CS212310B2 - Method of making the new 2-iminoimidazolidine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of the novel 2-iminoimidazolidine derivatives of the general formula I

in which

R ¹ , R ² and R ³ are each independently hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, halogen or trifluoroethyl and is hydrogen, (C 1 -C 6) alkyl (C 1 -C 6), (C 3 -C 6) cycloalkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 1 -C 6) dialkylaminoalkyl, (C 1 -C 6) -alkyl; (C 1 -C 6) alkyl, (C 2 -C 6) carboxyalkenyl, (C 1 -C 6) hydroxyalkyl, (C 1 -C 6) cyanalkyl, (C 1 -C 6) phenylalkyl , (C 1 -C 6) alkylthioalkyl, (C 1 -C 6) alkoxycarbonylalkyl, (C 1 -C 6) alkoxyalkoxyalkyl; xyl and alkyl, C 1 -C 6 aminocarbonylalkyl, C 1 -C 6 monoalkylaminocarbonylalkyl, C 1 -C 6 dialkylaminocarbonylalkyl, C 1 -C 6 alkoxycarbonylalkenyl and (C 2 -C 6) alkenyl moiety, C 1 -C 6 alkoxyalkyl group containing 1 to 6 carbon atoms, C 1 -C 6 aminoalkyl, (2,2,8-trimethyl-4H-m-dioxino [4] , 5-e] pyridin-5-yl) methyl, [5-hydroxy-4- (hydroxymethyl) -6-methyl-3-pyridyl] methyl, alpha-carboxybenzyl, alpha-alkoxycarhonyl-alpha-alkylphenyl a (C 1 -C 6) -alkoxy or alkyl moiety bonded via a -CH (R) group, optionally -COOR substituted with a 5-membered or optionally C 1 -C 6 -alkyl or a C 1 -C 6 -alkoxy-substituted aromatic a heterocyclic group having 1 or 2 heteroatoms, wherein the heteroatoms are oxygen, nitrogen or sulfur and R is hydrogen or methyl and R is hydrogen or (C1-C6) -alkyl, as well as pharmaceutically usable addition salts thereof; acids.

The term alkyl - alone or in combination - means within the scope of this invention straight and branched alkyl groups of 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isohutyl, tert-butyl, amyl, hexyl and the like

The term oycloalkyl refers to cyclic, saturated hydrocarbon radicals having 3 to 6 carbon atoms, such as cyclopropyl, cyclohexyl and the like.

The term alkoxy means alkyl ether groups in which my term alkyl as defined above.

The term alkenyl includes straight and branched chain hydrocarbon radicals having 2 to 6 carbon atoms in which at least one carbon-carbon bond is unsaturated, such as allyl, butenyl and the like.

The term alkynyl refers in a similar manner to straight and branched hydrocarbon radicals having 2 to 6 carbon atoms in which at least one carbon-carbon triple bond such as propargyl and the like is present.

The term halogen includes four halogen atoms fluorine, chlorine, bromine and iodine. Examples of 5 or 6 membered aromatic heterocyclic radicals with one or two heteroatoms are thienyl, furyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, phthalazinyl, pyrimidinyl or pyrazinyl.

As used herein, a leaving group refers to known groups within the scope of the present invention, such as halogen, preferably chlorine or bromine, an arylsulfonyloxy group such as a sesyloxy group, an alkylsulfonyloxy group such as mesyloxy, quaternary ammonium and sulfonium salts and the like.

A preferred group of compounds of formula I are those compounds wherein ^J is R 2 VO1 dik. Further preferred are those compounds of formula I wherein R and R are located in the 2, 2, 6 of the phenyl ring. R and R preferably have the same meaning and are preferably halogen, particularly preferably chlorine.

Another group of preferred compounds of formula I are those in which R ⁴ is an alkynyl group, preferably of 3 to 5 carbon atoms, a carboxyalkyl group, preferably a carboxymethyl or carboxypropyl group, an alkoxycarbonylalkenyl group, preferably an ethoxycarbonylalkenyl group, or via a -CH (R) group. - a bonded, optionally -COOR group substituted with a 5- or optionally alkyl-substituted, 6-membered aromatic heterocyclic group with one or two heteroatoms, wherein the heteroatoms are oxygen, nitrogen or sulfur and R is hydrogen or methyl, and R is hydrogen or an alkyl group; preferably it is a pyridyl group or an unsubstituted 5-membered aromatic heterocyclic group with one oxygen or sulfur atom.

Very particularly preferably, R ⁴ represents a propargyl, carboxymethyl, unbranched ethoxycarbonylalkenyl group or a pyridyl or furyl group via a -CH 2 - group and R 6 is as defined above.

Accordingly, particularly preferred are those compounds of formula I wherein R 1 is hydrogen, R ¹ and R ² are halogen, preferably chloro, at the 2, 6 s positions is propargyl, carboxymethyl, unbranched ethoxycarbonylalkenyl or via -CH (R 6) - bound pyridyl or furyl and R 6 is as defined above.

Preferred compounds of formula I are:

2- [2,6-Dichlorophenyl) imino] -1-hydroxyimidazole,

2 - [(2,6-dibromophenyl) imino] -1-hydroxyimidazolidine,

-hydroxy-2- (2-iodophenyl) imino] imidazole din, ethyl 4 - [[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] butyrate,

4- [N - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] butyric acid, ethyl 2 - [[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] butyrate ,

2 - [(2,6-di-chlorophenyl) imino] -1- (2-propinyloxy) imidazolidine, [2/2 - [(2,6-di-chlorophenyl) imino] -1-imidazolidinyl / oxy] acetic acid, ethyl 4 - [[- [(2,6-diohlorophenyl) imino] -1-imidazolidinyl] oxy] crotonet,

2 - [(2,6-Dichlorophenyl) imino] -1-ethoxyimidazolidine,

- (2-butinyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazole din,

2 - [(2,6-dichlorophenyl) imino] -1- (furfuryloxy) imidazolidine,

2 - [/ {2 - [(2,6-dichlorophenyl) imino] -1-imidazolinyl} oxy] methyl / pyridine,

3- [[[2 - [(2,6-dichlorophenyl) imino] -1-imidazolinyl} oxy] methyl] pyridine,

2 - [[2 - [(2,6-dichloro-4-fluorophenyl) imino] -1-imidazolinyl] oxy] methyl / pyridine,

5H-2 - [(2,6-dichlorophenyl) imino] -1-imidazolinyl] oxy] methyl (-3-hydroxy-2-methyl-4-pyridinmethanol).

The compounds of the above formula (I) and their pharmaceutically usable acid addition salts can be prepared according to the invention by the compound of the formula (11)

(II) wherein X

A is -N = C or -NH-CN,

Y where

X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio and 1 2 3

R, R and R are as defined above, with a compound of formula IV

H ₂ N-CH ₂ -CH ₂ -NH-OR ⁴ (IV) wherein 4

R is as hereinbefore defined, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt.

The reaction of the compound of formula II with the compound of formula IV can be carried out in a manner known per se. Conveniently, the reaction is carried out in an organic solvent which is inert under the reaction conditions or, in the case of the reaction of a compound of formula II in which A is -N = C (X) (Y), where X and Y are as defined above, in a biphasic system, such as a mixture of water and toluene and the like, at a temperature between about 0 and 180 ° C, optionally depending on residues X and X. Non-polar or polar aprotic solvents are also suitable as solvents depending on residues X and X. or in the case of the reaction of compound II wherein A is -N = C (X) (Y), wherein X and X are as defined above, also polar aprotic solvents such as ethers, for example diethyl ether, tetrahydrofuran, dioxane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; alkanoic acid esters such as ethyl acetate and the like; for example tert-butanol, amyl alcohol and the like, acetonitrile and the like.

The reaction is preferably carried out in the presence of an acid binding agent such as triethylamine, N-ethyl-N, N-diisopropylamine, pyridine and carbonates and the like when one of X and Y is halogen. The duration of the reaction depends on the reactivity of the starting materials used and lies between a few minutes and several hours.

The compounds of the above formula (I) may be converted into pharmaceutically usable acid addition salts, for example by treatment with an inorganic acid such as hydrohalic acid, for example hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid and the like, or by treatment with an organic acid such as tartaric acid, tartaric acid. acids, oitronic acids, sethanesulfonic acids and the like.

The pharmaceutically unacceptable acid addition salt of a compound of formula I can be converted into the free base in a manner known per se, for example by treatment with an alkali, and this base is optionally converted into a pharmaceutically acceptable acid addition salt.

