CS212311B2 - Method of making the new 2-iminoimidazoline derivatives - Google Patents

Description

The term alkyl - alone or in combination - means within the scope of the present invention straight and branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iaopropyl, n-butyl, isobutyl, tert-butyl, amyl, The term cycloalkyl 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 alkyl is 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 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, oxezolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, phthalazinyl, pyrimidinyl. or pyrazinyl. The term leaving group in the context of the present invention means known groups such as halogen, preferably chlorine or bromine, arylsulfonyloxy, such as tosyloxy, alkylsulfonyloxy, such as mesyloxy, quaternary ammonium and sulfonium salts and the like.

A preferred group of compounds of formula X are those in which R @ 1 is hydrogen. Further preferred are those compounds of formula I wherein R and R are located in the 2-position of the 2,6-phenyl ring. R and R preferably have the same meaning and are preferably halogen, particularly preferably chlorine.

Another group of preferred compounds of formula 1 are those in which R ⁴ is a -CH ^{5 (} R ⁾ -bonded 5- or optionally alkyl-substituted 6-membered aromatic heterocyclic group β with one or two heteroatoms, oxygen, nitrogen or sulfur being the heteroatoms; ??? represents hydrogen or methyl; preferably a pyridyl group or a 5-membered aromatic heterocyclic group with one oxygen or sulfur atom. Very particularly preferably R ⁴ or pyridyl or furyl is attached via a -CH (R 6) - linked group.

With the above it follows that the very particularly preferred are those compounds of formula I, λ 2 Λ 1 wherein R ^J is hydrogen, R and R are halo, preferably chloro, in the 2,6-position and R 'is through -CH (R -) a bound pyridyl or furyl group.

Preferred compounds of formula I are:

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

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

2 - [{[2- (2,6-Dichlorophenyl) imino] -1-imidazolinyl] oxy] methyl] pyridine,

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

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

The compounds of the above formula (1) and their pharmaceutically usable acid addition salts can be prepared according to the invention by cyclizing the compound of formula (11)

, 1

Α _{χ from} CH ₂ CH ₂ -NH _{2 (2} )

OR ⁴ «,, on SR ° in which i,,

A represents a group of formula -N-C- or -N = C- wherein R 0 represents an alkyl group having 1 to carbon atoms, t 2 X A

R, R, R and R are as defined above and the compound or a pharmaceutically unusable acid addition salt thereof is optionally converted into a pharmaceutically usable acid addition salt.

The cyclization of the compound of formula II is carried out in a manner known per se, for example by heating to a temperature between about 25 and 200 ° C, preferably between about 35 and 120 ° C. This reaction may be carried out in the absence or presence of a solvent. Solvents suitable for this purpose are chlorinated hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, acetonitrile, dimethylformamide and the like. The cyclization can also be carried out by treating compounds of formula II, preferably those in which A is N = C-, wherein R 0 is alkyl of 1 to 6 carbon atoms, is subjected in a polar solvent

S-R ° at a temperature between 0 ° C and the reflux temperature of the reaction mixture, treatment with a suitable basic condensing agent. Suitable base condensing agents include ammonium acetate, methylamine, pyridine and the like. Suitable polar solvents are water, alcohols such as methanol, and aprotic solvents such as acetonitrile and the like.

The compounds of formula (I) above may be converted into pharmaceutically usable acid addition salts, for example by treatment with an inorganic acid such as hydrohalic acid, for example hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid and the like, or by treatment with an organic acid such as tartaric acid, tartaric acid. acids, citric acid, methanesulfonic acid, and the like. A non-pharmaceutically acceptable acid addition salt of a compound of formula 1 can be converted into the free base in a manner known per se, for example by alkali treatment, and optionally converted into a pharmaceutically acceptable acid addition salt.

The compounds of the formula II which are used as starting materials are novel and can be prepared, for example, by reacting the isothiocyanate of the formula III

V- N = CS where 1 2 3

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

Z - CH ₂ CH ₂ - NH - OR ⁴ (III) (IV) wherein

R ⁴ is as defined above and

Z is phthalimido or succinimido, to form a compound of formula V

K -CH ₂ CH ₂ -ZN (A)

OR 'in which

14

R, R, R, R and Z are as defined above.

