MX2008009466A - Use of 4-imidazole derivatives for cns disorders - Google Patents

Abstract

The present invention relates to the use of compounds of formula (I) wherein R is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, phenyl, S-phenyl or O-phenyl, which are optionally substituted by lower alkoxy or halogen, or is benzyloxy, C(O)O-lower alkyl, cycloalkyl, or is lower alkyl or lower alkoxy substituted by halogen;Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl or pyrazole;R1/R1'are independently from each other hydrogen, hydroxy, lower alkyl, lower alkoxy or are phenyl or benzyl, which are optionally substituted by halogen;R2is hydrogen or lower alkyl;n is 1, 2, 3 or 4;and to their pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders suchas 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 DERIVATIVES OF 4-IMIDAZOL FOR DISORDERS OF THE CENTRAL NERVOUS SYSTEM DESCRIPTION OF THE INVENTION The present invention relates to the use of compounds of the formula wherein R is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, phenyl, S-phenyl or O-phenyl, which are optionally substituted by lower alkoxy or halogen, or is benzyloxy, C (0) 0-lower alkyl, cycloalkyl , or is lower alkyl or lower alkoxy substituted by halogen; Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl and pyrazolyl; R1 / R1 'independently of each other are hydrogen, hydroxy, lower alkyl, lower alkoxy, or are phenyl or benzyl, which are optionally substituted by halogen; R2 is hydrogen or lower alkyl; n is the number 1, 2, 3 or 4; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms, for the preparation of medicaments for the Ref. 194758 treatment of depression, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, and disorders metabolic, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption disorders and energy uptake, disorders and malfunction of homeostasis of body temperature, sleep disorders and circadian rhythm. 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 1-23 and 44-80 are new. Classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous systems [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]. One second A group of endogenous amine compounds, so-called trace amines (TA), overlap significantly with classical biogenic amines in terms of 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 anatomically discrete TA of the 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 System of receptors [9,12,13]. This opinion has changed significantly when several components of the GPCR group, the receptors associated with the tracking amines (TAAR), have recently been identified [7,14]. There are 9 TAAR genes in man (including 3 pseudogenes) and 16 genes in the mouse (including 1 pseudogene). TAAR genes do not contain introns (except one exception), TAAR2 contains 1 intron) and are located next to each other 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 of food, metabolic disorders and therefore the TAAR1 ligands have a high potential for the treatment of these diseases. There is, therefore, a broad interest to improve the knowledge that we have about the recipients associated with amines of tracking. 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, Nat. 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 _4JL, 237-260, 2001; 4 Tuite, P. and Riss, J., Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs 12, 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. Cpin. 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 novel compounds of the formula I and the use of the compounds of the formula I and their pharmaceutically acceptable salts for the preparation of drugs for the treatment of affinity-related diseases with respect to the receptors associated with trace amines, the new specific compounds are encompassed by the scope of formula I, its preparation, the medicines based on a compound according to the invention and its preparation as well as the use of the compounds of formula I for the control or prevention of diseases, for example depression, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, schizophrenia, neurological diseases, for example Parkinson's disease, neurodegenerative disorders, for example Alzheimer's disease, epilepsy, migraine, and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, upheavals of consumption and assimilation of energy, disorders and malfunction of the homeostasis of body temperature al, sleep disorders and circadian rhythm. Preferred indications for the use of the compounds of the present invention are depression, psychosis, Parkinson's disease, and attention deficit hyperactivity disorder (ADHD). As used herein, the term "lower alkyl" denotes a saturated, straight chain or branched, 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, wherein the alkyl residue 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, for example CF3, CHF2, CH2F, CH2CF3, CH2CF2CF3 and similar. 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. Preferred compounds of the formula I for the aforementioned use are those, in which aryl is phenyl, at least one of R1 / R1 'is lower alkyl and R2 is hydrogen, for example the following compounds: rac-4- (1-phenyl-butyl) -lH-imidazole rac-4- [1- (2-fluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1 - (3,5-difluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-propyl) -lH-imidazole rac-4- [1- (2-fluoro-phenyl) -propyl] - lH-imidazole rac-4- [1- (3-fluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-ethyl) -lH-imidazole rac-4- [1- (3-fluoro -phenyl) -ethyl] -lH-imidazole rac-4- [1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1- (2,3-difluoro-phenyl) - propyl] -lH-imidazole trifluoroacetate of 5- (1-methyl-1-phenyl-ethyl) -1H-imidazole, or 4- [(R) -1- (2,3-difluoro-phenyl) -ethyl] -lH -imidazole Other preferred compounds of the formula I for the aforementioned use are those, in which aryl is phenyl, R1 / R1 'and R2 are hydrogen, for example the following compounds: 4- (4-methoxy-2,3-dimethyl- benzyl) -lH-imidazole 4- (2-chloro-6-fluoro-benzyl) -lH-imidazole 4- (2,3-dimethyl-benzyl) -lH-imidazole; Detomidine 4- (2,6-diethyl-benzyl) -lH-imidazole 4- (2-bromo-benzyl) -lH-imidazole 4- (2,6-dimethyl-benzyl) -lH-imidazole 4-benzyl-1H- imidazole 4- (2, 3, 5, ß-tetramethyl-benzyl) -lH-imidazole 4- (2,6-dichloro-benzyl) - ?? - imidazole 4- (2-ethyl-6-methyl-benzyl) -lH -imidazole 4- (2-cyclopropyl-6-ethyl-benzyl) -lH-imidazole 4- [3- (4-chloro-phenoxy) -benzyl] -lH-imidazole 4- (2-chloro-6-ethyl-benzyl) ) -lH-imidazole 4-biphenyl-2-ylmethyl-lH-imidazole 4- (2,6-diethyl-4-methoxy-benzyl) -lH-imidazole 4- (2,6-diethyl-3-methoxy-benzyl) -lH-imidazole 4-biphenyl-3-ylmethyl-lH-imidazole 4- (4-ethoxy-2, β-diethyl-benzyl) -lH-imidazole 4- (4-benzyloxy-2,6-diethyl-benzyl) - lH-imidazole 4- (3-ethoxy-2, β-diethyl-benzyl) -lH-imidazole 4- (2-ethyl-6-fluoro-benzyl) -lH-imidazole 4- (2,6-diethyl-4-) phenoxy-benzyl) -lH-imidazole or 4- (2,6-diethyl-3-phenoxy-benzyl) -lH-imidazole. Other preferred compounds of formula I for swimming above are those, in which aryl, for example the following compounds: 4-naphthalen-2-ylmethyl-1H-imidazole or rac-4- (1-naphthalene-1-yl) ethyl) -lH-imidazole. Other preferred compounds of formula I for swimming above are those, in which aryl ran-7-yl, for example the following compounds: 4- (5-bromo-benzofuran-7-ylmethyl) -1-imidazole or 4-benzofuran-7-ylmethyl-1-imidazole. Other preferred compounds of the formula I for the aforementioned use are those, in which aryl is dihydrobenzofuran-7-yl, for example the compound 4- (2,3-dihydro-benzofuran-7-ylmethyl) -1-imidazole. Other preferred compounds of formula I for the aforementioned use are those, wherein aryl is pyrazolyl. Other preferred compounds of formula I for the aforementioned use are those, wherein aryl is pyridinyl. The new preferred compounds of formula I are those, in which aryl is phenyl, at least one of R1 / R1 'is lower alkyl for example the following compounds rac-4- (1-phenyl-butyl) -lH-imidazole rac-4- [1- (2-fluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1- (3 , 5-difluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-propyl) -lH-imidazole rac-4- [1- (2-fluoro-phenyl) -propyl] -lH-imidazole rac-4- [1- (3-fluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-ethyl) -lH-imidazole rac-4- [1- (3-fluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1 - (2,3-difluoro-phenyl) -propyl] -lH-imidazole 4- [(R) -1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole. Other new preferred compounds of the formula are for example the following compounds 4- (4-methoxy-2,3-dimethyl-benzyl) -lH-imidazole 4- (2-chloro-6-fluoro-benzyl) -lH-imidazole 4- (2-ethyl-6-) methyl-benzyl) -lH-imidazole 4- (2-cyclopropyl-6-ethyl-benzyl) -IH-imidazole 4- [3- (4-chloro-phenoxy) -benzyl] -lH-imidazole 4- (2-chloro -6-ethyl-benzyl) -lH-imidazole 4-biphenyl-2-ylmethyl-lH-imidazole 4- (2,6-diethyl-4-methoxy-benzyl) -lH-imidazole 4- (2,6-diethyl) 3-methoxy-benzyl) -lH-imidazole 4-biphenyl-3-ylmethyl-lH-imidazole 4- (4-ethoxy-2,6-diethyl-benzyl) -lH-imidazole 4- (4-benzyloxy-2, β -diethyl-benzyl) -lH-imidazole 4- (3-ethoxy-2, β-diethyl-benzyl) -lH-imidazole 4- (2-ethyl-6-fluoro-benzyl) -lH-imidazole 4- (2, 6-diethyl-4-phenoxy-benzyl) -lH-imidazole or 4- (2,6-diethyl-3-phenoxy-benzyl) -lH-imidazole.

The present compounds of the formula I and their pharmaceutically acceptable salts can be prepared by methods well known in the art, for example, by the processes described below, said process consists of: e) catalytically hydrogenating a compound of the formula with Pd / C, H2 to obtain a compound of the formula wherein R1 'is an alkenyl group, R1 is alkyl and R, R2 and n have the meanings defined before, or with CF3C02H and Et3SiH to obtain a compound of the formula wherein R1 is hydrogen, and R, R2 and n have the meanings defined above, or g) catalytically hydrogenating a compound of the formula with Pd / C, H2 to obtain a compound of the formula wherein R1 is lower alkyl, and R, R2 and n have the meanings defined above, or h) deprotect a compound of the formula with hydrochloric acid to obtain a compound of the formula wherein R, R2 and n have the meanings defined above, or e) alkylating a compound of the formula with to obtain a compound of the formula wherein R1 is lower alkyl or benzyl optionally substituted by halogen, R, R2 and n have the meanings defined above and X is halogen, and subsequent deprotection with hydrochloric acid to obtain a compound of the formula wherein R, R2 and n have the meanings defined above, or deprotect a compound of the formula XII with sodium in ammonia or by catalytic hydrogenation with Pd / C, H2 to obtain a compound of the formula N ^ NH RS NV-N Rb, RC 1-6 wherein Ra, Rb and Rc are hydrogen, lower alkyl or phenyl, or g) reacting a compound of the formula with two equivalents of a Grignard reagent of the formula IX to obtain a compound of the formula 1-7 wherein R is hydrogen, halogen, lower alkyl, lower alkoxy or phenyl and n has the meaning defined above, or h) catalytically hydrogenating a compound of the formula with Pd / C, H2 to obtain a compound of the formula wherein R is hydrogen, lower alkyl, lower alkoxy or phenyl and n has the meaning defined above, or k) reducing a compound of the formula with Pd / C, H2 or with CF3C02H and Et3SiH to obtain a compound of the formula wherein R1 is hydrogen, and R, R2 and n have the meanings defined above, or 1) deprotect a compound of the formula with hydrochloric acid in the presence of an alcohol of the formula Alk-OH to obtain a compound of the formula wherein Alk-0 is lower alkoxy, and R, R2 and n have the meanings defined above, and, if desired, convert the obtained compounds to pharmaceutically acceptable acid addition salts. The 4-imidazole derivatives are obtained in a manner similar to the processes of the technical literature, following the synthetic routes represented in the schemes from 1 to 6. The starting materials are commercially available products, they are known compounds of the chemical literature or compounds that can be prepared according to methods known in the art.

