NO148555B - ANALOGY PROCEDURE FOR PREPARATION OF PHARMACOLOGICALLY ACTIVE 2-PHENYLIMINO-IMIDAZOLIDINES - Google Patents

Abstract

1. Claims for the contracting states : BE, CH, DE, FR, GB, IT, LU, NL, SE 3,4-Disubstituted 2-phenylimino-imidazolidines of general formula (I) see diagramm : EP0012822,P5,F1 wherein Z represents a radical selected from the group comprising 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-chlorophenyl and 4-fluoro-3-aminophenyl, and the acid addition salts thereof. 1. Claims for the contracting state : AT Process for the preparation of 3,4-disubstituted 2-phenylimino-imidazolidines of general formula (I) see diagramm : EP0012822,P6,F1 wherein Z represents a radical selected from the group comprising 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-chlorophenyl and 4-fluoro-3-aminophenyl, and the acid additions salts thereof, characterised in that a) a compound of the formula (II) see diagramm : EP0012822,P6,F3 wherein Z is as hereinbefore defined and X and Y, which may be the same or different, represent a chlorine atom, an alkylthio group with 1 to 4 carbon atoms or an amino or ammonium group, is reacted with ethylenediamine or an acid addition salt thereof ; or b) the aliphatic acyl group is hydrolytically split off from a 1-acyl-2-phenylamino-imidazoline of general formula (III) see diagramm : EP0012822,P6,F5 wherein Z is as hereinbefore defined and R represents an aliphatic acyl group ; or c) in order to prepare 2-(4-fluoro-3-aminophenylimino)-imidazolidine, 2-(4-fluoro-3-nitrophenylimino)-imidazoline is hydrogenated and, if desired, the compound thus obtained is converted into a physiologically acceptable acid addition salt.

Description

Due to their excellent pharmacological and therapeutic properties, 2-phenylimino-imidazolidines have long been the subject of strong interest. Connections of this type are thus described in many places in the literature and are e.g. described in the Belgian patents 623,305, 653,933, 687,656,

687,657 and 705,944. In these patent documents, the essential

similar methods for the preparation of 2-phenylimino-imidazolidines are described. Hitherto, the 2,6-disubstituted phenylimino-imidazolidines and their effect on the central nervous system have been the subject of particular interest.

It has now been found that a number of 3,4-disubstituted 2-phenylimino-imidazolidines effect virtually no central,

but on the other hand predominantly a peripheral presynaptic α-adrenergic stimulation.

According to the invention, new 2-phenylimino-imidazolidines disubstituted in the 3- and 4-position are prepared with the general formula

and physiologically compatible acid addition salts thereof, with valuable therapeutic properties. In formula I, Z means a residue from the group 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3-aminophenyl1.

The new compounds of formula I are disclosed according to

one of the following methods:

a. Reaction of a compound with the general formula

where Z has the meaning given above, and X and Y, which may be the same or different, mean a halogen atom, preferably chlorine, a sulfhydryl, alkylthio, alkoxy, hydroxy, amino

or nitroamino group, the alkyl residues containing 1-4 carbon atoms, with ethylenediamine, resp. salts thereof.

The starting compound with formula II is e.g. isocyanide dihalides, especially isocyanide dichlorides, thioureas, O-alkylureas or their acid addition salts, S-alkylthioureas resp. their acid addition salts, since the alkyl residues in the two latter compound classes contain 1-4 carbon atoms, guanidines, also in the form of acid addition salts, carbamic acid esters .. thiocarbamic acid chlorides, alkyl-thiocarbamic acid chlorides or nitroguanidines.

The reaction is carried out at temperatures between 0 and 200°C depending on the residues X and Y. Polar, protic, polar aprotic or non-polar solvents can be used. Depending on the residues X and Y, the reaction can also be carried out without the use of solvents at an elevated temperature. If one or both of the residues X and Y represents a halogen atom, it is recommended to use an acid-binding agent in the reaction. The reaction time depends on the reactivity of the components used and varies between a few minutes and several hours.

b. Reaction of an aniline with the formula

where Z is as above, with a compound of the formula

where R" means a nucleophilic replaceable group, eg halogen, preferably chlorine or methylthio, methoxy or hydroxy, and R'" means a hydrogen atom or aliphatic acyl.

