KR20090010093A - N-oxides of pyridylmethylpiperazine and pyridylmethylpiperidine derivatives - Google Patents

Abstract

The present invention relates to N-oxides of certain pyridylmethylpiperazines and pyridylmethylpiperidine derivatives, as alternatives or as 'prodrugs' of their respective parent compounds, pharmaceutical compositions containing such N-oxides, It relates to a manufacturing method and a method for producing a composition. The present invention relates to N-oxides, tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates of the compounds of formula a. The invention also relates to infections or diseases of the central nervous system, particularly caused by disorders of the dopamine or serotonin systems, such as Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially It relates to the use of N-oxides and compositions for the manufacture of a medicament useful in the treatment of schizophrenia and other psychotic disorders.

Formula a

In the formula a above,

Radicals are as defined in the specification,

The oxidized nitrogen atom is the nitrogen atom in the pyridyl ring of R ₅ , the nitrogen atom in the piperidine ring (if Z is carbon), or the nitrogen atoms in the piperazine ring (if Z is nitrogen). Or a nitrogen atom bonded to R ₅ through a methylene group and a nitrogen atom in the pyridyl ring of R ₅ .

Description

N-oxides of pyridylmethylpiperazine and -piperidine derivatives}

Psychotropic pyridylmethylpiperazine and pyridylmethylpiperidine derivatives are described in European Patent Publication No. 0 908 458. Among them, 3-[[4- () is known in the patent publication as SLV313, dopamine-D ₂ receptor antagonist and serotonin-5-HT _1A receptor agonist, and in clinical trials as an antipsychotic. 2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] methyl] -5- (4-fluorophenyl) pyridine is described. Human metabolism studies have shown that one of the major metabolites of SLV313 is its pyridine-N-oxide. This is surprising because the N-oxide could not be demonstrated in the plasma of rats and dogs to which the compound was administered in toxin studies. In either human or animal species used for toxicological studies, piperazine-N-oxide of SLV313 was not detected as a metabolite of the compound.

3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] methyl] -5- (4-fluorophenyl) -pyridine,

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1-oxido-3-pyridinyl] -methyl] Piperazine,

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -3-pyridinyl] methyl] -4-oxido- Piperazine

(SLV313, pyridine-N-oxide and piperazine-N-oxide thereof, respectively)

)이다. 그러나, 더 많은 경우, N- 옥사이드는 이들의 상응하는 3급 아민보다 덜 효능있는 것으로 밝혀졌고, N-산화는 대부분 통상적으로 대사적 불활성화인 것으로 여겨진다. N-옥사이드가 화학적 방법에 의해 이들의 상응하는 3급 아민으로 용이하게 환원되는 반면에, 사람의 몸에서, 이는 변하는 정도로 발생한다. N-옥사이드는 상응하는 3급 아민으로 거의 정량적 환원성 전환을 수행하며, 다른 경우, 전환은 거의 미미한 반응이거나, 심지어 완전히 존재하지 않는다[참조: Bickel, 1969]. 따라서, N-옥사이드 및 이들의 상응하는 3급 아민의 형성은 예상할 수 없다. 형성되면, N-옥사이드는 이들의 상응하는 3급 아민보다 더 활성이거나, 덜 활성이거나, 심지어 완전히 불활성이 될 수 있다. N-옥사이드는 상응하는 3급 아민으로 환원되거나 되지 않을 수 있다. 이들이 존재하면, 반응은 거의 미량이거나 거의 정량적일 수 있다.N-oxides have been known since 1894. To date, N-oxides are metabolites of many tertiary amines, and in most cases are also very well known as intermediates between tertiary amines and their N-dealkylated homologs. Most, but not all, tertiary amine drugs produce N-oxides. This is the case, for example, with only a few named morphine, imipramine, promazine, cinnarizine and nicotine. The extent of how much N-oxidation occurs varies from traces to near quantitative conversions. Some N-oxides have been shown to be more potent than their corresponding tertiary amines. The most famous of these is chlorrium, one of the most frequently used drugs in psychosis and general medicine.

)to be. In more cases, however, N-oxides have been found to be less potent than their corresponding tertiary amines, and N-oxidation is most commonly believed to be metabolic inactivation. While N-oxides are readily reduced to their corresponding tertiary amines by chemical methods, in the human body, this occurs to varying degrees. N-oxides perform almost quantitative reductive conversion with the corresponding tertiary amine, in other cases the conversion is almost insignificant or even completely absent (Bickel, 1969). Thus, the formation of N-oxides and their corresponding tertiary amines is unpredictable. Once formed, the N-oxides can be more active, less active or even completely inactive than their corresponding tertiary amines. N-oxides may or may not be reduced to the corresponding tertiary amines. If they are present, the reaction can be almost trace or almost quantitative.

Paracelsus (' Sola dosis facit Since venenum '), it is generally accepted that not only the toxic effects of drugs, but also the therapeutic effects are related to their concentration at the relevant target sites. Generally speaking, the plasma level is used as an approximation of the relevant drug concentration since the latter is not easily accessible. In the course of drug development, a window of appropriate plasma concentrations is defined that provides a lower limit or range for efficacy and an upper range in which side effects begin to occur. In an ideal situation, the two concentrations are so far away that it is effective but easy to administer the drug in a way that does not cause side effects. In fact, the situation is rarely ideal, and most drugs have side effects. In most cases, the occurrence of side effects may be linked to peak plasma concentrations above the lower levels associated with the occurrence of side effects. When administered orally in standard formulations, SLV313 produces peak plasma concentrations that cause unwanted side effects. This phenomenon is very unusual due to the peak plasma concentrations observed after oral administration because it does not occur in any of the animal species used in the toxin studies. The problem can be overcome by special dosing regimens or by the sophisticated slow release formulation of SLV313. Another solution may be a different compound. They have the same pharmacokinetic profile, but with much more useful pharmacokinetic profiles.

In vitro, the pyridine-N-oxides or their analogs of SLV313 are approximately as effective as their parent compounds and, depending on the route of administration, even in vivo, they have been described for these compounds [see; EP 0 908 458, which provides the same therapeutic possibilities. N-oxides formed by oxidation of the tertiary N-atoms of a piperazine or piperidine ring are actually inert in vitro. However, upon oral administration, they act as prodrugs: they are quickly converted to their parent compound.

