ME01208B - Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists - Google Patents

Description

Field of invention

This invention relates to compounds that are rapidly dissociating dopamine 2 receptor antagonists, to a process for the preparation of these compounds, and to pharmaceutical compositions containing these compounds as active ingredients. The mentioned compounds are used as drugs for the treatment or prevention of disorders of the central nervous system, for example schizophrenia, by showing antipsychotic action without incidental motor effects.

State of the art

J. Med. Chem. (1999), 42 (4), 730-741 discloses 6-phenyl-N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridazinamine and analogous compounds as acetylcholinesterase inhibitors.

Farmaco, Vol. 35, no. 11, 1980, p. 951-964 describe substituted N-[4-piperidinyl]-2-aminopyrimidines that possess dopaminergic activity, ie. most of the described compounds are dopamine D2 receptor agonists. Since none of these tested compounds antagonized stereotypic behavior induced by a subsequent dose of apomorphine, they can be considered to be devoid of dopamine receptor blocking ability. The compounds of the present invention differ in that they contain pyridazine instead of pyrimidine and in the unexpected finding that they exhibit antagonistic activity at the dopamine D2 receptor.

Description of the invention with examples of implementation

Schizophrenia is a severe chronic mental illness that affects approximately 1% of the human population. Clinical symptoms appear relatively early in life, generally during adolescence or early adulthood. Schizophrenia symptoms are usually divided into those described as positive, which include hallucinations, apparitions, and disorganized thoughts, and those described as negative, which include social withdrawal, lack of emotion, inability to speak, and inability to feel pleasure. Then, patients suffering from schizophrenia suffer from cognitive disorders, such as lack of concentration and poor memory. The etiology of this disease is still unknown, but it is assumed that the malfunctioning of neurotransmitters is responsible for the symptoms of schizophrenia. The dopaminergic hypothesis is the one most often considered - according to it, increased dopamine transmission activity is responsible for the positive symptoms that can be observed in

patients suffering from schizophrenia. This hypothesis is based on the observation that drugs that increase dopamine, such as amphetamine and cocaine, can cause psychosis, and on the correlation that exists between the clinical dose of antipsychotics and their strength with which they can block dopamine D2 receptors. All labeled antipsychotics mediate their therapeutic efficacy against positive symptoms by blocking dopamine D2 receptors. Regardless of clinical efficacy, most of the side effects caused by antipsychotics, such as extrapyramidal symptoms (EPS) and tardive dyskinesia, appear to be related to dopamine antagonism. The mentioned side effects most often occur with typical antipsychotics or first-generation antipsychotics (eg, haloperidol). They are less pronounced with atypical antipsychotics or second-generation antipsychotics (eg, risperidone, olanzapine) or completely absent with clozapine, which we consider a prototypical atypical antipsychotic. Among the various theories proposed to explain the lower incidence of EPS observed with atypical antipsychotics, the one that has attracted much attention during the last fifteen years is the multireceptor hypothesis. Receptor binding studies show that many atypical antipsychotics interact with various other neurotransmitter receptors in addition to dopamine D2 receptors, specifically serotonin 5‑HT2 receptors, while typical antipsychotics such as haloperidol bind more selectively to D2 receptors. This theory has been reexamined in recent years because all major atypical antipsychotics fully occupy serotonin 5‑HT2 receptors at clinically relevant doses but still differ in causing motor side effects. As an alternative to the multireceptor hypothesis, Kapur and Seeman ("Does rapid dissociation from dopamine D2 receptors explain the action of atypical antipsychotics?: A new hypothesis", Am. J. Psychiatry 2001, 158:3 pp. 360-369) proposed that atypical antipsychotics can we distinguish them from typical antipsychotics by the speed with which they dissociate from dopamine D2 receptors. Rapid dissociation from the D2 receptor would make the antipsychotic better adapted to the physiological transmission of dopamine, which would enable an antipsychotic effect without incidental motor effects. This hypothesis is particularly convincing when considering clozapine and quetiapine. These two drugs show the highest dissociation rate from dopamine D2 receptors and they have the lowest risk of causing EPS in humans. Conversely, the typical antipsychotics associated with a high prevalence of EPS are the most slowly dissociating dopamine D2 receptor antagonists. Thus, finding new drugs based on their rate of dissociation from D2 receptors seems to be the right strategy to obtain new atypical antipsychotics. An additional goal is to combine rapid dissociation properties with dopamine D2 receptor selectivity. The multiple receptor profiles of current atypical antipsychotics are thought to account for their side effects, such as weight gain and diabetes. The search for selective D2 antagonists has been overlooked as an approach for some time but we believe that using

of more selective compounds in clinical use may reduce the occurrence of metabolic disorders associated with currently available atypical antipsychotic drugs.

The aim of this invention is to produce new compounds that are rapidly dissociating dopamine D2 receptor antagonists that have a desirable pharmacological profile as explained above, specifically reduce incidental motor side effects, and moderate to negligible interactions with other receptors resulting in a reduced risk of developing metabolic disorders .

This goal can be achieved with the following novel compounds of formula (I):

(I)

their pharmaceutically acceptable salts, hydrates and solvates, and their stereoisomeric forms, where

R is hydrogen or C1-6alkyl;

R 1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, C1-4alkyloxy, perfluoroC1-4alkyl, diC1-4alkylamino; thienyl; thienyl substituted with 1 or 2 substituents selected from the group consisting of halogen and C 1-4 alkyl; C3-8cycloalkyl; or C5-7cycloalkenyl;

R 2 is hydrogen or C 1-6 alkyl;

R3 is halogen, C1-4alkyl or perfluoroC1-4alkyl; i

R4 and R5 are each independently hydrogen or halogen.

