MXPA01001438A - Utilization of aryl(or heteroaryl)azolylcarbinol derivatives in the preparation of a medicament for the treatment of troubles mediated by an excess of substance p - Google Patents

Abstract

The derivatives of aryl(or heteroaryl)azolylcarbinol (I) wherein Ar is optionally substituted phenyl or thienyl, R1 is a hydrogen atom, a cyclohexyl group, N-methylpiperidyl group, phenyl group, vinyl group or C1-C4 alkyl group;R2 is H, dialkylaminoalkyl, alkylazaheterocycloalkyl or azaheterocyclylalkyl and Het is a nitrogenated aromatic heterocycle of 5 members which contains from 1 to 3 nitrogen atoms and is optionally substituted, are useful for the treatment of troubles which are mediated by an excess of substance P, specially certain troubles of the central nervous system such as anxiety, depression, schizophrenia, maniaco-depressive psychosis, sexual dysfunction, drug addiction, cognitive troubles, locomotion troubles, etc. in mammals, including human beings.

Description

USE OF ARITHY DERIVATIVES HETEROARIÜAZOLILCARBINOLES IN THE ELABORATION OF A MEDICINE FOR THE TREATMENT OF MEDIATED DISORDERS FOR AN EXCESS OF SUBSTANCE P FIELD OF THE INVENTION The present invention relates to the use of aryl (or heteroaryl) azolylcarbinoles derivatives of the general formula (I), as well as their physiologically acceptable salts, in the manufacture of medicaments, useful in human and / or veterinary therapeutics, for the treatment of disorders that are mediated by an excess of substances P, especially certain disorders of the central nervous system such as anxiety, depression, schizophrenia, cognitive disorders, locomotor disorders, etc.

BACKGROUND OF THE INVENTION Substance P is a peptide, a takiquinine, which can be isolated from brain tissue and the gastrointestinal tract. In the brain, the substantia nigra and the basal ganglia contain relatively high amounts of substance P. There is evidence to suggest that substance P functions as a neurotransmitter. In the basal ganglia, substance P is synthesized in striatal neurons of medium size and with spines, which project to the substantia nigra pars reticulata. Studies of receptor distribution indicate that NKi receptors are found in the striatum at a relatively high density, but they are virtually absent from the substantia nigra; however, the substantia nigra contains one of the highest tissue P levels of the central nervous system. Although this seems to indicate a receptor-ligand mismatch, substance P can interact with its receptors in the striatum by releasing it from the collateral local axons of the striatonigral neurons. The terminals containing substance P have been shown to make synaptic contact with the cholinergic cell bodies in the striatum. In the striatum, NKi receptors seem to be expressed mainly by cholinergic interneurons, although a small population of non-cholinergic striatal neurons can also express these receptors. In addition, the stimulation of NKi receptors by substance P has been shown to increase the release of acetylcholine (Ach), both in vitro and in vivo. Accordingly, an anatomical circuit has been described in which substance P, locally released in the striatum from the collateral axons of striatonigral neurons, can bind to the NK-i receptors of cholinergic striatal interneurons to stimulate the release of acetylcholine (JJ Anderson, J. Pharmacol. Exp. Ther., 1995, 274, 928-936). Substance P has also been implicated in the pathophysiology of various neuropsychiatric disorders such as schizophrenia, manic depressive psychosis, sexual dysfunction, drug dependence, cognitive disorders, locomotor disorders, or depression (M. Bianchi, Inflamm. Res., 1995, 44 (11), 466-469). Thus, a clear relation between depressive states and levels of substance P can be presumed, since products with inhibitory activity on the release of substance P have a clear component as an antidepressant when they are studied in contrasted models of depression in laboratory animals. On the other hand, there is also a relationship between anxiety processes (anxiolysis / ansiogenesis) and levels of substance P. It has been shown that products with an NKi receptor antagonist activity have anxiolytic activity in the social interaction test (S. File, Pharmacol., Biochem. Behav., 1997, 58 (3), 747-752), with little propensity for tolerance. Likewise, the administration of substance P is an anxiogenic agent when studied in the elevated-plus-maze labyrinth test (RM Teixeira, Eur.J. Pharmacol., 1996, 31 (1), 7-14). ), and blockers of the substance P receptor have an opposite effect, so it can be said that the existing levels of substance P play an important role in the expression of anxiety. In our patent applications EP 289380 and ES 9800793 we have described carbinole derivatives of general formula (I) (I) wherein Ar represents a substituted or unsubstituted benzene ring or thiophene ring, R1 represents a hydrogen atom or a lower alkyl group (C-1-C4); R 2 represents a dialkylaminoalkyl or azaheterocyclylalkyl radical and Het represents an azole, as well as its physiologically acceptable salts, which are claimed for the treatment of pain. In our patent applications PCT / EP 96/05596, ES 9701538, ES9701728 and ES 9800793 we have also described various processes for the preparation of enantiomerically pure compounds of general formula (I). We have now discovered that the compounds of general formula (I), as well as their physiologically acceptable salts, are especially useful in the preparation of medicaments, useful in human and / or veterinary therapeutics, for the treatment of disorders that are mediated by a excess of substance P, especially certain disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotor disorders, etc.