Synthesis and blocking activities of isoindolinone- and isobenzofuranone-containing phenoxylalkylamines as potent α1- adrenoceptor antagonists

Article abstract of DOI:10.1248/cpb.59.96

This paper describes the synthesis and blocking activities of twelve new isoindolinone- and isobenzofura-none-containing phenoxylalkylamines as potent α₁-Adrenoceptor antagonists. These compounds were synthesized in moderate to good yields starting from 3,4-dimethylphenol, and characterized with ¹H-NMR, MS, IR and elemental analysis. Their blocking activities toward α₁-Adrenoceptors were evaluated on isolated rat anococcygeus muscles. The results indicated that these compounds were very strong in blocking α₁-Adrenoceptors, and most of them exhibited activities that were comparable to that of known potent α₁- Adrenoceptor antagonist 1-(2,6-dimethylphenoxy)-2-(3,4- dimethoxyphenylethylamino)propane hydrochloride (DDPH).

Full text of DOI:10.1248/cpb.59.96

96
Regular Article
Chem. Pharm. Bull. 59(1) 96—99 (2011)
Vol. 59, No. 1
Synthesis and Blocking Activities of Isoindolinone- and Isobenzofuranone-
a
Containing Phenoxylalkylamines as Potent 1-Adrenoceptor Antagonists
Shou-Hua ZHANG,a,d Chun-Ye WANG,a Zhen-Zhou JIANG,b Pei-Zhou NI,c Jin-Pei ZHOU,d
,a
,a
*
*
Bao-Min XI, and Wen-Hua CHEN
a School of Pharmaceutical Sciences, Southern Medical University; Guangzhou 510515, China: b National Drug Screening
Center, China Pharmaceutical University; c Department of Organic Chemistry, China Pharmaceutical University; and
d Center of Drug Discovery, China Pharmaceutical University; Nanjing 210009, China.
Received September 11, 2010; accepted October 1, 2010; published online October 4, 2010
This paper describes the synthesis and blocking activities of twelve new isoindolinone- and isobenzofura-
none-containing phenoxylalkylamines as potent a1-Adrenoceptor antagonists. These compounds were synthe-
sized in moderate to good yields starting from 3,4-dimethylphenol, and characterized with 1H-NMR, MS, IR and
elemental analysis. Their blocking activities toward a1-Adrenoceptors were evaluated on isolated rat anococ-
cygeus muscles. The results indicated that these compounds were very strong in blocking a1-Adrenoceptors, and
most of them exhibited activities that were comparable to that of known potent a1-Adrenoceptor antagonist 1-
(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH).
Key words a1-Adrenoceptor antagonist; phenoxylalkylamine; synthesis; blocking activity
During the past decades, considerable interests have been dolinones and isobenzofuranones into phenoxylalkylamines
attracted in the development of potent a1-Adrenoceptor (a1- may lead to strong a1-AR antagonists. With this rationale in
AR) antagonists.1—3) These efforts have been prompted pri- mind, we describe herein the synthesis and blocking activi-
marily by their wide applications, for example, in the treat- ties toward a1-ARs of isoindolinone- and isobenzofuranone-
ment of benign prostatic hyperplasia (BPH)4) and high blood containing phenoxylalkylamines 1—12 (Chart 1, Table 1). In
pressure.5) To date, several types of a1-AR antagonists, such these compounds, the bulkiness and/or the potential H-bond-
as prazosin,6) terazosin,7) tamsuolosin,8) have been developed ing ability of isoindolinone and isobenzofuranone subunits
as effective antihypertensive and BPH therapeutic drugs. In are expected to impart enhanced interaction with a1-AR. To
these respects, we have keenly become interested in the de- the best of our knowledge, this represents an unprecedented
sign and synthesis of promising a1-AR antagonists by using example of a1-AR antagonists containing isoindolinones and
readily available phenoxylalkylamines. Noteworthy among isobenzofuranones.
them is 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenyl-
ethylamino)propane hydrochloride (DDPH) (Fig. 1), which is Results and Discussion
very effective in blocking a1-ARs, and presently under Phase
Synthesis of Compounds 1—12 The synthetic ap-
II clinic trials in China.9—11) From the viewpoint of new drug proaches that were used to synthesize compounds 1—12 are
discovery, however, it is of highly practical importance to outlined in Chart 1. Compounds 13—16 were prepared start-
synthesize a1-AR antagonists that have diverse structures.
