ES2964230B2 - N-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine derivatives, their method of production and their use - Google Patents

Description

N-((9-doro-3,4-dihydro-2H-benzo[b][1,4]dioxepm-7-M)metM)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine derivatives, their method of production and their use

Technical sector

The object of the invention is the derivatives W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine of general formula 1, where R1 is a chlorine or hydrogen substituent and R2 is a fluorine or hydrogen substituent, a method of their preparation and their use.

Background

In the known state of the art only W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine, designated as formula 2, is described, which is a ligand for the serotonin receptors 5-HTm and 5-HT2A (Kaczor et al. ChemMedChem 2016). Currently, there are no published reports on the synthesis of substances containing it.

In the known state of the art, there are no data on the derivatives according to the invention, their pharmacological properties and the possible therapeutic applications of substances based on this system.

Brief description

The object of the invention is the N-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine derivatives of general formula 1, where R1 is a chlorine or hydrogen substituent and R2 is a fluorine or hydrogen substituent.

The compounds of the invention are obtained by reacting 4-, 5- or 7-fluorotryptamine or tryptamine with 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carbaldehyde; 4-, 5-, 6- or 7-fluorotryptamine or tryptamine with 3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carbaldehyde under anhydrous conditions in the absence of air, carrying out the reaction in methanol containing sodium sulfate for 4 hours and continuing for 12 hours after the addition of sodium borohydride, and the product obtained after extraction with dichloromethane is converted into hydrochloride, which is purified by crystallization from ethanol or a mixture of ethanol and ether.

The compounds of the invention are multi-target ligands of monoamines, in particular of the serotonin receptors 5-HT1A and 5-HT2A, capable, due to their receptor profile, of exhibiting beneficial anxiolytic, pro-cognitive and antidepressant effects in the treatment of mental illnesses, in particular depression.

The derivatives according to the invention show affinity for 5-HTm and 5-HT2A receptors (Table 3), which are considered among the most important molecular targets considered for the treatment of nervous system diseases, in particular depression, anxiety disorders and neurodegenerative diseases (Celada et al. J. Psychiatry Neurosci 2004; Xiang et al. Am. J. Transl. Res. 2019). It should be noted that a beneficial feature of the compounds presented is their relative inactivity towards dopamine D2 receptors. The data from the literature highlight the importance of this last feature, as it allows to compensate for the severity of side effects experienced by patients, which constitute a major limitation of application for some groups of drugs, for example, classical antipsychotics. The determined values of lipophilicity (LogP) and blood-brain barrier permeability (logBBB) coefficients suggest that the derivatives presented in the patent application can penetrate biological barriers and exhibit pharmacological effects in the central nervous system. Furthermore, the in vitro receptor profile of the compounds, determined by in vitro studies, suggests that they may exert anxiolytic, pro-cognitive and antidepressant effects, which creates a broad therapeutic potential for the derivatives presented.

The invention solves the problem of obtaining W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine derivatives of general formula 1, which are multitarget ligands of G-protein-coupled aminergic receptors, in particular serotonin 5-HT1A and 5-HT2A receptors, and their applications in the treatment of diseases of the nervous system, in particular depression, anxiety disorders and neurodegenerative diseases.

The essence of the invention relates to W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)ethane-1-amine derivatives of general formula 1, where R1 is a chloro or hydrogen substituent and R2 is a fluorine or hydrogen substituent shown in the figure of general formula 1.

