Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

Article abstract of DOI:10.1016/j.bmc.2009.03.044

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC₅₀ value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.

Full text of DOI:10.1016/j.bmc.2009.03.044

Bioorganic & Medicinal Chemistry 17 (2009) 3283–3294
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of novel phenoxypropanolamine derivatives
containing acetanilides as potent and selective b3-adrenergic receptor agonists
*
Tatsuya Maruyama , Kenichi Onda, Masahiko Hayakawa, Norio Seki, Takumi Takahashi,
Hiroyuki Moritomo, Takayuki Suzuki, Tetsuo Matsui, Toshiyuki Takasu, Itsuro Nagase, Mitsuaki Ohta
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the search for potent and selective human b3-adrenergic receptor (AR) agonists as potential drugs for
the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanol-
amine derivatives containing acetanilides were prepared and their biological activities were evaluated at
the human b3-, b2-, and b1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic
activity at the b3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylace-
tanilide derivative (21b) was found to be the most potent and selective b3-AR agonist, with an EC50 value
Received 6 February 2009
Revised 23 March 2009
Accepted 24 March 2009
Available online 27 March 2009
Keywords:
of 0.28
lM and no agonistic activity for either the b1- or b2-AR. In addition, 21b showed significant hypo-
b3-Adrenergic receptor
Phenoxypropanolamine
Agonist
glycemic activity in a rodent diabetic model.
Ó 2009 Elsevier Ltd. All rights reserved.
Acetanilide
Diabetes
1. Introduction
tanilide 1, which showed potent b3-AR agonistic activity with
modest functional selectivity over b1-AR and oral hypoglycemic
activity in diabetic kk mice.12 However, compound 1 was found
to exhibit poor bioavailability in rats (F = 2%), probably due to
the rapid metabolism of the 4-hydroxyphenoxy moiety on the
left-hand side of 1. Since many kinds of phenoxypropanolamine-
based b3-agonists have been reported (Fig. 2),13,14 we decided to
explore the alternative structures instead of the 4-hydroxyphen-
oxy moiety of 1, after which further attempts at modification of
the pyridyl moiety on the right-hand side of 1 were made
(Fig. 3). In this paper, we describe the synthesis and structure–
activity relationships (SARs) of these newly designed phenoxypro-
panolamine derivatives containing acetanilides as b3-AR agonists.
A major increase in the prevalence of obesity and noninsulin-
dependent (type II) diabetes and related cardiovascular disorders
has led to the search for new pharmacological approaches in the
treatment of these conditions.1,2 In the early 1980s, b3-adrenergic
receptor (AR) was identified as a possible therapeutic opportunity
for the treatment of type II diabetes and obesity.3,4 Early potent
and selective b3-AR agonists, such as BRL-373445 and CL-316243,6
were reported to be effective anti-obesity and anti-diabetic agents
in rodents (Fig. 1).7 However, human clinical trials with these agents
for the treatment of metabolic disorders have been disappointing
due to a lack of efficacy or an unfavorable side-effect profile.8 The
clinical failure of such compounds has been attributed to a lack of
sufficient b3-AR potency and selectivity over b1- or b2-ARs resulting
from pharmacologic differences between rodent and human recep-
tors, which was supported by the discovery, cloning, and character-
ization of the human, rat, and mouse b3-ARs in 1989.9–11 The
availability of appropriate human receptors has given rise to the de-
sign and synthesis of a new generation of b3-AR agonists with high
potency. Subtype selectivity for b3-AR agonists specifically must be
kept in mind since activation of the b1- or b2-ARs would cause unde-
sirable side effects such as increased heart rate or muscle tremors.
We previously described efforts in this area that included the
disclosure of acetanilide analogues exemplified by 2-pyridylace-
2. Chemistry
2-Pyridylacetanilides 5a–f were prepared from an amine inter-
mediate 4, as illustrated in Scheme 1. Compound 4 was synthe-
sized from 2-pyridylacetic acid (2) and 4-aminobenzylcyanide,
OH
H
N
OH
H
N
O
Cl
Cl
O
O
ONa
ONa
OH
O
O
O
CL-316243
BRL-37344
* Corresponding author. Tel.: +81 29 863 6749; fax: +81 29 852 5387.
E-mail address: tatsuya.maruyama@jp.astellas.com (T. Maruyama).
Figure 1. Chemical structure of early b3-AR agonists.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.03.044

3284
T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
O
OH
H
N
OMe
O
O
N
H
OH
O O
S
H
H
N
O
O
N
N
L-750355
ZD-7114
O
H
N
OH
O
OH
H
N
H
N
O
OH
H
N
HN
HN
O
O
HN
O
NH2
NH2
O
N
O
N
CGP-12177A
LY-377327
LY-377604
Figure 2. Chemical structure of phenoxypropanolamine-based b3-AR agonists.
OH
H
N
OH
H
N
O
O
O
O
Ar
N
N
H
HO
N
N
H
1
OH
H
N
O
O
Ar
R1
N
R2
Figure 3. Design of phenoxypropanolamine analogues containing acetanilides based on compound 1.
H2N
a
O
NC
b
O
O
N
N
H
3
HO
N
N
H
4
N
2
5a : Ar = 3-pyridyl
OH
H
N
O
5b : Ar = 4-methylsulfonamidophenyl
5c : Ar = phenyl
c
O
Ar
N
N
H
5d : Ar = 2-benzimidazolon-4-yl
5e : Ar = indol-4-yl
5f : Ar = carbazol-4-yl
5a-f
Scheme 1. Reagents and conditions: (a) 4-aminobenzylcyanide, EDCꢀHCl, HOBt, DMF; (b) H2, Raney-Ni, NH3 aq, THF, EtOH; (c) (S)-2-aryloxymethyloxirane, Et3N, iPrOH,
reflux, and then 4 M HCl–dioxane, acetone.
followed by hydrogenation of the cyano group with Raney-nickel.
Compound 4 was coupled with appropriate (S)-2-aryloxymethy-
loxirane15–18 to afford the desired products (5a–f).
Acetanilides 8a–c were prepared from the corresponding ethyl
arylacetates 6a–c, as illustrated in Scheme 2. Compounds 6a–c
were treated with 4-aminobenzylcyanide in refluxing xylene to
provide anilides 7a–c. The anilides 7a–c were hydrogenated, fol-
lowed by coupling with (S)-2-phenoxymethyloxirane to afford
the desired products (8a–c).
Another route from aniline intermediate 12 was illustrated in
Scheme 3. 2-(4-Nitrophenyl)ethylamine hydrochloride (9) was
treated with (S)-2-phenoxymethyloxirane, followed by protection
of the amine with a tert-butoxycarbonyl (Boc) group to provide ni-
tro compound 11. Hydrogenation of 11 yielded aniline intermedi-
ate 12. The coupling of 12 with the appropriate acetic acids,
followed by deprotection of the Boc group, afforded the desired
products (14a–g). Deprotection of the 4-nitrobenzyl group of 13h
by catalytic hydrogenation, followed by deprotection of the Boc
group afforded the imidazol-2-ylacetanilide derivative (14h). On
the other hand, compound 12 was treated with propionaldehyde
and borane to yield an N-propylaniline analogue 15. The coupling
of 15 with 1-benzylimidazol-2-ylacetic acid, followed by deprotec-
tion of the Boc group afforded N-propyl-1-benzylimidazol-2-ylace-
tanilide derivative (17).
The synthesis of 1-benzylimidazol-2-ylacetanilide derivatives
(21a,b) are shown in Scheme 4. 4-(2-tert-Butoxycarbonylamino-
OH
H
N
O
O
NC
O
b,c
a
O
Ar
Ar
EtO
Ar
N
H
7a-c
N
H
6a-c
8a-c
8a : Ar = 3-methyl-2-pyridyl
7a : Ar = 3-methyl-2-pyridyl
8b : Ar = 4,6-dimethyl-2-pyridyl
7b : Ar = 4,6-dimethyl-2-pyridyl
8c : Ar = 1-benzylbenzimidazol-2-yl
7c : Ar = 1-benzylbenzimidazol-2-yl
i
Scheme 2. Reagents and conditions: (a) 4-aminobenzylcyanide, xylene, reflux; (b) H2, Raney-Ni, concd NH3 aq, EtOH–THF; (c) (S)-2-phenoxymethyloxirane, PrOH, reflux,
and then 4 M HCl–EtOAc, MeOH.

T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
3285
OH Boc
N
OH
H
N
H2N
O
O
b
a
NO2 HCl
NO2
NO2
11
10
9
OH Boc
N
OH Boc
O
e
c
N
O
O
Ar
N
H
NH2
13a-h
12
13a : Ar = 6-chloro-2-pyridyl
13b : Ar = 6-benzyloxy-2-pyridyl
13c : Ar = 1-phenylimidazol-2-yl
13d : Ar = 1-(4-chlorobenzyl)imidazol-2-yl
13e : Ar = 1-(4-bromobenzyl)imidazol-2-yl
13f : Ar = 1-(2-naphtylmethyl)imidazol-2-yl
13g : Ar = 1-benzylimidazol-4-yl
13h : Ar = 1-(4-nitrobenzyl)imidazol-2-yl
13i : Ar = imidazol-2-yl
g
f
d
14a : Ar = 6-chloro-2-pyridyl
14b : Ar = 6-benzyloxy-2-pyridyl
14c : Ar = 1-phenylimidazol-2-yl
OH
H
N
O
O
14d : Ar = 1-(4-chlorobenzyl)imidazol-2-yl
14e : Ar = 1-(4-bromobenzyl)imidazol-2-yl
14f : Ar = 1-(2-naphtylmethyl)imidazol-2-yl
14g : Ar = 1-benzylimidazol-4-yl
Ar
N
H
14a-h
14h : Ar = imidazol-2-yl
OH Boc
N
OH Boc
O
N
O
g
e
O
N
NH
N
N
15
16
OH
H
N
O
O
N
N
N
17
Scheme 3. Reagents and conditions: (a) (S)-2-phenoxymethyloxirane, Et3N, iPrOH, reflux; (b) (Boc)2O, THF; (c) H2, Pd/C, EtOH; (d) EtCHO, BH3–THF; (e) ArCH2CO2H, EDCꢀHCl,
HOBt, THF; (f) H2, Pd/C, HCl, MeOH; (g) 4 M HCl–EtOAc, EtOH.
BocHN
H2N
BocHN
18a,b
a
O
N
O
N
b
N
N
R
N
N
R
20a,b
NHR
19a,b
18a : R = H
18b : R = Me
19a : R = H
19b : R = Me
20a : R = H
20b : R = Me
OH
H
N
O
c
O
N
N
N
R
21a : R = H
21b : R = Me
21a,b
i
Scheme 4. Reagents and conditions: (a) 1-benzylimidazol-2-ylacetic acid, EDCꢀHCl, HOBt, DMF; (b) 4 M HCl–EtOAc, MeOH; (c) (S)-2-phenoxymethyloxirane, PrOH, reflux,
and then 4 M HCl–EtOAc, MeOH.
ethyl)anilines (18a,b) were coupled with 1-benzylimidazol-2-
ylacetic acid, followed by deprotection of the Boc group, to provide
amine intermediates 20a,b. Compounds 20a,b were treated with
(S)-2-phenoxymethyloxirane to afford the desired products
(21a,b).
Scheme 5 shows the synthesis of compounds 27a,b. (S)-1-Ami-
no-3-phenoxy-2-propanol (22) was treated with 4-nitrophenylac-
etone, followed by reduction with sodium borohydride to give
nitro compound 23 as diastereomeric mixture. Compound 23
was protected with a tert-butoxycarbonyl (Boc) group, followed
by separation using column chromatography to provide the less
polar compound 24a and the highly polar compound 24b as single
isomers. Hydrogenation of the nitro group of 24a,b furnished the
aniline intermediates 25a,b, and subsequent coupling reaction
with 1-benzylimidazol-2-ylacetic acid yielded anilides 26a,b.
Deprotection of the Boc group in 26a,b afforded the desired prod-
ucts (27a,b).
The 1,2,3,4-tetrahydroquinoline derivative (33) was synthe-
sized as illustrated in Scheme 6. 6-Bromoacetyl-1,2,3,4-tetrahydro-
quinolin-2-one (28) was treated with dibenzylamine, followed by
reduction with borane to yield the 1,2,3,4-tetrahydroquinoline
derivative (30). The coupling of 30 with 1-benzylimidazol-2-ylace-