The compounds of this invention are fast dissociating D2 receptor antagonists, which cannot be attributed to any 6-phenyl-N-[4-piperidinyl]-3-pyridazinamine derivative in J. Med. Chem. (1999), 42 (4), 730-741, nor to any substituted N-[4-piperidinyl]-2-aminopyrimidine in Farmaco, Vol. 35, no. 11, 1980, p. 951-964.

This feature makes the compounds of the present invention particularly suitable for use as drugs for the treatment or prevention of schizophrenia, a disorder having the form of schizophrenia, a disorder having an action like schizophrenia,

hallucination disorder, brief psychotic disorder, distributed psychotic disorder, psychotic disorder due to general health condition, psychotic disorder caused by taking drugs or medication, psychotic disorder not otherwise defined; psychosis associated with dementia; depressive disorder, dysthymic disorder, premenstrual dysphoric disorder, depressive disorder not otherwise defined, bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, bipolar disorder not otherwise defined, mood disorder due to a general medical condition, mood disorder caused by the action of drugs or drug, mood disorder not otherwise defined; general anxiety disorder, obsessive-compulsive disorder, panic, acute stress, disorder caused by post-traumatic stress; mental retardation; pervasive developmental disorders; disorders of lack of concentration, disorders of reduced attention/hyperactivity, disorders of disturbed behavior; paranoid-type personality disorders, schizoid-type personality disorders, schizotypal-type personality disorders; tic disorder, Tourette's syndrome; drug or drug addiction; consumption of medicines or drugs; withdrawal from medication or drugs; trichotillomania.

A person skilled in the art can select compounds based on the experimental data set forth in the experimental section below. Any choice of compounds is encompassed by this invention.

For example, the invention specifically relates to compounds of formula (I), wherein R 3 is trifluoromethyl; and R, R4 and R5 are hydrogen.

Other interesting compounds of formula (I) are those where R 2 is hydrogen or methyl.

Of particular interest are compounds of formula (I) where R 1 is 4-fluorophenyl or 3,4-difluorophenyl.

Among the compounds of group (I), the most interesting are N-[1-(4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine, and N-[1-(3,4-difluorobenzyl) Piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine.

In this patent application, the term "C1-4alkyl" when used alone and when used in combinations such as "C1-4alkyloxy", "perfluoroC1-4alkyl", "diC1-4alkylamino", includes, primer, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethyletil, term; "C1-6alkyl" includes methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl and hexyl; "perfluoroC1-4alkyl" includes primers trifluoromethyl, pentafluoroethyl, heptafluoropropyl and nonafluorobutyl; C3-8cycloalkyl

includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; C5-7cycloalkenyl includes cyclopentenyl, cyclohexenyl and cycloheptenyl.

Pharmaceutically acceptable salts are defined as containing therapeutically active forms of non-toxic acid addition salts capable of forming compounds according to formula (I). Said salts can be obtained by treating the base form of the compound according to formula (I) with appropriate acids, for example inorganic acids, for example hydrohalic acids, specifically hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic 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 acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and mandelic acid. Conversely, the forms of the mentioned salts can be converted into free forms by treatment with an appropriate base.

The term solvates refers to hydrates and alcoholates that can form compounds of formula (I).

The term "stereochemically isomeric forms" as used herein defines all possible isomeric forms in which the compound of formula (I) can exist. If not otherwise stated or indicated, the chemical designation of the compound means a mixture of all possible stereochemically isomeric forms, wherein said mixtures contain all diastereomers and enantiomers of the basic molecular structure. In particular, the stereogenic centers can have an R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals can be either cis- or trans-configuration. Compounds that have a double bond can have E or Z stereochemistry at said double bond. Stereochemically isomeric forms of compounds of formula (I) are within the scope of this invention.

The compounds of formula (I) prepared in the process described below can be synthesized in the form of a racemic mixture of enantiomers which can be separated from each other by following separation procedures known in the art. Racemic compounds of formula (I) can be converted into the corresponding diastereomeric salts by reaction with a suitable chiral acid. The mentioned forms of diastereomeric salts are then

they are separated, for example, by selective or fractional crystallization, and enantiomers are released from them by the action of alkali. An alternative method of separating enantiomeric forms of compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical forms of the corresponding starting materials, provided that the reactions occur stereospecifically. Preferably, if a specific stereoisomer is desired, said compound should be synthesized by stereospecific methods of preparation. These methods will use enantiomerically pure starting materials.

Pharmacology

In order to find antipsychotic compounds that are active in relation to positive symptoms and have an improved safety profile (low incidence of EPS and no metabolic disturbances), we screened for compounds that selectively interact with the dopamine D2 receptor and dissociate rapidly from this receptor. First, compounds were screened for their D2 affinity in a binding assay using [3H]spiperone and human D2L receptor cell membranes. Those compounds showing an IC50 of less than 1 mM were tested in an indirect assay adapted from a method published by Josee E. Leysen and Walter Gommeren, Journal of Receptor Research, 1984, 4(7), 817-845, to assess their dissociation rate.

These compounds were further screened on a panel of more than 50 common G-protein-coupled receptors (CEREP) and were found to have a clean profile, meaning they have a weak affinity for the tested receptors.

Some compounds were further tested in in vivo models such as the "Apomorphine-induced emesis test in dogs" and the "Apomorphine test in rats" and were found to be orally bioavailable.