PROCEDURE 1 Reaction Scheme 1 Preparation of compounds of formula I, wherein R 1 is hydrogen or lower alkyl, optionally substituted by halogen, from 4-iodoimidazole The compounds of formula 1-1 are obtained by reduction, preferably by catalytic hydrogenation of the corresponding 4- (1-aryl-alkenyl) -1H-imidazole II derivatives. The catalytic hydrogenation is usually carried out in the presence of Pd / C at room temperature and normal pressure in an appropriate solvent, preferably ethyl acetate. The 4- (1-aryl-alkenyl) -lH-imidazoles of the formula II are obtained by dehydration and deprotection of the corresponding 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the Formula VII. By treatment of the alcohol VII with trifluoroacetic acid (TFA) and triethylsilane in dichloromethane at an elevated temperature 4-alkenyl imidazole is obtained. If, wherein R1 is hydrogen, it is also possible to obtain the compounds of formula 1-2 directly from the compounds of formula VII, by treatment of alcohol VII with trifluoroacetic acid (TFA) and triethylsilane in dichloromethane at elevated temperature. The reaction can be carried out in a pressure tube so that the reaction can be carried out at temperatures between 20 ° C and 100 ° C. The 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the formula VII are synthesized by reaction of the corresponding aryl-ketones or aryl-aldehydes of the formula VI with 4-magnesium-N-trityl-imidazole which is generated in situ from the 4-iodo-N-trityl-imidazole V and an alkyl-Grignard reagent, preferably ethyl magnesium bromide, in an organic solvent, preferably dichloromethane, at room temperature for a period from 12 to 36 hours, preferably from 16 to 20 hours, according to the methodology described in J. Org. Chem. 56, 5739-5740, 1991. The aryl ketones or the aryl aldehydes of the formula VI are commercial products, are known compounds of the technical literature or can be prepared by methods known in the art.

PROCEDURE 2 Reaction Scheme 2 Preparation of compounds of the formula I, wherein R 1 is lower alkyl, from a 4-acyl-imidazole Ri is lower alkyl The compounds of the formula 1-1 are obtained by catalytic hydrogenation of the 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the formula 1-3. The catalytic hydrogenation is usually carried out in the presence of Pd / C under hydrogen pressure, usually 5 bar, in an appropriate organic solvent, preferably a lower alcohol or ethyl acetate or a mixture of both, which are combined with an acid, usually hydrochloric acid, between 20 ° C and 100 ° C, preferably at 50 ° C. The 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the formula 1-3 are obtained from a 4-acyl-imidazole VIII and an aryl-Grignard IX reagent according to procedures already known from the technical literature. PROCEDURE 3 Reaction Scheme 3 Preparation of compounds of formula 1-4 and 1-5, wherein R1 / R1 'are hydrogen, phenyl or benzyl lower alkyl optionally substituted by halogen, from 1- (N, N- dimethyl-sulfamoyl) -imidazole The compounds of formulas 1-5 and 1-4 can be prepared by deprotection of 4-arylmethyl-2-tert-butyl-dimethylsilanyl-imidazole-1-sulfonic acid dimethylamides of the formula IV by heating in a dilute strong acid, with Preference is given to aqueous hydrochloric acid from 1M to 5M, at the reflux temperature for a few hours. The dimethylamides of 4-arylmethyl-2-ter- butyl-dimethylsilanyl-imidazole-1-sulfonic acid of formula IV, wherein R1 / R1 '= H, can be deprotonated with a strong base, lithium diisopropyl amide is preferred, in an organic solvent, preferably tetrahydrofuran, and alkylated with halides R1X, wherein R1 is lower alkyl or benzyl, optionally substituted by halogen, and X is Cl, Br or I. The 4-arylmethyl-2-tert-butyl dimethylsilanyl imidazole-1-sulfonic acid dimethylamides of the formula IV are synthesized by reaction of an appropriately substituted arylmethyl halide, preferably a bromide, with a 4-lithium dimethylamide -2-tert-butyl-dimethylsilanyl-imidazole-1-sulfonic acid, which is obtained from 1- (N, N-dimethyl-sulfamoyl) -imidazole X in two steps: a) deprotonation with n-butyllithium in tetrahydrofuran and subsequent addition of tert-butyldimethylsilyl chloride, which provides the dimethylamide of 2-tert-butyl-dimethylsilanyl-imidazole-1-sulfonic acid; b) n-butyl lithium in tetrahydrofuran which provides the dimethylamide of 4-lithium-2-tert-butyl-dimethylsilanyl-imidazole-1-sulfonic acid.

PROCEDURE 4 Reaction Scheme 4 Preparation of pyrazole derivatives of the formula 1-6 PG. benzyl or other groups compatible with the synthesis Ra, Rb and Rc are hydrogen, alkyl or phenyl. The pyrazole derivatives of the formula XII can be prepared by condensation of a hydrazine derivative of the formula XIII with a ß-dicarbonyl compound of the formula XI which, on carbon a, carries a l-benzyl-lH-imidazole-4 group (or -5) -ylmethyl. The β-dicarbonyl compounds can be prepared according to methods known in the art. The debenzylation of the pyrazole derivative of the formula XII can be carried out by catalytic hydrogenation or with sodium in liquid ammonia to obtain the deprotected compounds of the formula 1-6. The catalytic hydrogenation is usually carried out in the presence of Pd / C under normal conditions or under hydrogen pressure, generally from 3 to 100 bar, in an appropriate organic solvent, preferably a lower alcohol or ethyl acetate or a mixture of both, combined with an acid, usually hydrochloric acid, between 20 ° C and 120 ° C, preferably between 50 ° C and 100 ° C. PROCEDURE 5 Reaction Scheme 5 Preparation of compounds of the formula I, wherein R 1 is hydrogen or hydroxy and R 1 'is phenyl, optionally substituted by halogen, from an ester of an imidazole-4-carboxylic acid The compounds of the formula 1-8 can be prepared by catalytic hydrogenation of the 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the formula 1-7. The catalytic hydrogenation is normally carried out in the presence of Pd / C under pressure, usually 100 bar, in an organic solvent suitable, preferably a lower alcohol or ethyl acetate or a mixture of both, combined with an acid, usually hydrochloric acid, between 20 ° C and 120 ° C, preferably at 100 ° C. The 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the formula 1-7 can be prepared from an imidazole-4-carboxylic acid ester XIV and an aryl-Grignard IX reagent in accordance with already known procedures of the technical literature. PROCEDURE 6 Reaction Scheme 6 Preparation of compounds of the formula 1-5, wherein R 1 is hydrogen or 1-9, wherein R 1 is alkoxy, from a protected imidazole compound The dimethylamides of 4-arylmethyl-2-tert-butyl-dimethylsilanyl-imidazole-1-sulfonic acid of the formula XV can be synthesized by reacting an appropriately substituted aryl aldehyde with the 4-lithium-2-tert-butyl-dimethylsilanyl imidazole-1-sulfonic acid dimethylamide, which can be prepared in situ from the 1- (N, N) derivative -dimethyl-sulfamoyl) -imidazole X in two steps: a) deprotonation with n-butyllithium in tetrahydrofuran and subsequent addition of tert-butyldimethylsilyl chloride to obtain the dimethylamide of 2-tert-butyl-dimethylsilanyl-imidazole-1 -sulfonic; b) n-butyl lithium in tetrahydrofuran which provides the dimethylamide of 4-lithium-2-tert-butyl-dimethylsilanyl-imidazole-1-sulfonic acid. The required aryl aldehydes are commercial products, compounds already known from the technical literature or compounds that can be prepared by methods already known in organic chemistry. The compounds of formula 1-9 are obtained by deprotection of XV by heating in alcohol / hydrochloric acid mixtures for a few hours. The compounds of the formula 1-5 can be prepared by catalytic hydrogenation of the 1- (1H-imidazol-4-yl) -1-aryl-alkanols of the formula XV. The catalytic hydrogenation is usually carried out in the presence of Pd / C under pressure, generally 100 bar, in an appropriate organic solvent, preferably a lower alcohol or ethyl acetate or a mixture of both, between 20 ° C and 100 ° C, preferably at 100 ° C. The deprotection is then carried out by treatment with HC1 in EtOH between 20 ° C and 100 ° C, preferably at 100 ° C. As an alternative it is possible to obtain the compounds of the formula 1-5 by treatment of the XV alcohols with trifluoroacetic acid (TFA) and triethylsilane in dichloromethane at elevated temperature. The reaction can be carried out in a pressure tube for the purpose of the reaction can be carried out at a temperature comprised between 50 ° C and 100 ° C, preferably at 100 ° C. 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. The 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, glycolic acid, 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 the like. 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 into the corresponding free bases by treatment with at least one 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 TAAR1. 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) is used with 1.5 mM Mg2 + and the purified PCR products are cloned into a cloning vector of the type pCR2, l-toPO (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 their introduction into cell lines. HEK293 cells are cultured (ATCC # CRL-1573) essentially as described by Lindemann et al. (2005). For the 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 perof 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 EC50 during a culture perof 15 passages. Preparation of membrane and radioligand fixation The cells are rinsed in confluence with phosphate buffered saline and cooled with ice, without Ca + or Mg2 +, which contains 10 mM EDTA and are converted into pellets by centrifugation at 4 ° C at 1000 rpm during 5 min The granulate is then washed twice with phosphate buffered saline and cooled with ice and the cell pellet is frozen immediately by immersion in liquid nitrogen and It is stored at -80 ° C until the moment of 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 xg 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 pH A) and homogenize in a Polytron at 10,000 rpm for 10 s. Then the homogenized material is centrifuged at 4 ° C to 48,000? g for 30 min and the pellet is suspended again in 20 ml of pH A regulator and homogenized in a Polytron at 10,000 rpm for 10 s. The protein concentration is determined by the Pierce method (Rockford, IL). Then the homogenized material is centrifuged at 4 ° C to 48,000? g for 10 min, it is suspended again in HEPES-NaOH (20 mM), pH 7.0, which includes MgCl2 (10 mM) and CaCl2 g of protein per ml of y (2 mM) (pH regulator B) at 200 homogenates 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 of and with an incubation perof 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 around 0.1 % of the total radioligand concentration added and a specific fixation that represents 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 (10 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 fiberglass filter plates, preimpregnated for at least 2 h with 0.3% polyethyleneimine and using a Filtermate 96-type cell collector (Packard Instrument Company). The tubes and filters are washed 3 times with 1 ml aliquots of the cold pH B regulator. The filters are not dried and impregnated in Ultima gold (45 μ? / Cavity, Packard Instrument Company) and the fixed radioactivity accounts are determined with a device of the TopCount icroplate Scintillation Counter type (Packard Instrument Company). Preferred compounds have a Ki (μ?) Value in mouse on TAAR1 within the range of 0.003-0.050 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 preparations. The pharmaceutical preparations 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 compounds of the formula I can be processed with inorganic or organic, pharmaceutically inert carriers. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as carriers for tablets, coated tablets, dragees and hard gelatine capsules. The suitable carriers 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 carriers are usually not required in the case of soft gelatin capsules. The suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerin, vegetable oils and the like. The suitable carriers for suppositories are, for example, natural and hydrogenated oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations 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 present invention also relates to medicaments containing a compound of the formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as a process for their preparation, which comprises incorporating one or more compounds of the formula I and / or its pharmaceutically acceptable acid addition salts and, if desired, one or more additional therapeutically valuable substances, to a of galenic administration 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, Parkinson's disease, and attention deficit hyperactivity disorder (ADHD). The dosage can vary within wide limits andObviously, it 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 Preparation 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 1. Items 1, 2 and 3 are mixed in an 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.

