Discovery of a novel series of benzoic acid derivatives as potent and selective human β3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety

Article abstract of DOI:10.1021/jm800222k

We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds (10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC₅₀ = 0.38 nM) for β₃, high selectivity over β₁ and β₂, and good pharmacokinetic properties in rats, dogs, and monkeys.

Full text of DOI:10.1021/jm800222k

4804
J. Med. Chem. 2008, 51, 4804–4822
Discovery of a Novel Series of Benzoic Acid Derivatives as Potent and Selective Human ꢀ3
Adrenergic Receptor Agonists with Good Oral Bioavailability. 3. Phenylethanolaminotetraline
(PEAT) Skeleton Containing Biphenyl or Biphenyl Ether Moiety
Masashi Imanishi,† Yutaka Nakajima,† Yasuyo Tomishima,† Hitoshi Hamashima,† 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 &
Pharmacokinetic Research Laboratories, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
ReceiVed March 2, 2008
We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the
RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective
synthesis, to generate two structurally different lead compounds (10c, 10m) with a good balance of potency,
selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency
led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited
an excellent balance of high potency (EC50 ) 0.38 nM) for ꢀ3, high selectivity over ꢀ1 and ꢀ2, and good
pharmacokinetic properties in rats, dogs, and monkeys.
Introduction
ꢀ1- and ꢀ2-ARs has been an important goal of recent research.
In the past decade, drug discovery efforts have shifted toward
the design of selective agonists for the ꢀ3-AR. Furthermore,
several groups have reported a number of 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 5 (LY377604),9,10 6 (L796568),11
and 7 (solabegron)12 (see Figure 2), but these are still not
sufficient in terms of the pharmacokinetic properties.9,13,14
The ꢀ3-adrenergic receptor (ꢀ-ARa), which is present on the
surface of both white and brown adipocytes, plays a significant
role in regulating lipolysis and thermogenesis in rodent and
human adipocyte tissues.1,2 It has been reported that stimulation
of ꢀ3-AR induces a variety of pharmacological effects such as
an increase in fat oxidation, enhancement of energy expenditure,
and improvement of insulin-mediated glucose uptake in rodent
models, and thus, ꢀ3-AR agonists have been developed as
therapeutic candidates for obesity and type II diabetes.3 Recent
studies have indicated that in addition to adipocytes, the ꢀ3-
AR is also distributed in human heart, gall bladder, gastrointes-
tinal tract, prostate,4 and urinary bladder detrusor tissue;
therefore, new therapeutic applications of ꢀ3-AR agonists in the
treatment of gastrointestinal and overactive bladder (OAB) have
been studied.5–8 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 1 (BRL37344),9 2 (CL316243),9 3
(SR58611A),9 and 4 (FK175),8c as shown in Figure 1, have
been reported to be effective antiobesity and antidiabetic agents
in rodents. Unfortunately, 1, 2, and other ꢀ3-AR agonists
discovered during the 1980s were unsuccessful in the clinic
either because of a lack of efficacy or an unfavorable cardio-
vascular side effect profile, and/or poor pharmacokinetics.3 Thus,
a second generation of orally bioavailable human ꢀ3-AR agonists
with minimal side effects associated with activation of human
In our laboratory, our first clinical candidate 4, having a
benzocycloheptene ring and carboxylic ester functionality
(prodrug 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 ꢀ3-AR potency and long duration for
OAB treatment, since in the field of treatment of urinary bladder
dysfunction, there is an unmet medical need for a once daily
oral administration. On the other hand, in the early 1990s,
Sanofi-Midy (now Sanofi-Aventis) identified a series of a
phenylethanolaminotetralines (PEATs), similar to 4 as a com-
mon structure for the RHS region, as selective ꢀ3-AR agonists
in rodents.15 Among this series of PEATs, 3 was found to have
the best profile as a ꢀ3-AR agonist. Although 3 is less potent
than isoproterenol (a nonselective ꢀ-AR agonist) and 4, it was
developed as a potential treatment for irritable bowel syndrome
and obesity and then for depression.13
Recently, we have disclosed16 a novel series of biphenyl-
benzoic acid derivatives as potent and selective human ꢀ3-AR
agonists that are orally bioavailable with a long duration. We
demonstrated that the biphenyl 8 and biphenyl ether 9 templates
with a benzoic acid moiety are essential for the good pharma-
cokinetic properties in our previous series.16 To overcome
several problems of 3 and 4, we planned a discovery process
for a novel tetraline series of second generation ꢀ3-AR agonists,
as shown in Figure 3. Our designed general ꢀ3-AR agonist
structure 10 (see Figure 3) involved construction of the PEAT
skeleton with two chiral centers from 3 or 4, and the biphenyl
(8) or biphenyl ether (9) templates with a benzoic acid moiety,
* 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 & Pharmacokinetic Research Laboratories.
‡
§
#
a Abbreviations: ꢀ-AR, ꢀ-adrenergic receptors; OAB, overactive bladder;
SAR, structure-activity relationship; PEATs, phenylethanolaminotetralines;
RHS, right-hand side; LHS, left-hand side; cAMP, cyclic adenosine
monophosphate; ISP, isoproterenol; CHO, Chinese hamster ovary.
10.1021/jm800222k CCC: $40.75
2008 American Chemical Society
Published on Web 07/24/2008

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4805
Figure 1. Representative first generation of ꢀ3-AR agonists.
Figure 2. Representative second generation of ꢀ3-AR agonists.
which are important for not only ꢀ3-AR agonistic activity but
also pharmacokinetic properties.
by deprotection of TBS group, coupling with bromoethyl acetate,
alkaline hydrolysis of the ester, and deprotection of the Boc
group with 4 N HCl. Similarly, benzoic acid analogues (10c-f)
were prepared from Boc amine derivatives 29a-d, which were
obtained by coupling of phenol derivative 24 or 26 with
methoxycarbonylphenylboronic acid, followed by alkaline hy-
drolysis of the methyl ester derivatives (29a-d) and deprotec-
tion of the Boc group with 4 N HCl. The pyridine ether 10g
was obtained through nucleophilic displacement of commercially
available ethyl 6-chloronicotinate with phenol 24, followed by
alkaline hydrolysis and deprotection of the Boc group (Scheme
6). Also, pyridine ether 10h was obtained by selective oxidation
of aldehyde 31, followed by deprotection of the Boc group
(Scheme 6). The thiophene analogue 10i was prepared from
phenol 24 according to the procedure described for the conver-
sion of 24 to 10h. The synthetic route to c 11a-o is shown in
Scheme 5. Similar to the conversion of 24 to 10c in Scheme 3,
the targets 11a-d, 11k-l were prepared by coupling of 24 or
25 or 27 with commercially available boronic acid 34, 35, or
synthetic boronic acids 33 and 36 as shown in Scheme 11.16
The amino analogues 11e-j were synthesized from 4-amino
intermediate 39. Coupling of phenol 24 with nitrophenylboronic
acid 37, followed by reduction with Fe and NH4Cl, gave 39.
The target 11e was prepared by alkaline hydrolysis of 39,
followed by deprotection of the Boc group with 4 N HCl.
Aniline 39 was coupled with acetic anhydride in the presence
of pyridine, followed by the typical method to give acetyl
analogue 11g. The NMe2 analogue 11f was obtained through
reductive amination of aniline 39 with formaldehyde with
NaBH(OAc)3, followed by alkaline hydrolysis and deprotection
of the Boc group. In the same way, the p-chloropyridine
analogue 11p was prepared via coupling of phenol derivative
27 with nitrophenylboronic acid 37. Similarly, the amino
analogues 11i, 11j were prepared by reductive amination of
aniline 32 with the corresponding ketones. The NH-n-Pr
analogue 11h was obtained from coupling of aniline 39 with
n-Pr-I. The p-chlorophenyl or chloropyridine analogues 11k,l,n,o
were prepared via the coupling of phenol derivative 25 or 27
with commercially available boronic acids as shown in Scheme
5. In the same way, pyridine analogue 11m was obtained from
27, in an additional step, through dechlorination by catalytic
hydrogenation in the presence of HCO2NH4.
We investigated the structure-activity relationship (SAR) and
pharmacokinetic properties of a PEAT series of compounds 10,
employing a cassette dosing assay by in vivo dog pharmaco-
kinetic assay17 to generate two different lead compounds (10c,
10k) having biphenyl ether and biphenyl templates containing
a benzoic acid moiety, with a good balance of potency,
selectivity, and pharmacokinetic profile. Further optimization
of the two different lead compounds (general structures 11 and
12) to improve potency led to several potential candidates (i.e.,
11f, 11l, 11o, 12b). The synthesis of these compounds with two
chiral centers, the results of in vitro and cassette dosing assays,
and the PK profiles of our drug candidates are described in detail
in the following sections.
Chemistry
The requisite chiral amine intermediate 15 was prepared via
asymmetric hydrogenation of the enamide 14(Scheme 1). Since
there are similar examples of highly enantioselective hydro-
genation,18 we applied this reaction to the asymmetric synthesis
of the aminotetraline 18, as shown in Scheme 1. Conversion of
the 7-methoxy-2-tetralone 13 to the enamide 14 was ac-
complished by condensation with benzamide in the presence
of Amberlyst-15 resin under Dean-Stark conditions, followed
by asymmetric hydrogenation with a Ru complex. The screening
of chiral ligands identified Ru(II)-(S)-SEGPOS 19 (by Takasago
Co. Ltd.) as an optimal ligand to give a chiral amine 15 with
high enantioselectivity. After recrystallization, 15 was obtained
in 74% yield and 99.6% ee. Treatment of enantiomerically pure
15 with BH3 ·SMe2, affording the corresponding benzyl inter-
mediate 16, followed by removal methyl group with BBr3 and
hydrogenolysis of the benzyl group furnished aminotetraline 18
in 50% overall yield from 15. The requisite intermediate PEATs
derivatives 24-27 with two chiral centers were prepared as
shown in Scheme 2. In general, coupling of the chiral amine
18 or 19, which has previously been described,19 with the chiral
epoxides 21-23, followed by protection of the amine with a
Boc group gave phenol derivatives 24-27.
The general synthetic route to biphenyl ether targets (10a-i)
is shown in Schemes 3 and 4. The phenoxyacetic acid analogues
(10a,b) were obtained by coupling of phenol derivative 24 with
boronic acid using Cu(OAc)2 and MS4 Å in CH2Cl2, followed

4806 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
Figure 3. Design and discovery process of lead generation and lead optimization.
Scheme 1a
a (a) 3 N HCl, toluene; (b) PhCONH2, Amberlyst-15 (50% wt %), toluene, reflux; (c) H2 (30 atm), Ru(II)/SEGPHOS, MeOH, CH2Cl2; (d) BH3 ·SMe2,
THF, then 6 N HCl; (e) BBr3, CH2Cl2; (f) H2, 10% Pd/C, MeOH.
The general synthetic route to biphenyl targets (10j-p) is
shown in Scheme 6. Suzuki cross-coupling of triflate derivatives,
which were prepared by reaction of the corresponding phenol
derivative 24 or 26 with Tf2O/2,6-lutidine in CH2Cl2 at low
temperature, with commercially available boronic acids, fol-
lowed by alkaline hydrolysis of the methyl ester and deprotection
of the Boc group with 4N HCl, provided biphenyl targets
(10l-o). Similarly, the phenoxyacetic acid analogues 10j,k were
prepared from coupling product 38a,b, followed by using the
same method described for 10a,b. The thiophene analogue 10p
was prepared from coupling product 40 followed by using the
same method described for 10i. The general synthetic route to
biphenyl targets (12a,b,d-f,h) is shown in Scheme 7. The
requisite biphenyl intermediate 43 was prepared as follows: the
chiral aminotetraline 18 was protected with a Cbz group, and
protection of the phenol 41 with a triflate group, followed by
Suzuki coupling with boronic acid and deprotection of the Cbz
group, furnished biphenyl intermediate 43. As shown in Scheme
7, the required optically active epoxides (>97% ee) were
prepared through the our previous asymmetric synthetic pro-
cedures20 as shown in Scheme 10. Ring opening of epoxides
with amine 43 in ethanol under reflux followed by alkaline

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4807
Scheme 2a
a EtOH, reflux, then (Boc)2O, THF.
Scheme 3a
a (a) Boric acid, Cu(OAc)2, 4 Å molecular sieves, CH2Cl2; (b) Bu4NF (1 M in THF), THF, then BrCH2CO2Et, K2CO3, DMF; (c) 1 N aqueous NaOH,
MeOH, then 4 N HCl/AcOEt or dioxane.
Scheme 4a
a (a) K2CO3, DMSO, 80°C; (b) 1 N aqueous NaOH, MeOH, then 4 N HCl/AcOEt or dioxane; (c) 30% H2O2, 80% NaClO2, MeCN, then 4 N HCl/dioxane.
hydrolysis of the methyl ester provided the target compounds
as sodium salts. Similarly, the biphenyl targets 12c were
prepared as hydrochloride salts by coupling of amine 43 with
epoxide 44, followed by alkaline hydrolysis, deprotection of
the Boc group with 4 N HCl, as shown in Scheme 8. In a similar
manner, pyridine analogue 12g was obtained from 23 and 43,
in an additional step, through dechlorination by catalytic
hydrogenation in the presence of HCO2NH4.
Finally, the synthetic route to substituted biphenyl analogues
12i-n is shown in Scheme 9. Similar to the conversion of 24
to 1m in Scheme 6, reaction of p-chlorophenyl derivative 25
with Tf2O followed by Suzuki-coupling of the triflate derivative
with R-substituted boronic acid, the synthesis of which has been
previously described,16 and ester hydrolysis and deprotection
of the Boc group provided the target compounds 12i-n as
hydrochloride salts.
Results and Discussion
All compounds were evaluated for 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.16 The details are
described in the Experiment Section. Pharmacokinetic properties
of selected compounds were evaluated by cassette dosing assay

4808 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
Scheme 5a
a (a) Cu(OAc) , 4 Å molecular sieves, CH2Cl2; (b) 1 N aqueous NaOH, MeOH, then 4 N HCl/AcOEt or dioxane; (c) 30% H2O2, 80% NaClO2, MeCN,
2
then 4 N HCl/dioxane; (d) 1 N aqueous NaOH, EtOH, then HCO2NH4, 10% Pd/C, MeOH, H2O, reflux, then 4 N HCl/dioxane; (e) Fe (powder), NH4Cl,
EtOH, reflux; (f) 35% HCHO, NaBH(OAc)3, AcOH, CH2Cl2; (g) Ac2O, pyridine, CH2Cl2; (h) I-n-Pr, K2CO3, DMF, 80°C; (i) cyclohexanone or tetrahydro-
4H-pyran-4-one, NaBH(OAc)3, AcOH, CH2Cl2.
Scheme 6a
a (a) Tf2O, 2,6-lutidine, CH2Cl2, -78°C; (b) boric acid, Pd(PPh3)4, aqueous NaHCO3, DME, 70°C; (c) 1 N aqueous NaOH, MeOH, then 4 N HCl/AcOEt
or dioxane; (d) Bu4NF (1 M in THF), THF, then BrCH2CO2Et, K2CO3, DMF; (e) 30% H2O2, 80% NaClO2, MeCN, then 4 N HCl/dioxane.
in dogs.21 The results with reference compound isoproterenol
(ISP; nonselective ꢀ-AR agonist) are shown for comparison in
Table 1.
To assess the quality of our designed aminotetraline analogues
(compound 10) as potent, selective ꢀ3-AR agonists, we first
prepared a series of biphenyl ethers with six-membered rings
with phenoxyacetic acid in the terminal phenyl ring (Table 1,
10a,b). Although phenoxyacetic acid analogues 10a, 10b
showed moderate agonistic activity for the ꢀ3-AR, we felt that
the profile of these compounds was insufficient in terms of
potency for ꢀ3-AR. Next, we investigated the effect of
modification of the carboxylic acid moiety. Biphenyl ether
analogues (10c-f) having a benzoic acid moiety in both six-
and seven-membered rings were prepared and examined.
Analogues containing a meta carboxylic acid (10c, 10e) showed
improved ꢀ3-AR activity (10c, EC50 ) 7.1 nM; 10e, EC50
)
4.5 nM) relative to phenoxyacetic acid analogues (10a,b), 3 and
4. On the other hand, para-position analogues (10d, 10f) resulted
in poor potency for ꢀ3-AR. The seven-membered ring analogue
10e showed somewhat improved potency, although lower

