HK1139674A - Pyridine derivatives as fast dissociating dopamine 2 receptor antagonists - Google Patents

Description

Pyridine derivatives as fast dissociating dopamine 2 receptor antagonists

Technical Field

The present invention relates to (1-benzyl-piperidin-4-yl) - (pyridin-2-yl) -amines as fast dissociating dopamine 2 receptor antagonists, processes for preparing these compounds, pharmaceutical compositions comprising these compounds as an active ingredient. The compounds can be used as medicaments for the treatment or prevention of central nervous system disorders, such as schizophrenia, by exerting an antipsychotic effect without motor side effects.

Background

WO2007/001975 and WO96/18628 disclose (1-benzylpiperidin-4-yl) - (6-cyanopyridin-2-yl) amines as intermediates for the preparation of compounds having histamine H3 antagonistic activity and anti-HIV activity. The compounds of the present invention differ by the unexpected findings: it exerts an antagonistic effect on the dopamine D2 receptor.

Description of the invention

Schizophrenia is a serious and chronic disease that affects about 1% of the population. Clinical symptoms are evident relatively early in life, usually in adolescence or early adulthood. Symptoms of schizophrenia are generally classified into so-called positive symptoms including hallucinations, delusions, and disorganized thoughts, and so-called negative symptoms including social withdrawal, reduced emotion, speech deficits, and inability to experience pleasure. In addition, schizophrenic patients also suffer from cognitive deficits such as impaired attention and memory. The etiology of the disease is still unknown, but it has been postulated that aberrant neurotransmitter action underlies the symptoms of schizophrenia. The dopaminergic hypothesis is one of the most widely accepted hypothesis; it suggests that hyperactivity of dopamine transmission is responsible for the positive symptoms observed in schizophrenic patients. The hypothesis is based on the observation that: dopamine-enhancing drugs such as amphetamine or cocaine can induce psychosis, and are based on the correlation that exists between clinical doses of antipsychotics and their efficacy in blocking dopamine D2 receptors. All marketed antipsychotics mediate their therapeutic effect against positive symptoms by blocking dopamine D2 receptors. In addition to clinical effects, major side effects of antipsychotics have also emerged, such as extrapyramidal symptoms (EPS) and tardive dyskinesia, which are also associated with dopamine antagonism. Those aging side effects occur most frequently with typical or first generation antipsychotics (e.g., haloperidol). These side effects are less pronounced for atypical or second generation antipsychotics (e.g., risperidone, olanzapine), which are considered the prototype atypical antipsychotics, even though they are virtually absent for clozapine. To explain the low incidence of EPS observed in atypical antipsychotics, different theories have been proposed, one of which has attracted considerable attention during the last fifteen years being the multi-receptor hypothesis. This hypothesis was based on receptor binding studies showing that many atypical antipsychotics, in addition to the dopamine D2 receptor, also interact with various other neurotransmitter receptors, especially the 5-hydroxytryptamine 5-HT2 receptor, whereas typical antipsychotics, like haloperidol, bind the D2 receptor more selectively. This theory has been challenged in recent years because all major atypical antipsychotics fully occupy the 5-hydroxytryptamine 5-HT2 receptor at clinically relevant doses, but still differ in the induction of motor side effects. As an alternative theory to the multi-receptor hypothesis, Kapur and Seeman ("do fast dissociative from the dopamine D2 receptor expansion of antipsychotic drugs. The rapid dissociation from the D2 receptor results in a greater adaptation of the antipsychotic to the physiological transport of dopamine, resulting in an antipsychotic effect without motor side effects. Considering clozapine and quetiapine, this hypothesis is more convincing. Both drugs have the fastest rate of dopamine D2 receptor dissociation and their risk of inducing EPS in humans is lowest. In contrast, the typical antipsychotic associated with the high prevalence of EPS is the slowest dissociating dopamine D2 receptor antagonist. Therefore, identification of new drugs based on the rate of dissociation from the D2 receptor appears to be a useful strategy for providing new atypical antipsychotics. Another objective is to combine rapid dissociation with selectivity for the dopamine D2 receptor. The multi-receptor profile of current atypical antipsychotics is believed to be responsible for other side effects such as weight gain and diabetes. The search for selective D2 antagonists as a method has been ignored for some time, but we believe that the use of more selective compounds in the clinic may reduce the occurrence of metabolic disorders associated with current atypical antipsychotics.

It is an object of the present invention to provide novel compounds which are fast dissociating dopamine 2 receptor antagonists, as explained above, with advantageous pharmacological profiles, in particular reduced motor side effects, and with moderate or negligible interactions with other receptors, resulting in a reduced risk of developing metabolic disorders.

This object is achieved by the novel compounds of formula (I), their pharmaceutically acceptable salts and solvates and their stereoisomeric forms according to the invention:

wherein

R is hydrogen or C_1-6An alkyl group;

R¹is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from: halogen, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, perfluoro C_1-4Alkyl and perfluoro C_1-4An alkoxy group; a thienyl group; is substituted by 1 or 2 substituents selected from halogen and C_1-4Thienyl substituted with a substituent for alkyl; c_1-4An alkyl group; or by hydroxy, C_3-8Cycloalkyl or C_5-7Cycloalkenyl substituted C_1-4An alkyl group;

R²is hydrogen or C_1-6An alkyl group;

R³、R⁴、R⁵and R⁶Each independently of the others is hydrogen, halogen, C_1-4Alkyl, trifluoromethyl, cyano OR OR⁷；

R⁷Is hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-4Alkyl or perfluoro C_1-4An alkyl group;

with the following conditions: when R is¹Represents phenyl and R³、R⁴And R⁵When it is hydrogen, R⁶Is not cyano.

