Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety

Article abstract of DOI:10.1021/jm0509703

Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide compound 4, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus. We designed, synthesized, and evaluated the biological activities

Full text of DOI:10.1021/jm0509703

J. Med. Chem. 2006, 49, 2037-2048
2037
Highly Potent and Orally Active CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and
Biological Activities of 1-Benzazocine Derivatives Containing a Sulfoxide Moiety
Masaki Seto,*,† Katsuji Aikawa,† Naoki Miyamoto,† Yoshio Aramaki,† Naoyuki Kanzaki,† Katsunori Takashima,† Yoji Kuze,†
Yuji Iizawa,† Masanori Baba,‡ and Mitsuru Shiraishi†
Pharmaceutical Research DiVision, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan,
and DiVision 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 September 29, 2005
Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide
compound 4, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus. We designed,
synthesized, and evaluated the biological activities of ring-expanded [6,8]-, [6,9]-, and [6,10]-fused compounds
containing S-sulfoxide moieties, which led to the discovery of 1-benzazocine and 1-benzazonine compounds
that exhibited potent inhibitory activities (equivalent to compound 4) in a binding assay. In addition,
1-benzazocine compounds possessing the S-sulfoxide moiety ((S)-(-)-5a,b,d,e) showed greater potency
than compound 4 in a fusion assay. From further investigation in a multi-round infection assay, it was
found that 1-isobutyl-1-benzazocine compound (S)-(-)-5b, containing the S-{[(1-propyl-1H-imidazol)-5-
yl]methyl}sulfinyl group, showed the most potent anti-HIV-1 activity (IC90 ) 0.81 nM, in MOLT4/CCR5
cells). Compound (S)-(-)-5b (TAK-652) also inhibited the replication of six macrophage-tropic (CCR5-
using or R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) (mean IC90 ) 0.25
nM). It was also absorbed after oral administration in rats, dogs, and monkeys and was thus selected as a
clinical candidate. The synthesis and biological activity of the 1-benzazocine compound (S)-(-)-5b and its
related derivatives are described.
Introduction
host cells.7-11 Furthermore, it has been found that individuals
with a 32-base-pair deletion in the CCR5 coding region
(CCR5∆32-homozygotes) are highly resistant to R5 HIV-1
infection and that R5 HIV-1 infected CCR5∆32-heterozygotes
have been identified with a delay in disease progression.12-16
In addition, these individuals do not appear to have any
significant health problems. From these observations, CCR5
antagonists have attracted a great deal of attention as novel anti-
HIV-1 candidates, and many pharmaceutical companies have
started to search for CCR5 antagonists.17,18 We discovered the
first nonpeptide, small-molecule CCR5 antagonist 1 as an anti-
HIV-1 candidate for injection in 1999 (Figure 1).19,20 In the area
of orally bioavailable CCR5 antagonists, it has been reported
that Schering-Plough’s SCH-C21 and SCH-D,22 Pfizer’s UK-
427857,23 and Ono/Glaxo-SmithKline’s ONO4128/AK602/
GW87314024 were selected as clinical candidates; SCH-D and
UK-427857 are now in clinical trials. In addition, our colleagues
at Takeda have discovered an orally bioavailable clinical
candidate, TAK-220.25
Human immunodeficiency virus type 1 (HIV-1) infectious
disease remains a serious health problem around the world, and
efforts to develop anti-HIV-1 agents are being made by many
pharmaceutical companies. The discovery of HIV-1 protease
inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors,
and nonnucleoside transcriptase inhibitors has had a great impact
on the treatment of HIV-1 infection. Combination chemotherapy
using these three types of anti-HIV-1 agents, called HAART
(highly active antiretroviral therapy), has led to the achievement
of long-term, virtually complete suppression of viral replication
in HIV-1 infected individuals and reduction of mortality.1
Furthermore, a new anti-HIV-1 drug called enfuvirtide, a
member of the entry inhibitor class of drugs,2 was approved by
the FDA in March 2003. However, difficult dosing regimens,
the emergence of drug resistant HIV-1,3 and long-term adverse
effects4 are reported as significant problems with HAART. In
addition, it has been found that viral eradication is unfeasible
even with combination chemotherapy,5 and this has led to the
need for novel anti-HIV-1 agents with new mechanisms of
action.
Compound 1 was found to exhibit poor oral absorption due
to its polar quaternary ammonium moiety. To develop orally
active CCR5 antagonists, we previously reported chemical
modification of [6,7]-fused 1-benzoxepine, 1-benzthiepine 1,1-
dioxide, or 1-benzazepine compounds containing tertiary amine,
pyridine N-oxide, or sulfoxide moieties as polar substituents in
place of the quaternary ammonium moiety, which led to the
discovery of potent, orally bioavailable tertiary amine (2),
pyridine N-oxide (3), and S-sulfoxide (4) compounds (Figure
1).26-29 Through optimization of the tertiary amine compounds,
it was found that 1-benzazepine compounds containing bulky
alkyl groups at the 1-position, such as propyl, isobutyl, and (1-
methyl-1H-pyrazol-4-yl)methyl groups, showed potent CCR5
antagonism and potent inhibition of HIV-1 envelope (Env)-
mediated membrane fusion.27 In addition, we found that the
CC chemokine receptor 5 (CCR5) belongs to the super family
of seven-transmembrane G-protein coupled receptors (GPCRs),
and its natural ligands are known to be RANTES (regulated on
activation normal T-cell expressed and secreted) and macroph-
age inflammatory proteins (MIP)-1R and MIP-1â. First, it was
reported that natural ligands for CCR5 act on blocking R5 HIV-1
infection,6 and then it was discovered that CCR5 is a coreceptor
for entry of macrophage-tropic (CCR5-using or R5) HIV-1 into
* Corresponding author. Tel: +81-6-6300-6651. Fax: +81-6-6300-6306.
E-mail: Seto_Masaki@takeda.co.jp.
† Takeda Pharmaceutical Company Limited.
‡ Kagoshima University.
10.1021/jm0509703 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/01/2006

2038 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6
Seto et al.
Figure 1. Structure of CCR5 antagonists 1-4 and design of new compounds 5 containing a sulfoxide moiety.
Scheme 1. Synthesis of Cyclization Precursors 11a
a Reagents: (a) 4-methoxybenzyl chloride, KOH, (n-Bu)4NBr, tolune; (b) 4 N NaOH and then concentrated HCl; (c) 5-bromo-2-fluorobenzaldehyde,
Na2CO3, DMSO, water; (d) 10% Pd-C, 4-methoxybenzaldehyde, 1 N NaOH, MeOH, H2; and (e) MeI, K2CO3, DMF.
incorporation of a 4-[2-(butoxy)ethoxy] group on the 7-phenyl
group of the [6,7]-fused nucleus led to both enhanced binding
affinity and improved pharmacokinetic properties in rats.27
Further investigation of the 1-benzazepine compounds contain-
ing both the sulfoxide moiety and the heteroaryl groups led to
the discovery that the presence of a methylene group between
the sulfoxide moiety and the heteroaryl group was necessary
for the appearance of potent binding affinity and that S-sulfoxide
compounds were more active than the corresponding R-isomers
in the binding and fusion assays.29 Compounds 2-4 exhibited
potent inhibition in the fusion assay, comparable to compound
1 for injection; however, the plasma level of the tertiary amine
compound 2 after oral administration to rats was lower than
those of the pyridine N-oxide (3) and sulfoxide (4) com-
pounds.27-29 On the basis of these results, ease of synthesis,
and structural novelty, we selected the sulfoxide moiety as the
key polar substituent in our search for orally active and potent
CCR5 antagonists as anti-HIV-1 agents. In our first paper
concerning quaternary ammonium compounds,20 we reported
that replacement of the [6,6]-fused ring with a [6,7]-fused ring
increased the activity about 10-fold, suggesting sensitive SAR
effects in this region of the molecule. Considering these results,
we investigated chemical modification of the sulfoxide com-
pounds, focusing primarily on replacement of the 1-benzazepine
nucleus with a [6,8]-, [6,9]-, or [6,10]-fused ring. This led to
the discovery of the remarkably potent and orally bioavailable
CCR5 antagonist (S)-(-)-5b as an anti-HIV-1 agent. In this
paper, we describe the design, synthesis, and biological evalu-
ation of sulfoxide compounds containing [6,8]- to [6,10]-fused
ring nuclei.
Chemistry
The synthetic route to the cyclization precursors 11a-c is
illustrated in Scheme 1. Alkylation of piperidin-2-one 6 with
4-methoxybenzyl chloride gave 1-(4-methoxybenzyl) piperidin-
2-one (7). Conversion of piperidin-2-one 7 into carboxylic acid
10a was carried out in a one-pot reaction. Thus, hydrolysis of
7 with 4 N aqueous NaOH under reflux and subsequent reaction
of the resulting amino acid 8a with 5-bromo-2-fluorobenzal-
dehyde gave carboxylic acid 10a. Intermediate 11a was
synthesized by esterification of the carboxylic acid 10a using
iodomethane and potassium carbonate (K2CO3). Other precur-
sors (11b,c) were prepared by an alternative method. Reaction
of the amino acids 8b,c, prepared by the reductive amination

CCR5 Antagonists as Ani-HIV-1 Agents
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2039
Scheme 2. Synthesis of Carboxylic Acids 16a
a Reagents: (a) 28% NaOMe in MeOH, CO(OMe)2; (b) trifluoroacetic acid, toluene; (c) propionaldehyde or isobutyraldehyde, NaBH(OAc)3,
1,2-dichloroethane; (d) 4-[2-(butoxy)ethoxy]phenylboronic acid, K2CO3, Pd(PPh3)4, toluene, EtOH, water; and (e) 1 N NaOH, THF, MeOH.