ing from 3,4-dimethylphenol according to reported proce-
In our previous study on the structure–activity relationship dures.18—22) Demethylation of 15 by HI and 16 by HBr and
of DDPH and its analogs, we have shown that the sizes of the subsequent reaction with bromoacetone afforded compounds
substituents in aromatic ring A (Fig. 1) play a crucial role in 17 and 18 in good yields, respectively. It should be noted that
the blocking activity.12) That is, introducing bulky groups demethylation of compound 15 by HI proceeded in a higher
into the 3- or 4-positions of aromatic ring A may signifi- yield than by HBr. Reductive amination of 17 and 18 with
cantly ameliorate the activity, while Bremner’s work on the substituted phenylethylamines gave 1—12 in moderate to
pharmacophores of a1-ARs has suggested that the oxygen good yields. Among them, compounds 1, 2, 7—10 and 12
atom of the carbonyl group in KMD-3213 (Fig. 1) could in- were oily and therefore converted into hydrochloric acid salts
teract as an H-bonding acceptor with a1-ARs.13) On the other by treating with gaseous HCl. Compounds 1—12 were fully
1
hand, it is known that isoindolinones and isobenzofuranones characterized with H-NMR, MS, IR and elemental analysis.
that are widely distributed in nature, exhibit multiple phar- They afforded MS spectra with the m/z values corresponding
macological properties, such as antibacterial activity against to [MꢀH]ꢀ. Their NMR spectra were also in full agreement
Gram-positive and Gram-negative bacteria, anticancer activ- with the given structures (see Experimental). The purity of
ity and cardiovascular activity.14—17) These observations, each compound was judged from NMR and TLC.
taken together, make us reason that incorporating of isoin-
Blocking Activities of Compounds 1—12 The blocking
Fig. 1. Chemical Structures of DDPH and KMD-3213
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: xbm08@yahoo.com.cn; whchen71@hotmail.com

January 2011
97
Chart 1. The Synthetic Route for Compounds 1—12
Table 1. Structures and Blocking Activities (pA2) of Compounds 1—12 and DDPHa)
Compound
X
Ar
pA2
Compound
X
O
Ar
pA2
1
NH
8.09ꢃ0.17
7
8.18ꢃ0.19
2
3
4
NH
NH
NH
7.86ꢃ0.20
8.07ꢃ0.18
8.14ꢃ0.32
8
9
O
O
O
7.69ꢃ0.37
8.21ꢃ0.40
7.51ꢃ0.22
10
5
NH
NH
7.92ꢃ0.23
11
12
O
O
8.29ꢃ0.25
7.59ꢃ0.38
6
8.11ꢃ0.59
8.07ꢃ0.29
DDPH
a) pA2 values, expressed as meansꢃS.E.M. of three different concentrations, each tested at least three times.
activities of compounds 1—12 were then evaluated, by using ing ability of the substituents of DDPH analogs may make
methods similar to those described in the literatures.23—26) substantial contributions to the blocking activity. Given the
Here, anococcygeus smooth muscles, because of their selec- fact that compounds 1 and 7 showed comparable activity
tive contraction to a1-AR agonists and long in vitro survival, with DDPH, bulkiness may be the predominant factor for the
were used as the isolated tissues. The blocking activity is ex- potency of compounds 1—12. In addition, introducing at the
pressed as pA2ꢁꢂlog[1—12]2, in which [1—12]2 is defined aromatic group B of bulky groups, for example, 3,4-dihydro-
as the molar concentrations (M) of 1—12. These concentra- 2H-benzo[e][1,2]thiazine-1,1-dioxide, led to a dramatic de-
tions were measured according to Schild’s methods.27) The crease in the activity,23) suggesting that bulkiness at the aro-
obtained pA2 values of compounds 1—12, together with that matic group A may be preferable, which is in agreement with
of DDPH as a positive control, are listed in Table 1.
