DE1000384B - Process for the preparation of new derivatives of benzimidazole - Google Patents

Description

GERMAN

PATENT OFFICE

EXPLORATION PAPER 1000

C 10728IVb / 12 ρ REGISTRATION DATE: FEBRUARY 10, 1955

NOTICE THE REGISTRATION AND ISSUE OF THE ACSLE LETTERING: 10 J A N U A R 195

The therapeutic effect of the substitute products des Benzimidazole has been studied repeatedly. It has been found that the effect depending on the nature of the substitute notes varies greatly. With regard to the substituents in the The 2-position of the benzimidazois has been found to have hydrocarbon radicals as substituents in the 2-position lead to products with a very low spasmolytic effect (Journ. Am. Chem-Soc., 71, 2035), while substituents with basic N atoms in the 2-position of the benzimidazois then lead to practically useful products if the i-position is replaced by a substituted or unsubstituted aralkyl, aryl or heterocyclic radical or heterocyclic substituted alkyl is occupied (see. German Patent 890 644).

It has now been found that derivatives of benzimidazois with superior therapeutic effect are obtained if a p-halogenobenzyl radical is in the i-position of an ao on the benzene ring unsubstituted or substituted and a 1 to 4 in the 2-position. Introduces alkyl radical containing carbon atoms and optionally substituted by hydroxyl groups. The new Pro
according to the general formula

Process for the preparation of new derivatives of benzimidazois

Applicant:

Chemie Grünenthal G. mb H.,
Stolberg (RhId.)

DipL-Chem. Siegfried Herrling,

Dr. rer. nat. Dr. med. Herbert Keller

and DipL-Chem, Dr. med. Heinrich Mückter,

Stolberg (RhId.),
have been named as inventors

CH ₈ - / ~ AY

, where X is an alkyl radical containing 1 to 4 carbon atoms and optionally substituted by hydroxyl groups, Y is a halogen atom and R ₁ to R _{4 can be} identical or different roducts _a j and hydrogen, lower alkyl radicals, halogen atoms, nitro or mean unsubstituted or substituted amino groups.

The new products have a very strong spasmolytic effect. In addition, they have anaigetic effectiveness, and some work against certain skin fungi.

The superior spasmolytic effect of the new products results from comparative tests, in which the effect of the substances on those caused by acetylcholine or barium chloride Spasm of the isolated guinea pig intestine was compared with that of papaverine ». The values obtained can be seen from the table below.

substance

Effect after cramp generation
by BaCl, Acetylcholine IOO IOO 100 ISO 6O 220 180 140 3OO

Papaverine (known)

i-p-CUorbenzyl ^ -pyrrolidinomethyl-benzimidazole hydrochloride (known) '

i-p-Chlorobenzyl ^ -morphoUnomethyl-benzimidazole-hydrochloride (known)

i-p-Chlorobenzyl ^ -methyl-benzimidazole hydrochloride (Example 1 of the patent application)

i-p-Chlorobenzyl ^ -oxymethyl-benzimidazole (Example 5 of Patent application

3 4

With regard to the effect of the new products against skin fungi, there is a comparison with the previously known i-p-chlorobenzyl-benzimidazole the following numbers.

product

Limiting dilutions for the effectiveness against skin fungi

Epidermophyton Kaufiman-Wolfi

Sporotrichon Beurmann.

Trichophyton inter digital

Candida albicans

I.
II

ι: 2

ι: ioo ooo

ι: io ooo ι: ioo ooo

I == i-p-chlorobenzylbenzimidazole

ι:

ι: ioo ooo

ι: io ooo
ι: io ooo

II = example of the patent application

The production of the new valuable compounds takes place according to methods known per se:

1. It can be an o-phenylenediamine, which is substituted in one amino group by a p-halobenzyl radical and in the benzene nucleus by the substituents R ₁ to R ₄ , with a compound of the formula R - X, wherein R is one for Ring closure represents a suitable group and X represents an alkyl radical containing ι to 4 carbon atoms and optionally substituted by hydroxyl groups.

