Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human β3-adrenergic receptor agonists with good oral bioavailability. Part I

Article abstract of DOI:10.1021/jm701324c

A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human β₃ adrenergic receptor (β₃-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with β₃- AR agonists.

Full text of DOI:10.1021/jm701324c

J. Med. Chem. 2008, 51, 1925–1944
1925
Discovery of a Novel Series of Biphenyl Benzoic Acid Derivatives as Potent and Selective
Human ꢀ3-Adrenergic Receptor Agonists with Good Oral Bioavailability. Part I
Masashi Imanishi,† Yasuyo Tomishima, Shinji Itou,† Hitoshi Hamashima,† Yutaka Nakajima,† Kenichi Washizuka,†
Minoru Sakurai,† Shigeo Matsui,‡ Emiko Imamura,‡ Koji Ueshima,§ Takao Yamamoto,‡ Nobuhiro Yamamoto,‡
Hirofumi Ishikawa,‡ Keiko Nakano,§ Naoko Unami,‡ Kaori Hamada,‡ Yasuhiro Matsumura, Fujiko Takamura, and
Kouji Hattori*,†
Chemistry Research Laboratories, Pharmacological Research Laboratories, Applied Pharmacology Research Laboratories, and Analysis and
Pharmacokinetic Research Laboratories, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
ReceiVed October 22, 2007
A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have
been identified as potent and selective human ꢀ3 adrenergic receptor (ꢀ3-AR) agonists with good oral
bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal
phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position
improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading
candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds
10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such
as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing
with ꢀ3-AR agonists.
Introduction
cal differences between rodent and human receptors.8 Thus, a
second generation of orally bioavailable human ꢀ3-AR agonists
with minimal side effects associated with activation of human
ꢀ1- and ꢀ2-ARs has been an important goal of recent research.
The availability of appropriate human receptors has given rise
to the design and synthesis of a second generation of ꢀ3-AR
agonists with high potency and good selectivity with respect to
human ꢀ1- and ꢀ2-ARs as exemplified by the potent and selective
ꢀ3-AR agonists LY377604 (5),9 L796568 (6),10 and Solabegron
(7),11 as shown in Figure 2. These compounds were evaluated
in Chinese hamster ovary (CHO) cells expressing the cloned
human ꢀ3-AR.
ꢀ-Adrenergic receptors (ꢀ-ARsa) have been subclassified into
three types; ꢀ1-, ꢀ2-, and ꢀ3 -ARs.1 The ꢀ3-AR has been
demonstrated to mediate various pharmacological and physi-
ological effects such as lipolysis in white adipocytes and
thermogenesis (energy expenditure) in brown tissue adipocytes.2
Recent studies have indicated that, in addition to adipocytes,
the ꢀ3-AR is also distributed in human urinary bladder detrusor
tissue and its relaxation occurs mainly via ꢀ3-ARs.3–6 Therefore,
activators of the ꢀ3-AR are now recognized as potential drugs
for not only the treatment of obesity and noninsulin dependent
(type II) diabetes, but also overactive bladder (OAB). On the
other hand, the concomitant activation of ꢀ1- or ꢀ2-ARs would
lead to undesirable side effects, such as increased heart rate and/
or muscle tremors. Thus, ꢀ3-AR selectivity over ꢀ1-AR and ꢀ2-
AR has been required for new therapeutic agents.
Early ꢀ3 agonists (the “first generation” of potent and selective
rat ꢀ3-AR agonists), such as BRL37344 (1), CL316243 (2),
aminobegron (3), and FK175 (4), as shown in Figure 1, have
been reported to be effective antiobesity and antidiabetic agents
in rodents. Unfortunately, BRL37344 (1), CL316243 (2), and
other ꢀ3-AR agonists discovered during the 1980s were unsuc-
cessful in the clinic, either because of a lack of efficacy or an
unfavorable cardiovascular side-effect profile and poor phar-
macokinetics.7 The clinical failure of “first generation” ꢀ3-AR
agonists has been attributed to a lack of sufficient ꢀ3-AR potency
and ꢀ1-AR and ꢀ2-AR selectivities resulting from pharmacologi-
In the past decade, drug discovery efforts have shifted toward
the design of selective agonists for the ꢀ3-AR. Though several
groups have reported a number of potent and selective human
ꢀ3-AR agonists, many problems remain in terms of the phar-
macokinetic properties of these agonists.12 For example, a highly
potent and selective human ꢀ3-AR agonist L796568 (6) was
discovered by the Merck group, but it showed moderate to low
oral bioavailability in preclinical evaluation (rats, F ) 17%;
dogs, F ) 27%; monkeys, F ) 4%).10 Consequently, recent
efforts in this field have been directed mainly toward optimiza-
tion to discover orally bioavailable ꢀ3-AR agonists. Recently,
researchers at GlaxoSmithKline explored a series of aniline-
based biphenyl ꢀ3-AR agonists and identified potent, selective,
11
and orally bioavailable compounds. Solabegron (7), which
is currently in phase II clinical trials, displayed good oral
bioavailability in all species tested (rats, F ) 30%; dogs, F )
43%; monkeys, F ) 46%), while it also displayed a relatively
poor pharmacokinetic half-life in all species tested (t1/2,i.v.: rats,
2.1 h; dogs, 3.3 h; monkeys, 4.5 h). Because in the field of
treatment of urinary bladder dysfunction there is an unmet
medical need for a once daily oral administration (due to
compliance issues), an agent that possesses the pharmacokinetic
properties required for once daily oral administration is required
to meet these growing (due to an aging population) medical
needs. Therefore, we initiated a search for effective therapeutic
candidates against OAB, which have the following profile: (1)
* To whom correspondence should be addressed. Phone: 81-29-863-7179.
Fax: 81-29-852-5387. E-mail: kouji.hattori@jp.astellas.com.
†
Chemistry Research Laboratories.
Pharmacological Research Laboratories.
Applied Pharmacology Research Laboratories.
‡
§
Analysis and Pharmacokinetic Research Laboratories.
a Abbreviations: ꢀ-AR, ꢀ-adrenergic receptor; OAB, overactive bladder;
SAR, structure–activity relationship; RHS, right-hand side; cAMP, cyclic
adenosine monophosphate; ISP, isoproterenol; CHO, Chinese hamster ovary;
IVP, intravesical pressure; PAMPA, parallel artificial membrane permeation
assay.
10.1021/jm701324c CCC: $40.75
2008 American Chemical Society
Published on Web 02/29/2008

1926 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Imanishi et al.
Figure 1. Chemical structure of first generation of ꢀ3-AR agonists.
Figure 2. Chemical structure of second generation of ꢀ3-AR agonists.
Figure 3. Discovery process of lead generation and lead optimization.
potent human ꢀ3-AR agonist activity, (2) good selectivity over
ꢀ1- and ꢀ2-ARs, (3) good oral bioavailability, and (4) long
duration.
further optimization of the lead compound to improve potency
and selectivity led to identification of compounds 10a and 10e
as clinical drug candidates. The synthesis of these compounds,
the results of in vitro and cassette dosing assay, and the profiles
of our drug candidates 10a and 10e are described in detail in
the following sections.
In our laboratory, our first clinical candidate, FK175 (4),
having a carboxylic ester functionality (pro-drug form) in the
right-hand side (RHS) in Figure 1, showed good selectivity over
human ꢀ1 and ꢀ2-ARs and good oral absorption in phase I
clinical trials. However, it was still insufficient in terms of
potency of the ꢀ3-AR activity and long duration for OAB
treatment. To overcome these problems, we planned a discovery
process for novel ꢀ3-AR agonists as shown in Figure 3. We
initially intended to introduce a carboxylate group on the RHS
because introduction of a carboxylate group may contribute to
good oral absorption. As well as with FK175, several groups
have reported the importance of a carboxylic group on the RHS
of ethanolamine analogues for the subtype selectivity of ꢀ3-
AR agonists, as shown in Figure 1.13,14 Next, to enhance
potency, we incorporated a biaryl scaffold as a core structure
on the RHS, because L796568, LY374604, and solabegron,
containing a biaryl template on the RHS, have been reported to
be highly potent human ꢀ3-AR agonists, as shown in Figure 2.
We investigated the structure–activity relationship (SAR) and
pharmacokinetic properties of an extensive series of compounds
8, employing a cassette dosing assay by in vivo dog pharma-
cokinetic assay to generate the desired lead compound with high
oral bioavailability and long plasma half-life because the phase
1 study of FK175 indicated that the pharmacokinetic profile
was similar in humans and dogs, as shown in Table 5. Next,
Chemistry
The requisite intermediate Boc amine derivatives 16–22
containing the (3-chlorophenyl) ethanol moiety were prepared,
as shown in Scheme 1. Boc amine derivatives (16a-c, 18, 19,
and 20) were synthesized by coupling of commercially available
(1R)-2-amino-1-(3-chlorophenyl) ethanol (11) with phenylacetic
acid derivatives 12–15 to produce amide derivatives in good
yield, followed by selective reduction of the amide with
15
BH3 ·SMe2 followed by protection of the amine with a Boc
group. Trifluoromethanesulfonamide derivatives 17a-c were
obtained from selective protection of the phenol 16a-c with
Tf2O/2,6-lutidine in CH2Cl2 at low temperature. Aniline 21 was
prepared from nitro derivative 20 by reduction with Fe and
NH4Cl, followed by reductive amination with formaldehyde to
give N-Me 22, as shown in Scheme 1. Similarly, intermediate
25 containing the phenyl ethanol moiety was synthesized by
coupling of commercially available (R)-(-)-mandelic acid 23
with 4-bromophenyl ethylamine 24 to produce amide derivative
in good yield, followed by selective reduction of the amide with
BH3 ·SMe2 to give the unmasked amino ethanol hydrochloride,
followed by protection of the amine with a Boc group. Benzyl

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1927
Scheme 1. Preparation of Left and Center Part Intermediatesa
a Reagents and conditions: (a) HOBt, WSCD, N,N-DMF; (b) BH3 ·SMe2, THF, 6 N aq HCl, then (Boc)2O, aq NaOH (pH ) 7–8); (c) Tf2O, 2,6-lutidine,
CH2Cl2, -70°C; (d) Fe (powder), NH4Cl, EtOH, reflux; (e) 35% HCHO, NaBH(OAc)3, AcOH, CH2Cl2; (f) PhCHO, p-TsOH, toluene, reflux then NaBH4,
MeOH, room temp; (g) EtOH, reflux; (h) TBSCl, imidazole, N,N-DMF.
amine intermediate 28 was prepared by reductive amination of
4-bromo-phenylethyl amine 14 with benzaldehyde, followed by
coupling with (2R)-2-(3-chlorophenyl)oxirane 26. The secondary
alcohol of 28 was protected as a TBS ether to produce 29, as
shown in Scheme 1.
CH2Cl2 to give coupling products (42–44).17 Deprotection of
the silyl ether group in 42–44, followed by coupling with tert-
butyl bromoacetate gave Boc amine derivatives (47–49).
Removal of the Boc and tert-butyl ester functionalities using 4
N HCl in dioxane provided the final targets (8a-c) as hydro-
chloride salts. Similarly, compound 8f was prepared from Boc
amine silyl ether 45, and compound 8g was prepared from
phenol 46. Boc amine silyl ether 45 was synthesized via
lithiation of bromide 41 with n-BuLi at low temperature,
followed by coupling with Weinreb amide 36. Phenol 46 was
prepared by Suzuki coupling of bromide 18 with 4-OTBS-
phenylboronic acid, followed by deprotection of the silyl phenol
ether group. The preparation of the final target 8d is shown in
Scheme 4. The bromide intermediate 27 was lithiated with
n-BuLi at low temperature, followed by reaction with 4-OTBS-
benzaldehyde to give benzyl methanol 52. Deprotection of the
TBS groups with n-Bu4NF in THF, followed by catalytic
hydrogenation in the presence of chlorobenzene, to avoid
removal of the 3-chlorine atom on the benzene ring, produced
the benzyl phenol 54. Protection of the secondary amine in 54
with a Boc group followed by coupling with tert-butyl bro-
moacetate gave 56, and the compound 8d was prepared from
56 under acidic conditions. The biphenyl ether and aniline
analogues (8k-n) were obtained by coupling of phenol 16a or
aniline 21 with commercially available phenylboronic acids with
Cu(OAc)2 and MS 4 Å in CH2Cl2, followed by alkaline
hydrolysis and deprotection of the Boc group. The pyridine ether
8q was obtained through nucleophilic displacement of com-
mercially available chloro-pyridine with phenol 16a, followed
by alkaline hydrolysis and deprotection of the Boc group as
shown in Scheme 4.
As shown in Scheme 2, the requisite intermediate phenyl-
boronic acids (31a-g and 34a-g) were synthesized from the
corresponding bromide or triflate via boronic ester, followed
by hydrolysis of the pinacol ester group with NaIO4.16 The cross-
coupling reaction of bromide (30a-d, 33a-g) proceeded
smoothly in the presence of a catalytic amount of PdCl2 (PPh3)2,
while the reaction of triflate (30e-g) proceeded with a catalytic
amount of PdCl2 (dppf)·CHCl3. Noncommercially available
trisubstituted benzoic acid methyl ester analogues (33a-j) were
prepared from the commercially available 4-bromo-2-fluoroben-
zoic acid 32 by nucleophilic displacement with sodium alkoxide,
sulfide, amine, and Grignard reagent. The other requisite right
part intermediate Weinreb amide 36 was prepared from 4-hy-
droxybenzoic acid 35.
The general synthetic route to biphenyl targets (8h-j, 9a-h,
10a-j) is shown in Scheme 3. Boc amine derivatives (17a-c,
18, 19, 25) were coupled with phenylboronic acid derivatives
to give biphenyl coupling products. Alkaline hydrolysis of ester
followed by deprotection of the Boc group gave the biphenyl
target compounds. The target 8p was obtained by Suzuki
coupling followed by selective oxidation of aldehyde, followed
by deprotection of the Boc group. Similarly, targets 10k-n are
prepared from coupling products 37–40. The coupling products
(37, 38, 40) were synthesized from the corresponding trisub-
stituted phenyl bromide derivatives 33h-j via boronic ester,
followed by coupling with bromide intermediate 18. Sulfone
derivative 39 was obtained from selective oxidation of sulfide
38 with m-CPBA in CH2Cl2.
The synthesis of pyridyl analogue 8o is shown in Scheme 5.
N-Benzyl amine 27 was protected with a Boc group to give 57.
Conversion of the bromide intermediate 57 to boronic acid 58,
followed by coupling with commercially available ethyl 6-chlo-
ronicotinate, afforded biaryl compound 59. Removal of the Boc
group with HCl and then coupling with oxirane 26 in the
The phenoxy acetic acid analogues (8a-c,f,g) listed in Table
1 were prepared as shown in Scheme 4. Boc amine derivatives
(16a, 40, 41) were coupled with commercially available
4-TBSO-phenylboronic acid with Cu(OAc)2 and MS 4 Å in

1928 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Scheme 2. Preparation of Boric Acid Intermediates and 36a
Imanishi et al.
a Reagents and conditions: (a) KOAc, pinacol diborane, PdCl2 (PPh3)2, dioxane, 100 °C; (b) KOAc, pinacol diborane, PdCl2 (dppf)-CHCl3, dioxane,
100 °C; (c) NaIO4, NH4OAc, acetone, H2O; (d) NaH, alcohol or thiol, N,N-DMF, then MeI, K2CO3, N,N-DMF; (e) i-BuMgCl (2 M in THF), then MeI,
K2CO3, N,N-DMF; (f) i-PrNH2, pyridine, 100°C, then MeI, K2CO3, N,N-DMF; (g) HN(OMe)Me, HOBt, WSCD, N,N-DMF; (h) TBSCl, imidazole, N,N-DMF.
presence of Et3N gave N-benzyl derivative 60. Conversion of
the benzyl group to the Boc group compound 61, followed by
alkaline hydrolysis and subsequent deprotection of the Boc
group, afforded target compound 8o. Target compound 8e was
prepared from phenol 63. This compound was prepared by
coupling of (2R)-2-(3-chlorophenyl)oxirane 26 in the presence
of BSA with biphenyl sulfide 62 as has previously been
described.18
ꢀ3-AR agonist activity than 8a but similarly poor selectivity.
Likewise, the replacement of the oxygen with other linker groups
(Table 1, 8c-f) resulted in insufficient potency for ꢀ3 and
selectivity for ꢀ1. However, the biphenyl analogue 8g showed
an improvement of potency for ꢀ3 and good selectivity for ꢀ1
relative to 8a. Next, these compounds (8b-g) were evaluated
in the cassette dosing assay.19 The Cmax and AUC ratio value
of 8a are presented as 1.0 for comparison in Table 1. The
methylene and sulfide analogues 8d (ClogP ) 2.39) and 8e
(ClogP ) 2.70) exhibited better properties than 8a (ClogP )
2.42) at the Cmax and AUC level. On the other hand, the NH,
NMe, and carbonyl analogues 8b (ClogP ) 2.0), 8c (ClogP )
2.36), 8f (ClogP ) 1.67) resulted in decreased Cmax and AUC
levels relative to 8a. In particular, the carbonyl analogue 8f
showed Cmax level. Although the biphenyl analogue 8g (ClogP
) 2.21) showed a slightly lower Cmax ratio than 8a, and it
showed a comparable AUC level to 8a.
Because the biphenyl analogue 8g exhibited moderate in vitro
potency and PK profiles, we investigated the effect of modifica-
tion of the carboxylic acid moiety of 8g. The phenylacetic acid
analogue 8h showed slightly less ꢀ3-AR activity than 8g;
however, the benzoic acid analogue 8i had improved ꢀ3-AR
activity (EC50 ) 6.7 nM) and selectivity (ꢀ1/ꢀ3 ) 42, ꢀ2 EC50
> 10000 nM). The shift of the acid substituent to the meta
position 8j resulted in less potency relative to 8i, suggesting
that the position of the carboxylic acid in these biphenyl
analogues is important for ꢀ3-AR activity and selectivity.
Furthermore, the benzoic acid analogue 8i showed a drastic
improvement in Cmax and AUC ratio relative to 8g. The
pharmacokinetic parameters of this compound are shown in
Table 2. Compound 8i possessed lower clearance (CL ) 4.0
mL/min/kg) and displayed excellent oral bioavailability (F >
Results and Discussion
All compounds were evaluated for the ability to produce
cAMP in Chinese hamster ovary (CHO) cell lines expressing
cloned human ꢀ3- and ꢀ1-ARs. Selected compounds were also
evaluated for human ꢀ2 activity using a similar method. The
results for reference compounds, isoproterenol (ISP; nonselective
ꢀ-AR agonist) and FK175 (4), are shown for comparison in
Table 1. Pharmacokinetic (PK) properties of selected compounds
19
were evaluated by cassette dosing assay in dogs.
To assess the quality of biaryl phenoxy acetic acid analogues
as potent, selective ꢀ3-AR agonists with good oral absorption,
we first investigated the effect of the biphenyl junction (Table
1, 8a-g). As a baseline, biphenyl ether 8a was initially prepared
and characterized. While 8a showed moderate agonistic activity
for the ꢀ3-AR, it also displayed strong ꢀ1-AR activity and,
therefore, a low ꢀ1/ꢀ3 selectivity (ꢀ2-AR activity was not tested).
Furthermore, 8a was evaluated in the in vivo PK assay (p.o.
and i.v.) in dogs. The PK parameters are presented in Table 2.
Compound 8a showed moderate oral bioavailability (F ) 39%),
low clearance, and a moderate plasma half-life (t1/2 ) 4.7 h,
i.v).
We next performed initial SAR work on replacement of the
oxygen and found that the NH junction analogue 8b has stronger