The compounds of the general formulas II which are used as starting materials are partly known and partly novel. The novel compounds can be prepared in a manner known per se, i.e. in a manner analogous to that known for the preparation of known compounds.

Compounds of the pattern IV used as starting materials are novel and can be prepared for example by an O-benzylhydroxylamine of Formula V 9Š19Ž _R 4 is benzyl, is reacted with a compound of formula VI X-CH ₂ -CH ₂ - of (VI) wherein

Z is phthalimido or succinimido; and

X is a leaving group, or with ethyleneimine.

The reaction with a compound of formula VI is carried out by methods known per se in the presence or absence of a solvent at a temperature between about 50 to 100 ° C, preferably between about 80 and 90 ° C, and provides a compound of formula VIIa- _2- ch ₂ -h ₂ -oh ⁴ (Villa)

V IjětpŽ

R ⁴ and Z are as defined above.

Suitable solvents for this reaction are acetonitrile, tetrahydrofuran and the like.

The compound of formula (VIIa) in which R ^{@ 4} is benzyl may be converted, if appropriate, by cleavage of the benzyl group and, if appropriate, substitution at an oxygen atom, to the corresponding compound in which R ^{@ 4} has the meaning of R ^{@ 4} .

The cleavage of the benzyl group from the compound of formula (VIIa) is carried out by known methods by treatment with a hydrohalic acid, preferably hydrobromic acid, or catalytic hydrogenation, or preferably with boron tribromide or chloride in an inert organic solvent such as methylene chloride and the like.

The reaction with the hydrohalic acid is conveniently carried out in solvents which are inert under the reaction conditions, preferably in water, at a temperature between about room temperature and 180 ° C, preferably 100 ° C. The catalytic hydrogenation is preferably carried out in the presence of a catalyst such as palladium, palladium on carbon or platinum oxide in an inert solvent such as an alcohol such as methanol, ethanol, a carboxylic acid such as acetic acid, water or mixtures thereof and at a temperature between about 15 and 50 ° C. Suitably, the reaction is preferably carried out at room temperature. '

Substitution at the oxygen atom in the compound obtained by treatment with a compound of formula (vii)

R ⁴ - X (VIII) wherein

R ⁴ and X are as defined above, according to known methods in the presence of a base such as sodium hydride, sodium amide, potassium tert-butoxide, sodium ethoxide, thallium ethoxide, etc., in an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile and in an aprotic apolar solvent such as ethers such as tetrahydrofuran or diethyl ether, aromatic hydrocarbons such as toluene or xylene, cyclohexane and the like, in a protic polar solvent such as alcohols such as tert-butanol or isopropyl alcohol and the like, or in liquid ammonia etc. The choice of solvent depends on the base used. Thus, the reaction using alkoxides is carried out in a protic polar or aprotic non-polar solvent, using sodium hydride in an aprotic polar solvent, and using sodium amide in an aprotic polar solvent or liquid ammonia. The reaction is carried out at a temperature between about -50 and 100 ° C, preferably between about 20 and 45 ° C, depending on the base used.

When thallium ethoxide is used as the base, X in I is preferably iodine. Substitution on an oxygen atom can also be carried out using so-called phase transfer catalysis (cf., for example, Angew. Chem. 89, 521 (1975)). In this case, the base is preferably sodium hydroxide or sodium carbonate in a two-phase system, for example in a mixture of methylene chloride and water, in the presence of a salt such as tetrabutylammonium hydrogen sulfate. Advantageously, the reaction is carried out at room temperature.

The thus obtained compound of formula VII _{Z-CH2 CH2} HN-OR ⁴ (VII) in which

R ⁴ and Z are as defined above, according to known methods, can be converted to the corresponding compounds of formula IV, for example by hydrazinolysis or aminolysis. This reaction may be carried out in the presence or absence of a solvent at a temperature between about 0 and 40 ° C, preferably between about room temperature and 35 ° C.

Alternatively, the compound of formula (V) may be reacted in a manner known per se with ethyleneimine to form a compound of formula (IV):

R is benzyl.

This reaction is carried out in an organic solvent which is inert under the reaction conditions, such as an aromatic hydrocarbon such as benzene, toluene and the like in the presence of a weak aprotic Lewis acid such as boron trifluoride or a weak nucleophilic anion such as tetrafluoroboric acid, perchloric acid and the like at a temperature between about -20 and 50 ° C, preferably between 0 ° C and room temperature.

The compound of formula (IV) in which R @ 1 is benzyl may optionally be converted, after having been converted to the corresponding compound of formula (VIIa) as described above, into other compounds of formula (IV) in which R @ 4 represents a residue other than benzyl.

The compounds of formulas VI and VIII are known or can be prepared in an analogous manner to that known for the preparation of known compounds.

The compounds of formula I as well as their pharmaceutically usable acid addition salts and acids have valuable cardiovascular activity, in particular have a valuable blood pressure lowering effect, with possible central sympathetic-inhibitory properties, and can therefore be used in the treatment of hepertonia.

The blood pressure lowering effect can be determined by the following two sods

A) Systolic blood pressure and heart rate are measured before administration of the compound to several times spontaneously hypertonic female rats. 5 experimental animals weighing about 300 g are used per dose. Both parameters are measured 1, 3, 6a, 6 hours after application and the percentage change to control values is calculated. Systolic blood pressure is measured indirectly on the caudal artery of the rat by the arthode described by GEROLD et al. (Helv. Physiol. Acta 24: 58-69, 1966; Arzneimitteiforschung 2_S,

285-1287 (1968).

B) Systolic blood pressure and heart rate are measured prior to application of the compound to vigilant females of 10-15 kg body weight. A modified technique is used which is based on the irritation of Sinus caroticus and described by van Leersum (Pfluger's Arch. Ges. Physiol. Liz., 377-381, 1911). The substance is administered to animals not fed overnight. Both parameters are measured 0.5, 1, 1.5, 2, 3, 4, 6, and 16 hours after application and the percent change to control values is calculated. Simultaneous observation of the test animals is continued for 24 hours after the time to which both parameters have reached control values.

The central sympathetic inhibitory effect can be determined by the following method:

The effect of test substances on activity in the sympathetic area of the nervous system in cats under urethane narcosis is investigated. Preganglionic activity of the sympathetic is derived from Nervus splanehnicus using bipolar platinum electrodes. In addition, arterial blood pressure from the femoral artery (Arteria femoralis) and heart rate are measured. The test substance is administered intravenously by injection. If the test substance suppresses sympathetic activity by more than 30% for more than 30 minutes in blood pressure lowering periods, then it qualifies as a central sympathetic inhibitory agent.

The following table summarizes the results obtained, showing the maximum percentage changes from the control values or whether or not the compounds have a central sympathetic inhibitory effect.

Table

Merge- nina Spontaneously hypertonic rat Watchful dog Centrally inhibitory effect on sympathetic Dose mg / kg p.o. Blood pressure Δ% Cardiac frequency Δ « Dose mg / kg p.o. Blood pressure Δ * Cardiac frequency Δ « AND 3 -14 -15 3 -19 -41 No AND 10 -26 -24 (B) 3 -14 - 5 10 -17 -47 No C 3 -21 -20 10 -16 - 6 No D 3 -17 + 9 30 -20 -36 No E 10 (i. P.) -10 -17 10 -20 - 7 No F 3 -15 + 5 3 -18 -23 No G 30 -15 -54 1 -24 - 9 Yes H 3 -14 -11 10 -16 -47 Yes AND 30 -19 -21 3 -20 -13 Yes TO , 0 -15 -19 3 -14 -37 Yes L 3 -13 - 7 1 -20 - 8 Yes M 1 -13 -19 0.1 -21 -13 Yes 1 -32 - 3

A 2 - [(2,6-dichlorophenyl) imino] -1-hydroxyimidazolidine hydrobromide,

B 2 - [(2,6-dibromophenyl) amino] -1-hydroxyimidazolidine hydrobromide,

C, -hydroxy-2 - [(2-iodophenyl) imino] imidazolidine hydrobromide,

D ethyl 4 - ([2, 2 ((2,6-dichlorophenyl) imino) -1-imidazolidine / oxybutyrate hydrochloride),

E 4 - ([2 - [(2,6-dichlorophenyl) imino] -1-imidazolidine / oxy} butyric acid,

P ethyl 2 - ([2 - [(2,6-dichlorophenyl) imino] -1-imidazolidine / oxy} butyrate hydrochloride,

G 2 - [(2,6-dichlorophenyl) imino] -1- (2-propionyloxy) imidazolidine hydrochloride,

H ([2 - [(2,6-dichlorophenyl) imino] -1-imidazolidine / oxy] acetic acid,

Ethyl 4 - ([2 - [(2,6-dichlorophenyl) imino] -1-imidazolidine / oxy} crotonate hydrochloride,

K 2 - [(2,6-Dichlorophenyl) imino] -1-thoxyimidazole dinhydrochloride,

L 1- (2-butinyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazolidine hydrochloride,

M 2 - [(2,6-dichlorophenyl) imino] -1- (furfuryloxy) imidazolidine hydrochloride.

