PL243066B1 - Quinazoline derivatives with psychotropic and procognitive activity - Google Patents

Abstract

The subject of the invention are derivatives described by the formula (I), where the substituent R is: an alkoxy group, a halogen atom or two halogen atoms selected from the group consisting of the following atoms: F, Cl, Br, I; a perfluoroalkyl group or a monofunctional group containing a chalcogen atom, wherein R is substituted in the 2-, 3- and/or 4-position.

Description

Description of the invention

The subject of the invention are quinazoline derivatives with psychotropic and procognitive activity, i.e. showing affinity to selected serotonin receptors (5-HTia and 5-HTz) and the ability to inhibit phosphodiesterase type 10 (PDE10A).

The last decades have seen an increase in life expectancy and rapid aging of the world's population. This also applies to the population of people suffering from chronic schizophrenia who managed to achieve remission. Despite significant advances in pharmacotherapy, some patients are found to have persistent symptoms, i.e. a state in which positive symptoms (delusions, hallucinations), negative symptoms, cognitive or affective disorders still occur to a moderate degree after the psychotic episode has been overcome. It has been shown that persistent symptoms of schizophrenia are more common in older people, in whom age-related changes in the brain can lead to mild cognitive impairment (MCI). The essence of MCI is the deterioration of the efficiency of cognitive processes without accompanying dementia. This mainly concerns changes in activities such as attention, perception, memory, thinking and speech. In the course of MCI, there may be disturbances in the divisibility and persistence of attention, as well as disturbances in perception, especially in recognizing faces and objects. In addition, cognitive functions related to memory, association, inference and understanding may be impaired. Rapid and abrupt deterioration of cognitive processes can lead to dementia. Mood disorders (irritability, emotional lability, dysphoria) leading to depression are a very characteristic symptom for early-stage dementia or moderate dementia syndromes.

One of the most important pharmacological targets for drug action are transmembrane G protein-coupled receptors (GPCRs). Upon binding of the ligand molecule to the receptor binding site, it interacts with heterotrimeric GTP-binding regulatory proteins (G protein). Activation of one of the subunits of this protein (Ga) leads to the activation of enzymes that synthesize second messengers. The group of basic second messengers includes cyclic adenosine-3',5'-monophosphate (cAMP) and guanosine-3',5'-monophosphate (cGMP). Location, duration of action and concentrations of cyclic nucleotides in specific subcellular areas determine the further transmission of the chemical signal, regulate its strength and specificity. All changes in these parameters, through feedback, can contribute to changes in the functioning of the receptors. The regulation of the level of cyclic nucleotides was the subject of research aimed at elucidating the importance of phosphodiesterases (PDEs) - enzymes that degrade cAMP and/or cGMP by hydrolysis of the 3',5'-phosphodiester bond. PDEs form a family of proteins consisting of 11 subfamilies, characterized on the basis of amino acid sequence, substrate specificity, pharmacological properties and allosteric regulation. One of the isoforms - PDE10A, occurs in the regions of the central nervous system (CNS), associated with the site of action of psychotropic drugs.

Serotonin (5-hydroxytryptamine, 5-HT) belongs to the group of biogenic amines, has peripheral and central effects. The serotonin system is involved in the regulation of cognitive processes and mood. The variety of actions and effects that 5-HT can cause in the human body is due to the presence of seven types of serotonin receptors (5-HT1-7). Serotonin 5-HTia receptors are located in the central nervous system (CNS), mainly in: the limbic system (hippocampus, lateral septum), cortical areas (cingulate cortex and entorhinal cortex), raphe nuclei, basal ganglia and cerebellum. Stimulation of presynaptic 5-HTia receptors (autoreceptors) leads to the inhibition of secretion of endogenous serotonin into the synaptic space by negative feedback, which results in a weakening of transmission in serotonergic neurons. Stimulation of postsynaptic 5-HTia receptors (heteroreceptor) causes an increase in transmission in serotonergic neurons, which has an inhibitory effect on other neurons located in various areas of the brain. The role of 5-HTia receptors in disorders such as anxiety, depression, schizophrenia, Parkinson's disease and Alzheimer's disease has been demonstrated. Many of the available drugs show affinity, e.g. to 5-HT1a receptors. Most of them are agonists and partial agonists of 5-HTia receptors, e.g. buspirone, aripiprazole, clozapine, dihydroergotamine, gepirone, haloperidol or olanzapine. Compounds that are antagonists of these receptors form a smaller group, including e.g.