The compounds according to the invention are rapidly dissociating D₂A receptor antagonist. This property enables the combination according to the inventionThe compounds are particularly suitable as medicaments for the treatment or prophylaxis of the following diseases: schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, psychotic disorder not otherwise specified; psychosis associated with dementia; major depressive disorder, dysthymia, premenstrual dysphoric disorder, depression not otherwise specifically indicated, bipolar I disorder, bipolar II disorder, cyclothymia, bipolar disorder not otherwise specifically indicated, mood disorder due to a general medical condition, substance-induced mood disorder, mood disorder not otherwise specifically indicated; generalized anxiety disorder, obsessive compulsive disorder, panic disorder, acute stress disorder, post-traumatic stress disorder; mental retardation; pervasive developmental disorder; attention deficit disorder, attention deficit/hyperactivity disorder, schizobehavior disorder; paranoid personality disorder, schizophreniform personality disorder; tic disorders, tourette's syndrome; substance dependence; substance abuse; substance withdrawal; trichotillomania.

The skilled artisan will be able to select compounds based on the test data provided in the test section which follows. Any selection of compounds is included in the present invention.

The first group of compounds relates to R, R therein³、R⁵And R⁶Is hydrogen and R⁴A compound of formula (I) which is trifluoromethyl.

A second group of compounds relates to compounds R, R therein³、R⁵And R⁶Is hydrogen and R⁴A compound of formula (I) which is cyano.

A third group of compounds relates to the formula R, R³、R⁴And R⁶Is hydrogen and R⁵A compound of formula (I) which is cyano.

The fourth group of compounds relates to R, R⁴、R⁵And R⁶Is hydrogen and R³A compound of formula (I) which is cyano.

A fifth group of compounds of formula (I) is that wherein R²Those which are hydrogen or methyl.

Among the compounds of formula (I) and the stereoisomeric forms thereof, the most advantageous are, for example,

[1- (3, 4-difluoro-benzyl) -piperidin-4-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine (E1);

6- { methyl- [1- (4-trifluoromethyl-benzyl) -piperidin-4-yl ] -amino } -nicotinonitrile (E2);

6- [1- (3-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -nicotinonitrile (E3);

6- [1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -nicotinonitrile (E4);

6- [1- (3, 5-difluoro-benzyl) -piperidin-4-ylamino ] -nicotinonitrile (E5);

6- [1- (3, 4, 5-trifluoro-benzyl) -piperidin-4-ylamino ] -nicotinonitrile (E6);

2- { methyl- [1- (3-trifluoromethyl-benzyl) -piperidin-4-yl ] -amino } -isonicotinic acid nitrile (E7);

6- [1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -pyridine-2-carbonitrile (E8) and

(1-benzyl-piperidin-4-yl) - (5-trifluoromethyl-pyridin-2-yl) -amine (D1).

Throughout this application, the term "C" is used_1-4Alkyl radicals "used alone or in combination, e.g." C_1-4Alkoxy group and perfluoro C_1-4Alkyl group and di-C_1-4Alkylamino "includes, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1-dimethylethyl; the term "perfluoro C_1-4Alkyl "includes, for example, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, and nonafluorobutyl; "C_3-8Cycloalkyl "includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; "C_5-7Cycloalkenyl "includes cyclopentenyl, cyclohexenyl and cycloheptenyl. The term halogen includes fluorine, chlorine, bromine and iodine.

Pharmaceutically acceptable salts are defined to include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are capable of forming. The salts may be obtained by treating the base form of the compound of formula (I) with a suitable acid, for example an inorganic acid, such as a hydrohalic acid, especially hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids; organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, mandelic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and mandelic acid. Conversely, the salt form may be converted to the free form by treatment with an appropriate base.

The term solvate refers to hydrates and alcoholates which the compounds of formula (I) can form.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise stated or indicated, the chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More particularly, the stereogenic center may have the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. Compounds containing a double bond may have E or Z-stereochemistry at the double bond. Stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.

The compounds of formula (I) prepared in the following processes may be synthesized as racemic mixtures of enantiomers which can be separated from each other by resolution methods known in the art. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and liberation of the enantiomers therefrom by means of a base. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs in a stereospecific manner. Preferably, if a particular stereoisomer is desired, said compound should be synthesized by stereospecific methods of preparation. These processes will advantageously utilize enantiomerically pure starting materials.

Pharmacology of

In order to find antipsychotic compounds that are resistant to positive symptoms and have an improved safety profile (low EPS incidence and no metabolic disorders), we screened compounds that selectively interact with and rapidly dissociate from the dopamine D2 receptor. First, in the binding test, the term³H]The compounds were screened for their D2 affinity to the cell membrane of the spiroperone and human D2L receptor. In indirect experiments on IC's modified from the method published in Jose E.Leysen and Walter Gommeren, Journal of Receptor Research, 1984, 4(7), 817-845₅₀Compounds exhibiting less than 10. mu.M were tested to evaluate the dissociation rate.

The compounds were further screened in the group consisting of more than 50 common G-protein coupled receptors (CEREP) and found to have a clean character, i.e. low affinity for the test receptors.

Some compounds were further tested in vivo models, such as "antagonism of apomorphine-induced oscillation test in rats", and found to be orally active and physiologically available.

