MX2008009463A - 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) R1is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen;R2is hydrogen, hydroxy or lower alkyl;X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N;Q is CH2, O, NH, N-alkyl or N-SO2-alkyl or N-SO2-toluen-4-yl;W is CH2or a bond are independently from one another 1, 2 or 3;when m is 2 or 3, R2may m, n be the same or not;when n is 2 or 3, R1may be the same or not;the dotted lines may each be independently from one another a bond or not;and to their pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of compounds of formula (I) for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, 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-IMIDAZOLE DERIVATIVES FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM DESCRIPTION OF THE INVENTION The present invention relates to the use of compounds of the formula I wherein R 1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N e 'Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, O, NH, N-alkyl or N-S02-alkyl or N-S02-toluene-4-yl; W is CH2 or a bond; m and n independently of each other are number 1, 2 or 3; when m is 2 or 3, R2 can be the same or not; when n is 2 or 3, R1 may be the same or not; dotted lines with independence between them can be a link or not; and its pharmaceutically active salts, mixtures Ref. 194759 racemic, enantiomers, optical isomers and tautomeric forms, for the manufacture of drugs for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, for example schizophrenia , neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, hypertension, drug abuse and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, Consumption and assimilation of energy, disorders and malfunction of homeostasis of body temperature, sleep disorders, circadian rhythm and cardiovascular disorders. Some of the compounds encompassed by formula I are known compounds, described for example in the references mentioned below or included in public domain chemical libraries. The compounds of Examples 1-14, 26-55 and 57-74 are new. It has been found that the compounds of the formula I have good affinity with the receptors associated with the tracking amines (TAAR), especially with TAAR1. Classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system [1]. Its synthesis and storage, as well as its degradation and reabsorption after release are subject to strict regulation. It is known that the imbalance in the levels of biogenic amines results in an alteration of brain function in many disease states [2-5]. A second group of endogenous amine compounds, so-called trace amines (TA), significantly overlap with the classical biogenic amines with respect to structure, metabolism and subcellular localization. TAs include p-tyramine, β-phenylethylamine, tryptamine and octopamine and are present in the nervous system of mammals usually at lower levels than those of classical biogenic amines [6]. Its dysregulation has been linked to several psychiatric disorders, such as schizophrenia and depression [7] and other pathological conditions, such as attention deficit hyperactivity disorder, migraine and headaches, Parkinson's disease, abuse of drugs and eating disorders [8,9]. For a long time it has been hypothesized that the specific receptors of the TA were based on the high affinity binding sites of the TA anatomically Discrete CNS of humans and other animals [10,11]. It was believed, therefore, that the pharmacological effects of the AT were mediated by the well-known mechanisms of action of the classical biogenic amines, by the activation of their release, by the inhibition of their reabsorption or by the "cross reaction" with their receptor systems [9,12,13]. This opinion has changed significantly when several components of the GPCR group have been identified recently., the receptors associated with the tracking amines (TAAR) [7,14]. There are 9 TAAR genes in man (including 3 pseudogenes) and 16 genes in the mouse (including 1 pseudogene). The TAAR genes do not contain introns (except for one exception, TAAR2 contains 1 intron) and are located next to one another in the same chromosomal segment. The phylogenetic relationship of the receptor genes, in accordance with a GPCR pharmacophore similarity comparison in depth and with pharmacological data suggests that these receptors form three distinct subgroups [7,14]. TAAR1 is the first subgroup of four genes (TAAR1-4) highly conserved in humans and rodents. The TA activate the TAAR1 through the Gas. It has been found that the deregulation of AT contributes to the etiology of various diseases, for example depression, psychosis, attention deficit hyperactivity disorder, drug abuse, Parkinson's disease, migraine and headache, eating disorders, metabolic disorders and therefore the TAAR1 ligands have a high potential for the treatment of these diseases. There is, therefore, a broad interest in improving the knowledge we have about the receptors associated with trace amines. References used: 1 Deutch, A. Y. and Roth, R.H .: Neurotransmitters, in: Fundamental Neuroscience (2nd ed.) (Coordinators: Zigmond, M.J., Bloom, F.E., Landis, S.C., Roberts, J.L and Squire, L.R.), pp. 193-234, 1999, Academic Press; 2 ong, M.L. and Licinio, J.: Research and treatment approaches to depression, Wat. Rev. Neurosci. 2, 343-351, 2001; 3 Carlsson, A. et al., Interactions between monoamines, glutamate and GABA in schizophrenia: new evidence; Annu. Rev. Pharmacol. Toxicol 41, 237-260, 2001; 4 Tuite, P. and Riss, J., Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs Y2, 1335-1352, 2003, 5 Castellanos, F.X. and Tannock, R., Neuroscience of attention-deficit / hyperactivity disorder: the search for endophenotypes; Nat. Rev. Neurosci. 3, 617-628, 2002; 6 Usdin, E. and Sandler, M., coordinators, Trace Amines and the brain, Dekker, 1984; 7 Lindemann, L. and Hoener, M., A renaissance in trace amines inspired by a novel GPCR family; Trends in Pharmacol. Sci. 26, 274-281, 2005; 8 Branchek, T.A. and Blackburn, T.P., Trace amine receptors as targets for novel therapeutics: legend, myth and fact; Curr. Opin. Pharmacol. 3, 90-97, 2003; 9 Premont, R.T. et al., Following the trace of elusive amines; Proc. Nati Acad. Sci. U.S. A. 98, 9474-9475, 2001; 10 Mousseau, D.D. and Butterworth, R.F., A high-affinity [3H] tryptamine binding site in human brain; Prog. Brain Res. 106, 285-291, 1995; 11 cCormack, J.K. et al., Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system; J. Neurosci. 6, 94-101, 1986; 12 Dyck, L.E., Reléase of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor; Life Sci. 4_4, 1149-1156, 1989; 13 Parker, E.M. and Cubeddu, L.X., Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding; J. Pharmacol. Exp. Ther. 245, 199-210, 1988; 14 Lindemann, L. et al., Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors; Genomics 85, 372-385, 2005. The present invention relates to the novel compounds of the formula I and the use of the compounds of the formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to affinity for the receptors associated with trace amines, the new specific compounds are encompassed by the scope of the formula I, its preparation, the medicines based on a compound according to the invention and its manufacture as well as the use of the compounds of the formula I for the control or prevention of diseases, for example depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, for example schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy , migraine, hypertension, drug abuse and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption disorders and energy assimilation, disorders and malfunction of homeostasis of body temperature, sleep disorders and circadian rhythm and cardiovascular disorders. A further object of the present invention is the use of labeled compounds of the formula I as radioligands in a binding assay for receptors associated with the tracking amines. 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). The invention relates to new compounds of the formula I wherein R 1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, 0, NH, N-alkyl or N-S02-alkyl or N-S02-toluene-yl; W is CH2 or a bond; m and n independently of each other are number 1, 2 or 3; when m is 2 or 3, R2 can be the same or not; when n is 2 or 3, R1 may be the same or not; the dotted lines, independently of each other, can be a link or not; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms, with the exception of the following compounds: rac-2- (1,2,3,4-tetrahydro-l-naphthyl) -2-imidazoline rac-2 - (7-methyl-l, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole rac-2- (6-methyl-l, 2,3,4-tetrahydro) -naphthalene-l-yl) -4,5-dihydro-lH-imidazole rac-2- (6-chloro-l, 2, 3, 4-tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH -imidazole rac-2- (5-chloro-l, 2, 3, 4-tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH-imidazole rac-2- (7-methoxy-2, 3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole rac-2- (6-methoxy-1,2,3,4-tetrahydro-naphthalene-1-yl) -4, 5-dihydro-lH-imidazole rac-2- (5-methoxy-l, 2,3,4-tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH-imidazole rac-5- (4,5) -dihydro-lH-imidazol-2-yl) -5,6,7,8-tetrahydronaphthalen-2-ol, rac-4- (1,2,3-tetrahydro-naphthalen-1-yl) -1H-imidazole rac-5- (4,5-dihydro-1H-imidazol-2-yl) -5,6,7, 8-tetrahydro-naphthalene-2,3-diol or rae-5- (, 5-dihydro-lH-imidazol-2-yl) -5,6,7,8-tetrahydro-naphthalene-1,2-diol. The new compounds of the formula I can be used as radioligands in the binding assay of the amines associated with tracking amines. As used herein, the term "lower alkyl" denotes a saturated, straight or branched chain group having 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 of 1-4 carbon atoms. As used herein, the term "lower alkoxy" denotes a group, in which the alkyl group has the meaning just defined and which is linked through an oxygen atom. As used herein, the term "lower alkyl substituted by halogen" means an alkyl group as defined above, wherein at least one hydrogen atom has been replaced by halogen, e.g. CF3, CHF2, CH2F, CH2CF3, CH2CF2CF3 and the like. The term "halogen" means chlorine, iodine, fluorine or bromine. The term "pharmaceutically acceptable acid addition salts" embraces the salts of inorganic and organic acids, for example hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, acid succinic, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. One embodiment of the invention is the use of compounds of the formula wherein R 1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen or lower alkyl substituted by halogen; Q is CH2 or O; n is 1, 2 or 3; when n is 2 or 3, R1 may be the same or not; the dotted line can be a link or not; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of the compounds of the formula IA, for the manufacture of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, for example schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease , epilepsy, migraine, hypertension, drug abuse and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption disorders and energy assimilation, disorders and malfunction of homeostasis of body temperature, sleep disorders, circadian rhythm and cardiovascular disorders. Preferred compounds of formula I according to the use described above are those, wherein X is N. Preferred compounds of this group are those, wherein Q is CH2 and R1 is halogen, for example the following compounds: 2- (5-bromo-l, 2,3, -tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH-imidazole rac-2- (7-chloro-5-fluoro-1, 2,3 , 4-tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH-imidazole rac-2- (6-chloro-l, 2,3, -tetrahydro-naphthalene-l-yl) -4, 5- dihydro-lH-imidazole or rac-2- (5-chloro-l, 2,3, 4-tetrahydro-naphthalene-l-yl) - 4, 5-dihydro-lH-imidazole. Preferred compounds of formula I according to the use described above are those, wherein Q is CH2 and R1 is lower alkyl, for example the following compounds: rac-2- (5,7-dimethyl-1,2,3, 4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole or rac-2- (5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl) -lH -imidazole Preferred compounds of formula I according to the use described above are those, wherein Q is CH2 and R1 is lower alkoxy, for example the following compounds: rac-2- (7-methoxy-l, 2.3, 4- tetrahydro-naphthalene-l-yl) -4,5-dihydro-lH-imidazole rac-2- (6-methoxy-l, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro- lH-imidazole or rac-2- (5-methoxy-l, 2,3,4-tetrahydro-naphthalen-1-yl) -, 5-dihydro-1H-imidazole. Preferred compounds of formula I according to the use described above are those, wherein Q is O or NH and R 1 is hydrogen or halogen, for example rac-2- (6,8-dichloro-chroman-4-yl) - ??? imidazole or rae-4- (lH-imidazol-2-yl) -1,2,3,4-tetrahydro-quinoline. Preferred compounds of formula I according to the use described above are those, wherein X is CH.

