Novel hybrids of natural isochroman-4-one bearing N-substituted isopropanolamine as potential antihypertensive candidates

Article abstract of DOI:10.1016/j.bmc.2013.02.044

A series of novel hybrids of natural isochroman-4-one bearing isopropanolamine moiety were designed, synthesized and evaluated for their antihypertensive activity. It was found that compound IIId, prepared by hybridizing N-isopropyl substituted isopropanolamine functionality to a phenolic oxygen of isochroman-4-one, exhibited potent β₁-adrenoceptor blocking effect comparable to the well-known antihypertensive drug propranolol. Additionally, IIId significantly reduced the systolic and diastolic blood pressure in SHRs by over 40%, which was obviously stronger than the lead compounds 7,8-dihydroxy-3-methyl-isochroman-4-one (XJP) and its analogue XJP-B. Overall, IIId may be a promising antihypertensive candidate for further investigation.

Full text of DOI:10.1016/j.bmc.2013.02.044

Bioorganic & Medicinal Chemistry 21 (2013) 2495–2502
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Novel hybrids of natural isochroman-4-one bearing N-substituted
isopropanolamine as potential antihypertensive candidates
Renren Bai a,b, Xiaojing Huang a,b, Xue Yang a,b, Wen Hong c, Yiqun Tang c, Hequan Yao a,b, Jieyun Jiang d,
Jie Liu b,e, , Mingqin Shen f, Xiaoming Wu a,b, , Jinyi Xu a,b,
⇑
⇑
⇑
a Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
c Research Division of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
d Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA
e Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
f Jiangsu Provincial Institute of Traditional Chinese Medicine, Nanjing 210028, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel hybrids of natural isochroman-4-one bearing isopropanolamine moiety were designed,
synthesized and evaluated for their antihypertensive activity. It was found that compound IIId, prepared
by hybridizing N-isopropyl substituted isopropanolamine functionality to a phenolic oxygen of isochro-
man-4-one, exhibited potent b1-adrenoceptor blocking effect comparable to the well-known antihyper-
tensive drug propranolol. Additionally, IIId significantly reduced the systolic and diastolic blood pressure
in SHRs by over 40%, which was obviously stronger than the lead compounds 7,8-dihydroxy-3-methyl-
isochroman-4-one (XJP) and its analogue XJP-B. Overall, IIId may be a promising antihypertensive candi-
date for further investigation.
Received 4 January 2013
Revised 21 February 2013
Accepted 28 February 2013
Available online 14 March 2013
Keywords:
Hybrids
Isochroman-4-one
Isopropanolamine
b-Adrenoceptor blockers
Antihypertensive activity
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
more potent than S-(+)-XJP in a few cases.5 Searching for new isoch-
roman-4-one derivatives and analogues with potential antihyper-
Hypertension, the most common cardiovascular disease, is a ma-
jor risk factor in cardiovascular mortality. Intense efforts have been
made during the last three decades in the development of new anti-
hypertensive agents with different mechanism of action.1 Searching
for the active natural products from plants is always an important
strategy for development of new antihypertensive drugs.2 The ba-
nana peel has been widely used as a folk medicine for the treatment
of hypertension, fungous infection and constipation in China. Previ-
ously, we have firstly reported a novel and structurally unique
isochroman-4-one, ( )-7,8-dihydroxy-3-methyl-isochroman-4-one
[( )-XJP], isolated from the banana (Musa sapientum L.) peel, which
displayed potent antihypertensive activity in both acute and thera-
peutic antihypertensive tests in renal hypertensive rats (RHRs).3,4 In
the further structure modification, we synthesized ( )-XJP-B, an
analogue of ( )-XJP (Fig. 1), which was more active than ( )-XJP in
SHRs. Later on, we prepared R-(ꢀ)-XJP and S-(+)-XJP by chiral sepa-
ration of ( )-XJP and found that these two enantiomers possess sim-
ilar pharmacodynamic effects, whereas the R-(ꢀ)-XJP is somewhat
tensive properties has remained our interest for the last several
years and has been documented by several publications.6 However,
the antihypertensive effects of both ( )-XJP and ( )-XJP-B are still
not potent enough for therapeutic use.
The b-receptor blockers, one of the oldest available classes of car-
diovascular drugs, has established efficacy in achieving blood pres-
sure (BP) control.7 The therapeutic effects of b-receptor blockers are
normally explained by their capacity to block the b-adrenoceptors,
hindering the access of the endogenous agonists noradrenaline
and adrenaline.8 Since propranolol was commercially available in
1976, more than a dozen additional b-receptor blockers have been
clinically utilized worldwide.9,10
Most of the clinically useful b-adrenoceptor antagonists contain
a
phenoxypropanolamine moiety, typically with isopropyl or
tertbutyl as an N-substituent, linked to an aromatic or heterocyclic
ring system. Although the basic aryloxypropanolamine nucleus
should remain intact for significant b-adrenoceptor antagonist
activity, a wide variety of aromatic ring or nitrogen substituents
can be tolerated.11,12 When an isopropanolamine moiety, the
classic side chain of b-blockers, is attached to the phenolic hydro-
xyl of ( )-XJP and ( )-XJP-B, the structure of the derivatives ob-
tained quite resembles that of classic b-blockers (for instance,
⇑
Corresponding authors. Tel.: +86 025 83271445 (J.X.).
E-mail addresses: cpu-jill@163.com (J. Liu), xiaomingwu@cpu.edu.cn (X. Wu),
jinyixu@china.com (J. Xu).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.02.044

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R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
remain the significant b-adrenoceptor blocking activity in the de-
signed derivatives. Extending or shortening the carbon chain of
N-alkyl may decrease the inhibitory effect, especially exemplified
by those possessing N-ethyl (IIb and IIIb), N-butyl (Ie and IIe) or
N-tert-butyl (If, IIf and IIf).
2.3. In vivo evaluation of antihypertensive activity
Figure 1. The structures of ( )-XJP and ( )-XJP-B.
The active compounds Id, IId and IIId were selected for further
evaluation of antihypertensive activity in SHRs (Table 2 and Fig. 3).
After oral administration of the control drug propranolol (20 mg/
kg), Id, IId, IIId, XJP and XJP-B (80 mg/kg, respectively), the blood
pressure and heart rate of SHRs were determined. It was observed
that IIId showed the strongest antihypertensive activity, and sig-
nificantly reduced the systolic and diastolic blood pressure in SHRs
throughout the observation period. The maximum reduction rate
of blood pressure by IIId was over 40%, which was comparable to
that of propranolol (36%). Moreover, IIId reduced the blood pres-
sure much more significantly than the parent compounds XJP
and XJP-B. Curiously enough, the other two compounds Id and
IId which were more potent in vitro, reduced the blood pressure
not more than 30%. The heart rate changes caused by Id, IId and
IIId were much less than that by propranolol, suggesting that the
three compounds may possess better cardioprotective effects than
propranolol.
propranolol and indolol) (Fig. 2). Therefore, we attempted to con-
nect various N-substituted isopropanolamine functionalities to a
phenolic oxygen of ( )-XJP or ( )-XJP-B, and synthesized a series
of novel hybrids of isochroman-4-one derivatives. Herein, we re-
port the synthesis and biological evaluation of these hybrids of
isochroman-4-one derivatives.