From the aforementioned pharmacology of the compounds of formula (I), it is concluded that they are suitable for use as medicaments, in particular as antipsychotic medicaments. More particularly, the compounds are suitable for use as medicaments for the treatment or prevention of the following diseases: schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, psychotic disorder not otherwise specified; psychosis associated with dementia; major depressive disorder, dysthymia, premenstrual dysphoric disorder, depression not otherwise specifically indicated, bipolar I disorder, bipolar II disorder, cyclothymia, bipolar disorder not otherwise specifically indicated, mood disorder due to a general medical condition, substance-induced mood disorder, mood disorder not otherwise specifically indicated; generalized anxiety disorder, obsessive compulsive disorder, panic disorder, acute stress disorder, post-traumatic stress disorder; mental retardation; pervasive developmental disorder; attention deficit disorder, attention deficit/hyperactivity disorder, schizobehavior disorder; paranoid personality disorder, dysthymic personality disorder, schizophrenic personality disorder; spasticity, tourette's syndrome; substance dependence; substance abuse; substance withdrawal; trichotillomania.

In order to optimise the treatment of patients suffering from the conditions mentioned in the preceding paragraph, the compounds of formula (I) may be administered together with other psychotropic compounds. Thus, in the case of schizophrenia, negative and cognitive symptoms can be targeted.

The invention also provides a method of treating a warm-blooded animal having such a condition comprising the systemic administration of a therapeutically effective amount of a compound of formula (I) for the treatment of the above-mentioned condition.

The present invention also relates to the use of a compound of formula (I) as defined above for the preparation of a medicament, in particular an antipsychotic, more particularly for the treatment or prevention of: schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, psychotic disorder not otherwise specified; psychosis associated with dementia; major depressive disorder, dysthymia, premenstrual dysphoric disorder, depression not otherwise specifically indicated, bipolar I disorder, bipolar II disorder, cyclothymia, bipolar disorder not otherwise specifically indicated, mood disorder due to a general medical condition, substance-induced mood disorder, mood disorder not otherwise specifically indicated; generalized anxiety disorder, obsessive compulsive disorder, panic disorder, acute stress disorder, post-traumatic stress disorder; mental retardation; pervasive developmental disorder; attention deficit disorder, attention deficit/hyperactivity disorder, schizobehavior disorder; paranoid personality disorder, schizophreniform personality disorder; tic disorders, tourette's syndrome; substance dependence; substance abuse; substance withdrawal; trichotillomania.

Those skilled in the treatment of such diseases will be able to determine the therapeutically effective daily dose from the test results provided hereinafter. An effective daily therapeutic dose may be from about 0.01mg/kg to about 10mg/kg body weight, more preferably from about 0.05mg/kg to about 1mg/kg body weight.

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I).

For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. The compounds of the present invention, especially the compounds of formula (I), pharmaceutically acceptable acids or bases thereof, stereochemically isomeric forms thereof, N-oxide form thereof and prodrugs thereof, or any subgroup or combination thereof, may be formulated into various pharmaceutical forms for administration purposes. As suitable compositions, all compositions usually used as systemically administered drugs can be cited. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of an acid addition salt, as the active ingredient is admixed in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation intended for administration. Ideally, these pharmaceutical compositions are in unit dosage forms particularly suitable for oral, rectal, transdermal, parenteral injection or inhalation administration. For example, in preparing the compositions in oral dosage form, for oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like; or, for powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like may be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included, for example to aid dissolution. Injectable solutions, for example, may be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable solutions containing the compounds of formula (I) may be formulated in oils for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and mixtures of these with other oils. Injectable suspensions may also be prepared in which case liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, at the point of use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally mixed with minor amounts of any form of suitable additive that does not cause significant deleterious effects on the skin. The additives may aid in dermal administration and/or may aid in the preparation of the desired composition. These compositions can be administered by various means, for example as a transdermal patch, as a spot-on, ointment. The acid or base addition salts of the compounds of formula (I) have increased water solubility over the corresponding base or acid forms and are therefore more suitable for the preparation of aqueous compositions.

For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder product pouches, dry compressed tablets, suppositories, injectable solutions or suspensions, and the like, as well as divided multiple doses thereof.

Since the compounds according to the invention are effective orally administrable compounds, pharmaceutical compositions for oral administration comprising said compounds are particularly advantageous.

In order to improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions, it may be advantageous to employ alpha-, beta-or gamma-cyclodextrins or derivatives thereof, especially hydroxyalkyl-substituted cyclodextrins, for example 2-hydroxypropyl-beta-cyclodextrin. And co-solvents, such as alcohols, may improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions.

Preparation of

R, R therein¹、R²、R³、R⁴、R⁵And R⁶The compounds of formula (I) as defined above may be prepared in the following manner: in the presence of a base such as potassium carbonate or diisopropylethylamine in a suitable solvent such as acetonitrile under suitable reaction conditions such as a convenient temperature²、R³、R⁴、R⁵And R⁶A compound of formula (II) as defined above,

and formula R¹Reagent reaction of-CHY-R (III-a) in which R and R¹As defined above, Y represents a leaving group such as halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonylAcyloxy, trifluormethylsulfonyloxy, or methylphenylsulfonyloxy, the reaction is maintained under conventional heating or microwave irradiation for a period of time to ensure completion of the reaction.

Alternatively, R, R therein¹、R²、R³、R⁴、R⁵And R⁶The compounds of formula (I) as defined above may be prepared in the following manner: in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, a suitable acid catalyst such as acetic acid, in a suitable reaction-inert solvent, such as 1, 2-dichloroethane²、R³、R⁴、R⁵And R⁶A compound of formula (II) as hereinbefore defined with formula R¹Carrying out an N-alkylation reaction with a reagent of-C (═ O) -R (III-b), wherein R and R¹As previously defined.

Wherein R is²、R³、R⁴、R⁵And R⁶The compounds of formula (II) as defined above may be prepared in the following manner: deprotection of the protecting group in the intermediate of formula (IV) is carried out in the presence of a suitable base such as diisopropylethylamine, in dichloromethane when L represents benzyl or trifluoroacetic acid, or dichloromethane when L represents tert-butoxycarbonyl, under suitable conditions, for example with 1-chloroethyl chloroformate,

wherein L represents a suitable protecting group, e.g. benzyl or tert-butoxycarbonyl, R²、R³、R⁴、R⁵And R⁶As previously defined.

