HK1114085A - Cyclohexylamides as dopamine d3, d2 and 5ht1a antagonists - Google Patents

Description

As dopamine D3、D2And 5HT1ACyclohexyl amides of antagonists

Technical Field

The present invention relates to novel dopamine D of formula (I)₃And D₂And serotonin 5-HT_1AReceptor subtype preferential ligands and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvents thereofCompounds, processes for their production, pharmacological compositions containing them and their use in the treatment of dopamine and/or 5-HT_1AUse in the treatment and/or prevention of a receptor modulated disorder.

Description of the Prior Art

Cyclohexane derivatives which can be used in pain therapy are described in patent application WO 99/67206.

Compounds containing tetralin (tetraline) and piperazine rings are described in JP 1998152470. These compounds are of the pair D₄The receptor has strong blocking activity to serotonin-2 (5-HT)₂) Muscarinic compounds (M)₁) And adrenergic α 1 has a higher affinity for the α 2 receptor.

However, no mention is made in any publication of compounds in which cyclohexane, indane or tetralin and piperazine rings are contained together in one compound.

Furthermore, the compounds mentioned in the above publications are not announced or even suggested to have dopamine D₃And/or D₂And/or serotonin 5-HT_1AReceptor activity.

Summary of The Invention

Surprisingly, it was found that, in contrast to the known above-mentioned structurally similar compounds, the novel derivatives of the formula (I) according to the invention have a higher or very high dopamine D₃Receptor affinity and moderate to high dopamine D₂Receptor affinity and always such a combination, D₃Affinity ratio D₂The affinity is 5 to 150 times higher. Furthermore, these compounds also have high serotonin 5-HT_1AReceptor affinity, but their affinity for these receptors is greater than for dopamine D₃Receptors are 3-20 times lower. The receptor affinity potency sequence for the compounds of formula (I) is generally as follows: d₃＞5-HT_1A＞D₂. Their affinity for the alpha-1 adrenoreceptor is slight, ensuring a higher (i.e. 50-800 times) D₃And (4) selectivity.

Triplet of the above specified ratio (i.e. D)₃、D₂And 5-HT_1A) Antagonism of receptor function is particularly important as this allows the simultaneous expression of all three (D)₃、D₂And 5-HT_1A) The beneficial effects of receptor modulation do not suffer from the known disadvantages of the action of each individual receptor.

This type of novel molecule belonging to the structure of formula (I) will be referred to as "D" in the present application₃/5-HT_1A/D₂A ligand ".

The present invention relates to novel piperazine derivatives of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, to processes for their production, to pharmaceutical compositions containing them, and to their use in the treatment and/or prevention of pathological conditions requiring modulation of dopamine and/or serotonin receptors, such as psychoses (e.g. schizophrenia, psycho-affective disorders, etc.), abuse of drugs (e.g. alcohol, cocaine with nicotine, opioids, etc.), schizophrenia accompanied by cognitive decline, mild to moderate cognitive deficits, dementia-related psychotic states, eating disorders (e.g. bulimia nervosa, etc.), attention-deficit disorder, childhood hyperactivity disorder, psychotic depression, mania, bipolar disorder, paranoid psychotic disorder, delusional disorder, Dyskinesias (e.g. parkinson's disease, neuroleptic induced parkinsonism, tardive dyskinesia), depressive and depressive states, anxiety disorders, sexual dysfunction, sleep disorders, emesis, aggression, autism.

Detailed description of the invention

The present invention relates to novel piperazine derivatives of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

When A or R₁And/or R₂When represents an alkyl group, theThe alkyl moiety may be selected from optionally substituted straight or branched chains containing 1 to 6 carbon atoms.

When A or R₁And/or R₂When an alkenyl group is represented, the alkenyl segment may contain 2 to 7 carbon atoms and 1 to 3 double bonds.

When A or R₁And/or R₂When aryl is represented, the aryl moiety may be selected from optionally substituted monocyclic or bicyclic aryl, e.g. phenyl, naphthyl.

When A or R₁And/or R₂When represents cycloalkyl, the cycloalkyl moiety may be selected from an optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group, such as cyclohexyl or adamantyl.

When A or R₁And/or R₂When representing heteroaryl, the heteroaryl may be an optionally substituted monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing 1 to 6 heteroatoms selected from O, N or S.

When R is₁And R₂When the heterocyclic ring is formed with the adjacent nitrogen atom, it may be a saturated or unsaturated, optionally substituted monocyclic or bicyclic ring, and may contain another heteroatom selected from O, N or S.

The invention also relates to salts of the compounds of formula (I) with acids.

Both organic and inorganic acids may be used in the formation of the acid addition salts. Suitable inorganic acids may be, for example, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Representative of monovalent organic acids may be, for example, formic acid, acetic acid, propionic acid and the various butyric, valeric and capric acids. Representative of divalent organic acids may be, for example, oxalic acid, malonic acid, maleic acid, fumaric acid, and succinic acid. Other organic acids may also be used, such as hydroxy acids, e.g. citric acid, tartaric acid, or aromatic carboxylic acids, e.g. benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids, e.g. methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid. Particularly valuable acid addition salt groups are those in which the acid component itself is physiologically acceptable and has no therapeutic effect in the applied dose or which has no undesirable effect on the effect of the active ingredient. These acid addition salts are pharmaceutically acceptable acid addition salts. Acid addition salts which are not pharmaceutically acceptable acid addition salts are also encompassed by the present invention since they can facilitate the purification and isolation of the desired compound under the circumstances in which it is intended.