2. Results and discussions
2.1. Chemistry
( )-XJP, ( )-XJP-B and their intermediates 8–10 were synthe-
sized by the similar route reported by our group.3,4 And intermedi-
ate compounds 5, 6, and 8–10 were prepared as shown in Schemes
1 and 2. Substituted benzaldehyde 1 was reduced by sodium boro-
hydride to the corresponding benzyl alcohol 2. Subsequent alkyl-
ation of 2 with ethyl 2-bromopropionate in the presence of NaH
followed by saponification of the ethyl ester provided acid 4, which
was treated with n-butyllithium in THF at ꢀ85 °C to provide ring-
closing compounds 5 and 6. After deprotection of methyl ethers 5
and 6 by using aluminum chloride, the phenolic compounds 8–10
were obtained.
The synthetic route of the target compounds Ia–g, IIa–g and
IIIa–g was depicted in Scheme 3.13–16 Compounds 8–10 were trea-
ted with epichlorohydrin in the presence of potassium carbonate
to give corresponding epoxides 11–13. Subsequent ring opening
of the epoxides with various amines afforded the target com-
pounds Ia–g, IIa–g and IIIa–g, respectively.
2.4. Structure–activity relationships (SARs) analysis
In SARs analysis, it was found: (1) selecting the natural isochro-
man-4-one structure as the aromatic ring can successfully remain
the significant b-adrenoceptor antagonist activity; (2) for b1-adren-
ergic blocking activity in vitro, N-substituent of isopropylamine
played an important role; (3) compounds bearing isopropylamine
or propylamine moiety in their structures exhibited the most po-
tent inhibition; (4) extending or shortening the carbon chain of
N-substituents may influence the inhibitory effect; (5) N-substitu-
ents at different positions of isochroman-4-one did not cause sig-
nificantly affect on the b1-adrenergic blocking activity; (6) when
it comes to the evaluation in vivo, the place of substitution played
a key role. The most suitable substitution was at the 7-position,
and 7-substituted iso-propylamine derivatives played much higher
antihypertensive activity than 6-substituted and 8-substituted
ones.
2.2. b1-Adrenoceptor antagonism assay
b1-Adrenergic blocking activity of the tested compounds was
assessed using the rat isolated left atria. As shown in Table 1, the
compounds bearing N-isopropyl-isopropanolamine or N-propyl-
isopropanolamine moiety (Id, IIc, IId, IIIc and IIId) exhibited strong
inhibitory activity. The potency of Id [(54.7 4.9)%], IId
[(42.5 3.9)%] and IIId [(44.7 5.0)%] was comparable or even
superior to the reference drug propranolol [(49.7 3.7)%] at dose
of 10ꢀ7 M. The results demonstrated that selecting the natural
isochroman-4-one structure as the aromatic ring can successfully
3. Conclusions
By connecting various N-substituted isopropanolamine func-
tionalies to a phenolic oxygen of the natural product ( )-XJP or
its analogue ( )-XJP-B, a series of novel hybrids targeting b-adreno-
O
O
O
O
N
H
N
H
HO
HO
OH
O
O
HO
HO
N
H
OH
( )-XJP
( )-XJP-B
O
H
N
O
R
N
OH
O
O
R
O
O
O
O
O
R'
O
O
HO
O
R
O
O
H
N
H
N
N
R'
N
HO
R'
OH
HO
Indolol
Figure 2. Strategy for the design of b-receptor blockers derived from natural isochroman-4-one.
Propranolol
( )-XJP derivatives
( )-XJP-B derivatives

R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
2497
R1
Br
R1
O
Br
R1
O
Br
b
O
a
O
OH
O
O
CHO
R2
R2
R2
1
2
3
O
R1
R1
Br
O
c
d
O
O
O
O
OH
R2
1 = H, R2 = OCH3
R1 = OCH3, R2 = H
R2
5
6:
:
R
4
Scheme 1. Synthetic routes of compound 5 and 6. Reagents and conditions: (a) anhydrous MeOH, NaBH4, 0 °C, 85–95%; (b) anhydrous DMF, NaH, 0 °C, 75–80%; (c) MeOH,
10% NaOH, rt, then 10% HCl, 85–90%; (d) n-BuLi, anhydrous THF, ꢀ85 °C to rt, 50–60%.
O
O
O
P95%, as estimated by HPLC analysis. The major peak of the com-
pounds analyzed by HPLC accounted for P95% of the combined to-
tal peak area when monitored by a UV detector at 254 nm. Flash
chromatography was done on Merck silica gel 60 (230–400 mesh).
a
O
O
O
O
O
HO
O
O
O
OH
7
8
(trace)
O
5
6
4.1.1. General procedure for the preparation of compounds
11–13
O
O
Intermediat 8–10 were synthesized by our reported routes.3,4
K2CO3 (0.276 g, 2 mmol) was added to a solution of compound 8
(0.208 g, 1 mmol) in anhydrous acetone (10–12 mL) and the mix-
ture was refluxed for 30 min. Then epichlorohydrin (0.32 mL,
4 mmol) was added and the mixture was refluxed for 3 h. After fil-
trated and concentrated under reduced pressure, followed by puri-
fied by flash column chromatography with n-hexane/ethyl acetate
(5:1, v/v) as eluent, compound 11 was afforded as white solid in
yield of 80%. Compounds 12 and 13 were prepared by the above
method.
O
O
O
HO
O
a
O
O
HO
10
9
Scheme 2. Synthetic routes of key intermediates 8–10. Reagents and conditions:
(a) AlCl3, NaI, CHCl3, reflux, 50–55%.
ceptor were obtained. Compounds Id, IId and IIId bearing the
N-isopropyl substituted isopropanolamine moiety exhibited the
most powerful b1-adrenoceptor blocking effects in vitro, which
was comparable or superior to the reference drug propranolol.
The further antihypertensive evaluation in SHRs showed that IIId
significantly reduced the systolic and diastolic blood pressure in
SHRs by over 40%, which was comparable to propranolol at the
higher dose and obviously stronger than the lead compounds XJP
and XJP-B at the same doses. Meanwhile, the heart rate changes
caused by IIId were much less than that by propranolol, suggesting
that this compound may possess better cardioprotective effects
than propranolol. Biological evaluation proves that the hybrids
by introducing N-isopropyl substituted isopropanolamine to the
natural product isochroman-4-one possess more potent antihyper-
tensive activity. Collectively, the isochroman-4-one ring structure
can successfully remain intact for significant b-adrenoceptor
antagonist activity. These findings may provide new insights into
the development of novel therapeutic agents for the treatment of
hypertension.
4.1.1.1. 7-Methoxy-3-methyl-8-(oxiran-2-ylmethoxy) isochro-
man-4-one (11).