Example 1 rac-4- (1-phenyl-butyl) -lH-imidazole a) rac-1-phenyl-1- (1-trityl-1H-imidazol-4-yl) -butan- To a solution of 200 mg (0.46 mmol) of 4-iodo-1-trityl-imidazole in 3 ml of anhydrous dichloromethane is added 0.16 ml (0.48 mmol) of 3M ethylmagnesium bromide in diethyl ether at room temperature. The mixture is stirred for 1 hour, then a solution of 55 mg (0.37 mmol) of 1-phenyl-butan-1-one in 0.1 ml of anhydrous dichloromethane is added in one portion and the reaction mixture is stirred for 16 hours. A saturated aqueous solution of ammonium chloride (5 ml) is added to the reaction mixture and the whole is extracted with dichloromethane (3 x 5 ml). The organic phase is washed with water (3 x 5 ml), then with brine (3 x 5 ml), dried with MgSO 4, concentrated and purified by preparative HPLC, yielding 90 mg of rac-1-phenyl-1- (L-trityl-lH-imidazol-4-yl) -butan-1-ol as a colorless oil: MS (ISP) = 459.0 ((M + H) +); NMR-H1 (C DC 13): 0.80 (3H, t, CH3), 1.30 (2H, m), 2.05 (2H, m, CH2), 3.45 (1H, s, br, OH), 6.70 (1H, s) ), 7.05-7.45 (21H, m). b) (E / Z) -4- (1-phenyl-but-l-enyl) -lH-imidazole To a solution of 81 mg (0.182 mmol) of rac-1-phenyl-1- (1-trityl-1H-iraidazol-4-yl) -butan-1-ol in 10 ml of trifluoroacetic acid / dichloromethane (1: 1) ) was added at room temperature 85 mg of triethylsilane (115 μ ?, 0.79 mmol). The reaction mixture is heated to reflux for 16 hours and its progress is monitored by HPLC. Once all the starting materials are consumed, the reaction mixture is concentrated to dryness. The resulting residue is dissolved in dichloromethane and extracted with 1M HC1 (3 x 10 mL). The aqueous phases are combined, washed with dichloromethane (10 ml), neutralized to pH 7 with 1 M NaOH and extracted with dichloromethane (3 x 10 ml). The organic phases are combined, washed with brine (3 x 10 mL), dried with gSO4 and concentrated, obtaining 33 mg (98%) of the (E / Z -) - 4- (1-phenyl-1-but- 1 - in i 1) - 1 H-imi da zo 1 in the form of a colorless oil, which does not require further purification. LC at 215 nm, Rt = 1.07 & 1.09 (E and Z isomers)): 95%; MS (ISP) = 199.0 ((M + H) +); NMR-H1 (CDC13, E and Z isomers)): 0.85-1.10 (2H, t, CH3 and 1H, t, CH3). 2.00-2.30 (1.4H, m, CH2 and 0.6H, m, CH2), 5.95 (1H, t), 7.00 (1H, s), 7.15-7.40 (5H, m), 7.55 (1H, s). c) rac-4- (1-phenyl-butyl) -lH-imidazole A solution of 33 mg (0.18 mmol) of (E / Z) -4- (1-phenyl-but-1-enyl) -lH-imidazole in 5 ml of ethyl acetate is added to 10 mg of Pd at 10 ° C. % on C in nitrogen atmosphere. The nitrogen atmosphere is neutralized, replaced by hydrogen and the reaction mixture is stirred vigorously at room temperature and the progress of the reaction is monitored by HPLC until all the starting materials are consumed. The atmosphere of hydrogen is replaced by nitrogen and the reaction mixture is filtered through Celite®. The Celite® is then washed with ethyl acetate (3 x 5 ml). The filtrate was concentrated and the resulting residue was again dissolved in 5 ml of dichloromethane and extracted with 1M HC1 (3.5 ml). The aqueous phases are combined and washed with dichloromethane (5 ml)., then neutralized to pH 7 with 1M NaOH and extracted with dichloromethane (3 x 5 ml). The organic phases are combined, washed with brine (3 x 5 ml), dried with MgSO 4 and concentrated, obtaining the crude alkane in the form of an oil. The alkane was purified by preparative HPLC, yielding 8 mg (22%) of rac-4- (1-phenyl-butyl) -lH-imidazole as a colorless solid. LC at 215 nm; Rt = 1.21: 100%, MS (ISP) = 201.0 ((M + H) +); NMR-H1 (CDC13): 0.90 (3H, t, CH3), 1. 10 (2H, m, CH2), 2.00 (2H, m, CH2), 3.97 (1H, t), 6.89 (1H, s), 7.15-7.35 (5H, m), 7.97 (1H, s) 9.45 (1H , s, br, NH). Example 2 rac-4- [1- (2-fluoro-phenyl) -ethyl] -lH-imidazole The rac-4- [1- (2-fluoro-phenyl) -ethyl] -1H-imidazole is obtained from the 1- (2-fluoro-phenyl) -ethanone according to the procedure described for Example 1) : colorless powder; MS (ISP) = 191.0 ((M + H) +). Example 3 rac-4- [1- (3-trifluoromethyl-phenyl) -propyl] -1H-imidazole Rac-4- [1- (3-trifluoromethyl-phenyl) -propyl] -β-imidazole is obtained from 1- (3-trifluoromethyl-phenyl) -propan-l-one according to the procedure described for Example 1): colorless powder; MS (ISP) = 255.0 ((M + H) +). Example 4 rac-4- [1- (3,5-difluoro-phenyl) -propyl] -lH-imidazole Is obtained - [1- (3,5-difluoro-phenyl) -propyl] -lH-imidazole from 1- (3,5-difluoro-phenyl) - propan-l-one according to the procedure described for Example 1): colorless powder; MS (ISP) = 223.0 ((M + H) +). Example 5 rac-4- (1-phenyl-propyl) -lH-imidazole Via A (PROCEDURE 1): rac-4- (1-phenyl-propyl) -lH-imidazole is obtained from propiophenone according to the procedure described for Example 1): colorless powder; MS (ISP) = 187.0 ((M + H) +). Route B (PROCEDURE 3): a) To a solution of 0.30 g (1.71 mmol) of 1- (dimethylsulfamoyl) imidazole in 10 ml of tetrahydrofuran, 1.2 ml (1.88 mmol) of a 1.6 solution is added at -75 ° C. M butyllithium in hexane. After stirring for 15 min 0.30 g (2 mmol) of tert-butyldimethylsilyl chloride are added at -75 ° C and the mixture is stirred at room temperature for 2 h. The mixture is again cooled to -75 ° C and 1.2 ml (1.88 mmol) of a 1.6 M solution of butyllithium in hexane are added. After stirring for 30 min, 0.36 g (2.14 mmol) of benzyl bromide are added at -75 ° C and the mixture is allowed to warm to room temperature overnight. The mixture is partitioned between water and dichloromethane, extract again with dichloromethane. The combined organic phases are dried with MgSO 4, filtered and concentrated. b) For the step of -alkylation, an amount of 400 mg (1.05 mmol) of the residue is dissolved in 3 ml of tetrahydrofuran and added dropwise to a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (from 0.72 ml of BuLi). 1.6 and 0.128 mg of diisopropyl-amine). After stirring at -75 ° C for 1 h, 0.197 g (1.26 mmol) of ethyl iodide are added and stirring is continued at room temperature overnight. To interrupt the reaction, a saturated solution of NH 4 Cl is added. The aqueous phase is extracted with ethyl acetate (3 times), the combined organic extracts are dried with MgSO, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes / ethyl acetate 2: 1) to obtain 155 mg (36%) of 2- (tert-butyl-dimethyl-silanyl) dimethylamide. (1-phenyl-propyl) -imidazole-1-sulfonic acid in the form of a colorless oil. c) To remove the protecting groups, an amount of 155 mg (0.38 mmol) of 2- (tert-butyl-dimethyl-silanyl) -4- (1-phenyl-propyl) -imidazole-1-sulfonic acid dimethylamide is dissolved. in 10 ml of 1.5N hydrochloric acid and kept boiling at reflux for 1 h. The solution is cooled, adjusted to pH > 8 with 25% aqueous ammonia and the solution is extracted with dichloromethane (2 times). The phases The combined organic extracts are dried with MgSO 4, filtered and concentrated. The residue is purified by flash chromatography (silica gel, dichloromethane / methanol / conc. Aqueous ammonia = 90: 10: 1), obtaining 71 mg (99%) of rac-4- (1-phenyl-propyl) - 1H-imidazole as a white solid: MS (ISP) = 187.1 ((M + H) +). Example 6 rac-4- [1- (2-fluoro-phenyl) -propyl] -lH-imidazole The rac-4- [1- (2-fluoro-phenyl) -propyl] -1H-imidazole is obtained from the 1- (2-fluoro-phenyl) -propan-l-one according to the procedure described for Example 1): colorless powder; MS (ISP) = 205.0 ((M + H) +). Example 7 rac-4- [1- (3-fluoro-phenyl) -propyl] -lH-imidazole The rac-4- [1- (3-fluoro-phenyl) -propyl] -1H-imidazole is obtained from the 1- '(3-fluoro-phenyl) -propan-l-one according to the procedure described for Example 1): colorless powder; MS (ISP) = 205.1 ((M + H) +).

Example 8 rac-4- (2-methyl-l-phenyl-propyl) -lH-imidazole rac-4- (2-methyl-1-phenyl-propyl) -lH-imidazole from 2-methyl-1-phenyl-propan-1-one according to the procedure described for Example 1): colorless powder; MS (ISP) = 201.0 ((M + H) +). Example 9 rac-4-methyl-5- (1-phenyl-ethyl) -lH-imidazole CIH A 3.0 M solution of phenylmagnesium bromide (1.3 ml, 4 mmol) in ether is added at room temperature to a solution of 0.25 g (2.0 mmol) of 4-acetyl-5-methyl-imidazole in 20 ml. of dry tetrahydrofuran. The mixture is boiled at reflux for 2 h. The solvents are evaporated and the organic compounds are extracted twice with ethyl acetate. The combined organic extracts are concentrated and the residue is purified by flash chromatography (silica gel, dichloromethane / methanol 95: 5), obtaining a product containing mainly l- (5-methyl-3H-imidazol-4-yl) -1-phenyl-ethanol. This product is dissolved in 20 ml of ethanol / ethyl acetate (1: 1) and add 0.5 ml of 10 M hydrochloric acid. The mixture is hydrogenated (5% Pd on C, 0.07 g, 4 bar, H2, 50 ° C) for 4 h. The mixture is filtered through Celite® and the solvent is evaporated. The residue is partitioned between an aqueous solution of potassium carbonate and ethyl acetate. The organic phase is dried with magnesium sulfate and concentrated, obtaining a yellow oil which is purified by flash chromatography (silica gel, dichloromethane / methanol = 95: 5). An equimolar amount of hydrochloric acid in ethanol (5M) is added to the amine. Dilution with ether precipitated 4-methyl-5- (1-phenyl-ethyl) -lH-imidazole hydrochloride as a colorless solid, which was filtered off (45 mg, 12%); MS (El) = 186.1 (+), 171.1 (((M-CH3) +), 100%). Example 10 rac-4- [1- (2,3-dimethyl-phenyl) -ethyl] -5-methyl-lH-imidazole, hydrochloride or tautomer The rac-4- [1- (2,3-dimethyl-phenyl) -ethyl] -5-methyl-1H-imidazole, hydrochloride is obtained in a comparable yield according to the procedure described for Example 9 using the bromide of 2, 3-dimethylphenyl magnesium instead of phenyl magnesium bromide. MS (El) = 214.1 (M +), 199.1 (((M-CH3) +), 100%). Example 11 4- (4-methoxy-2,3-dimethyl-benzyl) -lH-imidazole 4- (4-methoxy-2,3-dimethyl-benzyl) -1H-imidazole, MS (ISP) = 217.2 (M + H +) is obtained, in comparable yield similar to the procedure described for Example , Route B, employing in step a) the 4-methoxy-2,3-dimethylbenzyl chloride in place of the benzyl bromide followed directly by the deprotection step c). Example 12 4- (2-Chloro-6-fluoro-benzyl) -lH-imidazole 4- (2-chloro-6-f luoro-benzyl) -1H-imidazole, MS (ISP) = 210.3 ((M + H) +) is obtained, in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) the 2-chloro-6-f luorbenzyl bromide in place of the benzyl bromide followed directly by the deprotection step c).

