DE2623377A1 - 2-IMIDAZOLINE AND THEIR APPLICATION IN PHARMACEUTICAL PREPARATIONS AND THE PROCESS FOR THEIR MANUFACTURING - Google Patents

Description

PATFNTA N ViAIi *

DR.-ING. VCN KRE ^ SLER DR.-iNG. BEAUTIFUL FOREST DR.-ING. TH. MEYER DR. FUES DIPL.-CHEM. ALEK VON KREISLER DIPL-CHEM. CAROLA KELLER «MMHHHI DIPL.-ING. SELTING

COLOGNE 1, DEICHM / * NHHAUS

Cologne, 24th Mail 976 AvK / IM

Scherico Ltd., Luζern / Switzerland

2-imidazolines and their use in pharmaceuticals Preparations, as well as processes for their

Manufacturing

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The lirfirich'xg refers to new 2-substituted imidazolines ηαά their acid addition salts, to pharmaceutical preparations that contain such compounds and to the production of such compounds and preparations «,

The compounds of this invention are those of the general formula I.

-N

C-Q-R (I)

wherein either Q is a cyclopropylene group or a mono-, di ~ or tri-substituted ethylene group, where the substituents are lower alkyl or cycloalkyl groups, and R is the group

YX.

(II)

-sr Q is a methylene group and R is the group

X Y

(III)

represent?

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where in the formulas R ^ is a hydrogen atom or a lower one Alkyl or cycloalkyl group, X and Y a hydrogen atom oo-sr an i'luoratcm and η an integer from 1 to 3.

Also included are the acid addition salts of those defined above Compounds of formula I.

The definition "lower alkyl group" includes straight and branched chain ones Hydrocarbon groups with up to 5 carbon atoms. The methyl group is preferred, but others are also preferred Groups such as ethyl, isopropyl, n-propyl, η-butyl, t-butyl etc. are important.

The term "cycloalkyl group" includes those with 3 to 6 Carbons. The preferred cycloalkyl group is cyclohexyl.

A preferred group of the compounds according to the invention are those of the general formula IV

(IV)

wherein Q is a Cyclopropy3 ^ .Group or a mono-, di- or tri-substituted ^T thylengruppe means, wherein the substituents, lower alkyl or cycloalkyl, and X and Y represent a hydrogen atom or a fluorine atom. Within this group of compounds of formula IV are those in which Q is the group

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-CH ₂ -C-

represents where R is a lower alkyl or cycloalkyl group and R- is a hydrogen atom or possibly a lower alkyl or Cyoloalkylgruppe are particularly important. Preferably R_ is a methyl group and R. is a hydrogen atom.

Palls X and / or Y represent a fluorine atom, then is in general a fluorine atom in ortho division.

Another group of very potent compounds is the general one Formula VII

(VII)

where η is an integer from 1 to 3? R- is a hydrogen atom or a lower alkyl or cycloalkyl group and X and Y represent a hydrogen atom or a fluorine atom. Preferred within this group are the compounds in which R is a hydrogen atom or a methyl group and η is 2 or 3,

Pharmaceutically acceptable acid addition salts of the invention Compounds are those with inorganic acids such as hydrochloric acid, hydrogen bromide acid, sulfuric acid and phosphoric acid, or with organic

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see acids, such as organic carboxylic acids, e.g. formic acid, acetic acid, propionic acid, glycolic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, Tartaric acid, citric acid, benzoic acid, cinnamic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, or organic sulfonic acids, e.g. Methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, Ethane-1,2-disulfonic acid, benzenesulfonic acid, p-tölucl sulfonic acid, Naphthol-2-sulfonic acid. Other Acid addition salts are used as intermediate products, e.g. in the purification of the free 3ase or in the manufacture other salts, especially pharmaceutically acceptable acid addition salts, as well as for identification and characterization purposes. Acid addition salts that are mainly used in this sense are, for example, those with certain inorganic Acids, e.g. perchloric acid with organic nitro compounds, e.g. picric acid or picrolonic acid, or with Metal complex acids, e.g. phosphotungstic acid, phosphomolybdenic acid, chloropiatic acid, pure corner acid etc.