Derivatives of W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1 H-indol-3-yl)ethane-1-amine of general formula 1, where R1 is a chloro or hydrogen substituent, while R2 is a fluoro or hydrogen substituent are obtained according to the invention by reaction of 4-, 5- or 7- fluorotryptamine or tryptamine with 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde; 4-, 5-, 6- or 7- fluorotryptamine or tryptamine with 3,4-dihydro-2H-benzo[b][1,4]dioxepino-7-carbaldehyde. The reactions are carried out under anhydrous conditions. Tryptamine or the corresponding fluorotryptamine is dissolved in methanol containing not less than 1 g of sodium sulfate and 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepino-7-carbaldehyde or 3,4-dihydro-2H-benzo[b][1,4]dioxepino-7-carbaldehyde is added to the mixture. The mixture is allowed to stand for 4 hours. Then, sodium borohydride is added and the reaction is carried out for 12 hours, stirring at room temperature. Then, distilled water is added to the reaction mixture and it is extracted with dichloromethane. After evaporation, the crude product is obtained, which is converted to hydrochloride. The resulting salt is purified by crystallization from ethanol or from a mixture of ethanol and ether.

The compounds obtained according to the invention may have applications in medicine, for the preparation of drugs due to their favorable profile of action on the receptors, which indicates anxiolytic, pro-cognitive and antidepressant properties, which is beneficial in mental illnesses, in particular in depression.

The compounds obtained according to the invention, in relation to known compounds, show better efficacy and their affinity for the 5-HTm receptor is several times higher than that of similar known compounds, which offers wide possibilities for their use in mental illnesses.

Example 1. Under anhydrous conditions, tryptamine (320 mg, 2 mmol) was dissolved in methanol (20 mL) containing 1 g of sodium sulfate. Then 3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde (532 mg, 2.5 mmol) was added. The reaction was carried out for 4 hours. Subsequently, NaBH4 (113 mg, 3 mmol) was added and the reaction was continued for 12 hours. After this time, the reaction was neutralized with water and extracted with DCM. The oily product obtained after evaporation was converted to hydrochloride, which was purified by crystallization from ethanol. 381 mg of W-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(1H-indol-3-yl)ethane-1-amine were obtained (48% yield).

!H NMR (600 MHz, D<2>O) 57.49 (dd,J =9.7; 8.5 Hz, 2H); 7.24 - 7.20 (m, 2H); 7.10 (t,J = 7.5 Hz,1H); 7.00 - 6.91 (m, 3H); 4.15 (dt,J= 15.7; 5.4 Hz, 4H); 4.05 (s, 2H); 3.27 (t;J= 7.2 Hz, 2H); 3.11 (t,J= 7.2 Hz, 2H); 2.15 (p,J= 5.5 Hz, 2H).

13C NMR (151 MHz, D<2>O) 5 151.5; 150.7; 136.4; 126.3; 126.1; 125.7; 124.2; 123.2; 122.4; 122.2; 119.4; 118.1; 112.0; 108.6; 71.4; 71.4; 49.7; 46.2; 31.2; 21.5.

Example 2. Under anhydrous conditions, tryptamine (320 mg, 2 mmol) was dissolved in methanol (20 mL) containing 1 g of sodium sulfate. Then 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde (532 mg, 2.5 mmol) was added. The reaction was carried out for 4 hours. NaBH4 (113 mg, 3 mmol) was added and the reaction was continued for 12 hours. After this time, the reaction was neutralized with water and extracted with DCM. The oily product obtained after evaporation was converted to hydrochloride, which was purified by crystallization from ethanol. 381 mg of W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(1H-indol-3-yl)ethane-1-amine were obtained (48% yield).

1H NMR (600 MHz, D<2>O) 57.41 - 7.35 (m, 2H); 7.16 - 7.11 (m, 2H); 7.04 - 6.98 (m, 1H); 6.93 (d,J= 2.2 Hz, 1H); 6.76 (d,J= 2.2 Hz, 1H); 4.14 (t,J= 5.5 Hz, 2H); 4.07 (t,J= 5.5 Hz, 2H); 3.92 (s, 2H); 3.20 (t,J= 7.0 Hz, 2H); 3.03 (t,J= 7.0 Hz, 2H); 2.10 (p,J= 5.6 Hz, 2H).

13C NMR (151 MHz, D<2>O) 5 151.8; 147.9; 136.4; 126.4; 126.0; 126.0; 125.9; 124.3; 122.2; 121.9; 119.4; 118.0; 112.0; 108.4; 71.6; 71.5; 49.2; 46.0; 30.8; 21.7.