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of aryl (or heteroaryl) azolylcarbinoles derivatives of the general formula (I) (O where Ar is a phenyl radical or a thienyl radical, unsubstituted or optionally substituted by 1, 2 or 3 same or different substituents, selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy; R1 is a hydrogen atom, a cyclohexyl group, an N-methylpiperidyl group, a phenyl group, a vinyl group or a CrC4 alkyl group; R2 is a hydrogen atom or a di (C? -C alkyl) amino (C2-C3 alkyl), (CrC2 alkyl) azaheterocyclyl (C2-C3 alkyl), or azaheterocyclyl (C2-C3 alkyl); and Het is a five-membered azotic heterocyclic ring containing from one to three nitrogen atoms, unsubstituted or optionally substituted by 1 or 2 identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, a C alquilo alkyl group; -C? 2) a benzyl radical, a cyano (C2-C3 alkyl) radical, a carboxyalkyl radical (C2-C3 alkyl), a methoxycarbonyl radical (C2-C3 alkyl), a hydroxy radical (C2-C3 alkyl), a amino radical (C2-C3 alkyl), a di (C1-C4 alkyl) amine radical (C2-C3 alkyl) and an azaheterocyclyl radical (Q2-C3 alkyl), or a physiologically acceptable salt thereof; in the development of a drug for the treatment of disorders that are mediated by an excess of substance P, especially certain disorders of the central nervous system that involve substance P receptors such as anxiety, depression, schizophrenia, manic depressive psychosis, dysfunction sexual, drug addiction, cognitive disorders, locomotor disorders, etc., in mammals, including man. The term "C1-C4 alkyl group" represents a straight or branched chain radical derived from a saturated hydrocarbon of 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl sec-butyl and fer -butyl. The term "di (C C4 alkyl) amino (C2-C3 alkyl), (CrC2 alkyl) azaheterocyclyl (C2-C3 alkyl), or azaheterocyclyl (C2-C3 alkyl)" represent an alkyl radical of two or three carbon atoms attached to a di (C? -C alkyl) amine or to a (C? -C2 alkyl) azaheterocycle or an azaheterocycle, respectively, such as dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidylethyl, N-ethylpiperidylethyl, N-metrilpyrrolidinylethyl, morpholinylpropyl, pyrrolidinylalkyl, etc. . The term "cyano (C2-C3 alkyl)" represents an alkyl radical of two or three carbon atoms attached to a cyano functional group. The term "carboxy (C2-C3 alkyl)" represents an alkyl radical of two or three carbon atoms attached to a carboxyl functional group.

The term "methoxycarbonyl (C2-C3 alkyl)" represents an alkyl radical of two or three atoms of carbon bound to a methoxycarbonyl functional group. The term "(C2-C3 alkyl) hydroxy" represents an alkyl radical of two or three carbon atoms attached to a hydroxyl functional group. The term "amino (C2-C3 alkyl)" represents an alkyl radical of two or three carbon atoms attached to an amino functional group. The compounds of general formula (I) can be synthesized according to the methods described in patent applications EP 289380 or ES 9800793. The compounds of general formula (I) have a stereogenic center and the invention relates both to the use of an enantiomer pure as a mixture of enantiomers. The enantiomers can be prepared by any of the methods described in our patent applications PCT / EP 96/05596, ES 9701538, ES 9701728 or ES 9800793. Examples of pharmaceutical compositions containing compounds of the general formula (I) are described in our patent applications EP 289380 or ES 9800793. Illustrative examples of compounds comprised in the present invention include the compounds they are characterized with the data indicated in tables 1 to 7.

TABLE 1 02 91 01- < H DMA = dimethylaminoethyl Pyr = pyrrolidinylethyl Pip = piperidylethyl MBA = (methyl-benzylamino) ethyl Mor = morpholinylethyl DIPA = diisopropylaminoethyl DMAP = dimethylaminopropyl PipP = piperidylpropyl PirP = pyrrodinilpropyl TABLE 2 DMA = dimethylaminoethyl DIPA = diisopropylaminoethyl DMAP = dimethylaminopropyl MorP = morpholinylpropyl PirP = pyrrodinilpropyl T & > $ ¿& ^ t TABLE 3 sS «^» ¿-AfJ TABLE 4 (4 TABLE 5 ) O LO., A, i ¿a.

TABLE 6 TABLE 7 NJ NJ 00 In the present invention, the activity of the compounds of general formula (I) has been experimentally demonstrated in the claimed applications, by studying the in vivo effect on the release of substance P and also in two in vivo tests of antidepressant activity. In the following examples some properties object of the invention are indicated for the citrate of (±) -5-. { a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 - / - pyrazole (example 191). The examples given below, given simply by way of illustration, describe biological assays and should not in any way limit the scope of the invention.