Scheme 3. Synthesis of Carboxylic Acid 16ga
a Reagents: (a) 4-[2-(butoxy)ethoxy]phenylboronic acid, K2CO3, Pd(PPh3)4, toluene, EtOH, water; (b) 1-methylpyrazol-4-carbaldehyde, NaBH(OAc)3,
1,2-dichloroethane; and (c) 1 N NaOH, THF, MeOH.
of 9a,b with 4-methoxybenzaldehyde and Pd-C/H2, with 5-bromo-
2-fluorobenzaldehyde and subsequent esterification, afforded
compounds 11b,c.
The synthetic route used for the S-sulfoxide compounds (S)-
(-)-5a,b,e-i is shown in Scheme 4. The di-p-toluoyl-D-tartaric
acid (D-PTTA) salt monohydrate of the aniline (S)-18 (com-
pound 19)31 was converted into the free base (S)-18 and
condensed with carboxylic acids 16a-g via acid chloride
formation to give the target S-sulfoxide compounds (S)-(-)-
5a,e-i and the free base of (S)-(-)-5b. Compound (S)-(-)-5b
was obtained as the monomethanesulfonate salt.
The synthetic route to the target sulfoxide triazole compounds
(S)-(-)-5c,d is illustrated in Scheme 5. Conversion of carboxylic
acids 16a,b into their acid chlorides and coupling with S-(4-
aminophenyl)-O-benzylthiocarbonate29 was followed by removal
of the S-carboxybenzyl (Cbz) group and subsequent alkylation
with 3-(chloromethyl)-4-propyl-4H-1,2,4-triazole to afford the
sulfide compounds 20a,b. The target S-sulfoxide compounds
(S)-(-)-5c,d were prepared by m-chloroperbenzoic acid (mCP-
BA) oxidation of 20a,b and subsequent optical resolution
utilizing chiral high-performance liquid chromatography (HPLC).
The key intermediates, carboxylic acids 16a-f with [6,8]-,
[6,9]-, or [6,10]-fused rings, were synthesized according to
Scheme 2. Synthesis of the [6,8]-fused 1-benzazocine compound
12a was accomplished by an intramolecular Claisen-Schmidt
type cyclization of compound 11a using sodium methoxide
(NaOMe) in dimethyl carbonate.30 Removal of the 4-methoxy-
benzyl group using trifluoroacetic acid (TFA) gave the 1-un-
substituted 1-benzazocine 13a. Reductive amination of 13a gave
the 1-alkyl-1-benzazocines 14a,b. The key 1-benzazocine-5-
carboxylic acids 16a,b were prepared by Suzuki coupling of
the 8-bromides 14a,b and subsequent alkaline hydrolysis of the
resulting 15a,b. The other key carboxylic acids 16c-f, with
[6,9]- or [6,10]-fused rings, were obtained by synthetic methods
similar to those described for the 1-benzazocine-5-carboxylic
acid 16a.
The 1-benzazocine-5-carboxylic acid 16g with a 1-[(1-methyl-
1H-pyrazol-4-yl)methyl] group was prepared according to
Scheme 3. The Suzuki coupling reaction of 1-unsubstituted
1-benzazocine 13a and subsequent reductive amination of the
resulting compound 17 gave 1-[(1-methyl-1H-pyrazol-4-yl)-
methyl]-1-benzazocine 15g. Alkaline hydrolysis of the ester 15g
gave the key carboxylic acid 16g.
Biological Results and Discussion
In a previous paper on 1-benzazepine compounds,29 we
reported that S-sulfoxide compounds were more active than the
corresponding R-sulfoxide, sulfide, or sulfone compounds and
that the presence of a methylene group between the sulfoxide
moiety and the heteroaryl group was necessary to exhibit potent

2040 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6
Scheme 4. Synthesis of S-Sulfoxides (S)-(-)-5a
Seto et al.
a Reagents: (a) 1 N HCl and then 25% aqueous K2CO3; (b) (1) SOCl2, cat. DMF, THF and (2) (S)-18, Et3N THF.
Scheme 5. Synthesis of S-Sulfoxides (S)-(-)-5c,da
a Reagents: (a) (1) SOCl2, cat. DMF, THF, (2) S-(4-aminophenyl)-O-benzylthiocarbonate, Et3N, THF and then 1 N NaOH, 3-(chloromethyl)-4-propyl-
4H-1,2,4-triazole hydrochloride, MeOH; (b) mCPBA, CH2Cl2; and (c) optical resolution by HPLC.
binding affinity. In addition, we found that compounds with
1-propylimidazol-5-yl or 4-propyl-4H-1,2,4-triazol-3-yl groups
exhibited potent CCR5 antagonistic activity. Representative
1-benzazepine compound 4 showed significantly potent CCR5
antagonistic activity. It inhibited R5 HIV-1 replication with an
IC50 value of 5.3 nM in a multi-round infection assay, but its
IC90 value was 860 nM, as shown in Table 2. Previously, in
the search for compound 1, we found that the fused ring size
and shape affected CCR5 activity.20 Therefore, to discover
CCR5 antagonists with greater anti-HIV-1 potency, we inves-
tigated the inhibitory effects of fused ring compounds 5
containing the (1-propylimidazol-5-yl)- or (4-propyl-1,2,4-
triazol-3-yl)methylsulfinyl group.
First of all, the compounds prepared were evaluated for their
inhibitory effects on chemokine binding to CCR5-expressing
CHO cells. Binding reactions were performed in the presence
of [125I]-RANTES at various concentrations of test compounds;
the results are summarized in Table 1 as IC50 values. The [6,8]-
fused 1-benzazocine compounds were first investigated. The
1-isobutyl-1-benzazocine (S)-(-)-5b, containing the 1-propyl-
imidazol-5-yl group, was as highly active as the corresponding
1-isobutyl-1-benzazepine 4, and replacement of the 1-isobutyl
group of (S)-(-)-5b with the 1-propyl ((S)-(-)-5a) or 1-[(1-
methyl-1H-pyrazol-4-yl)methyl] group ((S)-(-)-5e) also retained
potent activity. Compounds (S)-(-)-5c,d, containing the 4-pro-
pyl-1,2,4-triazol-3-yl group, also exhibited high activity, com-
parable to the 1-propylimidazol-5-yl compounds (S)-(-)-5a,b.
These results suggested that the 1-benzazocine ring was a
promising nucleus for the synthesis of compounds with high
binding affinity for CCR5. We next investigated ring expansion
of the bicyclic ring into [6,9]- and [6,10]-fused ring compounds.
Whereas the [6,9]-fused benzazonines (S)-(-)-5f,g exhibited
potent inhibition, comparable to 1-benzazepine 4, the [6,10]-
fused 1-benzazecines (S)-(-)-5h,i showed reduced activity. On
the basis of these results, the optimal scaffold size for receptor
binding is believed to be compounds containing [6,7]- to [6,9]-
fused rings.
Second, compounds with potent binding affinity were evalu-
ated for inhibition of HIV-1 Env-mediated membrane fusion.
The membrane fusion assay was carried out using R5 HIV-1
(JR-FL strain) Env-expressing COS-7 cells and MOLT-4/CCR5
cells. The results are summarized in Table 1 as IC50 values.
The 1-benzazocine compounds (S)-(-)-5a-d showed potent
inhibitory activity. In particular, compounds (S)-(-)-5a,b,d
exhibited higher potency than the 1-benzazepine compound 4
and quaternary ammonium compound 1 in the fusion assay,
while maintaining a similar level of potency in the binding assay.
The 1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-benzazocine (S)-
(-)-5e possessed the same level of high activity as the
corresponding 1-isobutyl compound (S)-(-)-5b. Enlarging the
ring size from a [6,8]-ring ((S)-(-)-5b) to a [6,9]-ring ((S)-
(-)-5g) retained potent activity, although (S)-(-)-5g showed a

CCR5 Antagonists as Ani-HIV-1 Agents
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2041
Table 1. Inhibitory Effects of Compounds 5 on Chemokine Binding to CCR5-Expressing CHO Cells and on HIV-1 Env-Mediated Membrane Fusion
CCR5
fusion
compd.
n
R
X
IC50a (nM)
IC50b (nM)
formula
anal.c
(S)-(-)-5a
(S)-(-)-5b
(S)-(-)-5c
(S)-(-)-5d
(S)-(-)-5e
1
1
1
1
1
Pr
i-Bu
Pr
CH
CH
N
N
CH
1.7
3.1
2.2
2.4
1.7
0.24
0.10
0.95
0.19
0.21
C40H50N4O4S‚0.25H2O
C41H52N4O4S‚CH3SO3H
C39H49N5O4S‚H2O
C40H51N5O4S‚0.5H2O
C42H50N6O4S‚0.5H2O
CHN
CHN
CHN
CHN
CHN
i-Bu
(S)-(-)-5f
(S)-(-)-5g
(S)-(-)-5h
(S)-(-)-5i
1
2
2
3
3
Pr
i-Bu
Pr
CH
CH
CH
CH
4.7
6.8
25
67
1.4
1.9
C41H52N4O4S
CHN
CHN
CHN
CHN
0.48
C42H54N4O4S‚0.25H2O
C42H54N4O4S‚0.25H2O
C43H56N4O4S‚0.25H2O
i-Bu
1.4
1.0
4
0
i-Bu
CH
a The concentration required to inhibit the binding of [125I]-RANTES to CCR5-expressing CHO cells by 50%. Data for new compounds were compared
to positive control compound 4 (IC50 for 4: 1.4-2.6 nM, a result of four experiments). b The concentration required to inhibit the membrane fusion between
HIV-1 Env-expressing COS-7 cells and MOLT-4/CCR5 cells by 50%. Data represent mean IC50 values from triplicate measurements. c All compounds gave
satisfactory elemental analysis ((0.4%) for C, H, and N.