Preferred compounds of this group are those, in which Q is CH2 and R1 is hydrogen, for example the following compounds: (4- (3,4-dihydro-naphthalen-1-yl) -IH-imidazole or rae-4 - (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -1H-imidazole The preferred compounds of this group are those, in which Q is 0 and R 1 is hydrogen, for example the following compound: -5-chroman-4-yl-lH-imidazole, hydrochloride or tautomer Preferred compounds of this group are also those, in which Q is O and R1 is lower alkyl, for example the following compounds: rac-5- ( 7-methyl-chroman-4-yl) -IH-imidazole or tautomer or rac-5- (5-methyl-chroman-4-yl) -IH-imidazole or tautomer The preferred compounds of this group are also those, in wherein Q is O and R1 is halogen, for example the following compounds: rac-5- (6-fluoro-chroman-4-yl) -IH-imidazole or tautomer 5- (8-chloro-2H-chromen-4-) il) -IH-imidazole or tautomer 5- (6-chloro-2H-chromen-4-yl) -IH-imidazole or tautomer rac-5- (7-fluoro-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5-fluoro-chroman-4-yl) -lH-imidazole or tautomer. The new preferred compounds are the following: Compounds of the formula I, wherein X is N, Q is CH2 and R1 is halogen, for example the following compounds rac-2- (5-bromo-1, 2.3, 4 -tetrahydro-naphthalene-1-yl) -, 5-dihydro-1H-imidazole or rac-2- (7-chloro-5-fluoro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -4 , 5-dihydro-lH-imidazole. - Compounds of the formula I, wherein X is N, Q is CH2 and R is tritium, for example rac-2- (7-trithio-l, 2,3, 4-tetrahydro-naphthalen-1-yl) - 4 , 5-dihydro-lH-imidazole. - Compounds of the formula I, wherein X is N and Q is -O-, for example the following compounds rac-2-chroman-4-yl-, 5-dihydro-lH-imidazole, rac-2-chroman-4 -yl-lH-imidazole or rac-2- (6-fluoro-chroman-4-yl) -lH-imidazole. - Compounds of the formula I, wherein X is N, Q is O or NH and R1 is hydrogen or halogen, for example rac-2- (6,8-dichloro-chroman-4-yl) -lH-imidazole or rac -4- (lH-imidazol-2-yl) -1, 2, 3, 4-tetrahydro- quinoline - Compounds of the formula I, wherein X is CH, Q is CH2 and R1 is hydrogen, for example the following compound: (4- (3,4-dihydro-naphthalen-1-yl) -lH-imidazole - Compounds of the formula I, wherein X is CH, Q is 0 and R1 is hydrogen, for example the following compound: rac-5-chroman-4-yl-lH-imidazole, hydrochloride or tautomer - Compounds of the formula I, wherein X is CH, Q is O and R1 is lower alkyl, for example the following compounds: rac-5- (7-methyl-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5- methyl-chroman-4-yl) -lH-imidazole or tautomer - Compounds of the formula I, wherein X is CH, Q is O and R1 is halogen, for example the following compounds: rac-5- (6-fluoro) -chroman-4-yl) -lH-imidazole or tautomer 5- (8-chloro-2H-chromen-4-yl) -lH-imidazole or tautomer 5- (6-chloro-2H-chromen-4-yl) - lH-imidazole or tautomer rac-5- (7-fluoro-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5-fluoro-chroman-4-yl) -lH-imidazole or tautomer. present compounds of the formula I and its pharmaceutically acceptable salts are prepared by methods known in the art, for example, by processes described below, said process consists of: a) reacting a compound of the formula the ethylenediamine of the formula H2 CH2CH2 H2 III obtain a compound of the formula wherein R1, R2, Q, m and n have the meanings defined above, or b) reduce a compound of the formula by catalytic hydrogenation in the presence of Pd / C or with a hydride complex to obtain a compound of the formula where R1, R2, Q, m and n have the meanings defined before, or c) reduce a compound of the formula by catalytic hydrogenation in the presence of Pd / C or with a hydride complex to obtain a compound of the formula wherein R1, R2, Q, m and n have the meanings defined above, or deprotect a compound of the formula with formic acid get a compound from the formula wherein R1, R2, Q, m and n have the meanings defined above, or e) reacting a compound of the formula with DMSO and oxalyl chloride in dichloromethane or permanganate absorbed on silica gel in acetonitrile or with Pd / C in toluene to obtain a compound of the formula wherein R1, R2, Q, m and n have the meanings defined above, or f) reacting a compound of the formula with NaOH and hydrated hydrazine to obtain a compound of the form where R1, R2, m and n have the meanings defined above, or g) reacting a compound of the formula with HBr, acetic acid and anisole to obtain a compound of the formula wherein R1, R2, m and n have the meanings defined above, or h) reacting a compound of the formula with NaOH and hydrated hydrazine to obtain a compound of the formula where R1, R2, m and n have the meanings defined above and Q is 0 or CH2, and, if desired, converting the resulting compounds to pharmaceutically acceptable acid addition salts. The substituted bicyclic 2-imido, 2-imidazole and 4-imidazole compounds described in this application are prepared in a manner similar to the procedures of the technical literature according to the synthetic routes depicted in the reaction schemes from 1 to 6. These procedures are described in the following references: [1] J. Med. Chem. 2_9, 1413, 1986 [2] Bull. Korean Chem. Soc. 24, 1354, 2003 [3] J. Med. Chem. 3_0, 1482, 1987 [4] Chem. Pharm. Bull. 3_5, 1058, 1987 Synthesis 78, 1990 [5] J. Med. Chem. 40, 3014, 1997 [6] Tetrahedron 60, 9857, 2004 [7] Synth. Commun. 20_, 2483, 1990 [8] Org. Lett. 4_, 3051, 2002 All starting materials are commercial products, are already known compounds of the chemical literature or compounds that can be obtained according to well-known methods of organic chemistry.

PROCEDURE A Synthesis of substituted bicyclic imidazolines Reaction Scheme 1 pTsOH, toluene, t.amb SAW VII The 2-imidazolines of the formula I-1 can be obtained by reaction of a nitrile of the formula II with the ethylenediamine of the formula III. This cyclisation with a diamine can be carried out by heating a mono-p-toluenesulfonic salt of a diamine with a nitrile between 100 ° C to 250 ° C, preferably between 140 ° C and 240 ° C, for several hours, preferably 2 to 6 hours, or by heating a solution of the nitrile in an excess of ethylenediamine or a derivative thereof in the presence of a catalytically sufficient amount of sulfur, preferably 10% 50 molar molar, in a sealed tube, with microwave irradiation, at 200 ° C for a period of time of 10 to 60 minutes, preferably between 15 and 30 minutes [2], or by reaction of a previously formed complex from trimethylaluminum and ethylenediamine or a derivative thereof in toluene below room temperature, preferably between 0 ° C and 10 ° C, with a nitrile in toluene at reflux temperature for a time of 4 to 24 hours , preferably between 16 and 20 hours [3]. In the latter process the nitrile can be replaced by the corresponding lower alkyl ester. The nitriles of the formula II derived from cyclic ketones of the formula V can be obtained in a three-step process according to known methods of organic chemistry. The series of reactions begins with the addition of a synthetic equivalent of hydrogen cyanide, for example, trimethylsilyl cyanide, which results in the formation of a protected cyanohydrin on formula VI, for example, trimethylsilyl-0. This addition is carried out in the presence of a catalyst, for example zinc iodide, at room temperature with vigorous stirring for 18-48 hours. By removing trimethylsilanol in the presence of a catalytic amount of an acid, preferably p-toluenesulfonic acid, in an organic solvent of the benzene, toluene, xylene type and the like, preferably toluene, at the reflux temperature for 1-6 hours, preferably 2-3 hours, the n-unsaturated nitrile of the formula VII is obtained. By reducing the double bond of this nitrile with a complex hydride, preferably sodium borohydride, in a lower alcohol, for example methanol, ethanol, isopropanol, preferably ethanol, at reflux temperature for 0.5-2 hours, with 0.5 - 1 hour preference, the nitrile of the formula II is obtained. PROCEDURE B Synthesis of substituted bicyclic imidazoles Reaction Scheme 2a: 2-imidazoles in which Q is O, CH2, N-alkyl or N-SQ2-aryl IV 1-2 The direct introduction of the 2-imidazole group is carried out by reacting an aryl ketone V with a N-protected metallated imidazole, which is previously prepared in situ by deprotonation of an N-protected imidazole with ? am H a strong base, of the alkyl- or aryl-lithium type, preferably with n-butyl lithium, in an inert organic solvent, for example, tetrahydrofuran or diethyl ether, below room temperature, preferably at -78 ° C. The primary product that is isolated is a tertiary alcohol of the formula VIII. The 2-imidazoles, -unsaturated of the formula IV are prepared from the corresponding tertiary alcohols by elimination of acid catalyzed water. The preferred catalyst is p-toluenesulfonic acid and the reaction is carried out in a solvent capable of forming azeotropic mixtures, for example, benzene or toluene, toluene is preferred, at the reflux temperature for 1-4 hours, with preference 2 - 3 hours. The reaction is also carried out by adding the corresponding alcohols to conc. Sulfuric acid. between 0 ° C and room temperature, preferably between 0 ° C and 10 ° C, and then stirring the mixture at room temperature for 5-30 minutes, preferably 10-15 minutes. The 2-imidazoles of formula 1-2 are prepared from the corresponding α, -unsaturated 2-imidazoles of formula IV by reduction of the double bond, either by catalytic hydrogenation in the presence of Pd / C in a polar solvent, preferably a lower alcohol, either with a complex hydride, for example lithium aluminum hydride, in an aprotic solvent of the tetrahydrofuran or ether type. diethyl, at room temperature or at elevated temperature, for 2-12 hours, preferably 4-8 hours. In the case that Q is N-SO2-aryl, the reduction using lithium aluminum hydride at elevated temperature makes it possible to obtain a mixture of the corresponding products of formula 1-2, wherein Q is N-S02-aryl and Q It's NH. The formation of the last compound is favored by prolonged periods of reaction or elevated temperatures. Reaction Scheme 2b: 4-imidazoles, where Q is 0 and CH2 imidazole by reaction of an aryl ketone of the formula V with an N-protected metalated imidazole, which is previously generated in situ from a 4-iodo-imidazole, protected on N, by treatment with an organomagnesium reagent, preferably the ethyl magnesium bromide, in an inert organic solvent, preferably in a mixture of dichloromethane and tetrahydrofuran, at room temperature. The isolated primary product is a tertiary alcohol of formula IX. The 4-imidazoles a, β-unsaturated and protected on N of the formula 1-3 are prepared from the corresponding tertiary alcohols by removal of water catalyzed with an acid, in the manner already described for the 2-imidazoles. The trityl group of imidazole is also removed by applying these reaction conditions. In addition to the processes mentioned for the preparation of the α, β-unsaturated 2-imidazoles, the reaction with 30% -80% trifluoroacetic acid in water, preferably at 60%, at room temperature for 12-24 hours, preferably 14-18 hours, it also allows to obtain 4-imidazoles, β-unsaturated and detritylated of the formula 1-3. The N-deprotected 4-imidazoles of formula 1-5 which still carry a tertiary alcohol are prepared by an acid catalyzed deprotection of the corresponding N-trityl-imidazole with a 1: 1: 0.1 mixture of formic acid / THF / water. In a similar way to the 2-imidazoles, the 4-imidazoles of the formula 1-4 from the corresponding α, β-unsaturated 4-imidazoles of the formula 1-3 by reduction of the double bond either by catalytic hydrogenation in the presence of Pd / C in a polar solvent, type methanol, ethanol, propanol, isopropanol or ethyl acetate, preferably a lower alcohol of the methanol or ethanol type, either by reduction using a complex hydride, for example lithium aluminum hydride, in an aprotic solvent of the tetrahydrofuran or diethyl ether at room temperature for 2 - 12 hours, preferably for 4 - 8 hours. PROCEDURE C (Cl and C2) Dehydrogenation of imidazolines in imidazoles Reaction Scheme 3 1-1 I-2 The 2-imidazoles of the formula 1-2 can also be obtained by dehydrogenation of the corresponding 2-imidazolines. For this transformation, two procedures described in the technical literature, the Swern type oxidation and catalytic dehydrogenation. PROCEDURE D Reaction Scheme 4 The direct introduction of the 4-imidazole group can also be carried out in a manner similar to the procedure published by S. Ohta et al. . { Synthesis 78, 1990) by reaction of an aryl ketone of the formula V with a double protected metalized imidazole on N (l) and on C (2), preferably dimethylamide of 2- (tert-butyl-dimethyl-silanyl) acid ) -imidazole-1-sulfonic acid, which is deprotonated in situ with a base strong, for example an alkyl- or aryl-lithium, preferably with n-butyl-lithium, in an inert organic solvent, for example, tetrahydrofuran or diethyl ether, below room temperature, preferably at -78 ° C . The isolated primary product is a tertiary alcohol of the formula X. By heating a solution of the tertiary alcohol X in a dilute inorganic acid, preferably in 1 N-4 N HCl, boiling under reflux for 2-6 hours gives the bicyclic product a , - unsaturated of formula 1-3 which carries an unprotected 4-imidazolyl group. The 4-imidazoles of the formula 1-4 are prepared from the corresponding α, β-unsaturated 2-imidazoles of the formula 1-3 by reduction of the double bond, either by catalytic hydrogenation with hydrogen pressure of 50 to 150 bar, preferably 100 bar, in the presence of Pd / C in a polar solvent of the type methanol, ethanol, propanol, isopropanol or ethyl acetate, preferably ethyl acetate, at a temperature between room temperature and 150 ° C, with preferably at 50 ° C, for 12-24 hours, preferably 16-20 hours, either by reduction with a complex hydride, for example lithium aluminum hydride, in an aprotic solvent of the tetrahydrofuran or diethyl ether type, room temperature for 2 - 12 hours, preferably for 4 - 8 hours.

PROCEDURE E Reaction Scheme 5 Ar is totuen- -ik) The 2-imidazole compounds of the formula 1-7 are prepared, wherein W is CH2 and Q is NH, N-alkyl, N-S02-alkyl or N-S02-toluene-4-yl as represented in the Scheme of Reaction 5. The starting materials are the 1,2,3,4-tetrahydro-quinoline-4-carboxylic acid compounds of the formula XI, which can be obtained by methods already published in the technical literature, for example by reduction with nickel Raney of the corresponding quinoline-4-carboxylic acid compound, as published in Khimiya Geterotsiklicheskikh Soedinenii 77-9, 1988. The carboxylic acid compounds of the formula XI are converted into the corresponding einreb amide compounds of the formula XII by treatment with N, 0-dimethylhydroxylamine hydrochloride and an addition reagent, for example l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) in the presence of a tertiary amine-type base, for example triethylamine or N-methylmorpholine. The reaction is carried out in a halogenated organic solvent, for example dichloromethane. After obtaining the Weinreb amide compounds of the formula XII, the nitrogen atom of the 1, 2, 3, 4-tetrahydro-quinoline ring system is protected, for example in the form of the corresponding arylsulfonylamide, by treatment with an arylsulfonyl chloride in the presence of a tertiary amine base of the triethylamine type, in a halogenated organic solvent, for example dichloromethane or 1,2-dichloroethane. The reaction can be carried out at room temperature or at the reflux temperature of the solvent used. The Weinreb amide group present in the compounds of the formula XIII can be reacted with a metallated and N-protected imidazole, for example with 2- (1-diethoxymethyl-1H-imidazol-2-yl) -lithium, which is prepared previously in situ by deprotonation of the corresponding protected imidazole on N with a strong base, for example an alkyl- or aryl-lithium, preferably with n-butyl lithium, in an inert ether solvent, for example, the tetrahydrofuran or diethyl ether, below room temperature, preferably at -78 ° C. The reaction between the Weinreb amide compound of the formula XIII and the metallated and protected imidazole on N is carried out in an inert ether solvent, for example tetrahydrofuran or diethyl ether, below room temperature, preferably at a temperature between -78 ° C and 0 ° C. The primary product that is isolated is a ketone of the formula XIV. The ketone of formula XIV can then be subjected to a Wolff-Kishner reduction, obtaining a compound of formula 1-6, for example by applying the procedure described in Arch. Pharm. 322, 363-367, 1989, which involves treatment with sodium hydroxide and hydrated hydrazine in a high boiling organic solvent, for example triethylene glycol, at elevated temperature, preferably at temperatures between 110 ° C and 200 ° C. Finally, the protective group of the compound of the formula 1-6 can be eliminated, for example by reaction with an aprotic acid, such as HBr, in acetic acid and in the presence of anisole, obtaining the desired compounds of the formula 1-7.