The present invention relates to N-oxide compounds of formula a, tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates thereof.

In the formula a above,

A is a heterocyclic group of 5 to 7 ring atoms comprising 1 to 3 heteroatoms selected from the groups O, N and S,

R ₁ is hydrogen or fluoro,

R ₂ is C _1-4 alkyl, C _1-4 alkoxy or oxo group,

p is 0, 1 or 2,

Z is carbon or nitrogen, dotted line is single bond if Z is nitrogen, single bond or double bond if Z is carbon,

R ₃ and R ₄ are independently hydrogen or C _1-4 alkyl,

n is a value of 1 or 2,

R ₅ is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position to the methylene bridge with group Y and optionally substituted by (R ₆ ) q,

Y is hydroxy, halogen, CF ₃ , C _1-4 alkoxy, C _1-4 alkyl, cyano, aminocarbonyl, mono- _1-4 alkylaminocarbonyl and di-C _1-4 alkylaminocarbonyl Phenyl, furanyl or thienyl, which may be substituted by 1 to 3 substituents,

R ₆ is halogen, hydroxy, C _1-4 alkoxy or C _1-4 alkyl,

q is 0, 1, 2 or 3,

Wherein the oxidized nitrogen atom may be a nitrogen atom in the pyridyl ring of R ₅ , or a nitrogen atom in a piperidine ring (if Z is carbon), or a piperazine ring (if Z is nitrogen) It may be one of the nitrogen atoms in, or may be both a nitrogen atom connected to R ₅ through a methylene group and a nitrogen atom in the pyridyl ring of R ₅ .

N-oxides of the invention are 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] -methyl] -5- (4-fluoro Rophenyl) pyridine may be substantially free.

The present invention relates to racemates, mixtures of diastereomers and individual stereoisomers of the compounds of the formula (a) and to their hydrates and solvates thereof. Pharmaceutically acceptable salts can be obtained using, for example, standard methods well known in the art, for example, by mixing the compound of the invention with an appropriate acid, such as an inorganic acid or an organic acid.

Preferred compounds according to the invention are N-oxides of compounds of formula a, wherein the oxidized nitrogen atoms are nitrogen atoms in the pyridyl ring of R ₅ , 'pyridine N-oxides' in the N-oxides of compounds of formula a And tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates thereof.

Also preferred are the N-oxides of the compounds of formula a, wherein the oxidized nitrogen atoms are nitrogen atoms bonded to R ₅ via a methylene group, and tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates thereof.

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1-oxido-3-pyridinyl of the formula ] Methyl] -piperazine, 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -3-pyridinyl] methyl ] -4-oxido-piperazine and 4- (2,3-dihydro-benzo [1,4] dioxin-5-yl-1- [5-4-fluorophenyl] -1-oxy-pyridine Most preferred are 3-ylmethyl) piperazin-1-oxides (these are 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-pipera, respectively) Genyl] -methyl] -5- (4-fluorophenyl) pyridine (SLV313) is 'pyridine N-oxide', 'piperazine N-oxide' and 'bis-N-oxide':

N-oxides and pharmacologically acceptable salts thereof of the compounds of the present invention have the dopamine-D ₂ receptor antagonist and 5-HT _1A receptor agonist activity. They are useful in the treatment of Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders.

The invention also includes:

For example, by containing an N-oxide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and by antagonizing the dopamine-D ₂ receptor and / or activating the 5-HT _1A receptor Pharmaceutical compositions for the treatment of disorders or conditions treatable;

N-oxide or pharmaceutically acceptable thereof of a compound of Formula a to a mammal in need of treatment of a disorder or condition that can be treated by antagonizing the dopamine-D ₂ receptor and / or activating the 5-HT _1A receptor A method of treating a disorder or condition that can be treated by antagonizing the dopamine-D ₂ receptor and / or activating the 5-HT _1A receptor, comprising administering a salt;

Pharmaceutical compositions for the treatment of disorders or conditions selected from, for example, Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders and especially schizophrenia and other psychotic disorders;

Disorders set forth herein, comprising administering an N-oxide or a pharmaceutically acceptable salt thereof of a compound of Formula a to a mammal in need thereof treating a disorder or condition selected from the group consisting of the disorders set forth herein A method of treating a disorder or condition selected from the group consisting of:

Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially mental, comprising N-oxides or pharmaceutically acceptable salts of compounds of formula a and pharmaceutically acceptable carriers Pharmaceutical compositions for the treatment of schizophrenia and other psychotic disorders;

N-oxides or pharmaceutical preparations of the compounds of Formula (A) in mammals in need of treatment for Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders A method of treating Parkinson's disease, aggression, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders, including administering acceptable salts thereof.

The invention also provides the use of an N-oxide or salt thereof of the compound of formula a for the manufacture of a medicament.

The present invention also relates to a method of combination therapy, wherein a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or formulation comprising a compound of the present invention is another therapeutic agent for treating one or more conditions presented. It may be administered simultaneously or sequentially with (s) or as a combination formulation. Such other therapeutic agent (s) may be administered before, concurrently with or after administration of the compound of the invention.

The invention also provides compounds, pharmaceutical compositions, kits for treating Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders; And administering an N-oxide or a pharmaceutically acceptable salt thereof of the compound of Formula a to a mammal in need thereof.

Compounds of the present invention have dopamine-D ₂ receptor antagonistic activity and 5-HT _1A receptor agonistic activity. The (antagonistic) potency activity of the compounds of the present invention is readily described using, for example, one or more assays described herein or known in the art.

The invention also provides a process for the preparation of the compounds of the invention and the intermediates used in the process.

The compounds of the present invention may contain one or more asymmetric centers, and thus may be produced as racemates and racemate mixtures, single enantiomers, diastereomeric mixtures and individual minor diastereomers.