risperidone, pindolol, propranolol. The compound used in studies on the functional profile of potential 5-HTia receptor ligands is LY-293284, a 5-HTia receptor agonist (Ki = 0.07 nM), which is an ergoline derivative. The serotonin 5-HTia receptor antagonists used as pharmacological tools include compounds from the group of phenylpiperazine derivatives: NAN-190, WAY-100135, WAY-100635.

The largest clusters of 5-HT7 receptors in the CNS were found in the cells of the thalamus, hippocampus, hypothalamus and cerebral cortex. Receptors located in the hypothalamus are responsible for the regulation of the circadian rhythm, thermoregulation and regulation of endocrine secretion. Receptors located in the thalamus and in the cerebral cortex play an important role in the regulation of sleep and mood. Localization in hippocampal cells indicates the involvement of these receptors in learning and memory processes. Physiologically, 5-HT7 receptors are involved in the following processes: regulation of the circadian rhythm, sleep phase, endocrine and pain conduction. The high affinity of some antipsychotic drugs (risperidone, clozapine) to the 5-HT7 receptor and the specific distribution of these receptors in the CNS suggest that it may play a role in the development of affective disorders. The direct action of antidepressants on 5-HT7 receptors and the reversal of sleep disorders in patients suffering from depression suggest that antagonists of this receptor may be used in the treatment of this disease. Compounds exhibiting intrinsic 5-HT7 receptor antagonistic activity can be divided from a pharmacological point of view into compounds that selectively and non-selectively block the said receptor. These compounds belong to various chemical groups, among which derivatives of long-chain arylpiperazines and arylpiperidines (ziprasidone, risperidone, pimozide) and arylsulfonamide ligands of the 5-HT7 receptor can be distinguished. It should be emphasized that atypical neuroleptics (risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole) do not reduce the impaired cognitive functions accompanying schizophrenia. These drugs act by antagonism of the D2 receptor, which results in the disinhibition of adenylate cyclase activity. In striatal neurons, inhibition of the D2 receptor results in increased levels of cAMP and cGMP, consistent with the neurochemical effects of PDE10A inhibition. In addition, PDE1 0A was found in the prefrontal cortex, where impaired cAMP transmission is responsible for cognitive decline. One of the selective inhibitors

PDE10A - a compound of PQ-10, was tested in the novel object recognition test (NORT) in rats with memory deficits induced by the administration of scopolamine or dizocilpine (MK-801). Compound PQ-10 at 0.3 mg/kg produced a reversal of the symptoms induced by both scopolamine and MK-801. This seems to support the view that PDE10A inhibitors may be suitable candidates for drugs capable of improving cognitive functions. In addition, different PDE10A variants have been identified in the hippocampus where they play a key role in the cellular process of long-term potentiation (LTP) related to learning and memory.

International patent application PCT WO03022214A2 describes derivatives containing a piperazine or homopiperazine ring for use in the treatment of thrombosis. Another international PCT application O2004010929A2 describes quinazoline derivatives for improving lung function by administering non-peptide small molecule TGF beta inhibitors specifically binding to the TGF-beta type I receptor (TGFbeta-R1). On the other hand, the international patent application PCT WO2012048775A1 describes methionine aminopeptidase inhibitors for use in the treatment of cancer. Another international PCT application WO9422839A1 discloses benzimidazole derivatives substituted at position 2 with a piperazinylmethyl or piperazinyl ethyl moiety as antagonists of brain dopamine receptor subtypes with selective affinity for the D4 dopaminergic receptor subtype over other dopamine receptor subtypes that are effective in treating and/ or preventing psychotic disorders such as schizophrenia while exhibiting slightly minor side effects. The review publication Phosphodiesterase 10 Inhibitors - Novel Perspectives for Psychiatrie and Neurodegenerative Drug Discovery (Current Medicinal Chemistry, 2018, 25, 3455-3481) presents numerous compounds that are PDE10 inhibitors, starting with derivatives such as theophylline and caffeine analogs, papaverine and dimethoxycatechol, TP -10, MP-10 through complex derivatives based on MP-10 /papaverine/quinazoline pharmacophores, and ending with the latest fragment-based lead discovery (FBLD) inhibitors. In addition, the publication summarizes recent PDE10A inhibition studies as