In light of the above-mentioned pharmacology of the compounds of formula (I), it follows that they are suitable for use as drugs, specifically for use as antipsychotics. In particular, the compounds are suitable for use as drugs in the treatment or prevention of schizophrenia, schizophrenia-like disorder, delusional disorder, brief psychotic disorder, distributed psychotic disorder, psychotic disorder due to a general medical condition, drug or medication-induced psychotic disorder, psychotic disorder not otherwise defined; psychosis associated with dementia; depressive disorder, dysthymic disorder, premenstrual dysphoric disorder, depressive disorder not otherwise defined, bipolar disorder type I, bipolar disorder type II, cyclothymic

disorder, bipolar disorder not otherwise defined, mood disorder due to general health condition, mood disorder caused by medication or drugs, mood disorder not otherwise defined; general anxiety disorder, obsessive-compulsive disorder, panic, acute stress, disorder caused by post-traumatic stress; mental retardation; pervasive developmental disorders; disorders of lack of concentration, disorders of reduced attention/hyperactivity, disorders of disturbed behavior; paranoid-type personality disorders, schizoid-type personality disorders, schizotypal-type personality disorders; tic disorder, Tourette's syndrome; drug or drug addiction; consumption of medicines or drugs; withdrawal from medication or drugs; trichotillomania.

In order to optimize the treatment of patients suffering from the disorders mentioned in the previous section, the compounds of formula (I) can be administered together with other psychotropic compounds. Therefore, in the case of schizophrenia, negative and positive cognitive symptoms can be targeted.

The present invention also defines a method for treating warm-blooded animals suffering from such disorders, said method comprising the systemic administration of a therapeutic amount of a compound of formula (I) effective in treating the aforementioned disorders.

The present invention also relates to the use of the compound of formula (I) as defined above for the manufacture of a medicament, specifically as an antipsychotic medicament, more specifically as a medicament in the treatment or prevention of schizophrenia, a disorder that acts like schizophrenia, delusional disorder, brief psychotic disorder, distributed psychotic disorder, psychotic disorder due to a general health condition, psychotic disorder caused by taking drugs or medication, psychotic disorder not otherwise defined; psychosis associated with dementia; depressive disorder, dysthymic disorder, premenstrual dysphoric disorder, depressive disorder not otherwise defined, bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, bipolar disorder not otherwise defined, mood disorder due to a general medical condition, mood disorder caused by the action of drugs or drug, mood disorder not otherwise defined; general anxiety disorder, obsessive-compulsive disorder, panic, acute stress, disorder caused by post-traumatic stress; mental retardation; pervasive developmental disorders; disorders of lack of concentration, disorders of reduced attention/hyperactivity, disorders of disturbed behavior; paranoid-type personality disorders, schizoid-type personality disorders, schizotypal-type personality disorders; tic disorder, Tourette's syndrome; drug or drug addiction; consumption of medicines or drugs; withdrawal from medication or drugs; trichotillomania.

Those persons who have experience in treating such diseases can determine the effective daily therapeutic amount based on the results of the experiments presented here. An effective daily therapeutic amount should be from about 0.01 mg/kg to about 10 mg/kg of body weight, more preferably from about 0.05 mg/kg to about 1 mg/kg of body weight.

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

Due to ease of administration, the subject compounds can be formulated into various pharmaceutical forms for the purpose of administration. The compounds of this invention, specifically the compounds of formula (I), their pharmaceutically acceptable acid or base addition salt, their stereochemical isomeric form, their N-oxide form and prodrug, or any subgroup or combination thereof can be formulated into various pharmaceutical forms. for application purposes. Suitable mixtures can be listed here as all mixtures that are standardly used for systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, optionally in the form of an addition salt, as the active ingredient is combined in an intimate mixture with a pharmaceutically acceptable carrier, and the carrier can be in a whole range of forms depending on the form in which it is desired to be a preparation for application. These pharmaceutical compositions are preferably in unit dosage form, specifically, for administration by oral, rectal, percutaneous, parenteral injection or inhalation. For example, if the compositions are prepared in an oral dosage form, a conventional pharmaceutical medium such as water, glycols, oils, alcohols and the like can be used in the case of liquid oral preparations such as suspensions, syrups, elixirs, emulsions and solutions. ; or solid carriers such as starch, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the best unit forms for oral dosage where solid pharmaceutical carriers are obviously used. For parenterally administered mixtures, the vehicle usually contains sterile water, at least for the most part, although other additives may be added, for example to increase solubility. Solutions for injection, for example, can be prepared so that the carrier contains a salt solution, a glucose solution or a mixture of salt and glucose. Solutions for injection containing

the compounds of formula (I) can be formulated in an oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be used. Also covered are preparations in solid form that can be translated, shortly before application, into preparations that are in liquid form. In compositions suitable for percutaneous application, the carrier optionally contains a penetration-enhancing agent and/or a suitable wetting agent, which is optionally combined with suitable additives of any nature in small proportions, and said additives do not cause adverse effects on the skin. Said additives may facilitate application to the skin and/or may be useful when preparing desired mixtures. These mixtures can be applied in several ways, e.g. as a transdermal patch, as a drop applied to the skin or as a pomade. Acidic or basic addition salts of compounds of formula (I) are more suitable for the preparation of aqueous mixtures due to their greater solubility in water compared to the corresponding acidic or basic form.

It is especially good to formulate the above pharmaceutical mixtures in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form as used herein refers to physically discrete units suitable for unitary dosage, each unit containing a predetermined amount 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 coated tablets), capsules, pills, powder packets, wafers, suppositories, solutions for injections or suspensions and the like, and segregated multiples thereof.