Example 13 6-tert-Butyl-3- (3H-imidazol-4-ylmethyl) -2,4-dimethyl hydrochloride The title is obtained, MS (ISP) 259.2 ((M + H) +), in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) 4-tert-butyl chloride 3-hydroxy-2,6-dimethyl-benzyl in place of benzyl bromide followed directly by the deprotection step c). Example 14 rac-4- (1-phenyl-ethyl) -lH-imidazole Obtain the title compound, MS (El) = 172.1 (M +), 157.1 (((M-CH3) +), 100%), in a comparable yield similar to the procedure described for Example 5, Route B, employing Step b) Methyl iodide instead of ethyl iodide. Example 15 rac-4- [1- (3-fluoro-phenyl) -ethyl] -lH-imidazole The title compound, MS (ISP) 191.1 (M + H +), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) 3-fluorobenzyl bromide in place of benzyl bromide and in step b) methyl iodide in place of ethyl iodide. Example 16 Rae-4- [1,2-bis- (3-fluoro-phenyl) -ethyl] -lH-imidazole The title compound, MS (ISP) = 285.0 (M + H +), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) 3-fluorobenzyl bromide in place of the bromide of benzyl and in step b) 3-fluorobenzyl bromide in place of ethyl iodide. Example 17 rac-4- [1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole The title compound, MS (El) = 208.1 (M +), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) the 2,3-difluorbenzyl bromide in place of benzyl bromide and in step b) methyl iodide instead of ethyl iodide. Example 18 4- (3-chloro-benzyl) -lH-imidazole The title compound, MS (ISP) = 193.4 (M + H +), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) 3-chlorobenzyl bromide in place of the bromide of benzyl followed directly by the deprotection step c). Example 19 rac-4- [1- (2,3-dimethyl-4-methoxy-phenyl) -ethyl] -1H-imidazole, hydrochloride The title compound, MS (ISP) 230.2 (M + H +), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) 2, 3-dimethyl-4-chloride methoxybenzyl instead of benzyl bromide and in step b) methyl iodide instead of ethyl iodide. Example 20 rac-4- [1- (2,3-difluoro-phenyl) -propyl] -lH-imidazole The title compound, MS (El) = 222.1 (M +), 193.1 (((M-C2H5) +), 100%), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, using step a) 2,3-difluoro-benzyl chloride in place of benzyl bromide. Example 21 rac-4- [1- (2,3-dimethyl-phenyl) -ethyl] -5-butyl-lH-imidazole, hydrochloride or tautomer The title compound, MS (ISP) = 257.2 (M + H +), is obtained in a comparable yield similar to the procedure described for Example 9 employing 2,3-dimethyl-phenylmagnesium bromide in place of the bromide of " f eni -magne sioy 4-acetyl-5-butyl imidazole in place of 4-a-ce ti 1 -5-methyl-1-imide zo 1.

Example 22 Rae- - [1,2-bis- (3,5-difluoro-phenyl) -ethyl] -1H-imidazole The title compound, E (ISP) = 321.1 (M + H +), is obtained in a comparable yield similar to the procedure described for Example 5, Route B, employing in step a) 3, 5-difluorbenzyl bromide in place of benzyl bromide and in step b) 3,5-difluorbenzyl bromide in place of ethyl iodide. Example 23 rac-5- [1- (2, 3-difluoro-phenyl) -propyl] -2-methyl-lH-imidazole, or tautomer The title compound is obtained, MS (El) = 236.1 (M +), 207.1 (((M-C2H5) +), 100%), similar to the procedure described for Example 5, Route B, using 1 - (dimethylsulfamoyl) -2-methyl-imidazole in place of 1- (dimethylsulfamoyl) -imidazole and 2,3-difluorbenzyl bromide in place of the benzyl bromide in step a).

Known compounds: Example 44 rac-5- (methoxy-phenyl-methyl) -lH-imidazole a) 2- (tert-butyl-dimethyl-silanyl) -4- (hydroxy-phenyl-methyl) -imidazole-1-sulfonic acid dimethylamide To a solution of 0.30 g (1.71 mmol) of 1- (dimethylsulfamoyl) -imidazole in 10 ml of tetrahydrofuran is added at -75 ° C 1.2 ml (1.88 mmol) of a 1.6 M solution of butyllithium in hexane. After stirring for 15 min, 0.30 g (2 mmol) of tert-butyl-dimethylsilyl chloride are added at -75 ° C and the mixture is stirred at room temperature for 2 h. The mixture is again cooled to -75 ° C and 1.2 ml (1.88 mmol) of a 1.6 M solution of butyllithium in hexane are added. After stirring for 30 min 0.22 ml (2.14 mmol) of benzaldehyde are added at -75 ° C and the mixture is allowed to warm to room temperature overnight. The mixture is distributed between water and dichloromethane, it is extracted again with dichloromethane, the combined organic phases are dried with MgSO, filtered and concentrated, obtaining 0.73 g of a yellow oil, which is used directly in the next step, E (El) = 338.1 ((M- tBu) +). b) rac-5- (methoxy-phenyl-methyl) -lH-imidazole A gentle stream of HC1 is bubbled gaseous through a refluxing solution of 2- (tert-butyl-dimethyl-silanyl) -4- (hydroxy-phenyl-methyl) -imidazole-1-sulfonic acid dimethylamide (0.2 g, 0.51 mmol) in methanol ( 5 mi) for 1 hour. The solvent is evaporated and a sodium hydroxide solution is added. The mixture is extracted with dichloromethane (2 times). The combined organic phases are dried with MgSO 4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane-methanol / conc. Aqueous ammonia = 90: 10: 1), yielding 25 mg (26%) of rac-5- (hydroxy-phenyl-methyl) ) -IH-imidazole, E (El) = 174.1 ((M +) and 5 mg (5%) of rac-5- (methoxy-phenyl-methyl) -1H-imidazole as a colorless oil: MS (ISP) = 189.1 ((M + H) +) Examples 45 and 46 4- [(S) -1- (2,3-difluoro-phenyl) -ethyl] -IH-imidazole and 4- [(R) -1 - (2, 3-difluoro-phenyl) -ethyl] -IH-imidazole Chiral a) 2- (tert-butyl-dimethyl-silanyl) -4- (2,3-difluoro-benzyl) -imidazole-1-sulfonic acid dimethylamide To a solution of 4.2 g (14.5 mol) of the dimethylamide of acid 2 - (te r-but i 1 -dime ti 1 - si lani 1) -imide zo 1 - 1 - its 1 phon i co in 50 ml of tetrahydrofuran 10.9 ml (17.4 mmoles) of a 1.6 M solution of butyllithium in hexane are added at -75 ° C. After stirring for 20 min, 3.6 g (17.4 mmoles) of the bromide of 2,3-dihydrogen chloride were added at -75 ° C and the mixture was allowed to warm to room temperature overnight. The mixture is partitioned between water and ethyl acetate, extracted again with ethyl acetate and the combined organic phases are dried with MgSO4, filtered and concentrated. The residue is purified by flash chromatography (silica gel, hexane / ethyl acetate = 4: 1), obtaining 3.0 g (49%) of 2- (tert-butyl-dimethyl-silanyl) -4-dimethylamide. - (2, 3-difluoro-benzyl) -imide zo 1 - 1 -sulphon as a light yellow solid; MS (ISP) = 416.1 ((M + H) +). b) (-) - and (+) -2- (tert-butyl dimethylsilanyl) -4- [1- (2,3-difluoro-phenyl) -ethyl] -imidazole-1-sulfonic acid dimethylamide ^ Quira ! Dissolve an amount of 2.9 g (7.0 mmol) of 2- (tert-butyl-dimethylsilanyl) -4- (2,3-difluoro-benzyl) -imidazole-1-sulfonic acid dimethylamide in 30 ml of tetrahydrofuran and add by dripping to a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (from 6.54 ml of BuLi 1.6M and 1.06 g of diisopropylamine). After stirring at -75 ° C for 1 h, 1.14 g (8.0 mmol) of methyl iodide are added and stirring is continued at room temperature overnight. Water is added to interrupt the reaction. The aqueous phase is extracted with ethyl acetate (3 times), the combined organic extracts are dried with MgSO 4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes / ethyl acetate = 4: 1), obtaining 2.47 g of the dimethylamide of rac-2- (tert-butyl-dimethyl-silanyl) -4- [ 1- (2,3-difluoro-phenyl) -ethyl] -imidazole-1-sulfonic acid (MS (ISP) = 430.3 ((M + H) +), slightly yellow oil). HE separates this material by chromatography on a chiral column (Chiral OD, isopropanol / heptane = 2:98), obtaining 0.785 g (26%) of the dimethylamide of the acid (+) -2- (tert-butyl-dimethyl-silanyl) - 4- [1- (2,3-difluoro-phenyl) -ethyl] -imidazole-1-sulphonic acid and 0.946 g (32%) of (+) - 2- (tert-butyl-dimethyl-silanyl) dimethylamide -4- [1- (2,3-difluoro-phenyl) -ethyl] -imidazole-1-sulfonic acid. c) 4- [(S) -1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole and 4- [(R) -1- (2,3-difluoro-phenyl) -ethyl] - lH-imidazole The (+) - 2- (tert-butyl-dimethyl-silanyl) -4- [1- (2,3-difluoro-phenyl) -ethyl] -imidazole-1-sulfonic acid dimethylamide (350) is dissolved mg, 0.81 mmol) in 10 ml of 1.5 N hydrochloric acid and maintained at boiling under reflux for 1 h. The solution is cooled, adjusted to pH > 8 with 25% aqueous ammonia and the solution is extracted with dichloromethane (2 times). The combined organic phases are dried with MgSO 4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane / methanol / conc. Aqueous ammonia = 90: 10: 1), obtaining 80 mg (47%) of 4- [1- (2,3-difluoro- phenyl) -ethyl] -lH-imidazole (enantiomer 1) in solid white mat form: MS (ISP) = 208.9 ((M + H) +), chiral HPLC (Reprosil Chiral-NR; heptane / ethanol - 90:10): t R = 9.9 min. 4- [1- (2, 3-difluoro-phenyl) -ethyl] -1H-imidazole (enantiomer 2) is obtained by the same procedure starting from of (-) -2- (tert-butyl-dimethyl-silanyl) -4- [1- (2,3-difluoro-phenyl) -ethyl] -imidazole-sulfonic acid dimethylamide in a yield of 73%; colorless oil, MS (ISP) = 208.9 ((M + H) +), chiral HPLC (Reprosil Chiral-NR, heptane / ethanol = 90: 10): t R = 11.1 min. Example 47 bis- (3, 5-difluoro-phenyl) - (1H-imidazol-4-yl) -methanol Methyl imidazolecarboxylate (0.80 g, 6.34 mol) and 50 ml (25 mmol) of a 0.5M solution of 3,5-difluorophenyl magnesium bromide in tetrahydrofuran are added under argon atmosphere. The mixture is kept boiling under reflux for 2 hours and most of the solvent is evaporated. Water is added with cooling and the mixture is extracted twice with ethyl acetate. The combined organic extracts are concentrated and the residue is purified by flash chromatography (silica gel, heptane / ethyl acetate = 8: 2), yielding 1.5 g (73%) of bi s - (3.5-di-1-chloro) - phen i 1) - (1 H-imi da z ol-4-i 1) -method 1 as a white solid; (ISP) = 305.1 ((M-OH) +); 323.4 ((M + H) Example 48 4- [bis- (3,5-difluoro-phenyl) -methyl] -lH-imidazole The bis- (3,5-difluoro-phenyl) - (1H-imidazol-4-yl) -methanol (0.5 g, 1.55 mmoles) is dissolved in 10 ml of ethanol and 0.66 ml of 12 M hydrochloric acid are added. The mixture is hydrogenated (5% Pd on C, 0.07 g, 100 baria H2, 100 ° C) for 20 h. The mixture is filtered through Celite® and the solvent is evaporated. The residue is partitioned between an aqueous solution of potassium carbonate and ethyl acetate. The organic phase is dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate), obtaining 0.2 g (42%) of 4- [bis- (3,5-difluoro-phenyl) -methyl] -1H-imidazole in the form of white solid; MS (ISP) = 307.1 ((M + H) +).

Example 49 4- (5-Bromo-benzofuran-7-ylmethyl) -2- (tert-butyl-dimethyl-silanyl) 4- (5-bromo-benzofuran-7-ylmethyl) -1-imidazole a) dimethylamide imidazole-l-sulfonic The 4- (5-bromo-benzofuran-7-ylmethyl) -2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid dimethylamide is obtained in a manner similar to that described in Example 5 (Route B, step a), using 5-bromo-7-bromomethyl-benzofuran instead of benzyl bromide: amorphous solid of a slightly yellow color; MS (ISP) = 500.0 ((M + H) +). b) 4- (5-bromo-benzofuran-7-ylmethyl) -1-imidazole 4- (5-Bromo-benzofuran-7-ylmethyl) -1-imidazole is obtained in a manner similar to that described in Example 5 (Route B, step c) from the 4- (5-bromo-) dimethylamide benzofuran-7-ylmethyl) -2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid: white solid; MS (ISP) = 277.0 ((M + H) +).

