Abstract:
New 3-substituted 4-(phenyl-N-alkyl)-piperazine and 4-(phenyl-N-alkyl)-piperidine compounds of Formula (1) wherein X is N, CH, or C, however X may only be C when the compound comprises a double bond at the dotted line; R 1  is OSO 2 CF 3 , OSO 2 CH 3 , SOR 5 , SO 2 R 5 , COR 5 , CN, NO 2 , CONHR 5 , CF 3 , 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, or I; R 2  is a C 1 -C 4  alkyl, an allyl, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or —(CH 2 )—R 6 ; R 3  and R 4  are independently selected from the group consisting of H and C 1 -C 4  alkyls, however both R 3  and R 4  cannot be H at the same time; R 5  is C 1 -C 3  alkyls, CF 3 , or N(R 2 ) 2 ; R 6  is a C 3 -C 6  cycloalkyl, 2-tetrahydrofurane, or 3-tetra-hydrofurane, as well as pharmaceutically acceptable salts thereof are disclosed. Also pharmaceutical compositions comprising the above compounds and methods wherein the above compounds are used are disclosed.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention relates to new modulators of dopamine neurotransmission, and more specifically to new substituted 4-(phenyl N-alkyl)-piperazines and 4-(phenyl N-alkyl)-piperidines, and use thereof.  
         BACKGROUND OF THE INVENTION  
         [0002]    Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.  
           [0003]    Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson&#39;s disease and schizophrenia. Currently available dopaminergic pharmaceuticals have severe side effects, such as extrapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti-Parkinson&#39;s agents. Therapeutic effects are unsatisfactory in many respects. To improve efficacy and reduce side effects of dopaminergic pharmaceuticals, novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for. In this context, also partial dopamine receptor agonists, i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive dopamine receptor blockade or excessive stimulation.  
           [0004]    Compounds belonging to the class of substituted 4-(phenyl-N-alkyl)-piperazine and substituted 4-(phenyl-N-alkyl)-piperidines have been previously reported. Among these compounds, some are inactive in the CNS, some display serotonergic or mixed serotonergic/dopaminergic pharmacological profiles while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.  
           [0005]    A number of 4-phenylpiperazines and 4-phenylpiperidine derivatives are known and described, for example Costall et al. European J. Pharm. 31, 94, (1975), Mewshaw et al. Bioorg. Med. Chem. Lett., 8, 295, (1998). The reported compounds are substituted 4-phenylpiperazine&#39;s, most of them being 2-, 3- or 4-OH phenyl substituted and displaying DA autoreceptor agonist properties.  
           [0006]    Fuller R. W. et al, J. Pharmacol. Exp. Therapeut. 218, 636, (1981) disclose substituted piperazines (e.g. 1-(m-trifluoro-methylphenyl)piperazine) which reportedly act as serotonin agonists and inhibit serotonin uptake. Fuller R. W. et al, Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3,4-dihydroxy-phenylacetic acid and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the comparative effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1-(p-chlorophenol)-piperazine.  
           [0007]    Boissier J. et al Chem Abstr. 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives, potentiators of barbiturates, and depressants of the central nervous system.  
           [0008]    A number of different substituted piperazines have been published as ligands at 5-HT 1A  receptors, for example Glennon R. A. et al J. Med. Chem., 31, 1968, (1988), Mokrosz, J. et al Arch. Pharm. (Weinheim) 328, 143-148 (1995), and van Steen B. J., J. Med. Chem., 36, 2751, (1993), Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R. A. discloses, in international patent applications WO 93/00313 and WO 91/09594 various amines, among them substituted piperazines, as sigma receptor ligands. Clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evidence of antipsychotic activity, or activity in any other CNS disorder. Two of the most extensively studied selective sigma receptor antagonists, BW234U (rimcazole) and BMY14802, have both failed in clinical studies in schizophrenic patients (Borison et al, 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al, 1994, Neuropsychopharmacology 10:37-40).  
         SUMMARY OF THE INVENTION  
         [0009]    The object of the present invention is to provide new pharmaceutically active compounds, especially useful in treatment of disorders in the central nervous system, which do not have the disadvantages of the above described substances.  
           [0010]    In the work leading to the present invention, it was found that it is desired to provide substances with specific pharmacological properties, namely substances that have modulating effects on dopamine neurotransmission. These properties have not been described earlier, and they are not possible to obtain with the earlier known compounds. The substances according to the present invention act preferentially on dopaminergic systems in the brain, and they have effects on biochemical indices in the brain with the characteristic features of dopamine antagonists. However, the substances according to the invention show no, or only limited, inhibitory effects on spontaneous locomotion unlike ordinary dopamine receptor antagonists that suppress behavioral activity and induce catalepsy. The substances according to the invention may even induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists.  
           [0011]    The present invention thus relates to new 3-substituted 4-(phenyl-N-alkyl)piperazines and 3-substituted 4-(phenyl-N-alkyl)piperidines in the form of free base or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and use of said compounds in therapy.  
           [0012]    One subject of the invention is to provide new compounds for therapeutic use, and more precisely compounds for modulation of dopaminergic systems in the mammalian brain, including human brain.  
           [0013]    Another subject of the invention is to provide compounds with therapeutic effects after oral administration.  
           [0014]    More precisely, the present invention relates to 3-substituted 4-(phenyl-N-alkyl)-piperazine or 4-(phenyl-N-alkyl)-piperidine compounds of Formula 1:  
                         
