FI68814B - FRAMEWORK FOR THE PHARMACOLOGICAL PROPERTIES OF VARIABLE 3,4-DISUBSTITUERADE 2-PHENYLIMINO-IMIDAZOLIDINE - 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

ΓΓβ ^ Π .. KU U LUTUSIU LK AISU

[β] (11) UTLÄGG Nl NGSSKRIFT 6 881 4 C (45) P .: exam «jZ: ic-tty 11 11 1985 (51) Kv.ik.> ta« C 07 D 233/50 (21) Patent application - Patentansökning 7939 ^ 8 (22) Application date - Ansökningsdag 17.12.79 (FI) (23) Starting date - Giltighetsdag 17.12.79 (41) Has become public - Blivit often tl ig 19-06.80

National Board of Patents and Registration (AA \ Date of Sight and Publication—

Patent- och register Styrelsen '' Ansökan utlagd och utl.skriften publicerad 31 .07.85 (32) (33) (31) Pyydetty etuoikeus - Begärd priority 1 8.1 2.78

Federal Republic of Germany-Förbundsrepubl i ken Tyskland (DE) P 285 ^ 659.0 (71) C.H. Boehringer Sohn, D-6507 Ingelheim am Rhein, Federal Republic of Germany1a-Förbundsrepubl iken Tyskland (DE) (72) Helmut Stähle, Ingelheim / Rhein, Herbert Köppe, Ingelheim / Rhein,

Werner Kummer, Ingelheim / Rhein, Alexander Walland, Ingelheim / Rhein,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (Jk) Leitzinger Oy (54) Method for the preparation of pharmacologically valuable 3-substituted 2-phenyl-imino-imidazolidines

The present invention relates to a process for the preparation of pharmacologically valuable 3,4-disubstituted 2-phenyliminoimidazolidines of the formula Γ

B

/ "Π Z - N = {(I) 'N-

B

wherein Z is 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-chlorophenyl or 4-fluoro-3-aminophenyl, and their acid addition salts.

2-Phenyliminoimidazolidines have long been the subject of intense interest due to their remarkable pharmacological and therapeutic properties. Compounds of this type have therefore been frequently described in the literature and disclosed, for example, in Belgian Patent Publication Nos. 623,305, 653,933, 687,656, 687,657 and 705,944. manufacturing methods.

To date, the primary areas of interest have been 2,6-disubstituted phenyliminoimidazolidines and their effect on the central nervous system.

It has now been found that some 3,4-disubstituted 2-phenyliminoimidazolidines have virtually no effect on the central nervous system, but primarily have a peripheral presynaptic β-adrenergic stimulating effect.

According to the invention, these compounds of the formula I can be prepared by the following process alternatives: a. The compound of the general formula TI Z - N = C (II)

^ Y

wherein Z is as defined above and X and Y, which may be the same or different, are a halogen atom, preferably chlorine, a sulfhydryl, alkylthio, alkoxy, hydroxy, amino or nitroamino group, wherein the alkyl group may have 1 -4 carbon atoms, is reacted with ethylenediamine or its salts.

The starting compounds of the formula TI are, for example, isocyanide di-halides, in particular isocyanide dichloride, thiourea, O-alkyl urea or its acid addition salts, S-alkylthiourea or its acid addition salt, both of the two classes of compounds also containing 1, as thio salts, carhamenic acid ester, thiocarbamic acid chloride, α1-thiocarbamic acid chloride or nitroguanidine.

The reaction takes place at temperatures between 0 and 200 ° C, depending on the groups X and Y. The solvents can be polar protic, polar aprotic or non-polar solvents. However, depending on the groups X and Y, the reaction can also take place without solvents at elevated temperatures. If one or both of X and Y is a halogen atom, it is recommended that an acid scavenger be used in the reaction. The reaction time depends on the reactivity of the components used and varies from a few minutes to several hours.

b. To prepare 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 a finely divided metal catalyst, for example palladium, platinum, Raney nickel at normal pressure or overpressure, or by evolving hydrogen, for example hydrazine in the presence of Raney nickel.

The intermediates or starting materials for the individual processes are all obtained from commercially available anilines of formula III

Z - NH 2 (III) wherein Z has the same meaning as above, and can also be prepared by methods known from the literature.

The 2-phenyliminoimidazolidines according to the invention can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable salts for salt formation include, for example, 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, malonic acid, malonic acid, malonic acid, , bentoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, 8-chloroheophylline and the like.

The new compounds as well as their acid addition salts have valuable therapeutic properties. Pharmacological experiments in rats and cats showed that they presynaptic stimulate peripheral ctf adrenoceptors and thus have a peripheral neurosympathetic and vagal inhibitory effect on transmission. Due to their lack of effect on the central nervous system, they have no detectable effect on blood pressure.

