DE1074588B - Process for the production of new \ - (ß diethylammoethyl) - 2 - (naphthyl-methyl) 5-nitro-benzimidazoles - Google Patents

Description

INTERNAT. KL. C 07 d

PATENT OFFICE

C 17133 IVb / 12p

REGISTRATION DATE: JULY 7, 1958

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: FEBRUARY 4, 1960

The invention relates to the preparation of l - (/ 3-diethylaminoethyl) benzimidazoles which are in the 2-position a naphthyl-methyl radical and a nitro group in the 5-position have, and their salts.

The new compounds are very effective in analgesia and have benzimidazoles compared to comparable compounds better pharmacological properties and can accordingly be used as medicinal products Find. The compound of formula is of particular interest because of its therapeutic properties

O.N-

C—. CH ₈ - ^

and their salts.

The new benzimidazoles are obtained by methods known per se, by adding a 5-nitro-2- (naphthyl-methyl) benzimidazole directly or stepwise with a reactive ester of an alcohol of the formula

HO-CH ₂ -CH ₂ -R

reacted, where R is a diethylamino group or a radical which can be converted into it, for example an oxy group and in the compounds obtained with a radical which can be converted into the diethylamino group, these into a converts such, an oxy group e.g. by chlorination and subsequent reaction with diethylamine. Reactive esters are especially those of strong inorganic or organic acids, such as hydrohalic acids or organic sulfonic acids such as p-toluenesulfonic acid. The introduction is preferred made in the presence of condensing agents, especially those with the 5-nitro-2-naphthylmethyl-benzimidazoles Able to form metal salts, such as alkali and alkaline earth metals, for example sodium, Lithium, calcium, their amides, hydrides, hydrocarbon compounds, alcoholates, oxides or hydroxides, e.g. sodium amide, sodium hydride, butyUithium, phenylpotassium, phenyllithium, potassium tert-butoxide, potassium tert-amylate, sodium ethylate, Sodium oxide or sodium hydroxide, or using the preformed metal salts of the benzimidazoles. In this implementation a mixture of 5- and 6-nitro derivatives is usually obtained, which can be obtained, for example, by crystallization of the Allow bases or their salts to separate.

Method of manufacture

new 1 - (j3-diethylamino ethyl) -

2- (naphthyl-methyl) -5-nitro-benzimidazole

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemarm, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority; Switzerland from July 17, 1957

Dr. Karl Hoffmann, Binningen, Basell., Dr. Alfred Hunger, Dr. Jindrich Kebrle and Dr. Alberto Rossi, Basel (Switzerland), have been named as the inventor

Another method for the preparation of the new compounds is that the in 2-position by a naphthylmethyl group and a benzimidazole ring substituted in 5-stelhmg by a nitro group Ring closure, formed starting from 2- (R'-NH) -5-nitroarrilines or their corresponding N-substituted derivatives where R 'is the diethylaminoethyl group or a radical which can be converted into it, e.g. a haloethyl group represents. The Regt which can be converted into the diethylaminoethyl group is then subsequently added to this group converted, in the case of the haloethyl group, for example, by reaction with diethylamine. So you can e.g. a 2 - (^ - diethylaminoäthylamino) -5-nitroanüin with a Naphthylacetic acid or its reactive functional derivatives, especially esters with easily cleavable ones Closing alcohols or imino ethers directly or in stages. For the production of the invention End products, it is also possible, instead of a naphthylacetic acid with a naphthylacetaldehyde or to condense its functional derivatives and to oxidize the product formed. With the above Reactions, the starting materials can also be formed under the reaction conditions. E.g. a 2-halogeno-S-nitro-naphthyl-acetyl-aniline with diethylaminoethylamine to the corresponding benzimidazole derivative ring.

The reactions according to the method are carried out in the presence or absence of diluents and / or condensation agents, if necessary at elevated temperature, im

909 7287508

open or in a closed vessel under pressure.

In the products of the process, substituents in the naphthylmethyl radical can be replaced by other groups, such as e.g. a hydroxyl group into an etherified or esterified hydroxyl group, TOe a lower alkoxy group, or a nitro group is converted into an amino group and this is converted into a lower alkoxy group or halogen atoms will.

Depending on the procedure, the new compounds are obtained in the form of the free bases or their salts. The free bases can be obtained from the salts in a manner known per se. The latter can be avoided obtain salts through reaction with acids that are suitable for the formation of therapeutically useful salts, such as hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, Oxyethanesulfonic acid, benzene or toluene sulfonic acid or therapeutically active acids.

The starting materials are known or can be obtained by methods known per se.

The new compounds can be used as medicaments, e.g. in the form of pharmaceutical preparations find which they or their salts in a mixture with one for enteral, parenteral or topical application suitable pharmaceutical, organic or inorganic, solid or liquid carrier material.