The compounds according to the invention can be prepared by known methods for making similar compounds. The preferred method is characterized in that a Compound of the general formula VIII

R-Q-Z (VIII)

wherein R and Q are as defined above and Z represents a carboxy group, or a reactive derivative thereof Connection with ethylenediamine or a reactive derivative is reacted therefrom so that the imidazoline obtained in this way is isolated in free form or in the form of an acid addition salt and that, if desired, a free imidazoline obtained in this way is converted into an acid addition salt, or a

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Acid addition obtained in this way is converted into a free irnidazoline or is converted into another acid addition salt.

The conversion of the free base into a salt, or the conversion a salt into the free base or into another salt is carried out according to known methods.

A variant of the above method is characterized in that that a nitrile of the formula VIII (Z = CN) is reacted with ethylenediarain:

NH,

RQ-GN +? ^H 2

CH

NH ₂

The reaction is preferred by heating the starting compounds in the presence of a catalyst, such as sulfur, at temperatures between about 100 and 200 C in an inert gas atmosphere such as nitrogen. Normally the reaction is complete after about 2 to 10 hours, but with certain starting compounds the reaction can be up to to take 24 hours or more.

The ethylenediamine can also be used in the form of its sulfonic acid salt. The resulting derivatives result the desired compound of the formula I is obtained by neutralization. If, for example, ethylenedxamyl tosylate is used, then one the corresponding imidazoline tosylate, known by Process, e.g., by treatment with sodium hydride, is converted into the desired compound.

Typical representatives of reactive derivatives (except for nitriles) are imido ethers, preferably in the form of their halo

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hydrogen acid salts, imidothioethers, imidohalides, Amidines or thioamidines etc. That means that Z can have the following meanings, for example: 0 0 0 p

H H ι Il Il ι

-C-O-lower alkyl; -C-NHR; -C halogen; -C-NHR; NH NH NH ■ NH

Il Il Il Il ι

-C-O-lower alkyl; -C-S-lower alkyl; -C halogen; -C-NHR, etc., preferred as halogen, chlorine and bromine and R being lower alkyl or a hydrogen atom.

Of course, the reaction conditions must be adapted to the respective reactive groups. Such conditions but are the usual standard conditions as they are known for similar reactions. For example, if you use the thioamide:

NH ₂ f TT

R-Q-C = S + ι 2> I.

ι NH, <f ^H 2

then the reaction is preferably in the presence of a basic Catalyst (e.g. triethylamine or N-methylpiperidine) carried out in an inert organic solvent (e.g. dimethylformamide, pyridine, etc.). The catalyst is preferably added in excess. The starting thioamide compound can be obtained by reacting the corresponding nitrile Kiit hydrogen sulfide.

The starting compounds of the formula VIII are either known Compounds or they can be obtained by known methods. A nitrile of the formula VIII can thus be obtained by reacting the corresponding ketone with a cyanomethyl Wittig reagent (e.g. diethyl cyanomethyl phosphate).

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The reaction usually occurs in the presence of sodium hydride in an alkyl ether, e.g. dimethoxyethane, under a nitrogen atmosphere and carried out at reflux temperature. The unsaturated nitrile obtained in this way is by catalytic hydrogenation, e.g. with the help of palladium on charcoal in ethyl acetate and at 2-4 at. Hydrogen pressure, converted into the nitrile. However, the reduction can also be carried out with the aid of magnesium in methanol.

As already mentioned, a derivative thereof can also be used instead of ethylenediamine. Typical derivatives are the sulfonic acid salts. Another alternative consists in taking and using ethylene urea as a derivative of ethylenediamine reacts with an acid of the formula VIII:

H
N

\ = 0 + HOOC-Q-R 1-1

- N
H

From the formula I it can be seen that the compounds as geometrical Isomers (e.g. cis and trans) and as stereoisomers (e.g. dextro and levo) can exist. Of course all such isomers and mixtures thereof are encompassed by the invention. If a mixture of isomers in the reaction was obtained, the components can be separated by conventional methods. It is also possible, if a specific one Isomer is desired to choose the starting materials so that this isomer is obtained. In general, seem but both isomeric forms have about the same activity.

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The following examples illustrate the process described above for the preparation of the compounds according to the invention.

example 1

2-r2- (2-fluorophenyl) propyl-2-iinidazoline infuTarate A.