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1929
Scheme 3. General Synthesis Route of Biphenyl Analoguesa
a Reagents and conditions: (a) Pd(PPh3)4, aq NaHCO3, DME, 70°C; (b) 1 N NaOH aq, EtOH or MeOH, then 4 N HCl/AcOEt or dioxane; (c) 30% H2O2,
80% NaClO2, MeCN, 40–50 °C, then 4 N HCl/dioxane; (d) KOAc, pinacol diborane, PdCl2 (PPh3)2, dioxane, 90–100 °C; (e) m-CPBA, CH2Cl2.
95%) and a long plasma half-life (t1/2 ) 12.3 h, i.v.) in Table
2. In consideration of the superior PK profile of 8i compared
to 8a and 8g, the benzoic acid moiety may contribute to the
improvement of PK properties. We attempted to utilize the
benzoic acid moiety with the biphenyl ether derivative 8a. As
expected, biphenyl ether derivatives 8k and 8l showed superior
Cmax and AUC ratio relative to the original compound 8a.
Indeed, benzoic acid analogue 8k possessed a lower clearance
(8o, 8p) resulted in decreased Cmax and AUC levels relative to
8i. Finally, the pyridine-ether analogue 8q, with a similar RHS
part to LY377604, was prepared and examined. For ꢀ3-AR
activity, 8q showed stronger potency than the phenyl ether
analogue 8k and a moderate PK profile but a substantial loss
of ꢀ1/ꢀ3 selectivity.
The results of preliminary SAR work and cassette dosing
assay led to the generation of lead compound 8i with an
excellent PK profile. Next, we focused our attention on further
optimization of the biphenyl analogue 8i, in which substituents
were introduced at the biphenyl ring to further improve in vitro
profile and to keep the good PK profile, as shown in Table 3.
First, we examined the effect of substituents at the R1 position
(9a-d). The methyl analogue 9a showed less potency and
maintained selectivity compared with 8i. Introduction of a
(CL ) 4.1 mL/min/kg) and a longer plasma half-life (t1/2
)
6.2 h, i.v.) relative to the corresponding phenoxy acetic acid
analogue 8a and showed acceptable oral bioavailability (F )
40%) in Table 2. However, the para- and meta-substituted 8k
and 8l did not have improved ꢀ3-AR activity compared to 8a.
In addition, the NH junction analogues (para, 8m; meta, 8n)
resulted in good potency for ꢀ3 but insufficient selectivity for
ꢀ1/ꢀ3. Next, we investigated replacement of the terminal phenyl
ring of the biphenyl analogue 8i with typical heterocycles.
Pyridine analogue 8o showed a 5-fold decrease in ꢀ3-AR
potency and a dramatic decrease in ꢀ1/ꢀ3 selectivity relative to
8i. Thiophene analogue 8p maintained ꢀ3-AR potency and
somewhat decreased ꢀ1/ꢀ3 selectivity than 8i. These data
suggested that introduction of a polar group such as pyridine
may cause reduction in ꢀ3-AR activity and ꢀ1/ꢀ3 selectivity. In
addition, cassette dosing assay of these heterocycle analogues
fluorine atom resulted in somewhat lower activity (9b, EC50
)
9.8 nM) and equal selectivity (ꢀ1/ꢀ3 ) 39), while chloro
analogue 9c was less potent than 8i. However, methoxy analogue
9d maintained potency (EC50 ) 4.8 nM) and slightly improved
selectivity (ꢀ1/ꢀ3 ) 52). Next, the effect of substituents at the
R2 position were examined. Introduction of the methyl group
(9e) provided stronger ꢀ3-AR activity (EC50 )1.8 nM), while
selectivity for ꢀ1/ꢀ3 decreased somewhat compared with 8i.
Fluoro and chloro analogues 9f and 9g showed good ꢀ3-AR

1930 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Table 1. SAR of Biaryl Analogues
Imanishi et al.
cassette assayc (p.o.)
cmpd
X
R
human ꢀ3 EC50,a nM (IA)b
human ꢀ1 EC50,a nM
ꢀ1/ꢀ3
Cmax ratiod
AUC ratioe
8a
8b
8c
8d
8e
8f
8g
8h
8i
O
p-OCH2CO2H
p-OCH2CO2H
p-OCH2CO2H
p-OCH2CO2H
p-OCH2CO2H
p-OCH2CO2H
p-OCH2CO2H
p-CH2CO2H
p-CO2H
m-CO2H
p-CO2H
m-CO2H
p-CO2H
48 ( 4 (0.72)
12 ( 2 (1.1)
37
9.2 ( 0.5
63
1.3
1.0
1.0
NH
NMe
CH2
S
CdO
bond
bond
bond
bond
O
0.77
<0.63
1.6
>1.1
>1.6
>5.5
9.4
42
>1
>1
>2.6
0.85
6.7
0.33
27
0.16
>200
0.087
0.42
0.37
1.39
1.66
0.05
0.69
NT
3.26
NT
2.11
2.89
NT
0.54
0.33
1.26
1.83
0.05
0.93
NT
6.83
NT
2.84
5.15
NT
NT
1.4
1.9
0.99
NT
>100 (0.45)
39 (0.66)
85 ( 2 (0.58)
61 (0.69)
64
>100
>100
>100
300
280 ( 40
>100
>100
>100
3.9
18 ( 2 (0.97)
32 ( 1 (0.81)
6.7 ( 0.3 (0.96)
91 ( 5 (0.53)
100 (0.51)
39 ( 1 (0.64)
4.6 ( 0.7 (0.97)
5.5 ( 0.4 (0.97)
33 ( 0.6 (0.79)
7.5 ( 0.4 (0.86)
8.7 ( 0.8 (0.90)
16 ( 2.0 (0.98)h
0.97 ( 0.1 (1.0)
8j
8k
8l
O
NH
NH
8m
8n
m-CO2H
36 ( 0.6
11
NT
8of
0.89
0.70
1.04
NT
8pf
200 ( 8.8
1.4
8qf
4 (FK175)g
ISP
>3200h
0.084 ( 0.02
NT
NT
a The results are shown as the mean ( SE (ng3) or are presented as the average of two experiments. b The intrinsic activity (IA) was defined as the ratio
between the maximal effect of test compound and the maximal effect produced by ISP (isoproterenol; 10-7 M). c Dose 0.32 or 1.0 mg/kg p.o. (n ) 2). See
references and notes19 for further details. d The ratio was defined between the Cmax of test compounds and the Cmax of 8a. The ratio value of 8a was
f
presented as 1.0. e The ratio was defined between the AUC of test compounds and the AUC of 8a. The ratio value of 8a was presented as 1.0.
g Data for the carboxylic acid form of FK175; NT ) not tested. h Results are the mean ( SE of five experiments.
activity but less selectivity than 8i. Furthermore, methoxy
analogue 9h showed 10-fold increased ꢀ3-AR activity (EC50
654) compared with the lead compound 8i. More lipophilic and
bulky substitutions, such as isobutyl (10b, ClogP ) 3.92) and
cyclohexyl (10c, ClogP ) 4.49) analogues resulted in further
improvement in ꢀ3-AR potency (10b, EC50 ) 0.59 nM; 10c,
EC50 ) 0.46 nM). The alkyl isobutyl-substituted analogue 10d
(ClogP ) 3.81) also displayed high potency and selectivity
(EC50 ) 0.54 nM, ꢀ1/ꢀ3 > 1850), suggesting that lipophilicity
and bulk at the R1 position might contribute to improvement in
ꢀ3-AR potency and selectivity for ꢀ1/ꢀ3. Furthermore, these
compounds 10a–10d were evaluated in the cassette dosing assay
in dogs. The Cmax ratio value of 8i is presented as 1.0 for
comparison in Table 4. The O-isopropyl analogue 10a had a
1.7-fold less Cmax ratio relative to the lead compound 8i.
Surprisingly, the O-isobutyl (10b), O-cyclohexyl (10c), and
isobutyl (10d) analogues resulted in dramatically decreased Cmax
levels, and especially 10b and 10c led to a complete loss of
Cmax, in spite of enhancing passive permeability data in
PAMPA.20
)
0.62 nM) compared to 8i. However, 9h has strong ꢀ1-AR
activity (EC50 ) 18 nM) and resulted in insufficient selectivity
for ꢀ1/ꢀ3. We next examined the effect of substituents at the R3
position of the central phenyl ring. The chloro and methoxy
analogues 9i and 9j were less potent and had greatly lowered
ꢀ1 selectivity. From the results of the SAR study, compounds
9d and 9e were selected and evaluated in a cassette dosing assay
in dogs because these compounds showed a good combination
of potency and moderate selectivity for ꢀ1/ꢀ3. Methoxy and
methyl analogues 9d and 9e retained a Cmax ratio relative to
the lead compound 8i (Cmax ratio: 8i ) 1.0, 9d ) 0.96, 9e )
0.87). Furthermore, 9d and 9e were evaluated in PK assay and
showed good pharmacokinetic profiles in dog (9d: t1/2,i.v. ) 7.1 h,
CL ) 4.9 mL/min/kg, F ) 58%; 9e: t1/2,i.v. ) 19.3 h, CL ) 2.1
mL/min/kg, F ) 40%, data not shown).
Comparison of the substituted biphenyl analogues in Table
3 indicated that the order of their potency was R2 > R1 > R3
and selectivity for ꢀ1/ꢀ3 was R1 > R2 > R3. These results
suggest that R2-substituted analogues might tend to be strong
for ꢀ1-AR. On the other hand, R1-substituted analogues may
tend to decrease the ꢀ1-AR activity (compare 9d vs 9h).
Therefore, our attention was focused on further exchange of
R1 substituents to improve potency and selectivity.
On the basis of these data, we attempted to adjust lipophilicity
of the molecules in this series by removal of the chloro atom
on the phenyl ring in the left-hand side (LHS) to keep oral
absorption. As shown in Table 4, O-i-Pr analogue 10e main-
tained ꢀ3-AR activity (EC50 ) 2.0 nM), selectivity, and Cmax
ratio relative to the corresponding chloro phenyl analogue (10a).
More lipophilic R1 ) O-i-Bu (10f, ClogP ) 3.20) and R )
O-c-hex (10g, ClogP ) 3.78) analogues relative to O-i-Pr group
(10e, ClogP ) 2.58), as expected, showed higher ꢀ3-AR activity
(10f, EC50 ) 0.81 nM; 10g, EC50 ) 0.30 nM) and good
selectivity compared with 8i. Unfortunately, in the cassette
dosing assay, the O-i-Bu (10f), O-c-hex (10g), and isobutyl (10i)
analogues resulted in dramatically decreased Cmax levels com-
pared with the O-i-Pr analogue 10e. Likewise, the O-phenyl
Initially, the effect of introduction of more lipophilic and/or
bulky substitution on the R1 position was examined, as shown
in Table 4. Replacement of the methoxy group (9d, ClogP )
2.46) with an isopropyl group at the R1 position resulted in
compound 10a having more lipophilicity (10a, ClogP ) 3.30)
and bulk, and resulted in a 6-fold increased potency (10a, EC50
) 1.1 nM) and a dramatic improvement in selectivity (ꢀ1/ꢀ3 )

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1931
Scheme 4. General Synthesis Route of Biaryl Analoguesa
a Reagents and conditions: (a) TBSCl, imidazole, N,N-DMF; (b) Cu(OAc)2, MS 4 Å, CH2Cl2; (c) BuLi (1.59 M in hexane), THF, -70 °C, 41; (d)
Pd(PPh3)4, aq NaHCO3, DME, 70 °C; (e) Bu4NF (1 N in THF), THF; (f) BrCH2CO2t-Bu, K2CO3, N,N-DMF; (g) 4 N HCl/dioxane; (h) HCl, 10% Pd/C,
EtOH, chlorobenzene; (i) (Boc)2O, THF, H2O; (j) 1 N NaOH aq, EtOH or MeOH, then 4 N HCl/AcOEt or dioxane; (k) K2CO3, DMSO, 80 °C.
(10h, ClogP ) 3.71) and isobutyl-substituted analogues (10i,
ClogP ) 3.09) resulted in high potency (10h, EC50 ) 0.34 nM;
10i, EC50 ) 0.60 nM) and good selectivity, while Cmax levels
decreased compared with 10e. These results showed the same
trends of SAR and Cmax levels as 3-chlorophenyl analogues
(10a-d) and phenyl analogues (10e-10i). Although these
compounds (10c, 10g, 10i) showed high passive permeability
in PAMPA, Cmax levels of these compounds were poor. We
next introduced an O-ethoxy ethyl group (10j) to reduce
lipophilicity (10j, ClogP ) 2.02) relative to O-i-Pr analogue
10e. As a result, O-ethoxy ethyl analogue 10j showed 2-fold
decreased potency (EC50 ) 4.3 nM), however, Cmax levels of
10j were improved relative to 10e. Tetrahydropyran analogue
10k, having reduced lipophilicity and maintaining the bulky size
relative to the corresponding O-c-hex analogue 10g, resulted
in 10-fold lower ꢀ3-AR activity relative to 10g and a poor Cmax
level. It was suggested that the lipophilicity at the R1 position
contributes to the strong ꢀ3-AR potency but not the bulky size.
We next turned our attention to the junction part of the
O-i-Pr group. Replacing the oxygen of 10e with a sulfur atom
yielded compound 10l, which displayed good activity (EC50
) 0.56 nM) and selectivity relative to 10e, but with a poor
Cmax level. Sulfone analogue 10m (ClogP ) 1.62), designed
to reduce the lipophilicity relative to 10e, retained activity
and good selectivity compared with 10e, but showed a low
Cmax level. The amino junction analogue 10n, having
increased lipophilicity (10n, ClogP ) 3.35) relative to 10e,
provided a greater improvement in ꢀ3-AR potency (EC50
)
0.29 nM) and good selectivity; however, the Cmax level was
decreased. Finally, we investigated the removal of the
carboxylic acid group of 9d. Actually, compound 10o21
resulted in a substantial loss of potency for ꢀ3 and selectivity
of ꢀ1/ꢀ3 relative to 9d, and the Cmax level was poor.
After SAR examination and study with the cassette dosing
assay, we selected 10a and 10e as potential candidates
because they showed a good combination of potency and
selectivity for ꢀ1- and ꢀ2-AR activity compared with lead
compound 8i and FK175. To confirm their PK profiles, 10a
and 10e were evaluated in a PK assay (p.o. and i.v.). Table
522 shows pharmacokinetic data in rats, dogs and monkeys
for 10a, 10e, and FK175. Compound 10a possessed a low
clearance in all three species (rats, 4.4 mL/min/kg; dogs, 4.9