our structure–activity correlation study.12) Secondly, isoin-
Some interesting observations can be extracted from Table dolinone-containing compounds 1—6 did not consistently
1. The first observation was that all the compounds exhibited show higher blocking activities than isobenzofuranone-con-
strong blocking activities, and most of them were very simi- jugated compounds 7—12, and vice versa. For example,
lar with potent DDPH. It is remarkable that compounds 1— isoindolinonyl derivative 4 was more potent than isobenzofu-
12 were much more active than DDPH analogs we have re- ranonyl derivative 10, however, isobenzofuranone-containing
ported to date.23,28) This result indicates that incorporating of compound 11 was better than isoindolinone-containing com-
naturally occurring isoindolinones and isobenzofuranones pound 5. Thirdly, for the same series, i.e. compounds 1—6 or
into phenoxylalkylamines may serve as one sophisticated ap- 7—12, the pA2 values also varied with the structures of aro-
proach to improve the blocking efficiency. According to the matic group B (Fig. 1), but with a very small range. Since
reports by us12) and others,13) the bulkiness and H-bond form- aromatic group B is an essential group for the activity of

98
Vol. 59, No. 1
etate (2/5 by volume) to give 1 (0.2 g, 34%) as a white hydrochloride salt
having mp 196.8—197.4 °C. 1H-NMR (400 MHz, DMSO-d6) d: 1.42 (d,
Jꢁ6.4 Hz, 3H, CHCH3), 3.01—2.97 (t, Jꢁ8.0 Hz, 2H, ArCH2), 3.21 (m, 2H,
NHCH2), 3.69 (m, 1H, CH2CHCH3), 3.73 and 3.75 (2s, 6H, 2ꢅArOCH3),
4.23—4.35 (m, 4H, ArCH2NH, ArOCH2), 6.78—7.62 (m, 6H, 6ꢅArH),
8.39 (s, 1H, CONH), 9.50 (br s, 2H, NH2ꢀ). IR (KBr) cmꢂ1: 3237, 2940,
2450, 1679, 1519, 1262, 1141, 1022. MS (ESI) m/z: 371 [MꢀH]ꢀ. Anal.
Cacld for C21H27ClN2O4: C, 61.99; H, 6.69; N, 6.88. Found: C, 61.93; H,
6.74; N, 6.83.
DDPH analogs, this result suggested that its substituents in
this case had minor effects on the interaction with a1-ARs.
Concluding Remarks
Twelve new isoindolinone- and isobenzofuranone-contain-
ing phenoxylalkylamines were successfully synthesized as
a1-AR antagonists, and characterized with IR, 1H-NMR, MS
and elemental analysis. All the compounds were strong in
blocking a1-ARs (pA2ꢄ7.5). compared with potent DDPH,
most of them exhibited similar activities, suggesting that they
may be exploitable as a new class of a1-AR antagonists.
5-(2-(2-Methoxyphenylethylamino)propoxy)-1-isoindolinone Hydro-
1
chloride 2·HCl (18%) as a white solid having mp 189.5—190.3 °C. H-
NMR (400 MHz, DMSO-d6) d: 1.39 (d, Jꢁ6.4 Hz, 3H, CHCH3), 2.97—3.01
(t, Jꢁ8.0 Hz, 2H, ArCH2), 3.17 (m, 2H, NHCH2), 3.71 (m, 1H,
CH2CHCH3), 3.77 (s, 3H, ArOCH3), 4.24—4.34 (m, 4H, ArCH2NH,
ArOCH2), 6.91—7.61 (m, 7H, 7ꢅArH), 8.36 (s, 1H, CONH), 9.21 (br s, 2H,
NH2ꢀ). IR (KBr) cmꢂ1: 3448, 2741, 2468, 1704, 1653, 1615, 1494, 1250.
Experimental
General 1H-NMR spectra were recorded in DMSO-d6 using a Bruker
unity ACF-400 spectrometer, and TMS as an internal reference. IR spectra MS (ESI) m/z: 341.2 [MꢀH]ꢀ. Anal. Cacld for C20H25ClN2O3: C, 63.74; H,
were measured on Nieolet Impact 410 (KBr). Electrospray ionization (ESI) 6.69; N, 7.43. Found: C, 63.71; H, 6.70; N, 7.48.