 
           [0015]    wherein:  
           [0016]    X is selected from the group consisting of N, CH, and C, however X may only be C when the compound comprises a double bond at the dotted line;  
           [0017]    R 1  is selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 5 , SO 2 R 5 , COR 5 , CN, NO 2 , CONHR 5 , CF 3 , 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R 5  is as defined below;  
           [0018]    R 2  is selected from the group consisting of C 1 -C 4  alkyls, allyls, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and —(CH 2 )—R 6 , wherein R 6  is as defined below;  
           [0019]    R 3  and R 4  are independently selected from the group consisting of H and C 1 -C 4  alkyls, however both R 3  and R 4  cannot be H at the same time;  
           [0020]    R 5  is selected from the group consisting of C 1 -C 3  alkyls, CF 3 , and N(R 2 )2, wherein R 2  is as defined above; and  
           [0021]    R 6  is selected from the group consisting of C 3 -C 6  cycloalkyls, 2-tetrahydrofurane, and 3-tetra-hydrofurane, and pharmaceutically acceptable salts thereof.  
           [0022]    The compounds according to the present invention possess dopamine-modulating properties and are useful in treating numerous central nervous system disorders including both psychiatric and neurological symptoms.  
           [0023]    Diseases in which compounds with modulating effects on dopaminergic systems may be beneficial are in disorders related to ageing, for preventing bradykinesia and depression and for the improvement of mental functions. They may also be used to improve cognitive functions and related emotional disturbances in neurodegenerative and developmental disorders as well as after brain damage.  
           [0024]    The compounds according to the invention can be used to improve all symptoms of psychosis, including schizophrenia and schizophreniform disorders as well as drug induced psychotic disorders. The compounds according to the invention may also be used in behavioral disorders usually first diagnosed in infancy, childhood, or adolescence as well as in impulse control disorders. Also, speech disorders such as stuttering may improve. They may also be used for treating substance abuse disorders as well as disorders characterized by misuse of food.  
           [0025]    Mood and anxiety disorders, personality disorders, and conversion hysteria may also be treated with the compounds according to the invention.  
           [0026]    Neurological indications include the treatment of Huntington&#39;s disease and other movement disorders as well as movement disorders induced by drugs. Restless legs and related disorders as well as narcolepsy may also be treated with compounds included according to the invention. They may also improve mental and motor function in Parkinson&#39;s disease, and in related parkinsonian syndromes. They may also be used to ameliorate tremor of different origins. They may be used in the treatment of headaches and used to improve brain function following vascular or traumatic brain injury. Moreover, they may be used to relieve pain in conditions characterized by increased muscle tone.  
           [0027]    The compounds according to the present invention have unexpectedly been found to act preferentially on dopaminergic systems in the brain. They have effects on biochemical indices in the brain with the characteristic features of dopamine antagonists, e.g. producing increases in concentrations of dopamine metabolites.  
           [0028]    Yet, dopamine receptor antagonists characteristically suppress behavioral activity and induce catalepsy, while the compounds of this invention show no, or only limited, inhibitory effects on spontaneous locomotion. In contrast they can induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists. The behavioral activation is limited, not reaching the profound increases in activity induced by direct or indirect dopaminergic agonists. On the other hand, the preferred substances reduce the increase in activity induced by direct or indirect dopaminergic agonists, i.e. d-amphetamine and congeners.  
           [0029]    Thus, the compounds of this invention surprisingly show an interesting dualistic dopaminergic action profile with antagonist like effects on brain neurochemistry and mild agonist like effects on normal behavior, but inhibition of behavior in states of hyperactivity. The action profile suggests modulatory effects on dopaminergic functions, clearly different from known compounds belonging to these chemical classes or effects anticipated of typical dopamine receptor antagonists or agonists from these or other chemical classes.  
           [0030]    Given the involvement of dopamine in a large variety of CNS functions and the clinical shortcomings of presently available pharmaceuticals acting on dopamine systems, the novel class of dopaminergic modulators presented in this invention may prove superior to presently known dopaminergic compounds in the treatment of several disorders related to dysfunctions of the CNS, in terms of efficacy as well as side effects.  
           [0031]    These compounds are thus suitable for the preparation of orally administered pharmaceuticals. There is no guidance in the prior art how to obtain compounds with this effect on behavior and dopamine systems in the brain.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0032]    Pharmacology  
