Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological activities of 1-benzazepine derivatives containing a sulfoxide moiety

Article abstract of DOI:10.1016/j.bmc.2004.10.021

In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl

Full text of DOI:10.1016/j.bmc.2004.10.021

Bioorganic & Medicinal Chemistry 13 (2005) 363–386
Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3:
Synthesis and biological activities of 1-benzazepine
derivatives containing a sulfoxide moiety
Masaki Seto,a,* Naoki Miyamoto,a Katsuji Aikawa,a Yoshio Aramaki,a
Naoyuki Kanzaki,a Yuji Iizawa,a Masanori Babab and Mitsuru Shiraishia
aPharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85 Jusohonmachi,Yodogawa-ku,
Osaka 532-8686, Japan
bDivision of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences,
Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan
Received 17 September 2004; revised 8 October 2004; accepted 8 October 2004
Abstract—In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulf-
oxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyr-
idyl group were first investigated, which led to discovering that the presence of a methylene group between the sulfoxide moiety and
2-pyridyl group was necessary for increased inhibitory activity in a binding assay. After further chemical modification, it was found
that replacement of the pyridyl group with an imidazolyl or 1,2,4-triazolyl group enhanced activity in the binding assay and that S-
sulfoxide compounds were more active than R-isomers. Particularly, compounds (S)-4r, (S)-4s, and (S)-4w exhibited highly potent
CCR5 antagonistic activities (IC50 = 1.9, 1.7, 1.6nM, respectively) and inhibitory effects (IC50 = 1.0, 2.8, 7.7nM, respectively) in the
HIV-1 envelope mediated membrane fusion assay, together with good pharmacokinetic properties in rats. In addition, we estab-
lished the synthesis of (S)-4r and (S)-4w by asymmetric oxidation with titanium-(S)-(ꢀ)-1,10-bi-2-naphthol complex.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
cities.4 Therefore, HIV-1 entry inhibitors are considered
to be attractive candidates in HAART to circumvent the
above problems.5 Since the CC chemokine receptor 5
(CCR5) was identified as a co-receptor for entry of
macrophage-tropic (CCR5-using or R5) HIV-1 into
host cells in 1996,6–10 CCR5 antagonists have attracted
a great deal of attention as anti-HIV-1 agents. CCR5
is a member of the seven-transmembrane G-protein cou-
pled receptors, and its natural ligands are regulated on
activation normal T-cell expressed and secreted (RAN-
TES), macrophage inflammatory protein (MIP)-1a and
MIP-1b. Natural ligands for CCR5 and their modifica-
tions are reported to inhibit R5 HIV-1 infection.11
Therefore, CCR5 antagonists are thought to be new
and promising agents against HIV-1 infection, and
many pharmaceutical companies have searched for
CCR5 antagonists as anti-HIV-1 agents.12 The first non-
peptide, small molecule CCR5 antagonist was com-
pound 1, which we reported in 1999.13,14 Compound 1
exhibited poor oral absorption because of its polar
quaternary ammonium moiety, but it was selected as a
Human immunodeficiency virus type 1 (HIV-1) is the
causative agent of AIDS, and it is well documented that
suppression of HIV-1 replication leads to delay of dis-
ease progression. Establishment of the highly active
anti-retroviral therapy (HAART) using HIV-1 reverse
transcriptase inhibitors and protease inhibitors has been
successful in suppressing viral replication, which led to
reduction of mortality in HIV-1 infected individuals.1
However, development of novel anti-HIV-1 agents with
new mechanisms of action is thought to be essential be-
cause of several problems associated with combination
chemotherapy, such as the unfeasibility of viral eradica-
tion,2 emergence of drug resistance3 and long-term toxi-
Keywords: CCR5 antagonist; HIV-1; Sulfoxide; S-isomer; 1-Benz-
azepine.
*
Corresponding author. Tel.: +81 663006651; fax: +81 663006306;
e-mail: seto_masaki@takeda.co.jp
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.10.021

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M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
R1
N
H
N
H
N
Cl
Me
N
Me
Me
N
BuO
O
O
O
Me
O
1
2a: R1=Pr
O
2b: R1=i-Bu
i-Bu
R1
N
N
H
N
H
CF3
OH
N
O
BuO
BuO
O
O
S
R2
O
O
N
O
m
n
3
4: m=0 or1, m=0 or 1
Figure 1.
clinical candidate for a subcutaneous injectable agent.
For orally active CCR5 antagonists, it was reported that
Schering–Ploughꢀs clinical candidate, SCH-C has started
clinical trials.15,16
we designed the 1-benzazepine derivatives 4, which
had a sulfoxide moiety containing a heteroaryl group,
and performed chemical modifications of the sulfoxide
derivatives. In this paper, we describe the design, synthe-
sis, and structure–activity relationships (SAR) of the
1-benzazepine derivatives containing a sulfoxide moiety
(Fig. 1).
In order to develop an orally active CCR5 antagonist,
we had investigated the replacement of the quaternary
ammonium moiety of 1 with other polar substituents.
First, the chemical modification of the tertiary amine
derivatives was performed. Consequently, we discovered
the potent, orally active 1-propyl-1-benzazepine 2a and
1-isobutyl-1-benzazepine 2b. For the tertiary amine
derivatives, it was found that introduction of the 2-(but-
oxy)ethoxy group at the 4-position on the 7-phenyl
group of the [6,7]-fused nucleus led to both enhanced
binding affinity and improvement of the pharmacoki-
netic profiles, and that substitution of the 1-(bulky)alkyl
groups on the 1-benzazepine ring further enhanced the
activity in both the binding assay and HIV-1 envelope
(Env)-mediated membrane fusion assay.17,18 We next
investigated the pyridine N-oxide derivatives, which
resulted in the finding of the potent, orally active 2-(a-
hydroxybenzyl)pyridine N-oxide 3 containing the 1-
isobutyl-1-benzazepine moiety.19 We continued a search
for new polar substituents in place of the quaternary
ammonium moiety. On the basis of our experiences,
2. Chemistry
The synthetic method to the target compounds is out-
lined in Scheme 1. The target sulfoxide derivatives 4
were prepared by m-chloroperbenzoic acid (mCPBA)
oxidation of the corresponding sulfide compounds 6.
The sulfide compounds were prepared by two methods.
Condensation of the two key intermediates, the 1-benz-
azepine-4-carboxylic acids 518 and the aniline derivatives
7 containing the sulfide moieties, gave the sulfide
compounds 6 (method A). The alternative synthetic
route to the sulfide derivatives 6 used the other two
key intermediates, S-Cbz protected 4-aminothiophenol
8 and heteroarylmethylchlorides 9 (method B). The
synthetic methods for the key aniline derivatives 7, 8,
and heteroarylmethylchlorides 9 are illustrated in
Schemes 2–9.
R1
N
R1
N
a or b
H
N
CO2H
BuO
BuO
O
S
R2
O
O
5a: R1=Pr
m
n
6: m=0 or 1, n=0 or 1
5b: R1=i-Bu
R1
N
c (d)
BuO
H
N
O
O
S
R2
O
m
n
4: m=0 or 1, n=0 or 1
Scheme 1. Reagents: (a) (1) SOCl2 or (COCl)2, cat. DMF, THF, (2) 7, Et3N, THF; (b) (1) SOCl2, cat. DMF, THF, (2) 8, Et3N, THF, then 1N
NaOH, 9, MeOH; (c) mCPBA, CH2Cl2; (d) optical resolution by HPLC.

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
365
O2N
H2N
H2N
O
a
a or b
S
N
SH
S
8
O
m
HS
N
10b
10a
11a: m=0
11b: m=1
Scheme 5. Reagents: (a) benzyl chlorocarbonate, Et3N, THF.
H2N
c
S
N
m
7a: m=0
7b: m=1
NH
NH2
16
N
a
HCl
Cl
Cl
N
Scheme 2. Reagents: (a) 1-fluoro-4-nitrobenzene, NaH, DMF; (b)
4-nitrobenzylbromide, Et3N, THF; (c) Fe, AcOH.
9a
Scheme 6. Reagents: (a) 1,1,3,3-tetramethoxypropane.
H2N
H2N
a or b
The key O-benzyl-S-(4-aminophenyl)thiocarbonate (8)
was synthesized by reaction of 4-aminothiophenol
(10b) with benzyl chlorocarbonate (Scheme 5).
R2
SH
S
7c: R2=pyridin-2-yl
7d: R2=pyridin-3-yl
7e: R2=pyridin-4-yl
7f: R2=pyridazin-3-yl
7g: R2=pyrazin-2-yl
10b
2-(Chloromethyl)pyrimidine (9a) was prepared by reac-
tion of 2-chloroacetamidine (16) with 1,1,3,3-tetrameth-
oxypropane (Scheme 6).
Scheme 3. Reagents: (a) heteroarylmethylchloride, 1N NaOH, EtOH;
(b) (1) pyrazin-2-ylmethanol, MsCl, Et3N, THF, (2) 1N NaOH.
The synthetic route to the imidazole derivatives 9b,c,e is
illustrated in Scheme 7. Alkylation of formylimidazoles
12, 17 and LiAlH4 reduction gave the alcohols 14e,f,h.
The key intermediates 9b,c,e were prepared by chlorina-
tion of the corresponding alcohols 14e,f,h using thionyl
chloride.
The key aniline derivatives 7a,b were prepared according
to Scheme 2. Alkylation of the 2-mercaptopyridine 10a
with the alkyl or aryl halides gave the nitro compounds
11a,b. The aniline derivatives 7a,b were prepared by Fe
reduction of the nitro compounds 11a,b.
The 5-(chloromethyl)-1-propyl-1H-imidazole hydro-
chloride (9d) and 4-alkyl-3-(chloromethyl)-4H-1,2,4-
triazole derivatives 9f,g were prepared according to
Scheme 8. Reaction of dihydroxyacetone (19) with
potassium thiocyanate and propylamine hydrochloride
gave 2-mercaptoimidazole 21a.22 The 3-mercaptotriaz-
oles 21b,c were synthesized by reaction of ethyl glycolate
(20) with hydrazine hydrate, followed by reaction with
methyl- or propylisothiocyanate and cyclization reac-
tion under basic condition using aqueous NaOH.23
The key chloromethylazoles 9d,f,23g were prepared by
desulfurization of the compounds 21a–c and chlorina-
tion of the resulting alcohols 14g,i,j.
The synthetic route to the anilines 7c–g is shown in
Scheme 3. Alkylation of the 4-aminothiophenol (10b)
with the corresponding heteroarylmethylchlorides gave
the aniline derivatives 7c–f. The aniline derivative 7g
was prepared by methanesulfonylation of pyrazin-2-
ylmethanol and subsequent reaction of the resulting
methanesulfonate with 10b.
The aniline derivatives 7h–m containing azole moieties
were prepared according to Scheme 4. Alkylation of
the 2-formylimidazole 12 and lithium aluminum hydride
(LiAlH4) reduction afforded the 2-(hydroxymethyl)imid-
azoles 14a–d. The aniline derivatives 7h–m were pre-
pared by chlorination of the alcohols 14a–d, 15a20, b21
and subsequent coupling with the 4-aminothiophenol
(10b).
The 1-methyl-1H-1,2,4-triazole compound 9h was syn-
thesized by the literature procedure24 illustrated in
Scheme 9.
H2N
R3
N
R3
N
H
N
OHC
OHC
a
b
c
X
c
HO
HO
X
S
Z
Z
N
12
N
N
Y
Y
13a: R3=Me
13b: R3=Et
13c: R3=Pr
13d: R3=i-Pr
14a: R3=Me
14b: R3=Et
14c: R3=Pr
14d: R3=i-Pr
15a: X=NMe, Y=CH, Z=N
15b: X=S, Y=N, Z=CH
7h: X=NMe, Y=CH, Z=N
7i: X=S, Y=N, Z=CH
7j: X=NMe, Y=N, Z=CH
7k: X=NEt, Y=N, Z=CH
7l: X=NPr, Y=N, Z=CH
7m: X=Ni-Pr, Y=N, Z=CH
Scheme 4. Reagents: (a) R3I, K2CO3, DMF; (b) LiAlH4, THF; (c) (1) SOCl2, cat. DMF, CHCl3, (2) 10b, 1N NaOH, EtOH or MeOH.

366
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
R3 R3
R3
H
N
OHC
OHC
OHC
a
a
b
c
N
N
N
HO
Cl
Cl
HCl
N
N
N
N
9b: R3=Bu
12
13e: R3=Bu
13f: R3=i-Bu
14e: R3=Bu
14f: R3=i-Bu
9c: R3=i-Bu
OHC
N
b
c
N
N
N
N
HO
HCl
N
H
N
N
Pr
Pr
Pr
17
18
14h
9e
Scheme 7. Reagents: (a) R3I, K2CO3, DMF or PrI, NaH, THF; (b) LiAlH4, THF; (c) SOCl2.
R3
N
R3
N
R3
N
O
a
b
c
d
HO
HO
Cl
HO
HO
OH
HCl
SH
Y
Y
Y
N
N
N
19
21a: Y=CH, R3=Pr
21b: Y=N, R3=Me
21c: Y=N, R3=Pr
14g: Y=CH, R3=Pr
14i: Y=N, R3=Me
14j: Y=N, R3=Pr
9d: Y=CH, R3=Pr
9f: Y=N, R3=Me
9g: Y=N, R3=Pr
O
OEt
20
Scheme 8. Reagents: (a) KSCN, propylamine hydrochloride, BuOH; (b) (1) hydrazine monohydrate, MeOH, (2) R3NCS, MeOH, (3) aq NaOH;
(c) NaNO2, HNO3; (d) SOCl2.
Me
Me
Me
mCPBA oxidation of the sulfide derivatives 6a–y. The
racemates 4r,s,v,w were optically resolved with chiral
high performance liquid chromatography (HPLC) to
afford optically pure compounds (S)- and (R)-4r,s,v,w.
The absolute configuration was determined by X-ray
crystallographic analysis of the compound (S)-4r (Fig.
2). The sulfone compound 25 was obtained by mCPBA
oxidation of 6r (Scheme 11).
a
b
N
N
N
HO
Cl
HCl
N
N
N
N
N
N
22
14k
9h
Scheme 9. Reagents: (a) formalin; (b) SOCl2.
The 1,2,3-triazole derivative 9i was synthesized accord-
ing to Scheme 10. Alkylation of methyl 1,2,3-trizole-4-
carboxylate 23 gave a mixture of propyl-substituted
1,2,3-triazoles, which was separated by column chroma-
tography to afford the desired 24. The key intermediate
9i was synthesized by a procedure similar to that used
for the above (chloro) methylazoles.
The target sulfoxide derivatives 4a–y were prepared
according to Scheme 1. Conversion of the key 1-benz-
azepine-4-carboxylic acids 5a,b into acid chlorides and
coupling with the key aniline derivatives 7a–m afforded
the sulfide derivatives 6a–g, 6i–o. The other sulfide
derivatives 6h, 6p–y were synthesized by condensation
of the carboxylic acids 5a,b with S-Cbz-protected 4-
aminothiophenol
8 by an acid chloride method,
followed by removal of the S-Cbz group and subsequent
reaction with the heteroarylmethyl chlorides 9. The
target sulfoxide derivatives 4a–y were prepared by
Figure 2. Molecular structure of (S)-4r as determined by X-ray
crystallographic analysis.
Pr
Pr
Pr
H
N
MeO2C
MeO2C
a
b
c
N
N
N
HO
Cl
HCl
N
N
N
N
N
N
N
N
23
24
14l
9i
Scheme 10. Reagents: (a) 1-iodopropane, K2CO3, DMF; (b) LiAlH4, THF; (c) SOCl2.

