Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs
Abstract
Schizophrenia is a complex disease with not fully understood pathomechanism, involving many neurotransmitters and their receptors. This is why it is best treated with multi-target drugs, such as second generation antipsychotics. Here we present 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles (1-20) which are ligands of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors and display affinity in the nanomolar range. These compounds were designed as modifications of the virtual hit experimentally confirmed, D2AAK1, and synthesized from indole or 5-alkoxyindoles and N-substituted piperidin-4-ones in methanol in the presence of potassium hydroxide. Compound 9 was subjected to X-ray studies and it crystallizes in the centrosymmetric monoclinic space group P21/c with one molecule in an asymmetric unit. Three most potent compounds (5, 9 and 17) turned out to be antagonists of both D2 and 5-HT2A receptors what is beneficial for their potential application as antipsychotics. Compound 5 was subjected to behavioral studies and exhibited antipsychotic, pro-cognitive and antidepressant activity in appropriate mice models. Structure-activity relationships for compounds 1-20 were rationalized using molecular docking. It was found that, in general, bulky C5-alkoxy substituents at the indole moiety are not favorable as they direct towards aqueous environment of the extracellular vestibule. Keywords: antipsychotics; behavioral studies, G protein-coupled receptors; indole derivatives; multi-target compounds; schizophrenia.
Full text
Supplementary Information Synthesis, pharmacological and structural studies of 5-substituted-3-(1arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs Magda Kondej1, Tomasz M. Wróbel1,2, Andrea G. Silva3, Piotr Stępnicki1, Oliwia Koszła1, Ewa Kędzierska4, Agata Bartyzel5, Grażyna Biała4, Dariusz Matosiuk1, Maria I. Loza3, Marián Castro3, Agnieszka A. Kaczor1,6* 1Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland 2Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark 3Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E15782 Santiago de Compostela, Spain 4Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland 5Department of General and Coordination Chemistry, Maria Curie-Skłodowska University, M. Curie-Skłodowskiej Sq. 2, PL-20031 Lublin, Poland 6School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI70211 Kuopio, Finland *Corresponding author: [email protected]
Content: Fig. S1. Partial packing diagram of compound 9 viewed along the axes a (a) and c (b) showing N‒H···N hydrogen bonds. Fig. S2. Crystal packing of compound 9 showing the formation of N‒H···H hydrogen bonds (dotted lines). Fig. S3. Competition binding curves of compounds in radioligand binding assays at human D2 receptors. Fig. S4. Competition binding curves of compounds in radioligand binding assays at human 5HT1A receptors. Fig. S5. Competition binding curves of compounds in radioligand binding assays at human 5HT2A receptors. Fig. S6. Concentration-response curves of selected compounds antagonizing dopamine response in functional assays of cAMP signalling at human D2 receptors.
Table S1. Lipophilicity calculated using ALOGPS 2.1 software and blood-brain permeability (BBB) calculated using On-line BBB predictor. Table S2. Crystal data and structure refinement of the compound 9. Table S3. Interatomic distances and selected bond angles for the compound 9. Table S4. Experimental conditions employed in radioligand binding assays. 1H NMR, 13C NMR and HRMS spectra of reported compounds.
Fig. S1. Partial packing diagram of compound 9 viewed along the axes a (a) and c (b) showing N‒H···N hydrogen bonds.
Fig. S2. Crystal packing of compound 9 showing the formation of N‒H···H hydrogen bonds (dotted lines).