Wherein R is²、R³、R⁴、R⁵And R⁶Compounds of formula (IV) as defined above and L represents a suitable protecting group may be prepared in the following manner: in the absence or presence of a base such as diisopropylIn the case of ethylamine, the compound of formula (V) is reacted in a suitable solvent, such as acetonitrile, under suitable reaction conditions, such as a convenient temperature,

wherein R is²L represents a suitable protecting group such as benzyl or tert-butoxycarbonyl, as defined above, with a chloropyridine of formula (VI)

Wherein R is³、R⁴、R⁵And R⁶As previously defined, the reaction is ensured to be complete by holding for a period of time under conventional heating or microwave radiation.

When R is³、R⁵And R⁶Is hydrogen and R⁴When R is trifluoromethyl or cyano³、R⁴And R⁶Is hydrogen and R⁵When it is cyano and when R⁴、R⁵And R⁶Is hydrogen and R³The chloropyridines of formula (VI) in the case of cyano groups are commercially available or can be prepared according to methods known to the skilled worker.

R, R therein¹、R²、R³、R⁴、R⁵And R⁶The compounds of formula (I) as defined above may also be prepared in the following manner: in the presence of a suitable base such as diisopropylethylamine in a suitable solvent such as acetonitrile under suitable reaction conditions, e.g. at a convenient temperature³、R⁴、R⁵And R⁶Chloropyridines of the formula (VI) as defined above with R, R therein¹And R²The piperidine derivative of formula (VII) as described above,

the reaction is maintained under conventional heating or microwave radiation for a period of time to ensure completion of the reaction.

R, R therein¹And R²The compounds of formula (VII) as defined above may be prepared in the following manner: using the formula R in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, a suitable acid catalyst such as acetic acid, in a suitable reaction-inert solvent such as 1, 2-dichloroethane, or in the presence of a suitable reducing agent such as hydrogen, a suitable catalyst such as palladium on carbon, in a suitable inert reaction solvent such as methanol¹-C (═ O) -R (III-b) reagents, wherein R and R¹Tert-butyl piperidin-4-ylcarbamate (VIII) is subjected to a reductive N-alkylation reaction as previously defined,

the t-butoxycarbonyl group in the intermediate of formula (IX) is then deprotected by treatment with an acid, such as trifluoroacetic acid, to give a compound wherein R is²A compound of formula (VII) as hereinbefore defined.

Optionally, R, R therein¹And R²The compounds of formula (VII) as defined above may also be prepared in the following manner: reacting tert-butyl piperidin-4-ylcarbamate (VIII) with formula R in the presence of a base such as diisopropylethylamine in a suitable solvent such as dichloromethane¹Reagent reaction of-CHY-R (III-a) in which R and R¹As defined above, Y represents a leaving group, e.g. halogen, such as chlorine, bromine or iodine, or a sulfonyloxy group, such as methanesulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy, which is then treated with an acid, e.g. trifluoroacetic acid, to reactDeprotection of the tert-butoxycarbonyl group in an intermediate of formula (IX) to give a compound wherein R²A compound of formula (VII) as hereinbefore defined.

Wherein R is²Compounds of formula (VII) not being equal to H can be prepared as follows: in the presence of a suitable reducing agent such as hydrogen, a suitable catalyst such as palladium on carbon, in a suitable inert reaction solvent such as ethanol¹A compound of formula (X) as defined above and formula R²-NH₂(XI) reacting the amine of (XI),

wherein R and R¹The compounds of formula (X) as defined above may be prepared in the following manner: reacting 4, 4-ethylenedioxypiperidine (XII) with R and R in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, a suitable acid catalyst, and a suitable reaction-inert solvent such as 1, 2-dichloroethane¹Formula R as defined above¹-C (═ O) -R (III-b),

and then treated with an acid such as hydrochloric acid to thereby render R and R¹Deprotection of an intermediate of formula (XIII) as hereinbefore defined

Test section

Chemistry

In a single mode reactor: emrys^TMMicrowave-assisted reactions were carried out in an Optimizer microwave reactor (Personal chemistry a.b., current Biotage). The description of the apparatus can be found inwww.personalchemistry.comIs found in (1).

¹H spectra were recorded on a Bruker DPX 360, DPX 400 or Bruker AV-500 spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane.

Melting points were determined on a Mettler FP62 apparatus.

The HPLC gradient was provided using HP1100 from Agilent Technologies, which HP1100 included a four-way pump with degasser, an autosampler, a column oven (all set at 40 ℃ except for method 4 where the temperature was set at 60 ℃), a Diode Array Detector (DAD), and columns as specified in the methods described below. The stream from the column was split to the MS detector. The MS detector was equipped with an electrospray ionization source. Nitrogen was used as the nebulizer gas. The source temperature was maintained at 140 ℃. And acquiring data by using MassLynx-Openlynx software.

Method 1

In addition to the general method: reverse phase HPLC was also performed on an ACE-C18 column (3.0 μm, 4.6X30mm) from Advanced chromatography technologies at a flow rate of 1.5ml/min, 40 ℃. The gradient conditions used were: from 80% A (0.5g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 min, 100% B was reached at 7min, equilibrated to initial conditions at 7.5 min until 9.0 min. The injection volume was 5. mu.l. High resolution mass spectra (time of flight, TOF) were obtained in positive ionization mode only, with a dwell time of 0.1 seconds, scanning from 100 to 750 in 0.5 seconds. For positive ionization mode, the capillary pinhole voltage was 2.5kV and the cone voltage was 20V. The standard substance used for lock mass calibration was leucine-enkephalin.