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
367
i-Bu
i-Bu
N
N
a
H
H
N
N
Pr
N
Pr
BuO
BuO
O
O
O
O
N
6r
25
S
S
O2
N
N
Scheme 11. Reagents: (a) mCPBA, CH2Cl2.
From the results of the biological evaluation, it was
found that the absolute configuration of the sulfoxide
moiety significantly influenced the inhibitory effect on
a HIV-1 Env-mediated membrane fusion. Therefore,
we investigated the asymmetric synthesis of the imidaz-
ole compound (S)-4r and triazole compound (S)-4w by
asymmetric oxidation of the sulfide compounds 6r,w.
thol (BINOL) as a ligand and found improved
enantioselectivity and chemical yields could be achieved
(entries 5 and 6). Reactions performed at room temper-
ature gave the same results as those performed at 0ꢁC.
Thus, oxidation of 6w using titanium complex
[Ti(Oi-Pr)4/(S)-BINOL/H2O/6w = 0.1:0.2:2.0:1.0]intolu-
ene at room temperature gave the target (S)-4w in a high
optical yield (96% ee) and good chemical yield (84%)
(entry 6).
First, we examined the asymmetric oxidation of the sul-
fide compound 6w containing the 1,2,4-triazole moiety.
The results are illustrated in Table 1. Cumene hydroper-
oxide (CHP) was used as the oxidant in all reactions.
Oxidation of the compound 6w by Kaganꢀs method25
Next, asymmetric synthesis of (S)-4r was investigated.
The results are summarized in Table 2. Oxidation by
Kaganꢀs method at 0ꢁC afforded target (S)-4r in a low
optical yield (42% ee) and low chemical yield (42%)
(entry 1). The combination of Ti(Oi-Pr)4/(R,R)-DPED/
H2O/6r = 0.1:0.2:0.1:1.0, using the method that gave a
good result for oxidation of 6w, resulted in a decreased
enantioselectivity and chemical yield (entry 2). Next, we
examined Uemuraꢀs method, using the optimized condi-
tion for the 1,2,4-triazole compound 6w. However,
this reaction condition gave (S)-4r in a low optical
yield (30% ee) and low chemical yield (28%) (entry 3).
In this case, the reaction rate was very slow and the
starting material 6r was recovered. Therefore, excess
oxidant (3.0equiv) was used and the reaction was per-
formed for a long time (six days). As a result, the target
sulfoxide compound (S)-4r was obtained in a fair optical
yield (84% ee) but low chemical yield (45%) (entry 4),
[Ti(Oi-Pr)4:(D)-(ꢀ)-diethyl
tartarate
(DET)/H2O/
6w = 1:2:1:1] in dichloromethane (CH2Cl2) at ꢀ23ꢁC
gave (S)-4w in a low optical yield (26% ee) and low
chemical yield (42%) (entry 1). We next examined the
catalytic asymmetric oxidation of 6w using (R,R)-1,2-
diphenylethan-1,2-diol (DPED) as a ligand26 [Ti(Oi-
Pr)4:(R,R)-DPED/H2O/6w = 0.1:0.2:1.0:1.0] and found
it also resulted in a low optical yield (23% ee) (entry
2). Interestingly, reduction of the amount of water
(0.2equiv) led to great increases in both the optical
(87% ee) and chemical (71%) yields (entry 3) and
performing the reaction at room temperature was
also found to give a high enantioselectivity and good
chemical yield (91% ee, 71%, entry 4). Next, we exam-
ined Uemuraꢀs method27 using (S)-(ꢀ)-1,10-bi-2-naph-
Table 1.
Pr
N
Pr
N
a
H
N
H
N
Pr
Pr
N
BuO
BuO
O
O
O
N
O
(S)-4w
6w
S
S
N
N
O
N
N
Entry
Ti(Oi-Pr)4 (equiv)
Diol (equiv)b
H2O (equiv)
Conditions
Solvent
Yield (%)
ee (%)c
1
1.0
0.1
0.1
0.1
0.1
0.1
(D)-DET (2.0)
1.0
1.0
0.1
0.1
2.0
2.0
ꢀ20ꢁC, 7d
0ꢁC, 4d
0ꢁC, 5d
rt, 3d
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
42
54
71
71
83
84
26
23
87
91
95
96
2
(R,R)-DPED (0.2)
(R,R)-DPED (0.2)
(R,R)-DPED (0.2)
(S)-BINOL (0.2)
(S)-BINOL (0.2)
3
4
5d
6e
0ꢁC, 7d
rt, 30h
aTi(Oi-Pr)4, diol, H2O, 80% cumene hydroperoxide (CHP, 2.0equiv), solvent.
b (D)-DET = (D)-(ꢀ)-diethyl tartarate, (R,R)-(+)-DPED = (R,R)-1,2-diphenylethan-1,2-diol, (S)-BINOL = (S)-(ꢀ)-1,10-bi-2-naphthol.
c Determined by HPLC on a CHIRAL PAK AD (DAICEL).
d 80% CHP (3.0equiv).
e 80% CHP (1.5equiv).

368
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
Table 2.
i-Bu
i-Bu
N
N
a
H
N
H
N
Pr
Pr
N
BuO
BuO
O
O
O
N
O
(S)-4r
6r
S
S
O
N
N
Entry
Ti(Oi-Pr)4 (equiv)
Diol (equiv)b
H2O (equiv)
Conditions
Solvent
Yield (%)
ee (%)c
1
1.0
0.1
0.1
0.1
(D)-DET (2.0)
1.0
0.1
2.0
2.0
0ꢁC, 20h
0ꢁC, 11d
rt, 16h
CH2Cl2
Toluene
Toluene
Toluene
42
42
18
30
84
2
(R,R)-DPED (0.2)
(S)-BINOL (0.2)
(S)-BINOL (0.2)
32d
28d
45f
3
4e
rt, 6d
aTi(Oi-Pr)4, diol, H2O, 80% cumene hydroperoxide (CHP, 2.0equiv).
b (D)-DET = (D)-(ꢀ)-diethyl tartarate, (R,R)-DPED = (R,R)-(+)-1,2-diphenylethan-1,2-diol, (S)-BINOL = (S)-(ꢀ)-1,10-bi-2-naphthol.
c Determined by HPLC on a CHIRAL PAK AD (DAICEL).
d 6r was recovered.
e 80% CHP (3.0equiv).
f Sulfone compound 25 was obtained.
whereas the sulfone compound 25 was obtained as a
byproduct.
azole ring was enlarged from the methyl (4l) to the ethyl
(4m) or propyl (4n) group, the activities were found to
become more potent. However, substitution of the more
bulky isopropyl (4o), butyl (4p), or isobutyl (4q) group
led to a slight decrease of activity compared with the
1-propylimidazol-2-yl compound 4n. Shifting the bond
position of the 1-propylimidazole ring from the 2-posi-
tion (4n) to the 5-position (4r) retained potent activity,
and the corresponding 1-propyl-1-benzazepine 4s was
as highly active as the 1-isobutyl-1-benzazepine 4r.
However, the 1-propylimidazol-4-yl compound 4t re-
sulted in a ca. 10-fold reduction of activity, when com-
pared with the imidazol-2-yl compound 4n. From the
above results, it was considered that the position of
the nitrogen atom of the heteroaryl group played an
important part in the appearance of potent inhibitory
activity. In addition, the results of the imidazole com-
pounds indicated that introduction of an alkyl group,
with suitable bulkiness, on the N-atom neighboring the
connecting bond contributed to further increase of
activity.
3. Results and discussion
The compounds prepared were evaluated for their inhibi-
tory effects on chemokine binding to CCR5-expressing
CHO cells. Binding reactions were performed in the
presence of [125I]RANTES and various concentrations
of the test compounds. The results are summarized in
Tables 3 and 4 as IC50 values.
First of all, the 1-propyl-1-benzazepine derivatives con-
taining the 2-pyridyl groups were investigated. Among
the 2-pyridyl compounds 4a–c, compound 4c with a
methylene group between the sulfoxide and pyridine
moieties exhibited the most potent activity. Therefore,
we targeted the compounds with a [(N-containing
heteroaryl)methyl]sulfinyl moiety and performed further
chemical modification. Replacing the propyl group of 4c
with the isobutyl group (4d) enhanced activity and this
result was similar to that of the pyridine N-oxide deriv-
ative previously reported. Moving the nitrogen atom of
the pyridine ring from the 2-position (4d) to the 3-posi-
tion (4e) led to increased activity, but replacement of the
2-pyridyl group with the 4-pyridyl group (4f) decreased
activity. Next, we investigated the aromatic azine or
azole compounds 4g–l containing two hetero atoms,
keeping the 1-isobutyl-1-benzazepine ring. Replacement
of the 3-pyridyl group of 4e with the pyridazin-3-yl
group (4g) retained activity, but the pyrimidin-2-yl
(4h) or pyrazin-2-yl (4i) compounds showed reduced
activity, compared with the compound 4e. Among the
azole compounds (4j–l), the 1-methylimidazol-2-yl com-
pound 4l was the most active and equivalent to the
3-pyridyl compound 4e. We selected the imidazole com-
pound 4l as a new lead compound and investigated the
effects of the N-substituent and the connecting position
of the imidazolyl group. The results are summarized in
Table 4. As the size of the 1-alkyl group on the imid-
Secondly, we examined the effects of the triazole groups
with an N-alkyl group at the a-position of the connect-
ing bond, keeping the 1-isobutyl-1-benzazepine ring
(Table 4). 4-Methyl-1,2,4-triazol-3-yl compound 4u
was more active than the 2-methyl-1,2,4-triazol-3-yl
compound 4x. Thus, compound 4u inhibited the chemo-
kine binding with an IC50 value of 4.4nM, and was as
highly active as the imidazole compound 4r. Consider-
ing the results of the imidazole compounds, replacement
of the methyl group of 4u with the propyl group (4v) led
to a slight increase of activity, and the corresponding
1-propyl-1-benzazepine compound 4w also exhibited
highly potent activity, comparable to the compound
4v. The propyl-substituted 1,2,3-triazole compound 4y
exhibited relatively potent activity, but its activity was
less potent than that of the 1,2,4-triazole compound
4v. In order to investigate the effect of the configura-
tion of the sulfoxide group, we next prepared the opti-
cally active compounds ((R)- and (S)-4r,s,v,w) and

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
369
Table 3. Physical properties and inhibitory effects of compounds 4 on Chemokine binding to CCR5-expressing CHO cells
R1
N
H
N
BuO
O
O
R4
4
a
IC50 (nM)
Compd.
R1
Pr
R4
Yield (%)
20
Formula
Analb
4a
450
C37H41N3O4SÆ0.25H2O
CHN
CHN
S
O
N
O
S
N
N
4b
Pr
250
32
C38H43N3O4SÆ0.5H2O
S
O
4c
4d
Pr
67
38
45
34
C38H43N3O4S
CHN
CHN
N
S
O
i-Bu
C39H45N3O4SÆ0.25H2O
S
O
N
4e
4f
4g
4h
4i
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
15
160
22
30
41
40
61
51
68
66
58
C39H45N3O4SÆ0.7H2O
C39H45N3O4S
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
S
O
N
N
N
N
S
O
C39H44N4O4S
S
O
100
46
C39H44N4O4SÆ0.5H2O
C39H44N4O4S
N
N
S
O
N
S
4j
35
C38H46N4O4SÆ0.3H2O
C37H43N3O4S2
O MeN
N
S
S
O
4k
4l
43
N
N
Me
N
S
O
14
C38H46N4O4SÆ0.8H2O
a The concentration required to inhibit the binding of [125I]RANTES to CCR5-expressing CHO cells by 50%.
b All compounds gave satisfactory elemental analysis ( 0.4%) for C, H, and N.
examined their inhibitory effects. As shown in Table 4, it
was found that S-configuration sulfoxide compounds
(S)-4r,s,v,w were slightly more active than the corres-
ponding R-isomers. Interestingly, the less active R-iso-
mers (R)-4r,s,v,w also showed potent inhibitory
activities with IC50 values of 4.4–8.3nM in the binding
assay. Furthermore, we investigated the imidazole com-
pounds containing a sulfide or sulfone moiety in place
of the sulfoxide moiety. As expected, it was found that
sulfoxide compounds 4r, (S)-4r, (R)-4r were more
active than the sulfide (6r) and sulfone (25) compounds
(Table 4).
expressing MOLT-4 cells. The results are summarized
in Table 5 as IC50 values. The 1-propylimidazol-2-yl
compound 4n exhibited relatively potent inhibitory
activity (IC50 = 11nM). The 1-propylimidazol-5-yl com-
pound 4r showed potent activity in comparison with
the imidazol-2-yl compound 4n, and its activity
(IC50 = 3.0nM) in the fusion assay was equivalent to
that in the binding assay. Among the 1,2,4-triazole com-
pounds, the 4-propyl-1,2,4-triazole 4v showed potent
activity with an IC50 value of 8.7nM, whereas the
1-methyl-1,2,4-triazole 4u had remarkably reduced activ-
ity in the fusion assay. The optically active 1-isobutyl-1-
benzazepine compounds (S)-4r and (S)-4v exhibited
remarkably potent activities (IC50 = 1.0, 2.2nM, respec-
tively), comparable to compound 1. The 1-propyl-1-benz-
azepine compounds (S)-4s and (S)-4w also showed
highly potent activities (IC50 = 2.8, 7.7nM, respec-
tively). Compared to the 1-isobutyl-1-benzazepines and
Next, we examined the inhibitory effects of the com-
pounds with potent RANTES binding inhibition on
the HIV-1 Env-mediated membrane fusion. The mem-
brane fusion assay was carried out using R5 HIV-1
(JR-FL strain) Env-expressing COS-7 cells and CCR5-

370
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
Table 4. Physical properties and inhibitory effects of compounds 6r, 4, 25 on Chemokine binding to CCR5-expressing CHO cells
R1
N
R1
N
H
N
H
N
BuO
BuO
O
O
O
O
S
R2
S
R2
4
6r (n=0)
O
25 (n=2)
(O)n
Compd.
R1
R2
Yield (%)
58
Formula
Anal.b
CHN
a
IC50 (nM)
Me
N
4l
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
14
C38H46N4O4SÆ0.8H2O
C39H48N4O4SÆ0.2H2O
C40H50N4O4SÆ0.3H2O
C40H50N4O4SÆ0.3H2O
C41H52N4O4SÆ0.5H2O
C41H52N4O4SÆ0.4H2O
N
Et
N
4m
4n
4o
4p
4q
6.6
4.3
8.4
14
55
36
43
68
68
CHN
CHN
CHN
CHN
CHN
N
N
Pr
N
i-Pr
N
N
Bu
N
N
N
i-Bu
N
8.7
Pr
N
4r
i-Bu
i-Bu
i-Bu
Pr
3.6
6.8
1.9
4.3
8.3
83
C40H50N4O4S
CHN
CHN
CHN
CHN
CHN
N
Pr
N
(R)-4r
(S)-4r
4s
C40H50N4O4SÆ0.5H2O
C40H50N4O4SÆ0.5H2O
N
Pr
N
N
Pr
N
57
C39H48N4O4SÆ0.25H2O
C39H48N4O4SÆ0.5H2O
N
Pr
N
(R)-4s
Pr
N
Pr
N
(S)-4s
Pr
1.7
44
C39H48N4O4SÆ0.5H2O
CHN
CHN
N
4t
i-Bu
72
66
C40H50N4O4S
NPr
N
N
Me
N
4u
i-Bu
i-Bu
i-Bu
i-Bu
4.4
2.6
4.4
1.5
C37H45N5O4SÆ2H2O
C39H49N5O4SÆ0.5H2O
C39H49N5O4SÆ0.5H2O
C39H49N5O4S
CHN
CHN
CHN
CHN
N
Pr
N
4v
75
N
N
Pr
N
(R)-4v
(S)-4v
N
N
N
Pr
N
N
Pr
N
4w
Pr
Pr
4.3
5.8
57
C38H47N5O4S
C38H47N5O4S
CHN
CHN
N
N
N
Pr
N
(R)-4w
N

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
371
Table 4 (continued)
a
IC50 (nM)
Compd.
R1
Pr
R2
Yield (%)
Formula
Anal.b
CHN
Pr
N
(S)-4w
1.6
C38H47N5O4S
N
N
Me
N
4x
i-Bu
i-Bu
i-Bu
i-Bu
35
12
19
33
89
64
91
39
C37H45N5O4S
CHN
CHN
CHN
CHN
N
N
Pr
N
4y
6r
25
C39H49N5O4SÆ0.2H2O
C40H50N4O3S
N
N
Pr
N
N
Pr
N
C40H50N4O5SÆEtOAc
N
a The concentration required to inhibit the binding of [125I]RANTES to CCR5-expressing CHO cells by 50%.
b All compounds gave satisfactory elemental analysis ( 0.4%) for C, H, and N.
1-propyl-1-benzazepines retaining the [(N-propylazol-
yl)methyl]sulfinyl group, the 1-isobutyl compound (S)-
4r with an imidazole moiety was about three times more
active than the 1-propyl compound (S)-4s, and the 1-
isobutyl compound (S)-4v with a triazole moiety was
also more active than the 1-propyl compound (S)-4w.
Surprisingly, the R-isomers (R)-4r and (R)-4v, which
inhibited the chemokine binding with IC50 values of
4.4–6.8nM, showed significantly reduced activity in the
fusion assay. The above-mentioned results suggested
that an S-configuration sulfoxide moiety was necessary
to exhibit the potent activity in the fusion assay. It has
been reported that the binding site of b-chemokines on
CCR5 does not completely overlap with that of either
recombinant gp120 or virions,28 thus, it is considered
possible that the difference in the inhibitory effects of
S- and R-isomers in the binding and fusion assays may
have a similar origin. Namely, the above-mentioned re-
sults suggest that the binding site of the S-isomers on
CCR5 is more closely related to that of the HIV-1 enve-
lope gp120 than is that of the R-isomers. Alternatively,
it may be that S-isomers give more steric interference
to binding between CCR5 and the HIV-1 envelope gly-
coprotein, through direct or allosteric interactions, than
do the R-isomers. In addition, the results in the binding
and fusion assays suggested that the position of the
sp2 nitrogen atom of the azole and the presence of an
N-alkyl group with suitable bulkiness on the azolyl
group were essential for the appearance of highly potent
activity.
derivatives (S)-4r and (S)-4v, which was opposite to
the results in the fusion assay.
4. Conclusion
In order to develop orally active CCR5 antagonists, we
investigated whether sulfoxide moieties containing a
heteroaryl group can be used as new polar substituents
to replace the quaternary ammonium moiety of the
anilide derivative 1. Based on our experience, the 1-pro-
pyl- or 1-isobutyl-1-benzazepine ring with a 7-[4-(2-but-
oxy)ethoxy]phenyl group was selected as a [6,7]-fused
nucleus. Investigation of the sulfoxide compounds con-
taining a 2-pyridyl group led to the discovery that inser-
tion of a methylene group between the sulfoxide moiety
and the 2-pyridyl group resulted in an increase of activ-
ity in the binding assay. From further investigation of
the [(N-containing heteroaryl)methyl]sulfinyl group, it
was found that the compounds with 1-propylimidazol-
5-yl or 4-propyl-1,2,4-triazol-3-yl groups exhibited
highly potent binding inhibitory activities and that S-
configuration sulfoxide compounds were more active
than the corresponding R-isomers. Especially, the S-iso-
mers showed greatly potent activities compared with the
R-isomers in the HIV-1 Env-mediated membrane fusion
assay. Among the S-sulfoxide compounds, 1-isobutyl-1-
benzazepine (S)-4r and 1-propyl-1-benzazepines (S)-4s
and (S)-4w exhibited highly potent CCR5 antagonistic
activities (IC50 = 1.9, 1.7, 1.6nM, respectively) in the
binding assay and inhibitory effects (IC50 = 1.0, 2.8,
7.7nM, respectively) in the fusion assay, comparable
to compound 1, together with good pharmacokinetic
properties in rats. Additionally, we established a
synthetic method to the chiral compounds (S)-4r and
(S)-4w, by asymmetric oxidation of the corresponding
sulfide compounds using titanium-(S)-(ꢀ)-1,10-bi-2-
naphthol complex. The above results suggested that
the S-sulfoxide moieties containing the 1-propylimid-
azol-5-yl or 4-propyl-1,2,4-triazol-3-yl groups might
replace the previous tertiary amine and 2-(a-hydroxy-
benzyl)pyridine N-oxide moieties as polar substituents
for orally active CCR5 antagonists.
Finally, preliminary pharmacokinetic studies of com-
pounds with potent activity were investigated. Com-
pounds ((S)-4r,s,v,w) were orally administered at
10mg/kg to SD (IGS) rats and the results are indicated
in Table 6. Consequently, the compounds (S)-4r, (S)-4s,
and (S)-4w exhibited high plasma levels after oral
administration. Thus, the AUC0–24h values of com-
pounds (S)-4r, (S)-4s, and (S)-4w were 14.1, 75.1,
22.4lgÆh/mL, respectively. These results indicated that
the plasma concentration levels of the 1-propyl-1-benz-
azepine derivatives (S)-4s and (S)-4w were higher than
those of the corresponding 1-isobutyl-1-benzazepine

