3-(2,6-Dichlorophenyl)-1,6-naphthyridin-2(1H)-ones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3141
2CH2), 1.03 (t, J ) 7.2 Hz, 6 H, 2CH3); 13C NMR δ 160.78,
159.86 (2 s, C-2,7), 150.76 (d, C-5), 147.25 (s, C-8a), 138.28 (d,
C-4), 135.85 (s, 2 C, C-2′,6′), 134.87 (s, C-1′), 129.53 (d, C-4′),
127.92 (d, 2 C, C-3′,5′), 124.05 (s, C-3), 109.30 (s, C-4a), 86.61
(d, C-8), 52.73 (t, NCH2), 46.86 (t, 2 C, N(CH2)2), 42.47 (t,
NCH2), 29.38 (q, NCH3), 29.15, 26.85, 25.07 (3 t, 3CH2), 11.59
(q, 2 C, 2CH3). Anal. (C24H30Cl2N4O) C, H, N.
treatment of 17 with 4-(3-aminopropyl)morpholine (10 equiv)
in 2-pentanol at reflux for 16 h, followed by chromatography
on silica gel, eluting with 3-5% MeOH/CH2Cl2, treatment with
aqueous Na2CO3 and extraction with CH2Cl2 (3 × 50 mL), gave
7k (93%): mp (CH2Cl2/light petroleum) 157-159 °C; 1H NMR
(CDCl3) δ 8.33 (s, 1 H, H-5), 7.52 (s, 1 H, H-4), 7.40 (d, J ) 7.9
Hz, 2 H, H-3′,5′), 7.24 (dd, J ) 8.6, 7.6 Hz, 1 H, H-4′), 6.03 (s,
1 H, H-8), 5.87 (br t, J ) 5.2 Hz, 1 H, NHCH2), 3.77 (t, J ) 4.7
Hz, 4 H, O(CH2)2), 3.65 (s, 3 H, NCH3), 3.45 (q, J ) 6.1 Hz, 2
H, NHCH2), 2.54 (t, J ) 6.6 Hz, 2 H, NCH2), 2.50 (br m, 4 H,
N(CH2)2), 1.87 (pentet, J ) 6.5 Hz, 2 H, CH2); 13C NMR δ
160.77, 159.95 (2 s, C-2,7), 150.82 (d, C-5), 147.18 (s, C-8a),
138.29 (d, C-4), 135.83 (s, 2 C, C-2′,6′), 134.86 (s, C-1′), 129.53
(d, C-4′), 127.92 (d, 2 C, C-3′,5′), 123.99 (s, C-3), 109.27 (s,
C-4a), 86.73 (d, C-8), 67.02 (t, 2 C, O(CH2)2), 57.20 (t, NCH2),
53.77 (t, 2 C, N(CH2)2), 41.61 (t, NCH2), 29.36 (q, NCH3), 25.29
(t, CH2). Anal. (C22H24Cl2N4O2) C, H, N.
3-(2,6-Dich lor op h en yl)-1-m eth yl-7-[[3-(4-m eth ylp ip er -
azin -1-yl)pr opyl]am in o]-1,6-n aph th yr idin -2(1H)-on e (7h ).
Similar treatment of 17 with 1-(3-aminopropyl)-4-methylpip-
erazine (11 equiv) in 2-pentanol at reflux for 16 h, followed by
chromatography on silica gel, eluting with 3-6% MeOH/CH2-
Cl2 containing 0.3% Et3N, treatment with aqueous Na2CO3 and
extraction with EtOAc (3 × 50 mL) gave 7h (87%): mp (CH2-
1
Cl2/hexane) 164-166 °C; H NMR [(CD3)2SO] δ 8.40 (s, 1 H,
H-5), 7.74 (s, 1 H, H-4), 7.56 (d, J ) 7.9 Hz, 2 H, H-3′,5′), 7.43
(dd, J ) 8.7, 7.5 Hz, 1 H, H-4′), 7.21 (br t, J ) 5.6 Hz, 1 H,
NHCH2), 6.24 (s, 1 H, H-8), 3.50 (s, 3 H, NCH3), 3.34 (q, J )
6.4 Hz, 2 H, NHCH2), 2.6-2.1 (br s, 8 H, N(CH2)4N), 2.36 (t,
J ) 7.1 Hz, 2 H, NCH2), 2.14 (s, 3 H, NCH3), 1.71 (pentet, J )
6.9 Hz, 2 H, CH2); 13C NMR δ 160.15, 159.80 (2 s, C-2,7), 150.73
(d, C-5), 146.07 (s, C-8a), 138.32 (d, C-4), 135.07 (s, 3 C,
C-1′,2′,6′), 130.23 (d, C-4′), 127.97 (d, 2 C, C-3′,5′), 122.04 (s,
C-3), 108.10 (s, C-4a), 87.73 (br d, C-8), 55.53 (t, NCH2), 54.70,
52.66 (2 t, 2 × 2 C, N(CH2)4N), 45.67 (q, NCH3), 39.43 (t,
NCH2), 28.81 (q, NCH3), 26.07 (t, CH2). Anal. (C23H27Cl2N5O)
C, H, N.
