Drug metabolism-based design, synthesis, and bioactivities of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) analogs as α1-adrenoceptors antagonists

Article abstract of DOI:10.1016/j.bmc.2010.12.020

1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is a potent α₁-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at the 3-, or 4-position of aromatic ring B to extend the duration time. These compounds were synthesized in moderate to good yields from the reductive amination of substituted phenoxyacetones with substituted phenylethylamines, and fully characterized with ¹H NMR, IR, and HRMS. Biological evaluation indicated that most of the compounds exhibited strong blocking and moderate to good antihypertensive activities. It is clear that the compounds having 4-OH/3-OMe on group B exhibited higher blocking activities and longer duration time than their corresponding analogs having 4-OMe/3-OMe (and also 3-OH/4-OMe). Among them, compound 13 having bromo group at the 4-position of ring A and 4-OH/3-OMe on group B, exhibited the highest blocking activity, whereas compound 17 that had a methyl group at the 4-position of ring A and a hydroxyl group at the 4-position of ring B, was more active than potent DDPH in terms of both blocking and antihypertensive activities. In addition, the possible correlations between the blocking and antihypertensive activities are also briefly discussed.

Full text of DOI:10.1016/j.bmc.2010.12.020

Bioorganic & Medicinal Chemistry 19 (2011) 783–788
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Drug metabolism-based design, synthesis, and bioactivities
of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane
hydrochloride (DDPH) analogs as a1-adrenoceptors antagonists
Bao-Min Xi a, Zhen-Zhou Jiang b, Jian-Wei Zou c, Pei-Zhou Ni d, , Wen-Hua Chen a,
⇑
⇑
a School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
b New Drug Research and Development Center, China Pharmaceutical University, Nanjing 210038, China
c Key Laboratory for Molecular Design and Nutrition Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo 315104, China
d Department of Organic Chemistry, China Phramacetical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is
a
Received 14 October 2010
Revised 6 December 2010
Accepted 6 December 2010
Available online 13 December 2010
potent
a1-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast
metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to
the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano
groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at
the 3-, or 4-position of aromatic ring B to extend the duration time. These compounds were synthesized
in moderate to good yields from the reductive amination of substituted phenoxyacetones with substi-
tuted phenylethylamines, and fully characterized with 1H NMR, IR, and HRMS. Biological evaluation indi-
cated that most of the compounds exhibited strong blocking and moderate to good antihypertensive
activities. It is clear that the compounds having 4-OH/3-OMe on group B exhibited higher blocking
activities and longer duration time than their corresponding analogs having 4-OMe/3-OMe (and also
3-OH/4-OMe). Among them, compound 13 having bromo group at the 4-position of ring A and 4-OH/
3-OMe on group B, exhibited the highest blocking activity, whereas compound 17 that had a methyl
group at the 4-position of ring A and a hydroxyl group at the 4-position of ring B, was more active than
potent DDPH in terms of both blocking and antihypertensive activities. In addition, the possible correla-
tions between the blocking and antihypertensive activities are also briefly discussed.
Keywords:
a1-adrenoceptor antagonist
DDPH
Synthesis
Bioactivity
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
1-(2,6-dimethyl-phenoxy)-2-(3,4-dimethoxyphenylethylamino)pro-
pane hydrochloride (DDPH, Chart 1).12 DDPH is currently under
a
1-Adrenoceptors (
a
1-ARs) belong to the seven transmem-
phase II clinic trials as an antihypertensive drug in China. Recent
studies have shown that DDPH has protective effects against neu-
ron damage induced by acute ischemia in mice and rats,14 and can
efficiently cross the blood brain barrier and inhibit the contraction
of vascular smooth muscle in the brain.15
brane-domain receptor super-family and play a crucial role in reg-
ulating of the functions of several physiological processes, in
particular in the cardiovascular system.1–5 This biological impor-
tance has prompted major efforts to develop new agents that are
capable of blocking the function of
a
1-ARs. These agents, namely
However, DDPH presented one major problem in phase II clinic
trials. That is, it metabolized so fast that patients had to be served
3–4 times daily. This drawback has largely restricted its clinic use.