372
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
Table 5. Inhibitory effects of compounds 4 on HIV-1 Env-mediated
membrane fusion
Table 6. Pharmacokinetic parameters of compounds 4 in rats
R1
N
R1
N
H
N
H
N
BuO
O
O
S
R2
BuO
O
O
4
S
R2
O
4
O
Compd.
R1
R2
Oral administrationa
Compd.
R1
R2
RANTES
Fusion
Cmax
(lg/mL)b
Tmax
(h)c
AUC0–24h
(lgh/mL)d
a
IC50 (nM)
b
IC50 (nM)
Pr
N
1
—
—
1.4
4.3
1.4
11
(S)-4r
(S)-4s
i-Bu
2.00
8.56
2.0
2.0
14.1
Pr
N
N
4n
i-Bu
N
Pr
N
Pr
75.1
1.39
Pr
N
N
4r
i-Bu
3.6
3.0
N
Pr
N
(S)-4v
i-Bu
0.16
3.3
Pr
N
N
N
N
(R)-4r
(S)-4r
(S)-4s
4u
i-Bu
i-Bu
Pr
6.8
1.9
1.7
4.4
410
1.0
2.8
210
N
Pr
N
Pr
N
(S)-4w
Pr
2.13
3.3
22.4
N
N
a Compounds (10mg/kg) suspended in 0.5% aqueous methylcellulose
solution were orally administered to SD (IGS) rats (male, eight weeks
old, n = 3).
Pr
N
N
b Maximum plasma concentration after 10mg/kg oral dosing.
Me
N
c Time to reach Cmax
.
i-Bu
d Area under the plasma concentration–time curve for 0–24h after
10mg/kg oral dosing.
N
N
N
Pr
N
4v
i-Bu
2.6
8.7
N
Pr
N
phy was carried out on a silica gel column (Kieselgel
60, 63–200 mesh, Merck or Chromatorexꢂ NH-
DM1020, 100–200 mesh, Fuji Silysia chemical). Yields
were not optimized.
(R)-4v
(S)-4v
(S)-4w
i-Bu
i-Bu
Pr
4.4
1.5
1.6
280
2.2
7.7
N
N
N
N
Pr
N
N
Pr
N
5.1. 2-[(4-Nitrophenyl)sulfanyl]pyridine (11a)
N
To a solution of 10a (10.0g, 90.0mmol) in N,N-dimeth-
ylformamide (DMF) (100mL) was added NaH (60%
dispersion in mineral oil, 3.60g, 90.0mmol) at room
temperature. After being stirred at room temperature
for 15min, 1-fluoro-4-nitrobenzene (9.75g, 69.1mmol)
was added dropwise to the reaction mixture at room
temperature. The mixture was stirred at room tempera-
ture for 1h. Water was added to the reaction mixture,
and the precipitated crystals were collected by filtration,
washed with diisopropyl ether (i-Pr2O) to give 12.6g
a The concentration required to inhibit the binding of [125I]RANTES
to CCR5-expressing CHO cells by 50%.
b The concentration required to inhibit the membrane fusion between
HIV-1 Env-expressing Cos-7 cells and CCR5-expressing MOLT-4
cells by 50%.
5. Experimental
1
(79%) of 11a as pale brown crystals, mp 84–85ꢁC. H
Melting points were determined on a Yanagimoto micro
melting point apparatus, and are uncorrected. Proton
nuclear magnetic resonance (1H NMR) spectra were re-
corded on a Varian Gemini-200 (200MHz) spectro-
meter. Chemical shifts are given in parts per million
(ppm) with tetramethylsilane as an internal standard,
and coupling constants (J values) are given in Hertz
(Hz). Optical resolutions were recorded with a Jasco
DIP-370 or P-1030 digital polarimeter. Elemental analy-
ses were carried out by Takeda Analytical Research
Laboratories, Ltd., and results obtained were within
0.4% of the theoretical values. Column chromatogra-
NMR (CDCl3) d 7.15–7.23 (2H, m), 7.58–7.69 (3H,
m), 8.15–8.22 (2H, m), 8.50–8.55 (1H, m). Anal. Calcd
for C11H8N2O2S: C, 56.88; H, 3.47; N, 12.06. Found:
C, 57.28; H, 3.61; N, 11.85.
5.2. 2-[(4-Nitrobenzyl)sulfanyl]pyridine (11b)
To a solution of 10a (2.60g, 23.4mmol) and triethyl-
amine (Et3N) (3.90mL, 28.0mmol) in tetrahydrofuran
(THF) (52mL) was added dropwise a solution of 4-
nitrobenzyl bromide (4.80g, 22.2mmol) at room tem-

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
373
perature, and the mixture was stirred at room temper-
ature for 30min. The reaction mixture was added to
the water, and the mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc =
5:1 ! 4:1) to give 4.20g (77%) of 11b as pale brown
93–94ꢁC. 1H NMR (CDCl3) d 3.83 (2H, br s), 3.88
(2H, s), 6.51–6.58 (2H, m), 7.05–7.11 (2H, m), 7.13–
7.20 (1H, m), 7.43–7.49 (1H, m), 8.29–8.31 (1H, m),
8.44 (1H, dd, J = 4.8, 1.8Hz). Anal. Calcd for
C12H12N2S: C, 66.63; H, 5.59; N, 12.95. Found: C,
66.43; H, 5.46; N, 13.01.
1
crystals. H NMR (CDCl3) d 4.51 (2H, s), 6.98–7.05
5.7. 4-{[(4-Pyridyl)methyl]sulfanyl}aniline (7e)
(1H, m), 7.16 (1H, d, J = 8.4Hz), 7.44–7.53 (1H, m),
7.58 (2H, d, J = 8.8Hz), 8.13 (2H, d, J = 8.8Hz),
8.42–8.47 (1H, m). Anal. Calcd for C12H10N2O2S: C,
58.52; H, 4.09; N, 11.37. Found: C, 58.52; H, 4.20;
N, 11.39.
This compound was prepared in 89% yield from 10b and
4-(chloromethyl)pyridine hydrochloride by a method
similar to that described for 7c, colorless crystals, mp
111–112ꢁC. H NMR (CDCl3) d 3.62 (2H, br s), 3.84
1
(2H, s), 6.56 (2H, d, J = 8.4Hz), 7.02–7.10 (4H, m),
8.46 (2H, d, J = 6.4Hz). Anal. Calcd for C12H12N2S:
C, 66.63; H, 5.59; N, 12.95. Found: C, 66.60; H, 5.63;
N, 13.00.
5.3. 4-[(2-Pyridinyl)sulfanyl]aniline (7a)
A mixture of 11a (8.00g, 34.4mmol) and reduced iron
(24.0g, 430mmol) in AcOH (64mL) was stirred at room
temperature for 16h. The solid was removed by filtra-
tion, and the filtrate was concentrated in vacuo. The resi-
due was purified by column chromatography (hexane/
EtOAc = 1:2) to give 6.3g (91%) of 7a as a pale yellow
5.8. 4-{[(3-Pyridazinyl)methyl]sulfanyl}aniline (7f)
This compound was prepared in 55% yield from 10b and
3-(chloromethyl)pyridazine29 by a method similar to
that described for 7c. Compound 7f was used in the next
reaction without further purification. 1H NMR (CDCl3)
d 3.78 (2H, br s), 4.26 (2H, s), 6.51–6.56 (2H, m), 7.08–
7.13 (2H, m), 7.36–7.41 (2H, m), 9.02 (1H, dd, J = 4.6,
2.0Hz).
1
solid, mp 89–91ꢁC. H NMR (CDCl3) d 4.05 (2H, br
s), 6.72 (2H, d, J = 8.8Hz), 6.76 (1H, d, J = 8.8Hz),
6.89–6.96 (1H, m), 7.38 (2H, d, J = 8.8Hz), 7.39–7.45
(1H, m), 8.37–8.41 (1H, m). Anal. Calcd for
C11H10N2S: C, 65.32; H, 4.98; N, 13.85. Found: C,
65.26; H, 4.86; N, 13.91.
5.9. 4-{[(2-Pyrazinyl)methyl]sulfanyl}aniline (7g)
5.4. 4-{[(2-Pyridyl)sulfanyl]methyl}aniline (7b)
To
a
solution of pyrazin-2-ylmethanol (1.00g,
This compound was prepared in 53% yield from 11b by
a method similar to that described for 7a. H NMR
9.08mmol) and Et3N (2.00mL, 14.3mmol) in THF
(100mL) was added methanesulfonyl chloride (MsCl)
(1.00mL, 12.9mmol) under ice cooling. After being stir-
red at room temperature for 1h, the reaction mixture
was added to water, and the mixture was extracted with
EtOAc. The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. To a solution
of the residue and 10b (1.02 g, 8.15mmol) in MeOH
(20mL) was added 3N NaOH (9.1mL) at room temper-
ature. The mixture was stirred at room temperature for
16h and concentrated in vacuo. Water was added to the
residue and the mixture was extracted with EtOAc. The
organic layer was washed with water and brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (hexane/
EtOAc = 1:2) to give 0.71g (40%) of 7g as colorless crys-
tals. Compound 7g was used in the next reaction with-
1
(CDCl3) d 3.68 (2H, br s), 4.34 (2H, s), 6.61 (2H, d,
J = 8.4Hz), 6.93–7.01 (1H, m), 7.11–7.26 (3H, m), 7.45
(1H, td, J = 7.4, 1.8Hz), 8.43–8.48 (1H, m). Anal. Calcd
for C12H12N2S: C, 66.63; H, 5.59; N, 12.95. Found: C,
66.68; H, 5.65; N, 12.90.
5.5. 4-{[(2-Pyridyl)methyl]sulfanyl}aniline (7c)
To a solution of 10b (1.00g, 7.99mmol) and 2-(chloro-
methyl)pyridine hydrochloride (1.44g, 8.78mmol) in
MeOH (50mL) was added 1N NaOH (24mL,
24.0mmol) at room temperature, and the mixture was
stirred at room temperature for 2h. The mixture was
concentrated in vacuo. Water was added to the residue
and the mixture was extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by col-
umn chromatography (hexane/EtOAc = 1:1 ! 1:3 !
1:9) to give 1.58g (91%) of 7c as colorless crystals, mp
64–65ꢁC. 1H NMR (CDCl3) d 3.70 (2H, br s), 4.08
(2H, s), 6.52–6.57 (2H, m), 7.08–7.17 (2H, m), 7.51–
7.60 (1H, m), 8.49–8.53 (1H, m). Anal. Calcd for
C12H12N2S: C, 66.63; H, 5.59; N, 12.95. Found: C,
66.43; H, 5.46; N, 13.01.
1
out further purification. H NMR (CDCl3) d 3.75 (2H,
br s), 4.05 (2H, s), 6.52–6.57 (2H, m), 7.09–7.13 (2H,
m), 8.32 (1H, d, J = 1.6Hz), 8.39 (1H, d, J = 2.4Hz),
8.46–8.48 (1H, m).
5.10. 1-Ethyl-1H-imidazole-2-carbaldehyde (13b)
To a mixture of 12 (2.50g, 26.0mmol) and K2CO3
(4.31g, 31.2mmol) in DMF (25mL) was added iodo-
ethane (4.87g, 31.2mmol) at room temperature. After
being stirred at 50ꢁC for 5h, the solid was removed by
filtration. Water was added to the filtrate and the mix-
ture was extracted with EtOAc. The organic layer was
washed with water and brine, dried over MgSO4, and
concentrated in vacuo to give 2.90g (90%) of 13b as a
5.6. 4-{[(3-Pyridyl)methyl]sulfanyl}aniline (7d)
This compound was prepared in 76% yield from 10b and
3-(chloromethyl)pyridine hydrochloride by a method
similar to that described for 7c, colorless crystals, mp

