MX2008002649A - N-oxides as prodrugs of piperazine&piperidine derivatives - Google Patents

Abstract

The present invention relates to N-oxides of certain piperazine and piperidine derivatives and to methods for the preparation of these compounds. The invention also relates to the use of compounds disclosed herein for the manufacture of a medicament giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of CNS-disorders, in particular the treatment of anxiety disorders, including generalized anxiety disorder and panic disorder, obsessive compulsive disorder, aggression, addiction (including craving), depression, autism, vertigo, schizophrenia and other psychotic disorders, Parkinson's disease and disturbances of cognition and memory. The compounds have the general formula (1) wherein the symbols have the meanings given in the specification.

Description

N-OXIDES AS PROFARMACS OF DERIVATIVES OF PIPERAZINE AND PIPERIDINE The present invention relates to N-oxides of certain piperazine and piperidine derivatives and to methods for the preparation of these compounds. The invention also relates to the use of the compounds described herein for the manufacture of a medicament that provides a beneficial effect. A beneficial effect is described herein or is evident to a person skilled in the art from descriptive memory and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition described herein or apparent to a person skilled in the art from descriptive memory and general knowledge in the art. In embodiments of the invention, specific compounds described herein are used for the manufacture of a medicament useful in the treatment of CNS disorders, in particular the treatment of anxiety disorders, including generalized anxiety disorder and panic disorder, obsessive-compulsive disorder. , aggression, addiction (including anxiety and relapse), depression, autism, vertigo, schizophrenia and other psychotic disorders, Parkinson's disease and other movement disorders and disturbances of cognition and memory.

PSYCHOTROPIC PIPERAZINE AND PIPERIDINE DERIVATIVES Psychotropic piperazine and piperidine derivatives are known, for example from WO 97/036893, WO 00/029397 and WO 01/085725. There are relevant similarities between bifeprunox, SLV308 and SLV318, the protagonists of these three patent applications. Equally relevant, however, are the differences between their pharmacological properties, and consequently their therapeutic possibilities. Bifeprunox is a partial agonist of the dopamine D2 receptor and a total serotonin 5-HT1A receptor agonist, in clinical trials as an atypical antipsychotic agent (see R. Feenstra et al., Bioorqanic &Medicinal Chemistry Letters, 1_1_, 2345 -2349, 2001). SLV318 is a total dopamine D2 receptor agonist and a partial serotonin 5-HT- | A receptor agonist, whose potential as an antidepressant and anxiolytic is currently being evaluated. SLV308 is a partial agonist of the dopamine D2 receptor and simultaneously a total serotonin 5-HT? A receptor agonist. It is in clinical trials for the treatment of Parkinson's disease (see R. Feenstra et al., Drugs of the future, 26 (2), 128-132, 2001).

SLV308 Bifeprunox SLV318 Metabolism studies in rats, monkeys and - much later - in humans, revealed that SLV308 is metabolized mainly by oxidation followed by glucuronidation. But its N-demethylated analogue and its N-oxide were also detected in the plasma of the three species, after oral administration of SLV308. In man, N-oxide reaches approximately 30% of the dose administered. In the development of drugs, metabolites are routinely investigated for activity, toxicity, etc. After it was shown that the N-oxide of SLV308 was a metabolite in man, the compound was synthesized and studied. It proved to be virtually inactive in vitro: its affinity for receptors for which the parent compound showed high affinity was too low or below the detection limit. These findings confirmed that in this case one of the most common situations with an N-oxide had occurred: metabolic deactivation.

The first in vivo experiments, in which N-oxide was administered intravenously, the in vitro findings seemed to hold: the N-oxide seemed to have only about one tenth of the activity of the parent compound. The surprise arose when the N-oxide was tested after oral administration: it appeared to be equipotent with the SLV308.

