DK145494B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2-PHENYL BENZIMIDAZOLD DERIVATIVES - Google Patents

Description

• * "14549 /,

This invention relates to an analogous process for the preparation of novel 2-phenylbenzimidazole derivatives of the general formula II

Eitx;> E2 'π wherein ^ is hydrogen, halogen, C1-C6 alkyl or C1-C (alkoxy, 5 and R2 are an ethyl group and the process is peculiar to the characterizing part of claim 1.

The compounds of the invention are fermentaceous. tically active agents. They are useful as antiinflammatory agents and / or as anaigetics. . j- <. J .. 'r. · 10 A number of 2-phenylbenzimidazolderiya are already known.

British Patent No. 1,113,808 ^ Australian Patent. Ci 404,383, Belgian Patent No. 631,490, Archiv der Sharmaze, 301, 177 (1968) and Chem.Abst. 69, 360892, e.g.

2-Phenylbenzimidazole derivatives, as in 5 (6) - The position of the benzimidazole ring has a substituent such as halogen, lower alkyl or lower alkoxy. These literature sites also describe derivatives of 2-phenylbenzimidazole, whose 2-phenyl group is substituted by a substituent, especially methyl. However, none of these literature sites discloses the 2-ethylphenyl = 20 benzimidazoles defined by the above formula II.

Surprisingly, it has now been found that the compounds of the above Formula II are better than the closely related known compounds with respect to a particular pharmacological action. l; 2 UG /, 94

These compounds of formula II can be prepared according to the invention by reacting a compound of formula III

XC;

having the same meaning as in Formula II, or an acid addition salt thereof, with a compound of Formula VII

wherein R2 has the same meaning as in Formula II, in the presence of a condensing agent, preferably under a stream of nitrogen gas. Examples of preferred condensing agents include polyphosphoric acid, esters thereof, hydrochloric acid, hydrogen bromic acid and boric acid. The reaction can be carried out at a temperature of 100 ° 200 ° C and, if desired, in an inert solvent such as o-dichlorobenzene, nitrobenzene or diglyme. Polyphosphoric acid and its esters are particularly preferred because they give compound II in a higher yield by simply diluting the reaction mixture with water and neutralizing.

The compounds of formula II may also be prepared by reacting the starting compound III with a compound of formula VIII

"O" wherein R 2 has the previously defined meaning and Y is 20 -CN, -CSSH, -CHO or -COOR wherein R is C 1 -C 4 alkyl, in a polar solvent, first under basic conditions and then under slightly acidic conditions. Examples of preferred polar solvents include dimethylformamide, d1 = methylacetamide, N-methylpyrrolidone, hexamethylphosphoramides, dimethylsulfoxides, methanol or ethanol, and methanol or ethanol preferred. Examples of bases which may be used in the above reaction include alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium t-butoxide, and alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. Examples of acids which may be used in the aforementioned reaction include acetic acid, citric acid, oxalic acid, carboxylic acid, hydrochloric acid or hydrobromic acid, and acetic acid is preferred. The reaction can preferably be carried out by heating the reactants III and VIII in a polar solvent in the presence of a base at a temperature of from room temperature to the boiling point of the solvent, adding an acid to the reaction mixture to make the mixture slightly acidic and the reaction proceeds. at a temperature of 60 ° C to the boiling point of the solvent.

The compounds of the invention have useful pharmacological effects. To illustrate the anti-inflammatory effect of these compounds, the compounds listed in the following table were given daily at a dose of 100 mg / kg given to male Wistar rats weighing 110-130 g. of the Society for Experimental Biology and Medicine ", 111, 544 (1962).

The percent inhibition of edema after 3 hours was determined.

i- · .-.

The data obtained are shown in the following table.

Table I also shows data obtained for some 30 known 2-phenylbenzimidazole compounds and phenylbutazone, 4 U549 /, a typically known anti-inflammatory agent, for comparison purposes.

TABLE I.

