PL219283B1 - Benzylamine sulfonamide derivatives for the treatment of central nervous system diseases - Google Patents

Description

Description of the invention

Field of the Invention

The present invention relates to novel benzylamine sulfonamide derivatives with affinity for dopaminergic, serotonergic and adrenergic receptors, a process for their preparation, pharmaceutical compositions containing them and their use. These compounds may be useful in the treatment of diseases of the central nervous system, for example schizophrenia, bipolar disorder, depression, anxiety disorders, sleep disorders, and Alzheimer's disease.

State of the art

Central nervous system (CNS) diseases are a huge and growing health problem. The number of people suffering from this type of disease is constantly increasing, especially in highly developed and intensively developing countries. About 20% of the population in highly developed societies may suffer from diseases related to the CNS, and expenditure on the treatment of these diseases accounts for about 35% of the costs of combating all diseases in the seven countries that are the largest pharmaceutical markets.

The main psychiatric diseases include schizophrenia, depression, bipolar disorder, anxiety disorders, as well as sleep and wake disorders and addictions. Neurological diseases include, among many others, Alzheimer's disease, Parkinson's disease, epilepsy or a wide range of pain treatment issues.

The mechanism of action of the currently used antipsychotic drugs is based on their regulating effect on the dopaminergic system, the dysfunction of which is currently recognized as the main neurochemical basis of schizophrenia. Neuroleptics are divided into: typical classic drugs (chlorpromazine, haloperidol), characterized by a strong activity blocking dopaminergic D2 receptors, and atypical ones, which, apart from blocking dopaminergic receptors, also interact with many other receptors, mainly serotonergic type 5-HT2A (risperidone, olanzapine). A recently introduced antipsychotic drug with a slightly different mechanism of action than other atypical drugs is aripiprazole - a partial agonist of D2 receptors. These drugs eliminate the positive symptoms of schizophrenia, however, they show a significantly limited effectiveness in combating negative symptoms, which is the main challenge in the search for new, more effective drugs and therapies. Serious neurological disorders (including poneuroleptic Parkinson's syndrome), which characterize typical neuroleptics, have been significantly reduced in the case of atypical drugs, however, other side effects (e.g. metabolic disorders, obesity, cardio- and myelotoxicity) have remained or have appeared. a serious problem of therapy with these drugs.

D2-type dopaminergic receptors are the primary biological target in antipsychotic therapy. It is widely accepted that the blockade of these receptors in the mesolimbic system is responsible for the antipsychotic effect of neuroleptics, especially the prevention of productive symptoms. All antipsychotics currently in use in the clinic have at least moderate affinity for D2 dopaminergic receptors. Blockade of these receptors in the nigrostriatal system, not compensated by partial agonism at these receptors or by interaction with other receptors (5-HT2A, 5-HT1A, alpha2c), may cause extrapyramidal disorders, such as drug-induced parkinsonism, and within the tuberculosis system - hyperprolactinaemia (Miyamoto S., Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol. Psychiatry, 2005, 10, 79-104).

D3-type dopaminergic receptors are located in the limbic cortex, and the preferential blockade of these receptors offers local selective anti-dopaminergic activity, resulting in an enhanced effect in the elimination of productive symptoms, without blockade of the extrapyramidal system, and thus without the risk of inducing pseudoparkinsonian symptoms. There are also preclinical data suggesting the role of D3 receptor antagonism in more effectively combating the negative symptoms of schizophrenia and improving working memory (Gray J., Roth B., The pipeline and future of drug development in schizophrenia. Mol. Psychiatry, 2007, 12 (10) , 904-22).

Serotonergic neurons interact with dopaminergic neurons. Antagonism of antipsychotic drugs at serotonergic 5-HT2A receptors may stimulate the release of dopamine in the extrapyramidal, nodular funnel and prefrontal cortex, but not in the limbic system, which may alleviate unwanted extrapyramidal symptoms and hyperprolactinaemia caused by blockade of D2 receptors and increase drug efficacy to

Some of the negative symptoms of schizophrenia, without exacerbating the productive symptoms. It is recognized that the high affinity of a compound for 5-HT2A-type receptors, higher than for D2-type receptors, is one of the reasons for the atypicality of second-generation antipsychotic drugs. Similar effects as those caused by the blockade of 5-HT2A receptors are due to the stimulation of serotoninergic 5-HT1A receptors (aripiprazole, ziprazidone). Stimulation of 5-HT1A receptors, additional to the blockade of D2 receptors, may have a beneficial effect both on the neurological safety profile of the compound and may have potential benefits in combating the affective and cognitive symptoms of schizophrenia (Kim D., Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia, Neurotherapeutics, 6 (1), 78-85, 2009).

Currently used antidepressants are ineffective in about 30% of cases, and are also characterized by a number of side effects (including sedation, vegetative disorders, sexual dysfunctions). In addition to the effect on the reuptake of biogenic amines, the currently used LPDs show antagonistic activity against various types of monoaminergic receptors. Thus, blockade of 5-HT2A receptors may also have an additional, beneficial effect enhancing the antidepressant effect of serotonin reuptake inhibitors (serotonin transporter blockers SERT) or 5-HT2C serotonergic receptor antagonists (Milian M., Dual- and Triple Acting Agents for Treating Core and Co -morbid Symptoms of Major Depression: Novel Concepts, New Drugs, Neurotherapeutics, 6 (1), 53-77, 2009). Blockade of 5-HT2A receptors is also one of the elements of the pharmacological profile of antidepressants, including mianserin and mirtazapine. Partial agonism at 5-HT1A receptors is also the basis of the mechanism of action of buspirone, an anxiolytic drug used in the treatment of generalized anxiety disorder, and tandospirone used as an anxiolytic and antidepressant drug.

Serotonergic receptors of the 5-HT6 type are found almost exclusively in the CNS. The specific location of these receptors and the fact that certain antipsychotics (clozapine, olanzapine, sertindole) and antidepressants (mianserin, amitriptyline) have high affinity for them prompted behavioral and biochemical studies exploring its potential role in the pathophysiology and therapy of CNS diseases. Experimental data have shown that blocking this receptor may cause a procognitive effect due to the enhancement of cholinergic transmission, an antidepressant effect due to the enhancement of noradrenergic and dopaminergic transmission, and an anxiolytic effect. These data indicate the possibility of using 5-HT6 receptor antagonists in the treatment of various clinical conditions associated with cognitive impairment, such as e.g. Alzheimer's disease, schizophrenia, depression and anxiety (Liu K. and Robichaud A., 5-HT6 Antagonists as Potential Treatment for Cognitive Dysfunction, Drug Development Research, 70, 145-168, 2009; Wesołowska A. and Nikiforuk A., Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression, Neuropharmacology, 59, 664-671, 2007). In addition, 5-HT6 receptor antagonists have a tendency to suppress appetite and reduce body weight, and several of them are currently undergoing clinical trials for the treatment of obesity (Heal D. et al., Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders, Pharmacol. Ther., 117 (2), 207-31, 2008).

Intensive research conducted since 1993 has indicated the potential involvement of the 5-HT7 serotonergic receptor in the regulation of many physiological processes, such as: circadian rhythm, thermoregulation, memory and cognitive processes, as well as neuronal excitability and relaxation of the cerebral arteries. The high affinity for the 5-HT7 receptor (being its non-selective antagonists) for the 5-HT7 receptor has suggested its role in the pathophysiology and therapy of neuropsychiatric diseases. Animal behavioral studies have confirmed the potential antidepressant and anxiolytic activity of selective 5-HT7 receptor antagonists (Wesołowska A. et al., Effect of the selective 5-HT7 receptor antagonist SB-269970 in animal models of anxiety and depression. Neuropharmacology, 51 (3) , 578 586, 2006). The 5-HT7 receptor antagonist, SB-269970 has also been found to have a potential antipsychotic effect in the murine models of psychosis Galici R. et al., Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity. , Behav. Pharmacology, 19 (2), 153-9, 2008).

Serotonergic 5-HT2C receptors and H1 histaminergic receptors located in the hypothalamus are associated with the control of food intake. The blockade of these receptors (e.g. caused by antipsychotics) may lead to an increase in appetite and therefore undesirable weight gain. However, blockade of 5-HT2C receptors may have a beneficial antidepressant and procognitive effect and potentiate the mediated antagonism towards the receptors.

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5-HT2A, protection against extrapyramidal disorders induced by blockade of the striatal D2 receptors (Kim D., Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia, 2009). H1 receptor blockade, on the other hand, induces sedation, which may be a desirable effect of the antipsychotic drug, especially in controlling agitation accompanying the acute phase of psychosis. Therefore, it seems that lowering the affinity (especially simultaneous) for both types of these receptors may be an element that protects against excessive weight gain, however, due to the potential benefits of blocking these receptors, the complete elimination of affinity for these receptors from the profile of the new compound does not have to be necessary.

The blockade of alpha1-adrenergic receptors, in addition to the potentially unfavorable peripheral blood pressure lowering effect, may also have beneficial central effects, reducing the risk of poneuroleptic extrapyramidal symptoms. This is due to the interaction between noradrenergic and serotonergic neurons (Horacek J. et al., Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia, CNS Drugs, 20 (5), 389-409, 2006).

Due to the important role that the cholinergic system plays in the control of cognitive processes, substances are currently being sought that could directly or indirectly increase the activity of the cholinergic system. These substances include agonists of the appropriate nicotinic or muscarinic receptor subtypes and, for example, 5-HT6 receptor antagonists. On the other hand, in order to prevent cognitive dysfunction and masking possible beneficial procognitive effects caused by other receptors, substances lacking the ability to block the receptors of the cholinergic system, i.e. devoid of the so-called cholinolytic activity. In addition, it also avoids a number of other peripheral side effects from the group of vegetative disorders such as constipation, dry mouth and increased heart rate (Miyamoto S., Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs, Mol. Psychiatry, 10, 79-104, 2005). In addition, it was found that M3 muscarinic receptors are involved in the control of insulin release, and their stimulation stimulates the secretion of this hormone in the pancreas. Hence, it is concluded that blockade of M3 receptors may be particularly unfavorable for the development of type II diabetes in patients treated with second-generation antipsychotics (e.g. olanzapine, clozapine, quetiapine), and new substances devoid of this effect are sought (Silvestre J. and Prous J., Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes, Mrthods Find. Exp. Clin. Pharmacol., 27 (5), 289-304, 2005).

Serious undesirable effects caused by antipsychotics, e.g. sertindole, ziprasidone, are arrhythmias resulting from delayed repolarization of the heart muscle. These disturbances as measured by an electrocardiogram with prolongation of the calculated Q-T interval (QTc) are most often caused by substances having the ability to block hERG potassium channels. In order to prevent the introduction of potentially arrhythmogenic preparations into the development, new substances are currently screened at the stage of in vitro research, when their ability to block the hERG potassium channel by electrophysiological methods (Recanatini M. et al., QT Prolongation Through hERG K + Channel Blockade) : Current Knowledge and Strategies for the Early Prediction During Drug Development, Med. Res. Rev., 25 (2), 133-66, 2005).

Despite the undisputed breakthrough, which was the successive introduction from the 1950s of new classes of drugs affecting the CNS (including neuroleptics, antidepressants (antidepressants), benzodiazepines, acetylcholinesterase inhibitors), the treatment of neuropsychiatric diseases remains far from ideal both in relation to with its limited effectiveness and a number of side effects caused by the available drugs, and is still a serious problem and challenge from the pharmacotherapy point of view. Therefore, there is a continuous search for drugs that can be used in the treatment of these diseases.

WO96 / 40100 describes arylsulfonamidobenzene derivatives which inhibit thrombin production by inhibiting factor Xa and are useful in the treatment of atherosclerosis, inflammation and neoplasms.

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WO98 / 27081 discloses sulfonamides having the following general formula

having 5-HT6 receptor antagonist activity and potentially useful in the treatment of CNS diseases such as anxiety, depression, epilepsy, Alzheimer's disease etc.

The publication WO02 / 44126 describes a large group of compounds having an affinity for proteins of the type (CyP), potentially useful in, inter alia, the treatment of neurological diseases.

DE10053794 describes sulfonamide derivatives represented by the following general formula, which exhibit 5-HT6 receptor antagonistic activity and are potentially useful in the treatment of CNS diseases.

GB2228933A describes compounds that have a smooth muscle relaxant effect and therefore have potential use as vasodilators or cerebral circulation enhancers.

WO2010 / 023448 discloses tertiary sulfonamide derivatives of the following general formula

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being potassium channel inhibitors. Compounds in this group are potentially useful in the treatment of autoimmune diseases, chronic inflammatory diseases, or metabolic diseases.

WO2010 / 118055 describes compounds of the general formula as shown below

R "is useful in inhibiting, treating and ameliorating cognitive impairment and / or Alzheimer's disease. JP6072979 describes sulfonamide derivatives of the general formula shown below that are potentially useful in the treatment of gastric ulcer.

Y

AND

Ra

Publication CN101817767A discloses compounds of the following general formula, useful in the treatment of GPR40 mediated diseases such as diabetes and breast cancer.

None of the above publications describe a specific group of benzylamine sulfonamide compounds as in the invention described below.