Since the compounds of this invention are potent orally administered compounds, pharmaceutical compositions containing said compounds for oral administration are particularly preferred.

In order to increase the solubility and/or stability of compounds of formula (I) in pharmaceutical mixtures, it is good to use α-, β- or γ-cyclodextrins or their derivatives, specifically hydroxyalkyl substituted cyclodextrins, e.g. 2‑hydroxypropyl-β-cyclodextrin. Also co-solvates such as alcohols can improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions.

Arranging

Compounds of formula (I),

(I)

where R, R1, R2, R3, R4 and R5 are as previously defined, prepared by the reaction of intermediates of formula (II),

(II)

wherein R2, R3, R4 and R5 are as defined in formula (I), with an intermediate of the formula R1-C(=O)-R, where R and R1 are as previously defined, in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, a suitable catalyst, such as acetic acid, in a suitable reaction-inert solvent such as 1,2-dichloroethane.

Intermediates of the formula (II), were prepared by the reaction of the protected piperidine derivative of the formula (IV),

(IV)

where P represents a suitable protecting group, such as tert-butyloxycarbonyl, with 3-chloropyridazine of formula (V),

(IN)

in the presence of a suitable catalyst, such as potassium iodide, under appropriate reaction conditions, such as melt, followed by deprotection of the protected group to intermediate (VI)

(WE)

with appropriate conditions, such as hydrochloric acid in methanol for the tert-butyloxycarbonyl group.

Intermediates of formula (V) can be obtained either commercially or prepared by procedures similar to those described in the chemical literature (for R 3 = CF 3 , see Tetrahedron, 1999, 55 (52), 15067-15070).

Compounds of formula (I) can also be prepared by reacting 3-chloropyridazine of formula (V) with a piperidine derivative of formula (VII)

(VII)

in the presence of a suitable base such as diisopropylamine in a suitable solvent such as an alkanol, eg 1-butanol, at elevated temperature.

Intermediates of the formula (VII) were prepared by the reaction of 4,4-ethylenedioxypiperidine (VIII) with the intermediate of the formula R1-C(=O)-R, in the presence of a suitable

a reducing agent such as sodium triacetoxyborohydride, a suitable catalyst such as acetic acid, in a suitable reaction inert solvent such as 1,2-dichloroethane.

The resulting intermediate of formula (IX)

(IX)

is deprotected by treatment with an acid such as hydrochloric acid to give an intermediate of formula (X)

(X)

which is then reacted with an amine of formula R 2 -NH 2 (XI), in the presence of a suitable reducing agent such as hydrogen, a suitable catalyst such as palladium on carbon in a suitable reaction inert solvent such as ethanol.

Intermediates of formula (II) where R5 represents chlorine were prepared by reaction of piperidine of formula (XII)

(XII)

where L represents a leaving group such as tosyl, with pyridazine of formula (XIII)

(XIII)

wherein R 3 is as previously defined, in the presence of a suitable base such as sodium hydride in an aprotic solvent such as dimethylformamide, followed by deprotection of the intermediate of formula (VI) under appropriate conditions such as hydrochloric acid in methanol for tert-butyloxycarbonyl group.

Intermediates of formula (XIII) can be prepared from pyridazines of formula (V) by amination followed by halogenation.

Experimental deo

Chemistry

Final purification of examples (E1-E45) was performed either by column chromatography on silica gel using the described eluent or reverse-phase preparative HPLC on a Hyperprep RP 18 BDS (Shandon) (8 μm, 200 mm, 250 g) column. Three mobile phases were used (mobile phase A: 90% 0.5% ammonium acetate + 10% acetonitrile; mobile phase B: methanol; mobile phase C: acetonitrile) to perform a gradient method starting from 75% A and 25% B with a flow rate 40 ml/min, lasting 0.5 minutes with the same conditions, after which the flow rate was increased to 80 ml/min in 0.01 minutes to 50% B and 50% C in 41 minutes, to 100% C in 20 minutes while maintaining these same conditions lasting 4 minutes.

1H spectra were recorded on a Bruker DPX 360 spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane.

Description 1

tert-Butyl 4-{[6-(trifluoromethyl)pyridazin-3-yl]amino}piperidin-1-carboxylate (D1)

A mixture of 3-chloro-6-trifluoromethyl-pyridazine (4.4 g, 24.1 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070), 4-amino-1-tert-butyloxycarbonylpiperidine ( 9.63 g, 48.1 mmol) and potassium iodide

(cat.) was heated in the melt at 150 oC for 30 min. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, dried and the solvent was evaporated in vacuo. The crude product was purified by chromatography (silica gel; 1 %-4 % ammonia in methanol (7 M) / dichloromethane) to give D1 (7.06 g, 85 %). C15H21F3N4O2 requires 346; 347 (MH+) found

Description 2

N-Piperidin-4-il-6-(trifluormetil)piridazin-3-amin (D2)

A solution of D1 (7.06 g, 20.4 mmol) and hydrochloric acid/isopropanol (6N, 100 ml) in methanol (100 ml) was stirred at room temperature for 2 h. After this period, the solvents were evaporated in vacuo and the residues were stirred with acetonitrile. The solid product was filtered off and dried to give D2 as the dihydrochloride salt (6.05 g, 95 %). C10H13F3N4 requires 246; 247 (MH+) were found.

