PL241482B1

PL241482B1 - 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives, their preparation and application

Info

Publication number: PL241482B1
Application number: PL430108A
Authority: PL
Inventors: Agnieszka Anna Kaczor; Magda Kondej; Tomasz M. Wróbel; Piotr Stępnicki; Dariusz Matosiuk; María De Los Ángeles Castro Pérez; Los Ángeles Castro Pérez María De; Andrea García Silva; Silva Andrea García; María Isabel Loza García; García María Isabel Loza
Original assignee: Uniwersytet Medyczny W Lublinie; Universidade De Santiago De Compostela
Priority date: 2019-05-31
Filing date: 2019-05-31
Publication date: 2022-10-10
Also published as: PL430108A1

Abstract

Przedmiotem wynalazku są pochodne 5-podstawione-3-(1-arylometylo-1,2,3,6-tetrahydropirydyn-4-ylo)-1H-indolu o wzorze ogólnym 1, gdzie R1 oznacza podstawnik furan-2-ylometylowy, natomiast R2 oznacza wodór, podstawnik etoksylowy lub izopropoksylowy, lub R1 oznacza podstawnik tiofen-2-ylometylowy natomiast podstawnik R2 oznacza wodór lub podstawnik C1-3alkoksylowy, lub R1 oznacza podstawnik benzylowy, natomiast R2 oznacza podstawnik izopropoksylowy, lub R1 oznacza podstawnik 3-metoksybenzylowy natomiast podstawnik R2 oznacza wodór lub podstawnik C1-3alkoksylowy, lub R1 oznacza podstawnik 4-metoksybenzylowy, natomiast podstawnik R2 oznacza podstawnik etoksylowy lub izopropoksylowy. Niniejsze zgłoszenie obejmuje także sposób otrzymywania powyższych związków. Związki będące przedmiotem wynalazku otrzymuje się w reakcji 5-podstawionych indoli z 1-arylometylopodstawionymi pochodnymi piperydyn-4-onu w metanolu w obecności wodorotlenku potasu. Reakcję prowadzi się przez 18 godzin w temperaturze wrzenia rozpuszczalnika. Mieszaninę reakcyjną wylewa się do wody dejonizowanej i pozostawia na 48 godzin do swobodnej krystalizacji lub oziębia się, a po ochłodzeniu otrzymuje się osad produktu. Produkt reakcji oczyszcza się przez przemycie wodą, metanolem, eterem i rekrystalizuje się z odpowiedniego rozpuszczalnika, korzystnie metanolu lub DMF albo oczyszcza metodami chromatograficznymi, korzystnie za pomocą chromatografii kolumnowej(żel krzemionkowy, gradient 2 - 5% bezw. NH3 w MeOH/DCM). Zgłoszenie zawiera również zastosowanie przedmiotowych związków. Związki te są wielocelowymi ligandami monoamin, w szczególności receptora dopaminowego D2 oraz receptorów serotoninowych 5-HT1A i 5-HT2A, mogące ze względu na profil receptorowy wykazywać działanie przeciwpsychotyczne, przeciwlękowe, prokognitywne i przeciwdepresyjne korzystne w leczeniu chorób psychicznych, w szczególności schizofrenii, choroby afektywnej dwubiegunowej i depresji.The present invention relates to 5-substituted-3- (1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl) -1H-indole derivatives of the general formula 1, where R1 is furan-2-ylmethyl and R2 is hydrogen, ethoxy or isopropoxy substituent, or R1 is thiophen-2-ylmethyl and R2 is hydrogen or C1-3alkoxy, or R1 is benzyl and R2 is isopropoxy or R1 is 3-methoxybenzyl and R2 is hydrogen or a C1-3alkoxy substituent, or R1 is 4-methoxybenzyl and R2 is ethoxy or isopropoxy. The present application also covers the preparation of the above compounds. The inventive compounds are prepared by reacting 5-substituted indoles with 1-arylmethyl substituted piperidin-4-one derivatives in methanol in the presence of potassium hydroxide. The reaction is carried out for 18 hours at the reflux temperature of the solvent. The reaction mixture is poured into deionized water and allowed to crystallize freely for 48 hours or cooled to give a precipitate of the product upon cooling. The reaction product is purified by washing with water, methanol, ether and recrystallized from a suitable solvent, preferably methanol or DMF, or purified by chromatographic methods, preferably by column chromatography (silica gel, gradient 2 - 5% anhydrous NH3 in MeOH / DCM). The application also includes the use of the compounds in question. These compounds are multi-target ligands of monoamines, in particular the dopamine D2 receptor and serotonin 5-HT1A and 5-HT2A receptors, which, due to their receptor profile, may have antipsychotic, anxiolytic, procognitive and antidepressant effects, beneficial in the treatment of psychiatric diseases, in particular schizophrenia, affective disorder. bipolar and depression.

