrochloride (prepared as described above in Example 4) in 75 ml of thionyl chloride is heated to reflux for 2 hours; The excess thionyl chloride is removed by vacuum distillation, leaving a brown solid. This solid is triturated with 200 ml of toluene and the toluene is evaporated in vacuo. The residue is added to a solution of 3.64 ml of triethylamine in 250 ml of tert-butanol and the mixture is heated at reflux for 3 hours. Apri ^ ay f i.

> 52 cooling, the excess residue is evaporated, -butanol under vacuum and the residue is suspended in 150 ml of ethyl acetate. The suspension is heated to reflux for 10 minutes and filtered while hot. The filtrate is cooled and the resulting solid is collected. This solid is washed with ethanol (2 times 50 ml) then with diethyl ether (2 times 50 ml) and dried, which gives 5.5 g of 2-n-pentadecyl-benzimidazolecarboxylate hydrochloride. 5 of tert.-butyl in the form of a whitish solid, mp 165-168 ° C.

EXAMPLE 57 10 e ° mP ° s É NI ·!

A mixture of 15 g of 2-pentadecyl-benzxmidazolecarbonyl-5 chloride (prepared as described above in Example 44) and JOO ml of allyl alcohol is treated in a similar manner to that described above in 1 Example 44, which gives 10.4 g of the hydrochloride of 15 n-pentadecyl-2 ben "allyl dazcleearboxylate-5 in the form of a white solid, mp 196-200 ° C.

EXAMPLE 56

Compose M

To a stirred solution of 9.8 C of 3,4-diamino methyl benzoate in 200 ml of methanol is added a solution of 23.6 g of cupric acetate in 300 ml of water, followed by a solution of 10 g of n-decanal in 40 ml of methanol. The mixture is heated to reflux for 1 hour and allowed to cool, then the purple solid is collected. This solid is dissolved in 600 ml of 75% by volume aqueous methanol and hydrogen sulfide is passed through the solution until the. copper sulfide precipitation ceases. The copper sulfide is collected and the filtrate is concentrated to obtain a red oil. This oil is dissolved in 100 ml of methanol containing 15 ml of concentrated hydrochloric acid (at 36.5 $ by weight / vol) and the solution is heated at reflux for 4 hours. After cooling, the greyish green solid is collected and dissolved in 100 ml of tetrahydrofuran containing 5 ml of ammonia (concentration 35% by weight), Gn dilutes the solution with 400 ml of water and the pink solid is collected. This solid is chromatographed on silica with, / 35 as eluent, a mixture (25 / I by volume) of chloroform and methanolyy tf 55> Λ

The isolated substance is dissolved in 25 ml of methyl ethyl ketone and 2.5 ml of concentrated hydrochloric acid (56.5% w / v) are added, with stirring. The resulting solid is collected and washed with diethyl ether (2 times 50 ml), which gives 5 * 3 g of methyl 2-n-nonyl-2-benzimidazolecarboxylate 5 in the form of a white solid. , P.?. 234-237 ° C. (With decomposition).

EXAMPLE 59

PP compound

120 ml of concentrated hydrochloric acid (36.5% w / v) are added over 20 minutes to a refluxed solution of 165.3 g of bis (n-hexadecanamido) acid -2, 3 crude benzoic acid in 1200 ml of methyl ethyl ketone and the mixture is heated to reflux for 6 hours. The resulting solution is cooled and the solvent is removed by vacuum distillation. After trituration of the residue with 2000 ml of water, the granular solid is collected and washed with warm petroleum ether (PE 60-80 ° C) (twice 500 ml), then with ether diethyl (500 ml). This solid is dissolved in 250 ml of boiling methyl ethyl ketone, the solution is treated with black and filtered while hot. The filtrate is evaporated in vacuo, which leaves a chamois-colored solid. This solid is chromatographed on silica with a 9/1 by volume mixture of chloroform and methanol as eluent. The resulting product is recrystallized from ethyl acetate, which gives 5 * 4 ε of 2-n-pentadeeyl-2-benzimidazolecarboxylic-4 in the form of a buff-colored solid, m.p. 160-166 ° C.

