HK1011207B - New imidazoline compounds, process for preparing them and pharmaceutical compositions containing them - Google Patents

Description

Imidazoline compound, its preparing method and medicinal composition containing said compound

The present invention relates to novel imidazoline compounds, to processes for their preparation, and to pharmaceutical compositions containing them.

From a chemical structure point of view, the literature has provided many examples of imidazoline derivatives.

For example, the compounds containing imidazoline units claimed in patents JP-07010871 and EP-501074 are very close to the compounds of the present invention, which are useful as crosslinkers for epoxy resins.

The study by e.uhlig et al (z.anorg. allg.chem., 534, (1986), 188-198) gave imidazoline derivatives useful as complexing agents for copper ions.

Imidazoline derivatives are also very widely disclosed when used in therapy.

For example, JP-60209571 discloses tetrahydropyrimidines and imidazolines with analgesic properties.

Furthermore, numerous publications (J.N.Sengupta et al, Nauyn-Schniedeeberg's Arch, Pharmacol, 335(4) (1987), 391-396; H.Fuder et al, Pharmacol. Adrenoreceptors, (1984), 335-336; R.R.Ruffolo, Eur.J.Pharmacol, 157(2-3), (1988), 235-239) give pharmacological studies of imidazoline derivatives useful as ligands for adrenergic receptors.

It is an object of the present invention to provide imidazoline derivatives having the original structure and showing a high affinity for imidazoline receptors.

It is clear that these derivatives are important in the treatment of cardiovascular diseases such as hypertension. Thus, clonidine, which has been widely used for many years to treat hypertension, has been known.

It is also known that imidazoline receptors are involved in the stimulation of insulin release by pancreatic beta cells (Schutz et al, Nauyn-Schniedeeberg's Arch, Pharmacol., (1989), 340(6), 712, 714).

The importance of imidazoline receptor ligands in the treatment of psychiatric and neurological disorders such as depression, Parkinson's disease and anorexia has also been reported (D.J. NUTT et al, Annals New York academyo of sciences, (1995), 125-.

In addition to their affinity for imidazoline receptors, most of the imidazoline derivatives known to date also have a high affinity for adrenergic receptors, which can cause the appearance of strong cardiovascular effects.

The applicants have now found novel derivatives having an imidazoline structure, potent imidazoline receptor ligands, and lacking adrenergic receptor affinity.

Thus, by virtue of their high affinity potency for imidazoline receptors, the compounds of the present invention find particularly important use in therapeutic methods for the treatment of pathologies associated with imidazoline receptors; the compounds have no side effects on central origin due to their low affinity for adrenergic receptors. The derivatives of the invention are therefore of great importance not only in the treatment of cardiovascular diseases, but also in the treatment of diabetes and in the treatment of psychiatric and neurological disorders such as depression, parkinson's disease and anorexia, a precedent that is not present in the prior art for imidazolines.

More particularly, the present invention relates to compounds of formula (I), isomers and pharmaceutically acceptable acid addition salts thereof:wherein R represents: ● formula (α):wherein R is₁Represents: - (C)₁-C₆) Alkyl, at this time, R₂And R₃And R₅Represents a hydrogen atom, in which case R₄Represents a halogen atom, or R₂And R₄And R₅Represents a hydrogen atom, in which case R₃Represents a halogen atom other than chlorine, or R₂Represents cyano, R₃、R₄And R₅Each represents a hydrogen atom,. or a halogen atom, in which case R₃Also represents and R₁Different halogen atoms, and R₂、R₄And R₅Each represents a hydrogen atom, R₃And R₂And R₅Represents a hydrogen atom, R₄Is represented by (C)₁-C₆) Alkyl,. or a hydrogen atom, in which case R₂、R₃And R₄Simultaneously represents a hydrogen atom, R₅Represents phenyl, or R₂And R₃While representing mutually different halogen atoms, R₄And R₅Each represents a hydrogen atom, or R₂Represents a halogen atom or (C)₂-C₆) Alkyl or (C)₁-C₆) Alkylcarbonyl group, R₃、R₄And R₅Each represents a hydrogen atom, or R₂And R₄And R₅Represents a hydrogen atom, in which case R₃Is selected from ethyl, n-propyl, n-butyl, trifluoromethyl and (C)₁-C₆) Alkylthio, trifluoromethoxy, phenyl, phenoxy, (C)₁-C₆) Acylamino, aminosulfonyl, by one or two (C) on nitrogen atom₁-C₆) Alkyl-substituted aminosulfonyl, or R₂Represents nitro, R₃Represents hydroxy, R₄Represents a halogen atom and R₅Represents a hydrogen atom, or R₃And R₅Each represents a hydrogen atom, R₂And R₄Each represents a halogen atom and cannot simultaneously represent chlorine; ● or naphthyl of formula (. beta.):wherein R is₆Represents a halogen atom, (C)₁-C₆) Alkyl or methoxy; ● or is selected from: indol-5-yl1-phenyl-1-cyclohexylmethyl, cycloheptyl, 4- (benzothiazol-2-yl) benzyl, and the groups