Description

PL 241 482 B1

Description of the invention

The subject of the invention are 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives of the general formula 1, where Ri is a furan-2-ylmethyl substituent and R2 is hydrogen, ethoxy or isopropoxy, or Ri is thiophen-2-ylmethyl and R2 is hydrogen or C1-3alkoxy, or Ri is benzyl and R2 is isopropoxy, or Ri is 3-methoxybenzyl and R2 is hydrogen or a C1-3alkoxy substituent, or Ri is a 4-methoxybenzyl substituent and R2 is an ethoxy or isopropoxy substituent, a method for their preparation.

The substance 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one ( D2AAK1) of the formula 2, which has beneficial antipsychotic, procognitive and anxiolytic effects in animal models (Kaczor AA et al. Neurochem. Int. 2016, 96, 84-99).

In the known art, 3-(1-substituted-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are prepared by reacting indole with 1-substituted piperidin-4-one derivatives (e.g., Cole, DC et al Bioorg Med Chem Lett 2005, 15, 379-383 Deskus, JA et al Bioorg Med Chem Lett 2007, 17, 3099-3104 Kondej M et al Molecules 2018 , 23, pii: E2249) or by reacting 1H-indole-2,3-dione with 1-substituted piperidin-4-one derivatives (Bartels B. et al. PCT Int. Appl., 2010015588, 2010). 3-(1-Arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives have also been prepared by reacting 3-(piperidin-4-yl)-1H-indole with substituted benzyl halides (Klaveness, J. et al., PCT Int. Appl., 2007007072, 2007) or reaction of 2-propenoic acid methyl ester with substituted benzylamines and indole (Xue S. et al., Faming Zhuanli Shenqing, 102276581, 2011).

Derivatives numbered 1, 3, 4, 6, 7, 8, 12, 15, 16, 17, 18, 19, 20 (compound numbering as in Tables 1-4) were obtained for the first time. Derivative 2 is known as a CD14 monoclonal antibody conjugate for the treatment of leukemia (Sun C. et al., Faming Zhuanli Shenqing, CN 102898523, 2013). Derivative 5 is not described in the literature but is commercially available. Derivative 9 is known as an inhibitor of a constitutively active thrombopoietin receptor mutant involved in the pathomechanism of myeloproliferative neoplasms (Ngo A. et al. Comb. Chem. High ThroughputScreen. 2016, 19, 824-833), as a compound with antimalarial activity (e.g. Santos N et al. Eur. J. Med. Chem. 2015, 102, 320-333), CCR5 receptor ligand (Li S. et al. Faming Zhuanli Shenqing CN

101481323 A 20090715, 2009). Derivative 10 is known as a CD14 monoclonal antibody conjugate for the treatment of leukemia (Sun C. et al., Faming Zhuanli Shenqing, CN 102898523, 2013), an anticancer compound (Xue S. et al. Faming Zhuanli Shenqing, CN 102276581 A 20111214 , 2011) and CCR5 receptor ligand (Bondinell W. et al., PCT Int. Appl., WO 9917773 A1 19990415, 1999). Derivative 11 has been described as a D2 dopamine receptor ligand (Kondej M. et al. Molecules 2018, 23, pii: E2249). Derivatives 13 and 14 are known as CD14 monoclonal antibody conjugates for the treatment of leukemia (Sun C. et al., Faming Zhuanli Shenqing, CN 102898523, 2013) and anticancer compounds (Xue S. et al. Faming Zhuanli Shenqing, CN 102276581 A 20111214, 2011).