White power, yield 80%, mp 102–104 °C;
IR (KBr), cmꢀ1: 2982, 2931, 2833, 1687, 1593, 1491, 1400, 1337,
1284, 1218, 1123, 1074, 865; 1H NMR (CDCl3, 300 MHz) d: 1.49
(d, 3H, J = 6.7 Hz, –CH3), 2.66–2.69 (m, 1H, –CH2–), 2.87–2.89 (m,
1H, –CH2–), 3.28–3.31 (m, 1H, –CH–), 3.87–3.98 (m, 1H, –CH2–),
3.96 (s, 3H, –OCH3), 4.19 (q, 1H, J = 6.7 Hz, –CH–), 4.26–4.36 (m,
1H, –CH2–), 4.82 (d, 1H, J = 15.7 Hz, –CH2–), 5.20 (q, 1H,
J = 7.5 Hz, –CH2–), 6.93 (d, 1H, J = 8.7 Hz, Ar-H), 7.83 (d, 1H,
J = 8.7 Hz, Ar-H); MS (ESI) m/z: 265.1 [M+H]+.
4.1.1.2. 7-Methoxy-3-methyl-6-(oxiran-2-ylmethoxy) isochro-
man-4-one (12).
White power, yield 75%, mp 104–106 °C;
IR (KBr), cmꢀ1: 3024, 2844, 1671, 1637, 1602, 1512, 1400, 1358,
1276, 1201, 1110, 870; 1H NMR (CDCl3, 300 MHz) d: 1.50 (d, 3H,
J = 6.7 Hz, –CH3), 2.76–2.78 (m, 1H, –CH2–), 2.90–2.93 (m, 1H, –
CH2–), 3.38–3.44 (m, 1H, –CH–), 3.93 (s, 3H, –OCH3), 4.00–4.06
(m, 1H, –CH2–), 4.24 (q, 1H, J = 6.7 Hz, –CH–), 4.30–4.35 (m, 1H,
–CH2–), 4.85 (s, 1H, –CH2–), 6.62 (s, 1H, Ar-H), 7.51 (s, 1H, Ar-H);
MS (ESI) m/z: 265.1 [M+H]+.
4. Experimental
4.1. Chemistry
Most chemicals and solvents were of analytical grade and, when
necessary, were purified and dried by standard methods. Melting
points were taken on an XT-4 micro melting point apparatus and
uncorrected. IR spectra were recorded in KBr on a Nicolet Impact
410 grating infrared spectrophotometer (mmax in cmꢀ1) and 1H
NMR spectra were recorded with 300 MHz spectrometers in the
indicated solvents (TMS as internal standard): the values of the
chemical shifts are expressed in d values (ppm) and the coupling
constants (J) in Hz. High-resolution mass spectra were recorded
using Agilent QTOF 6520. Purity of all tested compounds was
4.1.1.3. 6-Methoxy-3-methyl-7-(oxiran-2-ylmethoxy) isochro-
man-4-one (13).
White power, yield 82%, mp 98–100 °C; IR
(KBr), cmꢀ1: 3001, 2838, 1672, 1602, 1514, 1400, 1279, 1111,
870; 1H NMR (CDCl3, 300 MHz) d: 1.51 (d, 3H, J = 6.7 Hz, –CH3),
2.77–2.79 (m, 1H, –CH2–), 2.92–2.95 (m, 1H, –CH2–), 3.40–3.42
(m, 1H, –CH–), 3.92 (s, 3H, –OCH3), 4.00–4.10 (m, 1H, –CH2–),
4.22 (q, 1H, J = 6.7 Hz, –CH–), 4.34–4.40 (m, 1H, –CH2–), 4.85 (s,
2H, –CH2–), 6.68 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H); MS(ESI) m/z:
265.1 [M+H]+.

2498
R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
O
O
O
a
b
O
O
O
O
O
O
OH
O
O
R3
N
8
O
R4
HO
Ia-g
11
Ia:
R
3 = H, R4 = CH3
Ie: R3 = H, R4 = CH2CH2CH2CH3
If
Ig
:
R3 = H, R4 = CH2CH3
R3 = H, R4 = CH2CH2CH3
R3 = H, R4 = CH(CH3)2
Ib
Ic
:
R
3 = H, R4 = C(CH3)3
:
R3 = R4 = CH3
:
Id
:
O
R5
O
OH
O
HO
O
O
O
N
O
O
a
b
R6
O
O
O
O
9
12
IIa-g
IIa: R5 = H, R6 = CH3
IIe: R5 = H, R6 = CH2CH2CH2CH3
R
5 = H, R6 = CH2CH3
IIb:
IIc:
IId:
R5 = H, R6 = C(CH3)3
R5 = H, R6 = CH2CH2CH3
R5 = H, R6 = CH(CH3)2
IIf:
IIg:
R
5 = R6 = CH3
O
O
O
O
O
O
O
O
a
b
O
R8
N
O
O
O
HO
R7
OH
10
13
IIIa-g
IIIa: R7 = H, R8 = CH3
IIIe: R7 = H, R8 = CH2CH2CH2CH3
:
R
R
7 = H, R8 = CH2CH3
IIIb
IIIc
:
:
R
7 = H, R8 = C(CH3)3
7 = R8 = CH3
7 = H, R8 = CH2CH2CH3
IIIf
:
R7 = H, R8 = CH(CH3)2
IIIg
IIId
:
R
Scheme 3. General synthetic procedure of the target compounds. Reagents and conditions: (a) anhydrous acetone, epichlorohydrin, K2CO3, reflux, 75–82%; (b) MeOH, RR0NH,
reflux, 75–90%.
J = 6.7 Hz, –CH–), 4.82 (d, 1H, J = 15.7 Hz, –CH2–), 5.19 (d, 1H,
J = 15.7 Hz, –CH2–), 6.94 (d, 1H, J = 8.7 Hz, Ar-H), 7.84 (d, 1H,
J = 8.7 Hz, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.9, 156.5, 136.1,
124.2, 111.0, 77.7, 76.0, 75.8, 68.7, 68.6, 62.8, 55.9, 53.7, 36.4,
15.6; MS (ESI) m/z: 296.1 [M+H]+; HRMS (ESI) m/z: calcd for
Table 1
b1-Adrenoceptor antagonism in vitro of the synthesized compounds
Compd
Inhibition rate (%)
Compd
Inhibition rate (%)
10ꢀ7
M
10ꢀ6
M
10ꢀ7
M
10ꢀ6
M
C
15H22NO5[M+H]+ 296.1492, found 296.1494.
Ia
Ib
Ic
Id
Ie
If
<10
<10
IIe
IIf
IIg
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
<10
<10
46.0 4.2
19.8 2.0
54.7 4.9
<10
60.7 5.0
28.9 3.1
79.5 6.2
<10
14.6 1.4
22.1 1.4
<10
34.8 3.1
36.4 3.8
<10
4.1.2.2.
8-(3-Ethylamino-2-hydroxypropoxy)-7-methoxy-3-
White power, yield 75%, mp
methylisochroman-4-one (Ib).
<10
<10
110–112 °C; IR (KBr), cmꢀ1: 2972, 2833, 1691, 1593, 1432, 1400,
1284, 1273, 1123, 1076, 1033, 788; 1H NMR (CDCl3, 300 MHz) d:
1.45 (t, 3H, J = 7.1 Hz, –CH3), 1.49 (d, 3H, J = 6.7 Hz, –CH3), 2.70–
2.87 (m, 4H, –CH2–, –CH2–), 3.93 (s, 3H, –OCH3), 3.80–4.09 (m,
3H, –CH–, –CH2–), 4.19 (q, 1H, J = 6.7 Hz, –CH–), 4.82 (d, 1H,
J = 15.7 Hz, –CH2–), 5.19 (d, 1H, J = 15.7 Hz, –CH2–), 6.94 (d, 1H,
J = 8.6 Hz, Ar-H), 7.84 (d, 1H, J = 8.6 Hz, Ar-H); 13C NMR (CDCl3,
75 MHz) d: 194.9, 156.5, 136.1, 124.2, 111.0, 77.8, 76.0, 75.8,
68.8, 68.7, 62.9, 55.9, 51.3, 44.1, 15.7, 15.2; MS (ESI) m/z: 310.2
[M+H]+; HRMS (ESI) m/z: calcd for C16H24NO5[M+H]+ 310.1649,
found 310.1652.