EXAMPLE 1 Effect on spinal release of substance P in rats: The study was carried out in vivo in rats anesthetized with halothane. The test consists of intrathecal perfusion with an artificial cerebrospinal fluid, in order to collect the peptides released from the superficial layers of the spinal cord while local or systemic administration of the product under study takes place. The method used was that described by Collin, E. and cois. (Naunyn-Schimedeberg's Arch. Pharmacol., 1994, 349, 387-393). The citrate activity of (±) -5- was studied. { - [2-dimethylamino) ethoxy] benzyl} -1-methyl-1 - / - pyrazole (example 191) administered intrathecally in the perfusion liquid, at a concentration of 1 μM. As summarized in Table 8, the product inhibited the release of substance P. Systemic administration of 46 mg / kg of the product also reduced the release of substance P. 5 It is noteworthy that the effect of systemic administration of product on release Intrathecal substance P lasted 2 hours, with 50% inhibition the average effect during this time.

EXAMPLE 2 10 Study of antidepressant activity: The antidepressant activity of citrate of (±) -5-. { a- [2- dimethylamino) ethoxy] benzyl} -1-methyl-1/7-pyrazole (example 191) has been studied and shown in two different tests in mice, in the inhibition of ptosis induced by reserpine and in the test of the effect on mobility in an aversive situation. 2. 1 Inhibition of ptosis induced by reserpine in mice: The method used was that described by S. Garattini et al. (Med.20 Exp., 1960, 3, 315-320). The test consists in observing the possible inhibition of ptosis induced by reserpine (25 mg / kg, ip: intraperitoneal) in mice, after oral administration of the products under study.

The citrate activity of (±) -5- has been determined. { a- [2-dimethylamino) ethoxy] benzyl} -1-methyl-1H-pyrazole (example 191) administered orally at different doses, as summarized in table 9, citrate of (+) - 5. { a- [2-dimethylamino) ethoxy] benzyl} -1-methyl-1H-pyrazole (example 191) has demonstrated a clear antidepressant activity by inhibiting the effects of reserpine with a good dose-response relationship. 2. 2 Effect on mobility in an aversive situation: The method used was that described by R. D: Porsolt et al. (Arch. Int. Pharmacodyn., 1987, 288, 11-30). The test consists of suspending the mice by tail for 6 minutes in an ITEMATIC-TST device, which measures the mobility and power of the movements of the animals. Animals exposed to this aversive situation after a start of vigorous activity become desperate and end up staying immobile. The products with antidepressant activity significantly reduce the immobility time. As summarized in table 10, the citrate of (±) -5-. { a- [2-dimethylamino) ethoxy] benzyl} -1-methyl-1H-pyrazole (example 191) has been clearly active in this test by decreasing the immobility time significantly and related to the dose. The pharmacological tests carried out show that the citrate of (±) -5-. { a- [2-dimethylamino) ethoxy] benzyl} -1-methyl-1 Hp¡razol (example 191), as an example of the properties object of the invention, has a clear activity as an inhibitor of the release of substance P, which gives it an application in disorders of the central nervous system which imply a relationship with the release of substance P. In addition, and by way of example, antidepressant activity has been demonstrated in two different tests performed with experimental animals.

TABLE 8 Effect of citrate of (±) -5 a-f2-dimethylamino) ethoxy-1-benzyl > -1-methyl-1-pyrazole (Example 191) on the intrathecal release of substance P TABLE 9 Inhibition of pituitary-induced reserpine in mouse "Dose expressed in mg / kg of the base of the compound of example 191 sassw &% ag »* j -« .. w5a TABLE 10 Inhibition of immobility time in aversive situation in mouse

Claims (2)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of an aryl (or heteroaryl) azolylcarbinol derivative of the general formula (I) (I) where Ar is a phenyl radical or a thienyl radical, unsubstituted or optionally substituted by 1, 2 or 3 same or different substituents, selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy; R1 is a hydrogen atom, a cyclohexyl group, an N-methylpiperidyl group, a phenyl group, a vinyl group or a C C alkyl group; R2 is a hydrogen atom or a di (C? -C4 alkyl) amino (C2-C3 alkyl), (C C2 alkyl) azaheterocyclyl (C2-C3 alkyl), or azaheterocyclyl (C2-C3 alkyl); and Het is a five-membered azotic heterocyclic ring containing one to three nitrogen atoms, unsubstituted or optionally substituted by 1 or 2 same or different substituents selected from the group consisting of fluorine, chlorine, bromine, an alkyl group CrCl2, a benzyl radical, a cyano (C2-C3 alkyl) radical, a carboxyalkyl radical (C2-C3 alkyl), a methoxycarbonyl radical < üü í ^ '^^ n ^ ^ &? ', s ^ S ^^ iX? ^. ^ Aí > '& t < et, (C2-C3 alkyl), a hydroxy radical (C2-C3 alkyl), an amino radical (C2-C3 alkyl), a di (C-1-C4 alkyl) amino (C2-C3 alkyl) radical and a radical azaheterocyclyl (C2-C3 alkyl), or a physiologically acceptable salt thereof; in the preparation of a drug for the treatment of central nervous system disorders involving substance P receptors, said disorders include anxiety disorders, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, or locomotor disorders, etc., in mammals, including man.

