Synthesis and blocking activities of a new class of α1-Adrenoceptor Antagonists

Article abstract of DOI:10.1111/j.1747-0285.2010.01040.x

Finding effective chemotherapeutic agents for clinical use is a long-lasting goal in medicinal chemistry. In this study, we report a new class of α₁-adrenoceptor (α₁-AR) antagonists. Specifically, we describe the synthesis and the bl

Full text of DOI:10.1111/j.1747-0285.2010.01040.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.01040.x
Chem Biol Drug Des 2010; 76: 505–510
Research Article
Synthesis and Blocking Activities of a New Class
of a1-Adrenoceptor Antagonists
Bao-Min Xi1,*, Pei-Zhou Ni2, Zhen-Zhou
particular in the cardiovascular and central nervous systems (1).
Recent study has further revealed that a1-ARs are also involved in
such diseases as ischemia induced by cardiac hypertrophy or
arrhythmia (2). This biological and practical importance has
Jiang3, Dian-Qing Wu1,4, Shou-Hua
Zhang1,4, Hui-Bin Zhang4, Tao Wang3 and
Wen-Hua Chen1,*
prompted major efforts in finding effective a1-AR antagonists.
1School of Pharmaceutical Sciences, Southern Medical University,
Such agents can find wide applications, for example, in the treat-
ment of benign prostatic hyperplasia (BPH) and high blood pres-
sure (3).
Guangzhou 510515, China
2Department of Organic Chemistry, China Pharmaceutical University,
Nanjing 210038, China
3National Drug Screening Center, China Pharmaceutical University,
Nanjing 210038, China
To date, several types of a1-AR antagonists have been reported,
such as tamsulosin (4,5), BMY-7378 (3,6), prazosin (3,7–10) and
spiperone (3) (Figure 1). These antagonists, albeit diverse in
their structures, have two common structural features (11). First of
all, they possess a basic center (generally amino group) that can
exist in a protonated state under physiological conditions. This is
their most important characteristic. Secondly, they have a lipophilic
aromatic ring that is located in proximity to the basic center.
4Center of Drug Discovery, China Pharmaceutical University, Nanjing
210009, China
*Corresponding authors: Bao-Min Xi, xbm08@yahoo.com.cn;
Wen-Hua Chen, whchen71@hotmail.com
Finding effective chemotherapeutic agents for
In this study, we report a new class of a1-AR antagonists that
have no aforementioned basic center. Specifically, we describe
the synthesis and the blocking activities of 7-(2-hydroxypropoxy)-
3,4-dihydroisoquinoline (compound 1, Figure 1) and its structurally
perturbed analogs 2–11 (Schemes 1–3). These compounds were
designed according to the principle of bioisosterism, among
which compounds 1–3 and 11, 4–8 and 9–10 have six-
membered rings, open structures and five-membered rings,
respectively.
clinical use is
a long-lasting goal in medicinal
chemistry. In this study, we report a new class
of a1-adrenoceptor (a1-AR) antagonists. Specifi-
cally, we describe the synthesis and the blocking
activities toward a1-AR of 7-(2-hydroxypropoxy)-
3,4-dihydroisoquinolin-1(2H)-one 1 and its struc-
turally perturbed analogs 2–11 that were
designed according to the principle of bioisoster-
ism. Their structures were identified with IR, 1H
NMR, MS, HRMS and elemental analysis. The
blocking activities of compounds 1–11 were eval-
uated on isolated rat anococcygeus muscles. The
results indicated that these compounds showed
moderate to good activities. Among them, com-
pound 1 exhibited the highest activity that was
comparable to those of known a1-AR antagonists
tamsulosin and DDPH (1-(2,6-dimethylphenoxy)-2-
(3,4-di- methoxyphenylethylamino)propane hydro-
chloride) and thus may be exploitable as a lead
compound for the discovery of promising a1-AR
antagonists.
Experimental Section
General
1H spectra were recorded in CDCl3 or DMSO-d6 using a Bruker
unity ACF-400 (300) spectrometer and TMS as an internal refer-
ence. IR spectra were measured on Nicolet Impact 410 (KBr). ESI
and HR-LC mass spectra were measured on HP 1100 and Agilent
1100-Applied Biosystems Mariner System 5303, respectively. Ele-
mental analysis was conducted on Elementar Vario EL III. Melting
points (mp) were measured on RDCSY-I, and the temperature was
uncorrected. Thin-layer chromatography (TLC) was performed on an
aluminum plate precoated with silica gel and a fluorescence indica-
tor (Branch of Qingdao Haiyang Chemical Plant, Qingdao, Shandong
Province, China). Detection on TLC was made by UV (254 nm). Com-
pounds 12, 14, 15, 16, 18 and 20 were prepared according to
the reported protocols (12–14). All other reagents and chemicals
were obtained from commercial sources and used as received
unless otherwise stated.