Depending on the nature of the various substituents, the molecule may have additional asymmetric centers. These asymmetric centers will each independently generate two optical isomers. All possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, belong to the invention. The present invention includes all such isomeric forms of these compounds. Formula a shows the structure of a compound group in the absence of preferred stereochemistry. Independent synthesis of these diastereomers or their chromatographic separation can be accomplished as known in the art by appropriate modifications of the methods described herein. Their absolute stereochemistry can be estimated by X-ray crystallography of crystalline products or crystalline intermediates, which are optionally derivatized with reagents containing asymmetric centers of known absolute configuration. Racemic mixtures of compounds are well known in the art, for example by coupling a racemic mixture of compounds to an enantiomeric pure compound to form a diastereomeric mixture, followed by standard methods (eg Separate diastereomers can be separated by separate enantiomers. This coupling often involves enantiomerically pure acids or bases, such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid. It consists of the formation of the salt used. The diastereomeric derivative can then be converted to pure enantiomers by cleavage of the added chiral residues. Racemic mixtures of compounds can also be separated directly by chromatographic methods using chiral stationary phases, which are well known in the art. In addition, the enantiomers of the compounds can be obtained by stereoselective synthesis using optically pure starting materials or reagents in coordination known by methods well known in the art.

The cis and trans isomers of the N-oxides of the compounds of formula a, or pharmaceutically acceptable salts thereof, also belong to the present invention, which also includes the N-oxides of the N-oxides of the compounds of formula a or pharmaceutically acceptable salts thereof. Applies to tautomers.

Some crystalline forms for the compounds may exist as allotropes, which are also intended to be included in the present invention. In addition, some of the compounds may form solvates (ie hydrates) with water or solvates with conventional organic solvents. Such solvates also fall within the scope of the present invention.

In addition, N-oxides or pharmaceutically acceptable compounds of isotopically-labelled compounds of Formula a, including N-oxides of N-oxides of isotope-labeled compounds of Formula a detectable by PET or SPECT Salts thereof belong to the scope of the present invention. This is accomplished by [ ¹³ C]-, [ ¹⁴ C]-, [ ³ H]-, [ ¹⁸ F]-, [ ¹²⁵ I]-or other isotope-rich atoms suitable for receptor binding or metabolism studies. The same applies to the N-oxides of the N-oxides of the compound of formula a.

The opportunity to find N-oxide metabolites of certain pyridylmethylpiperazine and pyridylmethylpiperidine derivatives as alternatives or as 'prodrugs' of their respective parent compounds may lead to improved side effects profiles. It offers the possibility of using these compounds as an alternative with clinical advantages of prolonged duration of action and blunted peak plasma concentrations. Thus, in some embodiments of the invention, the compound of the invention is a parent compound 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl]- Methyl] -5- (4-fluorophenyl) pyridine (SLV-313) may be provided to be substantially free. “Substantially free” means that the compound of the present invention contains less than about 50%, 40%, 30%, 20%, 10%, 1%, 0.5%, or, within the detectable range, as an impurity, 3-[[ 4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] -methyl] -5- (4-fluorophenyl) pyridine (SLV-313) is absent It means. Pharmaceutical compositions containing the N-oxides of SLV-313, substantially free of SLV-313, are contemplated in accordance with the present invention.

Definition of Chemicals and Other Terms

"Alkyl" means a straight or branched chain saturated hydrocarbon radical. 'C _1-3 alkyl' means methyl, ethyl, n-profile or isopropyl, and 'C _1-4 alkyl' means methyl, ethyl, n-profile, isopropyl, n-butyl, 2-butyl, iso Butyl or 2-methyl-n-profile. 'Halo' or 'halogen' means chloro, fluoro, bromo or iodo, and 'hetero' in 'heteroalkyl', 'hetero aromatic', etc. means containing one or more N, O or S atoms do. 'Heteroalkyl' includes an alkyl group having a hetero atom at a specific position, including an N-bonded, O-bonded or S-bonded alkyl group. As used herein as part of another group, 'oxy', 'thio' and 'carbo' are each represented as a bond between two groups, such as, for example, hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl and the like. Oxygen atoms, sulfur atoms and carbonyl (C═O) groups which act. The term 'amino' as used herein alone or as part of another group refers to a nitrogen atom that may be terminal or a bond between two other groups, where the group is a primary (two hydrogen atom) It may be bonded to a nitrogen atom), secondary (one hydrogen atom is bonded to a nitrogen atom) or tertiary (no hydrogen atom is bonded to a nitrogen atom).

For substituents, the term 'independently' means that if one or more such substituents are possible, they can be the same or different from one another. To provide a more specific description, some quantitative expressions provided herein are not characterized by the term 'about'. Whether the term 'about' is used explicitly or not explicitly, it is to be understood that all quantities given herein mean the values actually provided, and also include approximations due to experimental and / or measurement conditions for the values provided, It is meant that the stated values define approximations that can reasonably be inferred based on the person skilled in the art. Throughout the description and claims of this specification, variations of the terms 'comprise' and 'comprising' are not intended to exclude other additives, components, integers, or steps. As used herein, a 'composition' includes any product produced directly or indirectly by combining the specified ingredients in the specified amounts, as well as products comprising the specified ingredients in a predetermined amount or proportion. In the context of a pharmaceutical composition, the term refers to a product comprising one or more active ingredients and any carrier comprising an inert ingredient, as well as from mixing, complexing or agglomerating two or more ingredients, or from dissociation of one or more ingredients, or And products produced directly or indirectly from reactions or interactions with other forms of one or more components. In general, pharmaceutical compositions are prepared by uniformly and thoroughly binding the active ingredient to liquid carriers or finely divided solid carriers or both and then optionally molding the product into the desired formulation. The pharmaceutical composition comprises an active target compound sufficient to produce the desired effect depending on the extent or condition of the disease. Accordingly, the pharmaceutical composition of the present invention includes a composition prepared by mixing the compound of the present invention and a pharmaceutically acceptable carrier.

