CS199247B2 - Method of producing novel 1-/2-delta up 2-imidazolinyl/-2,2-diarylcyclopropanes - Google Patents

Description

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel 1- (2-A ^2- imidazolinyl) -2,2-diarylcyclopropanes and their acid addition salts. The invention also describes their use as therapeutics and also relates to novel intermediates enabling the synthesis of said compounds.

The novel compounds of the present invention include a group of compounds of Formula I,

where it means

R is hydrogen, fluoro, bromo, C1-C3alkyl, and

R ¹ is hydrogen, C 1 -C 5 alkyl, C 1 -C 4 alkenyl, preferably allyl, C 1 -C 3 hydroxyalkyl, preferably hydroxyethyl, or phenylalkyl, the alkyl radical of which is 1; wherein the aromatic radical is optionally substituted by one to four radicals from the group consisting of bromine, fluorine, an alkyl radical of one to three carbon atoms and an alkenyl radical of one to three carbon atoms, bj their acid addition salts.

The hydrocarbon chains of said alkyl, alkoxy, hydroxyalkyl, alkenyl groups are straight or branched.

As mentioned above, the aromatic nucleus of the phenylalkyl group R 1 may be substituted by one to four radicals from the group consisting of fluorine, bromine, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms.

Of the compounds of formula I wherein R 1 is a phenylalkyl radical, preferred compounds are those of formula 1b,

where

R is as defined above

A represents a divalent hydrocarbon straight or branched chain and

Ar is a phenyl radical optionally substituted by one to four fluorine, bromine, C1-C3alkyl or C1-C3alkoxy groups.

In particular, A may be -CH ₂ -, -CH ₂ CH ₂ and -CH (CH 3) -, and Ar may in particular be -C 6 H 5, P-CH 3 -C 6 H ₄ -, (CH 3 O) -C 6 H 4 -, (CH 2 O 2 C 6 H 3 -, (CH 3 O) 13CeH2-, for example the 3,4,5-trimethoxyphenyl radical.

The compounds of the formula I according to the invention are obtained from 1-cyano-2,2-diarylcyclopropane of the formula II,

wherein R is as defined above, by:

a) a nitrile of the formula II is reacted with ethylenediamine monotosylate of the formula III and p-CH 3 -C 6 H 4 -SO 3 H, H 2 N-CH 2 -CH 2 -NH 2

b) optionally metalating the compound of formula Ia thus obtained,

wherein R is as defined above, and the metallated derivative thus formed is reacted with a halide of formula IV,

R 2 -hal (IV) wherein hal represents a halogen atom and

R2 has the meaning as R1, except for a hydrogen atom, to obtain a product of formula I wherein R1 is different from a hydrogen atom.

According to a preferred embodiment, the reaction of the nitrile of the formula II with ethylenediamine monotosylate is carried out at a temperature of 200 ° C without. solvents must be used; it is easy to work in excess of ethylenediamine monosylate, for example 2 moles of ethylenediamine monotosylate per 1 mol of nitriles of the formula II.

The metallation reaction is preferably carried out using sodium hydride or organolithium of the formula R 2 L 1, wherein R 2 is a C 1 -C 5 alkyl group or a phenyl group as the metallating agent.

The metalation of the compound of formula (Ia) with sodium hydride NaH is preferably carried out in hexamethylphosphoric triamide of the formula [(CH3) 2N] 3PO, which is also called hexamethapol, abbreviated to HMPT. The reaction is run at 60 ° C for 6 hours.

According to another preferred variation, the metalation of a compound of formula Ia with organolithium of the formula RaLi can be carried out in an inert solvent at a temperature in the range of 15-25 ° C for about 1 to 3 hours. In this case, a small excess of organolithium can be used, i.e. 1.1 to 1.2 moles of R2L1 per mole of the compound of formula (Ia), with butyllithium being the preferred organolithium. Inert solvents which can be used for metallation with organolithium R2L1 include, in particular, aliphatic and aromatic hydrocarbons, ethers and tetrahydrofuran. Preferred solvents for this reaction are hexane, benzene, toluene, xylene, diethyl ether and tetrahydrofuran.