The reaction products and their pharmaceutically usable salts can be used as medicaments, for example in the form of pharmaceutical preparations containing them or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier, such as water, gelatin, acacia, milk sugar, Starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, etc., suitable for enteral or parenteral administration.

The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or in liquid form, for example in the form of solutions of suspensions or emulsions. These preparations are optionally sterilized and optionally contain adjuvants such as preservative stabilizers, wetting or emulsifying agents, salts for affecting the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

Daily oral dosage of Sini between about 1 and 200 mg. For intrevenous administration, the daily dose is between 0.1 and 20 mg. However, the dosages given are merely exemplary and may vary according to the difficulty of the case being treated and the experience of the attending physician.

The following examples illustrate the invention. All temperatures are in degrees Celsius and melting points are uncorrected.

Example 1

To a solution of 24.93 g (150 mmol) of N- (benzyloxy) ethylenediamine, 75 mL of N-ethyl-N, N-diisopropylamine and 300 mL of absolute ethyl acetate was added dropwise a solution of 36.44 g (150 mmol) with stirring.

2,6-dichlorophenylimidocarbonyl chloride such that the temperature does not exceed 30 ° C. After the addition was complete, the reaction mixture was further stirred at room temperature overnight. The mixture was then extracted five times with water and the ethyl acetate phase was dried over sodium sulfate. After evaporation of the solvent, the residue was recrystallized from isopropyl ether to give 1-benzyloxy-2-C (2,6-dichlorophenylamino) imidazolidine, m.p. 115-117 ° C.

The starting material can be produced as follows:

A) A mixture of 12.30 g (48.4 mmol) of 2-bromoethylphthalimide and 12.31 g (100 mmol) of O-benzylhydroxylamine was heated at 80 ° C for 48 hours. Ethyl acetate was then added and the resulting precipitate was filtered off. The mother liquor was evaporated in vacuo. 35 ml of methanol are added to the oily residue and the mixture is left to stand overnight at room temperature. The crystalline precipitate was filtered off and dried. The crude product obtained melts at 90-91 ° C. Recrystallization from methanol gave analytically pure N '2 - [(benzyloxy) amino] ethyl / phthalimide, m.p. 92-94 ° C.

B) A mixture of 2-bromoethyl amide 50.0 g (197 mmol), O-benzylhydroxylamine (100 g, 812 mmol) and acetonitrile (500 ml) was refluxed for 4 hours. Then, 100 g (812 mmol) of O-benzylhydroxylamine is added again and the mixture is again heated to reflux for 24 hours. The solvent is again evaporated in vacuo and excess O-benzylhydroxylamine is distilled off under high vacuum (2.7 Pa). The residue was crystallized from methanol to give N- [2- [(benzyloxy) amino] ethyl] phthalimide, m.p. 89-91 ° C. Recrystallization from methanol raised the melting point to 92-94 ° C.

C) 26.96 g (91 mmol) of N- [2 - [(benzyloxy) amino] ethyl] phthalimide was suspended in 300 ml of absolute alcohol and 40.5 ml of hydrazine hydrate was added. After stirring at room temperature for 3 hours, the resulting precipitate was filtered off and the mother liquor was evaporated completely. The residue and the precipitate are combined and 600 ml of 1 N hydrochloric acid solution are added, and the mixture is stirred vigorously for 3 hours. The resulting precipitate was filtered off and dried. The mother liquor is adjusted to pH 9 by addition of 1 N sodium hydroxide solution, saturated with sodium chloride and extracted several times with diethyl ether. After drying over sodium sulfate, the solvent was evaporated in vacuo. The oily residue is distilled under high vacuum to give N- (benzyloxy) ethylenediamine, bp 110-115 ° / 2.7 Pa. The corresponding hydrochloride melts at 157-159 ° C (from methanol / acetonitrile).

D) To 29.6 g (100 mmol) of N- [2 - [(Benzyloxy) amino] ethyl] phthalimide ee was added 200 ml of 40% methylamine and the mixture was stirred at room temperature for 48 hours. The resulting solution was extracted three times with methylene chloride. The organic extracts were evaporated in vacuo and the residue taken up in ether. The ethereal solution was extracted with 1M tartaric acid solution. The acidic extracts are mixed with ice and then adjusted to pH 11 by addition of sodium hydroxide. After extraction five times with ether, the organic extracts are dried over sodium sulphate and evaporated to dryness in vacuo to give N- (benzyloxy) ethylenediamine.

E) 2.15 g (50 mmol) of aziridine was dissolved in 30 ml of methylene chloride and 5.8 ml of a 9.47 N solution (55 mmol) of tetrafluoroboric acid in ether was added at 5 ° C. To this mixture was added 6.18 g of O-benzylhydroxylamine in 40 mL of methylene chloride. After 24 hours, the solution was poured into 5% sodium carbonate solution. The organic phases are washed with saturated sodium chloride solution, dried and evaporated in vacuo. The residue was purified by high vacuum distillation to give N- (benzyloxy) ethylenedlamine.

P) 500 g (3.0 mol) of 2,6-dichloroaniline are dissolved in 1000 ml of formic acid and the solution is heated under reflux for 4 hours. After cooling to 5 ° C, the crystals formed are filtered off and washed with about 1000 ml of ice-cooled isopropyl alcohol. It is obtained

M.p. 180 DEG-182 DEG C. 2.6-dichloroformanilide. Yet another product of the same melting point can be obtained from the mother liquor.

G) To a mixture of 910 ml of thionyl chloride and 220 ml of sulfonyl chloride (2.72 mol) was added 485 g (2.55 mol) of 2,6-dichloroanilide at about 10 ° C over 45 minutes. The solution was then heated at reflux for 9 hours and then allowed to stand overnight at room temperature. After evaporation of the solvent under reduced pressure, the oily residue is distilled under vacuum to give (2,6-dichlorophenylimidocarbonyl chloride, bp 135-138 ° / 1800 Pa).

Example 2

12.5 g (150 mmol) of O-methylhydroxylamine hydrochloride are suspended in 50 ml of acetonitrile. 12.92 g (300 mmol) of aziridine are added dropwise at 25 ° C. After 1 hour, N-ethyl-ethyl, Ν-diisopropylamine (75 mL) was added and the mixture was cooled to 10 ° C. With further cooling, 36 g (148 mmol) of 2,6-dichlorophenylimidocarbonyl chloride are added dropwise and the temperature is not to exceed 15 ° C.

The mixture was then further stirred at room temperature for 4 hours. The reaction mixture was then poured into water and extracted four times with ether. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 400 g of silica gel (eluent: chloroform / ether 9: 1) to give 2 - [(2,6-dichlorophenyl) imino] -1-methoxyimidazolidine, which melts at 123 to 124 after recrystallization from isopropyl ether. Deň: 32 ° C. This base is dissolved in acetonitrile and adjusted to pH 1 by addition of hydrochloric acid in dioxane. The hydrochloride obtained melts at 228-229 ° C.

Example 3

To 143.5 g (0.6 mol) of N- (benzyloxy) ethylenediamine dihydrochloride was added 400 ml of water.

To this suspension was gradually added cautiously 207.0 g (1.5 mol) of potassium carbonate. 200 ml of toluene are then added dropwise with vigorous stirring, and 145.7 g (0.6 mol) are then slowly added dropwise.

2,6-dichlorophenylimidokerbonyl chloride in 100 ml toluene over 45 minutes. After 15 minutes the product began to precipitate. The mixture was stirred overnight and then poured into 1 liter of n-hexane. The precipitate was filtered off and washed with water and n-hexane to give 1-benzyloxy-2- 2,6-dichlorophenyl) imino] imidazolidine, m.p. 1.4-117 ° C.