Example 3. Under anhydrous conditions, 7-fluorotryptamine (395 mg, 2.22 mmol) was dissolved in methanol (20 mL) containing 1 g of sodium sulfate. Then 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde (589 mg, 2.77 mmol) was added. The reaction was carried out for 4 hours. NaBH4 (126 mg, 3.32 mmol) was added and the reaction was continued for 12 hours. After this time, the reaction was neutralized with water and extracted with DCM. The oily product obtained after evaporation was converted to hydrochloride, which was purified by crystallization from ethanol. 97 mg of W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(7-fluoro-1H-indol-3-yl)ethane-1-amine were obtained (11% yield).

1H NMR (600 MHz, D<2>O) 57.2 (s, 1H); 7.2 (d,J= 7.9 Hz, 1H); 7.0 - 6.9 (m, 2H); 6.9 - 6.9 (m, 1H); 6.8 (d,J= 1.6 Hz, 1H); 4.2 (t,J= 5.3 Hz, 2H); 4.1 (t,J= 5.3 Hz, 2H); 4.0 (s, 2H); 3.2 (t,J= 6.9 Hz, 2H); 3.0 (t,J= 6.9 Hz, 2H); 2.1 (p,J= 5.5 Hz, 2H).

13C NMR (75 MHz; MeOD) 5 154.19; 151.24 (d,J= 243.5 Hz); 150.12; 132.09 (d,J= 5.7 Hz); 128.00; 127.56; 126.70; 126.23 (d,J= 13.4 Hz); 125.34; 123.16; 120.42 (d,J= 6.3 Hz); 115.00(d,J= 3.1 Hz); 111.18 (d,J= 2.4 Hz); 107.38 (d,J= 16.6 Hz); 72.30; 72.16; 51.03; 32.49; 23,21.

The physicochemical, spectral and pharmacological data of the W-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(6-fluoro-1 H-indol-3-yl)ethane-1-amine derivatives obtained by the method described in the examples are shown in Tables 1-3.

Table 1Characteristics and details of the purification process of the derivatives object of the invention.

No. R1 R2 Formula sum Molecular weight Yield [%] Purification method

Table 2: Spectral data of the substances object of the invention.

Table 3Pharmacological properties of the derivatives. Affinity of the derivatives for human D2, 5-HT1A, 5-HT2A and 5HT7 receptors.

Data are expressed as % inhibition at 10 ^M or Ki (nM). The logBBB parameter indicates the calculated permeability of the compound across the blood-brain barrier. The logP parameter indicates the calculated lipophilicity.

Claims (6)

CLAIMS 1 Compounds of general formula 1 where R1 is chlorine and R2 is hydrogen or fluorine, consisting of the following: - N-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(1H-indol-3-yl)ethane-1-amine, - N-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(4-fluoro-1H-indol-3-yl)ethane-1-amine, - N-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(5-fluoro-1H-indol-3-yl)ethane-1-amine, and - N-((9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-(7-fluoro-1H-indol- 3-yl)ethane-1-amine. 2. Method for obtaining the compounds of claim 1, characterized in that they are obtained by a reaction of tryptamine or 4-, 5- or 7-fluorotryptamine with 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde, where the reaction is carried out under anhydrous conditions, in which tryptamine or fluorotryptamine is dissolved in methanol containing sodium sulfate in an amount not less than 1 g and 9-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde is added to the mixture, then sodium borohydride is added, then distilled water is added to the reaction mixture and it is extracted with dichloromethane, and after evaporation the crude product is obtained, from which the hydrochloride is formed. 3. The method according to claim 2, characterized in that the reaction is carried out under anhydrous conditions in the absence of air. 4. The method according to claim 2, characterized in that the reaction product is obtained in the form of salts, preferably hydrochlorides. 5. The method according to claim 2, characterized in that the reaction product is purified by crystallization from ethanol or a mixture of ethanol and ether. 6. The compounds described in claim 1, for use in the treatment of psychiatric diseases, in particular depression.