3-(2,6-Dich lor op h en yl)-1-m eth yl-7-[[4-(4-m or p h olin o)-
bu tyl]am in o]-1,6-n aph th yr idin -2(1H)-on e (7l). Similar treat-
ment of 17 with 4-(4-aminobutyl)morpholine39 (10 equiv) in
2-pentanol at reflux for 15 h, followed by chromatography
(three times) on silica gel, eluting with 2.5-4% MeOH/CH2-
Cl2, treatment with aqueous Na2CO3 and extraction with CH2-
Cl2 (4 × 50 mL), gave 7l (95%): foam; 1H NMR (CDCl3) δ 8.32
(s, 1 H, H-5), 7.52 (s, 1 H, H-4), 7.39 (d, J ) 8.1 Hz, 2 H,
H-3′,5′), 7.24 (dd, J ) 8.6, 7.7 Hz, 1 H, H-4′), 6.02 (s, 1 H, H-8),
5.48 (br s, 1 H, NHCH2), 3.75 (t, J ) 4.6 Hz, 4 H, O(CH2)2),
3.65 (s, 3 H, NCH3), 3.36 (br t, J ) 6.6 Hz, 2 H, NHCH2), 2.47
(br m, 4 H, N(CH2)2), 2.41 (t, J ) 7.1 Hz, 2 H, NCH2), 1.76,
1.66 (2 pentet, J ) 7.0 Hz, 2 × 2 H, 2CH2); 13C NMR δ 160.76,
159.85 (2 s, C-2,7), 150.76 (d, C-5), 147.18 (s, C-8a), 138.27 (d,
C-4), 135.81 (s, 2 C, C-2′,6′), 134.84 (s, C-1′), 129.52 (d, C-4′),
127.89 (d, 2 C, C-3′,5′), 123.97 (s, C-3), 109.23 (s, C-4a), 86.61
(d, C-8), 66.88 (t, 2 C, O(CH2)2), 58.37 (t, NCH2), 53.66 (t, 2 C,
N(CH2)2), 42.36 (t, NCH2), 29.34 (q, NCH3), 27.02, 24.11 (2 t,
2CH2). Anal. (C23H26Cl2N4O2‚H2O) C, H, N.
