MX2008009456A - Use of 2-imidazoles for the treatment of cns disorders - Google Patents

Abstract

The present invention relates to the use of compounds of formula ( I ), wherein R is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, lower alkyl substituted by halogen, or is 4-(CH2)2C(O)-naphthyl;X is -S- or -NH-;aryl is an aromatic group, selected from phenyl, naphthalen-1-yl, naphthalen- 2-yl or 5,6,7,8-tetrahydronaphthalen-1-yl,;hetaryl is an aromatic group, containing at least one N or S ring atom, selected from the group consisting of thiophen-3-yl or pyrimidin-5-yl;n is 1, 2 or 3;and to their pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Description

USE OF 2-I IDAZOLS FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM DESCRIPTION OF THE INVENTION The present invention relates to the use of compounds of formula I wherein R is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, lower alkyl substituted with halogen, or is 4- (CH2) 2C (O) -naphthyl; X is -S- or -NH-; aryl is an aromatic group, selected from phenyl, naphthalene-1-yl, naphthalene-2-yl or 5,6,7,8-tetrahydronaphthalene-1-yl; hetaryl is an aromatic group, containing at least one N or S atom in the ring, selected from the group consisting of thiophen-3-yl or pyrimidin-5-yl; n is 1, 2 or 3; and its salts, racemic mixtures, enantiomers, optical isomers and pharmaceutically active tautomeric forms for the preparation of medicaments for the treatment of depression, anxiety disorders, Ref. 194760 bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, abuse of substances and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders in the consumption and assimilation of energy, disorders and defects in the homeostasis of body temperature, sleep disorders and circadian rhythm, and disorders cardiovascular The compounds described by formula I are known compounds, described for example in US 6,268, 389 or in the references mentioned below, or are included in public chemical libraries. It has been found that the compounds of formula I have a good affinity for the receptors related to the tracking amines (TAAR), especially for the TAARl. The classic biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) have an important role as neurotransmitters in the central and peripheral nervous system [1]. Its synthesis and storage, as well as its degradation and resorption after its release They are extremely regulated. It is known that an imbalance in the levels of biogenic amines is responsible for alterations in brain function in many disease states [2-5]. A second class of endogenous amine compounds, called trace amines (TA), show a significant overlap with classical biogenic amines regarding their structure, metabolism and subcellular localization. TAs include p-tyramine, β-phenylethylamine, tryptamine and octopamine, and are present in the nervous system of mammals at generally lower levels than classical biogenic amines [6]. Its dysregulation has been related to different psychiatric illnesses such as schizophrenia and depression [7], and to other conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse and eating disorders [8, 9]. For a long time, TA-specific receptors had only been hypothesized based on anatomically discrete and high-affinity binding sites of ATs in the CNS of humans and other mammals [10,11]. Accordingly, it was believed that the pharmacological effects of ATs were mediated by the well-known machinery of classical biogenic amines, by stimulating their release, inhibiting their reabsorption or by a "cross reaction" with its receptor systems [9,12,13]. This view changed significantly with the recent identification of many members of a new GPCR family, the receptors related to the tracking amines (TAAR) [7,14]. There are 9 genes of TAAR in humans (including 3 pseudogenes) and 16 genes in mice (including 1 pseudogene). TAAR genes do not contain introns (with one exception), TAAR2 contains 1 intron) and are located contiguously in the same chromosomal segment. The phylogenetic relationship of the receptor genes, according to an in-depth comparison of pharmacophore similarity of GPCRs, and pharmacological data suggest that these receptors form three different subfamilies [7,14]. TAAR1 is in the first subclass of four genes (TAAR1-4) highly conserved between humans and rodents. The TA activate the TAAR1 through Gas. Deregulation of AT has been shown to contribute to the etiology of several diseases such as depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine, eating disorders , metabolic disorders, and therefore the ligands of TAAR1 have a high potential in the treatment of these diseases. Therefore, there is a great interest in increasing knowledge about recipients related to amines of tracking. References used: 1. Deutch, A. Y. and Roth, R.H. (1999) Neurotransmitters. In Fundamental Neuroscience (2nd Ed.) (Zigmond, M.J., Bloom, F.E., Landis, S.C., Roberts, J.L, and Squire, L.R., Eds.), P. 193-234, Academic Press; 2. Wong, M.L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat. Rev. Neurosci. 