In the context of the present application, 'combination agent' means an N-oxide or a pharmaceutically acceptable salt thereof of a compound of formula a and other agents which are physically combined in one agent (e.g. tablet or liquid for injection). Actual blends; And N-oxides or pharmaceutically acceptable salts thereof of the compound of Formula (a), with optional instructions for optional use (e.g., label or drawing) to facilitate compliance in the administration of the component compounds; 'Kit-of-parts' comprising SLV313 or other agents in a separate dosage form. In actual formulations, pharmacotherapy by definition occurs simultaneously. The contents of the 'partial kit' can be administered simultaneously or at different time intervals. Concurrent or continuous treatment methods depend on the nature of the other agents used, such as the onset and duration of action, plasma levels, transparency as well as the disease, its stages and the characteristics of the individual patient.

'Pharmaceutically acceptable' means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not be harmful to its taker. Dose: The affinity of the compounds of the invention for the dopamine-D ₂ and 5-HT _1A receptors is determined as described below. From the binding affinity measured for the compounds of formula a shown, the theoretical lowest effective dose can be determined. At the concentration of the compound corresponding to twice the K _i -value measured, nearly 100% of the receptor will be occupied by the compound. By converting this concentration into the amount of compound per mg of body weight in mg, the theoretical lowest effective dose assuming an ideal bioavailability is obtained. Pharmacokinetics, pharmacodynamics and other considerations may alter the actual administered dose to a higher or lower amount. The dose of the compound administered depends on the relevant indication, the age, weight and sex of the patient and can be determined by the physician. Dosage doses preferably range from 0.01 to 10 mg / kg. In general, the daily dosage of the active ingredient varies over a wide range and depends on various factors such as the relevant indication, route of administration, age, weight and sex of the patient and can be determined by the physician. Generally, oral and parenteral doses range from 0.1 to 1,000 mg / day of total active ingredient. As used herein, 'therapeutically effective amount' means an amount of therapeutic agent for treating or preventing a condition that can be treated by administering a composition of the present invention. This amount is an amount sufficient to produce a detectable therapeutic, prophylactic or palliative response in the tissue system, animal or human. The effect can include, for example, treating or preventing the conditions set forth herein. The exact effective amount for an individual will depend on the size and health of the individual, the nature and extent of the condition being treated, the therapeutic agent or combination of therapeutic agents selected for the recommendation and administration of the therapist (researcher, veterinarian, doctor or other clinician). Therefore, it is not useful to specify the exact amount in advance. 'Pharmaceutically acceptable salts' are suitable for use in contact with tissues of humans and lower animals without reasonable toxicity, irritation and allergic reactions, within the judgment of the physician, and at reasonable benefit / risk ratios. Means a suitable salt. Pharmaceutically acceptable salts are well known in the art. The salts may be prepared in situ by finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. have. 'Treatment' as used herein refers to the treatment of a condition or disease in a mammal, preferably a human, and (1) prevention of a disease or condition that occurs in a subject who is not yet diagnosed as having a disease but is susceptible to the disease. , (2) inhibiting the disease or condition, ie, preventing the onset of the disease or condition, (3) alleviating the disease or condition, ie, causing the degeneration of the condition or (4) stopping the symptoms of the disease. As used herein, the term 'medical therapy' is intended to include prophylactic, diagnostic and therapeutic regimens which are performed in vivo or ex vivo in humans or other mammals. As used herein, 'individual' means an animal, preferably a mammal, most preferably a human being, being the subject of a treatment, observation or experiment.

Example  1: method

Liquid Chromatography-Mass Spectrometry (LC-MS)

The LC-MS system consists of two Perkin elmer series 200 micro pumps. The pumps are connected to each other by a 50 μl tee mixer, connected to a Gilson 215 automatic sampler. The method is as follows.

step Total time Flow rate (μl / min) A (%) B (%) 0 0 2000 95 5 One 1.8 2000 0 100 2 2.5 2000 0 100 3 2.7 2000 95 5 4 3.0 2000 95 5

A = 100% water with 0.025% HCOOH and 10 mmol NH ₄ HCOO (pH = ± 3)

B = 100% ACN with 0.025% HCOOH

The auto sampler has a 2 μl injection loop. The auto sampler is connected to a Waters Atlantis C18 30 × 4.6 mm column with 3 μm particles. This column is the thermo mentioned in the Perkin elmer series 200 column oven at 40 ° C. The column is connected to a Perkin elmer series 200 UV meter with 2.7 μl flow cell. The wavelength is adjusted to 254 nm. Connect the UV meter to the Sciex API 150EX mass spectrometer. The mass spectrometer is scan range: 150 to 900a.mu, polarity: positive, scan mode: profile, resolution Q1: UNIT, step size: 0.10amu, time per scan: 0.500 sec, NEB: 10, CUR: 10, IS : 5200, TEM: 325, DF: 30, FP: 225 and EP: 10. Connect the light scattering detector to the Sciex API 150. The light scattering detector is Sedere Sedex 55 operating at 50 ° C. and 3 bar N ₂ . The complete system is controlled by a G3 PowerMac.

Example 2: Synthesis of Specific Compounds

Its synthesis is intended to further illustrate the invention in more detail the specific compounds described below, and therefore should not limit the scope of the invention in any way. Other aspects of the invention will be apparent to those skilled in the art upon consideration of the specification and practice of the invention described herein. Accordingly, the specification and examples are to be regarded only as an example.

1- (2,3- Dehydro -1,4- Benzodioxin -5-yl) -4-[[5- (4- Fluorophenyl )-One- Oxygen -3-p Reedy Neil] methyl Piperazine, Compound 1, SLV313 Pyridine N- Oxide '

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1-oxido-3-pyridinyl] methyl] pipe The synthesis of Razine (1) is shown in Scheme 1. N-oxidation of pyrifenchloride (2) gives pyriphene-chloride-N-oxide (3), which is coupled with eltoprazine (4) to give the desired N-oxide.