Description of the invention

The subject of the invention are new compounds, sulfonamide derivatives of benzylamine, represented by the general formula (I):

wherein

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A means:

- phenyl unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-alkyloxy, OH and phenyl, or

- a 9- or 10-membered bicyclic group connected to - (O) x- (CH2) y- via one of its aromatic carbon atoms, consisting of a benzene ring fused with:

- a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, which bicyclic group may be unsubstituted or substituted by halogen; or

- a non-aromatic 5- or 6-membered heterocyclic ring containing 1 or 2 O atoms, the heterocyclic ring may be unsubstituted or substituted with one or more C1-C3-alkyl;

D denotes a group selected from:

- phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C4-alkyl, C1-C3-alkyloxy, halo-C1-C3-alkyl, halo-C1-C3-alkyloxy, halogen, -CN and phenyl;

- naphthyl unsubstituted or substituted with one halogen atom;

- a thiophene unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C3-alkyl, halogen, 5-membered heteroaromatic ring having 1 or 2 heteroatoms independently selected consisting of N and O;

- a bicyclic group consisting of an imidazole ring fused to a non-aromatic 5-membered carbocyclic ring connected to a sulfonamide moiety through one of its aromatic carbon atoms;

- a bicyclic group consisting of a benzene ring fused to a 5-membered heteroaromatic ring, containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C3-alkyl and halogen linked to the sulfonamide moiety through one of its aromatic carbon atoms; and

- a bicyclic group consisting of a benzene ring fused to a 5- or 6-membered non-aromatic heterocyclic ring, containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, unsubstituted or substituted with one = O, linked to a sulfonamide moiety via one of benzene ring carbon atoms;

R is H or -CH3;

x is 0 or 1;

n is 2 or 3;

and their pharmaceutically acceptable salts.

One group of compounds of the invention are compounds of formula (I) wherein A is phenyl unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-alkyloxy, OH and phenyl.

Another group are the compounds of formula (I) wherein A is a 9- or 10-membered bicyclic group linked to - (O) x- (CH2) y- through one of its aromatic carbon atoms, consisting of a benzene ring fused with A 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, such bicyclic group may be unsubstituted or substituted by halogen. Preferably, in this group A is 1H-indolyl, in particular 1H-indol-4-yl, 1,2-benzoxazolyl, in particular 1,2-benzoxazol-3-yl, preferably substituted with halogen.

In a further group of compounds of formula (I) according to the invention, A represents - a 9- or 10-membered bicyclic group, linked to - (O) x- (CH2) y- through one of its aromatic carbon atoms, consisting of a fused benzene ring with a 5- or 6-membered non-aromatic heterocyclic ring containing 1 or 2 O atoms, the heterocyclic ring may be unsubstituted or substituted with one or more C1-C3-alkyl. Preferably, in this group A is 2,3-dihydro-1,4-benzodioxanyl, in particular 2,3-dihydro-1,4-benzodioxan-5-yl or 2,3-dihydro-1-benzofuranyl, preferably substituted with C1- C3-alkyl, in particular 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl (otherwise: 2,2-dimethyl-3H-benzofuran-7-yl).

In yet another group of compounds of formula (I) according to the invention, D is phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C4-alkyl, C1-C3-alkyloxy, halo-C1-C3-alkyl, halo -C1-C3-alkyloxy, halogen,

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-CN and phenyl. Preferably, D in this group of compounds is phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C4-alkyl, C1-C3-alkyloxy, halo-C1-C3-alkyl, halo-C1-C3-alkyloxy and halogen. In particular, D represents in this group phenyl, methylphenyl, especially 3-methylphenyl, propylphenyl, especially -4-propylphenyl, methoxyphenyl, especially 3-methoxyphenyl, trifluoromethoxyphenyl, especially 4-trifluoromethoxyphenyl, monochlorophenyl, especially 4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl or 4-iodophenyl or dihalophenyl, in particular 3-chloro-4-fluorophenyl.

The next group are compounds of formula (I) wherein D is naphthyl unsubstituted or substituted with one halogen atom. Preferably, in this group of compounds, D is unsubstituted naphthyl. The point of attachment of the naphthyl to the sulfur atom of the sulfonamide moiety can be in the 1 (alpha) or 2 (beta) position of the naphthalene ring.

Another group of compounds of the invention are compounds of formula (I) wherein D is unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C3-alkyl, halogen and a 5-membered heteroaromatic ring having 1 or 2 heteroatoms independently selected from the group consisting of N and O. Preferably, within this group of compounds, D is unsubstituted thiophene. Preferably, in this group, D is thiophen-2-yl or thiophenyl, in particular thiophen-3-yl.

In a further group of compounds of formula (I) according to the invention, D represents a bicyclic group consisting of an imidazole ring fused to a non-aromatic 5-membered carbocyclic ring connected to a sulfonamide moiety through one of its aromatic carbon atoms. Preferably, in this group of compounds, D is 6,7-dihydro-5H-pyrrolo [1,2-a] -imidazol-3-yl.

Still another group are compounds of formula (I) wherein D is a bicyclic group consisting of a benzene ring fused to a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C3-alkyl and halogen, bonded to the sulfonamide moiety through one of its aromatic carbon atoms. Preferably in this group of compounds, D is a bicyclic group consisting of a benzene ring fused to a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from N, S, unsubstituted or substituted with one or more substituents independently selected from the group consisting of with C1-C3-alkyl and halogen. More preferably, in this group of compounds, D is 1-methyl-indol-4-yl, 1-methyl-indol-5-yl, benzothiophenyl, in particular benzothiophen-3-yl, 5-fluoro-3-methyl-benzothiophen-2. -yl, 5-chloro-3-methyl-benzothiophen-2-yl or 1,3-benzoxazol-5-yl.

In a further group of compounds of formula (I), D is a bicyclic group consisting of a benzene ring fused to a 5- or 6-membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, unsubstituted or substituted with one = O, linked to the sulfonamide moiety through one of the carbon atoms of the benzene ring. Preferably in this group of compounds, D is an unsubstituted bicyclic group consisting of a benzene ring fused to a 5-membered non-aromatic heterocyclic ring containing 2 O atoms, linked to a sulfonamide moiety through one of the carbon atoms of the benzene ring. Preferably, in this group of compounds, D is 1,3-benzodioxol-5-yl in this group.

A particular group of compounds of the present invention are compounds of formula (I) wherein R is H represented by the general formula (IA):

and A, D and x and y are as described above.

Another particular group of compounds of formula (I) are compounds wherein R is -CH3, represented by general formula (IB):

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and A, D and x and y are as described above.

In one embodiment of the compounds of the invention in formulas (I), (IA) and (IB), x is 1 and y is 2.

In another variation for the compounds in formulas (I), (IA) and (IB) x is 0 and y is 3.

One group of compounds according to the invention are compounds of formula (I) wherein R is H, represented by the general formula (IA):

wherein A, D, x and y are as defined above for formula (I).

In a particular variation of the compounds of Formula (IA), A is phenyl unsubstituted or substituted with one C1-C3-alkyloxy substituent. Preferably in this variant, A is phenyl or methoxyphenyl, in particular 3-methoxyphenyl.

In a further variant of the compounds of formula (IA), the moiety A is preferably a 9- or 10-membered bicyclic group linked to - (O) x- (CH2) y- via one of its aromatic carbon atoms, consisting of a benzene ring fused with:

- a 5-membered heteroaromatic ring containing 1 N atom which bicyclic group is unsubstituted; or

- a 6-membered non-aromatic heterocyclic ring containing 2 O atoms, the heterocyclic ring being unsubstituted,

In the above variant, the moiety A is preferably selected from the group consisting of indolyl, in particular 1H-indol-4-yl, 2,3-dihydro-1,4-benzodioxinyl, in particular 2,3-dihydro-1,4-benzodioxins -5-yl.

Another group of compounds of the invention are compounds of formula (IA) wherein x is is 1 and y is 2.

Another group of compounds according to the invention are compounds of formula (I) wherein R is

-CH3, represented by the general formula (IB):

wherein A, D, x and y are as defined above for formula (I).

In a particular variation of the compounds of formula (IB), the moiety A is a 9-membered bicyclic group linked to - (O) x- (CH2) y- via one of its aromatic carbon atoms, consisting of a benzene ring fused to a 5-membered ring heteroaromatic containing 2 heteroatoms independently selected from the group consisting of N and O, said bicyclic group being substituted with a halogen atom. Preferably in this variant, A is 6-fluoro-1,2-benzoxazol-3-yl.

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Another variant of the compounds according to the invention are compounds of formula (IB) wherein x is 0 and y is 3.

Particular compounds of formula (I) according to the invention that can be mentioned:

1. N- [3 - [(phenylethylamino) methyl] phenyl] naphthalene-2-sulfonamide,

2. N- [3 - [(2-phenoxyethylamino) methyl] phenyl] naphthalene-2-sulfonamide,

3. N- [3 - [(3-phenylpropylamino) methyl] phenyl] naphthalene-2-sulfonamide,

4. N- [3 - [[2- (3-fluorophenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

5. N- [3 - [[3- (3-fluorophenoxy) propylamino] methyl] phenyl] naphthalene-2-sulfonamide,

6. N- [3 - [[2- (3-chlorophenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

7. N- [3 - [[2- (3-chlorophenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

8. N- [3 - [[2- (3-methylphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

9. N- [3 - [[2- (2-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

10. N- [3 - [[2- (2-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

11. N- [3 - [[2- (3-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

12. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-propylbenzenesulfonamide,

13. N- [3 - [[2- (3-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

14. N- [3 - [[2- (4-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

15. N- [3 - [[2- (4-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

16. N- [3 - [[3- (4-methoxyphenyl) propylamino] methyl] phenyl] naphthalene-2-sulfonamide,

17. N- [3 - [[2- (3-hydroxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

18. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide,

19. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-fluorobenzenesulfonamide,

20. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-fluoro-benzenesulfonamide,

21. 4-chloro-N- [3 - [[2-2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -benzenesulfonamide,

22. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-iodo-benzenesulfonamide,

23. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide,

24. N- [3 - [[2 '(2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3- (trifluoromethyl) benzenesulfonamide.

25. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-methoxy-benzenesulfonamide,

26. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-methoxy-benzenesulfonamide,

27. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4- (trifluoromethoxy) benzenesulfonamide,

28. 3-cyano-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -benzenesulfonamide,

29. 4-cyano-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -benzenesulfonamide,

30. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-phenyl-benzenesulfonamide,

31. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] thiophene-2-sulfonamide

32. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] thiophene-3-sulfonamide,

33. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -2,5-dimethylthiophene-3-sulfonamide,

34. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -5-isoxazol-5-ylthiophene-2-sulfonamide,

35. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-1-sulfonamide,

36. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

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37. 6-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

38. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1,3-benzodioxole-5-sulfonamide,

39. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole -3-sulfonamide,

40. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1-methyl-indole-4-sulfonamide,

41. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamno] methyl] phenyl-1-methyl-indole-5-sulfonamide,

42. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzofuranan-2-sulfonamide,

43. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzothiophene-3-sulfonamide,

44. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -5-fluoro-3-methyl-benzothiophene-2-sulfonamide,

45. 3-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-fluorobenzenesulfonamide,

46. N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide,

47. N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] naphthalene-1-sulfonamide,

48. N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

49. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide,

50. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -4-phenylbenzenesulfonamide,

51. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] naphthalene-1-sulfonamide,

52. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

53. N- [3 - [[3- (5-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] -3-methyl-benzenesulfonamide,

54. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] naphthalene-1-sulfonamide,

55. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] naphthalene-2-sulfonamide,

57. N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethyl-methylamino] methyl] phenyl] -benzenesulfonamide,

58. N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethyl-methylamino] methyl] phenyl] benzenesulfonamide,

59. N- [3 - [[2- (1H-indol-4-yloxy) ethyl-methyl-amino] methyl] phenyl] benzenesulfonamide,

60. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] benzenesulfonamide,

61. 4-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide,

62. 3,4-difluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide,

63. 3-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -benzenesulfonamide,

64. 4-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide,

65. 3,4-dichloro-N- [3 - [[- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide

66. 3-bromo-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide,

67. 4-bromo-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide,

68. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -4-iodo-benzenesulfonamide,

69. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -3-methyl-benzenesulfonamide,

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70. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -4-methyl-benzenesulfonamide,

71. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -4-propyl-benzenesulfonamide,

72. 4-tert-butyl-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] -phenyl] -benzenesulfonamide,

73. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3- (trifluoromethyl) benzenesulfonamide,

74. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4- (trifluoromethyl) benzenesulfonamide,

75. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methoxy-benzenesulfonamide,

76. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4-methoxy-benzenesulfonamide,

77. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4- (trifluoromethoxy) benzenesulfonamide,

78. 3-cyano-N- [3 - [[3- {6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide,

79. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4-phenyl-benzenesulfonamide,

80. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] thiophene-2-sulfonamide,

81. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] thiophene-3-sulfonamide,

82. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -2,5-dimethylthiophene-3-sulfonamide,

83. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -5-isoxazol-5-yl-thiophene-2-sulfonamide,

84. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] naphthalene-1-sulfonamide,

85. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] naphthalene-2-sulfonamide

86. 6-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -naphthalene-2-sulfonamide,

87. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -2,3-dihydro-1,4-benzodioxine-6-sulfonamide ,

88. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -1,3-benzodioxole-5-sulfonamide,

89. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -2-oxo-indoline-5-sulfonamide,

90. N- [3 - [[3- {6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -6,7-dihydro-5H-pyrrolo [1,2-a ] imidazole-3-sulfonamide,

91. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -1-methyl-indole-4-sulfonamide,

92. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -1-methyl-indole-5-sulfonamide,

93. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -1,3-benzothiazole-4-sulfonamide,

94. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -1,3'-benzothiazole-5-sulfonamide,

95. N- [3 - [[3- {6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] benzofuran-2-sulfonamide,

96. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -benzothiophene-3-sulfonamide,

97. 5-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methyl-benzothiophene-2-sulfonamide,

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98. 5-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methyl-benzothiophene-2-sulfonamide,

99. 3-chloro-4-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide,

100. N- [3 - [[2- (3-methylphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

101. N- [3 - [[2- (3-hydroxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide,

102. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -4-propyl-benzenesulfonamide,

103. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] thiophene-2-sulfonamide,

104. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] thiophene-3-sulfonamide,

105. N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -2,5-dimethyl-thiophene-3-sulfonamide, and pharmaceutically acceptable salts thereof.