The new compounds can be used, for example, in the treatment of migraine. The compounds of the general formula I and their acid addition salts can be administered enterally or also parenterally. The dosage is 0.5 to 50 mg, preferably 1 to 10 mg when administered orally.

Pharmacological comparison results A. Measurement of blood pressure

The antihypertensive effect of the test compounds was tested in urethane-anesthetized rabbits. Five experimental animals were used for each dose. The test compound was administered in doses of 0.03; 0.1; 0.3; 1.0; 3.0 and 10 mg / kg. The blood pressure of the test animal was continuously measured directly from the artery of the head with a mercury manometer after i.v. administration of the test compound, in addition to which ED20-α 2 v ° r was determined, i.e. a dose that causes a 20 mm Hg drop in blood pressure for at least 20 minutes. The following results were obtained in the experiments.

Imidazolidine ΕΕ> 20 * mg / kg (Group 2) a) 2- (3-Fluoro-4-methyl-phenyl) of formula I up to 10 mg / kg 2- (4-fluoro-3-methyl-phenyl) ) no effect b) Reference compounds (IJS 3 622 579) 2- (2-methyl-5-fluorophenyl) 0.03 2- (2-fluoro-4-methylphenyl) 1.0 2- (2-methyl -4-fluorophenyl) 2.7

The results show that the reference compounds show clear activity, while the compounds according to the invention have not been shown to have an antihypertensive effect.

5 68814 Pre- and postsynaptic effect of B. o <-adrenergic compounds.

The experiment was performed by the following modified method (cf.

G.M. Drew, European J. Pharmacol. 3j6, 313-320 (1976)):

Male Chbb: THOM (SBF) male rats weighing approximately 370 g were anesthetized with 1.1 g / kg urethane at an i.p. dose. With a trakeal cannula and a starling pump, the experimental animal was given artificial respiration. The body temperature was maintained with a heat lamp at 36-37 ° C. The forehead was cleaned and an isolated metal rod was inserted through the brain and neck opening into the spinal canal, destroying the spinal cord up to the lumbar region. In the area between the last cervical vertebra and the first cervical vertebra, the rod was uninsulated, allowing electrical stimulation of the sympathetic nerve accelerating the heart every 10 minutes. This was done with a Grass stimulator S 4 E (8 consecutive pulses of 50 V and a duration of 1 ms every four seconds), increasing the heart rate by 50 to 100 beats per minute. Varicose vein pressure was measured and heart rate was recorded. The test compound was injected into the tibial vein, giving each test animal only one dose. Each dose was tested on 5-7 animals.

The decrease in electrically induced cardiac tachycardia as an indication of sympathetic attenuation by a ci antagonist can be considered an indication of presynaptic efficacy. The experiments determined the dose of test compounds that reduced the heart rate by 50%, a value denoted ED50. Injection of the test compound caused an increase in resting blood pressure, an effect indicative of a postsynaptic, vasoconstrictive effect. The dose-response diagram was used to graphically determine the dose that raises vascular blood pressure by 30 mm Hg (ED30). The ED50 / ED3O ratio is a measure of pre- and postsynaptic effect, the lower this ratio, the greater the presynaptic selectivity.

The following values were obtained in the experiment.

Imidazolidine (Z group) ED50 / ED3O

2- (3-fluoro-4-methylphenyl) 0.10 2- (4-fluoro-3-methylphenyl) 0.20 6 68814

The compounds of the formula I or their acid addition salts can also be used with other active ingredients. Suitable galenic administration forms are, for example, tablets, capsules, sticks, solutions or powders; in this case, galenical auxiliaries, carriers, enhancers or lubricants or substances which produce a lasting effect may be used in their preparation.

The following examples illustrate the invention.

PREPARATION EXAMPLES

Example 1 2- (3-Fluoro-4-methyl-phenylimino) -imidazolidine 14.03 g (0.043 mol) of N- (3-fluoro-4-methyl-phenyl) -5-methyl-thiouronium iodide and 4.35 ml ( about 150%) ethylenediamine in 58 ml of methanol is heated at reflux for 8 hours with stirring. The solvent is then distilled off in vacuo and the residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is buffered with 5 N potassium hydroxide to pH 7 and extracted twice with ether (ether extracts are discarded) and then made alkaline with 50% potassium hydroxide. This precipitates an oil which rapidly crystallizes rapidly. Separate with suction, wash with water and dry.

Yield: 6.1 g = 73.41% of theory.

Melting point: 109.5 - 110.5 ° C Rf: 0.1

System: benzene 50, dioxane 40, ethanol 5, conc. NH4OH 5 Carrier: Kieselgel G + light pigment, evolution: UV and potassium iodine platinum.