If R" means a hydroxy group, it is advantageous that

R<1>" means an acyl group, e.g. acetyl. The reaction which takes place in this case between an aniline of formula III and an 1-acylimidazolidin-2-one is conveniently carried out in the presence of phosphorus oxychloride at a moderate temperature, approx. 50 to 100° C. The reaction time is advantageously several hours to days. For the preparation of compounds of formula I, a subsequent hydrolytic removal of the acyl group is necessary, which can best be carried out with lower alcohols, e.g. methanol, in which

The 1-acyl compounds coconut under reflux.

The reaction of an aniline of formula III with 2-methyl-thioimidazoline-(2) or 2-chloroimidazoline-(2) requires the use of elevated temperature (100 to 180°C). Solvents are not necessary, but can be used. As such, polar protic and polar aprotic are used in particular. c. For the preparation of 2-(4-fluoro-3-aminophenylimino)-imidazolidine, 2-(4-fluoro-3-nitrophenylimino)-imidazolidine is reduced.

The reduction can be carried out by hydrogenation in the presence of finely divided metal catalysts, e.g. palladium, platinum, Raney nickel at normal pressure or overpressure or with

nascent hydrogen, e.g. with hydrazine in the presence of Raney nickel.

Between or the starting products for the individual methods are all derived from the commercially available anilines of formula III and can be prepared by known literature methods.

The new 2-phenyl-iminoimidazolidine compounds of formula I can be converted in the usual way to their physiologically compatible acid addition salts. Acids suitable for salt formation,

is e.g. hydrochloric acid, hydrobromic acid, hydroiodic 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-amino-benzoic acid, rphthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphonic acid,. 8-ChlorotheophyHin et al.

The new compounds and their acid addition salts have valuable therapeutic properties. In case of pharmacological sub-

researches on rats and cats have found that they cause a presynaptic stimulation of the peripheral ot-adrenoceptors and thereby exert a peripheral neurosympathetic and -vagal transmission inhibition. Due to the practically absent central effect, an effect on blood pressure cannot be observed. The new connections can e.g. used in the treatment of migraine. The compounds of the general formula I and their acid addition salts can be used enterally or also parenterally. The dosage is 0.5 to 50 mg, preferably 1 to 10 mg for oral administration.

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 production of these the commonly used galenic aids, carriers, explosives or lubricants or substances which provide a depot effect can be used.

The following examples shall serve to further illustrate the invention.

Example 1

2-(3-fluoro-4-methylphenylimino)-imidazolidine

14.03 g (0.043 mol) of N-(3-fluoro-4-methylphenyl)-S-methyl-thiuronium iodide is heated together with 4.35 ml (^150%) of ethylenediamine in 58 ml of methanol for 8 hours with stirring at reflux -temperature. Ten Ueres of solution are then removed in vacuo, and the residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N KOH and extracted twice with ether (the ether extracts are discarded) and then alkalized with 50% potassium hydroxide. This precipitates an oil which crystallizes through within a short time. After vacuuming, wash with water and dry.

Yield: 6.1 g = 73.41% of the theoretical

M.p.: 109.5-110i5<0>C.

Rf: 0.1 system: benzene 50, dioxane 40, ethanol 5 r k. NH40H 5 Carrier: silica gel G + light pigment, visualization: UV and potassium iodoplatinate.

Example 2

2-(4-Fluoro-3-methylphenylimino)-imidazolidine

46 g (0.141 mol) N-(4-fluoro-3-methylphenyl)-S-mcty1-thiuronium iodide is heated together with 14.1 ml h'150%) ethylcndiamine in 190 ml methanol for 5 hours with stirring at reflux running temperature. The solvent is then distilled off in vacuo, and the residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is buffered with 5N KOH to pH 7 and extracted twice with ether (the ether extracts are discarded). After adding activated charcoal and filtering, the mixture is alkalized with 50% KOH. The base first precipitates oily and later crystallizes after covering with petroleum ether (40-80°) and good stirring. It is extracted, washed with water and dried.

Yield: 9.4 g = 34.50% of the theoretical.

Melting point: 113-114°C

Rf: 0.3 system: benzene 50, dioxane 40, ethanol 5, k. NH40H 5 Carrier: silica gel G + light pigment, visualization: UV and potassium iodoplatinate.