Example 4

The following compounds were prepared in an analogous manner to that described in Example 1:

From 2,6-dimethylphenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, there is obtained, -benzyloxy-2 - [(2,6-dimethylphenyl) imino] imidazolidine hydrobromide, m.p. 88-189 ° C (from acetonitrile / diethyl ether). .

From phenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, there is obtained, -benzyloxy-2- (phenylimino) imidazolidine, m.p. 78-79 ° C (from isopropyl ether).

2123.0

From 2-isopropylphenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine to give 1-benzyloxy-2 - [(2- (1-propylphenyl) imino] imidazolidine) as an oil.

1-Benzyloxy-2 - [(3,4-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 178 DEG-80 DEG C. (from a mixture of methanol and acetonitrile), is obtained from 3,4-dichlorophenylimidocarbonyl chloride and N- (benzyloxy) ethylenedlamine. .

From 2-chloro-6-methylphenylimidocarbonyl chloride and K- (benzyloxy) ethyl indamine, 1-benzyloxy-2 - [(6-chloro-2-methylphanyl) imino] imidazolidine hydrochloride is obtained, m.p. .

From 2,6-dibromophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, there is obtained, -benzyloxy-2 - [(2,6-dibromophanyl) imino] imidazolidine, m.p.

From 4-chloro-2,6-diethylphenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, 1-benzyloxy-2 - [(4-chloro-2,6-diethylphenyl) imino] imidazolidine is obtained as an oil.

From 2-iodophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, 1-benzyloxy-2 - [(2-iodophenyl) imino] imidazole dihydrochloride is obtained, m.p. 192-194 ° C (from methanol and acetone).

From 2-chlorophenylimidocarbonyl chloride and N- (benzyloxyethylenediamine) to give, -benzyloxy-2 - [(2-chlorophenyl) imino] imidazolidine hydrochloride, m.p. 198 DEG-201 DEG C. (with methanol, acetone and acetone).

From 2-trifluoromethylphenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine to give, -benzyloxy-2 - [(2-trifluoromethylphenyl) imidazolidine hydrochloride, m.p. 91-193 ° C (from acetonitrile).

From 2-bromophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, 1-benzyloxy-2-L '(2-bromophenyl) imino] imidazolidine hydrochloride is obtained, m.p. 199-200 ° C (from acetonitrile).

Example 5

The following compounds were prepared in an analogous manner to that described in Example 3:

From 2-trifluoromethylphenylimidocarbonyl chloride and N- (benzyloxy) ethylenedlamine dihydrochloride, 1-benzyloxy-2 - [(2-trifluoromethylphenyl) imino] -imidazolidine hydrochloride is obtained, m.p. 191-193 ° C (from acetonitrile).

From 2-bromophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine hydrochloride at a temperature, -benzyloxy-2 - [(2-bromophenyl) imino] imidazolidine hydrochloride, m.p. 199-200 ° C (from acetonitrile).

Example 6

1.2 g (0.5 mmol) of N- (benzyloxy) ethylenediamine dihydrochloride were heated and 20 ml of 48% hydrobromic acid at 80 ° C for 3 hours. The warm aqueous solution is then washed rapidly with cyclohexane. N-hydroxyethylenediamine dihydrobromide crystallizes from this acid solution, m.p. 172 DEG C. (decomposition).

2.38 g (10 mmol) of N-hydroxyethylenediamine dihydrobromide, 5 ml of glacial acetic acid and 5.6 g (about 40 mmol) of potassium carbonate are heated on a steam bath until carbon dioxide evolution ceases.

, ι

2123.0

The mixture is then cooled, 2,66 g (11 mmol) of 2,6-dichlorophenylimidocarbonyl chloride are added, then the mixture is heated vigorously on a steam bath for 3 minutes and then left to stand at room temperature for 1 hour.

The reaction product is poured into 100 ml of water and 40 ml of a 3 N sulfuric acid solution. Excess 2,6-dichlorophenylimidocarbonyl chloride was extracted with methylene chloride. The aqueous solution is adjusted to pH 6 with concentrated sodium hydroxide solution and then 50 ml of saturated sodium carbonate solution are added, whereby 2 - [(2,6-dichlorophenyl) imino-3-1-hydroxyimidazolidine, m.p. 220 DEG.

Example 7

The following compounds were prepared analogously to Example 3:

From 2,5-dichlorophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, 1- (benzyloxy) -2 - ((2,5-dichlorophenyl) amino) imidazolidine hydrochloride is obtained, m.p. 206-207 ° C (from acetonitrile).

From 2,3-dichlorophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, 1- (benzyloxy) -2-β-2,3-dichlorophenyl) imino-3-imidazolidine hydrochloride is obtained, m.p. 200-20 ° C (from acetonitrile: hydrochloric acid in dioxane). ).

From 2,4-dichlorophenylimidocarbonyl chloride and N- (benzyloxy) ethylenediamine, 1- (benzyloxy) -2 - [(2,4-dichlorophenyl) imino] imidazolidine hydrochloride is obtained, m.p. hydrochloric acid).

Example 8

6.95 g of hydroxylamine hydrochloride (100 mmol) and 13.61 g of sodium acetate trihydrate (100 mmol) were dissolved in 50 ml of water and 4.31 g of aziridine (pH 7.61) was added.

After 10 minutes, the temperature rose to 42 ° C and the pH was lowered to 6.74. The aqueous solution was then evaporated under reduced pressure at 30 ° C. The residue was taken up in glacial acetic acid and 24.23 g of (2,6-dichlorophenyl) imidocarbonyl chloride (100 mmol) was added as in Example 6, second paragraph. 221 DEG-222 DEG C. (from acetonitrile).

Example 9

To 24.6 g of O-benzylhydroxylamine was added 25 ml of 50% tetrafluoroboric acid, the temperature rising to 70 ° C. To this solution is added a solution of 3 ml of aziridine in 13 ml of water at 50 ° C such that the temperature does not exceed 60 ° C. At the end of the exothermic reaction, the reaction mixture is cooled to 5 ° C and a solution of 56 g of potassium carbonate in 100 ml of water is added. 60 ml of toluene and 35 ml of (2,6-dichlorophenyl) imidocarbonyl chloride are added under vigorous stirring.

With the evolution of carbon dioxide, the temperature rises to 43 ° C. The reaction mixture is further stirred for 90 minutes and then 150 ml of hexane and 200 ml of water are added. The crystalline mass was washed thoroughly with water and hexane and dried overnight under reduced pressure. The dried material was recrystallized from isopropyl ether to give 1- (benzyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazolidine, m.p. 115-117 ° C.

He did

The following compound was prepared in an analogous manner to that described in Example 3:

From (2,6-diohloro-4-fluorophenyl) imidocarbonyl chloride and 1- (benzyloxy) -2 - [(2,6-dlchlorophenyl) imino] imidazolidine, 1- (benzyloxy) -2 - [(2,6) is obtained. -dichloro-4-fluorophenyl) imino] imidazolidine of melting point 112 and 113 ° C (from cyclohexane).

The starting material is prepared as follows:

97.8 g of 4-fluoroaniline (0.88 mol) were dissolved in 600 ml of glacial acetic acid and a few drops of concentrated sulfuric acid were added dropwise thereto, followed by 90 ml of acetic anhydride. The solution was heated on a steam bath for 1 hour and then cooled to 20 ° C. Chlorine gas is then introduced for 2 hours at 40 ° C.

The solution was then heated to 80 ° C and chlorine gas was introduced for a further 2 hours. The solution was cooled to 20 ° C and 150 mL concentrated hydrochloric acid was added. While cooling, 90 ml of 30% hydrogen peroxide are added dropwise so that the temperature does not exceed 25 ° C. The solution was heated at 80 ° C for 1 hour, then cooled and the solvent was evaporated under reduced pressure. Fractional crystallization of the residue gives 2,6-dichloro-4-fluoro-acetanilide, m.p. 186-187 ° C (from ethanol).

19.2 g of 2,6-dichloro-4-fluoroacetanilide was heated to reflux in 48% hydrobromic acid for 90 minutes. The solution was then cooled and the crystalline precipitate was filtered off to give 2,6-dichloro-4-fluoroaniline hydrobromide, which was used directly for the next step.

Dissolve 1.3 g of 2,6-dichloro-4-fluoroaniline hydrobromide in 0.5 g of triethylamine and 3.1 ml formic acid and reflux for 4 hours. The solution was cooled to -10 ° C and the resulting precipitate was filtered off, washed with water and dried to give 2,6-dichloro-4-fluoroformanilide, mp 165-168 ° C.