This reaction is carried out by methods known per se in an organic solvent inert under the reaction conditions such as aromatic hydrocarbons such as benzene or toluene, ethers such as tetrahydrofuran, alkanols such as ethanol, chlorinated hydrocarbons such as methylene chloride and the like. at about room temperature and the reflux temperature of the reaction mixture.

2.2311

Compounds of formula V can also be converted into compounds of formula VI by known methods

N = C

SR c \ ^ _N .CH ₂ CH ₂ -2 (VI) in which

R 0, R ¹ , R ² , R ³ , R ⁴ or ^m and Z are as defined above, for example by reacting a compound of formula V with a trialkyloxonium tetrafluoroborate such as triethyloxonium tetrafluoroborate in an organic solvent such as for example benzene or toluene and the like, at a temperature between about 0 and 40 ° C, preferably at room temperature.

The compounds of formulas V and VI can be converted according to known methods into the corresponding compounds of formula 11, 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.

The compounds of formulas 111 are known or can be prepared in an analogous manner to that known for the preparation of known compounds.

The compounds of the formula IV are novel and can be prepared, for example, by the use of -benzylhydroxylamine of the formula VII

H ₂ N - OR ⁴ (VII) i

R ⁴ represents a benzyl group, reacted with a compound of the formula VIII x-ch, -ch ₂ -z (VIII) in which:

X is a leaving group and

From my above meaning, or with ethyleneimine.

The reaction with a compound of formula (VIII) 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 IVa

Z-CH ₂ CH ₂ -HN-OR ⁴ (IVa) wherein

R ⁴ and Z are as defined above.

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

The compound of formula (IVa) obtained, if appropriate, can be converted to the corresponding compound of formula (IV) in which R ^{@ 4} has the meaning of R ^{@ 4 by means of} cleavage of the benzyl group and optional substitution at oxygen, but is different from benzyl.

21231 1

The cleavage of the benzyl group from the compound of formula IVa is carried out by known methods by treatment with a hydrohalic acid, preferably hydrobromic acid, or by catalytic hydrogenation or, preferably, with boron tribromide or boron trichloride in an inert organic solvent such as methylene chloride. 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 an oxygen atom in the compound obtained by treatment with a compound of formula IX

R ⁴ - X - (IX) 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 and the like, in an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile and in an aprotic non-polar solvent such as ethers such as tetrahydrofuran or diethyl ether, aromatic hydrocarbons such as toluene or xylene, cyclohexane and the like; 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 hydroxide 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, the symbol X in the compound of formula IX is preferably iodine. Substitution on an oxygen atom can also be carried out using so-called phase transfer catalysis / cf. for example, Angew. Chem. 2, 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 process is preferably carried out at room temperature.

The compounds of formulas VIII and IX are known or can be prepared in a manner analogous to the preparation of known compounds.

The compounds of formula I, as well as their pharmaceutically usable acid addition salts, 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 hypertonia.

The blood pressure lowering effect can be determined using the following two methods: «

A. Systolic blood pressure and heart rate are measured several times prior to dosing in alert, spontaneously hypertonic female rats. 5 test animals weighing about 300 g are used per dose. The substance is administered by gavage. Both parameters are measured 1, 3, 6 and 16 hours after application and the percent change to control values is calculated. Systolic blood pressure is measured indirectly on the rat tail artery by the method of GEROLD et al. (Helv. Physiol. Acta 24, 58-69, 1966; Arzneimittelforschung 18.

285-187, 1968).

