Design, synthesis and biological evaluation of CB1 cannabinoid receptor ligands 225
chromatography(CHCl3/MeOH, 8/1) to afford the titled
J= 2.3 Hz, 1H), 7.31–7.28(m, 4H), 7.14(s, 1H), 7.07–7.06(m,
2H), 3.47–3.42(m, 2H), 2.61–2.55(m, 6H), 2.37(s, 3H),
1.73–1.71(m, 6H), 1.99–1.63(m, 2H), 1.49(m, 2H); 13C-
NMR(CDCl3) δ 162.82, 144.97, 143.01, 135.92, 135.91,
134.88, 132.91, 130.8, 130.58, 130.27, 128.87, 127.89,
127.24, 117.61, 58.18, 54.06, 38.42, 27.59, 24.69, 23.64,
23.11, 9.41. ESI-MS: m/z [M]+: 519.3.
compound as a white solid in 63.4% yield. 1H-NMR(CDCl3)
δ 8.12(t, J=10.8 Hz, 1H), 7.43(d, J=1.7 Hz, 1H), 7.33–
7.28(m, 4H), 7.09–7.07(m, 2H), 3.65–3.62(m, 4H), 3.53(q,
J=18.1 Hz, 2H), 2.49(t, J=12.7 Hz, 2H), 2.44(br s, 4H),
2.39(s, 3H), 1.81–1.74(m, 2H); 13C-NMR(CDCl3) δ 162.68,
145.27, 142.94, 136.03, 135.93, 134.81, 132.95, 130.81,
130.5, 130.26, 128.86, 127.86, 127.31, 117.55, 66.74, 57.97,
53.77, 38.78, 25.25, 9.44. ESI-MS: m/z [M]+: 507.4.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-[2-(7-
methoxynaphthalen-2-yl)ethyl] -1H-pyrazol-3-carboxamide
(12g)
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-[3-(N,
N-diethylamino) propyl]-1H -pyrazol-3-
carboxamide (12c)
Starting with compound 10a and 2-(7-methoxynaph-
thalen-2-yl)ethanamine, then recrystallised from EtOAc
to afford the titled compound as a white solid in 42.9%
yield. 1H-NMR(CDCl3) δ 7.74(d, J= 9 Hz, 1H), 7.63(m,
1H), 7.51(m, 1H), 7.41(d, J= 2.2 Hz, 1H), 7.33(m, 1H),
7.31–7.26(m, 5H), 7.22(m, 1H), 7.21(m, 1H), 7.14(m, 1H),
7.06(m, 1H), 3.94(s, 3H), 3.78(q, J= 14.5 Hz, 2H), 3.36(t,
J= 14.8 Hz, 2H), 2.4(s, 3H); 13C-NMR(CDCl3) δ 162.85,
157.97, 145.03, 143.04, 135.94, 134.95, 133.89, 133.27,
132.98, 130.82, 130.48, 130.32, 130.21, 129.34, 128.92,
127.85, 127.26, 127.17, 126.97, 123.24, 118.32, 117.68,
102.5, 55.46, 39.78, 33.5, 9.42. ESI-MS: m/z [M]+: 564.2.
Starting with compound 10a and N,N-diethyl-1,3-
propanediamine, then purified with flash column
chromatography(CHCl3/MeOH, 8/1) to afford the titled
compoundasawhitesolidin56.4%yield.1H-NMR(CDCl3)
δ 7.45–7.42(m, 2H), 7.32–7.3(m, 4H), 7.08–7.06(m, 2H),
3.57–3.56(m, 2H), 3.15–3.14(m, 6H), 2.35(s, 3H), 2.21–
2.17(m, 2H), 1.41–1.38(m, 6H); 13C-NMR(CDCl3) δ 163.43
144.51, 143.15, 136.02, 135.76, 134.96, 132.71, 130.79,
130.6, 130.25, 128.9, 128, 127.07, 117.58, 49.44, 46.55,
36.24, 24.35, 9.37, 8.55. ESI-MS: m/z [M]+: 493.4.
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-
methylcyclohexyl)-1H-pyrazol -3-carboxamide (12d)
5-(4-Chlorophenyl)-4-methyl-1-(pyridin-2-yl)-N-(piperidin-
1-yl) -1H-pyrazole-3-carboxamide (12h)
Starting with compound 10a and 4-methylcyclohexy-
lamine, then purified with flash column chromatography
(n-hexane/AcOEt, 6/1) to afford the titled compound as
a white solid in 63% yield. 1H-NMR(CDCl3) δ 7.95(s, 1H),
7.42(d, J= 1.3 Hz, 1H), 7.3–7.27(m, 4H), 7.07–7.03(m, 3H),
4.19–4.17(m, 1H), 2.37(s, 3H), 1.78–1.75(m, 2H), 1.71–
1.67(m, 1H), 1.65–1.6(m, 3H), 1.59–1.24(m, 2H), 0.93(d,
J= 6.4 Hz, 3H); 13C-NMR(CDCl3) δ 161.95, 145.26, 142.95,
136.06, 135.86, 134.83, 133.02, 130.84, 130.64, 130.31,
128.86, 127.83, 127.4 117.68, 45.26, 30.32, 30.14, 29.33,
20.9, 9.46. ESI-MS: m/z [M]+: 476.1.