           [0033]    Evidence is available that neurotransmission in the CNS is disturbed in psychiatric and neurologic diseases. In many instances, for example in schizophrenia or Parkinson&#39;s disease, pharmacotherapies based on antagonism or agonism at dopamine receptors are useful, but not optimal. In recent years much efforts have been put on finding novel and selective ligands for dopamine receptor subtypes (D1, D2, D3, D4, D5) with the aim to improve efficacy and reduce side effects.  
           [0034]    The present invention offers another principle for novel therapeutics based on interactions with dopamine systems. The compounds according to the invention have effects on brain neurochemistry similar to antagonists at dopamine D2 receptors. In contrast to currently used dopamine receptor antagonists the compounds according to the invention show no, or only limited inhibitory, effects on spontaneous locomotion. They can induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists. The behavioral activation is limited, not reaching the profound increases in activity induced by direct or indirect dopamine receptor agonists. Surprisingly, the preferred substances can actually reduce the increase in activity induced by direct or indirect dopaminergic agonists, i.e. d-amphetamine and congeners.  
           [0035]    The preferred structures are substituted in the meta position on the aromatic ring. This is exemplified by cis-4-(3-methanesulfonyl-phenyl)-2,6-dimethyl-1-propyl-piperazine, which is the compound of Example 3, which increases 3,4-dihydroxy-phenylacetic acid in the striatum from 1247±65 (for controls) to 3140±169 ng/g tissue at 100 μmol/kg s.c., p&lt;0.05, n=4. This increase in dopamine turnover is accompanied by an increase in motor activity from 27±11 cm/30 min (for the controls), to 253±73 cm/30 min p&lt;0.05, n=4, at 100 μmol/kg, 30-60 min post injection. Surprisingly, although cis-4-(3-methane-sulfonyl-phenyl)-2,6-dimethyl-1-propyl-piperazine is stimulant in itself it reduces d-amphetamine induced hyperactivity from 21140±4656 cm/60 min to 2492±530 cm/60 min, p&lt;0.05, n=4, at 100 μmol/kg s.c.  
           [0036]    Furthermore, it is important that both R3 and R4 are not H at the same time. This is further exemplified by cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine, which is the compound of Example 2. Similar to cis-4-(3-methanesulfonyl-phenyl)-2,6-dimethyl-1-propyl-piperazine, which is the compound of Example 3, cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine increases 3,4-dihydroxy-phenylacetic acid in the striatum from 996±18 (for controls) to 1388±60 ng/g tissue at 100 μmol/kg-s.c., p&lt;0.05, n=4. Furthermore, cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine does not inhibit motoractivity in the behavioral assay; 3239±194 cm/60 min (for the controls) to 3619±483 cm/60 min, p&gt;0.05, n=4, at 100 μmol/kg s.c. This is very surprising since the similar substance 1-propyl-4-(3-triflouro-methyl-phenyl)-piperazine, which corresponds to cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine wherein R3 and R4 have been substituted by H, does inhibit motoractivity in the behavioral assay. 1-propyl-4-(3-triflouro-methyl-phenyl)-piperazine increases 3,4-dihydroxyphenyl-acetic acid in the striatum from 1066±46 (for controls) ng/g tissue to 3358±162 ng/g tissue at 50 μmol/kg s.c., p&lt;0.05, n=4, followed by strong behavioral inhibition from 1244±341 cm/60 min (for the controls) to 271±137 at 50 μmol/kg s.c., p&lt;0.05, n=4, thus, lacking the properties sought for in the present invention. Further, 1-propyl-4-(3-triflouro-methyl-phenyl)-piperazine reduces serotonin in the striatum from 395±11 (controls) ng/g tissue to 308±18 ng/g tissue at 50 μmol/kg s.c., p&lt;0.05, n=4. An effect not seen for the compound of Example 2 [cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine]; 427±5 (controls) ng/g tissue to 419±23 ng/g tissue at 100 μmol/kg s.c., p&gt;0.05, n=4.  
           [0037]    cis-2,6-Dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine thus has the propertied desired according to the present invention, whereas 1-propyl-4-(3-triflouro-methyl-phenyl)-piperazine is not a substance according to the present invention.  
           [0038]    cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine, which is the compound of Example 4, has the ability to increase 3,4-dihydroxyphenyl-acetic acid in the striatum from 1111±13 (for controls) ng/g tissue to 1884±98 ng/g tissue at 100 μmol/kg s.c., p&lt;0.05, n=4. Further, it increases spontaneous motoractivity in the behavioral assay; from 3275±290 cm/60 min (for the controls) to 4948±577 cm/60 min, p&lt;0.05, n=4, 0-60 min, at 100 μmol/kg s.c. cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine thus displays the properties desired according to the invention.  
           [0039]    The compounds according to the invention can thus be used to treat symptoms in e.g.:  
           [0040]    schizophrenia and other psychotic disorders, such as catatonic, disorganized, paranoid, residual or differentiated schizophrenia; schizophreniform disorder; schizo-affective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; psychotic disorder due to a general medical condition with delusions and/or hallucinations;  