1.0 g of 2,6-dichloro-4-fluoroformanilide was added portionwise to a mixture of 1.82 ml of thionyl chloride and 0.40 ml of sulfuryl chloride at 10 ° C. The solution was heated at reflux for 10 hours, then allowed to stand at room temperature, then evaporated under reduced pressure, then treated with benzene three times and evaporated again. The oily residue is distilled under high vacuum to give (2,6-dichloro-4-fluorophenyl) imidocarbonyl chloride having a boiling point of 65 ° / 0.7 Pa,

They did

The following compounds can be prepared in an analogous manner to that described in Examples 1 to 10:

1-Benzyloxy-2 - [(3,4-dimethoxyphenyl) imino] imidazolidine-L-tartrate m.p. 90-95 ° C 1-Benzyloxy-2 - [(alpha, alpha, alpha-trifluoro-m-tolyl) imino 154-155 ° C (from ethanol / ethyl acetate), -benzyloxy-2- [4- (methylthio) phenyl] imino / imidazolidine, mp 96-97 ° C (from methylene chloride / diisopropyl ether) )

1-benzyloxy-2 - [(3,4-dimethylphenyl) imino] imidazolidine,

1-hydroxy-2 - [(2,6-dimethylphenyl) imino] imidazolidine hydrobromide, m.p. 77 DEG-179 DEG C. (from acetone);

1-hydroxy-2- (phenylimino) imidazolidine hydrobromide, m.p. 52-154 ° C (from acetonitrile),

1-hydroxy-2 - [(2-isopropylphenyl) imino] imidazolidine hydrobromide, m.p. 42-44 ° C (from acetone),

1-hydroxy-2 - [(alpha, alpha, alpha-trifluoro-m-tolyl) amino] imidazolidine hydrobromide, m.p. 217 DEG C. (dec.), (From a mixture of acetonitrile and diethyl ether).

2 - [(3,4-dichlorophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 204-206 ° C with decomposition (from methanol / acetonitrile),

1-hydroxy-2 - [(3,4-dimethylphenyl) imino] imidazolidine hydrobromide, m.p. 198-200 ° C (from acetonitrile / diethyl ether),

2 - [(6-chloro-2-methylphenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 206-207 ° C (from acetonitrile),

2- (2,6-dibromophenyl) imino-1-hydroxyimidazolidine hydrobromide, m.p. 260 ° C (from methanol / acetonitrile),

2 - [(4-chloro-2,6-diethylphenyl) imino] -1-hydroxyimidazolidine, m.p. 170-171 ° C (from diisopropyl ether), -hydroxy-2 - [(2-iodophenyl) imino] imidazolidine hydrobromide, m.p. mp 189-190 ° C (from acetonitrile),

2 - [(2-chlorophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 198-200 ° C (from methanol / acetonitrile),

2 - [(2-bromophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 194-196 ° C (from acetonitrile),

182 DEG-183 DEG C. (from acetonitrile), 1-hydroxy-2 - [(2-trifluoromethylphenyl) imino] imidazolidine hydrobromide;

2 - [(2,6-dichlorophenyl) imino] -1- [2- (dimethylamino) ethoxy] imidazolidine hydrochloride, m.p. 313-215 ° C (from acetonitrile / ethyl acetate),

2 - [(2,6-dichlorophenyl) imino] -, - (2-proplonyloxy) imidazolidine hydrochloride, m.p. 198-199 ° C (from methanol / acetonitrile),

2 - [(2,6-dichlorophenyl) imino] -1- (phenethyloxy) imidazolidine, m.p. 111-112 ° C (from a mixture of diisopropyl ether and hexane),

2- f (2,6-dichlorophenyl) imino] -1- [3- (diethylamino) -2,2-dimethylpropoxy] imidazolidine- (R, R) tartrate (1: 1), which crystallizes with 1.1 mol of acid; 156 DEG-157 DEG C. (from acetone / ether);

156 [deg.] C. (decomposition), ethyl 4 - {[- (2,6-dihlorophenyl) imino] 2 - [(2,6-dichlorophenyl) imino] -, - [2- (methylthio) ethoxy] imidazolidine hydrochloride ] -1-imidazolidinyl / oxy butyrethydrochloride, m.p. 113-115 ° C (from a mixture of isopropanol and acetone),

4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} butyric acid, m.p. 115 DEG-116 DEG C. (from acetonitrile),

3- {[2-L (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} -1-propanol, m.p. 115-117 ° C (from methylene chloride / diisopropyl ether), tert-butyl [{2- [(2,6-dichlorophenyl) imino] -1-imidazolidinyl} oxy] phenylacetate, m.p. 88-90 ° C (cyclohexane), {[2 - [(2,6-dlchlorophenyl) amino] -1-imidazolidinyl] hydrochloride oxyjphenyloetic acid, m.p. 184-186 ° C (from a mixture of chloroform and acetonitrile),

1- (allyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 169-171 ° C (from acetonitrile), ethyl {[2 - [(2,6-dichlorophenyl) imino] -1- imidazolidinoxy} acetate hydrochloride, m.p. 171-73 ° C (from acetonitrile / diethyl ether),

2 - [(2,6-dichlorophenyl) imino] -1-propyloxyimidazolidine hydrochloride, m.p. 217 DEG-218 DEG C. (from a mixture of methylene chloride and ethyl acetate),

183-185 ° C (from a mixture of acetone and diethyl ether), 5 - {[2 - [(2,6-dichlorophenylamino) -1-imidazolidinyl / oxy} valeronitrile hydrochloride,

2 - [(2,6-dichlorophenyl) imino] -1- [2- (2-methoxyethoxy) imidazolidine methanesulfohate (1: 1), m.p. 103-104 ° C (from acetone / diethyl ether),

1- (3-butenyl) -2- (2,6-dichlorophenyl) imino] imidazolidine methanesulfonate, m.p. 155-57 ° C (from a mixture of acetone and diethyl ether),

2 - [(2,6-dihlorophenyl) iminol-1- (4-pentenyl) imidazolidine hydrochloride, m.p. 203-207 ° C (from acetone), isopropyl 4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} butyrate hydrochloride, m.p. 134-135 ° C (from ethyl acetate);

2- [η 2,6-dichlorophenyl) imino] -, - [(3,4-dimethoxyphenethyl) oxy] imiaazoliain oxalate (1: 1), m.p. 167-168 ° C (from acetonitrile),

4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} butyronitrile hydrochloride, m.p. 183-184 ° C (from acetonitrile / ethyl acetate), ethyl 5 - {/ 2- L (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} valerate oxalate (1: 1), m.p. 96 DEG C. (from ethyl acetate), ethyl 4- [2- (phenylamino) -1-imidazolidinyl] m.p. ] oxy / butyrate as an oil;

ethyl 4 - {[2 - [(6-chloro-2-methylphenyl) imino] -1-imidazolidinyl / oxybutyrate as an oil, ethyl 4 - {[2-Q (2,6-dimethylphenyl) imino] -1- imidazolidinyl / oxy} butyrate as an oil,

4 - {[2 - [(2,6-dichlorophenyl) imino] -, - imidazolidinyl / oxy] - butanol hydrochloride, m.p. 175 DEG-76 DEG C. (from methanol / acetonitrile),

5- (2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] valeric acid, m.p. 148-150 ° C (from acetonitrile / ethyl acetate), {/ 2 - [(2,6- dihlorophenyl) imino] -1-imidazolidinyl / oxy} acetic acid, m.p. 75 DEG-176 DEG C. (from acetonitrile),

4 - [(2-phenylimino) -1-imidazolidinyl] oxybutyric acid in the form of a glassy substance,

4 - {[2 - [(6-chloro-2-methylphenyl) imino] -, - imidazolidinyl / oxy} butyric acid, m.p. 101-0.03 ° C (dec.), (From acetonitrile),

4 - [[2- (2,6-dimethylphenyl) -1-imidazolidinyloxy] butyric acid, m.p. 130-132 ° C (from acetonitrile), 4 - {[2 - [(2,6-dichlorophenyl) imino] amide] -1-imidazolidinyl / oxy} butyric acid, m.p. 140-14 ° C (from benzene / cyclohexane), methyl 4 - {[2 - [} (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy butyrate of melting point to 96 ° C (from cyclohexane), ethyl 4 - [/ 2 - [(2,6'-dichlorophenyl) imino] -1-imidazolidinyl / oxy] crotonate, melting point, 37 to 138 ° C (from acetonitrile) )