2, 343-351; 3. Carlsson, A. and others (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu. Rev. Pharmacol. Toxicol 41, 237-260; 4. Tuite, P. and Riss, J. (2003) Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs 12, 1335-1352; 5. Castellanos, F.X. and Tannock, R. (2002) Neuroscience of attention-deficit / hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci. 3, 617-628; 6. Usdin, E. and Sandler, M. Eds. (1984), Trace Amines and the brain, Dekker; 7. Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends in Pharmacol. Sci. 26, 274-281; 8. Branchek, T.A. and Blackburn, T.P. (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr. Opin. Pharmacol. 3, 90-97; 9. Premont, R.T. and others (2001) Following the trace of elusive amines. Proc. Nati Acad. Sci. U. S. A. 98, 9474-9475; 10. Mousseau, D.D. and Bütterworth, R.F. (1995) A high-affinity [3H] tryptamine binding site in human brain. Prog. Brain Res. 106, 285-291; 11. McCormack, J.K. and others (1986) Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system. J. Neurosci. 6, 94-101; 12. Dyck, L.E. (1989) Relase of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor. Life Sci. 44, 1149-1156; 13. Parker, E.M. and Cubeddu, L.X. (1988) Comparative effects of amphetamine, phenylethilamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J. Pharmacol. Exp. Ther. 245, 199-210; 14. Lindemann, L. et al. (2005) Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 85, 372-385. Objects of the present invention are the use of the compounds of formula I and their salts, racemic mixtures, enantiomers, optical isomers or forms pharmaceutically acceptable tautomers for the preparation of medicaments for the treatment of diseases related to the affinity to the receptors related to the trace amines, of medicines based on a compound according to the invention and its production, as well as the use of the compounds of Formula I in the control or prevention of diseases such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease , neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders in the consumption and assimilation of energy, disorders and defects in the homeo stasis of body temperature, sleep disorders and circadian rhythm, and cardiovascular disorders. Preferred indications for the use of the compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD). As used herein, the term "lower alkyl" denotes a saturated straight or branched chain group which contains from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms. As used here, the term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above and is attached through an oxygen atom. As used herein, the term "lower alkyl substituted by a halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atom has been replaced with a halogen, for example CF3, CHF2, CH2F, CH2CF3, CH2CF2CF3 and the like. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "pharmaceutically acceptable acid addition salts" encompasses salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, acid succinic acid, tartaric acid, methansulonic acid, p-toluensulonic acid and the like. The compounds of formula I preferable according to with the use described above are those in which X is N and aryl is phenyl, for example the following compounds (4,5-dihydro-lH-imidazol-2-yl) - (2, β-dimethyl-phenyl) -amine or tautomer, (2,6-diethyl-phenyl) - (4,5-dihydro-lH-imidazol-2-yl) -amine or tautomer, (2,6-dibromo-phenyl) -imidazolidin-2-ylidene-amine or tautomer, (4, 5-dihydro-lH-imidazol-2-yl) - (2-ethyl-6-methyl-phenyl) -amine or tautomer, '(4,5-dihydro-lH-imidazol-2-yl) ) - (2-isopropyl-6-methyl-phenyl) -amine or tautomer, (5-chloro-2-methyl-phenyl) -imidazolidin-2-ylidene-amine or tautomer or 3- [4- (4,5) dihydro-lH-imidazol-2-ylamino) -phenyl] -1-naphthalen-2-yl-propan-l-one or tautomer. The most preferable compounds are those in which X is N, and aryl / hetaryl is naphtha-1-yl, 