<10
<10
17.3 1.8
<10
22.4 2.6
44.7 5.0
36.2 2.6
<10
<10
49.7 3.7
47.6 3.8
63.3 5.1
59.4 4.8
13.7 2.1
16.4 2.0
73.8 6.8
Ig
IIa
IIb
IIc
IId
<10
<10
<10
41.9 3.3
42.5 3.9
15.7 1.8
51.9 4.4
65.8 4.8
IIIg
Propranolol
4.1.2. General procedure for the preparation of compounds Ia–g
Corresponding amine (0.5–0.8 mL) was added to a solution of
epoxide 8 (0.264 g, 1 mmol) in methanol (15 mL), respectively.
The mixture was refluxed for 2–4 h and then concentrated under
reduced pressure, and the residue was recrystallized with n-hex-
ane/ethyl acetate (3:1, v/v) to afford compounds Ia–g as white so-
lid in yields of 75–88%.
4.1.2.3. 8-(2-Hydroxy-3-(propylamino)propoxy)-7-methoxy-3-
methylisochroman-4-one (Ic).
White power, yield 85%, mp
108–110 °C; IR (KBr), cmꢀ1: 3274, 2944, 2870, 2811, 1690, 1594,
1493, 1399, 1287, 1270, 1230, 1129, 1077, 1026; 1H NMR (CDCl3,
300 MHz) d: 0.94 (t, 3H, J = 7.4 Hz, –CH3), 1.50 (d, 3H, J = 6.7 Hz,
–CH3), 1.54–1.57 (m, 2H, –CH2–), 2.56–2.66 (m, 2H, –CH2–),
2.72–2.85 (m, 2H, –CH2–), 3.94 (s, 3H, –OCH3), 3.99–4.09 (m, 3H,
–CH–, –CH2–), 4.19 (q, 1H, J = 6.7 Hz, –CH–), 4.82 (d, 1H,
J = 15.7 Hz, –CH2–), 5.20 (d, 1H, J = 15.7 Hz, –CH2–), 6.94 (d, 1H,
4.1.2.1. 8-(2-Hydroxy-3-(methylamino)propoxy)-7-methoxy-3-
methylisochroman-4-one (Ia).
White power, yield 77%, mp
109–111 °C; IR (KBr), cmꢀ1: 3276, 2936, 2838, 2802, 1691, 1594,
1491, 1400, 1284, 1270, 1224, 1075, 1030, 793; 1H NMR (CDCl3,
300 MHz) d: 1.49 (d, 3H, J = 6.7 Hz, –CH3), 2.49 (s, 3H, –CH3), 3.94
(s, 3H, –OCH3), 4.00–4.09 (m, 3H, –CH–, –CH2–), 4.19 (q, 1H,

R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
2499
Table 2
Effects on blood pressure of compounds Id, IId and IIId in SHRsa
Groups
Dose
Parameter
Time of observation
(mg/kg)
0 h
0.5 h
1 h
2 h
4 h
6 h
8 h
Control
SAP (mmHg) 177.70 9.81
DAP (mmHg) 141.10 7.75
MAP (mmHg) 156.20 12.60 156.20 7.21
HR (BPM) 410.90 10.84 406.50 13.15
178.50 10.13
138.70 9.20
181.20 16.37
146.20 13.19
158.90 13.65
403.90 12.41
172.60 17.30
142.90 18.07
157.41 9.62
399.50 19.68
172.90 10.21
141.40 7.11
154.40 20.10
403.10 15.92
176.70 15.21
141.20 7.34
155.80 7.97
405.10 24.00
174.00 12.10
135.30 8.21
155.80 11.54
397.20 24.87
Propranolol 20
SAP (mmHg) 175.10 13.22 168.70 12.75
DAP (mmHg) 138.60 12.23 127.20 10.04
MAP (mmHg) 152.80 16.04 145.00 12.75
156.80 13.52** 160.60 15.07
105.50 9.05* 94.10 10.17**
122.60 10.07* 116.80 11.10** 108.30 8.92**
158.40 13.06* 161.00 15.20
163.90 18.14
116.90 10.79
88.30 7.04** 100.30 9.50**
120.90 13.07** 132.60 15.25
HR (BPM)
405.90 17.43 340.00 30.66** 339.90 28.53** 350.60 26.73** 349.60 16.65** 360.10 20.37* 362.30 22.70*
Id
80
80
80
SAP (mmHg) 183.30 14.44 175.30 17.41
DAP (mmHg) 148.00 11.16 129.60 11.14
MAP (mmHg) 159.80 13.46 144.80 12.22
170.10 10.82
114.60 9.59*
133.10 9.87*
169.00 15.64
109.50 9.10**
170.90 14.03
117.70 12.76* 124.40 11.32
138.90 11.63
168.00 11.71
166.30 15.81
122.90 12.94
137.40 9.61
129.30 12.40* 135.40 14.21
HR (BPM)
412.90 12.72 383.40 17.82
375.00 19.16* 368.80 19.22* 373.20 20.87* 374.70 20.65* 372.80 26.27*
*
*
*
*
*
IId
IIId
SAP (mmHg) 179.20 12.72 174.10 10.72
DAP (mmHg) 139.30 13.14 113.70 9.11
MAP (mmHg) 151.10 14.97 134.00 10.35
164.50 14.36
113.90 10.63
128.80 11.67
165.70 10.64
101.00 11.19**
166.60 14.72
99.80 10.26**
164.20 15.58
99.00 9.77**
162.60 17.57
107.70 11.08*
124.20 11.20*
122.10 11.73* 118.10 10.52** 121.00 9.25*
HR (BPM)
407.00 8.06
367.00 12.41* 365.60 16.52* 356.90 10.64* 358.50 15.55* 355.20 22.52* 367.70 24.69*
SAP (mmHg) 176.00 16.70 169.20 13.50
DAP (mmHg) 140.90 11.32 128.70 10.54
MAP (mmHg) 154.60 12.99 142.20 11.25
160.90 15.12
102.80 8.80**
152.80 14.61** 141.00 10.90** 150.50 13.48** 158.30 11.34**
84.10 9.73** 83.00 8.35** 91.40 11.73** 98.00 9.30**
97.80 10.46** 114.00 12.44** 119.00 9.59**
365.10 13.57* 361.40 18.62* 370.00 22.45* 372.80 24.44
123.10 11.10** 103.90 9.96**
HR (BPM)
408.00 13.61 385.40 20.63
378.30 23.24
a
Data are represented as mean SEM (n = 8). Significance levels.
*
p <0.05.
**
p <0.01 as compared with the respective control.