The compounds according to the invention of formula (I) above show an affinity for receptors that are recognized therapeutic targets for the treatment of CNS disorders, such as dopaminergic receptors, in particular D2 and D3, serotonergic receptors, in particular 5-HT1A, 5-HT2A, 5-HT6, 5 -HT7, adrenergics, in particular a2C, and have no or weak affinity for biological targets associated with side effects, such as hERG potassium channels, M3 muscarinic receptors, H1 histaminergic, α1 adrenergic receptors, and 5-HT2C serotoninergic receptor. Due to such a broad pharmacological profile, they can be used in medicine as drugs, for the treatment and / or prevention of central nervous system diseases such as: schizophrenia, schizoaffective disorders, schizophrenic disorders, delusional syndromes and other psychotic states not related to and related to the use of psychoactive substances , affective disorder, bipolar disorder, mania, depression, anxiety disorders of various etiology, stress reactions, disturbances of consciousness, coma, delirium of alcohol and other etiology, attacks of aggression, psychomotor agitation and other behavioral disorders, sleep disorders of various etiologies, abstinence syndromes of various etiology, addictions, pain syndromes of various etiologies, poisoning with psychoactive substances, cerebral circulation disorders of various etiologies, psychosomatic disorders of various etiologies, conversion disorders, dissociative disorders, urination disorders, autism and other neurodevelopmental disorders in e.g. bedwetting, stuttering, tics, cognitive impairment of various kinds, incl. Alzheimer's disease, psychopathological symptoms and neurological disorders in the course of other diseases of the central and peripheral nervous system.

The invention therefore also relates to compounds of formula (I) as defined above for use as a medicament.

The compounds of formula (I) can be administered in the treatment of diseases of the central nervous system in the form of a pharmaceutical composition or a pharmaceutical preparation containing them.

The invention therefore also relates to a pharmaceutical composition containing, as active ingredient, a compound or compounds of formula (I) as defined above, in admixture with pharmaceutically acceptable excipients.

The invention also relates to compounds of formula (I) as defined above for use in the treatment of schizophrenia.

The invention also relates to the use of compounds of formula (I) as defined above in the manufacture of a medicament for the treatment of schizophrenia.

Terms used in the description of the present invention have the following meanings.

Unless specifically indicated otherwise, the term "C ₁ -C ₃ -alkyl" means a saturated hydrocarbon group of the indicated number of carbon atoms and which may be a straight chain or branched chain group. Specific examples of groups encompassed by this term are methyl, ethyl, n-propyl, iso-propyl groups.

The term "C ₁ -C ₄ -alkyl" denotes a saturated hydrocarbon group of the indicated number of carbon atoms and which may be a straight chain group or a branched chain group. Specific examples of groups encompassed by this term are methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, and sec-butyl groups.

The term "C ₁ -C ₃ -alkyloxy" denotes the -OC ₁ -C ₃ -alkyl group, the C ₁ -C ₃ -alkyl group of which is a saturated hydrocarbon group having the indicated number of carbon atoms, and which may be a straight chain or branched chain group. Specific examples of groups encompassed by this term are methoxy, ethoxy, n-propoxy, iso-propoxy groups.

The term "halogen" denotes a substituent selected from F, Cl, Br and I.

PL 219 283 B1

The term "halo-C ₁ -C ₃ -alkyl" denotes a saturated hydrocarbon group having the number of carbon atoms indicated and which may be a straight chain or branched chain group and the carbon atom of which, depending on its order, may be substituted by 1 to 3 halogen atoms including 1, 2 or 3 halogen atoms. The halogen atom is as defined above. A particularly preferred example of a group encompassed by this term is trifluoromethyl -O-CF ₃ .

Depending on the order of the amino group of the benzoamine moiety, compounds of formula (I) can be obtained by one of the methods described below.

Compounds of formula (I) in which R is H, i.e. compounds represented by the general formula (IA), can be prepared by the method shown in the following scheme:

In a first step, the corresponding halogen derivative (Va) is converted into the primary amine (IVa) by treatment with an ammonia solution. The obtained amine (IVa) and 3-nitrobenzaldehyde are subjected to a reductive amination reaction in the presence of sodium triacetoxyborohydride as reducing agent,

In a solvent for example methylene chloride. In the next step, the amino group of the nitro derivative (IIIa) is protected by treatment with ditert-butyl dicarbonate in the presence of triethylamine. The obtained protected nitro derivative (Boc-IIa) is reduced with hydrogen in the presence of Raney nickel catalyst to give derivative (Boc-IIa) which is then reacted with sulfonyl chloride (IIb) in the presence of a base, for example pyridine to give the protected compound Boc -IA. The Boc-IA derivative is deprotected by treatment with trifluoroacetic acid in an organic solvent, for example methylene chloride, to give the compound of the invention IA.

Compounds of formula (I) in which R is methyl, i.e. compounds represented by general formula (IB), can be prepared by the method shown in the following scheme:

In a first step, 3-nitrobenzaldehyde and methylamine are subjected to a reductive amination reaction in the presence of sodium borohydride as reducing agent. The resulting N-methylbenzylamine derivative is reacted with a halogen derivative (Va) in the presence of a base, for example potassium carbonate, to give the nitro derivative (Me-IIIa). In the next step, the nitro group of the derivative (Me-IIIa) is reduced with tin chloride to give the amine derivative (Me-IIa), which is then converted into the compound of the invention (IB) by reaction with sulfonyl chloride (M-IIa) in the presence of a base. for example pyridine.

The starting compounds of formulas (Va), (IIb) and 3-nitrobenzaldehyde are either known or commercially available compounds, or they can be prepared from commercially available starting materials by adapting and using known methods.

PL 219 283 B1

Preparation of exemplary compounds of formula (I) according to the invention and exemplary intermediates (IVa), (IIIa), (Boc-IIIla), (Boc-IIIla), (Boc-Ia), (Me-IIla) and (Me-IIla) ) is described in detail in the experimental part.

As the compounds of formula (I) are basic compounds (containing one secondary or tertiary amine group), they can form acid addition salts.

Acid salts can be pharmaceutically acceptable salts, especially when intended to be an active ingredient of a pharmaceutical composition. The invention, however, also includes salts with acids other than pharmaceutically acceptable, which may, for example, be intermediates in the preparation of the compounds of the invention in the final purity required for medicinal products. In practice, it is often desirable, for example to purify the compound, to pre-isolate the compound from the reaction mixture in the form of a pharmaceutically unacceptable salt, then convert it to the free base by treatment with a basic agent and isolate, optionally re-convert to a pharmaceutically acceptable salt.

Acid addition salts can be formed with inorganic (mineral) acids or with organic acids. Examples of acids include, in particular, hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric, carbonic, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, pamic, xinaphonic, hexane.

An acid addition salt can be prepared simply by reacting a compound of formula (I) with an appropriate inorganic or organic acid in an amount substantially equimolar to compound (I), optionally in a suitable solvent, such as an organic solvent, to form a salt which is usually isolated, for example, by crystallization and filtration. For example, the free bases of the compounds can be converted to the corresponding hydrochloride salts by treating a solution of the compound, for example, in methanol, with a stoichiometric amount of hydrochloric acid or a solution of hydrogen chloride in methanol, ethanol or diethyl ether followed by evaporation of the solvents.

Central nervous system diseases are diseases selected from schizophrenia, schizoaffective disorders, schizophrenic disorders, delusional syndromes and other psychotic states unrelated to and related to the use of psychoactive substances, affective disorder, bipolar disorder, mania, depression, anxiety disorders of various etiology, stress, consciousness disorders, coma, deliriums of alcohol and other etiology, attacks of aggression, psychomotor agitation and other behavioral disorders, sleep disorders of various etiologies, abstinence syndromes of various etiologies, addictions, pain syndromes of various etiologies, intoxication with psychoactive substances, cerebral circulation disorders of various etiologies, psychosomatic disorders of various etiologies, conversion disorders, dissociative disorders, urination disorders, autism and other neurodevelopmental disorders, e.g. bedwetting, stuttering, tics, cognitive disorders of various types rakterem, incl. Alzheimer's disease, psychopathological symptoms and neurological disorders in the course of other diseases of the central and peripheral nervous system.

In the treatment of the aforementioned diseases, the compounds of formula (I) according to the invention may be administered as a chemical compound, but will usually be used in the form of pharmaceutical compositions containing a compound according to the invention or a pharmaceutically acceptable salt thereof as defined above as an active ingredient, in combination with acceptable compounds. pharmaceutical carriers and excipients.

In the treatment of the aforementioned conditions, the pharmaceutical compositions according to the invention may be administered by any route, preferably orally or parenterally, and will take the form of a preparation intended for use in medicine, depending on the intended route of administration.

Compositions for administration by the oral route may take the form of solid or liquid preparations. Solid preparations may take the form of, for example, tablets or capsules prepared in a conventional manner from pharmaceutically acceptable inactive ingredients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); bulking agents (e.g. lactose, sucrose, carboxymethyl cellulose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g., crospovidone, corn starch or sodium starch glycolate); wetting agents (e.g. sodium lauryl sulfate). Tablets may be coated by methods well known in the art with plain coatings, delay / control release coatings, or enteric coatings. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means from pharmaceutically acceptable inactive ingredients such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oil esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain suitable buffering systems, flavoring, coloring and sweetening agents.

Formulations for oral administration can be formulated appropriately by methods known to those skilled in the art to provide controlled-release of the active compound.

The parenteral route of administration includes administration by intramuscular and intravenous injection, and intravenous infusion (infusion). Compositions for parenteral administration may be in unit dosage form, for example, in ampoules or multi-dose containers, with a preservative added. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The method of treatment using the compounds of this invention will involve administering a therapeutically effective amount of a compound of the invention, preferably in the form of a pharmaceutical composition, to a subject in need of such treatment.

A proposed dose of the compounds of the invention is from 0.1 to about 1000 mg per day, in a single dose or in divided doses. It will be appreciated by those skilled in the art that the selection of the dose necessary to achieve the desired biological effect will depend on a number of factors, for example the specific compound, application, mode of administration, age and condition of the patient, and that the precise dose will ultimately be determined at the discretion of the attending physician.

P r z k ł a d 1.

Preparation of starting materials of the general formula (Boc-IIIa) - general procedure

a) Preparation of starting materials of formula (IVa)

The appropriate halogen derivative (Va) (17 mmol) is dissolved in methanol (200 ml). Excess NH3aq (2x250 ml of a 25% solution) is added to the solution and the mixture is stirred at room temperature

PL 219 283 B1 for 2 days. The methanol is then evaporated off under reduced pressure. The residue is partitioned between methylene chloride and 2N NaOH aq. The organic phase was dried over anhydrous magnesium sulfate and, after the desiccant had been filtered off, concentrated to dryness under reduced pressure, the product was obtained with a purity of more than 85% (UPLC / MS) with a yield ranging from 85-98%.

Starting halogen derivatives (Va):

(2-bromoethyl) benzene (Va-1), (2-bromoethoxy) benzene (Va-2),

1- (2-bromoethoxy) -3-fluorobenzene (Va-3),

1- (3-bromopropoxy) -3-fluorobenzene (Va-4),

1- (2-bromoethyl) -3-chlorobenzene (Va-5),

1- (2-bromoethoxy) -3-chlorobenzene (Va-6),

1- (2-bromoethyl) -3-methylbenzene (Va-7),

1- (2-bromoethoxy) -3-methylbenzene (Va-8),

1- (2-bromoethyl) -2-methoxybenzene (Va-9),

1- (2-bromoethoxy) -2-methoxybenzene (Va-10),

1- (2-bromoethyl) -3-methoxybenzene (Va-11),

1- (2-bromoethoxy) -3-methoxybenzene (Va-12),

1- (2-bromoethyl) -4-methoxybenzene (Va-13),

1- (2-bromoethoxy) -4-methoxybenzene (Va-14),

3- (2-bromoethyl) phenol (Va-15),

3- (2-bromoethoxy) phenol (Va-16),

5- (2-bromoethoxy) -2,3-dihydro-1,4-benzodioxin (Va-18), 7- (2-bromoethoxy) -2,2-dimethyl-2,3-dihydro-1-benzofuran (Va -19),

4- (2-bromoethoxy) -1 H-indole (Va-20),

3- (3-chloropropyl) -6-fluoro-1,2-benzoxazole (Va-21), (3-bromopropyl) benzene (Va-22),

1- (3-bromopropyl) -4-methoxybenzene (Va-23).