PL 243066 Β1 of a promising therapeutic strategy in psychiatric and neurodegenerative diseases, based on the activity of PDE10A inhibitors in animal models of schizophrenia, Parkinson's, Huntington's and Alzheimer's diseases.

The technical problem faced by the invention would be to provide compounds with affinity for selected serotonin receptors (5-HTia and 5-HTα) and the ability to inhibit phosphodiesterase type 10 (PDE10A), whereby these compounds should have antipsychotic, antidepressant and anxiolytic activity and at the same time beneficial pro-cognitive effect.

The subject of the invention are derivatives described by the formula (I),

Where

- R is: an alkoxy group, which is a methoxy group, one halogen atom or two halogen atoms selected from the group consisting of the following atoms: F, Cl, Br, I; a perfluoroalkyl group which is a trifluoromethyl group, a monofunctional group containing an oxygen atom which is a hydroxyl group or a hydrogen atom where R is in the 2-, 3- and/or 4-position

In a preferred embodiment of the invention, the halogen atom or atoms is a chlorine atom or two chlorine atoms.

In yet another preferred embodiment of the invention, the derivatives are selected from the set of derivatives described by formulas (II) to (VIII):

PL 243066 B1

(viii)

PL 243066 B1

Structural design, synthesis and in vitro and in vivo pharmacological studies aimed to investigate the properties of the new compounds with regard to their ability to induce cognitive enhancement in animal models of depression, anxiety and schizophrenia. The compounds were designed using in silico methods based on the structural modification of the PQ-10 compound - a known, selective PDE10A inhibitor (IC50 < 6 nM), by introducing an arylpiperazine moiety responsible for receptor affinity in the appropriate position of PQ-10 (described below) .

(PQ-1O)

The compounds showed nanomolar affinity for 5-HTia receptors, of which 4 compounds strongly bound to this receptor (5-HTia Ki < 40 nM). Activity on the 5-HT receptor? was variable but most compounds were Ki 5-HT active? < 350nM. Of the compounds tested, 3 showed PDE10 inhibition capacity comparable to the reference papaverine compound. All compounds are antagonists of both 5-HT1a and 5-HTα receptors, with the IC50 values of the compounds for 5-HT1a being micro- and nanomolar. The pharmacological activity of compounds POA-AZ1, PQA-AZ2, PQA-AZ4, PQA-AZ5, PQA-AZ6, PQA-AZ7 and PQA-AZ8 has been determined in behavioral tests.