25 Benzo (n-hexadecanamido) -2.3 acid used as starting material is prepared as follows:

A solution of 40 g of 2,3-diamino benzoic acid in 600 ml of dimethylformamide, containing 79 * 7 S (109 * 5 ml) of trlethylamine, is treated. per 144.5 g of n ~ hexadecanoyl chloride. The speed of addition is such that it allows the temperature of the mixture

reaction to rise from room temperature to 45-50cC. The mixture is then stirred for a further 3 hours and allowed to stand at room temperature overnight. This mixture is added to 1200 ml of water containing 50 ml of concentrated hydrochloric acid (at $ 36.5 / 35 w / v) and the resulting solid is collected and washed with // V

5½ ”1200 ml of water. This solid is stirred with 4000 ml of hot water (65 ° C) for JO minutes, it is collected and dried under vacuum at "J0 ° C. the resulting product, bis acid (n-hexadecanamido) -2 , 3 benzoic, is used without further purification in the above preparation.

* 5 Reference example 1

A stirred solution of 152 g of 3,4-diamino benzoic acid in 15ΟΟ ml of dimethylformamide, containing 303 g of triethylamine per 549.0 g of n-hexadecanoyl chloride, is treated dropwise in 1 hour 1/2. The rate of addition of n-hexadecanoyl chloride 10 is such that it allows the temperature of the reaction mixture to rise from the asbestos temperature to 35- ^ 0 ° C. The mixture is then stirred at room temperature for another 2 hours, then poured into 10 liters of hot water maintained at 70 ° C, containing 150 ml of concentrated hydrochloric acid (at 36.5% w / v).

The resulting solid is collected, which gives bOO g of bis (n-he-xadecan “mido) -j, 4 benzoic acid in the form of a buff-colored solid, mp 180-190 ° g, usable in the preparation described above in Example 15.

Reference Example 2 Using a procedure similar to that described above in Example 38 for the preparation of 4-amino-n-nonadeca-nar.ido-3 benzoic acid but replacing the chloride of n -ncnadecanoyl with n-octanoyl chloride, 4-amino-n-octanamido-3 benzoic acid is prepared in the form of a whitish solid, F, 7. 202-203 ° C after recrystallization from methanol.

Reference example 3

By proceeding in a similar manner to that described above in Example 36 For the preparation of 4-amino-n-nonadéeana-raido-J benzoic acid but by replacing the n-nonadecanoyl chloride by chloride de n-dodecanoyl, 4-amino acid n-dodec / canamido-J benzoic acid is prepared in the form of a white solid, mp 183-185 ° Q * /

Reference example 4 55

By proceeding in a similar manner to that described above in Example 58 for the preparation of 4-amino-n-nonadecana-mido-3 benzoic acid but by replacing n-nonadecanoyl chloride by 5 of n- octadecanoyl, anino-4 n-octadeeana-mido-3 benzoic acid is prepared in the form of a light brown solid, mp 185-187 ° C. after recrystallization from methylethyletone.

Reference example 5

A solution of 3,4-diamino-benzo-10 ate methyl (83.1 g) in 900 ml of anhydrous dimethylformamide, containing 50.8 g of triethylamine, is treated dropwise with 81.3 E of n- chloride. oeta-nucleus for 30 minutes at a temperature maintained between 5 and 8 ° C.

The mixture is stirred for a further 2 hours. The solid is removed by filtration and the filtrate is poured into ml000 ml of water. The resulting solid was collected and recrystallized twice from methanol to give 65.5 g of 4-amino-n-octanamido-3 benzoate as a white solid, m.p. 120 ° C.

Reference example 6

By proceeding in a similar manner to that described above in reference example 5 but by replacing the n-octa-nucleus chloride with n-dodecanoyl chloride, the 4-amino-n-dodé-canamido is prepared. -3 methyl benzoate in the form of a whitish solid, mp 102-105 ° C after recrystallization from methanol.

Reference example 7 By proceeding in a similar manner to that described above in reference example 5 but by replacing the n-octa- * nucleus chloride with n-tridecanoyl chloride, the 4-amino is prepared. methyl n-tride-canamido-3 benzoate in the form of a light brown solid, 1 mp 101-104 ° c after recrystallization from methanol.