2. The use according to claim 1, further characterized in that a compound of general formula (I) is selected from: [1] 2-. { a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-imidazole; [2] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -methylbenzyl} -1-methyl-1 H-imidazole; [3] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-imidazole; [4] 2-. { 3-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-imidazole; [5] 2-. { 4-chloro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1-methyl-1 H-imidazole; [6] 2-. { 4-Fluoro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1-methyl-1 H-imidazole; [7] 2-. { a- [2- (D-methylamino) ethoxy] -a-methyl-3- (trifluoromethyl) benzyl} -1-methyl-1 H-imidazole; [8] 2-. { 3-Chloro- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1-methyl-1 H-imidazole; [9] 2-. { 3-Chloro-a- [2- (dimethylamino) ethoxy] -a-propylbenzyl} -1-methyl-1 H-imidazole; [10] 1 -butyl-2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -methylbenzyl} -1 H-imidazole; [11] 2-. { a- [2- (dimethylamino) ethoxy] -a -methyl-4-methoxybenzyl} -1-methyl-1 H-imidazole; [12] 2-. { 3- ' j-A? ¿ii.'¿s, ^ rf.¡? < .i chloro-a-methyl- - [2- (N-pyrrolidyl) ethoxy] benzyl} -1-methyl-1 H-imidazole; [13] 2-. { a- [2- (dimethylamino) ethoxy] -a-propyl-3,4,5-trimethoxybenzyl} -1-dodecyl-1 H-imidazole; [14] 1-butyl-2-. { a- [2- (dimethylamino) ethoxy] -4- (trifluoromethyl) benzyl} -1 H-imidazole; [15] 1-methyl-2-. { α-methyl-α- [2- (N-piperidyl) ethoxy] -3- (trifluoromethyl) benzyl} -1 H-imidazole; [16] 2-. { a-cyclohexyl-3,4-dichloro-a- [2- (dimethylammon) ethoxy] benzyl} -1-methyl-1 H-imidazole; [17] 2-. { 3,4-dichloro-a- [2- (dimethylamino) ethoxy] -a-propylbenzyl} -1-methyl-1 H-imidazole; [18] 2-. { 3,4-dichloro-a- [2- (dimethylamino) ethoxy] -methylbenzyl} -1-methyl-1 H-imidazole; [19] 2-. { 3,4-dichloro-a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-imidazole; [20] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1- [2- (N-piperidyl) ethyl] -1 H-imidazole; [21] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1- [2- (N-piperidyl) propyl] -1 H-imidazole; [22] 1- (3-cyanopropyl) -2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -1 H-imidazole; [23] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -a- (N-methyl-4-piperidyl) benzyl} -1-methyI-1 H-imidazole; [24] 1-benzyl-2-. { a- [2- (N-benzyl-N-methylamino) ethoxy] -4-chlorobenzyl} -1 H-imidazole; [25] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -7-methyl-6,7,8,9-tetrahydro-1 H-imidazole [1,5-a] [1,4] diazepine; [26] 2-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -7-methyl-6,7,8,9-tetrahydro-1 H-imidazole [1, 5-a] [1,4] diazepine; [27] 1 -butyl-5-. { a- [2- (dimethylamino) ethoxy] benzyl} -1 H-pyrazole; [28] 5-. { a- (4-chlorophenyl) -a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [29] 1-butyl-5-. { a- [2- (dimethylaminoJethox-SA-trimethoxybenzyl] -1-H-pyrazole; [30] 1-butyl-5-. {4-chloro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl}. -1 H-pyrazole; [31] 5- { - [2- (dimethylamino) ethoxy] benzyl.} -1-methyl-1 H-pyrazole; [32] 5- { A- [2- (dimethylamino) ethoxy] α-methylbenzyl} -1-methyl-1 H-pyrazole; [33] 5- { a- [2- (dimethylamino) ethoxy] -3,4,5-trimethoxybenzyl}. -1-methyl-1 H-pyrazole; [34] 1-methyl-5- { A- [2- (N-pyrrolidyl) ethoxy] benzyl.] -1 H-pyrazole; [35] 1-methyl -5- { A- [2- (N-morpholinyl) ethoxy] benzyl.