Mass spectra were measured on HP 1100 spectrometer. Elemental analysis
was conducted on Elementar Vario EL III. Melting points (mp) were meas-
ured on RDCSY-I, and the temperature was uncorrected. Thin-layer chro-
5-(2-(3-Methoxyphenylethylamino)propoxy)-1-isoindolinone 3 (20%)
as a white solid having mp 74.3—75.6 °C. H-NMR (400 MHz, DMSO-d6)
d: 1.17 (d, Jꢁ6.4 Hz, 3H, CHCH3), 1.64 (br s, 1H, NH), 2.78—2.82 (t,
1
matography (TLC) was performed on an aluminum plate precoated with sil- Jꢁ6.8 Hz , 2H, ArCH2), 2.86—3.01 (m, 2H, NHCH2), 3.13—3.17 (m, 1H,
ica gel and a fluorescence indicator (Merck, U.S.A.). Detection on TLC was
made by UV (254 nm). Compounds 13—16 were prepared according to re-
ported protocols.18—22) All the other reagents and chemicals were obtained
from commercial sources and used as received unless otherwise stated.
CH2CHCH3), 3.78 (s, 3H, ArOCH3), 3.85—3.93 (m, 2H, ArOCH2), 4.39 (s,
2H, ArCH2NH), 6.77—7.76 (m, 8H, 7ꢅArH, CONH). IR (KBr) cmꢂ1
:
3401, 2930, 1676, 1615, 1454, 1262, 1082, 775. MS (ESI) m/z: 341
[MꢀH]ꢀ. Anal. Cacld for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23. Found: C,
70.61; H, 7.14; N, 8.20.
Synthesis of 5-Oxypropoxy-1-isoindolinone 17
A solution of 5-
methoxyisoindolin-1-one 15 (0.8 g, 4.9 mmol) in hydroiodic acid (20 ml)
was heated at 100 °C for 12 h. After the reaction mixture was concentrated
under reduced pressure, the obtained residue was dissolved in acetone
(50 ml), followed by addition of anhydrous potassium carbonate (2.0 g,
14.5 mmol), bromoacetone (0.5 ml) and a catalytic amount of potassium io-
dide. The resulting mixture was refluxed for 3 h and then filtered. The filtrate
was concentrated under reduce pressure and purified by chromatography on
5-(2-(4-Methoxyphenylethylamino)propoxy)-1-isoindolinone 4 (34%)
as a white solid having mp 113.2—114.9 °C. H-NMR (400 MHz, DMSO-
1
d6) d: 1.17 (d, Jꢁ6.4 Hz, 3H, CHCH3), 1.73 (br s, 1H, NH), 2.76—2.80 (t,
2H, Jꢁ6.8 Hz, ArCH2), 2.83—2.99 (m, 2H, NHCH2), 3.12—3.17 (m, 1H,
CH2CHCH3), 3.79 (s, 3H, ArOCH3), 3.84—3.95 (m, 2H, ArOCH2), 4.39 (s,
2H, ArCH2NH), 6.77—7.75 (m, 8H, 7ꢅArH, CONH); IR (KBr) cmꢂ1
:
3230, 2968, 2484, 1654, 1396, 1247, 1222, 1028. MS (ESI) m/z: 341
a silica-gel column (CH2Cl2/CH3OH, 60/1 by volume) to give compound 17 [MꢀH]ꢀ. Anal. Cacld for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23. Found: C,
(0.3 g, 30%) as a white solid having mp 156.9—157.9 °C. 1H-NMR 70.50; H, 7.16; N, 8.27.
(400 MHz, DMSO-d6) d: 2.16 (s, 3H, COCH3), 4.28 (s, 2H, ArCH2NH),
5-(2-(2-(5-Methoxy-1H-indol-3-yl)ethylamino)propoxy)isoindolin-1-
4.91 (s, 2H, ArOCH2), 6.97—7.54 (m, 3H, 3ꢅArH), 8.33 (s, 1H, CONH). one 5 (18%) as a white solid having mp 197.7—198.6 °C. 1H-NMR
IR (KBr) cmꢂ1: 3472, 2962, 2849, 1751, 1612, 1485, 1431, 1155, 773, 603.
MS (ESI) m/z: 206 [MꢀH]ꢀ, 411 [2MꢀH]ꢀ. Anal. Cacld for C11H11NO3: C,
64.38; H, 5.40; N, 6.83. Found: C, 64.42; H, 5.38; N, 6.89.