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M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
1
brown oil. H NMR (CDCl3) d 1.44 (3H, t, J = 7.2Hz),
4.45 (2H, q, J = 7.2Hz), 7.17–7.19 (1H, m), 7.28–7.29
(1H, m), 9.82 (1H, s).
5.17. (1-Propyl-1H-imidazol-2-yl)methanol (14c)
Yield 75%, colorless oil. 1H NMR (CDCl3) d 0.95 (3H, t,
J = 7.4Hz), 1.74–1.92 (2H, m), 3.96 (2H, t, J = 7.4Hz),
4.65 (2H, s), 6.86 (1H, d, J = 1.4Hz), 6.90 (1H, d,
J = 1.4Hz).
The following compounds (13c–f) were prepared from
2-formylimidazole (12) by a method similar to that
described for 13b.
5.18. (1-Isopropyl-1H-imidazol-2-yl)methanol (14d)
5.11. 1-Propyl-1H-imidazole-2-carbaldehyde (13c)
Yield 87%, brown crystals (EtOAc–hexane), mp 87–
89ꢁC. 1H NMR (CDCl3) d 1.45 (6H, d, J = 6.8Hz),
4.53–4.67 (1H, m), 4.68 (2H, s), 6.91 (1H, d,
J = 1.2Hz), 6.94 (1H, d, J = 1.2Hz). Anal. Calcd for
C7H12N2O: C, 59.98; H, 8.63; N, 19.98. Found: C,
59.90; H, 8.53; N, 20.07.
Yield quant., brown oil. 1H NMR (CDCl3) d 0.93 (3H, t,
J = 7.4Hz), 1.73–1.91 (2H, m), 4.37 (2H, t, J = 7.4Hz),
7.16 (1H, s), 7.29 (1H, s), 9.82 (1H, s).
5.12. 1-Isopropyl-1H-imidazole-2-carbaldehyde (13d)
1
Yield 93%, brown oil. H NMR (CDCl3) d 1.47 (6H, d,
J = 7.0Hz), 5.41–5.55 (1H, m), 7.31–7.33 (2H, m), 9.83
(1H, s).
5.19. (1-Butyl-1H-imidazol-2-yl)methanol (14e)
1
Yield 88%, yellow oil. H NMR (CDCl3) d 0.95 (3H, t,
J = 7.4Hz), 1.26–1.42 (2H, m), 1.69–1.85 (2H, m), 4.00
(2H, t, J = 7.4Hz), 4.64 (2H, s), 6.85 (1H, d,
J = 1.0Hz), 6.88 (1H, d, J = 1.0Hz).
5.13. 1-Butyl-1H-imidazole-2-carbaldehyde (13e)
Yield quant., brown oil. 1H NMR (CDCl3) d 0.95 (3H, t,
J = 7.2Hz), 1.20–1.50 (2H, m), 1.60–1.90 (2H, m), 4.40
(2H, t, J = 7.2Hz), 7.15–7.17 (1H, m), 7.26–7.29 (1H,
m), 9.82 (1H, s).
5.20. (1-Isobutyl-1H-imidazol-2-yl)methanol (14f)
1
Yield 91%, colorless oil. H NMR (CDCl3) d 0.93 (6H,
d, J = 6.6Hz), 2.00–2.20 (1H, m), 3.79 (2H, d,
J = 7.6Hz), 4.66 (2H, s), 6.84 (1H, d, J = 1.4Hz), 6.92
(1H, d, J = 1.4Hz).
5.14. 1-Isobutyl-1H-imidazole-2-carbaldehyde (13f)
1
Yield 75%, brown oil. H NMR (CDCl3) d 0.92 (6H, d,
J = 7.0Hz), 2.01–2.15 (1H, m), 4.22 (2H, d, J = 7.4Hz),
7.13 (1H, s), 7.29 (1H, s), 9.82 (1H, s).
5.21. 4-[[(1-Methyl-1H-pyrazol-5-yl)methyl]sulfanyl]ani-
line (7h)
5.15. (1-Methyl-1H-imidazol-2-yl)methanol (14a)
5.21.1. Step 1: (1-Methyl-1H-pyrazol-5-yl)methanol (15a).
This compound was prepared in quantitative yield
To a suspension of LiAlH4 (758mg, 20.0mmol) in THF
(10mL) was added dropwise a solution of 13a (2.00g,
18.2mmol) in THF (20mL) under ice cooling. After
being stirred under ice cooling for 5min, water
(0.80mL), 15% aqueous NaOH (0.80mL) and water
(2.40mL) were added dropwise to the reaction mixture
under ice cooling. The mixture was stirred at room tem-
perature for 2.5h. MgSO4 was added to the mixture and
the solid was removed by filtration. The filtrate was con-
centrated in vacuo. The residue was purified by recrys-
tallization from EtOAc–hexane to give 1.82g (81%) of
14a as colorless crystals, mp 114–116ꢁC. 1H NMR
(CDCl3) d 3.73 (3H, s), 4.63 (2H, s), 6.81 (1H, d,
J = 1.2Hz), 6.86 (1H, d, J = 1.2Hz). Anal. Calcd for
C5H8N2O: C, 53.56; H, 7.19; N, 24.98. Found: C,
53.42; H, 7.45; N, 24.57.
from 1-methyl-1H-pyrazole-5-carbaldehyde20 by
a
method similar to that described for 14a, colorless oil. 1H
NMR (CDCl3) d 3.90 (3H, s), 4.68 (2H, s), 6.19 (1H, d,
J = 2.0Hz), 6.39 (1H, d, J = 1.8Hz).
5.21.2. Step 2: 4-{[(1-Methyl-1H-pyrazol-5-yl)methyl]sulf-
anyl}aniline (7h). To a solution of 15a (645mg,
5.75mmol) and DMF (cat. amount) in CHCl3 (10mL)
was added SOCl2 (0.55mL, 7.54mmol) under ice
cooling. After being stirred at room temperature for
4h under a nitrogen atmosphere, the mixture was con-
centrated in vacuo. To a solution of the residue in
MeOH (10mL) was added a solution of 10b (600mg,
4.79mmol) and NaOH (460mg, 11.5mmol) in MeOH
(10mL) and water (6.0mL) under ice cooling. The mix-
ture was stirred at room temperature for 0.5h, and con-
centrated in vacuo. Water was added to the residue and
the mixture was extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by
recrystallization from EtOAc–hexane to give 972mg
(93%) of 7h as brown crystals, mp 115–116ꢁC. 1H
NMR (CDCl3) d 3.75 (3H, s), 3.89 (2H, s), 5.92 (1H,
d, J = 1.8Hz), 6.57 (2H, d, J = 8.8Hz), 7.10 (2H, d,
J = 8.8Hz), 7.31 (1H, d, J = 1.8Hz). Anal. Calcd for
C11H13N3S: C, 60.24; H, 5.97; N, 19.16. Found: C,
60.09; H, 6.08; N, 19.11.
The following compounds (14b–f) were prepared from
13b–f by a method similar to that described for 14a.
5.16. (1-Ethyl-1H-imidazol-2-yl)methanol (14b)
Yield 72%, colorless crystals (EtOAc–hexane), mp
d
93–94ꢁC. 1H NMR (CDCl3)
1.44 (3H, t,
J = 7.4Hz), 4.06 (2H, q, J = 7.4Hz), 4.65 (2H, s),
6.87–6.89 (2H, m). Anal. Calcd for C6H10N2O: C,
57.12; H, 7.99; N, 22.21. Found: C, 57.06; H, 7.98; N,
22.20.

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
375
The following compounds (7i–m) were prepared from
15b, 14a–d and 10b by a method similar to that de-
scribed for 7h.
16h. The mixture was added to the water and extracted
with CH2Cl2. The organic layer was washed with brine,
dried over MgOS4, and concentrated in vacuo to give
2.00g (10%) of 9a as a colorless oil. H NMR (CDCl3)
d 4.76 (2H, s), 7.27–7.30 (1H, m), 8.78 (2H, d,
J = 5.2Hz).
1
5.22. 4-[(1,3-Thiazol-2-ylmethyl)sulfanyl]aniline (7i)
1
Yield 25%, colorless oil. H NMR (CDCl3) d 3.72 (2H,
br s), 4.28 (2H, s), 6.58 (2H, d, J = 8.6Hz), 7.18–7.25
(3H, m), 7.65 (1H, d, J = 3.2Hz).
5.29. 1-Propyl-1H-imidazole-4-carbaldehyde (18)
To a suspension of NaH (60% dispersion in mineral
oil, 3.12g, 78.0mmol) in THF (400mL) was added 17
(5.00g, 52.0mmol) under ice cooling. The mixture
was refluxed for 2h under a nitrogen atmosphere.
The mixture was cooled to room temperature and
1-iodopropane (88.4g, 520mmol) was added to the
mixture. The mixture was refluxed for 2h. The solid
was removed by filtration and water was added to
the filtrate. The mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (EtOAc/MeOH =
8:1) to give 4.45g (62%) of 18 as a brown oil. 1H
NMR (CDCl3) d 0.96 (3H, t, J = 7.2Hz), 1.77–1.95
(2H, m), 3.97 (2H, t, J = 7.2Hz), 7.56 (1H, s), 7.63
(1H, s), 9.88 (1H, s).
5.23. 4-{[(1-Methyl-1H-imidazol-2-yl)methyl]sulfanyl}-
aniline (7j)
Yield quant., colorless oil. 1H NMR (CDCl3) d 3.53
(3H, s), 4.03 (2H, s), 6.57 (2H, d, J = 8.6Hz), 6.78
(1H, d, J = 1.2Hz), 6.90 (1H, d, J = 1.2Hz), 7.14 (2H,
d, J = 8.6Hz).
5.24. 4-{[(1-Ethyl-1H-imidazol-2-yl)methyl]sulfanyl}-
aniline (7k)
Yield quant., colorless oil. 1H NMR (CDCl3) d 1.40
(3H, t, J = 7.2Hz), 3.91 (2H, q, J = 7.2Hz), 4.04 (2H,
s), 6.58 (2H, d, J = 8.8Hz), 6.85 (1H, d, J = 1.0Hz),
6.92 (1H, d, J = 1.0Hz), 7.15 (2H, d, J = 8.8Hz).
5.25. 4-{[(1-Propyl-1H-imidazol-2-yl)methyl]sulfanyl}-
aniline (7l)
5.30. (1-Propyl-1H-imidazol-4-yl)methanol (14h)
This compound was prepared in 87% yield from 18 by a
method similar to that described for 14a, yellow oil. H
NMR (CDCl3) d 0.93 (3H, t, J = 7.4Hz), 1.71–1.89 (2H,
m), 3.80 (2H, t, J = 7.0Hz), 4.60 (2H, s), 6.87 (1H, d,
J = 1.4Hz), 7.42 (1H, d, J = 1.4Hz).
1
Yield 99%, colorless oil. 1H NMR (CDCl3) d 0.93 (3H, t,
J = 7.4Hz), 1.68–1.86 (2H, m), 3.80 (2H, t, J = 7.4Hz),
4.04 (2H, s), 6.57 (2H, d, J = 8.8Hz), 6.83 (1H, d, J =
1.2Hz), 6.91 (1H, d, J = 1.2Hz), 7.15 (2H, d, J = 8.8Hz).
5.26. 4-{[(1-Isopropyl-1H-imidazol-2-yl)methyl]sulfanyl}-
aniline (7m)
5.31. 1-Butyl-2-(chloromethyl)-1H-imidazole hydrochlo-
ride (9b)
1
Yield 97%, colorless oil. H NMR (CDCl3) d 1.41 (6H,
SOCl2 (30mL, 411mmol) was added to 14e (3.00g,
19.5mmol) under ice cooling. The mixture was stirred
at 90ꢁC for 0.5h. The mixture was concentrated in
vacuo. The crystals were collected by filtration, washed
with EtOAc to give 3.50g (86%) of 9b as brown crystals,
mp 161–162ꢁC. 1H NMR (DMSO-d6) d 0.92 (3H, t,
J = 7.8Hz), 1.23–1.41 (2H, m), 1.71–1.87 (2H, m), 4.21
(2H, t, J = 7.6Hz), 5.17 (2H, s), 7.73 (1H, d,
J = 2.0Hz), 7.84 (1H, d, J = 2.0Hz). Anal. Calcd for
C8H14N2Cl2: C, 45.95; H, 6.75; N, 13.40. Found: C,
46.25; H, 6.93; N, 13.53.
d, J = 6.6Hz), 3.71 (2H, br s), 4.06 (2H, s), 4.38–4.60
(1H, m), 6.58 (2H, d, J = 8.8Hz), 6.92–6.93 (2H, m),
7.16 (2H, d, J = 8.8Hz).
5.27. S-(4-Aminophenyl)-O-benzylthiocarbonate (8)
To a mixture of 10b (9.60g, 76.7mmol) and Et3N
(54.0mL, 387mmol) was added dropwise benzyl chloro-
formate (13.1g, 76.8mmol) at ꢀ78ꢁC. After being stir-
red at ꢀ78ꢁC for 0.5h, the mixture was warmed to
room temperature. Water was added to the reaction
mixture and the mixture was extracted with EtOAc.
The organic layer was washed with water and brine,
dried over MgSO4, and concentrated in vacuo to give
colorless crystals. The crystals were purified by recrystal-
lization from EtOAc–hexane to give 19.3 g (97%) of 8
The following compounds (9c,e) were prepared
from 14f,h by a method similar to that described for
9b.
5.32. 2-(Chloromethyl)-1-isobutyl-1H-imidazole hydro-
chloride (9c)
1
as colorless crystals, mp 92–93ꢁC. H NMR (CDCl3) d
3.85 (2H, br s), 5.23 (2H, s), 6.63–6.70 (2H, m), 7.26–
7.35 (7H, m). Anal. Calcd for C14H13NO2S: C, 64.84;
H, 5.05; N, 5.40. Found: C, 64.83; H, 5.00; N, 5.39.
Yield 67%, brown crystals (MeOH–EtOAc), mp 164–
166ꢁC. 1H NMR (DMSO-d6) d 0.90 (6H, d, J =
6.6Hz), 2.05–2.25 (1H, m), 4.05 (2H, d, J = 7.8Hz),
5.18 (2H, s), 7.75 (1H, d, J = 2.2Hz), 7.81 (1H, d,
J = 2.2Hz). Anal. Calcd for C8H14N2Cl2: C, 45.95;
H, 6.75; N, 13.40. Found: C, 45.79; H, 7.08; N,
13.37.
5.28. 2-(Chloromethyl)pyrimidine (9a)
A mixture of 16 (19.7g, 153mmol) and 1,1,3,3-tetra-
methoxypropane (50mL) was stirred at 100ꢁC for

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M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
5.33. 4-(Chloromethyl)-1-propyl-1H-imidazole
hydrochloride (9e)
cation. 1H NMR (CDCl3) d 0.96 (3H, t, J = 7.4Hz),
1.76–1.94 (2H, m), 3.97 (2H, t, J = 7.2Hz), 4.63 (2H,
s), 6.97 (1H, s), 7.48 (1H, s).
1
Yield quant., brown oil. H NMR (DMSO-d6) d 0.85
(3H, t, J = 7.4Hz), 1.60–2.00 (2H, m), 4.13 (2H, t,
J = 6.6Hz), 4.88 (2H, s), 7.84 (1H, s), 9.16 (1H, s).
5.37. (4-Propyl-4H-1,2,4-triazol-3-yl)methanol (14j)
This compound was prepared in 73% yield from 21c by a
method described similar to that for 14g. Compound 14j
was used in the next reaction without further purifica-
tion. 1H NMR (CDCl3) d 0.97 (3H, t, J = 7.5Hz),
1.76–1.98 (2H, m), 4.05 (2H, t, J = 7.3Hz), 4.80 (2H,
s), 5.11–5.49 (1H, m), 8.07 (1H, s).
5.34. (1-Propyl-2-sulfanyl-1H-imidazol-5-yl)methanol
(21a)
A mixture of KSCN (119.2g, 1.23mol), 19 (73.9g,
410mmol) and propylamine hydrochloride (100g,
1.05mmol) was added to a mixture of AcOH (89mL)
and 1-BuOH (590mL) at room temperature. After
being stirred at room temperature for 24h, water
(118mL) was added to the reaction mixture. The
mixture was stirred at room temperature for 30min,
and the precipitated crystals were collected by
filtration. The crystals were washed with water and
hexane to give 71.2g (50%) of 21a as colorless crys-
tals, mp 173–175ꢁC. 1H NMR (CDCl3) d 0.87 (3H,
t, J = 7.4Hz), 1.61–1.79 (2H, m), 3.91 (2H, t,
J = 7.4Hz), 4.32 (2H, s), 5.26 (1H, br), 6.79 (1H, s),
11.95 (1H, s). Anal. Calcd for C7H12N2OSÆ0.25H2O:
C, 47.57; H, 7.13; N, 15.85. Found: C, 47.22; H,
6.94; N, 15.99.
The following compounds (9d,g) were prepared
from 14g,j by a method similar to that described for
9b.
5.38. 5-(Chloromethyl)-1-propyl-1H-imidazole
hydrochloride (9d)
1
Yield 96%, colorless crystals (EtOAc), 167–169ꢁC. H
NMR (DMSO-d6) d 0.92 (3H, t, J = 7.4Hz), 1.84–1.95
(2H, m), 4.18 (2H, t, J = 7.2Hz), 5.04 (2H, s), 7.82
(1H, s), 9.24 (1H, s). Anal. Calcd for C7H12N2Cl2Æ0.25-
H2O: C, 42.12; H, 6.31; N, 14.04. Found: C, 42.16; H,
6.30; N, 14.14.
5.35. (4-Propyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)methanol
(21c)
5.39. 3-(Chloromethyl)-4-propyl-4H-1,2,4-triazole
hydrochloride (9g)
To a solution of hydrazine monohydrate (9.66g,
193mmol) in EtOH was added dropwise 20 (20.09g,
200mmol) under ice cooling. The mixture was stirred
at room temperature for 4h. To the reaction mixture
was added dropwise propyl isothiocyanate (20.0mL,
193mmol) under ice cooling, and the mixture was stirred
at 40ꢁC for 64h. To the reaction mixture was added ice
water (50mL) at room temperature and the mixture was
stirred at room temperature for 15min. 5N NaOH
(40mL) was added to the mixture and the mixture was
stirred at 60ꢁC for 4h. The mixture was neutralized
using conc. HCl under ice cooling. The precipitated
solid was removed by filtration and the filtrate was con-
centrated in vacuo. The precipitated solid was collected
by filtration, washed with water to give 23.45g (70%) of
21c as a colorless solid. Compound 21c was used in the
next reaction without further purification. 1H NMR
(DMSO-d6) d 0.88 (3H, t, J = 7.4Hz), 1.62–1.84 (2H,
m), 3,92 (2H, t, J = 7.7Hz), 4.49 (2H, s), 5.32–5.90
(1H, m).
Yield 34%, pale yellow crystals (EtOAc), mp 91–94ꢁC.
1H NMR (DMSO-d6) d 0.80 (3H, t, J = 7.3Hz), 1.73–
1.94 (2H, m), 4.11 (2H, t, J = 7.4Hz), 5.10 (2H, s), 9.26
(1H, s). Anal. Calcd for C6H11N3Cl2Æ0.25H2O: C,
35.93; H, 5.78; N, 20.95. Found: C, 36.13; H, 5.77; N,
21.23.
5.40. Methyl 1-propyl-1H-1,2,3-triazole-5-carboxylate
(24)
A mixture of 23 (17.6g, 138mmol), 1-iodopropane
(14.9mL, 153mmol) and K2CO3 (11.5g, 83.2mmol) in
DMF (210mL) was stirred at room temperature for
16h. The solid was removed by filtration, and the filtrate
was concentrated in vacuo. Water was added to the resi-
due, and the aqueous layer was extracted with CH2Cl2.
The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc =
3:1 ! 2:1 ! 1:1 ! 1:2) to give 3.20g (14%) of 24,
10.3g (44%) of methyl 2-propyl-2H-1,2,3-triazole-4-
carboxylate, and 2.6g (11%) of methyl 1-propyl-1H-
1,2,3-triazole-4-carboxylate. 24: 1H NMR (CDCl3) d
0.96 (3H, t, J = 7.4Hz), 1.86–2.02 (2H, m), 3.94 (3H,
s), 4.71 (2H, t, J = 7.4Hz), 8.13 (1H, s).
5.36. (1-Propyl-1H-imidazol-5-yl)methanol (14g)
NaNO2 (1.14g, 16.5mmol) was added to 5N HNO3
(370mL) at room temperature, and then 21a (71.0g,
412mmol) was added to the mixture under ice cooling.
After being stirred at room temperature for 2h, water
(200mL) was added to the mixture. The mixture was
neutralized using K2CO3 under ice cooling and concen-
trated in vacuo. The residue was purified by column
chromatography on NH silica gel (EtOAc/MeOH = 8:1)
to give 33.6g (58%) of 14g as brown crystals. Compound
14g was used in the next reaction without further purifi-
5.41. (1-Propyl-1H-1,2,3-triazol-5-yl)methanol (14l)
This compound was prepared in quantitative yield from
24 by a method similar to that described for 14a. H
1
NMR (CDCl3) d 0.92 (3H, t, J = 7.2Hz), 1.86–2.03
(2H, m), 4.31 (2H, t, J = 7.2Hz), 4.71 (2H, s), 7.41
(1H, s).