Surprisingly, it turned out that compounds of the general formula 1, where R1 is furan-2-ylmethyl, thiophen-2-ylmethyl, benzyl, 3-methoxybenzyl and 4-methoxybenzyl, and R2 is hydrogen or C1-3alkoxy can exhibit pharmacological in the central nervous system and in particular antipsychotic, anxiolytic, procognitive and antidepressant, which is beneficial in mental diseases, in particular schizophrenia.

The compounds obtained according to the invention are multitargeted ligands of G protein-coupled aminergic receptors (GPCRs), in particular the dopamine D2 receptor and the serotonin 5-HT1a and 5-HT2A receptors.

The novel compounds of the present invention are 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives of the general formula I, wherein R1 and R2 are as described above.

Compounds of the invention of the general formula 1, wherein R1 is furan-2-ylmethyl and R2 is hydrogen, ethoxy or isopropoxy, or R1 is thiophen-2-ylmethyl and R2 is hydrogen or C1-3alkoxy, or Ri is a benzyl substituent and R2 is an isopropok substituent

PL 241 482 B1 is syl, or Ri is 3-methoxybenzyl and R2 is hydrogen or C1-3alkoxy, or R1 is 4-methoxybenzyl and R2 is ethoxy or isopropoxy, according to the invention, 5- substituted indoles (general formula 3) with 1-arylmethyl substituted piperidin-4-one derivatives (general formula 4) in methanol in a basic medium, preferably in the presence of potassium or sodium hydroxide.

The appropriate indole is dissolved in methanol, preferably containing potassium or sodium hydroxide, then 1-arylmethyl substituted piperidin-4-one derivatives are added and the reaction is carried out for 10 to 24 hours, preferably 18 hours at the reflux temperature of the solvent. The reaction mixture is cooled and upon cooling, a precipitate of the product is obtained. The precipitate is filtered off, washed with water, methanol, ether and dried in vacuo. Alternatively, the reaction mixture is poured into deionized water and allowed to crystallize freely for 48 hours. The obtained product is recrystallized from a suitable solvent, preferably methanol or DMF, or purified by chromatographic methods, preferably by column chromatography (silica gel, gradient 2-5% anhydrous NH3 in MeOH/DCM).

The compounds obtained according to the invention can be used in medicine, especially in the preparation of medicinal preparations, due to their antipsychotic, anxiolytic, procognitive and antidepressant effects, which is beneficial in mental diseases, in particular schizophrenia.

Example 1 Indole (0.122 g, 1.04 mmol) was dissolved in methanol (10 ml) containing potassium hydroxide (0.69 g, 0.0123 mol). 1-[(furan-2-yl)methyl]piperidin-4-one (0.5 g, 2.79 mmol) was added and the reaction mixture was refluxed at the solvent reflux temperature for 18 h. After cooling, the reaction mixture was poured into 50 ml of deionized water and allowed to crystallize freely for 48 hours. The obtained product was crystallized from methanol. 0.2 g (yield 69%) of 3-{1-[(furan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1H-indole (Compound No. 1) is obtained. in the form of yellow crystals.

Ή NMR spectrum (δ, ppm, DMSO-d6, vs. TMS):

11.11 (s, 1H); 7.80 (d, J=8.0Hz, 1H); 7.61 (dd, J=1.8; 0.8Hz, 1H); 7.40-7.35 (m, 2H); 7.13-7.07 (m, 1H); 7.02 (td, J = 7.6; 7.1; 1.0 Hz, 1H); 6.43 (dd, J=3.1; 1.9Hz, 1H); 6.34 (d, J=3.0Hz, 1H); 6.11 (t, J=3.5Hz, 1H); 3.62 (s, 2H); 3.12 (d, J = 3.1 Hz, 2H); 2.68 (t, J = 5.7 Hz, 2H); 2.54-2.51 (m, 2H). ¹³ C NMR spectrum (δ, ppm, DMSO-d6, vs. TMS):

152.6; 142.8; 137.4; 130.0; 125.1; 123.2; 121.7; 120.5; 119.7; 117.9; 116.3; 112.2; 110.8; 109.0; 54.3; 52.6; 50.0; 29.0.