The dihydrochloride salt (D2) was then used either directly in the preparation of the following example compounds or alternatively converted to the free base prior to use. The free base was prepared by dissolving the dihydrochloride salt in water, basing with sodium carbonate and extracting with dichloromethane. After drying (MgSO4), the solvents were evaporated in vacuo to give the free base (D2a).

Description 3

8-(3,4-Difluorobenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (D3)

A solution of 3,4-difluorobenzaldehyde (4.40 g, 30.9 mmol), 4,4-ethylenedioxy-piperidine (4.40 g, 30.9 mmol), sodium triacetoxyborohydride (6.40 g, 30.2 mmol) and acetic acid (1.8 g, 30.0 mmol) in dichloroethane. (200 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was washed with 1N sodium hydroxide. The organic layer was separated, dried (MgSO 4 ) and the solvents were evaporated in vacuo to give D 3 (7.9 g, 98 %). C14H17F2NO2 requires 269; 270 (MH+) were found.

Description 4

1-(3,4-Difluorobenzyl)piperidin-4-one (D4)

A solution of D3 (7.9 g, 29.4 mmol) in hydrochloric acid (5N, 150 ml) was heated at 50 oC for 2 h. After this period, the reaction mixture was washed with diisopropyl ether (100 ml) and then with saturated sodium bicarbonate solution (100 ml). The mixture was then extracted with dichloromethane and the extracts dried (MgSO 4 ) and the solvents evaporated in vacuo to give D 4 (5.4 g, 82 %). C12H13F2NO requires 225; 226 (MH+) were found.

Description 5

1-(3,4-Difluorobenzil)-N-metilpiperidin-4-amin (D5)

A suspension of D4 (5.4 g, 24 mmol), a solution of thiophene (4% in diisopropylether; 2 ml), a solution of methylamine (40% in water, 10 ml) and 10% palladium on carbon (2 g) in methanol (150 ml) was hydrogenated at atmospheric pressure and temperature until 1 equiv is consumed. (~600 ml) of hydrogen. After this period, the reaction mixture is

filtered and the filtrate was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 5%-10% ammonia in methanol/dichloromethane) to give D5 (4.7 g, 81 %). C13H18F2N2 requires 240; 241 (MH+) found

Description 6

6-Trifluorometil-3-piridazinamin (D6)

A mixture of 3-chloro-6-trifluoromethyl-pyridazine (1.6 g, 8.8 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070) and ammonium hydroxide (30 ml) in THF (10 ml) was heated at 100 oC and a microwave reactor (Emrys optimizer; 0-9 bar) for 1 h. After this period, the reaction mixture was evaporated and the residue extracted with dichloromethane. The combined extracts were dried (MgSO 4 ), filtered and the solvents were evaporated in vacuo to give D 6 (1.3 g, 93 %). C5H4F3N3 requires 163; 164 (MH+) were found.

Description 7

4-Hloro-6-trifluorometil-3-piridazinamin (D7)

A mixture of D6 (4.0 g, 24.5 mmol) and N-chlorosuccinimide (3.3 g, 24.5 mmol) in acetonitrile (160 ml) was heated at 70 oC for 18 h. After this period, the reaction mixture was cooled to room temperature and the solvents were evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 3 %-5 % methanol / dichloromethane) to give D7 (1.6 g, 33 %). C5H3ClF3N3 requires 197; 198 (MH+) were found.

Description 8

tert-butyl 4-{[4-chloro-6-(trifluoromethyl)pyridazin-3-yl]amino}piperidin-1-carboxylate (D8)

NaH (60% in oil; 390 mg, 8.1 mmol) was added portionwise to a solution of D7 (1.6 g, 8.1 mmol) in dimethylformamide (50 mL) at 0 °C, under nitrogen, with stirring. The reaction mixture was stirred for 1 h, before 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 8.1 mmol), dissolved in dimethylformamide (10 ml), was added dropwise. . The reaction mixture was then heated between 80-90 oC for 6 hours. After cooling to room temperature, the solvents were evaporated in vacuo. The residues were dissolved in dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and the solvents were evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 3% methanol in dichloromethane) to give D8 (1.1 g, 37 %). C15H20ClF3N4O2 requires 380; 381 (MH+) were found.

Description 9

4-Chloro-N-piperidin-4-yl-6-(trifluoromethyl)pyridazin-3-amine (D9)

A solution of D8 (1.1 g, 2.9 mmol) and hydrochloric acid/isopropanol (6N, 20 ml) in methanol (100 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was evaporated in vacuo, the residue was redissolved in methanol and the solution was made alkaline with methanolic ammonia. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel; 5% - 15% ammonia in methanol in dichloromethane) to give D9 (70 mg, 9%). C10H12ClF3N4 requires 280; 281 (MH+) were found.

First 1

N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E1)

With stirring, 3,4-difluorobenzaldehyde (1.52 g, 10.6 mmol) and sodium triacetoxyborohydride (2.24 g, 10.6 mmol) were added to a solution of D2a (2.61 g, 10.6 mmol) and acetic acid (0.64 g, 10.6 mmol) in dichloroethane (200 mL). mmol) at room temperature. After stirring for 18 h, the reaction was quenched with 1N sodium hydroxide, the organic layer was removed, dried and the solvents were evaporated in vacuo. The crude product was purified by chromatography (silica gel; 2%-5% ammonia in methanol (7 M) / dichloromethane) to give E1 (2.39 g, 61 %). C17H17F5N4 requires 372; 373 (MH+) were found; mp: 167.7 – 168.9 oC. 1H NMR (DMSO-D6) � 1.50 (qd, J=11.5, 3.7 Hz, 1 H), 1.96 (br.d, J=12.4 Hz, 2 H), 2.12 (td, J=11.4, 2.6 Hz, 2 H), 2.78 (no. d, J=11.3 Hz, 2 H), 3.48 (s, 2 H), 3.90 (no. s, 1 H), 6.94 (d, J=9.4 Hz, 1 H), 7.13 - 7.19 (m, 1 H), 7.32 - 7.42 (m, 2 H), 7.53 (br.d, J=7.3 Hz, 1 H), 7.63 (d, J=9.4 Hz, 1 H)

