FI61883C - FOERFARANDE FOER FRAMSTAELLNING AV FYSIOLOGISKT AKTIV 2- (2-FLUOR-6-TRIFLUORMETHYL-PHENYLIMINO) -IMIDAZOLIDINE - Google Patents

Description

I- ^ Γβ, .... KU RELEASE PUBLICATION s * ο Ο 7 4βΓφ B 11 UTLÄGGNINGSSKRIFT 6l883 c Patent oySnne-lty 11 10 1932

Pateirt. E? Ddelat v (51) Kv.lkr /int.ci. c 07 D 233/50 FINLAND-FINLAND <«> Patent application - Patent dansöknlng 752728 (22) Hakemlspllvl - Ansöknlngsdag 30.09.75 (23) Primary cloud - Glltighetsdsg 30.09.75 (41) Become Public - Bllvlt offentllg 02.0¾.7

Patent and Registration Office ...., * (44) Date of publication and publication of the publication. -

Patent · och registerstyrelsen Ansttkan utlagd och utl.skrlften publlcerad 30.06.62 (32) (33) (31) Pyydetty etuoikeus — Begird prloritet 01.10. jk

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2UU6758.1 (71) C.H. Boehringer Sohn, Ingelheim am Rhein, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Helmut Stähle, Ingelheim, Herbert Köppe, Ingelheim, Werner Kumrner,

Ingelheim, Wolfgang Hoefke, Budenheim, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (7¾) Leitzinger Oy (5¾) Process for the preparation of physiologically active 2- (2-fluoro-6-trifluoromethyl-phenylimino) -imidazolidine - Förfarande för framstiskt Aktiv 2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine 2-Phenylimino-imidazolidines have long been of great interest due to their excellent pharmacological and therapeutic properties. Compounds of this type have therefore been described many times in the literature and disclosed, for example, in Belgian Patents 623,305, 653,933, 687,656, 687,657 and 705,944. Essential methods for the preparation of 2-phenyliminoimidazolidine are also given in these publications.

Recent studies have shown that conformation is crucial for the structural properties of 2-phenyliminoimidazolidines required for central, α-adrenergic stimulation. Based on structural-efficacy studies, it has been found that only derivatives whose phenyl and imidazolidine rings are in the aplanal conformation with respect to each other have a good antihypertensive effect.

In this case, the phenyl ring cannot rotate freely around a simple C-N bond, and both rings are perpendicular or almost perpendicular to each other.

2 61 e 8 3

Aplanarity can be achieved in 2-phenyliminoimidazolidines by substituting the ortho positions of the aromatic moiety:

R

φ-ά R 'The space-consuming atoms or groups of atoms at these positions prevent the phenyl ring from rotating freely around a simple C-N bond and thus allowing both rings to settle coplanar with respect to each other.

Clonidine, i.e. 12- (2,6-dichlorophenylimino) -imidazolidine, is one compound in this group that has a very potent antihypertensive effect, but its use causes some undesirable side effects. The object of the invention is to provide a novel compound having a strong hypotensive effect and a favorable effect profile.

According to the invention, therapeutically active 2- (2-fluoro-6-trifluoromethylphenylimino) imidazolidine and its physiologically acceptable acid addition salts are prepared. The invention is characterized in that 2-fluoro-6-trifluoromethyl-phenyl-isocyanide dichloride is reacted with ethylenediamine, and optionally the compound thus obtained is converted into an acid addition salt.

The reaction takes place at temperatures between 0 and 200 ° C. Polar protic, polar aprotic or non-polar compounds can be used as the solvent. However, the reaction can also be carried out without the use of solvents at elevated temperature. It is recommended to use an acid scavenger in the reaction. The reaction time depends on the reactivity of the components used and varies from a few minutes to several hours.

3,61883 The preparation of the new 2-fluoro-6-trifluoromethylaniline used as starting material generally takes place according to the following schematic reaction route: {t-butyllithium. \ V T <* C ° 2 v

Mp =-- * -60 - -70 ° C

CF o '3 CF3

F

r (\ S n H, ΓΚ In this synthesis, in addition to benzoic acids, their isomers are also formed, which are best separated by column chromatography (silica gel).

Isocyanide dichloride can be prepared from aniline as follows:

.F F

ii_LH £ ooH-.

\ / i 2. + S02C12 / S0C12 \ _ / "OI

CF3 cf3 61883 4

2- (2-Fluoro-6-trifluoromethyl-phenyliminoimidazolidine prepared according to the invention can be converted into its physiologically acceptable acid addition salts in a customary manner. 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, etaanifosfori acid and 8-chloroheophylline.

This new compound and its acid addition salts have valuable therapeutic properties, in particular an antihypertensive property, and can therefore be used in the treatment of various manifestations of hypertension. The compound can be administered enterally or also parenterally. The dose is 0.1 to 80 mg, preferably 0.5 to 30 mg.

The new compound or its 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, the galenic auxiliaries, carriers, enhancers or lubricants normally used in their manufacture or substances which produce a lasting effect may be used.

The antihypertensive effects of the novel compound of the invention and clonidine were studied in rabbits under urethane-nembutalnarcosis. Blood pressure was measured directly from the head artery.

ED2Q is the dose that produces a 20 mmHg reduction in blood pressure.

Compound ed20 (blood pressure) LD50, ng * mg / kg_mg / kg 2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine 0.023 44

Clonidine 0.010 18 5 61 883

The effect of both compounds on the abdominal secretion of rats was studied with a Shay device. The ED50 is the dose that causes a 50% reduction in gastric fluid volume and acidity.

Compound ed50 »rat _mg / kg_ 2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine 0.163

Clonidine 0.039

Both compounds have an anesthetic-enhancing effect. The sleep time induced by hexabarbital sodium is prolonged compared to the control group. D ^ gO is the value that doubles the sleep time.

Compound D100 'mouse _mg / kg_ 2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine 0.082

Clonidine 0.0093

The following values have been obtained in "sloping level" experiments and refer to the suppression of exercise and desire for research in mice.

attenuation of the desire to exercise research attenuation

Compound mouse, ED50 mouse, ED50 _mg / kg_mg / kg_ 2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine 18 3.5

Clonidine 0.36 0.25

The following example further illustrates the invention.

61883 6

Example 2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine hydrochloride_

P

I jj

(o> - -Q

cf 39 g of N- (2-fluoro-6-trifluoromethylphenyl) isocyanide dichloride are prepared from 3-fluorobenzotrifluoride according to the reaction described above through the following steps: 2-fluoro-6-trifluoromethylbenzoic acid (m.p. 81-84 ° C) , 2-fluoro-6-trifluoromethylaniline (oily) and 2-fluoro-6-trifluoromethylformanilide (m.p. 116-111 ° C) J and 21.6 ml of ethylenediamine (10-fold excess) are reacted with each other at 10 ° C: while stirring in 100 cm3 of absolute ether. After a reaction time of 30 minutes, the reaction mixture is evaporated to dryness in vacuo and the residual oil is dissolved in dilute hydrochloric acid. Extract twice with ether and separate the aqueous phase and treat with activated carbon. The fraction is then extracted with ether at increasing pH (alkali with sodium hydroxide). The thin ether chromatographically pure ether fractions are combined, dried and, to precipitate imidazolidine hydrochloride, ethereal hydrochloric acid is added until the solution reacts acidically with Congo red. The yield of pure 2- (2-fluoro-6-trifluoromethyl-phenylimino) -imidazolidine hydrochloride is 4.35 g or 44.9% of theory. Melting point 262-264 ° C. The white crystalline substance is soluble in water and lower alcohols.