1932 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Scheme 5. Synthesis Route of 8e and 8oa
Imanishi et al.
a Reagents and conditions: (a) (Boc)2O, THF; (b) KOAc, pinacol diborane, PdCl2 (PPh3)2, dioxane, 90–100 °C; (c) NaIO4, NH4OAc, acetone, H2O; (d)
Pd(PPh3)4, aq NaHCO3, DME, 70 °C; (e) 4 N HCl/dioxane, then Et3N, 20, EtOH, reflux; (f) HCl, 10% Pd/C, EtOH, chlorobenzene, then (Boc)2O, aq NaOH
(pH ) 7–8), THF; (g) 1 N NaOH aq, EtOH, then 4 N HCl/dioxane; (h) BSA, DMSO, 80 °C; (i) (Boc)2O, THF, H2O; (j) BrCH2CO2t-Bu, K2CO3, N,N-DMF;
(k) 4 N HCl/dioxane.
Table 2. Pharmacokinetic Profiles of Compounds 8a, 8i, and 8k in Dogsa
p.o.
i.v.
cmpd
dose (mg/mL)
Cmax (ng/mL)
AUC0–24 h (ng·hr/mL)
dose (mg/mL)
T1/2ꢀ (hr)
CLtot (mL/min/kg)
F (%)b
8a
8i
8k
1.0
0.32
1.0
118.9
110.7
236.1
869.7
1976.1
2469.9
0.1
0.1
0.1
4.7
12.3
6.2
6.4
4.0
4.1
39
>95
40
a Cassette assay data, n ) 2. The results are presented as the average of two experiments. b F ) bioavailability.
Table 3. SAR of Substituted Biphenyl Analogues
cmpd
R1
R2
R3
human ß3 EC50,a nM (IA)b
human ꢀ1 EC50,a nM
ꢀ1/ꢀ3
human ꢀ2 EC50,a nM
8i
H
Me
F
Cl
OMe
H
H
H
H
H
H
H
H
H
H
Me
F
Cl
OMe
H
H
H
H
H
H
H
H
H
6.7 ( 0.3 (0.96)
15 ( 1 (0.82)
9.8 ( 0.1 (0.85)
17 ( 0.3 (0.87)
4.8 ( 0.4 (0.99)
1.8 ( 0.1 (0.99)
4.9 ( 1 (0.87)
2.0 (0.96)
280 ( 40
570 ( 60
380 ( 29
260 ( 5.7
251 ( 26
63 ( 8
20 ( 0.3
30
42
38
39
15
52
35
4
15
29
0.32
0.54
>10000
NT
NT
9a
9b
9c
9d
9e
9f
9g
9h
9i
NT
>10000
>10000
NT
NT
NT
H
Cl
OMe
0.62 (0.97)
9.7 (0.92)
12 (0.90)
18
3.1
6.5
NT
NT
9j
H
H
a The results are shown as the mean ( SE (ng3) or presented as the average of two experiments. b The intrinsic activity (IA) was defined as the ratio
between the maximal effect of test compound and the maximal effect produced by isoproterenol (10-7 M).
mL/min/kg; monkeys, 0.9 mL/min/kg) and a long plasma
half-life in dogs (9.8 h) and monkeys (18.6 h). Oral
bioavailability for 10a was moderate to high in all three
species (rats, 61%; dogs, 45%; monkeys, 83%). Compound
10e possessed both low clearance and a long plasma half-
life in all three species (t1/2,i.v., rats, 9.5 h; dogs, 14.5 h;
monkeys, 22.2 h; CL, rats, 7.5 mL/min/kg; dogs, 4.8 mL/
min/kg; monkeys, 1.4 mL/min/kg). Compound 10e also
displayed good oral bioavailability in all three species (rats,
F ) 80%; dogs, F ) 68%; monkeys, F ) 62%). In
comparison with FK175, biphenyl benzoic acid analogues
10a and 10e displayed great improvement in not only oral
bioavailability in rats and monkeys but also plasma half-life
in all three species, which might contribute to their lower
total clearance.
Furthermore, compounds 10a and 10e did not shown
significant inhibitory activity of the major liver enzymes
CYP1A2, CYP3A4, CYP2D6, CYP2C9, and CYP2C19 (IC50
> 10µM). In liver microsomes, 10a and 10e showed good
stability to human and all other species in terms of in vitro
clearance (Table 6). These results indicate that 10a and 10e
are predicted to display a good PK profile with a once daily
dosing (u.i.d.) in humans.
Next, we examined the inhibitory effect of compounds 10a
and 10e on carbachol-induced increase of intravesical pressure
(IVP) in anesthetized dogs for OAB model, in comparison with
the effect of FK175. Before conducting in vivo experiments,
we confirmed the in vitro potency of 10a and 10e for not only
human ꢀ3-AR activity, but also dog ꢀ3-AR activity in CHO cell
lines. As shown in Table 7, both 10a and 10e showed more

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1933
Table 4. SAR of Substituted Biphenyl Analogues
a The results are shown as the mean ( SE (ng3) or presented as the average of two experiments. b The intrinsic activity (IA) was defined as the ratio
between the maximal effect of test compound and the maximal effect produced by isoproterenol (10-7 M). c Dose 0.10 or 0.20 mg/kg p.o. (n ) 2–3). d The
f
ratio was defined between the Cmax of test compounds and the Cmax of 8i. The ratio value of 8i was presented as 1.0. e See ref 20.
g Data for the carboxylic acid form of FK175. h Results are the mean ( SE of five experiments; NT ) not tested.
potent dog and human ꢀ3-AR activity relative to FK175. On
the other hand, in the in vivo experiment, intraduodenally
administered 10a and 10e reduced the IVP in a dose-dependent
manner with the ED50 and EC50 values listed in Table 7,
respectively, and these efficacies were significantly improved
compared with FK175. The improvement of in vitro potency
led to an increase in in vivo efficacy. As shown in Figure 4,
intraduodenally administered 10e inhibited the IVP increase in
a dose-dependent manner with a long duration of action. This
in vivo result was first demonstrated with ꢀ3-AR agonists as an

1934 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Imanishi et al.
Table 5. Pharmacokinetic Profiles of Compound 10a, 10e, and FK175a
p.o., (n ) 3)
i.v., (n ) 2–3)
T1/2ꢀ (hr)
cmpd
10a
species
dose (mg/kg)
Cmax (ng/mL)
AUC0–24 h (ng·hr/mL)
dose (mg/kg)
CLtot (mL/min/kg)
Fb (%)
c
rat
0.32
0.1
0.32
0.32
0.2
146 ( 51
13.0 ( 1.1
171 ( 59
94.7 ( 12
25.0 ( 1.8
185 ( 86
38
700 ( 19
149 ( 8.7
4980 ( 1200
565 ( 23
438 ( 45
209 ( 65
83
0.32
0.1
0.32
0.32
0.1
0.186
0.83
0.83
0.83
NT
4.8
4.4
61
45
83
80
68
62
29
73
35
dog
monkey
rat
dog
monkey
rat
9.9 ( 0.4
18.6 ( 2.3
9.5
14.5 ( 1.9
22.2 ( 4.0
0.3
1.63
2.28 ( 0.45
NT
4.9 ( 0.6
0.9 ( 0.2
7.5
4.8 ( 0.4
1.4 ( 0.1
47.9
3.7
11.8 ( 0.8
NT
c
c
10e
0.32
1.0
d
4 (FK175)
dog
3.2
2070
10600
monkey
human
1.0
1.0
184 ( 22
1340 ( 300
398 ( 46
4100 ( 800
e
a The results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. b F ) bioavailability. c Cassette assay data. d All
parameters were calculated from the mean plasma concentration of the carboxylic acid form of FK175. The dose of 0.83 mg/kg the carboxylic acid form of
FK175 was equivalent to 1 mg/kg FK175. e The results are shown as the mean ( SD (n ) 8)., NT: Not tested.
Table 6. In Vitro Metabolism in Liver Microsomes CLint (mL/min/
kg)a,b
for not only potency and selectivity but also good pharmaco-
kinetic properties (Table 4, and compare 9d vs 10o). Further-
more, we investigated the effect of substituents on the terminal
phenyl ring of lead compound (8i) and have discovered that
the lipophilicity at the R1 position contributes to the high potency
and selectivity. Although some of the most potent and selective
compounds (e.g., 10b-d, 10f-i, 10l, 10n) showed poor Cmax
levels, compounds 10a and 10e, with the best balance of
potency, selectivity, and pharmacokinetic profile, were identified
and selected as the leading candidates. In PK assay, compounds
10a and 10e displayed good oral bioavailability and long plasma
half-lives in all three species. Furthermore, in an OAB model,
10a and 10e exhibited a carbachol-induced increase of IVP in
our dog model. As a result of these studies, 10a and 10e were
identified as clinical candidates with a superior balance of
potency, selectivity, and pharmacokinetic profiles relative to our
previous clinical candidate FK175. These findings suggest that
10a and 10e could be attractive therapeutic candidates for the
treatment of OAB.
cmpd
10a
rat
dog
monkey
human
NT
<1.0
NT
<1.0
NT
<1.0
<1.0
18.2 ( 1.4
10e
N.D.c
106 ( 5.8
N.D.c
4 (FK175)d
35.4 ( 3.4
a Each compound was incubated at 37 °C with live microsomes from
rats, dogs, monkeys, and humans in the presence of the NADPH-generating
system. b The results are shown as the mean ( SE (n ) 3). c N.D. ) not
determined (<0.1 mL/min/kg). d Data for the carboxylic acid form of
FK175; NT ) not tested.
Table 7. Inhibitory Effect of Intraduodenal Administration of 10a,e and
FK175 on the Increase in IVP (intravesical pressure) Induced by
Carbachol in Anesthetized Dogsa
in vitro (n ) 3)
dog ꢀ3 EC50, nM (IA)b
in vivo (n ) 2–3)
ED50 (µg/kg) EC50 (ng/mL)
cmpd
10a
10e
1.0 ( 0.17 (0.99)
2.9 ( 0.4 (0.97)
30 ( 9 (0.91)c,d
20.6
25.9 ( 4.6
270 ( 12
6.9
8.40 ( 1.5
4 (FK175)
137 ( 6.2c
a The results are shown as the mean ( SE (n ) 3) or presented as the
average of two experiments. b The intrinsic activity (IA) was defined as
the ratio between the maximal effect of test compound and the maximal
effect produced by isoproterenol (10-7 M). c Data for the carboxylic acid
form of FK175. d Results are the mean ( SE of five experiments.
Experimental Section
Chemistry. General Methods. Reactions involving air- or
moisture-sensitive reagents were carried out under a nitrogen
atmosphere. If not specified, reactions were carried out at ambient
temperature. Silica gel (Kanto Chemical, 63-210 µm) was used for
chromatographic purification, unless otherwise indicated. Anhydrous
solvents were obtained from commercial sources. 1H NMR spectra
were recorded on a Brucker Biospin Avance400 or DPX200. Values
in ppm relative to tetramethylsilane are given. The following
abbreviations are used to describe peak patterns when appropriate:
b ) broad, s ) singlet, d ) doublet, t ) triplet, q ) quartet, m )
multiplet. High resolution mass spectra were recorded with Mi-
cromass LCT. Chemical purity was given by HPLC analysis with
a Shiseido capcell pack C18 column (detection at 254 nm). Results
of elemental analysis were recorded with Perkin-Elmer 2400II and
were within 0.4% of the theoretical values calculated for C, H,
and N.
tert-Butyl-2-(4-hydroxyphenyl)ethyl[(2R)-2-(3-chlorophenyl)
-2-hydroxyethyl]carbamate (16a). Typical Procedure A. To a
mixture of 4-hydroxyphenylacetic acid 12a (2.4 g, 15.8 mmol),
(1R)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride 11 (3.0 g,
17.5 mmol), and 1-hydroxybenzotriazole (2.14 g, 17.4 mmol) in
N,N-DMF (20 mL) was added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide (2.46 g, 17.4 mmol), and the mixture was stirred
at room temperature for 2 h. The mixture was partitioned between
ethyl acetate and water. The organic layer was separated, washed
successively with NaHCO3 solution and brine, dried over MgSO4,
and evaporated under reduced pressure to give an amide product.
ToaTHF(30mL)solutionoftheproduct,2Mboran-dimethylsulfide
complex in THF (23 mL) was added at room temperature, and the
mixture was refluxed for 30 min. To the mixture, 6 N HCl (29.5
mL) was added dropwise below 10 °C, and the mixture was stirred
Figure 4. Time course of inhibitory effect of intraduodenal administra-
tion of 10e on the increase in IVP (intravesical pressure) induced by
carbachol in anesthetized dogs. Values are mean ( SE of n ) 3.
OAB model. From these results, it is thus expected that 10a
and 10e may be effective in clinical use against OAB.
Conclusions
Replacement of the biphenyl junction and carboxylic acid
moiety on the RHS part of the biaryl template afforded lead
compound (8i) with high oral availability and a long plasma
half-life. Importantly, our results suggested that the biphenyl
template and the benzoic acid moiety on the RHS are essential