To gain insight into exactly how DDPH was deactivated in vivo, Lu
et al. synthesized the probable metabolites of DDPH, that is, 1–8
(Chart 1),16 among which compounds 1–6 were detected as the
actual metabolites by LC–MS and compounds 1–4 were the main
metabolites with the contents being in the order of 1 > 2 > 3 >
4.17,18 Study on the biological activities indicated that, compared
with DDPH, the compounds that were hydroxylated at the 3- or
4-position of ring A, that is, compounds 1, 3, 4, 6, and 8 (but except
5), had significantly shorter duration time, whereas the com-
pounds that had no hydroxyl groups on ring A (i.e., compounds 2
a1-AR antagonists, can find wide applications as effective thera-
peutic drugs, for example, for benign prostatic hypertrophy and
high blood pressure.6,7
In these aspects, readily available phenoxylalkylamines repre-
sent one class of
a
1-AR antagonists.8,9 In our previous study, we
have shown that some novel phenoxylalkylamines exhibit
promising blocking activities,10–13 remarkable among which is
⇑
Corresponding authors. Tel.: +86 25 86185180; fax: +86 25 86185179 (P.-Z.N.);
tel.: +86 20 61648589; fax: +86 20 61648533 (W.-H.C.).
E-mail addresses: peizhouni@hotmail.com (P.-Z. Ni), whchen@fimmu.com
(W.-H. Chen).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.12.020

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B.-M. Xi et al. / Bioorg. Med. Chem. 19 (2011) 783–788
HO
H
3
H
N
H
N
3
4
OMe
OMe
N
OMe
OMe
OMe
OH
A
O
O
O
O
O
O
O
4
B
DDPH (120 min)
1 (23 min)
2 (119 min)
H
H
N
H
N
N
O
OH
OMe
OMe
OMe
OH
HO
HO
HO
OMe
3 (8.3 min)
4 (6.5 min)
5 (149 min)
HO
HO
H
H
N
H
N
OH
OH
OMe
OH
N
O
OMe
OMe
6 (15 min)
7 (113 min)
8 (67 min)
Chart 1. Chemical structures of DDPH and compounds 1–8. Shown in the parentheses is the duration time of each compound. The data were from Ref. 16, and measured by
using the protocols similar to those described in Section 4 of this paper.
and 7) or one hydroxyl group at the 4-position of ring B (i.e., com-
pounds 2, 5, but except 8), had comparable antihypertensive ef-
fects and duration time. These results strongly suggested that
DDPH might be metabolized via the hydroxylation at the 3- or 4-
position of phenyl ring A and that the demethylation at the 4-posi-
tion of phenyl ring B may help to extend the duration time. How-
ever, how the demethylation at the 3-position of ring B affected the
bioactivity is not presently clear.
Based on this result as well as the principles of drug metabolism
retardation, we designed 11 DDPH analogs 9–19 (Chart 2) in which
halogen, methyl, and cyano groups were introduced to block the
hydroxylation at the 3-, or 4-position of aromatic ring A,19 and
one hydroxyl group into the 3- or 4-position of ring B to clarify
how the demethylation at one of these two positions affects the
bioactivity. Their blocking and antihypertensive activities were
evaluated. In addition, the possible correlation between the block-
ing and antihypertensive activities is also briefly discussed.
reductive amination of substituted phenylethylamines 20 with
substituted phenoxyacetones 21, and converted into hydrochloric
acid salts by treating with gaseous HCl. It should be noted that
all the compounds were racemates and did not be resoluted based
on the fact that the stereochemistry of DDPH had no significant
influence on the bioactivity.20 Compounds 20 were prepared from
the reaction of substituted benzaldehyde with nitromethane, fol-
lowed by reduction by Zn/HCl.21 Compounds 21 were obtained
from the alkylation of substituted phenols with bromoacetone in
the presence of potassium carbonate, according to reported proce-
dures.21,22 Compounds 9–19 were fully characterized with 1H
NMR, IR, and HRMS. 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 Section 4). The purity
was judged from NMR and TLC.
2.2. Biological activities of compounds 9–19
2.2.1. Blocking activities
2. Results and discussion
The blocking activities of compounds 9–19 were evaluated on
anococcygeus smooth muscles as the isolated tissues, by using
methods similar to those described in the literatures.21–24 The
activity is expressed as pA2 = ꢀlog [9–19]2, in which [9–19]2 is de-
fined as the concentrations of 9–19 that were measured according
2.1. Synthesis of compounds 9–19
The synthetic route of compounds 9–19 is shown in Scheme 1.