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T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
OH
Boc
N
OH
OH
H
N
O
O
b
O
c
NH2
a
NO2
NO2
22
23
24a,b
24a : less polar
24b : high polar
OH Boc
OH Boc
O
N
O
O
N
d
O
N
N
N
H
NH2
O
26a,b
25a,b
OH
H
N
e
N
N
N
H
27a,b
Scheme 5. Reagents and conditions: (a) 4-nitrophenylacetone, benzene, reflux, then NaBH4, MeOH; (b) (Boc)2O, THF; (c) H2, Pd/C, EtOH; (d) 1-benzylimidazol-2-ylacetic acid,
EDCꢀHCl, HOBt, DMF; (e) 4 M HCl–EtOAc, MeOH.
O
O
Br
Bn2N
b
a
Bn2N
N
H
O
N
H
O
d
N
H
28
29
30
H2N
Bn2N
O
N
O
N
c
N
N
N
N
32
31
OH
H
N
O
e
O
N
N
N
33
i
Scheme 6. Reagents and conditions: (a) dibenzylamine, Pr2NEt, DMF, 80 °C; (b) BH3–THF, 80 °C; (c) 1-benzylimidazol-2-ylacetic acid, EDCꢀHCl, HOBt, DMF; (d) HCO2NH4,
i
Pd/C, MeOH; (e) (S)-2-phenoxymethyloxirane, PrOH, reflux, then 4 M HCl–EtOAc, MeOH.
tic acid, followed by deprotection of the benzyl group, provided
amine intermediate 32. Compound 32 was treated with (S)-2-phe-
noxymethyloxirane to afford the desired product (33).
matic moieties was tolerated and allowed the potency of b3-AR to
be maintained, but this change may decrease its intrinsic activity
at the b3-AR. Thus, we selected the phenoxy derivative (5c) as our
new leading candidate, because only this compound showed full
b3-AR agonistic activity after altering the aromatic ring on the left-
hand side of 1. In addition, 5c exhibited improved bioavailability in
rats (F = 27%). In order to improve b3-AR agonistic activity while
maintaining functionalselectivity over b1- and b2-ARs, modification
of the 2-pyridyl moiety in 5c was examined.
The effects of pyridine ring modification in 5c are shown in Ta-
ble 2. Initially, the effects of the substituent on the pyridine ring in
5c was investigated: introduction of a methyl group at this site (8a
and 8b) resulted in a dramatic increase in potency at both the b3-
3. Results and discussion
The prepared compounds were evaluated for their agonistic
activities in stimulating an increase in cyclic AMP (cAMP) levels
in Chinese hamster ovary (CHO) cells expressing the cloned human
b3-, b2-, and b1-ARs. The results for the reference compound, iso-
proterenol (ISO; non-selective b-AR agonist), are also shown for
comparison in Table 1.
Modification of the 4-hydroxyphenyl moiety in 1 with the several
aryloxy moieties illustrated in Figure 2 was investigated (Table 1).
Replacement of the 4-hydroxyl group of 1 with the 4-methanesulfo-
nylamino group (5b) resulted in a substantial loss of b3-AR agonistic
activity. Removal of the 4-hydroxyl group (5c) of 1 resulted in a dra-
(EC50 = 0.33 and 0.28
lM, respectively) and b1-ARs (EC50 = 0.39
and 0.31 M, respectively) relative to that of 5c, but even with this
l
increase, the agonistic activity was still only partial. The agonistic
activity of the 6-chloro-2-pyridyl derivative (14a) at the b3-AR
(EC50 = 0.043
lM, IA = 0.39) was much greater than that of 5c,
matic decrease in the potency of b3-AR (EC50 = 120 lM), while 5c re-
but it also increased b1-AR agonistic activity (EC50 = 0.055
lM,
tained full agonistic activity (IA = 0.93) at the b3-AR. Next,
replacement of the 4-hydroxyphenyl moiety in 1 with the 3-pyridyl
(5a) and 2-benzimidazolinon-4-yl (5d) moieties resulted in a con-
siderable decrease in intrinsic activity at the b3-AR (IA = 0.28 and
0.20, respectively). The indol-4-yl (5e) and carbazol-4-yl (5f) deriv-
atives exhibited a decrease in agonistic activity at the b1-AR; how-
ever their b3-agonistic activity was only partial (‘partial’ is defined
as IA < 0.75 in this paper). These results revealed that the replace-
ment of the 4-hydroxyphenyl moiety in 1 with several heteroaro-
IA = 0.36). The 6-benzyloxy-2-pyridyl derivative (14b) showed re-
sults similar to that of 8a. These results indicated that the introduc-
tion of a substituent on the pyridine ring in 5c can improve the
potency of b3-AR with lower intrinsic activity, but it may not be
efficacious for improving functional selectivity over b1-AR. Next,
we decided to replace the pyridine ring in 5c with an imidazole
ring because, like pyridine, it is a basic heteroaromatic ring.
Replacement of the 2-pyridyl moiety in 5c with the imidazol-2-yl

T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
3287
Table 1
Table 2
b-AR agonistic activity of 2-pyridylacetanilide derivatives
b-AR agonistic activity of phenoxypropanolamine derivatives containing acetanilides
OH
OH
H
N
H
N
O
O
O
O
Ar
Ar
N
N
H
N
H
Compound
Ar
EC50
b2-AR
, l
Ma (IAb)
Compound
5c
Ar
EC50, l
Ma (IAb)
b3-AR
b1-AR
b3-AR
b2-AR
b1-AR
1
0.29 (0.74)
>100 (0)
>100 (0)
2.7 (0.14)
120 (0.93)
>100 (0.01)
>100 (0.11)
HO
N
5b
>100 (0.01)
>100 (0.01)
>100 (0.11)
MeSO2HN
Me
8a
0.33 (0.36)
0.28 (0.35)
0.043 (0.39)
2.5 (0.47)
>100 (0.01)
>100 (0)
0.39 (0.18)
0.31 (0.17)
0.055 (0.36)
0.20 (0.12)
0.51 (0.26)
>100 (0.09)
N
5c
5a
5d
120 (0.93)
0.18 (0.28)
0.28 (0.20)
>100 (0.01)
>100 (0.02)
>100 (0)
Me
N
8b
Me
Cl
>100 (0.06)
>100 (0.01)
N
14a
>100 (0.02)
>100 (0)
N
N
NH
N
H
O
14b
14h
14c
O
5e
5f
1.3 (0.49)
>100 (0.02)
>100 (0)
N
N
N
H
9.6 (0.62)
>100 (0.09)
>100 (0)
N
H
0.25 (0.42)
0.10 (1.00)
>100 (0.01)
0.003 (1.00)
>100 (0.01)
0.012 (1.00)
N
N
N
N
H
0.65 (0.52)
ISO
N
N
a
21a
8c
0.18 (0.77)
0.14 (0.48)
0.13 (0.46)
>100 (0)
0.13 (0.20)
>100 (0.02)
0.28 (0.06)
Agonistic activity was assessed by measuring cAMP accumulation in CHO cells
expressing b-ARs.
b
Values in parentheses represent the intrinsic activity (IA) given as a fraction of
the maximum stimulation with isoproterenol.
>100 (0)
moiety (14h) resulted in a 12-fold increase in potency at the b3-AR
(EC50 = 9.6
(EC50 = 0.51
us to synthesize the substituted imidazole analogues. The 1-phen-
ylimidazol-2-ylacetanilide derivative (14c) showed a 15-fold in-
l
M, IA = 0.62) with partial b1-AR agonistic activity
M, IA = 0.26) relative to that of 5c. This encouraged
l
14g
>100 (0.02)
N
N
crease in potency at the b3-AR (EC50 = 0.65 lM, IA = 0.52) relative
to that of 14h. Furthermore, the 1-benzylimidazol-2-ylacetanilide
derivative (21a) exhibited a 53-fold increase in potency at the
N
N
N
N
N
N
14d
14e
0.27 (0.53)
0.19 (0.63)
0.26 (0.54)
>100 (0)
0.074 (0.13)
0.071 (0.30)
0.069 (0.17)
Cl
b3-AR with good intrinsic activity (EC50 = 0.18
lM, IA = 0.77) and
partial b1-AR agonistic activity (EC50 = 0.13
to 14h.
lM, IA = 0.20) relative
>100 (0.02)
>100 (0.01)
To improve the potency of b3-AR and functional selectivity over
b1-AR of 21a, we then examined the modification of the 1-ben-
zylimidazol-2-yl moiety in 21a. Replacement of the 1-ben-
zylimidazol-2-yl moiety in 21a with 1-benzylbenzimidazol-2-yl
moiety (8c) resulted in a decrease in the intrinsic activity of b3-
Br
14f
AR (EC50 = 0.14 lM, IA = 0.48). The 1-benzylimidazol-4-yl deriva-
a
Agonistic activity was assessed by measuring cAMP accumulation in CHO cells
tive (14g) displayed similar results to that of 8c. These results indi-
cated that such modification of the 1-benzylimidazol-2-yl moiety
in 21a may not improve the potency of b3-AR. On the other hand,
the introduction of the chloro or bromo group (14d and 14e) on the
benzyl group of the imidazole ring in 21a allowed the potency of
b3-AR to be maintained, but induced a twofold increase in potency
at the b1-AR. The results obtained for the 2-naphthylmethyl deriv-
ative (14f) were similar to that of 14d. These results indicated that
expressing b-ARs.
b
Values in parentheses represent the intrinsic activity (IA) given as a fraction of
the maximum stimulation with isoproterenol.
the modification of the benzyl group of the imidazol-2-yl moiety in
21a may not be efficacious for improving a functional selectivity
over b1-AR.

