FI63752C - PROCEDURE FOR THE FRAMSTATION OF AV 1-BENZOYL-2- (2 ', 6'-DICHLOROPHENYLAMINO) -2-IMIDAZOLINE AND DESS SALTER - Google Patents

Description

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Patent application VTV (51) Kv.ik.3 / int.a.3 C 07 D 233/50 ENGLISH - FI N LAN D (21) Pw * nttlh * k * mu «- PmMWMWuang 7Ö2025 (22) Mtkemtapilvl - Ai »eknlnpd · * 12.07.76 (23) Alkupllvt — GiMgh« t * dt | 12.07 76 (41) Tullut JulklMksI - Ulvh offwitHg 26 03 77

Patent and Registry Administrators .... ........ * '' _ ^. , (44) Date of Nlhavikslpanon And the Moon. - on nl ""

Patent · och registrerttyrelten Amekan utlagd och utl. $ KrJft «n puMkend 29.04.83 (32) (33) (31) Requested« toik «i> .- B * g« rd priorim 25.09.75

Austria-Österrike (AT) A 7355/75 (71) Chemie Linz Aktiengesellschaft, Postfach 296, A-4021 Linz,

Austria-Österrike (AT) (72) Rudolf Franzmair, Linz-Ebelsberg, Austria-Österrike (AT). (7 * 0 Leitzinger Oy (5 * +) Process for the preparation of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline and its salts - Preparation of framställnirig av 1 - benzoyl-2- (2' , 6'-dichlorophenylamino) -2-imidazoline and salt

It is known from OE-PS 248 428, 250 344 and 250 345 that 2-arylamino-2-imidazoline, in particular 2- (21,6'-dichlorophenylamino) -2-imdazoline, has a clear hypotensive effect with an edative effect.

BE-PS 741 947 further discloses N-aroyl derivatives of this 2-arylamino-2-imidazoline, for example 2- [N-benzoyl- (2,6,6-dichlorophenyl) -amino] -2-imidazoline, which also has this hypotensive and concomitantly sedative effect. They are obtained by aroylating the free 2-arylamino-2-imidazolines with the corresponding acid chlorides of aromatic carboxylic acids, whereby the acid group is exchanged with hydrogen bound to the aniline nitrogen.

It has now been found that reacting 2,6-dichlorophenylisocyanide with an idihalide with N-benzoylethylenediamine to form a benzoyl derivative of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline with interesting pharmacological properties and wherein the benzoyl group is not in the aniline nitrogen but in the imidazoline nitrogen, as is clear from the synthesis. This compound, known from Finnish patent application 750653, is a structural isomer of the benzoyl derivative described in patent publication 2 63752, οδ7, BE-PS 741. .

. .-oη is indicated by physical measurements, including the melt void08 ". ia pKa value.

mispisteen J "*

The present invention therefore relates to a process for the preparation of 1-benzoyl-, N'-cyclophenylamino) -2-imidateolinyl of the formula 2- (2 ', o-f1-

C/O

° 6H5 or / 01 "Q-0

Cl ώ or a salt thereof, characterized in that 2,6-dichlorophenyl isocyanide dihalide of the general formula 'nji in which X represents halogen, preferably chlorine, is reacted with N-benzoylethylenediamine in a reaction-inert solvent at temperatures between 0 ° C and the solvent used. boiling point while adding an acid scavenger.

N-Bentoylethylenediamine is known in the literature and can be prepared by Aspinallin, J.Org.Chem. 6,895,899 (1941) or analogously.

In principle, all the processes known in the alkylation reactions can be used in the reaction according to the invention, provided that only solvents and acid scavengers which do not react or react only so slowly with the aryl isocyanide dichloride of the formula II are not affected or affected. only insignificantly to the desired reaction. As solvents, both apolar or low polar solvents such as benzene, toluene, xylene, cyclohexane, halogenated hydrocarbons such as methylene chloride, chloroform, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethers such as esters, esters can be used. alcohol, especially alcohols having more than two carbon atoms, acetonitrile, dimethylformamide, dimethyl sulfoxide.

The reaction can be carried out both homogeneously and heterogeneously. In the heterogeneous reaction, aqueous sodium or potassium hydroxides or NaH are particularly suitable as acid scavengers, and in the homogeneous reaction, sodium or potassium alcoholate.

Since the compound of the invention is a weak base, further work-up is best carried out by diluting the reaction product, optionally after evaporation and taking up in an inert solvent such as benzene or methylene chloride, with dilute aqueous acid, preferably hydrochloric acid, and basifying the hydrochloric acid extract. crystalline. After filtration, it is recrystallized from a suitable solvent, for example isopropanol, acetonitrile, ethyl acetate, benzene or toluene, to give the compound of the invention in high purity.

The reaction is carried out between 0 ° C and the boiling point of the solvent used, preferably between + 10 ° C and + 50 ° C. The reaction time is conveniently from a few hours to 24 hours.

Surprisingly and unforeseen, the amide nitrogen in N-benzoylethylenediamine readily reacts with the halogen of the aryl isocyanide halide even in a mild acylation process such as the Schatten-Baumann reaction.