Solvates and/or hydrates of the compounds of formula (I) are also included within the scope of the present invention.

The compounds of formula (I) exist in cis and trans isomeric forms with respect to the cyclohexane ring configuration. These and mixtures thereof also fall within the scope of the present invention. The compounds of the invention are preferably in the trans configuration.

Certain compounds of formula (I) contain C in the compound_2-7Alkenyl groups may exist as cis-and/or trans-isomers. These also fall within the scope of the present invention, including all such isomers and mixtures thereof.

Certain compounds of formula (I) may also exist as stereoisomers and diastereomers. These and mixtures thereof also fall within the scope of the present invention.

Since the invention also relates to salts of the compounds of the formula (I) with acids, especially pharmaceutically acceptable acids, the compounds of the formula (I) are meant as free bases or salts, even if not mentioned separately.

Preferred compounds of the invention are those of formula (I):

wherein

A represents alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl, or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

Particularly preferred compounds of the invention are those of formula (I):

wherein

A represents C_1-4Alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4Substituents of alkyl radicals, or R₁And R₂A morpholine ring is formed with adjacent nitrogen atoms and oxygen atoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

The invention also relates to pharmaceutical compositions containing a compound of formula (I) as active ingredient.

Further subjects of the invention are the pharmaceutical manufacture of medicaments containing compounds of formula (I), as well as the therapeutic and/or prophylactic methods using these compounds, which means that an effective amount of a compound of formula (I) according to the invention per se or a medicament is administered to a mammal to be treated, including man.

The invention also provides a process (method a) for preparing a compound of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

reacting an acid chloride or a carbamoyl chloride of formula (II):

wherein a is as defined above for formula (I);

with an amine of formula (III) or a derivative thereof:

wherein the meanings of m and n are as described above for formula (I).

The reaction can be carried out by known methods, preferably by suspending or dissolving the appropriate amine of formula (III) or a salt thereof in a suitable solvent (e.g. tetrahydrofuran, dimethylformamide, chlorinated hydrocarbons or hydrocarbons), preferably in the presence of a base (e.g. triethylamine), to which suspension or solution the appropriate acid chloride or carbamoyl chloride of formula (II) is added. The reaction can advantageously be carried out at a temperature between-10 ℃ and 60 ℃. The reaction was followed by thin layer chromatography. The necessary reaction time is about 6-60 h. The treatment of the reaction mixture can be carried out by means of different known methods. The product may be purified, for example, by crystallization or column chromatography.

Another inventive process (method B) for preparing compounds of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₂Represents hydrogen, and

R₁represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

is reacting an isocyanate of formula (IV):

R₁-N＝C＝O

(IV)

wherein R is₁The meaning of (A) is as described above for formula (I),

with an amine of formula (III) or a derivative thereof:

wherein the meanings of m and n are as described above for formula (I).

The reaction can be carried out by known methods, preferably by suspending or dissolving the appropriate amine of the formula (III) or a salt thereof in a suitable solvent, for example tetrahydrofuran, dimethylformamide, a chlorinated hydrocarbon or a hydrocarbon, to which suspension or solution the appropriate isocyanate of the formula (IV) is added, if necessary in the presence of a base, for example triethylamine. The reaction can advantageously be carried out between 5 ℃ and 50 ℃. The reaction was followed by thin layer chromatography. The necessary reaction time is about 6-10 h. The treatment of the reaction mixture can be carried out by means of different known methods. The product may be purified, for example, by crystallization or column chromatography.

Another inventive process (method C) for preparing compounds of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

is reacting an amine of formula (III):

wherein m and n have the meanings as described above for formula (I),

with carbonic acid derivatives to give isocyanate derivatives of the formula (V):

wherein m and n have the meanings as described above for formula (I),

reacting in situ a novel isocyanate derivative of formula (V) with an amine or derivative thereof of formula (VI):

wherein R is₁And R₂As described above for formula (I).

The above reaction can be carried out by a known method. Preferably, the conversion of the amine of formula (III) into the isocyanate derivative of formula (V) can be carried out using an appropriate carbonic acid derivative (e.g. phosgene, diphosphine, triphosgene) in an aprotic solvent (e.g. tetrahydrofuran, chlorinated hydrocarbons) in the presence of a base (e.g. triethylamine), advantageously between-5 ℃ and room temperature. To the resulting solution or suspension is added the appropriate base form of the amine of formula (VI) or the salt form with an organic or inorganic acid. The necessary reaction time is 2 to 24 hours. The treatment of the reaction mixture can be carried out by means of different known methods. The product may be purified, for example, by crystallization or column chromatography.

Acid chlorides or carbamoyl chlorides of formula (II) and isocyanates of formula (IV) with amines of formula (VI) wherein R is₁And R₂Are as defined above, are commercially available or can be synthesized by different known methods.

Amines of the formula (III) in which m is 0 or 1 and n is 1 or 2 and isocyanates of the formula (V) are novel compounds and are also included in the scope of the present invention.

The novel amines of the formula (III) are synthesized by known methods, for example in the context of reductive amination by reacting an aldehyde of the formula (VII):

wherein m has the meaning as described above for formula (I), Boc is tert-butoxycarbonyl,

with a piperazine of formula (VIII):

wherein n has the meaning as described above for formula (I),

the protecting group is then removed.