A solution of 54 g of 3- (2-fluorophenyl) butyronitrile and 16 ml anhydrous methanol in 125 ml of anhydrous ether is saturated at 0 C with HCl. The solution will be on for five days O held, whereby a white precipitate forms. Then add another 100 ml of ether, the product is filtered off and washed with ether (two 100 ml portions). The HCl salt of the imino ether thus obtained is in 100 ml with Ammonia saturated methanol and the solution is left to stand overnight at room temperature. The solvent is distilled off under reduced pressure and the precipitate is recrystallized from isopropanol ether. 54 g of 3- (2-fluorophenyl) butyramidine hydrochloride are obtained; F.P. 173-175 C.

A solution of 10 g of the salt obtained according to (A) and 8.3 g of ethylenediamine in 125 ml of ethanol is refluxed for 3 hours heated, cooled, acidified with ethanolic hydrochloric acid and filtered to remove excess ethylenediamine dihydrochloride to remove. The filtrate is evaporated and the residue is treated with 20 ml of 15% sodium hydroxide solution. The free base is isolated with chloroform and dried over sodium sulfate. After the solvent is removed an oil is obtained which is converted into the fumarate. 12.7 g of 2- [2- (2-fluorophenyl) propyl] -2-imidazoline fumarate, -F.P. are obtained. 154 ° -157 ° C.

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Example 2

2 - {2-phenylpropyl ) -2 -imidazole iniaaleate A

A solution of 35 g of 3-phenylbutyronitrile and 11 ml of anhydrous Methanol in 100 ml of anhydrous ether is saturated with HCl at 0 ° C. and then kept at 0 ° C. for 15 hours, additional 300 ml of ether are added and the imino ether hydrochloride salt precipitates and is filtered off; F.P. 115 ° C.

15 g of the product from stage A are added with cooling to a solution of 4.3 ml of ethylenediamine in 90 ml of methanol. The resulting mixture is refluxed for 3 days, the methanol is evaporated off under vacuum and "the residue is treated with ethanolic HCl". It is then filtered, the filtrate evaporated, the residue treated with 15% NaOH, the imidazoline treated with chloroform isolated and converted to the maleate is obtained 2- (2-phenylpropyl) -2-imidazolinmaleat;.. ^O FP 92.5 -94.5 ° C (recrystallized from ethanol-ether).

Example 3

2- (2-Cyclohexyl-2-phenylethyl) -2-imidazoline furnarate A

A solution of 13 g of 3-cyclohexyl-3-phenyl-propionitrile and 10 ml of triethylamine in 150 ml of dimethylformamide is saturated with H_S. The H ₂ S atmosphere is maintained over the solution and the mixture is stirred for 20 hours. The mixture is then poured into water and the thioamide formed is isolated with benzene. FP 128-130 ° C (from hexane).

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3 g of the thioamide from A are refluxed with 10 ml of ethylenediamine for 3 hours. After cooling, the mixture is poured into ethanol and acidified with ethanolic HCl. The ethylenediamine hydrochloride is filtered off, the filtrate is evaporated under reduced pressure, the precipitate is treated with an aqueous 15% NaOH solution and the imidazoline formed is isolated with chloroform. This product is converted into the 2- (2-cyclohexyl-2-phenylethyl) -2-imidazoline fumarate salt; FP 177 ^O -178.5 ° C (ethanol-ether).

Example 4

2-r2 ~ (3-Fluororhenyl) -propyll -2-iraidazolinf u marat A mixture of 16 g 3- (3-fluorophenyl) -butyronitrile and 23 g ethylenediamine tosylate is heated at 210 C until no more NH_ is formed (3 ,5 hours). This dark oily substance is treated with 15% aqueous NaOH and the imidazoline is isolated with chloroform. The solvent is removed and the oil obtained is converted into the fumarate. 2- [2- (3-fluorophenyl) propyl] -2-imidazoline fumarate is obtained; FP 132.5 ° -134.5 ° C (ethanol-ether).