Table 2. Anti-HIV-1 Activity of Compounds 4 and 5 in MOLT4/CCR5
Cells
Table 3. Inhibitory Effects of (S)-(-)-5b on Replication of HIV-1
HIV-1 strain
IC50a (nM)
IC90a (nM)
KK
0.043
0.070
0.049
0.087
0.089
0.024
0.061
0.19
0.31
0.16
0.36
0.32
0.13
0.25
CTV
HKW
HNK
HTN
HHA
mean
a The concentration required to inhibit the viral replication in PBMCs
by 50 or 90%. Assays were performed in triplicate and repeated 3 or 4
times using PBMCs obtained from different donors. Data represent mean
values.
CCR5 fusion Anti-HIV
a
b
c
c
IC50
IC50
IC50
IC90
compd.
n
R
X
(nM) (nM)
(nM)
(nM)
investigated for their inhibitory effects on R5 HIV-1 (Ba-L
strain) replication in MOLT-4/CCR5 cells. The results are
illustrated in Table 2. The 1-isobutyl-1-benzazocine compound
(S)-(-)-5b containing the imidazol-5-yl moiety strongly inhib-
ited R5 HIV-1 replication with IC50 and IC90 values of 0.20
and 0.81 nM, respectively, and its activity was significantly more
potent than 1-benzazepine compound 4. IC50 values for the
corresponding 1-propyl ((S)-(-)-5a) and 1-[(1-methyl-1H-
pyrazol-4-yl)methyl] ((S)-(-)-5e) compounds were 1.4 and 2.3
nM, respectively, and these compounds were found to be less
active than the 1-isobutyl derivative (S)-(-)-5b. The [6,9]-fused
1-isobutyl-1-benzazonine compound (S)-(-)-5g with an imi-
dazole moiety was also less active than the 1-isobutyl-1-
benzazocine (S)-(-)-5b. Triazole compound (S)-(-)-5d exhib-
ited potent inhibition with an IC50 value of <1.6 nM, but its
IC90 value (IC90 ) 10 nM) was larger than that of the
corresponding imidazole compound (S)-(-)-5b. These results
suggested that the 1-benzazocine ring is optimal and that both
the 1-isobutyl group and the 1-propyl-1H-imidazol-5-yl group
are essential for highly potent anti-HIV-1 activity in the multi-
round infection assay. From these results, we selected compound
(S)-(-)-5b as a candidate for further biological evaluation.
Further biological evaluation of compound (S)-(-)-5b is
summarized in Table 3. Compound (S)-(-)-5b was found to
greatly inhibit the replication of six R5 HIV-1 clinical isolates
(KK, CTV, HKW, HNK, HTN, HHA) in human peripheral
(S)-(-)-5a
(S)-(-)-5b
(S)-(-)-5d
(S)-(-)-5e
1
1
1
1
Pr
i-Bu
i-Bu
CH
CH
N
1.7
3.1
2.4
1.7
0.24
0.10
0.19
0.21
1.4
0.20
<1.6
2.3
72%d
0.81
10
CH
11
(S)-(-)-5g
4
2
0
i-Bu
i-Bu
CH
CH
6.8
1.9
0.48
1.0
2.1
5.3
19
860
a ,bSee corresponding footnotes in Table 1. c The concentration required
to inhibit the replication of R5 HIV-1 (Ba-L) in MOLT-4/CCR5 cells by
50 or 90%. IC50 or IC90 values shown are the means of duplicate
measurements. d Percent inhibition at 5 nM.
slightly lower IC50 value of 0.48 nM. The previously mentioned
results suggested that the [6,8]-fused 1-benzazocine ring was
the optimal nucleus for obtaining potent fusion inhibition. In
general, compounds (S)-(-)-5a,b,d,e,g show greater potency
in the fusion assay than in the binding assay. It has been reported
that the binding site for â-chemokines on CCR5 does not
completely overlap with that for either recombinant gp120 or
virions.32 While we do not yet have detailed structural informa-
tion on the binding sites for these compounds, it appears likely
that they may be binding in a region that provides more efficient
inhibition of gp120 binding than of chemokine binding. This
would lead to the differences in potency observed for (S)-(-
)-5a,b,d,e,g in the fusion and binding assays.
In addition, compounds (S)-(-)-5a,b,d,e,g with high potency
in the inhibition of HIV-1 Env-mediated membrane fusion were

2042 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6
Seto et al.
Table 4. Inhibitory Effects of (S)-(-)-5b on Ligand Binding to
or [6,10]-fused rings led to the discovery that the [6,8]-fused
1-benzazocine and [6,9]-fused 1-benzazonine compounds ex-
hibited potent RANTES binding inhibition, equivalent to the
[6,7]-fused 1-benzazepine 4, while providing superior potency
for the [6,8]-fused 1-benzazocine compounds in an HIV-1 Env-
mediated membrane fusion assay. Furthermore, the 1-isobutyl-
1-benzazocine (S)-(-)-5b containing the S-[(1-propyl-1H-
imidazol-5yl)methyl]sulfinyl group was found to exhibit the
most potent inhibition of R5 HIV-1 replication in MOLT4/CCR5
cells. Compound (S)-(-)-5b also greatly inhibited replication
of six R5 HIV-1 clinical isolates in PBMCs, and its mean IC90
value was found to be 0.25 nM. In addition, compound (S)-
(-)-5b was absorbed after oral administration in rats, dogs, and
monkeys despite its relatively high molecular weight. From these
results, compound (S)-(-)-5b (TAK-652) is thought to be a
promising anti-HIV-1 agent and was selected as a clinical
candidate for development.
Chemokine Receptors
IC50a (nM)
CCR5b CCR1b CCR2bb CCR3b CCR4b CCR7b
(S)-(-)-5b
3.1
>10000
5.9
2400
1100
>10000
a The concentration required to inhibit the ligand binding to chemokine
receptor by 50%. b Inhibitory effects on the binding of [125I]-RANTES,
[
125I]-RANTES, [125I]-MCP-1, [125I]-eotaxin, [125I]-TARC, or [125I]-MIP-
3â to CCR5-, CCR1-, CCR2b-, CCR3-, CCR4-, or CCR7-expressing CHO
cells, respectively. Data represent the mean IC50 values from triplicate
measurements.
blood mononuclear cells (PBMCs), and its activity appeared to
be greater than that of compound 1. The mean IC50 and IC90
values were 0.061 and 0.25 nM, respectively.33 Compound (S)-
(-)-5b did not affect the viability and proliferation of uninfected
PBMCs at concentrations up to 10 000 nM33 and thus is thought
to possess low cytotoxicity. To evaluate the biological activity
of compound (S)-(-)-5b against other chemokine receptors,
binding inhibition was measured in CHO cells stably expressing
the chemokine receptors CCR1, CCR2b, CCR3, CCR4, and
CCR7 (in a manner similar to that for the examination of CCR5
inhibition).33 The results are shown in Table 4. The IC50 values
of compound (S)-(-)-5b for CCR1 and CCR7 were over 10
µM. Compound (S)-(-)-5b modestly inhibited the binding of
Experimental Section
Melting points were determined on a Yanagimoto micromelting
point apparatus and are uncorrected. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Varian Gemini-
200 (200 MHz) spectrometer or Varian Mercury-300 (300 MHz)
spectrometer. 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 analyses were carried out by Takeda Analytical Research
Laboratories, Ltd., and results obtained were within (0.4% of the
theoretical values. Column chromatography was carried out on a
silica gel column (Kieselgel 60, 63-200 mesh, Merck or Chro-
matorex NH-DM1020, 100-200 mesh, Fuji Silysia Chemical).
Yields were not optimized.
[
125I]-eotaxin to CCR3 and [125I]-thymus and activation-
regulated chemokine (TARC) to CCR4 with IC50 values of 2400
and 1100 nM, respectively, and these IC50 values were over
350 times greater than that for CCR5. Thus, compound (S)-(-
)-5b exhibited high selectivity for CCR5 over CCR1, CCR3,
CCR4, and CCR7. However, the IC50 value of compound (S)-
(-)-5b for CCR2b was 5.9 nM, which is comparable to that
for CCR5. We next confirmed that (S)-(-)-5b abrogated
RANTES-induced Ca2+ mobilization in CCR5-expressing HeLa
cells.33 On the other hand, (S)-(-)-5b did not affect RANTES-
induced Ca2+ mobilization in CCR1-expressing HeLa cells.33
These results indicate that (S)-(-)-5b interacts with CCR5 but
not with RANTES and is thus an antagonist for CCR5.
Furthermore, we performed studies with anti-CCR5 monoclonal
antibodies (MAbs) in an attempt to determine the binding site
of (S)-(-)-5b. It was found that (S)-(-)-5b did not affect the
binding of the anti-CCR5 MAbs 45531.111 and 2D7, which
recognize different regions of the second extracellular loop
(ECL2) of CCR5, nor did it affect the binding of 3A9, which
is specific to the N-terminus of CCR5.33 In addition, unlike
RANTES, (S)-(-)-5b did not induce CCR5 internalization. It
is possible that (S)-(-)-5b could induce a conformational change
in the gp120 binding site upon binding to a domain of CCR5
other than ECL2 or the N terminus, leading to inhibition of the
HIV-1 gp 120 and CCR5 interaction.