Example 50 4- (2,3-dihydro-benzofuran-7-ylmethyl) -1-imidazole Treat a solution of 4- (5-bromo-ben zo fu n an- 7-i lme ti 1) -1-imide zo 1 (21 mg, Example 49) in E t OH (2 ml) with Pd at 10 ° C. % on C (10 mg) and hydrogenated at normal pressure for 20 h. The reaction mixture is filtered and concentrated. The crude product was purified by column chromatography (Isolute® Flash-NH2 (Separtis), gradient: CH2C12 -> CH2C12 / MeOH = 95: 5), yielding 4 - (2,3-dihydro-benzofluoride). - i lme ti 1) - 1 - imide zo 1 (7 mg) as a white solid. Example 51 4-benzofuran-7-ylmethyl-1-imidazole The 4-benzofur an- 7-i lme t i 1-1-imidazole is obtained in a manner similar to that described in Example 49 from 7-bromomethyl-benzofurane: slightly yellow solid; MS (ISP) = 199.1 ((M + H) +).

Example 52 4- (2-methyl-naphthalen-1-ylmethyl) -lH-imidazole 4- (2-Methyl-naphthalen-1-ylmethyl) -1H-imidazole is obtained in a manner similar to that described in Example 49 from l-bromomethyl-2-methyl-naphthalene: white solid; MS (ISP) = 223.1 ((M + H) +). Example 53 Rae-7- [Hydroxy- (lH-imidazol-4-yl) -methyl] -5-methyl-benzofuran-2-carboxylic acid ethyl) a) 7-formyl-5-methyl-benzofuran-2-carboxylic acid ethyl ester Treat a solution of 2-hydroxy-5-methylisophthai-aldehyde (1 g) in DMF (10 mL) under an atmosphere of argon with potassium carbonate (1.01 g) and diethyl bromomalonate (1.60 g). The reaction mixture is heated at 100 ° C 20 h, then cooled to rt, the reaction is quenched with water and the mixture is extracted with EtOAc. The organic phase is dried with MgSO 4, filtered and concentrated to obtain 7-yl-5-methyl-benzofuran-2-ethyl carboxylate (1.34 g). in the of matt white solid. MS (ISP) = 233.1 ((M + H) +). The crude product is used without further purification the next reaction step. b) rac-7-. { [2- (tert-butyl-dimethyl-silanyl) -1-dimethylsulfamoyl-lH-imidazol-4-yl] -hydroxy-methyl} -5-methyl-benzofuran-2-carboxylate ethyl A solution of the dimethylamide of 2- (tert-butyl-dimethyl-silanyl) -imidazole-1-sulfonic acid (1.0 g) in THF (10 mL) is cooled under an argon atmosphere at -78 ° C. A solution of n-butyllithium (1.6 M in heptane, 2.37 ml) is added dropwise. After stirring at -78 ° C 1 h, a solution of 7-yl-5-methyl-benzofuran-2-carboxylic acid ethyl ester (963 mg) in THF (10 ml) was added dropwise. Stirring is continued at -78 ° C 15 min, then the reaction mixture is warmed to t.amb. during one night. The reaction is quenched with water and the mixture is extracted with EtOAc. The organic phase is dried with MgSO 4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: cyclohexane -> cyclohexane / EtOAc = 1: 1), yielding rac-7. { [2- (tert-butyl-dimethyl-silanyl) - 1-dimethylsulfamoyl-lH-imidazol-4-yl] -hydroxy-methyl} Ethyl-methyl-benzofuran-2-carboxylate in the of an amorphous solid of a slightly yellow color; MS (ISP) = 522.3 ((M + H) +). c) rae-7- [hydroxy- (lH-imidazol-4-yl) -methyl] -5-methyl-benzofuran-2-carboxylic acid ethyl ester The rac-7- [ethyl hydroxy- (lH-imidazol-4-yl) -methyl] -5-methyl-benzofuran-2-carboxylate is obtained in a manner similar to that described in Example 5 (Route B, step c) from 7-. { [2- (tert-butyl-dimethyl-silanyl) -1-dimethylsulfamoyl-lH-imidazol-4-yl] -hydroxy-methyl} Ethyl-methyl-benzofuran-2-carboxylate: white solid; MS (ISP) = 301.3 ((M + H) +). Example 54 7- (1H-imidazol-4-ylmethyl) -5-methyl-benzofuran-2-carboxylic acid ethyl ester A solution of rac-7- is treated. { [2- (tert-butyl dimethyl-silanyl) -1-dimethylsulfamoyl-lH-imidazol-4-yl] - hydroxy-methyl} Ethyl-methyl-benzofuran-2-carboxylate (470 mg, example 52. b) in EtOH (16 ml) with 10% Pd on C (117 mg) and hydrogenated at 100 ° C with a pressure of 100 barias during 48 h. The reaction mixture is cooled to RT, filtered and concentrated. The residue is dissolved in EtOH (5 mL) and treated with 3N HC1 (5 mL). The solution is heated at 100 ° C 3 h, then concentrated. The residue is collected in water. The solution is made basic by the addition of K2C03 and extracted with CH2Cl2 / MeOH = 4: 1. The organic phase is dried with gS04, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: CH2C12 -> CH2Cl2 / MeOH = 9: 1), yielding 7- (lH-imidazol-4-ylmethyl) -5-methyl-benzofuran- Ethyl 2-carboxylate (10 mg) as a white matte amorphous solid. MS (ISP) = 285.1 (M + H +). Example 55 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -lH-pyrazole to) . 4- (3-benzyl-3H-imidazol-4-ylmethyl) -heptane-3,5-dione or 4- (l-benzyl-lH-imidazol-4-ylmethyl) -heptane-3,5-dione To a solution of 3.75 ml (10 mmol, solution ~ 21% in ethanol) of sodium enolate in 40 ml of dry ethanol is added 1.30 mg (10 mmol) of 3,5-heptanedione and stirred at 50 °. C 30 min. A potassium iodide spatula tip is then added and then a solution of 1-benzyl-5-chloromethyl-1H-imidazole (obtained from 2.27 g. (9.4 mmol) l-benzyl-5-chloromethyl-lH-imidazole, hydrochloride), in 10 ml of ethanol and 3.5 ml (9.4 mmol; solution ~ 21% in ethanol). The mixture is heated at 50 ° C a further 5 min and then immediately cooled to room temperature and concentrated under reduced pressure at 30 ° C maximum. Purification by flash chromatography through silica gel using a 1: 1 mixture of heptane / ethyl acetate as eluent gives 4- (3-benzyl-3H-imidazol-4-ylmethyl) -heptane-3, 5-dione as a slightly yellow waxy solid: MS (ISP) = 299.2 ((M + H) +). bj 4- (3-benzyl-3H-imidazol-4-ylmethyl) -3,5-diethyl-1H-pyrazole or 4- (1-benzyl-1H-imidazol-4-ylmethyl) -3,5-diethyl-1H -pirazol To a solution of 140 mg (0.47 mmol) of the 4- (3-benzyl-3H-imidazol-4-ylmethyl) -heptane-3,5-dione in 1.5 ml of Ethanol is added a solution of 24 mg (0.48 mmoles) of hydrazine monohydrate in 0.5 ml of ethanol and the mixture is heated at reflux for 10 min. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in a 1N aqueous solution of HC1 and extracted three times with methyl ether and t-butyl. The aqueous phase is adjusted to pH 12 and extracted three times with methyl ether and t-butyl, the extracts are combined, washed with brine, dried with sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography through silica gel, using ethyl acetate as eluent, gives 4- (3-benzyl-3H-imidazol-4-ylmethyl) -3,5-diethyl-1H-pyrazole. in the form of a colorless viscous oil: MS (ISP) = 295.3 (M + H +). c) 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -lH-pyrazole By hydrogenation at 60 ° C for 2 h of a solution of 110 mg (0.37 mmol) of 4- (1-benzyl-lH-imidazol-2-ylmethyl) -3,5-diethyl-1H-pyrazole in 10 ml of ethanol and 1 ml of 2N aqueous HC1 in the presence of a catalytic amount of 10% Pd on C and subsequent purification in the usual way yields 3,5-diethyl-4- (lH-imidazol-2-ylmethyl) -lH-pyrazole pure, as a colorless solid: MS (ISP) = 205.2 ((M + H) +).