The acid addition salts of the compounds of the formula I are obtained in a manner known per se by reaction with mineral or organic acids.

Among the acids which may be used are, in particular, hydrochloric, sulfuric, phosphoric, oxalic, succinic, methanesulfonic, cyclohexylamidosulfonic, formic, aspartic, glutamic, N-acetylaeparagic, N-acetylglutaminic, ascorbic, fumaric, maleic. lactic, benzoic, cinnamon and p-toluenesulfonic.

Mixtures of at least one compound of formula I or at least one of its addition salts with non-toxic acids, with a physiologically acceptable carrier, are recommended as therapeutic agents, in particular for the treatment of cardiovascular diseases.

The invention furthermore relates to novel intermediates, i.e. 1-cyano-2,2-diarylcyclopropanes of the general formula II, in which the substituent R has a meaning different from the hydrogen atom. These intermediates are obtained by treatment of acrylonitrile with diaryldiazomethane in an anhydrous solvent such as, in particular, petroleum ether, hexane, cyclohexane, heptane, chloroform or diethyl ether.

Other advantages and characteristics of the compounds of this invention will become apparent from the following description wherein are listed the results of pharmacological tests performed on the compounds _t by multiplying 'climb.

I - Antiarrhythmic effect

Arrhythmia induced by the action of aconitine nitrate

(a) Method

Groups of 6 male Wistar rats weighing 200-250 g were anesthetized by intraperitoneal injection of 1.2 g / kg urethane. The jugular vein is opened by perfusion of a 50 J / ml aconitin nitrate solution at a rate of 0.2 ml / min using a Braun perfuser. Test substances were also administered via the jugular vein 1 minute before the start of perfusion.

All solutions are prepared in 9 g / l aqueous sodium chloride solution.

The electrocardiogram at Dz is recorded (the term “electrocardiogram at D2” means an electrocardiogram that is scanned by placing the receiving electrodes on the right front paw and the left hind paw and the glass electrode on the right hind paw) and recording the perfusion time necessary to obtain the first ventricular arrhythmia. Calculate the dose of intravenously perfused aconitine in j / kg and the percentage increase compared to control animals.

A dose which increases by 60% the amount of aconitine required to achieve the first ventricular arrhythmia is used as a reference; this dose is called an effective dose of 60% (DA 60).

(b) Results

The results are shown in Table I; the figures represent mean values of aconitin perfused in j / kg and DA 60 values.

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Coronary ligature - induced arrhythmia (also Method

Dogs of all breeds are anesthetized by intravenous injection of 120 mg / kg chloral hydrate, followed by artificial respiration. The chest is opened at the level of the fourth intercostal space, the pericardium is incised, and the interventricular artery is exposed about 1 cm below the branching site of the ciccumflex artery. A first ligation is performed, leaving a lumen of 0.9 mm, and after half an hour a final ligation is performed. After chest closure, normal breathing is resumed and after 24 hours dogs are ready for experiments.

Record the electrocardiogram at D2, indicating:

= arrhythmia record

0.5 = background sinus pulses arrhythmia = background sinus pulses = sinus rhythm (b) Results

The succinate of the compound of Example 3, administered at a dose of 10 mg / kg I.V., induces records in 5 dogs.

0.5; 2; 2; 2; 2, ie the practical restoration of sinus rhythm in all cases.

The hydrochloride of the compound of Example 6, administered at a dose of 2.5 mg / kg I.V, induces records on 6 dogs

2; 1; 2; 2; O; 2, ie restoration of sinus rhythm in five cases out of six.

The oxalate of the compound of Example 10, administered at a dose of 5 mg / kg I.V, induces records on 3 dogs.

2; 2; 2, '*

ie restoration of sinus rhythm in all cases.