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4809
Scheme 7a
a (a) Cbz-Cl, THF, H2O with aqueous NaOH (pH 7-8); (b) Tf2O, 2,6-lutidine, CH2Cl2; (c) boric acid, Pd(PPh3) , aqueous NaHCO3, DME, 70°C; (d)
4
H2, 10% Pd/C, MeOH; (e) EtOH, reflux; (f) 1 N aqueous NaOH, EtOH.
Scheme 8a
a (a) EtOH, reflux, then (Boc)2O, THF; (b) 1 N aqueous NaOH, MeOH, then 4 N HCl/AcOEt; (c) 1 N aqueous NaOH, EtOH, then HCO2NH4, 10% Pd/C,
MeOH, H2O, reflux; (d) 4 N HCl/dioxane.
Scheme 9a
a (a) Tf2O, 2,6-lutidine, CH2Cl2, -78°C; (b) boric acid, Pd(PPh3)4, aqueous NaHCO3, DME, 70°C; (c) 1 N aqueous NaOH, MeOH, then 4 N HCl/AcOEt
or dioxane.
selectivity over ꢀ1 activity (10e, ꢀ1/ꢀ3 ) 35) compared to the
six-membered ring analogue 10c (ꢀ1/ꢀ3 > 138). Also, both 10c
and 10e exhibited low activity for the ꢀ2-AR (EC50 > 1000
nM).
Furthermore, biphenyl ether analogues (10a, 10c, 10e) were
evaluated in the in vivo PK assay (cassette dosing assay, po) in
dogs. As a baseline, the Cmax and AUC ratio value of 10a are
presented as 1.0 for comparison in Table 1. The benzoic acid
group (six-membered ring analogue 10c) showed a superior Cmax
and AUC ratio relative to the phenoxyacetic acid analogue 10a.
On the other hand, seven-membered ring analogue 10e showed
a low Cmax and AUC level relative to 10c. This result (10a vs
10c) in which the benzoic acid moiety may result in improve-
ment of the Cmax and AUC level indicated the same trend as
we have previously demonstrated.16 Actually, the Cmax and AUC
ratio of compound 10c displayed a superior level compared with
our previous compounds 8 and 9.
Next, we investigated replacement of the terminal phenyl ring
of the biphenyl ether analogues with typical heterocycles. A
pyridine analogue containing a p-carboxylic acid 10g showed
strong ꢀ3-AR agonistic activity (EC50 ) 1.4 nM) but a lower
ꢀ1/ꢀ3 selectivity (ꢀ1/ꢀ3 ) 50) relative to the biphenyl ether

4810 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
Scheme 10. General Synthetic Route to Optically Active
superior in vitro profiles (potency and selectivity) and PK
profiles (Cmax and AUC revel) relative to the seven-membered
ring series. Table 2 shows pharmacokinetic data in dogs (cassette
dosing assay, po and iv) of selected compounds (10c,e,g,k,m).
All three biphenyl ether analogues (10c, 10e, 10g) showed good
oral bioavailability (F > 60%). In particular, the benzoic acid
six-membered ring analogue 10c displayed lower total clearance
(CL ) 2.4 (mL/min)/kg), longer plasma half-life (t1/2 ) 7.9 h),
and better bioavailability relative to seven-membered ring
analogue 10e and pyridine ring analogue 10g. Likewise,
biphenylbenzoic acid analogue 10m exhibited a superior PK
profile with lower total clearance (CL ) 1.2 (mL/min)/kg), long
plasma half-life (t1/2 ) 12.2 h), and good oral bioavailability
(F ) 71.4%) relative to the corresponding phenoxyacetic acid
analogue 10k. In comparison with 3 and 4 (see Table 5), both
compounds 10c and 10m displayed an improvement of plasma
half-life and lower total clearance and maintained good oral
bioavailability. The results of the SAR study and cassette dosing
assay led to the generation of two structurally different lead
compounds 10c and 10m with a superior balance of potency,
selectivity, and pharmacokinetic profile relative to both 3 and
our previous clinical candidate 4. Next, we focused our attention
on further optimization of these series of biphenyl ether (see
Table 3) and biphenyl analogues (see Table 4) to improve ꢀ3-
AR potency.
Epoxidesa
a (a) AD-mix-ꢀ, t-BuOH·H2O, 0°C; (b) TMSCl, MeC(OMe)3, CH2Cl2,
4 °C, then K2CO3, MeOH.
Scheme 11. Preparation of Phenylboronic Acids 33 and 36a
a (a) KOAc, pinacol diborane, PdCl2 (PPh3)2, dioxane, 100°C; (b) NaIO4,
NH4OAc, acetone, H2O; (c) Tf2O, 2,6-lutidine, CH2Cl2; (d) KOAc, pinacol
diborane, PdCl2(dppf)·CHCl3, dioxane, 100°C.
First, in an effort to improve ꢀ3-AR potency of the biphenyl
ether analogue 10c, we initially investigated the effect of R2-
substituents on the terminal phenyl ring. Introduction of various
substituents (Me, Cl, OMe) at the 4-position gave biphenyl ether
analogues (11a-c). 4-Methoxy analogue 11c maintained po-
tency; however, 11a and 11b had less potency and selectivity
for ꢀ1 than the original compound 10c. Also, 5-methoxy
analogue 11d showed somewhat improved potency relative to
10c. Next, we examined some amino substituents at the
5-position. The 5-NH2 analogue 11e and 5-N-Me2 analogue 11f
displayed increased ꢀ3 potency ꢀ3 (EC50 ) 3.2 nM), and 11f
showed good selectivity (ꢀ1/ꢀ3, ꢀ2/ꢀ3 > 312) relative to 10c.
In addition, 5-NH-acetyl analogue 11g showed increased ꢀ3
potency by about 5.5-fold (EC50 ) 1.3 nM) relative to 1c and
good selectivity for ꢀ1 (ꢀ1/ꢀ3 ) 277).
Furthermore, compounds 11e-g were evaluated in a cassette
dosing assay. As a result, the 3-NH2 analogue 11e and NH-
acetyl analogue 11g had a greatly lowered Cmax and AUC ratio
relative to the parent compound 11c. On the other hand, 5-NMe2
analogue 11f maintained a good Cmax and AUC level, similar
to 11c. We next tried to replace the acetyl group of 11g (ClogP
) 2.72) with a lipophilic alkyl group to improve potency and
the PK properties of 11g. The NH-n-Pr analogue 11h (ClogP
) 4.31) showed improved ꢀ3 potency (EC50 ) 0.77 nM) but
slightly lower selectivity (ꢀ1/ꢀ3 ) 224). The more lipophilic
and bulky cyclohexyl analogue 11i (ClogP ) 5.28) resulted in
the same potency for ꢀ3 (EC50 ) 0.78 nM) relative to the n-Pr
analogue 11h while showing increased potency for ꢀ1 and
therefore a lower ꢀ1/ꢀ3 selectivity (ꢀ1/ꢀ3 ) 88) compared with
11h. This increased ꢀ1 activity of 11i is likely due to the high
lipophilicity of the cyclohexyl group; therefore, we tried to
replace the cyclohexyl group with a tetrahydropyran group to
adjust the lipophilicity of 11i. As a result, 5-NH-tetrahydropyran
analogue 11j (ClogP ) 2.88) maintained good ꢀ3 potency (EC50
) 1.0 nM) and improved selectivity (ꢀ1/ꢀ3 ) 340) by about
4-fold relative to cyclohexyl analogue 11i. However, in the
cassette dosing assay, the Cmax and AUC levels of 11j showed
poor results.
analogue 10c. Thiophene analogue 10i showed somewhat
increased potency (EC50 ) 5.7 nM) and slightly decreased ꢀ1/
ꢀ3 selectivity (ꢀ1/ꢀ3 ) 117) relative to 10c. These data (10c,
10g, 10i) suggested that a polar group such as pyridine appeared
to influence the activity of ꢀ1 and ꢀ3-AR. In addition, cassette
dosing assay of the heterocycle analogues (10g, 10i) resulted
in decreased Cmax and AUC levels relative to phenyl analogue
10c.
In analogy to the biphenyl ether analogues, a series of
biphenyl analogues with six-membered rings (10j-p) were also
synthesized. As seen in Table 1, p-phenoxyacetic acid analogue
10k showed good potency (EC50 ) 5.8 nM) and selectivity (ꢀ1/
ꢀ3 > 170) relative to the m-phenoxyacetic acid analogue 10j
(EC50 ) 10 nM). Furthermore, p-benzoic acid analogue 10m
showed higher potency (EC50 ) 2.8 nM) relative to m-benzoic
acid analogue 10l (EC50 ) 29 nM) and good selectivity for ꢀ1
(ꢀ1/ꢀ3 > 138) and ꢀ2. However, a seven-membered ring
analogue having a p-benzoic acid moiety (10n) resulted in
dramatically decreased potency for ꢀ3-AR (EC50 > 100 nM)
relative to the six-membered ring analogue 10m. In addition,
we attempted replacement of the terminal phenyl ring of 10m
with pyridine and thiophene. Although a pyridine analogue
containing a p-carboxylic acid 10o resulted in decreased potency
(EC50 ) 9.6 nM) and selectivity for ꢀ1 (ꢀ1/ꢀ3 ) 51), thiophene
analogue 10p maintained good potency (EC50 ) 2.4 nM) and
ꢀ1/ꢀ3 selectivity (ꢀ1/ꢀ3 > 417) relative to 10m.
Next, biphenyl analogues 10k, 10m, 10p with good in vitro
profiles were evaluated in a cassette dosing assay. As expected,
analogue 10m having a benzoic acid moiety displayed a good
Cmax and AUC ratio similar to the biphenyl ether analogue 10c.
On the other hand, analogue 10k having a phenoxyacetic acid
moiety showed lower Cmax and AUC revel relative to benzoic
acid analogue 10m. While thiophene analogue 10p resulted in
good Cmax and AUC levels, the AUC ratio of 10p showed 2.5-
fold lower level relative to 10m.
In consideration of the SAR study in Table 1, for both the
biphenyl ether and biphenyl template, the position of the
carboxylic acid moiety is important for ꢀ3-AR activity and
selectivity. In addition, the six-membered ring series showed

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4811
Table 1. SAR of Aminotetraline Analogues
cassette assay (po)c
human ꢀ3 EC50,
human ꢀ1 EC50,
nMa
human ꢀ2
compd
n
X
Y
R
nMa (IAb)
ꢀ1/ꢀ3
EC50, nMa
Cmax ratiod
AUC ratioe
10a
10b
10c
10d
10e
10f
10g
10h
10i
1
1
1
1
2
2
1
1
1
1
1
1
1
2
1
1
O
O
O
O
O
O
O
O
CH
CH
CH
CH
CH
CH
N
m-OCH2CO2H
p-OCH2CO2H
m-CO2H
p-CO2H
m-CO2H
p-CO2H
p-CO2H
o-CO2H
-CO2H
m-OCH2CO2H
p-OCH2CO2H
m-CO2H
p-CO2H
p-CO2H
p-CO2H
-CO2H
22 ( 4 (0.88)
24 ( 2 (0.88)
7.1 ( 0.05 (0.89)
37 (0.74)
4.5 ( 0.7 (0.98)
>100
1.47 ( 0.3 (1.03)
49 (0.72)
5.7 ( 2 (0.99)
10 ( 1 (0.78)
5.8 ( 0.4 (0.80)
29 (0.68)
>100
>4.5
>4.2
>138
>2.7
35
NT
NT
>1000
NT
>1000
NT
>1000
NT
>1000
NT
>1000
NT
>1000
NT
NT
1.0
NT
2.96
NT
0.84
NT
0.62
NT
0.57
NT
0.44
NT
1.98
NT
1.0
NT
5.27
NT
1.03
NT
0.59
NT
0.47
NT
0.58
NT
5.33
NT
>100
>1000
>100
160 ( 30
>100
70 ( 7.1
>100
670 ( 96.2
>100
>1000
>100
>1000
>100
490
50
>2.0
117
>10
>170
>3.4
>357
N
f
O
10j
10k
10l
10m
10n
10o
10pf
3g
bond
bond
bond
bond
bond
bond
bond
CH
CH
CH
CH
CH
N
2.8 ( 0.3 (0.97)
>100
9.6 ( 0.4 (0.95)
2.4 ( 0.06 (0.95)
39
51
>417
38
>200
>2.6
42
NT
1.45
NT
NT
2.17
NT
>1000
NT
1500
>10000
>10000
NT
>1000
2.0 ( 0.9
4g
8
16 ( 2.0 (0.98)h
39 ( 1 (0.64)
6.7 ( 0.3 (0.96)
0.97 ( 0.14 (1.0)
>3200h
>100
NT
NT
1.60
1.80
NT
2.96
3.92
NT
9
280 ( 40
0.084 ( 0.02
ISPh
0.087
a The results are shown as the mean ( SE (n g 3) or presented as the average of two experiments. NT: not tested. b The intrinsic activity (IA) was defined
as the ratio of the maximal effect of test compound to the maximal effect produced by isoproterenol (10-7 M). c Dose 0.32 or 0.2 mg/kg po (n ) 2-3). See
References for further details. NT: not tested. d The ratio was defined as the Cmax of test compounds to the Cmax of 10a. The ratio value of 10a was presented
f
as 1.0. e The ratio was defined as the AUC of test compounds to the AUC of 10a. The ratio value of 10a was presented as 1.0.
g Data for the carboxylic acid form. h Results are the mean ( SE of five experiments.
Table 2. Pharmacokinetic Profiles of Selected Compounds in Dogsa
po
iv
compd
dose (mg/kg)
Cmax (ng/mL)
AUC0-24h (ng·h/mL)
dose (mg/mL)
T1/2ꢀ (h)
CLtot ((mL/min)/kg)
F (%)b
10c
10e
10g
10k
10m
0.32
0.32
0.32
0.2
151.0
65.7
49.0
21.8
97.4
1998
537.6
319.7
197.2
1983
0.1
0.1
0.1
0.1
0.1
7.9
3.0
2.8
1.9
12.2
2.4
6.8
10.8
8.3
81
69
61
48
71
0.2
1.2
a Cassette assay data. n ) 2-3. The results are presented as the average of two or three experiments. b F ) bioavailability.
Next, we investigated replacement of the 3-chlorophenyl ring
on the left-hand side (LHS) with 4-chlorophenyl or pyridyl ring
groups, as shown in Table 3. 4-Chlorophenyl ring analogues
11k, 11l resulted in slightly improved potency relative to
3-chlorophenyl ring analogues (10c, 11c), and 4-methoxy
analogue 11l showed superior selectivity (ꢀ1, ꢀ2; EC50 > 1000
nM, ꢀ1, ꢀ2/ꢀ3 > 217) relative to nonsubstituted analogue 11k.
Nonsubstituted pyridyl ring analogue 11m showed decreased
potency for ꢀ3 relative to 10c. On the other hand, the
4-chloropyridyl ring derivatives (11n, 11o) also had improved
potency relative to 10c, and 4-methoxy analogue 11o exhibited
higher selectivity for ꢀ1 (ꢀ1, ꢀ2; EC50 > 1000 nM, ꢀ1, ꢀ2/ꢀ3
> 277) relative to 11n. In addition, the 5-NMe2 substituted
4-chloropyridyl ring analogue 11p showed significantly in-
creased potency (EC50 ) 1.8 nM) but lower selectivity relative
to the 4-methoxy analogue 11o. Therefore, 4-methoxy analogues
11l and 11o with good selectivity for ꢀ1 and ꢀ2 were evaluated
in the cassette dosing assay. The 4-chlorophenyl ring analogue
11l showed slightly decreased Cmax and AUC ratio relative to
the lead compound 10c. The 4-chloropyridyl ring analogue 11o
also showed acceptable Cmax and AUC levels.
Second, as can be seen in Table 4, in an effort to improve
the ꢀ3-AR potency of biphenyl analogue 10m, we initially
attempted to modify the LHS because this modification in the
biphenyl ether series in Table 3 resulted in improved potency
for ꢀ3. Shift of the chloro group to the 2-position (12a) led to
a substantial loss of potency. On the other hand, 4-chlorophenyl
analogue 12b resulted in 5.5-fold increased potency (EC50
)
0.38 nM) for ꢀ3 relative to 3-chlorophenyl analogue 10m and
high selectivity for ꢀ1 and ꢀ2 (ꢀ1/ꢀ3 ) 2413, ꢀ2/ꢀ3 > 2630).
On the basis of this result, we investigated replacement of chloro
group with other substituents at the 4-position. As a result, the
methyl analogue (12c) had 2-fold less potency (EC50 ) 0.79
nM) for ꢀ3 relative to the chloro analogue 12b, while the CN
(12d) and CF3 (12e) analogues showed decreased potency
relative to 12b. 3,4-Dichloro analogue 12f was unfavorable for
ꢀ3 agonistic activity relative to monochloro analogues 10m and
12b. In addition, we attempted replacement of the phenyl ring
with a pyridine ring. Nonsubstituted pyridyl ring analogue 12g
showed decreased ꢀ3 potency relative to the lead compound
10m. The 4-chloropyridyl ring analogue 12h, as expected,
showed increased potency relative to 12g, although in com-