Figure 3. (A) The acute antihypertensive activities of Id, IId, IIId and propranolol in SHRs (SAP, systolic arterial pressure); (B) the acute antihypertensive activities of Id, IId,
IIId and propranolol in SHRs (DAP, diastolic arterial pressure); (C) the acute antihypertensive activities of Id, IId, IIId and propranolol in SHRs (MAP, mean artery pressure);
(D) the changes of DAP of XJP, XJP-B and IIId in SHRs. Data are represented as mean SEM (n = 8). Significance levels ⁄p <0.05 and ⁄⁄p <0.01 as compared with the respective
control.
J = 8.7 Hz, Ar-H), 7.84 (d, 1H, J = 8.7 Hz, Ar-H); 13C NMR (CDCl3,
75 MHz) d: 194.9, 156.5, 136.1, 124.2, 111.0, 77.8, 76.0, 75.8,
68.8, 68.7, 62.9, 56.0, 51.7, 51.4; 23.2, 15.7, 11.7; MS (ESI) m/z:
324.2 [M+H]+; HRMS (ESI) m/z: calcd for C17H26NO5[M+H]+
324.1805, found 324.1802.
4.1.2.4. 8-(2-Hydroxy-3-(isopropylamino)propoxy)-7-methoxy-
3-methylisochroman-4-one (Id).
White power, yield 80%,
mp 117–119 °C; IR (KBr), cmꢀ1: 3276, 2962, 2813, 1697, 1595,
1492, 1400, 1288, 1271, 1126, 1076, 1025, 927. 1H NMR (CDCl3,
300 MHz) d: 1.09 (s, 3H, –CH3), 1.11 (s, 3H, –CH3), 1.49 (d, 3H,

2500
R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
J = 6.6 Hz, –CH3), 2.68–2.75 (m, 1H, –CH–), 2.82–2.87 (m, 2H, –
CH2–), 3.96 (s, 3H, –OCH3), 3.98–4.07 (m, 3H, –CH–, –CH2–), 4.19
(q, 1H, J = 6.6 Hz, –CH–), 4.81 (d, 1H, J = 15.7 Hz, –CH2–), 5.21 (d,
1H, J = 15.7 Hz, –CH2–), 6.94 (d, 1H, J = 8.7 Hz, Ar-H), 7.84 (d, 1H,
J = 8.7 Hz, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.9, 156.5, 136.1,
124.2, 111.0, 77.8, 76.0, 75.8, 69.0, 62.9, 55.9, 49.0, 23.0, 22.8,
15.7; MS(ESI) m/z: 324.2 [M+H]+; HRMS (ESI) m/z: calcd for
6.60 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H); 13C NMR (CDCl3, 75 MHz) d:
194.7, 154.5, 148.0, 137.4, 122.4, 110.2, 106.1, 78.0, 72.2, 67.8,
66.6, 56.1, 53.7, 36.2, 15.8; MS (ESI) m/z: 296.1 [M+H]+; HRMS
(ESI) m/z: calcd for C15H22NO5[M+H]+ 296.1492, found 296.1489.
4.1.3.2.
6-(3-Ethylamino-2-hydroxypropoxy)-7-methoxy-3-
White power, yield 79%,
methylisochroman-4-one (IIb).
C
17H26NO5[M+H]+ 324.1805, found 324.1800.
mp 114–116 °C; IR (KBr), cmꢀ1: 2979, 2928, 2821, 1685, 1602,
1513, 1400, 1356, 1274, 1210, 1112; 1H NMR (CDCl3, 300 MHz)
d: 1.32 (t, 3H, J = 7.2 Hz, –CH3), 1.49 (d, 3H, J = 6.7 Hz, –CH3),
2.91–3.13 (m, 4H, –CH2–, –CH2–), 3.90 (s, 3H, –OCH3), 4.08–4.09
(m, 2H, –CH2–), 4.20 (q, 1H, J = 6.7 Hz, –CH–), 4.37–4.40 (m, 1H,
–CH–), 4.83 (s, 2H, –CH2–), 6.58 (s, 1H, Ar-H), 7.46 (s, 1H, Ar-H);
13C NMR (CDCl3, 75 MHz) d: 194.7, 154.5, 148.0, 137.4, 122.4,
110.1, 106.1, 78.0, 72.4, 68.0, 66.6, 56.1, 51.5, 44.1, 15.9, 15.3; MS
(ESI) m/z: 310.2 [M+H]+; HRMS (ESI) m/z: calcd for
C16H24NO5[M+H]+ 310.1649, found 310.1645.
4.1.2.5.
8-(3-Butylamino-2-hydroxypropoxy)-7-methoxy-3-
White power, yield 78%, mp
methylisochroman-4-one (Ie).
108–110 °C; IR (KBr), cmꢀ1: 3274, 2929, 2870, 2831, 1697, 1686,
1595, 1491, 1400, 1288, 1271, 1124, 1076; 1H NMR (CDCl3,
300 MHz) d: 0.92 (t, 3H, J = 7.4 Hz, –CH3), 1.26–1.47 (m, 4H, –
CH2–, –CH2–), 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.58–2.86 (m, 4H, –
CH2–, –CH2–), 3.88 (s, 3H, –OCH3), 3.90–4.09 (m, 3H, –CH–, –
CH2–), 4.19 (q, 1H, J = 6.7 Hz, –CH–), 4.82 (d, 1H, J = 15.7 Hz, –
CH2–), 5.19 (d, 1H, J = 15.7 Hz, –CH2–), 6.94 (d, 1H, J = 8.7 Hz, Ar-
H), 7.84 (d, 1H, J = 8.7 Hz, Ar-H); 13C NMR (CDCl3, 75 MHz) d:
194.9, 156.5, 136.1, 124.2, 111.0, 77.8, 76.0, 75.8, 68.8, 68.7, 62.9,
55.9, 49.6, 32.3, 20.4, 15.7, 14.0; MS (ESI) m/z: 338.2 [M+H]+; HRMS
(ESI) m/z: calcd for C18H28NO5[M+H]+ 338.1962, found 338.1958.
4.1.3.3. 6-(2-Hydroxy-3-(propylamino)propoxy)-7-methoxy-3-
methylisochroman-4-one (IIc).
White power, yield 85%, mp
116–118 °C; IR (KBr), cmꢀ1: 3232, 2968, 2816, 1672, 1601, 1513,
1400, 1355, 1277, 1112, 87; 1H NMR (CDCl3, 300 MHz) d: 0.94 (t,
3H, J = 7.2 Hz, –CH3), 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.65 (t, 3H,
J = 7.2 Hz, –CH2–), 2.75–2.89 (m, 2H, –CH2–), 3.91 (s, 3H, –OCH3),
4.00–4.13 (m, 3H, –CH–, –CH2–), 4.22 (q, 1H, J = 6.7 Hz, –CH–),
4.85 (s, 2H, –CH2–), 6.60 (s, 1H, Ar-H), 7.51 (s, 1H, Ar-H); 13C
NMR (CDCl3, 75 MHz) d: 194.7, 154.5, 148.0, 137.4, 122.4, 110.1,
106.1, 78.0, 72.3, 68.0, 66.6, 56.1, 51.7, 51.6, 23.2, 15.9, 11.7; MS
(ESI) m/z: 324.2 [M+H]+; HRMS (ESI) m/z: calcd for
4.1.2.6. 8-(3-(tert-Butylamino)-2-hydroxypropoxy)-7-methoxy-
3-methylisochroman-4-one (If).