30 Reference example 8

By proceeding in a similar manner to that described in reference example 5 but by replacing the n-octanoyl chloride with n-tetradéoanoyl chloride, the 4-amino-n-tetradecanamido-3 ^ / methyl benzoate is prepared. in the form of a light brown solid, PF, 108-10955 / 35 after recrystallization from methanol. / ta 0 56

Reference example 9

By proceeding in a similar manner to that described above in reference example 5 but by replacing the n-octa-nucleus chloride with n-hexadecanoyl chloride, the 4-amino-n-hexa-5 decanamido is prepared. -3 methyl benzoate in the form of a white solid, F, F. 109-110 ° C after recrystallization from methanol.

Reference example 10

A solution of 5 g of methyl 3,4-diaraino benzoate in 50 ml of dimethylformamide, containing 6.1 g of triethylamine, is treated dropwise with a solution of 16.54 g of hexadeca chloride in 40 ml of anhydrous dimethylformamide in 5 minutes. The temperature is allowed to rise from 20 to 50 ° C. The mixture is stirred for a further 3 hours. The resulting suspension is poured into 800 ml of water containing 10 ml of concentrated hydrochloric acid (36> 5 by weight / vo-15 lume). The resulting solid is collected and recrystallized from a mixture (l / l) of chloroform and acetone, which gives 12.1 g of bis (n-hexaûéeanaraido) -p> 4 methyl benzoate in the form of a white solid, mp 129-132 ° C, identical to the starting material used in Example 16.

20 Reference example 11

By proceeding in a similar manner to that described above in reference example 10 but by replacing n-hexadecanoyl chloride with n-octanoyl chloride, the bis (n-neta-namido) -3.4 is prepared. methyl benzoate as a white solid, PF

25 145-1Λ7 ° C after recrystallization from acetone.

Reference example 12 v By proceeding in a similar manner to that described above in reference example 10 but by replacing t n-hexadecanoyl chloride with n-dodecanoyl chloride, 30 bis (n-dodecanamido) is prepared. ) - 3,4 methyl benzoate in the form of a solid / whitish, PF, -129-1310C anres recrystallization from acetone ^ / 7 57

Reference example 13

By proceeding in a similar manner to that described above in reference example 10 but by replacing the n-hexa-decanoyl chloride with n-tridecanoyl chloride, the bis (n-tride-5 canamido) is prepared. -3.4 methyl benzoate in the form of a white solid, mp 152-134 ° C after recrystallization from acetone.

Reference example l4

By proceeding in a similar manner to that described above in reference example 10 but by replacing the n-hexa-10 decanoyl chloride with n-tetradecanoyl chloride, the bis (n-tee-tradecanamido) is prepared - 3,4 methyl benzoate in the form of a white solid, mp 132-133 ° C after recrystallization from acetone.

Reference example 15

By proceeding in a similar manner to that described above in reference example 10 but by replacing the n-hexa-decanoyl chloride with n-octadecanoyl chloride, the bis (n-octa-decanamldo) is prepared - 3,4 methyl benzoate in the form of a white solid, mp 120 ° C. after recrystallization from a mixture (l / l) of acetone and methanol.

20 Reference example 16

12.1 g of 3-amino-n-octanamido-4 benzoic acid in 200 ml of methanol are treated with an ethereal solution of diazomethane until the reaction is completed, as can be seen by thin layer chromatography on silica. using a mixture (10/90 / 0.5) of methanol, chloroform and glacial acetic acid as eluent. 0.2 ml of acetic acid is then added and the reaction mixture is concentrated under reduced pressure. The resulting solid is recrystallized from ethyl acetate, which gives 9> 2 g of methyl amino-3 / n-octanamldo-4 benzoate in the form of a color / cream solid, PF 125- l51eC. ^ "58

Reference example 17 η

25 g of 3-nitro-n-octanamido-4 benzoic acid dissolved in 500 ml of ethanol at 50 ° C. are hydrogenated, shaking in the presence of 2.5 g of palladium on black at $ 5 by weight, at 50 ° C. and at atmospheric pressure for 3 hours. The mixture is filtered hot and the filtrate is evaporated in vacuo. The residue is recrystallized from a mixture (l / i) of ethanol and water, which gives 8 g of 3-amino-n-octanamido-4 benzoic acid in the form of a yellow solid, PF 155 -156 ° C.