2. One can also use a Schiff base of the formula

N = CH-X

NH-CH ₈ / V-

in which X, Y and R ₁ to R _{4 have} the aforementioned meaning, converted into the benzimidazole by oxidative means (cf., for example, H ins be rg, Ber. dtsch. former Ges., 20 [1887], 1565; Hinsberg and Koller , ibid, 29 [1896], 1497; Fischer, ibid, 26 [1893], 203; Jacobsen, Jenicke and Meyer, ibid, 29 [1896], 2682 Weidenhagen, ibid, 69 [1936], 2263; Weidenhagen and Train, ibid, 75 [1942], 1936; Stevens and Bower, Journ. Chem. Soc, [1949], 2971, and [1950], 1722; Jerch el, Fischer and Kracht, Ann. Chem., 575 [1952], 162; Jerchel, Kracht and Krucker, Ann. Chem., 590 [1955], 232).

3- You can also, a benzimidazole, which is unsubstituted in the ι-position, substituted in the 2-position by the radical X and can be substituted in the benzene nucleus by the substituents R ₁ to R ₄ , react with a halobenzyl halide, or

4. an N- (p-halobenzyl) -o-nitroaniline, which _{can be substituted in the benzene nucleus by the substituents R 1} to R ₄ , with a compound of the formula R - X in which R is a group suitable for acylation and X has the above meaning, acylate and close the imidazole ring after reduction of the nitro group. The following examples illustrate the invention.

41.2 gp-chlorobenzyl bromide and then boil x 6 hours long on the reflux & cooler. Then the dioxane distilled off, the residue stirred well with dilute hydrochloric acid and the resulting crystalline

ao line mass recrystallized from water after suction The colorless crystals obtained on cooling are dissolved in hot water and these Dilute ammonia solution is added to the solution until it has a weakly alkaline reaction. The first

The liquid base of ip-chlorobenzyl-2-methylbenzimidazole solidifies with hydrate formation to form a white mass which can be crystallized from aqueous alcohol and has a melting point of 67 to 68 °. Work-up can also be carried out in such a way that the dioxane has been distilled off the residue is distilled in vacuo. The base of the IP-Chlorbenizyl methylbenzimidazols 2 is at 12 mm pressure at 240-242 ⁰ C as a colorless oil over, from the by trituration with Wagner the hydrate are obtained of melting point 67-68 ° canoe.

The following further i-p-chlorobenzylbenzimidazole derivatives were obtained using the same procedure: i-p-Chlorobenzyl-z-ethyl-benzimidazole (m.p.

116 to II8 °)) ip-chlorobenzyl-2-propyl-benzimidazole (mp. 115 to ii6 °) and IP-chlorobenzyl-2- (isobtrtyl) -berazimidazol, Hydrocblorid mp. 240 ⁰ (dec..

Example 2

13.2 g of 2-methylbenzimidazole are in 2000 cm

Toluene with 5 g sodium amide and 20.6 g p-chlorobenzyl bromide offset. After boiling for 5 hours on the reflux condenser, the toluene is distilled off and the residue worked up as in Example 1.

Example 3

26.4 g of 2-methylbenzimidazole are dissolved in 200 ecm of dimethylformamide, 12 g of potassium hydroxide are added and this mixture is refluxed for 10 to 15 minutes, the potassium hydroxide going into solution. ^{A solution 1} of 20.6 g of p-chlorobenzyl bromide in 50 ecm of dimethylformamide is then added to the solution thus obtained and the mixture is then heated to the boil for 2 hours on a reflux condenser. The residue obtained after the dimethylformamide has been distilled off is worked up as in Example 1.
65

Example 1 Example 4

26.4 g of 2-methylbenizimidazole will be in 350 ecm ² 3> 3 & p-chlorobenzyl-o-phenylenediamine

Dissolved dioxane and mixed with 10 g of sodium amide - with 75 ecm of glacial acetic acid for 3 hours at reflux -

After about 5 minutes you admit. this mixture j _o cooked cooler. The bulk of acetic acid

is then distilled off, the residue with dilute Sodium hydroxide solution added to a weakly alkaline reaction and. the resulting base des i-p-chlorobenzyl-z-methylbenzimidazole either Purified as such by recrystallization or converted into the hydrochloride and this as in Example ι described worked up.

