Supporting Information Synthesis and SAR Studies of 2-Oxoquinoline Derivatives as CB2 Receptor Inverse Agonists Katri H. Raitio*, Juha R. Savinainen, Jouko Vepsäläinen, Jarmo T. Laitinen, Antti Poso, Tomi Järvinen and Tapio Nevalainen Contents: Elemental analysis (S2) and spectroscopic data (S3-S5). S1
Elemental Analyses Compound Formula %C %H %N 9a C 24 H 26 N 2 O 6 0.18 hexane a Calc. 66.12 6.25 5.78 66.35 6.33 6.17 9b C 24 H 26 N 2 O 6 Calc. 65.47 6.05 6.43 65.75 5.98 6.39 9c C 23 H 26 N 2 O 4 Calc. 70.16 6.78 7.16 70.03 6.64 7.10 9d C 24 H 28 N 2 O 4 Calc. 70.32 6.95 7.12 70.57 6.91 6.86 9e C 25 H 30 N 2 O 4 Calc. 70.86 7.25 6.53 71.07 7.16 6.63 9f C 24 H 27 N 3 O 6 0.18 hexane 0.18 EtOAc a Calc. 63.84 63.95 6.49 6.48 8.31 8.60 9g C 24 H 27 ClN 2 O 4 Calc. 64.84 6.14 6.32 65.08 6.26 6.22 9h C 24 H 28 N 2 O 5 0.12 H 2 O a Calc. 67.18 6.77 6.56 67.56 6.67 6.57 9i C 24 H 29 N 3 O 4 0.75 H 2 O a Calc. 66.02 7.08 9.22 65.96 7.03 9.61 9j C 24 H 28 N 2 O 6 Calc. 65.54 6.47 6.19 65.44 6.41 6.36 9k C 23 H 26 N 2 O 6 0.25 H 2 O a Calc. 63.71 6.36 6.18 64.10 6.20 6.50 9l C 22 H 25 N 3 O 4 0.18 EtOAc a Calc. 66.71 6.51 10.05 66.60 6.42 10.44 9m C 26 H 29 N 3 O 4 Calc. 69.90 6.54 9.30 69.78 6.53 9.39 a based on 1 H NMR S2
Spectroscopic data 3-Hydroxy-4-methoxy-2-nitro-benzaldehyde (2) 1 H NMR (DMSO) δ: 10.72 (bs, 1H), 9.76 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H). 4-Methoxy-2-nitro-3-pentyloxy-benzaldehyde (3) 1 H NMR (DMSO) δ: 9.80 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.05 (t, J = 6.5 Hz, 2H), 4.00 (s, 3H), 1.64-1.59 (m, 2H), 1.34-1.30 (m, 4H), 0.90-0.87 (m, 3H). 2-Amino-4-methoxy-3-pentyloxy-benzaldehyde (4) 1 H NMR (CDCl 3 ) δ: 9.74 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 8.8 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 1.80-1.75 (m, 2H), 1.48-1.35 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid ethyl ester (5) 1 H NMR (DMSO) δ: 10.86 (s, 1H), 8.42 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.98 (t, J = 6.9 Hz, 2H), 3.92 (s, 3H), 1.80-1.74 (m, 2H), 1.39 1.34 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.06 Hz, 3H). 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (6) 1 H NMR (DMSO) δ: 14.74 (s, 1H), 12.35 (s, 1H), 8.9 (s, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 4.01 (t, J = 6.9 Hz, 2H), 3.97 (s, 3H), 1.82-1.76 (m, 2H), 1.39-1.33 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H). 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide (7) 1 H NMR (CDCl 3 ) δ: 9.34 (bs, 1H), 9.18 (bs, 1H), 8.88 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.80 (bs, 1H), 4.14 (t, J = 6.9 Hz, 2H), 3.98 (s, 3H), 1.85-1.79 (m, 2H), 1.49-1.37 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H). 