C H F N

Calculated: 62.16 6.26 9.83 21.75

Found: 62.44 6.44 9.84 22.04

Example 2 7 68814 2- (4-Fluoro-3-methylphenylimino) imidazolidine 46 g (0.141 mol) of N- (4-fluoro-3-methylphenyl) -5-methylthiouronium iodide and 14.1 ml (about 150%) of ethylenediamine in 190 ml of methanol is heated at reflux for 5 hours with stirring. The solvent is then distilled off in vacuo and the residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N potassium hydroxide and extracted twice with ether (the ether extracts are discarded). Activated carbon is added and filtered, then aliquoted with 50% potassium hydroxide. The base first precipitates as an oil, but crystallizes after covering with petroleum ether (40-80 °) and stirring well. Separate with suction, wash with water and dry.

Yield: 9.4 g = 34.50% of theory Melting point: 113-114 ° C Rf: 0.3

System: benzene 50, dioxane 40, ethanol 5, conc. NH4OH 5 Carrier: Kieselgel G + light pigment, evolution: UV and potassium iodine platinum.

C H F N

Calculated: 62.16 6.26 9.83 21.75

Found: 62.04 6.13 9.85 21.78

Example 3 2- (4-Fluoro-3-chloro-phenylimino) -imidazolidine 20.8 g (0.06 mol) of N- (3-chloro-4-fluoro-phenyl) -5-methyl-thiouronium iodide and 6 ml (about 150%) of ethylenediamine in 82 ml of methanol are heated at reflux for 4 hours with stirring.

The solvent is then distilled off in vacuo and the residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N potassium hydroxide and extracted twice with ether (ether-____ - TTT ----- 8 68814 phases are discarded). It is then made alkaline with 50% potassium hydroxide. This precipitates an oil which rapidly crystallizes rapidly. Separate with suction, wash with water and dry.

Yield: 7.2 g = 56.17% of theory Melting point: 118.5-119.5 ° C Rf: 0.5,

System: benzene 50, dioxane 40, ethanol 5, conc. NH4OH 5 Carrier: Kieselgel (3 + light pigment, evolution: UV and potassium iodoplatinate.

C H Cl F N

Calculated: 50.59 4.25 16.60 8.89 19.67

Found: 49.80 4.64 16.57 9.25 19.42

Example 4 2- (4-Fluoro-3-aminophenylimino) imidazolidine 5.5 g (0.0225 moles) of 2- (4-fluoro-3-nitrophenylimino) imidazolidine are dissolved in 40 ml of methanol. and hydrogenated at normal pressure until the theoretical amount of hydrogen has been consumed (Raney nickel). The Raney nickel is then removed by filtration through activated carbon and the filtrate is evaporated in vacuo. For purification, the residue is fractionated on a column containing 400 g of silica gel (Elution mixture: ethyl acetate 7, isopropanol 3, conc. NH 4 OH 1). The TLC uniform fractions are combined and evaporated in vacuo to constant weight. The remaining thick oil is dissolved in a small amount of methanol and ethereal hydrochloric acid is added to the solution until the reaction is acidic. It is then precipitated with ether and the precipitated salt is filtered off with suction, washed with ether and dried.

Yield: 3.7 g = 61.56% of theory Melting point: 222 ° C Rf: 0.08,

System: benzene 50, dioxane 40, ethanol 5, conc. NH4OH 5,9681414

Carrier. Kieselgel G + light pigment, development: UV and potassium iodine platinum.

C H Cl F N

Calculated: 40.46 4.90 26.55 7.11 20.57

Found: 39.53 5.18 26.26 6.58 20.37

Claims (1)

A process for the preparation of pharmacologically valuable 3,4-disubstituted 2-phenyliminoimidazolidines of the formula I H_ / N- | Z'N = \ J 'n-1H where Z is 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-nitrophenyl, 4-fluoro-3-chlorophenyl or 4-fluoro- 3-aminophenyl, and for the preparation of their acid addition salts, characterized in that a) a compound of formula (II) / XZ - N = C (II) ^ Y wherein Z is as defined above and X and Y, which may be the same or different, are a halogen atom, preferably chlorine, sulfhydryl, an alkylthio, alkoxy, hydroxy, amino or nitroamino group, wherein the alkyl group contains 1 to 4 carbon atoms, is reacted with ethylenediamine, or b) 2- (4-fluoro-3-aminophenyl 2- (4-Fluoro-3-nitrophenylimino) -imidazolidine is prepared to prepare -imino) -imidazolidine, and optionally the compound thus obtained is converted into a physiologically harmless acid addition salt.