SLV308 N-desmethyl SLV308 N-OXIDES The N-oxides are known since 1894. It is now well known that N-oxides are metabolites of many tertiary amines, and in most cases they are also intermediates between tertiary amines and their N-dealkylated analogues. Most, but not all, tertiary amine drugs give rise to N-oxides. This is for example the case with morphine, imipramine, promazine, cinnarizine and nicotine, to name just a few. The degree to which N-oxidation takes place varies from trace amounts to near quantitative conversion. Some N-oxides proved to be more potent than their corresponding tertiary amines. The most famous example of these is chlordiazepoxide (Librium®), one of the most frequently used drugs in psychiatric and general medicine. In many more cases, however, it was found that N-oxides were less potent than their corresponding tertiary amines, and N-oxidation is more commonly considered as metabolic deactivation. While N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens in varying degrees. Some N-oxides undergo almost quantitative reductive conversion to the corresponding tertiary amines, in other cases the conversion is a mere trace reaction or is even completely absent. (M.H. Bickel: "The Pharmacology and Biochemistry of N-oxides", Pharmacoloaical Reviews, 21. (4), 325-355, 1969). The conclusion regarding the N-oxides and their corresponding tertiary amines is that anything is possible: there are examples of all kinds of extremes and anything between the extremes. The tertiary amines may or may not give rise to N-oxide metabolites. When they do, the N-oxidation can be a trace reaction or a quantitative conversion. The N-oxides may be more active than their corresponding tertiary amines, less active or even completely inactive. The N-oxides can be reduced to the corresponding tertiary amines or not. When they are, the reaction may be mere traces or almost quantitative.

Slv308 N-Oxide The combination of the fact that SLV308 N-oxide is inactive in vitro, moderately active in vivo when given intravenously, and virtually equipotent in vivo when delivered orally, can only be explained in one sense . Accordingly, the finding that after oral dosing of rats with the N-oxide of SLV308, the plasma levels of the N-oxide and the parent compound were approximate, was not a surprise.

The N-'oxides of Bifeprunox and Slv318 In humans, neither bifeprunox nor SLV318 are metabolized to their respective N-oxides. Or, more precisely, these N-oxides were never detected in significant concentrations in the blood plasma of man after administration of bifeprunox or SLV318. For this reason there was never an incentive to synthesize and study these compounds, until the unexpected findings with the N-oxide of SLV308. The N-oxides of bifeprunox and SLV318 were synthesized and administered to mice, both intravenously and orally. With sufficient safety, especially after oral dosing, both compounds proved to be prototypical prodrugs In mice and in man As in the case of man, SLV318, when given to mice, both intravenously and orally, does not give rise to a significant amount of N-oxide as the metabolite. With the SLV308 the situation is different: in man N-oxide is a major metabolite, but in mice this conversion apparently does not occur. The opposite case is the case of bifeprunox: in mice the compound is significantly oxidized to N-oxide, while in humans this route seems to be irrelevant.

Pharmacodynamics Since Paracelsus ('Sola dose facit venenum') it is generally accepted that the therapeutic as well as toxic effects of drugs are related to their concentration in relevant target sites. Because of thatGenerally speaking, the latter are not easily accessible, plasma levels are used as approximations of relevant drug concentrations. During the development of the drugs, plasma concentrations are known which are the lower limit of efficacy and also concentrations at which side effects begin to be evident. In ideal situations the two concentrations are so far apart that it is easy to administer the drug in such a way that it is effective, and still does not give rise to side effects. In reality, situations are almost never ideal, and most drugs show side effects. In most cases the occurrence of effects Secondary effects may be linked to peak plasma concentrations that exceed the lower level associated with the occurrence of side effects. The casual finding that N-oxide metabolites of certain inactive piperazine and piperidine derivatives in themselves, are converted almost quantitatively into the corresponding tertiary amine compounds when provided orally, created the opportunity to use them as "prodrugs", offering the benefits clinical signs of an extended duration of action and a blunt peak of plasma concentration, leading to an improved profile of side effects. The present invention relates to compounds of the general formula (1): wherein R is hydrogen, halogen, alkyl (C? .3), CN, CF3, OCF3, SCF3, alkoxy (C? .3), amino or mono- or di-alkyl (d-3) substituted amino, or hydroxy, - Z represents = C or -N, R2 is hydrogen or alkyl (C? -3), R3 and R4 independently represent H or alkyl (C? -3), or R3 and R4 together can form a bridge of 2 or 3 C atoms, Q is methyl, ethyl or cyclopropylmethyl which ethyl or cyclopropylmethyl groups are optionally substituted with one or more fluorine atoms, or Q is benzyl or 2-, 3- or 4-pyridylmethyl, which groups are optionally substituted with one or more substituents of the halogen, nitro, cyano, amino, mono- or dialkyl (C? 3) amino, alkoxy (C? -3), CF3, OCF3, SCF3, alkyl (C? -3), alkyl (C? -3) sulfonyl or hydroxyl, or Q is a group of the formula: wherein -R5 is halogen, hydroxy, (C -? - 3) alkoxy or (C -? - 3) alkyl, and q is 0, 1, 2 OR 3 -Y is phenyl, furanyl or thienyl, which groups can be substituted with 1-3 substituents of the hydroxy group, halogen, (C? -3) alkoxy, (C? .3) alkoxy, cyano, aminocarbonyl, monoalkyl (C -? 3) aminocarbonyl, and tautomers, stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable.