The invention is described in more detail in the following examples.

example 1

Hydrochloride iminoether-to the a-naphthyl-acetic acid, which is obtained from 12.5 g of a-naphthyl-acetonitrile, 4.3 cm ³ of absolute ethanol in 50 ml "dry chloroform by introducing hydrochloric acid gas at - 10 ⁰ C, standing for For 16 hours at 25 ° C. and evaporation under reduced pressure, 7.2 g of 2- (β-diethylaminoethylamino) -5-nitroaniline-hydrochloric! In 90 ml of glacial acetic acid are added, followed by stirring at 40 to 45 ° C. for 20 hours reaction mixture is evaporated at reduced pressure, the residue is taken up in aqueous hydrochloric acid, made the washed with chloroform acidic solution with ammonia solution, extracted with chloroform and washed with sodium carbonate and dried with magnesium sulfate, chloroform extract is evaporated. the resulting crude i- (ß-di- äthylaminoäthyl) -2- (a-naphthyl-methyl) -5-nitro-benzimidazole is conducted by dissolving in ethanol and adding an equivalent of ethanolic hydrochloric acid into the hydrochloride of mp. 225-226 ⁰ C.

Example 2

Dioxane entered. The suspension is stirred for 18 hours at 45 ° C., the red-orange color of the suspension gradually changing to yellow-orange. At the conclusion of 2 hours is heated to 8O ⁰ C and the hot reaction mixture with 16.5 cm ³ Sn hydrogen chloride essigester added. The precipitated hydrochloride is filtered off with suction, washed with a little dioxane, ^{suspended in 200 cm 3 of} water, and ammonia is added at 100 ° C. until the reaction is clearly alkaline.

The granular crystallized 2- (a-naphthyl-methyl) -5-nitro-benzimidazole is suction filtered, dried and recrystallized from dioxane-ligroin. The pure product melts at 234 ° C.

7.6 g of 2- (a-naphthyl-methyl) -5-nitro-benzimidazole is dissolved in 100 cm ^{3 of} dioxane, 1 g of finely powdered sodium amide is added and the reaction mixture is heated to 60 ° C. with stirring, after which 3.5 g Diethylaminoethyl chloride, dissolved in 3 cm ^{3 of} dioxane, is added dropwise. After the addition has ended, the mixture is _{stirred for a further 2} hours, nitrated from the precipitated sodium chloride and evaporated in vacuo.

The brown colored viscous base is a mixture of about 65 to 70% l - (/? - diethylammoethyl) -2- (a-naphthyl-methyl) -6-nitro-benzimidazole and 30 to 35% l (/ 3-diethylaminoethyl) -2- (a-naphthyl-methyl) -5-nitro-benzimidazole. The two isomers can be separated by chromatography. The hydrochloride of the 5-nitro base melts 225 to 226 ° C, the hydrochloride of the 6-nitro base, on the other hand, at 252 to 253 ° C.

Claims (1)

PATENT COOK: 1. Process for the production of new l - (/? - diethylaminoethyl) -2- (naphthyl-methyl) -5-nitro-benzimidazoles, characterized in that in per se known way a) a 5 - nitro - 2 - (naphthyl - methyl) - benzimidazole directly or gradually with a reactive one Ester of an alcohol of the formula HIGH, CH ₂ -R 55 To the imino ether hydrochloride of a-naphthyl-acetic acid, which is obtained from 16.7 g of a-naphthyl-acetonitrile, 4.3 cm ^{3 of} absolute ethanol in 50 ml of chloroform by introducing dry hydrochloric acid gas at -10 ° C, leaving to stand for 16 Hours at 25 ° C and evaporation under reduced pressure, a suspension of 7.65 g of 2-amino-4-nitroanihn in 200 cm ^{3 is} reacted with stirring, where R is a diethylamino group or a residue convertible therein, in compounds obtained with a convertible into a diethylamino group converts this into such and isolates the 5-nitro derivative formed, or b) the benzimidazole ring substituted in the 2-position by a naphthylmethyl group and in the 5-position by the nitro group directly or stepwise by ring closure, starting from 2- (R'-NH) -5-nitro-anuines or their corresponding N-substituted derivatives , where R 'represents a diethylaminoethyl group or a radical convertible therein, and in compounds obtained with a radical convertible into a diethylaminoethyl group converts this into such, and, if desired, converts the basic compounds obtained into salts.
2. The method according to claim 1, characterized in that a 2- (diethyIaminoäthylamino) -5-nitroaniline is reacted with an imino ether of a naphthylacetic acid. When the registration was announced, a test report and a priority document were displayed. © 909 728/508 1.60