5,6,7,8-tetrahydronaphthalene-1-yl or thiophen-3-yl, for example the following compounds: imidazolidin-2-ylidene-naphthalene-1-yl-amine or tautomer, (4,5-dihydro-lH-imidazol-2-yl) - (5,6,7,8-tetrahydro-naphthalene-1-yl) - amine or tautomer or (2-chloro-4-methyl-thiophen-3-yl) - (4,5-dihydro-lH-imida-zol-2-yl) -amine or tautomer. Preferable compounds are, in addition, those in which X is S and aryl is phenyl, for example 2- (2,6-dihydro-phenylsulfane) -4,5-dihydro-1H-imidazole. The present compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods known in the art, for example, by the processes described above, which process comprises a) reacting a compound of formula with an ethylenediamine of formula H2 CH2CH2 H2 III to give a compound of formula 1-1 wherein R and n are as defined above, or b) reacting a compound of formula N NH \ I IV with a compound of formula to give a compound of formula wherein the substituents are as defined above, and if desired, converting the compounds obtained to pharmaceutically acceptable acid addition salts. All starting materials are known compounds or can be obtained by methods known in the art. The 2-aryl / hetaryl-imidazolines were obtained analogously to the procedures of the literature following the route indicated in reaction scheme 1 and reaction scheme 2. [1] Synthesis 1984, 825 [2] DE 0842065 [3] J. Heterocycl. Chem. 11, 257 (1974) Reaction Scheme 1 Synthesis of 2-arylamino-imidazolines [1] [2] The formation of the imidazoline ring was achieved by cyclization of an arylisothiocyanate (II) with ethylenediamine or an analogue thereof in an alcohol, preferably methanol or ethanol, from room temperature to reflux temperature, preferably at reflux temperature, for between 6 and 48 hours, preferably between 18 and 24 hours. The isothiocyanates were obtained from aniline (V) or derivatives thereof by reaction with phenylisothiocyanate in an inert solvent or in a pure form, preferably in a pure form, at reflux temperature. Reaction Scheme 2 Synthesis of 2-arylthio-imidazolines [3] IV then at TA HX = HCI, H 2S04 The 2-aryl / hetaryl-thio-imidazolines can be obtained following the procedure of the literature is shown in Reaction Scheme 2. The compounds mentioned in the following table can be obtained according to the description in Example 2. (4, 5-Dihydro-lH-imidazol-2-yl) - (2, 6 dimethyl-phenyl) -amine or tautomer (Example 2) a) 2-isothiocyanato-1,3-dimethyl-benzene A mixture of 4.00 g (33.0 mmoles) of 2,6-dimethylaniline and 9.80 g (72.5 mmoles) of phenylisothiocyanate was heated to reflux (oil bath 190 ° C to 200 ° C) for 6 hours. The mixture formed a solid mass upon cooling to room temperature. To this solid was added 40 ml of n-hexane and the suspension was stirred for 15 minutes, the precipitate was removed by filtration, washed with n-hexane and the filtrate was evaporated. The resulting yellow oil was purified by flash chromatography on silica gel with heptane as the eluent, and the resulting colorless oil was subjected to a Kugelrohr distillation to remove the phenyl isocyanate. The 2-isothiocyanato-1,3-dimethylbenzene was isolated as a colorless oil with e.g. 110-120 ° C / 1.2 mbar; MS (El): 163.1 (? + ·). b) (4,5-Dihydro-lH-imidazol-2-yl) - (2,6-dimethyl-phenyl) -amine or tautomer A mixture of 343 mg (806 mmol) of sodium hydroxide (crushed granules) and 0.41 ml (368 mg, 6.1 mmol) of ethylenediamine in 6 ml of ethanol was stirred at room temperature until a solution was obtained. To this solution was added dropwise a solution of 1.00 g (6.1 mmol) of 2-isothiocyanato-1,3-dimethyl-benzene in 2 ml of ethanol and the resulting mixture was heated to reflux for 20 hours. The resulting yellow solution was cooled to room temperature and acidified to pH ~ 2 by bubbling through hydrochloric acid. The suspension was filtered, the residue was washed well with ethanol and the filtrate was evaporated. The residue was dissolved in water, the pH was adjusted to between 10 and 11, and the solution was extracted with tert-butylmethyl ether. The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated. The resulting crude product was purified by flash chromatography on ca gel, the impurities were eluted with methanol followed by elution of the title compound with methanol / concentrated ammonium 95: 5. (4,5-Dihydro-lH-imidazol-2-yl) - (2,6-dimethyl-phenyl) -amine was isolated as a colorless oil which crystallized at room temperature: colorless solid, m.p. 155-157 ° C, MS (ISP): 190.4 (M + H + ").