Following the general procedure above, the following compounds were obtained:

2-phenylethylamine (IVa-1),

2-phenoxyethylamine (IVa-2),

2- (3-fluorophenoxy) ethylamine (IVa-3),

2- (3-fluorophenoxy) propyl-1-amine (IVa-4),

2- (3-chlorophenyl) ethylamine (IVa-5),

2- (3-chlorophenoxy) ethylamine (IVa-6),

2- (3-methylphenyl) ethylamine (IVa-7),

2- (3-methylphenoxy) ethylamine (IVa-8),

2- (2-methoxyphenyl) ethylamine (IVa-9),

2- (2-methoxyphenoxy) ethylamine (IVa-10),

2- (3-methoxyphenyl) ethylamine (IVa-11),

2- (3-methoxyphenoxy) ethylamine (IVa-12),

2- (4-methoxyphenyl) ethylamine (IVa-13),

2- (4-methoxyphenoxy) ethylamine (IVa-14),

3- (2-aminoethyl) phenol (IVa-15),

3- (2-aminoethoxy) phenol (IVa-16),

2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamine (IVa-18), 2 - [(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl) oxy] ethylamine (IVa-19),

2- (1H-indol-4-yloxy) ethylamine (IVa-21),

3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-1-amine (IVa-21),

3-phenylpropylamine (IVa-22),

2- (4-methoxyphenyl) propylamine (IVa-23)

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b) Preparation of starting materials of formula (IIa) - general procedure

3-Nitrobenzaldehyde (20 mmol) and the appropriate amine (IVa) are dissolved in methylene chloride (200 ml). Then sodium triacetoxyborohydride (37 mmol) is added and the mixture is stirred for 4 h, then poured onto ice NaHCO3. After phase separation, the organic phase is washed with brine and water and dried over magnesium sulfate. After the desiccant was filtered off, the filtrate was evaporated to dryness, giving the product more than 90% pure (UPLC // MS analysis). Yield: 75-84%.

Following the general procedure above, the following compounds were obtained:

N- (3-nitrobenzyl) -2-phenylethylamine (IIla-1),

N- (3-nitrobenzyl) -2-phenoxyethylamine (IIla-2),

2- (3-fluorophenoxy) -N- (3-nitrobenzyl) ethylamine (IIa-3),

3- (3-fluorophenoxy) -N- (3-nitrobenzyl) propyl-1-amine (IIla-4),

2- (3-chlorophenyl) -N- (3-nitrobenzyl) ethylamine (IIla-5),

2- (3-chlorophenoxy) -N- (3-nitrobenzyl) ethylamine (IIla-6),

2- (3-methylphenyl) -N- (3-nitrobenzyl) ethylamine (Illa-7),

2- (3-methylphenoxy) -N- (3-nitrobenzyl) ethylamine (11a-8),

2- (2-methoxyphenyl) -N- (3-nitrobenzyl) ethylamine (Illa-9),

2- (2-methoxyphenoxy) -N- (3-nitrobenzyl) ethylamine (Illa-10),

2- (3-methoxyphenyl) -N- (3-nitrobenzyl) ethylamine (11a-11),

2- (3-methoxyphenoxy) -N- (3-nitrobenzyl) ethylamine (11a-12),

2- (4-methoxyphenyl) -N- (3-nitrobenzyl) ethylamine (Illa-13),

2- (4-methoxyphenoxy) -N- (3-nitrobenzyl) ethylamine (Illa-14),

3- {2 - [(3-nitrobenzyl) amino] ethyl} phenol (IIa-15),

3- {2 - [(3-nitrobenzyl) amino] ethoxy} phenol (IIa-16),

2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) -N- (3-nitrobenzyl) ethylamine (IIa-18),

2 - [(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl) oxy] -N- (3-nitrobenzyl) methylamine (11a-19),

2- (1H-indol-4-yloxy) -N- (3-nitrobenzyl) ethylamine (IIla-20),

3- (6-fluoro-1,2-benzoxazol-3-yl) -N- (3-nitrobenzyl) propyl-1-amine (11a-21),

N- (3-nitrobenzyl) -3-phenylpropylamine (IIla-22),

3- (4-methoxyphenyl) -N- (3-nitrobenzyl) propylamine (11a-23).

c) Preparation of starting materials of formula (Boc-IIIa) - general procedure

The appropriate nitro derivative (IIa) (11 mmol) is dissolved in methylene chloride (100 ml) and then triethylamine (5 ml) and di-tert-butyl dicarbonate (12.7 mmol) are added to the solution sequentially. The mixture is stirred for 1 h, then washed successively with 1N aq. NaOH, 1N aq. HCl, and brine. The organic phase is dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was evaporated to dryness, giving the product with purity above 95% (UPLC / MS analysis) with yield: 86-95%.

Following the general procedure above, the following compounds were obtained:

Tert-Butyl (3-nitrobenzyl) (2-phenylethyl) carbamates (Boc-Illa-1), (3-nitrobenzyl) (2-phenoxyethyl) carbamate (Boc-Illa-2)

Tert-butyl [2- (3-fluorophenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-IIa-2),

Tert-Butyl [3- (3-fluorophenyl) propyl] (3-nitrobenzyl) carbamate (Boc-IIIla-4),

Tert-butyl [2- (3-chlorophenyl) ethyl] (3-nitrobenzyl) carbamate (Boc-IIIa-5),

Tert-butyl [2- (3-chlorophenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-11a-6),

Tert-butyl [2- (3-methylphenyl) ethyl] (3-nitrobenzyl) carbamate (Boc-IIIa-7),

Tert-Butyl [2- (3-methylphenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-IIIa-8),

Tert-butyl [2- (2-methoxyphenyl) ethyl] (3-nitrobenzyl) carbamate (Boc-11a-9),

Tert-butyl [2- (2-methoxyphenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-10),

Tert-Butyl [2- (3-methoxyphenyl) ethyl] (3-nitrobenzyl) carbamate (Boc-IIIa-11),

Tert-butyl [2- (3-methoxyphenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-12),

Tert-Butyl [2- (4-methoxyphenyl) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-13),

Tert-butyl [2- (4-methoxyphenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-14),

Tert-butyl [2- (3-hydroxyphenyl) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-15),

Tert-butyl [2- (3-hydroxyphenoxy) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-16),

Tert-butyl [2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethyl] (3-nitrobenzyl) carbamate (Boc-Illa-18),

PL 219 283 B1

Tert-butyl [{2 - [(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl) oxy] ethyl} (3-nitrobenzyl) carbamate (Boc-11a-19),

Tert-Butyl [2- (1H-indol-4-yloxy) ethyl] (3-nitrobenzyl) carbamate (IIa-20),

Tert-Butyl [3- (6-fluoro-1,2-benzoxazol-3-yl) propyl] (3-nitrobenzyl) carbamate (IIla-3521), (3-nitrobenzyl) (3-phenylpropyl) carbamate (Boc-Illa-22),

Tert-butyl [3- (4-methoxyphenyl) propyl] (3-nitrobenzyl) carbamimate (Boc-IIIa-23).

d) Preparation of starting materials of formula (Boc-IIa) - general procedure

The corresponding derivative of formula (Boc-IIIa) (8mmol) is dissolved in methanol (50ml) and reduced with hydrogen at atmospheric pressure (supplied hydrogen balloon) in the presence of Raney nickel catalyst. After 18 h of stirring at room temperature, the catalyst is filtered off, the filtrate is evaporated to dryness and the crude product with a purity of over 90% (UPLC / MS) is used in the next step without purification. Yield: 95-99%.

Following the general procedure above, the following compounds were obtained:

Tert-Butyl (3-aminobenzyl) (2-phenylethyl) carbamate (Boc-11a-1), tert-butyl (3-aminobenzyl) (2-phenoxyethyl) carbamate (Boc-11a-2), (3-aminobenzyl) [ Tert-Butyl 2- (3-fluorophenoxy) ethyl] carbamate (Boc-11a-3), (3-aminobenzyl) [3- (3-fluorophenyl) propyl] carbamate (Boc-11a-4), (3 -aminobenzyl) tert-butyl [2- (3-chlorophenyl) ethyl] carbamate (Boc-11a-5), tert-butyl (3-aminobenzyl) [2- (3-chlorophenoxy) ethyl] carbamate (Boc-11a-6 ), Tert-butyl (3-aminobenzyl) [2- (3-methylphenyl) ethyl] carbamate (Boc-11a-7), (3-aminobenzyl) [2- (3-methylphenoxy) ethyl] carbamate (Boc -1la-8), tert-butyl (3-aminobenzyl) [2- (2-methoxyphenyl) ethyl] carbamate (Boc-11a-9), (3-aminobenzyl) [2- (2-methoxyphenoxy) ethyl] carbamate tert -butyl (Boc-11a-10), (3-aminobenzyl) [2- (3-methoxyphenyl) ethyl] carbamate tert-butyl (Boc-11a-11), (3-aminobenzyl) [2- (3-methoxyphenoxy) tert-butyl ethyl] carbamate (Boc-11a-12), tert-butyl (3-aminobenzyl) [2- (4-methoxyphenyl) ethyl] carbamate (Bo c-11a-13), tert-butyl (3-aminobenzyl) [2- (4-methoxyphenoxy) ethyl] carbamate (Boc-11a-14), (3-aminobenzyl) [2- (3-hydroxyphenyl) ethyl] carbamate tert-butyl (Boc-11a-15), (3-aminobenzyl) [2- (3-hydroxyphenoxy) ethyl] carbamate tert-butyl (Boc-11a-16), (3-aminobenzyl) [2- (2,3 tert-Butyl-dihydro-1,4-benzodioxin-5-yloxy) ethyl] carbamate (Boc-11a-18) (3-aminobenzyl) {2 - [(2,2-dimethyl-2,3-dihydro-1- benzofuran-7-yl) oxy] ethyl} tert-butyl carbamates (Boc-11a-19), (3-aminobenzyl) [2- (1H-indol-4-yloxy) ethyl] carbamate (Boc-11a- 20), tert-butyl (3-aminobenzyl) [3- (6-fluoro-1,2-benzoxazol-3-yl) propyl] carbamate (Boc-11a-21), (3-aminobenzyl) (3-phenylpropyl) tert-butyl carbamate (Boc-11a-22), tert-butyl (3-aminobenzyl) [3- (4-methoxyphenyl) propyl] carbamate (Boc-11a-23).

P r z k ł a d 2.

General procedure for the preparation of compounds of formula (IA) according to the invention

PL 219 283 B1

Compound of formula (Boc-IIa) (0.75 mmol), prepared as described in Example 1, is dissolved in dry methylene chloride (10 ml), pyridine (1 ml) and the appropriate sulfonyl chloride (IIb) (0.75 mmol). The mixture is stirred overnight at room temperature. The pyridine is then evaporated off by adding a small amount of toluene beforehand, and the residue is partitioned in water / ethyl acetate. The organic phase is dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was evaporated to dryness to give the crude product (Boc-IA) as an oil. The crude protected sulfonamide (Boc-IA) was dissolved in methylene chloride (10 ml) and trifluoroacetic acid (5 ml) was added. The mixture is stirred for 1 h at room temperature, then the solvents are evaporated off under reduced pressure. The residue is partitioned in an extraction system of ethyl acetate / 2N NaOH aq. The organic phase is washed successively with water and brine, then dried over magnesium sulfate and, after the desiccant has been filtered off, evaporated to dryness. The residue is purified by flash column chromatography (methylene chloride / methanol 9: 1 v / v).

The yields of the obtained compounds (IA) were in the range of 65-90%, and their HPLC purity was in the range of 90-100%.

The structure of the products obtained was examined by mass spectroscopy and / or proton nuclear magnetic resonance.