Finally, we investigated the pharmacokinetic profile of
compound (S)-(-)-5b in animals. The [14C]-labeled analogue
of compound (S)-(-)-5b34 was intravenously administered at 1
mg/kg and orally administered at 3 mg/kg to SD (IGS) rats,
beagle dogs, and cynomolgus monkeys; the results are indicated
in Table 5. The Cmax values for (S)-(-)-5b after oral administra-
tion in rats, dogs, and monkeys were 0.485, 0.570, and 0.116
µg/mL, and the AUC0-24h values were 2.32, 6.01, and 0.67 µg
h/mL, respectively. The oral bioavailabilities were 10.2, 88.5,
and 15.6% in rats, dogs, and monkeys, respectively.
1-(4-Methoxybenzyl)piperidin-2-on (7). A mixture of 85%
KOH (18.6 g, 282 mmol) and tetrabutylammonium bromide (4.88
g, 15.1 mmol) in toluene (250 mL) was refluxed using a Dean-
Stark apparatus overnight under a nitrogen atmosphere. To the
mixture was added a solution of 6 (25.0 g, 252 mmol) and
4-methoxybenzyl chloride (51.3 g, 328 mmol) in toluene (50 mL)
at 80 °C. After being refluxed for 8 h, the mixture was cooled to
room temperature. The mixture was washed with water and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc)1:1) to give
1
28.8 g (52%) of 7 as a colorless oil. H NMR (200 MHz, CDCl3)
δ 1.70-1.85 (4H, m), 2.40-2.50 (2H, m), 3.15-3.25 (2H, m), 3.80
(3H, s), 4.53 (2H, s), 6.85 (2H, d, J ) 8.8 Hz), 7.19 (2H, d, J )
8.8 Hz).
5-[(4-Bromo-2-formylphenyl)(4-methoxybenzyl)amino]pen-
tanoic Acid (10a). A mixture of 7 (50.0 g, 228 mmol) and 4 N
NaOH (228 mL) was refluxed for 24 h. The mixture was neutralized
using concentrated HCl under ice cooling. To the mixture was added
Na2CO3 (53.8 g, 508 mmol) and DMSO (600 mL) at room
temperature. Then 5-bromo-2-fluorobenzaldehyde (38.6 g, 190
mmol) was added dropwise to the mixture at 135 °C. After being
refluxed for 5 h, the mixture was neutralized using 3 N HCl under
ice cooling, 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 77.2 g (97%) of 10a as a brown oil.
1H NMR (300 MHz, CDCl3) δ 1.50-1.65 (4H, m), 2.25-2.33 (2H,
m), 3.00-3.10 (2H, m), 3.78 (3H, s), 4.21 (2H, s), 6.79 (2H, d, J
) 8.7 Hz), 6.97 (1H, d, J ) 8.7 Hz), 7.33 (2H, d, J ) 8.7 Hz),
7.53 (1H, dd, J ) 8.7, 2.4 Hz), 7.89 (1H, d, J ) 2.4 Hz), 10.30
(1H, s).
6-[(4-Bromo-2-formylphenyl)(4-methoxybenzyl)amino]hex-
anoic Acid (10b). A mixture of 9a (20.0 g, 152 mmol), 4-meth-
oxybenzaldehyde (20.8 g, 153 mmol), and 10% Pd-C (50% wet,
4.15 g) in 1 N NaOH (152.5 mL) and MeOH (240 mL) was stirred
at room temperature for 24 h under a hydrogen atmosphere. Pd-C
was removed by filtration. The filtrate was neutralized using 6 N
Conclusion
We performed the chemical modification of orally bioavail-
able 1-benzazepine compound 4 containing the S-sulfoxide
moiety. Ring-expansion of the [6,7]-fused ring to [6,8]-, [6,9]-,

CCR5 Antagonists as Ani-HIV-1 Agents
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2043
Table 5. Pharmacokinetic Parameters of Compound (S)-(-)-5b
IV (1 mg/kg)
PO (3 mg/kg)
C
5min (µg/mL)a
AUC0-24h (µg‚h/mL)b
T1/2â (h)c
Cmax (µg/mL)d
Tmax (h)e
AUC0-24h (µg‚h/mL)b
BA(%)f
rat
dog
monkey
8.019
2.315
3.114
7.61
2.31
1.45
4.85
5.04
6.09
0.485
0.570
0.116
1.3
2.7
2.0
2.32
6.01
0.67
10.2
88.5
15.6
a Plasma concentration at 5 min after dosing. b Area under the plasma concentration-time curve for 0-24 h after dosing. c Half-life of compound (S)-
(-)-5b in the plasma. d Maximum plasma concentration after oral dosing. e Time to reach Cmax f Bioavailability.
.
HCl under ice cooling and concentrated in vacuo. To a mixture of
the residue and Na2CO3 (40.4 g, 381 mmol) in DMSO (170 mL)
and water (114 mL) was added dropwise a solution of 5-bromo-
2-fluorobenzaldehyde (25.8 g, 127 mmol) in DMSO (52 mL) at
135 °C. After being stirred at 135 °C overnight, the mixture was
neutralized using 6 N HCl under ice cooling, 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
) 2:1 f 1:1) to give 32.5 g (49%) of 10b as a brown oil. 1H NMR
(200 MHz, CDCl3) δ 1.20-1.70 (6H, m), 2.30 (2H, t, J ) 7.4
Hz), 3.06 (2H, t, J ) 7.4 Hz), 3.78 (3H, s), 4.22 (2H, s), 6.81 (2H,
d, J ) 8.8 Hz), 6.98 (1H, d, J ) 8.8 Hz), 7.05 (2H, d, J ) 8.8 Hz),
7.54 (1H, dd, J ) 8.8, 2.6 Hz), 7.90 (1H, d, J ) 2.6 Hz), 10.31
(1H, s).
under ice cooling. The mixture was neutralized using 1 N HCl under
ice cooling, and the mixture was extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated
in vacuo to give a yellow solid. Recrystallization from EtOAc-
hexane gave 32.2 g (74%) of 12a as yellow crystals, mp 130.5-
1
132 °C. H NMR (200 MHz, CDCl3) δ 1.40-1.50 (2H, m), 2.57
(2H, t, J ) 4.0 Hz), 3.47 (2H, t, J ) 3.8 Hz), 3.80 (3H, s), 3.81
(3H, s), 4.39 (2H, s), 6.54 (1H, d, J ) 6.0 Hz), 6.88 (2H, d, J )
7.8 Hz), 7.07-7.13 (3H, m), 7.26 (1H, d, J ) 1.6 Hz), 7.74 (1H,
s). Anal. (C21H22BrNO3) C, H, N.
The following compounds (12b,c) were prepared from 11b,c by
a method similar to that described for 12a.
Methyl 9-Bromo-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-
1
1-benzazonine-6-carboxylate (12b). Yield 45%, yellow oil. H
NMR (300 MHz, CDCl3) δ 1.50-1.68 (2H, m), 1.70-1.85 (2H,
m), 2.25 (2H, t, J ) 6.3 Hz), 3.16 (2H, t, J ) 6.3 Hz), 3.80 (3H,
s), 3.85 (3H, s), 4.14 (2H, s), 6.83 (2H, d, J ) 8.1 Hz), 6.91 (1H,
d, J ) 7.8 Hz), 7.06 (2H, d, J ) 8.1 Hz), 7.24-7.27 (2H, m), 7.58
(1H, s).
7-[(4-Bromo-2-formylphenyl)(4-methoxybenzyl)amino]hep-
tanoic Acid (10c). This compound was prepared in 72% yield from
9b, 4-methoxybenzaldehyde, and 5-bromo-2-fluorobenzaldehyde by
1
a method similar to that described for 10b, brown oil. H NMR
(200 MHz, CDCl3) δ 1.15-1.65 (8H, m), 2.31 (2H, t, J ) 7.8
Hz), 3.05 (2H, t, J ) 7.4 Hz), 3.78 (3H, s), 4.22 (2H, s), 6.81 (2H,
d, J ) 8.8 Hz), 6.98 (1H, d, J ) 8.8 Hz), 7.06 (2H, d, J ) 8.8 Hz),
7.54 (1H, dd, J ) 8.8, 2.2 Hz), 7.89 (1H, d, J ) 2.2 Hz), 10.30
(1H, s).
Methyl 10-Bromo-1-(4-methoxybenzyl)-1,2,3,4,5,6-hexahydro-
1-benzazecine-7-carboxylate (12c). Yield 26%, yellow oil. 1H
NMR (200 MHz, CDCl3) δ 1.20-1.35 (2H, m), 1.40-1.65 (4H,
m), 2.11 (2H, t, J ) 6.4 Hz), 2.87 (2H, t, J ) 6.2 Hz), 3.78 (3H,
s), 3.82 (2H, s), 3.84 (3H, s), 6.77 (2H, d, J ) 8.8 Hz), 6.98-7.02
(3H, m), 7.17 (1H, d, J ) 2.2 Hz), 7.36 (1H, dd, J ) 8.8, 2.2 Hz),
7.45 (1H, s).
Methyl 5-[(4-Bromo-2-formylphenyl)(4-methoxybenzyl)ami-
no]pentanoate (11a). To a mixture of 10a (77.2 g, 184 mmol),
K2CO3 (30.5 g, 221 mmol) in N,N-dimethylformamide (DMF) (500
mL) was added a solution of iodomethane (36.5 g, 257 mmol) in
DMF (100 mL) under ice cooling. After being stirred at room
temperature for 2 h under a nitrogen atmosphere, water was added
to the mixture, 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 ) 9:1 f 4:1) to give 45.7 g (57%)
Methyl 8-Bromo-1,2,3,4-tetrahydro-1-benzazocine-5-carboxy-
late (13a). To a solution of 12a (10.0 g, 24.0 mmol) in toluene (50
mL) was added TFA (50 mL) at room temperature. After being
stirred at 65 °C for 2 h, the mixture was concentrated in vacuo,
and water was added to the residue under ice cooling. The mixture
was neutralized using K2CO3 and 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 ) 9:1) to give 6.59 g
(93%) of 13a as yellow crystals. Compound 13a was used in the
1
of 11a as a brown oil. H NMR (200 MHz, CDCl3) δ 1.50-1.65
(4H, m), 2.20-2.30 (2H, m), 3.05-3.15 (2H, m), 3.64 (3H, s),
3.78 (3H, s), 4.22 (2H, s), 6.80 (2H, d, J ) 8.6 Hz), 6.98 (1H, d,
J ) 8.4 Hz), 7.05 (2H, d, J ) 8.6 Hz), 7.54 (1H, dd, J ) 8.4, 2.6
Hz), 7.90 (1H, d, J ) 2.6 Hz), 10.32 (1H, s).