The reaction can be carried out in an inert solvent such as a chlorinated hydrocarbon, an alkanol or an ether, in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction temperature is generally between 0 ℃ and room temperature. The necessary reaction time is about 2-24 h. Deprotection can be carried out using trifluoroacetic acid or hydrochloric acid in a suitable solvent.

Compounds of formulae (VII) and (VIII) are known (e.g. Bioorg. Med. chem. Lett.2001: 11(16) 2177-80; J.Med. chem.2000: 43(9) 1878-85; WO 2004/99150; Collection of Czech. chem.Comm.1975: 40(5) 1612-22).

The resulting compound of formula (I) may be converted into its salt with an acid and/or the compound of formula (I) is released from the resulting acid addition salt by treatment with a base and/or the cis-and/or trans-isomers and/or stereoisomers and/or diastereomers may be isolated and/or may be converted into hydrates and/or solvates thereof.

The separation of the cis-and trans-isomers of the compounds of formula (I) or (III) or of the protected derivatives of the latter, or of the compounds of formula (V), is carried out by conventional methods, for example chromatography and/or crystallization, or the cis-and trans-isomers of the compounds of formula (I) can be prepared from pure cis-or trans-precursors.

The compounds of formula (I) according to the invention, contrary to the known psychotropic agents, have been found to exhibit a very high dopamine D content₃Receptor affinity, higher serotonin 5-HT_1AReceptor affinity, moderate D₂Receptor activity and lower affinity for adrenergic alpha-1 receptors. These compounds are expected to be useful in the treatment and/or prevention of disease states in which dopamine D is involved₃And/or D₂And/or serotonin 5-HT_1AReceptors are involved in the pathology of this disease and their regulation is therefore desirable.

Dysfunction of the dopaminergic neurotransmitter system is involved in the pathology of several neuropsychiatric and neurodegenerative disorders, such as schizophrenia, drug abuse and parkinson's disease, respectively. The effects of dopamine are mediated via at least five different dopamine receptors, which belong to D₁-(D₁，D₅) Or D₂-(D₂，D₃，D₄) A family. D₃Receptors have been shown to have a characteristic distribution in the brain dopaminergic system. That is, higher densities are found in limbal structures such as the auditory nucleus and Kayerha island. Thus, preferentially targeting D₃Receptors may be a promising more selective means of regulation of dopaminergic function and are therefore also successful therapeutic interventions for several abnormalities, such as schizophrenia, emotional or cognitive dysfunction (Sokoloff, p.et al: Nature1990, 347: 146; Schwartz, j.c.et al: clinin.neuropharmacol.1993, 16: 295; Levant, b.et al: pharmacol.rev.1997, 49: 231), addiction (pila, c.et al: Nature 1999, 400, 371), parkinson's disease (Levant, b.et al: CNS Drugs 1999, 12:391, Joyce, j.n.: pharmacol, therapeutic, 2001, 90: 231) anxiety (Rogoz et al, pol.j. pharmacol.2000, 52: 459) or pain (Levant, b.et al.: neurosci.lett.2001, 303: 9).

Dopamine D₂Receptors are widely distributed in the brain and are known to be involved in numerous physiological functions and pathological states. D₂Antagonists are commonly used drugs, such as antipsychotics. However, D is well known₂The large antagonism of the receptor causes undesirable side effects such as extrapyramidal motor symptoms, psychomotor sedation, cognitive disturbances and endocrine changes. These side effects severely limit D₂Therapeutic use of antagonist compounds (Wong, A.H.C.et al: Neurosci.Biobehav.Rev.2003, 27: 269).

In animal experiments, 5-HT was found_1APartial agonism of the receptor enhances the antipsychotic effect of dopamine antagonism (Evenden, j.l.: psychopharmacol.1992, 109: 134.), and may inhibit the appearance of catalepsy (a precursor to extrapyramidal side effects), which is striatal dopamine D₂The consequences of receptor blockade (Lucas, G.et a., l.: Psychopharmacol.1997, 131: 57., Prenssen, E.P.et al.: Eur.J.Pharmacol.2002, 453: 217., Haleem, D.J.et al.: progr.neuro-Psychopharmacol.2004, 28: 1323.). It has also been demonstrated that 5-HT_1AAgonism contributes to an increase in prefrontal dopamine release, an effect that may be beneficial for negative symptoms and cognitive deficits in schizophrenia (Li, x. -m.et al: psychopharmacol.1998, 136: 153, Millan, m.j.: j.pharmacol.exp.ther.2000, 295: 853; lchikawa, j.et al.j.pharmacol.exp.ther.1999, 291: 1227).

Depression and anxiety are often concomitant diseases of schizophrenia (Stahl, S.M.: 2002, ESSential Psychopharmacology of antibactychrotics and MoodStabilizers. Cambridge University Press). 5-HT_1AReceptors are potential targets in the treatment of anxiety (Barret, J.E.et al: Psychopharmacol.1993, 112: 1; De Vry, J.: Psychopharmacol.1995, 121: 1). In fact, 5-HT_1APartial agonists of the receptor have been described for the treatment of anxiety (Fulton, b.et al: CNS Drugs 1997, 7: 68), others are in clinical trials. Animal experiments also show that 5-HT_1AAgonists may be useful in the treatment of depression (De Vry, J.Ps ychopharmacol.1995, 121: 1, Koek, W.et al: J.Pharmacol.exp.Ther.1998, 287: 266). 5-HT of some known antipsychotics is believed_1AAgonist properties (Newman-Tancredi, A.et al.: Eur.J.Pharmacol.1998, 355: 245, Saller, C.F.et al: Psychopharmacol.1993, 112: 285, Jordan, S.et al.: Eur.J.Pharmacol.2002, 441: 137) greatly contribute to their beneficial effects in the treatment of bipolar depression or the depressive syndrome of schizophrenia.