The compounds of formula I and their pharmaceutically useful addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have a high affinity for the receptors related to the tracking amines (TAAR), especially with the TAARl. The compounds were analyzed according to the tests indicated here below. Materials and Methods Construction of TAAR expression plasmids and stably transfected cell lines For the construction of expression plasmids they amplified the coding sequences of TAAR1 from human, rat and mouse from genomic DNA, essentially as described in Lindemann et al [14]. The Expand High Fidelity PCR system (Roche Diagnostics) with 1.5 mM Mg2 + was used and the purified PCR products were cloned into the cloning vector pCR2.1-T0P0 (Invitrogen) following the manufacturer's instructions. The PCR products were subcloned into the vector pIRESneo2 (BD Clontech, Palo Alto, California), and the sequence of the expression vectors was verified before their introduction into cell lines. HEK293 cells (ATCC No. CRL-1573) were grown essentially as described in Lindemann et al. (2005). For the preparation of stably transfected cell lines HEK293 cells were transfected with pIRESneo2 expression plasmids containing the coding sequences of the TAARs (described above) with Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions, and 24 hours after the transfection the culture medium was supplemented with G418 1 mg / ml (Sigma, Buchs, Switzerland). After a culture period of around 10 days, clones were isolated, expanded and their response to the trace amines (all the compounds acquired in Sigma) was analyzed with the enzyme immunoassay system cAMP Biotrak (EIA, for its acronym in Spanish). English) (Amersham) following the EIA procedure without acetylation provided by the maker. The monoclonal cell lines that showed a stable CE5o during a culture period of 15 steps were used for subsequent studies. Obtaining membranes and joining radioligands The cells in confluence were rinsed with pH regulated saline with ice-cooled phosphate without Ca2 + or Mg2 + containing 10 mM EDTA, and were precipitated by centrifugation at 1000 rpm for 5 min. at 4 ° C. The granulate was then washed twice with saline regulated at pH with ice-cold phosphate and the cell pellet was immediately frozen by immersion in liquid nitrogen and stored until use at -80 ° C. The cell pellet was then resuspended in 20 ml of HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA, and homogenized with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 s. The homogenate was centrifuged at 48,000 * g for 30 min. at 4 ° C and the pellet was resuspended in 20 ml of HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA (pH A regulator), and homogenized with a Polytron at 10,000 rpm for 10 minutes. s. The homogenate was then centrifuged at 48,000xg for 30 min. at 4 ° C and the granulate was resuspended in 20 ml of buffer A, and homogenized with a Polytron at 10,000 rpm for 10 s. Protein concentration was determined by the Pierce method (Rockford, IL). The homogenate was then centrifuged at 48, 000 <; g for 10 min. at 4 ° C, resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl2 (10 mM) and CaCl2 g of protein per ml, and homogenized (2 mM) (buffer B) at 200- with a Polytron at 10, 000 rpm for 10 s. The binding assay was performed at 4 ° C in a final volume of 1 ml, and with an incubation time of 30 min. The [3 H] -rac-2- (1, 2, 3, 4-tetrahydro-l-naphthyl) -2-imidazoline radioligand was used at a concentration equal to the calculated Kd value of 60 nM to give a binding of about 0.1% of the total radioligand concentration added, and a specific binding representing approximately 70-80% of the total binding. The non-specific binding was defined as the amount of [3 H] -rac-2- (1, 2, 3, -tetrahydro-l-naphthyl) -2-imidazoline bound in the presence of the appropriate unlabeled ligand (10 μ?). Competitive ligands were tested in a broad spectrum of concentrations (10 pM-30 μ?). The final concentration of dimethyl sulfoxide in the assay was 2%, and this did not affect the radioligand binding. Each experiment was performed in duplicate. All incubations were completed with rapid filtration through UniFilter-96 plates (Packard Instrument Company) and GF / C glass fiber filters, pre-wetted for at least 2 h in 0.3% polyethylenimine, and using a Filtermate cell harvester 96 (Packard Instrument Company). The tubes and filters were then washed 3 times with aliquots of 1 ml of pH B cold regulator. The filters were not dried and soaked in Ultima gold (45 μl / well, Packard Instrument Company), and the bound radioactivity was counted by a TopCount microplate scintillation counter (Packard Instrument Company). Preferred compounds show a Ki (μ?) Value over mouse TAAR1 within the range of 0.026-0.500 as shown in the table below.

The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, rigid and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories, and parenterally, for example in the form of injectable solutions. The compounds of formula I can be processed with inorganic or organic carriers, pharmaceutically inert, for the production of pharmaceutical preparations. Lactose, maize starch or derivatives thereof, talc, stearic acids or their salts and the like can be used, for example, as carriers in tablets, coated tablets, dragees and rigid gelatine capsules. Suitable carriers in soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and the like. However, depending on the nature of the active substance, carriers are often not necessary in the case of soft gelatine capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, and the like. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, pH regulators, masking agents or antioxidants.