The benzoic-3-n-octanamido-4-nitro acid used as starting material is prepared as follows:

A solution of 18.2 g of 4-amino-3-nitro-benzoic acid and 19.4 g of n-octa-nucleus chloride in 100 ml of anhydrous dimethylformamide is treated at 97 ° 0 for 90 minutes. The solution is cooled and poured onto 300 g of ice. The resulting solid is collected and washed with water (3 times 100 ml), dried and recrystallized from a mixture (8/1) of methanol and water (with treatment in black), which gives 22 g of 3-nitro-n-octanamido-4 benzoic acid in the form of a pale yellow solid, mp 153-15 ^ ° C.

Reference Example 18 20 21 g of 3-nitro-n-dodecanamido-4 benzoic acid dissolved in 500 ml of ethyl acetate are hydrogenated by shaking in the presence of 2.5 g of palladium on black at 5% by weight, 50 ° C and at atmospheric pressure. The resulting mixture is filtered hot, giving a cream-colored solid upon cooling. This product is recrystallized from methanol, which gives 7j4 g of 3-amino-n-dodé-canamido-4 benzoic acid in the form of a beige solid, m.p. 153-160 ° C.

^ Reference example 19 * * Proceeding in a similar manner to that described above “· in reference example 5 but replacing the n-octa-,, 30 chloride chloride with n-decanoyl chloride, we prepares the amino-4 n-decanami- / do-3 methyl benzoa.te souk form of a white solid, mp 96-100 ° C / yi 59

Reference example 20

By proceeding in a similar manner to that described above in the reference example 10 but by replacing the n-hexa-decanoyl chloride with n-deeanoyl chloride, the bis (n-decana-5 raido) is prepared - 3,4 methyl benzoate in the form of a white solid, mp 139-144 ° C. after recrystallization from ethanol.

Reference example 21

A stirred solution of 10 g of dlamine-3 * 4 benzoic acid in 100 ml of anhydrous dimethylformamide 10, containing 28 g of potassium carbonate, is treated dropwise over 5 minutes with a solution of 33.1 g of n-ciodecanoyl chloride in 30 ml of anhydrous dimethylformamide. The temperature is allowed to rise from 20 to 50 ° C. The mixture is stirred for a further 3 hours. The resulting suspension is filtered and the filtrate is poured into 700 ml of water containing 10 ml of 15-hydrochloric acid (36.5% w / v). The resulting solid is collected and re-crystallized from glacial acetic acid; the product is then washed with water and recrystallized from methyl ethyl ketone, which gives 12.5 E of bis (n-dodeeanamido) -3.4 benzoic acid in the form of a white solid, PF 195 "197 ° 0.

20 Reference example 22

By proceeding in a similar manner to that described above in reference example 21 but by replacing the n-do-decanoyl chloride with n-hexadeaneanl chloride and the potassium carbonate with sodium carbonate, 'bis (n-hexadecana-25 mido) -3.4 benzoic acid in the form of a white solid, mp 198-202 ° C after successive recrystallizations from glacial acetic acid and methyl ethyl ketone.

* Reference example 23 'By proceeding in a similar manner to that described above 30 in the reference example 21 but by replacing the n-do-decanoyl chloride by n-oetanoy chloride? I, the bis (n-octa-namido) -3.4 benzoic acid in the form of a white solid, mp 195-197 ° C / after successive recrystallizations from glacial acetic acid and methyl ethyl ketone. (_Jf

Example of reference 24 • r 6o

By proceeding in a similar manner to that described above in reference example 21 but by replacing the n-dodecanoyl chloride with · n-tetradeanoyl chloride, the bis (n-tetradecanamido) -3 acid is prepared. , 4 benzoic in the form of a white solid, mp 201-206 ° C after recrystallizations sucessi-ves from glacial acetic acid and methyl ethyl ketone.

Reference example 2p

21 g of methyl n-dodecanamido-3-nitro-benzoate 10 dissolved in 500 ml of ethyl acetate are hydrogenated at 50-55 ° C by shaking in the presence of 2.0 g of palladium on black at 5 / J sn weight, at 60 ° C and at atmospheric pressure for 2 hours. The mixture is filtered hot and the filtrate is allowed to cool. The solid is collected to obtain 1 * 1.1 g of 3-amino-n-docecanamido-4 15 methyl benzoate under the cover of a white solid, m.p. 134-137 ° C.