Step 1: H ₂ O ₂ Of pyrifen chloride (2) by

3- (chloromethyl) -5- (4-fluorophenyl) pyridine (pyriphenchloride (2), obtainable as described in EP 0 908 458) 4.66 g (21.0 mmol), acetic acid 70 The mixture of ml and 6 ml of 35% H ₂ O ₂ is heated to 70 ° C. After reacting for 95 hours, another portion of ₂ ml of 35% H ₂ O ₂ is added. Stir again at 70 ° C. for 23 h, then add ₂ ml of excess 35% H ₂ O ₂ . The reaction mixture is further stirred at 70 ° C. overnight. The reaction mixture is concentrated to a brown oil using a rotary evaporator. The residue is dissolved in 100 ml of dichloromethane. 50 ml of 10% aqueous sodium carbonate solution is added, and then the layers are separated. The organic layer is extracted with 100 ml of dichloromethane and 50 ml of dichloromethane, respectively. The combined organic layers are concentrated under reduced pressure using a rotary evaporator. The crude product was purified using preparative HPLC (Inertsil ODS-3 column, eluent gradient from 10/90% acetonitrile / water containing 0.1% HCOOH to 90/10% acetonitrile / water), corresponding N 1.48 g (29 mmol, 30% yield) of oxide (3) are obtained.

Step 1 ^a : Oxidation of pyriphene chloride (2) by metachloroperbenzoic acid (mCPBA)

1.11 g CPBA is stirred in 20 mL DCM. 1.0 g of pyrifenchloride (2) is dissolved in 20 ml of DCM and the yellow solution is added as m-CPBA solution under stirring at room temperature. After stirring the clear yellow solution for 90 minutes, another 0.55 g of m-CPBA is added. Stirring is continued for another hour, at which time 25 ml of water and 1 g of NaHCO ₃ are added and the reaction mixture is stirred for 10 minutes. The layer is separated and 10 ml of water and 2 ml of 2N NaOH are added. After stirring, the layers are separated and the water layer is extracted with EtOAc. The combined organic layers are washed with water and concentrated to dryness to yield 0.98 g (91% c / c) of the corresponding N-oxide as an orange solid.

At large scale, the synthesis proceeds as follows.

192 g (0.745 mol) of 3- (chloromethyl) -5- (4-fluorophenyl) pyridine (2) as a monohydrochloride salt are suspended in 1 L of DCM. 140 g NaHCO ₃ is added, followed by 2 liters of water for 15 minutes. 239 g of mCPBA (1.25 equiv) are stirred in 1350 mL DCM and the solution is added dropwise to the pyrifenchloride suspension in DCM / water for 20 minutes. The clear yellow solution is stirred for 90 minutes. The layer is separated. The water layer is extracted with 335 mL DCM. The combined organic layers are extracted with a mixture of 1675 mL water and 670 mL 2N NaOH. The layer is separated and the water layer is extracted with 670 mL of DCM. Approximately 2.4 liters of DCM is distilled off. Addition of 2.7 L of MtBE (methyl-tert-butyl ether) results in crystallization of the product. 2.5 L of the DCM / MtBE mixture is distilled off. The mixture is cooled to 5 ° C. for 30 minutes and stirred at that temperature for 30 minutes. The solid material is separated by filtration to give 161 g (91%) of the corresponding N-oxide of white crystalline.

Step 2: Coupling of Pyrifenchloride N-oxide (3) and Eltoprazine (4)

1.48 g (6.23 mmol) of pyrifenchloride N-oxide (3), 1.63 g (1.0 equiv) of eltoprazine-HCl (4 equivalent), 1.04 g of potassium carbonate, obtainable as described in EP 0 189 612 (1.2 equiv) and 27.5 mL of 2-butanone are added 1.5 mL of water. The mixture is heated to reflux (74 ° C.) for 20 hours. After cooling to room temperature, 27.5 ml of water are added. Dissolve all material. The layer is separated. The water layer was extracted twice with 45 mL of 2-butanone and then the combined organic layers were washed with 30 mL of water. The combined organic layers are concentrated using a rotary evaporator. The crude product was purified using preparative HPLC (Inertsil ODS-3 column, eluent gradient from 10/90% acetonitrile / water containing 0.1% HCOOH to 90/10% acetonitrile / water) to correspond to the corresponding SLV313- N-oxide 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1-oxido-3-pyridinyl ] 1.83 g (4.34 mmol, 70% yield) of methyl] piperazine [melting point (DSC): 171 ° C.].

At large scale, the synthesis proceeds as follows.

155 ml of water was added to a stirred suspension of 155 g (652 mmol) of N-oxide (3), 167.5 g (1 equivalent) of eltoprazineHCl (4), 108.2 g (781 mmol) of powdered potassium carbonate and 2.5 L of 2-butanone. Add. The mixture is refluxed (76 ° C.) for 3 hours. The mixture is cooled to about 50 ° C. and extracted three times with 500 ml of water at that temperature. The combined water layers are extracted with 200 ml of MEK. The organic layers are combined and 1.6 L of 2-butanone is distilled off. The mixture is cooled to 0 ° C. The solution is seeded at 35 ° C. The resulting suspension is stirred at 0 ° C. for 30 minutes. The solid material was separated by filtration to give 257.3 g (94%) of crude SLV313-N-oxide. Crude N-oxide was recrystallized from 3.5 L of EtOAc to give 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1 404 g (84% yield) of -oxido-3-pyridinyl] methyl] piperazine [melting point (DSC): 171 ° C] (compound 1) were obtained.

1- (2,3- Dehydro -1,4- Benzodioxin -5-yl) -4-[[5- (4- Fluorophenyl ) -3- Pyridi Neil] methyl ]-4- Oxygen Piperazine, compound 2, SLV313 'Piperazine-N- Oxide '

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -3-pyridinyl] methyl] piperazine monohydrochloride ( 4.4 g (10 mmol) of SLV313.HCl) (1) are suspended in 25 ml of DCM. Add 42 ml of 5% sodium bicarbonate solution. 3.08 g (1.25 equiv) of mCPBA are dissolved in 20 mL of DCM. The solution is added to the stirred SLV313 suspension in DCM / water for 1 minute. The mixture is stirred at room temperature for 2.5 hours. The layer is separated. The water layer is extracted with 10 mL of EtOAc. The combined organic layers are extracted with 25 ml of water and 10 ml of 2N NaOH. The organic layer is concentrated until dry. The crude product (2.83 g) is crystallized from 40 ml of acetonitrile. Solid material is separated by filtration. After drying (50 ° C., vacuum), the white 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -3- 1.63 g (39%) of compound 2, which is pyridinyl] methyl] -4-oxido-piperazine, are obtained. Melting point (DSC): 181 to 182 ° C.