The present invention provides novel compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, which have a very high dopamine D₃Receptor affinity (IC50 value less than 2nM) and at the same time higher 5-HT1A receptor affinity (IC)₅₀: 1-20nM) and moderate D₂Receptor affinity (IC)₅₀Values between 10 and 40nM) and always such a combination, D₃Affinity ratio D₂5 to 150 times higher affinity than 5-HT_1AThe affinity is 3-20 times higher. The order of receptor binding potency of the compounds of formula (I) is generally as follows: d₃＞5-HT_1A＞D₂。

In another aspect, the invention provides a method of treating a condition requiring dopamine D₃And/or D₂And/or serotonin 5-HT_1AMethods of disorders of preferential modulation of receptors, such as psychosis (e.g., schizophrenia, psycho-affective disorders), schizophrenia with accompanying cognitive decline, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), eating disorders (e.g., bulimia nervosa), attention-deficit disorder, childhood hyperactivity disorder, attention-deficit disorder, treatment disorders with a combination of two or more of the foregoing,Depression and depressive state, anxiety disorders, sexual dysfunction, sleep disorders, emesis, aggression, autism and drug abuse comprising administering to a subject in need thereof an effective amount of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

The invention also provides the use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment of a condition requiring modulation of dopamine and/or serotonin receptors, in particular dopamine D₃And/or D₂And/or serotonin 5-HT_1AA receptor.

According to the invention D₃/5-HT_1A/D₂Preferred uses of the ligands are in schizophrenia, psycho-affective disorders, schizophrenia with accompanying cognitive decline, mild to moderate cognitive deficits, dementia-related psychotic states, psychotic depression, mania, paranoia and delusional disorders, movement disorders such as parkinson's disease, psychotic inhibitor-induced parkinsonism, depressive and depressive states, anxiety disorders, substance abuse (e.g. cocaine abuse).

The specific combination of the actions of the three receptors mentioned above allows the simultaneous expression of D₃Antagonism and 5-HT_1AFunctional antagonistic beneficial effects (e.g. cognitive enhancing effects, suppression of extrapyramidal motor symptoms, inhibition of drug abuse, anxiolytic and antidepressant effects) and D₂Antagonism of beneficial effects (e.g. antipsychotic effects). Furthermore, the same combination surprisingly leads to D₂Disappearance of antagonistic adverse properties (e.g. extrapyramidal symptoms, psychomotor sedation, cognitive disturbances).

For pharmaceutical use, the compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof according to the invention are generally administered as standard pharmaceutical compositions. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a novel compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof and a physiologically acceptable carrier.

The compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof according to the present invention may be administered by any convenient method, for example, orally, parenterally, buccally, sublingually, nasally, rectally or transdermally, with the pharmaceutical compositions adjusted accordingly.

The compounds of formula (I) according to the invention which are active on oral administration and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

The liquid preparations of the compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof according to the present invention generally consist of a suspension or solution of the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof in a suitable liquid carrier, for example an aqueous solvent, for example water, ethanol or glycerol, or a non-aqueous solvent, for example polyethylene glycol or oil. The formulations may also contain suspending agents, preservatives, flavoring or coloring agents.

Solid form tablet compositions may be prepared using any suitable pharmaceutical carrier conventionally used for the preparation of solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, cellulose, and the like.

Solid form capsule compositions can be prepared using conventional encapsulation techniques. For example, granules containing the active ingredient may be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, a dispersion or suspension may be prepared using any suitable pharmaceutical carrier, such as an aqueous gum, cellulose, silicate or oil, and then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of a compound of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a sterile aqueous carrier or a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration.

Compositions of the invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for nasal administration may be suitably formulated as aerosols, drops, gels and powders. The aerosol formulations of the present invention generally comprise a solution or fine suspension of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a physiologically acceptable aqueous or non-aqueous solvent, typically in single or multiple doses in sterile form in a sealed container which may take the form of a cartridge or be refilled with an atomising device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or aerosol dispenser, fitted with a metering valve and disposable once the container contents have been depleted. If the dosage form comprises an aerosol dispenser, it will contain a propellant, which may be a compressed gas, such as compressed air, or an organic propellant, such as chlorofluorocarbon. Aerosol formulations may also take the form of pump atomizers. Compositions of the invention comprising a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, suitable for buccal or sublingual administration include tablets, lozenges and pastilles wherein the active ingredient is formulated with a carrier, for example sugar and acacia, tragacanth, or gelatin and glycerin and the like.

Compositions of the invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for rectal administration are suitably in the form of suppositories, containing conventional suppository bases, for example cocoa butter.

Compositions of the present invention comprising a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for transdermal administration include ointments, gels and patches.

The compositions according to the invention containing the compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof are preferably in unit dosage form, for example in the form of tablets, capsules or ampoules.

Each dosage unit of the invention for oral administration preferably contains 1 to 250mg of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, calculated as the free base.

Each dosage unit of the invention for parenteral administration preferably contains 0.1 to 2mg of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, calculated as the free base.