Synthesis of 5-Oxypropoxy-1-isobenzofuranone 18 A solution of 5-
methoxy-1-isobenzo furanone 16 (2.8 g, 3.6 mmol) in 48% hydrobromic acid
(50 ml) was heated at 100 °C for 24 h. After the reaction mixture was con-
(400 MHz, DMSO-d6) d: 1.09 (d, Jꢁ6.4 Hz, 3H, CHCH3) 1.69 (br s, 1H,
NH), 2.79—2.84 (m, 4H, ArCH2CH2NH), 3.03—3.05 (m, 1H, CH2CHCH3),
3.72 (s, 3H, ArOCH3), 3.88—3.90 (m, 2H, ArOCH2), 4.28 (s, 2H,
ArCH2NH), 6.71—7.54 (m, 7H, 7ꢅArH), 8.27 (s, 1H, CONH), 10.61 (s,
1H, ArNH). IR (KBr) cmꢂ1: 3395, 2900, 2826, 1683, 1615, 1485, 1266,
1213. MS (ESI) m/z: 380 [MꢀH]ꢀ. Anal. Cacld for C22H25N3O3: C, 69.64;
centrated under reduced pressure, the obtained residue was dissolved in ace- H, 6.64; N, 11.07. Found: C, 69.70; H, 6.68; N, 11.01.
tone (50 ml) and then anhydrous potassium carbonate (7.1 g, 51.4 mmol),
bromoacetone (1.7 ml, 20.2 mmol) and a catalytic amount of potassium io-
dide were added. The resulting mixture was refluxed for 3 h, and then fil-
5-(2-(2-(Benzo[d][1,3]dioxol-5-yl)ethylamino)propoxy)isoindolin-1-one
6
(44%) as a white solid having mp 120.4—121.8 °C. 1H-NMR (400 MHz,
DMSO-d6) d: 1.18 (d, Jꢁ6.4 Hz, 3H, CHCH3), 1.67 (br s, 1H, NH), 2.75—
tered. The filtrate was concentrated under reduced pressure and purified by 2.78 (t, 2H, Jꢁ6.8 Hz, ArCH2), 2.85—2.96 (m, 2H, NHCH2), 3.13—3.15
chromatography on a silica-gel column (CH2Cl2/CH3OH, 60/1 by volume), (m, 1H, CH2CHCH3), 3.86—3.94 (m, 2H, ArOCH2), 4.40 (s, 2H,
followed by re-crystallization (acetone/petroleum ether, 1/3 by volume), to
ArCH2NH), 5.93 (s, 2H, OCH2O), 6.68—7.77 (m, 7H, 6ꢅArH, CONH). IR
(KBr) cmꢂ1: 3194, 2485, 1709, 1628, 1488, 1450, 1257, 1094. MS (ESI)
m/z: 355 [MꢀH]ꢀ. Anal. Cacld for C20H22N2O4: C, 67.78; H, 6.26; N, 7.90.
Found: C, 67.84; H, 6.29; N, 7.93.
afford compound 18 (1.7 g, 48%) as a white solid having mp 135.0—
1
135.8 °C. H-NMR (400 MHz, DMSO-d6) d: 2.28 (s, 3H, COCH3), 4.64 (s,
2H, ArOCH2), 5.22 (s, 2H, OCH2Ar), 6.87—7.82 (m, 3H, 3ꢅArH). IR
(KBr) cmꢂ1: 3444, 3197, 3078, 2896, 1914, 1706, 1462, 1362, 1163. MS
5-(2-(3,4-Dimethoxyphenethylamino)propoxy)isobenzofuran-1(3H)-
(ESI) m/z: 207 [MꢀH]ꢀ. Anal. Cacld for C11H10O4: C, 64.07; H, 4.89. one hydrochloride 7·HCl (40%) as a white solid having mp 82.5—
Found: C, 64.15; H, 4.86.