PROCEDURE F Reaction Scheme 6 XVII I-8 Where Q s CH2 or O The starting material, a Weinreb-type amide of the formula XVI, is obtained from the corresponding carboxylic acid of the formula XV by known methods of organic chemistry (see Reaction Scheme 5). The direct introduction of the 2-imidazole group is carried out by reaction of the Weinreb type amide with a metallated and protected N-imidazole generated in situ from an N-protected imidazole with a strong base, for example an alkyl- aryl lithium, preferably n-butyl lithium, in an inert organic solvent, for example, tetrahydrofuran or diethyl ether, below room temperature, preferably at -78 ° C. The isolated primary product is a ketone of the formula XVII. By reducing this ketone by applying the already known procedures of organic chemistry, for example, a Wolff-Kishner type reduction (see Reaction Scheme 5), the final product of formula 1-8 is obtained. The corresponding 4-imidazoles are accessible through the route represented in Reaction Scheme 4, using the doubly protected imidazoles at positions 1 and 2, represented in Reaction Scheme 4. The compounds of the formula I, wherein R is tritium, can be obtained from the corresponding halogenated (chlorine, bromine or iodine), preferably a compound substituted by bromine, by catalytic hydrogenation with tritium gas. Isolation and purification of the compounds The isolation and purification of the compounds and intermediates described herein can be carried out, if desired, by any suitable separation or purification process, for example, filtration, extraction, crystallization, column chromatography, thin layer, thick layer chromatography, preparative high or low pressure liquid chromatography or a combination of these procedures. The specific illustrations of the proper separation and isolation procedures can be found with reference to the following varieties and examples. However, as is obvious, other equivalent separation or isolation methods can also be used. Racemic mixtures of Chiral compounds of the formula I can be separated by a chiral HPLC. Salts of compounds of the formula I The compounds of the formula I are basic and can be converted into the corresponding acid addition salts. The conversion is effected by treatment with at least a stoichiometric amount of an appropriate acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic acids, for example acetic acid, propionic acid, acid glycolic, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and similar. For example, the free base is dissolved in an inert organic solvent, for example diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like and the acid dissolved in a similar solvent is added. The temperature is maintained between 0 ° C and 50 ° C. The resulting salt precipitates spontaneously and can be removed from the solution with a less polar solvent. The acid addition salts of the basic compounds of the formula I can be converted to the corresponding free bases by treatment at least with a stoichiometric equivalent of a suitable base, for example sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like. The compounds of the formula I and their pharmaceutically usable acid addition salts possess valuable pharmacological properties. In particular, it has been found that the compounds of the present invention have good affinity with the receptors associated with trace amines (TAAR), especially with TAARl. The compounds are investigated with the assay described below. Materials and methods Construction of TAAR expression plasmids and stably transfected cell lines For the construction of the expression plasmids, the sequences encoding human, rat and mouse TAAR 1 are amplified starting from a genomic DNA, essentially in the same way as described by Lindemann et al. [14] The system called Expand High Fidelity PCR (Roche Diagnostics) with 1.5 mM Mg2 + is used and the purified PCR products are cloned into a cloning vector of the pCR2.1-TOPO type (Invitrogen) according to the manufacturer's instructions. The PCR products are subcloned into the vector pIRESneo2 (BD Clontech, Palo Alto, California) and the sequences of the expression vectors are verified before the introduction in cell lines. HEK293 cells (ATCC # CRL-1573) are grown essentially as described by Lindemann et al. (2005). For generation of stably transfected cell lines, HEK293 cells are transfected with the pIRESneo2 expression plasmids containing the sequences encoding the TAAR (described above) with Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions and 24 h after transfection, the culture medium is supplemented with 1 mg / ml G418 (Sigma, Buchs, Switzerland). After a culture period of about 10 d, the clones are isolated, extended and their capacity to respond to the trace amines is verified (all compounds are acquired from Sigma) with the immunoassay system called cAMP Biotrak Enzyme Immunoassay (EIA). ) (Amersham) applying the EIA non-acetylation procedure provided by the manufacturer. For the following studies monoclonal cell lines are used that present a stable EC5o during a culture period of 15 passages. Preparation of membrane and radioligand fixation The cells are rinsed in confluence with ice-cold phosphate-buffered saline, without Ca2 + or Mg2 +, which contains 10 mM EDTA and are converted to pellets by centrifugation at 4 ° C at 1000 rpm for 5 minutes. min. The granulate is then washed twice with buffered saline with phosphate and cooled with ice and the cell pellet is frozen immediately by immersion in liquid nitrogen and stored at -80 ° C until use. The cell pellet is then suspended in 20 ml of HEPES-NaOH (20 mM), pH 7.4, containing 10 mM EDTA and homogenized in a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 s. The homogenized material is centrifuged at 48,000 * g for 30 min at 4 ° C and the pellet is suspended again in 20 ml of HEPES-NaOH (20 mM), pH 7.4, containing 0.1 mM EDTA (buffer A) and homogenized in a Polytron at 10,000 rpm for 10 s. The homogenized material is then centrifuged at 4 ° C at 48,000xg for 30 min and the pellet is resuspended in 20 ml of buffer A and homogenized in a Polytron at 10,000 rpm for 10 s. The protein concentration is determined by the Pierce method (Rockford, IL). After the homogenized material is centrifuged at 4 ° C at 48,000 * g for 10 min, it is suspended again in HEPES-NaOH (20 mM), pH 7.0, which includes MgCl 2 (10 mM) and CaCl 2 g protein per mi of y ( 2 mM) (pH regulator B) at 200 homogenized in a Polytron at 10,000 rpm for 10 s. The fixation test is carried out at 4 ° C in a final volume of 1 ml and with an incubation period of 30 min. The radioligand [H3] -rac-2- (1, 2, 3, 4-tetrahydro-l-naphthyl) -2-imidazoline in a concentration equal to the calculated Kd value of 60 nM is used to obtain a fixation in about 0.1% of the total concentration of radioligand added and a specific fixation representing approximately 70-80% of the total fixation. The amount of [H3] -rac-2- (1, 2, 3, 4-tetrahydro-l-naphthyl) -2-imidazoline fixed in the presence of the appropriate unlabeled ligand (?? μ?) Is defined as non-specific binding. . The competing ligands are tested over a wide range of concentrations (10 pM - 30 μ?). The final concentration of dimethyl sulfoxide in the assay is 2% and does not affect the fixation of the radioligand. Each test is carried out in duplicate. All incubations are terminated with rapid filtration through UniFilter-96 (Packard Instrument Company) and GF / C glass fiber filter plates, preimpregnated for at least 2 h with 0.3% polyethyleneimine and using a Filtermate 96-type cell collector. Cell Harvester (Packard Instrument Company). The tubes and filters are washed 3 times with aliquots of 1 ml of cold buffer B. The filters are not dried and impregnated in Ultima gold (45 μ? / Cavity, Packard Instrument Company) and the radioactivity counts are determined using a TopCount Microplate Scintillation Counter (Packard Instrument Company). The preferred compounds have a Ki value (μ?) In mice on the TAAR1 within the range of 0.009 - 0.060 as shown in the following table.

The compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injectable solutions. The pharmaceutical compositions just mentioned can be manufactured by processing the compounds according to this invention with inorganic or organic excipients, pharmaceutically inert. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as excipients of tablets, coated tablets, dragees and hard gelatine capsules. Suitable excipients for 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 ingredient it is possible that, usually, no excipients are required in the case of soft gelatine capsules. Suitable excipients for the production of solutions and syrups are, for example, water, polyols, glycerin, vegetable oils and the like. Suitable excipients for suppositories are, for example, natural and hydrogenated oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical compositions may also contain preservatives, solubilizers, humectants, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, pH regulators, masking agents and antioxidants. They may also contain other therapeutically valuable substances. The subject of the present invention are also medicaments containing a compound of the formula I or a pharmaceutically acceptable salt thereof and a carrier Therapeutically inert, as well as a process for its manufacture, which consists of incorporating one or more compounds of the formula I and / or their pharmaceutically acceptable acid addition salts and, if desired, one or more additional therapeutically valuable substances, to a galenic administration form together with one or more therapeutically inert carriers. The most preferred indications according to the present invention are those which include disorders of the central nervous system, for example, the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD, for its acronym in English). The dosage can vary within wide limits and, obviously, should be adjusted to the individual requirements of each particular case. In the case of oral administration, the dosage for adults may vary between 0.01 mg and 1000 mg of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof per day. The daily dose can be administered in a single dose or divided into sub-doses and, in addition, the upper limit can be exceeded if considered appropriate.