Example 5

2- (2-Methyl-2-phenylpropyl) -2-imidazoline umarate A mixture of 8.4 g of 3-methyl-3-phenylbutyronitrile, 5 ml of ethylenediamine and 0.2 g of sulfur is heated under reflux. The dark mixture formed is treated with benzene and the oily substance, after removing the benzene, is converted into the fumarate under reduced pressure. 2- (2-Methyl-2-phenylpropyl) -2-imidazoline fumarate is obtained; FP 132 ° - 133 ° C (ethanol-ether).

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Example 6

2-Γ (i, 2 _f 3,4-tetrahydro-1-naphthyl ·) methyl ·] -2-imidazoline hydrochloride
A.

To a mixture of 7.2 g (0.3 mol) of sodium hydride in 35 ml. Dimethoxyethane is added dropwise 53.1 g (0.3 mol) of diethyl cyanomethylphosphonate under a nitrogen atmosphere, the temperature being kept at 25-30 ° C. After the reaction mixture has been stirred for 1.5 hours, it is added slowly 29.2 g (0.2 mol) of 3,4-dihydro-l (2H) -naphthaienone are added and The mixture is stirred for 1/2 hour at room temperature and then under reflux for a further 2 hours. After cooling it adds

water is added and the product is isolated with ether. The 1,2,3,4-tetrahydro-A ^{1 (2H)} 'formed ⁽
is purified by distillation.

formed 1,2,3,4-tetrahydro-A '-naphthbene acetonitrile

16.8 g (0.1 mol) of the nitrile obtained above are hydrogenated for 2 days with the aid of 5% Pa ^ adium on charcoal in 200 ml of ethyl acetate under 4 atmospheres of H "pressure. The mixture is filtered, the solvent is distilled off and the resulting oil is also distilled. 1,2,3,4-tetrahydro · ^ naphthalene acetonitrile · is obtained.

A solution of l · 5 g ^ 2,3,4-Γ6 ^ 3ηγαΓθ ^ -η3ρ1νΙ:] ^ ΐ6η3σ6 ^ ηϊ ^ ϋ and 15 ml of anhydrous methanol in 75 ml of anhydrous ether is saturated with HCl at 0 C. The mixture is 18 hours Hewn long at 0 ° C. Thereafter, ether is added to the IminoatherhydrocMoridsaiZ to fill out. The product is through To flourish.

To a solution of the imino ether salt obtained above in H) O ml Methanol is added 5 g of aeti ^ enediamine. The mixture will

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Heated under reflux for 3 days, then cooled, with ethanol sham HCl acidified and filtered to remove unused ethylenediamine. The filtrate is evaporated and the residue is recrystallized from acetonitrile. 2 - [(1,2,3,4, -Tetrahydro-1-naphthyl) methyl)] - 2-imidazoline hydrochloride are obtained; F.P. 195.5 ° -197 ° C.

Example 7

2% 6.7 _{tons of} 8,9-tetrahydro-5H-5-benzocycloheptene-methyl-1-2-imidazoline maleate

A solution of 17.4 g of 5 ~ cyanomethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene and 10 ml of methanol in 100 ml of anhydrous ether is saturated with HCl at 0 C. The mixture is 3 days held at 0 C. Then additional ether is added to precipitate the imino ether formed as a hydrochloride salt, which is filtered off; F.P. 142 ° -143 ° C.

19.8 g of imino ether hydrochloride are added to 350 ml of an anhydrous NH_ ethanol solution and the mixture is 17 hours kept at room temperature. The methanol is distilled off in vacuo and the residue is triturated with ether. You get the corresponding amidine hydrochloride.

A solution of 13.4 g of amidine hydrochloride and 10.1 g of ethylenediamine in 100 ml of ethanol is refluxed for 5 hours. After cooling, add ethanolic HCl and filter the excess ethylenediamine dihydrochloride. The filtrate is evaporated, 15% aqueous NaOH is added and the imidazoline formed isolated with the aid of chloroform and converted into the maleate salt. The 2- [6,7,8,9-tetrahydro-SH-S-benzocycloheptenylmethyl] -2-imidazoline maleate is obtained; F.P. 126.5 ° -128 ° C.