The invention relates to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having the formula (1), as well as to the salts and hydrates and solvates thereof. ? alkyl (C? -3) 'means' methyl, ethyl, n-propyl or isopropyl'. Preferred compounds according to the invention are the compounds of the formula (1) wherein Ri, R2, R3 and R4 are hydrogen, and '-Z' and Q have the above meanings, and tautomers, stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable. Especially preferred are compounds wherein R 2 R 3 and R are hydrogen, and Z 2 represents -N and Q is methyl, ethyl, benzyl or (1,1'-biphenyl) -3-yl-methyl, and tautomers , stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable. Most preferred are compounds wherein Q is methyl, benzyl or (1,1'-biphenyl) -3-yl-methyl, the N-oxides of SLV308, SLV318 and bifeprunox respectively, thus represented by the formulas (2-4) ): General aspects of synthesis The synthesis of the compounds having the formula (I) is outlined in Scheme 1: The selection of particular synthesis procedures depends on factors known to those skilled in the art such as the compatibility of functional groups with the reagents used, the possibility of using protecting groups, catalysts, activating and coupling reagents and the final structural characteristics present. in the final compound to be prepared. The pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for example an inorganic acid or an organic acid. The preferred salts of the compounds of the invention are the mesylates.

PHARMACEUTICAL PREPARATIONS The present invention relates to pharmaceutical compositions containing N-oxides of certain piperazine and piperidine derivatives, or pharmaceutically acceptable salts thereof, as active ingredients. For clinical use, the compounds of the invention are formulated in a pharmaceutical formulation for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or some other mode of administration. The pharmaceutical formulation contains compounds of the invention in a mixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. The total amount of active ingredients is suitably in the range of from about 0.1% (w / w) to about 95% (w / w) of the formulation, suitably from 0.5% to 50% (w / w) and preferably from 1 % to 25% (p / p). In the preparation of the pharmaceutical formulations of the present invention, the active ingredients can be mixed with solid, powdery ingredients, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other ingredient suitable, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed as pellets or compressed as tablets. The active ingredients can be premixed separately with the other non-active ingredients, before being mixed to form a formulation. The active ingredients can also be mixed together before being mixed with the non-active ingredients to form a formulation. Soft gelatin capsules can be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat or other suitable vehicle for soft gelatine capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients in combination with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration (i) can be prepared in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in admixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a micro enema already prepared; or (iv) in the form of a formulation of micro enema dry to be reconstituted in a suitable solvent immediately before its administration. Liquid preparations can be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredients and the remaining ones consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent before use. Solutions for parenteral administration can be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and / or pH regulating ingredients. Solutions for parenteral administration can also be prepared as a dry preparation to be reconstituted with a suitable solvent before use. The dose of compound to be administered will depend on the relevant indication, the age and sex of the patient and can be determined by the doctor. The dosage will preferably be in the range from 0.01 mg / kg to 10 mg / kg. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as relevant indication, the route of administration, the age, weight and sex of the patient and can be determined by the doctor. In general, oral and parenteral dosages will be in the range of 0.1 to 1,000 mg per day of total active ingredients.