4812 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Table 3. SAR of Biphenyl Ether Analogues
Imanishi et al.
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 of the maximal effect of test compound to the maximal effect produced by isoproterenol (10-7 M). c Dose 0.10 or 0.20 mg/kg po (n ) 2-
3). d The Cmax ratio was defined as the Cmax of test compounds to the Cmax of 10c, where the ratio value of 10c was presented as 1.0. The AUC ratio was
defined as the AUC of test compounds to the AUC of 10c, where the ratio value of 10c was presented as 1.0.
parison with 12b, it exhibited a somewhat inferior in vitro profile
(potency and selectivity). Furthermore, we examined the effect
of R2-substituents at the 2,3-position at the terminal phenyl ring
of 12b, since the 4-chloro analogue 12b showed the best profile
of potency and selectivity among 12a-h. We introduced some
substituents (2-Me, F, OMe) to give biphenyl analogues
(12i-k). The 2-F and 2-OMe analogues 12j and 12k displayed
good potency (EC50 ) 0.81 and 0.78 nM, respectively) and good
selectivity but decreased potency (∼2-fold) relative to 12b. In
addition, our previous report had shown for a different biphenyl
series that replacement of the R2-substituents (OMe, F) at the
2-position with an O-i-Pr group provided improvement in
potency and selectivity. This modification was incorporated into
the current series at the 2-R2-substituent. However, O-i-Pr
analogue 12l showed maintained potency for ꢀ3 (EC50 ) 0.70
nM) and somewhat decreased selectivity relative to 12j and 12k.
Finally, we examined the effect of R2-substituents (Me, F) at
the 3-position in 12b. The 3-Me and 3-F analogues 12m and
12n showed lower potency (EC50 ) 2.0 and 1.4, respectively)
relative to 12b.
Next, we selected compounds (12b,c,h,k,m,n) in Table 4,
which exhibited good in vitro profiles, and evaluated them in a
cassette dosing assay. The 4-chlorophenyl ring analogue 12b
showed somewhat a decreased Cmax ratio and improved AUC
ratio relative to the 3-chloro analogue 10m. The methyl analogue
12c showed slightly decreased AUC ratio relative to 10m. On
the other hand, 4-chloropyridyl ring analogue 12h showed
decreased Cmax and AUC levels (0.42-fold less). The R2-
substituented analogues 12k,m,n (R2 ) 2-OMe, 3-Me, 3-F) were
also evaluated. The 3-fluoro analogue 12n displayed a good Cmax
ratio relative to 12k and 12m and the same AUC ratio relative
to 10m. As a result of the SAR study in Table 4, the
4-chlorophenyl ring analogue 12b displayed the best profile of
potency, selectivity, and oral exposure.
After SAR examination and study in the cassette dosing assay,
we selected 11f, 11l, and 11o in Table 3 and 12b in Table 4 as

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4813
Table 4. SAR of Biphenyl Analogues
cassette assay (po)c
human ꢀ3 EC50,
human ꢀ1 EC50,
human ꢀ2 EC50,
Cmax
compd
R1
3-Cl
X
R2
nMa (IAb)
nMa
ꢀ1/ꢀ3
nMa
ratiod
AUC ratioe
10m
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
CH
CH
CH
CH
CH
CH
CH
N
H
H
H
H
H
H
H
H
H
2.8 ( 0.3 (0.97)
38 (0.78)
0.38 ( 0.02 (1.02)
0.79 ( 0.02 (1.04)
28 (0.78)
3.5 ( 0.5 (0.91)
33 (0.81)
13 (0.82)
0.85 ( 0.03 (0.80)
1.8 (0.92)
0.81 ( 0.06 (0.93)
0.78 ( 0.02 (0.95)
0.70 ( 0.04 (0.93)
2.0 (0.87)
>100
620
917 ( 83
>1000
>1000
775
>1000
>1000
200
>4.5
16.3
2413
>1265
>36
221
>30
>77
>1265
458
802
>1282
443
400
700
NT
NT
>1000
NT
NT
>1000
NT
NT
>1000
NT
NT
NT
NT
NT
1.0
NT
0.71
1.06
NT
NT
NT
NT
0.73
NT
NT
0.62
NT
0.72
1.13
1.0
NT
1.25
0.77
NT
NT
NT
NT
0.53
NT
NT
0.53
NT
0.64
1.01
2-Cl
4-Cl
4-Me
4-CN
4-CF3
3,4-di-Cl
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
N
CH
CH
CH
CH
CH
CH
2-Me
2-F
2-OMe
2-O-i-Pr
3-Me
3-F
825
650 ( 86
>1000
310
800
980
1.4 ( 0.3 (0.84)
NT
a The results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. NT: not tested. b The intrinsic activity (IA) was defined
as the ratio of the maximal effect of test compound to the maximal effect produced by isoproterenol (10-7 M). c Dose 0.10 or 0.20 mg/kg po (n ) 2-3).
NT: not tested. d The ratio was defined as the Cmax of the of test compounds to the Cmax of 10m. The ratio value of 10m was presented as 1.0. e The ratio
was defined as the AUC of test compounds to the AUC of 10m. The ratio value of 10m was presented as 1.0.
Table 5. Pharmacokinetic Profiles of Selected Compoundsa
po (n ) 2-3)
iv (n ) 2-3)
dose
(mg/kg)
Cmax
(ng/mL)
AUC0-24h
(ng·h/mL)
dose
T1/2ꢀ
CLtot
F
compd
species
(mg/kg)g
(h)g
((mL/min)/kg)g
(%)b
11fc
dog
rat
dog
monkey
rat
dog
monkey
rat
0.20
0.52
0.21
1.0
1.0
0.2
1.0
0.5
0.2
0.32
1.0
189 ( 25
367 ( 0.5
103 ( 2.5
319 ( 51
164 ( 0.5
64.4
59 ( 3.3
65 ( 26
113 ( 1.8
91.2 ( 14
28.1 ( 7.7
92.5 ( 14
38
1467 ( 170
4584 ( 616
1530 ( 72
1562 ( 212
1937 ( 552
860.1
313 ( 44
470 ( 107
1980 ( 37
722 ( 144
177 ( 14
902 ( 99
83
0.10
0.50
0.10
0.32
0.51
0.1
0.32
0.50
0.10
0.32
0.32
0.12
0.83e
0.83e
0.83e
NT
3.94
11.9
2.38
2.0
>95
>95
64.2
48.0
27.3
76.8
28.8
63.4
>95
81.7
60.0
83.2
29
11lc
8.3 ( 0.4
6.7 ( 0.7
15.3
5.9 ( 1.0
8.2 ( 0.3
13.6
14.3 ( 1.6
7.7 ( 0.4
1.18
3.8 ( 0.2
0.3
1.63
2.28 ( 0.45
NT
1.4 ( 0.1
5.3 ( 0.7
2.5
3.1 ( 0.1
15.7 ( 1.5
11.4
1.7 ( 0.1
6.7 ( 1.3
52.6
3.0 ( 0.5
47.9
3.7
11.8 ( 0.8
NT
11oc
12bc
dog
monkey
rat
3d
4d
dogc
rat
0.2
1.0
3.2
1.0
dog
2070
184 ( 22
1340 ( 300
10600
398 ( 46
4100 ( 800
73
35
monkey
humanf
1.0
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 3 and 4. See ref 22. e The dose of 0.83 mg/kg the carboxylic
acid form of 4 was equivalent to 1 mg/kg 4. f The results are shown as the mean ( SD (n ) 8). g NT: not tested.
attractive compounds, since these compounds exhibited greater
ꢀ3 potency relative to the corresponding lead compounds (10c
or 10m), high selectivity over ꢀ1 and ꢀ2, and good oral exposure.
Table 5 shows the pharmacokinetic profiles in dog, rat, and
monkey. The biphenyl ether analogue having a 5-NMe2 group
11f showed excellent oral bioavailability in dog (F > 95%),
while the plasma half-life (t1/2 ) 3.9 h) was somewhat decreased
relative to the lead compound 10c (shown in Table 2). The
4-chlorophenyl ring analogue containing a 2-OMe group 11l
displayed low total clearance (CL, rats, 2.0 (mL/min)/kg; dogs,
1.4 (mL/min)/kg; monkeys, 5.3 (mL/min)/kg), long plasma half-
life (t1/2, iv, rats, 11.9 h; dogs, 8.3 h; monkeys, 6.7 h) and good
oral bioavailability (rats, F > 95%; dogs, F ) 64%; monkeys,
F ) 48%) in all three species. On the other hand, the
4-chloropyridyl ring analogue 11o displayed a good pharma-
) 27%; monkeys, F ) 29%) and long plasma half-life in rats
(11.4 h) and monkeys (6.7 h). Next, biphenyl analogue 12b
having a 4-chlorophenyl ring on the LHS displayed good oral
bioavailability in all three species (F > 63%), and a long plasma
half-life in dog (14.3 h), rat (13.6 h), and monkey (7.7 h).
Compound 12b provided a superior pharmacokinetic profile
relative to both 3 and 4 in all two or three species.
Next, we examined the inhibitory effect of selected com-
pounds (11o, 12b) on carbachol-induced increase of intravesical
pressure (IVP) in anesthetized dogs as an OAB model,16 in
comparison with the effects of our previous clinical compound
4. Before conducting in vivo experiments, we confirmed the in
vitro potency of these compounds to not only human ꢀ3-AR
but also dog ꢀ3-AR activity in CHO cell lines, as shown in
Table 6. In general, these tetraline analogues display some
species differences between human and dog ꢀ3-AR activity,
and the EC50 values for the dog ꢀ3-AR of compounds 11o and
cokinetic profile (F ) 76.8%, CL ) 3.1 (mL/min)/kg, t1/2
)
5.9 h) in dog and showed moderate oral bioavailability (rats, F

4814 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
Table 6. Inhibitory Effect on Intravenous Administration of Selected Compounds (11o, 12b) and 4 on Increase in IVP (Intravesical Pressure), Induced
by Carbachol in Anesthetized Dogsa
in vitro
in vivo
human ꢀ3
EC50, nM
dog ꢀ3
EC50, nM
% inhibition
(dose 32 µg/kg)
dog serum protein
binding, %
compd
ClogPd
control
4
11o
12b
0.0
16 ( 2.0b,c
3.6 ( 0.3
0.38 ( 0.02
30 ( 9.0b,c
46
25
40.8 ( 2.6b
94b
90
97
57
33
1.7
3.2
a The results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. b Data for the carboxylic acid form of 4. c Results are
the mean ( SE of five experiments. d Biobyte CLOGP, version 4.3.
appropriate: b ) broad, s ) singlet, d ) doublet, t ) triplet, q )
quartet, m ) multiplet. High resolution mass spectra were recorded
with Micromass 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 unless otherwise noted.
12b showed significantly reduced potency (11o, 12.8-fold; 12b,
65.8-fold) relative to human ꢀ3-AR activity. Compound 12b
showed the same potency level, and compound 11o showed less
potent dog ꢀ3-AR activity relative to 4. In the in vivo
experiment, when intravenously (iv) administered, these com-
pounds inhibited IVP increase at a dose of 32 µg/kg (Table 6).
The 4-chloropyridyl analogue 11o resulted in some improvement
in inhibition % value, due to lower protein binding (11o, ClogP
) 1.7, PB ) 90%) relative to 4 (PB ) 94%). On the other
hand, 4-chlorophenyl analogue 12b, having comparable in vitro
dog ꢀ3-AR activity relative to 4, showed a decreased inhibition
% value due to higher protein binding (12b, ClogP ) 3.2, PB
) 97%) relative to 4. However, compound 12b displays higher
human ꢀ3-AR activity (42-fold) compared to our previous
clinical compound 4 and therefore may be an attractive candidate
for the treatment of OAB.
N-[(2S)-7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl]benza-
mide (15). To a mixture of 7-methoxy-3,4-dihydronaphthalen-
2(1H)-one sodium hydrogen carbonate 13 (20 g, 71.36 mmol) in
toluene (150 mL) was added 3 N HCl (88 mL). The mixture was
stirred at room temperature for 3 h. The mixture was partitioned
between toluene and water. The organic layer was separated, washed
with water, and concentrated in vacuo to give 7-methoxy-3,4-
dihydronaphthalen-2(1H)-one (11.69 g, 92%). To the product (10.76
g, 60.55 mmol) in toluene (60 mL) was added benzamide (14.67
g, 121.1 mol) and Amberlyst 15E (6.8 g), and the mixture was
refluxed for 5 h with continuous removal of water using a
Dean-Stark trap. To the reaction mixture was added MeOH (30
mL) at 65 °C, and the mixture was cooled to room temperature.
The mixture was filtered, and the residue of Amberlyst was washed
with toluene-MeOH (1: 1). The combined solution was evaporated
under reduced pressure. To the crude yellow solid was added
MeOH, and the mixture was stirred at 50 °C for 1 h. The slurry
was cooled to room temperature for 1 h, filtered, and washed with
MeOH. After the sample was dried at 60 °C in vacuo, 7.54 g (41%)
of the enamide 14 was obtained as a yellow solid.
A solution enamide 14 (5.55 g, 19.9 mmol) and Ru(II)-(S)-
SEGPOS (0.0199 mmol) in MeOH (22 mL) and CH2Cl2 (22 mL)
was deoxygenated using N2 and charged into a stirred autoclave.
The autoclave was pressurized with 30 atm of H2 and stirred at 60
°C for 10 h. The solution was evaporated under reduced pressure.
To the crude product was added MeOH (55 mL), and the mixture
was stirred at 60 °C for 0.5 h. The slurry was cooled to room
temperature for 3 h, filtered, and washed with cold MeOH. After
the sample was dried at 60 °C in vacuo for 5 h, 3.95 g (74%) of
the title compound was obtained as colorless crystals, mp 164.6
°C. MS (ES) m/e: 282 (M + H). 1H NMR (400 MHz, DMSO-d6):
δ 1.7-1.8 (1H, m), 2.0-2.1 (1H, m), 2.7-2.8 (3H, m), 2.9-3.0
(1H, m), 3.70 (3H, s), 4.1-4.2 (1H,m), 6.6-6.7 (2H, m), 7.01 (1H,
d, J ) 8.4 Hz), 7.44-7.55 (3H, m), 7.86-7.89 (2H, m), 8.40 (1H,
d, J ) 7.6 Hz). The optical purity was determined as 99.6% ee,
given by HPLC analysis with two connected DAICELL Chiralcel
OD-H columns (4.6 mm i.d. × 25 cm × 2.5 µm) eluted with
hexane/2-propanol (70:30, 0.6 mL/min). Detection at 215 nm light;
tR (R isomer) ) 24.26 min, tR (S isomer) ) 26.55 min.
Conclusions
Incorporation of the biphenyl ether or biphenyl template with
a benzoic acid moiety on the RHS in 3 or 4 afforded two
structurally different lead compounds (10c, 10m) with improved
ꢀ3 potency and plasma half-life relative to 3 and 4, without the
prodrug form. Importantly, our results suggested that the benzoic
acid moiety on the RHS of either biphenyl ether and biphenyl
analogues is essential for not only potency and selectivity but
also the good pharmacokinetic properties of our current tetraline
series, similar to our previous series. Next, in Tables 3 and 4,
we investigated the effect of substituents on the terminal phenyl
ring in the RHS and the replacement of the 3-chlorophenyl ring
in the LHS of lead compounds (10c, 10m). As a result, biphenyl
ether analogues (11f, 11l, 11o) with a superior balance of
potency, selectivity, and pharmacokinetic profiles, compared
with 3 and our previous clinical candidate 4, were identified
and selected as the leading candidates. Furthermore, biphenyl
analogue 12b provided an excellent balance of high potency
(EC50 ) 0.38 nM), selectivity, and good pharmacokinetic
properties (F > 60%, t1/2 > 7 h in three species). In addition,
compound 12b, containing a 4-chlorophenylethanolaminote-
traline skeleton, was prepared by high stereoselective synthesis
of the two chiral centers. These findings suggest that these
compounds (11f, 11l, 11o, 12b) had the good profiles and may
be potential candidates for the treatment of OAB.
(2S)-N-Benzyl-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-
amine (16). To a suspension of 15 (88.0 g, 313 mmol) in THF
(500 mL) was added 2 M BH3 ·SMe2 in THF solution (380 mL)
dropwise at approximately 4 °C over 40 min under nitrogen
atomosphere. The reaction mixture was warmed to room temper-
ature and refluxed for 4 h. To the mixture was added 6 N HCl
(135 mL) dropwise at approximately 4 °C. The mixture was refluxed
for1.5 h, and the solvent was removed. To the mixture, 3 N NaOH
(500 mL) was added dropwise below 10 °C (pH ≈ 11). The mixture
was partitioned between EtOAc and water. The organic layer was
separated, washed with brine, dried over MgSO4, and evaporated
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. An-
hydrous solvents were obtained from commercial sources. Proton
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