Example 2 Indole (0.117 g, 1 mmol) was dissolved in 1M KOH in MeOH (5 mL). 1-[(thiophen-2-yl)methyl]piperidin-4-one (0.215 g, 1.1 mmol) was then added and the solvent refluxed for about 18 h. The reaction mixture was cooled and the product precipitated upon cooling. The precipitate was filtered off, washed with water, methanol, ether and dried under vacuum. The precipitate is filtered off, washed with water, methanol, ether and dried in vacuo. 0.144 g (yield 49%) of 3-{1-[(thiophen-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1H-indole (compound No. 5) was obtained. Ή NMR spectrum (δ, ppm, DMSO-d6, vs. TMS):

11.11 (s, 1H); 7.81 (d, J=8.0Hz, 1H); 7.45 (dd, J=5.1; 1.3Hz, 1H); 7.39-7.36 (m, 2H); 7.12-7.08 (m, 1H); 7.04-6.98 (m, 3H); 6.12 (t, J=3.5Hz, 1H); 3.81 (s, 2H); 3.17 (q, J = 2.3 Hz, 2H); 2.69 (t, J = 5.7 Hz, 2H); 2.52 (s, 2H).

¹³ C NMR spectrum (δ, ppm, DMSO-d6, vs. TMS):

142.7; 137.4; 130.1; 127.0; 126.3; 125.8; 125.1; 123.2; 121.7; 120.5; 119.7; 117.9; 116.3; 112.2; 56.7; 53.0; 50.0; 29.0.

The physicochemical, spectral and pharmacological data of the remaining 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives obtained by the method as described in Examples 1 or 2 are presented in Tables 1 -4.

PL 241 482 B1

Table 1. 5-Substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives, with an indication of the new compounds being the subject of the invention and the second use of the remaining compounds.

Substance Ri R2 New compound/new use 1 h A new relationship 2 OMe A new use 3 OEt A new relationship 4 OiPr A new relationship 5 h A new relationship 6 OMe A new relationship 7 OEt A new relationship 8 OiPr A new relationship 9 aJO h A new use 10 OMe A new use 11 OEt A new use 12 OiPr A new relationship 13 ^x.0C ^h 3 h A new use 14 OMe A new use 15 OEt A new relationship 16 OiPr A new relationship 17 oh ₃ h A new relationship 18 OMe A new relationship 19 OEt A new relationship twenty OiPr A new relationship

PL 241 482 B1

cd (Μ

Purification method Crystallization from MeOH | Crystallization from MeOH | The product crystallized from the reaction mixture and washed with MeOH Crystallization from DMF using method A Crystallization from DMF | The product crystallized from the reaction mixture and washed with MeOH The product crystallized from the reaction mixture and washed with MeOH Crystallization from MEOH No purification | No purification Crystallization from MeOH | Crystallization from DMF | The product crystallized from the reaction mixture and washed with MeOH. DCVC chromatography (silica gel, 2-5% gradient without NH 3 in MeOH/DCM) Efficiency ' [%l I 69 69 42 | 99 FF 0 twenty rj fn £ 52 Molecular weight | | | 10FTZE I 336,427 294.41 | 324.440 | 338.466 352.493 346.465 1,362.465 | 376.491 I 318.412 | | 348.438 | 362.465 376.491 Summary formula th Λ X ω oh r u O X u CisHisNjS C1,H _W N ₂ OS I er O r X C21H24N2OS CijIIjóNiO Oh hey X U _C24H28N2O2 _{_} _{_} Ó M 'i X rł u 0' M X Ci u _C24H28N2O2 ri ta x And in | about x 1 OM 1 OEt OiPr ABOUT I OEt 1 OiPr x | Ome | OEt ABOUT what I 0 0 oh ₃ No TT r- se 00 3^ twenty

PL 241 482 B1

Table 3. Spectral data of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives.