Fig. S3. (Continues on the following page). Competition binding curves of compounds in radioligand binding assays at human D2 receptors. Concentration-dependent displacement of the specific binding of the D2 antagonist radioligand [3H]-Spiperone by compounds 1, 2, and 5−14 (present page) (compound 11 [1]), and 15−20 and reference compound haloperidol (following page) in membranes from CHO-K1 cells overexpressing the human cloned dopamine D2 receptor (isoform D2short). The graphs show the data (media ± SEM) of a representative experiment out of 2-3 independent experiments performed in duplicate. log [1], M [3H]-Spiperone specific binding (% ) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [2], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [5], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [6], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [7], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [8], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [9], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [10], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [11], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [12], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [13], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [14], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120
(Fig. S3. Continues from previous page). log [15], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [16], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [17], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [18], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [19], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [20], M [3H]-Spiperone specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [haloperidol], M [ 3 H]-Spiperone specific binding (%) -11 -10 -9 -8 -7 -6 -5 0 20 40 60 80 100 120
Fig. S4. (Continues on the following page). Competition binding curves of compounds in radioligand binding assays at human 5-HT1A receptors. Concentration-dependent displacement of the specific binding of the 5-HT1A agonist radioligand [3H]-8-OH-DPAT by compounds 1−12 (present page), and 13−20 and reference compound 5carboxamidotryptamine (5-CT) (following page) in membranes from HEK293 cells overexpressing the human cloned serotonin 5-HT1A receptor. The graphs show the data (media ± SEM) of a representative experiment out of 2-3 independent experiments performed in duplicate. log [1], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [2], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [3], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [4], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [5], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [6], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [7], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [8], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [9], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [10], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [11], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [12], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120
(Fig. S4. Continues from previous page). log [13], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [14], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [15], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [16], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [17], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [18], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [19], M [ 3 H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [20], M [3H]-8-OH-DPAT specific binding (%) -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 120 log [5-C T], M [3H]-8-OH-DPAT specific binding (%) -11 -10 -9 -8 -7 -6 -5 0 20 40 60 80 100 120
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1) 0102030405060708090100110120130140150 f1 (ppm) 29.00 49.99 52.62 54.30 108.98 110.79 112.19 116.35 117.91 119.69 120.54 121.68 123.19 125.12 130.04 137.39 142.78 152.55
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1)
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole (2) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5 f1 (ppm) 2.11 2.05 2.07 2.08 3.05 1.03 0.92 0.89 0.97 1.01 0.91 1.05 0.84 1.02 2.62 2.62 2.80 2.81 2.82 3.28 3.28 3.29 3.74 3.87 6.13 6.30 6.30 6.37 6.37 6.37 6.38 6.87 6.87 6.88 6.89 7.13 7.14 7.26 7.27 7.28 7.28 7.34 7.34 7.43 7.43 7.44 8.12