Formulation of tablets (wet granulation) Elem. Ingredient mg / tablet 5mg 25mg lOOmg 500mg 1. Compound of the 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 Manufacturing procedure: 1. Mix elements 1, 2, 3 and 4 and granulate with purified water. 2. The granulate is dried at 50 ° C. 3. The granulate is passed through a suitable mill. 4. Element 5 is added and mixed for three minutes; It is compressed in an appropriate press. Formulation of capsules: Elem. Ingredient mg / capsule 5mg 25mg lOOmg 500mg 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 Manufacturing procedure: 1. The elements are mixed appropriate mixer for 30 minutes. 2. Add elements 4 and 5 and mix for 3 minutes. 3. It is packaged in suitable capsules. Experimental section The following examples illustrate the invention but they are not intended to limit its scope. PROCEDURE A Example 1 rac-2- (5-bromo-1,2,3-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole A mixture of 400 mg (1.7 mmol) of rac-5-bromo-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile and 511 mg (2.2 mmol) of the mono-p salt is heated at 150 ° C. ethylene diamine sulfonate and the liquid is stirred at this temperature for 6 hours. The reaction mixture is cooled, diluted with water and a saturated aqueous solution of potassium carbonate. The solution is extracted with ethyl acetate, the combined extracts are washed with brine, dried with Na 2 SO 4, filtered and concentrated. Purification of the crude product by flash chromatography through silica gel using as eluent a 98: 2 mixture of methanol / concentrated ammonia gives pure rac-2- (5-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole in form of colorless solid; MS (ISP) 281.0 and 279.0 ((M + H) +). Example 2 rac-2- (5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole Rac-2- (5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole is obtained from rae-5, 7-dimethyl -l, 2,3,4-tetrahydro-naphthalene-1-carbonitrile in a manner similar to that described in Example 1: colorless solid; MS (El) = 228.3 (M +). Example 3 rac-2- (7-chloro-5-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole a) rac-7-chloro-5 -fluoro-l-trimethylsilanyloxy-1,2,3,4-tetrahydro-naphthalene-l-carbonitrile To 2.00 g (11.3 mmol) of the 7-chloro-5-fluoro-3,4-dihydro-2H-naphthalen-1-one 0.11 g (0.35 mmol) are added. of zinc iodide and with vigorous stirring, 3.72 g (4.69 ml, 37.4 mmol) of trimethylsilyl cyanide are added dropwise over 15 min. The mixture is stirred at room temperature overnight and then diluted with ethyl acetate. The organic phase is washed twice with a saturated aqueous solution of sodium bicarbonate, brine, dried with Na 2 SO 4, filtered and concentrated. The crude product is filtered through a pad of silica gel using a 4: 1 mixture of heptane / ethyl acetate as eluent: rac-7-chloro-5-fluoro-l-trimethylsilanyloxy-1,2 is obtained. , 3,4-tetrahydro-naphthalene-l-carbonitrile as a slightly yellow liquid: MS (El) = 297.2 (M +), 282.2 ((M-CH3) +), 271.2 (M-CN +), 255.1 ((( M- (CH3 + HCN)) +, 100%), 207.1 ((M- (CH3) 3SiOH) +). B) 7-Chloro-5-fluoro-3,4-dihydro-naphthalene-1-carbonitrile To 4.5 ml of concentrated sulfuric acid (96%) cooled to 0 ° C is added dropwise for 5 min with vigorous stirring 1.00 g (3.4 mmol) of rac-7-chloro-5-fluoro-1-trimethylsilanyloxy-1 , 2,3, 4-tetrahydro-naphthalene-1-carbonitrile. The cooling bath is removed and the mixture is stirred for 10 min. Ice is then added and the mixture made basic by the addition of an aqueous solution concentrated sodium hydroxide. The aqueous solution is extracted with dichloromethane, the combined organic extracts are washed with brine, dried with Na 2 SO 4, filtered and concentrated. The crude product is filtered through silica gel using a 1: 1 heptane / ethyl acetate mixture as eluent: 0.63 g (90%) of 7-chloro-5-fluoro-3, -dihydro-naphthalene-1. -carbonitrile. c) rac-7-chloro-5-fluoro-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile To a solution of 300 mg (1.44 mmol) of 7-chloro-5-fluoro-3,4-dihydro-naphthalene-1-carbonitrile in 4 ml of ethanol is added 328 mg (8.67 mmol) of sodium borohydride and heated the mixture refluxed for 30 min. The reaction mixture is cooled and concentrated. The residue is partitioned between water and dichloromethane. The combined organic extracts are washed with brine, dried with a2SO4, filtered and concentrated. The crude product is purified by flash chromatography using a gradient of heptane / ethyl acetate as eluent. Rac-7-chloro-5-fluoro-1,2,3,4-tetrahydro-naphthalene-l-carbonitrile is obtained as a colorless oil: MS (El) = 209.2 (M +), 182.1 ((M-HCN ) +), 156.1 ((M-CH2 = CHCN) +), 147.2 (((M- (Cl + HCN)) +), 100%). d) rac-2- (7-chloro-5-fluoro-1, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole Rac-2- (7-chloro-5-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole is obtained from rac-7-chloro -5-fluoro-1, 2,3,4-tetrahydro-naphthalene-1-carbonitrile in a manner similar to that described in Example 1 but heating at 240 ° C for 2 hours: colorless crystalline solid; MS (ISP) = 253.1 ((M + H) +). Example 4 rac-2- (7-fluoro-1,2,3-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole a) rac-7-fluoro-1-trimethylsilanyloxy-1, 2,3,4-tetrahydro-naphthalene-1-carbonitrile Rac-7-fluoro-l-trimethylsilanyloxy-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile is obtained from 7-fluoro-3,4-dihydro-2H-naphthalene-1-one. similar mode to that described in Example 3 a): slightly yellow liquid; MS (El) = 263.2 (M +), 248.2 ((M-CH3) +), 237.2 ((M-CN) +), 221.2 (M- (CH3 + HCN)) +), 173.2 (((M- (CH3) 3SiOH) +), 100%). b) 7-fluoro-3, 4-dihydro-naphthalene-l-carbonitrile 7-Fluoro-3,4-dihydro-naphthalene-1-carbonitrile is obtained from rac-7-fluoro-l-trimethyl-silanyloxy-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile so similar to that described in Example 3 b). c) rac-7-fluoro-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile Rac-7-fluoro-1,2,3,4-tetrahydro-naphthalene-l-carbonitrile is obtained from 7-fluoro-3,4-dihydro-naphthalene-l-carbonitrile in a manner similar to that described in Example 3 c): slightly yellow liquid; MS (El) = 175.2 (M +), 148.2 (((-HCN) +), 100%), 122.1 ((M-CH2 = CHC) +). d) rac-2- (7-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole The rac-2- (7-fluoro-1, 2, 3, 4-tetrahydro- naphthalen-1-yl) -4,5-dihydro-1H-imidazole from rac-7-fluoro-1,2,3,4-tetrahydro-naphthalene-l-carbonitrile in a manner similar to that described in Example 3 d ): slightly yellow solid; MS (El) = 218.2 (M +). Example 5 rac-2- (8-methoxy-l, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole Rac-2- (8-methoxy-1,2,3-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole is obtained from rac-8-methoxy-1,2, 3,4-tetrahydro-naphthalene-l-carbonitrile in a manner similar to that described in Example 3 d): slightly yellow gum; MS (ISP) = 231.2 ((M + H) +). Example 6 rac-2- (7-bromo-1, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole a) rac-7-bromo-1-trimethylsilanyloxy-1 , 2,3,4-tetrahydro-naphthalene-l-carbonitrile Rac-7-bromo-l-trimethylsilanyloxy-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile is obtained from 7-bromo-3,4-dihydro-2H-naphthalene-1-one. similar to described in Example 3 a): colorless solid, m.p. = 45-47 ° C EM (El) = 325.1 and 323.1 (M +), 310.1 and 308.1 ((M-CH3) +), 283. and 281.0 ((M- (CH3 + HCN)) +), 235.1 and 233.1 (((M- (CH3) 3SiOH) +) 100%), 202.2 ((M- (CH3 + HCN + Br)) +). b) 7-bromo-3,4-dihydro-naphthalene-l-carbonitrile 7-Bromo-3,4-dihydro-naphthalene-1-carbonitrile is obtained from rac-7-bromo-l-trimethylsilanyloxy-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile in a similar manner to described in Example 3 b): colorless solid, mp = 113-115 ° C; R N-H1 (CDC13): 2.48-2.55 m, 2H (= CH-CH2), 2.81 t, J = 8.1 Hz, 2H (CH2-aryl), 6.94 t, J = 4.2 Hz, 1H (= CH), 7.03 d, J = 7.8 Hz, 1H, and 7.38 dd, J = 7.8 and 1.8 Hz, 1H, and 7.59 d, J = 1.8 Hz, 1H (aril-H). c) rac-7-bromo-l, 2, 3, 4-tetrahydro-naphthalene-1-carbonitrile Rac-7-bromo-l, 2, 3, 4-tetrahydro-naphthalene-1-carbonitrile is obtained from 7-bromo-3, -dihydro-naphthalene-1-carbonitrile in a similar manner to that described in Example 3 c): colorless oil; EM (El) = 236.0 and 234.9 (M +), 210. 0 and 207.9 ((-HCN) +), 129.0 (((M- (HCN + Br)) +), 100%). d) rac-2- (7-bromo-l, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole naphthalen-1-yl) -4,5-dihydro-1H-imidazole from rac-7-bromo-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile in a manner similar to that described in Example 1 but heating at 210 ° C for 2 hours: colorless solid, mp = 156-158 ° C; MS (ISP) = 281.1 and 279.0 ((M + H) +). Example 7 rac-2- (5,7-dibromo-1,2,4,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole a) rac-5, 7-dibromo-1 -trimethylsilanyloxy- 1, 2, 3, 4-tetrahydro-naphthalene-l-carbonitrile The ra c-5, 7-dibrino-1-trimethylsilanyloxy-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile is obtained from 5,7-dibromo-3,4-dihydro-2H- naphthalen-1-one in a manner similar to that described in Example 3 a): gray solid. b) 5, 7-dibromo-3,4-dihydro-naphthalene-1- carbonitrile ,7-Dibromo-3,4-dihydro-naphthalene-1-carbonitrile is obtained from rac-5,7-dibromo-1-trimethylsilanyloxy-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile in a manner similar to that described in Example 3 b): matt white solid. c) rac-5, 7-dibromo-l, 2, 3, 4-tetrahydro-naphthalene-1-carbonitrile Rac-5, 7-dibromo-l, 2, 3, 4-tetrahydro-naphthalene-l-carbonitrile is obtained from 5,7-dibromo-3,4-dihydro-naphthalene-1-carbonitrile in a similar manner to described in Example 3 c): colorless liquid. d) rac-2- (5,7-dibromo-1,2,4,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole Rac-2- (5,7-dibromo-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole is obtained from of rac-5, 7-dibromo-l, 2, 3, 4-tetrahydro-naphthalene-1-carbonitrile in a manner similar to that described in Example 1 but heating at 210 ° C for 2 hours: slightly brown solid; EM (El) = 360.0 and 358.0 (100%) and 356.0 (M +). Example 8 rac-4-methyl-2- (1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole or tautomer Rac-4-methyl-2- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole is obtained from 1,2,3,4-tetrahydro methyl-naphthalene-l-carboxylate and the trimethylaluminum complex with 1,2-diaminopropane in toluene at reflux for 1 hour in a manner similar to that described in [3]: orange gum; MS (ISP) = 215.1 ((M + H) +). PROCEDURE Cl Example 9 rac-2- (1,2,3,4-tetrahydro-naphthalen-1-yl) -1H-imidazole To a solution of 390 mg (0.354 ml, 5 mmol) dimethyl sulfoxide in 20 ml of cooled dichloromethane 78 ° C is added a solution of 634 mg (0.422 ml, 5 mmol) of oxalyl chloride in 20 ml of dichloromethane. The mixture is stirred for 30 minutes at -78 ° C and then a solution of 200 mg (2 mmoles) of rac-2- (1, 2, 3, 4-tetrahydro-l-naphthyl) -2- is added. Imidazoline in 20 ml of dichloromethane and stirring is continued at -78 ° C for 1 hour. Then 1.01 g (1.4 ml) of triethylamine is added, the reaction mixture is heated to room temperature and stirring is continued for 20 minutes. Concentrated ammonia is added and the reaction mixture is extracted with dichloromethane, the combined extracts are washed with brine, dried with Na 2 SO 4, filtered and concentrated. By purification by flash chromatography through silica gel with a gradient of heptane / ethyl acetate, 71 mg of rac-2- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -lH are prepared. -imidazole as a colorless solid: MS (El) = 198.1 (M +) - PROCEDURE C2 Example 10 rac-2- (5,7-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-yl) - lH-imidazole heat at reflux for 40 hours a mixture 57 mg (0.25 mmol) of rac-2- (5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole and 57 mg of Pd 10% on carbon in 10 ml of toluene. Then another 30 mg of 10% Pd on carbon are added and the boiling is continued at reflux for a further 24 hours. This is repeated after 8 hours and 16 hours. After a total of 88 hours at reflux temperature the reaction mixture is cooled and filtered through a pad of silica gel: 28 mg of a brown oil, which is purified by flash chromatography via gel of silica using ethyl acetate as eluent. The rac-2 - (5, 7 -dime ti 1 - 1, 2, 3, 4 - 1 et ra h idro -na phta 1 en- 1 - i 1) - 1 H- imi da zo 1 in form of colorless crystalline solid, mp = 161-163 ° C; MS (El) = 226.3 (M +). EXAMPLE 11 PROCEDURE A-chroman-4-yl-4,5-dihydro-lH-imidazole Rac-2-chroman-4-yl-4,5-dihydro-1H-imidazole is obtained from rac-chroman-4-carbonitrile in a manner similar to that described in Example 1 but heating at 210 ° C. for 2 hours: colorless solid; MS (ISP) = 202.8 ((M + H) +). PROCEDURE B Example 12 rac-2-chroman-4-yl-lH-imidazole Rae-4 - (1H-imide z ol -2-i 1) -chroman-4-ol is obtained from 4-chromanone and 2- (1-di ethoxymethyle 1 - 1 H- imide zo 1 - 2 - i 1) - 1 itio (obtained in situ from 1- (diethoxy-methyl) imidazole by treatment with butyl lithium in tetrahydrofuran at 78 ° C) according to the Ohta procedure. { Synthesis 78, 1990): colorless solid; MS (El) = 216.2 (M +), 95.1 (((0 = C-2-imidazole) +), 100%). b) 2- (2H-chromen-4-yl) -lH-imidazole The 2 - (2 H - cr ornen- 4 - i 1) - 1 H- imi da z ol is obtained from r ac- 4 - (1 H- imi da zo 1 - 2 - i 1) - corn - 4 - or 1 in a manner similar to that described in Example 3 b) but maintaining the temperature at 0 ° C: solid slightly green: MS (ISP) = 199.1 ((M + H) +). c) rac-2-chroman-4-yl-lH-imidazole a solution of 100 mg (0.50 mmol) of (2H-chromen-4-yl) -lH-imidazole in 5 ml of tet rahydrofuran was added 2.02 ml of a 1M solution of lithium aluminum hydride in tet rahydrofuran and the mixture was heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and the reaction is stopped by the slow addition of isopropanol. Water is added and the mixture is extracted with methyl ether and tert-butyl, the combined organic phases are washed with brine, dried with Na 2 SO 4, filtered and concentrated. Purification of the crude product by flash chromatography through a Si-NH 2 column using ethyl acetate gives rac-2-chroman-4-yl-lH-imidazole as a colorless solid; MS (El) = 200.1 (M +), 185.1 (((M-CH3) +), 100%). In a manner similar to that described in Example 12, the compound of the example is obtained Example 13 rac-2- (6-f luoro-chroman-4-yl) -lH-imidazole a) rac-6-fluoro-4- (lH-imidazol-2-yl) -chroman-4-ol Rac-6-fluoro-4- (lH-imidazol-2-yl) -chroman-4-ol is obtained from 6-fluoro-chroman-4-one in a manner similar to that described in Example 12 a) : colorless solid; EM (ISP) = 234.9 ((M + H) +). b) 2- (6-fluoro-2H-chromen-4-yl) -lH-imidazole 2- (6-Fluoro-2H-chromen-4-yl) -1H imidazole is obtained from rac-6-fluoro-4- (lH-imidazol-2-yl) chroman-4-ol in a similar manner to described in Example 12 b) colorless solid: MS (El) = 216.2 (M +). c) rac-2- (6-fluoro-chroman-4-yl) -lH-imidazole Rac-2- (6-fluoro-chroman-4-yl) -1H-imidazole is obtained from 2- (6-fluoro-2H-chromen-4-yl) -IH-imidazole similarly to that described in Example 12 c): colorless solid: MS (El) = 218.2 (M +), 203.2 (((M-CH3) +), 100%). Tritium-labeled compounds Synthesis of compounds marked with [H3] by dehalogenation reaction with tritium, catalysed with Pd, of previous brominated compounds with tritium gas: general procedure. A 2 ml flask, containing a solution of 25-50 moles of the previous brominated compound, 15-20 mg of 10% Pd on C and 6-10 μ? of triethylamine in 1 ml of methanol is connected to a lithium system (RC TRITEC AG, Teufen, Switzerland). The flask and its contents are degassed by a freeze-thaw cycle with vacuum and then exposed to 10-18 Ci of carrier-free tritium gas. Stirring is continued at room temperature for 2-5 h. The solution is concentrated in vacuo and all exchangeable tritium is removed by repeated lyophilization in 3 x 1 ml of methanol. The residue is dissolved in 1-2 ml of ethanol and filtered through a PTFE syringe filter (0.2 μp?) To remove the catalyst. The filter is rinsed with 4-8 ml of ethanol and the solvent is evaporated, the residue is dissolved in methanol and then purified by HPLC on a standard C-18 or C-8 column.