^1H NMR spectrum (3.ppm, DMSO-d6, vs. TMS): | 11.11 (s, 1H); 7.80 (d, J = 8.0 Hz, 1H); 7.61 (dd, 1 = 1.8; 0.8 Hz, 1H); 7.40-7.35 (m, 2H); 7.13-7.07 (m, 1H); 7.02 (td J = 7.6; 7.1; 1.0 Hz, 1H); 6.43 (dd, J=3.1; 1.9Hz, 1H); 6.34 (d. J = 3.0 Hz. 1H); 6.11 (t, J = 3.5 Hz, 1H); 3.62 (s, 2Hk 3.12 (d. J = 3.1 Hz, 2H), 2.68 (t. J = 5.7 Hz. 2H), 2.54-2.51 (m. 2H)________ 10.95 (s, 1H); 7.61 (ddJ=1.9; 0.8Hz, 1H); 7.32 (d, J=2.6Hz, 1H); 7.25 (d, J = 8.7 Hz, 1H); 7.22 (d, J = 2.3 Hz, 1H); 6.75 (dd, J=8.7; 2.4 Hz. 1H); 6.43 (dd, J=3.1; 1.9Hz, 1H); 6.33 (d, J = 3.1 Hz, 1H); 6.06 6.02 (m, 1H); 4.01 (q. J = 6.9 Hz, 2H); 3.61 (s, 2H); 3.13 - 3.09 (m2H); 2.67 (t J = 5.7 Hz, 2H); 2.50 - 2.48 (m, 2H); 1.33 (t J = 7.0 Hz, 3H) 8.06 (s, 1H); 7.45-7.42 (m, 1H); 7.41 - 7.37 (m.1H); 7.26 (dd1=8.7; 1.2Hz, 1H); 7.15-7.12 (m, 1H); 6.89-6.86 (m, 1H); 6.39 - 6.36 (m, 1H); 6.31-6.28 (m, 1H); 6.14-6.10 (m, 1H); 4.57-4.49 (m, 1H); 3.73 (s, 2H); 3.31 - 3.24 (m2H); 2.84 - 2.77 (m, 2H); 2.66 - 2.59 (m, 2H); 1.36 (d, 1 = 6.1Hz, 6H) 11.11 (s, 1H); 7.81 (d, J = 8.0 Hz. 1H); 7.45 (dd, 1=5.1; 1.3 Hz. 1H); 7.39-7.36 (m, 2H); 7.12-7.08 (m.1H); 7.04-6.98 (m, 3H); 6.12 (t, J = 3.5 Hz. 1H); 3.81 (s, 2H); 3.17 (q, J = 2.3 Hz, 2H); 2.69 (t, J = 5.7 Hz. 2H); 2.52 (p. 2H) 10.98 (s, 1H); 7.45 (dd, J=5.1; 1.3Hz, 1H); 7.34 (d, J=2.6Hz, 1H); 7.27 (d, J=8.7Hz, 1H); 7.24 (d, J = 2.4 Hz, 1H); 7.02 (dd, 1 = 3.4, 1.0 Hz. 1H); 6.99 (dd, J = 5.1; 3.4 Hz. 1H); 6.76 (dd, J=8.7; 2.4Hz, 1H); 6.07 (t J = 3.5 Hz, 1H); 3.80 (s, 2H); 3.76 (s, 3H); 3.16 (d, J = 3.1 Hz, 2H); 2.69 (t, J = 5.7 Hz, 2H); 2.50 (s, 