} -1 H-pyrazole; [36] 5- { A- [2- (dimethylamino) ethoxy] -a-methyl -3,4,5-trimethoxybenzyl) -1- methyl-1 H-pyrazole; [37] 4-bromo-5- { A- [2- (dimethylamino) ethoxy] benzyl.} -1 - methyl-1 H-pyrazole; [38] 1,3-dimethyl-5- { a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1 H-pyrazole; [39] 1, 3 -dimethyl-5 { - [2- (dimethylamino) ethoxy] benzyl} -1 H-pyrazole; [40] 5- { a- [2- (dimethylamino) ethoxy] -2-methylbenzyl} -1-methyl-1 H-pyrazole; [41] 4-chloro-5-. {4-chloro-a- [2- (dimethylamino) ethoxy] benzyl} - 1-methyl-1 H-pyrazole; [42] 5-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [43] 5-. { 3-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [44] 5-. { α- [2- (dimethylamino) ethoxy] -4-methylbenzyl} -1-methyl-1 H-pyrazole; [45] 5-. { 2-Chloro-a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [46] 1-methyl-5-. { a- [2- (N-piperidyl) ethoxy] benzyl} -1 H-pyrazole; [47] 1-methyl-5-. { a- [2- (N-propyl-2-piperidyl) ethoxy] benzyl} -1 H-pyrazole; [48] 5-. { a- [2- (N-Ethyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [49] 1-methyl-5-. { a- [2- (N-methyl-2-pyrrolidyl) ethoxy] benzyl} -1 H-pyrazole; [50] 5-. { a- [2- (Diisopropylammon) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [51] 1-methyl-5-. { a- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1 H-pyrazole; [52] 2-. { 4-chloro-a- [3- (dimethylamino) propoxy] -a-methylbenzyl} -1-methyl-1 H-imidazole; [53] 2-. { 3-Chloro-a- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H-imidazole; [54] 2-. { 4-chloro-a- [3- (dimethylamino) propoxy] -a-ethylbenzyl} -1-methyl-1 H-imidazole; [55] 2-. { a-butyl-3-chloro-a- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H-imidazole; [56] 2-. { a-cyclohexyl-4- * **. i ^? "chloro- - [3- (dimethylamino) propoxy] benzyl) -1-methyl-1 H-imidazole; [57] 2- { a- [3- (dimethylamino) propoxy] -4-fluoro-a-methylbenzyl .} -1-methyl-1 H-imidazole; [58] 2- { A- [3- (dimethylamino) propoxy] -a-methyl-3- (trifluoromethyl) benzyl.} -1-methyl- 1 H-pyrazole; [59] 2-. {2-chloro-a- [3- (dimethylamino) propoxy] -a-methylbenzyl} -1- methyl-1 H-imidazole; [60] 2- {3-chloro-a- [3- (dimethylamino) propoxy] -a-methylbenzyl} -1- methyl-1H-imidazole; [61] 2-. {- - a- [3- (dimethylamino) propoxy] -a-methyl-3,4,5-trimethoxybenzyl] -1- methyl-1H-imidazole; [62] 2-a- [3- (dimethylamino) propoxy] α-methyl-4-methoxybenzyl.) -1-methyl-1H-imidazole; [63] 2-. {4-chloro-a- [3- (dimethylamino) propoxy] -benzyl.} -1 -methyl-1 H- imidazole; [64] 2- { a- (dimethylamino) propoxy] -3,4,5-trimethoxybenzyl} -1- methyl-1 H-10 imidazole; [65] 2- {. a- [3- (dimethylammon) propoxy] -a-methyl-4 (trifluoromethyl) benzyl} -1- methyl-1 H-imidazole; [66] 2-. {a. 3- (dimethylamino) propoxy] -3- (trifluoromethyl) benzyl} -1-methyl-1 H-imid azole; [67] 2-. { - [3- (dimethylamino) propoxy] -4- (trifluoromethyl) benzyl} -1- methyl-1 H-imidazole; [68] 2-. { a- [3- (dimethylamino) propoxy] -4-methoxybenzyl} -1-methyl-1 H-imidazole; [69] 2-. { a-butyl-a- [3- (dimethylamino) propoxy] -3- (trifluoromethyl) benzyl} - 1-methyl-1 H-imidazole; [70] 1-butyl-2-. { 4-Chloro- [3- (dimethylamino) propoxy] -a- methylbenzyl} -1 H-imidazole; [71] 1-butyl-2-. { -butyl-a- [3- (dimethylamino) propoxy] -3,4,5-trimethoxybenzyl} -1 H-imidazole; [72] 1 -butyl-2-. { a-butyl-2-chloro-a- [3- (dimethylamino) propoxy] benzyl} -1 H-imidazole; [73] 1 -butyl-2-. { a-butyl-2,4-dichloro-a- [3- (dimethylamino) propoxy] benzyl} -1 H-imidazole; [74] 1 -butyl-2-. { a- [3- (dimethylamino) propoxy] -4- (trifluoromethyl) benzyl} -1 H-imidazole; [75] 2-. { 