As starting materials for the preparation of compounds (IA) of the invention, the corresponding compounds of formula (Boc-IIIa) and commercially available sulfonyl chlorides (IIb) as described in Example 1 d) were used:

benzenesulfonyl chloride (IIb-1), 3-fluorobenzenesulfonyl chloride (IIb-2), 4-fluorobenzenesulfonyl chloride (IIb-3), 3,4-difluorobenzenesulfonyl chloride (IIb-4), 3-chlorobenzenesulfonyl chloride (IIb-5), 4-Chlorobenzenesulfonyl chloride (llb-6), 3,4-dichlorobenzenesulfonyl chloride (llb-7), 3-bromobenzenesulfonyl chloride (llb-8), 4-bromobenzenesulfonyl chloride (llb-9), 4-iodobenzenesulfonyl chloride (llb-10) , 3-chloro-4-fluoro-benzenesulfonyl chloride (llb-48), 3-methylbenzenesulfonyl chloride (llb-11), 4-methylbenzenesulfonyl chloride (llb-12), 4-propylbenzenesulfonyl chloride (llb-13), 4- tert-butylbenzenesulfonyl (lb-14), 3- (trifluoromethyl) benzenesulfonyl chloride (llb-15), 4- (trifluoromethyl) benzenesulfonyl chloride (llb-16), 4-fluoro-3-methyl-benzenesulfonyl chloride (llb-17) , 3-methoxybenzenesulfonyl chloride (llb-18), 4-methoxybenzenesulfonyl chloride (llb-19), 4- (trifluoromethoxy) benzenesulfonyl chloride (llb-20), 3-cyanobenzenesulfonyl chloride (llb-21), chlorine k 4-cyanobenzenesulfonyl (IIb-22), 4- (phenyl) benzenesulfonyl chloride (IIb-23), benzothiophene-2-sulfonyl chloride (IIb-24), benzothiophene-3-sulfonyl chloride (IIb-25), chloride 2, 5-Dimethylthiophene-2-sulfonyl (IIb-26), 5-isoxazol-5-ylthiophene-2-sulfonyl chloride (IIb-27), naphthalene-1-sulfonyl chloride (IIb-28), naphthalene-2-sulfonyl chloride ( IIb-29), 6-chloronaphthalene-2-sulfonyl chloride (IIb-30), 2,3-dihydro-1,4-benzodioxin-5-sulfonyl chloride (IIb-31), 2,3-dihydro-1 chloride, 4-benzodioxine-6-sulfonyl (IIb-32), 1,3-benzodioxole-5-sulfonyl chloride (IIb-33), 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (IIb- 34), 6,7-dihydro-5H-pyrrolo [1,2-a] imidazole-3-sulfonyl chloride (IIb-35), 1H-indole-5-sulfonyl chloride (IIb-36), 1-methyl chloride 1H-indole-4-sulfonyl (IIb-37),

PL 219 283 B1 1-Methyl-1H-indole-5-sulfonyl chloride (IIb-38), 1-3-benzothiazole-4-sulfonyl chloride (IIb-39), 1,3-benzothiazole-5-sulfonyl chloride (IIb -40), 1-benzofuran-2-sulfonyl chloride (IIb-41), 1-benzothiophene-2-sulfonyl chloride (IIb-42), 1-benzothiophene-3-sulfonyl chloride (IIb-43), 6-chloro chloride -1-benzothiophene-2-sulfonyl (IIb-44), 5-methyl-1-benzothiophene-2-sulfonyl chloride (IIb-45), 5-fluoro-3-methyl-1-benzothiophene-2-sulfonyl chloride (Ib -46), 5-chloro-3-methyl-1-benzothiophene-2-sulfonyl chloride (IIb-47).

Following the general procedure described above, the following compounds (IA) of the invention were obtained.

Relationship 1.

N- [3 - [(phenylethylamino) methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-1) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.34 (d, 1H, J = 1.8 Hz), 7.88-7.80 (m, 3H), 7.71 (dd, 1H, J = 1.8 and 8.7 Hz), 7.62-7.52 ( m, 2H), 7.30-7.10 (m, 6H), 7.03-6.92 (m, 3H), 3.68 (s, 2H), 2.76-2.68 (m, 4H); MS: 417 [M + H ⁺ ].

Relationship 2.

N- [3 - [(2-phenoxyethylamino) methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-IIa-2) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.32 (d, 1H, J = 1.8 Hz), 7.86-7.78 (m, 3H), 7.70 (dd, 1H, J = 1.8 and 8.7 Hz), 7.62-7.39 ( m, 2H), 7.19-7.00 (m, 5H), 6.44-6.36 (m, 3H), 3.90 (t, 2H, J = Hz), 3.55 (s, 2H), 2.80 (t, 2H, J = 4.8 Hz); MS: 449 [M + H ⁺ ].

Relationship 3.

N- [3 - [(3-phenylpropylamino) methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-22) and sulfonyl chloride (IIb-29). MS: 431 [M + H ⁺ ].

Relationship 4.

N- [3 - [[2- (3-fluorophenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-IIIa-3) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.21 (d, 1H, J = 1.8 Hz), 7.94-7.86 (m, 3H), 7.68-7.58 (m, 3H),

24-7.22 (m, 2H), 7.18-7.10 (m, 1H), 7.06-7.04 (m, 1H), 6.98-6.90 (m, 1H), 6.66-6.58 (m, 1H), 6.52 (dd, 1H , J = 2.0 and 8.2 Hz), 6.42 (dt, 1H, J = 2.4 and 11.0 Hz), 4.15-4.11 (m, 2H), 4.02-3.98 (m, 2H), 3.98 (s, 2H); MS: 451 [M + H ⁺ ].

Compound 5.

N- [3 - [[3- (3-fluorophenoxy) propylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-IIa-4) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.17 (d, 1H, J = 1.8 Hz), 7.92-7.84 (m, 3H), 7.68-7.54 (m, 3H),

7.25-7.20 (m, 2H), 7.19-7.12 (m, 1H), 7.06-7.02 (m, 1H), 6.92-6.88 (m, 1H), 6.65-6.54 (m, 2H), 6.48 (dt, 1H , J = 2.3 and 10.7 Hz), 4.00-3.96 (m, 2H), 3.80-3.77 (m, 2H), 1.99-1.90 (m, 2H), 1.85-1.80 (m, 2H); MS: 465 [M + H ⁺ ].

Compound 6.

N- [3 - [[2- (3-Chlorophenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-IIa-5) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.34 (d, 1H, J = 1.8 Hz), 7.89-7.80 (m, 3H), 7.70 (dd, 1H, J = 1.8 and 8.7 Hz), 7.63-7.52 ( m, 2H), 7.20-7.10 (m, 4H), 7.04-6.98 (m, 4H), 3.62 (s, 2H), 2.78-2.64 (m, 4H); MS: 451 [M + H ⁺ ].

Relationship 7.

N- [3 - [[2- (3-Chlorophenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-IIa-6) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.23 (d, 1H, J = 1.8 Hz), 7.92-7.84 (m, 3H), 7.64-7.52 (m, 3H),

7.40-7.34 (m, 2H), 7.16 (t, 1H, J = 7.9 Hz), 7.04 (t, 1H, J = 7.9 Hz), 6.90-6.80 (m, 2H), 6.64 (t, 1H, J = 2.0 Hz), 6.54 (dd, 1H, J = 1.8 and 8.7 Hz), 4.02-3.88 (m, 6H); MS: 467 [M + H ⁺ ].

Relationship 8.

N- [3 - [[2- (3-Methylphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-IIa-7) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.31 (d, 1H, J = 1.8 Hz), 7.86-7.79 (m, 3H), 7.70 (dd, 1H, J = 1.8 and 8.7 Hz), 7.62-7.50 (m, 2H), 7.18-7.08 (m, 1H), 7.04-6.88 (m, 6H), 3.68 (s, 2H), 2.72-2.64 (m, 4H), 2.29 (s, 3H); MS: 431 [M + H ⁺ ].

Relationship 9.

N- [3 - [[2- (2-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-9) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.33 (d, 1H, J = 1.8 Hz), 7.88-7.78 (m, 3H), 7.68 (dd, 1H, J = 2.0 and 8.7 Hz), 7.62-7.52 ( m, 2H), 7.24-7.18 (m, 1H), 7.16-7.04 (m, 2H), 7.03-6.98 (m, 2H), 6.96-6.92 (m, 1H), 6.90-6.82 (m, 2H), 3.78 (s, 3H), 3.76 (s, 2H), 2.90-2.87 (m, 4H); MS: 447 [M + H ⁺ ].

Compound 10.

N- [3 - [[2- (2-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-10) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.20 (d, 1H, J = 1.8 Hz), 7.92-7.84 (m, 3H), 7.68-7.55 (m, 3H), 7.24-7.22 (m, 2H), 7.17-7.15 (m, 1H), 6.98-6.94 (m, 1H), 6.92-6.86 (m, 1H), 6.84-6.80 (m, 3H), 4.21-4.18 (m, 2H), 4.07-4.00 (m , 2H), 3.76 (s, 2H), 3.75 (s, 3H); MS: 463 [M + H ⁺ ].

Relationship 11.

N- [3 - [[2- (3-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-11) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.32 (d, 1H, J = 1.8 Hz), 7.86-7.80 (m, 3H), 7.70 (dd, 1H, J = 1.8 and 8.7 Hz), 7.62-7.50 ( m, 2H), 7.21-7.10 (m, 2H), 7.06-6.92 (m, 3H), 6.78-6.68 (m, 3H), 3.80 (s, 3H), 3.62 (s, 2H), 2.78-2.64 ( m, 4H); MS: 447 [M + H ⁺ ].

Relationship 12.

N- [3 - [[2 '(2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-propyl-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-13).

MS: 484 [M + H ⁺ ].

Relationship 13.

N- [3 - [[2- (3-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-12) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.20 (d, 1H, J = 1.8 Hz), 7.98-7.92 (m, 3H), 7.65-7.56 (m, 3H), 7.18-7.00 (m, 3H), 6.98-6.96 (m, 1H), 6.56-6.50 (m, 1H), 6.35-6.30 (m, 1H), 6.25-6.20 (m, 1H), 4.15-4.10 (m, 2H), 4.00-3.95 (m , 2H), 3.80-3.75 (m, 2H), 3.65 (s, 3H); MS: 463 [M + H ⁺ ].

Relationship 14.

N- [3 - [[2- (4-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-13) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.34 (d, 1H, J = 1.8 Hz), 7.86-7.80 (m, 3H), 7.50 (dd, 1H, J = 1.8 and 8.9 Hz), 7.62-7.51 ( m, 2H), 7.12 (t, 1H, J = 8.2 Hz), 7.08-6.94 (m, 5H), 6.84-6.78 (m, 2H), 3.78 (s, 3H), 3.67 (s, 2H), 2.76 -2.64 (m, 4H); MS: 447 [M + H ⁺ ].

Compound 15.

N- [3 - [[2- (4-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-14) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CDCl 3): 8.34 (d, 1H, J = 1.8 Hz), 7.88-7.80 (m, 3H), 7.71 (dd, 1H, J = and 8.7 Hz), 7.62-7.50 (m , 2H), 7.20-7.14 (m, 1H), 7.07-7.00 (m, 3H), 6.84-6.76 (m, 4H), 3.86 (t, 2H, J = 4.8 Hz), 3.78 (s, 3H), 3.74 (s, 2H), 2.78 (t, 1H, J = 4.8Hz); MS: 463 [M + H ⁺ ].

Relationship 16.

N- [3 - [[3- (4-methoxyphenyl) propylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-23) and sulfonyl chloride (IIb-29). MS: 461 [M + H ⁺ ].

Relationship 17.

N- [3 - [[2- (3-hydroxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-15) and sulfonyl chloride (IIb-29).

¹ H-NMR (300 MHz, CD 3 OD): 8.29 (d, 1H, J = 1.8 Hz), 7.88-7.82 (m, 3H), 7.72 (dd, 1H, J = 2.0 and 8.7 Hz),. 62-7.50 (m, 2H), 7.18-7.10 (m, 1H), 7.06-7.00 (m, 3H), 6.98-6.92 (m, 1H), 6.66-6.61 (m, 1H), 6.60-6.55 (m, 2H) , 3.65 (s, 2H), 2.70-2.60 (m, 2H); MS: 433 [M + H ⁺ ].

Relationship 18.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-1). MS: 442 [M + H ⁺ ].

PL 219 283 B1

Relationship 19.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-fluoro-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-2). MS: 460 [M + H ⁺ ].

Compound 20.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-fluoro-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-3). MS: 460 [M + H ⁺ ].

Relationship 21.

chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide The title compound was obtained from the compound (Boc-11a-18) and chloride sulfonyl (IIb-6). MS: 476 [M + H ⁺ ].

Relationship 22.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-iodo-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-10). MS: 567 [M + H ⁺ ].

Relationship 23.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-11). MS: 456 [M + H ⁺ ].

Relationship 24.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3- (trifluoromethyl) benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-15). MS: 510 [M + H ⁺ ].

Compound 25.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-methoxy-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-18). MS: 472 [M + H ⁺ ].

Relationship 26.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-methoxy-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-19). MS: 472 [M + H ⁺ ].

Relationship 27.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4- (trifluoromethoxy) benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-20). MS: 526 [M + H ⁺ ].

Relationship 28.

3-cyano-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-21). MS: 467 [M + H ⁺ ].

Relationship 29.

4-cyano-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide

The title compound was prepared from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-22), MS; 467 [M + H ⁺ ].

Relationship 30.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-phenyl-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-23). MS: 518 [M + H ⁺ ].

Relationship 31.

N- [3 - [[2- (2,3-Dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] thiophene-2-sulfonamide The title compound was obtained from the compound (Boc-11a-18) and sulfonyl chloride (IIb-24). MS: 448 [M + H ⁺ ].

Relationship 32.