           [0041]    mood disorders, such as depressive disorders, e.g., dysthymic disorder or major depressive disorder; bipolar disorders, e.g., bipolar I disorder, bipolar II disorder, and cyclothymic disorder; mood disorder due to a general medical condition with depressive, and/or manic features; and substance-induced mood disorder;  
           [0042]    anxiety disorders, such as acute stress disorder, agoraphobia without history of panic disorder, anxiety disorder due to general medical condition, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, specific phobia, social phobia, and substance-induced anxiety disorder;  
           [0043]    eating disorders, such as anorexia nervosa, bulimia nervosa, and obesitas;  
           [0044]    sleep disorders, such as dyssomnias, e.g., breathing-related sleep disorder, circadian rhythm sleep disorder, hypersomnia, insomnia, narcolepsy, and “jet lag”;  
           [0045]    impulse-control disorders not elsewhere classified, such as intermittent explosive disorder, kleptomania, pathological gambling, pyromania, and trichotillomania;  
           [0046]    personality disorders, such as paranoid, schizoid or schizotypal disorder; antisocial, borderline, histrionic, and narcissistic disorder; and avoidant, dependent, obsessive-compulsive disorder;  
           [0047]    medication-induced movement disorders, such as neuroleptic induced parkinsonism, neuroleptic malignant syndrome, neuroleptic induced acute and tardive dystonia, neuroleptic induced akathisia, neuroleptic induced tardive dyskinesia, medication induced tremor, and medication induced dyskinesias;  
           [0048]    substance-related disorders, such as abuse, dependence, anxiety disorder, intoxication, intoxication delirium, psychotic disorder, psychotic disorder with delusions, mood disorder, persisting amnestic disorder, persisting dementia, persisting perception disorder, sexual dysfunction, sleep disorder, withdrawal, and withdrawal delirium due to use ore misuse of alcohol, amphetamine (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or phencyclidine-like substances), sedative substances, hypnotic substances, and/or anxiolytic substances;  
           [0049]    disorders usually first diagnosed in infancy, childhood, or adolescence, such as mental retardation; learning disorders; motor skills disorders, e.g. developmental coordination disorder; communication disorders, e.g. expressive language disorder, phonological disorder, receptive-expressive language disorder and stuttering; pervasive developmental disorders, e.g. Asperger&#39;s disorder, autistic disorder, childhood disintegrative disorder, and Rett&#39;s disorder; attention-deficit and disruptive behavior disorders, e.g. attention-deficit/hyperactivity disorder, conduct disorder, and oppositional defiant disorder; feeding and eating disorders of infancy or early childhood, e.g. feeding disorder of infancy or early childhood, pica, rumination disorder; tic disorders, e.g. chronic motor or vocal tic disorder, and Tourette&#39;s disorder; other disorders of infancy, childhood, or adolescence, e.g. selective mutism, and stereotypic movement disorder;  
           [0050]    delirium, dementia, amnestic and other cognitive disorders, such as Alzheimer&#39;s, Creutzfeldt-Jakob disease, dead trauma, Huntington&#39;s disease, HIV disease, Pick&#39;s disease, and diffuse Lewy body dementia;  
           [0051]    conversion hysteria;  
           [0052]    conditions connected to normal aging, such as disturbances in motor functions and mental functions;  
           [0053]    Parkinson&#39;s Disease and related disorders, such as multiple system atrophies, e.g. striatonigral degeneration, olivopontocerebellar atrophy, and shydrager syndrome; progressive supranuclear palsy; corticobasal degeneration; and vascular parkinsonism;  
           [0054]    tremors, such as essential, orthostatic, rest, cerebellar, and secondary tremor  
           [0055]    headaches, such as migraine, cluster headache, tension type headache, and paroxysmal headache;  
           [0056]    movement disorders, such as dyskinesias, e.g. in deneral medicine condition, secondary to trauma or vascular insult, hemiballism, athetosis, Sydenham&#39;s chorea, and paroxysmal; dystonias; Ekbom&#39;s syndrome (restless legs); Wilson&#39;s Disease; Hallerworden-Spatz disease;  
           [0057]    rehabilitation medicine, e.g. to improve rehabilitation after vascular or traumatic brain injury;  
           [0058]    pain in conditions characterized by increased muscular tone, such as fibromyalgia, myofascial syndrome, dystonia, and parkinsonism; as well as  
           [0059]    conditions related to the above that fall within the larger categories but does not meet the criteria of any specific disorder within those categories.  
           [0060]    Synthesis  
           [0061]    The synthesis of the present compounds is carried out by methods that are conventional for the synthesis of related known compounds. The syntheses of compounds in Formula 1, in general, comprise the reaction of an intermediate that supplies the alkyl group with an intermediate piperidine or piperazine that supplies the amine group of Formula 2:  
                         