Method 2

In addition to the general method: reverse phase HPLC was also performed on a small column (1.8 μm, 4.6X30mm) of XDB-C18 from Agilent, flow rate 1.5ml/min, 60 ℃. The gradient conditions used were: from 80% A (0.5g/l ammonium acetate solution), 20% B (acetonitrile/methanol, 1/1 mixture) to 100% B over 6.5 minutes, hold for 7 minutes, and equilibrate to the initial conditions at 7.5 minutes until 9.0 minutes. The injection volume was 5. mu.l. Low resolution mass spectra were obtained by scanning from 100 to 1000 in 1.0 second with a dwell time of 0.3 second (ZQ detector; quadrupole). The capillary pinhole voltage was 3 kV. The cone voltage was 20V and 50V for positive ionization mode and 20V for negative ionization mode.

Description 1

(1-benzyl-piperidin-4-yl) - (5-trifluoromethyl-pyridin-2-yl) -amine (D1)

A mixture of 2-chloro-5-trifluoromethyl-pyridine (0.33g, 1.82mmol) and 4-amino-1-benzylpiperidine (0.70ml, 3.43mmol) was heated at 180 ℃ for 1h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with saturated sodium carbonate solution (15 ml). The organic layer was separated and dried (Na)₂SO₄) The solvent was evaporated under vacuum. The crude product was purified by column chromatography (silica gel; 0-2% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated under vacuum to yield D1(0.34g, 81%) as a solid. C₁₈H₂₀F₃N₃Required values: 335; measured value: 336 (MH)⁺)。Rt：4.61min。

¹H NMR (400MHz, chloroform-d) delta ppm 1.47-1.61(m, 2H)1.95-2.07(m, 2H)2.12-2.26(m, 2H)2.78-2.91(m, 2H))3.53(s，2H)3.62-3.78(m，1H)4.75(d，J＝7.46Hz，1H)6.36(d，J＝8.91Hz，1H)7.26(dd，1H)7.29-7.37(m，4H)7.55(dd，J＝8.81，2.38Hz，1H)8.31(s，1H)。

Description 2

Piperidin-4-yl- (5-trifluoromethyl-pyridin-2-yl) -amine (D2)

To a stirred solution of (1-benzyl-piperidin-4-yl) - (5-trifluoromethyl-pyridin-2-yl) -amine (D1) (0.41g, 1.22mmol) and diisopropylethylamine (0.64ml, 3.67mmol) in dichloromethane (15ml) was added 1-chloroethyl chloroformate (0.40ml, 3.67mmol) at 0 ℃. The reaction mixture was allowed to slowly warm to room temperature, after which it was stirred for 1 hour. After this period of time, the solvent was evaporated under vacuum and the crude product was dissolved in methanol (15 ml). The reaction mixture was stirred at reflux for 1.5 h. After evaporation of the solvent in vacuo, the residue was diluted with 1M hydrochloric acid solution and extracted with dichloromethane (15 ml). The aqueous layer was separated, basified by addition of saturated sodium carbonate solution and extracted with dichloromethane (2 × 25 ml). The organic layer was separated and dried (Na)₂SO₄) And the solvent was evaporated under vacuum. The crude product was purified by column chromatography (silica gel; 5-10% ammonia (7M) in methanol/dichloromethane). The desired fractions were collected and evaporated under vacuum to yield D2(0.25g, 84%) as a solid. C₁₁H₁₄F₃N₃Required values: 245; measured value: 246 (MH)⁺)。Rt：1.86min。

Melting point: 128.2 ℃.

¹H NMR (400MHz, chloroform-d) δ ppm 1.34-1.46(m, 2H)2.01-2.12(m, 2H)2.70-2.82(m, 2H)3.13(dt, J ═ 12.75, 3.52, 3.42Hz, 2H)3.72-3.85(m, 1H)4.77(d, J ═ 7.26Hz, 1H)6.38(d, J ═ 8.91Hz, 1H)7.56(dd, J ═ 8.71, 2.28Hz, 1H)8.32(s, 1H).

Description 3

Methyl- [1- (3-trifluoromethyl-benzyl) -piperidin-4-yl ] -amine (D3)

A mixture of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (26g, 120mmol) and 4- (trifluoromethyl) -benzaldehyde (22g, 120mmol) in methanol (250ml) was hydrogenated in the presence of a solution of 10% palladium and 0.005% thiophene on activated carbon (3g) in methanol (3ml) at room temperature. After the absorption of hydrogen was complete, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated under vacuum. The crude product was dissolved in a 5N solution of hydrochloric acid in isopropanol and the reaction mixture was refluxed for 30 minutes. After this period of time, it was further diluted with a 5N solution of hydrochloric acid in isopropanol (50ml) and refluxed for a further 30 minutes. The solvent was evaporated under vacuum and the crude product precipitated from acetone. The solid formed is filtered off, suspended in dichloromethane and extracted with a saturated solution of ammonia. The organic layer was separated and dried (Na)₂SO₄) And the solvent was evaporated under vacuum to give D3(27.6g, 85%) as a solid. C₁₄H₁₉F₃N₂Required values: 272; measured value: 273 (MH)⁺)。

¹H NMR (360MHz, chloroform-d) δ ppm 1.31-1.45(m, 3H)1.83-1.91(m, 2H)2.05(dt, J ═ 11.53, 2.20Hz, 2H)2.32-2.41(m, 1H)2.43(s, 3H)2.77-2.87(m, 2H)3.54(s, 2H)7.38-7.45(m, 1H)7.48-7.54(m, 2H)7.58(s, 1H).