4 63752

The compound of formula Ia or Ib is a uniform, highly crystalline product. The structure of this compound cannot be determined so unambiguously that it could be said whether the double bond is in the imidazoline ring (Ia) or whether it is located outside the ring (Ib).

It has very interesting pharmaceutical properties.

It also has an antihypertensive effect such as the known compound 1 having a hydrogen atom instead of a benzoyl group, and the aniline-substituted benzoyl derivative described in Be-PS 741 947, but the sedative activity component is substantially less clear. When this compound is used as a hypotensive agent, it thus omits e.g. fatigue as an unpleasant side effect. The compound of formula Ia or Ib is excellently absorbed orally.

The absence of a sedative effect on the central nervous system can be readily demonstrated by establishing the presence of a carotene reflex in anesthetized rabbits after said compound. 100 micrograms / kg has been administered. This reflex, on the other hand, is almost completely attenuated by administration of the same dose of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline. Furthermore, this can be seen from the unchanged behavior of awake mice when 5 or 10 mg / kg of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imdazoline was administered.

The compound of formula Ia or Ib can therefore be used in medicine as a hypotensive agent in all conventional formulations for pharmaceutical purposes, such as tablets, granules, capsules, suppositories, emulsions, solutions or injectable solutions.

In addition, depending on the form of administration, they can be used either as free bases or as salts. As the melt, for example, salts with inorganic or organic acids such as hydrohalide, phosphate, oxalate, β-chlorophenophyllinate or salts with acidic synthetic resins can be used.

The method according to the invention is further clarified by means of the following examples: i 5

Example 1: 6 3752 1.64 g (10 mMol) of N-benzoylethylenediamine are dissolved in 100 ml of benzene, a 25 ml error layer is applied, heated to 50 ° C with vigorous stirring and a solution is added dropwise and simultaneously within 75 minutes. contains 2.31 g (10 mMol) of 2,6-dichlorophenyl-iocyanide dichloride in 20 ml of absolute benzene, and 20 ml of 1N sodium hydroxide. It is then stirred for a further 3 hours at 50 [deg.] C., cooled to room temperature and the phases are separated. The aqueous phase is extracted once with 100 ml of benzene. The two benzene phases are combined, washed with water and extracted three times with 75 ml of 1N hydrochloric acid. The hydrochloric acid extracts are combined, washed once with ether and then soda adjusted to give 650 mg (19.4%) of crude 1-benzoyl-2- (2 ', 6, -dichlorophenylamino) -2-imidazoline. After recrystallization from isopropanol, 480 mg of product are obtained, m.p. 160-162 ° C.

Example 2: 3.28 g (20 mMol) of N-benzoylethylenediamine, 4.62 g (20 mMol) of 2,6-dichlorophenyl-β-cyanide dichloride and 40 ml of 1N sodium hydroxide are reacted according to Example 1 at 10-15 ° C and further treated as described above. 1. 1.20 g (18.0% of theory) of crude 1-benzoyl-2- (2 ', 6, -dichloro-phenylamino) -2-imidazoline are obtained. After recrystallization from isopropanol, 950 mg (14.2% of theory) of compound are obtained, m.p. 160-162 ° C.

Example 3: 1.64 g (10 mMol) of N-benzoylethylenediamine are dissolved in 60 ml of absolute tetrahydrofuran, 0.48 g (20 mMol) of sodium hydride (i.e. 0.90 g of a 55% dispersion) are kept and stirred for 30 minutes until gas evolution ceases. . A solution of 2.31 g (10 mMol) of 2,6-dichlorophenylisocyanide dichloride in 20 ml of absolute tetrahydrofuran is then added dropwise to the mixture with stirring at room temperature, whereby the reaction solution is slightly warmed. Stirring is continued for 2 hours at room temperature, any remaining NaH is carefully decomposed with water and evaporated. The residue is taken up in methylene chloride and extracted three times with 75 ml of 1N hydrochloric acid. f The hydrochloric acid extracts are combined and then made alkaline with soda solution, whereupon crystals precipitate. These are separated by filtration and recrystallized while still wet from isopropanol.

1.02 g of 1-bentoyl-2- (2 ', 6'-dichlorophenylamino) -2-l are obtained.

imidazoline (30.5% of theory), m.p. 160-162 ° C.

* *

Claims (2)

7 Claims 63752 A process for the preparation of 1-bentoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline of the formula ^ -Sjx h »J (I ·) CO r" Q-O ,,, Cl CO i. C6H5 or its salts, characterized in that 2,6-dichlorophenyl isocyanide dihalide of the general formula N31 in which X represents halogen, preferably chlorine, is reacted with benzoylethylenediamine in a solvent inert to 0 ° C in a solvent inert to the reaction component. by adding an acid scavenger, after which the compound of formulas (Ia) or (Ib) obtained is isolated as the free base or salt with inorganic or organic acids Process according to Claim 1, characterized in that the reaction is carried out at - + 50 ° C.