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole (2) 0102030405060708090100110120130140150160170180 f1 (ppm) 29.16 49.95 52.65 54.56 56.00 102.92 108.74 110.09 111.89 112.22 117.92 118.74 122.02 125.66 129.83 131.91 142.20 151.95 154.40
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole (2)
5-ethoxy-3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5 f1 (ppm) 3.05 2.18 1.94 2.02 1.96 2.01 1.00 0.97 0.96 0.99 1.00 1.00 1.00 0.93 1.00 1.32 1.33 1.34 2.50 2.66 2.67 2.68 3.11 3.11 3.11 3.12 3.61 3.99 4.01 4.02 4.03 6.03 6.04 6.05 6.33 6.34 6.43 6.43 6.43 6.43 6.74 6.74 6.75 6.75 7.22 7.22 7.25 7.26 7.31 7.32 7.61 7.61 7.61 7.62 10.95
5-ethoxy-3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3) 1520253035404550556065707580859095100105110115120125130135140145150155160 f1 (ppm) 15.39 29.03 50.06 52.65 54.34 63.88 103.62 108.99 110.79 112.09 112.71 116.07 117.49 123.83 125.38 130.07 132.51 142.79 152.56 153.24
5-ethoxy-3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3)
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxy-1H-indole (4) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.50.0 f1 (ppm) 5.92 2.10 2.09 2.11 2.09 1.04 0.99 0.92 0.90 0.96 0.95 1.01 1.06 0.86 1.00 1.35 1.36 2.62 2.79 2.80 2.81 2.81 3.28 3.73 4.50 4.51 4.52 4.52 4.53 4.53 4.54 4.54 4.55 4.56 6.12 6.12 6.29 6.30 6.37 6.37 6.37 6.37 6.86 6.87 6.87 6.88 6.88 7.13 7.25 7.25 7.26 7.27 7.39 7.43 7.43 7.44 8.06
3-(1-(furan-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxy-1H-indole (4) 0102030405060708090100110120130140150160170 f1 (ppm) 22.28 29.11 49.93 52.64 54.56 71.57 107.37 108.71 110.08 111.69 114.37 117.89 118.77 121.96 125.78 129.73 132.23 142.18 151.96 152.28
5-methoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (6)
5-ethoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (7) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0 f1 (ppm) 3.01 2.36 1.93 1.94 1.93 2.06 1.03 1.01 0.93 0.96 0.96 0.98 1.00 0.92 0.93 0.00 TMS 1.31 1.32 1.33 2.49 2.67 2.68 2.68 3.15 3.15 3.16 3.16 3.79 3.99 4.00 4.02 4.03 6.05 6.05 6.06 6.74 6.74 6.75 6.76 6.98 6.98 6.99 6.99 7.01 7.01 7.01 7.01 7.23 7.23 7.25 7.26 7.32 7.32 7.44 7.44 7.44 7.45 10.95
5-ethoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (7) 0102030405060708090100110120130140150160 f1 (ppm) -0.00 TMS 14.81 28.42 49.44 52.40 56.13 63.34 103.15 111.52 112.14 115.47 116.88 123.29 124.80 125.26 125.76 126.41 129.61 131.97 142.15 152.68
5-ethoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (7)
5-isopropoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (8) -0.0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5 f1 (ppm) 6.22 2.08 1.95 1.96 1.95 1.03 0.99 1.00 0.95 0.97 2.03 0.97 0.91 0.98 0.00 TMS 1.24 1.25 2.49 2.66 2.67 2.68 3.15 3.16 3.16 3.79 4.50 4.51 4.52 4.53 4.54 4.55 4.56 6.03 6.03 6.04 6.74 6.74 6.75 6.76 6.98 6.98 6.99 6.99 7.01 7.01 7.01 7.01 7.25 7.25 7.25 7.26 7.32 7.33 7.44 7.44 7.44 7.45 10.94 10.95
5-isopropoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (8) 102030405060708090100110120130140150160170 f1 (ppm) 21.97 28.40 49.42 52.39 56.12 70.19 106.16 112.08 112.98 115.39 116.87 123.37 124.92 125.26 125.76 126.41 129.59 132.24 142.15 151.26
5-isopropoxy-3-(1-(thiophen-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (8)
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (9) -0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5 f1 (ppm) 2.11 1.95 2.00 1.96 0.99 1.00 1.00 0.98 6.04 1.01 0.97 2.52 2.65 2.66 2.67 3.10 3.11 3.11 3.11 3.60 6.11 6.12 6.13 7.00 7.01 7.02 7.02 7.02 7.03 7.03 7.08 7.09 7.10 7.10 7.10 7.11 7.11 7.26 7.26 7.26 7.27 7.27 7.28 7.28 7.28 7.33 7.34 7.34 7.35 7.36 7.36 7.36 7.37 7.37 7.38 7.38 7.79 7.81 11.10
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (9) -100102030405060708090100110120130140150 f1 (ppm) 29.05 50.28 53.30 62.52 112.19 116.37 118.08 119.68 120.55 121.67 123.19 125.13 127.36 128.66 129.25 130.11 137.40 139.12
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (9)
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxy-1H-indole (12) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0 f1 (ppm) 6.00 2.00 1.99 1.96 2.00 1.01 0.99 0.99 3.05 5.07 0.94 1.24 1.25 2.50 2.51 2.64 2.65 2.66 3.10 3.10 3.58 4.50 4.51 4.52 4.53 4.54 4.55 4.56 6.03 6.04 6.04 6.75 6.75 6.76 6.76 7.26 7.26 7.27 7.28 7.28 7.28 7.32 7.33 7.34 7.34 7.36 7.36 7.37 7.37 10.95
