Carboxamide DeriVatiVes as Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 20 5953
with water, and the precipitate formed was collected by filtration,
whereas for 16, the solvent was evaporated in vacuo and the solid
obtained was treated with water and collected by filtration.
N-(4′-Methylcyclohexyl)-1-benzyl-7-methyl-1,8-naphthyridin-
4(1H)-on-3-carboxamide (6). Yield 0.310 g, 80%; mp 239-241
3H, Ar), 4.70 (m, 2H, CH2), 3.80 (m, 1H, CH), 3.03 (m, 4H,
piperazinyl), 2.73 (m, 2H, CH2), 2.66 (s, 3H, CH3), 2.60 (m, 4H,
piperazinyl), 1.85-1.08 (m, 10H, cyclohexyl). Anal. (C28H35N5O2)
C, H, N
N-Cyclohexyl-7-methyl-1-phenethyl-1,8-naphthyridin-4(1H)-
on-3-carboxamide (16). Purified by flash chromatography (ethyl
acetate/hexane, 2:3), yield 0.110 g, 28%; mp 148-150 °C (crystal-
1
°C (crystallized from ethyl acetate); MS m/z 389 (M+); H NMR
δ 10.20, 9.75 (2d, 1H, NH), 9.08, 9.06 (2s, 1H, H2), 8.52, 8.60
(2d, 1H, H5), 7.48 (d, 1H, H6), 7.33 (m, 5H, Ar), 5.80 (s, 2H, CH2),
4.12, 3.69 (2m, 1H, CH), 2.63 (s, 3H, CH3), 2.20-0.86 (m, 12H,
cyclohexyl + CH3). Anal. (C24H27N3O2) C, H, N.
1
lized from hexane); MS m/z 389 (M+); H NMR δ 9.86 (d, 1H,
NH), 8.85 (s, 1H, H2), 8.54 (d, 1H, H5), 7.48 (d, 1H, H6), 7.24 (m,
5H, Ar), 4.76 (m, 2H, CH2), 3.90 (m, 1H, CH), 3.10 (m, 2H, CH2),
2.69 (s, 3H, CH3), 1.85-1.23 (m, 10H, cyclohexyl). Anal.
(C24H27N3O2) C, H, N.
N-(4′-Methylcyclohexyl)-1-(p-fluorobenzyl)-7-methyl-1,8-naph-
thyridin-4(1H)-on-3-carboxamide (7). Yield 0.270 g, 66%; mp
1
167-169 °C (crystallized from n-hexane); MS m/z 407 (M+); H
N-Cyclohexyl-7-methyl-1-(4-methoxybenzyl)-1,8-naphthyri-
din-4(1H)-on-3-carboxamide (17). Purified by flash chromatog-
raphy (ethyl acetate/hexane, 2: 1), 0.283 g, 70%; mp 170-172 °C
NMR δ 10.18, 9.77 (2d, 1H, NH), 9.12, 9.10 (2s, 1H, H2), 8.59,
8.52 (2d, 1H, H5), 7.50 (m, 3H, Ar + H6), 7.16 (m, 2H, Ar), 5.77
(s, 2H, CH2), 4.18, 3.70 (2m, 1H,CH), 2.65 (s, 3H, CH3), 1.98-
0.86 (m, 12H, cyclohexyl + CH3). Anal. (C24H26FN3O2) C, H, N.
N-(4′-Methylcyclohexyl)-1-(o-fluorobenzyl)-7-methyl-1,8-naph-
thyridin-4(1H)-on-3-carboxamide (8). Yield 0.245 g, 60%; mp
1
(crystallized from hexane); MS m/z 405 (M+); H NMR: δ 9.90
(d, 1H, NH), 9.05 (s, 1H, H2), 8.54 (d, 1H, H5), 7.47 (d, 1H, H6),
7.35 (d, 2H, Ar), 6.89 (d, 2H, Ar), 5.70 (s, 2H, CH2), 3.80 (m, 1H,
CH), 3.70 (s, 3H, OCH3), 2.67 (s, 3H, CH3), 1.90-1.30 (m, 10H,
cyclohexyl). Anal. (C24H27N3O3) C, H, N.
1
183-185 °C (crystallized from n-hexane); MS m/z 407 (M+); H
NMR δ 10.18, 9.77 (2d, 1H, NH), 9.09, 9.07 (2s, 1H, H2), 8.58,
8.52 (2d, 1H, H5), 7.46 (d, 1H, H6), 7.36-7.14 (m, 4H, Ar), 5.81
(s, 2H, CH2), 4.15, 3.70 (2m, 1H, CH), 2.61 (s, 3H, CH3), 2.00-
0.86 (m, 12H, cyclohexyl + CH3). Anal. (C24H26FN3O2) C, H, N.