These may also contain other therapeutically valuable substances. Medicaments containing a compound of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier are also an object of the present invention, as is a process for its production, which comprises grouping one or more compounds of formula I and / or their pharmaceutically acceptable acid addition salts, and if desired, one or more other therapeutically valuable substances in a form of galenic administration, with one or more therapeutically inert carriers. The most preferable indications according to the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive disability and Alzheimer's disease. The dose can vary within wide limits, and of course, should be adjusted to the needs of the individual in each particular case. In the case of oral administration, the dose for adults may vary from between about 0.01 mg and about 1000 mg per day of a compound of general formula I or the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose can be administered as a unit dose or in divided doses and, in addition, the upper limit it can also be overcome when it is believed to be indicated. Formulation of the tablet (wet granulation) Article Ingredients mg / tablet 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline cellulose 30 30 30 150 . Magnesium stearate 1 1 1 1 Total 167 167 167 831 Preparation procedure 1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granulate at 50 ° C. 3. Pass the granulate through an appropriate spray equipment. 4. Add article 5 and mix for three minutes; Compress in a suitable press. Capsule Formulation Article Ingredients mg / capsule 5 mg 25 mg 100 mg 500 1. Compound of formula I 5 25 100 500 2. Lactose hydrated 159 123 148 - 3. Corn starch 25 35 40 70 4. Talc 10 15 10 25 . Magnesium stearate 1 2 2 5 Total 200 200 300 600 Processing procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Insert into a suitable capsule. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (2)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The use of compounds of formula I wherein R is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, lower alkyl substituted with a halogen, or is 4- (CH2) 2C (O) -naphthyl; X is -S- or -NH-; aryl is an aromatic group, selected from phenyl, naphthalene-1-yl, naphthalene-2-yl or 5,6,7,8-tetrahydronaphthalene-1-yl; hetaryl is an aromatic group, containing at least one N or S atom in the ring, selected from the group consisting of thiophen-3-yl or pyrimidin-5-yl; n is 1, 2 or 3; and its salts, racemic mixtures, enantiomers, optical isomers and pharmaceutically active tautomeric forms for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, hyperactivity disorder with attention deficit, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and disorders metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders in the consumption and assimilation of energy, disorders and defects in the homeostasis of body temperature, sleep disorders and circadian rhythm, and cardiovascular disorders. 2. The use of compounds of formula I according to claim 1, wherein X is N, and aryl is phenyl. 3. The use of compounds of formula I according to claim 2, wherein the compounds are (4,5-dihydro-lH-imidazol-2-yl) - (2,6-dimethyl-phenyl) -amine or tautomer, (2,6-diethyl-phenyl) - (4,5-dihydro-lH-imidazol-2-yl) -amine or tautomer, (2,6-dibromo-phenyl) -imidazolidin-2-ylidene-amine or tautomer, (4, 5-dihydro-lH-imidazol-2-yl) - (2-ethyl-6-methyl- phenyl) -amine or tautomer, (4,5-dihydro-lH-imidazol-2-yl) - (2-isopropyl-6-methyl-phenyl) -amine or tautomer, (5-chloro-2-methyl-phenyl) -imidazolidin-2-ylidene-amine or tautomer or 3- [4- (, 5-dihydro-lH-imidazol-2-ylamino) -phenyl] -1-naphthalen-2-yl-propan-l-one or tautomer. 4. The use of compounds of formula I according to claim 1, wherein X is N, and aryl / hetaryl is naphtha-1-yl, 5, 6, 7, 8-tetrahydronaphthalen-1-yl or thiophene 3-ilo. 5. The use of compounds of formula I according to claim 4, wherein the compounds are imidazolidin-2-ylidene-naphthalene-1-yl-amine or tautomer, (4,5-dihydro-1H-imidazole trifluoroacetate) -2-yl) - (5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -amine or tautomer or (2-chloro-4-methyl-thiophen-3-yl) - (4,5-dihydro) -lH-imida-zol-2-yl) -amine or tautomer. 6. The use of compounds of formula I according to claim 1, wherein X is S and aryl is phenyl. 7. The use of compounds of formula I according to claim 6, wherein the compound is
2. 2- (2,6-dichloro-phenylsulfanyl) -4,5-dihydro-lH-imidazole. 8. - The methods for the preparation of compounds of formula I according to claims 1-7, characterized in that the processes comprise a) reacting a compound of formula with an ethylenediamine of formula H2NCH2CH2NH2 III to give a compound of formula wherein R and n are in accordance with claim 1, or b) reacting a compound of formula with a compound of formula III to give a compound of formula wherein the substituents are in accordance with claim 1, and if desired, converting the obtained compounds to pharmaceutically acceptable acid addition salts. 9. - A medicine containing one or more compounds according to claims 1-7, characterized in that it is for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders in the consumption and assimilation of energy, disorders and defects in the homeostasis of body temperature, sleep disorders and circadian rhythm, and cardiovascular disorders. 10.- A medication in accordance with the claim 9, characterized in that it contains one or more compounds according to claims 1-7 for the treatment of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).