Description 4

4- (5-cyano-pyridin-2-ylamino) -piperidine-1-carboxylic acid tert-butyl ester (D4)

A mixture of 6-chloro-nicotinonitrile (0.5g, 3.60mmol) and tert-butyl 4-amino-piperidine-1-carboxylate (0.94g, 4.68mmol) and diisopropylethylamine (0.94ml, 5.40mmol) in acetonitrile (4ml) was stirred at 160 ℃ under microwave irradiation for 1h. After this time period, the reaction mixture was diluted with dichloromethane and extracted with saturated ammonium chloride solution (15 ml). The organic layer was separated and dried (MgSO)₄) And the solvent was evaporated under vacuum. The crude product was purified by short open column chromatography (silica gel; 0-5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated under vacuum to yield D4(0.93g, 85%) as a white solid. C₁₆H₂₂N₄O₂Required values: 302; measured value: 303 (MH)⁺)。

Description 5

6- (piperidin-4-ylamino) -nicotinonitrile (D5)

To a stirred solution of tert-butyl 4- (5-cyano-pyridin-2-ylamino) -piperidine-1-carboxylate (D4) (0.93g, 3.06mmol) in dichloromethane (10ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1 hour. After this period of time, the solvent was evaporated under vacuum, the crude product was dissolved in dichloromethane and extracted with saturated sodium carbonate solution (15 ml). The organic layer was separated and dried (MgSO)₄) And the solvent was evaporated under vacuum. The crude product was precipitated from diethyl ether to yield D5(0.595g, 96%) as a white solid. C₁₁H₁₄N₃Required values: 202; measured value: 203 (MH)⁺)。

Description 6

1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamine (D6)

A mixture of tert-butyl piperidin-4-ylcarbamate (4g, 20.0mmol), 3-fluoro-5- (trifluoromethyl) benzyl bromide (4.6g, 18.1mmol) and diisopropylethylamine (4.7ml, 27.1mmol) in dichloromethane (25ml) was stirred at room temperature for 2h. After this period of time, trifluoroacetic acid (32ml) was added and the reaction stirred for a further 2h. The solvent was evaporated in vacuo and saturated sodium carbonate solution was added. The mixture was extracted with dichloromethane and the separated organic layer was dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo afforded D7(4.0g, 80%) as a solid. C₁₃H₁₆F4₂N₂Required values: 276; measured value: 277 (MH)⁺)。

Example 1

[1- (3, 4-difluoro-benzyl) -piperidin-4-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine (E1)

A mixture of piperidin-4-yl- (5-trifluoromethyl-pyridin-2-yl) -amine (D2) (0.050g, 0.2mmol), 3, 4-difluorobenzyl bromide (0.031ml, 0.24mmol) and potassium carbonate (0.055g, 0.4mmol) in acetonitrile (2.5ml) was stirred at 100 ℃ under microwave irradiation for 10 minutes. After this time period, the reaction mixture was diluted with dichloromethane and filtered. The filtrate was evaporated in vacuo and the crude product was converted to its hydrochloride salt in diethyl ether to give E1(0.061g, 74%) as a solid. C₁₈H₁₈F₅N₃HCl free base requirement: 371; measured value: 372 (MH)⁺). Rt (method 1): 5.15 min.

Melting point: 268.7 deg.C.

¹H NMR(400MHz，DMSO-d₆)δppm 1.75-2.19(m，4H)2.87-3.45(m，4H)3.92-4.08(m，0.8H)4.12-4.20(m，0.2H)4.29(d，J＝4.35Hz，0.8H)4.32(d，J＝5.18Hz，0.2H)6.70(d，J＝8.71Hz，0.8H)6.82(d，J＝8.91Hz，0.2H)7.41-7.61(m，2H)7.65-7.99(m，3H)8.28(br.s.，0.8H)8.32(br.s.，0.2H)10.85(br.s.，0.2H)11.03(br.s.，0.8H)。

Example 2

6- { methyl- [1- (3-trifluoromethyl-benzyl) -piperidin-4-yl ] -amino } -nicotinonitrile (E2)

Under microwave irradiation at 200 deg.C, 6-chloro-nicotinonitrile (0.272g, 1mmol), methyl- [1- (3-trifluoromethyl-benzyl) -piperidin-4-yl]A mixture of amine (D3) (0.138g, 1mmol) and diisopropylethylamine (0.35ml, 2mmol) in n-butanol (4ml) was stirred for 2h. After this period of time, the solvent was evaporated under vacuum. The crude product was diluted with dichloromethane and extracted with 10% sodium carbonate solution. The organic layer was separated and dried (Na)₂SO₄) And the solvent was evaporated under vacuum. The crude product was purified by short open column chromatography (silica gel; 1% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated under vacuum to give E2(0.333g, 89%) as a syrup. C₂₀H₂₁F₃N₄A desired value 374; measured value 375 (MH)⁺). Rt (method 2): 4.77 min.

¹H NMR (360MHz, chloroform-d) δ ppm 1.62-1.70(m, 2H)1.86(qd, J-12.26, 3.84Hz, 2H)2.18(td, J-11.71, 2.20Hz, 2H)2.95(s, 3H)2.95-3.00(m, 2H)3.58(s, 2H)4.53-4.67(m, 1H)6.47(d, J-9.15 Hz, 1H)7.40-7.47(m, 1H)7.50-7.55(m, 2H)7.58(dd, J-9.15, 2.56Hz, 1H)7.61(br.s., 1H)8.39(d, J-2.20 Hz, 1H).