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxy-1H-indole (12) 0102030405060708090100110120130140150160170180 f1 (ppm) 22.54 29.06 50.33 53.31 62.57 70.75 106.73 112.66 113.56 116.03 117.64 123.91 125.51 127.35 128.65 129.28 130.14 132.82 139.11 151.83
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxy-1H-indole (12)
3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (13) 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5 f1 (ppm) 2.25 2.02 1.92 2.01 3.03 0.96 1.97 1.01 0.99 1.95 1.97 0.98 0.94 2.50 2.50 2.62 2.63 2.64 3.08 3.08 3.08 3.08 3.52 3.75 6.11 6.11 6.12 6.90 6.91 7.00 7.00 7.01 7.02 7.02 7.03 7.03 7.08 7.08 7.09 7.10 7.11 7.11 7.26 7.26 7.28 7.28 7.36 7.37 7.38 7.79 7.80 11.11
3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (13) 0102030405060708090100110120130140150160170 f1 (ppm) 29.07 50.14 53.21 55.48 61.90 112.18 114.03 116.39 118.14 119.67 120.54 121.66 123.17 125.13 130.11 130.45 130.89 137.40 158.72
3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (13)
5-methoxy-3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (14) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5 f1 (ppm) 2.29 2.15 1.95 2.04 3.03 2.68 0.96 0.97 2.01 1.00 2.97 1.00 0.96 2.49 2.62 2.63 2.64 3.07 3.07 3.08 3.08 3.52 3.75 3.76 6.05 6.06 6.07 6.74 6.74 6.76 6.76 6.90 6.90 6.91 6.91 7.22 7.23 7.26 7.26 7.27 7.28 7.32 7.32 10.95
5-methoxy-3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (14) 0102030405060708090100110120130140150160170 f1 (ppm) 29.11 50.23 53.22 55.48 55.86 61.97 102.61 111.66 112.75 114.02 116.17 117.74 123.82 125.36 130.15 130.50 130.90 132.52 154.06 158.73
5-methoxy-3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (14)
5-ethoxy-3-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (15) 1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.01.5 f1 (ppm) 3.04 1.90 2.03 1.95 2.03 3.01 2.00 0.99 0.98 2.02 1.01 3.06 1.01 0.99 1.31 1.32 1.33 2.49 2.62 2.62 2.63 3.07 3.07 3.07 3.07 3.51 3.75 3.99 4.00 4.01 4.02 6.04 6.04 6.05 6.73 6.74 6.75 6.75 6.89 6.90 6.90 6.91 6.91 6.91 7.22 7.22 7.25 7.26 7.26 7.27 7.27 7.31 7.32 10.95
3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (17) 102030405060708090100110120130140150160170 f1 (ppm) 29.05 50.27 53.32 55.42 62.43 112.19 112.86 114.54 116.38 118.10 119.69 120.56 121.42 121.68 123.19 125.13 129.67 130.11 137.41 140.82 159.76
3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (17)
5-methoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (18) 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.52.0 f1 (ppm) 2.24 1.96 1.99 1.86 2.96 2.89 1.01 1.00 1.02 2.05 3.08 1.02 0.94 2.51 2.64 2.65 2.66 3.11 3.11 3.11 3.11 3.57 3.76 3.76 6.07 6.07 6.07 6.75 6.75 6.76 6.76 6.83 6.83 6.84 6.85 6.93 6.94 7.23 7.24 7.24 7.26 7.26 7.27 7.27 7.33 7.33 10.96
5-methoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (18) 102030405060708090100110120130140150160 f1 (ppm) 29.08 50.35 53.34 55.42 55.86 62.50 102.63 111.67 112.76 112.85 114.60 116.14 117.69 121.48 123.86 125.35 129.67 130.15 132.52 140.80 154.07 159.75
5-methoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (18)
5-ethoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (19) -0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0 f1 (ppm) 3.09 1.84 1.97 1.98 1.98 3.04 2.04 1.00 0.99 1.00 2.02 3.07 1.01 0.96 1.31 1.33 1.34 2.50 2.64 2.65 2.66 3.11 3.11 3.56 3.76 3.99 4.01 4.02 4.03 6.05 6.06 6.07 6.74 6.75 6.76 6.76 6.83 6.83 6.83 6.83 6.84 6.84 6.84 6.85 6.93 6.93 6.94 7.23 7.24 7.24 7.25 7.26 7.27 7.27 7.32 7.33 10.94
5-ethoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (19) 0102030405060708090100110120130140150160170 f1 (ppm) 0.00 TMS 14.81 28.50 49.76 52.75 54.84 61.91 63.34 103.16 111.52 112.13 112.27 114.02 115.54 117.09 120.89 123.25 124.82 129.07 129.57 131.98 140.24 152.68 159.18
5-ethoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (19)
5-isopropoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (20) -0.0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5 f1 (ppm) 6.24 1.85 1.97 1.93 1.92 3.02 1.02 0.98 1.00 1.06 2.01 3.11 0.99 0.91 -0.00 TMS 1.23 1.24 2.50 2.63 2.64 2.65 3.10 3.10 3.56 3.75 4.50 4.51 4.52 4.53 4.54 4.55 4.56 6.03 6.03 6.04 6.74 6.74 6.75 6.75 6.82 6.82 6.82 6.83 6.83 6.84 6.92 6.94 7.24 7.24 7.25 7.25 7.26 7.26 7.32 7.32 10.94
5-isopropoxy-3-(1-(3-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (20) -10010203040506070809010011012013014015016017080 f1 (ppm) 0.00 TMS 21.96 28.47 49.74 52.75 54.84 61.90 70.18 106.15 112.07 112.27 112.98 114.00 115.45 117.08 120.88 123.33 124.92 129.08 129.55 132.24 140.23 151.25 159.17