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1935
at room temperature for 3 h. To the reaction mixture, 3 N aqueous
NaOH solution (58 mL) below 10 °C was added, and di-tert-butyl
dicarbonate (3.46 g, 17.4 mmol) was added portionally at room
temperature. The pH value was kept between 7 and 8 by using 1
N aqueous NaOH solution. The mixture was stirred at room
temperature for 1 h. The mixture was partitioned between EtOAc
and water. The organic layer was separated, washed with brine,
dried over MgSO4, and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel
(hexane/EtOAc )4/1–2/1) to give 5.5 g (97%) of the title
compound. 1H NMR (200 MHz, CDCl3): δ 1.45 (s, 9H), 2.66 (m,
2H), 3.25–3.49 (m, 4H), 4.70 (br, 1H), 4.79–4.87 (m, 1H), 5.49 (s,
1H), 6.74 (d, 2H, J ) 8 Hz), 6.98 (d, 2H, J ) 8 Hz), 7.21–7.31
(m, 3H), 7.34 (s, 1H). MS (ES) m/e: 414 (M+ Na).
4-(2-{(tert-Butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydro-
xyethyl]amino}ethyl)phenyl Trifluoromethanesulfonate (17a). To
a solution of 16a (5.0 g, 12.6 mmol) and 2,6-lutidine (2.97 mL,
25.5 mmol) in CH2Cl2 (75 mL) was added Tf2O (2.36 mL, 14.0
mmol) dropwise at -70 °C under nitrogen, and the mixture was
stirred at -70 °C for 30 min. The mixture was allowed to warm to
room temperature and evaporated under reduced pressure. The
residue was partitioned between EtOAc and water. The organic
layer was separated, washed with saturated Na2CO3 solution and
brine, dried over MgSO4, and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 3/1) to give 6.6 g (99%) of the title compound.
1H NMR (200 MHz, CDCl3): δ 1.43 (s, 9H), 2.76 (m, 2H),
3.20–3.42 (m, 4H), 4.35 (br, 1H), 4.88 (br, 1H), 7.20–7.29 (m, 7H),
7.37 (s, 1H). MS (ES) m/e: 546 (M+ Na).
layer was separated, washed with saturated Na2CO3 solution and
brine, dried over MgSO4, and evaporated under reduced pressure
to give 3.0 g (85%) of the title compound. H NMR (200 MHz,
CDCl3): δ 1.47 (s, 9H), 2.63–2.69 (m, 2H), 3.17–3.43 (m, 4H),
3.57 (s, 2H), 4.63 (s, 1H), 4.81-4.83 (m, 1H), 6.60–6.63 (m, 2H),
6.89–6.91 (m, 2H), 7.21–7.28 (m, 3H), 7.34 (s, 1H). MS (ES) m/e:
391 (M+ H).
1
tert-Butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]{2-[4-
(methylamino)phenyl]ethyl}carbamate (22). To a solution of 21
(1.75 g, 4.48 mmol) and formaldehyde (37% w/w solution in water,
390 µL, 4.8 mmol) in 1,2-dichloroethane (20 mL) was added
NaBH(OAc)3 (1.23 g, 5.8 mmol), and the mixture was stirred at
room temperature for 18 h under a nitrogen atmosphere. The
resulting mixture was poured into a mixture of 1 N NaOH and
CHCl3, and the mixture was stirred for 20 min. The organic layer
was separated, washed with brine, dried over MgSO4, and evapo-
rated under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane/EtOAc ) 2/1) to give 550
1
mg (30%) of the title compound. H NMR (200 MHz, CDCl3): δ
1.47 (s, 9H), 2.62–2.69 (m, 2H), 2.81 (s, 3H), 3.20–3.44 (m, 4H),
4.68–4.71 (m, 1H), 4.81–4.84 (m, 1H), 6.56 (d, 2H, J ) 8 Hz),
6.89–6.97 (m, 2H), 7.24–7.31 (m, 3H), 7.34 (s, 1H). MS (ES) m/e:
417 (M+ H).
tert-Butyl[2-(4-bromophenyl)ethyl][(2R)-2-hydroxy-2-phenyl-
ethyl]carbamate (25). To a mixture of (R)-(-)-mandelic acid 23
(23.7 g, 156 mmol), [2-(4-bromophenyl)ethyl]amine 24 (29.7g, 148
mmol), and 1-hydroxybenzotriazole (21.1g, 156 mmol) in N,N-
DMF (210 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide (30.0 g, 156 mmol), and the mixture was stirred at room
temperature for 16 h. The mixture was partitioned between ethyl
acetate and water. The organic layer was separated, washed
successively with 1 N aqueous HCl solution, 15% aqueous K2CO3
solution, and brine, dried over MgSO4, and evaporated under
reduced pressure to give an amide product (49.5 g, 99.8%). To a
solution of the product (49.5 g) in THF (150 mL) and DMI (150
mL) was added 1 M boran-dimethylsulfide complex in THF (470
mL) dropwise under an ice bath, and the mixture was refluxed for
3 h and cooled to about 5 °C. To the mixture, MeOH (35 mL) was
added carefully below 10 °C, followed by the addition of concd
HCl (60 g), and the mixture was stirred at room temperature for
1 h, refluxed for 1 h, and then evaporated. To the residue was added
30% aqueous K2CO3 solution (350 mL) under an ice bath. The
resulting mixture was extracted with EtOAc (600 mL × 2), and
the organic layers were washed with water and brine, dried over
MgSO4, and evaporated under reduced pressure. To the residue was
added i-PrOH (200 mL) and concd HCl (40 mL), and the mixture
was stirred at room temperature for 16 h. The resultant solid was
collected by filtration, washed with i-PrOH, and dried to give 51.6 g
(98%) of (1R)-2-{[2-(4-bromophenyl)ethyl]amino}-1-phenylethanol
hydrochloride as a white solid. 1H NMR (200 MHz, DMSO-d6): δ
2.96–3.19 (m, 6H), 4.97–5.04 (m, 1H), 7.21–7.57 (m, 9H), 8.95
(br, 1H), 9.41 (br, 1H). MS (ES) m/e: 320, 322 (M+ H).
To the mixture of the obtained product (7.6 g, 21.3 mmol) in
THF (30 mL) and water (30 mL) was added 3 N aqueous NaOH
solution (7.5 mL), and the mixture was stirred for 10 min (pH ≈
8.3). To the mixture was added di-tert-butyl dicarbonate (5.1 g,
23.4 mmol) portionally at room temperature. The pH value was
kept between 7 and 8 by using 3 N aqueous NaOH solution. The
mixture was stirred at room temperature for 1 h. The mixture was
partitioned between EtOAc and water. The organic layer was
separated, washed with brine, dried over MgSO4, and evaporated
under reduced pressure to give 8.9 g (99%) of the title compound.
1H NMR (200 MHz, CDCl3): δ 1.44 (s, 9H), 2.68 (m, 2H),
3.26–3.45 (m, 4H), 4.20 (br, 1H), 4.88–4.91 (m, 1H), 6.97–7.01
(m, 2H), 7.24–7.41 (m, 7H).
4-(2-{(tert-Butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydro-
xyethyl]amino}ethyl)-2-chlorophenyl Trifluoromethanesulfonate
(17b). Compound 17b was synthesized from 11 and 3-chloro(4-
hydroxyphenyl)acetic acid 12b according to the procedure described
for the conversion of 11 to 17a (84%). 1H NMR (200 MHz, CDCl3):
δ 1.43 (s, 9H), 2.72 (m, 2H), 3.35–3.50 (m, 4H), 4.32 (br, 1H),
+
4.89 (br, 1H), 7.19–7.38 (m, 7H). MS (ES) m/e: 581 (M Na).
4-(2-{(tert-Butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydro-
xyethyl]amino}ethyl)-2-methoxyphenyl
Trifluoromethane-
sulfonate (17c). Compound 17c was synthesized from 11 and
3-methoxy(4-hydroxyphenyl)acetic acid 19c according to the
procedure described for the conversion of 11 to 17a (88%). 1H
NMR (200 MHz, CDCl3): δ 1.43 (s, 9H), 2.76 (m, 2H), 3.20–3.42
(m, 4H), 4.35 (br, 1H), 4.88 (br, 1H), 7.20–7.29 (m, 7H). MS (ES)
+
m/e: 576 (M Na).
tert-Butyl[2-(4-bromophenyl)ethyl][(2R)-2-(3-chlorophenyl)-
2-hydroxyethyl]carbamate (18). Compound 18 was synthesized
from 11 using 4-bromophenylacetic acid 13 according to the
1
procedure A (91%). H NMR (200 MHz, CDCl3): δ 1.44 (s, 9H),
2.69 (m, 2H), 3.15–3.45 (m, 4H), 4.47 (br, 1H), 4.82–4.92 (m, 1H),
6.95–7.04 (m, 2H), 7.21–7.29 (m, 4H), 7.34–7.39 (m, 2H).
tert-Butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-
iodophenyl)ethyl]carbamate (19). Compound 19 was synthesized
from 11 using 4-iodophenylacetic acid 14 according to the
1
procedure A (94%). H NMR (200 MHz, CDCl3): δ 1.45 (s, 9H),
2.66 (m, 2H), 3.14–3.42 (m, 4H), 4.51 (br, 1H), 4.80–4.91 (m, 1H),
6.86 (d, 2H, J ) 8 Hz), 7.20–7.28 (m, 3H), 7.36 (s, 1H), 7.60 (d,
2H, J ) 8 Hz). MS (ES) m/e: 524 (M+ Na).
tert-Butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-
nitrophenyl)ethyl]carbamate (20). Compound 20 was synthe-
sized from 11 using 4-nitrophenylacetic acid 15 according to the
1
procedure A (93%). H NMR (200 MHz, CDCl3): δ 1.44 (s, 9H),
2.85 (m, 2H), 3.25–3.45 (m, 4H), 4.20 (br, 1H), 4.91 (br, 1H),
7.25–7.31 (m, 5H), 7.37 (s, 1H), 8.15 (d, 2H, J ) 4 Hz).
tert-Butyl[2-(4-aminophenyl)ethyl][(2R)-2-(3-chlorophenyl)-
2-hydroxyethyl]carbamate (21). To a solution of 20 (3.8 g, 9.0
mmol) in a mixed solution of EtOH (10 mL) and water (3.3 mL)
were added iron powder (1.51 g, 27.0 mmol) and NH4Cl (241 mg,
N-Benzyl-2-(4-bromophenyl)ethanamine (27). To a solution
of 2-(4-bromophenyl)ethanamine 24 (9.72 g, 48.6 mmol) in toluene
(100 mL) were added benzaldehyde (4.94 mL, 48.6 mmol) and
p-toluenesulfonic acid monohydrate (462 mg, 2.43 mmol), and the
mixture was refluxed for 4 h, while water was removed as a toluene
azeotrope. After cooling to room temperature, the solvent was
4.5 mmol). The solution was refluxed for
3 h. After
cooling to room temperature, the precipitate was filtered through a
pad of Celite. After concentrating under reduced pressure, the
residue was partitioned between EtOAc and water. The organic

1936 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Imanishi et al.
removed by evaporation to give a yellow solid. The solid was
dissolved in MeOH (100 mL) and cooled to 5 °C. To the solution
was added NaBH4 (1.84 g, 48.6 mmol) portionwise at 5 °C over 5
min. After stirring at the same temperature for 45 min, the mixture
was poured into water and extracted with EtOAc. The combined
extracts were washed with water and brine and dried over MgSO4.
Filtration followed by evaporation gave a yellow oil. The residue
was purified by column chromatography on silica gel (MeOH/
4-(Methoxycarbonyl)-2-methoxyphenylboronic Acid (31e).
Typical Procedure C. A procedure similar to procedure B was
followed except that the Pd-catalyst was PdCl2(dppf)·CHCl3.
Procedure C was employed using with methly-3-methoxy-4-
{[(trifluorpmethyl)sulfonyl]oxy}benzoate 30e (1.52 g, 4.84 mmol)
and PdCl2(dppf)·CHCl3 (120 mg, 0.147 mmol) to give 450 mg
1
(43%) of the title compound. H NMR (200 MHz, DMSO-d6): δ
3.85 (s, 3H), 3.91 (s, 3H), 7.43 (s, 1H), 7.53 (d, J ) 7.5 Hz, 1H),
7.57 (d, J ) 7.5 Hz, 1H), 7.96 (s, 2H). MS (ES) m/e: 209 (M- H).
[2-Fluoro-4-(methoxycarbonyl)phenyl]boronic Acid (31f). Com-
pound 31f was synthesized from methyl 3-fluoro-4-[[(trifluorom-
ethyl)sulfonyl]oxy]benzoate 30f according to the procedure C
(71%). 1H NMR (200 MHz, DMSO-d6): δ 3.87 (s, 3H), 7.50–7.82
(m, 3H), 8.47 (br s, 2H). MS (ES) m/e: 197 (M- H).
1
CHCl3 ) 3/97) to give 10.5 g (74%) of the title compound. H
NMR (200 MHz, CDCl3): δ 2.72–2.92 (m, 4H), 3.79 (s, 2H),
6.93–7.10 (m, 2H), 7.23–7.43 (m, 6H). MS (ES) m/e: 290 and 292
(M+ H).
(1R)-2-{Benzyl[2-(4-bromophenyl)ethyl]amino}-1-(3-chloro-
phenyl)ethanol (28). A solution of 27 (13.5 g, 46.5 mmol) in EtOH
(270 mL) was added (2R)-2-(3-chlorophenyl)oxirane 26 (8.63 g,
55.8 mmol), and the solution was refluxed for 48 h. After cooling
to room temperature, the solvent was removed by evaporation and
the residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 9/1) to give 18.6 g (90%) of the title compound.
1H NMR (400 MHz, CDCl3): δ 2.58 (dd, J ) 10, 13 Hz, 1H),
2.68–2.89 (m, 5H), 3.56 (d, J ) 13 Hz, 1H), 3.92 (d, J ) 13 Hz,
1H), 4.59 (dd, J ) 3.4, 10 Hz, 1H), 6.97 (d, J ) 8.3 Hz, 2H),
7.21–7.40 (m, 12H). MS (ES) m/e: 444 and 446 (M+ H).
(2R)-N-Benzyl-N-[2-(4-bromophenyl)ethyl]-2-{[tert-butyl-
(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethanamine (29). Com-
pound 29 was synthesized from 28 according to the procedure
described for the conversion of 18 to 41 (90%). 1H NMR (400
MHz, CDCl3): δ 0.15 (s, 6H), 1.01 (s, 9H), 2.72–2.82 (m, 5H),
2.92 (dd, J ) 5.9, 13 Hz, 1H), 3.75 (d, J ) 13.7 Hz, 1H), 3.86 (d,
J ) 13.7 Hz, 1H), 4.71 (t, J ) 6.2 Hz, 1H), 7.01 (d, J ) 8.3 Hz,
2H), 7.26–7.47 (m, 9H), 7.48 (d, J ) 8.3 Hz, 2H). MS (ES) m/e:
558 and 560 (M+ H).
[4-(methoxycarbonyl)-2-methylphenyl]boronic acid (31a).
Typical procedure B. To a solution of methyl-4-bromo-3-meth-
ylbenzoate 30a (7.7 g, 31.4 mmol) in dioxane (154 mL) was added
bis(pinacolate)diboron (8.6g, 31.4 mmol), PdCl2(PPh3)2 (298 mg,
0.42 mmol), and KOAc (9.2 g, 94.2 mmol), and the mixture was
stirred at 100 °C for 2–6 h under nitrogen. The mixture was diluted
with EtOAc and water. The organic layer was separated, washed
with brine, dried over MgSO4, and evaporated. The residue was
purified by column chromatography on silica gel (hexane/EtOAc
) 5/1) to give 8.77 g (94%) of methyl-3-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. 1H NMR (200 MHz,
CDCl3): δ 1.35 (s, 12H), 2.57 (s, 3H), 3.91 (s, 3H), 7.79–7.82 (m,
3H). MS (ES) m/e: 299 (M + Na). To a suspension of the above
product (8.76 g, 29.4 mmol) in acetone (175 mL) and water (175
mL) was added NH4OAc (5.1g, 66.2 mmol) and NaIO4 (14.2g, 66.4
mmol), and the mixture was stirred at room temperature for 15 h.
The solvent was evaporated, and the residue was diluted with
EtOAc. The organic layer was separated, washed with water and
brine, dried over MgSO4, and evaporated under reduced pressure
to give 5.0 g (81%) of the title compound as a white solid. 1H
NMR (200 MHz, DMSO-d6): δ 2.44 (s, 3H), 3.84 (s, 3H), 7.52 (d,
J ) 8.0 Hz, 1H), 7.70 (d, J ) 8.0 Hz, 1H), 7.72 (s, 1H), 8.24 (s,
2H). MS (ES) m/e: 193 (M- H).
[2-Chloro-4-(methoxycarbonyl)phenyl]boronic Acid (31 g).
Compound 31g was synthesized from methyl 3-chloro-4-
{[(trifluoromethyl)sulfonyl]oxy}benzoate 30g according to the
1
procedure C (17%). H NMR (200 MHz, DMSO-d6): δ 3.87 (s,
3H), 7.56 (d, J ) 8.0 Hz, 1H), 7.81–7.86 (m, 2H), 8.53 (s, 2H).
MS (ES) m/e: 213 (M- H).
Methyl 4-Bromo-9-isobutoxybenzoate (33c). Typical
Procedure D. To a suspension of NaH (60% w/w, 20.5 g, 2.25
equiv) in N,N-DMF (365 mL) was added 2-methyl-1-propanol (48.7
mL, 2.3 equiv) dropwise below 30 °C over 2.0 h under nitrogen
atmosphere. To the mixture was added 4-bromo-2-fluorobenzoic
acid 32 (50.0 g, 228 mmol) slowly below 35 °C. To the reaction
mixture was added N,N-DMF (600 mL), and the mixture was stirred
at room temperature for 1–4 days. The reaction mixture was
partitioned between water (2000 mL) and hexane (1000 mL). The
water layer was separated and acidified with 37% HCl (pH ) 2.50).
The precipitate was collected by filtration, washed with water, and
dried to give 4-bromo-2-isobutoxybenzoic acid (62.4 g, 86%) as a
1
white solid. H NMR (200 MHz, CDCl3): δ 1.10 (d, J ) 6.5 Hz,
6H), 2.17–2.31 (m, 1H), 4.02 (d, J ) 6.5 Hz, 2H), 7.20 (s, 1H),
7.28 (d, J ) 8.0 Hz, 1H), 8.05 (d, J ) 8.0 Hz, 1H). To a solution
of the above product (14.0 g, 51 mmol) in N,N-DMF (70 mL) was
added K2CO3 (14.2 g, 2.0 equiv) and MeI (4.79 mL, 1.5 equiv).
The mixture was stirred at room temperature for 1.0 h. The reaction
mixturewasfilteredandthefiltratewasextractedwithEtOAc-hexane
(1/1, 600 mL) and washed with water (500 mL). The water layer
was extracted with ethyl EtOAc-hexane (1/1, 200 mL), and the
extract was washed with water (200 mL). The combined organic
layer was washed with brine and dried over MgSO4. Filtration
followed by evaporation under reduced pressure to give 12.0 g
1
(81%) of the title compound as a pale yellow oil. H NMR (200
MHz, CDCl3): δ 1.06 (d, J ) 6.5 Hz, 6H), 2.07–2.21 (m, 1H),
3.78 (d, J ) 6.5 Hz, 2H), 3.88 (s, 3H), 7.08 (s, 1H), 7.10 (d, J )
8.0 Hz, 1H), 7.67 (d, J ) 8.0 Hz, 1H). MS (ES) m/e: 309, 311(M+
Na).
Methyl 4-Bromo-2-methoxybenzoate (33a). Compound 33a
was synthesized from 32 and methanol according to the procedure
1
D (89%). H NMR (200 MHz, CDCl3): δ 3.88 (s, 3H), 3.91 (s,
3H), 7.10–7.15 (m, 2H), 7.68 (d, J ) 8.5 Hz, 1H). MS (ES) m/e:
267, 269(M+ Na).
Methyl 4-Bromo-2-isopropoxybenzoate (33b). Compound 33b
was synthesized from 32 and 2-propanol according to the procedure
[4-(Methoxycarbonyl)-3-methylphenyl]boronic Acid (31b).
Compound 31b was synthesized from methyl 4-bromo-2-methyl-
benzoate 30b according to the procedure B (76%). 1H NMR (200
MHz, DMSO-d6): δ 2.57 (s, 3H), 3.91 (s, 3H), 7.36 (d, J ) 8.0
Hz, 1H), 7.51–7.63 (m, 2H), 8.26 (s, 2H). MS (ES) m/e: 193 (M-
H).
[2-Fluoro-4-(methoxycarbonyl)phenyl]boronic Acid (31c). Com-
pound 31c was synthesized from methyl 4-bromo-2-fluorobenzoate
30c according to the procedure B (82%). 1H NMR (200 MHz,
DMSO-d6): δ 3.85 (s, 3H), 7.59–7.93 (m, 3H), 8.45 (br s, 2H).
MS (ES) m/e: 197 (M- H).
[3-Chloro-4-(methoxycarbonyl)phenyl]boronic Acid (31d).
Compound 31d was synthesized from methyl 4-bromo-2-chlo-
robenzoate 30d according to the procedure B (70%). 1H NMR (200
MHz, DMSO-d6): δ 3.86 (3H, s), 7.73–7.81 (m, 2H), 7.90 (s, 1H),
8.46 (2H, s). MS (ES) m/e: 213 (M- H).
1
D (85%). H NMR (200 MHz, CDCl3): δ 1.38 (d, J ) 6.0 Hz,
6H), 3.88 (s, 3H), 4.50–4.63 (m, 1H), 7.09 (d, J ) 8.0 Hz, 1H),
7.12 (s, 1H), 7.68 (d, J ) 8.0 Hz, 1H).
Methyl 4-Bromo-2-(cyclohexyloxy)benzoate (33d). Compound
33d was synthesized from 32 and cyclohexanol according to the
procedure D (84%). 1H NMR (200 MHz, CDCl3): δ 1.36–1.95 (m,
10H), 3.88 (s, 3H), 4.31–4.39 (m, 1H), 7.06–7.12 (m,2H), 7.64 (d,
J ) 8.0 Hz, 1H).
Methyl 4-Bromo-2-isobutylbenzoate (33f). Under nitrogen, to
a solution of 4-bromo-2-fluorobenzoic acid 32 (6 g, 27.4 mmol) in
THF (48 mL) was added 2 M i-BuMgCl in THF (41 mL) dropwise
on an ice bath. The mixture was stirred at room temperature for
2 h. To the mixture, water (100 mL) was added dropwise below
10 °C, and the mixture was acidified with 1 N HCl (pH ) 2–3)
and extracted with EtOAc (100 mL × 2). The combined organic