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4815
under reduced pressure. The residue was purified by column
chromatography on silica gel (chloroform/methanol ) 97:3 to 95:
5) to give 83.8 g (100%) of the title compound. 1H NMR (200
MHz, DMSO-d6): δ 1.4-1.6 (1H, m), 1.8-2.1 (1H, m), 2.4-3.0
(5H, m), 3.68 (3H, s), 3.79 (2H, br s), 6.6-6.7 (2H, m), 6.94 (1H,
d, J ) 8.1 Hz), 7.19-7.38 (5H, m).
tert-Butyl (2R)-2-(6-Chloro-3-pyridinyl)-2-hydroxyethyl[(2S)-
7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl]carbamate (27).
The title compound was synthesized from 18 and 2-chloro-5-[(2R)-
oxiran-2-yl]pyridine 23 according to procedure A (47.7%). 1H NMR
(200 MHz, CDCl3): δ 1.51 (9H, s), 1.6-1.9 (2H, m), 2.7-2.9 (4H,
m), 3.2-3.4 (1H, m), 3.4-3.7 (1H, m), 4.0-4.2 (1H, m), 4.8-5.0
(1H, m), 5.42 (1H, br), 6.5-6.7 (2H, m), 6.93 (1H, dd, J ) 8.2
Hz), 7.32 (1H, d, J ) 8.2 Hz), 7.73 (1H, dd, J ) 2.3, 8.2 Hz), 8.34
(1H, d, J ) 2.3 Hz). MS (ES) m/e: 419 (M + H).
3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy-
]benzoic Acid Methyl Ester (29a). Typical Procedure B. To a
mixture of 24 (400 mg, 0.96 mmol) in dichlorometane (10 mL)
and triethylamine (1 mL) were added (3-methoxycarbonylphenyl-
)boric acid (400 mg, 2.22 mmol) and copper acetate (400 mg, 2.20
mmol) and 4 Å molecular sieves (1 g) at room temperature, and
the mixture was stirred at the same temperature for 12 h. The
resulting mixture was filtered by Celite, and the mother layer was
evaporated under pressure. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate ) 3/1) to give
240 mg (44%) of the title compound. 1H NMR (200 MHz, CDCl3):
δ 1.51 (9H, s), 1.7-1.9 (2H, m), 2.7-3.0 (4H, m), 3.2-3.4 (1H,
m), 3.4-3.7 (1H, m), 3.90 (3H, s), 4.0-4.2 (1H, m), 4.8-5.0 (1H,
m), 6.6-6.9 (2H, m), 7.05 (1H, d, J ) 8.4 Hz), 7.1-7.8 (8H, m).
MS (ES) m/e: 574 (M + Na).
(7S)-7-(Benzylamino)-5,6,7,8-tetrahydronaphthalen-2-ol (17).
To a solution of 16 (90.2 g, 337 mmol) in dichloromethane (600
mL) was added 2 M BBr3 in CH2Cl2 (420 mL) dropwise at 4 °C
over 1 h under nitrogen atomosphere. The mixture was warmed to
room temperature and stirred over 2.5 h at same temperature. To
the mixture was added 200 mL of cold water and 5 N NaOH (220
mL) dropwise at approximately 0 °C and then added saturated
NaHCO3 (500 mL). The organic layer was separated and washed
with saturated NaHCO3 (500 mL × 3) and brine, dried over MgSO4,
and evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel (chloroform/methanol) to
1
give 32.2 g (50.6%) of the title compound. H NMR (200 MHz,
DMSO-d6): δ 1.3-1.6 (1H, m), 1.9-2.1 (1H, m), 2.3-2.95 (5H,
m), 3.78 (2H, br s), 6.4-6.5 (2H, m), 6.81 (1H, d, J ) 8.1 Hz),
7.19-7.38 (5H, m), 8.97 (1H, br s). MS (ES) m/e: 254 (M + H).
(7S)-7-Amino-5,6,7,8-tetrahydronaphthalen-2-ol (18). A mix-
ture of 17 (7.0 g, 23.5 mmol) in MeOH (70 mL) was hydrogenated
over palladium on carbon (10% w/w, 50% wet, 700 mg) under
hydrogen atmosphere for 2 h. The catalyst was filtered off, and the
filtrate was evaporated to give 3.84 g (100%) of the title compound.
1H NMR (200 MHz, CDCl3): δ 1.5-1.7 (1H, m), 1.8-2.3 (2H,
br), 1.9-2.1 (1H, m), 2.4-2.6 (1H, m), 2.7-3.0 (3H, m), 3.1-3.25
(1H, m), 3.49 (1H, s), 6.52-6.63 (2H, m), 6.94 (1H, d, J ) 8.2
Hz). MS (ES) m/e: 164 (M + H).
tert-Butyl (2R)-2-(4-Chlorophenyl)-2-hydroxyethyl[(2S)-7-hy-
droxy-1,2,3,4-tetrahydro-2-naphthalenyl]carbamate (25). Typi-
cal Procedure A. A solution of 18 (11.2 g, 68.6 mmol) and (2R)-
2-(4-chlorophenyl)oxirane 22 (9.02 g, 58.3 mmol) in ethanol (100
mL) was refluxed for 18 h. The mixture was evaporated in vacuo.
The residue was purified by column chromatography on silica gel
(chloroform/methanol ) 97: 3) to give 9.74 g (44.7%) of (7S)-7-
{[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]amino}-5,6,7,8-tetrahy-
dro-2-naphthalenol. MS (ES) m/e: 318 (M + H).
3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]benzoic Acid Hydrochlo-
ride (10c). Typical Procedure C. To a solution of the above
coupling product 29a (240 mg, 0.434 mmol) in methanol (3 mL)
was added 1 N sodium hydroxide (1.5 mL) at room temperature,
and the mixture was stirred at the same temperature for 12 h. The
resulting mixture was evaporated under reduced pressure. The
residue was diluted with a mixture of ethyl acetate or chloroform
(30 mL) and 1 N HCl (1.5 mL), and the organic layer was washed
with brine, dried over magnesium sulfate, and evaporated under
reduced pressure. The obtained benzoic acid was diluted with 4 N
hydrogen chloride in dioxane or ethyl acetate (10 mL), and the
mixture was allowed to keep at room temperature for 4 h. The
mixture was evaporated under reduced pressure and the obtained
solid was washed with ether to give 100 mg (50%) of the title
1
compound. H NMR (200 MHz, DMSO-d6) δ; 1.7-2,0 (1H, m),
To a mixture of the obtained product (9.7 g, 30.7 mmol) in
tetrahydrofuran (100 mL) was added di-tert-butyl dicarbonate (6.7
g, 30.7 mmol) at room temperature, and the mixture was stirred at
the same temperature for 12 h. The resulting mixture was evaporated
under pressure and the residue was purified by column chroma-
tography on silica gel (hexane/ethyl acetate ) 2/1) to give 12.2 g
2.1-2.3 (1H, m), 2.7-3.5 (7H, m), 5.0-5.1 (1H, m), 6.4 (br s),
6.8-7.0 (2H, m), 7.1-7.8 (9H, m). MS (ES) m/e: 438 (M + H).
Anal. (C25H24 Cl1N1O4 ·1.0HCl·0.5H2O) C, H, N.
4-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy-
]benzoic Acid Methyl Ester (29b). The title compound was
synthesized from 24 and (4-methoxycarbonylphenyl)boric acid
1
(95.3%) of the title compound as a colorless form. H NMR (200
MHz, CDCl3): δ 1.52 (9H, s), 1.7-1.9 (2H, m), 2.7-3.0 (4H, m),
3.2-3.3 (1H, m), 3.4-3.7 (1H, m), 4.0-4.2 (1H, m), 4.8-5.0 (1H,
m), 5.10 (1H, br s), 6.4-6.5 (1H, m), 6.62 (1H, dd, J ) 2.5, 8.2
Hz), 6.93 (1H, d, J ) 8.2 Hz), 7.28 (1H, d, J ) 8.4 Hz), 7.2-7.4
(3H, m). MS (ES) m/e: 418 (M + H).
1
according to procedure B (49%). H NMR (200 MHz, CDCl3): δ
1.51 (9H, s), 1.7-1.9 (2H, m), 2.7-3.0 (4H, m), 3.2-3.4 (1H, m),
3.4-3.7 (1H, m), 3.89 (3H, s), 4.0-4.2 (1H, m), 4.8-5.0 (1H, m),
6.7-7.3 (8H, m), 7.39 (1H, s), 7.99 (2H, d, J ) 8.6 Hz). MS (ES)
m/e: 574 (M + Na).
tert-Butyl [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl][(2S)-7-
hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (24). The
title compound was synthesized from 18 and (2R)-2-(3-chlorophe-
4-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]benzoic Acid Hydrochlo-
ride (10d). The title compound was synthesized from 29b according
to procedure C (49%). 1H NMR (200 MHz, DMSO-d6): δ 1.7-2,0
(1H, m), 2.1-2.3 (1H, m), 2.7-3.5 (7H, m), 5.0-5.1 (1H, m), 6.4
(br s), 6.7-6.9 (2H, m), 6.99 (2H, d, J ) 8.6 Hz), 7.19 (1H, d, J
) 8.4 Hz), 7.2-7.5 (4H, m), 7.93 (2H, d, J ) 8.6 Hz). MS (ES)
m/e: 438 (M + H). Anal. (C25H24 Cl1N1O4 ·1.0HCl·1.3H2O) C, H,
N.
1
nyl)oxirane 21 according to procedure A (40.5%). H NMR (200
MHz, CDCl3): δ 1.51 (9H, s), 1.7-1.9 (2H, m), 2.7-3.0 (4H, m),
3.2-3.4 (1H, m), 3.4-3.7 (1H, m), 4.0-4.2 (1H, m), 4.7-4.9 (1H,
m), 6.03 (1H, br s), 6.5-6.6 (2H, m), 6.62 (1H, dd, J ) 2.4, 8.4
Hz), 6.90 (1H, d, J ) 8.4 Hz), 7.3-7.5 (3H, m), 7.37 (1H, s). MS
(ES) m/e: 440 (M + Na).
tert-Butyl [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl][(6S)-3-
hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]carbam-
ate (26). The title compound was synthesized from (8S)-8-amino-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol 20 and (2R)-2-(3-
chlorophenyl)oxirane 21 according to procedure A (38.4%). 1H
NMR (200 MHz, CDCl3): δ 1.50 (9H, s), 1.4-2.0 (4H, m), 2.6-2.8
(3H, m), 3.1-3.5 (4H, m), 4.8-5.0 (1H, m), 6.03 (1H, br s), 6.58
(2H, m), 6.92 (1H, m), 7.26 (3H, m), 7.41 (1H, s). MS (ES) m/e:
454 (M + Na).
{3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-
phenoxy}-tert-butyldimethylsilane (28a). The title compound was
synthesized from 24 and (3-{[tert-butyl(dimethyl)silyl]oxy}-
phenyl)boronic acid according to procedure B (59%). 1H NMR (200
MHz, CDCl3): δ 0.17 (6H, s), 0.95 (9H, s), 1.51 (9H, s), 1.7-1.9
(2H, m), 2.7-3.0 (4H, m), 3.2-3.4 (1H, m), 3.4-3.7 (1H, m),
4.0-4.2 (1H, m), 4.8-5.0 (1H, m), 6.4-6.9 (5H, m), 7.0-7.5 (6H,
m). MS (ES) m/e: 646 (M + Na).