Thus, these compounds were synthesized in 32–63% from the
H
H
N
H
N
OH
OMe
OH
N
OMe
OMe
NC
Br
O
O
O
O
Cl
Br
O
O
O
O
Cl
Br
O
O
O
OMe
9
10
11
H
N
H
N
H
N
OMe
OMe
OMe
OH
OH
OMe
12
13
14
H
N
H
N
H
N
OMe
OMe
OMe
OH
OMe
OH
15
16
17
H
N
H
N
OMe
OMe
OMe
OH
NC
18
19
Chart 2. Chemical structures of compounds 9–19. All the compounds were hydrochloride salt.

B.-M. Xi et al. / Bioorg. Med. Chem. 19 (2011) 783–788
785
R1O
R2O
R1O
R2O
R1O
R2O
a
b
CHO
CH=CHNO2
CH2CH2NH2
20
d
9-19
R1 = R2 = Me, H
R3
R3
c
OH
OCH2COCH3
R3 = 4-Cl, 4-Br, 4-CN, 3-Me, 4-Me
(See Chart 2)
21
Scheme 1. Synthetic route for compounds 9–19. Reagents and conditions: (a) CH3NO2, CH3NH2, MeOH; (b) Zn/HCl; (c) BrCH2COCH3, K2CO3, acetone, reflux; and (d) KBH4,
MeOH, HCl.
to Schild’s methods.25 The obtained pA2 values of compounds 9–19,
together with that of DDPH as a positive control, are listed in
Table 1.
high blocking activity, suggests that compound 17 may be exploit-
able as a potent antihypertensive agent.
Further analyses could afford some interesting structure–
activity correlations. Firstly, as similar to those observed in the
blocking activities of compounds 9–19 (Table 1), the compounds
having the same aromatic groups A had duration times in the order
of 4-OH/3-OMe > 4-OMe/3-OMe > 3-OH/4-OMe on group B, that is,
13 > 12 (>14), 10 > 11, 17 > 18, and 19 > 9. Secondly, for the analogs
having 4-OH/3-OMe on group B, the duration time increased in the
order of Me > Cl > Br > CN, that is, 17 > 10 > 13 > 19.
It can be seen from Table 1 that most of the compounds exhib-
ited strong blocking activities, among which compounds 13 and 17
were more active than potent DDPH, and that the pA2 values varied
with the structures of both aromatic groups A and B. The com-
pounds having 4-OH/3-OMe on group B, that is, 10, 13, 16, 17,
and 19, exhibited higher activities than their corresponding ana-
logs having 4-OMe/3-OMe (and also 3-OH/4-OMe), that is, 11, 12
(14), 15, 18, and 9. However, the activities of such compounds were
also dependent on the structures of aromatic group A. For example,
compound 17 showed up to 102-fold higher activity than com-
pound 19. It is clear that cyanated analogs had the lowest activity.
However, other analogs having halogen and methyl groups did not
show clear trend in their activities that varied in a large range, sug-
2.2.3. Is there any correlation between the blocking and
antihypertensive activities of compounds 9–19?
From the standpoint of new drug discovery for clinic use, it is
ideal for an
activity and long duration time. Thus, how to develop such an
1-AR antagonist represents a challenging topic. The aforemen-
a1-AR antagonist to boast of both potent blocking
gesting that blocking of
factors.
a1-AR might be modulated by multiple
a
tioned results, taken together, may provide some guidances for
future rational design. It is clear that the compounds having low
blocking activities (e.g., pA2 <7.5), that is, 9, 12, 14, 18, and 19,
had very short duration time being 4, 12, 4, 33, and 6 min, respec-
tively. However, it should be noted that this correlation may not be
necessarily positive. In other words, an analog having high block-
ing activity may have short duration time, as evident from the fact
that compound 13 had the highest pA2 value of 9.94, but short
duration time of 23 min.
2.2.2. Antihypertensive activities of compounds 9–19
The antihypertensive activities of compounds 9–19 were evalu-
ated by using methods similar to those described in the litera-
tures.16 The obtained values for pre-treated blood pressures
(mmHg) in terms of systolic arterial pressures (SAP), mean arterial
pressures (MAP), and diastolic arterial pressures (DAP), heart ratios
(HR, BMP) and duration time, together with those of DDPH and 5%
DMSO (background) for comparison, are listed in Table 2.