The hydrochloride of the compound of Example 18, administered at a dose of 2.5 mg / kg I.V, induces records in 5 dogs

0.5; 1; 1; 2; 2, and at a dose of 5 mg / kg I.V in two dogs records

2; 2, ie complete restoration of the sinus rhythm.

II - Toxicity by intravenous administration (a) Method

Test substances were administered intravenously rapidly to groups of 3 male Vistar rats weighing 110-130 g. Mortality was measured after 7 days.

The results are summarized in Table III, where the last non-lethal dose (DL OJ and the killing dose of all animals (DL 100)) is given in mg / kg.

Table II of Compound DL O of Example I. V.

DL 100 <I. V.

3 (i 32 64 4 (b) 16 64 5 (b) 16 64 6 (bj 8 16 7 (bj 16 32 8 (ref 16 32 9 (d) 16 32 10 d 16 32 11 (d) 8 16 12 d 16 32

(a) succinate (c) methanesulphonate (b) hydrochloride (d j oxalate)

In human medicine, the compounds of the formula I and their non-toxic acid addition salts can be administered, in particular, orally or by injection. For oral administration, suitable forms are soft capsules containing 50 mg of active ingredient and for injection, ampoules containing 5 mg of active ingredient are suitable.

The compound of Example 3, administered as a soft capsule, makes it possible to prevent and treat tachycardia by the right ventricular, nodal, auricular, extrasystoles.

Injections provide rapid rhythm recovery in ventricular extrasystoles.

In the following examples, which describe the preparation of the compounds of the invention without limiting the scope of the invention, Examples 1 and 2 relate to the synthesis of nitriles of formula II, Examples 3 to 5 of the compounds of formula Ia, Examples 6 to 12 describe sodium hydride methalation; up to 18 metalation with organolithium.RzLi.

Example 1-Cyano-2,2-dirp-tolylcyclopropane

To a solution of 0.5 mole of di-p-tolyldiazomethane in 300 ml of chloroform was added dropwise 0.55 mole of acrylonitrile while stirring, maintaining the reaction medium at 40 ° C with a cold water bath. After the addition was complete, the reaction mixture was further stirred for 5 hours, when the solution was already decolorized and nitrogen evolution ceased.

The solvent is evaporated off under reduced pressure, the residue is taken up in 400 ml of pentane and, after crystallization, the product is filtered off and dried. Yield 85%, mp 67 ° C. Analysis:

calculated N 5.67%, found N 5.82%.

Example 2 1-Cyano-2,2-di-p-fluorophenylcyclopropane

The procedure is as in Example 1 except that 0.5 mole of di-p-fluorophenyldiazomethane is used instead of di-p-tolylphenyldiazomethane. The reaction is carried out in 500 ml of ether at 30 ° C. After evaporation of the solvent, the residue is distilled under reduced pressure, the yield is 50%, the boiling point is 160-163 ° C / 0.5 torr and the melting point is 95 ° C.

Analysis:

calculated N 5.50%;

found N 5.44%.

EXAMPLE 1 ad 3 l- (2-A ² -Imidazolinyl) -2,2-difenylcyklopro-

A mixture of 0.5 mole of 1-cyano-2,2-diphenylcyclopropane and 1 mole of ethylenediamine monotosylate of formula III is gradually heated to 200 ° C, where it is heated for 2 hours. The mixture was allowed to cool and 1.2 moles of sodium hydroxide in 400 ml of water and 200 ml of chloroform were added. The chloroform was separated and the reaction mixture was extracted again by adding 100 ml of chloroform to the aqueous phase.

The reaction mixture was dried over sodium sulfate and the chloroform removed by distillation under reduced pressure. Addition of 300 ml of petroleum ether crystallizes the product, then is filtered off and dried. Yield 91%, melting point 103-104 ° C.

Analysis:

calculated N 10.68%;

found N 10.50%.