The n-dodecanamid o-4 nitro-3 methyl benzoate used as starting material is prepared as follows:

19.6 g of 4-amin-3-nitro-benzoate and 23 g of n-dodecanoyl chloride are heated in 100 ml of dimethylforma-20 mide for 2 1/2 hours at 9 ° C., shaking. time to time.

The resulting solution is poured onto 300 g of crushed ice, the solid is collected and it is recrystallized from a mixture (5/1) of methanol and chloroform, which gives 31 g of n-dodé-canamido-4 methyl nitro-3 benzoate in the form of a yellow solid, PF 75-80ÔC.

The methyl amino-3-nitro-benzoate is prepared as follows:

70 g of 4-amino-3-nitro benzoic acid are added to a "solution of anhydrous HCl in methanol (made from 78 g of 3 ° acetyl chloride and from 300 ml of anhydrous methanol). the resulting mixture at reflux for 10 hours, it is cooled in ice and the solid is collected, which gives é2 g / of 4-amino-3-nitro-3 benzoate in the form of a yellow solid // PF 195 -195 ° C »// 1 /

Reference example 26 61

By proceeding in a similar manner to that described above in reference example 25 for the preparation of 3-amino-n-dodecanamido-4 benzoate but by replacing the 5-n-dodé-canamido-4 nitro-3 methyl benzoate with methyl n-hexadecanamido-3 nitro-3 methyl benzoate, methyl amino-3 n-hexadecanamido-4 benzoate is prepared in the form of a white solid, FF 135 “137 ° c ·. Reference example 27

By proceeding in a similar manner to that described above 10 in the reference example 25 for the preparation of 2-araino-2 n-dodecanamido-4 benzoate but by replacing the 4-n-dodeca-naraido-nitro- 3 methyl benzoate with methyl n-deeanamido-4 3-nitro benzoate, methyl amino-3 n-decanamido-4 benzoate is prepared in the form of a white solid, mp 131-133 ° C.

15 Example of reference 28

A stirred solution of 8..4 g of 3,4-diamino benzoic acid in 100 ml of anhydrous dimethylformamide, containing 15.27 g of potassium carbonate is treated dropwise with a solution of 15.17 g of chloride. of n-hexadecanoyl in 30 ml of anhydrous dimethylformamide, in 30 minutes, at 0 ° -5 ° C. The mixture is stirred for a further 2 hours at 0 ° -5 ° C and allowed to warm to room temperature in 70 minutes.

The solution is then poured into 700 ml of water containing 10 ml of hydrochloric acid (at 36.5% by weight / volume), the solid is collected, it is heated with 300 ml of acetone at 50 ° C. and it is recrystallized. from methyl ethyl ketone, which gives 9 * 4 g of 4-amino-n-hexadecanamido-3 benzoic acid in the form of a white solid, PF 197-199 “C.

Reference example 29 30 Proceeding similarly to that described above in reference example 21 but replacing n-dodecanoyl chloride with n-deeanoyl chloride, the acid is prepared - bis (n -decanamidobenzoic acid in the form of a white solid, / PF 194-196eC after successive recrystallizations from glacial acetic acid and methyl ethyl ketone.

Reference example 3 ° 62

By proceeding in a similar manner to that described above in reference example 21 but by replacing the n-dodecanoyl chloride with n-tridecanoyl chloride, the 5 bfe acid (n-tridecanamido} -3) is prepared, 4 benzoic acid in the form of a whitish solid, mp 192-194 ° C after successive recrystallizations from glacial acetic acid and methylethyletone.

Reference example 31 'v 1 11 ^ - 1

By proceeding in a similar manner to that described above 10 in the reference example 21 but by replacing the n-dodecanoyl chloride with n-octadecanoyl chloride, the dis (n-octadecanaraido) -3 acid is prepared, 4 benzoic acid in the form of a white solid, mp 193-196 ° C after successive recrystallizations from glacial acetic acid and methylethyletone.

The present invention encompasses in its field pharmaceutical compositions which contain at least one of the compounds of general formula (i) or one of their pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the present invention may be administered parenterally, but it is preferred to administer them rectally or, better, orally.