4-chloro-a- [3-N-piperidyl) propoxy] benzyl} -1-methyl-1 H-imidazole; [76] 1 -methyl-2-. { α-methyl-α- [3- (N-piperidyl) propoxy] -4- (trifluoromethyl) benzyl} -1 H-imidazole; [77] 2-. { a-butyl-2-chloro- a- [3- (dimethylamino) propoxy] bencll} -1-methyl-1 H-imidazole; [78] 2-. { a-butyl-3,4-dichloro-a- [3- (dimethylamino) propox V] benzyl} -1-methyl-1 H-imidazole; [79] 2-. { 3,4-dichloro- [3- (dimethylamino) propoxy] -a-ra # ttbencil} -1-methyl-1 H-imidazole; [80] 2-. { 3,4-dichloro-a- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H-imidazole; [81] 2-. { a-cyclohexyl-3,4-dichloro-a- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H-imidazole; [82] 2-. { 4-Chloro-a- [3- (dimethyl) propoxy] benzyl} - - [2- [N-piperidyl) ethyl-1H-imidazole; [83] 2-. { 4-Chloro-a- [3- (dimethylamino) propoxy] -a -methylbenzyl} -1 - [2- (N-piperidyl] ethyl-1 H-imidazole; [84] 2-. {4-chloro- - [3- (dimethylamino) propoxy] -a- (N-methyl-4-piperidyl benzyl.} -1-methyl-1 H-imidazole; [85] 1-butyl-5- { a- [3- (dimethylamino) propoxy] benzyl] -1-H-pyrazole; [86] 1-butyl-5- { 4-chloro-a- [3- (dimethylamino) -a-methylbenzyl} -1 H-pyrazole; [87] 5- { A- [3- (dimethylamino) propoxy] benzyl.} -1-methyl-1 H-pyrazole; [88] 5- { a- [3- (dimethylamino) -propoxy] -a-methylbenzyl} -1-methyl-1 H-pyrazole; [89] 1, 3-dimethyl-5 { A- [3- (dimethylamino) -a-methylbenzyl} -1-H-pyrazole; [90] 1,3-dimethy1- 5- { A- [3- (d.methylamino) -propoxy] benzyl] -1 H-pyrazole; [91] 5- { A- [3- (dimethylamino) -propoxy] - 2-methylbenzyl.} -1-methyl-1 H-pyrazole; [92] 5-chloro-5-. {4-chloro-a- [3- (dimethylamino) propoxy] benzyl} -1-methyl -1 H-pyrazole; [93] 1-methyl-5 { A- [3- (N-piperidyl) propoxy] benzyl} -1 H-pyrazole; [94] 1-methyl-5 { a- [3- (N-pyrrolidyl) propoxy] benzyl] -1H-pyrazole; [95] 4-. {4-chloro- - [2- (dimethylamino) ethoxy] benzyl} - 1 -methyl-1 H-pi razol; [96] 4-. { 4-Chloro-a- [2- (dimethylamino) ethoxy] -a-methylbenzyl} -1-methyl-1 H-pyrazole; [97] 4-. { 4-Chloro-a- [2- (N-propyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [98] 4-. { 4-chloro-a- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [99] 4-. { 4-chloro-a- [2- (N-ethyl-2- piperidyl) ethoxy] benzyl} -1 -methyl-1 H-pirazsí [100] 4-. { 4-chloro-a- [2- (diisopropylamino) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [101] 4-. { 4-chloro-a- [2- (N-methyl-2-piperidyl) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [102] 4-. { a- [3- (dimethylamino) propoxy] benzyl} -1-methyl-1 H-pyrazole; [103] 4-. { 4-chloro-a- [3- (N-morpholinyl) propoxy] benzyl} -1-methyl-1 H-pyrazole; [104] 4-. { 4-chloro-a- [3- (N-pyrrolidyl) propoxy] benzyl} -1-methyl-1 H-pyrazole; [105] 2- (α-hydroxybenzyl) -1 H-imidazole; [106] 2- (4-chloro-α-hydroxybenzyl) -1 H-imidazole; [107] 2- (4-chloro-α-hydrobenzyl) -1-methyl-1 H-imidazole; [108] 2- (3-chloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [109] 2- (4-fluoro-α-hydroxybenzyl) -1- methyl-1 H-imidazole; [110] 2- { -hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H-imidazole; [111] 2- [α-hydroxy-4- (trifluoromethyl) benzyl] -1-methyl-1 H-imidazole; [112] 2- (α-hydroxy-3,4,5-trimethoxybenzyl) - 1-methyl-1 H-imidazole; [113] 2- (3,4-dichloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [114] 1-butyl-2- [-hydroxy-4-] (trifluoromethyl) benzyl] -1H-imidazole; [115] 1-butyl-2- (3,4-dichloro-a-hydroxybenzyl) -1 H-imidazole; [116] 1-butyl-2- (4- chloro-to-hydroxybenzyl) -1 H-imidazole; [117] 1-butyl-2- (α-hydroxy-3,4,5-trimethoxybenzyl) -1 