Preparation of amber:

0.1 mol of succinic acid is dissolved in 120 ml of isopropanol with heating, 0.1 mol of 1- (2-A ^2- imidazolinyl) -2,2-diphenylcyclopropane obtained as above in solution in 50 ml of isopropanol is added, then the mixture is cooled and 100 ml of ether are added. The crystallized product is filtered off and recrystallized from a mixture of ethanol and ether (70:30). Yield 85%, mp 165 ° C. Analysis:

N, 7.35%.

found N 7.28%.

Example 4 1- (2-A ² -imidazolinyl) -2,2-dl-p-tolylcyclopropylamine

ϋ

The procedure is as in Example 3 except that 1-cyano-2,2-diphenylcyclopropane is replaced by 0.5 mole of 1-cyano-2,2-di-p-tolylcyclopropane prepared as described in Example 1.

Preparation of hydrochloride:

After evaporation of the chloroform as described in Example 3, the residue is dissolved in 200 ml of isopropanol, ethereal hydrogen chloride solution is added until the pH reaches 1, and 150 ml of ether are then added. After trituration of the mixture, the crystallized product is filtered, washed with ether and dried. It was recrystallized from isopropanol / ether (80:20). Yield 70%, mp 260 ° C.

Analysis:

calculated Cl 10.86 N 8.56%;

found Cl 10.9 N 8.7

Example 1 a d 5

1- (2-A ^2- Imidazolinyl) -2,2-di-p-fluorophenylcyclopropane

The procedure is as in Example 3 except that 1-cyano-2,2-diphenylcyclopropane is replaced by 0.5 mole of 1-cyano-2,2-di'-p-fluorophenylcyclopropane prepared according to Example 2.

Preparation of hydrochloride:

The procedure is as in Example 4. Recrystallization of the hydrochloride of l- (2-A ² -imidazolinyl) -2,2-di-p-fluorfenylcyklopropanu from ethanol-ether (70: 30) gave the product, m.p. 266 ° C to yield 57%. Analysis:

N, 8.37% calculated;

found N 8.41 ° / o.

Example 6

1- [2- (N-benzyl) -Δ ² -imidazolinyl] -2,2-difluoro enylcyklopropan

To a solution of 0.1 mole of sodium hydride in 20 ml of hexamethylphosphoramide, at a temperature of 90 ⁹ C, with stirring, a solution of 0.1 mol of l- (2-A ² -imidazolinyl) -2,2-difenylcyklopropanu prepared by of Example 3, in 50 mL hexamethylphosphoric triamide. After the addition was complete, the mixture was allowed to stir at 90 ° C for 6 hours, then cooled in an ice bath and 0.12 mol of benzyl chloride was added dropwise, maintaining the temperature at approximately 25 degrees Celsius. After the heat evolution had ceased, the reaction medium was allowed to stir for 2 hours at ambient temperature (15-25 ° C), then poured into 300 ml of water, extracted with ether, dried over magnesium sulfate and the ether was distilled off.

Preparation of hydrochloride:

The evaporation residue is taken up in 50 ml of ether, ethereal hydrogen chloride solution is added until the pH reaches 1, and after trituration, the crystallized substance is filtered, washed with ether and dried. Recrystallization from isopropanol / ether (70:30) gave the product with a melting point of 202 ° C in 43% yield.

Analysis:

calculated N 7.20%;

found N 7.3%.

Example 7

1- (2- (N-p-methylbenzyl) -Δ ^{imidazoline-2-one]} -2,2-difenylcyklopropan

The procedure was as in Example 6, except that the benzyl chloride was replaced with 0.12 mole of p-methylbenzyl chloride p-CH3-CoHa-CH2Cl.

Preparation of hydrochloride:

Following the procedure of Example 6, 1- [2- (N-methylbenzyl) -N- ^2- imidazolinyl] -2,2-diphenyl-cyclopropane hydrochloride with a melting point of 204 DEG-206 DEG C. was obtained in a yield of 39%.