A physiologically acceptable daily dosage regimen (in the case of adult patients) of a compound of the formula (I) according to the invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, which is administered under normal circumstances, may be, for example, an oral dose of between 1mg and 500mg, preferably between 10mg and 400mg, for example between 10mg and 250mg, or an intravenous, subcutaneous or intramuscular dose of between 0.1mg and 100mg, preferably between 0.1mg and 50mg, for example between 1 and 25mg of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, calculated as the free base. The compounds of the present invention may be administered from 1 to 4 times per day. The compounds of the invention may suitably be administered for continuous therapy, for example for one week or more.

Biological assay method

1.D₃Receptor binding

Recombinant D against rat expressed in Sf9 cells₃The receptor (Perkin-Elmer, Cat. No.6110139) was used for the binding study³H]Spiroperidone (0.44-1.49nM) was used as ligand and haloperidol (10. mu.M) was used for the determination of non-specific binding. The measurements were carried out according to the supplier's protocol (Ca t.No.: 3110139).

2.D₂Receptor binding

D was determined for rat brain striatum membrane preparations as described by Creese et al (Eur.J.of Pharm., 60: 55-66, 1979)₂Receptor binding using³H]Spiroperidone (0.4-1.3nM) served as ligand. Nonspecific binding was determined in the presence of 1 μ M (+) butalamol.

3. Alpha-1 receptor binding

Alpha.for rat cortical membrane preparations was performed as described by Greengarss and Brerner (Eur.J.Pharmacol., 55: 323-326, 1979)₁Study of receptor binding Using [2 ]³H]Prazosin (0.22-0.37nM) as ligand. Nonspecific binding was determined in the presence of 10 μ M phentolamine.

4.5-HT_1ABonding of

5-HT was determined for rat hippocampal membrane preparations as described by Hall et al (J.neurohem.44: 1685-1696, 1985) and Gozlan et al (Nature 305: 140-142, 1983)_1AIn combination with, use³H]8-hydroxy-2- (di-n-butyl)Propylamino) -tetralin (1.6-2.37nM) was used as ligand. Nonspecific binding was determined in the presence of 10 μ M serotonin creatinine sulfate.

Dopamine D of selected Compounds of the invention₃And D₂Serotonin 5-HT_1AAnd adrenergic alpha-1 receptor binding data are listed in table 1. Give out IC₅₀(nM) data.

TABLE 1

Compound (I)	D3	D2	5-HT1A	α-1
					1	＜2	10 to 40	1 to 20	40 to 200
2	＜2	10 to 40	1 to 20	40 to 200
					3	＜2	10 to 40	1 to 20	40 to 200
4	＜2	10 to 40	1 to 20	40 to 200
					5	＜2	10 to 40	1 to 20	40 to 200
6	＜2	10 to 40	1 to 20	40 to 200
					9	＜2	10 to 40	1 to 20	＞200
10	＜2	10 to 40	1 to 20	＞200
					11	＜2	10 to 40	1 to 20	40 to 200
12	＜2	10 to 40	1 to 20	40 to 200
					Aripiprazole	7	12	26	285
Olanzapine	153	147	3575	46

The most major side effects of the first generation antipsychotic compounds (e.g., chlorpromazine and haloperidol) are extrapyramidal symptoms such as pseudoparkinsonism and tardive dyskinesia and orthostatic hypotension. The first two are D in the basal ganglia₂The result of the massive blockade of the receptors, the latter being a consequence of the antagonism of the alpha-1 receptor.

The compounds in Table 1 are very highly potent D₃Receptor ligands (IC)₅₀Values less than 2nM), highly potent serotonin 5-HT_1AReceptor ligands(IC₅₀Values between 1 and 20nM), and moderately potent dopamine D₂Receptor ligands (IC)₅₀Between 10 and 40nM), for D₂And 5-HT_1AThe receptors showed 5 to 150-fold and 3 to 20-fold selectivity (selectivity: D), respectively₂Or 5-HT_1AIC of₅₀Divided by D₃IC of₅₀). Very high D₃Affinity and higher 5-HT_1AAffinity and moderate D₂This specific proportionality of affinity allows retention of D₂Beneficial (e.g. antipsychotic) effects of antagonists while preventing massive D₂Receptor blockade (D)₃And 5-HT_1AEffects) like extrapyramidal symptoms or cognitive disturbances. It is therefore expected that the involvement of D in the therapeutic application of the compounds of the invention will not be, or will be largely eliminated during the therapeutic use of the compounds of the invention₂Adverse effects of the receptor. In addition, except for desirably modulating dopamine D₂In addition to receptor-mediated function, the compounds of the invention are useful for dopamine D₃And serotonin 5-HT_1AThe action of the receptor will also lead to additional therapeutically beneficial effects, such as cognitive improvement, reduction of negative and depressive symptoms, or anxiety relief. In addition, these compounds have slight or low affinity for the adrenergic alpha-1 receptor (IC for each compound)₅₀Both above 40nM) and thus have a very high D₃A-1 selectivity (from one hundred to several hundred fold). In view of the low affinity of the compounds for the adrenergic alpha-1 receptor, a lack of cardiovascular side effects (e.g., orthostatic hypotension) is expected.

With respect to the intended clinical applications of the compounds of the invention in addition to receptor binding behavior, their in vivo efficacy is also a critical issue. Thus, the in vivo efficacy and efficacy of the compounds of formula (I) was studied in an apomorphine climbing assay, an animal screening test for antipsychotic activity.

