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C. L. Viswanathan, A. S. Chaudhari / Bioorg. Med. Chem. 14 (2006) 6581–6585
Table 1. In vitro uterine relaxant activity and cAMP assay
ppm: 1.2 (m, 6H, 2 –CH3), 2.1 (s, 2H, 2 –OH), 2.3 (m,
2H, –CH2–CH3–), 2.8 (m, 2H, –COCH2–), 3.1 (m, 3H,
–NHCH2–, NHCH–), 3.8 (d, 2H, OCH2), 5.0 (m, 1H,
–CH(OH)), 5.7 (d, 1H, ArCH–), 6.9–7.6 (m, 8H, Ar–
H), 7.9 (s, 1H, –NH–), 8.8 (s, 2H, –+NH2–), 9.1 (s,
1H, Ar–OH); Elemental analysis (%): C 60.10 (60.19),
H 7.15 (7.11), N 6.38 (6.37).
Compound
Inhibition of
oxytocin induced
contraction IC50 (lM)
cAMP released
(pmol) at 10 mg (lM)
9a
9b
9c
9d
9e
9f
5.81
6.08
5.96
6.01
5.88
5.75
5.69
5.93
4.37 (23.4)
3.61 (22.1)
3.81 (22.8)
3.93 (22.1)
3.99 (21.16)
4.45 (20.26)
4.79 (21.66)
4.25 (24.78)
5.03 (29.6)
4.1.4. Compound 9d. Yield: 84%; mp 187–188 °C. IR
(KBr, cmÀ1): 3387–3305 O–H, N–H, stretch; 2964–
2926 C–H stretch; 1658 C@O stretch; 1H NMR d
ppm: 1.4 (s, 12H, 4 –CH3), 2.2 (s, 2H, 2 –OH), 3.2 (m,
3H, NHCH2–, NHCH–), 3.95 (d, 2H, –OCH2), 4.6 (m,
1H, –CH (OH)), 5.6 (d, 1H, ArCH–), 6.9–7.6 (m, 8H,
Ar–H), 8.35 (s, 1H, –NHCO–), 8.8 (s, 2H, –+NH2–),
9.2 (s, 1H, Ar–OH); Elemental analysis (%): C 61.22
(60.98), H 7.45 (7.34), N 6.10 (6.18).
9g
9h
Isoxsuprine HCl 8.57
in turn and stirred for 10–15 h. DMF was then removed
under vaccum and the residue was extracted with 100–
150 ml solvent ether. The extract was washed with 2 N
HCl for removal of unreacted 6 and then with water
and then dried over anhyd MgSO4. Dry HCl was passed
through the ether extract when hydrochloride salt sepa-
rated out. The salt was filtered and recrystallized from
ethanol.
4.1.5. Compound 9e. Yield: 86%; mp 214–215 °C. IR
(KBr, cmÀ1): 3382–3329 O–H, N–H, stretch; 1647
C@O stretch; 1H NMR d ppm: 1.25 (d, 3H, –CH3),
2.2 (s, 2H, 2 –OH), 3.2 (m, 3H, NHCH2–, NHCH–),
4.5 (d, 2H, –OCH2), 4.5 (m, 1H, –CH(OH)), 5.6 (d,
1H, ArCH–), 7.1–7.6 (m, 13H, Ar–H), 7.9 (s, 1H,
Ar–NH), 8.75 (s, 2H, –+NH2–), 9.05 (s, 1H, Ar–OH);
Elemental analysis (%): C 63.55 (63.48), H 6.02 (6.18),
N 5.97 (5.92).
4.1.1. Compound 9a. Yield: 85%; mp 158–159 °C. IR
(KBr, cmÀ1): 3374–3325 O–H, N–H, stretch; 2980–
2892 C–H stretch; 1178 C–O–C stretch; 1H NMR d
ppm: 1.4 (m, 9H, 3 –CH3), 2.2 (s, 2H, 2 –OH), 2.7 (t,
2H, ArCH2–), 3.3–3.4 (m, 6H, 2 –OCH2, –N–CH–,
–OCH–), 3.8 (d, 2H, Ar–OCH2–), 4.5 (m, 1H, –CH(OH)),
5.4 (d, 1H, Ar–CH–), 6.7–7.2 (m, 8H, Ar–H), 8.6 (s, 2H,
–+NH2–), 9.0 (s, 1H, Ar–OH); Elemental analysis (%): C
61.96 (62.18), H 7.83 (7.78), N 3.24 (3.18).