2,23,1

B. Systolic blood pressure and heart rate are measured prior to application of the compound to vigilant females weighing 0 to 15 kg. A modified technique is used which is based on the irritation of Sinus caroticus and described by van Leereum (Pfluger's Arch. Ges. Physiol. 142. 377-381, 1911). The substance is administered to animals not fed overnight. Both parameters are measured at 0.5, 1, 1.5, 2, 3, 4, 6, and 16 hours after application and calculate the ee percent change to control values. 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. Pregenglionic activity of the sympathetic is derived from the intestinal nerve (Nervus splanchnicus) using bipolar platinum electrodes, and the postganglionary activity is derived from the nerve branch to the kidney according to the method of G. Husler (Neunyn-Schmiedeberg's Arch. Pharmacol., 286. 97-111, 1974). In addition, erterial blood pressure from the femoral artery (Arteria femoralis) and heart rate are measured. The test substance is administered by intravenous injection. If the test substance suppresses sympathetic activity by more than 30% for more than 30 minutes at doses lowering blood pressure, 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

Spontaneously hypertonic rat Watchful dog Centrally inhi- the side effect on 3 sympatikus Blood Pressure Heart Δ% frequency Δ% Dose mg / kg p.o. Blood Pressure Heart mna mg / kg p.o. Δ # freq, Δ% TO 10 -15 -19 3 -14 -37 Yes M 1 -13 -19 0.1 -21 -13 Yes 1 -32 - 3

K 2 - [(2,6-dichlorophenyl) imino] -1-ethoxyimidazolidine chloride,

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, vaseline, 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, suspensions or emulsions. These preparations are optionally sterilized and optionally contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for affecting the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

The daily dose for oral administration is between about 1 and 200 mg. For intravenous administration, the daily dose is between about 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 I

370 mg (1 mmol) of 1- (2-aminoethyl) -1-benzyloxy-3- (2,6-dichlorophenyl) -2-thiourea were heated to 120 °. After cooling to room temperature, the residue was crystallized from isopropyl ether to give 1-benzyloxy-2 - [(2,6-dichlorophenyl) imino] imidazolidine, m.p. 115-117 °.

The starting material can be produced as follows:

6.12 g (30 mmol) of 2,6-dichlorophenylisothiocyanate are dissolved in 50 ml of absolute benzene and 8.89 g (30 mmol) of N- {2 - [(benzyloxy) amino] ethyl} phthalimide are added to this solution. After 24 hours at room temperature, the crystalline precipitate was filtered off to give 1-benzyloxy-3- (2,6-dichlorophenyl) -1- (2-phthalimidoethyl) -2-thiourea; mp 180-182 °.

g (8 mmol) of 1-benzyloxy-3- (2,6-dichlorophenyl) -1- (2-phthalimidoethyl) -2-thiourea were suspended in 30 ml of ethanol and 4 ml of hydrazine hydrate. After about 1 hour a clear solution was formed. This was further stirred for 3 hours, whereupon a precipitate formed which was filtered off. The mother liquor was evaporated in vacuo and the residue as well as the filtered precipitate were suspended in 60 ml of 1 N hydrochloric acid solution. After stirring at room temperature for 16 hours, the precipitate was filtered off, and the acidic solution was neutralized with 60 ml of 1 N sodium hydroxide solution. The precipitate formed is filtered off, dried and recrystallized from a mixture of methanol and isopropyl ether to give 1- (2-aminoethyl) -1-benzyloxy-3- (2,6-dichlorophenyl) -2-thiourea, m.p. , 09 °.

2.0 g of the base were dissolved in 10 ml of ethyl acetate and adjusted to pH 3 by addition of hydrochloric acid in dioxane. The oily suspension was evaporated in vacuo and the residue was recrystallized from acetonitrile. The hydrochloride obtained melts at 170-171 °.

Example 2

200 mg (0.5 mmol) of 3- (2-aminoethyl) -3-benzyloxy-1- (2,6-dichlorophenyl) -2-ethyl-2-isothiourea is stirred with 20 ml of methanol and 250 mg of ammonium acetate at a temperature of rooms. The reaction mixture is then evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate and the organic solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from isopropyl ether to give 1-benzyloxy-2 - [(2,6-dichlorophenyl) imino] imidazolidine, m.p. 117-118 °.