Example 14 rac-2- (7-trithio-1,2,4,4-tetrahydro-naphthalen-1-yl) -, 5-dihydro-1H-imidazole Rac-2- (7-trithio-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole is obtained from rac-2- (7-bromo-1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole by catalytic hydrogenation with tritium gas radiochemical purity > 98%, specific activity 32 Ci / mmoles Known compounds: Example 26 rac-2- (5-nitro-l, 2, 3, 4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole, hydrochloride Rac-2- (5-nitro-l, 2, 3, 4-tetrahydro-naphthalen-1-yl) -, 5-dihydro-1H-imidazole is obtained from 5-nitro-3, -dihydro- 2H-naphthalene-l-one in a manner similar to that described in Example 3: colorless solid; MS (ISP) = 246.1 ((M + H) +). Example 27 rac-8- (4,5-dihydro-lH-imidazol-2-yl) -5,6,7,8-tetrahydro-naphthalen-2-ylamine Rac-8- (4,5-dihydro-lH-imidazol-2-yl) -5,6,7,8 -hydro-naphthalen-2-ylamine is obtained from the 7-n-tr- 3, 4 -dihydro-2 H-na ft alen-1 -one so similar to that described in Example 3 obtaining rac-2- (7-nitro-1,2,3,4-tetrahydro-naph talen-1-yl) -4,5-dihydro-1H-imidazole which is reduced to the compound of the title by methods known in the art: colorless solid; MS (ISP) = 216.4 ((M + H) +). Example 28 2- (2H-chromen-4-yl) -lH-imidazole 2- (2H-Chromen-4-yl) -lH-imidazole is obtained from rac-4- (lH-imidazol-2-yl) -chroman-4-ol in a manner similar to that described in Example 3b ) but maintaining the temperature at 0 ° C: slightly green solid: MS (ISP) = 199.1 ((M + H) +). EXAMPLE 29 2- (6,8-dichloro-2H-chromen-4-yl) -lH-imidazole a) racj ^ 6, 8-dichloro-4- (lH-imidazol-2-yl) -chroman-4- Rac-6, 8-dichloro-4- (lH-imidazol-2-yl) -chroman-4-ol is obtained from 6,8-dichloro-chroman-4-one in a manner similar to that described in Example 12 a): colorless solid; MS (ISP) = 284.8 ((M + H) +). b) 2- (6,8-dichloro-2H-chromen-4-yl) -lH-imidazole 2- (6,8-dichloro-2H-chromen-4-yl) -1H-imidazole is obtained from rac-6, 8-dichloro-4- (lH-imidazol-2-yl) -chroman-4 -ol in a manner similar to that described in Example 3 b) but maintaining the temperature at 0 ° C: colorless solid: MS (El) = 266.1 ((M +), 100%). EXAMPLE 30 2- (8-chloro-2H-chromen-4-yl) -lH-imidazole a) rac-8-chloro-4- (lH-imidazol-2-yl) -chroman-4-ol Rac-8-chloro-4- (lH-imidazol-2-yl) -chroman-4-ol is obtained from 8-chloro-chroman-4-one in a manner similar to that described in Example 12 a) : colorless solid; MS (ISP) = 250.9 (((M + H) +), 100%). b) 2- (8-chloro-2H-chromen-4-yl) -lH-imidazole 2- (8-chloro-2H-chromen-4-yl) -1H imidazole is obtained from rac-8-chloro-4- (lH-imidazol-2-yl) chroman-4-ol in a manner similar to that described in Example 3b) but maintaining the temperature at 0 ° C: matt white solid: MS (El) = 232.1 ((M +), 100%). Example 31 2- (6-chloro-2H-chromen-4-yl) -lH-imidazole a) rac-6-chloro-4- (lH-imidazol-2-yl) -chroman-4-ol Rac-6-chloro-4- (lH-imidazol-2-yl) -chroman-4-ol is obtained from 6-chloro-chroman-4-one in a manner similar to that described in Example 12 a) : matt white solid; MS (ISP) = 250.9 (((M + H) +), 100%). b) 2- (6-chloro-2H-chromen-4-yl) -lH-imidazole 2- (6-chloro-2H-chromen-4-yl) -1H-imidazole is obtained from rac-6-chloro-4- (lH-imidazol-2-yl) -chroman-4-ol so similar to that described in Example 3 b) but maintaining the temperature at 0 ° C: slightly brown solid: MS (El) = 232.1 ((M +), 100%). Example 32 rac-2- (8-chloro-chroman-4-yl) -lH-imidazole Rac-2- (8-chloro-chroman-4-yl) -1H-imidazole is obtained from 2- (8-chloro-2H-chromen-4-yl) -IH-imidazole in a manner similar to that described in Example 12 c): colorless solid: MS (El) = 234.2 (M +), 219.1 (((M-CH3) +), 100%). Example 33 rac-2- (6-chloro-chroman-4-yl) -IH-imidazole The rac-2- (6-chloro-chroman-4-yl) -1H-imidazole is obtained from 2- (6-chloro-2H-chromen-4-yl) -IH-imidazole in a manner similar to that described in Example 12 c): colorless solid: MS (ISP) = 235.1 (((M + H) +), 100%). Example 34 rac-2- (6-methoxy-chroman-4-yl) -IH-imidazole a) rac-4- (lH-imidazol-2-yl) -6-methoxy-chroman-4-ol Rac-4- (lH-imidazol-2-yl) -6-methoxy-chroman-4-ol is obtained from 6-methoxy-chroman-4-one in a manner similar to that described in Example 12 a) : matt white solid; (ISP) = 247.0 ((M + H) b) 2- (6-methoxy-2H-chromen-4-yl) -IH-imidazole 2- (6-methoxy-2H-chromen-4-yl) -1H-imidazole is obtained from rac-6-fluoro-4- (lH-imidazol-2-yl) -chroman-4-ol so similar to that described in Example 12 b): matt white solid: MS (El) = 228.2 ((M +), 100%), 213.1 ((M-CH3) +). c) rac-2- (6-methoxy-chroman-4-yl) -lH-imidazole The rac-2- (6-methoxy-chroman-4-yl) -1H-imidazole is obtained from 2- (6-methoxy-2H-chromen-4-yl) -lH-imidazole in a manner similar to that described in Example 12 c): matt white solid: MS (El) = 230.2 ((M +), 100%), 215.2 ((M-CH3) +). Example 35 rac-2- (8-methoxy-chroman-4-yl) -lH-imidazole a) rac-4- (lH-imidazol-2-yl) -8-methoxy-chroman-4-ol The rac-4- (lH-imidazol-2-yl) -8-methoxy-chroman-4-ol is obtained from 8-methoxy-chroman-4-one in a manner similar to that described in Example 12 a) : colorless solid; MS (El) = 246.2 (M +), 228.2 ((M-H20) +), 95.2 (((C (= 0) -2-imidazolyl) +), 100%). b) 2- (8-methoxy-2H-chromen-4-yl) -lH-imidazole 2- (8-methoxy-2H-chromen-4-yl) -1H-imidazole is obtained from rac-4- (lH-imidazol-2-yl) -8-methoxy-chroman-4-ol so similar to that described in Example 12 b): matt white solid: E (El) = 228.1 ((M +), 100%). c) rac-2- (8-methoxy-chroman-4-yl) -lH-imidazole Rac-2- (8-methoxy-chroman-4-yl) -1H-imidazole is obtained from 2- (8-methoxy-2H-chromen-4-yl) -lH-imidazole in a manner similar to that described in Example 12 c): colorless solid: MS (ISP) = 231.1 ((M + H) +). Example 36 rac-2- (6,8-dichloro-chroman-4-yl) -lH-imidazole Rac-2- (6,8-dichloro-chroman-4-yl) -1H-imidazole is obtained from 2- (6,8-dichloro-2H-chromen-4-yl) -1H-imidazole so similar to that described in Example 3 b) but the temperature is maintained at room temperature for 2 hours hours: colorless solid: MS (El) = 268.1 (M +), 253.1 (((M-CH3) +), 100%). Example 37 rac-2- (7-methyl-chroman-4-yl) -lH-imidazole a) rac-4- (lH-imidazol-2-yl) -7-methyl-chroman-4-ol Rac-4- (lH-imidazol-2-yl) -7-methyl-chroman-4-ol is obtained from 7-methyl-chroman-4-one in a manner similar to that described in Example 12 a) : colorless solid; MS (El) = 230.2 (M +), 212.2 ((M-H20) +), 183.2 ((M- (H20 + H + CO)) +), 95.2 (((C (= 0) -2-imidazolyl) +), 100%). b) 2- (7-methyl-2H-chromen-4-yl) -lH-imidazole 2- (7-methyl-2H-chromen-4-yl) -1H imidazole is obtained from rac-4- (lH-imidazol-2-yl) -7-methyl chroman-4-ol in a similar manner to described in Example 12 b) slightly yellow solid: MS (El) = 212.2 ((M +), 100%). c) rac-2- (7-methyl-chroman-4-yl) -lH-imidazole Rac-2- (7-methyl-chroman-4-yl) -1H-imidazole is obtained from 2- (7-methyl-2H-chromen-4-yl) -lH-imidazole in a manner similar to that described in Example 3 b) but the temperature is maintained at room temperature for 18 hours: colorless solid: MS (El) = 214.2 (M +), 199.2 (((M-CH3) +), 100%). Example 38 2- (5-methyl-2H-chromen-4-yl) -lH-imidazole a) rac-4- (lH-imidazol-2-yl) -5-methyl-chroman-4-ol Rac-4- (lH-imidazol-2-yl) -5-methyl-chroman-4-ol is obtained from 5-methyl-chroman-4-one in a manner similar to that described in Example 12 a) : colorless solid; MS (El) = 230.2 ((M +), 100%), 95.2 ((C (= 0) -2-imidazolyl) +). b) 2- (5-methyl-2H-chromen-4-yl) -lH-imidazole 2- (5-methyl-2H-chromen-4-yl) -1H-imidazole is obtained by heating a solution of rac-4- (1H-imidazol-2-yl) -5-methyl-chroman-4- ol in 4N aqueous HC1 for 16 hours. The reaction mixture is cooled to room temperature, the pH is adjusted to 10 by addition of ammonia and extract with methyl ether and tert-butyl. The organic phases are collected, washed with brine, dried with Na2SC > 4, filtered and concentrated: colorless solid: E (ISP) = 213.1 ((+ H) +). Example 39 rac-2- (7-fluoro-chroman-4-yl) -lH-imidazole Rac-2- (7-fluoro-chroman-4-yl) -1H-imidazole is obtained from 7-fluoro-chroman-4-one in a manner similar to that described in Example 13: colorless solid; MS (El) 218.1 (M +), 203.1 (((M-CH 3) +), 100%). Example 40 rac-4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1,2,3,4-tetrahydro-quinoline a) 1-phenyl-azetidin-2-one 1-phenyl-azetidin-2-one is obtained from azetidin-2-one and iodobenzene by treatment with trans-1,2- diaminocyclohexane, copper (I) iodide and potassium carbonate according to the procedure described in J. Am. Chem. Soc. 123, 7727-7729, 2001; matt white crystalline solid; MS (ISP) = 148.4 ([M + H] +, 100%). 2,3-Dihydro-4 (1H) -quinolinone is obtained from 1-phenyl-azetidin-2-one by treatment with trifluoromethanesulfonic acid in 1,2-dichloroethane according to the procedure described in Tetrahedron 5_8, 8475- 8481, 2002; yellow oil; MS (ISP) = 148.3 ([M + H] +, 100%). c) 1- (toluene-4-sulfonyl) -2, 3-dihydro-lH-quinolin-4 -one To a solution of 2.57 g (17.5 mmol) of the 2,3-dihydro-4 (1H) -quinolinone in 20 ml of dichloromethane are added dropwise at 0 ° C 9.09 ml (65.6 mmoles) of triethylamine. Then 5.25 g (27.5 mmol) of p-toluenesulfonyl chloride is added and the reaction mixture is heated under reflux for 16 hours. The mixture is cooled to room temperature, diluted with dichloromethane and washed successively with 1 M aqueous hydrochloric acid, an aqueous solution. saturated sodium bicarbonate and a saturated solution brine. The phases are separated and the organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate / heptane) to obtain 1.55 g (29%) of the title compound as a white crystalline solid. MS (ISP) = 302.4 ([M + H] +, 100%). d) rac-4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1,2,3, 4-tetrahydro-quinolin-4-ol The rac-4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1, 2, 3, 4-tetrahydro-quinolin-4-ol is obtained from the 1- (toluene- 4-sulfonyl) -2,3-dihydro-1H-quinolin-4-one and 2- (1-diethoxymethyl-1H-imidazol-2-yl) -lithium in a manner similar to that described in Example 12 a) matt white foam; MS (ISP) = 370.1 ([M + H] +, 100%). e) 4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1,2-dihydro-quinoline 4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1,2-dihydro-quinoline is obtained from rac-4- (1H-imidazol-2-yl) -1 - (toluene-4-sulfonyl) -1,2,3,4-tetrahydro-quinolin-4-ol and sulfuric acid in ethanol at 0-20 ° C in a manner similar to that described in Example 12 b): white crystalline solid : MS (ISP) = 352.3 ([M + H] +, 100%). f) rac-4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1, 2, 3, 4-tetrahydro-quinoline Rac-4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1, 2, 3, 4-tetrahydro-quinoline is obtained from 4- (lH-imidazole-2) -yl) -1- (toluene-4-sulfonyl) -1,2-dihydro-quinoline and lithium aluminum hydride in refluxing tetrahydrofuran in a manner similar to that described in Example 12 c): matt white foam; MS (ISP) = 354.3 ([M + H] +, 100%). Example 41 rac-4- (lH-imidazol-2-yl) -1,2,3, 4-tetrahydro-quinoline The rac-4- (lH-imidazol-2-yl) -1, 2, 3, - is obtained tetrahydroquinoline as a by-product of the preparation of rac-4- (lH-imidazol-2-yl) -1- (toluene-4-sulfonyl) -1,2,3,4-tetrahydro-quinoline in the manner described in Example 40f): amorphous matt white solid; E (ISP) = 200.4 ([M + H] +, 100%). Example 42 rac-2- (5-methyl-chroman-4-yl) -lH-imidazole Rac-2- (5-methyl-chroman-4-yl) -1H-imidazole is obtained from 2- (5-methyl-2H-chromen-4-yl) -lH-imidazole by hydrogenation at 100 bar using as catalyst the 10% Pd on C in ethyl acetate at 50 ° C for 18 hours. After the usual separation, the residue is purified by flash chromatography on silica gel using a gradient of 5% -30% ethyl acetate in methanol as a eluent: colorless solid; MS (ISP) = 215.2 ((M + H) +). Example 43 rac-2- (5-fluoro-chroman-4-yl) -lH-imidazole Rac-2- (5-fluoro-chroman-4-yl) -1H-imidazole is obtained from 5-fluoro-chroman-4-one in a similar manner to that described in Example 13: colorless solid; MS (ISP) = 219.1 ((M + H) +). Example 44 Rae-4- (lH-imidazol-2-yl) -1-methyl-l, 2,3,4-tetrahydro-quinoline a) l-methyl-2, 3-dihydro-lH-quinolin-4-one This compound is obtained according to the procedure described in J. Med. Chem. 46, 1962-1979, 2003. To a solution of 220 mg (1.49 mmol) of the 2,3-dihydro-4 (1H) -quinolinone in 3 of acetone in a pressure tube is added 620 mg (4.48 mmol) of potassium carbonate. Then 0.38 ml (5.98 mmoles) of iodomethane are added dropwise, the tube is sealed, and the reaction mixture is heated at 80 ° C for 16 hours. The mixture is cooled to room temperature, diluted with ethyl acetate and washed with a saturated solution of brine. The phases are separated, the organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate / heptane), obtaining 147 mg (61%) of the compound of the title in the form of slightly yellow oil. MS = 162.1 ([M + H] +, 100%). b) rac-4- (lH-imidazol-2-yl) -1-methyl-l, 2, 3, 4-tetrahydro-quinolin-4-ol The ra c- 4 - (1 H- imi da zo 1 - 2 - i 1) - 1 -me ti 1 - 1, 2, 3, 4 - 1 etr ahidro-qui nol in- 4 -ol from of l-methyl-2, 3-di hi dr o- 1 H- qu i no 1 in-4 -one and 2- (l-diethoxymethyl-lH-imidazol-2-yl) -lithium in a manner similar to that described in Example 12 a): matt white crystalline solid; MS (ISP) = 230.4 ([M + H] +, 54%), 212.1 ([M + H-H20] +, 100%). c) 4- (lH-imidazol-2-yl) -1-methyl-1,2-dihydroquinoline 4- (lH-imidazol-2-yl) -1-methyl-l, 2-dihydro-quinoline is obtained from rac-4- (lH-imidazol-2-yl) -1-methyl-1, 2 , 3,4-tetrahydro-quinolin-4-ol and sulfuric acid in ethanol at 50 ° C in a manner similar to that described in Example 12 b): crystalline orange solid: MS (ISP) = 212.3 ([M + H] + , 100%). d) rae- - (lH-imidazol-2-yl) -1-methyl-1,2,4-tetrahydro-quinoline Rac-4- (lH-imidazol-2-yl) -1-methyl-1,2,3,4-tetrahydro-quinoline is obtained from 4- (lH-imidazol-2-yl) -1- methyl-1, 2-dihydro-quinoline and lithium aluminum hydride in refluxing tetrahydrofuran in a manner similar to that described in Example 12 c): white-colored crystalline solid; MS (ISP) = 214.1 ([M + H] +, 100%). Example 45 2- (3-methyl-2H-chromen-4-yl) -lH-imidazole a) rac-4- (lH-imidazol-2-yl) -3-methyl-chroman-4-ol You get e - (1H-imidazol-2-yl) -3-methyl-chroman-4-ol from 3-methyl-chroman-4-one in a manner similar to that described in Example 12 a): colorless solid; EM (ISP) = 231.1 ((M + H) +). b) 2- (3-methyl-2H-chromen-4-yl) -lH-imidazole 2- (3-methyl-2H-chromen-4-yl) -1H-imidazole is obtained from rac-4- (lH-imidazol-2-yl) -3-methyl-chroman-4-ol so similar to that described in Example 38 b): slightly brown solid; MS (ISP) = 213.0 ((M + H) +). Example 46 2- (2, 2-dimethyl-2H-chromen-4-yl) -lH-imidazole 2- (2,2-Dimethyl-2H-chromen-4-yl) -1H-imidazole is obtained from 2,2-dimethyl-chroman-4-one in a manner similar to that described in Example 38: solid yellow; MS (ISP) = 227.0 ((M + H) +). Example 47 rac-2- (2,2-dimethyl-chroman-4-yl) -lH-imidazole The ra c- 2 - (2, 2 -dime ti 1 -crornan-4-yl) -lH-imidazole is obtained from 2 - (2, 2 -dime ti 1 - 2 H -crornen- 4 -i 1 ) - 1 H - imidazole in a manner similar to that described in Example 42: colorless solid; MS (ISP) = 229.2 ((M + H) +).