It can be seen that most of the compounds showed moderate to
good antihypertensive activities. They were capable of reducing
the SAP, MAP, and DAP by 3–36%, 7–46%, and 8–49%, respectively,
while without signification effect on the heart ratios. Note worthy
among them was compound 17. Compared with DDPH, this
compound showed higher antihypertensive activity in terms of
SAP, MAP, and DAP. More importantly, its duration time was about
twofold longer than that of DDPH. This result, together with the
3. Concluding remarks
In this paper, 11 DDPH analogs were designed according to the
probable metabolism pathways of DDPH, synthesized in good
yields from the reductive amination of substituted phenols with
substituted phenylethylamines, and fully characterized with 1H
NMR, IR, and HRMS. Most of the compounds exhibited strong
blocking and moderate to good antihypertensive activities. Their
SAR indicated that the compounds having 4-OH/3-OMe on group
B exhibited higher activities and longer duration time than their
corresponding analogs having 4-OMe/3-OMe (and also 3-OH/
4-OMe). Among them, the compound having bromo group at the
4-position of ring A and 4-OH/3-OMe on group B, exhibited the
highest blocking activity, whereas the compound that was methyl-
ated at the 4-position of ring A and hydroxylated at the 4-position
of ring B, was more active than potent DDPH in terms of both
blocking and antihypertensive activities, thus may be exploitable
as a potent antihypertensive.
Table 1
Blocking activities (pA2) of compounds 9–19
and DDPHa
Compound
pA2
9
10
11
12
13
14
15
16
17
18
19
DDPH
5.61 0.50
8.60 0.81
8.18 0.19
6.93 1.26
9.94 0.46
7.02 0.69
7.71 0.70
8.02 0.50
8.86 0.07
7.25 1.24
6.65 0.34
8.07 0.29
4. Experimental section
General. Melting points (mp) were measured on RDCSY-I, and
the temperature was uncorrected. IR spectra were recorded on
a Nicolet Impact 410 spectrophotometer as KBr pellets. NMR
spectra were recorded on Bruker AM-500 (300) MHz spectrome-
ter with TMS as an internal standard. HRMS spectra were mea-
a
pA2 values, expressed as means SEM,
each tested at least three times.

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B.-M. Xi et al. / Bioorg. Med. Chem. 19 (2011) 783–788
Table 2
Effects of compounds 9–19, DDPH and DMSO on SAP, MAP, DAP, HR, and duration time
Compound
n
Item
Blood pressures and
Changes after treated (%) x
s
Duration time/min x
s
HR before treated x
s
9
3
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
SAP
MAP
DAP
HR
126 17.7
107 13.2
85 10.5
315 30.0
126 11.9
100 10.4
84 9.9
352 33.8
120 10.7
89 9.3
ꢀ8.2 12.5
ꢀ11.0 12.4
ꢀ14.2 11.8
ꢀ6.4 5.8
4
4.0
10
6
6
3
3
3
6
6
6
6
3
6
4
ꢀ12.1 5.1
ꢀ20.2 8.1
ꢀ25.1 10.5
ꢀ6.6 4.8
61 44.4
34 16.4
12 4.0
23 2.9
11
ꢀ13.3 3.5
ꢀ15.9 6.4
ꢀ18.5 10.3
ꢀ8.78 11.5
ꢀ9.2 4.1
84 7.6
338 43.9
125 10.6
100 9.9
75 9.6
323 36
113 4.2
89 7.1
12
ꢀ8.5 3.2
ꢀ7.8 2.1
ꢀ8.3 2.3
13
ꢀ7.6 2.2
ꢀ15.5 2.0
ꢀ19.1 4.9
ꢀ1.7 3.1
71 7.1
331 38.9
130 13.8
107 12.3
89 5.3
359 43.2
124 12.0
102 11.6
85 9.1
315 39.0
136 9.5
110 9.0
89 6.5
342 53.5
129 4.4
98 10.5
82 10.7
365 29.7
127 12.7
96 11.6
78 11.7
342 32.6
131 8.3
98 9.3
14
ꢀ3.5 3.8
4
3.5
ꢀ7.5 2.4
ꢀ12.8 5.0
ꢀ2.3 4.7
15
ꢀ17.4 7.3
ꢀ27.1 5.0
ꢀ34.2 2.1
ꢀ16.6 3.6
ꢀ7.9 3.9
57 19.5
80 25.0
205 77.0
33 11.6
16
ꢀ14.6 7.5
ꢀ20.5 8.9
ꢀ0.96 2.4
ꢀ36.45 8.7
ꢀ45.92 9.5
ꢀ48.99 7.2
ꢀ23.52 15.8
ꢀ19.03 9.2
ꢀ27.86 14.5
ꢀ28.23 24.2
ꢀ16.3 3.6
ꢀ17.3 13.1
ꢀ24.9 18.6
ꢀ29.61 20.1
ꢀ2.33 3.6
ꢀ19.79 5.6
ꢀ30.40 6.1
ꢀ26.0 11.0
ꢀ16.04 5.3
ꢀ8.44 5.1
ꢀ10.49 9.4
ꢀ10.06 10.4
ꢀ1.99 2.7
17
18
19
6
1.5
87 7.4
344 19.2
127 12.8
105 9.6
87 10.2
321 38.0
130 7.6
107 9.5
92 7.1
DDPH
DMSO
120 4.5
SAP
MAP
DAP
HR
9
4.2
320 37.0
sured on an Agilent 1100 LC–MS instrument. Chromatographic
separations were performed on silica-gel 60 (200–300 mesh).