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T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
Table 4
Next, the introduction of a methyl group at the
secondary amine on the central part of 21a was investigated as
shown in Table 3. One diastereomer of the -methyl derivative
threefold increase in potency at the b3-AR
M, IA = 0.64) relative to 21a, and was the most po-
a-position of the
Oral hypoglycemic activity in kk mice
Percent reduction in plasma glucosea
a
Compound
27a showed
(EC50 = 0.062
a
l
**b
**
21a
21b
43
38
tent b3-AR agonist in this study; however its functional selectivity
over b1-AR was not improved. Another diastereomer of the
methyl derivative 27b showed a decrease in potency at both the
b3- and b1-ARs relative to 21a.
a
The compounds were administered orally to male kk mice for 4 days at the dose
a
-
of 30 mg/kg.
b
Statistically significant at (**) p < 0.01.
Lastly, we examined the introduction of a methyl group on the
nitrogen of the acetanilide moiety in 21a. This new compound 21b
5. Experimental
5.1. Chemistry
maintained full agonistic activity at the b3-AR (EC50 = 0.28
IA = 0.89) and dramatically decreased agonistic activity at the b1-
AR (EC50 = >100 M). Furthermore, the agonistic activity of the N-
propylacetanilide derivative (17) at the b3-AR was comparable to
that of 21b (EC50 = 0.50 M, IA = 0.90), with excellent functional
lM,
l
Melting points were determined with a Yanaco MP-500D melt-
ing point apparatus and are uncorrected. 1H NMR spectra were re-
corded on a JEOL EX90, EX400, or GX500 spectrometer, and the
chemical shifts are expressed in d (ppm) values with tetramethyl-
silane as an internal standard (NMR description key: s = singlet,
d = doublet, t = triplet, m = multiplet, and br = broad peak). Mass
spectra were recorded on a Hitachi M-80 or JEOL JMS-DX300 spec-
trometer. The elemental analyses were performed with a Yanaco
MT-5 microanalyzer (C, H, N) and were within 0.4% of the theoret-
ical values. During the work-up, all organic solutions were dried
over anhydrous Mg2SO4.
l
selectivity over b1-AR. In contrast, the 1,2,3,4-tetrahydroquinoline
derivative (33), a cyclic analogue of 17, showed a decrease in
intrinsic activity at the b3-AR (EC50 = 0.17 lM, IA = 0.33) relative
to 21a. These results suggested that the substituent on the nitrogen
of the acetanilide moiety may play a very important role in dimin-
ishing b1-AR agonistic activity.
Given the results of the in vitro study, compounds 21a and 21b
were selected for in vivo evaluation in a rodent model of type II
diabetes (Table 4). The compounds were administered orally for
4 days in diabetic kk mice and the effects on plasma glucose were
measured. Both compounds exhibited a significant reduction in
plasma glucose levels at the dose of 30 mg/kg (43% and 38% de-
crease, respectively).
5.1.1. 40-Cyanomethyl-2-(2-pyridyl)acetanilide (3)
To a solution of 2-pyridylacetic acid hydrochloride (2) (10 g)
and 4-aminobenzylcyanide (9.1 g) in N,N-dimethylformamide
(500 mL) were added 1-ethyl-3-(30-dimethylaminopropyl)carbodi-
imide hydrochloride (11.6 g) and 1-hydroxybenzotriazole hydrate
(9.3 g), and the mixture was stirred at room temperature for 8 h.
To the resulting mixture was added triethylamine (16.5 mL), and
the mixture was diluted with water, and extracted with ethyl ace-
tate. The organic layer was washed with brine, and then dried and
concentrated in vacuo. The residue was purified using column
chromatography on silica gel with CHCl3/MeOH (20:1) as the elu-
ent to yield 3 (3.2 g) as a colorless solid. 22% yield; 1H NMR (CDCl3)
4. Conclusion
In this study, a new series of phenoxypropanolamine deriva-
tives containing acetanilides as b3-AR agonists was identified,
and their synthesis and SARs were described. Among these com-
pounds, 1-benzylimidazol-2-ylacetanilide derivatives (21a, 21b,
and 27a) showed potent agonistic activity at the b3-AR
d: 3.70 (2H, s), 3.88 (2H, s), 7.15–7.33 (7H, m), 8.61–8.65 (1H, m),
(EC50 = 0.18, 0.28, and 0.062 lM, respectively). With agonistic
10.02 (1H, br s); MS (FAB) m/z: 252 (MH+).
activity almost completely abolished at both the b1- and b2-ARs,
the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b)
was found to be the most potent and selective b3-AR agonist in this
study. In addition, 21b exhibited significant hypoglycemic activity
in diabetic kk mice.
5.1.2. 40-(2-Aminoethyl)-2-(2-pyridyl)acetanilide (4)
To a solution of 3 (3.65 g) and concentrated aqueous ammonia
solution (15 mL) in tetrahydrofuran (70 mL) and ethanol (70 mL)
Table 3
b-AR agonistic activity of 1-benzylimidazol-2-ylacetanilide derivatives
OH
H
N
O
N
O
R1
N
N
R2
Compound
R1
R2
EC50, l
Ma (IAb)
b3-AR
b2-AR
b1-AR
21a
27ac
27bd
21b
17
H
H
H
H
Me
n-Pr
0.18 (0.77)
0.062 (0.64)
0.35 (0.83)
0.28 (0.89)
0.50 (0.90)
>100 (0)
0.13 (0.20)
0.030 (0.16)
0.25 (0.19)
>100 (0.04)
>100 (0.01)
Me
Me
H
0.027 (0.09)
>100 (0.02)
>100 (0)
H
>100 (0)
OH
H
N
O
N
O
33
0.17 (0.33)
>100 (0)
0.12 (0.06)
N
N
a
Agonistic activity was assessed by measuring cAMP accumulation in CHO cells expressing b-ARs.
Values in parentheses represent the intrinsic activity (IA) given as a fraction of the maximum stimulation with isoproterenol.
Less polar compound of diastereomer.
b
c
d
High polar compound of diastereomer.

T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
3289
was added Raney-nickel, and the mixture was stirred under a
hydrogen atmosphere for 16 h. The catalyst was removed by filtra-
tion over Celite, and the filtrate was concentrated in vacuo to yield
4 (3.7 g) as a colorless oil. 99% yield; 1H NMR (DMSO-d6) d: 2.55–
3.18 (4H, m), 3.57 (2H, br s), 3.82 (2H, s), 7.06–7.77 (7H, m),
8.50–8.52 (1H, m), 10.15 (1H, s); MS (FAB) m/z: 256 (MH+).
(MH+); Anal. Calcd for C25H27N5O4ꢀHClꢀ0.9H2O: C, 58.40; H, 5.84; N,
13.62; Cl, 6.89. Found: C, 58.52; H, 5.71; N, 13.61; Cl, 6.59.
5.1.7. (S)-40-(2-{[2-Hydroxy-3-(indol-4-yloxy)propyl]amino}-
ethyl)-2-(2-pyridyl)acetanilide hydrochloride (5e)
The title compound was prepared in the same manner as de-
scribed for 5a using (S)-2-(indol-4-yloxymethyl)oxirane18 instead
of (S)-2-(3-pyridyloxymethyl)oxirane as a colorless powder. 27%
yield; 1H NMR (DMSO-d6) d: 2.80–3.30 (6H, m), 4.02–4.13 (2H,
m), 4.18 (2H, s), 4.26–4.34 (1H, m), 6.47–6.51 (2H, m), 6.96–7.03
(2H, m), 7.20–7.30 (3H, m), 7.58 (2H, d, J = 8.4 Hz), 7.72–7.78
(1H, m), 7.85 (1H, d, J = 8.0 Hz), 8.22 (1H, s), 8.25–8.35 (1H, m),
8.77 (1H, d, J = 4.4 Hz), 8.85 (1H, br s), 9.04 (1H, br s), 10.60 (1H,
s), 11.12 (1H, s); MS (FAB) m/z: 445 (MH+); Anal. Calcd for
C26H28N4O3ꢀ1.8HClꢀ1.6H2O: C, 57.94; H, 6.17; N, 10.40; Cl, 11.84.
Found: C, 58.35; H, 6.23; N, 9.93; Cl, 11.93.
5.1.3. (S)-40-(2-{[2-Hydroxy-3-(3-pyridyloxy)propyl]amino}-
ethyl)-2-(2-pyridyl)acetanilide hydrochloride (5a)
A mixture of 4 (0.51 g), (S)-2-(3-pyridyloxymethyl)oxirane15
(0.3 g), andtriethylamine (0.3 mL)in2-propanol(10 mL)washeated
at 70 °C for 2 h. After cooling to room temperature, the resultant
mixture was concentrated in vacuo. The residue was partitioned be-
tween chloroform and NaHCO3 aqueous solution, and the organic
layer was washed with brine, and then dried and concentrated in va-
cuo. The residue was purified using column chromatography on sil-
ica gel with CHCl3/MeOH as the eluent, followed by addition of 4 M
HCl–dioxane in acetone to yield 5a (0.14 g) as a colorless powder.
15% yield; 1H NMR (DMSO-d6) d: 2.80–3.30 (6H, m), 3.75 (2H, s),
4.09 (2H, d, J = 5.6 Hz), 4.25–4.27 (1H, m), 5.98 (1H, br s), 7.19 (2H,
d, J = 8.4 Hz), 7.34–7.41 (2H, m), 7.46–7.50 (2H, m), 7.59 (2H, d,
J = 8.4 Hz), 7.83–7.88 (1H, m), 8.22 (1H, s), 8.35 (1H, s), 8.55 (1H, d,
J = 3.6 Hz), 8.95 (1H, s), 9.19 (1H, s), 10.42 (1H, s); MS (FAB) m/z:
407 (MH+); Anal. Calcd for C23H26N4O3ꢀ1.2HClꢀ0.9H2O: C, 59.22; H,
6.27; N, 12.01; Cl, 9.12. Found: C, 59.32; H, 6.12; N, 11.96; Cl, 9.10.
5.1.8. (S)-40-(2-{[2-Hydroxy-3-(carbazol-4-yloxy)propyl]-
amino}ethyl)-2-(2-pyridyl)acetanilide hydrochloride (5f)
The title compound was prepared in the same manner as de-
scribed for 5a using (S)-2-(carbazol-4-yloxymethyl)oxirane instead
of (S)-2-(3-pyridyloxymethyl)oxirane as a colorless solid. 40%
yield; mp 208–210 °C (MeOH–EtOH); 1H NMR (DMSO-d6) d:
2.90–3.40 (6H, m), 3.84 (2H, s), 4.18–4.27 (2H, m), 4.40–4.50 (1H,
m), 6.04 (1H, d, J = 4.8 Hz), 6.71 (1H, d, J = 8.0 Hz), 7.09–7.47 (9H,
m), 7.59 (2H, d, J = 8.0 Hz), 7.73–7.78 (1H, m), 8.23 (1H, d,
J = 7.6 Hz), 8.50 (1H, d, J = 8.8 Hz), 8.92–9.03 (2H, m), 10.30 (1H,
s), 11.31 (1H, s); MS (FAB) m/z: 495 (MH+); Anal. Calcd for
C30H30N4O3ꢀHCl: C, 67.85; H, 5.88; N, 10.55; Cl, 6.68. Found: C,
67.82; H, 5.84; N, 10.48; Cl, 6.57.
5.1.4. (S)-40-(2-{[2-Hydroxy-3-(4-methylsulfonamidophenoxy)-
propyl]amino}ethyl)-2-(2-pyridyl)acetanilide hydrochloride (5b)
The title compound was prepared in the same manner as
described for 5a using (S)-2-[(4-methylsulfonylaminophen-
oxy)methyl]oxirane16 instead of (S)-2-(3-pyridyloxymethyl)-
oxirane as a colorless solid. 16% yield; mp 231–234 °C (dec.)
(MeOH–EtOH); 1H NMR (DMSO-d6) d: 2.80–3.30 (6H, m), 2.88 (3H,
s), 3.85 (2H, s), 3.92–3.98 (2H, m), 4.18–4.22 (1H, m), 5.90 (1H, d,
J = 5.2 Hz), 6.93–6.96 (2H, m), 7.15–7.20 (4H, m), 7.25–7.28 (1H,
m), 7.38–7.41 (1H, m), 7.57–7.60 (2H, m), 7.73–7.78 (1H, m), 8.48–
8.50 (1H, m), 8.84 (1H, br s), 9.05 (1H, br s), 9.42 (1H, s), 10.33 (1H,
s); MS (FAB) m/z: 499 (MH+); Anal. Calcd for C25H30N4O5SꢀHCl: C,
56.12; H, 5.84; N, 10.47; S, 5.99; Cl, 6.63. Found: C, 55.87; H, 5.80;
N, 10.36; S, 6.02; Cl, 6.69.
5.1.9. 40-Cyanomethyl-2-(3-methyl-2-pyridyl)acetanilide (7a)
The mixture of ethyl (3-methyl-2-pyridyl)acetate (6a) (2.62 g)
and 4-aminobenzylcyanide (1.63 g) in xylene (20 mL) was refluxed
for 13 h. After cooling to room temperature, the resultant mixture
was concentrated in vacuo. The residue was triturated in diethyl
ether and filtered to yield 7a (2.61 g) as a colorless solid. 65% yield;
1H NMR (CDCl3) d: 2.40 (3H, s), 3.70 (2H, s), 3.89 (2H, s), 7.14–7.26
(3H, m), 7.52–7.59 (3H, m), 8.44–8.46 (1H, m), 10.06 (1H, s); MS
(FAB) m/z: 266 (MH+).
5.1.5. (S)-40-(2-{[2-Hydroxy-3-phenoxypropyl]amino}ethyl)-2-
(2-pyridyl)acetanilide hydrochloride (5c)
5.1.10. 40-Cyanomethyl-2-(4,6-dimethyl-2-pyridyl)acetanilide (7b)
The title compound was prepared in the same manner as de-
scribed for 7a using 6b instead of 6a as a colorless solid. 87% yield;
1H NMR (CDCl3) d: 2.31 (3H, s), 2.59 (3H, s), 3.71 (2H, s), 3.77 (2H,
s), 6.90–6.93 (2H, m), 7.25–7.27 (2H, m), 7.56–7.60 (2H, m), 10.60
(1H, br s); MS (FAB) m/z: 280 (MH+).
The title compound was prepared in the same manner as de-
scribed for 5a using (S)-2-phenoxymethyloxirane instead of (S)-
2-(3-pyridyloxymethyl)oxirane as a colorless solid. 35% yield; mp
205–207 °C (MeOH–EtOH–Et2O); 1H NMR (DMSO-d6) d: 2.91–
3.07 (3H, m), 3.14–3.20 (3H, m), 3.90 (2H, s), 3.93–4.01 (2H, m),
4.20–4.22 (1H, m), 5.90 (1H, br s), 6.94–6.97 (3H, m), 7.19 (2H, d,
J = 8.8 Hz), 7.28–7.37 (3H, m), 7.48 (1H, d, J = 8.0 Hz), 7.58 (2H, d,
J = 8.8 Hz), 7.84–7.88 (1H, m), 8.55 (1H, d, J = 4.8 Hz), 8.80 (1H, br
s), 8.97 (1H, br s), 10.36 (1H, s); MS (FAB) m/z: 406 (MH+); Anal.
Calcd for C25H27N5O4ꢀ1.1HClꢀ0.5H2O: C, 63.41; H, 6.45; N, 9.24;
Cl, 8.58. Found: C, 63.12; H, 6.04; N, 9.13; Cl, 8.80.
5.1.11. 40-Cyanomethyl-2-(1-benzylbenzimidazol-2-yl)acetanilide
(7c)
The title compound was prepared in the same manner as de-
scribed for 7a using 6c instead of 6a as a colorless solid. 85% yield;
1H NMR (CDCl3) d: 3.71 (2H, s), 3.96 (2H, s), 5.43 (2H, s), 7.03–7.10
(2H, m), 7.24–7.38 (8H, m), 7.60 (2H, d, J = 8.8 Hz), 7.78–7.84 (1H,
m), 10.80 (1H, br s); MS (FAB) m/z: 381 (MH+).
5.1.6. (S)-40-(2-{[2-Hydroxy-3-(2-benzimidazolon-4-yloxy)-
propyl]amino}ethyl)-2-(2-pyridyl)-acetanilide hydrochloride (5d)
The title compound was prepared in the same manner as de-
scribed for 5a using (S)-2-[4-(2-benzimidazolon-4-yloxy)methyl]oxi-
rane17 instead of (S)-2-(3-pyridyloxymethyl)oxirane as a colorless
powder. 36% yield; 1H NMR (DMSO-d6) d: 2.92–3.02 (3H, m), 3.13–
3.20 (3H, m), 3.84 (2H, s), 3.97–4.09 (2H, m), 4.17–4.25 (1H, m),
5.79 (1H, d, J = 4.8 Hz), 6.59–6.64 (2H, m), 6.85–6.89 (1H, m), 7.20
(2H, d, J = 8.8 Hz), 7.25–7.28 (1H, m), 7.40 (1H, d, J = 8.0 Hz), 7.59
(2H, d, J = 8.8 Hz), 7.73–7.78 (1H, m), 8.48–8.51 (1H, m), 8.83 (2H,
br s), 10.31 (1H, s), 10.63 (1H, s), 10.69 (1H, s); MS (FAB) m/z: 462
5.1.12. (S)-40-(2-{[2-Hydroxy-3-phenoxypropyl]amino}ethyl)-2-
(3-methyl-2-pyridyl)acetanilide hydrochloride (8a)
To a mixture of 7a (0.91 g) and concentrated aqueous ammonia
solution (0.5 mL) in tetrahydrofuran (20 mL) was added Raney-
nickel, and the mixture was stirred under a hydrogen atmosphere
for 3 h. The catalyst was removed by filtration over Celite, and the
filtrate was concentrated in vacuo. The residue was added to a
solution of (S)-2-phenoxymethyl-oxirane (0.55 g) in 2-propanol
(20 mL), and the mixture was refluxed for 4 h. After cooling to
room temperature, the resultant mixture was concentrated in