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377
5.42. 5-(Chloromethyl)-1-propyl-1H-1,2,3-triazole
hydrochloride (9i)
The following compounds (6b,g, 6i–o) were prepared
from the carboxylic acids 5a,b18 and anilines 7b,f,g–m
by a method similar to that described for 6a.
This compound was prepared in 57% yield from 14l by
a method similar to that described for 9b. 1H
NMR (DMSO-d6) d 0.90 (3H, t, J = 7.2Hz), 1.79–
1.95 (2H, m), 4.34 (2H, t, J = 7.0Hz), 5.03 (2H, s),
9.53 (1H, br s).
5.44. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-({4-[(2-
pyridyl)sulfanyl]methyl}phenyl)-2,3-dihydro-1H-1-benz-
azepine-4-carboxamide (6b)
Yield 58%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 6.8Hz), 0.98 (3H, t, J = 7.4Hz), 1.33–1.45
(2H, m), 1.54–1.80 (4H, m), 2.89 (2H, m), 3.26–3.34
(4H, m), 3.55 (2H, t, J = 6.6Hz), 3.77–3.83 (2H, m),
4.12–4.18 (2H, m), 4.41 (2H, s), 6.88 (1H, d,
J = 8.4Hz), 6.94–7.02 (2H, m), 6.97 (2H, d,
J = 8.8Hz), 7.15 (1H, d, J = 8.0Hz), 7.35–7.56 (10H,
m), 8.45 (1H, d, J = 5.2Hz).
5.43. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-{4-[(2-
pyridyl)sulfanyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-
carboxamide (6a)
5.43.1. Step 1: 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-
2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (5a). To
a solution of methyl 7-{4-[2-(butoxy)ethoxy]phenyl}-1-
propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate18
(1.00g, 2.53mmol) and propionaldehyde (1.00mL,
13.9mmol) in 1,2-dichloroethane (30mL) sodium tri-
acetoxyborohydride (1.9g, 8.96mmol) at room temper-
ature. After being stirred at room temperature for
24h, 1N NaOH was added to the mixture and the mix-
ture was extracted with EtOAc. The organic layer was
washed with water and brine, dried over MgSO4, and
concentrated in vacuo. To a solution of the residue in
THF (50mL) and MeOH (50mL) was added 1N NaOH
(25mL, 25mmol). The mixture was refluxed for 1h and
the mixture was concentrated in vacuo. The residue was
acidified using 1N HCl and the mixture was extracted
with EtOAc. The organic layer was washed with
water and brine, dried over MgSO4, and concentrated
in vacuo to give 0.895g (84%) of 5a as yellow crystals,
mp 145–146ꢁC. 1H NMR (CDCl3) d 0.96–1.02 (6H,
m), 1.34–1.45 (2H, m), 1.54–1.80 (4H, m), 2.84 (2H,
m), 3.28–3.35 (4H, m), 3.55 (2H, t, J = 6.6Hz), 3.80
(2H, t, J = 5.0Hz), 4.16 (2H, t, J = 5.0Hz), 6.88 (1H,
d, J = 8.8Hz), 6.98 (2H, t, J = 8.8Hz), 7.39–7.52 (4H,
m), 7.88 (1H, s). Anal. Calcd for C26H33NO4: C,
73.73; H, 7.85; N, 3.31. Found: C, 73.68; H, 8.11; N,
3.23.
5.45. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-({4-
[(3-pyridazinyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (6g)
Yield 42%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.96 (6H, d, J = 6.6Hz), 1.33–1.45
(2H, m), 1.55–1.65 (2H, m), 1.96–2.07 (1H, m), 2.84–
2.93 (2H, m), 3.18 (2H, d, J = 6.8Hz), 3.28–3.38 (2H,
m), 3.55 (2H, t, J = 6.6Hz), 3.78–3.83 (2H, m), 4.13–
4.18 (2H, m), 4.38 (2H, s), 6.91 (1H, d, J = 8.8Hz),
6.97 (2H, d, J = 8.8Hz), 7.31–7.54 (11H, m), 7.70 (1H,
s), 9.01–9.05 (1H, m).
5.46. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-({4-
[(2-pyrazinyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (6i)
Yield 49%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.96 (6H, d, J = 6.6Hz), 1.33–1.45
(2H, m), 1.54–1.68 (2H, m), 1.98–2.14 (1H, m), 2.83–
2.94 (2H, m), 3.18 (2H, d, J = 7.2Hz), 3.32–3.37 (2H,
m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J = 5.2Hz),
4.15 (2H, t, J = 5.2Hz), 4.19 (2H, s), 6.91 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.28–7.61 (11H,
m), 8.41–8.50 (2H, m).
5.43.2. Step 2: 7-{4-[2-(butoxy)ethoxy]phenyl}-1-propyl-
N-{4-[(2-pyridyl)sulfanyl]phenyl}-2,3-dihydro-1H-1-benz-
azepine-4-carboxamide (6a). To a solution of 5a (1.00g,
2.36mmol) and DMF (cat. amount) in THF (20mL)
was added SOCl2 (0.34mL, 4.66mmol) at room temper-
ature. After being stirred at room temperature for 1h,
the mixture was added dropwise to a solution of 7a
(0.53g, 2.62mmol) under ice cooling. The mixture was
stirred at room temperature for 2h. Water was added
to the mixture and the mixture was extracted with
EtOAc. The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (hexane/
EtOAc = 2:1) to give 0.57g (38%) of 6a as a yellow
5.47. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-methyl-1H-pyrazol-5-yl)methyl]sulfanyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (6j)
Yield 81%, yellow amorphous. 1H NMR (CDCl3) d
0.89–0.99 (9H, m), 1.34–1.45 (2H, m), 1.54–1.64 (2H,
m), 2.00–2.20 (1H, m), 2.90 (2H, t, J = 4.2Hz), 3.19
(2H, d, J = 7.0Hz), 3.36 (2H, t, J = 4.4Hz), 3.55 (2H,
t, J = 6.6Hz), 3.78–3.83 (5H, m), 4.01 (2H, s), 4.16
(2H, t, J = 5.0Hz), 5.97 (1H, d, J = 1.8Hz), 6.90–7.00
(3H, m), 7.27–7.33 (3H, m), 7.37–7.58 (8H, m). Anal.
Calcd for C38H46N4O3SÆ0.25H2O: C, 70.94; H, 7.28;
N, 8.71. Found: C, 70.95; H, 7.22; N, 8.74.
amorphous. 1H NMR (CDCl3)
d 0.93 (3H, t,
J = 7.0Hz), 1.00 (3H, t, J = 7.2Hz), 1.33–1.45 (2H, m),
1.57–1.77 (4H, m), 2.87–2.95 (2H, m), 3.28–3.36 (4H,
m), 3.55 (2H, t, J = 7.0Hz), 3.80 (2H, t, J = 4.8Hz),
4.16 (2H, t, J = 4.8Hz), 6.85 (1H, d, J = 8.0Hz), 6.90
(1H, t, J = 8.8Hz), 6.95–7.00 (3H, m), 7.40–7.50 (6H,
m), 7.58 (2H, d, J = 8.8Hz), 7.66–7.71 (3H, m), 8.40–
8.43 (1H, m).
5.48. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1,3-thiazol-2-yl)methyl]sulfanyl}phenyl)-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (6k)
Yield 66%, yellow crystals (EtOAc–hexane), mp
97–98ꢁC. 1H NMR (CDCl3) d 0.90–0.98 (9H, m),

378
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
1.34–1.70 (4H, m), 1.95–2.20 (1H, m), 2.90 (2H, t, J =
4.4Hz), 3.18 (2H, d, J = 7.2Hz), 3.36 (2H, t,
J = 4.4Hz), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J =
4.8Hz), 4.16 (2H, t, J = 4.8Hz), 4.40 (2H, s), 6.92
(1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.24 (1H,
d, J = 3.2Hz), 7.35–7.55 (10H, m), 7.67 (1H, d,
J = 3.2Hz). Anal. Calcd for C37H43N3O3S2: C, 69.23;
H, 6.75; N, 6.55. Found: C, 69.34; H, 6.79; N, 6.60.
5.53. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-({4-[(2-
pyridyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-1-benz-
azepine-4-carboxamide (6c)
To a solution of 5a (0.80g, 1.89mmol) and DMF (cat.
amount) in THF (16mL) was added oxalyl chloride
(0.25mL, 1.87mmol) at room temperature. After being
stirred at room temperature for 1h, the mixture was
concentrated in vacuo. A solution of the residue in
THF (16mL) was added dropwise to a solution of 7c
(0.45g, 2.08mmol) and Et3N (2.1mL, 15.1mmol) in
THF (13.5mL) under ice cooling. The mixture was stir-
red at room temperature for 1h. Water was added to the
mixture and the mixture was extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo to give 0.68g (58%) of 6c as a
yellow solid. 1H NMR (CDCl3) d 0.93 (3H, t,
J = 7.4Hz), 0.98 (3H, t, J = 6.8Hz), 1.33–1.45 (2H, m),
1.57–1.76 (4H, m), 2.88 (2H, m), 3.26–3.35 (4H, m),
3.51–3.58 (2H, m), 3.77–3.83 (2H, m), 4.12–4.18 (2H,
m), 4.21 (2H, s), 6.89 (1H, d, J = 8.8Hz), 6.97 (2H, d,
J = 8.8Hz), 7.14–7.60 (13H, m), 8.51–8.55 (1H, m).
5.49. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-methyl-1H-imidazol-2-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6l)
Yield 56%, yellow amorphous. 1H NMR (CDCl3) d
0.90–0.99 (9H, m), 1.34–1.45 (2H, m), 1.54–1.80 (2H,
m), 2.00–2.15 (1H, m), 2.91 (2H, t, J = 5.6Hz), 3.18
(2H, d, J = 7.0Hz), 3.36 (2H, t, J = 5.6Hz), 3.52–
3.59 (5H, m), 3.80 (2H, t, J = 4.8Hz), 4.11 (2H, s),
4.16 (2H, t, J = 4.8Hz), 6.78 (1H, d, J = 1.0Hz), 6.89
(1H, d, J = 1.4Hz), 6.93–7.00 (3H, m), 7.31–7.55 (9H,
m), 7.80 (1H, s). Anal. Calcd for C38H46N4O3S: C,
71.44; H, 7.26; N, 8.77. Found: C, 71.28; H, 7.29; N,
8.38.
The following compounds (6d–f) were prepared from
the carboxylic acids 5b18 and anilines 7c–e by a method
similar to that described for 6c.
5.50. 7-{4-[2-(Butoxy)ethoxy]phenyl}-N-(4-{[(1-ethyl-1H-
imidazol-2-yl)methyl]sulfanyl}phenyl)-1-isobutyl-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (6m)
5.54. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-({4-
[(2-pyridyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (6d)
Yield 45%, yellow amorphous. 1H NMR (CDCl3) d
0.90–0.98 (9H, m), 1.34–1.50 (5H, m), 1.55–1.70 (2H,
m), 1.95–2.15 (1H, m), 2.85–2.95 (2H, m), 3.18 (2H, d,
J = 7.4Hz), 3.30–3.40 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.80 (2H, t, J = 4.8Hz), 3.94 (2H, q, J = 7.2Hz), 4.10–
4.18 (4H, m), 6.86 (1H, d, J = 1.4Hz), 6.89–7.00 (4H,
m), 7.31–7.55 (9H, m), 7.81 (1H, s).
Yield 56%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.96 (6H, d, J = 6.6Hz), 1.33–1.45
(2H, m), 1.57–1.68 (2H, m), 1.95–2.04 (1H, m), 2.84–
2.92 (2H, m), 3.17 (2H, d, J = 7.4Hz), 3.31–3.36 (2H,
m), 3.55 (2H, t, J = 6.2Hz), 3.80 (2H, t, J = 4.8Hz),
4.15 (2H, t, J = 4.8Hz), 4.21 (2H, s), 6.91 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.10–7.17 (1H,
m), 7.22–7.63 (12H, m), 8.51–8.54 (1H, m). Anal. Calcd
for C39H45N3O3S: C, 73.67; H, 7.13; N, 6.61. Found: C,
73.78; H, 7.37; N, 6.62.
5.51. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-2-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6n)
Yield 45%, yellow crystals (EtOH–hexane), mp 80–
1
82ꢁC. H NMR (CDCl3) d 0.90–0.99 (12H, m), 1.34–
1.45 (2H, m), 1.50–1.65 (2H, m), 1.75–1.85 (2H, m),
1.95–2.15 (1H, m), 2.85–2.95 (2H, m), 3.19 (2H, d,
J = 7.2Hz), 3.30–3.40 (2H, m), 3.56 (2H, t, J = 6.6Hz),
3.78–3.89 (4H, m), 4.14–4.19 (4H, m), 6.85–7.00 (5H,
m), 7.33–7.56 (9H, m), 7.64 (1H, s). Anal. Calcd for
C40H50N4O3SÆ0.1H2O: C, 71.84; H, 7.57; N, 8.38.
Found: C, 71.59; H, 7.59; N, 8.18.
5.55. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-({4-
[(3-pyridyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (6e)
Yield 32%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33–1.45
(2H, m), 1.54–1.68 (2H, m), 1.97–2.16 (1H, m), 2.83–
2.94 (2H, m), 3.18 (2H, d, J = 7.8Hz), 3.32–3.38 (2H,
m), 3.55 (2H, t, J = 6.2Hz), 3.80 (2H, t, J = 4.8Hz),
4.01 (2H, s), 4.15 (2H, t, J = 4.8Hz), 6.91 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.15–7.29 (3H,
m), 7.37–7.60 (9H, m), 8.38 (1H, d, J = 2.2Hz), 8.46
(1H, dd, J = 4.6, 1.8Hz).
5.52. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-isopropyl-1H-imidazol-2-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6o)
Yield 39%, yellow crystals (EtOH–hexane), mp 122–
1
124ꢁC. H NMR (CDCl3) d 0.90–0.99 (9H, m), 1.30–
1.45 (8H, m), 1.55–1.70 (2H, m), 1.95–2.10 (1H, m),
2.90 (2H, t, J = 4.8Hz), 3.18 (2H, d, J = 7.0Hz), 3.35
(2H, t, J = 4.8Hz), 3.56 (2H, t, J = 7.0Hz), 3.80 (2H,
t, J = 4.4Hz), 4.13–4.18 (4H, m), 4.40–4.60 (1H, m),
6.89–7.00 (5H, m), 7.32–7.55 (9H, m), 7.75 (1H, s). Anal.
Calcd for C40H50N4O3SÆ0.25H2O: C, 71.55; H, 7.58; N,
8.34. Found: C, 71.32; H, 7.52; N, 8.17.
5.56. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-({4-
[(4-pyridyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (6f)
Yield 27%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33–1.45
(2H, m), 1.54–1.65 (2H, m), 1.97–2.14 (1H, m), 2.84–

