RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2015, 348, 347–352
Tetrahydroisoquinoline Derivatives as Analgesia Drugs
Archiv der Pharmazie
–
1593, 1538 (aromatic); Anal. calcd. for C16H15N3O3: C, 64.64; H,
5.09; N, 14.13%. Found: C, 64.81; H, 5.21; N, 14.01%.
(nN–H), 1659 (nC O), 1596, 1531 (aromatic); Anal. calcd. for
–
C
16H14ClN3O3: C, 57.93; H, 4.25; N, 12.67%. Found: C, 57.64; H,
4.49; N, 12.61%.
N-(2-Ethylphenyl)-5-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxamide (I 5)
N-(2-Nitrophenyl)-5-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxamide (I 9)
Yield 26.7%, white solid, m.p. 143–145°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 8.20 (s, 1H, NH), 7.86 (d, J ¼ 7.74 Hz, 1H, Ar–H),
7.57 (t, J ¼ 7.29 Hz, 1H, Ar–H), 7.46 (t, J ¼ 7.74 Hz, 1H, Ar–H),
7.19–7.12 (m, 4H, Ar–H), 4.74 (s, 2H, CCH2N), 3.71 (s, 2H,
Ar–OCH3), 3.05 (s, 2H, CH2CH2N), 2.59–2.50 (m, 2H,
Ar–CH2CH3), 1.08 (t, J ¼ 7.43 Hz, 1H, Ar–CH2CH3); 13C NMR
(DMSO-d6, 75 MHz): d ppm 155.80, 149.11, 139.37, 137.36,
136.98, 131.65, 129.60, 128.11, 127.18, 126.88, 125.71, 125.30,
122.45, 45.70, 40.88, 25.53, 23.73, 13.93; MS (ESI, m/z): 348.4
Yield 35.4%, white solid, m.p. 153–155°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 9.42 (s, 1H, NH), 7.91 (q, 2H, Ar–H), 7.71–7.60
(m, 3H, Ar–H), 7.48 (t, J ¼ 7.84 Hz, 1H, Ar–H), 7.26–7.10 (m, 1H,
Ar–H), 4.76 (s, 2H, CCH2N), 3.72 (t, J ¼ 5.80 Hz, 2H, CH2CH2N),
3.09 (t, J ¼ 5.61 Hz, 2H, CH2CH2N); 13C NMR (DMSO-d6, 75 MHz):
d ppm 154.06, 149.01, 140.78, 136.72, 134.28, 134.00, 131.69,
129.59, 127.00, 124.98, 123.98, 123.10, 122.61, 45.37, 40.79,
25.60; MS (ESI, m/z): 365.3 [MþNa]þ; IR (KBr, cmꢁ1): 3362
[MþNa]þ; IR (KBr, cmꢁ1): 3035 (nN–H), 1620 (nC O), 1603, 1521
(nN–H), 1672 (nC O), 1607, 1525 (aromatic); Anal. calcd. for
–
–
–
(aromatic); Anal. calcd. for C18H19N3O3: C, 66.45; H, 5.89; N,
12.91%. Found: C, 66.22; H, 5.82; N, 12.75%.
–
C
16H14N4O5: C, 56.14; H, 4.12; N, 16.37%. Found: C, 56.35; H,
4.21; N, 16.09%.
N-(4-Fluorophenyl)-5-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxamide (I 6)
N-(o-Tolyl)-5-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxamide (I 10)
Yield 41.1%, white solid, m.p. 164–166°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 8.71 (s, 1H, NH), 7.87 (d, J ¼ 7.83 Hz, 1H, Ar–H),
7.51–7.44 (m, 3H, Ar–H), 7.08 (t, J ¼ 8.86 Hz, 1H, Ar–H), 4.74 (s,
2H, CCH2N), 3.70 (t, J ¼ 5.79 Hz, 2H, CH2CH2N), 3.05 (t,
J ¼ 5.55 Hz, 2H, CH2CH2N); 13C NMR (DMSO-d6, 75 MHz): d ppm
159.02, 154.86, 149.04, 137.09, 136.60, 131.67, 129.61, 126.90,
122.50, 121.54, 121.44, 114.90, 114.61, 45.56, 40.64, 25.69; MS
(ESI, m/z): 338.3 [MþNa]þ; IR (KBr, cmꢁ1): 3038 (nN–H), 1635
Yield 61.1%, white solid, m.p. 154–156°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 8.23 (s, 1H, NH), 7.86 (d, J ¼ 7.86 Hz, 1H, Ar–H),
7.57 (d, J ¼ 7.44 Hz, 1H, Ar–H), 7.46 (d, J ¼ 7.63 Hz, 1H, Ar–H),
7.22–7.05 (m, 4H, Ar–H), 4.74 (s, 2H, CCH2N), 3.71 (t, J ¼ 5.79 Hz,
2H, CH2CH2N), 3.06 (t, J ¼ 5.64 Hz, 2H, CH2CH2N), 2.16 (s,
Ar–CH3); 13C NMR (DMSO-d6, 75 MHz): d ppm 155.35, 149.08,
137.69, 137.29, 133.82, 133.14, 131.67, 129.63, 126.88, 126.47,
126.06, 124.69, 122.47, 45.64, 40.75, 25.59, 17.86; MS (ESI, m/z):
(nC O), 1607, 1526 (aromatic); Anal. calcd. for C16H14FN3O3: C,
334.3 [MþNa]þ; IR (KBr, cmꢁ1): 3204 (nN–H), 1718, 1621 (nC O),
–
–
–
–
1574, 1521 (aromatic); Anal. calcd. for C17H17N3O3: C, 65.58; H,
5.50; N, 13.50%. Found: C, 65.49; H, 5.56; N, 13.41%.