2H) 10.95 (s, 1H); 7.44 (dd, J=5.1; 1.3Hz, 1H); 7.32 (d, 1 = 2.6 Hz, 1H); 7.25 (d, J=8.7Hz, 1H); 7.23 (d, J=2.3Hz, 1H); 7.02 - 7.00 (m, 1H); 7.00 - 6.97 (m. 1H): 6.75 (dd, 1 = 8.7; 2.4 Hz, 1H); 6.05 (t, J = 3.5 Hz, 1H); 4.01 (q, J = 7.0 Hz, 2H); 3.79 (s, 2H); 3.18 - 3.13 (m, 2H); 2.68 (t, J = 5.7 Hz, 2H); 2.49 (s, 2H); 1.32 (t, J = 7.0Hz. 3H) 10.94 (s, 1H); 7.44 (dd, J=5.1; 1.3Hz, 1H); 7.32 (d, J = 2.6 Hz, 1H); 7.26 - 7.24 (m, 2H); 7.02-7.00 (m, 1H); 7.00 - 6.97 (m, 1H); 6.75 (dd, J=8.8; 2.3Hz, 1H); 6.03 (t, J = 3.5 Hz, 1H); 4.53 (hept. J = 6.1 Hz, 1H); 3.79 (s, 2H); 3.17 - 3.14 (m, 2H); 2.67 (t, .1 = 5.7 Hz, 2H); 2.50-2.48 (m, 2H); 1.24 (d, 1 = 6.0Hz, 6H) 10.95 (s, 1H); 7.39 - 7.31 (m, 5H); 7.29-7.23 (n, 3H); 6.75 (dd, 1 = 8.8; 2.2 Hz, 1H); 6.04 (t, J=3.4Hz, 1H); 4.53 (hept, J=6.0Hz, 1H); 3.58 (s, 2H); 3.12 - 3.08 (m, 2H); 2.65 (t, J = 5.7 Hz, 2H); 2.51 - 2.48 (m, 2H); 1.24 (d. J = 6.0 Hz, 6H) 10.95 (s, 1H); 7.31 (dJ = 2.6 Hz, 1H); 7.29-7.24 (m, 3H); 7.22 (d, J = 2.3 Hz, 1H); 6.93-6.88 (m, 2H); 6.74 (dd, J=8.7; 2.4Hz, 1H); 6.04 (t, J=3.5Hz, 1H); 4.01 (q, J = 7.0 Hz, 2H); 3.75 (s, 3H); 3.51 (s, 2H); 3.09 - 3.05 (m, 2H); 2.62 (t, J = 5.7 Hz, 2H); 2.50 - 2.46 (m, 2H); 1.32 (t, J = 7.0 Hz, 3H) 10.95 (s, 1H); 7.31 (s, 1H); 7.28 - 7.22 (m. 4H); 6.92 - 6.88 (m, 2H); 6.74 (dd J = 8.7; 2.3 Hz. 1H); 6.02 (t, J = 3.4 Hz, 1H); 4.52 (hept, J = 6.1 Hz. 1H); 3.74 (s, 3H); 3.51 (s, 2H); 3.09 - 3.04 (m2H); 2.62 (t, J = 5.7 Hz. 2H); 2.49 - 2.45 (m. 2H); 1.23 (d. J = 6.0 Hz. 6H) — OEt OiPr tC OMe OEt OiPr OiPr OEt OiPr and? OT and o.o ^IJN | TT ΙΛ r- x if,