N-Cycloheptyl-1-benzyl-7-methyl-1,8-naphthyridin-4(1H)-on-
3-carboxamide (9). Yield 0.225 g, 58%; mp 198-200 °C (crystal-
N-Cyclohexyl-1-(p-fluorbenzyl)-1,8-naphthyridin-4(1H)-on-3-
carboxamide (18). Yield 0.185 g, 49%; mp 193-195 °C (crystal-
1
lized from hexane); MS m/z 379 (M+); H NMR δ 9.80 (d, 1H,
NH), 9.15 (s, 1H, H2), 8.90 (dd, 1H, H7), 8.67 (dd, 1H, H5), 7.62
(m, 1H, H6), 7.37 (m, 2H, Ar), 7.15 (m, 2H, Ar), 5.81 (s, 2H, CH2),
3.85 (m, 1H, CH), 1.86-1.23 (m, 10H, cyclohexyl). Anal. (C22H22-
FN3O2) C, H, N.
1
lized from cyclohexane); MS m/z 389 (M+); H NMR δ 9.88 (d,
1H, NH), 9.07 (s, 1H, H2), 8.55 (d, 1H, H5), 7.48 (d, 1H, H6), 7.33
(m, 5H, Ar), 5.79 (s, 2H, CH2), 4.15 (m, 1H, CH), 2.64 (s, 3H,
CH3), 1.85-1.39 (m, 12H, cycloheptyl). Anal. (C24H27N3O2) C,
H, N.
N-Cycloheptyl-1-(p-fluorobenzyl)-7-methyl-1,8-naphthyridin-
4(1H)-on-3-carboxamide (10). Yield 0.300 g, 75%; mp 194-196
°C (crystallized from hexane); MS m/z 407 (M+); 1H NMR δ 9.91
(d, 1H, NH), 9.10 (s, 1H, H2), 8.55 (d, 1H, H5), 7.48 (m, 3H, Ar
+H6), 7.16 (m, 2H, Ar), 5.77 (s, 2H, CH2), 4.15 (m, 1H, CH),
2.64 (s, 3H, CH3), 1.85-1.39 (m, 12H, cycloheptyl). Anal. (C24H26-
FN3O2) C, H, N.
N-Cycloheptyl-1-(o-fluorbenzyl)-7-methyl-1,8-naphthyridin-
4(1H)-on-3-carboxamide (11). Yield 0.255 g, 63%; mp 188-189
°C (crystallized from cyclohexane); MS m/z 407 (M+); 1H NMR δ
9.90 (d, 1H, NH), 9.07 (s, 1H, H2), 8.55 (d, 1H, H5), 7.46 (d, 1H,
H6), 7.32-7.14 (m, 4H, Ar), 5.81 (s, 2H, CH2), 4.15 (m, 1H, CH),
2.61 (s, 3H, CH3), 1.85-1.39 (m, 12H, cycloheptyl). Anal. (C24H26-
FN3O2) C, H, N.
N-Cyclohexyl-1-benzyl-7-chloro-1,8-naphthyridin-4(1H)-on-
3-carboxamide (12). Yield 0.275 g, 70%; mp 258-260 °C
(crystallized from hexane); MS m/z 395 (M+); 1H NMR δ 9.72 (d,
1H, NH), 9.12 (s, 1H, H2), 8.66 (d, 1H, H5), 7.67 (d, 1H, H6), 7.32
(m, 5H, Ar), 5.73 (s, 2H, CH2), 3.85 (m, 1H, CH), 1.85-1.32 (m,
10H, cyclohexyl). Anal. (C22H22ClN3O2) C, H, N.
N-Cyclohexyl-1-benzyl-1,8-naphthyridin-4(1H)-on-3-carbox-
amide (19). Yield 0.200 g, 55%; mp 181-183 °C (crystallized from
hexane); MS m/z 361 (M+); 1H NMR δ 9.95 (d, 1H, NH), 9.12 (s,
1H, H2), 8.90 (dd, 1H, H7), 8.70 (dd, 1H, H5), 7.70 (m, 1H, H6),
7.29 (m, 5H, Ar), 5.84 (s, 2H, CH2), 3.85 (m, 1H, CH), 1.86-1.30
(m, 10H, cyclohexyl). Anal. (C22H23N3O2) C, H, N.
N-Cyclohexyl-1-(2-morpholin-4-yl-ethyl)-1,8-naphthyridin-
4(1H)-on-3-carboxamide (20). Yield 0.155 g, 40%; mp 142-144
°C (crystallized from hexane); MS m/z 384 (M+); 1H NMR δ 9.84
(d, 1H, NH), 8.98 (s, 1H, H2), 8.90 (dd, 1H, H7), 8.68 (dd, 1H,
H5), 7.60 (m, 1H, H6), 4.66 (t, 2H, CH2), 3.86 (m, 1H, CH), 3.49
(m, 4H, morpholine), 2.70 (m, 2H, CH2), 2.44 (m, 4H, morpholine),
1.85-0.82 (m, 10H, cyclohexyl). Anal. (C21H28N4O3 ) C, H, N.