174 DEG-175 DEG C. (from methanol / acetonitrile), ethyl 4 - {[2-Q (2-chlorophenyl) imino] 2 - [(2-chlorophenyl) imino] -1- (2-propynyloxy) imidazolidine hydrochloride] -1-imidazolidinyl / oxybutyrate as an oil, ethyl 4- [2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] -2-methylbutyrate as an oil,

2 - [(2,6-dichlorophenyl) imino] -1-isopropoxyimidazolidine hydrochloride, m.p. 204-205 ° C (from acetonitrile), ethyl 2 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl m.p. 176 DEG-177 DEG C. (from acetonitrile), ethyl 4 - {[2 - [(2-iodophenyl) imino] -1-imidazolidinyl] oxy} butyrate as an oil, ethyl 2- | (2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} -2-methylpropionate hydrochloride, m.p. 17-172 ° C (from ethyl acetate / hydrochloric acid in dioxane / diethyl ether),

2 - [(2,6-dichlorophenyl) imino] -1- (3-methoxypropyl) imidazolidine, m.p. 95 ° C (from isopropyl ether),

2 - [(2,6-dichlorophenyl) imino] -1-ethoxyimidazolidine hydrochloride, m.p. 2.9-22 ° C (from acetone),

1- (cinnamyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 23 DEG-125 DEG C. (from a mixture of acetonitrile and hydrochloric acid in a mixture of dioxane and diethyl ether),

4 - {[2- (2-iodophenyl) imino] -1-imidazolidinyl / oxy} butyric acid in the form of a foam,

2 - {[2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxybutyric acid in the form of a foam,

2-ζ / 2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] -2-methylpropionic acid, m.p. 194-195 ° C (from chloroform),

4 - {(2 - [(2-chlorophenyl) imino] -1-imidazolidinyl / oxy} butyric acid in the form of a foam,

4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl] oxy] -2-methylbutyric acid; hydrochloride melts at 202-203 ° C (from acetonitrile),

2 - {[/ 2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] [a] thiyl} -3-furanecarboxylic acid, m.p. 175 ° C (dec.) (From acetonitrile),

2-f (2,5-dichlorophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 214-215 ° C (from methanol / acetonitrile),

2-f (2,3-dichlorophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 190-191 ° C (from methanol / acetonitrile),

2-f (2,4-dichlorophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 217-218 ° C (from methanol / acetonitrile),

1- (2-aminoethoxy) -2- (2,6-dichlorophenyl) imino] imidazolidine, m.p. 129-130 ° C (from acetonitrile),

1- (4-aminobutoxy) -2-f (2,6-dichlorophenyl) imino] imidazolidine dihydrochloride, m.p. 234-237 ° C (from acetonitrile / methanol),

1- (2-butinyloxy) -2- (2,6-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 198 DEG C. (decomposition) (from a mixture of acetonitrile and hydrochloric acid in dioxane),

2- [(2,6-dichlorophenyl) imino] -1- (furfuryloxy) imidazolidine, m.p. 123-124 [deg.] C (from isopropyl ether); the corresponding hydrochloride melts at 162-164 ° C (from a mixture of acetonitrile, dioxane and diethyl ether), ethyl 2- |} {[2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] - M.p. 99 DEG C. (from isopropyl ether); the corresponding fumarate melts at 154 to 156 ° C (from a mixture of methanol and acetonitrile),

2-f (2,6-dichlorophenyl) imino] -1- (2-thienylmethoxy) imidazolidine, m.p. 101-102 ° C (from methylene chloride / cyclohexane); the corresponding hydrochloride melts at 211 ° C (dec.) (From acetone) and hydrochloric acid in dioxane),

2 - [(2,6-dichlorophenyl) imino] -1- (2-methoxyethoxy) imidazolidine hydrochloride, m.p. 125-127 ° C (from a mixture of acetone and hydrochloric acid in a mixture of dioxane and diethyl ether), methyl 4- (2 - [(2,6-dihlorophenyl) imino] imidazolidinyl / oxy} -3-methyl crotonetate as a 1: 1 mixture of cis-trans isomers, m.p. 84-85 ° C (from isopropyl ether), ethyl 2- { (2-f (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} propionate, m.p. 79-80 ° C (from cyclohexane); hydrochloride melts at 185-186 ° C (from a mixture of acetonitrile and hydrochloric acid in a mixture of dioxane and diethyl ether),

2 - [(2,6-dichlorophenyl) imino] -1- (3-thienylmethoxy) imidazolidine hydrochloride, m.p. 204-206 ° C (from a mixture of acetone and hydrochloric acid in a mixture of dioxane and diethyl ether),

2-f (2,6-dichlorophenyl) imino] -1- (3-methyl-2-butenyl) oxy] imidazolidine hydrochloride, m.p. 153-154 ° C (from acetonitrile / hydrochloric acid in dioxane / diethyl ether),

2-f (2,6-dichlorophenyl) imino-3- (3-fluoromethoxy) imidazolidine hydrochloride, m.p. 204-206 ° C (from acetonitrile),

147 - 149 ° C (from a mixture of methylene chloride and isopropyl ether), 4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} -N-methylbutyraraid,

4 - {[2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} -II, N-dimethylbutyramide, m.p. 126 DEG-128 DEG C. (from methylene chloride / isopropyl ether),

2- [f-2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine, m.p. 116-118 ° C (from isopropyl ether); the corresponding dihydrochloride melts at 175-176 ° C with decomposition (from a mixture of methanol and acetonitrile),

2 - [(2,6-dichlorophenyl) imino] -1- (3-pentinyloxy) imidazolidine, m.p. 104-105 ° C (from isopropyl ether),

2- f (2,6-dichloro-4-fluorophenyl) imino] -1-hydroxyimidazolidine hydrobromide, m.p. 230 ° C dec. (48% hydrobromic acid),

3- [{[2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine, m.p. 151-152 ° C (from a mixture of methylene chloride and isopropyl ether); the corresponding dihydrochloride melts at 222 ° C with decomposition (from a mixture of acetonitrile and dioxane),

4- [{[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine, m.p. 160-161 ° C (from acetonitrile / isopropyl ether); the corresponding dihydrochloride melts at 180 ° C with decomposition (methanol-acetonitrile),

2-f] [2 - [(2,3-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridinedihydrobromide, m.p. 154-155 ° C dec. (From methanol / acetone),

2-f / 2 - [(2,4-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine dihydrochloride, m.p. 179-180 ° C dec. (From acetone),

2-f] [2 - [(2,5-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine as an oil,

147-148 ° C (from a mixture of methylene chloride and isopropyl ether); 2-f {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] -5-methylpyridine; the corresponding dihydrobromide melts at 163-164 ° C with decomposition (from acetonitrile),

2 - [{[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] -6-methylpyridine, m.p. 132-133 ° C (from acetone / isopropyl ether); the corresponding dihydrochloride melts at 190 ° C with decomposition (from acetone),

2-f {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] -5-ethylpyridine, m.p. 103-104 ° C (from isopropyl ether), rac. - 2 - 1 - {[2 - [(2,6-dihlorophenyl) imino] -1-imidazolidinyl / oxy} ethyl] pyridine dihydrochloride, m.p. 218-219 ° C (from a mixture of acetonitrile and acetone),

5 - [] - 2 - [(2,6-dichlorophenyl) imino] -, - imidazolidinyl / oxy} methyl] isoxazole, m.p. 87-88 ° C (from isopropyl ether); the corresponding hydrochloride melts at 171 ° C with decomposition (from acetone),

2-f / 2 - [(2-Chloro-phenylamino) -1-imidazolinyl-oxy} -methyl] -pyridine dihydrochloride, m.p. 175-176 ° C (from a mixture of acetonitrile and dioxane),

2- [f] 2 - [(2-bromophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridinedihydrobromide, m.p. 186-187 ° C (from 3035 hydrogen bromide in glacial acetic acid),

2- [f / 2 - [(2,6-dibromophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine dihydrochloride, m.p. 187-188 ° C dec. (From methanol / acetonitrile),

2-f {[2 - [(2,6-dimethylphenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine dihydrochloride, m.p. 196-197 ° C dec. (From acetonitrile),

2- [f] 2 - [(6-chloro-2-methylphenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine dihydrochloride, m.p. 187 ° C (from acetonitrile),

3- [2 - [(6-chloro-2-methylphenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine, m.p. 1.0-1.1 ° C (from a mixture of methylene chloride and isopropyl ether); the corresponding dihydrochloride melts at 221 to 222 ° C with decomposition (from acetonitrile),