Key words: a1-adrenoceptor antagonist, blocking activity, synthesis
Received 29 December 2009, revised 8 September 2010 and accepted
for publication 8 September 2010
It is well known that a1-adrenoceptors (a1-ARs), as the members
of the G-protein-coupled receptor superfamily, play a crucial role
in regulating the functions of several physiological processes, in
505

Xi et al.
O
O
O
N
O
N
H
N
OMe
N
MeO
MeO
N
N
H2NO2S
MeO
O
N
N
OEt
NH2
(-)-Tamsulosin
O
BMY-7378
Prazosin
HN
O
N
OH
O
N
O
NH
Figure 1: The structures of
tamsulosin, BMY-7378, prazosin,
spiperone and compound 1.
F
Spiperone
1
HO
O
O
BrCH2COMe
BrCH2COMe
KBH4
KBH4
NH
NH
NH
O
HO
O
O
O
12
14
13
1
O
O
HO
HO
HO
HO
N
H
O
N
H
O
O
N
H
O
15
17
2
O
O
O
O
NH
NH
NH
BrCH2COMe
KBH4
O
O
Scheme 1: The synthetic route
for compounds 1–3.
16
3
O
O
OMe
KBH4
OH
H2N
H2N
O
OMe
O
OMe
O
BrCH2COMe
O
4
OMe
H2N
H2N
NH3
KBH4
OH
O
NH2
18
19
O
5
MeO
O
OH
MeO
O
Cl
KBH4
SOCl2
O
O
MeO
O
MeO
O
O
NH2
MeO
NH2
6
8
BrCH2COMe
OH
O
NH2
NH3
KBH4
NH2
NH2
20
21
O
O
NH2
7
Scheme 2: The synthetic route for compounds 4–8.
Synthesis of 7-(2-oxopropoxy)-3,4-dihydro-
1(2H)-isoquinolinone 13, 6-(2-oxopropoxy)-3,4-
dihydroisoquinolin-1(2H)-one 17, 2-methoxy-4-
(2-oxopropoxy)benzamide 19 and 2-methoxy-5-
(2-oxopropoxy)benzamide 21
A mixture of 3,4-dihydro-7-hydroxy-2(1H)-isoquinolinone 12 (8.1 g,
49.7 mmol), potassium carbonate (8.2 g) and potassium iodide
(0.1 g) in acetone (80 mL) was heated to reflux under the atmo-
sphere of nitrogen. Then, bromopropanone (8.2 g, 59.9 mmol) was
added drop wise. The resulting mixture was refluxed for 24 h and
filtered. The filtrate was concentrated under reduced pressure and
purified by chromatography on a silica-gel column (ethyl ace-
tate ⁄ petroleum ether, 4 ⁄ 7 by volume) to afford compound 13
1
(5.9 g, 54%) as a white solid having mp 134.1ꢀ135.2 ꢀC; H NMR
(CDCl3, 300 MHz) d 2.28 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 3.57 (t,
J = 6.4 Hz, 2H), 4.62 (s, 2H), 6.26 (s, 1H), 7.03ꢀ7.53 (m, 3H); IR
(KBr) m 3197, 1737, 1666, 1610 cm)1 and HRMS for C12H14NO3
([M+H]+) calcd: 220.09682, found: 220.09704.
506
Chem Biol Drug Des 2010; 76: 505–510

Synthesis and Activity of New a1-AR Antagonists
1,2-Epoxypropane
1,2-Epoxypropane
NaOH / H2O
OH
OH
O
OH
NaOH / H2O
O
O
O
O
N
H
N
H
N
H
N
H
OH
OH
O
23
22
24
9
10
1,2-Epoxypropane
NaOH / H2O
OH
O
N
H
N
H
11
Scheme 3: The synthetic route for compounds 9–11.
Compound 17 was obtained from compound 16, in 48% as a white
Compound 2 was obtained from 7-(2-oxopropoxy)-3,4-dihydro-1(2H)-
quinolinone 15, in 57% as a white solid having mp 78.3ꢀ80.4 ꢀC;
1H NMR (DMSO-d6, 300 MHz) d 1.28 (d, 3H, J = 6.6 Hz), 2.36 (t,
J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 3.88ꢀ3.94 (m, 2H),
4.13ꢀ4.18 (m, 1H), 4.82 (d, J = 4.9 Hz, 1H), 6.65ꢀ7.17 (m, 3H),
7.73 (s, 1H); IR (KBr) m 3394, 2927, 1453, 1053 cm)1 and HRMS for
C12H16NO3 ([M+H]+) calcd: 222.11247, found: 222.11297.