5. Inhibiting apomorphine-induced climb

Male CD-1 mice weighing 20-25g (n-12) were orally injected with test compounds or vehicle. After 50 minutes, the animals were placed in cylindrical cages with side wallsIs a vertical metal rod. After habituation for 10 minutes, mice were treated with apomorphine (1.5mg/kg sc.). 10 minutes after APO treatment, each animal was observed for 15 minutes and scored for their climbing behavior. The scores for each individual were summed and a group mean was calculated. Drug effects are expressed and plotted as percent inhibition of apomorphine-induced behavior. Determination of ED by means of linear regression₅₀(50% inhibitor dose) value.

The in vivo activity of selected compounds of the invention is shown in table 2. The ED obtained in the apomorphine climbing assay is given₅₀(mg/kg) data.

TABLE 2

Compound (I)	Inhibition of climbing
		1	0.14
2	0.21
		3	0.11
4	0.46
		5	0.47
6	0.16
		9	0.26
10	0.35
		11	0.23
12	0.20
		Aripiprazole	1.0
Olanzapine	1.3

All compounds tested showed exceptionally potent apomorphine inhibition in mice, 2 to 12 times more potent than the reference drug olanzapine or aripiprazole. The most active compounds were identified as compounds 1, 3 and 6.

The following non-limiting examples further illustrate the invention.

The structures of all intermediates and final products are elucidated by means of IR, NMR and MS spectra.

Example 1

Trans-4- {2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl } -cyclohexyl-carbamic acid tert-butyl ester (intermediate)

3.58g (15mmol) of 1- (indan-4-yl) -piperazine hydrochloride and 3.62g (15mmol) of trans-4- (2-oxoethyl) cyclohexyl-carbamic acid tert-butyl ester are dissolved in dichloroethane (120ml), 2.1ml (15mmol) of triethylamine are added, 4.6g (22mmol) of sodium triacetoxyborohydride are then added portionwise, the reaction mixture is stirred at ambient temperature for 20 hours, and then 20% aqueous potassium carbonate solution (40ml) is added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to obtain 5.5g (yield: 85.8%), m.p.: 115-8 ℃.

Example 2

Trans-4- {4- (indan-4-yl) -piperazin-1-yl-methyl } -cyclohexyl-carbamic acid tert-butyl ester (intermediate)

3.58g (15mmol) of 1- (indan-4-yl) -piperazine hydrochloride and 3.41g (15mmol) of trans- (4-formyl-cyclohexyl) -carbamic acid tert-butyl ester are dissolved in dichloroethane (120ml), 2.1ml (15mmol) of triethylamine are added, 4.6g (22mmol) of sodium triacetoxyborohydride are then added portionwise, the reaction mixture is stirred at ambient temperature for 20 hours, and then 20% aqueous potassium carbonate solution (40ml) is added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to obtain 5.1g (yield: 82.2%), m.p.: 131-4 ℃.

Example 3

Trans-4- {2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl } -cyclohexyl-amine (intermediate)

4.24g (10mmol) of trans-4- {2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl } -cyclohexyl-carbamic acid tert-butyl ester are deprotected at 10 ℃ with 80ml of ethyl acetate saturated with gaseous hydrochloric acid, and after 4 hours the precipitate is filtered to give 3.65g (yield: 92%) of the dihydrochloride of the title compound, which is melted at 319-25 ℃.

The following compounds were prepared using the above procedure: trans-4- [4- (indan-4-yl) -piperazin-1-yl-methyl ] -cyclohexyl-amine trihydrochloride, melting point: 305-10 ℃.

Method A

Trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea

0.4g (1mmol) of trans-4- {2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl } -cyclohexyl-amine dihydrochloride was suspended in dichloromethane (30ml) and triethylamine (0.56ml, 4mmol) was added followed by 0.12ml (1.3mmol) of N, N-dimethylcarbamoyl chloride. The reaction mixture was stirred at room temperature for 24 hours. The solution was extracted with water (2X 8ml), dried and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound (0.2g, 50%) as a melt at 150-2 ℃.

Method B

Trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3-ethyl-urea

0.4g (1mmol) trans-4- {2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl } -cyclohexyl-amine was dissolved in anhydrous dichloromethane (30ml), ethyl isocyanate (0.1ml, 1.3mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was recrystallized from acetonitrile to give the title compound (0.22g, 55%) which was melted at 198-200 ℃.

Method C

Trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-diethyl-urea

0.48g (1.2mmol) of trans-4- {2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl } -cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (50ml), triethylamine (0.67ml, 4.8mmol) was added and a solution of 0.14g (0.48mmol) of triphosgene in dichloromethane was added dropwise. After stirring at room temperature for 1 hour, diethylamine (0.62ml, 6mmol) was added and stirring was continued for 20 hours. The solution was extracted with water (2X 8ml), dried and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound (0.3g, 58%), m.p.: 157-9 ℃.

Using one of the above methods, using the appropriate reactants, the following compounds were prepared:

trans-N- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -acetamide (Compound 1) melting point: 202-4 ℃;

trans-N- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -propionamide (compound 2) melting point: 194-6 ℃;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea (compound 3) melting point: 150-2 ℃;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-diethyl-urea (compound 4) melting point: 157-9 ℃;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3-ethyl-urea (compound 5) melting point: 198-200 ℃;

trans-N- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -morpholine-4-carboxamide (Compound 6) melting point: 181-2 ℃;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -urea (compound 7) melting point: 204-6 ℃;

trans-1- {4- [ [4- (indan-4-yl) -piperazin-1-yl ] -methyl ] -cyclohexyl } -3, 3-dimethyl-urea (compound 8) melting point: 152 ℃ and 154 ℃;

trans-N- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -acetamide (Compound 9) melting point: 187-9 ℃;

trans-N- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -propionamide (compound 10) melting point: 182 to 5 ℃;

trans-1- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea (compound 11) melting point: 190-3 ℃;

trans-N- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -morpholine-4-carboxamide (compound 12) melting point: 178-80 ℃.