2 - {[2 - [(2,6-dichloro-4-fluorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridinedihydrobromide, m.p. 199-200 ° C dec. (From methanol / acetonitrile),

5 - [{[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] -2,2,8-trimethyl-4H-m-dioxino [4,5-c] pyridine, m.p. 190 DEG -192 DEG C. (from a mixture of methanol and acetonitrile),

4- (1-f / 2 - [(2,6-dichlorophenyl) imino] -, - imidazolidinyl / oxy) ethyl] pyridine dihydrochloride, m.p. > 300 DEG C. (from methanol / acetonitrile),

5-tert-2 - [(2,6-diohlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] -2,3-dimethoxypyridine dihydro chloride, m.p. 172-175 ° C with decomposition (from a mixture of acetonitrile and dioxane),

3- f 1 - f - 2 - [(2,6-Dichlorophenyl) imino] -1-imidazolidinyl / oxy] ethyl} pyridine dihydrochloride, m.p. 262 ° C dec. (From a mixture of acetonitrile and dioxane),

1- (cyclohexyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazolidine fumarate, m.p. 163-164 ° C (from acetone),

5 - {[[2 - [(2,6-Dichlorophenyl) imino] -1-imidazolidinyl / oxy] methyl} -3-hydroxy-2-methyl-4-oyridinomethanol dihydrochloride, m.p. 216-218 ° C (from methanol / acetonitrile).

Example A

Production of lacquer tablets of the following composition:

2 - [(2,6-dichlorophenyl) imino] -1- (furfuryloxy) imidazolidin-hydro-chloride 5.5 5.5 mg lactose powder 34.44 mg white corn starch 59.0 mg talc ® »5“ 8 Magnesium salt of stearic acid Weight of kernel Dry layer of varnish Weight of coated tablet

0.5 mg

100.0 mg about 7.0 mg about 107.0 mg

The active ingredient mixture with powdered lactose and one part of maize starch is moistened with a greasy starch prepared from another part of maize starch and water, blend, granulated, dried and sieved. The remaining corn starch, talc and magnesium stearate are admixed to this granulate. of acid and from the mixture pressed kernels weighing 100 mg each. These kernels are lacquered by conventional methods, applying about 7.0 mg of the dry weight of the lacquer.

Example B

Manufacture of coated tablets with the following composition:

Ethyl 2 - {[2 - [(2,6-dichlorophenyl) imino] -1 I-imidazolinyl / oxybutyrate t-hydrochloride d 110.1 mg powdered lactose 104.9 mg white corn starch 125.0 mg talc 9.0 mg magnesium salt of stearic acid 1.0 mg weight of the core 350.0 mg weight of paint in dry matter about 20.0 mg weight of the coated tablet about 370.0 mg

A mixture of the active ingredient with powdered lactose and one part of corn starch is moistened with a lubricated starch prepared from another part of corn starch and water, the mixture is bent, granulated, dried and sieved. The remaining corn starch, talc and magnesium stearic acid salt are admixed with this granulate and 350 mg of kernel is pressed from the mixture. These cores are lacquered by any of the usual methods using about 20 mg of lacquer (in dry matter).

Claims (27)