3290
T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
vacuo. To a solution of the residue in methanol (5 mL) was added
4 M HCl–EtOAc solution (280 L), and the mixture was concen-
filtration, and the filtrate was concentrated in vacuo. The residue
was purified using column chromatography on silica gel with
CHCl3/MeOH (30:1) as the eluent to yield 12 (5.15 g) as a colorless
oil. 69% yield; 1H NMR (CDCl3) d: 1.46 (9H, s), 2.67–2.80 (2H, m),
3.30–3.48 (4H, m), 3.57 (2H, br s), 3.82–4.00 (2H, m), 4.06–4.20
(2H, m), 6.61 (2H, d, J = 8.0 Hz), 6.87–7.00 (5H, m), 7.25–7.32
(2H, m); MS (FAB) m/z: 387 (MH+).
l
trated in vacuo. The residue was purified by recrystallization to
yield 8a (0.37 g) as a colorless solid. 24% yield; mp 192–193 °C
(MeOH–EtOH–Et2O); 1H NMR (DMSO-d6) d: 2.39 (3H, s), 2.87–
3.21 (6H, m), 3.74 (2H, s), 3.93–4.01 (2H, m), 4.15–4.25 (1H, m),
5.89 (1H, d, J = 4.8 Hz), 6.93–7.00 (5H, m), 7.19 (2H, d, J = 8.8 Hz),
7.28–7.32 (2H, m), 7.58 (2H, d, J = 8.8 Hz), 8.31 (1H, d, J = 4.4 Hz),
10.29 (1H, s); MS (FAB) m/z: 420 (MH+); Anal. Calcd for
C25H29N3O3ꢀHClꢀ0.5H2O: C, 64.58; H, 6.72; N, 9.04; Cl, 7.62. Found:
C, 64.63; H, 6.81; N, 9.00; Cl, 7.77.
5.1.18. tert-Butyl (S)-N-[2-(4-{[2-(6-chloro-2-pyridyl)acetyl]-
amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxypropyl)-
carbamate (13a)
To a solution of 12 (0.51 g) and 6-chloro-2-pyridylacetic acid
(0.25 g) in tetrahydrofuran (15 mL) were added 1-ethyl-3-(30-
dimethylaminopropyl)carbodiimide hydrochloride (0.25 g) and 1-
hydroxybenzotriazole (0.18 g), and the mixture was stirred at
room temperature for 14 h. The resulting mixture was concen-
trated in vacuo and diluted with ethyl acetate. The organic layer
was washed with water and brine, and then dried and concen-
trated in vacuo. The residue was purified using column chromatog-
raphy on silica gel with n-hexane/EtOAc (1:1) as the eluent to yield
13a (0.58 g) as a colorless powder. 81% yield; 1H NMR (CDCl3) d:
1.46 (9H, s), 2.75–2.85 (2H, m), 3.30–3.50 (4H, m), 3.83 (2H, s),
3.87–3.95 (2H, m), 4.09–4.13 (2H, m), 6.88–7.00 (3H, m), 7.06–
7.14 (2H, m), 7.25–7.30 (4H, m), 7.47 (2H, d, J = 8.0 Hz), 7.52–
7.68 (1H, m), 9.19 (1H, br s); MS (FAB) m/z: 540 (MH+).
5.1.13. (S)-40-(2-{[2-Hydroxy-3-phenoxypropyl]amino}ethyl)-2-
(4,6-dimethyl-2-pyridyl)-acetanilide hydrochloride (8b)
The title compound was prepared in the same manner as de-
scribed for 8a using 7b instead of 7a as a colorless solid. 30% yield;
mp 191–192 °C (MeOH–EtOH–Et2O); 1H NMR (DMSO-d6) d: 2.27
(3H, s), 2.40 (3H, s), 2.89–3.21 (6H, m), 3.74 (2H, s), 3.93–4.01
(2H, m), 4.15–4.25 (1H, m), 5.89 (1H, d, J = 4.8 Hz), 6.93–6.96
(4H, m), 7.01 (1H, s), 7.19 (2H, d, J = 8.4 Hz), 7.28–7.32 (2H, m),
7.58 (2H, d, J = 8.4 Hz), 10.29 (1H, s); MS (FAB) m/z: 434 (MH+);
Anal. Calcd for C26H31N3O3ꢀHCl: C, 66.44; H, 6.86; N, 8.94; Cl,
7.54. Found: C, 66.32; H, 6.85; N, 8.95; Cl, 7.84.
5.1.14. (S)-40-(2-{[2-Hydroxy-3-phenoxypropyl]amino}ethyl)-2-
(1-benzyl-benzimidazol-2-yl)-acetanilide hydrochloride (8c)
The title compound was prepared in the same manner as de-
scribed for 8a using 7c instead of 7a as a colorless solid. 12% yield;
mp 226–227 °C (MeOH–EtOH–Et2O); 1H NMR (DMSO-d6) d: 2.90–
3.30 (6H, m), 3.93–4.01 (2H, m), 4.11 (2H, s), 4.15–4.25 (1H, m),
5.58 (2H, s), 5.89 (1H, d, J = 4.8 Hz), 6.93–6.97 (3H, m), 7.17–7.42
(12H, m), 7.54–7.62 (3H, m), 8.74 (1H, br s), 8.85 (1H, br s),
10.49 (1H, s); MS (FAB) m/z: 535 (MH+); Anal. Calcd for
C33H34N4O3ꢀHClꢀ0.1H2O: C, 69.18; H, 6.19; N, 9.78; Cl, 6.19. Found:
C, 69.07; H, 6.14; N, 9.69; Cl, 6.22.
5.1.19. tert-Butyl (S)-N-[2-(4-{[2-(6-benzyloxy-2-pyridyl)acetyl]-
amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxypropyl)carbamate
(13b)
The title compound was prepared in the same manner as de-
scribed for 13a using 6-benzyloxy-2-pyridylacetic acid instead of
6-chloro-2-pyridylacetic acid as a colorless powder. 60% yield; 1H
NMR (CDCl 3)
1.46 (9H, s), 2.72–2.85 (2H, m), 3.30–3.50 (4H,
d:
m), 3.78 (2H, s), 3.86–3.94 (2H, m), 4.11 (1H, br s), 5.46 (2H, s),
5.58–7.09 (7H, m), 7.22–7.40 (7H, m), 7.45–7.48 (2H, m), 7.57–
7.61 (1H, m), 9.05 (1H, br s); MS (FAB) m/z: 612 (MH+).
5.1.15. (S)-1-[2-(4-Nitrophenyl)ethylamino]-3-phenoxy-2-
propanol (10)
5.1.20. tert-Butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-(4-
{[2-(1-phenylimidazol-2-yl)-acetyl]amino}phenyl)ethyl]-
carbamate (13c)
The title compound was prepared in the same manner as de-
scribed for 13a using 1-phenylimidazol-2-ylacetic acid hydrochlo-
The mixture of 2-(4-nitrophenyl)ethylamine hydrochloride (9)
(10.34 g), (S)-2-phenoxymethyloxirane (7.71 g), and triethylamine
(5.20 g) in 2-propanol (100 mL) was refluxed for 9 h. After cooling
to room temperature, the resultant mixture was concentrated in
vacuo and diluted with ethyl acetate. The organic layer was
washed with water and brine, and then dried and concentrated
in vacuo. The residue was purified using column chromatography
on silica gel with CHCl3/MeOH (10:1) as the eluent to yield 10
(6.35 g) as a colorless oil. 39% yield; 1H NMR (CDCl3) d: 2.78–3.01
(6H, m), 3.97 (2H, d, J = 4.9 Hz), 4.01–4.05 (1H, m), 6.89 (2H, d,
J = 7.9 Hz), 6.96 (1H, t, J = 7.3 Hz), 7.27 (2H, d, J = 7.3 Hz), 7.37
(2H, d, J = 9.2 Hz), 8.15 (2H, d, J = 8.6 Hz); MS (FAB) m/z: 317 (MH+).
ride19 instead of 6-chloro-2-pyridylacetic acid as
a colorless
powder. 75% yield; 1H NMR (CDCl3) d: 1.47 (9H, s), 2.75–2.85
(2H, m), 3.35–4.00 (4H, m), 3.73 (2H, s), 3.80–4.00 (2H, m), 4.05–
4.10 (1H, m), 6.89–7.00 (3H, m), 7.10–7.18 (4H, m), 7.28–7.30
(4H, m), 7.47–7.53 (5H, m), 10.44 (1H, br s); MS (FAB) m/z: 571
(MH+).
5.1.21. tert-Butyl (S)-N-{2-[4-({2-[1-(4-chlorobenzyl)imidazol-
2-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3-phenoxy-
propyl)carbamate (13d)
The title compound was prepared in the same manner as de-
scribed for 13a using 1-(4-chlorobenzyl)imidazol-2-ylacetic acid
hydrochloride20 instead of 6-chloro-2-pyridylacetic acid as a color-
less powder. 98% yield; 1H NMR (CDCl3) d: 1.46 (9H, s), 2.75–2.87
(2H, m), 3.30–3.50 (4H, m), 3.71 (2H, s), 3.80–4.00 (2H, m), 4.05–
4.10 (1H, m), 5.21 (2H, s), 6.89–7.20 (10H, m), 7.25–7.30 (3H, m),
7.45 (2H, d, J = 8.3 Hz), 10.15 (1H, br s); MS (FAB) m/z: 619 (MH+).
5.1.16. tert-Butyl (S)-N-(2-hydroxy-3-phenoxy)propyl-N-[2-(4-
nitrophenyl)ethyl]carbamate (11)
To a solution of 10 (6.35 g) in tetrahydrofuran (110 mL) was
added di-tert-butyl dicarbonate (4 g). The mixture was stirred at
room temperature for 2 h, and concentrated in vacuo to yield 11
(7.94 g) as a colorless powder. 95% yield; 1H NMR (CDCl3) d: 1.44
(9H, s), 2.91–3.05 (2H, m), 3.40–3.60 (4H, m), 3.85–4.00 (2H, m),
4.10–4.20 (1H, m), 6.90 (2H, d, J = 8.0 Hz), 6.98 (1H, t, J = 7.0 Hz),
7.09–7.32 (4H, m), 8.15 (2H, d, J = 8.8 Hz); MS (FAB) m/z: 417 (MH+).
5.1.22. tert-Butyl (S)-N-{2-[4-({2-[1-(4-bromobenzyl)imidazol-
2-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3-phenoxy-
propyl)carbamate (13e)
5.1.17. tert-Butyl (S)-N-[2-(4-aminophenyl)ethyl]-N-(2-hydroxy-
3-phenoxy)propylcarbamate (12)
To a solution of 11 (7.94 g) in ethanol (100 mL) was added pal-
ladium–carbon (10% w/w, 0.8 g), and the mixture was stirred un-
der a hydrogen atmosphere for 2 h. The catalyst was removed by
The title compound was prepared in the same manner as
described for 13a using 1-(4-bromobenzyl)imidazol-2-ylacetic
acid hydrochloride20 instead of 6-chloro-2-pyridylacetic acid as a

