Xi et al.
(ethyl acetate ⁄ petroleum ether, 5 ⁄ 7 by volume) to give compound 5
1.06 (d, J = 6.4 Hz), 3.38 (s, 2H), 3.49 (d, J = 6.2 Hz, 2H),
3.88ꢀ3.91 (m, 1H), 4.82 (d, J = 4.9 Hz, 1H), 6.37ꢀ6.99 (m, 3H),
9.33 (s, 1H); IR (KBr) m 3318, 2939, 2291, 1689, 1602, 1435, 1338,
1071 cm)1; ESI-MS m ⁄ z 230 ([M+Na]+) and elemental analysis for
C11H13NO3 calcd: C 63.76, H 6.32, N 6.76, found: C 63.58, H 6.40,
N 6.92.
1
(0.13 g, 40%) as a white solid having mp 125.9ꢀ127.2 ꢀC; H NMR
(CDCl3, 300 MHz) d 1.19 (d, J = 6.60 Hz, 3H), 3.34ꢀ3.40 (m, 1H),
3.58 (brs, 2H), 3.71ꢀ3.93 (m, 2H), 3.95 (s, 3H), 6.52ꢀ8.18 (m, 3H),
7.35 and 7.48 (2s, 2H); IR (KBr) m 3416, 3174, 2882, 2810, 1649,
1599, 1425, 1374, 1275, 1255, 1203 cm)1; ESI-MS m ⁄ z 225
([M+H]+) and elemental analysis for C11H16N2O3 calcd: C 58.91, H
7.19, N 12.49, found: C 58.87, H 7.49, N 12.27.
Compound 11 was obtained from 7-hydroxy-1,2,3,4-tetrahydroquino-
line 24, in 18% as a yellowish oil having 1H NMR (CDCl3,
400 MHz) d 1.22 (d, J = 6.4 Hz, 3H), 1.88ꢀ1.93 (m, 2H), 2.66ꢀ2.69
(m, 2H), 3.07ꢀ3.30 (m, 4H), 3.83ꢀ3.95 (m, 1H), 4.10ꢀ4.13 (m, 1H),
4.75 (d, J = 4.9 Hz, 1H), 6.12ꢀ6.78 (m, 3H); IR (KBr) m 3400, 2945,
2840, 1848, 1620, 1507, 1178 cm)1; ESI-MS m ⁄ z 208 ([M+H]+) and
elemental analysis for C12H17NO2 calcd: C 69.54, H 8.27, N 6.76,
found: C 69.78, H 8.43, N 6.58.
Compound 7 was obtained as a hydrochloride salt from 21, in 59%
as a white solid after re-crystallized with methanol, having mp
234.1ꢀ235.3 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d 1.29 (d,
J = 6.90 Hz, 3H), 3.51ꢀ3.63 (m,1H), 4.0 (s, 3H), 4.09ꢀ4.13 (m, 2H),
7.12ꢀ7.42 (m, 3H), 7.62 and 7.71 (2s, 2H), 8.29 (brs, 3H); IR (KBr) m
3410, 3256, 2918, 1647, 1587, 1491, 1431, 1267, 1216, 1051 cm)1
;
ESI-MS m ⁄ z 225 ([M+H]+) and elemental analysis for
C11H16N2O3ÆHCl calcd: C 50.67, H 6.75, N 10.74, found: C 50.93, H
6.77, N 10.50.
Determination of pA2 value of each compound
The blocking activity (pA2) of each compound was measured by
using the methods similar to those described previously (15–17).
Specifically, a male Sprague-Dawley rat (300–350 g) was killed by
cervical dislocation, and its anococcygeus smooth muscles were
isolated. The tissues were transferred to Krebs' physiological solu-
tion that was aerated with 5% CO2 ⁄ 95% O2 at 37 ꢀC. The solu-
tion (pH 7.4) was composed of 118.1 mM NaCl, 4.7 mM KCl,
2.5 mM CaCl2, 1.16 mM MgSO4, 1.0 mM NaH2PO4, 25 mM NaHCO3
and 11.1 mM glucose. Then, anococcygeus smooth muscles were
transferred and suspended in a 20-mL organ chamber containing
Krebs' solution at 37 ꢀC. The solution was aerated with 5%
CO2 ⁄ 95% O2. The muscle preparations were set at a resting ten-
sion of 1.0 g and allowed to equilibrate for 1 h in the Krebs' solu-
tion. During this period, the smooth muscles were replenished
with Krebs' solution every 20 min. After equilibration, cocaine
hydrochloride, hydrocortisone and propranolol were added to the
final concentrations of 30, 30 and 1 lM, respectively. After 20 min,
concentration–response curves with phenylephrine were obtained
by adding phenylephrine to the bath in the cumulative final con-
centrations of 3, 10, 30 lM. Each tissue was tested four times.