Compounds% inhibition

Compounds of the invention: 2- (p-ethylphenyl) benzimidazole 58 2- (p-ethylphenyl) -5 (6) -methoxybenzimidazole 88 2- (o-ethylphenyl) -5 (6) -methoxybenzimidazole 70 2- (m- ethylphenyl) benzimidazole 56

Known 2-phenyl =. Benzimidazole Compounds: 2-Phenylbenzimidazole 33 2- (m-toluyl) benzimidazole 43

control:

Phenylbutazone 43 As indicated in the preceding table, the compounds of the invention exhibit a higher anti-inflammatory effect than the known compounds, and the novel compounds of the invention even have an effect which is significantly better than that of the well-known compound. anti-inflammatory agent phenylbutazone.

The compounds of the invention can be used in warm blooded animals, especially mammals, as medicaments in the form of pharmaceutical products containing the compounds in admixture with or in association with a pharmaceutical organic or inorganic solid or liquid carrier, for oral, rectal or parenteral administration.

The total daily dose can range from approx. 1 mg / kg to approx.

10 mg / kg.

i; · * ''

The process according to the invention is further elucidated by the following examples.

EXAMPLE 1.

Preparation of 2- (p-ethylphenyl) benzimidazole, 5.5 g of o-phenylenediamine, 7.6 g of p-ethylbenzoic acid, 40 g of polyphosphoric acid was heated to 160-180 ° C under a nitrogen gas stream with stirring for 4 hours. The reaction mixture was diluted with 400 ml of water and then neutralized with sodium = 10 carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 8.2 g (73% of theoretical yield) of the product were obtained. Melting point 258 - 258.4 ° C.

In the same manner as described, the following compounds were prepared from a corresponding o-phenylenediamine and a suitably substituted benzoic acid: 2- (o-ethylphenyl) benzimidazole, mp 207-208 ° C, 2- (p-ethylphenyl) - 5 (6) -chlorobenzimidazole, m.p. 199.5 - 200.5 ° C, 2- (p-ethylphenyl) -5 (6) -methylbenzimidazole, mp 191.5 - 192.5 ° C, 2- (m- ethylphenyl) benzimidazole, m.p. 202 - 203 ° G, 2- (o-ethylphenyl) -5 (non-chlorobenzimictazole, mp 183 - 184 ° C.

EXAMPLE 2.

Preparation of 2- (p-ethylphenyl) -5 (6) -methoxybenzimidazole.

8.0 g of 4-methoxy-o-phenylenediarain hydrochloride, 6.0 g of p-ethyl = benzoic acid and 40 g of polyphosphoric acid ester were heated to 120 ° C under nitrogen gas flow with stirring for 1 hour. The reaction mixture was diluted with water and then neutralized with sodium carbonate. The mixture was extracted with ethyl acetate and then evaporated in vacuo. The resulting crystals were recrystallized from acetonitrile. 3.4 g (68% of theoretical yield) of the product was obtained.

Melting point 160 - 161 ° C.

In the same manner as described, the following compounds are prepared from a corresponding o-phenylenediamine and a suitably substituted benzoic acid: 2- (6-ethylphenyl) -5 (6) -methoxybenzimidazole, m.p. 121 - 122 ° C, 2- (o-ethylphenyl) -5 (6) -methylbenzimidazole, m.p. 166 - 166.7 ° C, Example 3.

Preparation of 2- (m-ethylphenyl) benzimidazole.

2.2 g of o-phenylenediamine and 3.1 g of m-ethylbenzonitrile were dissolved in 30 ml of methanol. To the solution was added 1.1 g of sodium = 20 methoxide in methanol. The mixture was stirred at 60 ° C for 2 hours, acidified with acetic acid, stirred again at 100 ° C for an additional 3 hours and poured into 100 ml of water. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate.

2.7 g of the product was obtained (60% of theoretical yield). The product was identical to that obtained in Example 1.

Claims (1)

An analogous process for the preparation of 2-phenylbenz = imidazole derivatives of formula II R 1 - / Y * H wherein R 1 is hydrogen, halogen / C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and R 2 is an ethyl group, characterized by reacting a compound of formula III with R 1 - "T 2 | pNH 2 wherein R 1 has the meaning defined above, or an acid in addition salt thereof with a compound of formula VII" wherein R 2 has the meaning defined above, in the presence of a condensing agent, or reacting a compound of formula III with a compound of formula VIII R 2