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Following the procedure illustrated above, using a suitable one Ingredients can produce the following compounds, among others will:

2- (1-methyl-2-phenylethyl) -2-imidazoline hydrochloride, F.P. 209 ° -21O.5 ° C>

2- (3-methyl-2-phenylbutyi) -2-imidazoline fumarate, P.P. 138 ° - 139 ° C (dec.) S

2- ( trans -2-phenyl-cyclopropyl) -2-imidazoline ^{maleate, m.p. 112 O} -114 ° C;

2- [2- (4-fluorophenyl) propyl] -2-imidazoline hydrochloride, F.P. 145 ° -146.5 ° C;

2- [2 ~ (2,4 ~ difluorophenyl) propyl] -2-imidazoline fumarate, F.P. 141.5 ° -143 ° C (dec.) J

2- [2- (3,4-Difluorophenyl) propyl] -2-imidazoline hydrochloride, FP 174 _e 5 ° -176 ° C (dec.) J

2- [2- (2,6 ~ Difluorophenyl) -propyl] -2-imidazoline fumarate,

F.P. 182 ° -183 ° Ci

2- (2-phenylbutyl) -2- imidazoline fumarate hemihydrate,

F. P. 70 ° -75 ° C, ·

2 - [(6-fluoro-1,2,3,4-tetrahydro-1-naphthyl) methyl] -2-imidazoline;

2 - [(5-fluoro-1,2,3,4-tetrahydro-1-naphthyl) methyl] -2-imidazoline;

2- [(8-fluoro-1,2,3,4-tetrahydrc-1-naphthyl) methyl] -2-imidazoline;

2 - [(6-fluoro-2-methyl-1,2,3,4-tetrahydro-1-naphthyl) methyl] -2-imidazoline;

2 - [(2-methyl-1,2,3,4-tetrahydro-1-naphthyl) methyl] -2 -imidazoline hydrochloride (M.p. 195.5-197 ° C); 2 - [(2-cyclopropyl-1,2,3,4-tetrahydro-1-naphthyl) methyl] -2-imidazoline;

2- [1-indanylmethyl] -2-imidazoline hydrochloride (m.p. 234-235 ° C);

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2- [5-fluoro-1-indany! Methyl] -2-imidazoline; 2 - [5-fluoro-2-methyl-1-indanylmethyl] -2-imidazoline; 2 - [7-fluoro-1-indany! Methyl1-2-imidazoline; 2- [6,7,8,9-Tetrahydrο-5H-5-benzocycloheptenylmethyl] ~ 2 ~ imida-

zoline maleate (FeP. 126.5 ^O- 128 ° C);

2- [2-fluoro-δ, 7,8,9-tetrahydro-SH-5-benzocycloheptenylmethyl 1 2-imidazoline;

2- [4-fluoro-6,7,8,9-tetrahydro-5H-5-benzocycloheptenylmethyl 1 2-imidazoline;

2- [6-methyl-6,7,8,9-tetrahydro-5H-5-benzocycloheptenylmethyl] ~ 2-imidazoline; and

2- [4-FluoroO-6-methyl-6,7,8,9-tetrahydro-5H-5-benzocycloheptenylmethyl] -2-imidazoline.

The compounds according to the invention reduce the blood sugar level in warm-blooded animals. The therapeutically effective amount of one of the compounds according to the invention can be determined by standard methods can be easily determined. The well-known test in which the effectiveness of the compounds is determined by the conversion of alanine is measured in glucose (Alanine Induced Hyperglycemia assay) (gluconeogenesis), is carried out with normal CF - ^ mice, by administering a certain amount of the test compound to mice that have previously fasted for 18 hours, 1 hour before intraperitoneally L-alanine (2g / kg) administered. One hour later, blood samples are taken and tested for plasma glucose, lactates, and insulin. For comparison purposes you can use e.g. phenformin, tolazamide and insulin. This test, possibly coupled with other known ones Tests, e.g. the well-known acute and chronic glucose tolerance test in genetic diabetic mice, and based on the test on hyperglycemia caused by glucagon in monkeys, it allows the effectiveness of the compounds according to the invention to be determined (both in terms of effectiveness and profile).