First 2

N-[1-(4-fluorobenzil)piperidin-4-il]-6-(trifluorometil)piridazin-3-amin (E2)

A suspension of D2 (1.7 g, 5.32 mmol), 4-fluorobenzaldehyde (0.66 g, 5.32 mmol), di-isopropylethylamine (1.37 g, 10.6 mmol) and triacetoxyborohydride on resin (Argonaut Technologies; 2.2 mmol/g; 3 eq.) in dichloroethane. (10 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was filtered and the solvents were evaporated in vacuo. The crude product was purified by chromatography (silica gel; 2 %-6 % ammonia in methanol (7 M) / dichloromethane) to give E2 (0.79 g, 42 %). C17H18F4N4 requires 354; 355 (MH+) were found; mp: 163.3 – 165.3 oC. 1H NMR (DMSO-D6) � 1.48 (q, J=10.8 Hz, 2 H), 1.95 (br.d, J=12.5 Hz, 2 H), 2.09 (t, J=11.1 Hz, 2 H), 2.78 (br.d, J=11.3 Hz, 2 H), 3.47 (s, 2 H), 3.89 (br.s, 1 H), 6.94 (d, J=9.4 Hz, 1 H), 7.15 (t, J =8.8 Hz, 2 H), 7.34 (dd, J=8.3, 5.7 Hz, 2 H), 7.53 (br.d, J=7.3 Hz, 1 H), 7.63 (d, J=9.4 Hz, 1 H)

First 12

N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine (E12)

A solution of D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol (4 ml) was heated to 190 oC in a microwave reactor ( Emrys Optimizer; 0-9 Barr) for 2 h. After this period, the reaction mixture was evaporated in vacuo and the residue extracted with dichloromethane. The organic layer was washed with saturated bicarbonate solution, dried (MgSO4) and the solvents were evaporated in vacuo. Purification by reverse-phase HPLC (conditions as described earlier) afforded E12 (210 mg, 54 %). C18H19F5N4 requires 386; 387 (MH+) were found. 1H NMR (CDCl3) � 1.74 (br.d, J=12.0 Hz, 2 H), 1.88 (qd, J=12.0, 3.9 Hz, 2 H), 2.17 (td, J=11.8, 2.5 Hz, 2 H) , 2.96 (br.d, J=11.6 Hz, 2 H), 3.00 (s, 3 H), 3.47 (s, 2 H), 4.85 (t, J=12.1 Hz, 1 H), 6.78 (d, J =9.6 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 7.10 (dt, J=10.2, 8.1 Hz, 1 H), 7.20 (ddd, J=11.4, 7.8, 2.1 Hz, 1 H), 7.46 (d, J=9.6 Hz, 1 H)

First 16

N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-chloropyridazin-3-amine (E16)

A solution of 1-(4-chlorobenzyl)-piperidin-4-yl amine (1 g, 4.45 mmol) (prepared by a procedure similar to that described in WO2001098273), 3,6-dichloropyridazine (670 mg, 4.45 mmol) and sodium carbonate (940 mg, 8.90 mmol) in dimethylacetamide (5 ml) was heated at 120 °C in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 40 minutes. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and the solvents were evaporated in vacuo. Purification by reverse-phase HPLC (conditions as described earlier) afforded E16 (228 mg, 15 %). C16H18Cl2N4 requires 336; 337 (MH+) were found. 1H NMR (360 MHz, CDCl3) �1.52 (qd, J=11.5, 3.5 Hz, 2 H), 2.08 (d, J=12.5 Hz, 2 H), 2.16

(t, J=11.3 Hz, 2 H), 2.82 (d, J=11.5 Hz, 2 H), 3.48 (s, 2 H), 3.77 - 3.87 (m, 1 H), 4.55 (d, J=7.8 Hz, 1 H), 6.59 (d, J=9.3 Hz, 1 H), 7.14 (d, J=9.3 Hz, 1 H), 7.25 (d, J=7.7 Hz, 2 H), 7.29 (d, J=7.7 Hz, 2 H)

First 45

(R,S)-N-[1-(3,4-difluoro-�-methylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E45)

A solution of D2a (123 mg, 0.5 mmol), 3,4-difluoroacetophenone (186 mg, 1.25 mmol) and titanium isopropoxide (875 mg, 3 mmol) was stirred at room temperature for 1 h, before ethanol (0.7 ml ) and the reaction mixture was stirred for a further 1 h. After this period, sodium cyanoborohydride (68 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloroethane (30 ml), water (1 ml) was added and the mixture was stirred and then filtered. The filtrate was evaporated in vacuo and the residue redissolved in dichloromethane (30 ml), washed with 10% sodium carbonate solution and dried (MgSO4). The mixture was filtered and the solvent was evaporated in vacuo. Purification by reverse-phase HPLC (conditions as described earlier) afforded E45 (106 mg, 55 %). C18H20F4N4 requires 368; 369 (MH+) were found. 1H NMR (360 MHz, CDCl3) � 1.33 (d, J=6.7 Hz, 3 H), 1.45 - 1.62 (m, 2 H), 2.00 - 2.08 (m, 1 H), 2.09 - 2.21 (m, 3 H ), 2.70 - 2.78 (m, 1 H), 2.90 - 3.00 (m, 1 H), 3.42 (q, J=6.7 Hz, 1 H), 3.85 (br.s, 1 H), 4.97 (d, J =7.3 Hz, 1 H), 6.65 (d, J=9.3 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 7.09 (dt, J=10.1, 8.2 Hz, 1 H), 7.18 (ddd, J=11.7, 7.8, 2.1 Hz, 1 H), 7.42 (d, J=9.3 Hz, 1 H)