Example 48 rac-2- (2-methyl-2H-chromen-4-yl) -lH-imidazole Rac-2- (2-methyl-2H-chromen-4-yl) -1H-imidazole is obtained from rac-2-methyl-chroman-4-one in a manner similar to that described in Example 38: solid slightly brown; MS (ISP) = 213.0 ((M + H) +). Example 49 (3R, 4S or 3S, 4R) -2- (3-methyl-chroman-4-yl) -lH-imidazole (3R, 4S or 3S, 4R) -2- (3-methyl-chroman-4-yl) -lH-imidazole is obtained by chromatographic separation of a mixture of diastereomers of rac-2- (3-methyl-chroman- 4-yl) -1H-imidazole (example 53) on a Chiralpak AD column using as eluent a 93: 7 mixture of heptane / ethanol: colorless solid; MS (ISP) = 215.1 ((M + H) +). Example 50 rac-2- (2-methyl-chroman-4-yl) -lH-imidazole Rac-2- (2-methyl-chroman-4-yl) -1H-imidazole is obtained from rac-2- (2-methyl-2H-chromen-4-yl) -1H-imidazole in a similar manner to described in Example 42: slightly green solid; MS (ISP) = 215.1 ((M + H) +). Example 51 (2R, 4S or 2S, 4R) -2- (2-methyl-chroman-4-yl) -lH-imidazole Chiral The (2R, 4S or 2S, 4R) -2- (2-methyl-chroman-4-yl) -lH-imidazole is obtained from rac-2- (2-methyl-chroman-4-yl) -1H -imidazole in a manner similar to that described in Example 49: colorless solid; MS (ISP) = 215.1 ((M + H) +). Example 52 (2S, 4R or 2R, 4S) -2- (2-methyl-chroman-4-yl) -lH-imidazole Chiral The (2S, 4R or 2R, 4S) -2- (2-methyl-chroman-4-yl) -lH-imidazole is obtained from rac-2- (2-methyl-chroman-4-yl) -1H -imidazole in a manner similar to that described in Example 49: colorless solid; MS (ISP) = 215.1 ((M + H) +).

Example 53 rac-2- (3-methyl-chroman-4-yl) -lH-imidazole Rac-2- (3-methyl-chroman-4-yl) -1H-imidazole is obtained from rac-4 - (lH-imidazol-2-yl) -3-methyl-chroman-4-ol by reduction with lithium in liquid ammonia for 30 min. The reaction of the blue mixture is stopped by the addition of solid ammonium chloride, the ammonia is evaporated and the residue is partitioned between water and methyl ether and t-butyl. The organic phase is washed with brine, dried with sodium sulfate, filtered and concentrated. Rac-2- (3-methyl-chroman-4-yl) -lH-imidazole is obtained as a colorless solid; MS (ISP) = 215.1 ((M + H) +). Example 54 (3S, 4S and 3R, 4R) -2- (3-methyl-chroman-4-yl) -lH-imidazole The racemic mixture of (3S, 4S and 3R, 4R) -2- (3-methyl-chroman-4-yl) -lH-imidazole (together with the two separated cis isomers) is obtained from rac-2- ( 3-methyl-chroman-4-yl) -1H-imidazole in a manner similar to that described in Example 49: colorless solid; MS (ISP) = 215.1 ((M + H) +).

Example 55 (4- (3,4-dihydro-naphthalen-1-yl) -lH-imidazole a) 1- (1-trityl-1H-imidazol-4-yl) -1, 2, 3, 4 tetrahydro-naphthalene -LOL The 1 - (1 - 1 riti 1 - 1 H - imide zo 1 - 4 - i 1) -1, 2, 3, 4 - 1 etr ah i dr o - na phta 1 en - 1 - or 1 a is obtained from 4-iodo-1-trityl-1H-imidazole and 1-fa-1-one-1a according to the procedure described by X. Zhang et al., J. Med. Chem. 4_0, 3014, 1997: colorless solid; E (ISP) = 457.5 ((M + H) +). b) (4- (3,4-dihydro-naphthalen-1-yl) -lH-imidazole 4 - (3, 4-di-hi-dr-na-1-en-1-y1) -lH-imidazole is obtained by reaction of 1 - (1 - 1 riti 1 - 1 H - imide zo 1 - 4 - i 1) - 1, 2, 3, 4 - 1 etr ah i d -na phta 1 en- 1 - or 1 with a solution of trifluoric acid 1 to 6 or 4 in water according to the procedure described by X. Zhang et al., J. Med. Chem. ^ 0_, 3014, 1997: colorless solid; MS (ISP) = 197.3 ((M + H) +).

Example 56 rac-4- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -1H-imidazole Rac-4- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -lH-imidazole is obtained from 4- (3,4-dihydro-naphthalen-1-yl) -lH-imidazole in a manner similar to that described in Example 42 but maintaining the hydrogen pressure at 3.5 bar and effecting the reaction at room temperature for 5 hours: colorless solid; E (El) = 198.2 ((M +), 100%). Example 57 (4- (3,4-dihydro-naphthalen-1-yl) -lH-imidazole a) dimethylamide of 2- (tert-butyl-dimethyl-silanyl) -4- (1-hydroxy-2, 3,4-tetrahydro-naphthalen-1-yl) -imidazole-1-sulfonic acid The dimethylamide of 2- (tert-butyl-dimethyl-silanyl) -4- (1-hydroxy-l, 2,3,4-tetrahydro-naphthalen-1-yl) -imidazole-1-sulfonic acid is obtained from dimethylamide of 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid and chroman-4-one in a manner similar to the procedure published by S. Ohta et al., Synthesis 78, 1990: slightly brown viscous oil; MS (ISP) = 438.5 ((M + H) +). b) 5- (2H-chromen-4-yl) -lH-imidazole or tautomer - (2H-Chromen-4-yl) -lH-imidazole is obtained from dimethylamide of 2- (tert-butyl-dimethyl-silanyl) -4- (1-hydroxy-l, 2,3, 4-tetrahydro-naphthalene-1-y1) -imidazole-1-sulfonic acid in a similar manner to that described in Example 38 b) but at reflux in a 2N aqueous solution of HC1 for 2 hours: colorless solid; MS (El) = 198.2 ((M +), 100%). Example 58 5- (6-fluoro-2H-chromen-4-yl) -lH-imidazole or tautomer The 5 - (6 - f 1 uo r o - 2 H - crornen - 4 - i 1) - 1 H imidazole is obtained from the dimethylamide of 2- (tert-butyl-dimethyl-silanyl) -imidazole- l-sulphonic acid and 6-f 1 or ro-ornan-4 -one in a manner similar to that described in Example 57: matt white solid; MS (El) = 216.1 ((M +), 100%).