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1937
layers were washed with water and brine, dried over MgSO4, and
evaporated under reduced pressure to give a crude 4-bromo-2-
isobutylbenzoic acid (6.45 g, 25.1 mmol). To a solution of the above
product in N,N-DMF (52 mL) was added K2CO3 (5.3 g, 38.3 mmol)
and MeI (2.05 mL, 32.9 mmol). The mixture was stirred at room
temperature for 4 h. The mixture was partitioned between EtOAc
and water. The organic layer was separated, washed with water
and brine, dried over MgSO4, and evaporated. The residue was
purified by column chromatography on silica gel (hexane/EtOAc
) 10/1) to give 3.4 g (46%) of the title compound. 1H NMR (200
MHz, CDCl3): δ 0.90 (d, J ) 6.5 Hz, 6H), 1.84 (m, 1H), 2.82 (d,
J ) 7.0 Hz, 2H), 3.87 (s, 3H), 7.36 (s, 1H), 7.38 (d, J ) 8.0 Hz,
1H), 7.73 (d, J ) 8.0 Hz, 1H).
Methyl 4-Bromo-2-(2-ethoxyethoxy)benzoate (33g). Com-
pound 33g was synthesized from 32 and 2-ethoxyethanol according
to the procedure D (85%). 1H NMR (200 MHz, CDCl3): δ 1.13 (t,
J ) 6.0 Hz, 3H), 3.52 (q, J ) 6.0 Hz, 2H), 3.70 (m, 2H), 3.88 (s,
3H), 4.25 (m, 2H), 7.08 (s, 1H), 7.10 (d, J ) 8.0 Hz, 1H), 7.67 (d,
J ) 8.0 Hz, 1H).
[3-(Cyclohexyloxy)-4-(methoxycarbonyl)phenyl]boronic Acid
(34d). Compound 34d was synthesized from 33d according to the
procedure B (58%). 1H NMR (200 MHz, DMSO-d6): δ 1.32–1.91
(m, 10H), 3.78 (s, 3H), 4.42–4.49 (m, 1H), 7.36 (d, J ) 8.0 Hz,
1H), 7.52 (s, 1H), 7.54 (d, J ) 8.0 Hz, 1H), 8.25 (s, 2H). MS (ES)
m/e: 277 (M- H).
[3-(Phenoxy)-4-(methoxycarbonyl)phenyl]boronic
Acid
(34e). Compound 34e was synthesized from the corresponding
bromide according to the procedure B (59%). MS (ES) m/e: 271
(M- H).
[3-Isobutyl-4-(methoxycarbonyl)phenyl]boronic Acid (34f).
Compound 34f was synthesized from 33f according to the procedure
B (63%). 1H NMR (200 MHz, DMSO-d6): δ 0.84 (d, J ) 6.5 Hz,
6H), 1.70–1.84 (m, 1H), 2.77 (d, J ) 7.0 Hz, 2H), 3.82 (s, 3H),
7.68–7.74 (m, 1H), 7.74 (s, 1H), 7.78–7.81 (m, 1H), 8.21 (s, 2H).
MS (ES) m/e: 235 (M- H).
[3-(2-Ethoxyethoxy)-4-(methoxycarbonyl)phenyl]boronic Acid
(34 g). Compound 34g was synthesized from 33g according to the
1
procedure B (84%). H NMR (200 MHz, DMSO-d6): δ 1.12 (t, J
) 6.0 Hz, 3H), 3.54 (q, J ) 6.0 Hz, 2H), 3.65 (m, 2H), 3.80 (s,
3H), 4.29 (m, 2H), 7.37 (d, J ) 8.0 Hz, 1H), 7.52 (s, 1H), 7.61 (d,
J ) 8.0 Hz, 1H), 8.26 (s, 2H). MS (ES) m/e: 267 (M- H).
4-{[tert-Butyl(dimethyl)silyl]oxy}-N-methoxy-N-methyl Ben-
zamide (36). To a mixture of 4-hydroxybenzoic acid 35 (5.0 g, 36.2
mmol), N-methoxymethanamine (2.87 g, 47 mmol), and 1-hydroxy-
benzotriazole (4.9 g, 36.2 mmol) in CH2Cl2 (120 mL) and N,N-
diisopropylethylamine (7.0 mL, 40 mmol) was added 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (6.9 g, 36.2 mmol) at
4 °C, and the mixture was stirred at room temperature for 16 h.
The mixture was partitioned between CH2Cl2 and water. The
organic layer was separated, washed successively with water and
brine, dried over MgSO4, and evaporated under reduced pressure
to give an amide product (3.2 g, 49%). To a solution of the above
product (800 mg, 4.41 mmol) and imidazole (330 mg, 4.85 mmol)
in N,N-DMF (8 mL) was added tert-butyl(dimethyl)silyl chloride
(670 mg, 4.45 mmol), and the mixture was stirred at room
temperature for 18 h. The mixture was partitioned between EtOAc
and water. The organic layer was separated, washed with 1 N aq
NaOH and brine, dried over MgSO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane/EtOAc ) 3/1) to give 860 mg (66%) of the title
Methyl 4-Bromo-2-(tetrahydro-2H-pyran-4-yloxy)benzoate
(33h). Compound 33h was synthesized from 32 and tetrahydro-
2H-pyran-4-ol according to the procedure D (86%). 1H NMR (200
MHz, CDCl3): δ 1.81–2.06 (m, 4H), 3.57–3.68 (m, 2H), 3.89 (s,
3H), 3.93–4.05 (m, 2H), 4.56–4.62 (m, 1H), 7.11 (s, 1H), 7.13 (d,
J ) 8.0 Hz, 1H), 7.67 (d, J ) 8.0 Hz, 1H). MS (ES) m/e: 337, 339
(M+ Na).
Methyl 4-Bromo-2-(isopropylsulfanyl)benzoate (33i). Com-
pound 33i was synthesized from 32 and 2-propanthiol according
to the procedure D (85%). 1H NMR (200 MHz, CDCl3): δ 1.27 (d,
J ) 6.5 Hz, 6H), 3.63–4.76 (m, 1H), 3.81 (s, 3H), 7.46 (d, J ) 8.5
Hz, 1H), 7.62 (s, 1H), 7.73 (d, J ) 8.5 Hz, 1H).
Methyl 4-Bromo-2-(isopropylamino)benzoate (33j). To a solu-
tion of 4-bromo-2-fluorobenzoic acid 32 (2 g, 9.14 mmol) in
pyridine (10 mL) was added isopropylamine (3.88 mL, 45.6 mmol)
at room temperature, and the mixture was stirred at 100 °C
overnight. The mixture was poured into 1 N aqueous hydrochloric
acid and extracted with ethyl acetate. The organic layer was washed
with brine, dried over magnesium sulfate, and evaporated. The
residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate ) 2/1) to give 4-bromo-2-(isopropylami-
no)benzoic acid (436 mg,18.5%) as a white solid. MS (ES) m/e:
450 (M- H).
To a suspension of the above product (428 mg, 1.66 mmol) and
potassium carbonate (480 mg, 3.47 mmol) in N,N-dimethylforma-
mide (9 mL) was added methyl iodide (0.16 mL, 2.6 mmol) at
room temperature, and the mixture was stirred at the same
temperature for 1 h. To the mixture was added water and extracted
with mixed solvent (n-hexane/ethyl acetate ) 1/1). The organic
layer was washed with brine, dried over magnesium sulfate, and
evaporated to give 423 mg (93.6%) of the title compound. 1H NMR
(200 MHz, CDCl3): δ 1.27 (d, J ) 6.2 Hz, 6H), 3.62–3.71 (m,
1H), 3.84 (s, 3H), 6.64 (dd, J ) 8.5, 1.9 Hz, 1H), 6.83 (d, J ) 1.8
Hz, 1H), 7.70–7.75 (m, 2H).
1
compound. H NMR (200 MHz, CDCl3): δ 0.22 (s, 6H), 0.99 (s,
9H), 3.35 (s, 3H), 3.56 (s, 3H), 6.84 (d, J ) 8.5 Hz, 2H), 7.64 (d,
J ) 8.5 Hz, 2H). MS (ES) m/e: 318 (M+ Na).
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
4′-biphenyl-4-carboxylic Acid Hydrochloride (8i). Typical
Procedure E. To a solution of 17a (435 mg, 0.96 mmol) in 1,2-
dimethoxyethane (6 mL) were added 4-methoxycarbonylphenyl
boronic acid (224 mg, 1.24 mmol), Pd(PPh3)4 (55 mg, 0.048 mmol),
and an aqueous solution of Na2CO3 (2 M, 1.0 mL), and the mixture
was stirred at 70 °C for 2–5 h under nitrogen. The mixture was
diluted with EtOAc and water. The organic layer was separated,
washed with brine, dried over MgSO4, and evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (hexane/EtOAc ) 3/1–2/1) to give 330 mg (67%)
of methyl-4′-(2-{(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-
hydroxyethyl]- amino}ethyl)-1,1′-biphenyl-4-carboxylate. 1H NMR
(200 MHz, CDCl3): δ 1.45 (s, 9H), 2.75–2.85 (m, 2H), 3.34–3.45
(m, 4H), 3.94 (s, 3H), 4.54 (br, 1H), 4.86–4.90 (m, 1H), 7.17–7.28
(m, 5H), 7.37 (s, 1H), 7.56 (d, J ) 8.0 Hz, 2H), 7.63 (d, J ) 8.0
Hz, 2H), 8.09 (d, J ) 9.0 Hz, 2H). MS (ES) m/e: 532 (M+ Na).
Typical Procedure F. To a solution of the obtained product (320
mg, 0.63 mmol) in EtOH or MeOH (2 mL) was added 1 N aq
NaOH (1.0 mL, 1.5–2.0 equiv), and the mixture was stirred at
40 °C for 2–4 h. The solvent was removed by evaporation, and the
aqueous solution was acidified with 1 N aq HCl and extracted with
EtOAc or CHCl3. The combined organic layers were washed with
water and brine, dried over MgSO4, and evaporated under reduced
pressure to give a benzoic acid product. To a solution of the product
in dioxane or EtOAc (2.0 mL) was added 4 N HCl in dioxane or
EtOAc (2.0 mL, 10–15 equiv), and the mixture was stirred at room
[3-Methoxy-4-(methoxycarbonyl)phenyl]boronic Acid (34a). Com-
pound 34a was synthesized from 33a according to the procedure
B (80%). 1H NMR (200 MHz, DMSO-d6): δ 3.78 (s, 3H), 3.88 (s,
3H), 7.40 (d, J ) 7.5 Hz, 1H), 7.57 (d, J ) 7.5 Hz, 1H), 7.58 (s,
1H), 8.29 (s, 2H). MS (ES) m/e: 209 (M- H).
[3-Isopropoxy-4-(methoxycarbonyl)phenyl]boronic
Acid
(34b). Compound 34b was synthesized from 33b according to the
procedure B (84%). 1H NMR (200 MHz, DMSO-d6): δ 1.27 (d, J
) 6.0 Hz, 6H), 3.77 (s, 3H), 4.57–4.70 (m, 1H), 7.37 (d, J ) 8.0
Hz, 1H), 7.52 (s, 1H), 7.61 (d, J ) 8.0 Hz, 1H), 8.26 (s, 2H). MS
(ES) m/e: 237 (M- H).
[3-Isobutoxy-4-(methoxycarbonyl)phenyl]boronic Acid (34c).
Compound 34c was synthesized from 33c according to the
1
procedure B (72%). H NMR (200 MHz, DMSO-d6): δ 1.0 (d, J
) 6.5 Hz, 6H), 1.96–2.11 (m, 1H), 2.52–2.48 (m, 2H), 3.78 (s,
3H), 7.38 (d, J ) 7.5 Hz, 1H), 7.50 (s, 1H), 7.58 (d, J ) 7.5 Hz,
1H), 8.26 (s, 2H). MS (ES) m/e: 251 (M- H).