Analysis:

calculated N 6.95%;

found N 7.0%.

Example 8 1- [2- (N-Benzyl) -A ² -imidazolinyl] * 2,2-di-p-tolylcyclopropane

The procedure is as in Example 6 except that 1- (2-A ^2- imidazolinyl) -2,2-diphenylcyclopropane is replaced by 0.1 mole of 1- (2-A ^2- imidazolyl) -2,2-di-p-tolylcyclopropane prepared according to Example 4.

Preparation of methanesulfonan:

The evaporation residue is dissolved in 100 ml of ether and 0.1 mol of methanesulfonic acid in 50 ml of ether is added. The product crystallized by trituration, filtered, washed with ether and dried.

Recrystallization from a mixture of isopropanol and ether (70:30) afforded a product with a melting point of 195 ° C in 40% yield.

Analysis:

calculated N 5.87%;

found N 5.9%.

Example 9

1 - [, 2- (N-a-Phenethyl) - ^2- imidazolyl] -2,2-diphenylcyclopropane

The procedure was as in Example 6 except that 0.12 mol of benzyl chloride was replaced with 0.11 mol of n-phenethyl chloride.

Preparation of oxalate:

The ether evaporation residue was purified by filtration on basic alumina (eluting with ether). Evaporation of the eluting ether yielded 0.015 mol of crude base which was dissolved in a solution of 0.015 mol of oxalic acid in 20 ml of isopropanol and 80 ml of ether was added. The crystallized product was filtered and recrystallized from isopropanol / ether (70:30). Yield 12%, mp 148 ° C.

Analysis:

calculated N 6.14%;

found N 6.07 ° / δ.

Example 10

1- (2- (N-Allyl) -A-amidazolinyl) -2,2-diphenylcyclopropane

The procedure was as in Example 6 except that 0.11 mol of allyl bromide was used instead of benzyl chloride.

Preparation of oxalate:

The evaporation residue is dissolved in 0.1 mol of oxalic acid in a mixture of 80 ml of acetone and 20 ml of ether. After trituration, the crystallized product is filtered off, washed with 20 ml of acetone and recrystallized from isopropanol / ether (65:35). Yield 51%, mp 146 ° C.

Analysis:

N, 7.14%.

found N, 7.20%.

Example 11

1- (2- (N-Butyl) -A ² -imidazolinyl) -2,2-diphenylcyclopropane

The procedure is as in Example 6, except that the benzyl chloride is replaced by 0.11 mol of n-butyl bromide.

Preparation of oxalate:

The ether evaporation residue is dissolved in 0.1 mol of oxalic acid in 100 ml of acetone. After trituration, the crystallized product is filtered, washed with 20 ml of acetone and crystallized from methanol / ether (60:40). The yield is 47%, the melting point is 176%.

Analysis:

calculated · N 6.85%;

found N 6.72%. ·

Example 12

1- (2- (N-isopropyl Me ² -ímidazolinyl] -2,2-dífenylcyklopropan

The procedure was as in Example 6, but using 0.11 mol of isopropyl bromide instead of benzyl chloride.

Preparation of oxalate:

The ether evaporation residue is taken up with 0.1 mole of oxalic acid in 100 ml of acetone. After trituration, the crystallized product is filtered, washed with 20 ml of acetone and recrystallized from isopropanol / ether (70: 30). The yield is 41bp, 166 ° C. Analysis:

calculated: N 7.09%;

found N 7.13%.

Example 13

1- (2- (N ^: Ally) - N ² -imidazolinyl) -2,2-diphenylcyclopropane

To 0.1 mol of 1- [2,2-imidazolinyl] -2,2-diphenylcyclopropane in 100 ml of anhydrous benzene was added 0.11 mol (44 ml) of a solution of butyllithium (2.5 IU in hexane) at the temperature of the reaction mixture. The mixture is kept under stirring at ambient temperature (15-25 ° C) for 2 hours, at which temperature 0.12 mol (10.4 ml) of allyl bromide is added dropwise to the reaction mixture. After stirring at ambient temperature until homogeneous (approximately 2 hours) After refluxing for three hours, the mixture is allowed to cool, 100 ml of water are added, stirred for 10 minutes, decanted, extracted with 200 ml of ether, dried over magnesium sulphate and the solvent was evaporated under reduced pressure.