PL 241 482 B1

Table 4. Pharmacological properties of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives.

Affinity of the derivatives for human Di, 5-ΗΤιαϊ 5-HT2A receptors (radioligand displacement studies).

news | MlogP 1 Os ri I 1.88 I 1 2.11 I 1 2.34 1 1 3.03 1 1 2.69 1 1 2.92 1 3.14 3.41 0 3.28 0 δ 1 2.74 I | 2.96 I 3.17 δ 2.74 1 2.96 1 3.17 AlogP oc \O \O 0 θ' 4.24 r^ CM 4.57 4.95 4.28 4.27 4.62 4.99 02 02 3 02 Value 0.104| 80l'0 0.086 | 0.079| 0.092| 0.087| 0.073| 0.057 0 0 0 0.097 | 0.079 0.069 | 0.097| 601'0 0.103| 0.081 0.097 | 60ΙΌ 0.103 | Ι80Ό 01 5-HTsa 1 173 47% | 5% | 171 | 1888 | 0 14% 125 & rt Θ. θ' with ri 32% | 52% 48% | 38% | 36% 194 | 24% 3% | 43% N* CL 'ET £ c 5-HTia UL 195 486 0 157 139 214 354 139 220 203 243 134 0 Ci 378 243 135 091 290 se Cl Q LU 62% 51% 71.9 141 O o 465 25.8 62.7 151 321 87.3 148 132 165 26.9 112 108 299 £ri 0^ K OMe | OET | OiPr | K OMC | OET | OiPr X OMe | OEt OiPr | x OMe | OEt 1 OiPr OMc OEt | OiPr Cż

Claims

PL 241 482 B1

Patent claims

1. 5-Substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives where Ri is furan-2-ylmethyl and R2 is hydrogen, ethoxy or isopropoxy, or Ri is thiophen-2-ylmethyl and R2 is hydrogen or C1-3alkoxy, or Ri is benzyl and R2 is isopropoxy, or R1 is 3-methoxybenzyl and R2 is hydrogen or C1-3alkoxy , or R1 is a 4-methoxybenzyl substituent and R2 is an ethoxy or isopropoxy substituent.

2. Method for obtaining 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives, where R1 is furan-2-ylmethyl and R2 is hydrogen, substituent ethoxy or isopropoxy, or R1 is thiophen-2-ylmethyl and R2 is hydrogen or C1-3alkoxy, or R1 is benzyl and R2 is isopropoxy, or R1 is 3-methoxybenzyl and R2 is hydrogen or C1 -3-alkoxy, or R1 is a 4-methoxybenzyl substituent, while R2 is an ethoxy or isopropoxy substituent, characterized in that they are obtained by reacting 5-substituted indoles (general formula 3) with 1-arylmethyl substituted piperidin-4-one derivatives (formula general 4) in a polar solvent, preferably in methanol, in a basic medium, preferably in the presence of potassium or sodium hydroxide, the reaction being carried out for 10 to 24 hours, preferably not for 18 hours at the reflux temperature of the solvent, after which the reaction mixture is cooled and a precipitate of the product is obtained.

3. The method according to claim 2, characterized in that the reaction product is purified by washing with water, methanol, ether.

4. Method for obtaining 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives, where R1 is furan-2-ylmethyl and R2 is hydrogen, substituent ethoxy or isopropoxy, or R1 is thiophen-2-ylmethyl and R2 is hydrogen or C1-3alkoxy, or R1 is benzyl and R2 is isopropoxy, or R1 is 3-methoxybenzyl and R2 is hydrogen or C1 -3-alkoxy, or R1 is a 4-methoxybenzyl substituent, while R2 is an ethoxy or isopropoxy substituent, characterized in that they are obtained by reacting 5-substituted indoles (general formula 3) with 1-arylmethyl substituted piperidin-4-one derivatives (formula general 4) in a polar solvent, preferably in methanol, in a basic medium, preferably in the presence of potassium or sodium hydroxide, the reaction being carried out for 10 to 24 hours, preferably not for 18 hours at the reflux temperature of the solvent, then the reaction mixture is poured into deionized water and allowed to crystallize freely for 48 hours.

5. The method according to claim 4, characterized in that the reaction product is purified by recrystallization from a polar solvent, preferably methanol or DMF, or by chromatographic methods, preferably by column chromatography (silica gel, gradient 2-5% anhydrous NH3 in MeOH/DCM ).

6. Derivatives of general formula 1 as described in claim 1, being multi-target ligands for monoamine receptors, in particular dopamine D2 receptor and serotonin 5-HT1a and 5-HT2A receptors for use in the treatment of mental illnesses, in particular schizophrenia, bipolar disorder and depression.