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Such tests have shown that the compounds according to the invention have a high hypoglycemic effect. they are Effective in genetically diabetic mice with little or no tolerance for hypoglycemic effects »They prevent the induction of hyperglycemia by glucagon (in monkeys), and they are hardly likely to cause overt hypoglycemia. The compounds not only increase blood levels of insulin in normal test animals, but also in genetically diabetic mice. In general, show the invention Compounds lack tolerance to insulinogenic effects, and they increase insulin excretion in monkeys. The compounds also don't seem to increase lactic acid levels. Various tests have shown that the compounds according to the invention are effective in an amount of about 1 to 6 mg per kg of body weight (MPK) (in particular in warm-blooded animals with a body weight of about 50 kg). This amount is preferably administered in three doses. Of course however, the treating physician must precisely determine the optimal therapeutic dose for a given diabetes patient to be determined. The compounds of the present invention also have relatively low toxicity. LD for 2- [2- (2-Fluoro-phenyl) -propyl] -2-imidazoline fumarate is 300 MPK (in mice) whereas ED_ for the same compound is 32 MPK.

For administration, the compounds according to the invention are preferably used with customary pharmaceutically acceptable carrier substances mixed for enteral and parenteral administration, the carriers making up the bulk of the preparation. The preparations can be administered in various forms, for example as tablets, capsules, suppositories, Elixirs, emulsions or injections. In the manufacture of such preparations, only substances can be used that are not

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react with the active compounds. Examples are water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, polyalkylene glycol, petrolatum, etc. The active compound is added in such amounts that the preparation contains about 0.1 % - 50 % active substance.

PREPARATIONUI-TGEN

Tablets
A: Production of I ¹ OOO tablets:

Gram

(1) 2 - [2 - (2 -Fluorophenyl) propyl] -2 imidazoline fumarate 25.0

(2) lactose ■ 181.0

(3) corn starch 92.5

(4) Magnesium stearate 1.5

A mixture of 72.5 g corn starch and the lactose with a paste made by dissolving 20 g corn starch in 100 ml of warm water is made thoroughly granulated. The granules are dried and a mixture from the active ingredient with magnesium stearate is added. After thorough mixing, the mass becomes tablets pressed each of 300 mg.

B: grams

(1) 2- [6,7,8,9-J-tetrahydro-5H-5-benzocycloheptenylmethyll-2-imidazoline-

maleate 25.0

(2) lactose 181.0

(3) corn starch 92.5

(4) Magnesium stearate 1.5

(Procedure as under A).

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Capsules
A: Production of I ¹ OOO capsules:

Gram

(1) 2- [2- (2-fluorophenyl) propyl] -2-imidazoline fumarate 25.0

(2) lactose 273.5

(3) Magnesium stearate l _f 5

The active compound (1) is mixed with the lactose and then the magnesium stearate is mixed in. In each 300 mg of the mixture are filled into the gelatin capsule.

B: grams

(1) 2 - [(1,2,3,4-tetrahydro-1-naphthyl) -

methyl] -2-imidazoline hydrochloride 25.0

(2) lactose 273.5

(3) Magnesium stearate 1.5

Procedure as under A.

Parenteral composition
A: Production of I ¹ 000 ampoules with 10 mg of active substance each:

Gram

(1) 2- [2- (2-fluorophenyl) propyl] ~ 2 ~
imidazoline fumarate 10.0

(2) Monobasic potassium phosphate 6.0

(3) Sterile water (fill up to 1 liter)

Ingredients (1) and (2) are about 80 % of the
Water (3) and the mixture is filtered. The remaining water is then added to the filtrate. The solution is subjected to a sterilizing filtration and in each case 1 ml of the sterile solution is filled into each 2 ml ampoule and then lyophilized. After the lyophilized cake has dried, sterile rubber

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stubble put on and sealed.

B: Grainia

(1) 2- [6,7,8,9-tetrahydro-5H-5-benzocyclohoptenylmethyl] ~ 2-iinidazoline maleate x 10.0

(2) Monobasic potassium phosphate 6.0

(3) Sterile water (fill up to 1 liter)

Procedure as under A.