1
solid having mp 165.7ꢀ166.3 ꢀC; H NMR (CDCl3, 300 MHz) d 2.29
(s, 3H), 2.98 (t, J = 6.5 Hz, 2H), 3.57 (t, J = 6.5 Hz, 2H), 4.60 (s,
2H), 6.25 (s, 1H), 6.71ꢀ8.02 (m, 3H); IR (KBr) m 3184, 1718, 1658,
1234 cm)1 and HRMS for C12H14NO3 ([M+H]+) calcd: 220.09682,
found: 220.09621.
Compound 19 was obtained from 4-hydroxy-2-methoxybenzamide
1
18, in 65% as a white solid having mp 161.2ꢀ162.7 ꢀC; H NMR
Compound 3 was obtained from 17, in 62% as a white solid hav-
ing mp 83.8ꢀ85.9 ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 1.27 (d,
J = 6.6 Hz, 3H), 2.96 (t, J = 6.5 Hz, 2H), 3.57 (t, J = 6.5 Hz, 2H),
3.87ꢀ3.93 (m, 2H), 4.10ꢀ4.15(m, 1H), 4.79 (d, J = 4.9 Hz, 1H), 6.20
(s, 1H), 6.95ꢀ7.41 (m, 3H); IR (KBr) m 3294, 2949, 1483, 1071 cm)1
and HRMS for C12H16NO3 ([M+H]+) calcd: 222.11247, found:
222.11234.
(DMSO-d6, 400 MHz) d 2.06 (s, 3H, COCH3), 3.86 (s, 3H, ArOCH3),
4.88 (s, 2H, ArOCH2), 6.51ꢀ7.79 (m, 3H, ArH), 7.35 and 7.47 (2s,
2H, CONH2); IR (KBr) m 3423, 3188, 1740, 1604, 1592, 1426, 1387,
1210 cm)1; ESI-MS m ⁄ z 224 ([M+H]+), 246 ([M+Na]+) and elemental
analysis for C11H13NO4 calcd: C 59.19, H 5.87, N 6.27, found: C
59.29, H 6.02, N 6.12.
Compound 21 was obtained from 5-hydroxy-2-methoxybenzamide
Compound 4 was obtained from 19, in 52% mp 137.3ꢀ137.8 ꢀC;
1
20, in 62% as a white solid having mp 117.5ꢀ118.8 ꢀC; H NMR
1H NMR (DMSO-d6, 400 MHz)
d 1.12 (d, J = 6.40 Hz, 3H),
(DMSO-d6, 400 MHz) d 2.05 (s, 3H), 3.80 (s, 3H), 4.73 (s, 2H),
6.97ꢀ7.29 (m, 3H), 7.65, 7.78 (s, 2H); IR (KBr) m 3436, 3160, 1720,
1665, 1595, 1582, 1489, 1209 cm)1; ESI-MS m ⁄ z 224 ([M+H]+), 246
([M+Na]+) and elemental analysis for C11H13NO4 calcd: C 59.19, H
5.87, N 6.27, found: C 59.36, H 5.74, N 6.13.
3.81ꢀ3.86 (m, 2H), 3.87 (s, 3H), 3.88ꢀ3.95 (m, 1H), 4.77 (d,
J = 4.9 Hz, 1H), 6.57ꢀ7.81 (m, 3H), 7.32, 7.46 (2s, 2H); IR (KBr) m
3445, 2932, 1722, 1640, 1590, 1424, 1377, 1200, 1094 cm)1; ESI-
MS m ⁄ z 226 ([M+H]+) and elemental analysis for C11H15NO4 calcd:
C 58.66, H 6.71, N 6.22, found: C 58.82, H 6.67, N 6.13.
Compound 6 was obtained from 21, in 89% as a crystal having mp
Synthesis of 7-(2-hydroxypropoxy)-3,4-dihydro-
1(2H)-isoquinolinone 1, 7-(2-hydroxypropoxy) -
3,4-dihydro-1(2H)-quinolinone 2, 6-(2-hydroxy-
propoxy)-3,4-dihydro-1(2H)-isoquinolinone
3, 2-methoxy-4-(2-hydroxypropoxy)benzamide
4 and 2-methoxy-5-(2-hydroxypropoxy)-
118.5ꢀ118.8 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d 1.26 (d,
J = 6.4 Hz, 3H), 3.94 (s, 3H), 3.96ꢀ4.00 (m, 2H), 4.15ꢀ4.21 (m, 1H),
4.79 (d, J = 4.9 Hz, 1H), 6.92ꢀ7.76 (m, 3H), 7.60, 7.71 (s, 2H); IR
(KBr) m 3345, 2932, 1657, 1580, 1491, 1434, 1218, 1050 cm)1; ESI-
MS m ⁄ z 226 ([M+H]+) and elemental analysis for C11H15NO4 calcd:
C 58.66, H 6.71, N 6.22, found: C 58.89, H 6.78, N 6.35.