The study of the antipsychotic activity of compounds in the dose range of 2.5-10 mg/kg was performed using the D-amphetamine induced motility test. Statistically significant effect of compounds on D-amphetamine-induced motor activity of mice was observed for compounds (II), (VII) and (VIII) at a dose of 2.5 mg/kg, (V) and (VI) at a dose of 5 mg/kg, while (III) and (IV) had no statistically significant effect on D-amphetamine-induced motor activity in mice. The standard PDE10A inhibitor, compound PQ-10, showed antipsychotic activity at the lowest dose tested in the test, 2.5 mg/kg. The reference antipsychotic drug, quetiapine, abolished the effects of D-amphetamine at a dose of 5 mg/kg. The antidepressant activity of the compounds was tested using the forced swim test. Compounds (IV) and (VIII) showed antidepressant activity at doses of 1.25 and 2.5 mg/kg, shortening the time of immobilization of animals in a statistically significant way compared to the control group. Compounds (III) and (VI) showed antidepressant activity at doses of 0.625 and 1.25 mg/kg, while compound (II) was active at 5 mg/kg. For compounds (V) and (VII) in the tested dose ranges, there were no statistically significant differences in the mean immobility time compared to the control group. The standard PDE10A inhibitor, compound PQ-10, showed antidepressant activity at a dose of 2.5 mg/kg, while quetiapine was not active in the forced swimming test. The study of anxiolytic activity was performed in a 4-plate test. Compounds (III), (IV), (VI) and (VIII) had no effect on the number of shock-penalized transitions in the 4-plate test, and thus showed no anxiolytic effect. Anxiolytic activity was observed for (II) and (VII) at the dose of 2.5 mg/kg and for (III) and (V) at the dose of 1.25 mg/kg. The benchmark PDE10A inhibitor, compound PQ-10, showed anxiolytic activity at doses of 1.25 and 2.5 mg/kg, significantly increasing the number of electrical impulses accepted by the mice compared to the control group. Quetiapine showed no anxiolytic activity in the 4-plate test. The study of the pro-cognitive activity of the compounds was carried out in NORT in Wistar rats. All animals, apart from the control group receiving the solvent, were given a memory-impairing tool substance MK-801 at a dose of 0.1 mg/kg 30 minutes before the first phase of the test. The criterion for assessing the pro-cognitive effect of the compound was the increase in the discrimination index compared to the group that received MK-801. Compound MK-801 significantly reduced the discrimination index compared to the solvent control group, which indicates the induction of memory impairment in rats treated with MK-801. Compounds (II) and (VIII) at 1 mg/kg, (III) and (VI) at 3 mg/kg, and (IV) at 1 and 3 mg/kg completely reversed MK-801-induced deficits memory. The reference PDE10A inhibitor, compound PQ10, was active in NORT at all tested doses of 0.3, 1 and 3 mg/kg, while quetiapine showed pro-cognitive activity only at the dose of 3 mg/kg.

For compounds (IV) and (VI), initial pharmacokinetic parameters were then calculated using the plot of the concentration-time curve in blood plasma and selected brain structures, after intraperitoneal administration of compounds in psychotropic active doses to mice. Parameter values (AUC, to.5, MRT, Cmax, tmax and Vd) indicate that the compounds accumulate in brain structures (hippocampus, striatum, frontal cortex). Pharmacological studies have been extended to include screening for safety pharmacology, taking into account the effects of compounds on body weight, glucose, cholesterol and triglyceride levels. In animals administered intraperitoneally compound (IV) at a dose of 1.25 mg/kg, a slight, statistically significant decrease in body weight was observed starting from the 11th day of administration. In animals administered intraperitoneally compound (VI) at a dose of 0.625 mg/kg, a slight, statistically significant decrease in body weight was observed starting from the 6th day of administration. The percentage of heart weight in relation to whole body weight after 15 times intraperitoneal administration of compound (VI) at a dose of 0.625 mg/kg was significantly lower than in control animals. There were no differences between the groups in the remaining tissues. In the group of mice administered compound (IV) intraperitoneally at a dose of 1.25 mg/kg body weight, the level of glucose increased statistically and the level of triglycerides decreased. Similarly, after intraperitoneal administration of compound (VI) at a dose of 0.625 mg/kg b.w. glucose levels increased significantly, and triglycerides and total cholesterol decreased. Intraperitoneal administration of compounds (IV) or (VI) did not lead to significant changes in ALAT or γ-GTP activity in mouse plasma. Both compound (IV) and (VI) administered intraperitoneally at a dose of 1.25 mg/kg b.w./day or 0.625 mg/kg b.w. day did not have a statistically significant effect on locomotor activity after a single or 15-times administration.

The MTT assay was used to determine the potential cytotoxicity of compounds (IV) and (VI). The cytotoxic activity was assessed by determining the concentration of the compound that corresponds to 50% cell survival compared to the control (IC50). Doxorubicin, a compound with anticancer activity, was used as a reference compound. (IV) and (VI) showed less activity against the cancer cell line than the reference compound, but their toxicity to/to normal cells was significantly lower than that of doxorubicin. This study demonstrated that long-term exposure of HaCaT cells to (IV) and (VI) should not result in irreversible cytotoxic effects (IC50 > 100 μM). The metabolic stability of (IV) and (VI) was also determined using mouse liver microsomes (MLMs). In the conditions of the experiments, the compounds were stable, after 120 min of incubation, the appearance of 1 metabolite (M1) was observed, which was structurally attributed to the hydroxylation product of the phenyl ring in the arylpiperazine system.