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Claims (1)

EXPECTATIONS )
Iy Process for the preparation of 2-substituted imidazolines of the general formula I. HI ■ N ■ N C-Q-R and their acid addition salts, where in the formula either Q is a cyclopropylene group or a mono-, di- or tri substituted ethylene group, where the substituents represent lower alkyl or cycloalkyl, and R represents the group II is; or Q is a methylene group and R is the group ^(0H 2> n CH-R III 609850/1062 -23-1976 SY / an denote where in the formulas R _{1 denotes} a hydrogen atom, a lower alkyl group or a cycloalkyl group, X and Y denote a hydrogen atom or a fluorine atom and η denotes an integer from 1 to 3; characterized in that a compound of the general formula VIII R-Q-Z (VIII) wherein R and Q are as defined above and Z is a carboxy group or a reactive derivative thereof means reacted with ethylenediamine or a reactive derivative thereof will; that the imidazoline compound thus obtained is isolated in free form or in the form of an acid addition salt and that, if desired, a free base obtained in this way is converted into an acid addition salt, or an acid addition salt obtained in this way is converted into the free base or into another acid addition salt will. 2. The method according to claim 1, characterized in that Z is a nitrile, imidoether, imidothioether, imidohalide, Represents amidino or thioamido group. 3. The method according to claim 2, characterized in that Z represents a nitrile group. 4. The method according to claim 2, characterized in that a sulfonic acid salt of ethylenediamine, preferably Ethylenediamine tosylate is used, and that the imidazoline salt thus formed is subsequently converted into the free base or converted into a pharmaceutically acceptable acid addition salt. 609850/1062 MIYERZ-2 3-19 76 • 209 / XI- ¹ TG -2 2 SK / an 5. The method according to any one of claims 1 to 4, characterized in that that one compounds of the general formula IV HI _N _χ ■ N -ch -c C Λ (ν) wherein Q is cyclopropylene or mono-, di- or tri-substituted Means ethylene group, where the substituents are a lower alkyl or cycloalkyl group, and X and Y represent a hydrogen atom or a fluorine atom. 6. The method according to claim 5, characterized in that one Formula V compounds H // -N wherein X and Y are as defined in claim 5, R represents a lower alkyl or cycloalkyl group and R _{4 represents} a hydrogen atom, a lower alkyl or a cycloalkyl group. 7. The method according to claim 5, characterized in that compounds of the formula VI 609850/1062 EHZ -2 3 -3,976 P.K / 'at Kr CH, \ / V C-CH-C // H-CH • Ν (VI) wherein X and Y are as defined in claim 5. 8. The method according to any one of claims 1 to 4, characterized in that that one compounds of the formula VII -N H- C-CH wherein R ,, n, X and Y are as defined in claim 1, manufactured 9. The method according to claim 8, characterized in that one compounds of the formula VII, wherein η 2 or 3, R .. a Hydrogen atom or a lower alkyl group and X and Y are as defined in claim 8. 10. The method according to any one of claims 1 to 9, characterized in that at least one of X and Y is a
Means fluorine atom. 6 0 9850/1062 MFlERZ-2 2-19 76 2G97X-FTG-24 SE / 'at - 24 - 11. The method according to any one of claims 1 to 10, characterized in, that a free base thus obtained is converted into an acid addition salt. 12. The method according to any one of claims 1 to 11, characterized in that that one of the connections: 2- (2-phenylpropyl) -2-imidazolimaleate? 2- [2- (3-fluorophenyl) propyl] -2-imidazoline fumarate; 2- [2- (2-fluorophenyl) propyl] -2-imidazoline infuitate; 2- [2- (2,4-Difluorophenyl) -propyl] -imidazoline quinarate; 2- (2-methyl-2-phenylpropyl) -2-imidazoline fumarate; 2- (3-methyl-2-phenylbutyl) -2-imidazoline fumarate; 2- (2-cyclohexyl-2-phenylethyl) -2-imidazoline fumarate; 2- ( trans- 2-phenylcyclopropyl) -2-imidazoline maleate; and 2- [2- (2,6-difluorophenyl) propyl] -2-imidazoline fumarate will be produced. 13. The method according to any one of claims 1 to 11, characterized in that that one of the connections: 2 - [(1,2,3,4-tetrahydro-1-naphthyl) methyl] -2-imidazoline hydrochloride;