H-imidazole; [118] 1-dodecyl -2- (α-hydroxy-3,4,5-trimethoxybenzyl) -1 H- imidazole; [119] 2- (α-butyl-3-chloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [120] 2- (3-chloro-α-hydroxy-α-methylbenzyl) -1-methyl-1 H-imidazole; [121] 2- (4-chloro-α-hydroxy-α-methylbenzyl) -1-methyl -1 H-imidazole; [122] 2- (4-chloro-a-hydroxy-a- (N-methyl-4-pipe ridyl) benzyl] -1-methyl-1 H-imidazole; [123] 2- (4-chloro-a-ethyl-hydroxy-benzyl) -1-methyl-1 H-imidazole; [124] 2- (α-Butyl-4-chloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [125] 2- (α-cyclohexyl-4-chloro-α-hydroxybenzyl) -1-methyl-1 H- it e ^ S ^^.? k ^ ~? S ^? i imidazole; [126] 2- (2-chloro-hydroxy-a-f-ylbenzyl) -1-methyl-1 H-imidazole; [127] 2- (α-Butyl-2-chloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [128] 2- [α-hydroxy-a-methyl-3- (trifluoromethyl) benzyl] -1-methyl-1 H-imidazole; [129] 2- [α-butyl-α-hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H-imidazole; [130] 2- [α-cyclohexyl-α-hydroxy-3- (trifluoromethyl) benzyl] -1-methyl-1 H-imidazole; [131] 2- [α-hydroxy-a-methyl-4- (trifluoromethyl) benzyl] -1-methyl-1 H-imidazole; [132] 2- (4-fluoro-α-hydroxy-α-methylbenzyl) -1-methyl-1 H-imidazole; [133] 2- (α-Hydroxy-methyl-4-methoxybenzyl) -1-methyl-1 H-imidazole; [134] 2- (3,4-dichloro-α-hydroxy-α-methylbenzyl) -1-methyl-1 H-imidazole; [135] 2- (α-Butyl-3,4-dichloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [136] 2- (α-cyclohexyl-3,4-dichloro-α-hydroxybenzyl) -1-methyl-1 H-imidazole; [137] 2- (α-hydroxy-α-methyl-3,4,5-trimethoxybenzyl) -1-methyl-1 H-imidazole; [138] 1-Butyl-2- (4-chloro-hydroxy-a-methylbenzyl) -1 H-imidazole; [139] 1-butyl-2- (α-butyl-4-chloro-α-hydroxybenzyl) -1 H-imidazole; [140] 1-Butyl-2- (4-chloro-α-hydroxy-a- (N-methyl-4-piperidyl) benzyl] -1 H -imidazole; [141] 1-butyl-2- (a-butyl) α-hydroxy-3,4,5-trimethoxybenzyl) -1 H -imidazole; [142] 1-butyl-2- (α-butyl-2-chloro-α-hydroxybenzyl) -1 H -imidazole; ] 1-butyl-2- (α-ethyl-α-hydroxy-3- (trifluoromethyl) -benzyl] -1H-imidazole; [144] 1-butyl-2- (a-butyl-2) , 4-dichloro- -hydroxybenzyl) -1 H-imidazole; [145] 2- (4-chloro-α-hydroxy-α-methylbenzyl-1- [2- (N-piperidyl) ethyl] -1 H- imidazole; [146] 2- (4-chloro-a-hydroxy-a-methylbenzyl) -1- (3-dimethylaminopropyl) -1H-imidazole; [147] 2- (a-butyl-a-hydroxy-3) , 4,5-trimethoxybenzyl) -1-dodecyl-1 H-imidazole; [148] 1-benzyl-2- [a-butyl-a-hydroxy-3- (trifluoromethyl) benzyl] -1 H-imidazole; [149] 1-benzyl-2- (4-chloro-α-hydroxy-a-methylbenzyl) -1 H-imidazole; [150] 1 - (2-cyanoethyl) -2- (4-chloro- a-hydroxybenzyl) -1 H-imidazole; [151] 1- (3A? -nopropyl) -2- (4-chloro-a-hydroxybenzyl) -1 H-imidazole; [152] 3- [2- ( 3-chloro-α-hydroxybenzyl) -1H-imidazol-1-yl-propanoic acid; [153] 2- (4-chloro-a-hydroxybenzyl) -1 - (3-hydroxypropyl) pil) -1 H-imidazole; [154] methyl 3- [2- (3-chloro-hydroxy-benzyl) -1H-imidazol-1-yl] propanoate; [155] 2- (α-hydroxybenzyl) -1- (3-hydroxypropyl) -1 H-imidazole; [156] 2- (α-hydroxy-4-methylbenzyl) -1 - (3-hydroxypropyl) -1 H -imidazole; [157] 2- (α-hydroxy-4-methoxybenzyl) -1- (3-hydroxypropyl) -1 H-imidazole; [158] 2- (3,4-dichloro-α-hydroxybenzyl) -1- (3-hydroxypropyl) -1 H-imidazole; [159] 3-. { 2- (α-hydroxybenzyl) -1 H-imidazol-1-yl} methyl propanoate; [160] 2- (4-chloro-α-hydroxybenzyl) -1- (4-hydroxybutyl) -1H-imidazole; [161] 1- (3-cyanopropyl) -2- (4-chloro-α-hydroxybenzyl) -1H-? Midazole; [162] 4- [2- (4-Chloro-α-hydroxybenzyl) -1H-imidazol-1-yl] butanoic