The compounds of the invention show both PDE10A inhibitory activity and receptor activity (5-HT1a, 5-HT7). In addition, in pharmacological tests, the compounds showed pro-cognitive and psychotropic effects at the same time.

This description has been supplemented by the accompanying drawings in order to better explain the invention. Figure 1 shows the results of testing the antipsychotic activity of the compounds in the D-amphetamine induced motility test. D-amphetamine statistically significantly increased the motility of the mice compared to the solvent control group (#p<0.05, ##p<0.01, ###p<0.001). The activity of the tested compounds and standard substances was compared with the group that received D-amphetamine (*p<0.05, ***p<0.001). Fig. 2 shows the results of testing the antidepressant activity of the compounds in the Swiss albino mouse forced swim test. The results are presented as % of control. Differences in means were considered statistically significant at p<0.05 (*p<0.05, ***p<0.001, ****p<0.0001). Fig. 3 shows the results of the study of anxiolytic activity in the 4-plate assay in Swiss albino mice. Results are presented as % of control. The activity of the test compounds was compared with the corresponding solvent control group. Mean differences were considered statistically significant at p<0.05 (*p<0.05, **p<0.01). Figure 4 shows the results of testing the procognitive activity of compounds in NORT in Wistar rats.

Example 1 Synthesis of derivatives (II)-(VIII)

The synthesis was carried out in two steps. First, the corresponding pyrrolidinoarylpiperazine derivative containing the unsubstituted phenyl ring (II) or the appropriate lateral substituent (III)-(VIII) was prepared.

In the first step of the synthesis, a mixture of 3-chloromethylpyrrolidine-1-carboxylic acid tert-butyl ester (1.0 eq.), appropriate arylpiperazine derivatives (1.5 eq.), cesium carbonate (1.0 eq.) and a catalytic amount of potassium iodide in DMF ( 5 ml) was heated at 120°C for 2 hours under microwave irradiation. After this time, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 ml). The organic layer was washed with water (20 ml) and then dried over anhydrous sodium sulfate. After evaporation of the ethyl acetate, the product was purified by column chromatography on silica gel using a dichloromethane/acetone mixture (70/30, v/v) as eluent. The crude products were obtained after deprotection of the tert-butyloxycarbonyl group according to the general procedure known from the literature.

Then, the pyrrolidinoarylpiperazine fragment obtained in the first step was reacted with commercially available 4-chloro-6,7-dimethoxyquinazoline. A mixture of 4-chloro-6,7-dimethoxyquinazoline (1.0 eq) and the corresponding 1-aryl-4-(pyrrolidin-3-ylmethyl)piperazine, potassium carbonate (5.0 eq) and 10 ml of isopropanol was stirred at 80°C for 72 hours. The precipitate was filtered off, the reaction mixture was concentrated and purified by column chromatography on silica gel using dichloromethane/methanol (9/1, v/v) as eluent.

Example 2 6,7-dimethoxy-4-(3-(phenylpiperazin-1-yl)methyl)pyrrolidin-1-yl)quinazoline

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 1-phenyl-4-(pyrrolidin-3-ylmethyl)piperazine (I) (0 .36 mmol, 0.088 g). Yield 57%, yellowish solid, m.p. 183-185°C.

^1H NMR (300MHz, CDCl3): δ8.50 (s, 1H), 7.49 (s, 1H), 7.32-7.24 (m, 2H), 6.96-6.81 (m, 4H), 4.04-3.93 (m, 11H) , 3.77-3.65 (m, 2H), 3.51-3.37 (m, 1H), 3.20 (t, J=4.98 Hz, 5H), 2.72-2.57 (m, 6H).