1
next reaction without further purification. H NMR (200 MHz,
CDCl3) δ 1.38-1.50 (2H, m), 2.72 (2H, t, J ) 6.2 Hz), 3.43-3.53
(2H, m), 3.78 (3H, s), 3.90 (1H, br s), 6.34 (1H, d, J ) 8.4 Hz),
7.06-7.11 (2H, m), 7.63 (1H, s).
The follwing compounds (13b,c) were prepared from 12b,c by
a method similar to that described for 13a.
The following compounds (11b,c) were prepared from the
carboxylic acids 10b,c and iodomethane by a method similar to
that described for 11a.
Methyl 6-[(4-Bromo-2-formylphenyl)(4-methoxybenzyl)ami-
no]hexanoate (11b). Yield 92%, brown oil. H NMR (200 MHz,
Methyl 9-Bromo-2,3,4,5-tetrahydro-1H-1-benzazonine-6-car-
boxylate (13b). Yield 82%, yellow crystals. Compound 13b was
used in the next reaction without further purification. 1H NMR (200
MHz, CDCl3) δ 1.60-1.80 (4H, m), 2.15-2.25 (2H, m), 3.15-
3.30 (2H, m), 3.65-3.80 (1H, m), 3.83 (3H, s), 6.88 (1H, d, J )
8.8 Hz), 7.10 (1H, d, J ) 2.2 Hz), 7.28 (1H, dd, J ) 8.8, 2.2 Hz),
7.54 (1H, s).
1
CDCl3) δ 1.20-1.35 (2H, m), 1.40-1.65 (4H, m), 2.25 (2H, t, J
) 7.4 Hz), 3.06 (2H, t, J ) 7.8 Hz), 3.65 (3H, s), 3.78 (3H, s),
4.22 (2H, s), 6.81 (2H, d, J ) 8.4 Hz), 6.97 (1H, d, J ) 8.8 Hz),
7.06 (2H, d, J ) 8.4 Hz), 7.54 (1H, dd, J ) 8.8, 2.6 Hz), 7.90 (1H,
d, J ) 2.6 Hz), 10.31 (1H, s).
Methyl 7-[(4-Bromo-2-formylphenyl)(4-methoxybenzyl)ami-
no]heptanoate (11c). Yield 96%, brown oil. 1H NMR (200 MHz,
CDCl3) δ 1.20-1.35 (4H, m), 1.40-1.65 (4H, m), 2.26 (2H, t, J
) 7.6 Hz), 3.05 (2H, t, J ) 7.2 Hz), 3.65 (3H, s), 3.78 (3H, s),
4.22 (2H, s), 6.81 (2H, d, J ) 8.4 Hz), 6.97 (1H, d, J ) 8.8 Hz),
7.06 (2H, d, J ) 8.4 Hz), 7.53 (1H, dd, J ) 8.8, 2.4 Hz), 7.89 (1H,
d, J ) 2.4 Hz), 10.30 (1H, s).
Methyl 8-Bromo-1-(4-methoxybenzyl)-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxylate (12a). To a solution of 11a (45.7 g,
105 mmol) in dimethyl carbonate (900 mL) was added a solution
of NaOMe in MeOH (28%, 26.4 g, 137 mmol) at room temperature.
After being stirred at 50 °C for 6 h, water was added to the mixture
Methyl 10-Bromo-1,2,3,4,5,6-hexahydro-1-benzazecine-7-car-
boxylate (13c). Yield 99%, yellow oil. 1H NMR (200 MHz, CDCl3)
δ 1.45-1.85 (6H, m), 2.10-2.25 (2H, m), 3.25-3.40 (2H, m), 3.68
(1H, br s), 3.82 (3H, s), 6.76 (1H, d, J ) 8.8 Hz), 7.10 (1H, d, J
) 2.0 Hz), 7.29 (1H, dd, J ) 8.8, 2.0 Hz), 7.46 (1H, s).
Methyl 8-Bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-
5-carboxylate (14a). To a solution of 13a (500 mg, 1.72 mmol)
and propionaldehyde (490 mg, 8.44 mmol) in 1,2-dichloroethane
(20 mL) was added sodium triacetoxyborohydride (NaBH(OAc)3)
(1.08 g, 5.10 mmol) at room temperature. The mixture was stirred
at room temperature overnight. Water was added to the reaction
mixture, and the mixture was extracted with EtOAc. The organic

2044 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6
Seto et al.
layer was washed with aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography (hexane/EtOAc)9:1) to give 531 mg
(91%) of 14a as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 0.95
(3H, t, J ) 7.6 Hz), 1.30-1.50 (2H, m), 1.55-1.80 (2H, m), 2.51
(2H, t, J ) 6.2 Hz), 3.00-3.20 (2H, m), 3.42 (2H, t, J ) 6.2 Hz),
3.78 (3H, s), 6.56 (1H, d, J ) 9.6 Hz), 7.15-7.21 (2H, m), 7.68
(1H, s).
low oil. 1H NMR (200 MHz, CDCl3) δ 0.89-0.97 (6H, m), 1.30-
1.95 (10H, m), 2.33 (2H, t, J ) 6.2 Hz), 3.00-3.08 (2H, m), 3.21
(2H, t, J ) 6.2 Hz), 3.55 (2H, t, J ) 6.6 Hz), 3.77-3.83 (5H, m),
4.15 (2H, t, J ) 5.0 Hz), 6.96 (2H, d, J ) 8.8 Hz), 7.03 (1H, d, J
) 8.4 Hz), 7.32 (1H, d, J ) 2.2 Hz), 7.39-7.48 (3H, m), 7.77
(1H, s).
Methyl 9-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-2,3,4,5-tet-
rahydro-1H-1-benzazonine-6-carboxylate (15d). Yield 98%, yel-
low oil. 1H NMR (200 MHz, CDCl3) δ 0.86-0.97 (9H, m), 1.30-
1.80 (9H, m), 2.20-2.30 (2H, m), 2.73 (2H, d, J ) 7.4 Hz), 3.09-
3.15 (2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.78-3.82 (5H, m), 4.16
(2H, t, J ) 4.8 Hz), 6.97 (2H, d, J ) 8.8 Hz), 7.19 (1H, d, J ) 8.6
Hz), 7.26-7.29 (1H, m), 7.42-7.50 (3H, m), 7.72 (1H, s).
Methyl 10-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-1,2,3,4,5,6-
hexahydro-1-benzazecine-7-carboxylate (15e). Yield 91%, yellow
The following compounds (14b-f) were prepared from 13a-c
and the appropriate aldehydes by a method similar to that described
for 14a.
Methyl 8-Bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-
5-carboxylate (14b). Yield quant., yellow oil. 1H NMR (200 MHz,
CDCl3) δ 0.96 (6H, d, J ) 6.6 Hz), 1.35-1.50 (2H, m), 2.00-
2.20 (1H, m), 2.49 (2H, t, J ) 6.2 Hz), 2.99 (2H, d, J ) 7.2 Hz),
3.42 (2H, t, J ) 6.0 Hz), 3.79 (3H, s), 6.62 (1H, d, J ) 9.2 Hz),
7.16-7.22 (2H, m), 7.69 (1H, s).
1
oil. H NMR (200 MHz, CDCl3) δ 0.80 (3H, t, J ) 7.4 Hz), 0.93
(3H, t, J ) 7.2 Hz), 1.20-1.67 (12H, m), 2.10-2.20 (2H, m), 2.74-
2.82 (2H, m), 2.95-3.05 (2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.78-
3.83 (5H, m), 4.16 (2H, t, J ) 4.6 Hz), 6.97 (2H, d, J ) 9.2 Hz),
7.22-7.26 (2H, m), 7.45-7.51 (3H, m), 7.71 (1H, s).
Methyl 9-Bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzazo-
1
nine-6-carboxylate (14c). Yield 95%, yellow oil. H NMR (200
MHz, CDCl3) δ 0.89 (3H, t, J ) 7.2 Hz), 1.40-1.90 (6H, m), 2.25
(2H, t, J ) 6.6 Hz), 2.95 (2H, t, J ) 8.0 Hz), 3.13 (2H, t, J ) 6.6
Hz), 3.81 (3H, s), 6.88 (1H, d, J ) 8.8 Hz), 7.23-7.32 (2H, m),
7.60 (1H, s).
Methyl 10-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-1,2,3,4,5,6-
hexahydro-1-benzazecine-7-carboxylate (15f). Yield 90%, yellow
oil. 1H NMR (200 MHz, CDCl3) δ 0.84-0.97 (9H, m), 1.15-1.80
(11H, m), 2.10-2.25 (2H, m), 2.65 (2H, d, J ) 7.0 Hz), 2.90-
3.05 (2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.78-3.83 (5H, m), 4.16
(2H, t, J ) 4.6 Hz), 6.97 (2H, d, J ) 8.8 Hz), 7.18 (1H, d, J ) 1.8
Hz), 7.28 (1H, d, J ) 8.8 Hz), 7.45-7.51 (3H, m), 7.76 (1H, s).