1938 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Imanishi et al.
temperature for 6–12 h. The resultant solid was collected by
filtration and dried to give 200 mg (74%) of the title compound.
1H NMR (200 MHz, DMSO-d6): δ 3.01–3.27 (m, 6H), 5.01–5.06
(m, 1H), 6.36 (br, 1H), 7.34–7.48 (m, 6H), 7.70–7.81 (m, 4H), 8.02
(d, 2H, J ) 8.4 Hz), 9.11 (1H, br). HRMS (M + H)+ found,
396.1371; calcd for C23H23Cl1N1O3, 396.1366. Anal.
(C23H22Cl1N1O3 ·1.0HCl) C, H, N.
[4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
4-biphenylyl]acetic Acid Hydrochloride (8h). Compound 8h was
synthesized from 17a and [4-(2-methoxy-2-oxoethyl)phenyl]boronic
acid according to the procedure described for the conversion of
17a to 8i (54%). 1H NMR (200 MHz, DMSO-d6): δ 2.90–3.40 (m,
6H), 3.62 (s, 2H), 4.90–5.10 (m, 1H), 7.30–7.70 (m, 12H). MS
(ES) m/e: 410 (M+ H). Anal. (C24H24Cl1N1O3 ·1.0HCl·0.25H2O)
C, H, N.
6H), 4.98–5.02 (m, 1H), 6.34 (br, 1H), 7.36–7.60 (m, 8H), 7.72
(d, 2H, J ) 8.0 Hz), 7.91 (d, 1H, J ) 8.0 Hz), 9.25 (br, 1H). MS
(ES) m/e: 408 (M - H). Anal. (C24H24Cl1N1O4 ·1.0HCl) C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)-2-fluoro-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9b). Compound 9b was synthesized from 18 and 31c according
to the procedure described for the conversion of 17a to 8i (50%).
1H NMR (200 MHz, DMSO-d6): δ 3.01–3.33 (6H, m), 4.98–5.03
(1H, m), 6.34 (1H, br), 7.35–7.47 (6H, m), 7.61–7.98 (5H, m),
9.10 (1H, br). MS (ES) m/e: 412 (M- H). Anal.
(C23H21Cl1F1N1O3 ·1.0HCl) C, H, N.
3-Chloro-4′-(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-
amino}ethyl)-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9c). Compound 9c was synthesized from 17a and 31d according
to the procedure described for the conversion of 17a to 8i (48%).
1H NMR (200 MHz, DMSO-d6): δ 3.01–3.28 (m, 6H), 5.00–5.04
(m, 1H), 6.36 (br, 1H), 7.35–7.47 (m, 6H), 7.70–7.91 (m, 5H), 9.07
(br, 1H). MS (ES) m/e: 428 (M- H). Anal. (C23H21Cl2N1O3 ·1.0HCl)
C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
4′-biphenyl-3-carboxylic Acid Hydrochloride (8j). Compound 8j
was synthesized from 18 and 3-ethoxycarbonylphenyl boronic acid
according to the procedure described for the conversion of 17a to
1
8i (54%). H NMR (200 MHz, DMSO-d6): δ 3.01–3.29 (m, 6H),
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
4.97–5.02 (m, 1H), 6.34 (br, 1H), 6.90 (m, 1H), 7.71–7.48 (m, 9H),
7.89–7.95 (m, 2H), 8.18 (d, J ) 1.5 Hz, 1H), 8.96 (br, 1H). MS
(ES) m/e: 394(M- H). Anal. (C23H22Cl1N1O3 ·1.0HCl) C, H, N.
2′-Chloro-4′-(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-
amino}ethyl)-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9i). Compound 9i was synthesized from 17b according to the
procedure described for the conversion of 17a to 8i (41%). 1H NMR
(200 MHz, DMSO-d6): δ 3.00–3.27 (m, 6H), 5.01–5.07 (m, 1H),
6.37–6.39 (br, 1H), 7.34–7.57 (m, 9H), 8.04 (d, 2H, J ) 8.0 Hz),
9.04–9.30 (br, 1H). MS (ES) m/e: 428 (M- H). Anal.
(C23H21Cl2N1O3 ·1.0HCl) C, H, N.
ethyl)-3-methoxy-4′-biphenyl-4-carboxylic
Acid
Hydro-
chloride (9d). Compound 9d was synthesized from 18 and 34a
according to the procedure described for the conversion of 17a to
1
8i (30%). H NMR (200 MHz, DMSO-d6): δ 3.01–3.34 (m, 6H),
3.92 (s, 3H), 5.02–5.06 (m, 1H), 6.37 (br, 1H), 7.26–7.74 (m, 11H),
9.25 (1H, br). HRMS (M + H)+ found, 426.1468; calcd for
C24H24Cl1N1O4, 426.1472. Anal. (C24H24Cl1N1O4 ·1.0HCl) C, H,
N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)-2-methyl-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9e). Compound 9e was synthesized from 17a and 31a according
to the procedure described for the conversion of 17a to 8i
(41%). 1H NMR (200 MHz, DMSO-d6): δ 2.28 (s, 1H), 3.01–3.27
(m, 6H), 5.00–5.04 (m, 1H), 6.36 (br, 1H), 7.28–7.48 (m, 9H),
7.79–7.90 (m, 2H), 9.02 (1H, br). HRMS (M + H)+ found,
410.1546; calcd for C24H25Cl1N1O3, 410.1523. Anal.
(C24H24Cl1N1O3 ·1.0HCl·1.0H2O) C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)-2-fluoro-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9f). Compound 9f was synthesized from 18 and 31f according to
the procedure described for the conversion of 17a to 8i (49%). 1H
NMR (200 MHz, DMSO-d6): δ 3.01–3.28 (6H, m), 5.02–5.05 (1H,
m), 6.38 (1H, br), 7.37–7.87 (11H, m), 9.10 (1H, br). MS (ES)
m/e: 412 (M- H). Anal. (C23H21Cl1F1N1O3 ·1.0HCl) C, H, N.
9-Chloro-4′-(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-
amino}ethyl)-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9g). Compound 9g was synthesized from 18 and 31 g according
to the procedure described for the conversion of 17a to 8i (41%).
1H NMR (200 MHz, DMSO-d6): δ 3.01–3.34 (m, 6H), 4.99–5.03
(m, 1H), 6.36 (br, 1H), 7.37–7.55 (m, 9H), 7.93–8.03 (m, 2H), 9.10
(br, 1H). MS (ES) m/e: 424 (M- H). Anal. (C23H21Cl2N1O3 ·1.0HCl)
C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
2′-methoxy-4′-biphenyl-4-carboxylic Acid Hydrochloride (9j).
Compound 9j was synthesized from 17c according to the procedure
1
described for the conversion of 17a to 8i (38%). H NMR (200
MHz, DMSO-d6): δ 3.03–3.27 (m, 6H), 3.80 (s, 3H), 5.03–5.07
(m, 1H), 6.38 (br, 1H), 6.96 (d, 1H, J ) 8.0 Hz), 7.06 (s, 1H),
7.29–7.48 (m, 5H), 7.58 (d, 1H, J ) 8.0 Hz), 7.96 (2H, d, J ) 8.0
Hz), 9.13–9.18 (br, 1H). MS (ES) m/e: 424 (M- H). Anal.
(C24H24Cl1N1O4 ·1.0HCl) C, H, N.
5-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]-2-thiophenecarboxylic Acid Hydrochloride
(8p). 5-Formyl-2-thiophene-boronic acid and 18 were reacted
according to the procedure E to give tert-butyl(2R)-2-(3-chlorophe-
nyl)-2-hydroxyethyl{2-[4-(5-formyl-2-thienyl)phenyl]ethyl} car-
bamat (35%). 1H NMR (200 MHz, CDCl3): δ 1.45 (s, 9H),
2.73–2.83 (m, 2H), 3.32–3.44 (m, 4H), 4.46 (br, 1H), 4.85–4.92
(m, 1H), 7.17–7.28 (m, 5H), 7.36–7.39 (m, 2H), 7.59 (d, J ) 8
Hz, 2H), 7.71–7.74 (m, 1H), 9.88 (s, 1H). MS (ES) m/e: 508 (M +
Na).
To a solution of the obtained product (180 mg, 0.37 mmol) in
MeCN (2 mL) and pH 4 buffer solution (sodium dihydrogenphos-
phate, 1 mL) was added 30% H2O2 solution (30 µL) and 80%
NaClO2 (67 mg, 0.74 mmol) below 10 °C. The reaction mixture
was stirred at 50 °C for 3 h. The mixture was diluted with EtOAc,
washed with water and brine, dried over MgSO4, and evaporated
under reduced pressure to give a thiophenecarboxylic acid
(160 mg, 86%). A solution of the product (160 mg, 0.32 mmol)
and 4 N HCl in dioxane was stirred at room temperature for
24 h. The resultant solid was collected with filtration and dried
to give 100 mg (62%) of the title compound. 1H NMR
(200 MHz, DMSO-d6): δ 3.00–3.25 (m, 6H), 4.95–4.99 (m, 1H),
6.34 (br, 1H), 7.33–7.47 (m, 6H), 7.55 (d, J ) 3.9 Hz, 1H),
7.70–7.81 (m, 3H), 9.05 (br, 1H). HRMS (M + H)+ found,
402.0934; calcd for C21H20Cl1N1O3S1, 402.0931. Anal.
(C21H20Cl1N1O3S1 ·1.0HCl·1.5H2O) C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
2-methoxy-4′-biphenyl-4-carboxylic Acid Hydrochloride (9h). Com-
pound 9h was synthesized from 18 and 31e according to the
procedure described for the conversion of 17a to 8i (23%). 1H NMR
(200 MHz, DMSO-d6): δ 3.02–3.27 (m, 6H), 3.82 (s, 3H), 4.98–5.02
(m, 1H), 6.35 (br, 1H), 7.30–7.64 (m, 11H), 9.05 (br, 1H). MS
(ES) m/e: 424 (M- H). Anal. (C24H24Cl1N1O4 ·1.0HCl) C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
3-isopropoxy-4′-biphenyl-4-carboxylic Acid Hydrochloride
(10a). Compound 10a was synthesized from 17a and 34b according
to the procedure described for the conversion of 17a to 8i (72%).
1H NMR (200 MHz, DMSO-d6): δ 1.31 (6H, d, J ) 6.0 Hz),
2.8–3.0 (6H, m), 4.79 (1H, q, J ) 6.0 Hz), 4.8–5.0 (1H, m), 6.33
(1H, m), 7.0–7.9 (11H, m). HRMS (M + H)+ found, 454.1792;
calcd
for
C26H29Cl1N1O4,
454.1785.
Anal.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)-3-methyl-4′-biphenyl-4-carboxylic Acid Hydrochloride
(9a). Compound 9a was synthesized from 17a and 31b according
to the procedure described for the conversion of 17a to 8i (35%).
1H NMR (200 MHz, DMSO-d6): δ 2.60 (s, 3H), 3.01–3.34 (m,
(C26H28Cl1N1O4 ·1.0HCl·1.0H2O) C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
3-isobutoxy-4-biphenylcarboxylic Acid Hydrochloride (10b). Com-
pound 10b was synthesized from 18 and 34c according to the

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1939
procedure described for the conversion of 17a to 8i (59%). 1H NMR
(400 MHz, DMSO-d6): δ 1.02 (6H, d, J ) 6.5 Hz), 2.03–2.07 (1H,
m), 3.04–3.23 (6H, m), 3.92 (1H, d, J ) 6.5 Hz), 4.98–5.01 (1H,
m), 6.35 (br, 1H), 7.25–7.48 (8H, m), 7.71–7.74 (3H, m), 9.92 (1H,
br), 12.5 (1H, br). MS (ES) m/e: 468 (M + H). Anal.
(C27H30Cl1N1O4 ·1.0HCl·0.75H2O) C, H, N.
16.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.38 g,
16.9 mmol) and potassium acetate (4.98 g, 50.7 mmol), and the
mixture was stirred at 90 °C for 2 h under nitrogen. The mixture
was diluted with ethyl acetate, washed with 1 N aqueous hydro-
chloride solution, water, and brine, dried over magnesium sulfate,
and evaporated under reduced pressure to give methyl 2-(isopro-
pylsulfanyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zoate 34i (4.77 g, 84%), which was used without any further
purifications.
To a solution of 18 (700 mg, 1.67 mmol) in 1,2-dimethoxyethane
(10 mL) were added the above product 34i (728 mg, 2.16 mmol),
Pd(PPh3)4 (192 mg, 0.167 mmol), and an aqueous solution of
NaHCO3 (2 M, 1.84 mL), and the mixture was stirred at 70 °C for
7 h under nitrogen. The mixture was diluted with EtOAc and water.
The organic layer was separated, washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (hexane/EtOAc
) 3/1) to give 768 mg (51%) of the title compound. 1H NMR (200
MHz, DMSO-d6): δ 1.27 (d, J ) 6.5 Hz, 6H), 1.28 (s, 9H),
2.70–2.91 (m, 2H), 3.2–3.5 (m, 4H), 3.83 (s, 3H), 3.73–3.77 (m,
1H), 4.73 (br s, 1H), 5.40–5.51 (m, 1H), 7.20–7.34 (m, 7H), 7.50
(d, J ) 8.2 Hz, 1H), 7.64 (s, 1H), 7.66 (d, J ) 8.2 Hz, 2H), 7.87
(d, J ) 8.2 Hz, 1H). MS (ES) m/e: 572 (M+ Na).
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
3-(cyclohexyloxy)-4-biphenylcarboxylic Acid Hydrochloride
(10c). Compound 10c was synthesized from 18 and 34d according
to the procedure described for the conversion of 17a to 8i (48%).
1H NMR (400 MHz, DMSO-d6): δ 1.34–1.86 (10H, m), 3.02–3.25
(6H, m), 4.62–4.66 (1H, m), 4.99 (1H, d, J ) 8.5 Hz), 6.34 (1H,
br), 7.24–7.48 (8H, m), 7.69–7.71 (3H, m), 9.95 (1H, br). m/e: 494
(M + H). Anal. (C29H32Cl1N1O4 ·1.0HCl·0.75H2O) C, H, N.
4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-
3-isobutyl-4-biphenylcarboxylic Acid Hydrochloride (10d). Com-
pound 10d was synthesized from 19 and 34f according to the
procedure described for the conversion of 17a to 8i (48%). 1H NMR
(200 MHz, DMSO-d6): δ 0.88 (d, 6H, J ) 6.6 Hz), 1.79–1.92 (m,
1H), 2.92 (d, 2H, J ) 7.0 Hz) 3.02–3.32 (m, 6H), 5.00 (br, 1H),
6.34 (1H, br), 7.36–7.89 (m, 11H), 9.0 (br, 1H). MS (ES) m/e: 450
(M- H). Anal. (C27H30Cl1N1O3 ·1.0HCl·0.25H2O) C, H, N.
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-isopro-
poxy-4-biphenylcarboxylic Acid Hydrochloride (10e). Compound
10e was synthesized from 18 and 34b according to the procedure
Methyl
4′-(2-{(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-
phenylethyl]amino}ethyl)-3-(tetrahydro-9H-pyran-4-yloxy)bi-
phenyl-4-carboxylate (37). Compound 37 was synthesized from
1
described for the conversion of 17a to 8i (79%). H NMR (200
1
MHz, DMSO-d6): δ 1.31 (6H, d, J ) 6.8 Hz), 2.9–3.41 (6H, m),
4.7–4.9 (1H, m), 6.22 (1H, m), 7.2–7.8 (12H, m). MS (ES) m/e:
420 (M+ H). Anal. (C26H29N1O4 ·1.0HCl) C, H, N.
33h according to the general procedure G (32%). H NMR (200
MHz, CDCl3): δ 1.44 (s, 9H), 1.78–2.04 (m, 4H), 2.70–2.85 (m,
2H), 3.30–3.40 (m, 4H), 3.56–3.67 (m, 2H), 3.91 (s, 3H), 3.96–4.07
(m, 2H), 4.28 (br s, 1H), 4.67 (m, 1H), 4.89–4.98 (m, 1H),
7.12–7.37 (m, 9H), 7.48 (d, J ) 8.0 Hz, 2H), 7.87 (d, J ) 8.0 Hz,
1H).
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-iso-
butoxy-4′-biphenyl-4-carboxylic Acid Hydrochloride (10f). Com-
pound 10f was synthesized from 18 and 34c according to the
procedure described for the conversion of 17a to 8i (73%). 1H NMR
(200 MHz, DMSO-d6): δ 1.02 (t, 6H, J ) 6.8 Hz), 1.9–2.1 (m,
1H), 2.9–3.4 (m, 6H), 3.92 (d, 2H, J ) 6.8 Hz), 4.9–5.1 (m, 1H),
6.22 (m, 1H), 7.2–7.8 (m, 12H). MS (ES) m/e: 434 (M+ H). Anal.
(C27H31N1O4 ·1.0HCl·0. 5H2O) C, H, N.
3-(Cyclohexyloxy)-4′-(2-{[(2R)-2-hydroxy-2-phenylethyl]-
amino}ethyl)-4-biphenylcarboxylic Acid Hydrochloride
(10g). Compound 10g was synthesized from 18 and 34d according
to the procedure described for the conversion of 17a to 8i (75%).
HPLC purity: 98%. 1H NMR (200 MHz, DMSO-d6): δ 1.2–2.0
(10H, m), 2.9–3.4 (6H, m), 4.64 (1H, m), 4.9–5.1 (1H, m), 6.22
(1H, m), 7.2–7.8 (12H, m). HRMS (M + H)+ found, 460.2494;
calcd for C29H34N1O4, 460.2488.
Methyl
4′-(2-{(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-
phenylethyl]amino}ethyl)-3-(isopropylsulfonyl)biphenyl-4-car-
boxylate (39). To a solution of 38 (338 mg, 0.615 mmol) in
chloroform (8 mL) and N,N-DMF (4 mL) was added m-chlorop-
erbenzoic acid (594 mg, 3.44 mmol) at room temperature, and the
mixture was stirred at the same temperature for 1 h. To the mixture
was added water and extracted with dichloromethane. The organic
layer was washed with brine, dried over magnesium sulfate, and
evaporated. The residue was purified by column chromatography
on silica gel (n-hexane/ethyl acetate ) 2/1) to give 340 mg (95%)
1
of the title compound. H NMR (400 MHz, CDCl3): δ 1.37 (d, J
) 6.8 Hz, 6H), 1.45 (s, 9H), 2.79 (m, 2H), 3.31–3.54 (m, 4H),
3.98 (s, 3H), 4.00–4.06 (m, 1H), 4.92 (br s, 1H), 7.25–7.43 (m,
7H), 7.58 (m, 2H), 7.76 (d, J ) 8.0 Hz, 1H), 7.83 (d, J ) 8.0 Hz,
1H), 8.23 (s, 1H). MS (ES) m/e: 604 (M+ Na).
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-phenoxy-
4′-biphenyl-4-carboxylic Acid Hydrochloride (10h). Compound 10h
was synthesized from 18 and 34e according to the procedure
1
Methyl
4′-(2-{(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-
described for the conversion of 17a to 8i (85%). H NMR (200
phenylethyl]amino}ethyl)-3-(isopropylamino)biphenyl-4-carbo-
MHz, DMSO-d6): δ 2.9–3.4 (6H, m), 4.9–5.1 (1H, m), 6.22 (1H,
m), 6.9–8.0 (17H, m). MS (ES) m/e: 454 (M+ H). Anal.
(C29H27N1O4 ·1.0HCl·1.0H2O) C, H, N.
xylate (40). Compound 40 was synthesized from 33j according to
1
the general procedure G (45%). H NMR (200 MHz, CDCl3): δ
1.30 (d, J ) 6.5 Hz, 6H), 1.44 (s, 9H), 2.78 (m, 2H), 3.3–3.5 (m,
4H), 3.75–3.81 (m, 1H), 3.86 (s, 3H), 4.33 (br s, 1H), 4.91 (m,
1H), 6.74 (dd, J ) 8.2, 1.5 Hz, 1 H), 6.82 (s, 1H), 7.20–7.42 (m,
7H), 7.51 (d, J ) 8.2 Hz, 1 H), 7.72 (d, J ) 7.2 Hz, 1H), 7.93 (d,
J ) 8.4 Hz, 1H). MS (ES) m/e: 555 (M+ Na).
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-10-iso-
butyl-4-biphenylcarboxylic Acid Hydrochloride (10i). Compound
10i was synthesized from 18 and 34f according to the procedure
1
described for the conversion of 17a to 8i (39%). H NMR (200
MHz, DMSO-d6): δ 0.89 (6H, d, J ) 8.0 Hz), 1.8–2.0 (1H, m),
2.9–3.4 (8H, m), 4.9–5.1 (1H, m), 7.3–8.0 (12H, m). MS (ES) m/e:
418 (M+ H). Anal. (C27H31N1O3 ·1.0HCl) C, H, N.
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-(tetra-
hydro-9H-pyran-4-yloxy)-4-biphenylcarboxylic Acid Hydro-
chloride (10k). Compound 10k was synthesized from 37 according
3-(2-Ethoxyethoxy)-4′-(2-{[(2R)-2-hydroxy-2-phenylethyl]-
amino}ethyl)biphenyl-4-carboxylic Acid Hydrochloride (10j).
Compound 10j was synthesized from 18 and 34 g according to the
procedure described for the conversion of 17a to 8i (51%). 1H NMR
(200 MHz, DMSO-d6): δ 1.12 (3H, t, J ) 6.2 Hz), 2.8–3.0 (6H,
m), 3.54 (2H, q, J ) 6.2 Hz), 3.70 (2H, m), 4.29 (2H, m), 4.8–5.0
(1H, m), 6.33 (1H, m), 7.0–7.9 (12H, m). MS (ES) m/e: 450 (M+
H). Anal. (C27H31N1O5 ·1.0HCl·0.35CHCl3) C, H, N.
Methyl 4′-(2-{(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-phenyl-
ethyl]amino}ethyl)-3-(isopropylsulfanyl)biphenyl-4-carboxylate
(38). General Procedure G. To a solution of 33i (4.89 g, 16.9 mmol)
in 1,4-dioxane (22 mL) was added bis(pinacolate)diboron (4.29 g,
1
to the general procedure F (72%). H NMR (200 MHz, DMSO-
d6): δ 1.55–1.71 (2H, m), 1.90–2.00 (2H, m), 3.0–3.54 (6H, m),
3.8–3.93 (2H, m), 4.8–5.0 (2H, m), 6.4 (1H, br), 7.26–7.41 (9H,
m), 7.69–7.74 (3H, m), 8.9 (1H, br). MS (ES) m/e: 460 (M- H).
Anal. (C28H31N1O5 ·1.0HCl·1.5H2O) C, H, N.
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-(iso-
propylthio)-4′-biphenyl-4-carboxylic Acid Hydrochloride
(10l). Compound 10l was synthesized from 38 according to the
general procedure F (78%). 1H NMR (200 MHz, DMSO-d6): δ
1.31 (6H, d, J ) 6.5 Hz), 2.99–3.33 (6H, m), 3.69–3.82 (1H, m),
4.96–5.00 (1H, m), 6.22 (1H, m), 7.30–7.92 (12H, m). Anal.