Medical and Pharmaceutical Use In accordance with the invention also formulations and equipment of parts for use in medical therapy are provided, the use of the formulations of the present invention in the manufacture of medicaments for use in the treatment of CNS disorders and methods of treatment. doctor comprising the administration of a total therapeutically effective amount of the compounds of the invention to a patient suffering from, or susceptible to suffering from, a CNS disorder. The term "medical therapy" as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo in humans or other mammals. The formulations of the invention contain compounds of the general formula (1) as such or, in the case of prodrugs, after administration. It is expected that the formulations of the invention will, therefore, be useful in the treatment of CNS disorders. The compounds of the invention can be brought into forms suitable for administration by the usual processes using auxiliary substances such as liquid or solid carrier material. The Pharmaceutical compositions of the invention can be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gel) or suppositories. Suitable excipients for such formulations are pharmaceutically customary liquid or solid fillers and spreading substances, solvents, emulsifiers, lubricants, flavors, colorants and / or pH regulators. Frequently used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as liver oil of fish, sunflower oil, peanuts or sesame, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol. The compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly the specific compounds described herein. The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions and other types described herein or apparent to a person skilled in the art to starting from the descriptive memory and general knowledge in art. The invention also includes the preparation or manufacture of said pharmaceutical compositions. In embodiments of the invention, a pharmaceutical assembly or equipment is provided comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such containers may be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical products, whose notice reflects the approval of the manufacturing agency, Use or sale for human or veterinary administration.

Pharmacological methods In vitro affinity for neurotransmitter receptors The binding data collected in the table below (Example 5: results of pharmacological tests) were obtained by CEREP (128, I Danton, 92500 Rueil-Malmaison, France) or in Solvay Pharmaceuticals B.V. (C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands), using well-documented standard procedures. Affinities were measured by the D2 receptors of dopamine and 5-HT1A for example, as described by Créese I, Schneider R and Snyder SH, [3H] -Spyroperidol labels dopamine receptors in rat pituitary and brain, Eur J Pharmacol 1997, 46 : 377- 381 and Gozlan H, The Mestikawy S, Pichat L, Glowinsky J and Hamon M, 1983, Identification of presynaptic serotonin autoreceptors using a new ligand 3H-PAT, Nature 1983, 305: 140-142.

(Ant) aqonist activity in vitro in neurotransmitter receptors The (ant) agonist activity was measured in vitro in different neurotransmitter receptors on, for example, the formation of adenylate cyclase in cell lines expressing these cloned receptors (eg D2 and Human 5-HT- | A receptors expressed in CHO cell lines according to the methods described by Solomon Y, Landos C, Rodbell M, 1974, A highly selective adenylyl cyclase assay, Anal Biochem 1974, 58: 541-548 and Weiss S , Sebben M and Bockaert JJ, 1985, Corticotropin-peptide regulation of intracellular cyclic AMP production in cortical neurons in primary culture, J Neurochem 1985, 45: 869-874).

Animal model in vivo for (ant) aqonist activity of the 5-HTI /? of serotonin Retraction of the lower lip was measured according to the method described by Berendsen et al. (Pharmacol. Biochem. Behav. 33, (1989), 821-827).