N- [3 - [[2- (2,3-Dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] thiophene-3-sulfonamide The title compound was obtained from the compound (Boc-11a-18) and sulfonyl chloride (IIb-25). MS: 448 [M + H ⁺ ].

Relationship 33.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -2,5-dimethyl-thiophene-3-sulfonamide

PL 219 283 B1

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-26). MS: 476 [M + H ⁺ ].

Relationship 34.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -5-isoxazol-5-yl-thiophene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-27). MS: 515 [M + H ⁺ ].

Relationship 35.

N- [3 - [[2- (2,3-Dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-1-sulfonamide The title compound was obtained from the compound (Boc-11a-18) and sulfonyl chloride (IIb-28). MS: 492 [M + H ⁺ ].

Relationship 36.

N- [3 - [[2- (2,3-Dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-11a-18) and sulfonyl chloride (IIb-29). MS: 492 [M + H ⁺ ].

Relationship 37.

6-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-30). MS: 526 [M + H ⁺ ].

Relationship 38.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1,3-benzodioxole-5-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-33). MS: 486 [M + H ⁺ ].

Relationship 39.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole -3-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-35). MS: 472 [M + H ⁺ ].

Relationship 40.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1-methyl-indole-4-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-37). MS: 495 [M + H ⁺ ].

Relationship 41.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1-methyl indole-5-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-38). MS: 495 [M + H ⁺ ].

Relationship 42.

N- [3 - [[2- (2,3-Dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzofuran-2-sulfonamide The title compound was obtained from the compound (Boc-11a-18) and sulfonyl chloride (IIb-41). MS: 482 [M + H ⁺ ].

Relationship 43.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzothiophene-3-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-43). MS: 498 [M + H ⁺ ].

Relationship 44.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -5-fluoro-3-methyl-benzothiophene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-46). MS: 530 [M + H ⁺ ].

Relationship 45.

3-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-fluoro-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-18) and sulfonyl chloride (IIb-48). MS: 494 [M + H ⁺ ].

Relationship 46.

N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-19) and sulfonyl chloride (IIb-11). MS: 468 [M + H ⁺ ].

Relationship 47.

N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] naphthalene-1-sulfonamide The title compound was obtained from the compound (Boc-11a-19) and sulfonyl chloride (IIb-28). MS: 504 [M + H ⁺ ].

PL 219 283 B1

Relationship 48.

N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Boc-11a-19) and sulfonyl chloride (IIb-29). MS: 504 [M + H ⁺ ].

Relationship 49.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-20) and sulfonyl chloride (IIb-11). MS: 436 [M + H ⁺ ].

Relationship 50.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -4-phenyl benzenesulfonamide

The title compound was obtained from the compound (Boc-IIa-20) and sulfonyl chloride (IIb-23). MS: 499 [M + H ⁺ ].

Relationship 51.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] naphthalene-1-sulfonamide

The title compound was obtained from the compound (Boc-IIa-20) and sulfonyl chloride (IIb-28). MS: 472 [M + H ⁺ ].

Relationship 52.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-20) and sulfonyl chloride (IIb-29). MS: 472 [M + H ⁺ ].

Relationship 53.

N- [3 - [[3- (5-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] -3-fetylbenzenesulfonamide The title compound was obtained from the compound (Boc-11a-21) and sulfonyl chloride ( 11b-11), MS: 455 [M + H ⁺ ].

Relationship 54.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] naphthalene-1-sulfonamide The title compound was prepared from the compound (Boc-11a-21) and sulfonyl chloride (llb-28). MS: 491 [M + H ⁺ ].

Relationship 55.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was prepared from the compound (Boc-11a-21) and sulfonyl chloride (llb-29). MS: 491 [M + H ⁺ ].

Compound 100.

N- [3 - [[2- (3-methylphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-8) and sulfonyl chloride (IIb-29). MS: 447 [M + H ⁺ ].

Relationship 101.

N- [3 - [[2- (3-hydroxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-16) and sulfonyl chloride (IIb-29). MS: 449 [M + H ⁺ ].

Compound 102.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -4-propyl-benzenesulfonamide The title compound was obtained from the compound (Boc-11a-20) and sulfonyl chloride (11b-13) . MS: 464 [M + H ⁺ ].

Relationship 103.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] thiophene-2-sulfonamide

The title compound was obtained from the compound (Boc-IIa-20) and sulfonyl chloride (IIb-24). MS: 428 [M + H ⁺ ].

Relationship 104.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] thiophene-3-sulfonamide

The title compound was obtained from the compound (Boc-IIa-20) and sulfonyl chloride (IIb-25). MS: 428 [M + H ⁺ ].

Compound 105.

N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -2,5-dimethyl-thiophene-3-sulfonamide The title compound was obtained from the compound (Boc-11a-20) and chloride sulfonyl (IIb-26).

MS: 456 [M + H ⁺ ].

PL 219 283 B1

P r z k ł a d 3.

Preparation of starting materials of the general formula (Me-11) - general procedure

a) Preparation of M-methyl-1- (3-nitrophenyl) methylamine

3-Nitrobenzaldehyde (80 mmol) is dissolved in methanol (60 ml), then the solution is cooled to 0 ° C, a solution of methylamine in water (93 mmol, 40% solution) is added and stirred for 1 h. Then sodium borohydride is added portionwise. (120 mmol). The mixture is allowed to warm to room temperature and after this has been reached, it is stirred for a further 2 h and then poured onto the NaHCO 3 / ice mixture. Methanol was evaporated from the resulting mixture and the residue was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and, after the desiccant had been filtered off, the filtrate was concentrated under reduced pressure to give the crude product with a purity of more than 90% (UPLC / MS) in 78% yield.

b) Preparation of the intermediate of formula (Me-IIIa)

N-Methyl-1- (3-nitrophenyl) methylamine (15 mmol) is dissolved in acetonitrile (100 ml) and the halogen derivative (Va) (15 mmol), potassium carbonate (45 mmol) and a catalytic amount of potassium iodide are added. The mixture is stirred under reflux for 18 h. Then it is cooled, the precipitate is filtered off and the solvent of the filtrate is evaporated. The residue is partitioned in methylene chloride / water. The organic phase is separated and dried over magnesium sulfate. After the drying agent was filtered off from the filtrate, the solvent was evaporated and the residue was purified by flash column chromatography (dichloromethane / methanol 9: 1 v / v). The product was obtained with a purity of more than 90% (UPLC / MS analysis) with a yield: 65-90 %.

Following the general procedure above, the following compounds were obtained:

2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) -N-methyl-N- (3-nitrobenzyl) ethylamine (Me-11a-2),

2 - [(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl) oxy] -N-methyl-N- (3-nitrobenzyl) ethylamine (Me-11a-3),

2- (1H-indol-4-yloxy) -N-methyl-N- (3-nitrobenzyl) ethylamine (Me-11a-4),

2 - [(6-fluoro-1,2-benzoxazol-3-yl) oxy] -N-methyl-N- (3-nitrobenzyl) ethylamine (Me-11-5).

PL 219 283 B1

c) Preparation of the intermediate of formula (Me-11) - general procedure

The corresponding nitro derivative of formula (Me-IIIa) (3.5 mmol) is dissolved in ethanol (100 ml), tin (II) chloride (17 mmol) is added and stirred at 60 ° C for 4 h. The ethanol is then evaporated off, and the residue is partitioned in ethyl acetate / water. The organic phase is separated and dried over magnesium sulfate. After the drying agent was filtered off from the filtrate, the solvent was evaporated and the product was obtained with a purity of more than 90% (UPLC / MS analysis) with a yield: 90-98%.

Following the general procedure above, the following compounds were obtained:

({[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethyl] (methyl) amino} methyl) aniline (Me-11-2), {[{2 - [(2.2 -dimethyl-2,3-dihydro-1-benzofuran-7-yl) oxy] ethyl} (methyl) amino] methyl} -aniline (Me-11-3),

3 - ({[2- (1H-indol-4-yloxy) ethyl] (methyl) amino} methyl) aniline (Me-IIa-4),

3 - {[{2 - [(6-fluoro-1,2-benzoxazol-3-yl) oxy] ethyl} (methyl) amino] methyl} aniline (Me-11-5).

P r z k ł a d 4.

Procedure for the preparation of compounds (IB) of the invention - general procedure

The appropriate compound of formula (Me-11) (0.32 mmol), prepared as described in Example 3, is dissolved in dry methylene chloride (10 ml), pyridine (1 ml) is added followed by sulfonyl chloride (0.32 mmol). . After stirring overnight at room temperature, the pyridine was evaporated (a little toluene was added first) and the residue was partitioned in water / ethyl acetate. The organic phase is separated and dried over magnesium sulfate. After the drying agent was filtered off from the filtrate, the solvent was evaporated and the residue was purified by flash column chromatography (methylene chloride / methanol 9: 1) to give the compounds of the invention (I) as oils.

The yields of the obtained compounds (IB) were in the range of 70-90%, and their HPLC purity was in the range of 90-100%.

The structure of the products obtained was examined by mass spectroscopy and / or proton nuclear magnetic resonance.

Following the general procedure described above and starting from the appropriate starting materials: (Mela) and sulfonyl chloride (IIb) (as mentioned in Example 2), the following compounds (IB) of the invention were obtained.

Relationship 57.

N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-IIa-2) and sulfonyl chloride (IIa-1). MS: 456 [M + H ⁺ ].

Relationship 58.

N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethyl-methylamino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Me-lla-3) and sulfonyl chloride (lb-1). MS: 468 [M + H ⁺ ].

PL 219 283 B1

Relationship 59.

N- [3 - [[2- (1H-indol-4-yloxy) ethyl-methyl-amino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Me-lla-4) and sulfonyl chloride (lb-1). MS: 436 [M + H ⁺ ].

Relationship 60.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] benzenesulfonamide The title compound was prepared from the compound (Me-11-5) and sulfonyl chloride (llb-1). MS: 455 [M + H ⁺ ].

Relationship 61.

4-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-3). MS: 473 [M + H ⁺ ].

Relationship 62.

3,4-difluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-4). MS: 491 [M + H ⁺ ].

Relationship 63.

3-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-5). MS: 489 [M + H ⁺ ].

Relationship 64.

4-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -5-benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-6). MS: 489 [M + H ⁺ ].

Relationship 65.

3,4-dichloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-7). MS: 523 [M + H ⁺ ].

Relationship 66.

3-bromo-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (II-8). MS: 533 [M + H ⁺ ].

Relationship 67.

4-bromo-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (Ib-9). MS: 533 [M + H ⁺ ].

Relationship 68.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -4-iodo-benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-10). MS: 580 [M + H ⁺ ].

Relationship 69.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methyl-benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-11). MS: 469 [M + H ⁺ ].

Relationship 70.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -4-methyl-benzenesulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-12). MS: 469 [M + H ⁺ ].

Relationship 71.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4-propyl-benzenesulfonamide

The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (II-13). MS: 497 [M + H ⁺ ].

Relationship 72.

4-tert-butyl-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-14). MS: 511 [M + H ⁺ ].

PL 219 283 B1

Relationship 73.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3- (trifluoromethyl) benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-15). MS: 523 [M + H ⁺ ].

Compound 74.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4- (trifluoromethyl) benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-16). MS: 523 [M + H ⁺ ].

Relationship 75.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methoxy-benzenesulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-18). MS: 485 [M + H ⁺ ].

Relationship 76.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4-methoxy-benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-19). MS: 485 [M + H ⁺ ].

Relationship 77.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -4- (trifluoromethoxy) benzenesulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-20). MS: 539 [M + H ⁺ ].

Relationship 78.

3-cyano-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] benzenesulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-21), MS: 480 [M + H ⁺ ].

Relationship 79.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -4-phenyl-benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-23). MS: 531 [M + H ⁺ ].

Relationship 80.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] thiophene-2-sulfonamide The title compound was obtained from the compound (Mella-5 ) and sulfonyl chloride (11b-24), MS: 461 [M + H ⁺ ].

Relationship 81.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] thiophene-3-sulfonamide The title compound was obtained from the compound (Me-5) and sulfonyl chloride (IIb-25). MS: 461 [M + H ⁺ ].

Relationship 82.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -2,5-dimethylthiophene-3-sulfonamide

The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (IIb-26). MS: 489 [M + H ⁺ ].

Relationship 83.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -5-isoxazol-5-yl-thiophene-2-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-27). MS: 528 [M + H ^+]

Relationship 84.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] naphthalene-1-sulfonamide The title compound was obtained from the compound (Me-11) and sulfonyl chloride (IIb-28). MS: 505 [M + H ⁺ ].

Compound 85.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] naphthalene-2-sulfonamide The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (IIb-29). MS: 505 [M + H ⁺ ].

Relationship 86.

6-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] naphthalene-2-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-30). MS: 539 [M + H ⁺ ].

Relationship 87.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -2,3-dihydro-1,4-benzodioxine-6-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-32). MS: 513 [M + H ⁺ ].

PL 219 283 B1

Relationship 88.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -1,3-benzodioxole-5-sulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-33). MS: 499 [M + H ⁺ ].

Relationship 89.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -2-oxo-indoline-5-sulfonamide

The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (IIb-34). MS: 510 [M + H ⁺ ].

Relationship 90.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole -3-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-35). MS: 485 [M + H ⁺ ].