 
           [0062]    A convenient method of synthesis of the present compounds is by use of an alkyl iodide (e.g. 1-propyl-iodide). Alternatively, other leaving groups besides iodide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like. The alkyl intermediate is reacted with the appropriate amine in the presence of any convenient acid scavenger. The usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines. The reaction medium for such reactions may be any convenient organic solvent which is inert to the basic conditions; acetonitrile, esters such as ethyl-acetate and the like and halogenated alkane solvents are useful. Usually the reactions will be carried out at elevated temperatures such as from ambient temperature to the reflux temperature of the reaction mixture, particularly from 50° C. to about 100° C.  
           [0063]    Another convenient method of synthesis of the present compounds involves reductive amination with an amine of Formula 2:  
                         
 
           [0064]    with an aldehyde or ketone, either in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride or followed by reduction, e.g. using catalytic hydrogenation, to give a corresponding compound of Formula 1.  
           [0065]    Compounds of Fomula 3 
                         
 
           [0066]    wherein X=N is accomplished by reacting compounds of Formula 4:  
                         
 
           [0067]    with compounds of Formula 5:  
                         
 
           [0068]    where Z is a leaving group like iodide. Other leaving groups besides iodide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like. The alkyl intermediate is reacted with the appropriate amine in the presence of any convenient acid scavenger. The usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines. The reaction is performed in a suitable solvent such as n-butanol by heating at about 50-150° C.  
           [0069]    Compounds of the Formula 1 wherein X=N is also accomplished by reacting compounds of Formula 6:  
                         
 
           [0070]    with an aryl substituted with a leaving group of Formula 7:  
                         
 
           [0071]    where Z is halide e.g. chloro, bromo, iodo, or sulfonate e.g. —OSO 2 CF 3 , or —OSO 2 F, in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according to known method (Tetrahedron Letters, vol 37, 1996, 4463-4466, J. Org. Chem., vol. 61, 1996, 1133-1135).  
           [0072]    The catalyst, preferably Pd will have the ability to form ligand complex and undergo oxidative addition. Typical Pd catalysts will be Pd 2 (dba) 3  (wherein dba refers to di-benzylidene acetone), Pd(PPh 3 ) 4 , Pd(OAc) 2 , or PdCl 2 [P(o-tol) 3 ] 2  and typical phosphine ligands will be BINAP, P(o-tol) 3 , dppf, or the like. The usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and alkyloxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines. The reaction medium for such reactions may be any convenient organic solvents, which are inert to the basic conditions; acetonitrile, toluene, dioxane, NMP (N-methyl-2-pyrrolidone), DME (dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide) and THF (tetrahydrofuran) solvents are useful. Usually the reactions will be carried out at elevated temperatures such as from ambient temperature to the reflux temperature of the reaction mixture, particularly from 50° C. to about 120° C.  
           [0073]    Compounds of the Formula 1 wherein X=N is also accomplished by reacting compounds of Formula 6 with an aryl substituted with a leaving group (e.g. F or Cl) via nucleophilic aromatic displacement reactions in the presence of a base as explained above.  
           [0074]    Compounds of the Formula 1 wherein X=CH is also accomplished by transition metal catalyzed cross-coupling reaction, known as, for example, Suzuki and Stille reactions, to those skilled in the art.  
           [0075]    The reaction may be carried out between compounds of Formula 8:  
                         
 
           [0076]    wherein Y is, for example, a dialkylborane, dialkenylborane or boronic acid (e.g. BEt 2 , B(OH) 2 ) or a trialkyltin (e.g. SnMe 3 , SnBu3), and an aryl substituted with a leaving group of Formula 7:  
                         
 
           [0077]    (for definition of Z, see above) in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according to known methods (Chem. Pharm. Bull., vol 33, 1985, 4755-4763, J. Am. Chem. Soc., vol. 109, 1987, 5478-5486., Tetrahedron Lett., vol. 33, 1992, 2199-2202). In addition, Y can also be a zink- or magnesium-halide group (e.g. ZnCl 2 , ZnBr 2 , ZnI 2 , MgBr 2 , MgI 2 ) according to known methods (Tetrahedron Lett., vol. 33, 1992, 5373-5374, Tetrahedron Lett., vol. 37, 1996, 5491-5494).  
           [0078]    The catalyst, preferably Pd will have the ability to form ligand complex and undergo oxidative addition. The definition of ligands, bases and solvents, is mentioned above.  
           [0079]    Alternatively, the transition metal catalyzed cross-coupling reaction can be performed with the opposite substitution pattern:  
                         
 
           [0080]    with an heteroaryl/alkenyl substituted with an leaving group of Formula 10:  
                         
 
           [0081]    in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according known methods discussed in the previous paragraph.  
           [0082]    Compounds of Formula 11:  
                         
 
           [0083]    can be prepared by catalytic hydrogenation of the tetra-hydropyridine or pyridine from the previous paragraph, using standard methods known in the art, generally with palladium on carbon, PtO 2 , or Raney nickel as the catalyst. The reaction is performed in an inert solvent, such as ethanol or ethyl acetate, either with or without a protic acid, such as acetic acid or HCl. When the pyridine ring is quaternized with an alkyl group the ring can be partly reduced by NaBH 4  or NaCNBH 4 , yielding the tetra-hydropyridine analog which can further be reduced with catalytic hydrogenation.  
           [0084]    Another convenient method of syntheses of compounds of the Formula 1, wherein X=CH is also accomplished by treating arylhalides of Formula 7:  
                         
 
           [0085]    wherein Z is Cl, Br, or I, with alkyllithium reagents, for example, butyllithium, sec-butyllithium or tert-butyllithium, preferably butyllitium or Mg (grignard reaction) in an inert solvent. Suitable solvents include, for example ether or tetrahydrofuran, preferably tetrahydrofuran. Reaction temperatures range from about −110° C. to about 60° C. The intermediate lithium anions or magnesium anions thus formed may then be further reacted with a suitable electrophile of Formula 12:  
                         
 
           [0086]    wherein A is defined as a protecting group like t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl) or a an alkylgroup like benzyl. The intermediates of Formula 13:  
                         