The starting material can be produced as follows:

10.0 g (20 mmol) of, -benzyloxy-3- (2,6-dichlorophenyl) -1- (2-phthalimidoethyl) -2-thiourea are dissolved in 100 ml of methylene chloride and 4.18 g ( 22 mmol) of triethyloxonium tetrafluoroborate. After stirring at room temperature for 3 hours, the solution was poured into 5% sodium carbonate solution. The organic phase was washed with water, dried over sodium sulphate and evaporated in vacuo. The residue was dissolved in 200 ml of hot isopropyl ether, and the solution was concentrated to 100 ml. There was thus obtained 3-benzyloxy-1- (2,6-dichlorophenyl) -2-ethyl-3- (2-phthalimidoethyl) -2-isothiourea, m.p.

1.06 g (2 mmol) of 3-benzyloxy-1- (2,6-dichlorophenyl) -2-ethyl-3- (2-phthalimidoethyl) -2-isothiourea was stirred with 6 ml of 40% methylamine overnight at room temperature. . The oily suspension was extracted with ether. The organic extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ether and hydrochloric acid in dioxane was added. The precipitate formed is filtered off and recrystallized from acetonitrile to give 3- (2-aminoethyl) -3-benzyloxy-1- (2,6-dichlorophenyl) -2-ethyl-2-isothiourea dihydrochloride, m.p. 148 DEG (decomposition). ).

Example 3

31.0 g (63.0 mmol) of 1-benzyloxy-3- (3,4-dimethoxyphenyl) -1- (2-phthalimidoethyl) -2-thiourea are suspended in 600 ml of ethanol and 34 ml of hydrazine hydrate are added. After stirring at room temperature for 8-12 hours, the mixture was acidified with concentrated hydrochloric acid and stirred overnight at room temperature. The precipitate was filtered off. The aqueous solution was basified with sodium carbonate and extracted with ethyl acetate. The organic extract was dried and evaporated in vacuo. The residue is chromatographed on 45µg silica gel (eluent: chloroform / ethyl acetate 3: 2). The oil obtained was dissolved in ether and excess L-tartaric acid in ether was added to give 1-benzyloxy-2 - [(3,4-dimethoxyphenyl) imino] imidazolidine-L-tartrate; mp 90-95 °.

The starting material can be produced as follows:

To a solution of 12.44 g (42 mmol) of N - [(2-benzyloxy) aminoethyl] phthalimide in 50 ml of benzene at room temperature was added 8.20 g (42 mmol) of 3,4-dimethoxyphenylisothiocyanate. After 36 hours, the resulting precipitate was filtered off to give 1-benzyloxy-3- (3,4-dimethoxyphenyl) -1- (2-phthalimidoethyl) -2-thiourea, m.p. 120-122 °.

Example 4

The following compounds were prepared in an analogous manner to that described in Example 1 (2) or Example 3 (3):

From 3,4-dimethylphenylisothiocyanate and N- {2 - [(henzyloxy) amino] ethyl} phthalimide is obtained

1-Benzyloxy-3- (3,4-dimethylphenyl) -1- (2-phthalimidoethyl) -2-thiourea, m.p. 90 ° -91 ° (from diethyl ether).

From 3-trifluoromethylphenylisothiocyanate and N- {2 - [(benzyloxy) amino] ethyl} phthalimide, one obtains:

1-Benzyloxy-1- (2-phthalimidoethyl) -3- (alpha, alpha, alpha-trifluoro-m-tolyl) -2-thiourea, m.p. 123-124 ° (from benzene).

From 4-methylthiophenyl isothiocyanate and N- {2 - [(benzyloxy) amino] ethyl} phthalimide is obtained

1-Benzyloxy-3- [4- (methylthio) phenyl] -1- (2-phthalimidoethyl) -2-thiourea.

Example 5

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

From 1-benzyloxy -, - (2-phthalimidoethyl) -3- (alpha, alpha, alpha-trifluoro-m-tolyl) -2-thiourea and hydrazine hydrate, 1-benzyloxy-2 - [(alpha, alpha, alpha, alpha- trifluoro-m-tolyl) imino] imidazolidine hydrochloride, m.p. 54 DEG-155 DEG (from ethanol / ethyl acetate).