Animal model in vivo for (ant) agonist activity of the D receptor? of dopamine Climber behavior induced by apomorphine in mice (Costall B, Naylor RJ and Nohria V, Differential actions of typical and atypical agents on two behavioral effects of apomorphine in the mouse, Brit J P? armaco / 1978, 63: 381-382) In vivo animal models predictive of anxiolytic / antidepressant activity The conditioned ultrasonic vocalization model in rats (Molewijk HE, Van der Poel AM, Mos J, Van der Heyden JAM and Olivier B (1995), Conditioned ultrasonic vocalizations in adult male rats as a paradigm for screening anti-panic drugs, Psychopharmacology 1995, 117: 32-40). The test of forced swimming in rats (Porsolt RD, Antón G, Blavet N and Jalfre M, 1978, Behavioral despair in rats: A new model sensitive to antidepressant treatments, Eur J Pharmacol 1978, 47: 379-391) The reinforcement model differential of low response rates in rats (McGuire PS and Seiden LS, The effects of tricyclic antidepressants on performance under a differential-reinforcement-of-low-rate schedule in rats, J Pharmacol Exp Ther 1980, 214: 635-641; van Hest et al., Differential reinforcement of low rate responses, Psychopharmacology, 1992, 107: 474-479). Deletion of locomotive activity (File SE and Hyde JRG, A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor tranquillisers or stimulants, Pharmacol Biochem Behav 1979, 11: 65-79) In vivo animal model predictive of antipsychotic activity Inhibition of conditioned prevention response in rats (Van der Heyden JAM, Bradford LD, A rapidly acquired one-way conditioned avoidance procedure in rats as a primary screening test for antipsychotics: influence of shock intensity on avoidance performance, Behav Brain Res 1988, 31: 61-67).

In vivo animal models predictive of anti-Parknian activity The marmoset monkey injured by MPTP (Nomoto M, Jenner P, Marsden CD: The dopamine agonist D2 agonist LY 141865 but not the D-i agonist SKF 38393, reverses Parknism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) in the common Marmoset. Neurosci. Lett., (1985) 57: 37-41). Turning behavior induced by 6-OH-dopamine in rats (Ungerstedt U, 6-OH-DA induced degeneration of central monoamine neurons, Eur. J. Pharmacol, 1968 5: 107-110). Specifically: Animals Male rats (Wistar, Harian, Holland, 400-500 g at the time of the experiment) are housed in an environment at controlled temperature (20-21 ± 2 ° C) and humidity and receive water ad libitum except during experimental sessions. The food is restricted to approximately 15 g per rat per day. A 12-hour light-dark cycle is used (lights on from 07.00-19.00). All experimental procedures were carried out in accordance with Dutch law and in accordance with the stipulations of the local animal care and use committee.

Surgery Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra zona compact were performed using a stereotactic procedure. One hour before surgery, desmethyl-imipramine (20 mg / kg, i.p.) was administered to protect the noradrenergic neurons. The rats are anesthetized with a mixture of halothane gases 3% + 0.8 l / min of N20 + 0.8 l / min from 02 to 1013 mbar. During surgery, the gas mixture is adjusted to halothane 1.75-2%, 0.6 l / min of N20 and 0.6 l / min of O2. The incision bar of the stereotaxic rument (Kopf, California, USA) is set to -3.3 mm, a drill hole was drilled on the substantia nigra pars compacta and 3 μl of a solution of 6-OHDA (3.33 mg / ml) was injected. ) (flow rate = 0.75 μl / min, the needle is left in its position for 4 minutes before removing it). The coordinates for this procedure are: anterior posterior +3.2 mm the interaural line; medial / lateral +1.8 mm of the midline and ventral -8.2 of the skull surface. It was left the animals will recover for approximately 2 weeks before the test. Good-looking rats were defined as those that produced at least 20 contralateral turns following amphetamine (2.5 mg / kg sc) in the 5 min time period beginning 25 min after administration and an average of at least 20 contralateral turns registered for a period of 30 min after administration of apomorphine (0.25 mg / kg sc). The regular test with apomorphine (0.1 or 0.25 mg / kg s.c.) is carried out to ensure the reliability of the animals in this procedure.

Apparatus Eight commercially available units (TSE Systems Bad Homburg, Germany) of "rotameters" (transparent plastic bowls, 57 x 55 x 52 cm) were used for the tests. The rats were clamped and harnessed to a rotation sensor in an interface with an IBM compatible personal computer (using the TSE Rotameter Software v. 1.11, TSE Systems Bad Homburg, Germany) which records movement in the sense of clock hands and counter clockwise. An internal software rotation filter of 10 is used.