Example 56 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -1-methyl-pyrazole a) 4- (l-Benzyl-lH-imidazol-2-ylmethyl) -3,5-diethyl-l-methyl-lH-pyrazole or 4- (l-benzyl-lH-imidazol-4-ylmethyl) -3, 5-diethyl-l-methyl-lH-pyrazole 4- (1-Benzyl-1H-imidazol-2-ylmethyl) -3,5-diethyl-1-methyl-1H-pyrazole is obtained from 4- (3-benzyl-3H-imidazol-4-ylmethyl) ) -heptane-3, 5-dione and methylhydrazine in a manner similar to that described in Example 55 b): colorless solid; MS (ISP) - 309.3 ((+ H) +). b) 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -1-methyl-lH-pyrazole 3, 5-Diethyl-4- (3H-imidazol-4-ylmethyl) -1-methyl-1H-pyrazole is obtained from 4- (1-benzyl-1H-imidazol-2-ylmethyl) -3,5 -diethyl-l-methyl-lH-pyrazole similarly to described in Example 55 c): colorless solid; MS (ISP) = 219.0 ((M + H) +). Example 57 4- (2-ethyl-6-methyl-benzyl) -lH-imidazole a) Butyl- [1- (2-chloro-6-fluoro-phenyl) -met- (E) -ylidene] -amine To a solution of 59.8 g (377 mmoles) of 2-chloro-6-f luorbenzaldehyde in 250 ml of toluene are added 41.0 ml (415 mmoles) of n-bu ti 1-amine and 1.44 g (7.54 mmoles) of p-toluenesulfonic acid. The mixture is heated at reflux for 5 h. The mixture is cooled to room temperature, diluted with toluene and washed successively with an aqueous solution of sodium bicarbonate, water and saturated brine solution. The organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo to obtain 80.1 g (99% of the title compound as a dark brown oil, which is used without further purification for the next step. ) = 216.2 ([ { 37C1.}. M + H] +), 214.2 ([ { 3 C1.}. M + H] +). b) Butyl- [1- (2-chloro-6-methyl-phenyl) -met- (E) -ylidene] -amine This compound is obtained by applying the methodology described in Synthesis 2138-2144, 1999. To a solution of 7.00 g (32.8 mmol) of butyl- [1- (2-chloro-6-fluoro-phenyl) -met- (E) -ylidene] -amine in 70 ml of tetrahydrofuran is added at 0 ° C 0.41 g (3.28 mmol) of manganese chloride (II). Then 21.8 ml (65.5 mmol) of a 3 M solution of methyl magnesium chloride in tetrahydrofuran are added dropwise maintaining the temperature of the reaction mixture at 5-10 ° C. After the addition is complete, the reaction mixture is stirred for an additional 30 minutes, during which time the temperature rises to 40 ° C (exothermic reaction). The reaction is stopped by the dropwise addition of water and the mixture is stirred for a further 30 minutes, then diluted with toluene. The mixture is filtered and the organic phase of the filtrate is washed with a saturated solution of brine. The phases are separated and the organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was again suspended in carbon tetrachloride and again concentrated in vacuo to obtain 6.90 g (100%) of the title in the form of yellow oil that is used without further purification for the next step. MS (ISP) = 212.1 ([ { 37C1.}. M + H] +), 210.1 ([ { 35C1.}. M + H] +). c) 2-ethyl-6-methyl-benzaldehyde obtain this compound by applying the methodology described in Synthesis 2138-2144, 1999. To a solution of 3.20 g (15.3 mmol) of butyl- [1- (2-chloro-6-methyl-phenyl) -met- (E) - ylidene] -amine in 30 ml of tetrahydrofuran is added at 0 ° C 0.19 g (1.53 mmoles) of manganese chloride (II). Then 15.3 ml (30.5 mmol) of a 2 M solution of ethyl magnesium chloride in diethyl ether are added dropwise maintaining the temperature of the reaction mixture at 5-10 ° C. After the addition is complete, the reaction mixture is stirred for an additional 90 minutes, during which time the temperature rises to 50 ° C (exothermic reaction). The reaction is stopped by the dropwise addition of water and then the mixture is diluted with ethyl acetate. The mixture is washed successively with water and 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 is purified by flash chromatography (silica gel, ethyl acetate / heptane gradient), obtaining 1.88 g (83%) of the title compound as a yellow oil. NMR-H1 (CDC13): 1.26 (3H, t, CH3), 2.60 (3H, s, CH3), 2.98 (2H, q, CH2), 7.09 (1H, d, ArH), 7.12 (1H, d, ArH ), 7.35 (1H, dd, ArH), 10.6 (1H, s, CHO). d) rae- (2-ethyl-6-methyl-phenyl) - (1-trityl-1H- This compound is obtained by applying the methodology described in J. Org. Chem. 56, 5739-5740, 1991. To a stirred suspension of 1.47 g (3.37 mmol) of 4-iodo-tritylimidazole in 5 ml of dichloromethane are added 1.12 ml (3.37 mmol) of a 3M solution of bromide. of ethyl magnesium in diethyl ether at a rate such that the temperature of the reaction mixture does not exceed 28 ° C. The resulting solution of (l-trityl-lH-imidazol-4-yl) -magnesium halide is stirred at room temperature for 30 minutes and then a solution of 0.50 g (3.37 mmol) of 2- ethyl-6-methyl-benzaldehyde in 2 ml of dichloromethane. The reaction mixture is stirred at room temperature for 5 h, then the reaction is stopped by the dropwise addition of water and the mixture is diluted with dichloromethane. The phases are separated and the organic phase with Na2SC > 4, they are filtered and concentrated with vacuum, obtaining 1.40 g (90%) of the title compound in the form of matt white foam that is used without further purification for the next step. e) 4- (2-ethyl-6-methyl-benzyl) -lH-imidazole This compound is obtained by applying the methodology described in J. Chem. Soc., Perkin Trans. 1, 1061-1066, 2002. To a stirred solution of 0.35 g (0.76 mmol) of rae- (2-ethyl-6-methyl-phenyl) - (1-trityl-1H-imidazol-4-yl). ) -methanol in 5 ml of dichloromethane is added dropwise 1.22 ml (7.63 mmoles) of triethylsilane and 0.69 ml (9.16 mmoles) of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 16 hours and then diluted with a 1: 1 mixture of tetrahydrofuran and ethyl acetate. The mixture is washed successively with a 2 N aqueous solution of sodium hydroxide and a saturated solution of brine, then the organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, methanol / dichloromethane gradient) to obtain 40 mg (26%) of the title compound as a yellow crystalline solid. 201. 3 ([M + H] +). Example 58 - (2-cyclopropyl-6-ethyl-benzyl) -lH-imidazole a) Butyl- [1- (2-chloro-6-ethyl-phenyl) -met- (E) -ylidene] -amine This compound is obtained by applying the methodology described in Synthesis 2138-2144, 1999. To a solution of 21.2 g (99.2 mmoles) of butyl- [1- (2-chloro-6-fluoro-phenyl) -met- (E) -ylidene] -amine in 150 ml of tetrahydrofuran is added dropwise at 0 ° C 38.0 ml (114 mmol) of a 3 M solution of ethyl magnesium bromide in ether at a rate such that the temperature of the reaction mixture Keep below 20 ° C. Once the addition is complete, the reaction mixture is stirred at room temperature for a further 1 h. The reaction is stopped by the dropwise addition of water and the mixture is diluted with ethyl acetate. The mixture is washed successively with water and with a saturated solution of brine, then the organic phase is dried with a2SO4, filter and concentrate with vacuum. The residue was again suspended in carbon tetrachloride and again concentrated in vacuo to give 19.7 g (89%) of the title compound as a yellow oil which is used without further purification for the next step. MS (ISP) = 226.3 ([ { 37C1.}. M + H] +), 224.3 ([ { 35C1.}. + H] +). The analysis of H-NMR and EM indicates that this material contains approx. 13% of the secondary product butyl- [1- (2-ethyl-6-fluoro-phenyl) -met- (E) -ylidene] -amine. MS (ISP) = 208.3 ([M + H] +). b) 2-cyclopropyl-6-ethyl-benzaldehyde Obtained in a manner similar to that described in Example 57 (c) from butyl- [1- (2-chloro-6-ethyl-phenyl) -met- (E) -ylidene] -amine, cyclopropyl bromide magnesium and manganese (II) chloride in tetrahydrofuran and ether with subsequent chromatography through silica gel. Yellow oil NMR-H1 (CDC13): 0.74 (2H, m, CH2), 1.02 (2H, m, CH2), 1.25 (3H, t, CH3), 2.40 (1H, m, CH), 2.98 (2H, q, CH2 ), 7.04 (1H, d, ArH), 7.12 (1H, d, ArH), 7.36 (1H, dd, ArH), 10.9 (1H, s, CHO). c) rae- (2-cyclopropyl-6-ethyl-phenyl) - (1-trityl-1H-imidazol-4-yl) -methanol It is obtained in a manner similar to that described in Example 57 (d) from 2-cyclopropyl-6-ethyl-benzaldehyde and a (l-trityl-1H-imidazol-4-yl) -magnesium halide prepared in situ in dichloromethane. d) 4- (2-cyclopropyl-6-ethyl-benzyl) -lH-imidazole Obtained in a manner similar to that described in Example 57 (e) from rae- (2-cyclopropyl-6-ethyl-phenyl) - (1-trityl-1H-imidazol-4-yl) -methanol, triethylsilane and acid trifluoroacetic in dichloromethane. Matte white crystalline solid. MS (ISP) = 227.4 ([M + H] +). Example 59 Rae- (2-chloro-6-ethyl-phenyl) - (1H-imidazol-4-yl) -methanol a) 2-chloro-6-ethyl-benzaldehyde To a solution of 19.7 g (88.1 mmol) of butyl- [1- (2-chloro-6-ethyl-phenyl) -met- (E) -ylidene] -amine in 70 ml of water are added dropwise to 0 ° C 18.9 ml of concentrated sulfuric acid. The mixture is heated at reflux for 90 min, then cooled to room temperature and diluted with ethyl acetate. The mixture is washed successively with water, a saturated aqueous solution of sodium bicarbonate and a saturated solution of brine. The organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate / heptane 1:30), yielding 11.4 g (77%) of the title compound as a yellow oil. NMR-H1 (CDC13): 1.22 (3H, t, CH3), 2.97 (2H, q, CH2), 7.20 (1H, d, ArH), 7.30 (1H, d, ArH), 7.39 (1H, dd, ArH ), 10.65 (1H, s, CHO). b) rae- (2-chloro-6-ethyl-phenyl) - (1-trityl-lH-imidazol-4-yl) -methanol It is obtained in a similar way to that described in Example 57 (d) from 2-o-o-o-6-e t i 1 -ben z a 1 deh gone and a halide of (l-trityl-lH-imidazol-4-yl) -magnesium prepared in situ in dichloromethane. Crystalline solid love i 11 o. c) rae- (2-chloro-6-ethyl-phenyl) - (lH-imidazol-4-yl) -methanol It is obtained in a similar way to that described in Example 57 (e) from rae- (2-chloro-6-ethyl-phenyl) - (1-trityl-lH-imidazol-4-yl) -methanol, triethylsilane and trifluoroacetic acid in dichloromethane at room temperature, is obtained the title compound as a by-product after the deprotection of the trityl group without concomitant reduction of the benzyl alcohol group. Yellow oil E (ISP) = 238.9 ([ { 37C1.}. M + H] +), 236.8 ([ { 35C1.}. M + H] +). Example 60 4- [3- (4-Chloro-phenoxy) -benzyl] -lH-imidazole It is obtained in a manner similar to that described in Example 57 (d) - (e) from 3- (4-chlorophenoxy) benzaldehyde and a (l-trityl-lH-imidazol-4-yl) -magnesium halide prepared in situ in dichloromethane and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane. Amorphous white solid. MS (ISP) = 287.2 ([ { 37C1.}. M + H] +), 285.1 ( { C135.}. M + H +). Example 61 4- (2-Chloro-6-ethyl-benzyl) -lH-imidazole It is obtained in a similar way to that described in Example 57 (e) from rae- (2-chloro-6-ethyl-phenyl) - (1-trityl-1H-imidazol-4-yl) -methanol, triethylsilane and trifluoroacetic acid in dichloromethane, except that the reaction is carried out in a pressure tube at 70 ° C for 16 h. White crystalline solid. EM '(ISP) = 223.3 ([ { 37C1.}. M + H] +), 221.2 ([ { 35C1.}. M + H] +). Example 62 4- (3-ethoxy-benzyl) -lH-imidazole It is obtained in a manner similar to that described in Example 57 (d) - (e) from 3-ethoxybenzaldehyde and a (l-trityl-1H-imidazol-4-yl) -magnesium halide prepared in in dichloromethane and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Yellow oil MS (ISP) = 203.4 ([M + H] +). Example 63 4- (2-Fluoro-5-methoxy-benzyl) -lH-imidazole It is obtained in a similar way to that described in Example 57 (d) - (e) from 2-fluoro-5-methoxybenzaldehyde and a halide of (1-trityl-1H-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. White crystalline solid. MS (ISP) = 207.3 ([M + H] +). Example 64 4- [3- (1, 1, 2, 2-tetrafluoro-ethoxy) -benzyl] -1H-imidazole Obtained in a manner similar to that described in Example 57 (d) - (e) from 3- (1, 1, 2, 2) tetrafluoroethoxy) benzaldehyde and a halide of (1-trityl-lH-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and further treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Yellow oil MS (ISP) = 275.3 ([M + H] +). Example 65 4- (3-benzyloxy-benzyl) -lH-imidazole Obtained in a similar manner to that described in the Example 57 (d) - (e) from 3-benzyloxybenzaldehyde and a halide of (1-trityl-1H-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Colorless oil MS (ISP) = 265.3 ([M + H] +). Example 66 4- (3-Chloro-biphenyl-2-ylmethyl) -lH-imidazole It is obtained in a manner similar to that described in Example 57 (c) from butyl- [1- (2-chloro-6-fluoro- phenyl) -met- (E) -ylidene] -amine and phenylmagnesium chloride in tetrahydrofuran and subsequent chromatography through silica gel, then in a manner similar to that described in Example 57 (d) - (e) by treatment with a halide of (1-trityl-1H-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and further treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Colorless oil MS (ISP) = 271.2 ([ { C137.}. M + H] +), 269.3 ([ { Cl35.}. M + H] +). Example 67 4-biphenyl-2-ylmethyl-1H-imidazole To a stirred solution of 50 mg (0.19 mmol) of the 4- (3-chloro-biphenyl-2-ylmethyl) -lH-imidazole in 40 ml of methanol is added 40 mg of 10% palladium on carbon and the mixture is stirred at room temperature for 16 h with an excess of pressure of hydrogen 0.6 bar. The mixture is filtered and the filtrate is concentrated in vacuo to give 25 mg (57%) of the title compound as a white crystalline solid. MS (ISP) = 235.1 ([M + H] +).