• 2- [1-indanylmethyl] ^ - imidazoline hydrochloride; 2- [6,7,8,9-tetrahydro-5H-5-benzocycloheptenyl-methyl] -2-imidazoline maleate; and 2- [1- (2Hviethyl- 1,2,3,4-tetrahydro-naphthyl) methyl] -2- imidazoline hydrochloride will be produced. 609850/1062 MARZ-23-1976 2O97X-FTC - 25 SK / an 14. Process for the production of pharmaceutically active preparations , characterized in that a compound which is defined in one of claims 1 to 13 is mixed with a therapeutically acceptable carrier. 15. 2-Substituted imidazolines of the general formula I. HI .N C-Q-R and their acid addition salts, where in the formula either Q is a cyclopropylene group or a mono-, di- or tri-substituted one Ethylene group bedexitet, with the substituents represent lower alkyl or cycloalkyl, and R represents the group / ⁴ V is; or Q is a methylene group and R is the group ^{CH 2 ⁾ n 609850/1062 MAERZ -2 3 -19 76 2O97X-FTG-26 S K / an mean, where in the formulas R is a hydrogen atom, a lower alkyl group or a cycloalkyl group, X and Y is a hydrogen atom or a fluorine atom and η is an integer from 1 to 3. 16. Compounds according to claim 35 with the general formula (IV) K \ C-Q (IV) wherein Q is cyclopropylene or mono-, di- or tri-substituted Represents ethylene group, where the substituents are lower alkyl or cycloalkyl groups; and X and Y represent a hydrogen atom or a fluorine atom. 17. Compounds according to claim 16 with the general formula V. 3 X wherein X and Y are as defined in claim 16, R_ is a represents lower alkyl or cycloalkyl group and R. represents a hydrogen atom or a lower alkyl or cycloalkyl group. 18. Compounds according to claim 16 with the general formula VI 609850/1062 MAERZ-2 3-19 76 7 Π 9 7X-Fl ¹ G -2 7 SK / an N CH. C-CH-CH wherein X and Y are as defined in claim 16. 19. Compounds according to / in claim 15 with the general formula VII HI -N ^(CH 2> n C-CH (VII) wherein R, a hydrogen atom or a lower alkyl or cycloalkyl group, η represent an integer of 1 to 3, and X and Y represent a hydrogen atom or a fluorine atom. 20. Compounds according to claim 19, wherein R. is a hydrogen atom or a lower alkyl group and η are 2 or 3 and X and Y are as defined in claim 19. 21. Compounds according to any one of claims 15 to 20, wherein at least one of X and Y is a fluorine atom » • 22ο connections according to one of claims 15 to 17 and 19 to 21, wherein any lower alkyl groups are methyl groups. 609850/1062 MAERZ-2 3-0.976 l'O97X-fv: G ~ 28 23. Acid addition salts of compounds of claims 15 to 22. 24. 2- (2-Phenylpropyl) -2-imidazoline maleate. 25. 2- [2- (3-Fluorophenyl) propyl] -2-iiiiidazoline infuraate. 26. 2 ~ [2- (2-Fluorophenyl) propyl] -2-imidazoline fumarate. 27. 2- [2- (2,4-Difluorophenyl) propyl] -2-imidazoline fumarate. 28. 2 "- (2-Methyl-2-phenylpropyl) -2-imidazoline fumarate. 23. 2- (3-Methyl-2-phenylbutyl) -2 -imidazoline fumarate. 30. 2- (2-Cyclohexyl ^ -phenylethyl) -2-imidazoline fumarate. 31. 2- ( trans- 2-phenylcyclopropyl) -2-imidazoline maleate. 32. 2- [2- (2,6-Difluorophenyl) propyl] -2-imidazoline fumarate. 33. 2 - [(1,2,3,4-Tetrahydro-1-naphthyl) methyl] -2-imidazoline hydrochloride. 34. 2- [1-indanylmethyl] ^ -imidazoline hydrochloride. 35. 2- [6,7,8,9 -Tetrahydro-5H-5-benzocycloheptenylmethyl] -2-imidazoline maleate. 36. 2- [1- (2-methyl-1,2,3,4-tetrahydro-naphthyl) methyl] -2-imidazoline hydrochloride. 609850/1062 MARZ-23-1976? Π97Χ-ΡΤι? · -29 SK / an 37, Pharmaceutically active preparations which contain a compound of Claims 15 to 36 as the active substance. ORIGINAL INSPECTED 609850/1062