3-(2,6-Dich lor oph en yl)-7-[[3-(im ida zol-1-yl)pr op yl]a m i-
n o]-1-m eth yl-1,6-n a p h th yr id in -2(1H)-on e (7m ). Similar
treatment of 17 with 1-(3-aminopropyl)imidazole (10 equiv) in
2-pentanol at reflux for 16 h, followed by chromatography twice
on silica gel, eluting with 3-6% MeOH/CH2Cl2, treatment with
aqueous Na2CO3 and extraction with CH2Cl2 (3 × 50 mL), gave
7m (82%): mp (CH2Cl2/hexane/Et2O) 175-178 °C; 1H NMR
(CDCl3) δ 8.34 (s, 1 H, H-5), 7.54, 7.53 (2 s, 2 H, H-4,2′′), 7.39
(d, J ) 8.1 Hz, 2 H, H-3′,5′), 7.24 (dd, J ) 8.5, 7.6 Hz, 1 H,
H-4′), 7.11, 6.97 (2 s, 2 H, H-4′′,5′′), 6.03 (s, 1 H, H-8), 5.09 (br
t, J ) 5.8 Hz, 1 H, NHCH2), 4.11 (t, J ) 6.8 Hz, 2 H, NCH2),
3.61 (s, 3 H, NCH3), 3.41 (q, J ) 6.4 Hz, 2 H, NHCH2), 2.17
(pentet, J ) 6.7 Hz, 2 H, CH2); 13C NMR δ 160.69, 159.52 (2 s,
C-2,7), 150.61 (d, C-5), 147.10 (s, C-8a), 138.17 (d, C-4), 137.18
(d, C-2′′), 135.77 (s, 2 C, C-2′,6′), 134.72 (s, C-1′), 129.83, 129.61
(2 d, C-4′,4′′), 127.93 (d, 2 C, C-3′,5′), 124.65 (s, C-3), 118.76
(d, C-5′′), 109.72 (s, C-4a), 87.76 (d, C-8), 44.32, 39.02 (2 t,
2NCH2), 30.82 (t, CH2), 29.39 (q, NCH3). Anal. (C21H19Cl2N5O)
C, H, N.
3-(2,6-Dich lor op h en yl)-1-m eth yl-7-(p h en yla m in o)-1,6-
n a p h th yr id in -2(1H)-on e (7n ). A mixture of 17 (86 mg, 0.27
mmol) and aniline (1.0 mL, 11.0 mmol) was stirred at 175 °C
for 100 min. The resulting mixture was diluted with aqueous
Na2CO3 (50 mL) and extracted with CH2Cl2 (2 × 50 mL).
Chromatography of the residue on silica gel, eluting with 1%
MeOH/CH2Cl2, gave 7n (88 mg, 83%): mp (CH2Cl2/light
petroleum) 237-239 °C; 1H NMR [(CD3)2SO] δ 9.52 (br s, 1 H,
NH), 8.59 (s, 1 H, H-5), 7.89 (s, 1 H, H-4), 7.68 (d, J ) 7.7 Hz,
2 H, H-2′′,6′′), 7.58 (d, J ) 8.2 Hz, 2 H, H-3′,5′), 7.45 (dd, J )
8.8, 7.5 Hz, 1 H, H-4′), 7.32 (t, J ) 7.9 Hz, 2 H, H-3′′,5′′), 6.98
(t, J ) 7.3 Hz, 1 H, H-4′′), 6.73 (s, 1 H, H-8), 3.56 (s, 3 H,
NCH3); 13C NMR δ 159.60, 156.99 (2 s, C-2,7), 150.07 (d, C-5),
145.91 (s, C-8a), 140.77 (s, C-1′′), 138.01 (d, C-4), 134.88 (s, 2
C, C-2′,6′), 134.71 (s, C-1′), 130.38 (d, C-4′), 128.70 (d, 2 C,
C-3′′,5′′), 127.97 (d, 2 C, C-3′,5′), 124.08 (s, C-3), 121.44 (d,
C-4′′), 118.94 (d, 2 C, C-2′′,6′′), 109.84 (s, C-4a), 91.30 (d, C-8),
28.83 (q, NCH3). Anal. (C21H15Cl2N3O‚0.75H2O) C, N; H: calcd,
4.1; found, 3.6.
3-(2,6-Dich lor op h en yl)-1-m eth yl-7-[[4-(4-m eth ylp ip er -
a zin -1-yl)bu tyl]a m in o]-1,6-n a p h th yr id in -2(1H)-on e (7i).