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
379
2.95 (2H, m), 3.18 (2H, d, J = 7.4Hz), 3.35 (2H, t,
J = 4.8Hz), 3.55 (2H, t, J = 6.6Hz), 3.78–3.82 (2H, m),
3.98 (2H, s), 4.12–4.18 (2H, m), 6.91 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.12 (2H, d,
J = 6.2Hz), 7.27 (2H, d, J = 8.8Hz), 7.38–7.58 (8H,
m), 8.47–8.51 (2H, m).
m), 1.95–2.10 (2H, m), 2.85–2.95 (2H, m), 3.18 (2H, d,
J = 7.6Hz), 3.30–3.42 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.70 (2H, d, J = 7.8Hz), 3.80 (2H, t, J = 4.8Hz), 4.14–
4.18 (4H, m), 6.81 (1H, d, J = 1.6Hz), 6.89–7.00 (4H,
m), 7.32–7.55 (9H, m), 7.71 (1H, s). Anal. Calcd for
C41H52N4O3S: C, 72.32; H, 7.70; N, 8.23. Found: C,
71.99; H, 7.64; N, 8.24.
5.57. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(2-pyrimidinyl)methyl]sulfanyl}phenyl)-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (6h)
5.60. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-5-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6r)
To a solution of 5b (1.00g, 2.29mmol) and DMF (cat.
amount) in THF (20mL) was added SOCl2 (0.25mL,
3.43mmol) at room temperature. After being stirred at
room temperature for 1h, the mixture was concentrated
in vacuo. A solution of the residue in THF (20mL) was
added dropwise to a solution of 8 (0.59g, 2.28mmol)
and Et3N (1.91mL, 13.7mmol) in THF (17.7mL) under
ice cooling. The mixture was stirred at room tempera-
ture for 2h. MeOH (40mL) and 1N NaOH (15mL)
were added to the mixture, and the mixture was stirred
at room temperature for 0.5h. To the mixture was added
9a (0.35g, 2.72mmol) at room temperature, and the
mixture was stirred at room temperature for 0.5h. The
mixture was concentrated in vacuo, and water was
added to the residue. The mixture was extracted with
EtOAc. The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (EtOAc/
EtOH = 15:1) to give 0.94g (64%) of 6h as a yellow
Yield 91%, yellow amorphous. 1H NMR (CDCl3) d
0.90–1.00 (12H, m), 1.30–1.48 (2H, m), 1.54–1.68 (2H,
m), 1.75–1.89 (2H, m), 2.00–2.20 (1H, m), 2.88–2.98
(2H, m), 3.19 (2H, d, J = 7.4Hz), 3.35–3.45 (2H, m),
3.55 (2H, t, J = 7.4Hz), 3.81 (2H, t, J = 4.8Hz), 3.92
(2H, t, J = 7.6Hz), 3.99 (2H, s), 4.16 (2H, t,
J = 4.8Hz), 6.70 (1H, s), 6.92 (1H, d, J = 8.8Hz), 6.98
(2H, d, J = 8.8Hz), 7.25–7.29 (2H, m), 7.38–7.56 (8H,
m), 7.66 (1H, s). Anal. Calcd for C40H50N4O3S: C,
72.04; H, 7.56; N, 8.40. Found: C, 71.76; H, 7.63; N,
8.16.
5.61. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfanyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (6s)
Yield 64%, yellow amorphous. 1H NMR (CDCl3) d
0.89–1.03 (9H, m), 1.27–1.50 (2H, m), 1.55–1.95 (6H,
m), 2.85–2.95 (2H, m), 3.25–3.40 (4H, m), 3.55 (2H, t,
J = 6.6Hz), 3.80 (2H, t, J = 4.8Hz), 3.92 (2H, t,
J = 7.4Hz), 3.99 (2H, s), 4.16 (2H, t, J = 4.8Hz), 6.70
(1H, s), 6.90 (1H, d, J = 7.8Hz), 6.98 (2H, d,
J = 8.4Hz), 7.25–7.30 (2H, m), 7.39–7.55 (8H, m), 7.62
(1H, s). Anal. Calcd for C39H48N4O3S: C, 71.75; H,
7.41; N, 8.58. Found: C, 71.54; H, 7.37; N, 8.53.
amorphous. 1H NMR (CDCl3)
d 0.93 (3H, t,
J = 7.4Hz), 0.96 (6H, d, J = 6.6Hz), 1.33–1.45 (2H,
m), 1.55–1.68 (2H, m), 2.00–2.17 (1H, m), 2.84–2.97
(2H, m), 3.17 (2H, d, J = 7.4Hz), 3.30–3.36 (2H, m),
3.55 (2H, t, J = 6.6Hz), 3.77–3.83 (2H, m), 4.15 (2H, t,
J = 4.8Hz), 4.34 (2H, s), 6.91 (1H, d, J = 8.4Hz), 6.97
(2H, d, J = 8.8Hz), 7.15 (1H, t, J = 4.8Hz), 7.34–7.60
(10H, m), 8.68 (2H, d, J = 4.6Hz).
5.62. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-4-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6t)
The following compounds (6p–y) were prepared from
the carboxylic acids 5a,b,18 the aniline 8 and heteroaryl-
methylchlorides 9b–i by a method similar to that de-
scribed for 6h.
Yield 20%, yellow crystals (hexane–i-Pr2O–EtOAc), mp
1
142–144ꢁC. H NMR (CDCl3) d 0.85–0.99 (12H, m),
5.58. 7{4-[2-(Butoxy)ethoxy]phenyl}-N-(4-{[(1-butyl-1H-
imidazol-2-yl)methyl]sulfanyl}phenyl)-1-isobutyl-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (6p)
1.30–1.48 (2H, m), 1.54–1.80 (4H, m), 1.95–2.15 (1H,
m), 2.85–2.95 (2H, m), 3.19 (2H, d, J = 7.2Hz), 3.30–
3.40 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.76–3.83 (4H,
m), 4.07 (2H, s), 4.16 (2H, t, J = 5.2Hz), 6.69 (1H, s),
6.92 (1H, d, J = 9.2Hz), 6.98 (2H, d, J = 8.8Hz), 7.32–
7.55 (11H, m). Anal. Calcd for C40H50N4O3S: C,
72.04; H, 7.56; N, 8.40. Found: C, 71.78; H, 7.41; N,
8.48.
Yield 24%, yellow amorphous. 1H NMR (CDCl3) d
0.90–0.99 (12H, m), 1.33–1.78 (8H, m), 2.00–2.10 (1H,
m), 2.85–2.95 (2H, m), 3.19 (2H, d, J = 6.8Hz), 3.30–
3.40 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78–3.92 (4H,
m), 4.07–4.18 (4H, m), 6.84 (1H, d, J = 1.2Hz), 6.89–
7.00 (4H, m), 7.32–7.55 (9H, m), 7.65 (1H, s). Anal.
Calcd for C41H52N4O3SÆ0.25H2O: C, 71.84; H, 7.72;
N, 8.17. Found: C, 71.61; H, 7.85; N, 8.21.
5.63. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(4-methyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl}phen-
yl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (6u)
5.59. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-isobuthyl-1H-imidazol-2-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6q)
Yield 49%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.4Hz), 0.98 (6H, d, J = 6.6Hz), 1.29–1.48
(2H, m), 1.51–1.68 (2H, m), 1.97–2.18 (1H, m), 2.86–
2.96 (2H, m), 3.19 (2H, d, J = 6.6Hz), 3.28–3.39 (2H,
m), 3.56 (2H, t, J = 6.6Hz), 3.60 (3H, s), 3.81 (2H,
t, J = 5.0Hz), 4.11 (2H, s), 4.16 (2H, t, J = 5.0Hz),
Yield 60%, yellow amorphous. 1H NMR (CDCl3) d
0.90–0.99 (15H, m), 1.34–1.45 (2H, m), 1.54–1.70 (2H,

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M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
6.89–7.00 (3H, m), 7.29–7.43 (5H, m), 7.46 (2H, d,
J = 8.4Hz), 7.57 (2H, d, J = 8.4Hz), 7.97 (1H, s), 806
(1H, br s).
5.68. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-[4-[(2-
pyridyl)sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-
carboxamide (4a)
5.64. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6v)
To a solution of 6a (150mg, 0.25mmol) in CH2Cl2
(7.5mL) was added mCPBA (70%, 95mg, 0.39mmol)
under ice cooling. After being stirred under ice cooling
for 15min, mCPBA (70%, 95mg, 0.39mmol) was
added to the mixture under ice cooling for 15min.
The mixture was stirred under ice cooling for 15min,
and the mixture was added to aqueous Na2S2O3. The
mixture was extracted with EtOAc. The organic layer
was washed with aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (hexane/
EtOAc = 1:3) to give 30mg (20%) of 4a as a yellow
Yield 63%, yellow amorphous. 1H NMR (CDCl3) d
0.89–2.99 (12H, m), 1.29–1.49 (2H, m), 1.53–
1.85 (4H, m), 1.96–2.17 (1H, m), 2.86–2.96 (2H,
m), 3.18 (2H, d, J = 7.0Hz), 3.28–3.38 (2H, m),
3.56 (2H, t, J = 6.6Hz), 3.79–3.86 (4H, m), 4.06
(2H, s), 4.16 (2H, t, J = 4.9Hz), 6.90 (1H, d, J =
8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.31–7.46 (7H, m),
7.60 (2H, d, J = 8.8Hz), 7.97 (1H, s), 8.42 (1H, br s).
Anal. Calcd for C39H49N5O3SÆ0.5H2O: C, 69.20;
H, 7.45; N, 10.35. Found. C, 69.12; H, 7.58; N,
10.41.
amorphous. 1H NMR (CDCl3)
d 0.93 (3H, t,
J = 7.4Hz), 0.98 (3H, t, J = 7.5Hz), 1.33–1.44 (2H,
m), 1.45–1.82 (4H, m), 2.82–2.92 (2H, m), 3.25–3.36
(4H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J = 5.0Hz), 4.15 (2H, t, J = 5.0Hz), 6.89 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.26–7.50 (6H,
m), 7.60–7.80 (5H, m), 7.82–7.93 (1H, m), 8.01–8.09
(1H, m), 8.50–8.57 (1H, m). Anal. Calcd for
C37H41N3O4SÆ0.25H2O: C, 70.73; H, 6.66; N, 6.69.
Found: C, 70.50; H, 6.65; N, 6.54.
5.65. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(4-
propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (6w)
Yield 67%, yellow amorphous. 1H NMR (CDCl3) d
0.89–1.03 (9H, m), 1.28–1.47 (2H, m), 1.51–1.88 (6H,
m), 2.85–2.96 (2H, m), 3.23–3.36 (4H, m), 3.56 (2H, t,
J = 6.6Hz), 3.77–3.84 (4H, m), 4.04 (2H, s), 4.16 (2H,
t, J = 4.8Hz), 6.87 (1H, d, J = 8.8Hz), 6.97 (2H, d,
J = 8.8Hz), 7.26–7.45 (7H, m), 7.60 (2H, d,
J = 8.8Hz), 7.96 (1H, s), 8.52 (1H, s). Anal. Calcd for
C38H47N5O3SÆ0.5H2O: C, 68.85; H, 7.30; N, 10.56.
Found: C, 68.54; H, 7.41; N, 10.70.
5.69. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(2-
pyridyl)sulfinyl]methyl}phenyl)-2,3-dihydro-1H-1-benz-
azepine-4-carboxamide (4b)
To a solution of 6b (300mg, 0.48mmol) in CH2Cl2
(15mL) was added mCPBA (70%, 83mg, 0.34mmol)
at ꢀ30ꢁC. After being stirred under ice cooling for 1h,
the mixture was added to aqueous Na2S2O3, and the
mixture was extracted with EtOAc. The organic layer
was washed with aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (hexane/
EtOAc = 1:3) to give 97mg (32%) of 4b as a yellow
5.66. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]sulfanyl}phen-
yl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (6x)
Yield 30%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.1Hz), 0.97 (6H, d, J = 6.6Hz), 1.30–1.48
(2H, m), 1.51–1.68 (2H, m), 1.98–2.16 (1H, m), 2.85–
2.95 (2H, m), 3.19 (2H, d, J = 7.2Hz), 3.33–3.78 (2H,
m), 3.55 (2H, t, J = 6.6Hz), 3.74 (3H, s), 3.80 (2H, t,
J = 5.0Hz), 4.12 (2H, s), 4.16 (2H, t, J = 5.0Hz), 6.92
(1H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.8Hz), 7.31–7.49
(7H, m), 7.55 (2H, d, J = 8.8Hz), 7.62 (1H, s), 7.76
(1H, s). Anal. Calcd for C37H45N5O3SÆ0.5H2O: C,
68.49; H, 7.15; N, 10.79. Found: C, 68.62; H, 7.14; N,
11.00.
amorphous. 1H NMR (CDCl3)
d 0.93 (3H, t,
J = 7.2Hz), 0.98 (3H, t, J = 7.4Hz), 1.33–1.45 (2H, m),
1.55–1.76 (4H, m), 2.89 (2H, m), 3.26–3.34 (4H, m),
3.55 (2H, t, J = 6.6Hz), 3.78 (2H, t, J = 4.8Hz), 4.05
(1H, d, J = 13.2Hz), 4.12–4.18 (2H, m), 4.34 (1H, d,
J = 13.2Hz), 6.86–6.89 (5H, m), 7.32–7.59 (9H, m),
7.70–7.76 (2H, m), 8.64–8.68 (1H, m). Anal. Calcd for
C38H43N3O4SÆ0.5H2O: C, 70.56; H, 6.86; N, 6.50.
Found: C, 70.59; H, 6.73; N, 6.61.
5.67. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-1,2,3-triazol-5-yl)methyl]sulfanyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (6y)
5.70. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(2-
pyridyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-1-benz-
azepine-4-carboxamide (4c)
Yield 50%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.97 (3H, t, J = 7.4Hz), 0.97 (6H, d,
J = 6.6Hz), 1.33–1.45 (2H, m), 1.57–1.66 (2H, m), 1.89–
2.05 (3H, m), 2.91 (2H, m), 3.18 (2H, d, J = 7.4Hz),
3.33–3.38 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.77–3.83
(2H, m), 3.89 (2H, s), 4.15 (2H, t, J = 4.8Hz), 4.24
(2H, t, J = 7.2Hz), 6.91 (1H, d, J = 8.8Hz), 6.97 (2H,
d, J = 8.8Hz), 7.24–7.29 (2H, m), 7.38–7.58 (8H, m),
7.72 (1H, s).
This compound was prepared in 45% yield from 6c by
a method similar to that described for 4b, yellow crys-
tals (EtOAc–i-Pr2O), 118–120ꢁC. 1H NMR (CDCl3)
d 0.93 (3H, t, J = 7.0Hz), 0.99 (3H, t, J = 7.0Hz),
1.33–1.45 (2H, m), 1.57–1.76 (4H, m), 2.83–2.93
(2H, m), 3.27–3.35 (4H, m), 3.55 (2H, t, J = 6.6Hz),
3.80 (2H, t, J = 4.8Hz), 4.13 (1H, d, J = 12.2Hz),
4.15 (2H, m), 4.25 (1H, d, J = 12.2Hz), 6.89 (1H,
d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.12–

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
381
7.25 (2H, m), 7.38–7.49 (7H, m), 7.61 (1H, td, J = 7.6,
5.74. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(3-pyridazinyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (4g)
1.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.90 (1H, s), 8.53–
8.57 (1H, m). Anal. Calcd for C38H43N3O4S: C, 71.56;
H, 6.80; N, 6.59. Found: C, 71.38; H, 7.06; N,
6.44.
To a solution of 6g (150mg, 0.24mmol) in CH2Cl2
(6.0mL) was added dropwise a solution of mCPBA
(70%, 61mg, 0.25mmol) in CH2Cl2 (4.5mL) at
ꢀ78ꢁC. After being stirred at ꢀ78ꢁC for 15min, the
mixture was added to aqueous Na2S2O3, and the mix-
ture was extracted with EtOAc. The organic layer
was washed with aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (EtOH/
EtOAc = 1:20) to give 62mg (40%) of 4g as yellow
crystals, mp 138–141ꢁC. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.98 (6H, d, J = 6.6Hz), 1.33–1.43
(2H, m), 1.54–1.62 (2H, m), 1.97–2.17 (1H, m), 2.84–
2.97 (2H, m), 3.20 (2H, d, J = 7.6Hz), 3.31–3.41 (2H,
m), 3.55 (2H, t, J = 6.6Hz), 3.78–3.83 (2H, m), 4.13–
4.19 (2H, m), 4.27 (1H, d, J = 13.2Hz), 4.38 (1H, d,
J = 13.2Hz), 6.89–7.00 (3H, m), 7.36–7.46 (9H, m),
7.72 (2H, d, J = 8.4Hz), 7.96–8.04 (1H, m), 9.08 (1H,
dd, J = 4.4, 1.8Hz). Anal. Calcd for C38H44N4O4S: C,
69.91; H, 6.79; N, 8.58. Found: C, 69.51; H, 6.80; N,
8.37.
5.71. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(2-pyridyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (4d)
This compound was prepared in 34% yield from 6d by a
method similar to that described for 4a, yellow crystals
1
(EtOAc–hexane), mp 114–117ꢁC. H NMR (CDCl3) d
0.93 (3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.2Hz), 1.33–
1.45 (2H, m), 1.54–1.62 (2H, m), 2.00–2.17 (1H, m),
2.84–2.95 (2H, m), 3.19 (2H, d, J = 7.0Hz), 3.36 (2H,
m), 3.55 (2H, t, J = 6.2Hz), 3.78–3.83 (2H, m), 4.13–
4.19 (2H, m), 4.15 (1H, d, J = 12.3Hz), 4.26 (1H, d,
J = 12.3Hz), 6.92 (1H, d, J = 8.8Hz), 6.98 (2H, d,
J = 8.8Hz), 7.14–7.26 (2H, m), 7.38–7.51 (7H, m), 7.63
(1H, td, J = 7.6, 1.8Hz), 7.69–7.78 (3H, m), 8.54–8.57
(1H, m). Anal. Calcd for C39H45N3O4SÆ0.25H2O: C,
71.37; H, 6.98; N, 6.40. Found: C, 71.14; H, 7.05; N,
6.37.
The following compounds (4e,f) were prepared from
6e,f by a method similar to that described for
4b.
The following compounds (4h–y) were prepared
from 6h–y by a method similar to that described for
4g.
5.72. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(3-pyridyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (4e)
5.75. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyll-N-(4-
{[(2-pyrimidinyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (4h)
Yield 30%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33–
1.45 (2H, m), 1.54–1.68 (2H, m), 2.00–2.17 (1H, m),
2.84–2.96 (2H, m), 3.19 (2H, d, J = 7.2Hz), 3.36
(2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J = 4.8Hz), 3.91 (1H, d, J = 12.8Hz), 4.05–4.12 (1H,
m), 4.16 (2H, t, J = 4.8Hz), 6.92 (1H, d, J = 8.8Hz),
6.98 (2H, d, J = 8.8Hz), 7.19–7.31 (3H, m), 7.39–
7.51 (6H, m), 7.70 (2H, d, J = 8.8Hz), 7.76–7.85 (1H,
m), 8.01–8.05 (1H, m), 8.52 (1H, dd, J = 4.8,
1.6Hz). Anal. Calcd for C39H45N3O4SÆ0.7H2O: C,
70.49; H, 7.04; N, 6.32. Found: C, 70.38; H, 6.82; N,
6.15.
Yield 61%, yellow amorphous. 1H NMR (CDCl3) d 0.93
(3H, t, J = 7.0Hz), 0.97 (6H, d, J = 6.6Hz), 1.33–
1.45 (2H, m), 1.57–1.67 (2H, m), 2.08 (1H, m), 2.92
(2H, m), 3.19 (2H, d, J = 7.4Hz), 3.33–3.39 (2H,
m), 3.55 (2H, t, J = 6.2Hz), 3.78–3.83 (2H, m),
4.13–4.18 (2H, m), 4.35 (1H, d, J = 12.4Hz), 4.52 (1H,
d, J = 12.4Hz), 6.92 (1H, d, J = 8.4Hz), 6.98
(2H, d, J = 8.8Hz), 7.22 (1H, t, J = 4.8Hz), 7.38–7.51
(5H, m), 7.58 (2H, d, J = 8.8Hz), 7.74 (2H, d, J =
8.8Hz), 7.83 (1H, m), 8.71 (2H, d, J = 5.2Hz).
Anal. Calcd for C38H44N4O4SÆ0.5H2O: C, 68.96;
H, 6.85; N, 8.46. Found: C, 68.78; H, 6.71; N,
8.65.
5.73. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(4-pyridyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (4f)
5.76. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(2-pyrazinyl)methyl]sulfinyl}phenyl)-2,3-dihydro-1H-1-
benzazepine-4-carboxamide (4i)
Yield 41%, yellow crystals (EtOAc–hexane), mp 155–
1
157ꢁC. H NMR (CDCl3) d 0.93 (3H, t, J = 7.2Hz),
Yield 51%, yellow crystals (EtOAc–hexane), mp 146–
149ꢁC. H NMR (CDCl3) d 0.93 (3H, t, J = 7.0Hz),
1
0.97 (6H, d, J = 6.6Hz), 1.33–1.45 (2H, m), 1.54–
1.68 (2H, m), 1.99–2.16 (1H, m), 2.84–2.97 (2H, m),
3.19 (2H, d, J = 7.2Hz), 3.44–3.50 (2H, m), 3.55 (2H,
t, J = 6.6Hz), 3.80 (2H, t, J = 4.8Hz), 3.92 (1H, d,
J = 12.6Hz), 4.05 (1H, d, J = 12.6Hz), 4.13–4.18 (2H,
m), 6.88–6.92 (3H, m), 6.98 (2H, d, J = 8.8Hz),
7.31–7.49 (7H, m), 7.69–7.82 (3H, m), 8.50 (2H, d,
J = 5.8Hz). Anal. Calcd for C39H45N3O4S: C, 71.86;
H, 6.96; N, 6.45. Found: C, 71.65; H, 7.04; N,
6.56.
0.97 (6H, d, J = 6.6Hz), 1.33–1.45 (2H, m), 1.54–1.64
(2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, d,
J = 7.4Hz), 3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80
(2H, t, J = 4.8Hz), 4.16 (2H, t, J = 4.8Hz), 4.32 (2H,
s), 6.92 (1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz),
7.38–7.59 (7H, m), 7.72–7.80 (3H, m), 8.36 (1H, s),
8.49 (1H, s), 8.51 (1H, s). Anal. Calcd for C38H44N4O4S:
C, 69.91; H, 6.79; N, 8.58. Found: C, 69.78; H, 6.98; N,
8.67.