 
           [0087]    which are formed require that the hydroxy group be removed so as to result in compounds of Formula 1 (X=CH).  
           [0088]    This step may be accomplished by one of several standard methods known in the art. For example, a thio-carbonyl derivative (for example a xanthate) may be prepared and removed by a free radical process, of which are known to those skilled in the art. Alternatively, the hydroxyl group may be removed by reduction with a hydride source such as triethylsilane under acidic conditions, using such as, for example, trifluoroacetic acid or boron trifluoride. The reduction reaction can be performed neat or in a solvent, such as methylene chloride. A further alternative would be to first convert the hydroxyl group to a suitable leaving group, such as tosylate or chloride, using standard methods. The leaving group is then removed with a nucleophilic hydride, such as, for example, lithium aluminium hydride. This last reaction is performed typically in an inert solvent, such as, ether or tetrahydrofuran.  
           [0089]    Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol to an olefin with a reagent such as Burgess salt (J. Org. Chem., vol 38, 1973, 26) followed by catalytic hydrogenation of the double bond under standard conditions with a catalyst such as palladium on carbon. The alcohol may also be dehydrated to the olefin by treatment with acid such as p-toluenesulfonic acid or trifluoroacetic acid.  
           [0090]    The protecting group, A, is removed under standard conditions known by those skilled in the art. For example, t-Boc cleavages are conveniently carried out with trifluoroacetic acid either neat or in combination with methylene chloride. F-moc is conveniently cleaved off with simple bases such as, ammonia, piperidine, or morpholine, usually in polar solvents such as DMF and acetonitrile. When A is Cbz or benzyl, these are conveniently cleaved off under catalytic hydrogenation conditions. The benzyl group can also be cleaved off under N-dealkylation conditions such as treatment with a-chloroethyl chloroformate (J. Org. Chem., vol 49, 1984, 2081-2082).  
           [0091]    It is further possible to convert a radical R 1  in a compound of the Formula 1 into another radical R1, e.g. by oxidizing methylsulfide to methylsulfone (for example by m-chloroperoxybenzoic acid), substitution of a triflate or halide group with a cyano group (for example palladium catalyzed cyanation), substitution of triflate or halide group with a ketone (for example palladium catalyzed Heck reaction with butyl vinyl ether), substitution of a triflate or halide group with a carboxamide (for example, palladium catalyzed carbonylation), or cleaving an ether by, for example, converting a methoxy group into the corresponding hydroxyl derivate, which can further be converted into the corresponding mesylate or triflate. The terms mesylate and triflate refers to OSO 2 CH 3 , CH 3 SO 3  or OSO 2 CF 3 , CF 3 SO 3 , respectively.  
           [0092]    In summary, the general process for preparing the present compounds has six main variations, which may briefly be described as follows:  
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
           [0093]    As used herein the term C 1 -C 4  alkyl refers to an alkyl containing 1-4 carbon atoms in any isomeric form. The various carbon moieties are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl.  
           [0094]    The term cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.  
           [0095]    The term “patient” used herein refers to an individual in need of the treatment according to the invention.  
           [0096]    The term “treatment” used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition. The treatment may either be performed in an acute or in a chronic way.  
           [0097]    Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds according to the invention. Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, ethane disulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid. These salts are readily prepared by methods known in the art.  
           [0098]    The pharmaceutical composition containing a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations. Such substances are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives.  
           [0099]    In clinical practice the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The carrier may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by a weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.  
           [0100]    To produce pharmaceutical preparations containing the compound according to the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-pyrrolidine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.  
           [0101]    For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.  
           [0102]    Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.  
           [0103]    Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from 0.5% to about 10% by weight. These solutions may also containing stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules. The use and administration to a patient to be treated in the clinic would be readily apparent to an ordinary skill in the art.  
           [0104]    In therapeutical treatment an effective amount or a therapeutic amount of the compounds according to the invention are from about 0.01 to about 500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily. The compounds may be administered in any suitable way, such as orally or parenterally. The daily dose will preferably be administered in individual dosages 1 to 4 times daily.  
           [0105]    It is known for those skilled in the art that replacing a hydrogen in a non-substituted position in the aromatic ring with a fluorine atom may block the possibility for enzymatic hydroxylation which render the compound low oral bioavailability. This type of exchange (H to F) seldom changes the pharmacological profile. Thus, it may be important, in some cases to introduce a fluorine atom in any non-substituted positions in the aromatic ring of compounds of Formula 1 to improve the oral bioavailability.  
           [0106]    Additionally, the present invention is also considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a cosequense of structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.  
           [0107]    The invention is further illustrated in the examples below, which in no way are intended to limit the scope of the invention. 
       
    
    