Protocol Following the statistical random distribution of the treatment groups, the rats are pretreated with compounds of the invention (0.1-3 mg / kg po) or vehicle (2 ml / kg) and placed in the rotameters, and the contralateral rotational behavior. In additional studies, the effects of L-DOPA (1-10 mg / kg p.o.) on contralateral rotations were evaluated. The peripheral decarboxylase inhibitor benserazide (30 mg / kg i.p.) can be used. In combination studies, a range of doses (1-10) of L-DOPA and doses of compounds of the invention (0.1-3 mg / kg po) can be combined. The compounds of the invention of the general formula (1), as well as the pharmacologically acceptable salts thereof are prodrugs of compounds having (partial) agonist activity of the dopamine D2 receptor combined with 5-HT1A receptor agonist activity. They are useful in the treatment of CNS disorders, in particular anxiety disorders, including generalized anxiety disorder and panic disorder, obsessive-compulsive disorder, aggression, addiction (including craving and relapse), depression, autism, vertigo, schizophrenia and others. psychotic disorders, Parkinson's disease and other disorders of movement and disturbances of cognition and memory.

Treatment The term "treatment" as used herein refers to any treatment of a mammal, preferably human condition or disease, and includes: (1) preventing the disease or condition from occurring in a subject who may be predisposed to the disease but that has not yet been diagnosed as having it, (2) inhibit the disease or condition, that is, stop its development, (3) alleviate the disease or condition, that is, cause the regression of the condition, or (4) ) alleviate the conditions caused by the disease, ie stop the symptoms of the disease.

Abbreviations In this application some abbreviations may be used which may not be completely unambiguous for the person skilled in the art. They are: 6-OH-DA = 6-hydroxy-dopamine bifeprunox = 7- [4 - ([1, r-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone CHO = ovary Chinese hamster SNC = central nervous system ip = intraperitoneally i.v. = intravenously MPTP = 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine p.o. = (per os) = orally SLV308 = 7 - [(4-methyl) -1-piperazinyl] -2 (3H) -benzoxazolone SLV318 = 7 - [(4-methylphenyl) -1-piperazinyl] -2 (3H) - benzoxazolone EXAMPLES The specific compounds of which the synthesis is described below are intended to illustrate the invention in more detail, and accordingly, do not entail restricting the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art of considering the specification and practice of the invention described herein. Accordingly, the descriptive memory and examples should be considered by way of example only.

EXAMPLE 1 Materials and Methods Flash chromatography refers to purification using the indicated eluent and silica gel (Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-0.063 mm). The melting points were recorded in a Büchi B-545 melting point apparatus.

Liquid Chromatography - Mass Spectrometry (LC-MS) The LC-MS system consists of 2 Perkin Elmer 200 series micropumps. The pumps are connected to each other by a 50 μl tea mixer, connected to a Gilson 215 autosampler. The method is as follows: stage total time flow (μl / min) A (%) B (%) 0 0 2000 95 5 1 1.8 2000 0 100 2 2.5 2000 0 100 3 2.1 2000 95 5 4 3.0 2000 95 5 A = 100% water with 0.025 % HCOOH and 10 mmol of NH 4 HCOO pH = ca. 3 B = 100% ACN with 0.025% HCOOH The autosampler has an injection cycle of 2 μl. The autosampler is connected to a Waters Atlantis C18 30 * 4.6 mm column with 3 μm particles. The column is thermostated in a Perkin Elmer series 200 column oven at 40 ° C. The column is connected to a Perkin Elmer 200 series UV meter with a 2.1 μl flow cell. The wavelength is set at 254 nm. The UV meter is connected to a Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters: scan range: 150-900 a.m.u .; positive polarity; profile scan mode; Resolution Q1: UNIT; Step size: 0.10 a.m.u .; time per scan: 0.500 sec; NEB: 10; CUR: 10; IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10. The light scattering detector is connected to the Sciex API 150. The light scattering detector is a Sedere Sedex 55 operating at 50 ° C and 3 bar of N2. The complete system is controlled by a Powermac G3. All reactions involving compounds or conditions sensitive to moisture were carried out under a nitrogen atmosphere. The reactions were monitored using thin layer chromatography (TLC) on silica-coated plastic sheets (Merck 60 F254 pre-coated silica gel) with the indicated eluent. The spots were visualized by UV light (254 nm) or iodine (12). Dichloromethane (phosphorus pentoxide and calcium hydride), tetrahydrofuran (sodium / cetyl benzophenone) and light oil (60-80) were distilled in fresh form before use. All other commercially available chemical agents were used without further purification.