A process for the preparation of novel 2-imidazolidine derivatives of the general formula I wherein 12 λ E, R and ^RJ are independently hydrogen, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, halogen or trifluoromethyl and r4 is hydrogen, C1-C6alkyl (C 6-Clo) cycloalkyl, (C až-C alk) alkenyl, (C až-C alk) alkynyl, (C až-C dial) dialkylaminoalkyl, (C až-C kar) carboxyalkyl a (C v-C kar kar) alkenyl moiety, (C až-C hydroxy hydroxy) hydroxyalkyl, (C až-C f) phenylalkyl, (C až-C alkyl alkyl) alkylthioalkyl2123, 0, 8 lech, C 1 -C 6 alkoxycarbonylalkyl, C 1 -C 6 alkoxyalkoxyalkyl, alkyl, aminocarbonylalkyl for (1-6C) alkyl, (1-6C) monoalkylaminocarbonylalkyl (1-6C) dialkylaminocarbonylalkyl (1-6C) alkoxycarbonylalkenyl (2-6C) alkoxycarbonylalkenyl in the alkenyl moiety, a (C 1 -C 6) alkoxyalkyl moiety in the alkoxy and alkyl moieties, a (C 1 -C 6) aminoalkyl group, (2,2,8-trimethyl-4H-m-dioxino [4,5-o] pyridine- 5-yl) methyl, [5-hydroxy-4- (hydroxymethyl) -6-methyl-3-pyridyl] methyl, alpha-carboxybenzyl, alpha-alkoxycarbonyl-alpha-alkylphenyl of 1 to 6 carbon atoms in the alkoxy and an alkyl moiety or a -CO (R ⁹ ) -bonded, optionally -COOR substituted with 5-membered, or optionally C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy substituted 6-membered aromatic heterocyclic group with 1 or 2 hetero atoms, wherein heteroatoms are oxygen, nitrogen or sulfur and ac R is hydrogen or methyl; and R is hydrogen or (C1-C6) -alkyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula II (II) in which: AND R ^1, R ^2, and R ³ represents -N = C or -NH-CN, Y where X and Y are halo mercapto, amino, methoxy or C 1 -C 3 alkylthio and are as defined above, with a compound of formula IV h ₂ n-ch ₂ -ch ₂ -nh-or ⁴ (IV) wherein: R < ⁴ > is as defined above, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 2. A process according to claim 1, wherein the compound of formula (II) wherein A is a group of formula -N = C or -NH-CN, wherein X and Y are halogen, mercapto, amino, methoxy or alkyl of 1 to 3 carbon atoms and R, R and R are each independently hydrogen, C1-C3 alkyl C-C, alko, C alko-C alko alko alko alkoxy, C až-C alkyl alkyl alkylthio, halogen or trifluoromethyl, act as a compound of formula IV wherein R ⁴ is hydrogen, C až-C alky alky alkyl, cycloalkyl C 3 -C 6 alkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 dialkylaminoalkyl, C 1 -C 6 carboxyalkyl, C 2 -C 6 carboxyalkenyl up to 6 carbon atoms in alkenyl, hydroxyalkyl of 1 to 6 carbon atoms in alkyl, cyanalkyl of 1 to 6 carbon atoms in alkyl, phenylalkyl of 1 to 6 carbon atoms in alkyl, alkylthioalkyls C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkoxy, C 1-6 alkoxy and C 1-6 alkylaminocarbonylalkyl , (C 1 -C 6) alkoxycarbonylalkenyl, (C 2 -C 6) alkoxy, (C 1 -C 6) alkoxyalkyl and alkyl, (C 1 -C 6) aminoalkyl, alpha-carboxybenzyl, alpha -alkoxycarbonyl-alpha-alkylphenyl of 1 to 6 carbon atoms in alkoxy and alkyl or via a -CH (R 6) - group bonded, optionally by a -COOR group substituted by a 5-membered or optionally C1-C6 alkyl group substituted by a membered aromatic heterocyclic a group having 1 or 2 heteroatoms, with oxygen, nitrogen or sulfur being the heteroatoms and F (representing hydrogen or methyl) and R is hydrogen or (C 1 -C 6) alkyl, whereupon the optionally obtained compound or a pharmaceutically unacceptable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 3. The method of claim 1 or 2, wherein the compound is reacted A compound of formula II wherein A, R and R are as defined in 1 or 2, and R is hydrogen, with a compound of formula IV wherein R 1 is as defined in 1 or 2, and optionally converting the obtained compound or a pharmaceutically unusable acid addition salt thereof into a pharmaceutically usable acid addition salt. 4. A process according to any one of Claims 1 to 3, wherein the compound of formula (II) is reacted wherein A, R, R and R are as defined in (1) to (3), wherein the R 2 substituents are: and R are in the 2,6-position of the phenyl ring, with a compound of formula IV wherein R 1 is as defined in 1 to 3, and optionally converting the compound or a pharmaceutically useless acid addition salt thereof to a pharmaceutically usable acid addition salt. acid. 5. A process according to any one of Claims 1 to 4 wherein the compound of formula (II) is reacted wherein A, R, R and R are as defined in (1) to (4), but wherein the substituents are R 1 and R 2 have the same meaning with the compound of formula IV wherein R 1 is as defined in 1 to 4, and optionally converting the compound or a pharmaceutically unusable acid addition salt thereof into a pharmaceutically usable acid addition salt. 6. A process as claimed in any one of Claims 1 to 5 wherein the compound of formula (II) wherein A and R are as defined in (1) to (5) and R and R are halogen is reacted with a compound of formula (II). and wherein optionally the compound or a pharmaceutically unusable acid addition salt thereof is converted to a pharmaceutically usable acid addition salt. 7. The process of claim 6, wherein the compound is reacted 3 1 2 of formula II in which A and R are as defined in points 1 to 5, and R and R are chlorine, with a compound of formula IV in which R 1 is as defined in points 1 to 5, the compound or a pharmaceutically unusable acid addition salt thereof is converted to a pharmaceutically usable acid addition salt. 8. A process according to any one of Claims 1 to 7, wherein the compound of formula II, wherein A, R, R and R are as defined in 1 to 7, is reacted with a compound of formula IV. wherein R 1 is C 2 -C 6 alkynyl, 123-10 k, carboxyalkyl of 1 to 6 carbon atoms in alkyl, alkoxycarbonylalkenyl of 1 to 6 carbon atoms in alkoxy and 2 to 6 carbon atoms in alkenyl, or through - CH (R ³ ) - bound, optionally -COOR substituted with 5-membered, or optionally C 1 -C 6 -alkyl, substituted with a 6-membered aromatic heterooyl group having 1 or 2 heteroatoms, wherein heteroatoms are oxygen, nitrogen or sulfur and are hydrogen or and R is hydrogen or (C1-C6) alkyl, whereupon the optionally obtained compound or its pharmaceutically unused acid addition salt converts into a pharmaceutically usable acid addition salt. 9. A process according to claim 8, which comprises reacting a compound of formula (II) wherein A, R, R and R are as defined in (1) to (7) with a compound of formula (IV): is (C 3 -C 5) alkynyl, carboxymethyl, carboxypropyl, (C 2 -C 6) ethoxycarbonylalkenyl or in the -CH (R) - linked pyridyl group or unsubstituted 5-membered heterooyl group with 1 oxygen atom, or sulfur, followed by converting the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof into a pharmaceutically usable acid addition salt. 10. A process according to claim 9, wherein a compound of formula (II) wherein A, R, R and R are as defined in (1 to 7) is reacted with a compound of formula (IV) wherein R is represents a propargyl group, a carboxymethyl group, an unbranched C 2 -C 6 ethoxycarbonylalkenyl group or an -CH (R 6) - linked pyridyl or furyl group, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted to a pharmaceutically acceptable acid addition salt. Process according to one of Claims 1 to 10, characterized in that a compound of the formula (II) is reacted, in which A is as defined in (1) to (10), R ³ is 12 hydrogen, R and R are halogen, preferably chloro, in positions 2 and 6 with a compound of formula IV in which R ⁴ is propargyl, carboxymethyl, unbranched ethoxycarbonylalkenyl of 2 to 6 carbon atoms in the alkenyl moiety or via a -CH (R 6) -pyridyl or furyl group a group, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 12. A process according to item 2 for the preparation of 2 - [(2,6-dichlorophenyl) imino] -1-hydroxyimidazolidine, which comprises reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, 1-3 methoxy or C 1 -C 3 alkylthio, R is hydrogen and R and R are chlorine at the 2- and 6-positions of the phenyl radical, with a compound of formula IV wherein R 1 is hydrogen. 13. The process of item 2 for the preparation of 2- (2,6-dibromophenyl) imino] -1-hydroxyimidazoline, comprising reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, C1-3, methoxy or alkylthio of 1 to 3 carbon atoms, R is hydrogen and R and R are bromine at the 2- and 6-positions of the phenyl moiety, with the compound of the formula IV in which it is hydrogen. 14. The process of item 2 for the preparation of 1-hydroxy-2 - [(2-iodophenyl) imino] imidazolidine, which comprises reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, R 3 and R 3 are hydrogen and R is iodo at the 2-position of the phenyl radical, with a compound of formula IV wherein R ⁴ is hydrogen. 15. A process according to item 2 for the preparation of 4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolinyl / oxy} butyrate, which comprises reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y), wherein X and Y are halogen, mercapto, amino, methoxy or C 1 -C 3 alkylthio, R ¹ is hydrogen and R ² and R 6 are chlorine in position 2 and 6 of the phenyl moiety, with a compound of formula IV wherein R ⁴ is 3-ethoxycarbonylprop-1-yl. 16. A process according to item 2 for the preparation of 4 - {[2 - [(2,6-dichloro-phenyl) -imino] -1-imidazolidinyl / oxy} -butyric acid, which comprises reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio, 1 2 λ R is hydrogen and R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is a 3-carboxyprop-1-yl group. 17. The process of item 2 for the preparation of ethyl 2 - [[2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} butyrate, which comprises reacting a compound of formula II wherein A is NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio, 1 2 3 R is hydrogen and R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is 1-ethoxycarbonylprop-1-yl. 18. The process of item 2 for the preparation of 2 - ['(2,6-dichlorophenyl) imino] -1- (2-propynyloxy) imidazolidine, which comprises reacting a compound of formula II wherein A is NH -CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio, R ¹ is Is hydrogen and R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is a 2-propyn-1-yl group. 19. A process according to item 2 for the preparation of {[2- (2,6-diethylphenyl) imino] -1-imidazolidinyl / oxy] acetic acid, characterized in that a compound of formula II in which A is -NH is reacted -CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio, 12 3 R is hydrogen and R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is a carboxymethyl group. 20. The process of item 2 for the preparation of ethyl 4 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} crotonate, characterized in that a compound of formula II is reacted in which A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or C 1 -C 3 alkylthio, R ¹ is hydrogen and R ² and R 6 are chlorine at the 2- and 6-position of the phenyl moiety, with a compound of formula IV wherein R ⁴ is 3-ethoxycarbonyl-2-propen-1-yl. 21. A process according to claim 2 for the preparation of 2-N- (2,6-dichlorophenyl) imino] -1-ethoxyimidazolidine, comprising reacting a compound of formula II wherein A is -NH-CN or - N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or C 1 -C 3 alkylthio, R ¹ is hydrogen And R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is ethyl. 22. A process according to item 2 for the preparation of 1- (2-butinyloxy) -2 - [(2,6-diohlorophenyl) imino] imidazolidine, which comprises reacting a compound of formula IX wherein A is -NH -CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or C 1 -C 3 alkylthio, E ¹ is hydrogen, and R ² and R ³ are chlorine position 2 and 6 of the phenyl moiety, with a compound of formula IV wherein R ⁴ is 2-butin-1-yl. 23. A process according to item 2 for the preparation of 2 - [(2,6-dichlorophenyl) imino] -1- (furfuryloxy) imidazolidine, comprising reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or alkylthio of 1 to 3 carbon atoms and R ¹ represents 2 hydrogen and R 3 and R ^J are each chlorine in position 2 and 6 of a phenyl moiety, with a compound of formula IV wherein R ⁴ is furylmethyl. 24. The process of item 1 for the preparation of 2- [1 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine, which comprises reacting a compound of formula II wherein: A depicted -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or C 1 -C 3 alkylthio, 1 2 3 and R is hydrogen, R and R ^J are each chlorine in position 2 and 6 of the phenyl residue, the compound of formula IV wherein R ⁴ is 2-pyridylmethyl. 25. The process of item 1 for the preparation of 3 - [{[2 - [(2,6-diohlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine, comprising reacting a compound of formula II wherein: A is -NH-CN or -N = C (X) (Y), wherein X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio, 12 3 R is hydrogen, R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is 3-pyridylmethyl. 26. The process of item 1 for the preparation of 2- [1] - [2 - [(2,6-dichloro-4-fluorophenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine, characterized in that the compound is reacted (II) wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or (C 1 -C 3) alkylthio, 1 2 3 R is fluorine at the 4-position, R and R are chlorine at the 2 and 6 positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ is 2-pyridylmethyl. 27. The method of item 1 for producing 5 - []] - 2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] methyl] -3-hydroxy-2-methyl-4-pyridinmethanol, characterized by: by reacting a compound of formula II wherein A is -NH-CN or -N = C (X) (Y) wherein X and Y are halogen, mercapto, amino, methoxy or C 1 -C 3 alkylthioacyl, R is hydrogen, and R and R are chlorine at the 2- and 6-positions of the phenyl moiety, with a compound of formula IV wherein R ⁴ represents a [5-hydroxy-4- (hydroxymethyl) -6-methyl-3-pyridyl] methyl group.