     EXAMPLE 1  
     3-(cis-3,5-Dimethyl-4-propyl-piperazin-1-yl)-benzonitrile  
       [0108]    A mixture of 3-bromo-benzonitrile (0.35 g), cis-2,6-dimethyl-1-propyl-piperazine (0.3 g), sodium tert-butoxide (0.28 g) BINAP (25 mg)-and [Pd 2 (dba) 3  (20 mg) in toluene (6 ml) was heated under argon at 80° C. for 24 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using CH 2 Cl 2 :MeOH (45:1 (v/v)). MS m/z (relative intensity, 70 eV) 257 (M+, 38), 242 (52), 228 (bp), 130 (45) 112 (74).  
       EXAMPLE 2  
     cis-2,6-Dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine  
       [0109]    The titled compound was prepared in a similar manner as described in Example 1 from 3-iodobenzotrifluoride and cis-2,6-dimethyl-1-propyl-piperazine. The amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 188° C. MS m/z (relative intensity, 70 eV) 300 (M+, 26), 271 (58), 112 (bp), 70 (73), 56 (93).  
       EXAMPLE 3  
     cis-4-(3-Methanesulfonyl-phenyl)-2,6-dimethyl-1-propyl-piperazine  
       [0110]    The titled compound was prepared in a similar manner as described in Example 1 from 3-bromo-methanesulfonyl benzene and cis-2,6-dimethyl-1-propyl-piperazine. The amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 233° C. MS m/z (relative intensity, 70 eV) 310 (M+, 24), 281 (57), 112 (bp), 70 (55) 56 (59).  
       EXAMPLE 4  
     cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine  
       [0111]    A suspension of cis-4-(3-methanesulfonyl-phenyl)-3-methyl-piperidine (0.28 g) and ground K 2 CO 3  (300 mg) was stirred in CH 3 CN (30 mL) at room temperature. A solution of 1-iodo-propane (220 mg) in CH 3 CN (5 mL) was added dropwise. The mixture was stirred at 50° C. overnight. The reaction mixture was filtered and the volatiles were evaporated in vacuum. The oily residue was chromatographed on a silica column with MeOH:CH 2 Cl 2  (1:9 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine. The amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 197° C. MS m/z (relative intensity, 70 eV) 295 (M+, 1), 266 (47), 84 (bp), 70 (49) 63 (27).  13 C-NMR (75.4 MHz, CDCl 3 ): 11.8, 12.7, 20.0, 24.7, 34.9, 44.5, 44.8, 54.7, 60.3, 60.6, 124.8, 126.2, 129.1, 132.7, 140.6, 146.7.  
       EXAMPLE 5  
     cis-2,6-Dimethyl-1-propyl-4-(3-trifluoromethane-sulfonyl-phenyl)-piperazine  
       [0112]    The titled compound was prepared in a similar manner as described in Example 4 from cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-piperazine and iodopropane. MS m/z (relative intensity, 70 eV) 364 (M+, 18), 335 (79), 112 (bp), 70 (56), 56 (60).  
       EXAMPLE 6  
     cis-1-[3-(3,5-Dimethyl-4-propyl-piperazin-1-yl)-phenyl]-ethanone  
       [0113]    The titled compound was prepared in a similar manner as described in Example 4 from cis-1-[3-(3,5-dimethyl-piperazin-1-yl)-phenyl]-ethanone and iodopropane. MS m/z (relative intensity, 70 eV) 274 (M+, 27), 259 (32), 245 (40), 132 (35) 112 (bp), Rf=0.36 (CH 2 Cl 2 :MeOH 19/1).  
       EXAMPLE 7  
     cis-2,6-Dimethyl-1-ethyl-4-(3-trifluoromethane-sulfonyl-phenyl)-piperazine  
       [0114]    The titled compound was prepared in a similar manner as described in Example 4 from cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-piperazine and bromo-ethane. MS m/z (relative intensity, 70 eV) 350 (M+, 17), 335 (48), 98 (bp), 71 (41), 56 (76).  
       EXAMPLE 8  
     cis-2,6-Dimethyl-1-allyl-4-(3-trifluoromethane-sulfonyl-phenyl)-piperazine  
       [0115]    The titled compound was prepared in a similar manner as described in Example 4 from cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-piperazine and allyl-bromide. MS m/z (relative intensity, 70 eV) 362 (M+, 22), 110 (bp), 83 (59), 68 (40), 56 (40).  
         [0116]    Synthesis of intermediates used in the above Examples are described in the preparations below.  
         [0117]    Preparation 1: 1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperidin-4-ol  
         [0118]    3-Bromothioanisole (3 g) dissolved in dry THF (40 ml) was added dropwise to a mixture of Mg (0.4 g) and THF under a stream of Argon (g). The mixture was then brought to reflux for. 1 h. The cloudy solution was cooled to 0° C. and 1-benzyl-3-methyl-4-piperidone (3 g) dissolved in dry THF (30 ml) was added dropwise. The mixture was then stirred at r.t. (30 min) and finally refluxed for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml). The mixture was extracted several times with EtOAc and the combined organic phases were dried (MgSO 4 ), filtered and evaporated to dryness. The oily residue was chromathographed on a silica column using CH 2 Cl 2 :MeOH (19:1 (v/v)) as eluent, yielded 3.12 g of 1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperidin-4-ol. MS m/z (rel. intensity, 70 eV) 327 (M+, 11), 160 (16), 148 (11), 91 (bp), 65 (15).  
         [0119]    Preparation 2: 1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine  
         [0120]    1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperidin-4-ol (3.12 g) was dissolved in trifluoroacetic acid (80 ml) and refluxed for 3 days. CH 2 Cl 2  (100 ml) was added and the mixture was washed with two portions of 10%-Na 2 CO 3 , dried (MgSO 4 ), filtered and evaporated to dryness (yield 1.35 g). MS m/z (rel. intensity, 70 eV) 309 (M+, 24), 143 (35), 128 (22), 91 (bp), 65 (23).  
         [0121]    Preparation 3: cis-1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperidine  