3-Amino-7-methoxy-8-pentyloxy-1H-quinolin-2-one (8) 1 H NMR (DMSO) δ: 10.66 (bs, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.70 (s, 1H), 5.21 (bs, 2H), 3.96 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 1.80-1.74 (m, 2H), 1.40-1.31 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). 2-Benzo[1,3]dioxol-5-yl-N-(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-quinolin-3-yl)-acetamide (9a) 1 H NMR (DMSO) δ: 11.25 (s, 1H), 9.41 (s, 1H), 8.55 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 1.1 Hz, 1H), 6.86-6.81 (m, 2H), 5.98 (s, 2H), 3.97 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 3.74 (s, 2H), 1.80-1.75 (m, 2H), 1.39-1.29 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H). 13 C NMR (DMSO) δ: 170.18, 157.65, 151.44, 147.11, 145.91, 132.77, 129.34, 128.84, 126.54, 122.42, 122.23, 121.20, 114.43, 109.56, 108.67, 108.02, 100.70, 72.69, 56.11, 42.50, 28.73, 27.36, 21.87, 13.86. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (benzo[1,3]dioxol-5- ylmethyl)-amide (9b) 1 H NMR (CDCl 3 ) δ: 9.94 (t, J = 6.1 Hz, 1H), 9.14 (bs, 1H), 8.89 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H), 6.85-6.82 (m, 1H), 6.76 (d, J = 7.9 Hz, 1H), 5.93 (s, 2H), 4.58 (d, J = 5.8 Hz, 2H), 4.13 (t, J = 6.9 Hz, 2H), 3.98 (s, 3H), 1.84-178 (m, 2H), 1.48-1.37 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H). S3
13 C NMR (CDCl 3 ) δ: 163.54, 162.12, 154.39, 147.83, 146.73, 145.08, 133.49, 132.58, 132.40, 125.35, 120.92, 119.53, 114.30, 109.08, 108.43, 108.25, 100.95, 73.84, 56.29, 43.35, 29.87, 28.01, 22.44, 14.01. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid benzylamide (9c) 1 H NMR (DMSO) δ: 11.39 (s, 1H), 10.12 (t, J = 6.6 Hz, 1H), 8.79 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.35-7.33 (m, 4H), 7.28-7.24 (m, 1H), 7.13 (d, J = 8.9 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.00 (t, J = 6.9 Hz, 2H), 3.93 (s, 3H), 1.81-1.75 (m, 2H), 1.41-1.31 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H). 13 C NMR (DMSO) δ:162.99, 162.25, 154.74, 144.17, 139.17, 133.94, 132.32, 128.33 (2C), 127.18 (2C), 126.81, 125.68, 118.83, 113.80, 109.23, 72.82, 56.28, 42.34, 28.73, 27.35, 21.88, 13.87. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid phenethylamide (9d) 1 H NMR (CDCl 3 ) δ: 9.67 (t, J = 5.2 Hz, 1H), 9.11 (bs, 1H), 8.86 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.34-7.21 (m, 5H), 6.93 (d, J = 8.8 Hz, 1H), 4.13 (t, J = 6.9 Hz, 2H), 3.97 (s, 3H), 3.76-3.71 (m, 2H), 2.95 (t, J = 7.3 Hz, 2H), 1.84-1.77 (m, 2H), 1.48-1.36 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H). 13 C NMR (CDCl 3 ) δ: 163.54, 162.10, 154.30, 144.77, 139.29, 133.45, 132.43, 128.85 (2C), 128.53 (2C), 126.40, 125.28, 119.71, 114.32, 109.05, 73.84, 56.30, 41.08, 35.87, 29.91, 28.02, 22.45, 14.00. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3-phenyl-propyl)-amide (9e) 1 H NMR (DMSO) δ: 11.37 (s, 1H), 9.82 (t, J = 5.5 Hz, 1H), 8.75 (s, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.30-7.27 (m, 2H), 7.24-7.22 (m, 2H), 7.20-7.26 (m, 1H), 7.12 (d, J = 8.9 Hz, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.93 (s, 3H), 3.34 (t, J = 6.7 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H), 1.88-1.76 (m, 4H), 1.40-1.30 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H). 13 C NMR (DMSO) δ: 162.84, 162.30, 154.65, 143.82, 141.36, 133.85, 132.33, 128.22 (2C), 128.20 (2C), 125.70, 125.59, 119.02, 113.81, 109.21, 72.84, 56.27, 38.10, 32.50, 30.82, 28.76, 27.37, 21.89, 13.87. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-nitro-phenyl)-ethyl]- amide (9f) 1 H NMR (CDCl 3 ) δ: 9.73 (t, J = 5.7 Hz, 1H), 9.14 (s, 1H), 8.84 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.46-7.42 (m, 3H), 6.94 (d, J = 8.8 Hz, 1H), 4.14 (t, J = 7.0 Hz, 2H), 3.98 (s, 3H), 3.79-3.75 (m, 2H), 3.07 (t, J = 7.1 Hz, 2H), 1.84-1.78 (m, 2H), 1.49-1.35 (m, 4H), 0.95 (t, J = 7.12 Hz, 3H). 13 C NMR (CDCl 3 ) δ: 163.75, 162.10, 154.46, 147.15, 146.80, 144.99, 133.46, 132.44, 129.71 (2C), 125.36, 123.80 (2C), 119.26, 114.26, 109.18, 73.86, 56.31, 40.30, 35.79, 29.91, 28.02, 22.45, 14.01. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-chlorophenyl)-ethyl]- amide (9g) 1 H NMR (DMSO) δ: 11.16 (bs, 1H), 9.80 (t, J = 5.8 Hz, 1H), 8.73 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.30-7.26 (m, 4H), 7.05 (d, J = 8.9 Hz, 1H), 4.02 (t, J = 6.9 Hz, 2H), 3.94 (s, 3H), 3.64-3.59 (m, 2H), 2.87 (t, J = 6.9 Hz, 2H), 1.84-1.77 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H). 13 C NMR (DMSO) δ: 163.00, 162.26, 154.61, 143.88, 138.12, 133.95, 132.46, 131.09, 130.35 (2C), 128.20 (2C), 125.41, 118.94, 113.87, 108.99, 72.98, 56.14, 40.13, 34.65, 28.94, 27.49, 22.04, 13.93. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)- ethyl]-amide (9h) 1 H NMR (CDCl 3 ) δ: 9.75 (t, J = 5.8 Hz, 1H), 9.23 (bs, 1H), 8.86 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 7.02 (bs, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 4.11 (t, J = 6.9 Hz, 2H), 3.96 (s, 3H), 3.73-7.69 (m, 2H), 2.86 (t, J = 7.1 Hz, 2H), 1.84-1.78 (m, 2H), 1.46-1.34 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). S4
13 C NMR (CDCl 3 ) δ: 163.72, 162.24, 155.00, 154.42, 145.07, 133.38, 132.46, 130.53, 129.85 (2C), 125.39, 119.32, 115.57 (2C), 114.33, 109.22, 73.88, 56.29, 41.43, 34.90, 29.87, 27.98, 22.44, 14.00. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-aminophenyl)-ethyl]- amide (9i) 1 H NMR (CDCl 3 ) δ: 9.64 (s, 1H), 9.18 (s, 1H), 8.85 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 7.9 Hz, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 2H), 4.12 (t, J = 6.9 Hz, 2H), 3.97 (s, 3H), 3.69-3.64 (m, 2H), 2.83 (t, J = 7.2 Hz, 2H), 1.84-1.78 (m, 2H), 1.48-1.36 (m, 4H), 0.94 (t, J = 6.7 Hz, 3H). 