It is to be understood that (C) is₁-C₆) Alkyl, (C)₂-C₆) Alkyl and (C)₁-C₆) Alkylthio refers to both straight-chain and branched groups.

Among the pharmaceutically acceptable acids capable of forming addition salts with the compounds of the present invention, illustrative examples include hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, malic acid, maleic acid, formic acid, oxalic acid, methanesulfonic acid, ethanesulfonic acid, camphoric acid and citric acid.

Used in the present invention, the term "Δ" is satisfied²"refers to the position of the double bond in the imidazoline ring.

Halogen present in the compounds of formula (I) is selected from bromine, chlorine, fluorine and iodine, but is not limited to the above examples.

Preferably, the present invention relates to compounds of the following formulae (α I/a) to (α I/f):wherein R is₁Represents a straight chain or branched chain (C)₁-C₆) An alkyl group;wherein R is₁Represents a halogen atom or a linear or branched chain (C)₁-C₆) Alkyl radical, R₃Represents and R₁A different halogen atom;wherein R is₁Represents a halogen atom, R₄Represents a straight chain or branched chain (C)₁-C₆) An alkyl group;wherein R is₂And R₃Each represents a halogen atom different from each other;wherein R is₃Represents a group selected from ethyl, n-propyl, n-butyl, trifluoromethyl and (C)₁-C₆) Alkylthio, trifluoromethoxy, phenyl, phenoxy, (C)₁-C₆) Acylamino, aminosulfonyl, by one or two straight or branched chains on the nitrogen atom (C)₁-C₆) An alkyl-substituted aminosulfonyl group;wherein R is₂Represents a halogen atom or a linear or branched chain (C)₂-C₆) Alkyl or straight or branched chain (C)₁-C₆) An alkylcarbonyl group.

More particularly, the invention relates to compounds of formula (I) wherein R is selected from the group consisting of:wherein R is₆Represents a halogen atom, a straight chain or a branched chain (C)₁-C₆) Alkyl, or methoxy, such as R represents 2-methoxy-1-naphthyl, 5-indolyl, cycloheptyl.

The present invention also relates to a process for the preparation of a compound of formula (I), which process comprises: reacting a nitrile of formula (II):

R-C≡N (II)

wherein R is as defined above, with ethylenediamine and, if desired, the crude product obtained

-purifying according to one or more methods selected from the group consisting of: crystallizing, purifying by silica gel chromatography, extracting, filtering, and treating with active carbon or resin;

the products, in pure form or in the form of mixtures, are separated, if appropriate, into the possible isomers according to customary separation methods;

and/or the formation of acid addition salts by means of acids.

The starting materials for the process for isolating the compounds of formula (I) are either commercially available or readily available to those skilled in the art.

The compounds of formula (I) have very important pharmacological properties for the clinician and physician.

The compounds of the present invention and pharmaceutical compositions containing them have proven to be potent ligands for the I1 and/or I2 imidazoline receptors.

Imidazoline receptors are also involved in anemia (especially sickle cell anemia) and cancerous hyperplasia.

Furthermore, as already mentioned, pharmacological studies of the compounds of the invention show no toxicity at all, except for their high imidazoline receptor affinity.

This makes the compounds of the present invention and pharmaceutical compositions containing them useful in the treatment of diseases associated with the central nervous system (especially depression, parkinson's disease, anorexia), cardiovascular diseases (especially hypertension), and in the treatment of diabetes, obesity, anemia (especially sickle cell anemia) and cancer.