4816 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
{3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]phenoxy}acetic Acid Hy-
drochloride (10a). To a solution of 28a (600 mg, 0.961 mmol) in
tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride
(5 mL, 1 M solution in THF) at room temperature, and the mixture
was stirred for 3 h. The mixture was poured into water and ethyl
acetate, and the organic layer was washed with 1 N HCl and brine
and then dried over magnesium sulfate. After filtration, the solvent
was evaporated, the residue was diluted in N,N-dimethylformamide
(10 mL). To the solution were added K2CO3 (240 mg, 1.73 mmol)
and bromoethylacetate (0.12 mL, 1.08 mmol) at room temperature,
and the mixture was stirred for 4 h. The mixture was poured into
water and ethyl acetate, and the organic layer was washed with 1
N HCl and brine and then dried over magnesium sulfate. After
filtration, the solvent was evaporated, and the obtained residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate ) 2/1) to give 450 mg (72%) of {3-[((7S)-7-{[(2R)-2-(3-
chlorophenyl)-2-hydroxyethyl]-tert-butyloxycarbonylamino}-5,6,7,8-
tetrahydro-2-naphthalenyl)oxy]phenoxy}acetic acid ethy ester. 1H
NMR (200 MHz, CDCl3): δ 1.25 (3H, t, J ) 6.8 Hz), 1.51 (9H, s),
1.7-1.9 (2H, m), 2.7-3.0 (4H, m), 3.2-3.4 (1H, m), 3.4-3.7 (1H,
m), 4.0-4.2 (1H, m), 4.21 (2H, q, J ) 6.8 Hz), 4.58 (2H, s),
4.8-5.0 (1H, m), 6.5-6.9 (5H, m), 7.0-7.5 (6H, m). MS (ES)
m/e: 618 (M + Na).
The title compound was synthesized from the obtained product
according to procedure C (83%). 1H NMR (200 MHz, DMSO-d6):
δ 1.7-2.0 (1H, m), 2.2-2.5 (1H, m), 2.6-3.6 (7H, m), 4.65 (2H,
s), 5.07 (1H, m), 6.36 (1H, m), 6.5-6.8 (5H, m), 7.0-7.6 (6H,
m), 8.97 (1H, m), 9.44 (1H, m). MS (ES) m/e: 468 (M + H). Anal.
(C26H26Cl1N1O5 ·1.0HCl·0.5H2O) C, H, N.
{4-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)ox-
y]phenoxy}-tert-butyldimethylsilane (28b). The title compound
was synthesized from 24 and (4-{[tert-butyl(dimethyl)silyl]oxy}-
phenyl)boronic acid according to procedure B (44%). 1H NMR (200
MHz, CDCl3): δ 0.17 (6H, s), 0.95 (9H, s), 1.51 (9H, s), 1.7-1.9
(2H, m), 2.7-3.0 (4H, m), 3.2-3.4 (1H, m), 3.4-3.7 (1H, m),
4.0-4.2 (1H, m), 4.8-5.0 (1H, m), 6.5-7.0 (6H, m), 7.2-7.4 (5H,
m). MS (ES) m/e: 646 (M + Na).
1.51 (9H, s), 1.8-2.1 (2H, m), 2.5-2.8 (2H, m), 3.0-3.4 (3H, m),
3.91 (3H, s). 4.91 (1H, m), 6.9-7.8 (11H, m). MS (ES) m/e: 588
(M + Na).
4-[((8S)-8-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl)oxy]benzoic Acid
Hydrochloride (10f). The title compound was synthesized from
29d according to procedure C (49%). 1H NMR (200 MHz, DMSO-
d6) δ; 1.2-1.4 (1H, m), 1.7-2.3 (3H, m), 2.7-3.4 (7H, m), 5.0
(1H, m), 6.32 (1H, s), 6.9-7.4 (9H, m), 7.93 (2H, d, J ) 8 Hz).
MS (ES) m/e: 452 (M
1.0HCl·1.2H2O) C, H, N.
+ H). Anal. (C26H26 Cl1N1O4 ·
6-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]ni-
cotinic Acid Ethyl Ester (30). Typical Procedure D. To a mixture
of 24 (300 mg, 0.718 mmol) in dimethyl sulfoxide (10 mL) were
added ethyl 6-chloronicotinate (300 mg, 1.61 mmol) and K2CO3
(800 mg, 5.78 mmol) at room temperature, and the mixture was
stirred at 80 °C for 2 h. The resulting mixture was poured into a
mixture of ethyl acetate and water, and the organic layer was washed
with brine. After the solvent was evaporated under pressure, the
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate ) 1/1) to give 300 mg (77%) of the title
1
compound. H NMR (200 MHz, CDCl3): δ 1.34 (3H, t, J ) 7.0
Hz), 1.52 (9H, s), 1.7-2.0 (2H, m), 2.6-3.0 (4H, m), 3.2-3.6 (2H,
m), 4.35 (2H, q, J ) 7.0 Hz), 4.90 (1H, m), 6.8-7.2 (4H, m),
7.2-7.4 (4H, m), 8.27 (1H, dd, J ) 2.2, 8.4 Hz), 8.81 (1H, dd, J
) 2.2 Hz). MS (ES) m/e: 589 (M + Na).
6-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]nicotinic Acid Dihydro-
chloride (10g). The title compound was synthesized from 30
according to procedure C (73%). 1H NMR (200 MHz, DMSO-d6)
δ; 1.7-2.0 (1H, m), 2.3-2.5 (1H, m), 2.7-3.7 (7H, m), 5.12 (1H,
m), 6.8-7.0 (2H, m), 7.0-7.3 (2H, m), 7.4-7.6 (4H, m), 8.27 (1H,
dd, J ) 2.2,8.6 Hz), 8.64 (1H, d, J ) 2.2 Hz), 9.0 (1H, br s), 9.6
(1H, br s). MS (ES) m/e: 439 (M + H). Anal. (C24H23
Cl1N2O4 ·2.0HCl·1.0H2O) C, H, N.
2-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-
3-pyridinylcarboxaldehyde (31). The title compound was syn-
thesized from 24 and 2-chloronicotinaldehyde according to procedure
{4-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]phenoxy}acetic Acid Hy-
drochloride (10b). The title compound was synthesized from 28b
according to the procedure described for the conversion of 28a to
1
D (91%). H NMR (200 MHz, CDCl3): δ 1.56 (9H, s), 1.7-2.0
(2H, m), 2.7-3.0 (4H, m), 3.1-3.7 (2H, m), 4.0-4.2 (1H, m), 4.88
(1H, m), 6.8-7.2 (7H, m), 7.39 (1H, s), 8.23 (1H, dd, J ) 2.2, 7.2
Hz), 8.36 (1H, dd, J ) 2.2 Hz), 10.52 (1H, s). MS (ES) m/e: 523
(M + H).
1
10a (58%). H NMR (200 MHz, DMSO-d6) δ: 1.7-2.0 (1H, m),
2.2-2.5 (1H, m), 2.6-3.6 (7H, m), 4.55 (2H, s), 5.04 (1H, m),
6.37 (1H, m), 6.6-7.0 (7H, m), 7.3-7.5 (4H, m). MS (ES) m/e:
468 (M + H). Anal. (C26H26Cl1N1O5 ·1.0HCl·1.5H2O) C, H, N.
2-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]nicotinic Acid Hydro-
chloride (10h). Typical Procedure E. To a mixture of 31 (300
mg, 0.573 mmol), acetonitrile (5 mL), pH 4 buffer solution (sodium
dihydrogen phosphate) (0.25 mL), and 30% hydrogen peroxide
solution (0.12 mL) was added sodium chlorite (500 mg, 5.52 mmol)
at room temperature. The reaction mixture was stirred at the same
temperature for 4 h, diluted with ethyl acetate (50 mL), washed
with water followed by brine, dried over magnesium sulfate, and
evaporated to give the corresponding acid. The obtained acid was
diluted with 4 N hydrogen chloride in dioxane (10 mL), and the
mixture was allowed to keep at room temperature for 4 h. The
mixture was evaporated under reduced pressure and the obtained
solid was washed with ether to give 200 mg (62%) of the title
3-[((8S)-8-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-6,7,8,9-tetrahydro-5H-benzo[a]cyclohep-
ten-2-yl)oxy]benzoic Acid Methyl Ester (29c). The title compound
was synthesized from 26 and (3-methoxycarbonylphenyl)boric acid
1
according to procedure B (44%). H NMR (200 MHz, CDCl3): δ
1.51 (9H, s), 1.8-2.1 (2H, m), 2.5-2.8 (2H, m), 3.0-3.4 (3H, m),
3.91 (3H, s), 4.91 (1H, m), 6.6-6.8 (1H, m), 6.9-7.1 (1H, m),
7.1-7.8 (9H, m). MS (ES) m/e: 588 (M + Na).
3-[((8S)-8-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl)oxy]benzoic Acid
Hydrochloride (10e). The title compound was synthesized from
29c according to procedure C (49%). 1H NMR (200 MHz, DMSO-
d6) δ; 1.2-1.4 (1H, m), 1.7-2.1 (2H, m), 2.2-2.3 (1H, m), 2.7-3.4
(7H, m), 4.99 (1H, m), 6.32 (1H, br s), 6.85 (1H, dd, J ) 2.4,8.0
Hz), 7.01 (1H, d, J ) 2.4 Hz), 7.1-7.6 (8H, m), 7.68 (1 h, d, J )
8 Hz). MS (ES) m/e: 452 (M + H). Anal. (C26H26 Cl1N1O4 ·
1.0HCl·0.8H2O) C, H, N.
1
compound. H NMR (200 MHz, DMSO-d6): δ 1.7-2.0 (1H, m),
2.3-2.5 (1H, m), 2.7-3.7 (7H, m), 5.12 (1H, m), 6.37 (1H, m),
6.7-7.0 (2H, m), 7.1-7.3 (2H, m), 7.4-7.7 (4H, m), 8.1-8.3 (2H,
m), 8.9 (1H, m), 9.5 (1H, m). MS (ES) m/e: 439 (M + H). Anal.
(C24H22 Cl1N2O4 ·1.0HCl·1.2H2O) C, H, N.
5-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-
2-thiophenecarboxaldehyde (32). The title compound was syn-
thesized from 24 and 5-bromothiophene-2-carbaldehyde according
4-[((8S)-8-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-6,7,8,9-tetrahydro-5H-benzo[a]cyclohep-
ten-2-yl)oxy]benzoic Acid Methyl Ester (29d). The title compound
was synthesized from 26 and (4-methoxycarbonylphenyl)boric acid
1
to procedure D (78%). H NMR (200 MHz, CDCl3): δ 1.51 (9H,
1
according to procedure B (33%). H NMR (200 MHz, CDCl3): δ
s), 1.7-2.0 (2H, m), 2.7-3.0 (4H, m), 3.1-3.3 (1H, m), 2.3-2.5