Compounds 20–21 were prepared according to the reported
procedures.21,22 All other reagents and chemicals were obtained
from commercial sources and used as received unless otherwise
stated.
mixture was stirred at room temperature for another 2 h, and con-
centrated under reduced pressure. The obtained residue was parti-
tioned between H2O (10 mL) and ethyl acetate (10 mL). After the
organic layer was separated, the aqueous layer was extracted with
ethyl acetate (10 mL ꢁ 2). The combined organic solution was
dried over anhydrous MgSO4 and concentrated under reduced
pressure. The obtained residue was purified by chromatography
on a silica-gel column (petroleum ether/ethyl acetate/triethyl-
amine, 20:20:1 by volume) to afford an oil residue that was dis-
solved in anhydrous methanol and saturated with HCl to afford
compound 9 (0.31 g, 42%) as a white crystal having mp 173–
4.1. Synthesis of compounds 9–19
4.1.1. N-(3-Hydroxy-4-methoxyphenethyl)-1-(4-cycno-2,6-
dimethylphenoxy)propan-2-amine hydrochloride 9
A mixture of 3,5-dimethyl-4-(2-oxopropoxy)benzonitrile (0.39
g, 1.9 mmol), 2-(3-hyroxy-4-methoxyphenyl)ethylamine (0.32 g,
0.19 mmol) and a catalytic amount of TsOH in methanol (10 mL)
was refluxed for 3 h. After cooled to room temperature, KBH4
(0.2 g) was added portion wise over a period of 1 h. The resulting
175 °C; IR (KBr, cmꢀ1
) m 3380, 2952, 1620, 1540, 1278, 1207,
1045; 1H NMR (DMSO-d6, 500 MHz) d 1.42 (d, 3H, J = 6.60 Hz,
CHCH3), 2.28 (s, 6H, 2 ꢁ ArCH3), 2.98 (t, 2H, J = 8.15 Hz, ArCH2),
3.25 (br s, 2H, NCH2), 3.64 (br s, 1H, CHN), 3.79 (s, 3H, ArOCH3),
3.95–4.02 (m, 2H, OCH2), 6.59–7.21 (m, 5H, ArH), 8.96 (s, 1H,

B.-M. Xi et al. / Bioorg. Med. Chem. 19 (2011) 783–788
787
OH), 10.21 (br s, 2H, NH2þ) and HRMS calcd for C21H26N2O3ꢂHCl
([MꢀHCl+H]+): 355.20217, found: 355.20194.
4.1.7. N-(3,4-Dimethoxyphenethyl)-1-(2,3,6-trimethylphenoxy)-
propan-2-amine hydrochloride 15
Similar procedures. 0.40 g (53%) from 2,3,6-trimethylphenoxyac-
etone (0.36 g, 0.19 mmol) and 2-(3,4-dimethoxyphenyl)ethyla-
4.1.2. N-(4-Hydroxy-3-dimethoxyphenethyl)-1-(4-chloro-2,6-
dimethylphenoxy)propan-2-amine hydrochloride 10
mine (0.34 g, 0.19 mmol). Mp 144–148 °C; IR (KBr, cmꢀ1
) m 3421,
Similar procedures. 0.28 g (37%) from 1-(4-chloro-2,6-dimethyl-
phenoxy) propan-2-one (0.40 g, 0.19 mmol) and 2-(4-hydroxy-3-
methoxyphenyl)ethylamine (0.32 g, 0.19 mmol). Mp 149–151 °C;
2953, 1591, 1516, 1258, 1207, 1026; 1H NMR (DMSO-d6,
500 MHz) d 1.45 (d, 3H, J = 6.70 Hz, CHCH3), 2.16, 2.19, 2.24 (3s,
9H, 3 ꢁ ArCH3), 2.96–3.03 (t, 2H, J = 8.10 Hz, ArCH2), 3.26 (br s,
2H, NCH2), 3.65–3.67 (m, 1H, CHN), 3.75, 3.76 (2s, 6H, 2 ꢁ ArOCH3),
3.88–3.94 (m, 2H, OCH2), 6.77–6.95 (m, 5H, ArH), 7.93(s, 1H, OH),
9.19 (d, 2H, J = 26.6 Hz, NH2þ) and HRMS calcd for C22H31NO3ꢂHCl
([MꢀHCl+H]+): 358.23767, found: 358.23437.