The subject of the invention is also pharmaceutical compositions comprising a product of formula (I) in association with one or more pharmaceutically acceptable excipients or, if appropriate, pharmaceutically acceptable acid addition salts comprising a product of formula (I) in association with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention, mention should be made in particular of pharmaceutical compositions suitable for oral, parenteral, nasal, dermal, rectal, lingual, ocular and respiratory administration, in particular plain or sugar-coated tablets, sublingual tablets, sachets, gelatin capsules, sublingual preparations, lozenges, suppositories, ointments, salves, skin gels, oral or injection ampoules and aerosols.

The dosage to be administered may vary according to the sex, age and body weight of the patient, the route of administration, the nature of the therapeutic indication or the treatment method which may be relevant, and may vary between 1 or 2 administrations of 0.1mg to 100mg per 24 hours, more particularly between 1mg to 10mg, such as 1 to 2 mg.

The following examples further illustrate the invention and are not intended to limit the invention in any way.

Examples 1 to 30 general procedure:

a mixture containing 25ml of ethylenediamine, 0.01 to 0.02mol of nitrile and a catalytic amount (about 0.5g) of phosphorus pentasulfide was heated under reflux for 4 to 8 hours with stirring. Purification by thin layer chromatography after disappearance of the nitrile. The cooled mixture was poured into 50ml of cold water, and the whole mixture was extracted twice with 50ml of dichloromethane. The residue was crystallized from cyclohexane after evaporation of the organic fraction.

By using the appropriate nitrile and carrying out the procedure described in the general procedure, the compounds in the following examples can be preparedAn object: example 1: 2- (4-Biphenyl) -Delta²Imidazoline (E)

Yield: 91 percent

Melting point: 200 ℃ example 2: 2- (4-trifluoromethoxyphenyl) -Delta²Imidazoline (E)

Yield: 77 percent

Melting point: 150 ℃ example 3: 2- (5-indolyl) -Delta²Imidazoline (E)

Yield: 60 percent of

Melting point: 181 ℃ example 4: 2- (1-cyclohexyl-1-phenylmethyl) - Δ²Imidazoline (E)

Yield: 41 percent

Melting point: 178 ℃ example 5: 2- [4- (benzothiazol-2-yl) benzyl]-Δ²Imidazoline (E)

Yield: 52 percent

Melting point: 157 ℃ example 6: 2- (6-methoxy-2-naphthyl) -Delta²Imidazoline (E)

Yield: 61 percent of

Melting point: 155 ℃ example 7: 2-cycloheptyl-delta²Imidazoline (E)

Yield: 77 percent

Melting point: 255 ℃ example 8: 2- (4-ethylphenyl) -Delta²Imidazoline (E)

Yield: 98 percent of

Melting point: 135 ℃ example 9: 1-methyl-4, 5-bis (. DELTA.)²-imidazolin-2-yl) imidazoles

Yield: 84 percent

Melting point: 162 ℃ example 10: 2- (4-n-propylphenyl) -Delta²Imidazoline (E)

Yield: 70 percent of

Melting point: 126 ℃ example 11: 2- (4-n-butylphenyl) -Delta²Imidazoline (E)

Yield: 61 percent of

Melting point: 98 ℃ example 12: 2- (3-cyano-2-methylphenyl) -Delta²Imidazoline (E)

Yield: 78 percent of

Melting point: 144 ℃ example 13: 2- (4-phenoxyphenyl) -Delta²Imidazoline (E)

Yield: 56 percent

Melting point: 129 ℃ example 14: 2- (3-chloro-4-fluorophenyl) -Delta²Imidazoline (E)

Yield: 41 percent

Melting point: 109 ℃ example 15: 2- (2-chloro-4-fluorophenyl) -Delta²Imidazoline (E)

Yield: 40 percent of

¹H NMR δ (ppm): 2.97 and 3.16(2m, 4H, 2 CH)₂) (ii) a 4.93(s, 1H, NH); 6.46(dd, 1H, J ═ 2.37 and 8.71Hz, H₅)；6.59(d，1H，J＝2.37Hz，H₃)；7.35(d，1H，J＝8.71Hz，H₆). Example 16: 2- (2-fluoro-5-methylphenyl) -Delta²Imidazoline (E)

Yield: 40 percent of

Melting point: 85 ℃ example 17: 2- (4-Ethiophenyl) -Delta²Imidazoline example 18: 2- (4-methylthiophenyl) -Delta²Imidazoline (E)

Yield: 72 percent

Melting point: 158 ℃ example 19: 2- (2-methoxy-1-naphthyl) -Delta²Imidazoline (E)

Yield: 70 percent of

Melting point: 157 ℃ example 20: 2- (4-trifluoromethylphenyl) -Delta²Imidazoline (E)

