IE49239B1 - Novel 2-(3,4-disubstituted-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

Thia invention relates to novel 2-[3,4-disubstituted-phenyliininoj-imidazolidine compounds and their acid addition salts, their preparation and pharmaceutical compositions thereof.

Aa a result of their pharmacological arid therapeutic properties, 2-phenylimino-imidazolidines have long been of interest. Consequently, compounds of this type have frequently been described in the literature and have been disclosed in, for example, Belgian Patent Specifications Nos. 623 305, 653 933, 687 656, 687 657 and 705 944. In these references the essential processes for the production of 2-phenylimino-imidazolidines have also been described.

Previously the major interest has been in the 2-[2,6-disubstituted-phenyliminoj-iaidazolidines and their action upon the central nervous system, as well as their blood15 pressure-lowering properties.

However, it has now been found that a number of 2-[3,4-disubatituted-phenyliminoj-imidazolidines surprisingly effect practically no central stimulation, instead predominantly effecting a peripheral pre-synaptic α-adrenergic stimulation.

According to one aspect of the present invention we therefore provide 2-[3,4-disubstituted-phenylimino]-imidazolidine compounds of general formula (I) H 48239 wherein Z represents a radical selected from the group consisting of 3-fluoro-4-methyl-phenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-ohlorophenyl and 4-fluoro-3-aminophenyl,and acid addition salts thereof.

According to a further aspect of the present invention there are provided processes for the preparation of compounds of general formula (I) (as hereinbefore defined) which comprise: a) reacting a compound of general formula (II) wherein Z is as hereinbefore defined and X and Y, which may be the same or different, each represents a chlorine atom or an amino or ammonium group or an alkythio group containing 1 to 4 carbon atoms, with ethylene diamine or an acid addition salt thereof; or b) hydrolytically splitting off an aliphatic acyl group from a l-aoyl-2-phenyl-amino-imidazoline of general formula (in) N III R wherein Z is as hereinbefore defined and R represents an 20 aliphatic acyl group; and (c) for the preparation of 2-[4-fluoro-3-aminophenyliaino]imidazolidine hydrogenating 2-[4-fluoro-3-nitro-phenylimino]imidazolidine.

Compounds of formula (II) used in process (a) according to the invention are preferably isocyanide dichlorides, guanidines (or acid addition salts thereof), S-alkyl thioureas (or acid addition salts thereof) in which the said alkyl groups contain 1 to 4 carbon atoms.

The reaction (a) is conveniently effected at temperatures between 0 and 200°C, the precise temperature depending upon the groups X and Y. Polar protic, polar aprotic and non-polar solvents may be used. Depending upon groups X and Y, the · reaction may also be effected at an elevated temperature without a solvent. Where one or both of groups X and Y represents a halogen atom, it is recommended to use an acid-binding agent for the reaction. The reaction time is determined by the reactivity of the reagents used and ranges from several minutes to several hours.

In process (b) according to the invention, the hydrolysis of the acyl group is preferably carried out using lower alcohols such as methanol or dilute mineral acids which serve as solvents for the 1-acyl compounds the resulting solutions being refluxed.

The l-acyl-2-phenylamino-imidazolines of general formula III used as starting materials are prepared by reacting an £ aniline of genial formula (IV) Z—nh2 IV [wherein Z is as hereinbefore defined] in the presence of phosphorus oxychloride according to the process disclosed in DE-A 23 16 377.

The reduction of process (c) above may be effected by 48239 hydrogenation in the presence of finely dispersed metal catalysts such as, for example, palladium, platinum, Raneynickel at normal or excess pressure or by means of nascent hydrogen, for'example produced by hydrazine in the presence of Raney-nickel.

The starting products of the processes (a) and (b) above can all be derived from anilines of formula (IV) and, as such, are readily accessible following methods described in in the literature.

The 2-phenyl-iminoimidazolidines of formula (I) according to the invention may be converted into their physiologically acceptable acid addition salts in a conventional manner. Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydriodic 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, jj-hydroxybenzoic acid, jj-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphonic acid and 8-chlorotheophylline.

It should be noted that acid addition salts of compounds of general formula (I) (as hereinbefore defined) other than those classified as physiologically acceptable may be useful in the preparation of compounds of general formula (I) and the physiologically acceptible acid addition salts thereof.

The novel compounds as well as their acid addition salts possess valuable therapeutic properties. In pharmacological examinations of rats and cats it was found that they effect a pre-synaptic stimulation of the peripheral a-adrenoreceptors and thus exert a peripheral neurosymphatic and • 49239 -vagal transmission inhibition. As there are practically no central activities, an influence on blood pressure is not observed.The novel compounds may be used, for example, for the treatment of migraine.

According to a still further aspect of the present invention we therefore provide pharmacueitcal compositions comprising at least one compound of formula (I) (as hereinbefore defined) or a physiologically acceptable acid 49238 addition salt thereof as active ingredient in association with a pharmaceutical carrier or excipient.