Relationship 91.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -1-methyl-indole-4-sulfonamide

The title compound was obtained from the compound (Me-11-5) and sulfonyl chloride (Ib-37). MS: 508 [M + H ⁺ ].

Relationship 92.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -1-methyl-indole-5-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-38). MS: 508 [M + H ⁺ ].

Relationship 93.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -1,3-benzothiazole-4-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-39). MS: 512 [M + H ⁺ ].

Relationship 94.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methyl-amino] methyl] phenyl] -1,3-benzothiazole-5-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-40). MS: 512 [M + H ⁺ ].

Relationship 95.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] benzofuran-2-sulfonamide

The title compound was obtained from the compound (Me-II-5) and sulfonyl chloride (IIb-41). MS: 495 [M + H ⁺ ].

Relationship 96.

N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzothiophene-3-sulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-43). MS: 511 [M + H ⁺ ].

Relationship 97.

fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methyl-benzothiophene-2-sulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-46). MS: 543 [M + H ⁺ ].

Relationship 98.

3-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -3-methylbenzothiophene-2-sulfonamide

The title compound was obtained from the compound (Me-11a-5) and sulfonyl chloride (IIb-47). MS: 559 [M + H ⁺ ].

Relationship 99.

3-chloro-4-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propyl-methylamino] methyl] phenyl] -benzenesulfonamide

The title compound was obtained from the compound (Me-lla-5) and sulfonyl chloride (lb-48). MS: 507 [M + H ⁺ ]. Example 5.

In the tests described below, the affinity of the compounds of the invention for dopaminergic, serotonergic, adrenergic, muscarinic M3 receptors, histamine H1 receptor, sigma receptor and serotonin transporter was tested by measuring their binding to these receptors by radioreceptor methods.

Specific ligand binding to a receptor is defined as the difference between total and non-specific binding determined in the presence of an excess of unlabeled ligand.

PL 219 283 B1

The results of the activity of the test compounds obtained in the screening tests are presented as the percentage of the specific binding of the test substance [(measured specific binding of the test substance / specific binding of the control substance) x 100%). The compounds were tested at a concentration of 1 x 10 ^-6 M.

The conditions and method (by reference) of the affinity tests are given in Table 1, and the test results for example compounds are given in Table 2 (for the D2 and D3 dopaminergic receptors), Table 3 (for the D1 and D4.4 dopaminergic receptors), in Table 4 (for serotonergic 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 receptors), Table 5 (for serotonergic receptors

5-HT2C), Table 6 (for sigma σ receptors), Table 7 (for α1 adrenergic, H1 histaminergic and M3 muscarinic receptors), Table 8 (for α2C adrenergic receptors), Table 9 (for serotonin transporter (SERT)).

T a b e l a 1: Conditions and methods of affinity tests for receptors

Test Material biological Radioligand Concentrations no Kd Tie non-specific ne Incubation Detection Bible. 1 2 3 4 5 6 7 8 9 α · ι (non-seed active) bark cerebral rat ^[3 H] prazosin 0.25 nM 0.09 nM prazosin (0.5 μΜ) 60 min 22 ° C method scintillation 1 a2c (h) human recombinant (CHO cell line) ^[3 H] RX 821002 2 nM 0.95 nM (-) epinephrine (100 μΜ) 60 min 22 ° C method scintillation 2 D1 (h) human recombinant (CHO cell line) ^[3 H] SCH 23390 0.3 nM 0.2 nM SCH 23390 (1 pM) 60 min 22 ° C method scintillation 3 D2S (h) human recombinant (HEK-293 cell line) ^[3 H] methyl spiperone 0.3 nM 0.15 nM (+) butaclamol (10 μΜ) 60 min 22 ° C method scintillation 4 D3 (h) human recombinant (CHO cell line) ^[3 H] methyl spiperone 0.3 nM 0.085 nM (+) butaclamol (10 μΜ) 60 min 22 ° C method scintillation 5 D4.4 (h) human recombinant (CHO cell line) ^[3 H] methyl spiperone 0.3 nM 0.19 nM (+) butaclamol (10 μΜ) 60 min 22 ° C method scintillation 6 H1 (h) human recombinant (HEK-293 cell line) ^[3 H] pyrilamine 1 nM 1.7 nM pyrilamin (1 μΜ) 60 min 22 ° C method scintillation 7 M3 (h) human recombinant (CHO cell line) ^[3 H] 4-DAMP 0.2 nM 0.5 nM atropine (1 μΜ) 60 min 22 ° C method scintillation 8 5-HT1A (h) human recombinant (HEK-293 cell line) ^[3 H] 8) OH-DPAT 0.3 nM 0.5 nM 8-OH-DPAT (10 μΜ) 60 min 22 ° C method scintillation 9 5-HT2A (h) human recombinant (HEK-293 cell line) ^[3 H] ketanserin 0.5 nM 0.6 nM ketanserin (1 μΜ) 60 min 22 ° C method scintillation 10 5-HT2C (h) human recombinant (HEK-293 cell line) ^[3 H] mesulergina 1 nM 0.5 nM RS 102221 (10 μΜ) 120 min 37 ° C method scintillation 11

PL 219 283 B1 cont. table 1

1 2 3 4 5 6 7 8 9 5-HTe (h) human recombi- new (line cellular CHO) ^[3 H] LSD 2 nM 1.8 nM serotonin (100 μΜ) 120 min 37 ° C method scintillation- ing 12 5-HT7 (h) Human recombi- new (line cellular CHO) ^[3 H] LSD 4 nM 2.3 nM serotonin (10 μΜ) 120 min 22 ° C method scintillation- ing 13 α (non-selective) the cerebral cortex rat ^[3 H] DTG 8 nM 29 nM halopendol (10 μΜ) 120 min 22 ° C method scintillation- ing 14 SERT (h) human recombi- new (line cellular CHO) ^[3 H] on imiprami- 2 nM 1.7 nM imipramine (10 μΜ) 60 min 22 ° C method scintillation- ing 15

Bibliography:

1. Greengrass, P. And Bremner, R. (1979), Eur. J. Pharmacol., 55: 323-326.

2. Devedjian et al. (1994), Eur. J. Pharmacol., 252: 43-49

3. Zhou et al. (1990), Nature, 347: 76-80.

4. Grandy et al. (1989), Proc. Natl. Acad. Sci. U.S.A., 86: 9762-9766.

5. Mackenzie et al. (1994), Eur. J. Pharmacol., 266: 79-85.

6. Van Tol et al. (1992), Nature, 358; 149-152.

7. Smit et al. (1996), Brit. J. Pharmacol. 117: 1071-1080.

8. Peralta et al. (1987), Embo. J, 6: 3923-3929.

9. Mulheron et al. (1994), J. Biol. Chem., 269: 12954-12962.

10. Bonhaus et al. (1995), Brit. J. Pharmacol., 115: 622-628.

11. Stam et al. (1994), Eur. J. Pharmacol., 269; 339-348.

12. Monsma et al. (1993), Mol. Pharmacol., 43: 320-327.

13. Shen et al. (1993), J. Biol. Chem., 268: 18200-18204.

14. Shirayama et al. (1993), Eur. J. Pharmacol., 237: 117-126.

15. Tatsumi et al. (1999), Eur. J. Pharmacol., 368: 277-283.

T a b e l a 2:

D2 and D3 dopaminergic receptor binding results for the exemplified compounds

Relationship no D2 [%] D3 [%] Relationship no D2 [%] D3 [%] 1 2 3 4 5 6 1 77 65 52 99 97 6 79 73 54 94 76 8 59 37 60 96 82 9 88 67 62 81 55 10 97 88 64 86 72 11 47 50 65 94 73 12 97 97 66 94 87 14 74 58 68 97 92 17 49 56 70 93 76 18 96 98 71 98 92 19 98 96 72 93 63

PL 219 283 B1 cont. table 2

1 2 3 4 5 6 twenty 98 94 73 90 72 22 96 95 77 96 80 24 98 99 79 94 81 25 98 94 80 92 74 26 99 97 81 96 81 31 97 96 82 96 79 32 101 99 84 98 84 33 97 91 85 99 92 35 100 96 91 94 82 36 99 95 92 99 89 39 98 95 94 98 85 43 98 97 95 88 73 44 96 93 96 96 92 45 98 96 97 98 89 49 99 97 98 92 83 51 99

T a b e l a 3:

The results of the binding tests to the D1 and D4.4 dopaminergic receptors for the exemplary compounds:

Relationship no D1 [%] D4.4 [%] Relationship no D1 [%] D4.4 [%] 1 2 3 4 5 6 1 57 15 52 43 97 6 41 25 54 27 54 8 32 11 60 58 98 9 39 24 62 57 89 10 12 77 64 79 87 11 26 4 65 73 77 12 23 81 66 75 95 14 4 12 68 86 59 17 2 40 70 66 66 18 12 95 71 85 81 19 25 92 72 45 60 twenty 29 89 73 82 90 22 49 92 77 73 63 24 27 88 79 68 56 25 17 95 80 72 81 26 27 93 81 70 92 31 19 93 82 64 92 32 23 97 84 72 96

PL 219 283 B1 cont. table 3

1 2 3 4 5 6 33 36 90 85 77 70 35 23 92 91 76 70 36 13 65 92 83 56 39 14 49 94 61 63 43 40 95 95 63 42 44 28 43 96 78 99 45 38 88 97 80 55 49 61 100 98 62 37 51 33 91

T a b e l a 4:

The results of the 5-HT1A, 5-HT2A, 5HT6 and 5-T7 serotonergic receptor binding test results for exemplary compounds

Relationship no 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%] 1 2 3 4 5 1 55 97 94 61 6 74 64 98 54 8 83 81 95 -159 9 66 84 97 61 10 93 83 93 74 11 80 70 101 35 12 98 93 79 99 14 18 69 91 27 17 90 61 96 87 18 98 79 58 100 19 98 84 72 103 twenty 102 67 61 96 22 98 97 94 101 24 98 62 80 101 25 98 85 64 99 26 101 80 79 98 31 97 77 40 100 32 99 83 67 98 33 98 82 73 100 35 100 78 87 99 36 100 82 88 99 39 100 54 72 90

PL 219 283 B1 cont. table 4

1 2 3 4 5 43 98 85 99 101 44 98 91 94 104 45 99 74 80 101 49 101 87 87 100 51 100 66 88 99 52 100 98 97 99 54 43 80 88 90 60 89 96 95 98 62 46 91 95 95 64 36 98 98 98 65 33 89 100 95 66 38 92 101 100 68 81 101 100 96 70 11 95 55 97 71 45 101 101 97 72 thirty 87 99 93 73 55 91 97 96 77 26 100 99 90 79 69 101 94 92 80 28 93 98 97 81 10 96 100 99 82 84 93 98 98 84 46 88 101 94 85 9 99 96 96 91 33 97 101 97 92 45 98 100 91 94 51 99 90 94 95 29 92 100 85 96 46 94 101 100 97 thirty 94 99 95 98 4 96 100 92

PL 219 283 B1

T a b e l a 5:

5-HT2C Serotonergic Receptor Binding Test Results for Exemplary Compounds

Relationship no 5-HT2C [%] Relationship no 5-HT2C [%] Relationship no 5-HT2C [%] 1 34 33 59 71 69 6 43 35 21 72 23 8 10 36 33 73 2 9 31 39 7 77 thirty 10 35 43 31 79 33 11 -1 44 33 80 31 12 65 45 39 81 37 14 21 49 10 82 24 17 91 51 -9 84 42 18 50 52 21 85 56 19 58 54 17 91 31 twenty twenty 60 40 92 57 22 59 62 16 94 12 24 34 64 51 95 22 25 40 65 23 96 59 26 54 66 39 97 21 31 51 68 77 98 12 32 46 70 43

T a b e l a 6:

Test results for binding to σ receptors

Relationship no a [%] Relationship no a [%] Relationship no a [%] 1 2 3 4 5 6 1 83 36 84 72 80 6 73 39 64 73 73 8 85 43 88 77 48 10 74 44 91 79 61 11 76 45 92 80 42 12 93 49 79 81 69 14 54 51 76 82 49 17 71 52 79 84 77 18 87 54 50 85 59 19 89 60 46 91 53 22 95 62 49 92 72 24 93 64 59 94 79 25 89 65 72 95 79

PL 219 283 B1 cont. table 6

1 2 3 4 5 6 31 80 66 61 96 59 32 88 68 73 97 74 33 92 70 60 60 35 83 71 82 98 62

T a b e l a 7: Results of affinity tests for a1 adrenergic, histaminergic H1 and muscarinic M3 receptors for example compounds