Pharmaceutical preparation

a) Intravenous injection

1-40mg of a compound of formula (I)

Buffer to pH about 7

Solvent/complexing agent to 100ml

b) Pellet injection

1-40mg of a compound of formula (I)

Buffer to pH about 7

Cosolvent to 5ml

Buffering agent: suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.

Solvent: usually water, but may also include cyclodextrin (1-100mg) and co-solvents such as propylene glycol, polyethylene glycol and ethanol.

c) Tablet formulation

1-40mg of a compound of formula (I)

Diluent/filtering agent (cyclodextrin may also be included) 50-250mg

5-25mg of adhesive

Disintegrating agent (cyclodextrin can also be included) 5-50mg

Lubricant 1-5mg

Cyclodextrin 1-100mg

Diluent agent: such as microcrystalline cellulose, lactose, starch.

Adhesive: such as polyvinylpyrrolidone, hydroxypropyl methylcellulose.

Disintegrating agent: such as sodium starch glycolate, crospovidone.

Lubricant: such as magnesium stearate, sodium stearyl fumarate.

d) Oral suspension

1-40mg of a compound of formula (I)

Suspending agent 0.1-10mg

20-60 mg of diluent

0.01-1.0mg of preservative

Buffering agent to pH of about 5-8

Cosolvent 0-40mg

0.01-1.0mg of flavoring agent

Colorant 0.001-0.1mg

Suspending agent: such as xanthan gum, microcrystalline cellulose.

Diluent agent: for example a sorbitol solution, usually water.

Preservative: such as sodium benzoate.

Buffering agent: such as citrate.

Cosolvent: such as ethanol, propylene glycol, polyethylene glycol, cyclodextrin.

Claims (20)

1. A derivative of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent a group selected from hydrogen, alkylAlkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

2. A compound of formula (I) as claimed in claim 1:

wherein

A represents alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl, or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

3. A compound of formula (I) as claimed in claims 1 and 2:

wherein

A represents C_1-4Alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4Substituents of alkyl radicals, or R₁And R₂A morpholine ring with the adjacent nitrogen atom and with the oxygen atom;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

4. A compound selected from the group consisting of:

trans-N- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -acetamide;

trans-N- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -propionamide;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-diethyl-urea;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3-ethyl-urea;

trans-N- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -morpholine-4-carboxamide;

trans-1- {4- [2- [4- (indan-4-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -urea;

trans-1- {4- [ [4- (indan-4-yl) -piperazin-1-yl ] -methyl ] -cyclohexyl } -3, 3-dimethyl-urea;

trans-N- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -acetamide;

trans-N- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -propionamide;

trans-1- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea;

trans-N- {4- [2- [4- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -morpholine-4-carboxamide.

5. An amine of formula (III):

wherein

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or a protected form thereof and/or a geometric isomer thereof and/or a salt and/or a hydrate and/or a solvate thereof.

6. An isocyanate of formula (V):

wherein

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.

7. A method of

a) Preparing a compound of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an acid chloride or a carbamoyl chloride of formula (II):

wherein a is as defined above for formula (I);

with an amine of formula (III) or a derivative thereof:

wherein m and n have the meanings as described above for formula (I),

or

b) Preparing a compound of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₂Represents hydrogen, and

R₁represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an isocyanate of formula (IV):

R₁-N＝C＝O

(IV)

wherein R is₁The meaning of (A) is as described above for formula (I),

with an amine of formula (III) or a derivative thereof:

wherein m and n have the meanings as described above for formula (I),

or

c) Preparing a compound of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl; or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an amine of formula (III):

wherein m and n have the meanings as described above for formula (I),

with carbonic acid derivatives to give isocyanate derivatives of the formula (V):

wherein m and n have the meanings as described above for formula (I),

reacting in situ a novel isocyanate derivative of formula (V) with an amine or derivative thereof of formula (VI):

wherein R is₁And R₂Is as described above for formula (I), and

interconversion of a compound of formula (I) obtained by any of methods a) to c) wherein A, m and n are as defined for a compound of formula (I) is a different compound of formula (I) wherein A, m and n are as defined for a compound of formula (I);

where appropriate, geometric isomers and/or stereoisomers and/or diastereomers of the compounds of formula (I) or intermediates thereof, wherein A, m and n are as defined for the compounds of formula (I), are isolated by conventional methods;

optionally followed by formation of a salt and/or hydrate and/or solvate of the compound of formula (I).

8. The method according to claim 7, for

a) Preparing a compound of formula (I):

wherein

A represents alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl, or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an acid chloride or a carbamoyl chloride of formula (II):

wherein a is as defined above for formula (I);

with an amine of formula (III) or a derivative thereof:

wherein m and n have the meanings as described above for formula (I),

or

b) Preparing a compound of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₂Represents hydrogen, and

R₁represents hydrogen or alkyl;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an isocyanate of formula (IV):

R₁-N＝C＝O

(IV)

wherein R is₁The meaning of (A) is as described above for formula (I),

with an amine of formula (III) or a derivative thereof:

wherein m and n have the meanings as described above for formula (I),

or

c) Preparing a compound of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl; or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an amine of formula (III):

wherein m and n have the meanings as described above for formula (I),

with carbonic acid derivatives to give isocyanate derivatives of the formula (V):

wherein m and n have the meanings as described above for formula (I),

reacting in situ a novel isocyanate derivative of formula (V) with an amine or derivative thereof of formula (VI):

wherein R is₁And R₂Is as described above for formula (I), and

interconversion of a compound of formula (I) obtained by any of methods a) to c) wherein A, m and n are as defined for a compound of formula (I) is a different compound of formula (I) wherein A, m and n are as defined for a compound of formula (I);

where appropriate, geometric isomers and/or stereoisomers and/or diastereomers of the compounds of formula (I) or intermediates thereof, wherein A, m and n are as defined for the compounds of formula (I), are isolated by conventional methods;

optionally followed by formation of a salt and/or hydrate and/or solvate of the compound of formula (I).