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M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
5.77. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-methyl-1H-pyrazol-5-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4j)
m), 2.85–3.00 (2H, m), 3.20 (2H, d, J = 7.2Hz), 3.30–
3.45 (2H, m), 3.55 (2H, t, J = 7.0Hz), 3.58–3.83 (4H,
m), 4.06–4.30 (4H, m), 6.87 (1H, d, J = 1.4Hz), 6.90–
7.00 (4H, m), 7.39–7.48 (7H, m), 7.73 (2H, d,
J = 8.4Hz), 7.89 (1H, s). Anal. Calcd for C40H50N4O4-
SÆ0.3H2O; C, 69.80; H, 7.41; N, 8.14. Found: C, 69.56;
H, 7.19; N, 7.92.
Yield 68%, yellow amorphous. 1H NMR (CDCl3) d 0.88–
0.99 (9H, m), 1.34–1.70 (4H, m), 2.00–2.20 (1H, m), 2.90–
2.97 (2H, m), 3.20 (2H, d, J = 7.2Hz), 3.30–3.45 (2H, m),
3.52–3.58 (5H, m), 3.81 (2H, t, J = 4.6Hz), 4.12–4.18 (4H,
m), 5.98 (1H, d, J = 2.2Hz), 6.91–7.02 (3H, m), 7.34–7.52
(8H, m), 7.72–7.76 (3H, m). Anal. Calcd for C38H46-
N4O4SÆ0.3H2O: C, 69.12; H, 7.11; N, 8.49. Found: C,
68.94; H, 6.96; N, 8.15.
5.82. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-isopropyl-1H-imidazol-2-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4o)
Yield 43%, yellow amorphous. 1H NMR (CDCl3) d
0.90–0.99 (9H, m), 1.22–1.49 (8H, m), 1.54–1.75 (2H,
m), 2.00–2.20 (1H, m), 2.90–3.00 (2H, m), 3.20 (2H, d,
J = 7.6Hz), 3.30–3.40 (2H, m), 3.55 (2H, t, J = 7.6Hz),
3.80 (2H, t, J = 4.4Hz), 4.10–4.30 (4H, m), 4.40–4.50
(1H, m), 6.90–7.02 (5H, m), 7.38–7.48 (7H, m), 7.73
(2H, d, J = 8.8Hz), 7.88 (1H, s). Anal. Calcd for
C40H50N4O4SÆ0.3H2O: C, 69.80; H, 7.41; N, 8.14.
Found: C, 69.56; H, 7.18; N, 7.91.
5.78. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1,3-thiazol-2-yl)methyl]sulfinyl}phenyl)-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (4k)
Yield 66%, yellow crystals (EtOAc–hexane), mp
142–144ꢁC. 1H NMR (CDCl3) d 0.89–0.99 (9H,
m), 1.30–1.70 (4H, m), 2.00–2.20 (1H, m), 2.92 (2H,
t, J = 5.2Hz), 3.19 (2H, d, J = 7.2Hz), 3.37 (2H, t,
J = 5.2Hz), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J =
4.8Hz), 4.16 (2H, t, J = 4.8Hz), 4.40 (1H, d, J =
13.2Hz), 4.48 (1H, d, J = 13.2Hz), 6.93 (1H, d,
J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.31 (1H, d, J =
3.4Hz), 7.39–7.49 (7H, m), 7.71–7.78 (4H, m). Anal.
Calcd for C37H43N3O4S2: C, 67.55; H, 6.59; N, 6.39.
Found: C, 67.46; H, 6.39; N, 6.39.
5.83. 7-{[4-(2-Butoxy)ethoxy]phenyl}-N-(4-{[(1-butyl-
1H-imidazol-2-yl)methyl]sulfinyl}phenyl)-1-isobutyl-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4p)
Yield 68%, yellow amorphous. 1H NMR (CDCl3) d
0.86–1.00 (12H, m), 1.17–1.70 (8H, m), 1.95–2.20 (1H,
m), 2.90–3.00 (2H, m), 3.17 (2H, d, J = 7.2Hz), 3.30–
3.43 (2H, m), 3.55 (2H, t, J = 7.0Hz), 3.70–3.95 (4H,
m), 4.03–4.25 (4H, m), 6.85 (1H, d, J = 1.2Hz), 6.89–
6.99 (4H, m), 7.38–7.46 (7H, m), 7.73 (2H, d,
J = 8.8Hz), 8.18 (1H, s). Anal. Calcd for C41H52N4O4-
SÆ0.5H2O: C, 69.76; H, 7.57; N, 7.94. Found: C, 69.98;
H, 7.84; N, 7.58.
5.79. 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-methyl-1H-imidazol-2-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4l)
Yield 58%, yellow crystals (EtOAc–hexane), mp 134–
1
136ꢁC. H NMR (CDCl3) d 0.90–1.00 (9H, m), 1.34–
1.50 (2H, m), 1.55–1.65 (2H, m), 2.00–2.20 (1H, m),
2.90–3.00 (2H, m), 3.20 (2H, d, J = 7.4Hz), 3.33–3.43
(2H, m), 3.46 (3H, s), 3.55 (2H, t, J = 6.6Hz), 3.80
(2H, t, J = 4.8Hz), 4.05–4.28 (4H, m), 6.81 (1H, d,
J = 1.2Hz), 6.90–7.00 (4H, m), 7.40–7.48 (7H, m), 7.74
(2H, d, J = 8.8Hz), 7.91 (1H, s). Anal. Calcd for
C38H46N4O4SÆ0.8H2O: C, 68.19; H, 7.17; N, 8.37.
Found: C, 68.13; H, 6.92; N, 7.97.
5.84. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-isobuthyl-1H-imidazol-2-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4q)
Yield 68%, yellow amorphous. 1H NMR (CDCl3) d 0.86
(6H, d, J = 6.6Hz), 0.89–0.99 (9H, m), 1.34–1.45 (2H,
m), 1.54–1.65 (2H, m), 1.80–2.20 (2H, m), 2.90–2.98
(2H, m), 3.20 (2H, d, J = 7.2Hz), 3.35–3.40 (2H, m),
3.45–3.70 (4H, m), 3.80 (2H, t, J = 4.4Hz), 4.07–4.18
(3H, m), 4.29 (1H, d, J = 13.4Hz), 6.81 (1H, d,
J = 1.6Hz), 6.90–7.00 (4H, m), 7.38–7.48 (7H, m), 7.73
(2H, d, J = 8.6Hz), 7.88 (1H, s). Anal. Calcd for
C41H52N4O4SÆ0.4H2O: C, 69.93; H, 7.56; N, 7.96.
Found: C, 69.79; H, 7.31; N, 7.66.
5.80. 7-{[4-(2-Butoxy)ethoxy]phenyl}-N-(4-{[(1-ethyl-1H-
imidazol-2-yl)methyl]sulfinyl}phenyl)-1-isobutyl-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4m)
Yield 55%, yellow crystals (EtOAc–hexane), mp 139–
1
141ꢁC. H NMR (CDCl3) d 0.90–1.00 (9H, m), 1.29–
1.68 (7H, m), 2.00–2.15 (1H, m), 2.90–2.98 (2H, m),
3.20 (2H, d, J = 7.6Hz), 3.30–3.42 (2H, m), 3.55 (2H,
t, J = 6.4Hz), 3.78–3.91 (4H, m), 4.07–4.30 (4H, m),
6.90–7.02 (5H, m), 7.39–7.48 (7H, m), 7.72–7.81 (3H,
m). Anal. Calcd for C39H48N4O4SÆ0.2H2O: C, 69.65;
H, 7.25; N, 8.33. Found: C, 69.51; H, 7.11; N, 8.23.
5.85. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4r)
Yield 83%, yellow amorphous. 1H NMR (CDCl3) d
0.86–0.99 (12H, m), 1.29–1.50 (2H, m), 1.55–1.77 (4H,
m), 1.95–2.20 (1H, m), 2.90–3.00 (2H, m), 3.20 (2H, d,
J = 7.4Hz), 3.30–3.45 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.74–3.83 (4H, m), 4.02 (1H, d, J = 14.4Hz), 4.07–4.18
(3H, m), 6.56 (1H, s), 6.92 (1H, d, J = 8.8Hz), 6.98
(2H, d, J = 8.8Hz), 7.32–7.50 (8H, m), 7.75 (2H, d,
J = 8.8Hz), 7.97 (1H, s). Anal. Calcd for C40H50N4O4S:
5.81. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-2-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4n)
Yield 36%, yellow amorphous. 1H NMR (CDCl3) d
0.84–1.00 (12H, m), 1.22–1.80 (6H, m), 2.00–2.20 (1H,

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
383
C, 70.35; H, 7.38; N, 8.20. Found: C, 70.03; H, 7.40; N,
8.06.
s). Anal. Calcd for C39H49N5O4SÆ0.5H2O: C, 67.60; H,
7.27; N, 10.11. Found: C, 67.25; H, 7.28; N, 9.82.
5.86. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4s)
5.90. 7-{[4-(2-Butoxy)ethoxy]phenyl}1-propyl-N-(4-{[(4-
propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4w)
1
Yield 81%, yellow amorphous. 1H NMR (300MHz,
CDCl3) d 0.88–1.025 (9H, m), 1.33–1.46 (2H, m),
1.56–1.79 (6H, m), 2.90–2.95 (2H, m), 3.31–3.37 (4H,
m), 3.55 (2H, t, J = 6.3Hz), 3.76–3.82 (4H, m), 4.02
(1H, d, J = 14.1Hz), 4.09 (1H, d, J = 14.1Hz), 4.16
(2H, t, J = 4.8Hz), 6.57 (1H, s), 6.91 (1H, d,
J = 9.0Hz), 6.98 (2H, d, J = 8.7Hz), 7.33–7.51 (8H,
m), 7.74 (2H, d, J = 9.0Hz), 7.84 (1H, s). Anal. Calcd
for C39H48N4O4SÆ0.25H2O: C, 69.56; H, 7.26; N, 8.32.
Found: C, 69.49; H, 7.23; N, 8.18.
Yield 57%, yellow crystals (EtOAc), mp 179–181ꢁC. H
NMR (CDCl3)d 0.89 (3H, t, J = 7.2Hz), 0.93 (3H, t,
J = 7.4Hz), 1.02 (3H, d, J = 7.3Hz), 1.27–1.48 (2H,
m), 1.51–1.86 (6H, m), 2.89–3.00 (2H, m), 3.28–3.41
(4H, m), 3.55 (2H, t, J = 6.6Hz), 3.78–3.89 (4H, m),
4.00 (1H, d, J = 14.4Hz), 4.12–4.19 (3H, m), 6.90 (1H,
d, J = 8.4Hz), 6.96 (2H, d, J = 9.2Hz), 7.27–7.44 (7H,
m), 7.84 (2H, d, J = 8.4Hz), 8.06 (1H, s), 8.54 (1H, br
s). Anal. Calcd for C38H47N5O4S: C, 68.13; H, 7.07;
N, 10.45. Found: C, 67.79; H, 7.10; N, 10.46.
5.87. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-4-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (4t)
5.91. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4x)
Yield 72%, yellow amorphous. 1H NMR (CDCl3) d
0.88–0.99 (12H, m), 1.30–1.50 (2H, m), 1.55–1.85 (4H,
m), 1.95–2.20 (1H, m), 2.85–2.95 (2H, m), 3.20 (2H, d,
J = 7.6Hz), 3.30–3.45 (2H, m), 3.55 (2H, t, J = 7.2Hz),
3.78–3.87 (4H, m), 3.98 (1H, d, J = 12.8Hz), 4.09 (1H,
d, J = 12.8Hz), 4.16 (2H, t, J = 4.8Hz), 6.80 (1H, s),
6.93 (1H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.8Hz), 7.39–
7.53 (8H, m), 7.70–7.75 (3H, m). Anal. Calcd for
C40H50N4O4S: C, 70.35; H, 7.38; N, 8.20. Found: C,
70.10; H, 7.34; N, 8.12.
Yield 89%, yellow crystals (EtOAc–hexane), mp 135–
138ꢁC. H NMR (CDCl3) d 0.93 (3H, t, J = 7.2Hz),
1
0.98 (6H, d, J = 6.6Hz), 1.35–1.47 (2H, m), 1.52–1.68
(2H, m), 1.96–2.17 (1H, m), 2.87–2.97 (2H, m), 3.20
(2H, d, J = 7.4Hz), 3.32–3.41 (2H, m), 3.55 (2H, t,
J = 6.6Hz), 3.76 (3H, s), 3.81 (2H, t, J = 4.9Hz), 4.16
(2H, t, J = 4.9Hz), 4.19 (1H, d, J = 13.6Hz), 4.28 (1H,
d, J = 13.6Hz), 6.91–7.01 (3H, m), 7.36–7.52 (7H, m),
7.74 (1H, br s), 7.78 (2H, d, J = 8.8Hz), 7.83 (1H, s).
Anal. Calcd for C37H45N5O4S: C, 67.76; H, 6.92; N,
10.68. Found: C, 67.52; H, 6.76; N, 10.43.
5.88. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(4-methyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4u)
5.92. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-1,2,3-triazol-5-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4y)
Yield 66%, yellow crystals (EtOH–EtOAc), mp 103–
105ꢁC. 1H NMR (CDCl3)d 0.93 (3H, t, J = 7.2Hz),
1.01 (6H, d, J = 6.2Hz), 1.29–1.47 (2H, m), 1.53–
1.72 (2H, m), 1.96–2.17 (1H, m), 2.89–3.01 (2H, m),
3.22 (2H, d, J = 7.8Hz), 3.30–3.40 (2H, m), 3.53–3.61
(5H, m), 3.81 (2H, t, J = 4.9Hz), 3.96 (1H, d,
J = 14.0Hz), 4.11 (1H, d, J = 14.0Hz), 4.16 (2H, t, J =
4.9Hz), 6.89–6.99 (3H, m), 7.16–7.22 (2H, m), 7.34–
7.48 (5H, m), 7.85 (2H, d, J = 8.4Hz), 8.00 (1H, s),
8.64 (1H, br s). Anal. Calcd for C37H45N5O4SÆ2.0H2O:
C, 64.23; H, 7.14; N, 10.12. Found: C, 64.44; H, 7.20;
N, 10.01.
Yield 64%, yellow amorphous. 1H NMR (CDCl3) d 0.90
(3H, t, J = 7.4Hz), 0.93 (3H, t, J = 7.0Hz), 0.97 (6H, d,
J = 6.6Hz), 1.33–1.45 (2H, m), 1.54–1.65 (2H, m), 1.77–
1.91 (2H, m), 2.07 (1H, m), 2.93 (2H, m), 3.19 (2H, d,
J = 7.4Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80
(2H, t, J = 4.8Hz), 3.97 (1H, d, J = 14.0Hz), 4.08–4.16
(4H, m), 4.21 (1H, d, J = 14.0Hz), 6.92 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.31 (2H, d, J =
8.8Hz), 7.32–7.50 (6H, m), 7.78 (2H, d, J = 8.8Hz),
8.07 (1H, s). Anal. Calcd for C39H49N5O4SÆ0.2H2O: C,
68.13; H, 7.24; N, 10.19. Found: C, 68.04; H, 7.08; N,
10.19.
5.89. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (4v)
5.93. 7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-
{[(1-propyl-1H-imidazol-5-yl)methyl]sulfonyl}phenyl)-
2,3-dihydro-1H-1-benzazepine-4-carboxamide (25)
1
Yield 75%, yellow amorphous. H NMR (CDCl3)d 0.88
(3H, t, J = 7.3Hz), 0.93 (3H, t, J = 7.1Hz), 1.01 (6H, d,
J = 6.6Hz), 1.28–1.47 (2H, m), 1.51–1.78 (4H, m), 1.95–
2.18 (1H, m), 2.90–3.01 (2H, m), 3.21 (2H, d,
J = 7.2Hz), 3.31–3.41 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.76–3.86 (4H, m), 3.97 (1H, d, J = 14.2Hz), 4.11 (1H,
d, J = 14.2Hz), 4.15 (2H, t, J = 4.9Hz), 6.91 (1H, d,
J = 8.8Hz), 6.96 (2H, d, J = 8.4Hz), 7.27–7.43 (7H,
m), 7.85 (2H, d, J = 8.8Hz), 8.04 (1H, s), 8.70 (1H, br
To a solution of 6r (300mg, 0.45mmol) in CH2Cl2
(10mL) was added a solution of mCPBA (70%,
221mg, 0.90mmol) at ꢀ78ꢁC. The mixture was stirred
at room temperature for 1h at ꢀ15ꢁC. To the mixture
was added dimethyl sulfide (0.1mL) and stirred at
room temperature for 0.5h. The mixture was extracted
with CH2Cl2. The organic layer was washed with
aqueous NaHCO3 and brine, dried over MgSO4, and