4- (2,3- Dehydro - Benzo [1,4] dioxin -5-yl-1- [5-4- Fluorophenyl ]-One- Oxy -Pyridine-3- Methyl Piperazine-1- Oxide , Compound 3, SLV313 of Vis -N- Oxide

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1-oxido-3-pyridinyl] methyl]- Piperazine, 0.5 g (1.19 mmol) of 'pyridine N-oxide' of SLV313 is suspended in 40 ml of acetone. Add 0.32 g (1.85 mmol) of mCPBA. The clear solution is stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DMA 1) to give 4- (2,3-dihydro-benzo [1,4] dioxin-5-yl-1- [5-4 0.26 g (50%) of Compound 3, which is -fluorophenyl] -1-oxy-pyridin-3-ylmethyl) piperazin-1-oxide. Melting point: 170-173 ° C.

Similarly, N-oxides of other compounds of formula a can be synthesized.

The choice of particular synthesis method depends on factors known to those skilled in the art, such as the compatibility of the reagents and functional groups used, the availability of protecting groups, catalysts, activation and coupling reagents, and the ultimate structural features present in the final compounds produced. It depends.

Example 3: Formulations Used in Animal Studies

For Oral Administration: Some glass beads were added to the desired amount (0.5-5 mg) of solid test compound in a glass tube and the solid was ground by vortex for 2 minutes. After addition of 1 ml of a solution of 1% methylcellulose and 2% (v / v) Poloxamer 188 (Lutrol F68) in water, the compound was suspended by vortexing for 10 minutes. pH was adjusted to 7. The remaining particles in the suspension were further suspended using an ultrasonic bath.

For Intravenous Administration: The compound was dissolved in physiological saline (0.9% NaCl) and the pH was adjusted to 7.

Example 4: Pharmacological Method

In vitro affinity for neurotransmitter receptors: The binding data collected below are either CEREP (128, rue Danton, 92500 Rueil-Malmaison, France) or Solvay Palmaticals V. V. Obtained by Solvay Pharmaceuticals BV) (CJ van Houtenlaan 36, 1381 CP Weesp, The Nethelands). Affinity for the dopamine-D ₂ and 5-HT _1A receptors was measured, for example, as described by Creese (1997) and Gozlan (1983), respectively.

In Vitro (antagonistic) Efficacy Activity: In humans, the D ₂ receptor and the 5-HT _1A receptor, respectively, are characterized by Solomon (1974) for the formation of adenylate cyclase in CHO cell lines expressing these cloned receptors. And according to the method described by Weiss (1985).

Lower Lip Contraction: In vivo animal models for serotonin 5-HT _1A receptor agonistic activity were measured according to the method described by Berendsen (1989).

Apomorphine-induced Climbing Behavior in Mice: In vivo animal models for dopamine-D ₂ receptor antagonistic activity were determined according to the method described by Costall (1978).

N-oxides and pharmacologically acceptable salts thereof of the compounds of the present invention are alternatives to parent compounds or prodrugs thereof having dopamine-D ₂ receptor antagonistic activity in combination with 5-HT _1A receptor agonistic activity. These are central nervous system infections or diseases caused by disorders in the dopamine or serotonin systems, such as Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychosis Useful in the treatment of sexual disorders.

Example 5: Pharmacological Test Results

Clearly, the in vitro and in vivo pharmacological profiles of SLV313 and its pyridine N-oxides are identical. Compared to these compounds, piperazine N-oxides are nearly inert in vitro but have the same efficacy in vivo. Round Prodrug.

SLV313 and its pyridine N-oxides are administered intravenously or orally individually to mice (3 animals per time point), and then their blood is subjected to LC-MS (see method above) for SLV313 and its pyridine N-oxides. Analyze The data are averaged (n = 3) and collected in Table 2.

When administered intravenously or orally at a marginal extent to mice, SLV313 is metabolized to its pyridine N-oxide. Its concentration never exceeds 1 to 2% of the concentration of the parent compound. When the N-oxide itself is administered, it is reduced to only a very small amount (less than 1%) of its parent compound.

In mice, pyridine N-oxide is an alternative to SLV313 rather than the prodrug of SLV313.

SLV313 and its piperazine N-oxides were administered intravenously or orally individually to mice (3 animals per time point), and then their blood was LC-MS (see method above for SLV313 and its piperazine N-oxides). Analyze with). The data are averaged (n = 3) and collected in Table 3.

When administered intravenously or orally to mice, SLV313 is not metabolized to its piperazine-N-oxide.

When piperazine-N-oxide itself is administered, within 30 minutes its concentration in plasma exceeds that of the parent molecule. Piperazine-N-oxide is certainly a prodrug of SLV313.

SLV313 and its piperazine N-oxides were administered intravenously or orally individually to mice (3 animals per time point), and then their brains were LC-MS (see method above for SLV313 and its piperazine N-oxides). Analyze with). The data are averaged (n = 3) and collected in Table 4.

When intravenously or orally administered to mice, piperazine-N-oxide is hardly detectable in the brain, but the presence of the parent compound SLV313 is evident.

Distribution volume

Distribution volume (V _D ), also known as 'apparent distribution volume', is a pharmacological term used to quantify the distribution of drugs through the body after oral or parenteral administration. The amount of drug is defined as the volume that must be uniformly distributed to produce the observed concentration (Widmark, 1919).

The distribution volume of SLV313 and its pyridine N-oxides is measured in mice using standard methods well known in the art.

From the data presented above, it can be readily seen that the volume of distribution for SLV313 is five times higher than that of its pyridine N-oxide.

The volume of distribution is not a physiological volume, but rather the ratio between the total amount of drug in the body and the concentration of drug in plasma. In general, the volume of distribution can be more or less than that for species, and it is allowed to make this a parameter with a high expected value for humans when measured in laboratory animals.

The calculated value of 350 L for a person with an average body weight of 70 kg is much larger than the volume of the person's body, indicating that the compound is widely distributed into tissues and remains at low concentrations in plasma. The pyridine N-oxide of SLV313 has a calculated distribution volume of 70 L for a person weighing 70 kg, indicating that the distribution is limited to water of the entire body.