The compounds of general formula fl) and the physiologically acceptable acid addition salts thereof may be used either enterally or else parenterally. Pharmaceutical compositions in dosage unit form, for example for oral administration, conveniently contain from 0.5 to 50 mg, preferably from 1 to 10 mg, of the active ingredient according to the invention.

The compounds of formula (I) and their physiologically acceptable acid addition salts may also be used together with other physiologically active substances. Suitable forms for pharmaceutical preparations are, for example, tablets (including coated tablets), capsules, suppositories, solutions, aerosol sprays or powders; together with conventional adjuvants, excipients, carriers, disintergrants or lubricants or substances for obtaining sustained release.

The following Examples serve to illustrate the invention without restricting its scope.

Example 1 2- (3-Fluoro-4-Kiethylphenylimino)-imidazo1idine 14.03 g (0.043 mol) of N-(3-fluoro-4-methylphenyl)-S-methvlthiouronium-iodide are refluxed together with 4.35 ml (λ-150%) of ethylenediamine in 58 ml of methanol for 8 hours while stirring. The solvent is then distilled off in vacuo and the residue is dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N KOH and extracted twice with ether (the ether extracts being abandoned) and subsequently made alkaline with 50% potassium hydroxide solution. This causes the precipitation of an oil, which crystallizes within a short time. After vacuum filtration, the residue, the title compound, is washed 239 with water and dried.

Yield: 6.1 g = 73.41% of theory Melting point: 109.5 - 110.5°C Rf: 0.1 system: benzene 50, dioxan 40, ethanol 5, cone. NH40H 5 Carrier: silicagel G + luminous pigment,made visible by: UV and potassium iodoplatinate Elemental analysis: Calc: Found: c H F N 62.16 6.26 9.83 21.75 4. O 62.44 6.44 9.84 22.04 % Example 2 2-(4-Fluoro-3-methylphenylimino)-imidazolidine g (0.141 mol) of N-(4-fluoro-3-methylphenyl)-S-methylth iouronium iodide are refluxed together with 14.1 ml (~150%) of ethylenediamine in 190 ml of methanol for 5 hours while stirring. The solvent is then distilled off in vacuo and the residue is dissolved in IN hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N KOH and extracted twice with ether (the ether extracts being abandoned). After admixing with active charcoal and subsequent filtration, the filtrate is made alkaline with 50% KOH. At first, the base precipiates as an oil, then, after covering with petroleum-ether at at a temperature of from 40 to 80°C and with vigourous stirring it crystallizes. After vacuum filtration the residue, the title compound, is washed with water and dried.

Yield: 9.4 g = 34.50% of theory Melting point: 113-114°C Rf:.0.3 system: benzene 50, dioxan 40, ethanol 5, cone.

NH.OH 5 4 Carrier: silicagel G + luminous pigment, made visible by UV and potassium iodoplatinate.

Elemental Analysis: C Calc: 62.16 Pound 62.04 H F N 6.26 9.83 21.75 6.13 9.85 21.78 % % Example 3 2-(4-Fluoro-3-nitrophenylimino)-imidazolidine 4.5 g (0.0173 mol) of l-acetyl-2-(4-fluoro-3-nitrophenylimino)-imidazolidine, m.p. 150 - 151°C, are refluxed for 10 hours in 66 ml of methanol while stirring. After cooling, the insoluble remnant is filtered off, the solvent is distilled off in vacuo and the residue remaining is dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is extracted at rising pH-values (made alkaline by the stepwise addition of 2 N sodium hydroxide solution) with ether, fractionated from pH 8.5, precipitated and vacuum filtered. The solid fractions, the title compound, are united and dried.

Yield: 1.7 g =43.81% of theory Melting point: 146 - 147°C Rf: 0.4 system: benzene 50, dioxan 40, ethanol 5, cone. NH^OH 5. Carrier: silicagel G + luminous pigment, Detector: UV; potassium iodoplatinate.

Elemental Analysis: C Calc.: 48.21 Found: 47.55 H F N 4.05 8.48 24.99 % 4.02 8.71 24.41 a Ό Example 4 2-(4-Fluoro-3-chlorophenylimino)-imidazolidine .8 g (0.06 mol) of N-(3-chloro-4-fluorophenyl)-S-methylthiouronium iodide are refluxed together with 6 ml (λ/150%) of ethylenediamine in 82 ml of methanol for 4 hours, while stirring. The solvent is then distilled off in vacuo and the residue dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is extracted twice with ether (the ether phases being abandoned) and subsequently made alkaline with 50% KOH. This results in the precipitation of an oil, which crystallizes within a short time. After vacuum filtration the residue, the title compound, is washed with water and dried.