N-(4′-Methylcyclohexyl)-7-chloro-1-(2-morpholin-4-yl-ethyl)-
1,8-naphthyridin-4(1H)-on-3-carboxamide (33). Purified by flash
chromatography (ethyl acetate/hexane, 1: 1), yield 0.130, 30%; mp
191-193 °C (crystallized from cyclohexane); MS m/z 432 (M+);
1H NMR δ 10.20, 10.00 (2d, 1H, NH), 8.65, 8,61 (2s, 1H, H2),
8.20, 8,18 (2d, 1H, H5), 6.87 (d, 1H, H6), 4.51 (m, 2H, CH2), 4.00
(m, 1H, CH), 3.51 (m, 4H, morpholine), 2.67 (m, 2H, CH2), 2.44
(m, 4H, morpholine), 1.89-0.76 (m, 12H, cyclohexyl + CH3). Anal.
(C22H29ClN4O3 ) C, H, N.
N-Cyclohexyl-1,8-naphthyridin-4(1H)-on-3-carboxamide (5).
A solution of 7-chloronaphthyridine 434 (0.40 g, 1.31 mmol) in
methanol (20 mL) was submitted to hydrogenation in the presence
of 10% Pd/C (0.04 g) at room pressure and temperature for 3 h.
The catalyst was filtered off, and the solvent was evaporated to
dryness under reduced pressure to give a residual solid, which was
purified by flash chromatography (ethyl acetate) and crystallized
from hexane to give 5 (0.110 g, 31%): mp 215-218 °C; 1H NMR
δ 9.85 (d, 1H, NH), 8.84 (dd, 1H, H7), 8.68 (s, 1H, H2), 8.65 (dd,
1H, H5), 7.55 (m, 1H, H6), 3.85 (m, 1H, CH), 1.86-1.22 (m, 10H,
cyclohexyl). Anal. (C15H17N3O2) C, H, N.
General Procedure for the Preparation of N1-Substituted
4-Hydroxy-7-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-3-car-
boxamides 24-26. NaBH4 (0.30 g, 8 mmol) was added to a
solution of the appropiate 7-methyl-1,8-naphthyridin-4(1H)-on-3-
carboxamide derivatives 21-2334 (0.38 mmol) in absolute ethanol
(7.5 mL), and the mixture was stirred at room temperature for 12
h. The organic solvent was evaporated from the reaction mixture
under reduced pressure to obtain a residue, which was treated with
H2O. In the cases of 24 and 26, the solid precipitate obtained was
collected by filtration and purified by crystallization from hexane,
whereas for 25 the mixture was extracted with chloroform, the
N-Cyclohexyl-7-chloro-1-(p-fluorbenzyl)-1,8-naphthyridin-
4(1H)-on-3-carboxamide (13). Purified by flash chromatography
(ethyl acetate/hexane, 5:6), yield 0.100 g, 25%; mp 198-200 °C
1
(crystallized from cyclohexane); MS m/z 413 (M+); H NMR δ
9.72 (d, 1H, NH), 9.14 (s, 1H, H2), 8.65 (d, 1H, H5), 7.68 (d, 1H,
H6), 7.44 (m, 2H, Ar), 7.18 (m, 2H, Ar), 5.71 (s, 2H, CH2), 3.89
(m, 1H, CH), 1.90-1.17 (m, 10H, cyclohexyl). Anal. (C22H21-
ClFN3O2) C, H, N.
N-Cyclohexyl-7-chloro-1-(o-fluorbenzyl)-1,8-naphthyridin-
4(1H)-on-3-carboxamide (14). Yield 0.300 g, 73%; mp 198-200
°C (crystallized from cyclohexane); MS m/z 413 (M+); 1H NMR δ
9.72 (d, 1H, NH), 9.11 (s, 1H, H2), 8.65 (d, 1H, H5), 7.67 (d, 1H,
H6), 7.41-7.12 (m, 4H, Ar), 5.76 (s, 2H, CH2), 3.85 (m, 1H, CH),
1.98-1.32 (m, 10H, cyclohexyl). Anal. (C22H21ClFN3O2) C, H, N.
N-Cyclohexyl-7-methyl-1-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,8-naphthyridin-4(1H)-on-3-carboxamide (15). Purified by flash
chromatography (ethyl acetate/hexane/triethylamine, 10:1:0.2), yield
0.120 g, 25%; mp 147-149 °C (crystallized from hexane); MS
m/z 473 (M+); 1H NMR δ 9.87 (d, 1H, NH), 8.94 (s, 1H, H2), 8.53
(d, 1H, H5), 7.46 (d, 1H, H6), 7.18 (m, 2H, Ar), 6.90-6.71 (m,