Example 59 5- (7-methyl-2H-chromen-4-yl) -lH-imidazole or tautomer - (7-Methyl-2H-chromen-4-yl) -1H-imidazole is obtained from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 7-methyl -chroman-4-one in a manner similar to that described in Example 57: slightly brown solid; MS (El) = 212.2 ((M +), 100%). Example 60 rac-5- (7-methyl-chroman-4-yl) -lH-imidazole or tautomer Rac-5- (7-methyl-chroman-4-yl) -1H-imidazole is obtained from 5- (7-methyl-2H-chromen-4-yl) -lH-imidazole in a manner similar to that described in Example 42: colorless solid; MS (El) = 214.2 ((M +), 100%). Example 61 5- (5-fluoro-2H-chromen-4-yl) -lH-imidazole or tautomer The 5- (5-fluoro-2H-chromen-4-yl) -1H- is obtained imidazole from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 5-fluoro-chroman-4-one in a manner similar to that described in Example 57: colorless solid; MS (El) = 216.2 ((M +), 100%). Example 62 Rae-5- (6-fluoro-chroman-4-yl) -1H-imidazole or tautomer Rac-5- (6-fluoro-chroman-4-yl) -1H-imidazole is obtained from 5- (6-fluoro-2H-chromen-4-yl) -lH-imidazole in a manner similar to that described in Example 12 c): colorless solid; MS (El) = 218.2 ((M +), 100%). Example 63 5- (8-Chloro-2H-chromen-4-yl) - ?? - imidazole or tautomer - (8-chloro-2H-chromen-4-yl) -1H-imidazole is obtained from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 8-chloro -chroman-4-one in a manner similar to that described in Example 57: matt white solid; MS (El) = 232.1 ((M +), 100%).

Example 64 5- (6-chloro-2H-chromen-4-yl) -lH-imidazole or tautomer - (6-chloro-2H-chromen-4-yl) -1H-imidazole is obtained from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 6-chloro -chroman-4-one in a manner similar to that described in Example 57: matt white solid; MS (El) = 232.1 ((M +), 100%). Example 65 rac-5- (7-fluoro-chroman-4-yl) - ?? - imidazole or tautomer Rac-5- (7-fluoro-chroman-4-yl) -1H-imidazole is obtained from 5- (7-fluoro-2H-chromen-4-yl) -IH-imidazole in a manner similar to that described in Example 42: colorless solid; MS (ISP) = 219.1 (, (M + H) +). Example 66 rac-5- (5-methyl-chroman-4-yl) -α-imidazole or tautomer a) 5- (5-methyl-2H-chromen-4-yl) -lH-imidazole tautomer - (5-Methyl-2H-chromen-4-yl) -1H-imidazole is obtained from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 5-methyl -chroman-4-one in a manner similar to that described in Example 57: colorless solid .; MS (El) = 212.2 ((M +), 100%). b) rac-5- (5-methyl-chroman-4-yl) -lH-imidazole or tautomer Rac-5- (5-methyl-chroman-4-yl) -1H-imidazole is obtained from 5- (5-methyl-2H-chromen-4-yl) -lH-imidazole in a manner similar to that described in Example 42: colorless solid; MS (ISP) = 215.2 ((M + H) +). Example 67 rac-5- (5-fluoro-chroman-4-yl) -lH-imidazole or tautomer The rac-5 - (5-f-1-one or -r-4-i-1) -lH-imidazole is obtained from 5 - (5-f-1 or-2 H- cr ornen-4-i 1 ) -lH-imidazole in a manner similar to that described in Example 42: colorless solid; MS (ISP) = 219.1 ((M + H) +).

Example 68 5- (7-Fluoro-2 H -chromen-4-yl) -lH-imidazole or tautomer - (7-Fluoro-2H-chromen-4-yl) -1H-imidazole is obtained from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 7-fluoro -chroman-4-one in a manner similar to that described in Example 57: slightly brown solid; MS (ISP) = 217.1 ((M + H) +). Example 69 rac-5-chroman-4-yl-lH-imidazole, hydrochloride or tautomer Rac-5-chroman-4-yl-lH-imidazole is obtained from 5- (2H-chromen-4-yl) -α-imidazole in a similar manner to that described in Example 12 c). The compound is isolated as the hydrochloride: matt white solid; MS (ISP) = 201.1 ((M + H) +). Example 70 5- (3-methyl-2H-chromen-4-yl) -lH-imidazole or tautomer The 5- (3-methyl-2H-chromen-4-yl) -1H- is obtained imidazole from 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide and 3-methyl-chroman-4-one in a manner similar to that described in Example 57: slightly brown solid; MS (ISP) = 213.0 ((M + H) +). Example 71 rac-1- (1H-imidazol-4-yl) -1,2,3,4-tetrahydro-naphthalene-1-ol or tautomer Rac-1- (1H-imidazol-4-yl) -1,2,3,4-tetrahydro-naphthalene-1-ol is obtained from rac-1- (1-trityl-1H-imidazole-4-) il) -1, 2, 3, 4-tetrahydro-naphthalene-l-ol (example 55 a)) by deprotection with formic acid / tetrahydrofuran / water 1: 1: 0.1 in a manner similar to the procedure described by A. Ojima et al. ., Org. Lett. 4, 3051, 2002: colorless solid; MS (ISP) = 215.3 ((M + H) +). Example 72 rac-2-chroman-4-ylmethyl-1H-imidazole a) methoxy-methyl-amide of rac-chroman-4-carboxylic acid To a solution of 500 mg (2.8 mmol) of acid Chroman-4-carboxylic acid in 10 ml of dichloromethane is added 330 mg (3.2 mmoles) of N, 0-dimethylhydroxylamine hydrochloride and 993 mg (3.2 mmoles) of N- (3-dimethylaminopropyl) -N '- hydrochloride. ethyl carbodiimide and the mixture is stirred at room temperature for 5 min. Then 710 mg (0.98 ml, 10 mmol) of triethylamine are added dropwise and the resulting mixture is stirred at room temperature for 4 hours. For separation, a 2M solution of HC1 is added, the organic solvent is evaporated and the residue is extracted with methyl ether and tert-butyl. The combined organic phases are washed with brine, dried over Na 2 SO 4, filtered and concentrated: 503 mg of the rac-chroman-4-carboxylic acid methoxy-methyl-amide are prepared as a slightly brown oil; MS (El) = 221.2 (M +), 133.1 (((M -C (= 0) N (CH3) OCH3) +), 100%). b) rac-chroman-4-yl- (lH-imidazol-2-yl) -metanone The rac-chroman-4-yl- (lH-imidazol-2-yl) -methanone is obtained from the methoxy-methyl-amide of rac-chroman-4-carboxylic acid in a manner similar to that described in Example 12 a ): colorless gum; MS (ISP) = 228.9 ((M + H) +). c) rac-2-chroman-4-ylmethyl-lH-imidazole Rac-2-chroman-4-ylmethyl-1H-imidazole is obtained from rac-chroman-4-yl- (1H-imidazol-2-yl) -methanone in an olff-Kishner type reduction according to procedure published by E. Reimann et al., Arch. Pharm. (einheim) 322, 363, 1989: yellow gum; MS (ISP) = 215.1 M + H) +). Example 73 Rae- - (lH-imidazol-2-ylmethyl) -1, 2, 3, 4-tetrahydro-quinoline a) rac-1, 2, 3, 4-tetrahydro-quinoline-4-carboxylic acid The rac-1, 2, 3, 4-tetrahydro-quinoline-4-carboxylic acid is obtained from the quinoline-4-carboxylic acid by treatment with Raney nickel in aqueous sodium hydroxide according to the procedure described in Khimiya Geterotsiklicheskikh Soedinenii 77-9, 1988; brown crystals; NMR-H1 (CDC13): 2.04 (1H, m), 2.29 (1H, m), 3.24-3.46 (br m, 3 H, CH2N and NH), 3.77 (1H, t, CHC02), 6.55 (1H, d , ArH), 6.67 (1H, dd, ArH), 7.04 (1H, dd, ArH), 7.15 (1H, d, ArH). b) rac-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methoxy-methyl-amide To a solution of 0.50 g (2.82 mmoles) of rac-1, 2, 3, 4-tetrahydro-quinoline-4-carboxylic acid in 12 ml of dichloromethane is added 0.36 g (3.67 mmoles) of the hydrochloride of N, 0-dime ti 1 hi droxi 1 ami na and 0.40 mi (3.67 mmoles) of N-me ti lmo r fo 1 i na. The mixture is cooled to 0 ° C, 0.70 g (3.67 mmol) of the 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) are added and the reaction mixture is stirred at room temperature for 16 hours. hours. The mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel, gradient of ethyl acetate / heptane) to obtain 0.29 g (47%) of the title compound as a yellow crystalline solid. MS (ISP) = 221.4 ([M + H] +, 100%). c) methoxy-methyl-amide of rac-1- (toluene-4-sulfonyl) -1,2,3,4-tetrahydro-quinoline-4-carboxylic acid To a solution of 0.29 g (1.32 mmol) of the methoxy-methyl-amide of rac-1 acid, 2, 3, 4-tetrahydro-quinoline-4-carboxylic acid in 5 ml of 1,2-dichloroethane are added dropwise 0.46 ml (3.29 mmol) of triethylamine. Then 0.33 g (1.71 mmol) of p-toluenesulfonyl chloride is added and the reaction mixture is heated at 70 ° C for 4 hours. The mixture was cooled to room temperature, concentrated in vacuo and the residue was purified by chromatography (silica gel, methanol / dichloromethane gradient) to obtain 0.44 g (90%) of the title compound as a brown crystalline solid. MS (ISP) = 375.1 ([M + H] +, 100%). d) rae- (lH-imidazol-2-yl) - [1- (toluene-4-sulfonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -metanone To a solution of 0.21 ml (1.29 mmol) of 1- (diethoxymethyl) imidazole in 2 ml of tetrahydrofuran was added. drip at -78 ° C 0.88 ml (1.41 mmol) of a 1.6 solution of n-butyllithium in hexane. The resulting solution of 2- (l-diethoxymethyl-lH-iitddazol-2-yl) -lithium is stirred at -78 ° C and added dropwise to a solution of 0.44 g (1.18 mmol) of the methoxy-methyl-amide. of rac-1- (toluene-4-sulfonyl) -1, 2, 3, 4-tetrahydro-quinoline-4-carboxylic acid in 4 ml of tetrahydrofuran at 0 ° C. The reaction mixture is stirred at 0 ° C for 1 h, the reaction is stopped by the dropwise addition of 2 M aqueous hydrochloric acid. The mixture is made basic with the addition of an aqueous solution of sodium bicarbonate and diluted with ethyl acetate. ethyl. The phases are separated and the organic phase is washed with a saturated solution of brine, dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate / heptane gradient) to obtain 0.23 g (52%) of the title compound as a slightly yellow crystalline solid. MS (ISP) = 382.3 ([M + H] +, 100%). e) rac-4- (lH-imidazol-2-ylmethyl) -1- (toluene-4-sulfonyl) -1, 2, 3, 4-tetrahydro-quinoline This compound is obtained according to the methodology published in Arch. Pharm. 322, 363-367, 1989. To a solution of 0.23 g (0.60 mmole) of the rae- (lH-imidazol- 2-yl) - [1- (toluene-4-sulfonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -methanone in 3 ml of triethylene glycol is successively added 96 mg (2.41 mmol) of Sodium hydroxide powder and 0.10 ml (1.99 mmol) of hydrated hydrazine. The reaction mixture is stirred at 110 ° C for 1 h and then at 200 ° C for 2 h. The mixture is cooled to room temperature, diluted with ethyl acetate and washed successively with 2N aqueous hydrochloric acid, an aqueous solution of sodium bicarbonate, water, and a saturated solution of brine. The phases are separated and the organic phase is dried with a2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, methanol / dichloromethane gradient) to obtain 41 mg (19%) of the title compound as a yellow crystalline solid. MS (ISP) = 368.1 ([M + H] +, 100%). f) rac-4- (lH-imidazol-2-ylmethyl) -1,2,3,4-tetrahydro-quinoline This compound is obtained according to the methodology published in J. Med. Chem. 40, 105-111, 1997. To 40 mg (0.11 mmoles) of rac-4 - (lH-imide zol-2-methylmethyl) -1 - (toluene-4-sulfonyl) -1,2, 3, 4-tetrahydro- quinoline are added successively 0.57 ml (3.27 mmol) of a 33% solution of HBr in acetic acid and 0.06 ml (0.54 mmol) of anisole. The reaction mixture is stirred at room temperature for 3 h and then poured into a 2 N aqueous solution of sodium hydroxide. The mixture is diluted with ethyl acetate, the phases are separated, and the organic phase is washed with a saturated solution of brine. The phases are separated, the organic phase is dried with Na 2 SO, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, methanol / dichloromethane gradient), yielding 16 mg (69%) of the title compound as a white foam. MS (ISP) = 214.3 ([+ H] +, 100%). Example 74 rac-2- (1, 2,3, -tetrahydro-naphthalen-1-ylmethyl) -1H-imidazole Rac-2- (1, 2, 3, 4-tetrahydro-naphthalen-1-ylmethyl) -lH-imidazole is obtained from the methoxy-methyl-amide of rac-1, 2, 3, 4-tetrahydro acid -naphthalene-l-carboxylic acid in a manner similar to that described in Example 72 b) and e): colorless solid; MS (ISP) = 213.0 M + H) +).