Preparation of hydrochloride:

The evaporation residue is dissolved in a mixture of isopropanol (30 ml) and ether (90 ml) and treated with ethereal hydrogen chloride solution with stirring until the pH reaches 1, then left to stand for 3 hours, filtered, washed with ether and dried.

The product obtained is recrystallized from isopropanol / ether (40:60). Yield 72%, melting point 194%.

Analysis:

calculated N 8.25%;

found N 8.19%.

Example 1 4

1- (2- (N-Butyl) - N ² -imidazolinyl] -2,2-diphenylcyclopropane

The procedure was as in Example 13 except that the allyl bromide was replaced with n-butyl bromide in an amount of 0.12 mol.

Preparation of oxalate:

The ether evaporation residue is taken up with 0.1 mole of oxalic acid in 100 ml of acetone. After trituration, the crystallized product is filtered off, washed with 20 ml of acetone and recrystallized from a mixture of methanol and ether (60:40). Yield 69, 176%.

Analysis:

calculated N 6.85%;

found N 6.79%.

The analytical results obtained are consistent with those of Example 11, Example 15

1- (2- (N-Benzyl) - N ² -imidazolinyl) -2,2-di-p-tolylcyclopropane

The procedure is as in Example 13 except that the allyl bromide is replaced with 0.12 mol of benzyl chloride and the 1- (2-A ² -imidazolinyl) -2,2-diphenylcyclopropane is replaced with 0.1 mol of 1- (2-A ² -imidazolinyl) -2 With 2-di-p-tolylcyclopropane in an amount of 0.1 mol.

Preparation of methanesulfonan:

The evaporation residue is dissolved in 100 ml of ether and 0.1 mol of methanesulfonic acid in solution in 100 ml of ether is added. The mixture was triturated, the crystallized product was filtered off, washed with ether and dried. After recrystallization from isopropanol / ether (70:30) the yield is 66% and the melting point is 195%.

Analysis:

calculated N 5.87 found N 5.9 ° / o.

The analytical results were consistent with those of Example 8.

EXAMPLE 1 ad 1 6 l- (2- (N-methyl) -Δ ² -imidazolinyl] -2,2-difenylcyklopropan

To a solution of 1- [2-A ^2- imidazolinyl] -2,2-diphenylcyclopropane in 100 mL of anhydrous benzene was added 0.11 mol (44 mL) of a solution of butyllithium (2.5 M) in hexane, while the reaction The mixture is maintained at about 20 ° C and the mixture is left under stirring at the same temperature for 2 hours. 0.12 mol (10.4 ml) of methyl iodide is then added dropwise while maintaining the temperature at approximately 25 ° C. The reaction mixture is allowed to stir at ambient temperature until homogeneous (about 2 hours) and then refluxed for 3 hours. After cooling, 100 ml of water are added, the mixture is stirred for 10 minutes, then decanted, extracted with 200 ml of ether, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. Hydrochloride preparation:

The ether evaporation residue is dissolved in 100 ml of acetone, ethereal hydrogen chloride solution is added until the pH of the mixture reaches 1, the mixture is allowed to stand for 1 hour, the product is filtered off and recrystallized from a mixture of ethanol and ether (70:30). The yield is 54%, the melting point is higher than 260 ° C.

Analysis:

calculated N 8.96%;

found N 8.83 ^lo / o.

Example 17

1- (2- (N-3 ', 4', 5'-Trimethoxy benzyl) - N ² -imidazolinyl] -2,2-diphenylcyclopropane

The procedure was as in Example 16 except that the methyl iodide was replaced with 0.11 mol of 3,4,5-trimethoxybenzyl chloride.