IR (KBr, cmꢀ1 3420, 2961, 1603, 1522, 1275, 1200, 1038; 1H
) m
NMR (DMSO-d6, 500 MHz) d 1.44 (d, 3H, J = 6.60 Hz, CHCH3), 2.27
(s, 6H, 2 ꢁ ArCH3), 2.96 (t, 2H, J = 8.10 Hz, ArCH2), 3.22 (br s, 2H,
NCH2), 3.64 (br s, 1H, CHN), 3.77 (s, 3H, ArOCH3), 3.98 (br s, 2H,
OCH2), 6.65–7.14 (m, 5H, ArH), 8.85 (s, 1H, OH), 9.32 (br s, 2H,
þ
NH2
)
and HRMS calcd for C20H26ClNO3ꢂHCl ([MꢀHCl+H]+):
4.1.8. N-(4-Hydroxy-3-methoxyphenethyl)-1-(2,3,6-trimethyl-
phenoxy) propan-2-amine hydrochloride 16
364.16740, found: 364.16404.
Similar procedures. 0.33 g (46%) from 2,3,6-trimethylphenoxyac-
etone (0.36 g, 0.19 mmol) and 2-(4-hydroxy-3-methoxyphenyl)-
4.1.3. N-(3,4-Dimethoxyphenethyl)-1-(4-chloro-2,6-
dimethylphenoxy)propan-2-amine hydrochloride 11
ethylamine (0.32 g, 0.19 mmol). Mp 206–207 °C; IR (KBr, cmꢀ1
) m
Similar procedures. 0.25 g (32%) from 1-(4-chloro-2,6-dimethyl-
phenoxy)propan-2-one (0.40 g, 1.9 mmol) and 2-(3,4-dimethoxy-
phenyl)ethylamine (0.34 g, 0.19 mmol). Mp 126–130 °C; IR (KBr,
3433, 2947, 1598, 1520, 1261, 1217, 1036; 1H NMR (DMSO-d6,
500 MHz) d 1.43 (d, 3H, J = 6.70 Hz, CHCH3), 2.15, 2.17, 2.25 (3s,
9H, 3 ꢁ ArCH3), 3.01 (br s, 2H, ArCH2), 3.28 (br s, 2H, NCH2), 3.65
(br s, 1H, CHN), 3.75, 3.77 (2s, 6H, 2 ꢁ ArOCH3), 3.92–4.01 (m,
cmꢀ1 3425, 2955, 1589, 1516, 1261, 1200, 1026; 1H NMR
) m
(DMSO-d6, 500 MHz) d 1.43 (d, 3H, J = 6.71 Hz, CHCH3), 2.27 (s,
6H, 2 ꢁ ArCH3), 2.97 (t, 2H, J = 8.13 Hz, ArCH2), 3.30 (br s, 2H,
NCH2), 3.55 (br s, 1H, CHN), 3.73, 3.76 (2s, 6H, 2 ꢁ ArOCH3),
2H, OCH2), 6.74–7.05 (m, 5H, ArH), 8.78(s, 1H, OH), 9.27 (s, 2H,
þ
NH2
)
and HRMS calcd for C21H29NO3ꢂHCl ([MꢀHCl+H]+):
344.22202, found: 344.22243.
