NO792368L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLAMINO-IMIDAZOLINE DERIVATIVES - Google Patents

Description

"Analogous process for the preparation of therapeutically active phenylamino-iinidazoline derivatives"

This invention relates to the preparation of new substituted 2-phenylamino-imidazoline-(2)-compounds with the general formula

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

In formula I, Ar means 2,6-dibromopheny1, 2,4-dibromopheny1

or 3-bromo-4-fluorophenyl, and X represents oxygen or sulfur.

The compounds of formula I are prepared by

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

where Ar has the above meaning, with a halide of the general formula where Hal means a chlorine, bromine or iodine atom, and X has the above meaning; or b) reacting a compound of the general formula where Ar and X are 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, is reacted 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 reaction according to method 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 to 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 required. It is appropriate that it as reaction-. component used ethylenediamine, resp. the acid addition salt thereof is used in excess.

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

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

The starting compounds of formula III can be prepared

by halogenation of the corresponding primary alcohols.

The 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 transferred to corresponding isouronium salts and isothiouronium salts respectively with alkylating agents. From these acid addition compounds, bases can be used to extract the corresponding isoureas and isothioureas. In the case of water separation from urea 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, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, •valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic 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. Effects on heart rate have been investigated in rabbits and in spinally anesthetized rats, in addition to intact, anesthetized rats.

The dosage is preferably 0.1 to 80 mg

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, and for the preparation one can use the commonly used galenic aids, carriers, explosives or lubricants or substances that have a depot effect.

The following examples shall serve to further illustrate the invention.

Example 1

2- [ N - ( 2, 6- dibromophenyl)- N - ( 2- thienylmethyl) amino]- 2- imidazoline hydrochloride

63.8 g (0.2 mol) of 2-(2,6-dibromophenylimino)imidazolidine are heated together with 33.1 g (125%) of 2-chloromethylthiophene and 30 ml of triethylamine in 400 ml of absolute toluene for 6 hours with stirring at reflux temperature . After this time suction is carried out,

and the filter residue, which consists of the new imidazoline derivative, is washed several times with toluene. It is then dissolved in approx. 3 liters of water while adding 25 ml of 2N HC1. The hydrochloric acid solution is extracted twice with 300 ml of ether each time (the ether extracts are discarded) and adjusted to pH 7 by adding

of 5N NaOH. After renewed extraction of the neutral solution with 300 ml of ether (the ether extract is discarded), fractional extraction with ether is carried out at increasing pH values (stepwise alkalization with 2N NaOH, each time approx. 3 ml), until all impurities have been removed from the aqueous phase ( continuous control using thin-layer chromatogram). 200 ml of 2N NaOH is then added to the aqueous solution, whereby the imidazoline base is separated in pure form. Yield after extraction, washing with water and drying: 48.4 g (58.3% of the theoretical). Melting point: 106-108°C. The hydrochloride melts at 239-240°C.

C14H13Br2N3S X HC1 (451'62)

Calculated: C 37.23 , H 3.12, Br 35.39, . Cl 7.85, N 9.30, S 7.10 Found: C 37.32, H 3.11, Br 35.22, Cl 8.19, N 9.12, S 6.91 Thin layer chromatogram:

Rf: 0.7; developer system: benzene : dioxane : ethanol-:

conc. NH^OH: 50:40:5:5, detection: iodoplatinate.

Analogously to the previous example, the following compounds were prepared, the melting points being those of 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 2,6-dibromophenyl, 2,4-dibromophenyl or 3-bromo-4-fluorophenyl, and X means oxygen or sulphur, and acid addition salts thereof, characterized by ata) a 2-phenylimino-imidazolidine of the general formula where Ar has the meanings stated above, is replaced by et halide with the general formula where Hal means a chlorine, bromine or iodine atom, and X has the meaning given above, orb) a compound of the general formula where Ar and X are as 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 an end product produced in this way is optionally transferred to an acid addition salt.