Example 3

6- [1- (3-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -nicotinonitrile (E3)

A mixture of 6- (piperidin-4-ylamino) -nicotine nitrile (D5) (0.10g, 0.49mmol), 3- (trifluoromethyl) benzyl bromide (0.082ml, 0.54mmol) and diisopropylethylamine (0.26ml, 1.47mmol) in acetonitrile (5ml) was stirred at room temperature for 18 h. After this time period, the reaction mixture was diluted with dichloromethane and extracted with saturated ammonium chloride solution. The organic layer was separated and dried (MgSO)₄) And the solvent was evaporated under vacuum. The crude product was purified by short open column chromatography (silica gel; 0-2% ammonia (7M)/dichloromethane in methanol). The desired fractions were collected and evaporated in vacuo to yield E3(0.062g, 35%) as a solid. C₁₉H₁₉F₃N₄Required values: 360; measured value: 361 (MH)⁺). Rt (method 1): 4.73 min.

Melting point: 111.6 ℃.

¹H NMR (400MHz, chloroform-d) δ ppm 1.55-1.77(m, 2H)2.02-2.11(m, 2H)2.22-2.36(m, 2H)2.84-2.99(m, 2H)3.57-3.72(m, 2H)3.73-3.88(m, 1H)4.90-5.00(m, 1H)6.37(d, J ═ 8.91Hz, 1H)7.47(t, J ═ 7.67Hz, 1H)7.52-7.64(m, 4H)8.35(d, J ═ 2.07Hz, 1H).

Example 7

2- { methyl- [1- (3-trifluoromethyl-benzyl) -piperidin-4-yl ] -amino } -isonicotinic acid nitrile (E7)

2-chloro-isonicotinitrile (0.272g, 1mmol), methyl- [1- (3-trifluoromethyl) at 190 deg.C under microwave irradiation-benzyl) -piperidin-4-yl]A mixture of amine (D3) (0.138g, 1mmol) and diisopropylethylamine (0.35ml, 2mmol) in n-butanol (4ml) was stirred for 2h. After this period of time, the solvent was evaporated under vacuum. The crude product was diluted with dichloromethane and extracted with 10% sodium carbonate solution. The organic layer was separated and dried (Na)₂SO₄) And the solvent was evaporated under vacuum. The crude product was purified by short open column chromatography (silica gel; 1% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated under vacuum to give E7(0.105g, 28%) as a syrup. C₂₀H₂₁F₃N₄Required values: 374; measured value: 375 (MH)⁺). Rt (method 1): 5.94 min.

¹H NMR (360MHz, chloroform-d) δ ppm 1.61-1.69(m, 2H)1.79-1.92(m, 2H)2.18(td, J ═ 11.71, 2.20Hz, 2H)2.91(s, 3H)2.93-3.00(m, 2H)3.58(s, 2H)4.43-4.54(m, 1H)6.65(s, 1H)6.68(dd, J ═ 4.94, 1.28Hz, 1H)7.40-7.48(m, 1H)7.49-7.55(m, 2H)7.61(s, 1H)8.24(dd, J ═ 4.76, 0.73Hz, 1H

Example 8

6- [1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -pyridine-2-carbonitrile (E8)

A mixture of 6-chloro-pyridine-2-carbonitrile (0.080g, 0.58mmol), 1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamine (D6) (0.191g, 0.69mmol) and diisopropylethylamine (0.201ml, 1.15mmol) in 1-methyl-pyrrolidin-2-one (1ml) was stirred at 200 ℃ under microwave irradiation for 1h. After this time period, the reaction mixture was diluted with dichloromethane and extracted with saturated ammonium chloride solution. The organic layer was separated and dried (Na)₂SO₄) And the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (silica gel; 0-2% ammonia (7M)/dichloromethane in methanol). Collecting the desired fraction and evaporating under vacuumThe crude product was purified by reverse phase HPLC. The desired fractions were collected and evaporated in vacuo to yield E8(0.90g, 41%) as a yellow solid. C₁₉H₁₈F₄N₄Required values: 378; measured value: 379 (MH)⁺). Rt (method 1): 5.25 min.

Melting point: 115.2 ℃.

¹H NMR (400MHz, chloroform-d) δ ppm 1.51-1.67(m, 2H)2.02-2.12(m, 2H)2.21-2.33(m, 2H)2.80-2.93(m, 2H)3.54-3.65(m, 2H)3.74-3.85(m, 1H)4.60(d, J ═ 7.46Hz, 1H)6.54(d, J ═ 8.71Hz, 1H)6.95(d, J ═ 7.05Hz, 1H)7.24(d, J ═ 8.29Hz, 1H)7.30-7.37(m, 1H)7.39-7.47(m, 2H).

Following a procedure analogous to example (E3), the following additional examples (E4-E6) were prepared from (D5) and the corresponding alkylating reagents.

In analogy to example (E8), further examples (E9-E11) were prepared from 6-chloro-pyridine-2-carbonitrile and the corresponding 1- (benzyl) -piperidin-4-ylamine derivative. The corresponding 1- (benzyl) -piperidin-4-ylamine derivatives are prepared from tert-butyl piperidin-4-ylcarbamate and the corresponding alkylating agent in analogy to the description (D6). 1- (benzyl) -piperidin-4-ylamine is commercially available.

Pharmacology of

To person D2 _L In vitro binding affinity of receptors

Mixing human dopamine D2_LFrozen films of recipient-transfected CHO cells were thawed, briefly homogenized using an Ultra-Turrax T25 homogenizer, and in the presence of NaCl, CaCl₂、MgCl₂KCl (50, 120, 2, 1 and 5mM respectively, adjusted to pH 7.7 with HCl) to the appropriate protein concentration optimized for specific and non-specific binding. The radioactive ligand [ alpha ]³H]Spiroperone (NEN, specific activity-70 Ci/mmol) was diluted in assay buffer at a concentration of 2 nmol/L. The prepared radioligand (501) was then combined with 50 μ L of 10% DMSO control, Dimethomorph (final concentration 10)^-6mol/l) or the compound of interest, with 400. mu.l of the prepared membrane solution (30min, 37 ℃). The membrane-bound activity was filtered through a Packard Filtermate collector to GF/B single filter plates and washed with ice-cold Tris-HCl buffer (50 mM; pH 7.7; 6 X0.5ml). The filtrate was dried and counted on a Topcount scintillation counter before addition of scintillation fluid. The percentage of specific binding and the competition binding curve were calculated using the S-Plus software (band shown). pIC of Compounds₅₀The value was > 5.0.