83.5 °C. 1H-NMR (400 MHz, DMSO-d6) d: 1.39 (d, Jꢁ6.4 Hz, 3H, CHCH3),
2.93—2.97 (t, 2H, Jꢁ7.6 Hz, ArCH2), 3.19 (m, 2H, NHCH2), 3.70—3.73
(m, 7H, 2ꢅOCH3, CH2CHCH3), 4.25—4.38 (m, 2H, ArOCH2), 5.33 (s, 2H,
Synthesis of 5-(2-(3,4-Dimethoxyphenylethylamino)propoxy)-1-isoin-
dolinone Hydrochloride 1·HCl To a solution of 5-oxypropoxy-1-isoin-
dolinone 17 (0.3 g, 1.46 mmol) in methanol (20 ml) were added 3,4- ArCH2O), 6.75—7.78 (m, 6H, 6ꢅArH), 9.36 (br s, 2H, NH2ꢀ). IR (KBr)
dimethoxyphenylethylamine (0.3 ml, 1.75 mmol) drop wise and a catalytic
amount of TsOH. The resulting mixture was refluxed under the atmosphere
of nitrogen for 3 h, and cooled to room temperature. Then KBH4 (0.3 g) was
added in portions, while keeping the temperature below 30 °C. The mixture
was stirred at room temperature for 2 h and then concentrated under reduced
pressure. The obtained residue was partitioned between water (15 ml) and
ethyl acetate (15 ml). The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (15 mlꢅ2). The organic layer was com-
bined, dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The obtained residue was purified by chromatography on a silica-
gel column (ethyl acetate/methanol, 5/1 by volume). The obtained oily prod-
uct was dissolved in a mixture of methanol–ether (1 : 3 by volume) and satu-
rated with anhydrous HCl gas. After filtered, the obtained solid was washed
with ethyl acetate and re-crystallized with a mixture of methanol–ethyl ac-
cmꢂ1: 3457, 2942, 2495, 1741, 1630, 1515, 1450, 1260. MS (ESI) m/z: 372
[MꢀH]ꢀ. Anal. Cacld for C21H26ClNO5: C, 61.84; H, 6.42; N, 3.43. Found:
C, 61.79; H, 6.40; N, 3.46.
5-(2-(2-Methoxyphenethylamino)propoxy)isobenzofuran-1(3H)-one
hydrochloride 8·HCl (34%) as a white solid having mp 216.3—217.6 °C.
1H-NMR (400 MHz, DMSO-d6) d: 1.40 (d, Jꢁ6.4 Hz, 3H, CHCH3), 2.95—
3.06 (t, 2H, Jꢁ7.6 Hz, ArCH2), 3.13—3.18 (m, 2H, NHCH2), 3.69—3.71
(m, 1H, CH2CHCH3), 3.76 (s, 3H, OCH3), 4.29—4.44 (m, 2H, ArOCH2),
5.34 (s, 2H, ArCH2O), 6.89—7.78 (m, 7H, 7ꢅArH), 9.51 (br s, 2H, NH2ꢀ).
IR (KBr) cmꢂ1: 3442, 2939, 2474, 1753, 1612, 1491, 1266, 761. MS (ESI)
m/z: 342 [MꢀH]ꢀ. Anal. Cacld for C20H24ClNO4: C, 63.57; H, 6.40; N,
3.71. Found: C, 63.61; H, 6.38; N, 3.67.
5-(2-(3-Methoxyphenethylamino)propoxy)isobenzofuran-1(3H)-one
hydrochloride 9·HCl (40%) as a white solid having mp 176.2—177.5 °C.

January 2011
99
1H-NMR (400 MHz, DMSO-d6) d: 1.42 (d, Jꢁ6.4 Hz, 3H, CHCH3), 2.99—
3.03 (t, 2H, Jꢁ7.6 Hz, ArCH2), 3.17—3.25 (m, 2H, NHCH2), 3.69—3.73
(m, 1H, CH2CHCH3), 3.75 (s, 3H, OCH3), 4.37—4.39 (m, 2H, ArOCH2),
5.36 (s, 2H, ArCH2O), 6.81—7.79 (m, 7H, 7ꢅArH), 9.52 (br s, 2H, NH2ꢀ).
IR (KBr) cmꢂ1: 3467, 2945, 2711, 2438, 1742, 1607, 1486, 1274, 1053. MS
(ESI) m/z: 342 [MꢀH]ꢀ. Anal. Cacld for C20H24ClNO4: C, 63.57; H, 6.40;
N, 3.71. Found: C, 63.51; H, 6.45; N, 3.65.
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5-(2-(4-Methoxyphenethylamino)propoxy)isobenzofuran-1(3H)-one-
hydrochloride 10·HCl (35%) as a white solid having mp 159.3—161 °C.