13 C NMR (CDCl 3 ) δ: 163.42, 162.08, 154.22, 144.70, 144.68, 133.37, 132.36, 129.59 (2C), 129.20, 125.22, 119.67, 115.34 (2C), 114.27, 108.97, 73.77, 56.23, 41.37, 34.93, 29.84, 27.95, 22.39, 13.96. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(3,4-dihydroxyphenyl)- ethyl]-amide (9j) 1 H NMR (DMSO) δ: 11.35 (bs, 1H), 9.73 (t, J = 5.7 Hz, 1H), 8.74 (s, 1H), 8.70 (bs, 1H), 8.62 (bs, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.639 (d, J = 2.0 Hz, 1H), 6.638 (d, J = 8.0 Hz, 1H), 6.50 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 3.99 (t, J = 6.9 Hz, 2H), 3.93 (s, 3H), 3.48-3.53 (m, 2H), 2.66 (t, J = 7.1 Hz, 2H), 1.81-1.75 (m, 2H), 1.40-1.32 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). 13 C NMR (DMSO) δ: 162.73, 162.17, 154.63, 145.05, 143.77, 143.52, 133.88, 132.32, 129.99, 125.55, 119.22, 118.97, 115.91, 115.44, 113.77, 109.09, 72.83, 56.24, 40.59, 34.60, 28.77, 27.37, 21.92, 13.89. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid 3,4-dihydroxy-benzylamide (9k) 1 H NMR (CDCl 3 ) δ: 10.07 (t, J = 5.3 Hz, 1H), 9.12 (bs, 1H), 8.81 (s, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.13 (bs, 1H), 6.94-6.90 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.73 (dd, J = 1.96 Hz, 8.1 Hz, 1H), 6.15 (bs, 1H), 4.53 (d, J = 6.01 Hz, 2H), 4.11 (t, J = 6.69 Hz, 2H), 3.97 (s, 3H), 1.82-1.76 (m, 2H), 1.46-1.35 (m, 4H), 0.93 (t, J = 7.17 Hz, 3H). 13 C NMR (CDCl 3 ) δ: 163.96, 162.14, 154.59, 145.30, 144.41, 143.83, 133.44, 132.54, 130.53, 125.45, 119.72, 119.07, 115.35, 114.81, 114.32, 109.43, 73.93, 56.33, 43.41, 29.88, 28.04, 22.43, 13.96. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-amino-phenyl)-amide (9l) 1 H NMR (CDCl 3 ) δ: 11.50 (br s, 1H), 9.31 (br s, 1H), 8.95 (s), 7.58 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.07-7.04 (m, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.85-6.81 (m, 2H), 4.16 (t, J = 6.9 Hz, 2H), 4.02 (br s, 2H), 3.99 (s, 3H), 1.85-1.79 (m, 2H), 1.49-1.37 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H). 13 C NMR (CDCl 3 ) δ: 162.38, 161.54, 154.58, 145.40, 140.10, 133.57, 132.50, 126.46, 125.47, 124.77, 124.72, 119.49, 119.16, 117.47, 114.37, 109.31, 73.91, 56.33, 29.90, 28.01, 22.45, 14.00. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(1H-indol-3-yl)-ethyl]- amide (9m) 1 H NMR (DMSO) δ: 11.34 (bs, 1H), 10.81, (bs, 1H), 9.82 (t, J = 5.5 Hz, 1H), 8.76 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.20 (bs, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.12-7.05 (m, 1H), 6.99-6.97 (m, 1H), 3.99 (t, J = 6.9 Hz, 2H), 3.92 (s, 3H), 3.68-3.63 (m, 2H), 2.97 (t, J = 6.98 Hz, 2H), 1.81-1.75 (m, 2H), 1.40-1.31 (m, 4H), 0.90 (t, J = 7.06 Hz, 3H). 13 C NMR (DMSO) δ: 162.76, 162.16, 154.62, 143.78, 136.25, 133.86, 132.30, 127.07, 125.57, 122.71, 120.84, 119.04, 118.25, 118.15, 113.77, 111.56, 111.27, 109.13, 72.80, 56.25, 39.77, 28.74, 27.34, 25.13, 21.88, 13.87. S5
S6