Starting with compound 10b and 1-aminopiperidin, then
purified with flash column chromatography (petroleum
ether/EtOAc, 5/1), and recrystallised from petroleum
ether/acetone to afford the titled compound as a white
1
solid in 40.4% yield. H-NMR(DMSO-d6) δ 9.12(s, 1H),
8.25(dd, J= 4.7 Hz, 0.8 Hz, 1H), 8.01–7.79(m, 1H), 7.77(d,
J= 8.2 Hz, 1H), 7.44(d, J= 8.4 Hz, 2H), 7.39–7.36(m, 1H),
7.22(d, J= 8.4 Hz, 2H), 2.82(t, J= 10.3 Hz, 4H), 2.17(s, 3H),
1.61–1.59(m, 4H), 1.36–1.34(m, 2H); 13C-NMR(DMSO-d6)
δ 159.95, 152.02, 148.43, 144.91, 140.98, 139.53, 133.5,
131.88, 129.35 128.81, 123.83, 119.45, 118.45, 55.82, 25.86,
9.3. ESI-MS: m/z [M]+: 396.3.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-
(pyrrolidin-1-yl)propyl)-1H-pyrazole-3-carboxamide (12e)
Starting with compound 10a and N-(3-aminopropyl)
tetrahydropyrrole, then purified with flash column
chromatography(CHCl3/MeOH, 8/1) to afford the
titled compound as a white solid in 23.1% yield. 1H-
NMR(CDCl3) δ 8.03(t, J= 10.4 Hz, 1H), 7.41(t. J= 3.1 Hz,
1H), 7.31–7.29(m, 4H), 7.07–7.05(m, 2H), 3.55–3.5(m,
2H), 2.61(t, J= 13.4 Hz, 2H), 2.51–2.5(m, 4H), 2.38(s, 3H),
1.83–1.72(m, 2H), 1.67–1.66(m, 4H); 13C-NMR(CDCl3)
δ 162.7, 145.37, 142.84, 136.13, 135.81, 134.79, 133.03,
130.81, 130.53, 130.2, 128.84, 127.75, 127.41, 117.55, 54.97,
54.1, 38.6, 27.96, 23.39, 9.43. ESI-MS: m/z [M]+: 491.4.
5-(4-Chlorophenyl)-4-methyl-1-(pyridin-2-yl)-N-(azepan-1-yl)-
1H-pyrazole-3-carboxamide (12i)
Starting with compound 10b and 1-aminoazepan, then
purified with flash column chromatography (petroleum
ether/EtOAc, 3/1), and recrystallised from petroleum
ether/EtOAc(5/1) to afford the titled compound as a white
solid in 17.8% yield. 1H-NMR(CDCl3) δ 8.34(dd, J= 4.8 Hz,
1.2 Hz, 1H), 8.21(s, 1H), 7.75–7.74(m, 1H), 7.38–7.32(m,
3H), 7.27–7.24(m, 1H), 7.13–7.1(m, 2H), 3.17(t, J= 11.1
Hz, 4H), 2.34(s, 3H), 1.79–1.76(m, 4H), 1.67–1.64(m, 4H);
13C-NMR(CDCl3) δ 160.36, 151.8, 148.57, 144.4, 141.3,
138.3, 134.44, 131.15, 128.64, 122.85, 119.87, 118.7, 58.4,
26.99, 26.51, 9.22. ESI-MS: m/z [M]+: 410.2.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-
(piperidin-1-yl)butyl)-1H-pyrazole-3-carboxamide (12f)
Starting with compound 10a and 4-(1-piperidyl)-1-
butylamine, then purified with flash column chromatog-
raphy (CHCl3/MeOH, 6/1) to afford the titled compound
5-(4-Chlorophenyl)-4-methyl-1-(pyridin-2-yl)-N-(4-
methylcyclohexyl)-1H-pyrazole-3-carboxamide (12j)
Starting with compound 10b and 1-aminoazepan, then
purified with flash column chromatography (petroleum
ether/acetone, 5/1), and recrystallised from petroleum
1
as a white solid in 31.6% yield. H-NMR(CDCl3) δ 7.42(t,
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