Distribution factor

The partition coefficient (logP) of SLV313 and its N-oxides is calculated and measured (at pH 7.0) by methods well known in the art.

Clearly, the N-oxides of SLV313 are less lipophilic than their parent compounds. When administered orally in the same amount, N-oxides enter the bloodstream more slowly than SLV313, so their peak concentrations are lower than those observed after SLV313.

The following scheme illustrates the invention: Different N-oxides of SLV313, one of the compounds of formula a. 'Pirazine N-oxide' is not found as a metabolite and is actually inert in vitro but rapidly reduced to the parent molecule SLV313 after oral administration. The human metabolite 'pyridine N-oxide' has a pharmacological profile that closely matches that of the parent compound. It is an active metabolite.

Similarly, SLV313-bis-N-oxides ('piperazine N-oxides' of pyridine N-oxides) are inert in vitro but can be identified as having equivalent efficacy to their corresponding parent molecule, pyridine N-oxides. . 'Bis-N-oxide' is a prodrug of an active metabolite.

Example 6: Pharmaceutical Formulations

For clinical use, the N-oxides of the compounds of formula a are formulated into pharmaceutical compositions, which are an important and novel aspect of the present invention because they contain compounds, more particularly the specific compounds described herein. Forms of pharmaceutical compositions that can be used include tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, and are described herein and Other forms, which are apparent to those skilled in the art from the specification and general knowledge of the disclosure, are included without limitation. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, nasal, pulmonary, transdermal, mouth, rectal, parenteral or other methods of administration. Pharmaceutical formulations contain one or more compounds of Formula (a) together with pharmaceutically acceptable adjuvants, diluents and / or carriers. The total amount of active ingredient suitably ranges from about 0.1 to about 95% (w / w), suitably from 0.5 to 50% (w / w), preferably from 1 to 25% (w / w) of the formulation. to be.

Compounds of the present invention may be used to prepare auxiliary substances such as liquid or solid, powdered components such as pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavoring agents, colorants and / or buffering substances. Can be used to form a form suitable for administration by conventional procedures. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars; Or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and derivatives thereof, animal and vegetable oils (e.g. liver oil, sunflower, peanut or sesame oil), polyethylene glycols and solvents (e.g. sterile water and 1 Divalent or polyhydric alcohols such as glycerol), disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into granules or compressed into tablets.

Prior to mixing the active ingredient to form the formulation, it may be premixed separately with the other inactive ingredients. The active ingredients can also be mixed with each other and then with the inert ingredients to form a formulation.

Soft gelatin capsules may be prepared in capsules containing a mixture of the active ingredient, vegetable oils, fats or other vehicles suitable for soft gelatin capsules of the present invention. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatin capsules may also contain the active ingredient together with solid powder ingredients (eg, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin). Dosage units for rectal administration are in the form of (i) suppositories containing the active substance mixed with natural fatty bases, and (ii) containing the active substance in combination with vegetable oils, paraffin oils or other vehicles suitable for gelatinous rectal capsules. In the form of gelatin rectal capsules, (iii) in the form of an immediate-prepared micro enema, or (iv) in the form of an anhydrous micro enema formulation reconstituted in a suitable solvent immediately prior to administration.

The liquid formulation is in the form of a syrup, elixir, concentrated dropping agent or suspension, for example the remainder consisting of a mixture of the active ingredient with, for example, sugars or sugar alcohols and ethanol, water, glycerol, propylene glycol and polyethylene glycol It can be prepared as a solution or suspension containing. If desired, such liquid formulations may contain colorants, flavors, preservatives, saccharin and carboxymethyl cellulose or other thickening agents. Liquid formulations are also prepared in the form of dry powder and can be reconstituted with a suitable solvent before use. Liquids for parenteral administration can be prepared as solutions of the formulations of the invention in pharmaceutically acceptable solvents. These solutions may also contain stabilizing ingredients, preservatives and / or buffering ingredients. Liquids for parenteral administration can also be prepared as dry preparations and reconstituted with a suitable solvent before use.

Also provided are formulations and 'partial kits' comprising one or more containers filled with one or more of the components of a pharmaceutical composition of the present invention for use in a method of medical treatment in accordance with the present invention. Such container (s) may be provided for instructions for use, a notice in the form described by the governmental department that controls the manufacture, the notice reflects approval by the manufacturing agency, or for use or sale of pharmaceutical products, for human or veterinary administration. It may be related to various documents such as usage or sales. Antagonism of the Dopamine-D ₂ Receptor and / or Use of the Formulations of the Invention in the manufacture of a medicament for use in the treatment of a condition in need or desire for activation of the 5-HT _1A Receptor, and antagonism of the Dopamine-D ₂ Receptor And / or one or more compounds of formula (a) are therapeutically effective after administration, either on their own or in the case of prodrugs, to patients suffering from or in need of activation of the 5-HT _1A receptor. Provided are methods of medical treatment comprising administration in a total amount.

References

Berendsen et al., Pharmacol. Biochem. Behav. 33 , 821-827, 1989.

Bickel, MH ,: "T he pharmacology and Biochemistry of N-oxides", Pharmacol. Reviews , 21 (4), 325-355, 1969.

Costall, B., Naylor, RJ and Nohria, V., ' Differential actions of typical and atypical agents on two behavioural effects of apomorphine in the mouse', Brit J Pharmacol, 63: 381-382, 1978.

Creese I, Schneider R and Snyder SH, '[ ³ H] -Spiroperidol labels dopamine receptors in rat pituitary and brain', Eur. J. Pharmacol, 46 , 377-381, 1997.

Gozlan H, El Mestikawy S., Pichat L., Glowinsky J. and Hamon, M., " Identification of presynaptic serotonin autoreceptors using a new ligand ³ H-PAT ", Nature , 305, 140-142, 1983.

Solomon, Y., Landos, C., Rodbell, M., " A highly selective adenylyl cyclase assay", Anal Biochem, 58, 541-548, 1974.