¹³ C NMR (75 MHz, CDCl3): δ 178.1, 157.98, 156.50, 151.12, 149.68, 148.06, 146.38, 127.20, 121.89, 120.45, 114.56, 112.12, 107.58, 104.75, 58.58, 53.50, 52.60, 52.52, 50.93, 50.64 , 49.73, 47.56, 46.11, 33.69. LC-MS (ESI) calcd for C25H32N5O2 434.56 [M+H+], found 434.24 [M+H+],

Example 3 2-(4-((1-(6,7-Dimethoxyquinazolin-4-yl)pyrrolidin-3-yl-)methyl)piperazin-1-yl)phenol (III)

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 2-(4-(pyrrolidin-3-ylmethyl)piperazin-1-yl)phenol (II) (0.36 mmol, 0.093 g). Yield 67%, yellowish solid, m.p. 144-145°C.

^1H NMR (300MHz, CDCl3): δ 8.50 (s, 1H), 7.45 (s, 1H), 7.09 (d, J=2.34 Hz, 2H), 6.99-6.91 (m, 3H) 4.21-3.90 (m, 11H), 3.79-3.64 (m, 2H), 3.56-3.35 (m, 5H), 3.20 (t, J=4.98 Hz, 4H), 2.72-2.57 (m, 2H).

¹³ C NMR (75 MHz, CDCl3): δ 178.1, 157.98, 156.50, 151.12, 149.68, 148.06, 146.38, 129.6, 121.89, 120.45, 119.6, 114.56, 112.12, 10 7.58, 104.75, 58.58, 53.50, 52.60, 52.52, 50.93 , 50.64, 49.73, 47.56, 46.11, 33.69. LC-MS (ESI) calcd for C25H32N5O3 450.56 [M+H+], found 450.26 [M+H+],

Example 4 6,7-Dimethoxy-4-(3-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)quinazoline (IV)

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 1-(3-methoxyphenyl)-4-(pyrrolidin-3-ylmethyl)piperazine ( III) (0.36 mmol, 0.099 g). Yield 84%, yellowish solid, m.p. 119-120°C.

^1H NMR (300MHz, CDCl3): δ 8.50 (s, 1H), 7.49 (s, 1H), 7.29-7.10 (m, 4H), 4.11-3.90 (m, 10H), 3.79 (s, 3H), 2.72 -2.54 (m, 6H), 1.42-1.13 (m, 8H).

¹³ C NMR (75 MHz, CDCl3): δ 157.98, 156.50, 151.12, 150.68, 150.06, 146.38, 146.01, 144.61, 127.20, 107.58, 106.26, 104.75, 102.09, 101.82, 99.92, 58.58, 53.50, 52.60, 52.52, 50.93 , 50.64, 49.73, 47.56, 46.52, 46.11, 33.69.

LC-MS (ESI) calcd for C26H34N5O3 464.58 [M+H+], found 464.28 [M+H+],

Example 5 6,7-Dimethoxy-4-(3-((4-(3-trifluoromethylphenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)quinazoline (V)

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 1-(3-trifluoromethylphenyl)-4-(pyrrolidin-3-ylmethyl)piperazine ( IV) (0.36 mmol, 0.133 g). Yield 79%, yellow oil.

^1H NMR (300MHz, CDCl3): δ8.51 (s, 1H), 7.54-7.41 (m, 2H), 7.40-7.30 (m, 1H), 7.29-7.24 (m, 1H), 7.24-7.18 (m, 1H), 7.16-6.98 (m, 2H), 4.16-3.91 (m, 12H), 3.79 (s, 3H), 3.24 (t, 7=7.8 Hz, 2H), 2.802.56 (m, 6H).

¹³ C NMR (75 MHz, CDCl3): δ 178.1, 157.98, 156.50, 151.12, 149.68, 146.38, 132.06, 129.6,

127.20, 141.89, 120.45, 114.56, 112.12, 107.58, 104.75, 58.58, 53.50, 52.60, 52.52, 50.93, 50.64,

49.73, 47.56, 46.11, 33.69.