9. Method according to claims 7 and 8 for

a) Preparing a compound of formula (I):

wherein

A represents C_1-4Alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4Substituents of alkyl radicals, or R₁And R₂A morpholine ring with the adjacent nitrogen atom and with the oxygen atom;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an acid chloride or a carbamoyl chloride of formula (II):

wherein a is as defined above for formula (I);

with an amine of formula (III) or a derivative thereof:

wherein m and n have the meanings as described above for formula (I),

or

b) Preparing a compound of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₂Represents hydrogen, and

R₁represents hydrogen or C_1-4An alkyl group;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an isocyanate of formula (IV):

R₁-N＝C＝O

(IV)

wherein R is₁The meaning of (A) is as described above for formula (I),

with an amine of formula (III) or a derivative thereof:

wherein m and n have the meanings as described above for formula (I),

or

c) Preparing a compound of formula (I):

wherein

A represents formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4A substituent of an alkyl group; or R₁And R₂A morpholine ring with the adjacent nitrogen atom and with the oxygen atom;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, the process comprising:

reacting an amine of formula (III):

wherein m and n have the meanings as described above for formula (I),

with carbonic acid derivatives to give isocyanate derivatives of the formula (V):

wherein m and n have the meanings as described above for formula (I),

reacting in situ a novel isocyanate derivative of formula (V) with an amine or derivative thereof of formula (VI):

wherein R is₁And R₂Is as described above for formula (I), and

interconversion of a compound of formula (I) obtained by any of methods a) to c) wherein A, m and n are as defined for a compound of formula (I) is a different compound of formula (I) wherein A, m and n are as defined for a compound of formula (I);

where appropriate, geometric isomers and/or stereoisomers and/or diastereomers of the compounds of formula (I) or intermediates thereof, wherein A, m and n are as defined for the compounds of formula (I), are isolated by conventional methods;

optionally followed by formation of a salt and/or hydrate and/or solvate of the compound of formula (I).

10. A pharmaceutical composition comprising a compound of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, and a physiologically acceptable carrier.

11. A pharmaceutical composition as claimed in claim 10 comprising a compound of formula (I):

wherein

A represents alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl, or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, and a physiologically acceptable carrier.

12. A pharmaceutical composition as claimed in claims 10 and 11 comprising a compound of formula (I):

wherein

A represents C_1-4Alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4Substituents of alkyl radicals, or R₁And R₂A morpholine ring with the adjacent nitrogen atom and with the oxygen atom;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, and a physiologically acceptable carrier.

13. Use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament:

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

the medicament is useful for the treatment and/or prevention of conditions requiring modulation of dopamine and/or serotonin receptors.

14. Use of a compound of formula (I) as claimed in claim 13 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament:

wherein

A represents alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl, or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

the medicament is useful for the treatment and/or prevention of conditions requiring modulation of dopamine and/or serotonin receptors.

15. Use of a compound of formula (I) as claimed in claims 13 and 14 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament:

wherein

A represents C_1-4Alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4Substituents of alkyl radicals, or R₁And R₂A morpholine ring with the adjacent nitrogen atom and with the oxygen atom;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

the medicament is useful for the treatment and/or prevention of conditions requiring modulation of dopamine and/or serotonin receptors.

16. Use of a compound according to any of claims 13 to 15, wherein the dopamine receptor is dopamine D₃And/or D₂The receptor, the serotonin receptor being serotonin 5-HT_1AA receptor.

17. A method of treating and/or preventing a condition requiring modulation of dopamine and/or serotonin receptors, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein

A represents alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl or cycloalkyl, or R₁And R₂A ring which forms a heterocycle with the adjacent nitrogen atom and optionally with further heteroatoms;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof.

18. A method as claimed in claim 17 for the treatment and/or prevention of a condition which requires modulation of dopamine and/or serotonin receptors, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein

A represents alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represents a substituent selected from hydrogen or alkyl, or R₁And R₂A ring forming a monocyclic saturated heterocyclic ring with the adjacent nitrogen atom and optionally with a further heteroatom selected from O, N or S;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

19. A method as claimed in claims 17 and 18 for the treatment and/or prevention of a condition which requires modulation of dopamine and/or serotonin receptors, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein

A represents C_1-4Alkyl, or

formula-NR₁R₂Group (a) in which

R₁And R₂Independently represent hydrogen or C_1-4Substituents of alkyl radicals, or R₁And R₂A morpholine ring with the adjacent nitrogen atom and with the oxygen atom;

m is an integer from 0 to 1;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof.

20. The method according to any of claims 17 to 19, wherein the dopamine receptor is dopamine D₃And/or D₂The receptor, the serotonin receptor being serotonin 5-HT_1AA receptor.