         [0122]    1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine (1.35 g) was dissolved in 35 ml MeOH. Solid ammonium formate (1.93 g) and Pd/C (0.25 g) were added. The mixture was refluxed under a nitrogen atmosphere for 4 h. The mixture was then filtered through a pad of Celite, and the solvent was evaporated in vacuo.  
         [0123]    The residue was redissolved in CH 2 Cl 2  and purified by flash-chromathography. Yield 0.51 g of the titled compound. MS m/z (rel. intensity, 70 eV) 311 (M+, 48), 310 (32), 160 (19), 91 (bp), 65 (15).  
         [0124]    Preparation 4: cis-1-Benzyl-4-(3-methanesulfonyl-phenyl)-3-methyl-piperidine  
         [0125]    cis-1-Benzyl-3-methyl-4-(3-methyl-sulfanyl-phenyl)-piperidine (0.49 g) and CF 3 COOH (0.27 g) was dissolved in CH 2 Cl 2  (40 ml) and cooled to 0° C. m-Chloroperoxybenzoic acid (0.57 g) was added portions wise and the mixture was stirred at r.t over night. The resulting clear solution was washed with 10%-Na 2 CO 3  solution, dried (MgSO 4 ), filtered and concentrated by evaporation and yielding an oily residue (0.5 g). MS m/z (relative intensity, 70 eV) 343 (M+, bp), 342 (92), 328 (17), 266 (22), 252 (85).  
         [0126]    Preparation 5: cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-piperidine  
         [0127]    A solution of cis-1-Benzyl-4-(3-methanesulfonyl-phenyl)-3-methyl-piperidine (0.38 g) in 1,2-dichloroethane (10 ml) was cooled to 0° C. Then α-chloroethyl chloroformate (1.6 g) dissolved in 1,2-dichloroethane (5 ml) was added dropwise at 0° C. The reaction mixture was then brought to reflux for 2 days. The volatiles were evaporated in vacuo and the residue triturated with methanol. The mixture was brought to reflux for 4 hours. The solvent was evaporated to afford the title compound as HCl salt (0.28 g). MS m/z (relative intensity, 70 eV) 253 (M+, 15), 115 (28), 70 (65), 57 (bp), 56 (86).  
         [0128]    Preparation 6: cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-piperazine  
         [0129]    The titled compound was prepared in a similar manner as described in Example 1 from 3-bromo-trifluoromethan-sulfonyl benzene and cis-2,6-dimethyl-piperazine. MS m/z (relative intensity, 70 eV) 322 (M+, 15), 253 (12), 252 (bp), 119. (27), 70 (40).  
         [0130]    Preparation 7: cis-1-[3-(3,5-dimethyl-piperazin-1-yl)-phenyl]-ethanone  
         [0131]    The titled compound was prepared in a similar manner as described in Example 1 from 3-bromo-acetophenone and cis-2,6-dimethyl-piperazine. MS m/z (relative intensity, 70 eV) 232 (M+, 8), 163 (10), 162 (bp), 132 (9), 70 (12).  
         [0132]    The following tests were used for evaluation of the compounds according to the invention.  
         [0133]    In vivo Test: Behavior  
         [0134]    For behavioral testing, the animals were placed in separate motility meter boxes 50×50×50 cm equipped with an array of 16×16 photocells (Digiscan activity monitor, RXYZM (16) TAO, Omnitech Electronics, USA), connected to an Omnitech Digiscan analyzer and a Apple Macintosh computer equipped with a digital interface board (NB DIO-24, National Instruments, USA). Behavioral data from each motility meter box, representing the position (center of gravity) of the animal at each time, were recorded at a sampling frequency of 2.5 Hz and collected using a custom written LABView™ application. The data from each recording session were analyzed with respect to distance traveled and small-scale movements, e.g. stops in the center of the behavior recording arena, during the recording session. To determine stops in the center, velocity at each time point is calculated as the distance traveled since the preceding sample divided by the time elapsed since the preceding sample. The number of stops is then calculated as the number of times that the velocity changes from a non-zero value to zero. The number of stops in the center of the behavioral recording arena is calculated as the number of stops occurring at a position at least ten centimeters from the edges of the recording arena. For behavioral testing of habituated rats, the animals were placed in the motility meter boxes 30 minutes before the administration of test compound. Each behavioral recording session lasted 60 or 30 minutes, starting immediately after the injection of test compound. Similar behavioral recording procedures was applied for non-habituated rats, habituated rats and drug pre-treated rats. Rats pretreated with d-amphetamine are given the dose 1.5 mg/kg s.c. 5 min before the behavioral session in the motility meter.  
         [0135]    In vivo Test: Neurochemistry  
         [0136]    After the behavioral activity sessions the rats were decapitated and their brains rapidly taken out and put on an ice-cold petri-dish. The limbic forebrain, the striatum, the frontal cortex and the remaining hemispheral parts of each rat were dissected and frozen. Each brain part was subsequently analyzed with respect to its content of monoamines and their metabolites. The monoaminergic indices analyzed were dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and noradrenaline (NA). All monoaminergic indices in the dissected tissue were analyzed by means of HPLC with electrochemical detection as described by Svensson K, et al., 1986, NaunynSchmiedeberg&#39;s Arch Pharmacol 334: 234-245 and references cited therein.