8-[4-{2-(Butoxy)ethoxy}phenyl]-1-propyl-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxylic Acid (16a). To a solution of 15a (294
mg, 0.65 mmol) in THF (21 mL) and MeOH (21 mL) was added
1 N NaOH (7.0 mL) at room temperature. The mixture was stirred
at 70 °C for 2 h. To the mixture was added water, and then it was
neutralized using 1 N HCl under ice cooling. The mixture was
extracted with EtOAc. The organic layer was washed with water
and brine, dried over MgSO4, and concentrated in vacuo to give a
yellow solid. Recrystallization from EtOAc-hexane gave 200 mg
Methyl 9-Bromo-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benza-
zonine-6-carboxylate (14d). Yield 91%, yellow oil. 1H NMR (300
MHz, CDCl3) δ 0.84 (6H, d, J ) 6.6 Hz), 1.50-1.75 (5H, m),
2.19 (2H, t, J ) 5.7 Hz), 2.64 (2H, d, J ) 7.2 Hz), 3.06 (2H, t, J
) 5.7 Hz), 3.81 (3H, s), 7.05 (1H, d, J ) 8.4 Hz), 7.21 (1H, d, J
) 2.1 Hz), 7.34 (1H, dd, J ) 8.4, 2.1 Hz), 7.57 (1H, s).
Methyl 10-Bromo-1-propyl-1,2,3,4,5,6-hexahydro-1-benzaze-
1
cine-7-carboxylate (14e). Yield 86%, yellow oil. H NMR (200
MHz, CDCl3) δ 0.78 (3H, t, J ) 7.2 Hz), 1.20-1.65 (8H, m), 2.09
(2H, t, J ) 6.4 Hz), 2.69-2.76 (2H, m), 2.97 (2H, t, J ) 4.8 Hz),
3.80 (3H, s), 7.08 (1H, d, J ) 8.4 Hz), 7.17 (1H, d, J ) 2.2 Hz),
7.38 (1H, dd, J ) 8.4, 2.2 Hz), 7.55 (1H, s).
Methyl 10-Bromo-1-isobutyl-1,2,3,4,5,6-hexahydro-1-benza-
zecine-7-carboxylate (14f). Yield 94%, yellow oil. 1H NMR (200
MHz, CDCl3) δ 0.82 (6H, d, J ) 6.6 Hz), 1.10-1.75 (7H, m),
2.12 (2H, t, J ) 6.2 Hz), 2.60 (2H, d, J ) 7.0 Hz), 2.93 (2H, t, J
) 5.6 Hz), 3.79 (3H, s), 7.09-7.14 (2H, m), 7.38 (1H, dd, J )
8.8, 2.4 Hz), 7.60 (1H, s).
1
(70%) of 16a as yellow crystals, mp 173-174 °C. H NMR (200
MHz, CDCl3) δ 0.89-1.02 (6H, m), 1.30-1.80 (8H, m), 2.50-
2.63 (2H, m), 3.11-3.27 (2H, m), 3.45-3.58 (4H, m), 3.80 (2H,
t, J ) 4.8 Hz), 4.15 (2H, t, J ) 4.6 Hz), 6.77 (1H, d, J ) 9.0 Hz),
6.96 (2H, d, J ) 8.8 Hz), 7.32-7.46 (4H, m), 7.99 (1H, s). Anal.
(C27H35NO4) C, H, N.
Methyl 8-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-1,2,3,4-tet-
rahydro-1-benzazocine-5-carboxylate (15a). A mixture of 14a
(700 mg, 2.07 mmol), 4-[2-(butoxy)ethoxy]phenylboronic acid27
(640 mg, 2.69 mmol), and K2CO3 (744 mg, 5.38 mmol) in toluene
(15 mL), EtOH (1.5 mL), and water (1.5 mL) was stirred at room
temperature for 0.5 h under an argon atmosphere. To the mixture
was added tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (120
mg, 0.104 mmol), and the mixture was stirred at 100 °C for 3 h
under an argon atmosphere. Water was added to the mixture,
followed by extraction 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/
The following compounds (16b-f) were prepared from 15b-f
by a method similar to that described for 16a.
8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxylic Acid (16b). Yield 20%, yellow crys-
tals (EtOAc-hexane), mp 121-122 °C. 1H NMR (200 MHz,
CDCl3) δ 0.89-1.01 (9H, m), 1.30-1.68 (6H, m), 2.10-2.20 (1H,
m), 2.50-2.65 (2H, m), 3.07 (2H, d, J ) 7.2 Hz), 3.45-3.58 (4H,
m), 3.80 (2H, t, J ) 4.8 Hz), 4.15 (2H, t, J ) 4.8 Hz), 6.82 (1H,
d, J ) 8.8 Hz), 6.96 (2H, d, J ) 8.8 Hz), 7.33-7.46 (4H, m), 8.01
(1H, s). Anal. (C28H37NO4) C, H, N.
9-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-2,3,4,5-tetrahydro-
1H-1-benzazonine-6-carboxylic Acid (16c). Yield 52%, yellow
1
EtOAc)10:1) to give 294 mg (31%) of 15a as a yellow oil. H
crystals (EtOAc-hexane), mp 111-112 °C.
1H NMR (300 MHz,
3) δ 0.91-0.97 (6H, m), 1.33-1.93 (10H, m), 2.36 (2H, t, J
NMR (300 MHz, CDCl3) δ 0.91-1.00 (6H, m), 1.30-1.50 (4H,
m), 1.55-1.75 (4H, m), 2.56 (2H, t, J ) 6.0 Hz), 3.18 (2H, t, J )
7.8 Hz), 3.47 (2H, t, J ) 6.0 Hz), 3.55 (2H, t, J ) 6.9 Hz), 3.78-
3.81 (5H, m), 4.14 (2H, t, J ) 5.1 Hz), 6.76 (1H, d, J ) 8.7 Hz),
6.95 (2H, d, J ) 9.0 Hz), 7.31 (1H, d, J ) 2.4 Hz), 7.38 (1H, dd,
J ) 8.7, 2.4 Hz), 7.43 (2H, d, J ) 9.0 Hz), 7.87 (1H, s).
The following compounds (15b-f) were prepared from 14b-f
by a method similar to that described for 15a.
CDCl
) 6.3 Hz), 3.05-3.10 (2H, m), 3.24 (2H, t, J ) 6.3 Hz), 3.55 (2H,
t, J ) 6.6 Hz), 3.80 (2H, t, J ) 5.1 Hz), 4.16 (2H, t, J ) 5.1 Hz),
6.97 (2H, d, J ) 8.7 Hz), 7.04 (1H, d, J ) 9.0 Hz), 7.35 (1H, d,
J ) 2.1 Hz), 7.42-7.49 (3H, m), 7.92 (1H, s). Anal. (C
C, H, N.
28H37NO4)
9-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-2,3,4,5-tetrahydro-
1H-1-benzazonine-6-carboxylic Acid (16d). Yield 97%, yellow
oil. 1H NMR (300 MHz, CDCl3) δ 0.86-0.96 (9H, m), 1.30-1.85
(9H, m), 2.25-2.35 (2H, m), 2.75 (2H, d, J ) 7.2 Hz), 3.14 (2H,
t, J ) 5.7 Hz), 3.55 (2H, t, J ) 6.6 Hz), 3.81 (2H, t, J ) 4.8 Hz),
4.16 (2H, t, J ) 4.8 Hz), 6.98 (2H, d, J ) 8.7 Hz), 7.20 (1H, d, J
) 8.4 Hz), 7.31 (1H, d, J ) 2.4 Hz), 7.45-7.50 (3H, m), 7.86
(1H, s).
Methyl 8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-1,2,3,4-tet-
rahydro-1-benzazocine-5-carboxylate (15b). Yield 82%, yellow
oil. 1H NMR (200 MHz, CDCl3) δ 0.89-1.01 (9H, m), 1.30-1.70
(6H, m), 2.05-2.25 (1H, m), 2.50-2.60 (2H, m), 3.06 (2H, d, J )
7.4 Hz), 3.40-3.60 (4H, m), 3.77-3.82 (5H, m), 4.14 (2H, t, J )
5.2 Hz), 6.80 (1H, d, J ) 8.4 Hz), 6.95 (2H, d, J ) 8.8 Hz), 7.32-
7.46 (4H, m), 7.88 (1H, s).
Methyl 9-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-2,3,4,5-tet-
rahydro-1H-1-benzazonine-6-carboxylate (15c). Yield 79%, yel-
10-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-1,2,3,4,5,6-hexahy-
dro-1-benzazecine-7-carboxylic Acid (16e). Yield quant., yellow

CCR5 Antagonists as Ani-HIV-1 Agents
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2045
1
oil. H NMR (200 MHz, CDCl3) δ 0.81 (3H, t, J ) 7.4 Hz), 0.93
(4H, m), 3.75-3.83 (4H. m), 4.02 (1H, d, J ) 13.8 Hz), 4.08-
4.17 (3H, m), 6.56 (1H, d, J ) 1.0 Hz), 6.80 (1H, d, J ) 8.8 Hz),
6.96 (2H, d, J ) 8.8 Hz), 7.31-7.46 (7H, m), 7.55 (1H, s), 7.76
(2H, d, J ) 8.8 Hz), 7.98 (1H, s). Anal. (C40H50N4O4S‚0.25H2O)
C, H, N.
(3H, t, J ) 6.8 Hz), 1.23-1.80 (12H, m), 2.10-2.22 (2H, m), 2.75-
2.83 (2H, m), 3.00-3.10 (2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.81
(2H, t, J ) 4.8 Hz), 4.16 (2H, t, J ) 4.8 Hz), 6.98 (2H, d, J ) 8.8
Hz), 7.24-7.28 (2H, m), 7.46-7.51 (3H, m), 7.84 (1H, s).