T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
3291
colorless powder. 68% yield; 1H NMR (CDCl3) d: 1.46 (9H, s), 2.75–
2.85 (2H, m), 3.30–3.50 (4H, m), 3.70 (2H, s), 3.80–4.00 (2H, m),
4.05–4.15 (1H, m), 5.11 (2H, s), 6.89–6.98 (6H, m), 7.00–7.15 (3H,
m), 7.20–7.35 (2H, m), 7.40–7.50 (4H, m), 10.14 (1H, br s); MS
(FAB) m/z: 665 (MH+).
crude solid was purified by recrystallization from methanol–etha-
nol–diethyl ether to yield 14a (0.38 g) as a colorless solid. 77%
yield; mp 234–236 °C (MeOH–EtOH–Et2O); 1H NMR (DMSO-d6)
d: 2.92–3.08 (3H, m), 3.13–3.24 (3H, m), 3.89 (2H, s), 3.92–4.05
(2H, m), 4.24–4.29 (1H, m), 5.94 (1H, br s), 6.93–7.01 (3H, m),
7.20 (2H, d, J = 8.8 Hz), 7.27–7.32 (2H, m), 7.39–7.45 (2H, m),
7.61 (2H, d, J = 8.8 Hz), 7.80–7.86 (1H, m), 9.01 (1H, br s), 9.29
(1H, br s), 10.51 (1H, s); MS (FAB) m/z: 440 (MH+); Anal. Calcd
for C24H26N3O3ClꢀHCl: C, 60.51; H, 5.71; N, 8.82; Cl, 14.88. Found:
C, 60.40; H, 5.98; N, 8.71; Cl, 14.71.
5.1.23. tert-Butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-{2-[4-
({2-[1-(2-naphtylmethyl)-imidazol-2-yl]acetyl}amino)phenyl]-
ethyl}carbamate (13f)
The title compound was prepared in the same manner as de-
scribed for 13a using 1-(2-naphtylmethyl)imidazol-2-ylacetic acid
hydrochloride20 instead of 6-chloro-2-pyridylacetic acid as a color-
less powder. 63% yield; 1H NMR (CDCl3) d: 1.46 (9H, s), 2.75–2.85
(2H, m), 3.30–3.50 (4H, m), 3.76 (2H, s), 3.80–4.00 (2H, m), 4.00–
4.05 (1H, m), 5.30 (2H, s), 6.89–7.12 (7H, m), 7.20–7.30 (3H, m),
7.44–7.50 (5H, m), 7.74–7.83 (3H, m), 10.30 (1H, br s); MS (FAB)
m/z: 635 (MH+).
5.1.28. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(6-benzyloxy-2-pyridyl)-acetanilide hydrochloride (14b)
The title compound was prepared in the same manner as de-
scribed for 14a using 13b instead of 13a as a colorless solid. 45%
yield; mp 227–229 °C (MeOH–EtOH–EtOAc); 1H NMR (DMSO-d6)
d: 2.88–3.05 (3H, m), 3.14–3.20 (3H, m), 3.77 (2H, s), 3.93–4.01
(2H, m), 4.22 (1H, br s), 5.32 (2H, s), 5.90 (1H, br s), 6.73 (1H, d,
J = 8.3 Hz), 6.94–7.00 (4H, m), 7.20 (2H, d, J = 8.8 Hz), 7.26–7.33
(5H, m), 7.42–7.45 (2H, m), 7.60 (2H, d, J = 8.3 Hz), 7.65–7.70
(1H, m), 8.83 (1H, br s), 9.02 (1H, br s), 10.28 (1H, s); MS
(FAB) m/z: 512 (MH+); Anal. Calcd for C31H33N3O4ꢀHCl: C,
67.94; H, 6.25; N, 7.67; Cl, 6.47. Found: C, 67.79; H, 6.31; N,
7.67; Cl, 6.47.
5.1.24. tert-Butyl (S)-N-[2-(4-{[2-(1-benzylimidazol-4-yl)acetyl]-
amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxypropyl)carbamate
(13g)
The title compound was prepared in the same manner as de-
scribed for 13a using 1-benzylimidazol-4-ylacetic acid instead of
6-chloro-2-pyridylacetic acid as a colorless powder. 81% yield; 1H
NMR (CDCl3) d: 1.46 (9H, s), 2.78 (2H, br s), 3.30–3.50 (4H, m),
3.62 (2H, s), 3.89–3.94 (2H, m), 4.11 (1H, br s), 5.09 (2H, s), 6.80
(1H, s), 6.89 (2H, d, J = 8.3 Hz), 6.98 (1H, t, J = 7.2 Hz), 7.07 (2H,
br s), 7.18 (2H, dd, J = 2.1, 7.2 Hz), 7.26–7.31 (2H, m), 7.36–7.40
(3H, m), 7.46 (2H, d, J = 8.3 Hz), 7.56 (1H, s), 9.44 (1H, br s); MS
(FAB) m/z: 585 (MH+).
5.1.29. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(1-phenylimidazol-2-yl)-acetanilide dihydrochloride (14c)
The title compound was prepared in the same manner as de-
scribed for 14a using 13c instead of 13a as a colorless powder.
79% yield; 1H NMR (DMSO-d6) d: 2.90–3.05 (3H, m), 3.05–3.25
(3H, m), 3.97 (2H, t, J = 5.4 Hz), 4.10–4.25 (3H, m), 5.92 (1H, br s),
6.93–6.98 (3H, m), 7.18 (2H, d, J = 8.6 Hz), 7.30 (2H, t, J = 8.0 Hz),
7.44 (2H, d, J = 8.0 Hz), 7.60–7.63 (5H, m), 7.85 (1H, d, J = 1.6 Hz),
7.97 (1H, d, J = 2.2 H), 8.90 (1H, br s), 9.16 (1H, br s), 10.62 (1H,
5.1.25. tert-Butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-{2-[4-
({2-[1-(4-nitrobenzyl)imidazol-2-yl]acetyl}amino)phenyl]-
ethyl}carbamate (13h)
The title compound was prepared in the same manner as de-
scribed for 13a using 1-(4-nitrobenzyl)imidazol-2-ylacetic acid21
instead of 6-chloro-2-pyridylacetic acid as a colorless powder.
95% yield; 1H NMR (CDCl3) d: 1.47 (9H, s), 2.75–2.85 (2H, m),
3.30–3.50 (4H, m), 3.80–4.00 (4H, m), 4.05–4.10 (2H, m), 5.50
(2H, s), 6.88–6.98 (4H, m), 7.05–7.15 (3H, m), 7.25–7.75 (4H, m),
8.19 (2H, d, J = 8.8 Hz), 9.78 (1H, br s); MS (FAB) m/z: 639 (MH+).
s);
MS
(FAB)
m/z:
471
(MH+);
Anal.
Calcd
for
C28H30N4O3ꢀ2HClꢀ1.8H2O: C, 58.40; H, 6.23; N, 9.73; Cl, 12.31.
Found: C, 58.39; H, 6.16; N, 9.50; Cl, 12.44.
5.1.30. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
[1-(4-chlorobenzyl)imidazol-2-yl]acetanilide dihydrochloride
(14d)
The title compound was prepared in the same manner as de-
scribed for 14a using 13d instead of 13a as a colorless solid. 57%
yield; mp 200–205 °C (EtOH–EtOAc); 1H NMR (DMSO-d6) d:
2.94–3.17 (6H, m), 3.94–4.04 (2H, m), 4.23–4.25 (1H, m), 4.44
(2H, s), 5.47 (2H, s), 5.92 (1H, br s), 6.93–6.97 (3H, m), 7.21 (2H,
d, J = 8.8 Hz), 7.28–7.33 (2H, m), 7.37–7.45 (4H, m), 7.51–7.57
(2H, m), 7.69–7.71 (2H, m), 8.94 (1H, br s), 9.22 (1H, br s), 10.91
(1H, s); MS (FAB) m/z: 519 (MH+); Anal. Calcd for
C29H31N4O3Clꢀ2HClꢀ0.1H2O: C, 58.66; H, 5.64; N, 9.44; Cl, 17.91.
Found: C, 58.41; H, 5.47; N, 9.39; Cl, 18.08.
5.1.26. tert-Butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-(4-
{[2-(1H-imidazol-2-yl)acetyl]-amino}phenyl)ethyl]carbamate (13i)
To a solution of 13h (2.15 g) in methanol (200 mL) was added
4 M HCl–EtOAc solution (1.0 mL). The mixture was stirred at room
temperature for 5 min and concentrated in vacuo. To a solution of
the residue in methanol (150 mL) was added palladium on carbon
(10% w/w, 0.67 g), and the mixture was stirred under hydrogen
atmosphere for 5 h. The catalyst was removed by filtration, and
the filtrate was concentrated in vacuo. The residue was partitioned
between chloroform and 1 M NaOH aqueous solution. The organic
layer was washed with brine, and then dried and concentrated in
vacuo. The residue was purified using column chromatography
on silica gel with CHCl3/MeOH (50:1) as the eluent to yield 13i
(0.96 g) as a colorless powder. 56% yield; 1H NMR (CDCl3) d: 1.46
(9H, s), 2.75–2.85 (2H, m), 3.30–3.55 (4H, m), 3.80–4.00 (2H, m),
3.90 (2H, s), 4.05–4.15 (1H, m), 6.88–6.98 (3H, m), 7.00–7.20 (4H,
m), 7.30–7.40 (2H, m), 7.50 (2H, d, J = 7.8 Hz), 10.03 (1H, br s);
MS (FAB) m/z: 495 (MH+).
5.1.31. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
[1-(4-bromobenzyl)imidazol-2-yl]acetanilide dihydrochloride
(14e)
The title compound was prepared in the same manner as de-
scribed for 14a using 13e instead of 13a as a colorless solid. 89%
yield; mp 207–210 °C (EtOH–EtOAc); 1H NMR (DMSO-d6) d:
2.95–3.18 (6H, m), 3.94–4.04 (2H, m), 4.23–4.25 (1H, m), 4.42
(2H, s), 5.46 (2H, s), 5.92 (1H, br s), 6.93–6.97 (3H, m), 7.21 (2H,
d, J = 8.8 Hz), 7.28–7.33 (4H, m), 7.49–7.55 (4H, m), 7.70 (2H, s),
8.91 (1H, br s), 9.17 (1H, br s), 10.86 (1H, s); MS (FAB) m/z: 565
(MH+); Anal. Calcd for C29H31N4O3Brꢀ2HCl: C, 54.73; H, 5.23; N,
8.80; Cl, 11.14, Br, 12.56. Found: C, 54.56; H, 5.04; N, 8.76; Cl,
11.02, Br, 12.35.
5.1.27. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(6-chloro-2-pyridyl)acetanilide hydrochloride (14a)
To a solution of 13a (0.56 g) in ethanol (10 mL) was added 4 M
HCl–EtOAc (10 mL), and the mixture was stirred at room tempera-
ture for 1 h. The resulting mixture was concentrated in vacuo. The