White power, yield 77%,
mp 99–101 °C; IR (KBr), cmꢀ1: 3298, 2967, 2880, 2836, 1695,
1686, 1594, 1492, 1444, 1363, 1312, 1286, 1222, 1125, 1076,
878; 1H NMR (CDCl3, 300 MHz) d: 1.38–1.50 (m, 12H, –CH3, –
C(CH3)3), 3.01–3.20 (m, 2H, –CH2–), 3.93 (s, 3H, –OCH3), 4.01–
4.05 (m, 1H, –CH–), 4.06–4.20 (m, 2H, –CH2–), 4.30–4.35 (q, 1H,
J = 6.7 Hz, –CH–), 4.80 (d, 1H, J = 15.7 Hz, –CH2–), 5.15 (d, 1H,
J = 15.7 Hz, –CH2–), 6.92 (d, 1H, J = 8.7 Hz, Ar-H), 7.82 (d, 1H,
J = 8.7 Hz, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.9, 156.5, 136.1,
124.1, 111.0, 77.7, 76.0, 75.8, 69.3, 62.9, 55.9, 50.3, 44.4, 29.1,
15.7; MS (ESI) m/z: 338.3 [M+H]+; HRMS (ESI) m/z: calcd for
C
17H26NO5[M+H]+ 324.1805, found 324.1803.
4.1.3.4. 6-(2-Hydroxy-3-(isopropylamino)propoxy)-7-methoxy-
3-methylisochroman-4-one (IId). White power, yield 85%,
mp 98–100 °C; IR (KBr), cmꢀ1: 3294, 2979, 2940, 1693, 1600,
1512, 1448, 1400, 1356, 1273, 1113, 1010; 1H NMR (CDCl3,
300 MHz) d: 1.08 (s, 3H, –CH3), 1.10 (s, 3H, –CH3), 1.50 (d, 3H,
J = 6.7 Hz, –CH3), 2.72–2.90 (m, 3H, –CH–, –CH2–), 3.91 (s, 3H, –
OCH3), 3.98–4.13 (m, 3H, –CH–, –CH2–), 4.22 (q, 1H, J = 6.7 Hz, –
CH–), 4.85 (s, 2H, –CH2–), 6.60 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H);
13C NMR (CDCl3, 75 MHz) d: 194.8, 154.5, 148.0, 137.3, 122.4,
110.0, 106.1, 78.0, 72.4, 68.1, 66.6, 56.1, 49.1, 48.8, 23.1, 23.0,
15.9; MS (ESI) m/z: 324.2 [M+H]+; HRMS (ESI) m/z: calcd for
C17H26NO5[M+H]+ 324.1805, found 324.1805.
C
18H28NO5[M+H]+ 338.1962, found 338.1956.
4.1.2.7. 8-(3-Dimethylamino-2-hydroxypropoxy)-7-methoxy-3-
methylisochroman-4-one (Ig).
White power, yield 76%, mp
56–58 °C; IR (KBr), cmꢀ1: 2983, 2934, 2836, 2777, 1297, 1686,
1594, 1495, 1456, 1400, 1288, 1272, 1127, 1076; 1H NMR (CDCl3,
300 MHz) d: 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.33 (s, 6H, –CH3,
–
CH3), 2.38–2.58 (m, 2H, –CH2–), 3.93 (s, 3H, –OCH3), 3.99–4.08
(m, 3H, –CH–, –CH2–), 4.18 (q, 1H, J = 6.7 Hz, –CH–), 4.82 (d, 1H,
J = 15.7 Hz, –CH2–), 5.22 (d, 1H, J = 15.7 Hz, –CH2–), 6.93 (d, 1H,
J = 8.6 Hz, Ar-H), 7.83 (d, 1H, J = 8.6 Hz, Ar-H); 13C NMR (CDCl3,
75 MHz) d: 195.0, 156.6, 136.1, 124.1, 111.0, 77.7, 75.5, 75.4,
66.8, 62.9, 61.5, 55.9, 45.6, 15.7; MS (ESI) m/z: 310.2 [M+H]+; HRMS
(ESI) m/z: calcd for C16H24NO5[M+H]+ 310.1649, found 310.1650.
4.1.3.5. 6-(3-Butylamino-2-hydroxypropoxy)-7-methoxy-3
-
methylisochroman-4-one (IIe). White power, yield 80%, mp
100–102 °C; IR (KBr), cmꢀ1: 3289, 2956, 2928, 2827, 1677, 1600,
1513, 1400, 1355, 1273, 1212, 1113, 1007; 1H NMR (CDCl3,
300 MHz) d: 0.94 (t, 3H, J = 7.2 Hz, –CH3), 1.33–1.48 (m, 2H, –
CH2–), 1.57 (d, 3H, J = 6.7 Hz, –CH3), 1.63–1.73 (m, 2H, –CH2–),
2.83–2.88 (m, 2H, –CH2–), 2.96–3.12 (m, 2H, –CH2–), 3.90 (s, 3H,
–OCH3), 4.07–4.09 (m, 2H, –CH2–), 4.21 (q, 1H, J = 6.7 Hz, –CH–),
4.35–4.37 (m, 1H, –CH–), 4.84 (s, 2H, –CH2–), 6.58 (s, 1H, Ar-H),
7.47 (s, 1H, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.7, 154.5,
148.0, 137.4, 122.4, 110.1, 106.1, 78.0, 72.3, 68.0, 66.6, 56.1, 51.6,
49.6, 32.3, 20.4, 15.9, 14.0; MS (ESI) m/z: 338.3 [M+H]+; HRMS
(ESI) m/z: calcd for C18H28NO5[M+H]+ 338.1962, found 338.1962.
4.1.3. General procedure for the preparation of compounds IIa–
g
Corresponding amine (0.5–0.8 mL) was added to a solution of
epoxide 9 (0.264 g, 1 mmol) in methanol (15 mL), respectively.
The mixture was refluxed for 2–4 h and then concentrated under
reduced pressure, and the residue was recrystallized with n-hex-
ane/ethyl acetate (3:1, v/v) to give compounds IIa–g as white solid
in yields of 77–89%.
4.1.3.6. 6-(3-(tert-Butylamino)-2-hydroxypropoxy)-7-methoxy-
4.1.3.1. 6-(2-Hydroxy-3-(methylamino)propoxy)-7-methoxy-3-
3-methylisochroman-4-one (IIf).
White power, yield 83%,
methylisochroman-4-one (IIa).