EXAMPLE 2 Synthesis of intermediaries The N-oxides of the invention were synthesized from the corresponding tertiary amines, compounds whose syntheses were described in WO 97/036893, WO 00/029397 and WO 01/085725.

EXAMPLE 3 Synthesis of specific compounds The specific compounds whose syntheses are described below are intended to further illustrate the invention in more detail and accordingly, do not imply to restrict the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention described herein. Accordingly this descriptive memory and examples should be considered by way of example only.

Compound 1: SLV308 N-oxide A suspension of 1.17g (5.00 mmol) of 7 - [(4-methyl) -1-piperazinyl] -2 (3H) -benzoxazolone in 30 ml of absolute ethanol is heated until it is obtained a clear solution. Then 0.41 ml of 30% H2O2 is added to the hot solution in one portion after which the mixture is heated to reflux in an oil bath. After 5 hours of reflux, another 0.41 ml portion of 30% H2O2 is added and the reflux is continued for 16 hours. Then a small amount of Pd / C 10% is added and after 45 minutes of reflux, the reaction mixture is allowed to cool to room temperature to give a brown suspension. The suspension is concentrated using a rotary evaporator to a brown solid which is purified by flash chromatography on silica gel (230-400 mesh, eluent DCM: MeOH: NH3 68: 30: 2) to obtain 1.06 g (4.25 mmol, 85% yield) of the corresponding N-oxide, compound 1 (mp 242-). 243 ° C).

Compound 2: N-oxide of SLV318 To a solution of 1.5 g (4.85 mmol) of SLV318 (7 - [(4-methylphenyl) -1-piperazinyl] -2 (3H) -benzoxazolone) in 150 ml of acetone was added 1.26 g (5.14 mmol) of 70% m-chloroperbenzoic acid, and the mixture is stirred for one hour and evaporated on silica. The N-oxide of SLV318 (compound 2) is isolated by flash chromatography (DCM: MeOH: NH3 84: 15: 1). Yield 1.48 g (94%). P.f. 238-240 ° C Compound 3: Bifeprunox N-oxide 30 g (66 mmol) of bifeprunox (7- [4 - ([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone) are dissolved in 500 ml of acetonitrile and 130 ml of water. Then, 20 ml of 35% H 2 O 2 are added and the mixture is stirred at 50 ° C. More H2O2 is added after 2 hours (100 ml), 24 hours (100 ml) and 48 hours (100 ml). After 120 hours, part of the acetonitrile is evaporated and 3000 ml of water are added. The product is isolated by extraction with DCM and evaporation. The bifeprunox N-oxide (compound 3) is purified by crystallization from 700 ml of acetonitrile and 100 ml of water and recrystallization from 200 ml of isopropanol. P.f .: 178-181 ° C.

EXAMPLE 4 Formulations used in animal studies For oral administration (p.o.): at the desired amount (0.5-5 mg) of the solid test compound in a glass tube, some glass beads were added and the solid was milled by whirling for 2 minutes. After the addition of 1 ml of a solution of 1% methylcellulose in water and of Poloxamer 188 (Lutrol F68) 2% (v / v), the compound was suspended by whirling for 10 minutes. The pH was adjusted to 7. The remaining particles in the suspension were further suspended using an ultrasonic bath. For intravenous (iv) administration: the compounds were dissolved in physiological saline (0.9% NaCl) and the pH was adjusted to 7. For intraperitoneal (ip) administration: to the desired amount (0.5-15 mg) of the solid test compound In a glass tube, some glass beads were added and the solid was ground by whirling for 2 minutes. After the addition of 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by whirling for 10 minutes. Finally the pH was adjusted to 7.