From 1-benzyloxy-3- [4- (methylthio) phenyl] -, - (2-phthalimidoethyl) -2-thiourea and hydrazine hydrate, 1-benzyloxy-2 - {[4- (methylthio) phenyl] imino} imidazolidine is obtained. m.p. 96-97 ° (from a mixture of methylene chloride and diisopropyl ether).

From 1-benzyloxy-3- (3,4-dimethylphenyl) -1- (2-phthalicidoethyl) -2-thiourea and hydrazine hydrate, 1-benzyloxy-2 - [(3,4-dimethylphenyl) imino] imidazolidine is obtained.

The following compounds can be prepared in an analogous manner to those described in Examples 1 to 3 and 5:

1-benzyloxy-2 - [(2,6-dimethylphenyl) imino] imidazolidine hydrobromide, m.p. 88 DEG-89 DEG (from acetonitrile / diethyl ether),

1-Benzyloxy-2- (phenylimino) imidazolidine, m.p. 78 DEG-79 DEG (from isopropyl ether);

1-benzyloxy-2 - ((2-isopropylphenyl) imino] imidazolidine as an oil,

1-Benzyloxy-2 - [(3,4-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 178-180 ° (from methanol / acetonitrile),

1-Benzyloxy-2- E (6-chloro-2-methylphenyl) imino] imidazolidine hydrochloride, m.p. 188-191 ° (from acetonitrile),

1-benzyloxy-2 - [(2,6-dibromophenyl) imino] imidazolidine, m.p. 89-90 ° (from a mixture of diisopropyl ether and cyclohexane),

1-Benzyloxy-2 - [(4-chloro-2,6-diethylphenyl) imino] imidazolidine as an oil,

1-benzyloxy-2 - [(2-iodophenylimino)] imicazolidine hydrochloride, m.p. 192-194 ° (from methanol / acetonitrile),

1-benzyloxy-2 - [(2-chlorophenyl) imino] imidazolidine hydrochloride, m.p. 198 DEG-201 DEG (from a mixture of methanol, acetonitrile and acetone),

1-benzyloxy-2 - [(2-trifluoromethylphenyl) imino] imidazolidine hydrochloride, m.p. 191-193 ° (from acetonitrile),

1-benzyloxy-2 - [(2-bromophenyl) imino] imidazolidine hydrochloride, m.p. 199-200 ° (from acetonitrile),

2 - [(2,6-dichlorophenyl) iminol-1-methoxyimidazolidine hydrochloride, m.p.

2 - [(2,6-dichlorophenyl) imino3-1- 2- (dimethylamino) ethoxy imidazolidine hydrochloride, m.p. 213-215 ° (from acetonitrile / ethyl acetate),

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

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

2 - [(2,6-diohlorophenyl) imino] -1- [2- (methylthio) ethoxy] imidazolidine hydrochloride, m.p. 156 DEG (decomposition),

1- (allyloxy) -2 - [(2,6-dichlorophenyl) iminolimidazolidine hydrochloride, m.p. 169-171 ° (from acetonitrile),

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

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

1- (3-butenyl) -2- (2,6-dichlorophenyl) imino imidazolidine methanesulfonate, m.p. 155-157 ° (from acetone / diethyl ether),

2 - [(2,6-dichlorophenyl) imino] -1- (4-pentenyl) imidazolidine hydrochloride, m.p. 203 DEG-207 DEG (from acetone),

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

2 - [(2,6-dichlorophenyl) imino] -1-isopropoxyimidazolidine hydrochloride, m.p. 204 DEG-205 DEG (from acetonitrile),

2 - [(2,6-dichlorophenyl) imino] -1- (3-methoxypropoxy) imidazolidine, m.p. 95-96 ° (from isopropyl ether),

2 - [(2,6-dichlorophenyl) imino] -1-ethoxyimidazolidine hydrochloride, m.p. 219-221 ° (from acetone),