The first concentration–response curve was the basic one, and the
other three with phenylephrine were repeated by adding tested
compound or tamsulosin or DDPH (1-(2,6-dimethylphenoxy)-2-(3,4-di-
methoxyphenylethylamino) propane hydrochloride), respectively. The
pA2 values of each compound, tamsulosin and DDPH, were calcu-
lated according to Schild's graphical method (18) and listed in
Table 1.
Synthesis of 2-methoxy-4-(2-chloropropoxy)
benzamide 8
To a solution of compound 6 (1.4 g, 6.2 mmol) in chloroform
(50 mL) was added SOCl2 (0.5 mL). The reaction mixture was ref-
luxed for 3 h, cooled to room temperature and concentrated under
reduced pressure. The obtained residue was purified by chromatog-
raphy on a silica-gel column (ethyl acetate ⁄ petroleum ether, 4 ⁄ 7 by
volume) to afford compound
8 (0.86 g, 57%) having mp
1
114.5ꢀ115.8 ꢀC; H NMR (CDCl3, 400 MHz) d 1.59 (d, J = 6.60 Hz,
3H), 3.95 (s, 3H), 4.02ꢀ4.16 (m, 2H), 4.17ꢀ4.31 (m, 1H), 6.93ꢀ7.76
(m, 3H), 7.68, 7.79 (s, 2H); IR (KBr) m 3447, 1659, 1599, 1494, 1220,
1046 cm)1; ESI-MS m ⁄ z 266 ([M+Na]+) and elemental analysis for
C11H14ClNO3 calcd: C 54.22, H 5.79, N 5.75, found: C 54.01, H 5.98,
N 5.46.
Synthesis of 5-(2-hydroxypropoxy)-2-indolone 9,
6-(2-hydroxypropoxy)-2-indolone 10 and 7-(2-
hydroxypropoxy)-1,2,3,4-tetrahydroquinoline 11
To a mixture of sodium hydroxide (0.6 g) and 5-hydroxy-2-indolone
22 (1.1 g, 7.38 mmol) in water (10 mL) was added drop wise 1,2-
epoxypropane (0.7 mL, 10.00 mmol). The reaction mixture was stir-
red at room temperature for 24 h, acidified with concentrated
hydrochloride and extracted with ethyl acetate (20 mL · 4). The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The obtained residue was
purified with chromatography on a silica-gel column (ethyl ace-
tate ⁄ petroleum ether, 2 ⁄ 1 by volume) to afford compound 9
Results and Discussion
1
(0.21 g, 14%) as a colorless crystal having mp 154.6ꢀ156.0 ꢀC; H
NMR (DMSO-d6, 400 MHz) d 1.04 (t, J = 6.4 Hz, 3H), 3.45 (s, 2H),
3.46ꢀ3.51 (m, 2H), 3.87ꢀ3.91 (m, 1H), 4.77 (d, J = 4.9 Hz, 1H),
6.60ꢀ6.82 (m, 3H), 8.97 (s, 1H); IR (KBr) m 3469, 2735, 1668,
1491, 1378, 1138; ESI-MS m ⁄ z 208 ([M+H]+) and elemental analy-
sis for C11H13NO3 calcd: C 63.76, H 6.32, N 6.76, found: C 64.01,
H 6.19, N 6.51.
Synthesis of compounds 1–11
The synthetic approaches that were used for the synthesis of com-
pounds 1–11 are outlined in Schemes 1–3.
Compounds 1–7 were synthesized in good yields from the reaction
of their corresponding substituted phenols 12, 14, 16, 18 and 20
with bromopropanone, respectively, followed by reduction (KBH4) or
by reductive amination (NH3-KBH4). Treatment of compound 6 with
SOCl2 afforded compound 8. Compounds 9–11 were obtained from
Compound 10 was obtained in 11% from 6-hydroxy-2-indolone 23.
1
mp 149.9ꢀ151.9 ꢀC (discomposed); H NMR (DMSO-d6, 400 MHz) d
508
Chem Biol Drug Des 2010; 76: 505–510