Solid compositions for oral administration include tablets, pills, powders and granules. In such compositions, one or more of the active compounds are mixed with at least one inert diluent such as starch, sucrose or lactose. These compositions can also '. contain, as is common practice, related substances other than inert diluents, for example /) / 30 lubricants such as magnesium stearate.

i f 63 ♦

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing the inert diluents commonly used in the art, such as water and paraffin oil. In addition to the inert diluents, these compositions can contain adjuvants, such as wetting agents, suspending agents, sweetening and flavoring agents, perfumes and preservatives. The compositions according to the invention for oral administration also include capsules of ingestible material, such as gelatin, containing one or more active substances with or without the addition of diluents or excipients.

The preparations according to the invention for parenteral administration include aqueous, hydro-organic and organic sterile solutions, suspensions and emulsions. As examples of organic solvents or suspension media, mention may be made of propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants.

These compositions can be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents, by irradiation or by heating. They can also be manufactured: in the form of sterile solid compositions which can be dissolved extemporaneously in sterile water or another sterile injectable medium.

Solid compositions for rectal administration include suppositories prepared according to known methods - and containing one or more of the compounds of formula (I) or one of 1: their pharmaceutically acceptable salts.

The percentage of active ingredient in the compositions / according to the invention may vary, but it is necessary that it cons-W 'y c 64 titrate a proportion such that a suitable dosage can be obtained. Of course, several unit dosage forms can be administered at about the same time. The dose to be used will be determined by the doctor, and depends on the desired therapeutic effect, the method of administration and the duration of treatment, as well as the condition of the patient. In adults, the doses are generally between 0.1 and 50 mg per kg of body weight per day, by oral administration. For example, as a lipid-lowering and anti-atheroma agent and in associated cardiovascular disease, between 10 and 50 mg per kg of body weight per day, orally; in the treatment of diabetes, between 5 and 40 mg per kg of body weight per day, by oral administration; and in the treatment of arthritis and related diseases, between 0.1 and 10 mg per kg of body weight per day, by oral administration.

The following example illustrates the pharmaceutical compositions according to the present invention EXAMPLE 60

Size 20 gelatin capsules size 2 are prepared according to the usual method, each containing: sodium n-pentadecyl-2-benzimidazolecarboxylate-5 20 mg lactose 100 mg starch 60 mg 25 dextrin 40 mg, magnesium stearate 1 mg / ml v.

L v

Claims (10)