60.95; H, 4.48; N, 13.33%. Found: C, 60.77; H, 4.63; N, 13.17%.
N-(2-Chlorophenyl)-5-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxamide (I 7)
N-(2-Methyl-5-chlorophenyl)-5-nitro-3,4-
Yield 25.9%, white solid, m.p. 156–158°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 8.38 (s, 1H, NH), 7.88 (d, J ¼ 7.86 Hz, 1H, Ar–H),
7.59 (d, J ¼ 7.53 Hz, 1H, Ar–H), 7.52–7.40 (m, 3H, Ar–H), 7.32–
7.27 (m, 1H, Ar–H), 7.18–7.06 (m, 1H, Ar–H), 4.75 (s, 2H, CCH2N),
3.73 (t, J ¼ 5.79 Hz, 2H, CH2CH2N), 3.07 (t, J ¼ 5.59 Hz, 2H,
CH2CH2N); 13C NMR (DMSO-d6, 75 MHz): d ppm 154.83, 149.06,
137.08, 136.38, 131.68, 129.61, 129.21, 128.30, 127.20, 126.92,
125.76, 122.52, 45.53, 40.79, 25.53; MS (ESI, m/z): 354.3
dihydroisoquinoline-2(1H)-carboxamide (I 11)
Yield 28.7%, white solid, m.p. 181–183°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 8.28 (s, 1H, NH), 7.87 (d, J ¼ 7.14 Hz, 1H, Ar–H),
7.59–7.46 (m, 1H, Ar–H), 7.35 (s, 1H, Ar–H), 7.21–7.09 (m, 2H,
Ar–H), 4.74 (s, 2H, CCH2N), 3.71 (s, 2H, CH2CH2N), 3.06 (s, 2H,
CH2CH2N), 2.15 (s, Ar–CH3); 13C NMR (DMSO-d6, 75 MHz):
d ppm 155.04, 148.99, 139.09, 137.00, 131.68, 131.49, 129.58,
126.94, 124.94, 124.12, 122.53, 45.55, 40.73, 25.52, 17.28; MS
(ESI, m/z): 368.0 [MþNa]þ; IR (KBr, cmꢁ1): 3200 (nN–H), 1701,
[MþNa]þ; IR (KBr, cmꢁ1): 3203 (nN–H), 1625 (nC O), 1583,
–
–
1520 (aromatic); Anal. calcd. for C16H14ClN3O3: C, 57.93; H,
4.25; N, 12.67%. Found: C, 58.11; H, 4.34; N, 12.51%.
–
1623 (nC O), 1560, 1522 (aromatic); Anal. calcd. for
–
C
17H16ClN3O3: C, 59.05; H, 4.66; N, 12.15%. Found: C, 59.24;
H, 4.51; N, 11.02%.
N-(3-Chlorophenyl)-5-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxamide (I 8)
Biological studies
Yield 44.2%, white solid, m.p. 148–150°C; 1H NMR (DMSO-d6,
300 MHz): d ppm 8.86 (s, 1H, NH), 7.87 (d, J ¼ 7.83 Hz, 1H, Ar–H),
7.67 (s, 1H, Ar–H), 7.59 (d, J ¼ 7.50 Hz, 1H, Ar–H), 7.50–7.42 (m,
2H, Ar–H), 7.27 (t, J ¼ 8.08 Hz, 1H, Ar–H), 7.00–6.98 (m, 1H,
Ar–H), 4.75 (s, 2H, CCH2N), 3.71 (t, J ¼ 5.79 Hz, 2H, CH2CH2N),
3.06 (t, J ¼ 5.58 Hz, 2H, CH2CH2N); 13C NMR (DMSO-d6, 75 MHz):
d ppm 154.45, 149.01, 141.96, 136.94, 132.70, 131.69, 129.92,
129.59, 126.92, 122.54, 121.37, 118.85, 117.74, 45.54, 40.69,
25.69; MS (ESI, m/z): 354.2 [MþNa]þ; IR (KBr, cmꢁ1): 3405
Evaluation of TRPV1 antagonism activity
The TRPV1 aequorin cells (PerkinElmer, USA) were collected
from culture plates with Ca2þ and Mg2þ-free phosphate-
buffered saline supplemented with 5 mM ethylenediaminete-
tra-acetic acid; pelleted for 2 min at 1000g; resuspended in
Dulbecco’s minimum essential medium–F12 medium with
15 mM HEPES (pH 7.0) and 0.1% BSA (assay buffer) at a density
of 3 ꢃ 105 cells/mL; incubated for 4 h in the dark in the presence
of 5 mM coelenterazine h (Promega, USA). After loading, cells
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