Yield: 81 percent of

Melting point: at 180 deg.CExample 21: 2- (3-ethylphenyl) - Δ²Imidazoline example 22: 2- (2-phenylphenyl) -Delta²Imidazoline example 23: 2- (5-fluoro-2-methylphenyl) -Delta²Imidazoline example 24: 2- (4-hydroxy-5-iodo-3-nitrophenyl) -delta²Imidazoline example 25: 2- (4-Aminosulfonylphenyl) -Delta²Imidazoline example 26: 2- (4-Acetaminophenyl) -Delta²Imidazoline example 27: 2- (4-methyl-1-naphthyl) -Delta²Imidazoline example 28: 2- (4-fluoro-1-naphthyl) -Delta²Imidazoline example 29: 2- (4-bromo-2-methylphenyl) -Delta²Imidazoline example 30: 2- (3, 5-difluorophenyl) -Delta²Imidazoline (E)

Pharmacological study example a: to I₁And I₂Binding model for imidazoline receptors objective:

by determining the substitution of the compounds of the invention for the specific compounds of formula I₁And I₂(ii) the ability of a radioligand at the imidazoline receptor, in vitro assay of said compound for I₁And I₂Binding affinity of the receptor. Original recording:

the table below indicates the radioligand used to label the receptor, the products and concentrations chosen to determine the non-specific components, and the tissues chosen.

Receptors or sites	Radioligands	Non-specificity	Structure of the product
				I1	[3H]-clonidine +10 μ M noradrenaline	10-5M Cold clonidine	Medulla bovis Seu Bubali
I2	[3H]Idazoxan +10 μ M noradrenaline	10-5M Cold imidazole killer	Cortex of rabbit kidney

As a result:

in vitro results obtained in the central and peripheral receptors under our experimental conditions show that: the compound of the invention has high rabbit renal cortex I₁And/or I₂Affinity of the position, K_iValues varied from a few nM to hundreds of nM. Example B: for alpha₁And alpha₂Binding model for adrenergic central receptors objective:

by determining the substitution of the compounds of the invention for alpha₁And alpha₂The ability of the radioligand at the central receptors, the binding affinity of these receptors of the product was determined in vitro. Original recording:

the table below indicates the radioligand used to label the receptor, the products and concentrations chosen to determine the non-specific fractions and the tissues chosen.

Receptors or sites	Radioligands	Non-specificity	Structure of the product
				α1	[3H]-prazosin	10-5M Phenolamine oxazoline	Lateral sural cortex
α2	[3H]-RX821002	10-5M yohimbine	Lateral sural cortex

As a result:

in vitro results obtained in adrenergic receptors under our experimental conditions show that: the compounds of the invention have very low alpha₁-adrenergic receptors (K)_i> 7. mu.M) and alpha₂-adrenergic receptors (K)_i> 10. mu.M) affinity. Example C: behavioral despair test

The mice used in this experiment were placed in a cylinder filled with water, from which they could not slip out. After several attempts to escape, the animal becomes warm and calm, and now only performs some movements that must maintain its head exposed to water. At this point 10 animals per group were placed in the cylinder for 6 minutes and the time to stabilization was measured over the last 4 minutes.

The stabilization time enables the characterization of the antidepressant activity of the test compounds. Antidepressants (such as imipramine or desipramine) therefore reduce this stabilization time.

The compounds of the invention show activity comparable to imipramine and desipramine, with measured stabilization times of the same order of magnitude as the reference products. Example D: affinity assay for monoamine oxidase in vitro (in vitro)

According toOriginal records described by Carpen (Annals. N.Y.Acad. Sci., 1995, 763, p.380) for I₂Binding at the imidazoline site and affinity of monoamine oxidase.

The reference radioligand used was tritiated BFI. To demonstrate the ability of the compounds of the present invention to replace reference radioligands, competition experiments were performed using the compounds of the present invention. In vitro (ex vivo)

The animals used were genetically hypertrophic Zucker rats which were treated sub-chronically with test compounds. At the end of the experiment, pair I was determined after extraction of adipose tissue in vitro according to the method described by c.carene (j.lipids.res., 1990, 31, p.811)₂Binding at the imidazoline site and monoamine oxidase activity. Results

The test shows that: the compound of the invention has high para I₂Affinity of the imidazoline binding site (in the order of 1 to 100 nM); by having an order of 10 for monoamine oxidase in adipocytes^-6The binding of affinity of M, the compounds of the present invention have an inhibitory effect on this oxidase.