3.96–4.07 (m, 2H, OCH2) 6.78–7.14 (m, 5H, ArH), 9.18 (br s, 2H,
þ
NH2
)
and HRMS calcd for C21H28ClNO3ꢂHCl ([MꢀHCl+H]+):
4.1.9. N-(4-Hydroxy-3-methoxyphenethyl)-1-(2,4,6-
378.18305; found: 378.18009.
trimethylphenoxy)-propan-2-amine hydrochloride 17
Similar procedures. 0.26 g (36%) from 2,4,6-trimethylphenoxyac-
etone (0.36 g, 0.19 mmol) and 2-(4-hydroxy-3-methoxyphenyl)-
4.1.4. N-(3,4-Dimethoxyphenethyl)-1-(4-bromo-2,6-
dimethylphenoxy)propan-2-amine hydrochloride 12
ethylamine (0.32 g, 0.19 mmol). Mp 164–166 °C; IR (KBr, cmꢀ1
) m
Similar procedures. 0.55 g (63%) from 4-bromo-2,6-dim-
ethylphenoxyacetone (0.49 g, 0.19 mmol) and 2-(3,4-dimethoxy-
phenyl)ethylamine(0.34 g, 0.19 mmol). Mp 171–173 °C; IR (KBr,
3427, 2934, 1610, 1524, 1269, 1217, 1034; 1H NMR (DMSO-d6,
500 MHz) d 1.43 (d, J = 6.70 Hz, 3H, CHCH3), 2.19 (s, 3H, ArCH3),
2.22 (s, 6H, 2 ꢁ ArCH3), 2.93–2.97 (m, 2H, ArCH2), 3.21 (br s, 2H,
NCH2), 3.63 (br s, 1H, CHN), 3.73, 3.76 (2s, 6H, 2 ꢁ ArOCH3), 3.91
cmꢀ1 3441, 2951, 1593, 1518, 1265, 1200, 1030; 1H NMR (CDCl3,
) m
300 MHz) d 1.64 (d, 3H, J = 6.42 Hz, CHCH3), 2.24 (s, 6H, 2 ꢁ ArCH3),
3.27 (br s, 2H, ArCH2), 3.40 (br s, 2H, NCH2), 3.65 (br s, 1H, CHN),
3.82, 3.85 (2s, 6H, 2 ꢁ ArOCH3), 3.92–4.28 (m, 2H, OCH2), 6.73–
7.09 (m, 5H, ArH), 9.95 (d, 2H, J = 46.68 Hz, NH2þ) and HRMS calcd
for C21H28BrNO3ꢂHCl ([MꢀHCl+H]+): 422.13253, found: 422.13091.
(m, 2H, OCH2), 6.29–6.93 (m, 5H, ArH), 8.56(s, 1H, OH), 9.06 (d,
þ
2H, J = 37.35 Hz, NH2
)
and HRMS calcd for C21H29NO3ꢂHCl
([MꢀHCl+H]+): 344.22202, found: 344.22145.
4.1.10. N-(3,4-Dimethoxyphenethyl)-1-(2,4,6-trimethylphenoxy)-
propan-2-amine hydrochloride 18
4.1.5. N-(4-Hydroxy-3-methoxyphenethyl)-1-(4-bromo-2,6-
dimethylphenoxy)propan-2-amine hydrochloride 13
Similar procedures. 0.36 g (48%) from 2,4,6-trimethylphenoxyac-
etone (0.36 g, 0.19 mmol) and 2-(3,4-dimethoxyphenyl)ethyla-
Similar procedures. 0.29 g (34%) from 4-bromo-2,6-dimethyl-
phenoxy-acetone (0.49 g, 0.19 mmol) and 2-(4-hydroxy-3-meth-
oxyphenyl)ethylamine (0.32 g, 0.19 mmol). Mp 150–152 °C; IR
mine (0.34 g, 0.19 mmol). Mp 181–182 °C; IR (KBr, cmꢀ1
) m 3423,
2959, 1595, 1514, 1259, 1213, 1028; 1H NMR (DMSO-d6,
500 MHz) d 1.43 (d, 3H, J = 6.70 Hz, CHCH3), 2.19, 2.22(3s, 9H,
3 ꢁ ArCH3), 2.94–2.99 (m, 2H, ArCH2), 3.26 (br s, 2H, NCH2), 3.63
(br s, 1H, CHN), 3.73, 3.76 (2s, 6H, 2 ꢁ ArOCH3), 3.90–3.93 (m,
(KBr, cmꢀ1 3420, 2926, 1605, 1524, 1279, 1207, 1032; 1H NMR
) m
(DMSO-d6, 500 MHz) d 1.43 (d, 3H, J = 6.47 Hz, CHCH3), 2.26 (s,
6H, 2 ꢁ ArCH3), 2.94 (t, 2H, J = 8.10 Hz, ArCH2), 3.21 (br s, 2H,
NCH2), 3.63 (br s, 1H, CHN), 3.76 (s, 3H, ArOCH3), 3.98 (br s,
2H, OCH2), 6.65–7.27 (m, 5H, ArH), 8.85 (s, 1H, OH), 9.34 (br s,
2H, NH2þ) and HRMS calcd for C20H26BrNO3ꢂHCl ([MꢀHCl+H]+):
408.11688, found: 408.11425.