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4817
(1H, m), 4.0-4.3 (1H, m), 4.8-5.0 (1H, m), 6.5-6.8 (2H, m),
6.8-7.6 (7H, m), 9.70 (1H, s). MS (ES) m/e: 550 (M + Na).
5-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-thiophenecarboxylic Acid
Hydrochloride (10i). The title compound was synthesized from 32
according to procedure E (56%). 1H NMR (200 MHz, DMSO-d6) δ;
1.8-2.2 (2H, m), 2.4-3.4 (7H, m), 5.05 (1H, m), 6.36 (1H, m),
6.5-7.5 (9H, m), 8.93 (1H, m), 9.38 (1H, m). MS (ES) m/e: 444(M
+ 1). HRMS (M + H)+ found: 444.1034. Calcd for C23H22Cl1N1O4S
444.1036. Anal. (C24H26Cl1N1O4S1 ·1.0HCl·1.0H2O) C, H, N.
3-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)ben-
zoic Acid Methyl Ester (39a). Typical Procedure F. To a mixture
of 24 (400 mg, 0.957 mmol) in dichloromethane (10 mL) were
added 2,6-lutidine (0.22 mL, 1.89 mmol) and trifluoromethane-
sulfonic anhydride (0.162 mL, 0.96 mmol) at -78 °C under N2,
and the mixture was stirred for 1 h at the same temperature.
The mixture was poured into water, and the organic layer was
washed with 1 N HCl and brine, then dried over magnesium
sulfate. After filtration, the solvent was evaporated, and the
obtained residue was purified by column chromatography on
silica gel with ethyl acetate and hexane (1: 2) to give 473 mg
(90%) of (7S)-7-{(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-
2-hydroxyethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl trif-
luoromethanesulfonate. 1H NMR (400 MHz, CDCl3): δ 1.51 (9H,
s), 1.8-2.0 (2H, m), 2.8-3.0 (4H, m), 3.31 (1H, m), 3.4-3.6
(1H, m), 3.9-4.1 (1H, m), 4.91 (1H, m), 6.97 (1H, s), 7.01 (1H,
m), 7.14 (1H, m), 7.22-7.305 (3H, m), 7.40 (1H, s). MS (ES)
m/e: 572 (M + Na). To a solution of the sulfonate (470 mg,
0.855 mmol) in diethoxymethane (10 mL) were added (3-
methoxycarbonylphenyl)boric acid (200 mg, 1.11 mmol) and
Pd(PPh3)4 (110 mg, 0.095 mmol) and 2 N Na2CO3 (2.0 mL) at
room temperature, and the mixture was stirred at 80 °C for 2 h.
The resulting mixture was filtrated by Celite, and the mother
layer was evaporated under pressure. The residue was purified
by column chromatography on silica gel (hexane/ethyl acetate
DMSO-d6): δ 1.2-1.4 (1H, m), 1.8-2.1 (2H, m), 2.2-2.3 (1H,
m), 2.7-2.8 (2H, m), 3.0-3.4 (5H, m), 5.0 (1H, m), 6.33 (1H, br
s), 7.26 (1H, m), 7.35-7.65 (5H, m), 7.68 (1H, s), 7.76 (2H, d, J
) 8.4 Hz), 8.01 (2H, d, J ) 8.3 Hz). MS (ES) m/e: 436 (M + H).
Anal. (C26H26Cl1N1O3 ·1.0HCl·1.7H2O) C, H, N.
6-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)nicotinic Acid Dihydrochlo-
ride (10o). 39d was synthesized from 24 and (4-methoxycarbon-
ylphenyl)boric acid according to procedure F (52%). MS (ES) m/e:
559 (M + Na). The title compound was synthesized from 39d
1
according to procedure C (83%). H NMR (200 MHz, CDCl3): δ
1.74-1.99 (2H, m), 2.32-2.49 (2H, m), 2.85-3.04 (4H, m), 3.38
(1H, br), 3.52 (1H, br), 5.07 (1H, d, J ) 8.0 Hz), 7.28 (1H, d, J )
7.9 Hz), 7.47-7.59 (4H, m), 7.94 (1H, d, J ) 7.8 Hz), 7.96 (1H,
s), 8.07 (1H, d, J ) 8.3 Hz), 8.29-8.34 (1H, m), 8.97 (1H, br),
9.12 (1H, s), 9.31 (1H, br). MS (ES) m/e: 421 (M - H). Anal.
(C24H23Cl1N2O3 ·2.0HCl·2.5H2O) C, H, N.
[4-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)phe-
noxy]-tert-butyldimethylsilane (38a). The title compound was
synthesized from 24 and (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-
boronic acid according to procedure F (38%). 1H NMR (200 MHz,
CDCl3): δ 0.21 (6H, s), 1.01 (9H, s), 1.57 (9H, s), 1.8-2.0 (2H,
m), 2.8-3.1 (4H, m), 3.2-3.7 (2H, m), 4.0-4.3 (1H, m), 4.9 (1H,
m), 6.89 (2H, d, J ) 8 Hz), 7.12 (1H, d, J ) 8 Hz), 7.2-7.5 (8H,
m). MS (ES) m/e: 630 (M + Na).
4-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)phenoxy]acetic Acid Hydro-
chloride (10k). The title compound was synthesized from 38a
according to the procedure described for the conversion of 28a to
1
10a (40%). H NMR (200 MHz, DMSO-d6): δ 1.7-2.0 (1H, m),
2.1-2.3 (1H, m), 2.5-3.7 (7H, m), 4.71 (2H, s), 5.08 (1H, m),
6.38 (1H, m), 6.98 (2H, d, J ) 8.4 Hz), 7.09 (1H, d, J ) 8.4 Hz),
7.2-7.7 (8H, m), 8.97 (1H, m), 9.41 (1H, m). MS (ES) m/e: 452
(M + H). Anal. (C26H26Cl1N1O4 ·1.0HCl·1.0H2O) C, H, N.
[3-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-tert-bu-
tyloxycarbonylamino}-5,6,7,8-tetrahydro-2-naphthalenyl)phe-
noxy]-tert-butyldimethylsilane (38b). The title compound was
1
) 2/1) to give 350 mg (69%) of the title compound. H NMR
(200 MHz, CDCl3): δ 1.52 (9H, s), 1.8-2.0 (2H, m), 2.8-3.1
(4H, m), 3.2-3.7 (2H, m), 3.95 (3H, s), 4.0-4.3 (1H, m), 4.93
(1H, m), 7.0-7.5 (8H, m), 7.78 (1H, d, J ) 8 Hz), 7.99 (1H, d,
J ) 8 Hz), 8.26 (1H, s). MS (ES) m/e: 558 (M + Na).
synthesized
from
24
and
(3-{[tert-butyl(dimethyl)-
silyl]oxy}phenyl)boronic acid according to procedure F (33%). 1H
NMR (200 MHz, CDCl3): δ 0.19 (6H, s), 0.96 (9H, s), 1.54 (9H,
s), 1.8-2.0 (2H, m), 2.8-3.1 (4H, m), 3.2-3.7 (2H, m), 4.0-4.3
(1H, m), 4.9 (1H, m), 6.8-7.0 (1H, m), 7.0-7.4 (10H, m). MS
(ES) m/e: 630 (M + Na).
3-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)benzoic Acid Hydrochloride
(10l). The title compound was synthesized from 39a according to
1
procedure C (64%). H NMR (200 MHz, DMSO-d6): δ 1.7-2.0
[3-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)phenoxy]acetic Acid Hydro-
chloride (10j). The title compound was synthesized from 38b
according to the procedure described for the conversion of 28a to
(1H, m), 2.1-2.3 (1H, m), 2.5-3.7 (7H, m), 5.07 (1H, m), 6.4
(1H, m), 7.24 (1H, d, J ) 8.0 Hz), 7.3-7.7 (7H, m), 7.90 (2H, m),
8.16 (1H, s), 8.94 (1H, m), 9.28 (1H, m). MS (ES) m/e: 422 (M +
H). Anal. (C25H24Cl1N1O3 ·1.0HCl·1.5H2O) C, H, N.
1
10a (68%). H NMR (200 MHz, DMSO-d6): δ 1.7-2.0 (1H, m),
4-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)benzoic Acid Methy Ester
(39b). The title compound was synthesized from 24 and (4-
methoxycarbonylphenyl)boric acid according to procedure F (78%).
1H NMR (200 MHz, CDCl3): δ 1.52 (9H, s), 1.8-2.0 (2H, m),
2.8-3.1 (4H, m), 3.2-3.7 (2H, m), 3.94 (3H, s), 4.0-4.3 (1H, m),
4.93 (1H, m), 7.1-7.4 (8H, m), 7.64 (2H, d, J ) 8.4 Hz), 8.09
(2H, d, J ) 8.4 Hz), 8.48 (1H, s). MS (ES) m/e: 558 (M + Na).
4-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)benzoic Acid Hydrochloride
(10m). The title compound was synthesized from 39b according
to procedure C (77%). 1H NMR (200 MHz, DMSO-d6): δ 1.7-2.0
(1H, m), 2.1-2.3 (1H, m), 2.5-3.7 (7H, m), 5.07 (1H, m), 6.38
(1H, m), 7.24 (1H, d, J ) 8.0 Hz), 7.3-7.6 (6H, m), 7.76 (2H, d,
J ) 8.4 Hz), 8.01 (2H, d, J ) 8.4 Hz). MS (ES) m/e: 422 (M +
H). Anal. (C25H24Cl1N1O3 ·1.0HCl·0.5H2O) C, H, N.
2.1-2.3 (1H, m), 2.5-3.7 (7H, m), 4.79 (2H, s), 5.05 (1H, m),
6.38 (1H, m), 6.89 (1H, dd, J ) 8.4, 2.2 Hz), 7.0-7.4 (10H, m).
MS (ES) m/e: 452 (M
1.0HCl·1.5H2O) C, H, N.
+ H). Anal. (C26H26Cl1N1O4 ·
5-((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)-2-thiophenecarboxylic Acid
Hydrochloride (10p). Compound 40 was synthesized from 24 and
(5-formyl-2-thienyl)boronic acid according to procedure F (36%).
MS (ES) m/e: 512 (M + H). The title compound was synthesized
from 40 according to procedure E (33%). 1H NMR (400 MHz,
DMSO-d6) δ; 1.74-1.77 (1H, m), 1.80-1.95 (1H, m), 2.30-2.33
(1H, m), 2.80-2.95 (3H, m), 3.13-3.16 (1H, m), 3.29-3.36 (1H,
m), 3.52-3.62 (2H, m), 5.04 (1H, d, J ) 9.2 Hz), 6.36 (1H, br),
7.20 (1H, d, J ) 8.0 Hz), 7.39-7.53 (7H, m), 7.71 (1H, d, J ) 4.0
Hz), 9.01 (1H, br), 13.1 (1H, br). MS (ES) m/e: 426 (M - H).
Anal. (C23H23Cl1N1O3S1 ·1.0HCl·1.4H2O) C, H, N.
4-[(8S)-8-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]benzoic Acid Hy-
drochloride (10n). 39c was synthesized from 26 and (4-
methoxycarbonylphenyl)boric acid according to procedure F (61%).
MS (ES) m/e: 572 (M + Na). The title compound was synthesized
5-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-methylbenzoic Acid
Hydrochloride (11a). The title compound was synthesized from
24 and [3-(methoxycarbonyl)-4-methylphenyl]boronic acid 33 ac-
cording to the procedure described for the conversion of 24 to 10c
(33%). 1H NMR (200 MHz, DMSO-d6): δ 1.71-1.90 (1H, m),
1
from 39c according to procedure C (80%). H NMR (200 MHz,

4818 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
2.14-2.21 (1H, m), 2.46 (3H, s), 2.65-3.50 (7H, m), 4.88-4.93
(1H, m), 6.72-7.47 (10H, m). MS (ES) m/e: 450 (M - H). Anal.
(C26H26Cl1N1O4 ·1.0HCl·0.25H2O) C, H, N.
(1H, br s), 9.33 (1H, br s). MS (ES) m/e: 453 (M + H). Anal.
(C25H25Cl1N2O4 ·2.0HCl·2.5H2O) C, H, N.
3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-5-(dimethylamino)ben-
zoic Acid Dihydrochloride (11f). To a solution of 39 (80 mg,
0.141mmol) in dichloromethane (2 mL) were added sodium
triacetoxyborohydride (49.0 mg, 0.232mmol), acetic acid (47 µL),
and 35% formaldehyde solution (0.328 mL, 1.41 mmol). The
solution was stirred at room temperature for 17 h. The solution
was concentrated under reduced pressure. The residue was extracted
with ethyl acetate and washed with saturated aqueous sodium
hydrogen carbonate and water. The extract was dried over
magnesium sulfate, filtered, and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel with ethyl acetate and hexane to give 70.5 mg (84%) of methyl
3-[((7S)-7-{(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hy-
droxyethyl]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-5-(dim-
ethylamino)benzoate. 1H NMR (200 MHz, DMSO-d6): δ 1.36 (9H,
s), 1.8-2.0 (2H, m), 2.5-2.9 (4H, m), 3.33 (6H, s), 3.2-3.4 (3H,
m), 3.78 (3H, s), 4.7-4.8 (1H, m), 5.5-5.6 (1H, m), 6.3-6.4 (1H,
m), 6.6-6.8 (4H, m), 6.95-7.15 (2H, m), 7.25-7.42 (4H, m). MS
(ES) m/e: 617 (M + Na).
2-Chloro-5-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethy-
l]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]benzoic Acid
Hydrochloride (11b). The title compound was synthesized from
24 and [3-(methoxycarbonyl)-4-chlorophenyl]boronic acid 34 ac-
cording to the procedure described for the conversion of 24 to 10c
(51%). 1H NMR (200 MHz, DMSO-d6): δ 1.12-1.28 (1H, m),
1.83-1.91 (2H, m), 2.32-2.57 (1H, m), 2.83-3.13 (2H, m),
3.24-3.56 (2H, m), 3.64-3.73 (1H, m), 5.09-5.13 (1H, m), 6.38
(1H, m), 6.84-7.71 (10H, m), 9.03 (1H, br s), 9.61 (1H, br s),
13.38 (1H, br s). MS (ES) m/e: 470 (M - H). Anal. (C25H23Cl2N1-
O4 ·1.0HCl·1.75H2O) C, H, N.
5-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-methoxybenzoic Acid
Hydrochloride (11c). The title compound was synthesized from
24 and (3-formyl-4-methoxyphenyl)boronic acid 35 according to
procedures B and E (20%). 1H NMR (200 MHz, DMSO-d6): δ
1.79-1.91 (1H, m), 2.28-2.33 (1H, m), 2.77-2.91 (2H, m),
3.16-3.61 (5H, m), 3.80 (3H, s), 5.04-5.08 (1H, m), 6.34-6.36
(1H, m), 6.69-7.50 (10H, m), 8.94 (1H, br s), 9.40 (1H, br s),
12.72 (1H, br s). MS (ES) m/e: 482 (M + Na). Anal.
(C26H26Cl1N1O5 ·1.0HCl·3.5H2O) C, H, N.
The title compound was synthesized from the obtained product
according to procedure C (78%). 1H NMR (200 MHz, DMSO-d6):
δ 1.51-1.55 (1H, m), 1.75-1.90 (2H, m), 2.28-2.33 (1H, m),
2.73-2.85 (2H, m), 2.93 (6H, s), 3.14-3.27 (2H, m), 3.38-3.50
(1H, m) 5.02-5.06 (1H, m), 6.63-6.64 (1H, m), 6.77-7.50 (10H,
m), 8.90 (1H, br s), 9.26 (1H, br s). MS (ES) m/e: 479 (M - H).
Anal. (C27H29Cl1N2O4 ·2.0HCl·4.5H2O) C, H, N.
3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-5-methoxybenzoic Acid
Hydrochloride (11d). The title compound was synthesized from
24 and [3-methoxy-5-(methoxycarbonyl)phenyl]boronic acid 36
according to the procedure described for the conversion of 24 to
10c (40%). 1H NMR (200 MHz, DMSO-d6): δ 1.15-1.25 (1H,
m), 1.83-1.88 (2H, m), 2.27-2.32 (1H, m), 2.78-2.86 (2H, m),
3.08-3.48 (2H, m), 3.68-3.73 (1H, m), 3.80 (3H, s), 5.02-5.05
(1H, m), 6.35-6.37 (1H, m), 6.82-7.50 (10H, m), 8.91 (1H, br s),
3-(Acetylamino)-5-[((7S)-7-{[(2R)-2-(3-chlorophenyl)-2-hy-
droxyethyl]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]ben-
zoic Acid Hydrochloride (11g). To a solution of 39 (73 mg, 0.129
mmol) and pyridine (0.021 mL, 0.257 mmol) in dichloromethane
(1.0 mL) was added acetic anhydride (13.4 µL, 0.142 mmol)
dropwise at 4 °C. The solution was stirred at room temperature for
2 h. To the solution was added water, and the solution was extracted
with ethyl acetate and washed with water and brine. The extract
was dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel with ethyl acetate and hexane to give 75 mg
(95%)ofmethyl3-(acetylamino)-5-[((7S)-7-{(tert-butoxycarbonyl)[(2R)-
2-(3-chlorophenyl)-2-hydroxyethyl]amino}-5,6,7,8-tetrahydro-2-
naphthalenyl)oxy]benzoate. 1H NMR (200 MHz, DMSO-d6): δ 1.36
(9H, s), 1.9-2.1 (2H, m), 2.08 (3H, s), 2.2-2.3 (2H, m), 2.7-3.0
(2H, m), 3.2-3.4 (3H, m), 3.82 (3H, s), 4.7-4.8 (1H, m), 5.5-5.6
(1H, m), 6.7-6.9 (2H, m), 7.1-7.2 (2H, m), 7.3-7.4 (4H, m), 7.50
(1H, br s), 7.97 (1H, s), 10.20 (1H, s). MS (ES) m/e: 607 (M-H).
The title compound was synthesized from the obtained product
according to procedure C (89%). 1H NMR (200 MHz, DMSO-d6):
δ 1.45-1.65 (1H, m), 1.74-1.91 (2H, m), 2.03 (3H, s), 2.28-2.33
(1H, m), 2.78-2.93 (2H, m), 3.10-3.64 (3H, m), 4.97-5.02 (1H,
m), 6.33-6.36 (1H, m), 6.88-7.88 (10H, m), 8.95 (2H, br), 10.21
(1H, s), 13.06 (1H, br s). MS (ES) m/e: 493 (M - H). Anal.
(C27H27Cl1N2O5 ·1.0HCl·2.5H2O) C, H, N.
3-{[(7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-5-(propylamino)benzo-
ic Acid Dihydrochloride (11h). To a mixture of 39 (123 mg, 0.217
mmol) in DMF (2.0 mL) was added ethyl n-propyl iodide (47 µL,
0.60 mmol) and K2CO3 (100 mg, 0.72 mmol) at room temperature,
and the mixture was stirred at 80 °C for 22 h. The resulting mixture
was poured into a mixture of ethyl acetate and water, and the
organic layer was washed with brine. After the solvent was
evaporated under pressure, the residue was purified by column
chromatography on silica gel (hexane/ethyl acetate ) 3/1) to give
54 mg (41%) of methyl 3-{[(7S)-7-{(tert-butoxycarbonyl)[(2R)-2-
(3-chlorophenyl)-2-hydroxyethyl]amino}-5,6,7,8-tetrahydronaphtha-
len-2-yl]oxy}-5-(propylamino)benzoate. 1H NMR (200 MHz, DMSO-
d6): δ 0.8-1.0 (5H, m), 1.36 (9H, s), 1.4-1.6 (2H, m), 1.8-2.0
(2H, m), 2.5-2.9 (4H, m), 3.33 (6H, s), 3.2-3.4 (3H, m), 3.78
(3H, s), 4.7-4.8 (1H, m), 5.5-5.6 (1H, m), 6.3-6.4 (1H, m),
9.32 (1H, br s). MS (ES) m/e: 466 (M
(C26H27Cl1N1O5 ·1.0HCl·1.5H2O) C, H, N.
- H). Anal.
Methyl 3-[((7S)-7-{(tert-butoxycarbonyl)[(2R)-2-(3-chlorophe-
nyl)-2-hydroxyethyl]amino}-5,6,7,8-tetrahydro-2-naphthaleny-
l)oxy]-5-nitrobenzoate (38). The title compound was synthesized
from 24 and [3-(methoxycarbonyl)-5-nitrophenyl]boronic acid 37
according to procedure B (54%). 1H NMR (200 MHz, DMSO-d6):
δ 1.36 (9H, s), 1.9-2.1 (2H, m), 2.6-3.0 (4H, m), 3.3-3.4 (3H,
m), 3.90 (3H, s), 4.7-4.9 (1H, m), 5.5-5.6 (1H, m), 6.8-7.0 (2H,
m), 7.1-7.4 (5H, m), 7.7-7.8 (1H, m), 7.9-8.0 (1H, m), 8.30-8.35
(1H, m). MS (ES) m/e: 619 (M + Na).
Methyl 3-Amino-5-[((7S)-7-{(tert-butoxycarbonyl)[(2R)-2-(3-
chlorophenyl)-2-hydroxyethyl]amino}-5,6,7,8-tetrahydro-2-naph-
thalenyl)oxy]benzoate (39). To a solution of 38 (150 mg, 0.25
mmol) in a mixed solution of ethanol (1.5 mL) and water (0.5 mL)
were added iron powder (42.1 mg, 0.75 mmol) and ammmonium
chloride (6.72 mg, 0.126 mmol). The solution was heated under
reflux for 2 h. After the mixture was cooled to room temperature,
the precipitate was filtered through a pad of Celite. After concentra-
tion under reduced pressure, the residue was extracted with ethyl
acetate, successively washed with saturated aqueous sodium
hydrogen carbonate and brine, and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified
by column chromatography on silica gel with ethyl acetate and
hexane (1: 3) to give 132 mg (93%) of the title compound. 1H
NMR (200 MHz, DMSO-d6): δ 1.36 (9H, s), 1.9-2.0 (2H, m),
2.5-2.9 (4H, m), 3.2-3.4 (3H, m), 3.76 (3H, s), 4.7-4.8 (1H, m),
5.50-5.7 (3H, br), 6.3-6.4 (1H, m), 6.5-6.8 (2H, m), 6.75 (1H,
d, J ) 8.3 Hz), 6.9-7.0 (1H, m), 7.08 (1H, d, J ) 8.3 Hz), 7.2-7.4
(4H, m). MS (ES) m/e: 589 (M + Na).
3-Amino-5-[((7S)-7-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethy-
l]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]benzoic Acid
Dihydrochloride (11e). The title compound was synthesized from
39 according to procedure C (57%). 1H NMR (200 MHz, DMSO-
d6): δ 0.83-0.89 (1H, m), 1.45-1.51 (1H, m), 1.84-1.91 (1H,
m), 2.29-2.35 (1H, m), 2.80-2.93 (2H, m), 3.13-3.89 (3H, m),
5.03-5.07 (1H, m), 6.60-6.61 (1H, m), 6.76-7.50 (13H, m), 8.94