Yield: 7.2 g = 56.17% of theory Melting point: 118.5 - 119.5°C Rf: 0.5, system: benzene 50, dioxan 40, ethanol 5, cone. NHa0H 5 Carrier: silicagel G + luminous pigment Detector: UV, potassium iodoplatinate Elemental Analysis : C H Cl F N Calc.: 50.59 4.25 16.60 8.89 19.67 % Found: 49.80 4.64 16.57 9.25 19.42 % Example 5 2-(4-Fluoro-3-aminophenylimino)-imidazolidine .5 g (0.0225 mol) of 2-(4-fluoro-3-nitrophenylimino)imidazolidine are dissolved in 40 ml of methanol and hydrogenated under normal pressure over Raney-nickel until the theoretical uptake of hydrogen is reached. Then the Raney-nickel is removed by vacuum filtration over active charcoal and the filtrate is evaporated in vacuo. For purification the residue is eluted in fractions over a 400 g silicagel column. (Mixture of eluents: ethylacetate 7, isopropanol 3, cone. NH^OH 1). The thin-layer chromato3Q graphically uniform fractions are united and evaporated in vacuo up to constant weight. The remaining thick oil is dissolved in a little methanol and admixed with etheric hydrochloric acid to form the acid salt of the title compound. Subsequently, it is precipated with ether and A9 2 39 the precipitated salt is vacuum filtered, washed with ether and dried.

Yield: 3.7 g = 61.56% of theory Melting point: 222°C Rf: 0.08; system: benzene 50, dioxan 40, ethanol 5, cone. NHjOH 5.

Carrier: silicagel G + luminous pigment, Detector: UV, potassium iodoplatinate Elemental Analysis: Cl Calc.: Found: 40.46 39.53 4.90 26.55 .18 26.26 F 7.11 6.58 .57 % .37 % 4-9 239 Example 6: Tablets Active ingredient according to the invention corn starch sec. calcium phosphate mg 160 mg 250 mg magnesium stearate total mg 420 mg Production : The individual components are admixed intensely and the mixture is granulated in the conventional manner and sub sequently pressed to form tablets,each of which weighs 420 mg and contains 5 mg of the active ingredient according to the invention.

Example 7: Gelatin Capsules The content of each capsule is as follows: Active ingredient according to the invention 3 mg corn starch 172 mg total 175 mg Production: The components are admixed intensely and portions of 175 20 mg of the mixture are filled into gelatin capsules of suitable size. Each capsule thus contains 3 mg of the active ingredient according to the invention.

Example 8: Injectible Soultion The solution is produced of the following components: Active ingredient according to capsule is as follows: the invention 1.0 part by weight sodium salt of ethylenediamine tetra-acetic acid 0.2 parts by weight distilled water ad 1000.0 parts by weight Production; The active ingredient according to the invention and the sodium salt of ethylene-diamine tetra-acetic acid are dissolved in sufficient distilled water and made up with distilled water to the desired volume. The solution is filtered free from suspended particles and 2 ml fractions are filled into ampoules under aseptic conditions. Subsequently the ampoules are sterilized and sealed. Each ampoule thus contains 2 mg of the active substance.

Example 9; Drops Active ingredient according to the invention 0.20 g methyl p-hydroxybenzoate 0.07 g propyl p-hydroxybenzoate 0.03 g demineralized water ad 100 ml The active ingredient according to the invention and the methyl p-hydroxybenzoate and propyl p-hydroxybenzoate are dissolved in sufficient demineralized water and made up with demineralized water to the desired volume.

Claims (6)

1. 3,4-Disubstituted 2-phenylimino-imidazolidines of general formula (I) H If H 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.

2. Process for the preparation of compounds according to claim 1, 10 characterised in that (a) a compound of formula (II) (Π) 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 15 to 4 carbon atoms or an amino or ammonium group, is reacted with ethylenediamine or an acid addition salt thereof; or - 49239 b) the aliphatic acyl group is hydrolytically split off from a l-acyl-Z-phenylamino-imidazoline of general fonnula (III) (III) wherein Z is as hereinbefore defined and 5 R represents an aliphatic acyl group; or c) in order to prepare 2-(4-fluoro-3-aminophenylimino)imidazolidine, 2-(4-fluoro-3-nitro-phenylimino)-imidazoline is hydrogenated and,if desired, the compound thus obtained is converted into a 10 physiologically acceptable acid addition salt.

3. Pharmaceutical preparations, characterised in that they contain, as active substance, one or more compounds of general formula (I) or the physiologically acceptable acid addition salts thereof according to claim 1. 15

4. Process for the preparation of pharmaceutical compositions according to claim 3, characterised in that one or more compounds as claimed in claim 1 are processed with conventional galenic excipients, carriers, disintegrants or lubricants or substances for obtaining delayed release, to form tablets, capsules, 20 suppositories, solutions or powders. 5. Compounds according to claim 1 for use in the treatment of migraine.

5. A process for the preparation of compounds of claim 1 substantially as herein described in any one of Examples 1 to 5. 5 7. Pharmaceutical ^reparations substantially as herein described with reference to any of Examples 6 to 9.

6. 8. Product of a process according to claim 4 or claim 6.