NO792334L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLAMINO IMIDAZOLE DERIVATIVES - Google Patents

Description

"Analogy procedure for the preparation of therapeutic

active phenylamino-imidazoline derivatives"

This invention relates to the preparation of new, substituted 2-phenylamino-rimidazoline- (2) compounds with the

■ general formula

and physiologically compatible acid addition salts thereof, with valuable therapeutic properties.

In formula I, the Ar radical means 2,4,6-tribromophenyl, 2-bromo-6-fluorophenyl, 2-bromophenyl, 2-bromo-6-chlorophenyl, 2,6-difluorophenyl or 2-bromo-3-chlorophenyl.

The compounds of formula I are prepared by

a) reaction of a 2-phenylimino-imidazolidine of the general formula

where Ar has the meanings given above, with a halide of the general formula

wherein Hal means a chlorine, bromine or iodine atom; or

b) turnover of a compound with the general formula

where Ar is as above, and A means a cyano group or the residue

, with Y representing an alkoxy or

alkylthio group with up to 4 C atoms or a sulfhydryl or amino group, with ethylenediamine or acid addition salts thereof.

In the alkylation of the 2-arylimino-imidazolidines of formula II by method a), the substitution takes place exclusively on the bridge nitrogen atom. In the case of turnover according to procedure b)

the constitution of the final compound is determined by the synthesis. In addition to the synthesis, the position of the substituents can also be determined by NMR spectroscopy (cf. H. Stahle and K.H. Pook, Liebigs Ann. Chem. 751, 159 ff (1971)).

The reaction according to method a) conveniently takes place by heating the reaction components, preferably in the presence of a polar or non-polar organic solvent, to temperatures of approx. 50-150°C. The special reaction conditions are strongly dependent on the reactivity of the reaction components. It is recommended to use the halide in excess during the alkylation and carry out the reaction in the presence of an acid-binding agent.

In method b), it is necessary to work at an elevated temperature, between 60 and 180°C. Solvents are not necessary. It is appropriate that the ethylenediamine used as reaction component resp. acid addition salts thereof, are used in excess.

The starting compounds of formula II are e.g. described

in Belgian patents 623,305, 687,657 and 705,944.

Starting compounds of formula III can be prepared by halogenation of the corresponding primary alcohols.

Compounds of formula IV are obtained by starting from anilines, by reaction with compounds of formula III and subsequent reaction of the resulting secondary amines with cyanates or thiocyanates, whereby ureas or thioureas are formed, respectively. Ureas and thioureas can then be further transferred with alkylating agents to respectively corresponding isouronium salts or isothiouronium salts. From these acid addition compounds, bases can be used to extract the corresponding isoureas or isothioureas. In the case of water separation from urine substances or H^S cleavage from thioureas with the help of lead or mercury salts yields cyanamides to which ammonia can be added to form guanidines.

The new 2-phenylamino-imidazoline-(2) compds

the general formula I can be conventionally transferred to its physiologically compatible acid addition salts. Acids that are suitable for salt formation are e.g. hydrochloric acid, hydrobromic acid, iodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valerian acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxy- benzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chlorotheophy Hin and others.

The new compounds of the general formula I and

their acid addition salts have a strong bradycardic effect and are therefore suitable for the treatment of coronary disorders. The effect on heart rate was investigated in rabbits and in spinally anesthetized rats as well as intact, anesthetized rats. The dosage is 0.1 to 80 mg, preferably 1 to 30 mg.

The compounds of formula I and their acid addition salts can also be used together with other active substances. Suitable galenic preparations are e.g. tablets, capsules, suppositories, solutions or powders. For the production of such preparations, the commonly used galenic auxiliaries, carriers, explosives or lubricants or substances that provide a depot effect can be used.

The following examples shall serve to further illustrate the invention.

Example 1

2-[ N-( 2- bromo- 6- chlorophenyl)- N-( cyclopropylmethyl)- amino]- 2- imidazoline

4.3 g (0.0157 mol) of 2-(2-bromo-6-chlorophenylimino)-imidazolidine are heated together with 1.6 g (110%) of chloromethylcyclopropane in 50 ml of ethanol for 24 hours with stirring at reflux temperature . Both the solvent and volatile components are then removed in a vacuum, the residue is dissolved in a mixture (1:1)

of dilute hydrochloric acid (2N) and water, and the solution is extracted twice with ether (the ether extracts are discarded). The hydrochloric acid solution is then fractionally extracted with ether at increasing pH values (stepwise alkalization with 2N caustic soda). The thin-layer chromatographically uniform ether extracts are collected, dried over MgSO^, filtered over activated charcoal, and the filtrate is evaporated in

vacuum. In this way, the new imidazoline falls out as white crystals. Yield: 1.2 g (23.3% of the theoretical). Melting point: 136-137°C. Rf: 0.2. System: benzene 50, dioxane 40, ethanol 5, conc. NH 3 OH 5 ; carrier: silica gel G + light pigment; detector: UV and potassium iodine-platinate.

C13H15BrlC1lN3 <328'64)

Calculated: C 47.51%, H 4.60%, Hal 35.10%, N 12.79%

Found: C 47.61%, H 4.48%, Hal 34.93%, N 12.73%.

According to the previous example, the following compounds were prepared. The melting points apply to the bases of formula I.

Claims (1)

Analogous process for the preparation of therapeutically active, substituted 2-phenylamino-imidazoline-(2)-compounds of the general formula where Ar means the residue 2,4,6-tribromophenyl, 2-bromo-6-fluorophenyl, 2-bromophenyl, 2-bromo-6-chlorophenyl, 2,6-difluorophenyl or 2-bromo-3-chlorophenyl, and acid addition salts thereof, vessel, acted by at a) a 2-phenyl-iminoimidazolidine with the general formula where Ar has the meaning given above, is reacted with a halide of the general formula where Hal means a chlorine, bromine or iodine atom, or b) a compound of the general formula where Ar is as indicated above, and A means a cyano group or the rest where Y represents an alkoxy or alkylthio group with up to 4 carbon atoms or a sulfhydryl or amino group, is reacted with ethylenediamine or acid addition salts thereof, and a compound, prepared as indicated above, is optionally transferred to an acid addition salt thereof.