Weiss, S., Sebben, M. and Bockaert, JJ, ' Corticotropin-peptide regulation of intracellular cyclic AMP production in cortical neurons in primary culture', J Neurochem, 45, 869-874, 1985.

Widmark, EPM, 'S tudies in the concentration of indifferent narcotics in blood and tissues', Acta Med. Scand., 52, 87-164, 1919.

[Cited patents and patent applications]

European Patent 0 189 612 and European Patent 0 908 458

Claims (20)

N-oxides, tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates of pyridylmethylpiperazine and pyridylmethylpiperidine derivatives of formula a. Formula a

In the formula a above, A is a heterocyclic group of 5 to 7 ring atoms comprising 1 to 3 heteroatoms selected from the groups O, N and S, R ₁ is hydrogen or fluoro, R ₂ is C _1-4 alkyl, C _1-4 alkoxy or oxo group, p is 0, 1 or 2, Z is carbon or nitrogen, dotted line is single bond if Z is nitrogen, single bond or double bond if Z is carbon, R ₃ and R ₄ are independently hydrogen or C _1-4 alkyl, n is a value of 1 or 2, R ₅ is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position to the methylene bridge with group Y and optionally substituted by (R ₆ ) q, Y is hydroxy, halogen, CF ₃ , C _1-4 alkoxy, C _1-4 alkyl, cyano, aminocarbonyl, mono- _1-4 alkylaminocarbonyl and di-C _1-4 alkylaminocarbonyl Phenyl, furanyl or thienyl, which may be substituted by 1 to 3 substituents, R ₆ is halogen, hydroxy, C _1-4 alkoxy or C _1-4 alkyl, q is 0, 1, 2 or 3, Wherein the oxidized nitrogen atom may be a nitrogen atom in the pyridyl ring of R ₅ , or a nitrogen atom in a piperidine ring (if Z is carbon), or a piperazine ring (if Z is nitrogen) It may be one of the nitrogen atoms in, or may be both a nitrogen atom connected to R ₅ through a methylene group and a nitrogen atom in the pyridyl ring of R ₅ . The compound of claim 1, wherein 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] -methyl] -5- (4-fluoro N-oxide, substantially free of phenyl) -pyridine. The N-oxide, tautomer, stereoisomer, pharmacologically acceptable salt, hydrate and solvate of claim 1, wherein the oxidized nitrogen atom is a nitrogen atom in a pyridyl ring of R ₅ . The N-oxide, its tautomer, stereoisomer, pharmacologically acceptable salt, hydrate and solvate of claim 1, wherein the oxidized nitrogen atom is nitrogen linked to R ₅ via a methylene group. The chemical formula of claim 1 wherein

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -1-oxido-3-pyridinyl] methyl] A compound that is piperazine. The compound of claim 5, wherein 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] -methyl] -5- (4-fluoro Phenyl) -pyridine substantially free. The chemical formula of claim 1 wherein

1- (2,3-dihydro-1,4-benzodioxin-5-yl) -4-[[5- (4-fluorophenyl) -3-pyridinyl] methyl] -4-oxido -Piperazine, compound. 8. The compound of claim 7, wherein 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] -methyl] -5- (4-fluoro Phenyl) -pyridine substantially free. The chemical formula of claim 1 wherein

4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl)-[5-4-fluorophenyl] -1-oxy-pyridin-3-ylmethyl) piperazine-1 An oxide. The compound of claim 9, wherein 3-[[4- (2,3-dihydro-1,4-benzodioxin-5-yl) -1-piperazinyl] -methyl] -5- (4-fluoro Phenyl) -pyridine substantially free. A pharmaceutical comprising a compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt, hydrate or solvate thereof. In addition to a pharmaceutically acceptable carrier and / or one or more pharmaceutically acceptable auxiliary substances, as an active ingredient, one or more of the compounds according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, hydrate thereof or A pharmaceutical composition comprising solvate in a pharmacologically active amount. N-oxides or pharmacologically acceptable salts, hydrates or solvates (i) of compounds of formula (a) and Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and in particular schizophrenia and A combination pharmaceutical formulation comprising another therapeutic agent (ii) for use simultaneously, separately or sequentially in the treatment of other psychotic disorders. The combination pharmaceutical formulation of claim 13, wherein the another therapeutic agent is SLV313. The compound according to any one of claims 1 to 10, for the treatment of Parkinson's disease, aggressiveness, anxiety disorder, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders. Any one of claims 1 to 10 for the manufacture of pharmaceutical compositions for the treatment of Parkinson's disease, aggressiveness, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders. Use of a compound according to claim 1. Compounds of formula (a) according to claim 1 for Parkinson's disease, aggression, anxiety disorders, autism, dizziness, depression, cognitive impairment, memory disorders, and especially human or animal patients in need of treatment for schizophrenia and other psychotic disorders Requiring treatment of Parkinson's disease, aggression, anxiety disorders, autism, dizziness, depression, cognitive disorders, memory disorders, and especially schizophrenia and other psychotic disorders, comprising administering N-oxides in therapeutically effective amounts Parkinson's disease, aggression, anxiety disorders, autism, dizziness, depression, cognitive impairment, memory impairment, and especially schizophrenia and other psychotic disorders in human or animal patients. Of the combination pharmaceutical preparation according to claim 13 for the preparation of a pharmaceutical composition for the treatment of Parkinson's disease, aggression, anxiety disorder, autism, dizziness, depression, cognitive disorder, memory disorder and especially schizophrenia and other psychotic disorders. Usage. A process for preparing a compound according to claim 1, characterized in that the compound of formula a is oxidized with hydrogen peroxide to yield a compound of formula a ^* as in the following scheme.

In the above scheme, The radicals are as defined in claim 1. A compound of formula Hal-CH ₂ -R ₅ , wherein Hal is halogen and R ₅ is as defined in claim 1, is preferably oxidized to its N-oxide using hydrogen peroxide or metachloroperbenzoic acid, The N-oxide is subsequently formulated by heating the mixture to reflux in a polar solvent such as 2-butanone, preferably under mildly basic conditions, for example in the presence of potassium carbonate.

A process for preparing a compound according to claim 1, wherein the compound is coupled with a compound of formula wherein the radicals are as defined in claim 1.