Example E: blood glucose lowering activity

The hypoglycemic activity of the derivatives of the invention was tested in 3-month Witsar male rats at approximately 250 g. Experimental rats with diabetes were obtained by intravenous injection of small doses of streptozotocin dissolved in citrate buffer (171) under Ketamine HCl anesthesia (75mg/kg, IP). These rats are called "STZ" and normal rats are also injected with citrate buffer under the same conditions.

The homeostasis was evaluated by a glucose tolerance test performed two weeks after the injection of streptozotocin. Intravenous glucose tolerance test (IVGTT)

Glucose was dissolved in 0.9% NaCl aqueous solution and administered to rats anesthetized with pentobarbital (60mg/kg, IP) via the saphenous vein. Blood samples were collected sequentially through the vessels on the tail before and at 5, 10, 15, 20 and 30 minutes after glucose injection. The plasma was then centrifuged and separated and the plasma glucose concentration was immediately determined on a 10. mu.l aliquot and the remaining plasma was stored at-20 ℃.

One IP injection of test product was performed on rats anesthetized with pentobarbital 20 minutes prior to IVGTT. Oral glucose tolerance test (OGTF)

The drug was orally administered (2g/kg) to conscious rats. Blood samples were collected before and 10, 20, 30, 40, 60, 90 and 120 minutes after administration of glucose. Blood samples were processed according to the same method as described above.

Test products were administered orally 30 minutes prior to OGTT. Analysis method

Plasma glucose concentrations were determined using a glucose analyzer (Beckman inc., Fullerton, CA). Glucose tolerance is determined by two related parameters: Δ G and K. Δ G represents an increase in blood glucose from baseline; from integration over the 30 min (IVGIT) and 120 min (OGTF) intervals after glucose excess accumulation.

K is the rate of glucose disappearance (IVGTT) between 5 and 30 minutes after glucose administration. The coefficient K is calculated only during IVGTT.

The results show that: the compounds of the invention have comparable activity to gliclazide and have the advantage of not inducing the same basal hypoglycemia. Example F: acute toxicity study

After oral administration, the acute toxicity of 8 mice (26 ± 2g) was determined by increasing the dose of study product. Animals were observed at regular intervals on day 1 and daily for two weeks after treatment.

The results show that: the compounds of the present invention exhibit minimal toxicity. Example G: the pharmaceutical composition comprises: tablet formulation

Preparation of 1000 tablets containing 1mg of 2- (4-ethylphenyl) -Delta²-imidazoline tablets. 2- (4-ethylphenyl) -Delta²Imidazoline (E)1g of wheat starch, 20g of corn starch, 20g of lactose, 30g of magnesium stearate, 2g of silica, 1g of hydroxypropyl cellulose and 2g of starch

Claims (15)

1. A compound of formula (I), isomers and pharmaceutically acceptable acid addition salts thereof:wherein R represents: ● formula (α):wherein R is₁Represents: - (C)₁-C₆) Alkyl, in this case, a halogen atom other than chlorine atom, R₂And R₃And R₅Represents a hydrogen atom, in which case R₄Represents a halogen atom, or R₂And R₄And R₅Represents a hydrogen atom, in which case R₃Represents a halogen atom other than chlorine, or R₂Represents cyano, R₃、R₄And R₅Each represents a hydrogen atom,. or a halogen atom, in which case R₃Also represents and R₁Different halogen atoms, and R₂、R₄And R₅Each represents a hydrogen atom, R₃And R₂And R₅Represents a hydrogen atom, R₄Is represented by (C)₁-C₆) Alkyl,. or a hydrogen atom, in which case R₂、R₃And R₄Simultaneously represents a hydrogen atom, R₅Represents phenyl, or R₂And R₃While representing mutually different halogen atoms, R₄And R₅Each represents a hydrogen atom, or R₂Represents a halogen atom other than chlorine or fluorine atom or (C)₂-C₆) Alkyl or (C)₁-C₆) Alkylcarbonyl group, R₃、R₄And R₅Each represents a hydrogen atom, or R₂And R₄And R₅Represents a hydrogen atom, in which case R₃Is selected from ethyl, n-propyl, n-butyl, trifluoromethyl and (C)₁-C₆) Alkylthio, trifluoromethoxy, phenyl, phenoxy, (C)₁-C₆) Acylamino, aminosulfonyl, by one or two (C) on nitrogen atom₁-C₆) Alkyl-substituted aminosulfonyl, or R₂Represents nitro, R₃Represents hydroxy, R₄Represents a halogen atom and R₅Represents a hydrogen atom, or R₃And R₅Each represents a hydrogen atom, R₂And R₄Each represents a halogen atom and cannot simultaneously represent chlorine; ● or naphthyl of formula (. beta.):wherein R is₆Represents a halogen atom, (C)₁-C₆) Alkyl or methoxy; ● or is selected from: indol-5-yl1-phenyl-1-cyclohexylmethyl, cycloheptyl, 4- (benzothiazol-2-yl) benzyl, and the groupsIt is to be understood that (C) is₁-C₆) Alkyl, (C)₂-C₆) Alkyl and (C)₁-C₆) Alkylthio refers to both straight-chain and branched groups.