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4819
6.5-6.6 (1H, m), 6.7-6.95 (4H, m), 7.1-7.2 (1H, m), 7.3-7.5
(4H, m). MS (ES) m/e: 631 (M + Na).
m), 2.30-2.40 (1H, m), 2.70-3.30 (7H, m), 3.80 (3H, s), 5.00-5.10
(1H, m), 6.65-6.80 (2H, m), 7.00-7.20 (4H, m), 7.55 (1H, d, J )
8 Hz), 7.90 (1H, dd, J ) 2 Hz, 8 Hz), 8.45 (1H, d, J ) 2 Hz). MS
(ES) m/e: 469 (M + H). Anal. (C25H25Cl1N2O5 ·2.0HCl·0.5H2O)
C, H, N.
3-[((7S)-7-{[(2R)-2-(6-Chloro-3-pyridinyl)-2-hydroxyethyl]ami-
no}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-5-(dimethylamino)ben-
zoic Acid Dihydrochloride (11p). The title compound was
synthesized from 27 according to the procedure described for the
conversion of 24 to 11f (22%). HPLC purity: 95%. 1H NMR (200
MHz, DMSO-d6): δ 1.8-2.0 (1H, m), 2.96 (6H, s), 3.0-4.0 (5H,
m), 5.15 (1H, m), 6.5-7.3 (6H, m), 7.56 (1H, d, J ) 8.4 Hz), 7.91
(1H, m), 8.46 (1H, m), 9.01 (1H, m), 9.58 (1H, m). MS (ES) m/e:
482 (M + H). HRMS(M + H)+ found: 482.1836. Calcd for
C26H28Cl1N3O4 482.1847.
The title compound was synthesized from the above product
according to procedure B (94%). 1H NMR (200 MHz, DMSO-d6):
δ 0.8-1.0 (5H, m), 1.4-1.6 (2H, m), 1.7-1.9 (1H, m), 2.2-2.4
(1H, m), 2.7-3.0 (4H, m), 3.04-3.2 (2H, m), 3.4-3.6 (2H, m),
4.2-4.8 (1H, br), 5.0-5.1 (1H, m), 6.45 (1H, br s), 6.5 (1H, m),
6.77-6.87 (3H, m), 6.95 (1H, s), 7.1-7.2 (1H, m), 7.35-7.51 (3H,
m), 8.92 (1H, br s), 9.27 (1H, br s). MS (ES) m/e: 493 (M - H).
Anal. (C28H31Cl1N2O4 ·2.0HCl·2.5H2O) C, H, N.
3-{[(7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-5-(cyclohexylamino)ben-
zoic Acid Dihydrochloride (11i). The title compound was syn-
thesized from 39 and cyclohexanone according to the procedure
1
described for the conversion of 39 to 11f (40%). H NMR (200
MHz, DMSO-d6): δ 1.1-2.0 (11H, m), 2.2-2.4 (1H, m), 2.7-3.2
(6H, m), 2.4-2.63 (2H, m), 4.22 (1H, br), 5.08 (1H, m), 6.72-6.88
(4H, m), 7.16 (2H, d, J ) 8.3 Hz), 7.41-7.51 (4H, m), 8.95 (1H,
br), 9.47 (1H, br). MS (ES) m/e: 533 (M - H). Anal. (C31H35Cl1-
N2O4 ·2.0HCl·2.0H2O) C, H, N.
[3-(Methoxycarbonyl)-4-methylphenyl]boronic Acid (33). To
a solution of methyl 5-bromo-2-methylbenzoate (6.4 g, 27.9 mmol)
in 1,4-dioxane (70 mL) were added bis(pinacolate)diboron (7.09
g, 27.9 mmol), potassium acetate (8.23 g, 83.8 mmol), and
dichlorobis(triphenylphosphine)palladium(II) (1.57 g, 2.24 mmol).
The mixture was stirred at 100 °C for 2 h. To the mixture was
added 1 N hydrogen chloride. The mixture was extracted with ethyl
acetate and washed with 1 N hydrogen chloride and water. The
extract was dried over magnesium sulfate, filtered, and concentrated
under reduced pressure to give the corresponding boronic ester.
To a solution of the boronic ester in a mixed solution of acetone
(120 mL) and water (120 mL) were added sodium periodate (17.9
g, 83.7 mmol) and ammonium acetate (6.45 g, 83.7 mmol). The
mixture was stirred at room temperature for 17 h. The precipitate
was filtered, and the filtrate was concentrated under reduced
pressure. The residue was extracted with ethyl acetate and washed
with water. The extract was dried over magnesium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel with ethyl acetate and
hexane (1:1) to give 4.05 g (75%) of the title compound as a pale-
brown solid. 1H NMR (400 MHz, DMSO-d6): δ 2.53 (3H, s), 3.86
(3H, s), 7.29 (1H, d, J ) 8.0 Hz), 7.87 (1H, d, J ) 8.0 Hz), 8.27
(1H, s),.8.31 (2H, s). MS (ES) m/e: 193 (M - H).
3-[((7S)-7-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-5-(tetrahydro-2H-pyran-
4-ylamino)benzoic Acid Dihydrochloride (11j). The title com-
pound was synthesized from 39 and tetrahydro-4H-pyran-4-one
according to the procedure described for the conversion of 39 to
1
11f (34%). H NMR (200 MHz, DMSO-d6): δ 1.5-2.2 (5H, m),
2.1-3.0 (3H, m), 3.0-3.8 (8H, m), 4.66 (1H, m), 4.97 (1H, m),
6.33 (1H, m), 6.8-7.0 (4H, m), 7.18 (2H, d, J ) 8.4 Hz), 7.3-7.6
(4H, m). MS (ES) m/e: 537 (M + H). Anal. (C301H33Cl1N2-
O5 ·2.0HCl·2.0H2O) C, H, N.
3-[((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]benzoic Acid Hydrochlo-
ride (11k). The title compound was synthesized from 25 according
to the procedure described for the conversion of 24 to 10c (46%).
1H NMR (200 MHz, DMSO-d6): δ 1.85-2.05 (1H, m), 2.30-2.50
(1H, m), 2.70-3.60 (7H, m), 5.10-5.20 (1H, m), 6.80-6.90 (2H,
m), 7.20-7.80 (9H, m). MS (ES) m/e: 438 (M + H). Anal.
(C25H24Cl1N1O4 ·1.0HCl·2.6H2O) C, H, N.
[3-Methoxy-5-(methoxycarbonyl)phenyl]boronic Acid (36). To
a mixture of methyl 3-hydroxy-5-methoxybenzoate (1.5 g, 8.23
mmol) in dichloromethane (15 mL) were added 2,6-lutidine (1.05
mL, 9.06 mmol) and trifluoromethanesulfonic anhydride (1.52 mL,
9.06 mmol) at 4 °C under N2, and the mixture was stirred for 1 h
at the room temperature. The mixture was poured into water, and
the organic layer was washed with 1 N HCl and brine and then
dried over magnesium sulfate to give the corresponding sulfonate.
The title compound was synthesized from the obtained sulfonate
according to the procedure described for the conversion of methyl
5-bromo-2-methylbenzoate to 33 except that the Pd catalyst was
PdCl2(dppf)·CHCl3 (21%). 1H NMR (200 MHz, DMSO-d6): δ 3.81
(3H, s), 3.85 (3H, s), 7.46 (1H, m), 7.61 (1H, m), 8.01 (1H, s),
8.27 (2H, s). MS (ES) m/e: 209 (M - H).
5-[((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-methoxybenzoic Acid
Hydrochloride (11l). The title compound was synthesized from
25 according to the procedure described for the conversion of 24
to 11c (35%). 1H NMR (200 MHz, DMSO-d6): δ 1.75-2.00 (1H,
m), 2.20-2.40 (1H, m), 2.60-3.60 (7H, m), 3.80 (3H, s), 5.05-5.15
(1H, m), 6.75-6.90 (2H, m), 7.05-7.25 (4H, m), 7.40-7.50 (4H,
m). MS (ES) m/e: 468 (M
O5 ·1.0HCl·2.5H2O) C, H, N.
+ H). Anal. (C26H26Cl1N1-
3-[((7S)-7-{[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}-5,6,7,8-
tetrahydro-2-naphthalenyl)oxy]benzoic Acid Dihydrochloride
(11m). The title compound was synthesized from 27 according to
procedure B (20%), followed by the procedure described for the
1
conversion of 46 to 12g (38%). H NMR (200 MHz, DMSO-d6):
δ 1.90-2.05 (1H, m), 2.30-2.40 (1H, m), 2.70-3.10 (3H, m),
3.20-3.60 (4H, m), 5.30-5.45 (1H, m), 6.80-6.95 (2H, m),
7.10-7.70 (6H, m), 8.00 (1H, dd, J ) 5 Hz, 8 Hz), 8.60 (1H, d, J
) 8 Hz), 8.85 (1H, d, J ) 5 Hz). MS (ES) m/e: 405 (M + H).
Anal. (C24H24N2O4 ·2.0HCl·1.0H2O) C, H, N.
3-[((7S)-7-{[(2R)-2-(6-Chloro-3-pyridinyl)-2-hydroxyethyl]ami-
no}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]benzoic Acid Dihy-
drochloride (11n). The title compound was synthesized from 27
according to the procedure described for the conversion of 24 to
10c (11%). 1H NMR (200 MHz, DMSO-d6): δ 1.80-1.90 (1H,
m), 2.30-2.40 (1H, m), 2.50-3.50 (7H, m), 5.10-5.20 (1H, m),
6.80-7.00 (2H, m), 7.15-7.70 (6H, m), 7.90-8.00 (1H, m), 8.48
(1H,s).MS(ES)m/e:439(M+H).Anal.(C24H23Cl1N2O4 ·2.0HCl·3.5H2-
O) C, H, N.
Benzyl [(2S)-7-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]-
carbamate (41). To a mixture of (7S)-7-amino-5,6,7,8-tetrahydro-
2-naphthalenol 18 (7.16 g, 43.9 mmol) in THF(70 mL) and water
(50 mL) was added benzyl chlorocarbonate (6.58 mL, 46.1 mmol)
at room temperature. The pH was kept between 7 and 8 by using
1 N aqueous NaOH. The mixture was stirred at room temperature
for 1 h. The mixture was partitioned between ethyl acetate and
water. The organic layer was separated, washed with brine, dried
over magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
(chloroform/methanol ) 20/1) to give 12.5 g (96%) of the title
1
compound. H NMR (200 MHz, CDCl3): δ 1.60-1.85 (1H, m),
1.92-2.12 (1H, m), 2.4-3.1 (4H, m), 3.87-4.12 (1H, m), 4.8-5.0
(1H, m), 5.11 (2H, s), 5.86 (1H, s), 6.51 (1H, d, J ) 2.6 Hz), 6.63
(1H, dd, J ) 2.6, 8.2 Hz), 7.26-7.40 (5H, m).
5-[((7S)-7-{[(2R)-2-(6-Chloro-3-pyridinyl)-2-hydroxyethyl]ami-
no}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-methoxybenzoic Acid
Dihydrochloride (11o). The title compound was synthesized from
27 according to the procedure described for the conversion of 24
to 11c (20%). 1H NMR (200 MHz, DMSO-d6): δ 1.75-1.85 (1H,
Methyl 4-((7S)-7-{[(Benzyloxy)carbonyl]amino}-5,6,7,8-tet-
rahydro-2-naphthalenyl)benzoate (42). The title compound was
synthesized from 41 and 4-(methoxycarbonyl)phenylboronic acid
1
according to procedure F (72%). H NMR (200 MHz, CDCl3): δ