1- (cinnamyloxy) -2 - [(2,6-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 123-125 ° (from a mixture of acetonitrile and hydrochloric acid in a mixture of dioxane and diethyl ether),

1- (benzyloxy) -2 - [(2,5-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 206 DEG-207 DEG (from acetonitrile),

1- (benzyloxy) -2 - [(2,3-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 200 DEG-201 DEG (from a mixture of acetonitrile and hydrochloric acid in dioxane),

1- (benzyloxy) -2 - [(2,4-dichlorophenyl) imino] imidazolidine hydrochloride, m.p. 178-180 ° (from acetone / hydrochloric acid in dioxane), ethyl 2 - {[2 - [(2,6)] -dichlorophenyl) imino] -1-imidazolidinyl / oxy} methyl] -3-furoate, m.p. 99 DEG (from isopropyl ether); the corresponding fumarate melts at 154 to 156 ° (from a mixture of methanol and acetonitrile),

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

2-j (2,6-dichlorophenyl) imino] -1- (2-methoxyethoxy) imidazolidine hydrochloride, m.p. 125-127 ° (from a mixture of acetone 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 ° (from a mixture of acetone and hydrochloric acid in a mixture of dioxane and diethyl ether),

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

2 - [(2,6-diethylphenyl) imino] -1- (3-furylmethoxy) imidazolide hydrochloride, m.p. 204-206 ° (from acetonitrile),

2- [{[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine, m.p. 116-118 ° (from isopropyl ether), corresponding dihydrochloride melts 175-176 ° with decomposition (from mixtures of methanol and acetonitrile),

1- (benzyloxy) -2 - [(2,6-dichloro-4-fluorophenyl) imino] imidazolidine, m.p. 112 DEG-113 DEG (from cyclohexane);

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

160-161 ° (from acetonitrile / isopropyl ether); the corresponding dihydrochloride melts at 180 ° with decomposition; (a mixture of methanol and acetonitrile),

2- [] / 2 - [(2,3-dichlorophenyl) imino] -1-imidazolidinyl / oxy] methylpyridine dihydrobromide, m.p. 154-155 ° dec. (From methanol / acetone),

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

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

147 DEG-148 DEG (from a mixture of methylene chloride and isopropyl ether), m.p. 147 DEG-148 DEG; 2 - [(2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] methyl; 164 ° with decomposition (from acetonitrile),

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

2 - [(2 - ((2,6-dichlorophenyl) imino] -1-imidezolidinyl / oxyjmethyl] -5-ethylpyridine, m.p. 103-104 ° (from isopropyl ether), rac.-2- | 2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] ethyl] pyridine dihydrochloride, m.p. 218-219 ° (from acetonitrile / acetone),

5- R / 2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy] methyl] isoxazole, m.p. 87-88 ° (from isopropyl ether), corresponding hydrochloride melts at 171 ° with decomposition (from acetone) ,

2- [{/ 2 - [(2-chlorophenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine dihydrochloride, m.p. 175-176 ° (from acetonitrile / dioxane),

2 - [{[2 - [(2-bromophenyl) imino] -, - imidazolidinyl oxy] methyl] pyridine dihydrobromide, m.p. 186-187 ° (from 30% hydrogen bromide in glacial acetic acid),

2- [] / 2- ((2,6-dibromophenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine dihydrochloride, m.p. 87-188 ° (dec.) (From methanol / acetonitrile),

2 - [{[2 - [(2,6-dimethylphenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine dihydrochloride, m.p. 96-197 ° dec. (From acetonitrile),

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

3- [{[2- (6-chloro-2-methyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine, m.p. 1.0-111 ° (from methylene chloride / isopropyl ether), corresponding dihydrochloride melts at 221 to 222 ° with decomposition (from acetonitrile),

2123.1

2- [] / 2 - [(2,6-dlchloro-4-fluorophenyl) imino] -1-imidazolidinyl / oxy} methyl] pyridine dihydrobromide, m.p. 199-200 ° dec. (From methanol / acetonitrile),