1H-NMR (400 MHz, DMSO-d6) d: 1.39 (d, Jꢁ6.4 Hz, 3H, CHCH3), 2.93—
2.97 (t, 2H, Jꢁ7.6 Hz, ArCH2), 3.14—3.26 (m, 2H, NHCH2), 3.66—3.71
(m, 1H, CH2CHCH3), 3.73 (s, 3H, OCH3), 4.29—4.39 (m, 2H, ArOCH2),
5.36 (s, 2H, ArCH2O), 6.90—7.80 (m, 7H, 7ꢅArH), 9.24 (br s, 2H, NH2ꢀ).
IR (KBr) cmꢂ1: 3444, 2933, 2764, 2464, 1772, 1613, 1514, 1252, 1033. MS
(ESI) m/z: 342 [MꢀH]ꢀ. Anal. Cacld for C20H24ClNO4: C, 63.57; H, 6.40;
N, 3.71. Found: C, 63.55; H, 6.47; N, 3.74.
5-(2-(2-(5-Methoxy-1H-indol-3-yl)ethylamino)propoxy)isobenzofuran-
1(3H)-one 11 (35%) as a white solid having mp 124.8—125.8 °C. 1H-
NMR (400 MHz, DMSO-d6) d: 1.18 (d, Jꢁ6.4 Hz, 3H, CHCH3) 1.65 (br s,
1H, NH), 2.95—3.08 (m, 4H, ArCH2CH2NH), 3.13—3.15 (m, 1H,
CH2CHCH3), 3.81 (s, 3H, OCH3), 3.86—3.92 (m, 2H, ArOCH2), 5.20 (s,
2H, ArCH2O), 6.74—7.77 (m, 7H, 7ꢅArH), 7.94 (s, 1H, ArNH). IR (KBr)
cmꢂ1: 3443, 2827, 1744, 1610, 1487, 1451, 1279, 1061. MS (ESI) m/z: 381
[MꢀH]ꢀ. Anal. Cacld for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C,
69.53; H, 6.34; N, 7.32.
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5-(2-(2-(Benzo[d][1,3]dioxol-5-yl)ethylamino)propoxy)isobenzofuran-
1(3H)-one Hydrochloride 12·HCl (43%) as a white solid having mp
207.0—208.3 °C. 1H-NMR (400 MHz, DMSO-d6) d: 1.40 (d, Jꢁ6.4 Hz, 3H,
CHCH3), 2.93—2.97 (t, 2H, Jꢁ7.6 Hz, ArCH2), 3.17—3.22 (m, 2H,
NHCH2), 3.68—3.72 (m, 1H, CH2CHCH3), 4.35 (m, 2H, ArOCH2), 5.36 (s,
2H, ArCH2O), 5.98 (s, 2H, OCH2O), 6.86—7.80 (m, 6H, 6ꢅArH), 9.30
(br s, 2H, NH2ꢀ). IR (KBr) cmꢂ1: 3447, 2961, 2772, 2475, 1766, 1604,
1501, 1448, 1261. MS (ESI) m/z: 356 [MꢀH]ꢀ. Anal. Cacld for
C20H22ClNO5: C, 61.30; H, 5.66; N, 3.57. found: C, 61.35; H, 5.63; N, 3.61.
Determination of pA2 Value of Each Compound The blocking activ-
ity (pA2) of each compound was measured by using the methods similar to
those described previously.23—26) 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’ physi-
ological solution 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 aer-
ated with 5% CO2/95% O2. The muscle preparations were set at a resting
tension of 1.0 g and allowed to equilibrate for 1 h in the Krebs’ solution.
During this period, the smooth muscles were replenished with Krebs’ solu-
tion every 20 min. After equilibration, cocaine hydrochloride, hydrocorti-
sone and propranolol were added to the final concentrations of 30 mmol·lꢂ1
,
30 mmol·lꢂ1 and 1 mmol·lꢂ1, respectively. After 20 min, concentration–re-
sponse curves with phenylephrine were obtained by adding phenylephrine to
the bath in the cumulative final concentrations of 3, 10, 30 mmol·lꢂ1. 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
compounds 1—12 or DDPH, respectively. The pA2 values of compounds
1—12 and DDPH were calculated according to Schild’s graphical method,
and listed in Table 1.
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401—405 (2008).
Acknowledgment This work was financially supported by the National
Natural Science Foundation of China (No. 30600776).