CH361286A - Process for the preparation of new benzimidazoles - Google Patents

Description

  

  Process for the preparation of new benzimidazoles The invention relates to a process for the preparation of 1- (tert-amino-lower-alkyl) -2- (p-alkoxy-benzyl) -benzimidazoles of the formula
EMI0001.0007
    in which A is a lower alkylene radical, R is a tertiary amino group and alkyl is an alkyl group, and in which one of the radicals R1 and R is hydrogen or halogen and the other is halogen.

   The tertiary amino group is, for example, a lower alkyleneimino group optionally interrupted by a heteroatom, such as a piperidino, pyrrolidino or morpholino group, but especially a di-lower alkylamino group, especially the diethylamino group.



  The new compounds are effective as analgesics and muscle relaxants and can accordingly be used as drugs. The compounds of the formula are of particular interest because of their therapeutic properties
EMI0001.0025
    wherein alkyl is a lower alkyl radical, such as methyl, propyl, primarily ethyl, and R1 undi or R2 are chlorine, such as 1- (ss-diethylamino-ethyl) -2- (p-ethoxy-benzyl) -5-chloro- benzimidazole,

          1- (ss diethylamino-ethyl) -2 (p-methoxy-benzyl) -5-chloro-benzimidazole and their salts.



  The process according to the invention is characterized in that a 2- (p-alkoxy-benzyl) -5- and / or -6-halogen-benzimidazole is reacted with a reactive ester of an alcohol of the formula HO-A-R.

   Reactive esters are in particular those strong inorganic or organic acids, such as hydrohalic acids, or organic sulfonic acids, such as p-toluenesulfonic acid. The implementation is preferably carried out in the presence of condensation agents, especially those capable of forming metal salts with the 2- (p-alkoxy-benzyl) -benzimidazoles, such as alkali and alkaline earth metals, for example sodium, lithium and calcium, their amides , Hydrides, hydrocarbon compounds,

       Alcoholates, oxides and hydroxides, e.g. B. Sodium amide, sodium hydride, butyllithium, phenylpotassium, phenyllithium, potassium tert-butoxide, potassium tert-amylate, sodium ethylate, sodium oxide and sodium hydroxide, or using the preformed metal salts of benzimidazoles.



  The reactions can be carried out in the presence or absence of diluents and / or condensation agents, if necessary, at elevated temperature, in an open or in a closed vessel under pressure.



  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. Of the latter can be obtained by reacting with acids that are ge for the formation of therapeutically useful salts, salts such.

   B. of 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. B. in the form of pharmaceutical preparations, find use which they or their salts in a mixture with a suitable for enteral, parenteral or topical application, pharmaceutical rule, organic or inorganic, solid or liquid carrier material.



  In the following example the temperatures are given in degrees Celsius.



  <I> Example </I> 2.7 g of 2- (p-methoxy-benzyl) -5-chlorobenzimidazole are dissolved in 100 cm3 of absolute dioxane, 0.4 g of sodium amide are added with stirring. The reaction mixture is heated to 70.

   At this temperature, 1.4 g of β-diethylamino-ethyl chloride, dissolved in 10 cm3 of dioxane, are slowly added dropwise over the course of 1 hour. The reaction mixture is kept at 70 for 4 hours while stirring, then Norit (branded product) is added, the mixture is filtered, evaporated and taken up in 100 cm3 of ether.

   The ethereal solution is extracted three times with 20 cm3 of 1N hydrochloric acid, the hydrochloric acid extract is made alkaline with sodium hydroxide solution and the released base is taken up in ether, dried and freed from the solvent. The base is converted into its hydrochloride by dissolving in alcohol and adding one equivalent of alcoholic hydrochloric acid. The 1- (ß-diethylamino-ethyl) -2- (p-methoxy-benzyl) -5-chlorobenzimid'azole hydrochloride thus obtained melts at 183-184.



  The 2- (p-methoxy-benzyl) -5-chlorobenzimidazole used as starting material can be prepared as follows: 11.8 g of p-methoxy-benzyl cyanide are added in a mixture of 80 cm 3 of chloroform and 4.64 cm 3 Dissolved ethanol.

   The mixture is saturated with dry hydrochloric acid gas at 0 and left to stand for 12 hours at room temperature. 10 g of 2 amino-5-chloroanal, dissolved in 100 cm3 of chloroform, are now added to the above-mentioned reaction mixture and refluxed for 12 hours. 200 liters of water are added to the cooled reaction mixture, along with enough aqueous ammonia that, after the two phases have been shaken through, the aqueous layer reacts clearly alkaline.

   The chloroform layer is dried with magnesium sulphate, evaporated and the residue is crystallized from chloroform-ligroin. The 2- (p-methoxy-benzyl) -5-chlorobenzimidazole obtained melts at 169.



  The following compounds can be prepared in an analogous manner: 1- (ss-diethylamino-ethyl) -2- (p-ethoxy-benzyl) -5-chloro-benzimidazole, F. des hydrochloride 205-207; 1- (ss-diethylamino-ethyl) -2- (p-methoxy-benzyl) -5,6-dichlorobenzimidazole, F. des Hydrochlorids 220; 1- (ss diethylamino-ethyl) -2- (p-ethoxy-benzyl) -5,6-dichlorobenzimidazole, F. des hydrochloride 115; 1- (ss-dimethylamino-ethyl) -2- (p-ethoxy-benzyl) -5,6-dichloro-benzimidazole, m.p. 86-87;

   F. of the hydrochloride 120-130.

 

Claims (1)

PATENT CLAIM Process for the production of new benzimidazoles of the formula EMI0002.0077 where A is a lower alkylene radical, R is a tertiary amino group and alkyl is an alkyl group, and in which one of the radicals R1 and R is hydrogen or halogen and the other is halogen, characterized in that a 2- (p-alkoxybenzyl ) -5- and / or -6-halogen-benzimidazole with a reactive ester of an alcohol of the formula HO-AR. SUBClaims 1. A method according to claim, characterized in that the basic compounds obtained are converted into acid addition salts. 2. The method according to claim and sub-claim 1, characterized in that a 2- (p-alkoxy-benzyl) -5- undloder -6-halogen-benz- imidazole with a compound of the formula Hal-AR, wherein Hal is a halogen atom means, implements. 3. A method according to claim and the sub-claims 1 and 2, characterized in that a 2- (p-ethoxy-benzyl) -5- and / or -6-chlorobenzimidazole is reacted with a ss diethylamino-ethyl halide.