PL 243066 B1

LC-MS (ESI) calculated for C26H31F3N5O2 502.23 [M+H ⁺ ], obtained 502.17 [M+H ⁺ ],

Example 6 4-(3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-6,7-dimethoxyquinazoline (VI)

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 1-(4-chlorophenyl)-4-(pyrrolidin-3-ylmethyl)piperazine ( V) (0.36 mmol, 0.1 g). Yield 84%, yellowish solid, m.p. 171-172°C.

^1H NMR (300MHz, CDCl3): δ8.50 (s, 1H), 7.48 (s, 1H), 7.23-7.19 (m, 4H), 4.08-3.91 (m, 12H), 3.17-3.14 (m, 2H) , 2.70-2.45 (m, 10H).

¹³ C NMR (75 MHz, CDCl3): δ 181.56, 159.09, 153.63, 153.38, 151.96, 149.84, 148.81, 147.13, 128.93, 124.51, 120.77, 117.18, 110.21, 107 .45, 104.61, 66.73, 64.90, 61.10, 56.06, 55.02 , 53.39, 50.09, 49.19, 36.21, 30.15.

LC-MS (ESI) calcd for C25H31CIN5O2 468.20 [M+H ⁺ ], found 468.21 [M+H ⁺ ],

Example 7 4-(3-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-6,7-dimethoxyquinazoline (VII)

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 1-(2,3-dichlorophenyl)-4-(pyrrolidin-3-ylmethyl) piperazine (VI) (0.36 mmol, 0.113 g). Yield 59%, yellow oil.

^1H NMR (300MHz, CDCh): δ8.56 (s, 1H), 7.29-7.11 (m, 4H), 4.06-3.94 (m, 8H), 3.79-3.59 (m, 8H), 1.47-1.16 (m, 8H).

¹³ C NMR (75 MHz, CDCh): δ 178.1, 157.98, 156.50, 151.12, 150.68, 146.38, 133.22, 129.6, 127.20, 123.89, 120.45, 117.56, 112.12, 107.58 , 104.75, 58.58, 53.50, 52.60, 52.52, 50.93 , 50.64, 49.73, 47.56, 46.11, 33.69.

LC-MS (ESI) calcd for C25H30Cl2N5O2 503.43 [M+H ⁺ ], obtained 503.11 [M+H ⁺ ],

Example 8 4-(3-((4-(3,4-dichlorophenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-6,7-dimethoxyquinazoline (VIII)

The compound was obtained according to the general procedure by reacting 4-chloro-6,7-dimethoxyquinazoline (0.36 mmol, 0.09 g) and 1-(3,4-dichlorophenyl)-4-(pyrrolidin-3-ylmethyl) piperazine (VII) (0.36 mmol, 0.113 g). Yield 72%, yellow oil.

^1H NMR (300MHz, CDCh): δ 8.50 (s, 1H), 7.47 (s, 1H), 7.21-7.18 (m, 3H), 4.07-3.80 (m, 8H), 3.79-3.59 (m, 8H) , 1.46-1.17 (m, 8H).

¹³ C NMR (75 MHz, CDCh): δ 178.1, 157.98, 156.50, 151.12, 147.68, 146.38, 131.22, 129.6, 127.20, 122.89, 120.45, 113.86, 112.12, 107 .58, 104.75, 58.58, 53.50, 52.60, 52.52, 50.93 , 50.64, 49.73, 47.56, 46.11, 33.69.

LC-MS (ESI) calcd for C25H30Cl2N5O2 503.43 [M+H ⁺ ], derived 503.10 [M+H ⁺ ]

Claims (3)

1. Compound of formula (I): PL 243066 B1 where: - R is: an alkoxy group, which is a methoxy group, one halogen atom or two halogen atoms selected from the group consisting of the following atoms: F, Cl, Br, I; a perfluoroalkyl group which is a trifluoromethyl group, a monofunctional group containing an oxygen atom which is a hydroxyl group or a hydrogen atom where R is in the 2-, 3- and/or 4-position 2. A compound according to claim The process of claim 1, wherein one halogen atom or two halogen atoms are one chlorine atom or two chlorine atoms. 3. The compound of claim according to any one of claims 1 to 3, characterized in that it is selected from the group comprising the derivatives described by the formulas (II) to (VIII).