Example

23.3 g of p-chlorobenzyl-o-phenylenediamine are mixed with 50 ml of 18% hydrochloric acid and then a mixture of 35 ml of 36% glycolic acid solution and 22 ml of 36% hydrochloric acid are added. The reaction mixture is boiled for 2 hours on a reflux condenser and then, after adding an equal volume of water, carbon is added, the mixture is boiled and filtered off with suction. The filtrate is made weakly alkaline with Ammoniaklösung- and the base thereby obtained the ip-chlorobenzyl ao 2-oxymethylbenzimidazols recrystallized from aqueous alcohol (mp. 165 ^0).

Example 6 a ₅

6.1 g of N-acetyl-N-ip-chlorbenzy ^ -o-nitroaniline are refluxed for ^{5 hours with 50 ecm of 40 e} / oiger acetic acid and 4 g of iron powder. After cooling, the reaction mixture is diluted to about 200 ecm with water and then treated with 10 ecm 3 «concentrated hydrochloric acid. After some time, the hydrochloride of the crystallized ip-chlorobenzyl-2-methyl-benzimidazole from DLAs is recrystallized from water and it is melting after drying at 227-228 ^0th

Example 7

4 g of N-ip-chlorbenzy ^ -o-phenylenediamine hydrochloride are dissolved with gentle heating in S ecm 75 ° / own alcohol and a cooled solution of 6 g of copper acetate in 100 ecm of water, which has been mixed with 3.5 ecm of butyraldehyde is given. The deposition of a precipitate begins. The mixture is heated 15 minutes to 80 to 90 ⁰ and then allowed to cool. The supernatant liquid is decanted off from the sticky precipitate, the precipitate is stirred with a little water, whereupon it solidifies. Then 10 ecm of concentrated hydrochloric acid, 50 ecm of water and 50 ecm of methanol are poured over the precipitate. The mixture is heated to the boil and decoppered with hydrogen sulfide. The yellowish solution obtained after filtering off the copper sulfide is concentrated to half its volume, poured hot over charcoal and then made alkaline with sodium hydroxide solution. The precipitate which separates out is lp-chlorobenzyl-2-propylbenzimidazole, which, after drying, melts at 115 ° to 117 °

Claims (1)

PATENT CLAIM: Process for the preparation of new derivatives of benzimidazole of the general formula where X is an alkyl radical containing 1 to 4 carbon atoms and optionally substituted by hydroxyl groups, Y is a halogen atom and R ₁ to R _{4 can be} identical or different and are hydrogen, lower alkyl radicals, halogen atoms, nitro or unsubstituted or substituted amino groups , characterized in that in a known manner a) an o-phenylenediamine, which is substituted in one amino group by a p-halobenzyl radical and can be substituted in the benzene nucleus by the substituents R ₁ to R ₄ , with a compound of the formula R - X in which R is one suitable for ring closure Represents group and X has the above meaning, is implemented or b) a Schiff base of the formula wherein X and Y and R ₁ to R _{4 have} the aforementioned meaning, is converted into the benzimidazole by an oxidative route or c) a benzimidazole which is unsubstituted in the 1-position, substituted in the 2-position by the radical X and can be substituted in the benzene nucleus by the substituents R ₁ to R ₄ , is reacted with a halobenzyl halide or d) einiN- (p-halobenzyl) -o-nitroaniline, which _{can be substituted in the benzene nucleus by the substituents R 1} to R ₄ , with a compound of the formula R - X, in which R is a group suitable for acylation and X is the Has the above meaning, acylated and, after reduction of the nitro group, the imidazoking is closed. © 609 740/40 «12.56