Example 3

2-(4-fluoro-3-nitrophenylimino)-imidazolidine

4.5 g (0.0173 mol) 1-acetyl-2-(4-fluoro-3-nitrophenylimino)-imidazolidine, m.p. 150-151°C, heated for 10 hours in 66 ml methanol with stirring at reflux temperature. After cooling, insoluble components are filtered off, the solvent is distilled off in a vacuum, and the remaining residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is then fractionally extracted with ether at increasing pH values (step-by-step alkalization with 2N caustic soda) and fractionated from pH 8.5, precipitated and suctioned off. The solid fractions are collected and dried. Yield: 1.7 g = 43.81% of the theoretical,

Melting point: 146-147°C.

Rf: 0.4 system: benzene 50, dioxane 40, ethanol 5, k. NM^OH 5. Carrier: silica gel G + iyspigment, detector: UV; potassium iodoplatinate.

Example 4

2-(4-fluoro-3-chlorophenylimino)-imidazolidine

20.8 g (0.06 mol) of N-(3-chloro-4-fluorophenyl)-S-methyl-thiuronium iodide are heated together with 6 ml ('^1509;) of ethylenediamine in 82 ml of methanol for 4 hours with stirring at reflux -temperature. The solvent is then distilled off in a vacuum, and the residue is dissolved in IN hydrochloric acid. The hydrochloric acid solution

buffered to pH 7 with 5N KOH and extracted twice with ether (the ether phases are discarded) and then alkalized with 50% KOH. This precipitates an oil which crystallizes through after a short time. After vacuuming, it is washed with water and dried.

Yield: 7.2 g = 56.17% of the theoretical

Melting point: 118.5-119.5°C.

Rf: 0.5, system: benzene 50, dioxane 40, ethanol. 5, k. NH^OH 5 Carrier: silica gel G + light pigment

Detector: UV, potassium iodoplatinate.

Example 5" t

2-(4-Fluoro-3-aminophenylimino)-imidazolidine

5.5 g (0.0225 mol) of 2-(4-fluoro-3-nitrophenylimino)-imidazolidine are dissolved in 40 ml of methanol and hydrogenated under normal pressure until the theoretical amount of hydrogen is taken up (Raney nickel). The mixture is then freed from Raney nickel by suction

over activated charcoal, and the filtrate is evaporated in vacuo. For purification, the residue is fractionally eluted over a 400 g silica gel column (eluent mixture: ethyl acetate 7, isopropanol 3,

k. NH^OH 1). The thin-layer chromatographically uniform fractions are collected and evaporated in vacuo to constant weight. The remaining thick oil is dissolved in a little methanol and ethereal hydrochloric acid is added for an acidic reaction. Then precipitation is carried out with ether, and the precipitated salt is suctioned off, washed with ether and dried.

Yield: 3.7 g = 61.56% of the theoretical

Melting point: 222°C

Rf: 0.08, system: benzene 50, dioxane 40, ethanol 5, k. NII^OH 5 Carrier: silica gel G + light pigment, detector: UV, potassium iodoplatinate.

Claims (1)

Analogous process for the preparation of pharmacologically active 3,4-disubstituted 2-phenylimino-imidazolidine derivatives of the general formula where Z means a residue from the group 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-chloro-phenyl and 4-fluoro-3-aminophenyl, and acid addition salts thereof, characterized in that a) a compound with the formula where Z has the meaning given above, and X and Y, which may be the same or different, mean a halogen atom, preferably chlorine, a sulfhydryl, alkylthio, alkoxy, hydroxy, amino or nitroamino group, where the alkyl residue contains 1- 4 carbon atoms, react with ethylenediamine; or b) an aniline of the formula where Z has the meaning given above, is reacted with an imidazoline derivative of the formula where R" means a nucleophilic replaceable group, e.g. halogen, preferably chlorine, or mctylthio, methoxy or hydroxy oq R'" means hydrogen or aliphatic acyl, and optionally the aliphatic acyl residue is cleaved off hydrolytically; or c) for the production of 2-(4-fluoro-3-aminophenylimino)-imidazolidine, 2-(4-fluoro-3-nitrophenylimino)-imidazoline is hydrogenated, and optionally the compound thus obtained is transferred to a physiologically acceptable acid addition salt.