2. A compound according to claim 1 of formula (α I/a), isomers and pharmaceutically acceptable acid addition salts thereof:wherein R is₁Represents a straight chain or branched chain (C)₁-C₆) An alkyl group.

3. A compound according to claim 1 of formula (α I/b), isomers and pharmaceutically acceptable acid addition salts thereof:wherein R is₁Represents a halogen atom or a linear or branched chain (C)₁-C₆) Alkyl radical, R₃Represents and R₁Different halogen atoms.

4. A compound according to claim 1 of formula (α I/c):wherein R is₁Represents a halogen atom, R₄Represents a straight chain or branched chain (C)₁-C₆) An alkyl group.

5. A compound according to claim 1 of formula (α I/d), isomers and pharmaceutically acceptable acid addition salts thereof:wherein R is₂And R₃Each represents a halogen atom different from each other.

6. A compound according to claim 1 of formula (α I/e):wherein R is₃Selected from ethyl, n-propyl, n-butyl, trifluoromethyl and (C)₁-C₆) Alkylthio, triFluoromethoxy, phenyl, phenoxy, (C)₁-C₆) Acylamino, aminosulfonyl, by one or two straight or branched chains on the nitrogen atom (C)₁-C₆) Alkyl-substituted aminosulfonyl.

7. A compound according to claim 1 of formula (α I/f):wherein R is₂Represents a halogen atom other than a chlorine or fluorine atom or a linear or branched (C)₂-C₆) Alkyl or straight or branched chain (C)₁-C₆) An alkylcarbonyl group.

8. A compound of formula (I), isomers and pharmaceutically acceptable acid addition salts thereof, according to claim 1, wherein R represents the group β:wherein R is₆Represents a halogen atom, a straight chain or a branched chain (C)₁-C₆) Alkyl, or methoxy.

9. A compound of formula (I) according to claim 1, wherein the compound is 2- (4-biphenyl) - Δ²-imidazoline or a pharmaceutically acceptable acid addition salt thereof.

10. A compound of formula (I) according to claim 1, wherein the compound is 2- (3-cyano-2-methylphenyl) - Δ²-imidazoline or a pharmaceutically acceptable acid addition salt thereof.

11. A compound of formula (I) according to claim 1, wherein the compound is 2- (4-phenoxyphenyl) - Δ²-imidazoline or a pharmaceutically acceptable acid addition salt thereof.

12. A compound of formula (I) according to claim 1, wherein the compound is 2- (4-ethylphenyl) - Δ²-imidazoline or a pharmaceutically acceptable acid addition salt thereof.

13. A process for preparing a compound of formula (I), the process comprising: reacting a nitrile of formula (II):

R-C≡N (II)

wherein R is as defined above, with ethylenediamine; if desired, the crude product obtained can be subjected to

-purifying according to one or more methods selected from the group consisting of: crystallizing, purifying by silica gel chromatography, extracting, filtering, and treating with active carbon or resin;

the products, in pure form or in the form of mixtures, are separated, if appropriate, into the possible isomers according to customary separation methods;

and/or the formation of acid addition salts by means of acids.

14. A pharmaceutical composition for the treatment of diseases related to imidazoline receptors, comprising a compound of formula (I) according to one of claims 1 to 12, or a pharmaceutically acceptable acid addition salt thereof, in association with one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition according to claim 14, wherein the imidazoline receptor-related disease is a central nervous system-related disease, depression, parkinson's disease, anorexia, cardiovascular disease, hypertension, diabetes, obesity, anemia, and cancer.