White power, yield 77%, mp
mp 112–114 °C; IR (KBr), cmꢀ1: 3289, 2973, 2838, 1682, 1600,
1511, 1400, 1358, 1273, 1210, 1113, 1075, 1010; 1H NMR (CDCl3,
300 MHz) d: 1.12 (s, 9H, –C(CH3)3), 1.50 (d, 3H, J = 6.7 Hz, –CH3),
2.69–2.74 (m, 1H, –CH2–), 2.83–2.88 (m, 1H, –CH2–), 3.91 (s, 3H,
–OCH3), 3.98–4.03 (m, 2H, –CH2–), 4.05–4.13 (m, 1H, –CH–), 4.21
(q, 1H, J = 6.7 Hz, –CH–), 4.85 (s, 2H, –CH2–), 6.60 (s, 1H, Ar-H),
108–110 °C; IR (KBr), cmꢀ1: 2938, 2831, 1685, 1601, 1514, 1443,
1400, 1357, 1275, 1207, 1111, 1039, 868; 1H NMR (CDCl3,
300 MHz) d: 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.49 (s, 3H, –CH3),
2.74–2.84 (m, 2H, –CH2–), 3.91 (s, 3H, –OCH3), 4.00–4.17 (m, 3H,
–CH–, –CH2–), 4.21 (q, 1H, J = 6.7 Hz, –CH–), 4.85 (s, 2H, –CH2–),

R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
2501
7.50 (s, 1H, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.7, 154.5, 148.1,
137.3, 122.4, 110.0, 106.1, 78.0, 72.5, 68.1, 66.6, 56.1, 50.2, 44.4,
29.1, 15.9; MS (ESI) m/z: 338.2 [M+H]+; HRMS (ESI) m/z: calcd for
4.1.4.4. 7-(2-Hydroxy-3-(isopropylamino)propoxy)-6-methoxy-
3-methylisochroman-4-one (IIId). White power, yield 90%,
mp 134–136 °C; IR (KBr), cmꢀ1: 3271, 2982, 2941, 2833, 1676,
1602, 1512, 1400, 1358, 1278, 1214, 1157, 1111, 1048, 1010; 1H
NMR (CDCl3, 300 MHz) d: 1.46–1.52 (m, 9H, –CH3, –CH3, –CH3),
3.18–3.23 (m, 1H, –CH–), 3.34–3.69 (m, 2H, –CH2–), 3.87 (s, 3H, –
OCH3), 4.08–4.23 (m, 3H, –CH–, –CH2–), 4.66–4.68 (m, 1H, –CH–
),4.81 (s, 2H, –CH2–), 6.65 (s, 1H, Ar-H), 7.45 (s, 1H, Ar-H); 13C
NMR (CDCl3, 75 MHz) d: 194.9, 153.3, 149.0, 136.8, 122.7, 108.3,
107.5, 78.0, 72.3, 67.8, 66.5, 56.0, 49.1, 48.9, 23.1, 23.0, 15.9; MS
(ESI) m/z: 324.2 [M+H]+; HRMS (ESI) m/z: calcd for
C
18H28NO5[M+H]+ 338.1962, found 338.1964.
4.1.3.7. 6-(3-Dimethylamino-2-hydroxypropoxy)-7-methoxy-3-
methylisochroman-4-one (IIg). White power, yield 77%, mp
92–94 °C; IR (KBr), cmꢀ1: 2945, 2821, 2765, 1671, 1602, 1514,
1400, 1356, 1279, 1109, 1041, 878; 1H NMR (CDCl3, 300 MHz) d:
1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.33 (s, 6H, –CH3, –CH3), 2.35–2.40
(m, 1H, –CH2–), 2.51–2.58 (m, 1H, –CH2–), 3.92 (s, 3H, –OCH3),
3.97–4.17 (m, 3H, –CH–, –CH2–), 4.21 (q, 1H, J = 6.7 Hz, –CH–),
4.85 (s, 2H, –CH2–), 6.60 (s, 1H, Ar-H), 7.52 (s, 1H, Ar-H); 13C
NMR (CDCl3, 75 MHz) d: 194.8, 154.5, 148.1, 137.3, 122.4, 110.0,
106.1, 78.0, 71.9, 66.6, 66.2, 61.6, 56.1, 45.6, 15.9; MS (ESI) m/z:
310.2 [M+H]+; HRMS (ESI) m/z: calcd for C16H24NO5[M+H]+
310.1649, found 310.1644.
C
17H26NO5[M+H]+ 324.1805, found 324.1803.
4.1.4.5. 7-(3-Butylamino-2-hydroxypropoxy)-6-methoxy-3
-
methylisochroman-4-one (IIIe). White power, yield 80%,
mp 100–102 °C; IR (KBr), cmꢀ1: 3276, 2931, 1677, 1603, 1512,
1400, 1278, 1211, 1159, 1110, 1046; 1H NMR (CDCl3, 300 MHz)
d: 0.93 (t, 3H, J = 7.1 Hz, –CH3), 1.33–1.40 (m, 2H, –CH2–), 1.47–
1.49 (m, 2H, –CH2–), 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.66–2.70 (m,
2H, –CH2–), 2.80–2.92 (m, 2H, –CH2–), 3.90 (s, 3H, –OCH3), 4.06–
4.21 (m, 3H, –CH–, –CH2–), 4.22 (q, 1H, J = 6.7 Hz, –CH–), 4.84 (s,
2H, –CH2–), 6.66 (s, 1H, Ar-H), 7.49 (s, 1H, Ar-H); 13C NMR (CDCl3,
75 MHz) d: 194.9, 153.3, 149.0, 136.8, 122.7, 108.3, 107.5, 78.0,
72.2, 67.7, 66.5, 56.0, 51.6, 49.6, 32.3, 20.4, 15.9, 14.0; MS (ESI)
m/z: 338.3 [M+H]+; HRMS (ESI) m/z: calcd for C18H28NO5[M+H]+
338.1962, found 338.1962.
4.1.4. General procedure for the preparation of compounds IIIa-
g
Corresponding amine (0.5–0.8 mL) was added to a solution of
epoxide 10 (0.264 g, 1 mmol) in methanol (15 mL), respectively.
The mixture was refluxed for 2–4 h and then concentrated under
reduced pressure, and the residue was recrystallized with n-hex-
ane/ethyl acetate (3:1, v/v) to provide compounds IIIa–g as white
solid in yields of 75–90%.
4.1.4.6. 7-(3-(tert-Butylamino)-2-hydroxypropoxy)-6-methoxy-
4.1.4.1. 7-(2-Hydroxy-3-(methylamino)propoxy)-6-methoxy-3-
3-methylisochroman-4-one (IIIf).
White power, yield 82%,
methylisochroman-4-one (IIIa).
White power, yield 78%,
mp 72–74 °C; IR (KBr), cmꢀ1: 3307, 2965, 2864, 2823, 1683,
1600, 1512, 1450, 1399, 1353, 1274, 1213, 1109, 1043, 1007,
881; 1H NMR (CDCl3, 300 MHz) d: 1.12 (s, 9H, –C(CH3)3), 1.51 (d,
3H, J = 6.7 Hz, –CH3), 2.74–2.77 (m, 1H, –CH2–), 2.86–2.92 (m,
1H, –CH2–), 3.90 (s, 3H, –OCH3), 4.00–4.13 (m, 3H, –CH–, –CH2–),
4.22 (q, 1H, J = 6.7 Hz, –CH–), 4.84 (s, 2H, –CH2–), 6.65 (s, 1H, Ar-
H), 7.48 (s, 1H, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.9, 153.4,
149.0, 136.8, 122.7, 108.3, 107.4, 78.0, 72.5, 72.4, 67.8, 67.7, 66.5,
56.0, 50.4, 44.4, 29.1, 15.9; MS(ESI) m/z: 338.3 [M+H]+; HRMS
(ESI) m/z: calcd for C18H28NO5[M+H]+ 338.1962, found 338.1951.