EXAMPLE S Results of pharmacological tests From the in vitro data (see Table 1, below) it is evident that the N-oxide of SLV308 is much less active than the parent compound. It is also clear that the measured activity of the N-oxide is real, and not caused by, for example, the possibility that the N-oxide was "contaminated" with small amounts of SLV308. This can be concluded from observations that the power ratios are not constant: their affinities for dopamine D4 receptors differ by a factor of 10, whereas for affinity for the dopamine D2 receptor this ratio is a factor of 100 or plus. The ED50 of SLV308 as an antagonist of climber behavior induced by apomorphine is 0.07 mg / kg i.v. Under the same test conditions, the ED50 of the N-oxide is more than ten times higher: 0.90 mg / kg. However, when tested orally, both compounds, SLV308 and its N-oxide, were shown to be equipotent (ED50 values of 0.75 and 0.79 mg / kg respectively). From these data it is evident that after oral dosing the N-oxide of SLV308 is reduced to its corresponding tertiary amine: SLV308. These findings were corroborated by measurements of plasma levels of SLV308 and its N-oxide after oral dosing with SLV308 and N-oxide. After oral administration of SLV308, only they found trace amounts of the N-oxide in blood plasma, however, after oral administration of the N-oxide, the plasma levels of the N-oxide and of the SLV308 were approximately equal.

TABLE 1 In vitro and in vivo pharmacology of SLV308 and its N-oxide S: (species): b = bovine, h - human, r = rat; *: to be quantified The pharmacological data collected in the previous table were obtained according to the protocols given above.

EXAMPLE 6 Concentrations in plasma of tertiary amines and their n-oxides Bifeprunox, SLV308 and SLV318 as well as their respective N-oxides were administered individually (intravenously (iv) or orally (po)) to mice (3 animals each time), after which their blood was analyzed by LC-MS (method, see above) regarding the amine mother and its N-oxide. The data were averaged (n = 3), and collected in the following tables.

Claims (3)

NOVELTY OF THE INVENTION CLAIMS

1. - Piperazine and piperidine derivatives of the general formula (1 ): wherein Q is methyl, benzyl, or (1,1'-biphenyl) -3-yl-methyl, and tautomers, stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable.

2. A compound of claim 1, wherein Q is methyl, represented accordingly by the formula (2): or HN 'or (2) N / "CH, and tautomers, stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable.

3. The compound according to claim 1 further characterized in that Q is benzyl, represented accordingly by the formula (3): and tautomers, stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable. 5. The compound according to claim 1, further characterized in that Q is (1, 1 '-biphenyl) -3-yl-methyl, represented accordingly by the formula (4): and tautomers, stereoisomers, salts, hydrates and solvates thereof pharmacologically acceptable. 6. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and / or at least one auxiliary substance pharmaceutically acceptable, a pharmacologically active amount of at least one compound of one of claims 1-4, or a salt thereof, as an active ingredient. 7. A method for preparing pharmaceutical compositions of claim 6, characterized in that a compound of one of claims 1-4 is brought into a form suitable for administration. 8. A compound of any of claims 1-4, or a salt thereof, for use as a medicament. 9. Use of a compound as claimed in any of claims 1-4 for the preparation of a pharmaceutical composition for the treatment of CNS disorders, including anxiety disorders, generalized anxiety disorder and panic disorder, obsessive-compulsive disorder , aggression, addiction, anxiety and relapse, depression, autism, vertigo, schizophrenia and other psychotic disorders, Parkinson's disease and other movement disorders and disturbances of cognition and memory. 10. Process for the preparation of compounds of claim 1, characterized in that a compound of the general formula (1 *) is oxidized with hydrogen peroxide to provide a compound of the general formula (1) wherein the symbols have the meanings given in the specification. 9A P08 / 84F