Preparation of p-toluenesulfonate:

The evaporation residue was dissolved in 100 ml of ethyl acetate and a solution of 0.1 mol of p-toluenesulfonic acid in 100 ml of ethyl acetate was added. The resulting mixture was allowed to stand for 3 hours, the precipitated product was filtered off, washed with 50 ml of ethyl acetate and dried. Yield 70%, mp 174 ° C.

Analysis:

calculated · N 4.56%;

found N 4.5%.

Example 1 8

1- (2- (N-hydroxyethyl) -Δ ² -imidazolinyl] -2,2-difenylcyklopropan

The procedure was as in Example 16 except that methyl iodide was replaced with 0.11 mol of bromoethanol pyranyl ether.

Hydrochloride preparation:

The ether evaporation residue is dissolved in 80 ml of ethanol, followed by the addition of 0.2 mol of concentrated hydrochloric acid, maintaining the temperature at approximately 20 ° C. The mixture is allowed to stand for 1 hour, 240 ml of water are added, the mixture is extracted with ether, the aqueous phase is made alkaline with sodium hydroxide, extracted with ether, dried over sodium sulfate and concentrated.

199 /

the ether was distilled off under reduced pressure. The residue was dissolved in a mixture of 150 ml of isopropanol and 100 ml of ether, ethereal hydrogen chloride solution was added until pH = 1, the mixture was allowed to stand for 3 hours, filtered, washed with isopropanol / ether (50:50).

Claims (7)

A process for the preparation of novel 1- (2-A ² -imidazolinyl) -2,2-diarylcyclopropanes of the general formula R @ 1 is hydrogen, bromine or fluorine or C1 -C3 alkyl; R 1 is hydrogen, C 1 -C 5 alkyl, C 4 -C 4 alkenyl, preferably allyl, C 1 -C 3 hydroxyalkyl, preferably hydroxyethyl, or C 1 -C 3 phenylalkyl an alkyl moiety having an aromatic nucleus optionally substituted with one to four radicals selected from the group consisting of bromine, fluorine, an alkyl radical of one to three carbon atoms and an alkoxy radical of one to three carbon atoms, and acid addition salts thereof, by reacting 1-cyano-2,2-diarylcyclopropane of formula II, wherein R is as defined above, with monotosylate of ethylenediamine of formula III, P-CH3 — CeHa — SOsH, H2N-CH2 — CH2 — NH2 (III) Severography, n. dried. Yield: 68%; melting point: 215 degrees Celsius. Analysis: N ^, 8.16% calculated; found N, 8.20%. And the thus obtained compound of formula Ia, wherein R is as defined above, is optionally metallized and the resulting metallized derivative is reacted with a halide of formula IV, R2-hal (IV) wherein hal represents a halogen atom and R2 is as R1 in formula I except hydrogen to give a compound of formula I wherein R1 is other than hydrogen, optionally converting the compound of formula I into an acid addition salt. 2. The process according to claim 1, wherein the reaction of 1-cyano-2,2-diarylcyclopropane of formula II with mono-ethylenediamine is carried out at 200 [deg.] C. in the presence of an excess of ethylenediamine monotosylate. 3. The process of claim 1, wherein the metalation is carried out with sodium hydride or organolithium of the formula R3-L1, wherein R3 is a C1 -C5 alkyl group or a phenyl radical. 4. The process of claim 3, wherein the sodium hydride metallation is carried out in hexamethylphosphoric triamide. 5. The method according to claim 4, wherein the metalation is carried out for 6 hours at a temperature of 90 [deg.] C. ; 6. The process of claim 3, wherein the metalation is carried out with butyllithium at a temperature of 15 to 25 [deg.] C. for 1 to 3 hours. 7. A process according to claim 6, wherein 1.1 to 1.2 moles of butyllithium are added per mole of the compound of formula (Ia). Race 7, Most