1. Benzimidazole derivatives having the general formula: R ^ OOC__ J ^ ~ R2 (1) H in which represents a hydrogen atom, a straight or branched alkyl group 5 containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of the same type chosen from the hydroxy group, the alkenyl groups containing from 2 to 5 carbon atoms and the alkanoyloxy groups containing from 2 to 7 carbon atoms) and R represents a straight chain alkyl group 10 or branched containing from 7 to 20 carbon atoms, the group R ^ OOC- being attached to position 4 or 5 of the benzimidazolic ring system, and the pharmaceutically acceptable salts of these derivatives. 2. 2-n-pentadecyl benzimidazolecarboxylic-5 aid, 2-n-undecyl-2 benzimidazolecarboxylic acid-5, 2-n-pentadecyl benzimidazolecarb.n-butyl 5-oxylate, 2-pentadecyl-2 benzimidazolecarboxylate -5 dihydroxy-2, p propyl-1, n-tridecyl-2 benzimidazolecarboxylic-5, n-dodecyl-2 benzimidazolecarboxylic-5, 20 (tetradecyl-2) -2 benzimidazolecarboxylic acid - (RS), 2-n-hexadylyl benzimidazolecarboxylic acid-5, 2-n-octadecyl acid benzimidazolecarboxylic-5, Lp, 2-n-heptadecyl acid benzimidazolecarboxylic-5, n-heptyl-2 methyl benzimidazolecarboxylate-5, methyl 2-pentadecyl-benzimidazoleearboxylate-5, methyl n-undecyl-2 benzimidazolecarboxylate-5, methyl n-tridecyl-2 benzimidazolecarboxylate-2, / n-dodecyl methyl benzimidazolecarboxylate-5, // Y c 66 * methyl n-decyl-2 benzimidazolecarboxylate-5, 2-n-decyl-benzimidazoleearboxylic-5, n-heptadecyl-2 benzimida2olecarboxy methyl late-5, methyl n-nonyl-2 benzimidazolecarboxylate-5, * 5 n-nonyl-2 bensimidazolecarboxylic-5, n-heptyl-2 benzimidazolecarboxylic-5, n-tetradecyl acid -2 benzimidazolecarboxylic-5, n-octyl-2 acid benzimidazolecarboxylic-5,. methyl n-tetradecyl-2 benzimidazolecarboxylate-5, methyl 2-n-hexadecyl benzimidazolecarboxylate-5, methyl n-eicosyl-2 benzimidazolecarboxylate-5, n-eicosyl-2 benzimidazolecarboxylic acid * methyl n-nonadecyl-2 benzimidazolecarboxylate-5, 2-n-nonadecyl benzimidazolecarboxylic-5, 15 acid (tridecyl - ^) - 2 benzimidazolecarboxylic-5- (RS), acid (trideoyl-7) -2 benzimidazolecarboxylic-5, (tridecyl-5) -2 benzimidazolecarboxylic-5- (RS), ethyl n-pentadeeyl-2 benzimidazolecarboxylate-5, n-hexyl n-pentadecyl-2 benzimidazolecarboxylate-5 , 20 n-pentadecyl-2 bcnz i mi d az isopropyl olecarboxylate-5, n-octadecyl-2 benzimirîazclecarboxylate-5, n-pentadecyl-2 benzimidazolecarboxylate-5 pivaloyloxymethyl, n-trideyl acid -2 benzimidazolecarboxylic-4, n-pentadecyl-2 benzimidazolecarboxylate-5 tert-butyl, 25 n-pentadecyl-2 benzimidazolecarboxylate-5, ally n-pentadecyl-2 acid zimidazolecarboxylic-4, and the pharmaceutically acceptable salts of these compounds, 5. Process for the preparation of a benzimidazole derivative according to claim 1, characterized in that a compound of general formula is cyclized: ^ NHCOR2 / R ^ OOC —Ç— dd (il) / il II ί 67 in which R ° represents a hydrogen atom or a group -COR, 1 2 and R and R are as defined in claim 1. 4. Method according to claim 3j characterized in that the cyclization of the compound of general formula (II) takes place, preferably at high temperature, by reaction with a mineral acid in the presence of water and within a organic solvent. 5. Method according to claim 3, R ° representing a hydrogen atom, characterized in that the cyclization of the compound of general formula (II) takes place by reaction with an organic acid in water or a solvent organic, preferably at elevated temperature. 6. Method according to claim 3 * characterized in that the cyclization of the compound of general formula (II) takes place either in the absence of an organic solvent and at elevated temperature, or in the presence of water and a mineral acid and within a suitable organic solvent. 7. Process for the preparation of a benzimidazole derivative according to claim 1, characterized in that a compound of general formula is reacted: 20 R100C _] _ l | (V) xA1 # 2 (in which R1 is as defined in claim l) with a compound of general formula: R2CH0 (VI) * - (in which R is as defined in claim l) and 'v 25 copper salt II in the presence of an inert hydro-organic solvent medium, between ambient temperature and the reflux temperature / of the reaction mixture, then the resuly copper salt is transformed? / ψ 68 * * * ^ T while corresponding compound of the general formula shown in claim 1. 8. A process for the preparation of a benzimidazole A derivative according to claim 1 in which Fr "represents a 5-hydrogen atom, characterized in that a corresponding ester of the general formula represented in claim 1 is hydrolyzed in which represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more substituents of the same type chosen from the hydroxy group, the alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms, and R is as defined in claim i. 9. Process for the preparation of a benzimidazole derivative λ according to claim 1, in which R represents an al-15 coyl group with a straight or branched chain containing from 1 to 6 carbon atoms, which may be substituted by one or more substituents of same type chosen from the hydroxyl group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms and R is as defined in claim 1, characterized in that esterifying a corresponding carboxylic acid of the general formula shown in claim 1 and wherein represents a hydrogen atom and R is as defined in claim 1. 25 10, Process according to any one of claims J to 9 followed by the step of transformation, by known methods, of a benzimidazole derivative thus obtained, of the general formula represented in claim 1, into one of its pharmaceu-tically acceptable salts. 11. Pharmaceutical compositions which contain, as active ingredient, at least one benzimidazole derivative according to claim i, or one of its pharmaceutically acceptable salts, in association with a pharmaceutical carrier or coating. Drawings: ....... plates 6¾ ........ pages of which ....... To ....... page of cover ..... Lb ..... ..description pages ........... ît ...... claims pages ............ short description ^. "1 mm" nxiK? ^ / L