2H, OCH2), 6.79–6.93 (m, 5H, ArH), 9.06 (d, 2H, J = 37.35 Hz,
þ
NH2
)
and HRMS calcd for C22H31NO3ꢂHCl ([MꢀHCl+H]+):
358.23767, found: 358.23562.
4.1.11. N-(4-Hydroxy-3-methoxyphenethyl)-1-(2,6-methyl-4-
cyanophenyl)propan-2-amine hydrochloride 19
4.1.6. N-(3-Hydroxy-4-methoxyphenethyl)-1-(4-bromo-2,6-
dimethylphenoxy)propan-2-amine hydrochloride 14
Similar procedures. 0.32 g (43%) from 3,5-dimethyl-4-(2-oxo-
propoxy) benzonitrile (0.39 g, 0.19 mmol) and 2-(4-hydroxy-3-
methoxyphenyl)ethylamine (0.32 g, 0.19 mmol). Mp 207–209 °C;
Similar procedures. 0.38 g (45%) from 4-bromo-2,6-dimethyl-
phenoxyacetone (0.49 g, 0.19 mmol) and 2-(3-hydroxy-4-meth-
oxyphenyl)ethylamine (0.32 g, 0.19 mmol). Mp 157–159 °C; IR
IR (KBr, cmꢀ1 3418, 2964, 1576, 1523, 1261, 1207, 1023; 1H
) m
(KBr, cmꢀ1 3410, 2924, 1603, 1524, 1275, 1208, 1034; 1H NMR
) m
NMR (DMSO-d6, 500 MHz) d 1.44 (d, 3H, J = 6.70 Hz, CHCH3),
2.19, 2.21(2s, 6H, 2 ꢁ ArCH3), 2.99 (br s, 2H, ArCH2), 3.31 (br s,
2H, NCH2), 3.64 (br s, 1H, CHN), 3.73 (s, 3H, ArOCH3), 3.91–3.97
(m, 2H, OCH2), 6.79–7.11 (m, 5H, ArH), 7.95(s, 1H, OH), 9.06 (br
s, 2H, NH2þ) and HRMS calcd for C21H26N2O3ꢂHCl ([MꢀHCl+H]+):
355.20217, found: 355.20193.
(DMSO-d6, 500 MHz) d 1.44 (d, 3H, J = 6.51 Hz, CHCH3), 2.25 (s,
6H, 2 ꢁ ArCH3), 2.95 (t, 2H, J = 8.08 Hz, ArCH2), 3.22 (br s , 2H,
NCH2), 3.54 (br s, 1H, CHN), 3.76 (s, 3H, ArOCH3), 4.13–4.23 (m,
2H, OCH2), 6.69–7.30 (m, 5H, ArH), 8.88 (s, 1H, OH), 9.41 (br s,
2H, NH2þ) and HRMS calcd for C20H26BrNO3ꢂHCl ([MꢀHCl+H]+):
408.11688, found: 408.11427.

788
B.-M. Xi et al. / Bioorg. Med. Chem. 19 (2011) 783–788
4.2. Determination of pA2 value of each compound
saline buffer containing less than 5% DMSO was used dissolve
the compounds to be tested and the final concentration was
2.0 mg mLꢀ1. After blood pressure and heart rate were stabilized,
drugs (5.0 mg kgꢀ1) were administered to observe the effect on
the blood pressure of rats (Table 2).
The blocking activity (pA2) of each compound was measured by
using the methods similar to those described previously.20–23
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 solution
(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 trans-
ferred 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 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’ solution
every 20 min. After equilibration, cocaine hydrochloride, hydrocor-
tisone and propranolol were added to the final concentrations of
Acknowledgment
This work was financially supported by the National Natural
Science Foundation of China (No. 30600776).
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