1940 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Imanishi et al.
(C26H29N1O3S1 ·0.5HCl) C, H, N. HRMS (M + H)+ found,
436.1934; calcd for C26H30N1O3S1, 436.1946.
collected by filtration and dried to give 220 mg (90%) of the title
compound as a white solid. 1H NMR (200 MHz, DMSO-d6): δ
2.95–3.33 (6H, m), 4.65 (2H, s), 4.99–5.04 (1H, m), 6.35 (1H, br),
6.83–7.00 (6H, m), 7.23 (9H, d, J ) 8 Hz), 7.39–7.47 (4H, m),
8.98–9.12 (1H, br). HRMS (M + H)+ found, 442.1409; calcd for
C24H24Cl1N2O5, 442.1421. Anal. (C24H24Cl1N2O5 ·1.0HCl ·0.25H2O)
C, H, N.
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-(iso-
propylsulfonyl)-4′-biphenyl-4-carboxylic Acid Hydrochloride
(10m). Compound 10m was synthesized from 39 according to the
general procedure F (31%). 1H NMR (200 MHz, DMSO-d6): δ
1.25 (6H, d, J ) 6.8 Hz), 2.99–3.33 (6H, m), 3.94–4.08 (1H, m),
4.96–5.00 (1H, m), 6.22 (1H, m), 7.27–8.12 (12H, m). MS (ES)
m/e: 466 (M- H). Anal. (C26H29N1O5S1 ·1.0HCl ·0.8H2O) C, H, N.
4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)-3-(iso-
propylamino)-4-biphenylcarboxylic Acid Dihydrochloride
(10n). Compound 10n was synthesized from 40 according to the
general procedure F (60%). 1H NMR (200 MHz, DMSO-d6): δ
1.23 (6H, d, J ) 6.2 Hz), 2.90–3.40 (6H, m), 3.82–3.94 (1H, m),
5.00 (1H, dd, J ) 9.9, 2.7 Hz), 6.82 (1H, dd, J ) 8.3, 1.3 Hz),
6.92 (1H, s), 7.27–7.42 (7H, m), 7.66 (2H, d, J ) 8.1 Hz), 7.86
(1H, d, J ) 8.3 Hz), 8.91 (1H, brs), 9.28 (1H, brs). MS (ES) m/e:
417 (M- H). Anal. (C26H30N2O3 ·2.0HCl) C, H, N.
tert-Butyl-2-(4-bromophenyl)ethyl[(2R)-2-{[tert-butyl(di-
methyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]carbamate (41). To a
solution of 18 (4.5 g) and imidazole (2.4 g) in N,N-DMF (55 mL)
was added tert-butyl(dimethyl)silyl chloride (2.7 g), and the mixture
was stirred at room temperature for 5 days. The mixture was
partitioned between EtOAc and water. The organic layer was
separated, washed with water and brine, dried over MgSO4, and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane/EtOAc ) 20/1) to
give 5.3 g (94%) of the title compound. 1H NMR (200 MHz,
CDCl3): δ -0.13 (s, 3H), 0.86 (s, 9H), 1.46 (d, 9H, J ) 6 Hz),
1.54 (d, 3H, J ) 6 Hz), 2.64–2.72 (m, 2H), 2.88–3.03 (m, 1H),
3.21–3.53 (m, 3H), 4.85 (m, 0.4H), 5.01–5.05 (m, 0.6H), 6.96–7.04
(m, 2H), 7.14–7.27 (m, 4H), 7.36–7.40 (m, 2H).
tert-Butyl-2-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)-
phenyl]ethyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carba-
mate (42). Typical Procedure H. To a suspension of 16a (710
mg, 1.81 mmol), 4-((tert-butyl(dimethyl)silyl)oxy)phenyl-boronic
acid (457 mg, 1.81 mmol), Et3N (1.26 mL, 9.06 mmol), and
powdered MS 4 Å (700 mg) in CH2Cl2 (18 mL) was added
Cu(OAc)2 (330 mg, 1.81 mmol), and the mixture was stirred at
room temperature for 18 h under ambient atmosphere. The resultant
slurry was filtered off, and the filtrate was evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane/EtOAc ) 2/1) to give 600 mg (55.4%) of the
title compound. 1H NMR (200 MHz, CDCl3): δ 0.18 (s, 6H), 0.99
(s, 9H), 1.46 (s, 9H), 2.70 (m, 2H), 2.27–3.39 (m, 4H), 4.56 (br,
1H), 4.83–4.86 (m, 1H), 6.75–6.91 (m, 6H), 7.02–7.07 (m, 2H),
7.23–7.28 (m, 3H), 7.36 (s, 1H). MS (ES) m/e: 569 (M- H).
tert-Butyl{4-[4-(2-{(tert-butoxycarbonyl)[(2R)-2-(3-chloro-
(4-{[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]amino}phenoxy)acetic Acid Hydrochloride (8b).
Compound 8b was synthesized from 20 according to the procedure
1
described for the conversion of 16a to 8a (39%). H NMR (200
MHz, DMSO-d6): δ 2.84–3.30 (6H, m), 4.39 (1H, br), 4.59 (2H,
s), 4.97–5.03 (1H, m), 6.37 (1H, br), 6.80–7.07 (8H, m), 7.34–7.48
(4H, m), 8.85 (1H, br), 9.11 (1H, br). HRMS (M + H)+ found,
441.1535; calcd for C24H25Cl1N2O4, 441.1581. Anal.
(C24H25Cl1N2O4 ·2.0HCl) C, H, N.
{4-[[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl](methyl)-amino]phenoxy}acetic Acid Hydro-
chloride (8c). Compound 8c was synthesized from 21 according
to the procedure described for the conversion of 16a to 8a (28%).
HPLC purity: 97%. 1H NMR (200 MHz, DMSO-d6): δ 2.85–3.23
(6H, m), 3.17 (3H,s), 3.89–4.15 (1H, br), 4.65 (2H, s), 4.98–5.02
(1H, m), 6.68–7.08 (8H, m), 7.34–7.46 (4H, m), 8.86 (1H, br), 9.14
(1H, br). HRMS (M + H)+ found, 455.1754; calcd for
C25H27Cl1N2O4, 455.1738.
tert-Butyl-2-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}benzoyl)-
phenyl]ethyl-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-
chlorophenyl)ethyl]carbamate (45). To a solution of 41 (880 mg,
1.55 mmol) in THF (13 mL) was added a solution of n-BuLi in
n-hexane (1.59 M, 1.07 mL) dropwise at -70 °C under nitrogen
and the mixture was stirred at -70 °C for 30 min. To the reaction
mixture was added 36 (480 mg, 1.62 mmol) at -70 °C, and the
mixture was stirred at -70 °C for 1 h. The mixture was allowed to
warm to room temperature and partitioned between EtOAc and
water. The organic layer was separated, washed with saturated
NaHCO3 solution and brine, dried over MgSO4, and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane/EtOAc ) 10/1) to give 710
1
mg (63%) of the title compound. H NMR (200 MHz, CDCl3): δ
-0.11 (s, 3H), 0.01 (s, 3H), 0.25 (s, 6H), 0.87 (s, 9H), 1.00 (s,
9H), 1.45 (d, 9H, J ) 6 Hz), 2.76–2.97 (m, 3H), 3.23–3.63 (m,
3H), 4.82–4.84 (m, 0.4H), 5.01–5.06 (m, 0.6H), 6.85–6.92 (m, 2H),
7.13–7.38 (m, 6H), 7.66–7.75 (m, 4H). MS (ES) m/e: 746 (M+
Na).
{4-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)benzoyl]phenoxy}acetic Acid Hydrochloride (8f). Com-
pound 8f was synthesized from 45 according to the procedure
described for the conversion of 42 to 8a (54%). 1H NMR (200
MHz, DMSO-d6): δ 3.01–3.32 (6H,m), 4.81 (2H, s), 4.96–5.00 (1H,
m), 6.35 (1H, br), 7.07 (2H, d, J ) 8.8 Hz), 7.35–7.47 (6H, m),
7.66–7.75 (4H, m), 8.99 (1H, br). HRMS (M + H)+ found,
454.1435; calcd for C25H24Cl1NO5, 454.1421. Anal.
(C25H24Cl1NO5 ·1.0HCl) C, H, N.
tert-Butyl(2R)-2-(3-chlorophenyl)-2-hydroxyethyl[2-(4′-hy-
droxy-4′-biphenyl-4-yl)ethyl]carbamate (46). To a solution of 41
(580 mg, 1.27 mmol) in 1,2-dimethoxyethane (9 mL) was added
4-((tert-butyl(dimethyl)silyl)oxy)phenylboronic acid (385 mg, 1.53
mmol), Pd(PPh3)4 (117 mg, 0.10 mmol), and aqueous Na2CO3 (2M,
1.6 mL), and the mixture was stirred at 75 °C for 10 h under
nitrogen. The mixture was diluted with ethyl acetate and water.
The organic layer was separated, washed with brine, dried over
magnesium sulfate, and evaporated. To a solution of the residue in
THF (8 mL) was added 1 M tetrabutylammonium fluoride in THF
(3.0 mL), and the mixture was stirred at room temperature for 8 h
under nitrogen. The mixture was partitioned between EtOAc and
water. The organic layer was separated, washed with water and
brine, dried over MgSO4, and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 2/1) to give 350 mg (59%) of the title compound.
1H NMR (200 MHz, CDCl3): δ 1.46 (s, 9H), 2.76 (m, 2H),
3.27–3.48 (m, 4H), 4.59 (br, 1H), 4.87 (m, 1H), 4.95 (s, 1H),
phenyl)-2-hydroxy
ethyl]amino}ethyl)phenoxy]phenoxy}-
acetate (47). To a solution of 42 (370 mg, 0.62 mmol) in THF
(4.0 mL) was added 1 M tetrabutylammonium fluoride in THF (1.2
mL), and the mixture was stirred at room temperature for 1 h. The
mixture was partitioned between EtOAc and water. The organic
layer was separated, washed with water and brine, dried over
MgSO4, and evaporated under reduced pressure to give a phenol
product. To a solution of the product and K2CO3 (94 mg, 0.68
mmol) in N,N-DMF (4.0 mL) was added tert-butyl bromoacetate
(133 mg, 0.68 mmol), and the mixture was stirred at room
temperature for 5 h. The mixture was partitioned between EtOAc
and water. The organic layer was separated, washed with water
and brine, dried over MgSO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane/EtOAc ) 2/1) to give 360 mg (97%) of the title
1
compound. H NMR (200 MHz, CDCl3): δ 1.46 (s, 9H), 1.49 (s,
9H), 2.70 (m, 2H), 2.27–3.40 (m, 4H), 4.49 (s, 2H), 4.54 (br, 1H),
4.83–4.87 (m, 1H), 6.75–6.95 (m, 6H), 7.03–7.07 (m, 2H),
7.23–7.28 (m, 3H), 7.36 (s, 1H). MS (ES) m/e: 597 (M- H).
{4-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenoxy]phenoxy}acetic Acid Hydrochloride (8a). A solu-
tion of 47 (305 mg, 0.51 mmol) and 4 N HCl in dioxane (5.0 mL)
was stirred at room temperature for 24 h. The resultant solid was

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1941
6.87–6.91 (m, 2H), 7.17–7.29 (m, 6H), 7.37 (s, 1H), 7.42–7.47 (m,
CDCl3): δ 2.59–2.93 (m, 6H), 3.88 (s, 1H), 4.59–4.66 (m, 1H),
6.72–6.79 (m, 2H), 7.02–7.35 (m, 10H). MS (ES) m/e: 382 (M+
H).
3H). MS (ES) m/e: 490 (M+ Na).
tert-Butyl{[4′-(2-{(tert-butoxycarbonyl)[(2R)-2-(3-chloro-
phenyl)-2-hydroxyethyl]-amino}ethyl)-4′-biphenyl-4-yl]oxy}-
acetate (51). To a solution of 46 (240 mg, 0.51 mmol) and K2CO3
(78 mg, 0.56 mmol) in N,N-DMF (4 mL) was added tert-butyl
bromoacetate (110 mg, 0.56 mmol), and the mixture was stirred at
room temperature for 3 h. The mixture was partitioned between
EtOAc and water. The organic layer was separated, washed with
water and brine, dried over MgSO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane/EtOAc ) 3/1) to give 245 mg (82%) of the title
tert-Butyl{4-[4-(2-{(tert-butoxycarbonyl)[(2R)-2-(3-chloro-
phenyl)-2-hydroxyethyl]amino}ethyl)benzyl]phenoxy}acetate
(56). To a solution of 54 (390 mg, 1.02 mmol) in THF (3.5 mL)
and water (3.5 mL) was added di-tert-butyl dicarbonate (223 mg,
1.02 mmol), and the mixture was stirred at room temperature for
30 minites. The mixture was partitioned between EtOAc and water.
The organic layer was separated, washed with brine, dried over
MgSO4, and evaporated under reduced pressure to give 480 mg
(98%) of tert-butyl(2R)-2-(3-chlorophenyl)-2-hydroxyethyl{2-[4-
(4-hydroxybenzyl)phenyl]ethyl}carbamate (55). To a solution of
55 (470 mg, 0.98 mmol) and K2CO3 (148 mg, 1.07 mmol) in N,N-
DMF (4 mL) was added tert-butyl bromoacetate (190 mg, 0.98
mmol), and the mixture was stirred at room temperature for 3 h.
The mixture was partitioned between EtOAc and water. The organic
layer was separated, washed with water and brine, dried over
MgSO4, and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (hexane/EtOAc
) 3/1) to give 245 mg (42%) of the title compound. 1H NMR (200
MHz, CDCl3): δ 1.43 (s, 9H), 1.48 (s, 9H), 2.65–2.78 (m, 2H),
2.26–3.42 (m, 4H), 3.87 (s, 2H), 4.47 (s, 2H), 4.60 (br, 1H),
4.75–4.86 (m, 1H), 6.77–6.81 (m, 2H), 7.02–7.27 (m, 9H), 7.35
(s, 1H). MS (ES) m/e: 618 (M+ Na).
1
compound. H NMR (200 MHz, CDCl3): δ 1.45 (s, 9H), 1.50 (s,
9H), 2.76 (m, 2H), 3.32–3.43 (m, 4H), 4.55 (s, 2H), 4.62 (m, 1H),
4.86–4.88 (m, 1H), 6.93–6.98 (m, 2H), 7.15–7.26 (m, 6H), 7.37
(s, 1H), 7.45–7.51 (m, 3H). MS (ES) m/e: 582 (M+ H).
{[4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)-4′-biphenyl-4-yl]oxy}acetic Acid Hydrochloride (8g). Com-
pound 8g was synthesized from 51 according to the procedure
described for the conversion of 47 to 8a (99%). 1H NMR (200
MHz, DMSO-d6): δ 3.02–3.35 (6H, m), 4.72 (2H, s), 5.00–5.05
(1H, m), 6.37 (1H, br), 6.99 (2H, d, J ) 8.7 Hz), 7.30–7.61 (10H,
m), 9.04 (1H, br), 13.03 (1H, br). HRMS (M + H)+ found,
426.1499; calcd for C24H24Cl1N2O4, 426.1472. Anal.
(C24H24Cl1N2O4 ·0.5HCl) C, H, N.
{4-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)benzyl]phenoxy}acetic Acid Hydrochloride (8d). A solution
of 56 (240 mg, 0.40 mmol) and 4 N HCl in dioxane (3.0 mL) was
stirred at room temperature for 24 h. The mixture was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (methanol/acetic acid/chloroform )
10/1/100) to give a product. To a THF (2.0 mL) solution of the
product, 4 N HCl in dioxane (1.0 mL) was added. The mixture
was stirred for 5 min and evaporated under reduced pressure to
give 72 mg (38%) of the title compound. 1H NMR (200 MHz,
DMSO-d6) δ 2.91–3.24 (m, 6H), 3.84 (s, 2H), 4.61 (s, 2H),
4.94–4.99 (m, 1H), 6.32 (br, 1H), 6.80 (d, 2H, J ) 8.7 Hz),
7.10–7.21 (m, 6H), 7.29–7.46 (m, 4H), 8.89 (br, 1H). HPLC purity:
98%. HRMS (M + H)+ found, 440.1624; calcd for C25H26Cl1N1O4,
440.1629.
4-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenoxy]benzoic Acid Hydrochloride (8k). Compound 16a
(550 mg, 1.4 mmol) and 4-mthoxycarbonylphenylboronic acid (300
mg, 1.68 mmol) were reacted according to the general procedure
H to give methyl-4-[4-(2-{(tert-butoxycarbonyl)[(2R)-2-(3-chlo-
rophenyl)-2-hydroxyethyl]- amino}ethyl)phenoxy]benzoate (185
mg, 25%). 1H NMR (200 MHz, CDCl3): δ 1.48 (s, 9H), 2.70–2.80
(m, 2H), 3.30–3.45 (m, 4H), 3.90 (s, 3H), 4.46 (br, 1H), 4.85–4.89
(m, 1H), 6.95–7.02 (m, 4H), 7.10–7.29 (m, 5H), 7.37 (s, 1H),
7.95–7.99 (m, 2H).
Compound 8k was synthesized from the obtained product (183
mg, 0.35 mmol) according to the general procedure F (127 mg,
81%). 1H NMR (200 MHz, DMSO-d6): δ 3.00–3.28 (m, 6H),
4.99–5.04 (m, 1H), 6.35 (br, 1H), 6.97–7.12 (m, 4H), 7.32–7.48
(m, 6H), 7.90–7.98 (m, 2H), 9.03–9.35 (br, 1H). MS (ES) m/e:
410.2 (M- H). Anal. (C23H22Cl1N1O4 ·1.0HCl) C, H, N.
3-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenoxy]benzoic Acid Hydrochloride (8l). Compound 8l
was synthesized from 16a and 3-mthoxycarbonylphenylboronic acid
according to the procedure described for the conversion of 16a to
8k (32%). 1H NMR (200 MHz, DMSO-d6): δ 2.99–3.25 (m, 6H),
4.95–5.02 (m, 1H), 6.35 (br, 1H), 7.06 (d, J ) 3.5 Hz, 2H),
7.07–7.54 (m, 9H), 7.69 (d, J ) 4.0 Hz, 1H), 8.95 (br, 1H). MS
(ES) m/e: 410.2 (M - H). Anal. (C23H22Cl1N1O4 ·1.0HCl ·0.25H2O)
C, H, N.
[4-(2-{benzyl[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-
chlorophenyl)ethyl]amino}ethyl)-phenyl](4-{[tert-butyl(di-
methyl)silyl]oxy}phenyl)methanol (52). To a solution of 29 (2.1
g, 3.76 mmol) in THF (25 mL) was added a solution of n-BuLi in
n-hexane (1.59 M, 2.83 mL) dropwise at -70 °C under nitrogen,
and the mixture was stirred at -70 °C for 30 min. To the reaction
mixture was added 4-((tert-butyl(dimethyl)silyl)oxy)benzaldehyde
(977 mg, 4.13 mmol), and the mixture was stirred at the same
temperature for 1 h. The mixture was allowed to warm to room
temperature and partitioned between EtOAc and water. The organic
layer was separated, washed with saturated NaHCO3 solution and
brine, dried over MgSO4, and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 10/1) to give 1.1 g (40%) of the title compound.
1H NMR (200 MHz, CDCl3): δ -0.16 (s, 3H), 0.01 (s, 3H), 0.17
(s, 6H), 0.85 (s, 9H), 0.97 (s, 9H), 2.09–2.10 (m, 1H), 2.60–2.75
(m, 6H), 3.59 (d, J ) 13.7 Hz, 1H), 3.71 (d, J ) 13.7 Hz, 1H),
4.56 (t, J ) 6.2 Hz, 1H), 5.75–6.77 (m, 1H), 6.76–6.80 (m, 2H),
6.99 (d, 2H, J ) 8.0 Hz), 7.08–7.25 (m, 8H). MS (ES) m/e: 716
(M+ H).
4-[[4-(2-{Benzyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-
amino}ethyl)phenyl]-(hydroxy)methyl]phenol (53). To a solution
of 52 (1.1 g, 1.54 mmol) in THF (15 mL) was added 1 M
tetrabutylammonium fluoride in THF (5.0 mL) at 0 °C, and the
mixture was stirred at room temperature for 24 h under nitrogen.
The mixture was partitioned between EtOAc and water. The organic
layer was separated, washed with water and brine, dried over
MgSO4, and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (hexane/EtOAc
) 2/1) to give 550 mg (73%) of the title compound. 1H NMR (200
MHz, CDCl3): δ 2.24 (m, 1H), 2.49–2.91 (m, 6H), 3.57 (d, J )
13.5 Hz, 1H), 3.94 (d, J ) 13.5 Hz, 1H), 4.52–4.59 (m, 1H), 4.88
(br, 1H), 5.78 (s, 1H), 6.75–6.79 (m, 2H), 7.07–7.16 (m, 2H),
7.20–7.34 (m, 8H). MS (ES) m/e: 486 (M- H).
4-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)benzyl]phenol (54). A mixture of 53 (545 mg, 1.12 mmol)
in 4 N HCl in dioxane (1.0 mL) was stirred for 5 min. The solvent
was removed by evaporation. A suspension of the residue in EtOH
(2.2 mL) and chlorobenzene (5.2 mL) was hydrogenated over
palladium on carbon (10% w/w, 50% wet, 55 mg) under hydrogen
atmosphere for 2 h. The catalyst was filtered off, the filtrate was
evaporated. The residue was diluted with ethyl acetate and saturated
NaHCO3 solution. The organic layer was separated, washed with
brine, dried over MgSO4, and evaporated under reduced pressure
to give 395 mg (84%) of the title compound. 1H NMR (200 MHz,
4-{[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]amino}benzoic Acid Dihydrochloride (8m). Com-
pound 8m was synthesized from 21 and 4-mthoxycarbonylphenyl-
boronic acid according to the procedure described for the conversion
of 16a to 8k (42%). 1H NMR (200 MHz, DMSO-d6): δ 2.83–3.17
(m, 6H), 4.01 (m, 1H), 5.01 (m, 1H), 6.97–7.12 (m, 4H), 7.05–7.47