3292
T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
5.1.32. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
[1-(2-naphtylmethyl)imidazol-2-yl]acetanilide dihydrochloride
(14f)
5.1.37. (S)-N-Propyl-40-{2-[(2-hydroxy-3-phenoxypropyl)-
amino]ethyl}-2-(1-benzylimidazol-2-yl)acetanilide
dihydrochloride (17)
The title compound was prepared in the same manner as de-
scribed for 14a using 13f instead of 13a as a colorless solid. 75%
yield; mp 215–218 °C (EtOH–EtOAc); 1H NMR (DMSO-d6) d:
2.94–3.15 (6H, m), 3.94–4.04 (2H, m), 4.23–4.25 (1H, m), 4.47
(2H, s), 5.63 (2H, s), 5.92 (1H, br s), 6.94–6.97 (3H, m), 7.17
(2H, d, J = 8.0 Hz), 7.28–7.33 (2H, m), 7.48–7.55 (5H, m), 7.71–
7.93 (6H, m), 8.91 (1H, br s), 9.15 (1H, br s), 10.88 (1H, s); MS
(FAB) m/z: 535 (MH+); Anal. Calcd for C33H34N4O3Clꢀ2HClꢀ0.5H2O:
C, 64.28; H, 6.05; N, 9.09; Cl, 11.50. Found: C, 64.52; H, 5.96; N,
9.07; Cl, 11.52.
The title compound was prepared in the same manner as de-
scribed for 14a using 16 instead of 13a as a colorless powder.
62% yield; 1H NMR (DMSO-d6) d: 0.82 (3H, t, J = 7.0 Hz), 1.36–
1.46 (2H, m), 3.00–4.35 (9H, m), 3.56 (2H, t, J = 7.0 Hz), 3.95 (2H,
s), 5.34 (2H, s), 6.92–7.66 (16H, m); MS (FAB) m/z: 527 (MH+); Anal.
Calcd for C32H38N4O3ꢀ2HClꢀH2O: C, 62.23; H, 6.85; N, 9.07; Cl,
11.48. Found: C, 62.19; H, 7.01; N, 9.09; Cl, 11.72.
5.1.38. 40-[2-(tert-Butoxycarbonyl)aminoethyl]-2-(1-ben-
zylimidazol-2-yl)acetanilide (19a)
To a solution of 4-[2-(tert-Butoxycarbonyl)aminoethyl]aniline
(18a)22 (0.95 g) and 1-benzylimidazol-2-ylacetic acid hydrochlo-
ride (1.00 g) in N,N-dimethylformamide (20 mL) were added 1-
5.1.33. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(1-benzylimidazol-4-yl)-acetanilide dihydrochloride (14g)
The title compound was prepared in the same manner as de-
scribed for 14a using 13g instead of 13a as a colorless solid. 63%
yield; mp 121–123 °C (EtOH–EtOAc); 1H NMR (DMSO-d6) d:
2.89–3.17 (6H, m), 3.92 (2H, s), 3.95–4.11 (2H, m), 4.27–4.29
(1H, m), 5.44 (2H, s), 6.93–6.97 (4H, m), 7.20 (2H, d,
J = 8.3 Hz), 7.27–7.47 (7H, m), 7.58–7.66 (3H, m), 9.09 (1H, br
s), 9.34 (1H, s), 9.42 (1H, br s), 10.74 (1H, s); MS (FAB) m/z:
485 (MH+); Anal. Calcd for C29H32N4O3ꢀ2.4HClꢀ1.3H2O: C, 58.49;
H, 6.26; N, 9.41; Cl, 14.29. Found: C, 58.72; H, 6.12; N, 9.15;
Cl, 14.04.
ethyl-3-(30-dimethylaminopropyl)carbodiimide
hydrochloride
(0.85 g) and 1-hydroxybenzotriazole (0.68 g), and the mixture
was stirred at room temperature for 19 h. The resulting mixture
was concentrated in vacuo and diluted with ethyl acetate. The or-
ganic layer was washed with water and brine, and then dried and
concentrated in vacuo. The residue was purified using column
chromatography on silica gel with CHCl3/MeOH/concd NH3 aq
(300:10:1) as the eluent to yield 19a (1.14 g) as a colorless oil.
66% yield; 1H NMR (CDCl3) d: 1.48 (9H, s), 2.75 (2H, t, J = 6.8 Hz),
3.25–3.40 (2H, m), 3.74 (2H, s), 4.53 (1H, br s), 5.16 (2H, s), 6.94
(1H, d, J = 1.6 Hz), 7.06–7.14 (5H, m), 7.29–7.37 (3H, m), 7.47
(2H, d, J = 8.4 Hz), 10.44 (1H, s); MS (FAB) m/z: 435 (MH+).
5.1.34. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(1H-imidazol-2-yl)acetanilide dihydrochloride (14h)
5.1.39. 40-[2-(tert-Butoxycarbonyl)aminoethyl]-2-(1-
benzylimidazol-2-yl)-N-methyl-acetanilide (19b)
The title compound was prepared in the same manner as de-
scribed for 14a using 13i instead of 13a as a colorless solid. 94%
yield; mp 195–201 °C (EtOH–EtOAc); 1H NMR (DMSO-d6) d:
2.99–3.17 (6H, m), 3.94–4.01 (2H, m), 4.21–4.25 (1H, m), 4.27
(2H, s), 5.91 (1H, br s), 6.94–6.97 (3H, m), 7.22 (2H, d, J = 8.4 Hz),
7.28–7.32 (2H, m), 7.57–7.62 (4H, m), 8.93 (1H, br s), 9.19 (1H,
br s), 10.82 (1H, s); MS (FAB) m/z: 395 (MH+); Anal. Calcd for
C22H26N4O3ꢀ2HCl: C, 56.54; H, 6.04; N, 11.99; Cl, 15.17. Found: C,
56.37; H, 6.07; N, 11.78; Cl, 15.38.
The title compound was prepared in the same manner as de-
scribed for 19a using 4-[2-(tert-butoxycarbonyl)aminoethyl]-N-
methylaniline (18b)23 instead of 18a as a colorless oil. 95% yield;
1H NMR (CDCl3) d: 1.44 (9H, s), 2.80 (2H, t, J = 6.8 Hz), 3.26 (3H,
s), 3.36–3.38 (2H, m), 3.50 (2H, s), 5.17 (2H, s), 6.81 (1H, s), 6.95
(1H, s), 7.05 (2H, d, J = 6.8 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.22 (2H,
d, J = 8.0 Hz), 7.27–7.33 (4H, m); MS (FAB) m/z: 449 (MH+).
5.1.40. 40-(2-Aminoethyl)-2-(1-benzylimidazol-2-yl)acetanilide
(20a)
5.1.35. tert-Butyl (S)-N-(2-hydroxy-3-phenoxy)propyl-N-[2-(4-
propylaminophenyl)ethyl]-carbamate (15)
To a solution of 19a (0.81 g) in methanol (25 mL) was added
4 M HCl–EtOAc solution (25 mL), and the mixture was stirred at
room temperature for 2 h. The resulting mixture was concentrated
in vacuo and partitioned between chloroform and 1 M NaOH aque-
ous solution. The organic layer was washed with water and brine,
and then dried and concentrated in vacuo to yield 20a (0.48 g) as a
yellow oil. 77% yield; 1H NMR (CDCl3) d: 1.20 (2H, br s), 2.70 (2H, t,
J = 6.8 Hz), 2.93 (2H, t, J = 6.8 Hz), 3.74 (2H, s), 5.15 (2H, s), 6.94
(2H, d, J = 1.2 Hz), 7.07–7.08 (3H, m), 7.13 (2H, d, J = 8.4 Hz),
7.29–7.36 (3H, m), 7.47 (2H, d, J = 8.4 Hz), 10.36 (1H, s); MS
(FAB) m/z: 335 (MH+).
To a solution of 12 (1.52 g), propionaldehyde (0.23 g), and
acetic acid (0.34 mL) in tetrahydrofuran (30 mL) was added so-
dium triacetoxyborohydride (1.25 g). The mixture was stirred at
room temperature for 2 h, and partitioned between ethyl acetate
and water. The organic layer was washed with brine, and then
dried and concentrated in vacuo. The residue was purified using
column chromatography on silica gel with CHCl3/MeOH (50:1) as
the eluent to yield 15 (1.69 g) as a colorless powder. 99% yield;
1H NMR (CDCl3) d: 0.92 (3H, t, J = 7.0 Hz), 1.37 (9H, s), 1.45–1.75
(2H, m), 2.60 (2H, t, J = 7.0 Hz), 2.91 (2H, q, J = 7.0 Hz), 2.98–3.40
(4H, m), 3.78–4.00 (3H, m), 6.80–7.32 (7H, m); MS (FAB) m/z:
428 (M+).
5.1.41. 40-(2-Aminoethyl)-2-(1-benzylimidazol-2-yl)-N-methyl-
acetanilide (20b)
5.1.36. tert-Butyl (S)-N-[2-(4-{[2-(1-benzylimidazol-2-
yl)acetyl]-N-(propyl)amino}phenyl)-ethyl]-N-(2-hydroxy-3-
phenoxypropyl)carbamate (16)
The title compound was prepared in the same manner as de-
scribed for 13a using 15 and 1-benzylimidazol-2-ylacetic acid in-
The title compound was prepared in the same manner as de-
scribed for 20a using 19b instead of 19a as a yellow oil. 99% yield;
1H NMR (CDCl3) d: 1.53 (2H, br s), 2.76 (2H, t, J = 6.8 Hz), 2.98 (2H,
t, J = 6.8 Hz), 3.26 (3H, s), 3.50 (2H, s), 5.18 (2H, s), 6.81 (1H, s), 6.95
(1H, s), 7.06 (2H, d, J = 6.0 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.22–7.33
(5H, m); MS (FAB) m/z: 349 (MH+).
stead of 12 and 6-chloro-2-pyridylacetic acid as
a colorless
powder. 81% yield; 1H NMR (CDCl3) d: 0.81 (3H, t, J = 7.0 Hz),
1.32 (9H, s), 1.30–1.45 (2H, m), 2.81 (2H, t, J = 7.0 Hz), 3.00–
3.50 (4H, m), 3.26 (2H, s), 3.55 (2H, t, J = 7.0 Hz), 3.75–4.05
(3H, m), 5.04 (2H, s), 6.50–7.52 (16H, m); MS (FAB) m/z: 627
(MH+).
5.1.42. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(1-benzylimidazol-2-yl)-acetanilide hydrochloride (21a)
A mixture of 20a (0.46 g) and (S)-2-phenoxymethyloxirane
(0.2 g) in 2-propanol (10 mL) was heated at 90 °C for 22 h. After