Example 68 -chloro-biphenyl-3-ylmethyl) -lH-imidazole Obtained in a manner similar to that described in Example 57 (d) - (e) from 4'-chloro-biphenyl-3-carbaldehyde and a halide of (l-trityl-lH-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. White crystalline solid. MS (ISP) = 271.3 ([ { 37C1.}. + H] +), 269.3 ([(35C1.}. M + H] +) Example 69 4- (2,6-diethyl-4-methoxy) -benzyl) -lH-imidazole It is obtained in a similar way to that described in Example 57 (a) - (b) & (d) - (e) from 2, 6 -di f 1 uo ro-4-methoxybenzaldehyde, N-butylamine and acid or its 1-ion in toluene, then treatment with 3 equivalents of ethyl bromide. 1 -magne sioy manganese (II) chloride in tetrahydrofuran and ether and subsequent chromatography through silica gel, then treatment with a halide of (1 - 1 riti 1 - 1 H- imi da zo 1 - 4 -yl) -magnesium prepared in situ in dichloromethane, and then treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Light brown crystalline solid. E (ISP) = 245.3 (M + H +). Example 70 4- (2,6-diethyl-3-methoxy-benzyl) -lH-imidazole Obtained in a manner similar to that described in Example 57 (a) - (b) & (d) - (e) from 2,6-difluoro-3-methoxybenzaldehyde, N-butylamine and p-toluenesulfonic acid in toluene, treatment with 3 equivalents of ethyl magnesium bromide and manganese chloride. (II) in tetrahydrofuran and ether and subsequent chromatography through silica gel, treatment with a halide of (l-trityl-lH-imidazol-4-yl) -magnesium prepared in situ. in dichloromethane and then treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Light brown crystalline solid. MS (ISP) = 245.4 ([M + H] +).