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 (43)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The use of compounds of the formula I wherein R 1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, O, NH, N-alkyl or N-S02-alkyl or N-S02-toluene-4-yl; is CH2 or a bond; m and n independently of each other are number 1, 2 or 3; when m is 2 or 3, R2 can be the same or not; when n is 2 or 3, R1 may be the same or not; dotted lines with independence between them can be a link or not; and its pharmaceutically active salts, mixtures racemic, enantiomers, optical isomers and tautomeric forms, for the manufacture of drugs for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, for example schizophrenia , neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, hypertension, drug abuse and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, Consumption and assimilation of energy, disorders and malfunction of homeostasis of body temperature, sleep disorders, circadian rhythm and cardiovascular disorders.
2. 2.- The use of compounds of the formula IA wherein R 1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen or lower alkyl substituted by halogen; Q is CH2 or O; n is 1, 2 or 3; When n is 2 or 3, R1 can be the same or not; the dotted line can be a link or not; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of the compounds of formula IA, for the manufacture of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder , stress-related disorders, psychotic disorders, for example schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, hypertension, drug abuse and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, eating disorders and energy uptake, disorders and malfunction of homeostasis of body temperature, sleep disorders, circadian rhythm and cardiovascular disorders.
3. 3. The use of compounds of the formula I according to claim 1, wherein X is N.
4. 4. The use according to claim 3, wherein Q is CH2 and R1 is halogen.
5. 5. The use according to claim 4, wherein the compounds are: rac-2- (5-bromo-1, 2,3, -tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole rac-2- (7-chloro-5-fluoro-1,2) , 3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole rac-2- (6-chloro-l, 2,3,4-tetrahydro-naphthalene-1-yl) - 4 , 5-dihydro-lH-imidazole or rac-2- (5-chloro-l, 2, 3, 4-tetrahydro-naphthalen-1-yl) -, 5-dihydro-1H-imidazole.
6. 6. The use according to claim 3, wherein Q is CH2 and R1 is lower alkyl.
7. 7. The use according to claim 6, wherein the compounds are: rac-2- (5,7-dimethyl-1,2,3-tetrahydro-naphthalen-1-yl) -4,5-dihydro. -lH-imidazole or rac-2- (5,7-dimethyl-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-imidazole.
8. 8. The use according to claim 3, wherein Q is CH2 and R1 is lower alkoxy.
9. 9. The use according to claim 8, wherein the compounds are: rac-2- (7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro- lH-imidazole rac-2- (6-methoxy-l, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole or rac-2- (5-methoxy-1, 2,3, 4-tetrahydro-naphthalene-1-yl) - 4, 5-dihydro-lH-imidazole.
10. 10. The use according to claim 3, wherein Q is O or NH and R1 is hydrogen or halogen.
11. 11. The use according to claim 10, wherein the compounds are: rac-2- (6,8-dichloro-chroman-4-yl) -lH-imidazole or rac-4- (lH-imidazole-2) -yl) -1,2,3, 4-tetrahydro-quinoline.
12. 12. The use of compounds of the formula I according to claim 1, wherein X is CH.
13. 13. - Use in accordance with the claim 12, where Q is CH2 and R1 is hydrogen.
14. 14. - Use in accordance with the claim 13, wherein the compounds are: (4- (3,4-dihydro-naphthalen-1-yl) -lH-imidazole or rac-4- (1, 2,3, 4-tetrahydro-naphthalene-1-yl) -1H-imidazole
15. 15. The use according to claim 12, wherein Q is O and R1 is hydrogen
16. 16. Use according to claim 15, wherein the compound is: rac-5-chroman-4-yl-lH-imidazole, hydrochloride or tautomer.
17. 17. The use according to claim 12, wherein Q is O and R1 is lower alkyl.
18. 18. - Use in accordance with the claim 17, wherein the compounds are: rac-5- (7-methyl-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5-methyl-chroman-4-yl) -lH-imidazole or tautomer
19. 19. The use according to claim 12, wherein Q is O and R1 is halogen.
20. 20. The use according to claim 19, wherein the compounds are: rac-5- (6-fluoro-chroman-4-yl) -lH-imidazole or tautomer 5- (8-chloro-2H-chromen- 4-yl) -lH-imidazole or tautomer 5- (6-chloro-2H-chromen-4-yl) -lH-imidazole or tautomer rac-5- (7-fluoro-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5-fluoro-chroman-4-yl) -lH-imidazole or tautomer.
21. 21.- Compounds of the formula I characterized in that R1 is hydrogen, tritium, hydroxy, alkyl lower, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, 0, NH, N-alkyl or N-S02-alkyl or N-S02-toluene-yl; W is CH2 or a bond; m and n independently of each other are number 1, 2 or 3; when m is 2 or 3, R2 can be the same or not; when n is 2 or 3, R1 may be the same or not; the dotted lines, independently of each other, can be a link or not; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms, with the exception of the following compounds: rac-2- (1, 2,3, 4-tetrahydro-l-naphthyl) -2-imidazoline rac-2 - (7-methyl-l, 2,3, 4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-lH-imidazole rac-2- (6-methyl-1,2,3,4-tetrahydro) -naphthalene-l-yl) - 4,5-dihydro-lH-imidazole rac-2- (6-chloro-l, 2,3,4-tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH -imidazole rac-2- (5-chloro-1, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole rac-2- (7-methoxy-1,2,3-tetrahydro-naphthalen-1-yl) -4,5-dihydro-1H-imidazole rac-2- (6-methoxy-1,3,3,4) -tetrahydro-naphthalen-l-yl) -4,5-dihydro-lH-imidazole rac-2- (5-methoxy-1,2,4,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro -lH-imidazole rac-5- (4,5-dihydro-lH-imidazol-2-yl) -5,6,7,8-tetrahydronaphthalen-2-ol, rac-4- (1, 2, 3, 4 -tetrahydro-naphthalen-l-yl) -1H-imidazole rac-5- (4,5-dihydro-lH-imidazol-2-yl) -5,6,7,8-tetrahydro-naphthalene-2,3-diol or rac-5- (4,5-dihydro-lH-imidazol-2-yl) -5,6,7,8-tetrahydro-naphthalene-1,2-diol.
22. 22. Compounds of the formula I according to claim 21, characterized in that X is N.
23. 23. Compounds of the formula I according to claim 22, characterized in that Q is CH2 and R1 is halogen.
24. 24. Compounds of the formula I according to claim 23, characterized in that they are rac-2- (5-bromo-l, 2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro- lH-imidazole or rac-2- (7-chloro-5-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -4,5-dihydro-β-imidazole.
25. 25. - Compounds of the formula I according to claim 22, characterized in that Q is CH2 and R1 is tritium.
26. 26. Compounds of the formula I according to claim 25, characterized in that the compound is: rac-2- (7-trithio-1,2,3,4-tetrahydro-naphthalene-1-yl) -4,5 -dihydro-lH-imidazole.
27. 27. Compounds of the formula I according to claim 22, characterized in that Q is -O-.
28. 28. Compounds of the formula I according to claim 27, characterized in that they are: rac-2-chroman-4 -i1-4, 5-dihydro-lH-imidazole, rac-2-chroman-4-yl-lH -imidazole or rac-2- (6-fluo.ro-chroman-4-yl) -lH-imidazole.
29. 29. Compounds of the formula I according to claim 22, characterized in that Q is O or NH and R1 is hydrogen or halogen.
30. 30. Compounds of the formula I according to claim 29, characterized in that they are: rac-2- (6,8-dichloro-chroman-4-yl) -lH-imidazole or rac-4- (lH-imidazole) 2-yl) -1,2,3,4-tetrahydro-quinoline.
31. 31. Compounds of the formula I according to claim 21, characterized in that X is CH.
32. 32.- Compounds of formula I in accordance with Claim 31, characterized in that Q is CH2 and R1 is hydrogen.
33. 33. Compounds of the formula I according to claim 32, characterized in that the compound is: (4 - (3,4-dihydro-naphthalen-1-yl) -lH-imidazole
34. 34. - Compounds of the formula I according to claim 31, characterized in that Q is 0 and R1 is hydrogen
35. 35. Compounds of the formula I according to claim 34, characterized in that the compound is: rac-5-chroman-4-yl-lH imidazole, hydrochloride or tautomer
36. 36. Compounds of the formula I according to claim 31, characterized in that Q is O and R 1 is lower alkyl
37. 37. Compounds of the formula I according to claim 36, characterized in that are: rac-5- (7-methyl-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5-methyl-chroman-4-yl) -lH-imidazole or tautomer
38. 38. - Compounds of the formula I according to claim 31, characterized in that Q is O and R1 is halogen
39. 39.- Compounds of the formula I in accordance with n claim 38, characterized in that they are: rac-5- (6-fluoro-chroman-4-yl) -lH-imidazole or tautomer 5- (8-chloro-2H-chromen-4-yl) -lH-imidazole or tautomer 5- (6-chloro-2H-chromen-4-yl) -α-imidazole or tautomer rac-5- (7-fluoro-chroman-4-yl) -lH-imidazole or tautomer or rac-5- (5 -fluoro-chroman-4-yl) -lH-imidazole or tautomer.
40. 40.- Methods for obtaining compounds of the formula I according to claims 21 to 39, characterized in that the processes consist of: a) reacting a compound of the formula with the ethylenediamine of the formula H2NCH2CH2NH2 III to obtain a compound of the formula where R1, R2, Q, m and n have the meanings defined before, or Educate a compound of the formula by catalytic hydrogenation in the presence of Pd / C or with a hydride complex to obtain a compound of the formula wherein R1, R2, Q, m and n have the meanings defined above, or c) reduce a compound of the formula by catalytic hydrogenation in the presence of Pd / C or with a hydride complex to obtain a compound of the formula where R1, R2, Q, m and n have the meanings defined before, or Deprotect a compound of the formula with formic acid to obtain a compound of the formula wherein R1, R2, Q, m and n have the meanings defined above, or e) reacting a compound of the formula with DMSO and oxalyl chloride in dichloromethane or permanganate absorbed on silica gel in acetonitrile or with Pd / C in toluene to obtain a compound of the formula where R1, R2, Q, m and n have the meanings defined before, or f) reacting a compound of the formula with NaOH and hydrated hydrazine to obtain a compound of the formula wherein R1, R2, m and n have the meanings defined above, or g) reacting a compound of the formula with HBr, acetic acid and anisole to obtain a compound of the formula where R1, R2, m and n have the meanings defined above, or h) reacting a compound of the formula with NaOH and hexahydrate to obtain a compound of the formula wherein R1, R2, m and n have the meanings defined above and Q is 0 or CH2, and, if desired, convert the resulting compounds to pharmaceutically acceptable acid addition salts. .
41. 41.- The use of compounds of the formula I wherein R 1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, O, NH, N-alkyl or N-S02-alkyl or N-S02-toluene-4-yl; is CH2 or a bond; m and n independently of each other are number 1, 2 or 3; when m is 2 or 3, R2 can be the same or not; when n is 2 or 3, R1 may be the same or not; dotted lines with independence between them can be a link or not; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of the compounds of the formula I as radioligands for a binding assay of receptors associated with screening amines.
42. 42.- A medicament containing one or more compounds according to claim 1, characterized in that it is for the treatment of depression, anxiety disorders, bipolar disorder, hyperactivity disorder with attention deficit, stress-related disorders. , psychotic disorders, for example schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, hypertension, drug abuse and metabolic disorders, for example eating disorders, diabetes, complications diabetics, obesity, dyslipidemia, consumption disorders and energy assimilation, disorders and malfunction of homeostasis of body temperature, sleep disorders, circadian rhythm and cardiovascular disorders.
43. 43.- A medication according to claim 41, characterized in that it contains one or more compounds according to claim 1 for the treatment of depression, psychosis, Parkinson's disease, 'anxiety and deficit hyperactivity disorder. of attention (ADHD). SUMMARY OF THE INVENTION The present invention relates to the use of compounds of formula (I) characterized in that R1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, 0, NH, N-alkyl or N-S02-alkyl or N-S02-toluene-4-yl; W is CH2 or a bond and are independent of each other 1, 2, or 3; when m is 2 or 3, R2 can be m, n be the same or not; when n is 2 or 3, R1 may be the same or not; dotted lines with independence between them can be a link or not; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of compounds of the formula (I), for the manufacture of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, hyperactivity disorder with deficit of attention, stress-related disorders, psychotic disorders, for example schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, hypertension, drug abuse and metabolic disorders, for example, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption disorders and energy assimilation, disorders and malfunction of homeostasis of body temperature, sleep disorders and circadian rhythm and cardiovascular disorders.