T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
3293
cooling to room temperature, the resultant mixture was concen-
trated in vacuo. The residue was purified using column chromatog-
raphy on silica gel with CHCl3/MeOH/concd NH3 aq (200:10:1) as
the eluent, followed by addition of 4 M HCl–EtOAc in methanol.
The residue was purified by recrystallization to yield 21a (0.13 g)
as a colorless solid. 18% yield; mp 148–152 °C (EtOH–EtOAc); 1H
NMR (DMSO-d6) d: 2.90–3.22 (6H, m), 3.18–3.26 (3H, m), 3.80
(2H, s), 3.93–4.04 (2H, m), 4.20 (1H, br s), 5.25 (2H, s), 5.87 (1H,
br s), 6.86 (1H, d, J = 1.2 Hz), 6.93–6.97 (3H, m), 7.13 (1H, d,
J = 0.8 Hz), 7.18–7.22 (4H, m), 7.27–7.37 (5H, m), 7.54 (2H, d,
J = 8.8 Hz), 10.37 (1H, s); MS (FAB) m/z: 485 (MH+); Anal. Calcd
for C29H32N4O3ꢀHClꢀ0.1H2O: C, 66.62; H, 6.40; N, 10.72; Cl, 6.78.
Found: C, 66.38; H, 6.32; N, 10.74; Cl, 6.77.
yield; 1H NMR (CDCl3) d: 1.18–1.25 (3H, m), 1.38 (9H, s), 2.50–
2.75 (2H, m), 3.30–3.60 (4H, m), 3.80–4.20 (4H, m), 6.57 (2H, d,
J = 8.3 Hz), 6.85–7.00 (5H, m), 7.25–7.35 (2H, m); MS (FAB) m/z:
401 (MH+).
5.1.47. tert-Butyl (S)-N-{2-[3-(4-aminophenyl)]propyl}-N-(2-
hydroxy-3-phenoxypropyl)-carbamate (25b)
The title compound was prepared in the same manner as de-
scribed for 12 using 24b instead of 11 as a colorless powder. 99%
yield; 1H NMR (CDCl3) d: 1.15–1.25 (3H, m), 1.45 (9H, s), 2.55–
4.10 (8H, m), 6.55 (2H, d, J = 8.3 Hz), 6.85–7.00 (5H, m), 7.26–
7.32 (2H, m); MS (FAB) m/z: 401 (MH+).
5.1.48. tert-Butyl (S)-N-{2-[3-(4-{[2-(1-benzylimidazol-2-yl)-
acetyl]amino}phenyl)]propyl}-N-(2-hydroxy-3-phenoxypropyl)-
carbamate (26a)
5.1.43. (S)-N-Methyl-40-{2-[(2-hydroxy-3-phenoxypropyl)-
amino]ethyl}-2-(1-benzylimidazol-2-yl)acetanilide
dihydrochloride (21b)
The title compound was prepared in the same manner as de-
scribed for 19a using 25a instead of 18a as a colorless powder.
74% yield; 1H NMR (CDCl3) d: 1.15–1.25 (3H, m), 1.39 (9H, s),
2.60–4.20 (8H, m), 3.75 (2H, s), 5.14 (2H, s), 6.85–7.00 (4H, m),
7.03–7.12 (5H, m), 7.26–7.37 (5H, m), 7.45–7.50 (2H, m), 10.35
(1H, s); MS (FAB) m/z: 599 (MH+).
The title compound was prepared in the same manner as de-
scribed for 21a using 20b instead of 20a as a colorless powder.
32% yield; 1H NMR (DMSO-d6) d: 3.07–3.11 (3H, m), 3.18–3.26
(3H, m), 3.16 (3H, s), 3.96–4.03 (4H, m), 4.28 (1H, br s), 5.34 (2H,
s), 5.95 (1H, br s), 6.92–6.97 (3H, m), 7.28–7.45 (11H, m), 7.57
(1H, d, J = 1.6 Hz), 7.63 (1H, d, J = 1.6 Hz), 9.07 (1H, br s), 9.42
(1H, br s), 14.66 (1H, br s); MS (FAB) m/z: 499 (MH+); Anal. Calcd
for C30H34N4O3ꢀ2HClꢀ1.5H2O: C, 60.20; H, 6.57; N, 9.36; Cl, 11.85.
Found: C, 60.40; H, 6.72; N, 9.17; Cl, 11.77.
5.1.49. tert-Butyl (S)-N-{2-[3-(4-{[2-(1-benzylimidazol-2-
yl)acetyl]amino}phenyl)]propyl}-N-(2-hydroxy-3-
phenoxypropyl)carbamate (26b)
The title compound was prepared in the same manner as de-
scribed for 19a using 25b instead of 18a as a colorless powder.
82% yield; 1H NMR (CDCl3) d: 1.15–1.25 (3H, m), 1.46 (9H, s),
2.60–4.20 (8H, m), 3.71 (2H, s), 5.14 (2H, s), 6.85–7.00 (4H, m),
7.05–7.14 (5H, m), 7.26–7.37 (5H, m), 7.44–7.48 (2H, m), 10.31
(1H, s); MS (FAB) m/z: 599 (MH+).
5.1.44. (S)-1-{2-[3-(4-Nitrophenyl)propyl]amino}-3-phenoxy-2-
propanol (23)
A solution of (S)-1-amino-3-phenoxy-2-propanol (22) (4.90 g)
and 4-nitrophenylacetone (5.20 g) in benzene (150 mL) was re-
fluxed for 1 h using Dean-Stark trap. After cooling to room temper-
ature, the resultant mixture was concentrated in vacuo. To a
solution of the residue in methanol (80 mL) was added sodium
borohydride (0.59 g) at 5 °C, and the mixture was stirred for 2 hs
at 5 °C. The resultant mixture was concentrated in vacuo and di-
luted with ethyl acetate. The organic layer was washed with water
and brine, and then dried and concentrated in vacuo. The residue
was purified using column chromatography on silica gel with
CHCl3/MeOH (10:1) as the eluent to yield 23 (8.63 g) as a colorless
solid. 89% yield; 1H NMR (CDCl3) d: 1.10 (3H, d, J = 6.4 Hz), 2.68–
3.02 (5H, m), 3.91–4.02 (3H, m), 6.86–6.98 (3H, m), 7.28–7.52
(4H, m), 8.13–8.18 (2H, m); MS (FAB) m/z: 331 (MH+).
5.1.50. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]propyl}-
2-(1-benzylimidazol-2-yl)-acetanilide dihydrochloride (27a)
The title compound was prepared in the same manner as de-
scribed for 14a using 26a instead of 13a as a colorless powder. 71%
yield; 1H NMR (DMSO-d6) d: 1.11 (3H, d, J = 6.2 Hz), 2.60–2.66 (1H,
m), 3.00–4.00 (4H, m), 3.96–4.04 (2H, m), 4.28–4.30 (1H, m), 4.44
(2H, s), 5.46 (2H, s), 6.94–6.98 (3H, m), 7.21 (2H, d, J = 8.3 Hz),
7.29–7.38 (7H, m), 7.54 (2H, d, J = 8.8 Hz), 7.67–7.74 (2H, m), 8.85
(1H, s), 9.22 (1H, s), 10.90 (1H, s); MS (FAB) m/z: 499 (MH+); Anal.
Calcd for C30H34N4O3ꢀ2.5HClꢀ1.2H2O: C, 58.94; H, 6.41; N, 9.16; Cl,
14.50. Found: C, 58.88; H, 6.40; N, 9.19; Cl, 14.28.
5.1.45. tert-Butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-{2-[3-
(4-nitrophenyl)]propyl}-carbamate (24a) and tert-Butyl (S)-N-
(2-hydroxy-3-phenoxypropyl)-N-{2-[3-(4-nitrophenyl)]-
propyl}carbamate (24b)
5.1.51. (S)-40-{2-[(2-Hydroxy-3-phenoxypropyl)amino]propyl}-
2-(1-benzylimidazol-2-yl)-acetanilide dihydrochloride (27b)
The title compound was prepared in the same manner as de-
scribed for 14a using 26b instead of 13a as a colorless powder.
78% yield; 1H NMR (DMSO-d6) d: 1.13 (3H, d, J = 6.9 Hz), 2.58–
2.67 (1H, m), 3.07–3.10 (1H, m), 3.24–3.47 (3H, m), 3.98–4.02
(2H, m), 4.23–4.32 (1H, m), 4.43 (2H, s), 5.46 (2H, s), 6.94–6.98
(3H, m), 7.21 (2H, d, J = 8.3 Hz), 7.29–7.37 (7H, m), 7.54 (2H, d,
J = 8.3 Hz), 7.67–7.70 (2H, m), 8.78 (1H, s), 9.20 (1H, s), 10.87
(1H, s); MS (FAB) m/z: 499 (MH+); Anal. Calcd for
C30H34N4O3ꢀ2.2HClꢀ1.9H2O: C, 58.78; H, 6.58; N, 9.14; Cl, 12.72.
Found: C, 58.69; H, 6.53; N, 9.37; Cl, 12.95.
To a solution of 23 (2.81 g) in tetrahydrofuran (50 mL) was added
di-tert-butyl dicarbonate (1.93 g). The mixture was stirred at room
temperature for 15 h, and concentrated in vacuo. The residue was
purified using column chromatography on silica gel with benzene/
EtOAc (10:1) as the eluent to yield a less polar compound 24a
(1.24 g) and a highly polar compound 24b (1.06 g) as a colorless
powder. Compound 24a: 33% yield; 1H NMR (CDCl3) d: 1.24–1.30
(3H, m), 1.35 (9H, s), 2.75–3.50 (4H, m), 3.80–3.90 (1H, m), 3.95–
4.30 (3H, m), 6.89–7.00 (3H, m), 7.23–7.35 (4H, m), 8.15 (2H, d,
J = 8.3 Hz); MS (FAB) m/z: 431 (MH+); 24b: 28% yield; 1H NMR
(CDCl3) d: 1.25–1.28 (3H, m), 1.44 (9H, s), 2.80–3.40 (4H, m), 3.80–
3.90 (1H, m), 3.95–4.40 (3H, m), 6.85–7.00 (3H, m), 7.26–7.35 (4H,
m), 8.12 (2H, d, J = 8.3 Hz); MS (FAB) m/z: 431 (MH+).
5.1.52. 6-[2-(Dibenzylamino)acetyl]-1,2,3,4-tetrahydroquin-
olin-2-one (29)
A solution of 6-bromoacetyl-1,2,3,4-tetrahydroquinolin-2-one
(28) (8.63 g), dibenzylamine (7.60 g), and N,N-diisopropyl-N-ethyl-
amine (7.8 mL) in 2-butanone (200 mL) was heated at 80 °C for 3 h.
After cooling to room temperature, the resultant mixture was con-
centrated in vacuo. The resultant mixture was diluted with water
and extracted with ethyl acetate. The organic layer was washed
5.1.46. tert-Butyl (S)-N-{2-[3-(4-aminophenyl)]propyl}-N-(2-
hydroxy-3-phenoxypropyl)-carbamate (25a)
The title compound was prepared in the same manner as de-
scribed for 12 using 24a instead of 11 as a colorless powder. 99%