Example 71 4-biphenyl-3-ylmethyl-1H-imidazole Obtained in a manner similar to that described in Example 67 from 4- (4'-chloro-biphenyl-3-ylmethyl) -1H-imidazole, hydrogen and palladium in methanol. White crystalline solid. MS (ISP) = 235.1 ([M + H] +). Example 72 4- (4-ethoxy-2,6-diethyl-benzyl) -lH-imidazole a) 2, 6-diethyl-4-methoxy-benzaldehyde obtained in a manner similar to that described Example 57 (a) - (b) from 2,6-difluoro-4-methoxybenzaldehyde, N-butylamine and p-toluenesulfonic acid in toluene, then treatment with 3 equivalents of ethyl magnesium bromide and manganese (II) chloride in tetrahydrofuran and ether and then chromatography through silica gel EM (ISP) = 193.3 ([M + H] +). b) 2, 6-diethyl-4-hydroxy-benzaldehyde To a solution of 2.50 g (13.0 mmol) of 2,6-diethyl-4-methoxy-benzaldehyde in 15 ml of dichloromethane is added dropwise at -60 ° C 26.0 ml (26.0 mmoles) of a 1 M solution of tribromide of boron in dichloromethane. After the addition is complete, the reaction mixture is allowed to warm to room temperature and then heated to reflux for 16 h. The reaction mixture is cooled to room temperature and poured into an ice-water mixture. The mixture is diluted with dichloromethane, the phases are separated, the organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue is again suspended in a 1: 1 mixture of ethyl acetate and diethyl ether and extracted with a 1 N aqueous solution of sodium hydroxide. The phases are separated and the aqueous phase is acidified to pH 1 by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The phases are separated and the organic phase is washed with a saturated solution of brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain 1.48 g (64%) of the title compound as a brown crystalline solid. EM (ISP) = 177. 4 ([M-H] ~). c) 4-ethoxy-2,6-diethylbenzaldehyde To a solution of 0.30 g (1.68 mol) of 2,6-diethyl-4-hydroxy-benzaldehyde in 8 ml of N, N-dimethylformamide in a pressure tube is added 0.16 ml (2.02 mmol) of iodoethane and 0.35 g. (2.52 mmoles) of potassium carbonate. The tube is sealed and the reaction mixture is heated at 50 ° C for 16 h. The reaction mixture is cooled to room temperature, diluted with diethyl ether and washed successively with water and a saturated solution of 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 flash chromatography (silica gel, ethyl acetate / heptane = 1:30), obtaining 0.31 g (88%) of the title compound as a yellow oil. MS (ISP) = 207.3 ([M + H] +). d) rae- (4-ethoxy-2,6-diethyl-phenyl) - (1-trityl-1H- It is obtained in a manner similar to that described in Example 57 (d) from 4-ethoxy-2,6-diethyl benzaldehyde and a halide of (1-1-riti-1 H-imide zo 1-yl) -magnesium prepared in situ in dichloromethane Yellow crystalline solid. e) 4- (4-ethoxy-2,6-diethyl-benzyl) -lH-imidazole Obtained in a manner similar to that described in Example 57 (e) from rae- (4-ethoxy-2,6-diethyl-phenyl) - (1-trityl-1H-imidazol-4-yl) -methanol, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. White crystalline solid. MS (ISP) = 259.4 ([M + H] +). Example 73 4- (4-benzyloxy-2,6-diethyl-benzyl) -lH-imidazole It is obtained in a manner similar to that described in Example 72 (c) - (e) from 2,6-diethyl-4-hydroxy benzaldehyde, benzyl bromide and potassium carbonate in N, N-dimethylformamide, treatment with a halide of (1-trityl-lH-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Amorphous white solid. MS (ISP) = 321.1 ([M + H] +). Example 74 4- (3-ethoxy-2,6-diethyl-benzyl) -lH-imidazole Obtained in a manner similar to that described in Example 72 (a) - (e) from 2,6-difluoro-3-methoxybenzaldehyde, N-butylamine and p-toluenesulfonic acid in toluene, treatment with 3 equivalents of ethyl bromide -magnesium and manganese (II) chloride in tetrahydrofuran and ether and subsequent chromatography through silica gel, treatment with boron tribromide in dichloromethane, treatment with iodoethane and potassium carbonate in N, N-dimethylformamide, treatment with a halide of ( 1-trityl-lH-imidazol-4-yl) -magnesium prepared in situ in dichloromethane and further treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70 ° C for 16 h. Amorphous white solid. MS (ISP) = 259.3 Q ([M + H] +) Example 75 1, 3, 5-triethyl-4- (3H-imidazol-4-ylmethyl) -lH-pyrazole a) 4- (3-benzyl-3H-imidazol-4-ylmethyl) -1, 3, 5-triethyl-1H-pyrazole or 4- (1-benzyl-1H-imidazol-4-ylmethyl) 1.3, 5 -triethyl-lH-pyrazole 4- (3-Benzyl-3H-imidazol-4-ylmethyl) -1,3,5-triethyl-1H-pyrazole is obtained from 4- (3-benzyl-3H-imidazol-4-ylmethyl) - heptane-3, 5-dione and ethylhydrazine in a manner similar to that described in Example 55 b): matt white solid; MS (ISP) = 323.3 ((M + H) +). b) 1,3,5-triethyl-4- (3H-imidazol-4-ylmethyl) -1H-pyrazole 1, 3, 5-triethyl-4- (3H-imidazol-4-ylmethyl) -lH-pyrazole is obtained from 4- (3-benzyl-3H-imidazol-4-ylmethyl) -1, 3, 5 -triethyl-lH-pyrazole by debenzylation with sodium in liquid ammonia for 10 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. The 1,3,5-triethyl-4- (3H-imidazol-4-ylmethyl) -lH-pyrazole is obtained as a slightly yellow solid; E (ISP) = 233.0 ((M + H) +). Example 76 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -1-isopropyl-1H-pyrazole a) 4- (3-benzyl-3H-imidazol-4-ylmethyl) -3,5-diethyl-1-isopropyl-1H-pyrazole or 4- (1-benzyl-1H-imidazol-4-ylmethyl) -3, 5-diethyl-l-isopropyl-lH-pyrazole 4- (3-Benzyl-3H-imidazol-4-ylmethyl) -3,5-diethyl-1-isopropyl-1H-pyrazole is obtained from 4- (3-benzyl-3H-imidazol-4-ylmethyl) ) -heptane-3, 5-dione and isopropylhydrazine in a manner similar to that described in Example 55 b): colorless solid; MS (ISP) = 337.3 ((M + H) +). b) 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -1-isopropyl-1H-pyrazole 3, 5-Diethyl-4- (3H-imidazol-4-ylmethyl) -1-isopropyl-1H-pyrazole is obtained from 4- (3-benzyl-3H-imidazol-4-ylmethyl) -3,5 -diethyl-l-isopropyl-1H-pyrazole in a manner similar to that described in Example 75 b): matt white solid; E (ISP) = 247.2 ((M + H) +). Example 77 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -1-propyl-1H-pyrazole or tautomer a) 4- (3-benzyl-3H-imidazol-4-ylmethyl) -3,5-diethyl-1-propyl-1H-pyrazole or 4- (1-benzyl-1H-imidazol-4-ylmethyl) -3, 5-diethyl-l-propyl-lH-pyrazole The 4 - (3-benz i 1 - 3H-imide z or 1 - 4 - is obtained ilmethyl) -3,5-diethyl-1-propyl-1H-pyrazole from 4 - (3-benzyl-3H-imidazol-4-ylmethyl) -heptane-3,5-dione and propylhydrazine similarly to described in Example 55 b): matt white solid; MS (ISP) 337.1 ((M + H) +). b) 3, 5-diethyl-4- (3H-imidazol-4-ylmethyl) -1-propyl-1H-pyrazole or tautomer 3, 5-Diethyl-4- (3H-imidazol-4-ylmethyl) -1-propyl-1H-pyrazole is obtained from 4- (3-benzyl-3H-imidazol-4-ylmethyl) -3,5 -diethyl-l-propyl-lH-pyrazole in a manner similar to that described in Example 75 b): slightly yellow viscous oil; MS (ISP) = 247.1 ((M + H) +). Example 78 4- (2-ethyl-6-fluoro-benzyl) -lH-imidazole a) Butyl- [1-luoro-phenyl) -met-ylidene] -amine Obtained in the manner described in Example 58 (a) as a by-product of the reaction between butyl- [1- (2-chloro-6-fluoro-phenyl) -met- (E) -ylidene] -amine and the bromide of ethyl magnesium in tetrahydrofuran and ether. MS (ISP) = 208., 3 ([M + H] +). b) 2-ethyl-6-fluoro-benzaldehyde It is obtained in a similar way to that described in Example 59 (a) from butyl- [1- (2-ethyl-6-fluoro-phenyl) -met- (E) -ylidene] -amine and aqueous sulfuric acid. c) rac-2- (tert-butyl-dimethylsilanyl) -4- [(2-ethyl-6-fluoro-phenyl) -hydroxy-methyl] -imidazole-1-sulfonic acid dimethylamide It is obtained in a similar way to that described in Example 44 (a) from 1- (dimethylsulphamoyl) -imidazole, butyllithium and tert-butyldimethylsilyl chloride in tetrahydrofuran, forming the dimethylamide of 2- (tert-butyl-dimethylsilanyl) -imidazole-1-sulfonic acid and later treatment of this with butyl- lithium and 2-e t i 1 -6-f luo r o -ben z a 1 deh i do in tetrahydrofuran. White crystalline solid. MS (ISP) = 442 ([M + H] +). d) 4- (2-ethyl-6-fluoro-benzyl) -lH-imidazole Obtained in a manner similar to that described in Example 57 (e) from dimethylamide of rac-2- (tert-butyl-dimethyl-silanyl) -4- [(2-ethyl-6-fluoro-phenyl) - hydroxy-methyl] -imidazole-1-sulfonic acid, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100 ° C for 16 h. White crystalline solid. MS (ISP) = 205.3 ([M + H] +). Example 79 4- (2,6-diethyl-4-phenoxy-benzyl) -lH-imidazole a) 2, 6-diethyl-4-phenoxy-benzaldehyde To a solution of 1.50 g (8.42 mmol) of 2,6-diethyl-4-hydroxy-benzaldehyde in 60 ml of dichloromethane is added 1.64 g (13.5 mmoles) of phenylboronic acid, 2.29 g (12.6 mmoles) of acetate of copper (II), 30 g of molecular sieves of 4Á and 4.06 ml (50.5 mmoles) of pyridine. The reaction mixture is stirred at room temperature for 72 h and then filtered through Celite. The filtrate was extracted with a 1 N aqueous solution of hydrochloric acid, the phases were separated, the organic phase was dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate / heptane gradient), yielding 1.64 g (77%) of the title compound as a yellow oil. NMR-H1 (CDC13): 1-22 (6H, t, CH3), 2.95 (4H, q, CH2), 6.69 (2H, s, ArH), 7.08 (2H, d, ArH), 7.20 (1H, ArH), 7.39 (2H, dd, ArH), 10.5 (1H, s, CHO). b) rac-2- (tert-butyl-dimethylsilanyl) -4- [(2,6-diethyl-4-phenoxy-phenyl) -hydroxy-methyl] -imidazole-1-sulfonic acid dimethylamide It is obtained in a similar way to that described in Example 44 (a) from 1- (dimethylsulfamoyl) -imidazole, butyllithium and tert-butyldimethylsilyl chloride in tetrahydrofuran, obtaining dimethylamide of 2- (tert-butyl-dimethylsilanyl) -imidazole-1-sulfonic acid and then treating it with butyl lithium and 2,6-diethyl-4-phenoxy-benzaldehyde in tetrahydrofuran. White crystalline solid. MS (ISP) = 544.5 ([M + H] +). c) 4- (2,6-diethyl-4-phenoxy-benzyl) -lH-imidazole It is obtained in a similar way to that described in Example 57 (e) from the rac-2- (tert-butyl-dimethylsilanyl) -4- [(2,6-diethyl-4-phenoxy-phenyl) -hydroxy-methyl] -imidazole dimethylamide l-sulfonic acid, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100 ° C for 16 h. White crystalline solid. MS (ISP) = 307.3 ([M + H] +). Example 80 4- (2,6-diethyl-3-phenoxy-benzyl) -lH-imidazole It is obtained in a manner similar to that described in Example 72 (a) - (b) from 2,6-difluoro-3-methoxybenzaldehyde, N-butylamine and p-toluenesulfonic acid in toluene, treatment with 3. equivalents of bromide ethyl magnesium and manganese (II) chloride in tetrahydrofuran and ether and subsequent chromatography through silica gel, treatment with boron tribromide in dichloromethane, after similar manner to that described in Example 79 (a) - (c) by treatment with phenylboronic acid, copper (II) acetate, molecular sieves of 4Á and pyridine in dichloromethane, treatment with 2- (tert-butyl-dimethyl-silanyl) -imidazole-sulfonic acid dimethylamide prepared in situ and butyl- lithium in tetrahydrofuran and subsequent treatment with triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100 ° C for 16 h. White crystalline solid. MS (ISP) = 307.4 ([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 (6)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The use of the compounds of the formula I wherein R is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, phenyl, S-phenyl or O-phenyl, which are optionally substituted by lower alkoxy or halogen, or is benzyloxy, C (O) O-lower alkyl, cycloalkyl , or is lower alkyl or lower alkoxy substituted by halogen; Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl or pyrazolyl; R1 / R1 'independently of each other are hydrogen, hydroxy, lower alkyl, lower alkoxy, or are phenyl or benzyl, which are optionally substituted by halogen; R2 is hydrogen or lower alkyl; n is the number 1, 2, 3 or 4; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and forms tautomerics, for the preparation of medications for the treatment of depression, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine , and metabolic disorders, for example eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption disorders and energy uptake, disorders and malfunction of homeostasis of body temperature, sleep disorders, and circadian rhythm. 2. The use of the compounds of the formula I according to claim 1, wherein aryl is phenyl, at least one of R1 / R1 'is lower alkyl and R2 is hydrogen. 3. The use according to claim 2, wherein the compounds are: rac-4- (1-phenyl-butyl) -lH-imidazole rac-4- [1- (2-fluoro-phenyl) -ethyl] - lH-imidazole rac-4- [1- (3, 5-difluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-propyl) -lH-imidazole rac-4- [1- (2 -fluoro-phenyl) -propyl] -lH-imidazole rac-4- [1- (3-fluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-ethyl) -lH-imidazole rac-4- [1- (3-fluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1 - (2,3-difluoro-phenyl) -propyl] -lH-imidazole trifluoroacetate of 5- (1-methyl-1-phenyl-ethyl) -1H-imidazole, or 4- [(R) -1- (2, 3-difluoro-phenyl) -ethyl] -lH-imidazole. 4. The use of the compounds of the formula I according to claim 1, wherein aryl is phenyl and R1 / R1 'and R2 are hydrogen. 5. The use of compounds of the formula I according to claim 1, wherein the compounds are: 4- (4-methoxy-2,3-dimethyl-benzyl) -lH-imidazole 4- (2-chloro- 6-fluoro-benzyl) -lH-imidazole 4- (2,3-dimethyl-benzyl) -lH-imidazole; Detomidine 4- (2, β-diethyl-benzyl) -lH-imidazole 4- (2-bromo-benzyl) -lH-imidazole 4- (2,6-dimethyl-benzyl) -lH-imidazole 4-benzyl-1H- imidazole 4- (2, 3, 5, β-tetramethyl-benzyl) -lH-imidazole 4- (2, β-dichloro-benzyl) -lH-imidazole 4- (2-ethyl-6-methyl-benzyl) -lH -imidazole 4- (
2. 2-cyclopropyl-6-ethyl-benzyl) -lH-imidazole 4- [
3. 3- (4-chloro-phenoxy) -benzyl] -lH-imidazole 4- (2-chloro-6-ethyl-benzyl) -lH-imidazole
4. 4-biphenyl-2-ylmethyl-lH-imidazole 4- (2,6-diethyl-4-methoxy-benzyl) -lH-imidazole 4- (2,6-diethyl-3-methoxy-benzyl) -lH-imidazole 4 -biphenyl-3-ylmethyl-lH-imidazole 4- (4-ethoxy-2,6-diethyl-benzyl) -lH-imidazole 4- (4-benzyloxy-2,6-diethyl-benzyl) -lH-imidazole 4- (3-Ethoxy-2,6-diethyl-benzyl) -lH-imidazole 4- (2-ethyl-6-fluoro-benzyl) -lH-imidazole 4- (2,6-diethyl-4-phenoxy-benzyl) - lH-imidazole or 4- (2,6-diethyl-3-phenoxy-benzyl) -lH-imidazole. 6. The use of the compounds of the formula I according to claim 1, wherein aryl is naphthyl. 7. The use according to claim 6, wherein the compounds are: 4-naphthalen-2-ylmethyl-1H-imidazole or rae-4- (1-naphthalen-1-yl-ethyl) -lH-imidazole. 8. The use of the compounds of the formula I according to claim 1, wherein aryl is benzofuran-7-yl. 9. The use according to claim 9, wherein the compounds are: 4- (
5. 5-bromo-benzofuran-7-ylmethyl) -1-imidazole or 4-benzofuran-7-ylmethyl-1-imidazole. 10. The use of the compounds of the formula I of according to claim 1, wherein aryl is dihydrobenzofuran-7-yl. 11. The use according to claim 10, wherein the compound is 4- (2,3-dihydro-benzofuran-7-ylmethyl) -1-imidazole. 12. The use of the compounds of the formula I according to claim 1, wherein aryl is pyrazolyl. 13. The use of the compounds of the formula I according to claim 1, wherein aryl is pyridinyl. 14. - The compounds of the formula I according to claim 1 characterized in that less one of R1 / R1 'is lower alkyl, wherein the compounds are rac-4- (1-phenyl-butyl) -lH-imidazole rac-4- [1- (2-fluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1- (3, 5-difluoro-phenyl) -propyl] -lH-imidazole rac-4- (1-phenyl-propyl) -lH-imidazole rac-4- [1- ( 2-fluoro-phenyl) -propyl] -lH-imidazole rac-4- [1- (3-fluoro-phenyl) -propyl] -IH-imidazole rac-4- (1-phenyl-ethyl) -lH-imidazole rac-4- [1- (3-fluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole rac-4- [1 - (2,3-difluoro-phenyl) -propyl] -lH-imidazole or 4- [(R) -1- (2,3-difluoro-phenyl) -ethyl] -lH-imidazole. 15. Compounds of the formula I according to claim 1 characterized in that the compounds are 4- (4-methoxy-2,3-dimethyl-benzyl) -lH-imidazole 4- (2-chloro-
6. 6-fluoro-benzyl) -lH-imidazole 4- (2-ethyl-6-) methyl-benzyl) -lH-imidazole 4- (2-cyclopropyl-6-ethyl-benzyl) -lH-imidazol 4- [3- (-chloro-phenoxy) -benzyl] -lH-imidazole 4- (2-chloro- 6-ethyl-benzyl) -lH-imidazole 4-biphenyl-2-ylmethyl-lH-imidazole 4- (2,6-diethyl-4-methoxy-benzyl) -lH-imidazole 4- (2,6-diethyl-3 -methoxy-benzyl) -lH-imidazole 4-biphenyl-3-ylmethyl-lH-imidazole 4- (4-ethoxy-2,6-diethyl-benzyl) -lH-imidazole 4- (4-benzyloxy-2, 6- diethyl-benzyl) -lH-imidazole 4- (3-ethoxy-2,6-diethyl-benzyl) -lH-imidazole 4- (2-ethyl-6-fluoro-benzyl) -lH-imidazole 4- (2, 6 -diethyl-4-phenoxy-benzyl) -lH-imidazole or 4- (2,6-diethyl-3-phenoxy-benzyl) -lH-imidazole. 16. - Methods for obtaining compounds of the formula I according to claim 1, the processes characterized in that they comprise: e) catalytically hydrogenating a compound of the formula with Pd / C, H2 to obtain a compound of the formula wherein R1"is an alkenyl group, R1 is alkyl and R, R2 and n have the meanings defined above, or f) reduce a compound of the formula with CF3C02H and Et3SiH to obtain a compound of the formula wherein R1 is hydrogen, and R, R2 and n have the meanings defined above, or g) catalytically hydrogenating a compound formula with Pd / C, H2 to obtain a compound of the formula wherein R1 is lower alkyl, and R, R2 and n have the meanings defined above, or h) deprotect a compound of the formula IV with hydrochloric acid to obtain a compound of the formula wherein R, R2 and n have the meanings defined above, or e) alkylating a compound of the formula to obtain a compound of the formula wherein R1 is lower alkyl or benzyl optionally substituted by halogen, R, R2 and n have the meanings defined above and X is halogen, and subsequent deprotection with hydrochloric acid to obtain a compound of the formula wherein R, R2 and n have the meanings defined above, f) deprotect a compound of the formula with sodium in ammonia or by catalytic hydrogenation with Pd / C, H2 to obtain a compound of the formula wherein Ra, Rb and Rc are hydrogen, lower alkyl or phenyl, or g) reacting a compound of the formula H R2 AlkO xi with two equivalents of a Grignard reagent the formula IX to obtain a compound of the formula wherein R is hydrogen, halogen, lower alkyl, lower alkoxy or phenyl and n has the meaning defined above, or h) catalytically hydrogenating a compound of the formula with Pd / C, H2l to obtain a compound of the formula wherein R is hydrogen, lower alkyl, alkoxy lower or phenyl and n has the meaning defined above, or k) reduce a compound of the formula Pd / C, H2 or with CF3C02H and Et3SiH obtain a compound of the formula wherein R1 is hydrogen, and R, R2 and n have the meanings defined above, or 1) deprotect a compound of the formula with hydrochloric acid in the presence of an alcohol of the formula Alk-OH to obtain a compound of the formula wherein Alk-0 is lower alkoxy, and R, R2 and n have the meanings defined above, and, if desired, convert the obtained compounds to pharmaceutically acceptable acid addition salts. 17. - A medicine containing one or more compounds of the formula I according to claim 1, characterized in that it is for the treatment of depression, bipolar disorder, hyperactivity disorder with attention deficit, stress-related disorders, schizophrenia , neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, and metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption disorders and energy assimilation, disorders and malfunction of homeostasis. body temperature, sleep disorders, and circadian rhythm. . 18. - A medicine according to claim 21 characterized in that it contains one or more compounds according to claim 1 for the treatment of depression, Parkinson's disease, and attention deficit hyperactivity disorder (ADHD). SUMMARY OF THE INVENTION The present invention relates to the use of compounds of the formula (I) wherein R is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, phenyl, S-phenyl or 0-phenyl, which are optionally substituted by lower alkoxy or halogen, or is benzyloxy, C (0) 0-lower alkyl, cycloalkyl, or is lower alkyl or lower alkoxy substituted by halogen; Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl and pyrazole; R1 / R1 'independently of each other are hydrogen, hydroxy, lower alkyl, lower alkoxy, or are phenyl or benzyl, which are optionally substituted by halogen; R2 is hydrogen or lower alkyl; n is the number 1, 2, 3 or 4; and its pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms, for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, 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.