4- [1 - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxyethyl] pyridine dihydrochloride, m.p. > 300 [deg.] (From a mixture of methanol and acetonitrile),

3- [, - {[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy} ethyl] pyridine dihydrochloride, m.p. 262 [deg.] With decomposition (acetonitrile / dioxane),

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

Example A

Production of lacquered tablets of the following composition:

2-t (2,6-dichlorophenyl) imino] -1-

- (furfuryloxy) imidazolidine hydrochloride 5,56 mg powdered milk sugar 34.44 mg white corn starch 59.0 mg talc 0.5 mg magnesium salt of stearic acid 0.5 mg core weight 100.0 mg dry weight of varnish about 7.0 mg Total weight of the coated tablet about 107.0 mg

The mixture of active ingredient with powdered milk sugar and a portion of corn starch is moistened with a lubricated starch prepared from another portion of corn starch and water, the resulting mixture is bent, granulated, dried and sieved. The corn starch residue, talc and magnesium stearic acid salt are admixed with this granulate, and the resulting mixture is compressed to produce cores weighing 100 mg. These cores are coated according to conventional methods, the dry weight of the lacquer layer being about 7.0 mg.

Claims (15)

A process for the preparation of novel 2-iminoimidazolidine derivatives of the general formula I (I) wherein: 12 R, R and R ^j are independently hydrogen, alkyl of 1-6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, halogen or trifluoromethyl and R ⁴ is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 dialkylaminoalkyl, C 1 -C 6 phenylalkyl alkylthioalkyl having 1 to 6 carbon atoms in the alkyl, alkoxyalkoxyalkyl having 1 to 6 carbon atoms in the alkoxy moieties and in the alkyl moiety, alkoxyalkyl having 1 to 6 carbon atoms in the alkoxy and alkyl moieties, or through -CH (R @ 6); ) a 5-membered or, optionally, (C1-C6) alkyl substituted by a 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms, with oxygen, nitrogen or sulfur being the heteroatoms and R R being hydrogen or methyl, and their pharmaceutically usable editorial groups acid salts, characterized in that the compound of formula (II) / ^CH 2 ^CH 2 ^-NH 2 N (II) OFT v nčmž HS SR ¹ A represents a group of formula | h | ~ - N - C - or -N = C where R 0 represents an alkyl group having 1 to 6 carbon atoms, I O A R, R, ^RJ and R * are as hereinbefore defined, cyclizes, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 2. The process of claim 1, wherein the compound of formula (II) wherein A, r ' and B ' have the meanings given in 1, R ^ is hydrogen and R ⁴ is C 2 -C 6 alkenyl, C 1 -C 6 dialkylaminoalkyl, C 1 -C 6 phenylalkyl, C 1 -C 6 alkylthioalkyl; up to 6 carbon atoms in alkyl, alkoxyalkoxyalkyl of 1 to 6 carbon atoms in the alkoxy and alkyl moieties, alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy and alkyl moieties, or through a -CH (R 6) - linked 5-membered or or optionally C 1 -C 6 alkyl substituted by a 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms, with oxygen, nitrogen or sulfur being the heteroatoms and R 6 being hydrogen or methyl, whereupon the optionally obtained compound or a pharmaceutically unusable addition thereof the acid salts are converted into pharmaceutically usable acid addition salts. 3. A process according to claim 1 or 2, wherein the compound of formula II is cyclized in which A, R < ^{1 &gt}; and R ^ are as defined in 1 or 2, wherein the substituents r 'and R ^ are in the 2,6-position of the phenyl ring, and R ^ is as defined in 1 or 2, and optionally the compound obtained or a pharmaceutically unusable addition thereof converting the acid salt into a pharmaceutically acceptable acid addition salt. 4. A process according to any one of Claims 1 to 3, wherein the compound of formula II is cyclized, wherein A, R, R and R are as defined in 1 to 3, but wherein R and R are the same. have the same meaning, and R 'has the meaning given in 1 to 3, and optionally the obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 5. A process according to any one of claims 1 to 4, wherein the compound is cyclized A compound of formula II wherein A and ^RJ are as defined in 1 to 4, and R and R are halogen and R1 is as defined in 1 to 4, and optionally the compound obtained or a pharmaceutically unusable addition thereof converting the acid salt into a pharmaceutically acceptable acid addition salt. 6. A method according to claim 5, characterized by cyclising a compound of formula II wherein A and R are as defined in points 1 to 4 and R ¹ and B? are chlorine, and R1 is as defined in 1 to 4, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically acceptable acid addition salt. 7. A process according to any one of claims 1 to 6, wherein the compound is cyclized 19 A according to formula II, wherein A, R, R 'and R ^J are as defined in 1 to 6, and 8' 13 2) 2311 is over a group -CH (R ⁹⁾ - linked 5-membered or optionally by alkyl having 1 to 6 carbon atoms substituted 6-membered aromatic heterocycle having I or 2 heteroatoms, wherein the heteroatoms are, for oxygen, nitrogen or sulfur wherein the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted to a pharmaceutically usable acid addition salt. 8. A method according to claim 7, characterized by cyclising a compound of formula II wherein A, R ', R ² and R ³ are as defined in points 1 to 7, and ^R4 is through -CH (R ⁹ ) a bonded pyridyl group or a 5-membered aromatic heterocyclic group having 1 oxygen or sulfur atom, after which the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 9. The method according to claim 8, characterized by cyclising a compound of formula IX wherein A, R ^1, R ² and R ³ are as defined in points 1 to 7, and ^R4 is through -CH (R ⁹ ) a bonded pyridyl or furyl group, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 10. The method of any one of claims 1 to 9, wherein the compound is cyclized 1 2 3 Formula II wherein A is as defined in points 1 to 9, R ^J is hydrogen, R and R are halogen, preferably chlorine, in position 2 and 6, and R ⁴ represents a via --CH (R @ ⁹ - a bound pyridyl or furyl group, whereupon the optionally obtained compound or a pharmaceutically unusable acid addition salt thereof is converted into a pharmaceutically usable acid addition salt. 11. A process according to item 1 for the preparation of 2-t (2,6-dichlorophenyl) imino] -1-ethoxyimidazolidine, characterized in that the compound of formula II is cyclized, wherein A is as defined in item 1, R and R is chlorine in position 2 and 6 of the phenyl residue, R ^J is hydrogen and R ⁴ is ethyl. 12. A process according to claim 1 for the preparation of 2 - [(2,6-dichlorophenyl) imino] -1- (furfuryloxy) imidazolidine, characterized in that the compound of formula II is cyclized in which A has the meaning given in of R 1, R and R are chlorine at the 2 and 6 positions of the phenyl radical, R is hydrogen and R ⁴ is 2-furylmethyl. 13. The method of item 1 for producing 2 - [{[2 - [(2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy | methylpyridine, characterized in that the compound of formula (II) in which: A is as defined in 1, r 1 and R ² are chlorine at the 2 and 6 positions of the phenyl moiety, R ³ is hydrogen and R ⁴ is 2-pyridylmethyl. 14. A process according to item 1 for the preparation of 3 - [{[2- (2,6-dichlorophenyl) imino] -1-imidazolidinyl / oxy) methyl] pyridine, characterized in that the compound of formula II is cyclized in: which A is as defined in 1, R ¹ and R ² are chlorine at the 2- and 6-positions of the phenyl moiety, R ³ is hydrogen and R ⁴ is 3-pyridylmethyl. 15. A process according to item 1 for the preparation of 2 - [{[2 - [(2,6-dichloro-4-fluorophenyl) imino] -1-imidazolidinyl / oxy] methyl] pyridine, characterized in that a compound of the formula II wherein a is as defined in paragraph 1, R ¹ and R ² are chlorine in position 2 and 6 of the phenyl residue, R ³ represents fluorine in the 4-position of the phenyl radical and R ⁴ is 2-pyridylmethyl.