4.1.6. Compound 9f. Yield: 80%; mp 180–181 °C. IR
(KBr, cmÀ1): 3390–3323 O–H, N–H, stretch; 2928–
2851 C–H stretch; 1640 C@O stretch; 1H NMR d
ppm: 1.4 (d, 3H, –CH3), 1.9 (m, 10H, 5 –CH2–), 2.25
(s, 2H, 2 –OH), 3.2 (m, 4H, NHCH2–, 2 –NHCH–),
3.9 (d, 2H, –OCH2), 4.3 (m, 1H, –CH(OH)), 5.5 (d,
1H, ArCH–), 7.0–7.6 (m, 8H, Ar–H), 8.2 (s, 2H, 2
–CONH–), 8.9 (s, 2H, –+NH2–), 9.15 (s, 1H, Ar–OH);
Elemental analysis (%): C 60.89 (60.77), H 7.53 (7.34),
N 8.45 (8.50).
4.1.2. Compound 9b. Yield: 72%; mp 195–196 °C. IR
(KBr, cmÀ1): 3387–3294 O–H, N–H, stretch; 2976–
2922 C–H stretch; 1658 C@O stretch; 1H NMR d
ppm: 1.4 (m, 6H, 2 –CH3), 2.1 (s, 2H, 2 –OH), 2.65
(m, 2H, –CH2–CH3–), 2.9 (s, 2H, ArCH2–), 3.3 (m,
5H, 2 –NHCH2–, –NHCH), 4.0 (d, 2H, –OCH2–), 4.9
(m, 1H, –CH (OH)), 5.4 (d, 1H, –Ar–CH (OH)), 6.5–
7.4 (m, 8H, Ar–H), 7.7 (s, 1H, –NH–), 8.8 (s, 2H,
–+NH2–), 9.1 (s, 1H, Ar–OH); Elemental analysis (%):
C 66.28 (66.37), H 7.29 (7.34), N 6.15 (6.18).
4.1.7. Compound 9g. Yield: 78%; mp 202–203 °C. IR
(KBr, cmÀ1): 3366–3294 O–H, N–H, stretch; 1641
1
C@O stretch; H NMR d ppm: 1.4 (d, 3H, –CH3), 2.2
(s, 2H, 2 –OH), 3.2 (m, 3H, NHCH2–, –NHCH–), 3.9
(d, 2H, –OCH2), 4.6 (m, 1H, –CH(OH)), 5.6 (d, 1H,
ArCH–), 6.8–7.6 (m, 15H, Ar–H), 8.3 (s, 2H, 2
–CONH–), 8.8 (s, 2H, –+NH2–), 9.2 (s, 1H, Ar–OH);
Elemental analysis (%): C 64.57 (64.73), H 5.80 (5.99),
N 7.65 (7.80).
4.1.3. Compound 9c. Yield: 84%; mp 173–174 °C. IR
(KBr, cmÀ1): 3365–3295 O–H, N–H, stretch; 2962–
2874 C–H stretch; 1660 C@O stretch; 1H NMR d
Table 2. In vivo, uterine relaxant activity
Compound
Delay in onset of labour (h)a
Average weight of pups (g)
At 10 mg (lM)
At 15 mg (lM)
At 10 mg (lM)
At 15 mg (lM)
9a
9b
30.07 1.56 (23.4)
25.83 1.19 (22.1)
27.16 1.32 (22.8)
28.03 0.93 (22.1)
29.25 1.01 (21.16)
30.97 0.87 (20.26)
31.07 1.20 (21.66)
29.74 1.55 (24.78)
31.33 1.08 (29.6)
36.19 1.06 (35.16)
32.59 0.95 (33.15)
33.37 1.83 (34.21)
34.21 0.78 (33.15)
35.51 1.50 (31.7)
36.42 1.21 (30.39)
36.60 1.36 (32.5)
35.91 1.10 (37.17)
—
7.34 1.03 (23.4)
7.15 1.12 (22.1)
7.16 0.64 (22.8)
6.74 1.15 (22.1)
7.28 1.18 (21.16)
7.48 1.50 (20.26)
7.54 1.05 (21.66)
6.82 0.89 (24.78)
7.32 0.54 (29.6)
7.66 0.71 (35.16)
7.30 0.81 (33.15)
7.36 1.07 (34.21)
7.04 0.98 (33.15)
7.34 0.59 (31.7)
7.76 0.92 (30.39)
7.80 0.87 (32.5)
7.38 0.82 (37.17)
—
9c
9d
9e
9f
9g
9h
Isoxsuprine HCl
a P < 0.001.