3294
T. Maruyama et al. / Bioorg. Med. Chem. 17 (2009) 3283–3294
with water and brine, and then dried and concentrated in vacuo.
The residue was purified using column chromatography on silica
gel with CHCl3/MeOH (60:1) as the eluent to yield 29 (10.97 g) as
a colorless powder. 79% yield; 1H NMR (CDCl3) d: 2.64–2.69 (2H,
m), 2.94–2.98 (2H, m), 3.69–3.75 (6H, m), 6.78 (1H, d, J = 8.4 Hz),
7.23–7.35 (10H, m), 7.67–7.72 (2H, m), 8.91 (1H, s); MS (FAB) m/
z: 385 (MH+).
b1-ARs are compulsorily expressed were used). The agonistic
activity of the compound (10ꢁ10 to 10ꢁ4 M) was investigated by
incubating 105 cells/well of each type of cell on a 24-well plate
and checking the activity after 2 days’ incubation (subconfluent
state) using the production of cyclic AMP (cAMP) as an index.
The amount of cAMP produced in each cell (pmol/ml) was mea-
sured using a radioimmunoassay method with 125I-cAMP. The
intensity of action among compounds was compared by calculat-
ing the EC50 and intrinsic activity (IA where the maximum reaction
of 10ꢁ4 M isoproterenol was defined as 1.00) for each from the
resulting dose–reaction curve.
5.1.53. 6-(2-Dibenzylaminoethyl)-1,2,3,4-tetrahydroquinoline
(30)
A mixture of 29 (9.45 g) and 1 M borane–THF solution (150 mL)
was heated at 80 °C for 4 h. After cooling to room temperature, to
the resultant mixture was added methanol (150 mL) and concen-
trated HCl aqueous solution (150 mL), and the mixture was heated
at 100 °C for 1 h. After cooling to room temperature, the resultant
mixture was concentrated in vacuo and partitioned between chlo-
roform and 2 M NaOH aqueous solution. The organic layer was
washed with water and brine, and then dried and concentrated
in vacuo. The residue was purified using column chromatography
on silica gel with n-hexane/EtOAc (6:1) as the eluent to yield 30
(9.62 g) as a colorless oil. 99% yield; 1H NMR (CDCl3) d: 1.83–1.93
(2H, m), 2.65–2.71 (6H, m), 3.24–3.28 (2H, m), 3.56–3.71 (4H,
m), 6.37 (1H, d, J = 10.4 Hz), 6.66–6.70 (2H, m), 7.18–7.35 (10H,
m), 8.91 (1H, s); MS (FAB) m/z: 357 (MH+).
5.2.2. Hypoglycemic activity in kk mice
The blood sugar level of male kk mice (blood sugar level: not
lower than 200 mg/dl) was measured under fed conditions, and
then randomly classified into groups. The test compound was
administered orally once daily for 4 days, and the blood sugar level
15–18 h after final administration was compared with that before
administration (n = 6). Blood samples were collected from the tail
vein using a glass capillary tube (previously treated with heparin)
after which the blood was deproteinized, and the amount of glu-
cose in the supernatant (mg/dl) was determined calorimetrically
by means of the glucose oxidase method.
Acknowledgment
5.1.54. 1-[(1-Benzylimidazol-2-yl)acetyl]-6-(2-dibenzylamino-
ethyl)-1,2,3,4-tetrahydroquinoline (31)
The authors are grateful to the staff of the Division of Analytical
Science Laboratories for elemental analysis and spectral
measurements.
The title compound was prepared in the same manner as de-
scribed for 19a using 30 instead of 18a as a colorless oil. 64% yield;
1H NMR (CDCl3) d: 1.88–1.93 (2H, m), 2.61–2.76 (6H, m), 3.64 (4H,
s), 3.82–3.89 (4H, m), 5.25 (2H, s), 6.84–6.90 (3H, m), 7.00 (1H, d,
J = 1.6 Hz), 7.06–7.09 (2H, m), 7.18–7.33 (14H, m); MS (FAB) m/z:
555 (MH+).
References and notes
1. Nisoli, E.; Tonello, C.; Carruba, M. O. Curr. Med. Chem.: Cent. Nerv. Syst. Agents
2003, 3, 257.
2. Moneva, M. H.; Dagogo-Jack, S. Curr. Drug Targets 2002, 3, 203.
3. Arch, J. R.; Ainsworth, A. T.; Cawthorne, M. A.; Piercy, V.; Sennitt, M. V.; Thod, V.
E.; Wilson, C.; Wilson, S. Nature 1984, 309, 163.
4. Howe, R. Drugs Future 1993, 18, 529.
5. Cantello, B. C. C.; Smith, S. A. Drugs Future 1991, 16, 797.
6. Bloom, J. D.; Claus, T. H. Drugs Future 1994, 19, 23.
7. Arch, J. R. S.; Wilson, S. Int. J. Obesity 1996, 20, 191.
8. Lipworth, B. J. Br. J. Clin. Pharmacol. 1996, 42, 291.
9. Emorine, L. J.; Marullo, S.; Briend-Sutren, M.-M.; Patey, G.; Tate, K.; Delavier-
Klutchko, C.; Strosberg, A. D. Science 1989, 245, 1118.
10. Emorine, L. J.; Feve, B.; Pairault, J.; Briend-Sutren, M.-M.; Nahmias, C.; Marullo,
S.; Delavier-Klutchko, C.; Strosberg, A. D. Am. J. Clin. Nutr. 1992, 55, 215S.
11. Tate, K. M.; Briend-Sutren, M.-M.; Emorine, L. J.; Delavier-Klutchko, C.; Marullo,
S.; Strosberg, A. D. Eur. J. Biochem. 1991, 196, 357.
12. Maruyama, T.; Onda, K; Hayakawa, M; Matsui, T; Takasu, T; Ohta, M. Eur. J.
Med. Chem., in press.
5.1.55. 6-(2-Aminoethyl)-1-[(1-benzylimidazol-2-yl)acetyl]-
1,2,3,4-tetrahydroquinoline (32)
To a solution of 31 (4.56 g) in methanol (100 mL) were added
ammonium formate (1.30 g) and palladium on carbon (10% w/w,
0.95 g). The mixture was stirred at room temperature for 15 h, after
which the catalyst was removed by filtration, and the filtrate was
concentrated in vacuo. The residue was purified using column
chromatography on silica gel with CHCl3/MeOH/concd NH3 aq
(100:10:1) as the eluent to yield 31 (0.55 g) as a colorless oil.
17% yield; 1H NMR (CDCl3) d: 1.31 (2H, br s), 1.88–1.95 (2H, m),
2.67–2.72 (4H, m), 2.92–2.97 (2H, m), 3.84–4.05 (4H, m), 5.28
(2H, s), 6.86 (1H, d, J = 1.2 Hz), 6.97–7.11 (5H, m), 7.25–7.35 (4H,
m); MS (FAB) m/z: 375 (MH+).
13. Howe, R. Drugs Future 1993, 18, 529.
14. Hu, B.; Jennings, L. L.. In Progress in Medicinal Chemistry; King, F. D., Oxford, A.
W., Eds.; Elsevier Science B.V., 2003; Vol. 41, pp 167–194.
15. Fisher, M. H. Eur. Patent 611003, 1994.
16. Dingledine, R. J. PCT Int. WO2002072542, 2002.
17. Elsinga, P. H.; van Waarde, A.; Laeggi, K. A.; Schreiber, G.; Heldoorn, M.;
Vaalburg, W. J. Med. Chem. 1997, 40, 3829.
5.1.56. (S)-1-[(2-{1-[(1-Benzylimidazol-2-yl)acetyl]-1,2,3,4-tetra-
hydroquinolin-6-yl}ethyl)-amino]-3-phenoxy-2-propanol
dihydrochloride (33)
The title compound was prepared in the same manner as de-
scribed for 21a using 32 instead of 20a as a colorless powder.
29% yield; 1H NMR (DMSO-d6) d: 1.81–1.88 (2H, m), 2.67–2.71
(2H, m), 2.93–3.05 (6H, m), 3.67–3.71 (2H, m), 3.91–4.06 (4H,
m), 4.20–4.22 (1H, m), 5.17 (2H, s), 5.87 (1H, br s), 6.83 (1H, s),
6.93–6.97 (3H, m), 7.02–7.16 (5H, m), 7.25–7.35 (5H, m), 7.55
(1H, br s); MS (FAB) m/z: 525 (MH+); Anal. Calcd for
C32H36N4O3ꢀ2HClꢀH2Oꢀ0.5EtOAc: C, 61.91; H, 6.72; N, 8.49; Cl,
10.75. Found: C, 61.79; H, 6.69; N, 8.42; Cl, 10.67.
18. Amano, M. Jpn. Kokai Tokkyo Koho JP01287064, 1989.
19. The compound was prepared by treating 2-methyl-1-phenylimidazole24 with
ethyl chloroformate and triethylamine, followed by hydrolysis as
a
hydrochloride. 1H NMR (DMSO-d6) d: 4.16 (2H, s), 7.55–7.70 (5H, m), 7.88–
7.91 (1H, m), 7.98–8.00 (1H m); MS (FAB) m/z: 202 (MH+).
20. Jaeggi, K. A. Eur. Patent EP275821, 1987.
21. The compound was prepared by treating a commercially available 2-methyl-1-
(4-nitrobenzyl)-imidazole with ethyl chloroformate and triethylamine,
followed by hydrolysis as a hydrochloride. 1H NMR (DMSO-d6) d: 4.32 (2H,
s), 5,64 (2H, s), 7.58 (2H, d, J = 8.9 Hz), 7.73–7.78 (2H m), 8.25 (2H, d, J = 8.9 Hz),
14.00 (1H, br s); MS (FAB) m/z: 262 (MH+).
22. Fisher, M. H. Eur. Patent EP611003, 1994.
23. The compound was prepared by treating N-methyl-4-(2-aminoethyl)aniline25
with di-tert-butyldicarbonate intetrahydrofuran. 1HNMR (CDCl3)d:1.43 (9H, s),
2.68 (2H, d, J = 7.6 Hz), 2.83 (3H, s), 3.25–3.40 (2H m), 3.64 (1H, br s), 4.52 (1H, br
s), 6.57 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 8.4 Hz),; MS (FAB) m/z: 250 (MH+).
24. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947, 96.
5.2. Pharmacology
5.2.1. Agonistic activity on human b3-, b2-, and b1-ARs
The ability to stimulate human b3-, b2-, and b1-AR was investi-
gated using a CHO cell system (cells in which human b3-, b2-, and
25. Borovicka, M.; Sedivy, Z.; Jilek, J. O.; Protiva, M. Collect. Czech. Chem. Commun.
1955, 20, 437.