4820 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Imanishi et al.
1.6-1.9 (1H, m), 2.0-2.2 (1H, m), 2.6-2.8 (1H, m), 2.82-3.0
(1H, m), 3.1-3.3 (1H, m), 3.95 (3H, s), 4.0-4.2 (1H, m), 4.84
(1H, br s), 5.12 (2H, s), 5.86 (1H, s), 7.17-7.41 (7H, m), 7.61
(1H, d, J ) 8 Hz), 8.10 (1H, d, J ) 8 Hz). MS (ES) m/e: 416 (M
+ H).
Methyl 4-[(7S)-7-Amino-5,6,7,8-tetrahydro-2-naphthalenyl]-
benzoate (43). A mixture of 42 (580 mg, 1.4 mmol) in MeOH (50
mL) was hydrogenated over palladium on carbon (10% w/w, 50%
wet, 58 mg) under hydrogen atmosphere for 1 h. The catalyst was
filtered off, and the filtrate was evaporated to give 395 mg (100%)
of the title compound. 1H NMR (200 MHz, DMSO-d6): δ 1.6-1.9
(1H, m), 2.0-2.2 (1H, m), 2.6-2.8 (1H, m), 2.8-3.0 (3H, m),
3.2-3.6 (1H, m), 3.87 (3H, s), 3.8-3.9 (1H, m), 7.2-7.5 (3H, m),
7.82 (1H, d, J ) 8 Hz), 8.02 (1H, d, J ) 8 Hz), 8.19 (2H, br). MS
(ES) m/e: 282 (M + H).
(2R)-2-(4-Chlorophenyl)oxirane (22). Typical Procedure G.
To a solution of AD-mix-ꢀ (10.1 g) in tert-butanol (60 mL) and
water (60 mL) was added 1-chloro-4-vinylbenzene (1.0 g, 7.22
mmol) on ice-cooling, and the mixture was stirred at the same
temperature for 4 h. To the mixture was added sodium sulfite (19
g). The resulting mixture was poured into saturated aqueous sodium
bicarbonate solution 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 (hexane/ethyl acetate ) 1/1) to give 1.04 g (83.5%)
of (1R)-1-(4-chlorophenyl)-1,2-ethanediol. 1H NMR (200 MHz,
CDCl3): δ 3.50-3.80 (2H, m), 4.70-4.85 (1H, m), 7.20-7.40 (4H,
m).
(6H, m), 7.50 (2H, d, J ) 8.0 Hz), 7.90 (2H, d, J ) 8.0 Hz). MS
(ES) m/e: 422 (M + H). HRMS (M + H)+ found: 422.1523. Calcd
for C25H24Cl1N1O3 422.1523. Anal. (C25H23Cl1N1O3 ·1.0Na ·1.8H2O·
0.5CHCl3) C, H, N.
Sodium 4-((7S)-7-{[(2R)-2-(2-Chlorophenyl)-2-hydroxyethy-
l]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate (12a). The
title compound was synthesized from 43 according to procedure H
(45%). HPLC purity: 97%. 1H NMR (200 MHz, DMSO-d6): δ
1.8-3.0 (9H, m), 4.97 (1H, m), 7.0-7.7 (9H, m), 7.8-8.0 (2H,
m). MS (ES) m/e: 420 (M - H). HRMS (M + H)+ found:
422.1513. Calcd for C25H24Cl1N1O3 422.1523.
Sodium 4-((7S)-7-{[(2R)-2-(4-Cyanophenyl)-2-hydroxyethy-
l]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate (12d). The
title compound was synthesized from 43 according to procedure H
(71%). HPLC purity: 98%. 1H NMR (200 MHz, DMSO-d6): δ
1.4-3.0 (9H, m), 4.72 (1H, m), 7.12 (1H, d, J ) 8.2 Hz), 7.2-7.6
(6H, m), 8.82 (2H, d, J ) 8.4 Hz), 7.92 (2H, d, J ) 8.4 Hz). MS
(ES) m/e: 413 (M + H). HRMS (M + H)+ found: 413.1859. Calcd
for C26H24N2O3 413.1865.
Sodium 4-((7S)-7-{[(2R)-2-(4-trifluorophenyl)-2-hydroxyethy-
l]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate (12e). The
title compound was synthesized from 43 according to procedure H
(56%). 1H NMR (200 MHz, DMSO-d6): δ 1.8-3.2 (9H, m), 4.73
(1H, m), 7.11 (1H, d, J ) 8.6 Hz), 7.3-7.8 (8H, m), 7.88 (2H, d,
J ) 8.2 Hz). MS (ES) m/e: 456 (M + H). Anal. (C26H23F3-
N1O3 ·1.0Na·0.5H2O·1.0CHCl3) C, H, N.
Sodium 4-((7S)-7-{[(2R)-2-(3,4-Dichlorophenyl)-2-hydroxy-
ethyl]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate (12f).
The title compound was synthesized from 43 according to procedure
Trimethylsilyl chloride (0.956 mL, 7.53 mmol) was added to a
solution of (1R)-1-(4-chlorophenyl)-1,2-ethanediol (1.0 g, 5.79
mmol) and trimethyl orthoacetate (0.87 mL, 6.89 mmol) in
dichloromethane (30 mL) on ice-cooling. The mixture was stirred
for 1 h and evaporated. The crude product was dissolved in dry
methanol, and potassium carbonate (1.97 g, 14.3 mmol) was added.
The suspension was stirred vigorously for 100 min and then filtered,
and the residue was washed with dichloromethane. The filtrate was
washed with brine, dried over magnesium sulfate, and evaporated
to give 700 mg (83.2%) of the title compound as a colorless oil.
1H NMR (200 MHz, CDCl3): δ 2.75 (1H, dd, J ) 2.5, 5.5 Hz),
3.14 (1H, dd, J ) 4.0, 5.5 Hz), 3.80-3.86 (1H, m), 7.18-7.40
(4H, m). The optical purity was determined as 98.6% ee by chiral
HPLC (Chiralcel OD); eluent, 2-propanol/hexane ) 0.25%.
(2R)-2-(4-Methylphenyl)oxirane (44). The title compound was
synthesized from 1-methyl-4-vinylbenzene according to procedure
1
H (54%). HPLC purity: 97%. H NMR (200 MHz, DMSO-d6): δ
1.8-3.0 (9H, m), 4.66 (1H, m), 7.0-7.2 (1H, m), 7.2-7.9 (9H,
m). MS (ES) m/e: 472 (M + H). HRMS(M + H)+ found: 456.1126.
Calcd for C25H23Cl2N1O3 456.1133.
Sodium 4-((7S)-7-{[(2R)-2-(6-Chloro-3-pyridinyl)-2-hydroxy-
ethyl]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate (12h).
The title compound was synthesized from 43 according to procedure
1
H (42%). H NMR (200 MHz, DMSO-d6): δ 1.50-1.70 (1H, m),
1.90-2.10 (1H, m), 2.50-3.50 (7H, m), 4.70-4.80 (1H, m),
7.10-7.15 (1H, m), 7.20-7.60 (5H, m), 7.70-8.00 (3H, m), 8.40
1H, s). MS (ES) m/e: 423 (M + H). Anal. (C24H22Cl1-
N2O3 ·1.0Na·2.25H2O) C, H, N.
Methyl 4-[(7S)-7-{(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-
(4-methylphenyl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-
yl]benzoate (45). The title compound was synthesized from 43 and
(2R)-2-(4-methylphenyl)oxirane 44 according to procedure A (29%).
1H NMR (200 MHz, CDCl3): δ 1.52 (9H, s), 1.8-2.0 (2H, m),
2.34 (3H, s), 2.8-3.1 (4H, m), 3.2-3.7 (2H, m), 3.94 (3H, s),
4.1-4.2 (1H, m), 4.90 (1H, m), 7.13-7.42 (7H, m), 7.64 (2H, d,
J ) 8.5 Hz), 8.09 (2H, d, J ) 8.5 Hz). MS (ES) m/e: 516 (M +
H).
4-((7S)-7-{[(2R)-2-Hydroxy-2-(4-methylphenyl)ethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)benzoic Acid Hydrochloride
(12c). The title compound was synthesized from 45 according to
procedure C (46.4%). 1H NMR (200 MHz, DMSO-d6): δ 1.80-2.00
(1H, m), 2.31 (3H, s), 2.25-2.50 (1H, m), 2.70-3.70 (7H, m),
5.00-5.10 (1H, m), 6.85-6.95 (2H, m), 7.10-7.55 (7H, m), 7.80
(2H, d, J ) 8 Hz), 8.00 (2H, d, J ) 8 Hz). MS (ES) m/e: 402 (M
+ H). Anal. (C26H27NO3 ·1.0HCl) C, H, N.
1
G (93%). H NMR (200 MHz, CDCl3): δ 2.34 (3H, s), 2.80 (1H,
dd, J ) 2.5, 5.5 Hz), 3.13 (1H, dd, J ) 4 Hz, 5.5 Hz), 3.82 (1H,
dd, J ) 2.5, 4 Hz), 7.10-7.30 (4H, m). The optical purity was
determined as 97.8% ee by chiral HPLC (Chiralcel OD).
Sodium 4-((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethy-
l]amino}-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate (12b). Typi-
cal Procedure H. A solution of methyl 4-[(7S)-7-amino-5,6,7,8-
tetrahydro-2-naphthalenyl]benzoate 43 (142 mg, 0.505 mmol), and
(2R)-2-(4-chlorophenyl)oxirane 22 (70.2 mg, 0.454 mmol) in
ethanol (10 mL) was refluxed for 18 h. The mixture was evaporated
in vacuo. The residue was purified by column chromatography on
silica gel (chloroform/methanol ) 100:1) to give 130 mg (59.1%)
of methyl 4-((7S)-7-{[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]amino}-
1
5,6,7,8-tetrahydro-2-naphthalenyl)benzoate. H NMR (200 MHz,
DMSO-d6): δ 1.4-1.6 (1H, m), 1.9-2.0 (1H, m), 2.6-3.2 (6H,
m), 4.6-4.7 (1H, m), 5.4-5.5 (1H, m), 7.17(1H, d, J ) 8.5 Hz),
7.3-7.5 (6H, m), 7.78 (2H, d, J ) 8.4 Hz), 7.01 (2H, d, J ) 8.4
Hz). MS (ES) m/e: 436 (M + H).
Methyl 4-((7S)-7-{(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-
pyridinyl)-2-hydroxyethyl]amino}-5,6,7,8-tetrahydro-2-naphtha-
lenyl)benzoate (46). The title compound was synthesized from 43
and 2-chloro-5-[(2R)-oxiran-2-yl]pyridine 23 according to procedure
A (36.7%). 1H NMR (200 MHz, CDCl3): δ 1.52 (9H, s), 1.8-2.0
(2H, m), 2.8-3.1 (4H, m), 3.2-3.7 (2H, m), 3.94 (3H, s), 4.1-4.2
(1H, m), 4.97 (1H, m), 7.16-7.42 (4H, m), 7.63 (2H, d, J ) 8.4
Hz), 7.73 (1H, dd, J ) 2.4, 8.3 Hz), 8.09 (2H, d, J ) 8.4 Hz), 8.38
(1H, d, J ) 2.4 Hz). MS (ES) m/e: 537 (M + H).
4-((7S)-7-{[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}-5,6,7,8-
tetrahydro-2-naphthalenyl)benzoic Acid Dihydrochloride (12g).
To a solution of 46 (1.0 g, 1.86 mmol) in ethanol (15.0 mL) was
added 1 N sodium hydroxide (5.0 mL), and the mixture was stirred
To a solution of the obtained product (130 mg, 0.298 mmol) in
ethanol (3.0 mL) was added 1 N sodium hydroxide (0.75 mL), and
the mixture was refluxed for 3 h. After the mixture was cooled to
room temperature, the precipitates were collected by filtration,
washed with a small amount of ethanol, and dried under reduced
pressure at 40-50 °C to give 120 mg (92.1%) of the title compound
1
as a colorless powder. HPLC purity: 99%. H NMR (200 MHz,
DMSO-d6): δ 1.40-1.60 (1H, m), 1.90-2.10 (1H, m), 2.50-3.20
(6H, m), 4.60-4.70 (1H, m), 7.05 (1H, d, J ) 8.0 Hz), 7.30-7.40

Benzoic Acid DeriVatiVes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4821
for 2 h at room temperature. The mixture was diluted with ethyl
acetate and 1 N hydrochloride. The organic layer was separated,
washed with brine, dried over magnesium sulfate, and evaporated.
A mixture of the obtained benzoic acid (800 mg, 1.53 mmol),
ammonium formate (300 mg), and palladium on carbon powder
(100 mg) in methanol (25 mL) and water (5.0 mL) was refluxed
for 15 min. The reaction mixture was filtered, poured into water,
and extracted with ethyl acetate. The organic layer was washed
with brine, dried over magnesium sulfate, and evaporated in vacuo.
The residue was purified by column chromatography on silica gel
(chloroform-methanol) to give 620 mg (68%) of 4-((7S)-7-{(tert-
butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-5,6,7,8-
tetrahydro-2-naphthalenyl)benzoic acid as a colorless form. MS (ES)
m/e: 489 (M + H).
A solution of the obtained product (620 mg, 1.27 mmol) and 4
N hydrochloric acid in dioxane (10 mL) was stirred at room
temperature for 24 h. The resultant solid was collected by filtration
and dried to give 450 mg (75%) of the title compound as a white
solid. 1H NMR (200 MHz, DMSO-d6): δ 1.80-1.90 (1H, m),
2.30-2.40 (1H, m), 2.80-3.50 (6H, m), 5.30-5.40 (1H, m), 7.20
(1H, d, J ) 8 Hz), 7.40-7.50 (2H, m), 7.77 (2H, d, J ) 8 Hz),
7.90-8.05 (3H, m), 8.60 (1H, d, J ) 8 Hz), 8.88 (1H, d, J ) 8
Hz), 8.99 (1H, s). MS (ES) m/e: 389 (M + H). Anal.
(C24H24N2O3 ·2.0HCl·2.5H2O) C, H, N.
7.00-7.30 (4H, m), 7.35-7.45 (5H, m), 7.80-7.90 (1H, m). MS
(ES) m/e: 436 (M + H). Anal. (C26H26Cl1N1O3 ·1.0HCl·0.8H2O)
C, H, N.
4-((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)-3-fluorobenzoic Acid Hy-
drochloride (12n). The title compound was synthesized from 25
and [2-fluoro-4-(methoxycarbonyl)phenyl]boronic acid according
to the procedure described for the conversion of 24 to 10m (63%).
1H NMR (200 MHz, DMSO-d6): δ 1.70-1.95 (1H, m), 2.30-2.40
(1H, m), 2.70-3.50 (7H, m), 5.00-5.10 (1H, m), 7.20-7.90 (10H,
m). MS (ES) m/e: 440 (M + H). Anal. (C25H23Cl1F1N1O3 ·
1.0HCl·3.0H2O) 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-, ꢀ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 confluence
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 HEPES, 0.1% bovine serum albumin, pH7.4] and incubated
with 180 µL of assay buffer containing 0.5 mM 3-isobutylmeth-
ylxanthine (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 M 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
enzymeimmunoassay (EIA) kit (Amersham Biosciences). The
supernatant was frozen below -80 °C until the measurement of
cAMP levels.
4-((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)-2-methylbenzoic Acid Hy-
drochloride (12i). The title compound was synthesized from 25
and [4-(methoxycarbonyl)-3-methylphenyl]boronic acid according
to the procedure described for the conversion of 24 to 10m (44%).
1H NMR (200 MHz, DMSO-d6): δ 1.80-2.00 (1H, m), 2.30-2.40
(1H, m), 2.59 (3H, s), 2.70-3.70 (7H, m), 5.05-5.15 (1H, m),
7.24 (1H, d, J ) 8 Hz), 7.30-7.65 (8H, m), 7.90(1H, d, J ) 8
(3) Data Analysis. cAMP acumulation elicited by test com-
pounds were expressed as a percentage of the maximal response
to isoproterenol. Fifty percent effective concentration (EC50) values
were calculated using GraphPad Prism (version 3.03) from the
concentration-response curve.
Hz). MS (ES) m/e: 436 (M
O3 ·1.0HCl·2.5H2O) C, H, N.
+ H). Anal. (C26H26Cl1N1-
4-((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)-2-fluorobenzoic Acid Hy-
drochloride (12j). The title compound was synthesized from 25
and [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid according
to the procedure described for the conversion of 24 to 10m (34%).
1H NMR (200 MHz, DMSO-d6): δ 1.80-1.95 (1H, m), 2.25-2.40
(1H, m), 2.70-3.60 (7H, m), 5.00-5.10 (1H, m), 7.20 (1H, d, J )
8 Hz), 7.40-7.65 (8H, m), 7.90 (1H, d, J ) 8 Hz). MS (ES) m/e:
440 (M + H). HRMS (M + H)+ found: 440.1432. Calcd for
C25H23Cl1F1N1O3 440.1429. Anal. (C25H23Cl1F1N1O3 ·0.5HCl) C,
H, N.
Acknowledgment. We thank Dr. Xiaoyong Zhang (Takasa-
go Co.) for the screening of asymmetric hydrogenation to
prepare a chiral amine 15. We express our thanks to Dr. David
Barrett for his critical reading of the manuscript.
Supporting Information Available: Combustion analysis data
and biological method for in vivo experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
4-((7S)-7-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}-
5,6,7,8-tetrahydro-2-naphthalenyl)-2-methoxybenzoic Acid Hy-
drochloride (12k). The title compound was synthesized from 25
and [3-methoxy-4-(methoxycarbonyl)phenyl]boronic acid according
to the procedure described for the conversion of 24 to 10m (65%).
1H NMR (200 MHz, DMSO-d6): δ 1.80-1.90 (1H, m), 2.30-2.40
(1H, m), 2.80-3.20 (6H, m), 3.90 (3H, s), 5.00-5,05 (1H, m),
7.10-7.30 (3H, m), 7.50-7.60 (6H, m), 7.70 (2H, d, J ) 8 Hz).
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