The following examples (E3-E11) were prepared from D2 or D2a and the corresponding benzaldehyde by a procedure similar to that described in Examples 1 and 2. Examples (E13-E14) were prepared from the corresponding benzaldehyde by a procedure similar to that described in example 12.

First

R2

Mol. weight

MH+

E1

H

372

373

E2

H

354

355

E3

H

370

371

E4

H

404

405

E5

H

354

355

E6

H

390

391

E7

H

328

329

E8

H

354

355

E9

H

388

389

E10

H

388

389

E11

H

372

373

E12

CH3

386

387

E13

CH3

418

419

E14

CH3

342

343

The following examples (E15 - E39) were prepared by procedures similar to those described in descriptions 1-5 and examples 1, 2, 12 and 16.

First

R2

Mol. weight

MH+

E15

H

302

303

E16

H

336

337

E17

CH3

316

317

E18

CH3

352

353

E19

CH3

348

349

E20

CH3

352

353

E21

CH3

412

413

E22

CH3

418

419

E23

CH3

402

403

E24

CH3

402

403

E25

CH3

384

385

E26

CH3

344

345

E27

CH3

358

359

E28

CH3

402

403

E29

CH3

348

349

E30

CH3

400

401

E31

CH3

350

351

E32

CH3

308

309

E33

CH3

320

321

E34

CH3

320

321

E35

CH3

370

371

E36

CH3

400

401

E37

CH3

348

349

E38

CH3

359

360

The following examples (E40) were prepared by procedures similar to those described in descriptions 1-5 and examples 1, 2 and 12.

First

R2

Mol weight

MH+

E40

CH3

364

365

The following examples (E41-E45) were prepared by procedures similar to those described in descriptions 1-9 and examples 1, 2, 12, 16 and 45.

First

R

R5

Mol. weight

MH+

E41

H

H

384

385

E42

H

H

372

373

E43

H

Cl

406

407

First

R

R5

Mol. weight

MH+

E44

CH3

H

368

369

E45

CH3

H

386

387

The following names refer to the example numbers:

N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E1)

N-[1-(4-fluorobenzil)piperidin-4-il]-6-(trifluorometil)piridazin-3-amin (E2)

N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E3)

N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E4)

N-[1-(3-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E5)

N-[1-(3,4,5-trifluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E6)

N-[1-(cyclopentylmethyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E7)

N-[1-(2-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E8)

N-[1-(4-chloro-3-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E9)

N-[1-(3-chloro-4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E10)

N-[1-(3,5-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E11)

N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine (E12)

N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine (E13)

N-[1-(cyclopentylmethyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine (E14)

N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-chloropyridazin-3-amine (E16)

N-(1-benzylpiperidin-4-yl)-N-methyl-6-chloropyridazin-3-amine (E17)

N-[1-(3,5-difluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E18)

N-[1-(2-fluoro-5-methylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E19)

N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E20)

N-[1-(3-bromo-4-fluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E21)

N-[1-(4-hloro-3-trifluorometilbenzil)piperidin-4-il]-N-metil-6-hloropiridazin-3-amin (E22)

N-[1-(3-fluoro-5-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E23)

N-[1-(2-fluoro-5-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E24)

N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E25)

N-[1-(2,5-dimethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E26)

N-[1-(2,4,5-trimethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E27)

N-[1-(4-fluoro-3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E28)

N-[1-(4-fluoro-3-methylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E29)

N-[1-(5-bromothiophen-2-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E30)

N-[1-(4,5-dimethylthiophen-2-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E31)

N-[1-(cyclopentylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E32)

N-[1-(1-cyclohex-1-en-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E33)

N-[1-(1-cyclohex-3-en-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E34)

N-[1-(3,4,5-trifluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E35)

N-[1-(4-bromothiophen-2-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E36)

N-[1-(3-fluoro-6-methylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E37)

N-[1-(3-dimethylamino-benzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E38)

N-[1-(cyclohexylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine (E39)

N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-methylpyridazin-3-amine (E40)

N-[1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E41)

N-[1-(2,4-difluorobenzil)piperidin-4-il]-6-(trifluorometil)piridazin-3-amin (E42)

N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)-4-chloro-pyridazin-3-amine (E43)

N-[1-(4-fluoro-�-methylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E44)

N-[1-(3,4-difluoro-�-methylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E45)

Pharmacology

In vitro binding affinity for the human D2L receptor

Frozen membranes of human Dopamine D2L receptor-transfected CHO cells were harvested, briefly homogenized using an Ultra-Turrax T25 homogenizer, and diluted in Tris-HCl assay buffer containing NaCl, CaCl2, MgCl2, KCl (50, 120, 2, 1, and 5 mM, adjusted to pH 7.7 with HCl) to the appropriate protein concentration that is optimized for specific and non-specific binding. The radioligand [3H]Spiperone (NEN, specific activity ~70 Ci/mmol) was diluted in assay buffer at a concentration of 2 nmol/L. The prepared radioligand (50 µl), together with 50 µl of either 10% DMSO control, Butaclamol (10-6 mol/l final concentration) or the compound of interest, was then incubated (30 min, 37 °C) with 400 µl of the prepared of the membrane solution. Membrane-bound activity was filtered through a Packard Filtermate collector onto a GF/B Unifilter plate and washed with ice-cold Tris-HCl buffer (50 mM; pH 7.7; 6 × 0.5 ml). Filters were allowed to dry before addition of scintillation liquid and measured in a Topcount scintillation counter. Percent specific binding and competitive binding curves were calculated

using S-Plus software (Insightful). All compounds had pIC50 values > 6.0 except E8, E25, E41, E42, E44 and E45 (pIC50 > 5.2).