10-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-1,2,3,4,5,6-hexahy-
dro-1-benzazecine-7-carboxylic Acid (16f). Yield 97%, yellow
(S)-(-)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tet-
rahydro-1-benzazocine-5-carboxamide methanesulfonate ((S)-
(-)-5b). The free base of (S)-(-)-5b was prepared in 80% yield
from 16b and 19 by a method similar to that described for (S)-(-
)-5a. To a solution of the free base of (S)-(-)-5b (64.91 g, 93.1
mmol) in EtOAc (600 mL) was added dropwise a solution of
methanesulfonic acid (8.95 g, 93.1 mmol) in EtOAc (160 mL) at
room temperature. After being stirred at room temperature for 4 h,
the crystals were collected by filtration and washed with EtOAc to
give 69.09 g (94%) of (S)-(-)-5b as yellow crystals. The crystals
(68.0 g) were purified by recrystallization from 2-butanone to give
58.9 g (85%) of (S)-(-)-5b as yellow crystals, mp 145.5-147.5
1
crystals (EtOAc-hexane), mp 111-113 °C. H NMR (200 MHz,
CDCl3) δ 0.85-0.97 (9H, m), 1.20-1.80 (11H, m), 2.15-2.27 (2H,
m), 2.67 (2H, d, J ) 7.0 Hz), 2.90-3.05 (2H, m), 3.55 (2H, t, J )
6.6 Hz), 3.81 (2H, t, J ) 4.8 Hz), 4.16 (2H, t, J ) 4.8 Hz), 6.98
(2H, d, J ) 8.8 Hz), 7.20 (1H, d, J ) 2.2 Hz), 7.29 (1H, d, J ) 8.4
Hz), 7.47-7.51 (3H, m), 7.91 (1H, s). Anal. (C30H41NO4) C, H,
N.
Methyl 8-{4-[2-(Butoxy)ethoxy]phenyl}-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxylate (17). This compound was prepared in
39% yield from 13a and 4-[2-(butoxy)ethoxy]phenyl)boronic acid
by a method similar to that described for 15a, yellow crystals
1
1
°C, [R]D ) -191.2° (c ) 0.508%, EtOH). H NMR (300 MHz,
(EtOAc-hexane), mp 106-107 °C. H NMR (200 MHz, CDCl3)
DMSO-d6) δ 0.82-0.97 (12H, m), 1.29-1.39 (2H, m), 1.40-1.55
(4H, m), 1.65-1.85 (2H, m), 2.00-2.25 (1H, m), 2.29 (3H,s),
2.38-2.60 (2H, m), 3.10 (2H, d, J ) 7.8 Hz), 3.30-3.60 (4H, m),
3.70 (2H, t, J ) 4.8 Hz), 3.98 (2H, t, J ) 6.6 Hz), 4.10 (2H, t, J
) 4.8 Hz), 4.34 (1H, d, J ) 15.0 Hz), 4.68 (1H, d, J ) 15.0 Hz),
6.87 (1H, d, J ) 8.7 Hz), 6.99 (2H, d, J ) 8.7 Hz), 7.16 (1H, s),
7.42-7.60 (8H, m), 7.93 (2H, d, J ) 8.7 Hz), 9.05 (1H, s), 10.18
(1H, s). Anal. (C42H56N4O7S2) C, H, N.
The following compound ((S)-(-)-5e-i) were prepared from
carboxylic acids 16c-g and 19 by a method similar to that described
for (S)-(-)-5a.
(S)-(-)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyra-
zol-4-yl)methyl]-N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]-
sulfinyl}phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxam-
δ 0.93 (3H, t, J ) 7.4 Hz), 1.30-1.70 (6H, m), 2.77 (2H, t, J )
6.2 Hz), 3.51-3.58 (4H, m), 3.77-3.82 (5H, m), 3.93 (1H, br s),
4.14 (2H, t, J ) 4.2 Hz), 6.52 (1H, d, J ) 8.0 Hz), 6.94 (2H, d, J
) 8.8 Hz), 7.21-7.29 (2H, m), 7.41 (2H, d, J ) 8.8 Hz), 7.81
(1H, s). Anal. (C25H31NO4) C, H, N.
8-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyrazol-4-
yl)methyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic Acid
(16g). To a solution of 17 (500 mg, 1.22 mmol), 1-methyl-1H-
pyrazole-4-carbaldehyde (672 mg, 6.10 mmol), and acetic acid (0.35
mL, 6.11 mmol) in 1,2-dichloroethane (20 mL) was added NaBH-
(OAc)3 (776 mg, 3.66 mmol) at room temperature. The mixture
was stirred at room temperature overnight. Water was added to
the mixture, and it 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 ) 1:1 f 1:3) to give 15g as a
yellow oil. To a solution of 15g in THF (36 mL) and MeOH (36
mL) was added 1 N NaOH (12 mL) at room temperature. The
mixture was stirred at room temperature overnight. Water was added
to the mixture. It was then neutralized using 1 N HCl under ice
cooling and extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo to give
495 mg (83%) of 16g as yellow crystals, mp 162-164 °C. 1H NMR
(300 MHz, CDCl3) δ 0.93 (3H, t, J ) 7.2 Hz), 1.24-1.70 (6H,
m), 2.55-2.65 (2H, m), 3.50-3.60 (4H, m), 3.80 (2H, t, J ) 4.8
Hz), 3.87 (3H, s), 4.14 (2H, t, J ) 4.8 Hz), 4.34 (2H, s), 6.87 (1H,
d, J ) 9.9 Hz), 6.95 (2H, d, J ) 9.3 Hz), 7.24 (1H, s), 7.35-7.44
(5H, m), 7.98 (1H, s). Anal. (C29H35N3O4) C, H, N.
ide ((S)-(-)-5e). Yield 19%, yellow amorphous powder. [R]D
)
1
-123.2° (c ) 0.451%, EtOH). H NMR (300 MHz, CDCl3) δ
0.88-0.95 (6H, m), 1.35-1.43 (2H, m), 1.50-1.70 (6H, m), 2.60-
2.65 (2H, m), 3.52-3.57 (4H, m), 3.76-3.81 (4H, m), 3.87 (3H,
m), 4.01 (1H, d, J ) 14.1 Hz), 4.04-4.16 (3H, m), 4.35 (2H, s),
6.54 (1H, s), 6.89 (1H, d, J ) 8.7 Hz), 6.95 (2H, d, J ) 8.7 Hz),
7.33-7.45 (9H, m), 7.55 (1H, s), 7.75 (2H, d, J ) 8.7 Hz), 8.06
(1H, s). Anal. (C42H50N6O4S‚0.5H2O) C, H, N.
(S)-(-)-9-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3,4,5-tet-
rahydro-1H-1-benzazonine-6-carboxamide ((S)-(-)-5f). Yield
39%, yellow amorphous powder. [R]D ) -93.7° (c ) 0.460%,
EtOH). 1H NMR (200 MHz, CDCl3) δ 0.88-0.98 (9H, m), 1.25-
2.00 (12H, m), 2.38-2.50 (2H, m), 2.95-3.10 (2H, m), 3.15-
3.25 (2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.78-3.85 (4H, m), 4.03
(1H, d, J ) 14.2 Hz), 4.09-4.18 (3H, m), 6.57 (1H, s), 6.98 (2H,
d, J ) 9.2 Hz), 7.13 (1H, d, J ) 8.4 Hz), 7.34-7.52 (8H, m), 7.76
(2H, d, J ) 8.8 Hz), 7.84 (1H, s). Anal. (C41H52N4O4S) C, H, N.
(S)-(-)-9-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3,4,5-tet-
rahydro-1H-1-benzazonine-6-carboxamide ((S)-(-)-5g). Yield
35%, yellow amorphous powder. [R]D ) -121.0° (c ) 0.486%,
EtOH). 1H NMR (200 MHz, CDCl3) δ 0.89-0.95 (12H, m), 1.26-
1.85 (11H, m), 2.30-2.42 (2H, m), 2.74 (2H, d, J ) 7.2 Hz), 3.05-
3.18 (2H, m), 3.55 (2H, t, J ) 7.6 Hz), 3.81-3.85 (4H, m), 4.00-
4.18 (4H, m), 6.59 (1H, s), 6.99 (2H, d, J ) 8.8 Hz), 7.30-7.51
(9H, m), 7.75 (2H, d, J ) 8.4 Hz), 7.82 (1H, s). Anal. (C42H54N4O4S‚
0.25H2O) C, H, N.
(S)-(-)-10-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4,5,6-
hexahydro-1-benzazecine-7-carboxamide ((S)-(-)-5h). Yield 22%,
yellow amorphous powder. [R]D ) -125.0° (c ) 0.488%, EtOH).
1H NMR (200 MHz, CDCl3) δ 0.85-0.97 (9H, m), 1.25-1.81
(14H, m), 2.25-2.40 (2H, m), 2.83 (2H, t, J ) 7.0 Hz), 2.90-
3.10 (2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.75-3.85 (4H, m), 4.03
(1H, d, J ) 14.0 Hz), 4.08-4.19 (3H, m), 6.58 (1H, s), 6.99 (2H,
d, J ) 8.8 Hz), 7.27-7.55 (9H, m), 7.77 (2H, d, J ) 8.8 Hz), 7.89
(1H, s). Anal. (C42H54N4O4S‚0.25H2O) C, H, N.