mp 142–144 °C; IR (KBr), cmꢀ1: 3317, 3001, 2940, 2821, 1685,
1602, 1511, 1400, 1354, 1272, 1213, 1109, 1013; 1H NMR (CDCl3,
300 MHz) d: 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.50 (s, 3H, –CH3),
2.77–2.87 (m, 2H, –CH2–), 3.89 (s, 3H, –OCH3), 4.06–4.09 (m, 2H,
–CH2–), 4.11–4.16 (m, 1H, –CH–), 4.21 (q, 1H, J = 6.7 Hz, –CH–),
4.84 (s, 2H, –CH2–), 6.65 (s, 1H, Ar-H), 7.48 (s, 1H, Ar-H); 13C
NMR (CDCl3, 75 MHz) d: 194.9, 153.2, 149.0, 136.8, 122.8, 108.3,
107.6, 78.0, 72.1, 67.7, 66.5, 56.0, 53.7, 36.3, 15.9; MS(ESI) m/z:
296.2 [M+H]+; HRMS (ESI) m/z: calcd for C15H22NO5[M+H]+
296.1492, found 296.1493.
4.1.4.7. 7-(3-Dimethylamino-2-hydroxypropoxy)-6-methoxy-3-
4.1.4.2.
7-(3-Ethylamino-2-hydroxypropoxy)-6-methoxy-3-
White power, yield 78%,
methylisochroman-4-one (IIIg).
White power, yield 75%, mp
130–132 °C; IR (KBr), cmꢀ1: 2936, 2828, 2766, 1671, 1600, 1512,
1464, 1374, 1355, 1276, 1210, 1110, 1077, 1002, 881; 1H NMR
(CDCl3, 300 MHz) d: 1.50 (d, 3H, J = 6.7 Hz, –CH3), 2.04 (s, 6H, –
CH3, –CH3), 2.47–2.74 (m, 2H, –CH2–), 3.89 (s, 3H, –OCH3), 4.06–
4.09 (m, 2H, –CH2–), 4.11–4.26 (m, 2H, –CH–, –CH–), 4.83 (s, 2H,
–CH2–), 6.68 (s, 1H, Ar-H), 7.49 (s, 1H, Ar-H); 13C NMR (CDCl3,
75 MHz) d: 194.9, 153.4, 149.1, 136.7, 122.7, 108.3, 107.6, 78.0,
71.8, 71.7, 66.5, 66.1, 61.7, 56.0, 45.6, 15.9; MS(ESI) m/z: 310.2
[M+H]+; HRMS (ESI) m/z: calcd for C16H24NO5[M+H]+ 310.1649,
found 310.1646.
methylisochroman-4-one (IIIb).
mp 130–132 °C; IR (KBr), cmꢀ1: 2962, 2928, 2833, 1670, 1603,
1513, 1400, 1357, 1280, 1213, 1109, 1050, 881; 1H NMR (CDCl3,
300 MHz) d: 1.14 (t, 3H, J = 7.1 Hz, –CH3), 1.51 (d, 3H, J = 6.7 Hz, –
CH3), 2.68–2.79 (m, 2H, –CH2–), 2.80–2.92 (m, 2H, –CH2–), 3.89
(s, 3H, –OCH3), 4.05–4.13 (m, 3H, –CH–, –CH2–), 4.22 (q, 1H,
J = 6.7 Hz, –CH–), 4.84 (s, 2H, –CH2–), 6.65 (s, 1H, Ar-H), 7.48 (s,
1H, Ar-H); 13C NMR (CDCl3, 75 MHz) d: 194.9, 153.3, 149.0,
136.8, 122.7, 108.3, 107.5, 78.0, 72.2, 67.8, 66.5, 56.0, 51.4, 44.1,
15.9, 15.3; MS (ESI) m/z: 310.2 [M+H]+; HRMS (ESI) m/z: calcd for
C16H24NO5[M+H]+ 310.1649, found 310.1641.
4.2. Pharmacological evaluation
4.1.4.3. 7-(2-Hydroxy-3-(propylamino)propoxy)-6-methoxy-3-
methylisochroman-4-one (IIIc).
White power, yield 85%,
4.2.1. b1-Adrenoceptor blocking test in vitro using the rat
isolated left atria
mp 134–136 °C; IR (KBr), cmꢀ1: 3276, 2946, 2828, 1670, 1603,
1513, 1400, 1279, 1211, 1111; 1H NMR (CDCl3, 300 MHz) d: 0.93
(t, 3H, J = 7.1 Hz, –CH3), 1.51 (d, 3H, J = 6.7 Hz, –CH3), 2.64 (t, 3H,
J = 7.1 Hz, –CH2–), 2.78–2.93 (m, 4H, –CH2–, –CH2–), 3.89 (s, 3H,
–OCH3), 4.06–4.13 (m, 3H, –CH–, –CH2–), 4.22 (q, 1H, J = 6.7 Hz, –
CH–), 4.84 (s, 2H, –CH2–), 6.65 (s, 1H, Ar-H), 7.48 (s, 1H, Ar-H);
13C NMR (CDCl3, 75 MHz) d: 194.9, 153.3, 149.0, 136.8, 122.7,
108.3, 107.5, 78.0, 72.2, 67.7, 66.5, 56.0, 51.7, 51.5, 23.1, 15.9,
11.7; MS (ESI) m/z: 324.2 [M+H]+; HRMS (ESI) m/z: calcd for
Male Sprague Dawley (SD) rats (250–350 g) were stunned and
exsanguinated. The heart was rapidly removed and placed in ice
cold Krebs solution that was saturated with 5% CO2/95% O2, and
the left atria was excised. All procedures were performed in the
presence of a modified Krebs solution [composition (mmol/L):
NaHCO3, 24; Glucose, 10; KH2PO4, 1.2; CaCl2, 2.5; MgSO4, 1.2; KCl,
4.7; NaCl, 118; pH 7.4] which was being vigorously bubbled with
5% CO2 in oxygen at 37 °C. The left atria was removed from the
heart mounted longitudinally between two platinum electrodes
C
17H26NO5[M+H]+ 324.1805, found 324.1801.

2502
R. Bai et al. / Bioorg. Med. Chem. 21 (2013) 2495–2502
(approximately 3 cm apart, above and below the tissue) under 0.5 g
tension in 10 mL organ baths containing Krebs solution and allowed
to equilibrate for 30 min. During the equilibration period, the tis-
sues were washed by overflow.
(JKY2011027) and Project Program of State Key Laboratory of Nat-
ural Medicines, China Pharmaceutical University (JKGQ201115).
References and notes
Tissues were electrically stimulated at 2 Hz (3 mesc, 150%
threshold potential). 10ꢀ7 M isoprenaline was added twice until
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treated with new compounds (10ꢀ7 and 10ꢀ6 M), and 10ꢀ7 M iso-
prenaline was added after 5 min. The contraction change to iso-
prenaline was observed, then the inhibition ratio was calculated.
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Acknowledgments
This study was financially supported by a grant from ‘Eleventh
Five-Year’ Major Innovation Projects for New Drug Candidates (No.
2009ZX09103-128), Project for Research and Innovation of Gradu-
ates in Colleges and Universities of Jiangsu Province (CXZZ11-
0798), Fundamental Research Funds for the Central Universities