Fast dissociation

Compounds having an IC50 greater than 1 mM were tested in an indirect assay adapted from that published by Jose E. Leysen and Walter Gommeren, Journal of Receptor Research, 1984, 4(7), 817-845, to assess their rate dissociation. Compounds with a concentration 4 times higher than their IC50 were first incubated for one hour with membranes of human D2L receptor cells in a volume of 2 ml at 25°C, and then filtered through a glass fiber filter with suction using a 40-well multividor device. Immediately afterwards, the vacuum was released. 0.4 ml of pre-warmed buffer (25°C) containing 1 nM [3H]spiperone was added to the filter for 5 minutes. Incubation was stopped by starting the vacuum and immediately washing with 2 × 5 ml of ice-cold buffer. The radioactivity bound to the filter was measured in a liquid scintillation spectrometer. The principle of the analysis is based on the assumption that the faster the compound dissociates from the D2 receptor, the faster [3H]spiperone binds to the D2 receptor. For example, when D2 receptors were incubated with clozapine at a concentration of 1850 nM (4 × IC50), binding of [3H]spiperone was equivalent to 60-70% of its total binding capacity (measured in the absence of drug) after 5 min incubation on the filter. When incubated with other antipsychotics, binding of [3H]spiperone varies between 20 and 50%. Because clozapine is included in each filtration, we consider tested compounds to be rapidly dissociating D2 antagonists if they dissociate faster than or equal to clozapine. All measured compounds have a dissociation rate that is higher than that of clozapine, i.e. > 50%.

Claims (11)

1. The compound of formula (I) (I) or its pharmaceutically acceptable salt, its hydrate or solvate, or its stereoisomeric form, characterized by the fact that in the structure R is hydrogen or C1-6 alkyl; R 1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, C1-4alkyloxy, perfluoroC1-4alkyl, diC1-4alkylamino; thienyl; thienyl substituted with 1 or 2 substituents selected from the group consisting of halogen and C 1-4 alkyl; C3-8cycloalkyl; or C5-7cycloalkenyl; R 2 is hydrogen or C 1-6 alkyl; R3 is halogen, C1-4alkyl or perfluoroC1-4alkyl; and R 4 and R 5 are each independently hydrogen or halogen. 2. Compound according to claim 1, characterized in that R3 is trifluoromethyl; and R, R4 and R5 are hydrogen. 3. A compound according to claim 1, characterized in that R2 is hydrogen or methyl. 4. The compound according to claim 1, characterized in that R1 is 4-fluorophenyl or 3,4-difluorophenyl. 5. The compound according to claim 1, characterized in that the compound is specifically N-[1-(4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine. 6. The compound according to claim 1, characterized in that the compound is specifically N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine. 7. Pharmaceutical mixture, characterized in that it contains a therapeutically effective amount of the compound as defined in claim 1. 8. A compound as defined in claim 1, characterized in that it is used as a medicine. 9. A compound as defined in claim 8, characterized in that it is used as an antipsychotic. 10. A compound as defined in claim 8, characterized in that it is used as a drug for the treatment or prevention of schizophrenia, a disorder that acts like schizophrenia, a hallucination disorder, a brief psychotic disorder, a distributed psychotic disorder, a psychotic disorder due to a general medical condition, a psychotic disorders caused by taking drugs or medications, psychotic disorders not otherwise defined; psychosis associated with dementia; depressive disorder, dysthymic disorder, premenstrual dysphoric disorder, depressive disorder not otherwise defined, bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, bipolar disorder not otherwise defined, mood disorder due to a general medical condition, mood disorder caused by the action of drugs or drug, mood disorder not otherwise defined; general anxiety disorder, obsessive-compulsive disorder, panic, acute stress, disorder caused by post-traumatic stress; mental retardation; pervasive developmental disorders; disorders of lack of concentration, disorders of reduced attention/hyperactivity, disorders of disturbed behavior; paranoid-type personality disorders, schizoid-type personality disorders, schizotypal-type personality disorders; tic disorder, Tourette's syndrome; drug or drug addiction; consumption of medicines or drugs; withdrawal from medication or drugs; trichotillomania. 11. A process for the preparation of a compound of formula (I) where R, R1-R5 are as defined in claim 1, characterized in that it includes the following steps: (a) reaction with an intermediate of formula (II) where R2-R5 are as defined in claim 1, with an intermediate of the formula R1-C(=O)-R, where R and R1 are as defined in claim 1, in the presence of a reducing agent and an acid catalyst, in an inert reaction solvent; or (b) reaction with an intermediate of formula (V) wherein R 3 - R 5 are as defined in claim 1, with an intermediate of formula (VII) wherein R, R 1 and R 2 are as defined in claim 1, in the presence of a base in the reaction inert solvent.