1942 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Imanishi et al.
(m, 11H), 7.63 (m, 1H), 8.88 (br s, 1H), 9.13 (br s, 1H). MS (ES)
m/e: 409 (M- H). Anal. (C23H23Cl1N2O3 ·2.0HCl) C, H, N.
3-{[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]amino}benzoic Acid Hydrochloride (8n). Com-
pound 8n was synthesized from 21 and 3-methoxycarbonylphe-
nylboronic acid according to the procedure described for the
3.33–3.43 (m, 4H), 4.43 (q, J ) 7.0 Hz, 2H), 4.52 (br, 1H),
4.83–4.50 (m, 1H), 7.26–7.32 (m, 5H), 7.36 (s, 1H), 7.78 (d, J )
8.0 Hz, 1H), 7.99 (d, J ) 8.0 Hz, 2H), 8.33 (dd, J ) 8.0, 2.0 Hz,
1H), 9.26 (d, J ) 2.0 Hz, 1H). MS (ES) m/e: 547 (M+ Na).
6-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]nicotinic Acid Hydrochloride (8o). Compound 8o
was synthesized from 61 according to the general procedure F
(93%). 1H NMR (200 MHz, DMSO-d6): δ 3.08–3.24 (m, 6H),
5.00–5.07 (br, 1H), 7.34–7.47 (m, 6H), 8.09–8.17 (m, 3H),
8.31–8.38 (m, 1H), 8.98 (br, 1H), 9.12–9.16 (m, 1H), 9.30 (br, 1H).
MS (ES)m/e: 395 (M - H). Anal. (C22H21Cl1N2O3 ·2.0HCl ·0.5H2O)
C, H, N.
1
conversion of 16a to 8k (46%). H NMR (200 MHz, DMSO-d6):
δ 2.91–3.18 (m, 6H), 4.04 (m, 1H), 5.01 (m, 1H), 7.02 (d, J ) 8.7
Hz, 2H), 7.12–7.23 (m, 4H), 7.34–7.48 (m, 4H), 7.77 (d, J ) 8.7
Hz, 2H), 8.88 (br s, 1H), 9.13 (br s, 1H). MS (ES) m/e: 409 (M-
H). Anal. (C23H23Cl1N2O3 ·1.0HCl·1.0H2O) C, H, N.
6-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenoxy]nicotinic Acid Hydrochloride (8q). To a mixture
of 16a (200 mg, 0.51 mmol) in DMSO (6 mL) were added ethyl
6-chloronicotinate (142 mg, 0.76 mmol) and K2CO3 (210 mg, 1.52
mmol) at a room temperature, and the mixture was stirred at the
80 °C for 2 h. The resulting mixture was poured into a mixture of
EtOAc and water, and the organic layer was washed with brine.
After the solvent was evaporated under reduced pressure, the residue
was purified by column chromatography on silica gel to give a
coupling product (210 mg, 76%). Compound 8q was synthesized
from the coupling product according to the general procedure F
(79%). 1H NMR (200 MHz, DMSO-d6): δ 2.86–3.22 (m, 6H),
5.01–5.05 (m, 1H), 6.72 (d, J ) 8.5 Hz, 2H), 7.01–7.18 (m, 3H),
7.36–7.48 (m, 6H), 8.28 (dd, J ) 8.5, 2.0 Hz, 1H), 8.65 (d, J )
2.0 Hz, 12H), 8.91 (br, 1H), 9.20 (br, 1H). MS (ES) m/e: 411(M-
H). Anal. (C22H21Cl1N2O4 ·1.0HCl·1.0H2O) C, H, N.
tert-Butyl Benzyl[2-(4-bromophenyl)ethyl]carbamate (57). To
a solution of 27 (4.7 g, 16.2 mmol) in THF (60 mL) was added
di-tert-butyl dicarbonate (3.7 g, 16.9 mmol), and the mixture was
stirred at room temperature for 16 h. The mixture was partitioned
between EtOAc and water. The organic layer was separated, washed
with water and brine, dried over MgSO4 and evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (hexane/EtOAc ) 8/1–5/1) to give 5.8 g (92%)
of the title compound. 1H NMR (200 MHz, CDCl3): δ 1.46 (s,
9H), 2.72 (br, 2H), 3.36 (br, 2H), 4.32–4.38 (m, 2H), 6.99 (br, 2H),
7.21–7.41 (m, 7H). MS (ES) m/e: 390 (M+ H).
4-{[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]thio}phenol (63). A solution of 62 (295 mg, 1.2
mmol) and (2R)-2-(3-chlorophenyl)oxirane 26 (167 mg, 1.08 mmol)
in DMSO (3.5 mL) was added BSA (122 mg, 0.6 mmol), and the
mixture was stirred at 80 °C for 14 h. The reaction was quenched
with 5% AcOH in MeOH (2.0 mL). The mixture was partitioned
between EtOAc and water. The organic layer was separated, washed
with aq NaHCO3, water, and brine, dried over MgSO4, and
evaporated. The residue was purified by column chromatography
on silica gel (CHCl3/MeOH ) 20/1) to give 155 mg (32%) of the
title compound. 1H NMR (200 MHz, CDCl3): δ 2.60–2.97 (m, 6H),
2.88 (s, 1H), 4.61–4.67 (m, 1H), 6.79–6.83 (m, 2H), 7.04–7.38 (m,
10H). MS (ES) m/e: 400 (M+ H).
(4-{[4-(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-
ethyl)phenyl]thio}phenoxy)acetic Acid Hydrochloride (8e). Com-
pound 8e was synthesized from 63 according to the procedure
described for the conversion of 54 to 8d (64%). 1H NMR (200
MHz, DMSO-d6): δ 2.94–3.33 (m, 6H), 4.70 (s, 2H), 4.97–5.01
(m, 1H), 6.34 (br, 1H), 6.96 (d, J ) 8.7 Hz, 2H), 7.02–7.23 (m,
4H), 7.33–7.45 (m, 6H), 8.97–9.18 (br, 1H). HRMS (M + H)+
found, 458.1198; calcd for C24H25Cl1N1O4S1, 458.1193. Anal.
(C24H24Cl1N1O4S1 ·1.0HCl) C, H, N.
Biological Materials and Methods. In Vitro Experiments.
(1). Cell Culture. We used stably transfected Chinese hamster
ovary (CHO) cells expressing recombinant human ꢀ1-, ꢀ2-, and
ꢀ3-ARs and recombinant canine ꢀ3-AR. CHO cells were seeded 2
days before the assays in 96-well plates at a density of 1-1.3 ×
104 cell/well.
(2). cAMP Accumulation Assay. CHO cells grown to conflu-
ence were washed twice with assay buffer [130 mM NaCl, 5 mM
KCl, 1 mM MgCl2 ·6H2O, 1.5 mM CaCl2 ·2H2O, 10 mM glucose,
10 mM glucose, 10 mM HEPES, 0.1% bovine serum albumin, pH
7.4] and incubated with 180 µL of assay buffer containing 0.5 mM
3-isobutyl-methylxanthine (IBMX) at 37 °C for 10 min. Test
compound (20 µL) dissolved in assay buffer containing 1% DMSO
was then added and cells were incubated at 37 °C for 15 min, the
reaction was stopped by addition of 80 µL of 0.1 mol/L HCl. After
1 h at 4 °C, cells were centrifuged at 2000 rpm for 5 min at 4 °C.
The amount of cAMP in the supernatant was determined using a
cAMP enzyme immunoassay (EIA) kit (Amersham Biosciences).
The supernatant was frozen below –80 °C until the measurement
of cAMP levels.
(3). Data Analysis. cAMP accumulation elicited by test com-
pounds were expressed as a percentage of the maximal response
to isoproterenol. The 50% effective concentration (EC50) values
were calculated using GraphPad Prism (Ver.3.03) from the con-
centration–response curve.
In Vivo Experiments. (1). Materials and Methods. Female
beagle dogs (11.5–15.0 kg, Oriental Yeast Co., Ltd.) were deprived
of food and water from about 40 and 17 h before administration,
respectively. A group of five dogs were used for the whole study.
Under halothane anesthesia, a catheter was inserted into the urinary
bladder through the urethra and connected to a pressure transducer
to measure intravesical pressure (IVP). Carbachol (1.8 µg/0.2 mL/
kg, saline solution) was given intravenously (via the saphenous vein)
several times at intervals of about 30 min. A polyethylene tube for
intraduodenal (i.d.) administration was inserted into the duodenum
at about 15 cm from the pylorus using an endoscope. When
4-{2-[Benzyl(tert-butoxycarbonyl)amino]ethyl}phenylboronic
Acid (58). Compound 58 was synthesized from 57 according to
1
the general procedure B (63%). H NMR (200 MHz, CDCl3): δ
1.47 (s, 9H), 2.80 (br, 2H), 3.39 (br, 2H), 4.30–4.44 (m, 2H),
7.22–7.32 (m, 7H). MS (ES) m/e: 354 (M- H).
Ethyl
6-(4-{2-[Benzyl(tert-butoxycarbonyl)amino]ethyl}-
phenyl)nicotinate (59). Compound 59 was synthesized from 58
and ethyl 6-chloronicotinate according to the general procedure E
1
(80%). H NMR (200 MHz, CDCl3): δ 1.42 (t, J ) 7.0 Hz, 3H),
1.46 (s, 9H), 2.85 (br, 2H), 3.41 (br, 2H), 4.34–4.48 (m, 2H), 4.43
(q, J ) 7.0 Hz, 2H), 7.25–7.38 (m, 7H), 7.78 (d, J ) 8.0 Hz, 1H),
7.98 (d, J ) 8.0 Hz, 2H), 8.33 (dd, J ) 8.0, 2.0 Hz, 1H), 9.27 (d,
J ) 2.0 Hz, 1H). MS (ES) m/e: 461 (M+ H).
Ethyl
6-[4-(2-{Benzyl[(2R)-2-(3-chlorophenyl)-2-hydro-
xyethyl]amino}ethyl)phenyl]nicotinate (60). To the mixture of 59
(790 mg, 1.71 mmol) in THF (6 mL) was added 4 N HCl in dioxane
(3.5 mL). The mixture was stirred at room temperature for 20 h
and evaporated under reduced pressure to give crude solid. The
solid was washed with IPE to give 750 mg (quantitative yield) of
ethyl 6-{4-[2-(benzylamino)ethyl]phenyl}nicotinate hydrochloride.
MS (ES) m/e: 461 (M + H). Compound 60 was synthesized from
the above product using Et3N (1.5 equiv) according to the procedure
described for the conversion of 27 to 28 (39%). 1H NMR (200
MHz, CDCl3): δ 1.43 (t, J ) 7.0 Hz, 3H), 2.60–2.97 (m, 6H), 3.61
(d, J ) 13.5 Hz, 1H), 3.97 (d, J ) 13.5 Hz, 1H), 4.43 (q, J ) 7.0
Hz, 2H), 4.57–4.64 (m, 1H), 7.16–7.31 (m, 11H), 7.79 (d, J ) 8.0
Hz, 1H), 7.96–8.01 (m, 2H), 8.31 (dd, J ) 8.0, 2.0 Hz, 1H),
9.26–9.27 (m, 1H). MS (ES) m/e: 515 (M+ H).
Ethyl 6-[4-(2-{(tert-Butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-
2-hydroxyethyl]amino}ethyl)phenyl]nicotinate (61). Compound
61 was synthesized from 60 according to the procedure described
for the conversion of 53 to 55 (39%). 1H NMR (200 MHz, CDCl3):
δ 1.43 (t, J ) 7.0 Hz, 3H), 1.47 (s, 9H), 2.75–2.87 (m, 2H),

Human ꢀ3-Adrenergic Receptor Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1943
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reproducible responses (increase in IVP) were obtained, compound
10e (10, 32, and 100 µg /kg) was given intraduodenally. A total of
30 min after test compound administration, carbachol injection was
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comparison test compared to the vehicle group. ED50 values were
calculated by least-squares linear regression analysis using maxi-
mum percent inhibition at each dose. All values were expressed as
mean ( SE.
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Acknowledgment. We express our thanks to Dr. David
Barrett for his critical reading of this manuscript.
Note Added after ASAP Publication. This manuscript was
released ASAP on February 29, 2008 with an error in Results and
Discussion. The correct version was posted on March 4, 2008.
Supporting Information Available: Combustion analysis data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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