Relationship no α1 [%] H1 [%] M3 [%] Relationship no a1 [%] H1 [%] M3 [%] 1 26 17 17 52 41 2 0 6 53 24 6 54 48 7 2 8 17 18 1 60 80 22 17 9 56 23 -9 62 83 42 7 10 twenty -13 21 64 81 43 10 11 18 -8 13 65 70 50 19 12 53 49 17 66 86 49 5 14 13 27 19 68 84 84 26 17 31 -9 9 70 80 16 22 18 74 28 24 71 85 64 27 19 74 58 13 72 77 64 25 twenty 89 27 1 73 75 41 14 22 84 68 22 77 64 56 19 24 75 58 22 79 29 47 26 25 68 47 12 80 84 44 28 26 87 33 -5 81 88 24 35 31 68 50 31 82 85 14 32 83 0 15 84 75 twenty 13 33 73 27 twenty 85 78 6 22 35 57 31 -8 91 85 16 15 36 49 thirty 12 92 79 25 6 39 80 49 6 94 86 58 49 43 73 21 12 95 62 72 10 44 52 88 19 96 78 56 16 45 83 70 21 97 59 82 0 49 59 -3 7 98 42 59 16 51 34 -4 -8

PL 219 283 B1

T a b e l a 8: Results of the a2C Adrenergic Adrenergic Receptor Affinity Test for Exemplary Compounds

Relationship no a2C [%] Relationship no a2C [%] Relationship no a2C [%] 1 44 33 93 71 76 6 59 35 95 72 81 8 -thirty 36 87 73 51 9 72 39 86 77 53 10 75 43 98 79 87 11 45 44 89 80 51 12 90 45 90 81 48 14 32 49 90 82 68 17 91 51 84 84 79 18 88 52 89 85 74 19 88 54 32 91 80 twenty 86 60 52 92 79 22 95 62 43 94 71 24 87 64 73 95 49 25 88 65 73 96 81 26 92 66 66 97 73 31 83 68 83 98 84 32 90 70 53

T a b e l a 9: Results of the affinity tests for the serotonin transporter (SERT) for example compounds

Relationship no SERT [%] Relationship no SERT [%] Relationship no SERT [%] 1 2 3 4 5 6 1 46 33 60 71 59 6 26 35 78 72 42 8 51 36 68 73 17 9 91 39 41 77 41 10 40 43 75 79 16 11 45 44 63 80 33 12 46 45 35 81 40

PL 219 283 B1 cont. table 9

1 2 3 4 5 6 14 70 49 52 182 51 17 43 51 32 84 47 18 40 52 48 85 63 19 53 54 42 91 87 twenty 62 60 25 92 81 22 79 62 28 94 81 24 35 64 44 95 40 25 35 65 34 96 61 26 66 66 50 97 72 31 22 68 73 98 34 32 49 70 39

Affinity for the hERG potassium channel

The ability to block the hERG potassium channel was determined by an electrophysiological method. Cloned hERG channels (KCNH2 gene) expressed on CHO cells were used as biological material. The effect was assessed using the lonWorksTM System (MDS-AT). The hERG current was excited with constant amplitude signals (preconditioning signal: -80 mV for 25 ms; test signal: +40 mV for 80 ms) from 0 mV resting potential. The hERG current was measured as the difference between the 1 ms peak current after the test step to +40 mV and the steady state current at the end of the step to +40 mV. Data processing and analysis were performed using lonWorksTM software (version 2.0.2; Molecular Devices Corporation, Union City, CA). The data has been corrected for leakage current. The hERG blockage was calculated from the formula:% Blockage = (1 - I BZ / I Control) x 100%, where Ikontroli and IBZ are the test signal currents in the control and test compound respectively.

The results for exemplary compounds are given in Table 10.

T a b e l a 10: Results of hERG Potassium Channel Affinity Assays for Exemplary Compounds

Relationship no hERG [%] Relationship no hERG [%] Relationship no hERG [%] 11 -4 43 10 52 2 35 -11 49 2 60 6 36 11 51 1

The presented examples of activity of the compounds according to the invention demonstrate their high affinity for a number of monoaminergic receptors associated with potential activity in the treatment of diseases of the central nervous system. Compounds which simultaneously exhibit high affinity for dopaminergic D2 receptors and serotonergic 5-HT6 and / or 5-HT7 receptors are indicated as particularly preferred. Such action may be particularly beneficial for a new antipsychotic drug, effective not only in the treatment of positive symptoms, but also of negative and cognitive symptoms of schizophrenia. Moreover, substances with high affinity for 5-HT6 and / or 5-HT7 serotonergic receptors, and substances with lower affinity for D2 dopaminergic receptors, which could be used as an add-on therapy, in the treatment of negative and cognitive symptoms of schizophrenia are indicated as particularly preferred. as well as in the treatment of depression, anxiety disorders or other conditions in which such receptor modulation may have a therapeutic effect. An important feature of the compounds of the invention is, moreover, a significantly lower (moderate to very low) affinity for biological targets associated with side effects, such as receptors alpha1, H1, M3, 5-HT2C, or the hERG potassium channel. This is a particularly advantageous feature in the context of searching for drugs with an improved safety profile in relation to the currently used therapies.

Claims (19)

1. Compounds of general formula (I): where A is - phenyl unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-alkyloxy, OH and phenyl, or - a 9- or 10-membered bicyclic group connected to - (O) x- (CH2) y- via one of its aromatic carbon atoms, consisting of a benzene ring fused with: - a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, which bicyclic group may be unsubstituted or substituted by halogen; or - a non-aromatic 5- or 6-membered heterocyclic ring containing 1 or 2 O atoms, the heterocyclic ring may be unsubstituted or substituted with one or more C1-C3-alkyl; D denotes a group selected from: - phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C4-alkyl, C1-C3-alkyloxy, halo-C1-C3-alkyl, halo-C1-C3-alkyloxy, halogen, -CN and phenyl; - naphthyl unsubstituted or substituted with one halogen atom; - a thiophene unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C3-alkyl, halogen, and a 5-membered heteroaromatic ring having 1 or 2 heteroatoms independently selected consisting of N and O; - a bicyclic group consisting of an imidazole ring fused to a non-aromatic 5-membered carbocyclic ring connected to a sulfonamide moiety through one of its aromatic carbon atoms; - a bicyclic group consisting of a benzene ring fused to a 5-membered heteroaromatic ring, containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C3-alkyl and halogen linked to the sulfonamide moiety through one of its aromatic carbon atoms; or - a bicyclic group consisting of a benzene ring fused to a 5- or 6-membered non-aromatic heterocyclic ring, containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, unsubstituted or substituted with one = O, linked to a sulfonamide moiety via one of benzene ring carbon atoms; R is H or -CH3; x is 0 or 1; y is 2 or 3; and their pharmaceutically acceptable salts. 2. Compounds according to claim 1 2. The compound of claim 1 wherein A is phenyl unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-alkyloxy, OH, and phenyl. 3. Compounds according to claim 1 Wherein A is a 9- or 10-membered bicyclic group linked to - (O) x- (CH2) y- via one of its aromatic carbon atoms consisting of a benzene ring fused to a 5-membered heteroaromatic ring containing 1 or 2 Heteroatoms are independently selected from the group consisting of N and O, wherein said bicyclic group may be unsubstituted or substituted by halogen. 4. Compounds according to claim 1 In which A is a 9- or 10-membered bicyclic group connected to (O) x- (CH2) y- via one of its aromatic carbon atoms consisting of a benzene ring fused to a 5- or 6-membered heterocyclic ring non-aromatic containing 1 or 2 O atoms, wherein the heterocyclic ring may be unsubstituted or substituted with one or more C1-C3-alkyl. Compounds according to any of the preceding claims, wherein D is phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C4-alkyl, C1-C3-alkyloxy, halo-C1-C3-alkyl, halo -C1-C3-alkyloxy, halogen, -CN and phenyl. 6. Compounds according to any one of claims 1 to 6 1-4, wherein D is naphthyl unsubstituted or substituted with one halogen atom. Compounds as claimed in any one of claims 1 to 7 1-4, wherein D is thiophene unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-C4-alkyl, halogen, 5-membered heteroaromatic ring having 1 or 2 heteroatoms independently selected consisting of N and O . Compounds according to any one of claims 1 to 8 1-4, wherein D is a bicyclic group consisting of an imidazole ring fused to a non-aromatic 5-membered carbocyclic ring connected to a sulfonamide moiety through one of its aromatic carbon atoms. 9. Compounds according to any one of claims 1 to 9 1-4, wherein D is a bicyclic group consisting of a benzene ring fused to a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C3-alkyl and halogen, linked to the sulfonamide moiety through one of its aromatic carbon atoms. Compounds according to any one of claims 1 to 10 1-4 in which D is a bicyclic group consisting of a benzene ring fused to a 5- or 6-membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, unsubstituted or substituted with one = O, attached to the sulfonamide moiety through one of the carbon atoms of the benzene ring. 11. Compounds according to any one of claims 1 to 11 1-10 where R is H, substituted with the general formula (IA): 12. Compounds according to any one of claims 1 to 12 1-10, where R is -CH3, represented by the general formula (IB): Compounds according to any one of claims 1 to 13 the foregoing in which x is 1 and y is 2. 14. Compounds according to any one of claims 1 to 14 the previous ones where x is 0 and y is 3. 15. The compound of claim 1 1 selected from the group consisting of the following compounds: N- [3 - [(phenylethylamino) methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [(2-phenoxyethylamino) methyl] phenyl] naphthalene-2-sulfonamide, PL 219 283 B1 N- [3 - [(3-phenylpropylamino) methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-fluorophenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[3- (3-fluorophenoxy) propylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-chlorophenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-chlorophenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-methylphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (2-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (2-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-propylbenzenesulfonamide, N- [3 - [[2- (3-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (4-methoxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (4-methoxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[3- (4-methoxyphenyl) propylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-hydroxyphenyl) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-fluoro-benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-fluorobenzenesulfonamide, 4-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-iodo-benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3- (trifluoromethyl) benzenesulfonamide N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -3-methoxy-benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-methoxy-benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4- (trifluoromethoxy) benzenesulfonamide, 3-cyano-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide, 4-cyano-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-phenyl benzenesulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] thiophene-2-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] thiophene-3-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -2,5-dimethyl-thiophene-3-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -5-isoxazol-5-yl-thiophene-2-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-1-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, 6-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1,3-benzodioxole-5-sulfonamide, PL 219 283 B1 N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole -3-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1-methyl indole-4-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -1-methyl indole-5-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzofuran-2-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] benzothiophene-3-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -5-fluoro-3-methylbenzothiophene-2-sulfonamide, 3-chloro-N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethylamino] methyl] phenyl] -4-fluoro-benzenesulfonamide, N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide, N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] naphthalene-1-sulfonamide, N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -4-phenylbenzenesulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] naphthalene-1-sulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[3- (5-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] -3-methyl-benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] naphthalene-1-sulfonamide. N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-methylphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (3-hydroxyphenoxy) ethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -4-propyl benzenesulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] thiophene-2-sulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] thiophene-3-sulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylamino] methyl] phenyl] -2,5-dimethyl-thiophene-3-sulfonamide, N- [3 - [[2- (2,3-dihydro-1,4-benzodioxin-5-yloxy) ethyl-methyl-amino] methyl] phenyl] -benzenesulfonamide, N- [3 - [[2 - [(2,2-dimethyl-3H-benzofuran-7-yl) oxy] ethyl-methyl-amino] methyl] phenyl] -benzenesulfonamide, N- [3 - [[2- (1H-indol-4-yloxy) ethylmethylamino] methyl] phenyl] benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, 4- fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, 3.4- difluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, 3-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-1-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, 4-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, 3.4- dichloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, 3-bromo-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, PL 219 283 B1 4-bromo-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4-iodo-benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -3-methyl-benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4-methyl-benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4-propylbenzene sulfonamide, 4-tert-butyl-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -3- (trifluoromethyl) benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4- (trifluoromethyl) benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -3-methoxy-benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4-methoxy-benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4- (trifluoromethoxy) benzenesulfonamide, 3-cyano-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -4-phenylbenzenesulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] thiophene-2-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] thiophene-3-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -2,5-dimethyl-thiophene-3-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -5-isoxazol-5-yl-thiophene-2-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] naphthalene-1-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] naphthalene-2-sulfonamide, 6-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] naphthalene-2-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -2,3-dihydro-benzodioxine-6-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -1,3-benzodioxole-5-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -2-oxo-indoline-5-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -6,7-dihydro-5H-pyrrolo [1,2-a] imidazole-3 -sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -1-methyl indole-4-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -1-methyl indole-5-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -1,3-benzothiazole-4-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -1,3-benzothiazole-5-sulfonamide, PL 219 283 B1 N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzofuran-2-sulfonamide, N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzothiophene-3-sulfonamide, 5-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -3-methylbenzo-thiophene-2-sulfonamide, 5-chloro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] -3-methyl-benzothiophene-2-sulfonamide, 3-chloro-4-fluoro-N- [3 - [[3- (6-fluoro-1,2-benzoxazol-3-yl) propylmethylamino] methyl] phenyl] benzenesulfonamide, and pharmaceutically acceptable salts thereof. 16. Compounds of formula (I) as defined in claim 1 1-15 for use as a medicament. 17. A pharmaceutical composition containing as active ingredient a compound of formula (1) as defined in claim 1 1-15 in combination with pharmaceutically acceptable excipients. 18. Compounds of formula (I) as defined in claim 1 1-15 for use in the treatment of schizophrenia. 19. The use of compounds of formula (1) as defined in claim 1 1-15 for the manufacture of a medicament for the treatment of schizophrenia.