Similar treatment of 17 with 1-(4-aminobutyl)-4-methylpip-
erazine41 (10 equiv) in 2-pentanol at reflux for 16 h, followed
by chromatography on silica gel, eluting with 2-4% MeOH/
CH2Cl2 containing 0.3% Et3N, gave a crude product. Treatment
with aqueous Na2CO3 and extraction with CH2Cl2 (4 × 50 mL),
followed by chromatography on alumina, eluting with 1%
EtOH/CHCl3, gave 7i (94%): foam; 1H NMR (CDCl3) δ 8.32
(s, 1 H, H-5), 7.52 (s, 1 H, H-4), 7.39 (d, J ) 8.1 Hz, 2 H,
H-3′,5′), 7.23 (dd, J ) 8.6, 7.7 Hz, 1 H, H-4′), 6.03 (s, 1 H, H-8),
5.54 (br s, 1 H, NHCH2), 3.64 (s, 3 H, NCH3), 3.36 (td, J ) 6.2,
4.4 Hz, 2 H, NHCH2), 2.8-2.2 (br s, 8 H, N(CH2)4N), 2.42 (t,
J ) 7.1 Hz, 2 H, NCH2), 2.30 (s, 3 H, NCH3), 1.75 (pentet, J )
6.7 Hz, 2 H, CH2), 1.66 (pentet, J ) 6.9 Hz, 2 H, CH2); 13C
NMR δ 160.75, 159.85 (2 s, C-2,7), 150.74 (d, C-5), 147.13 (s,
C-8a), 138.27 (d, C-4), 135.81 (s, 2 C, C-2′,6′), 134.85 (s, C-1′),
129.49 (d, C-4′), 127.88 (d, 2 C, C-3′,5′), 123.88 (s, C-3), 109.19
(s, C-4a), 86.67 (d, C-8), 57.90 (t, NCH2), 55.02, 53.11 (2 t, 2 ×
2 C, N(CH2)4N), 46.00 (q, NCH3), 42.35 (t, NCH2), 29.34 (q,
NCH3), 27.08, 24.47 (2 t, 2CH2). Anal. (C24H29Cl2N5O‚0.5H2O)
C, H, N.
3-(2,6-Dich lor op h en yl)-1-m eth yl-7-[[5-(4-m eth ylp ip er -
a zin -1-yl)p en tyl]a m in o]-1,6-n a p h th yr id in -2(1H)-on e (7j).
Similar treatment of 17 with 1-(5-aminopentyl)-4-methylpip-
erazine41 (9 equiv) in 2-pentanol at reflux for 24 h, followed
by chromatography on silica gel, eluting with 2-4% MeOH/
CH2Cl2 containing 0.3% Et3N, gave a crude product. Treatment
with aqueous Na2CO3 and extraction with CH2Cl2 (4 × 50 mL),
followed by chromatography on alumina, eluting with 0.25-
0.5% MeOH/CH2Cl2, gave 7j (95%): foam; 1H NMR (CDCl3) δ
8.32 (s, 1 H, H-5), 7.52 (s, 1 H, H-4), 7.40 (d, J ) 8.0 Hz, 2 H,
H-3′,5′), 7.24 (dd, J ) 8.6, 7.8 Hz, 1 H, H-4′), 6.03 (s, 1 H, H-8),
5.01 (br t, J ) 5.4 Hz, 1 H, NHCH2), 3.65 (s, 3 H, NCH3), 3.34
(td, J ) 6.9, 5.8 Hz, 2 H, NHCH2), 2.8-2.1 (br s, 8 H,
N(CH2)4N), 2.37 (t, J ) 7.6 Hz, 2 H, NCH2), 2.29 (s, 3 H, NCH3),
1.73 (pentet, J ) 7.3 Hz, 2 H, CH2), 1.58 (pentet, J ) 7.5 Hz,
2 H, CH2), 1.47 (pentet, J ) 7.4 Hz, 2 H, CH2); 13C NMR δ
160.78, 159.84 (2 s, C-2,7), 150.77 (d, C-5), 147.26 (s, C-8a),
138.27 (d, C-4), 135.85 (s, 2 C, C-2′,6′), 134.86 (s, C-1′), 129.55
(d, C-4′), 127.93 (d, 2 C, C-3′,5′), 124.10 (s, C-3), 109.33 (s,
C-4a), 86.62 (d, C-8), 58.45 (t, NCH2), 55.11, 53.26 (2 t, 2 × 2
C, N(CH2)4N), 46.04 (q, NCH3), 42.43 (t, NCH2), 29.40 (q,
NCH3), 29.11, 26.60, 24.98 (3 t, 3CH2). Anal. (C25H31Cl2N5O‚
0.75H2O) C, H, N.
3-(2,6-Dich lor op h en yl)-1-m eth yl-7-[[3-(4-m or p h olin o)-
p r op yl]a m in o]-1,6-n a p h th yr id in -2(1H)-on e (7k ). Similar