Quick dissociation

IC's were tested in indirect experiments with adaptations of the method published by Jose E.Leysen and Walter Gommeren, Journal of Receptorb research, 1984, 4(7), 817-845₅₀Compounds exhibiting less than 10. mu.M were tested to evaluate the dissociation rate. The concentration at its IC was first determined at 25 ℃ with a 2ml volume of human D2L receptor cell membrane₅₀The 4-fold value of the compound was cultured for 1 hour, after which 40-well multividor was usedSuction filtration was performed on a glass fiber filter. The vacuum was released immediately thereafter. Will contain 0.4ml of 1nM [ alpha ]³H]Pre-warmed buffer (25 ℃) of spiperone was added to the filter. The culture was stopped by starting the vacuum and immediately washed with 2x5ml ice cold buffer. The filter-bound radioactivity was measured on a liquid scintillation spectrometer. The experimental principle is based on the following assumptions: the faster the compound dissociates from the D2 receptor, the³H]The faster the spiperone binds to the D2 receptor. For example, when using a concentration of 1850nM (4 xIC)₅₀) When the clozapine of (2) is cultured on the D2 receptor, the culture is carried out on a filter for 5 minutes³H]Binding of spiperone is equal to 60-70% of its total binding capacity (measured in the absence of drug). When cultured with another antipsychotic agent³H]The binding of spiperone varies between 20-50%. Since clozapine is included in each filtration run, a test compound is considered to be a rapidly dissociating D2 antagonist if it dissociates as quickly as or faster than clozapine. The compound has a dissociation rate greater than clozapine, i.e. > 50%.

Claims (11)

1. A compound of formula (I)

Or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomeric form thereof, wherein

R is hydrogen or C_1-6An alkyl group;

R¹is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from: halogenElement, cyano group, C_1-4Alkyl radical, C_1-4Alkoxy, perfluoro C_1-4Alkyl and perfluoro C_1-4An alkoxy group; a thienyl group; thiophene substituted with 1 or 2 substituents selected from halogen and C1-4 alkyl; c_1-4An alkyl group; c substituted by hydroxy_1-4Alkyl radical, C_3-8Cycloalkyl or C_5-7A cycloalkenyl group;

R²is hydrogen or C_1-6An alkyl group;

R³、R⁴、R⁵and R⁶Each independently of the others is hydrogen, halogen, C_1-4Alkyl, trifluoromethyl, cyano OR OR⁷；

R⁷Is hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-4Alkyl or perfluoro C_1-4An alkyl group;

with the following conditions: when R is¹Represents phenyl and R³、R⁴And R⁵When it is hydrogen, R⁶Is not cyano.

2. A compound according to claim 1, wherein R, R³、R⁵And R⁶Is hydrogen and R⁴Is trifluoromethyl.

3. A compound according to claim 1, wherein R, R³、R⁵And R⁶Is hydrogen and R⁴Is cyano.

4. A compound according to claim 1, wherein R, R³、R⁴And R⁶Is hydrogen and R⁵Is cyano.

5. A compound according to claim 1, wherein R, R⁴、R⁵And R⁶Is hydrogen and R³Is cyano.

6. A compound according to claim 1, wherein R²Is hydrogen or methyl.

7. The compound according to claim 1, wherein the compound is selected from the group consisting of:

[1- (3, 4-difluoro-benzyl) -piperidin-4-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine,

6- { methyl- [1- (4-trifluoromethyl-benzyl) -piperidin-4-yl ] -amino } -nicotinonitrile,

6- [1- (3-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -nicotinonitrile,

6- [1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -nicotinonitrile,

6- [1- (3, 5-difluoro-benzyl) -piperidin-4-ylamino ] -nicotinonitrile,

6- [1- (3, 4, 5-trifluoro-benzyl) -piperidin-4-ylamino ] -nicotinonitrile,

2- { methyl- [1- (3-trifluoromethyl-benzyl) -piperidin-4-yl ] -amino } -isonicotinic acid nitrile,

6- [1- (3-fluoro-5-trifluoromethyl-benzyl) -piperidin-4-ylamino ] -pyridine-2-carbonitrile and

(1-benzyl-piperidin-4-yl) - (5-trifluoromethyl-pyridin-2-yl) -amine.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1.

9. A compound as defined in claim 1 for use as a medicament.

10. A compound as defined in claim 9 for use as an antipsychotic.

11. A compound as defined in claim 9 for use as a medicament in the treatment or prevention of: schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, psychotic disorder not otherwise specified; psychosis associated with dementia; major depressive disorder, dysthymia, premenstrual dysphoric disorder, depression not otherwise specifically indicated, bipolar I disorder, bipolar II disorder, cyclothymia, bipolar disorder not otherwise specifically indicated, mood disorder due to a general medical condition, substance-induced mood disorder, mood disorder not otherwise specifically indicated; generalized anxiety disorder, obsessive compulsive disorder, panic disorder, acute stress disorder, post-traumatic stress disorder; mental retardation; pervasive developmental disorder; attention deficit disorder, attention deficit/hyperactivity disorder, schizobehavior disorder; paranoid personality disorder, schizophreniform personality disorder; tic disorders, tourette's syndrome; substance dependence; substance abuse; substance withdrawal; trichotillomania.