384
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
concentrated in vacuo. The residue was purified by
column chromatography on NH silica gel (hexane/
EtOAc = 1:1) and recrystallization from EtOAc to
give 122mg (39%) of 25 as yellow crystals, mp 101–
8.28. 1H NMR data of the chiral compounds were iden-
tical with those of 4s.
5.96. (R)-(+)-7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-
N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}-
phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide
((R)-4v) and (S)-(ꢀ)-7-{[4-(2-butoxy)ethoxy]phenyl}-1-
isobutyl-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]-
sulfinyl}phenyl)-2,3-dihydro-1H-1-benzazepine-4-carbox-
amide ((S)-4v)
1
103ꢁC. H NMR (CDCl3) d 0.85–0.99 (12H, m), 1.30–
1.50 (2H, m), 1.55–1.85 (4H, m), 1.95–2.15 (1H, m),
2.90–3.00 (2H, m), 3.20 (2H, d, J = 7.0Hz), 3.35–3.45
(2H, m), 3.56 (2H, t, J = 7.0Hz), 3.81 (2H, t,
J = 4.4Hz), 3.95 (2H, t, J = 7.8Hz), 4.16 (2H, t,
J = 4.4Hz), 4.32 (2H, s), 6.53 (1H, d, J = 0.8Hz), 6.92
(1H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.8Hz), 7.39–7.50
(6H, m), 7.60 (2H, d, J = 8.8Hz), 7.77 (2H, d,
J = 8.8Hz), 8.05 (1H, s). Anal. Calcd for C40H50N4O5SÆ
C4H8O2 (EtOAc): C, 67.15; H, 7.43; N, 7.12. Found:
C,67.24; H,7.21; N,7.21.
The racemate 4v (387mg) was resolved with HPLC to
afford optically pure (R)-4v (170mg) and (S)-4v
(171mg) [column, CHIRAL PAK AD (50mm ·
500mm), column temperature, 40ꢁC; mobile phase,
EtOH; flow rate 60mL/min; UV detection, 254nm,
amount injected 387mg]. Compound (R)-4v; yellow
amorphous, [a]D +146.6 (C 0.498%, EtOH). Anal. Calcd
for C39H49N5O4S: C, 68.49; H, 7.22; N, 10.24. Found:
C, 68.68; H, 7.36; N, 10.10. Compound (S)-4v; yellow
amorphous, [a]D ꢀ147.0 (C 0.506%, EtOH). Anal. Calcd
for C39H49N5O4SÆ0.5H2O: C, 67.60; H, 7.27; N, 10.11.
5.94. (R)-(+)-7-{[4-(2-Butoxy)ethoxy]phenyl}-1-isobutyl-
N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phen-
yl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide ((R)-
4r) and (S)-(ꢀ)-7-{[4-(2-butoxy)ethoxy]phenyl}-1-isobu-
tyl-N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}-
phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide
((S)-4r)
1
Found: C, 67.42; H, 7.34; N, 10.14. H NMR data of
the chiral compounds were identical with those of 4v.
The racemate 4r (1.33g) was resolved with HPLC to
afford optically pure (R)-4r (0.58g) and (S)-4r (0.60g)
[column, CHIRAL PAK AD (50mm · 500mm), col-
umn temperature, room temperature; mobile phase,
EtOH ! 2-propanol; flow rate 70mL/min (EtOH) !
80mL/min (2-propanol); UV detection, 254nm, amount
injected 400mg]. Compound (R)-4r; yellow amorphous,
[a]D +131.8 (C 0.498%, EtOH). Anal. Calcd for
C40H50N4O4SÆ0.5H2O: C, 69.43; H, 7.43; N, 8.10.
Found: C, 69.50; H, 7.54; N, 8.02. Compound (S)-4r;
yellow amorphous, [a]D ꢀ126.9 (C 0.497%, EtOH).
Anal. Calcd for C40H50N4O4SÆ0.5H2O: C, 69.43; H,
7.43; N, 8.10. Found: C, 69.53; H, 7.62; N, 8.04. Crystal-
lization from EtOAc gave (S)-4r as yellow crystals.
Anal. Calcd for C40H50N4O4SÆC4H8O2 (EtOAc): C,
68.54; H, 7.58; N, 7.27. Found: C, 68.35; H, 7.63; N,
7.35. 1H NMR data of the chiral compounds were iden-
tical with those of 4r.
5.97. (R)-(+)-7-{[4-(2-Butoxy)ethoxy]phenyl}-1-propyl-
N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}-
phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide
((R)-4w) and (S)-(ꢀ)-7-{[4-(2-butoxy)ethoxy]phenyl}-1-
propyl-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sul-
finyl}phenyl)-2,3-dihydro-1H-1-benzazepine-4-carbox-
amide ((S)-4w)
The racemate 4w (376mg) was resolved with HPLC to
afford optically pure (R)-4w (148mg) and (S)-4w
(164m) [column, CHIRAL PAK AD (50mm · 500mm),
column temperature, 25ꢁC; mobile phase, hexane/
EtOH = 20:80; flow rate 80mL/min ! 100mL/min;
UV detection, 254nm, amount injected 188mg]. Com-
pound (R)-4w; yellow crystals (EtOAc), mp 133–
135ꢁC, [a]D +141.8 (C 0.495%, EtOH). Anal. Calcd
for C38H47N5O4S: C, 68.13; H, 7.07; N, 10.45. Found:
C, 67.96; H, 6.92; N, 10.44. Compound (S)-4w; yellow
crystals (EtOAc), mp 133–135ꢁC, [a]D ꢀ140.8 (C
0.504%, EtOH). Anal. Calcd for C38H47N5O4S: C,
68.13; H, 7.07; N, 10.45. Found: C, 67.89; H, 7.16; N,
10.41. 1H NMR data of the chiral compounds were
identical with those of 4w.
5.95. (R)-(+)-7-{[4-(2-Butoxy)ethoxy]phenyl}-1-propyl-
N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phen-
yl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide ((R)-
4s) and (S)-(ꢀ)-7-{[4-(2-butoxy)ethoxy]phenyl}-1-propyl-
N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phen-
yl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide
((S)-4s)
5.98. Asymmetric oxidation of 6w
The racemate 4s (1.30g) was resolved with HPLC to
afford optically pure (R)-4s (0.60g) and (S)-4s (0.63g)
[column, CHIRAL PAK AD (50mm · 500mm), col-
umn temperature, room temperature; mobile phase,
EtOH ! 2-propanol; flow rate 70mL/min; UV detec-
tion, 254nm, amount injected 490mg]. Compound (R)-
4s; yellow amorphous, [a]D +136.0 (C 0.495%, EtOH).
Anal. Calcd for C39H48N4O4SÆ0.5H2O: C, 69.10; H,
7.29; N, 8.26. Found: C, 69.28; H, 7.51; N, 8.24. Com-
pound (S)-4s; yellow amorphous, [a]D ꢀ138.2 (C
0.499%, EtOH). Anal. Calcd for C39H48N4O4SÆ0.5H2O:
C, 69.10; H, 7.29; N, 8.26. Found: C, 69.16; H, 7.49; N,
To a (S)-(ꢀ)-1,10-bi-2-naphthol (0.88g, 3.07mmol) in
toluene (70mL) was added Ti(Oi-Pr)4 (0.454mL,
1.54mmol) and water (0.5mL, 30.5mmol) at room tem-
perature. After being stirred at room temperature for
1h, 6w (10.0g, 15.3mmol) and 80% cumenehydroperox-
ide (4.2mL, 22.7mmol) were added to the mixture. The
mixture was stirred at room temperature for 30h. To the
reaction mixture was added aq Na2S2O3 and the mixture
was extracted with EtOAc. The organic layer was
washed with aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated in vacuo. The residue was

M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
385
purified by column chromatography on NH silica gel
(EtOAc ! EtOAc/EtOH = 19:1) to give 8.69g (85%)
of (S)-4w as yellow crystals. Recrystallization from
EtOAc gave (S)-4w as yellow crystals, [a]D ꢀ189.2 (C
0.472%, CHCl3), mp 133–135ꢁC. Anal. Calcd for
C38H47N5O4S: C, 68.13; H, 7.07; N, 10.45. Found: C,
67.87; H, 7.10; N, 10.44. The enantiomeric excess of
(S)-4w was determined by HPLC as 96.0% ee [column,
CHIRALPAK AD (4mm · 25mm), column tempera-
ture, room temperature; mobile phase, hexane/2-prop-
anol = 6:4; flow rate, 0.5mL/min; UV detection, 254nm].
reactions were performed at room temperature for
40min. The binding reaction was terminated by washing
out the free ligand with cold phosphate-buffered saline,
and the cell-associated radioactivity was counted using
a TopCount scintillation counter (Packard).
5.102. HIV-1 envelope-mediated membrane fusion assay
COS-7 cells were maintained in Dulbeccoꢀs modified
Eagle medium (D-MEM) supplemented with 10% fetal
bovine serum (FBS), 100U/mL penicillin G, and 100lg/
mL streptomycin. MOLT-4/CCR5/Luc+ cells, a lympho-
blastoid cell line that expresses human CCR5 and that
has an integrated copy of the HIV-1 long terminal
repeat-driven luciferase reporter gene, were maintained
in RPMI 1640 medium supplemented with 10% FBS,
100U/mL penicillin G, 100lg/mL streptomycin, and
500lg/mL geneticin. Tat, Rev, and envelope cDNA were
amplified from total RNA of R5 HIV-1 (JR-FL)-infected
cells and cloned into an expression vector for mamma-
lian cells. Expression vectors encoding Tat, Rev, and
envelope were mixed at a ratio of 5:1:3 and co-trans-
fected into COS-7 cells using Lipofectamine 2000 (Invi-
trogen). After a 2-day incubation, transfected COS-7
cells and MOLT-4/CCR5/Luc+ cells were seeded in a
96-well plate at 104 cells in each well, and various concen-
trations of the test compounds were added to the wells.
The cell suspension was incubated at 37ꢁC. The mixture
of D-MEM and RPMI 1640 medium supplemented with
10% FBS, 100U/mL penicillin G, and 100lg/mL strepto-
mycin was used as medium for membrane fusion. After
an overnight incubation, Luc-Screen (Tropix) was added
to each well, and the mixtures were incubated at room
temperature for 10min. The luciferase activity was mea-
sured with a luminometer (Wallac 1420 ARVOsx).
5.99. Asymmetric oxidation of 6r
To a (S)-(ꢀ)-1,10-bi-2-naphthol (60mg, 1.05mmol) in
toluene (5.0mL) was added Ti(Oi-Pr)4 (31lL,
0.105mmol) and water (38lL, 2.1mmol) at room tem-
perature. After being stirred at room temperature for
1h, 6r (0.70g, 1.05mmol) and 80% cumenehydroperox-
ide (0.39mL, 2.1mmol) were added to the mixture. After
being stirred at room temperature for 30h, 80% cumene-
hydroperoxide (0.20mL, 1.08mmol) was added to the
reaction mixture. The mixture was stirred at room tem-
perature for 5days. To the reaction mixture was added
aq Na2S2O3 and the mixture was extracted with EtOAc.
The organic layer was washed with aqueous NaHCO3
and brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on
NH silica gel (EtOAc ! EtOAc/EtOH = 19:1) to give
320mg (45%) of (S)-4r as yellow amorphous, [a]D
ꢀ115.0 (C 0.492%, EtOH). Anal. Calcd for C40H50N4-
O4SÆ0.5H2O: C, 69.43; H, 7.43; N, 8.10. Found: C,
69.58; H, 7.40; N, 8.14. The enantiomeric excess of (S)-
4r was determined by HPLC as 85.0% ee [column,
CHIRALPAK AD (4mm · 25mm), column tempera-
ture, room temperature; mobile phase, hexane/2-propa-
nol = 1:1; flow rate, 0.7mL/min; UV detection, 254nm].
5.103. Preliminary pharmacokinetic analysis
5.100. X-ray crystallographic analysis
Compounds (10mg/kg) suspended in 0.5% aqueous
methylcellulose solution were orally administered to
SD (IGS) rats (male, eight weeks old). Blood samples
were collected at different time points (pre-dose, 15,
30min, 1, 2, 4, 8, 24h) from the tail vein. The blood
was centrifuged to obtain the plasma fraction. Acetonit-
rile (200ll) was added to each plasma sample (100L),
and the precipitated plasma proteins were removed by
centrifugation. The compound concentrations in the
supernatant were measured by HPLC but the column
used could not separate optically active compounds (col-
umn, Inertsil ODS-3, 4.6 · 150mm, 5lm particle size,
GL Sciences; column temperature, 40ꢁC; mobile phase,
acetonitrile–0.01mol/L ammonium acetate ((S)-4r:
70:30, (S)-4s: 68:32, (S)-4v: 65:35, (S)-4w: 67:33, v/v);
flow rate, 1.0mL/min; UV detection, 280nm).
Yellow prismatic crystals of (S)-4r as a solvate of ethyl
acetate were obtained from ethyl acetate solution. A dif-
fractometer, Rigaku RAXIS-RAPID Imaging Plate,
was used with graphite monochromated Mo-Ka radia-
tion at ꢀ173.0ꢁC to obtain the following crystal
˚
data: a = 40.699(9), b = 11.154(2), c = 19.379(3)A,
3
˚
b = 106.08(2)ꢁ, V = 8453(11)A , monoclinic, C2(#5),
Dcalcd = 1.212g/cm3, Z = 8. Of the 18133 collected
reflections, 15377 were unique (Rint = 0.135). Final R-
values were R1 = 0.070 and wR2(F2; all data) = 0.176.
The absolute configuration was determinated using the
Flack parameter30 of ꢀ0.02(6). Further details of
the X-ray structure data are available on request from
the Cambridge Crystallographic Data Centre (deposi-
tion number CCDC 246694).
5.101. Receptor binding assays
Acknowledgements
CHO-K1 and CCR5-expressing CHO cells13 were incu-
bated with various concentrations of test compound in
the binding buffer (Hamꢀs F-12 medium containing
20mM HEPES and 0.5% bovine serum albumin,
pH7.2) containing 200pM [125I]RANTES. Binding
We thank Mr. Kenichi Kuroshima for the CCR5 bind-
ing assay; Mr. Katsunori Takashima, Dr. Hiroshi
Miyake, and Ms. Shikiko Shiki for the membrane
fusion assay; Mr. Mitsutaka Tanaka for optical resolu-
tion by HPLC; Mr. Akira Fujishima and Ms. Keiko

386
M. Seto et al. / Bioorg. Med. Chem. 13 (2005) 363–386
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Atsutoshi Furuta for pharmacokinetic analysis.
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