benzamide 6
To a solution of 7-(2-oxopropoxy)-3,4-dihydro-1(2H)-isoquinolinone
13 (0.40 g, 1.8 mmol) in methanol (5 mL) was added potassium
borohydride (0.2 g). The resulting mixture was stirred at room tem-
perature for 3 h and concentrated under reduced pressure. The
obtained residue was partitioned between water (15 mL) and ethyl
acetate (15 mL). The aqueous layer was further extracted with ethyl
acetate (15 mL · 2). The combined organic solution was concen-
trated and purified by chromatography on a silica-gel column (ethyl
acetate ⁄ petroleum ether, 4 ⁄ 7 by volume) to give compound 1
Synthesis of 2-methoxy-4-(2-
aminopropoxy)benzamide 5 and 2-methoxy-5-(2-
aminopropoxy) benzamide 7
A solution of compound 19 (0.3 g, 1.3 mmol) and a catalytic
amount of p-methylbenzene sulfonic acid in methanol (20 mL) was
bubbled with dry ammonia. After the reaction mixture was cooled
to room temperature, potassium borohydride (0.2 g) was added and
the stirring continued at room temperature for 30 min. After the
reaction mixture was concentrated under reduced pressure, the
obtained residue was partitioned between water (15 mL) and ethyl
acetate (15 mL). After the organic layer was separated, the aqueous
layer was further extracted with ethyl acetate (15 mL · 2). The
combined organic solution was dried over anhydrous sodium sulfate,
concentrated and purified by chromatography on a silica-gel column
1
(0.21 g, 51%) as a white solid having mp 89.5ꢀ92.1 ꢀC; H NMR
(DMSO-d6, 300 MHz) d1.30 (d, 3H, J = 6.6 Hz), 2.97 (t, J = 6.5 Hz,
2H), 3.62 (t, J = 6.5 Hz, 2H), 3.92ꢀ3.98 (m, 2H), 4.13ꢀ4.16 (m, 1H),
4.77 (d, J = 4.9 Hz, 1H), 6.16 (s, 1H), 6.93ꢀ7.43 (m, 3H); IR (KBr) m
3297, 2951, 1484, 1065 cm)1 and HRMS for C12H16NO3 ([M+H]+)
calcd: 222.11247, found: 222.11283.
Chem Biol Drug Des 2010; 76: 505–510
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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

Synthesis and Activity of New a1-AR Antagonists
Table 1: Blocking activities (pA2) of compounds 1–11, tamsulo-
on the activity, whereas reduction of dihydroquinolinone 2 to tetra-
hydroquinoline 11 led to a significant decrease in the activity.
sin and DDPHa
Compound
pA2
Compound
pA2
Conclusions
1
2
3
4
5
6
7
8.12 € 1.28
7.24 € 0.21
6.43 € 0.29
6.29 € 0.19
6.12 € 0.43
6.76 € 0.05
6.67 € 0.06
8
6.39 € 0.31
6.00 € 0.40
5.94 € 0.06
6.15 € 0.60
8.77 € 0.13
8.14 € 0.19
9
10
In conclusion, a new class of a1-AR antagonists has been success-
fully synthesized and fully characterized with IR, 1H NMR, MS,
HRMS and elemental analysis. The in vivo assays indicated that all
these compounds exhibited moderate to good activities toward a1-
AR. Among them, compound 1 had the highest activity that was
comparable to those of tamsulosin and DDPH and thus may be
exploitable from the standpoint of new drug discovery. This finding
also raises the possibility of developing potent a1-AR antagonists in
fundamentally new ways.
11
Tamsulosin
DDPH
apA2 values, expressed as means € SEM of three different concentrations,
each tested at least three times.
the reaction of compounds 22–24 with 1,2-epoxypropane, respec-
tively. In this reaction, the equivalence of 1,2-epoxypropane proved
very important to afford the target compounds in good yields.
Because of the low boiling point and high volatility of 1,2-epoxypro-
pane, 1.2ꢀ1.5 equivalences were necessary; however, large excess
would lead to additional reaction on the 3-positions of compounds
22 and 23.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (No. 30600776).
1
Compounds 1–11 were fully characterized with IR, H NMR, MS,
HRMS and elemental analysis. They afforded MS spectra with the
m ⁄ z values corresponding to [M+H]+. Their NMR spectra were also
in full agreement with the given structures (see experimental sec-
tion). It should be noted that the protons in ArOCH2 appeared as
multiplets rather than theoretical doublets, because of the chirality
on the adjacent positions. The purity of each compound was judged
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