acid; [163] methyl 4- [2- (4-chloro-α-hydroxybenzyl) -1 H-imidazol-1-yl] butanoate; [164] 1-Butyl-5- (a-Hydroxybenzyl) -1 H-pyrazole; [165] 5- (4-chloro-α-hydroxybenzyl) -1-methyl-1 H-pyrazole; [166] 5- (α-hydroxy? -3,4,5-trimethoxybenzyl) -1-methyl-1 H-pyrazole; [167] 1-Butyl-5- (α-hydroxy-3,4,5-trimethoxybenzyl) -1 H-pyrazole; [168] 4-Bromo-5- (α-hydroxybenzyl) -1-methyl-1 H-ipirazole; [169] 5- [a- (4-chlorophenyl) -a-hydroxybenzyl] -1-methyl-1 H-pyrazole; [170] 1-Butyl-5- (4-chloro-α-hydroxy-α-methylbenzyl) -1 H-pyrazole; [171] 5- (α-hydroxy-α-methylbenzyl) -1-methyl-1 H-pyrazole; [172] 5- (α-hydroxy-α-methyl-3,4,5-trimethoxybenzyl) -1-methyl-1 H-pyrazole; [173] 1,3-dimethyl-5- (α-hydroxy-α-methylbenzyl) -1 H-pyrazole; [174] 1-Butyl-5- (a-hydroxy-a-vinylbenzyl) -1 H-pyrazole; [175] 1-Butyl-5- (4-chloro-α-hydroxy-α-vinylbenzyl) -1 H-pyrazole; [176] 4-Chloro-5- (a-hydroxybenzyl) -1-methyl-1 H-pyrazole; [177] 5- (α-hydroxy-2-methylbenzyl) -1-methι-1 H-pyrazole; [178] 5- (3-chloro-a- * a & hydroxybenzyl) -1-methyl-1 H-pyrazole; [17§ β- (α-hydroxy-4-methylbenzyl) -1-methyl-1 H-pyrazole; [180] 5- (2-chloro-α-hydroxybenzyl) -1-methyl-1 H-pyrazole; [181] 5- (α-hydroxy-4-methoxybenzyl) -1-methyl-1 H-pyrazole; [182] 5-. { a- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H-pyrazole; [183] 5-a- [2- (dimethylamino) ethoxy] -2-thienylmethyl citrate} -1-methyl-1 H-pyrazole; [184] 5-. { a- [2- (dimethylamino) ethoxy] -3-t-phenylmethyl} -1-methyl-1 H-pyrazole; [185] 2-. { a- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H-imidazole; [186] 5-. { a- [2 (dimethylamino) ethoxy] -3-methyl-2-thienylmethyl} -1-methyl-1 H-pyrazole; [187] 5-. { a- [2- (dimethylamino) ethoxy] -5-methyl-2-thienylmethyl} -1-methyl-1 H-pyrazole; [188] 5-. { 5-bromo-a- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H-pyrazole; [189] 5-. { 4-bromo-a- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H-pyrazole; [190] 5-. { a- [2- (dimethylammon) ethoxy] -a-methyl-2-thienylmethyl} -1-methyl-1 H-pyrazole; [191] Citrate of 5-. { a- [2- (dimethylamino) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [192] (±) -5-. { a- [2- (dimethylamino) -1 - (methyl-ethoxy] benzyl] -1- methyl-1 H-pyrazole; [193] (±) -5- { a- [2- (dimethylamino) -1- (methyl) ethoxy] benzyl} -1-methyl-1 H-pyrazole; [194] (±) -5- { A- [2- (dimethylamino) ethoxy] -2-thienylmethyl. -1-methyl-1 H-pyrazole; [195] (-) - 5- { A- [2- (dimethylamino) ethoxy] -2-thienylmethyl] -1- methyl-1 H-pyrazole; [196] (+) - 5- { A- [2- (dimethylamino) ethoxy] -2-thienylmethyl] -1- methyl-1H-pyrazole; [197] (-) - Citrate 5- {a- [2- (dimethylamino) ethoxy] -2-thienylmethyl} -1-methyl-1 H-pyrazole; [198] D-ditholuoyltartrate of (+) - 5 { a- [2- (dimethylamino) ethoxy] -2-thienylmethyl] -1. -methyl-1 H-pyrazole; [199] L-ditholuoyltartrate of (-) - 5- { a- [2- (dimethylamino) ethoxy] -2-thylmethylmethyl] -1- methyl-1 H-pyrazole; [200] (+) - 5- { a- [2- (dimethylamino) ethoxy] citrate] benzyl.} -1-methyl-1 H-pyrazole; [201] (-) - 5- { a- [2- (dimethylamino) ethoxy] benzyl] -1-methyl-1H- citrate pyrazole; [202] 5- (α-hydroxy-2-thienylmet |) fnetyl-1 H-pyrazole; [203] 5- (α-hydroxy-3-methyl-2-thienyl) methyl) -1-methyl-1 H-pyrazole; [204] 5- (α-hydroxy-5-methyl-2-thienylmethyl) -1-methyl-1 H-pyrazole; [205] 5- (5-bromo-α-hydroxy-2-thienylmethyl) -1-methyl-1 H-pyrazole; [206] 5- (4-bromo-α-hydroxy-2-thienylmethyl) -1-methyl-1 H-pyrazole; [207] 5- (α-hydroxy-α-methyl-2-thienylmethyl) -1-methyl-1 H-pyrazole.