(S)-(-)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tet-
rahydro-1-benzazocine-5-carboxamide ((S)-(-)-5a). The 1 N HCl
(160 mL) was added to 1931 (35.68 g, 53.4 mmol), and the mixture
was extracted with EtOAc. To the aqueous layer was added 25%
aqueous K2CO3 (160 mL), and the mixture was extracted with a
mixture of EtOAc and i-PrOH (4:1). The organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo to give
(S)-18. To a solution of 16a (18.0 g, 41.1 mmol) and DMF (0.5
mL) in THF (180 mL) was added thionyl chloride (SOCl2) (4.50
mL, 61.7 mmol) at room temperature. After being stirred at room
temperature for 1.5 h, the reaction mixture was concentrated in
vacuo. A solution of the residue in THF (200 mL) was added
dropwise to a mixture of (S)-18 and triethylamine (Et3N) (35.0 mL,
251 mmol) in THF (150 mL) under ice cooling. After being stirred
at room temperature for 4 h, water was added to the reaction
mixture. The mixture was washed with 10% aqueous AcOH,
saturated aqueous NaHCO3, and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on a NH silica gel (hexane/EtOAc ) 1:5 f 1:8
f 1:9) to give 21.14 g (75%) of (S)-(-)-5a as a yellow amorphous
1
powder, [R]D ) -132.5° (C ) 0.507%, EtOH). H NMR (300
MHz, CDCl3) δ 0.87-1.03 (9H, m), 1.34-1.49 (2H, m), 1.50-
1.85 (8H, m), 2.55-2.65 (2H, m), 3.15-3.25 (2H, m), 3.52-3.58

2046 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6
Seto et al.
(S)-(-)-10-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4,5,6-
hexahydro-1-benzazecine-7-carboxamide ((S)-(-)-5i). Yield 18%,
yellow amorphous powder. [R]D ) -125.3° (c ) 0.472%, EtOH).
1H NMR (200 MHz, CDCl3) δ 0.89-0.99 (12H, m), 1.25-1.85
(13H, m), 2.30-2.40 (2H, m), 2.69 (2H, d, J ) 7.0 Hz), 2.90-
3.00 (2H, m), 3.55 (2H, t, J ) 7.0 Hz), 3.78-3.85 (4H, m), 4.03
(1H, d, J ) 14.2 Hz), 4.08-4.19 (3H, m), 6.59 (1H, s), 6.99 (2H,
d, J ) 8.8 Hz), 7.24-7.60 (9H, m), 7.74 (2H, d, J ) 8.8 Hz), 7.83
(1H, s). Anal. (C43H56N4O4S‚0.25H2O) C, H, N.
m), 7.85 (2H, d, J ) 9.0 Hz), 8.07 (1H, s), 8.67 (1H, s). Anal.
(C39H49N5O4S‚0.25H2O) C, H, N.
8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(4-propyl-
4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxamide (5d). This compound was prepared
from 20b in 68% yield by a method similar to that described for
5c, yellow crystals (EtOAc-i-Pr2O), mp 105-110 °C. 1H NMR (300
MHz, CDCl3) δ 0.91 (3H, t, J ) 7.4 Hz), 0.94 (3H, t, J ) 7.2 Hz),
1.00 (6H, d, J ) 6.6 Hz), 1.32-1.45 (2H, m), 1.50-1.73 (6H, m),
2.08-2.26 (1H, m), 2.52-2.62 (2H, m), 3.08 (2H, d, J ) 6.9 Hz),
3.46-3.58 (4H, m), 3.61-3.82 (4H, m), 3.96 (1H, d, J ) 13.8
Hz), 4.11-4.16 (3H, m), 6.83 (1H, d, J ) 9.0 Hz), 6.93-6.96 (3H,
m), 7.32-7.39 (6H, m), 7.85 (2H, d, J ) 9.0 Hz), 8.07 (1H, s),
8.71 (1H, s). Anal. (C40H51N5O4S‚0.25H2O) C, H, N.
8-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(4-propyl-
4H-1,2,4-triazol-3-yl)methyl]sulfanyl}phenyl)-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxamide (20a). To a solution of 16a (0.80
g, 1.83 mmol) and DMF (cat. amount) in THF (10 mL) was added
SOCl2 (0.20 mL, 2.74 mmol) at room temperature. After being
stirred at room temperature for 1.5 h, the mixture was concentrated
in vacuo. A solution of the residue in THF (30 mL) was added to
a solution of S-(4-aminophenyl)-O-benzylthiocarbonate29 (0.47 g,
1.81 mmol) and Et3N (1.50 mL, 10.8 mmol) in THF (15 mL) under
ice cooling. After being stirred at room temperature for 20 h, MeOH
(30 mL) and 1 N NaOH (12.0 mL) were added to the mixture. The
mixture was stirred at room temperature for 0.5 h under an argon
atmosphere. To this was added 3-(chloromethyl)-4-propyl-4H-1,2,4-
triazole hydrochloride29 (0.39 g, 1.99 mmol) at room temperature.
The mixture was stirred at room temperature for 2 h under an argon
atmosphere, and then it 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 column
chromatography on NH silica gel (EtOAc) and recrystallization from
EtOAc-diisopropyl ether (i-Pr2O) to give 894 mg (73%) of 20a as
(R)-(+)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(4-
propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tet-
rahydro-1-benzazocine-5-carboxamide ((R)-(+)-5c) and (S)-
(-)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(4-propyl-
4H-1,2,4-tri azol-3-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahy-
dro-1-benzazocine-5-carboxamide ((S)-(-)-5c). The racemate 5c
(400 mg) was resolved with HPLC to afford optically pure (R)-
(+)-5c (185 mg) and (S)-(-)-5c (196 mg) [column, CHIRAL PAK
AD (50 mm×500 mm), column temperature, 30 °C; mobile phase,
EtOH; flow rate 80 mL/min; UV detection, 254 nm, amount injected
125 mg]. Compound (R)-(+)-5c; yellow crystals (EtOAc-i-Pr2O),
mp 97-98 °C, [R]D ) +127.5° (C ) 0.498%, EtOH). Anal.
(C39H49N5O4S‚H2O) C, H, N. Compound (S)-(-)-5c; yellow crystals
(EtOAc-i-Pr2O), mp 98-99 °C, [R]D ) -126.1° (C ) 0.537%,
1
EtOH). Anal. (C39H49N5O4S‚H2O) C, H, N. H NMR data of the
chiral compounds were identical with those of 5c.
(R)-(+)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(4-
propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tet-
rahydro-1-benzazocine-5-carboxamide ((R)-(+)-5d) and (S)-
(-)-8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(4-propyl-
4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxamide ((S)-(-)-5d). The racemate 5d (350
mg) was resolved with HPLC to afford optically pure (R)-(+)-5d
(161 mg) and (S)-(-)-5d (167 mg) [column, CHIRAL PAK AD
(50 mm × 500 mm), column temperature, 30 °C; mobile phase,
EtOH; flow rate 80 mL/min; UV detection, 254 nm, amount injected
105 mg]. Compound (R)-(+)-5d; yellow crystals (EtOAc-i-Pr2O),
mp 99-101 °C, [R]D ) +131.2° (C ) 0.4985%, EtOH). Anal.
(C40H51N5O4S‚H2O) C, H, N. Compound (S)-(-)-5d; yellow
crystals (EtOAc-i-Pr2O), mp 98-100 °C, [R]D ) -131.1° (C )
1
yellow crystals mp 166-169 °C. H NMR (300 MHz, CDCl3) δ
0.91-1.01 (9H, m), 1.36-1.43 (2H, m), 1.46-1.87 (8H, m), 2.53-
2.62 (2H, m), 3.12-3.24 (2H, m), 3.48-3.57 (4H, m), 3.80 (2H,
t, J ) 4.9 Hz), 3.91 (2H, t, J ) 7.1 Hz), 4.15 (2H, t, J ) 4.9 Hz),
4.17 (2H, s), 6.78 (1H, d, J ) 8.7 Hz), 6.96 (2H, d, J ) 8.7 Hz),
7.23-7.44 (6H, m), 7.48 (1H, s), 7.56 (2H, d, J ) 9.0 Hz), 7.87
(1H, s), 8.05 (1H, s). Anal. (C39H49N5O3S) C, H, N.
8-{4-[2-(Butoxy)ethoxy]phenyl}-1-isobutyl-N-(4-{[(4-propyl-
4H-1,2,4-triazol-3-yl)methyl]sulfanyl}phenyl)-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxamide (20b). This compound was prepared
from 16b, S-(4-aminophenyl)-O-benzylthiocarbonate, and 3-(chlo-
romethyl)-4-propyl-4H-1,2,4-triazole hydrochloride in 72% yield
by a method similar to that described for 20a, yellow crystals
(EtOAc-i-Pr2O), mp 122-126 °C. 1H NMR (200 MHz, CDCl3) δ
0.93 (3H, t, J ) 7.2 Hz), 0.96 (3H, t, J ) 7.4 Hz), 0.99 (6H, d, J
) 6.6 Hz), 1.34-1.49 (2H, m), 1.52-1.85 (6H, m), 2.02-2.29
(1H, m), 2.50-2.63 (2H, m), 3.06 (2H, d, J ) 7.4 Hz), 3.44-3.54
(2H, m), 3.55 (2H, t, J ) 6.6 Hz), 3.78-3.89 (4H, m), 4.11 (2H,
s), 4.15 (2H, t, J ) 5.0 Hz), 6.83 (1H, d, J ) 8.8 Hz), 6.95 (2H,
d, J ) 8.8 Hz), 7.16-7.17 (1H, m), 7.27-7.45 (6H, m), 7.58 (2H,
d, J ) 8.8 Hz), 8.03 (1H, s), 8.18 (1H, s). Anal. (C40H51N5O3S‚
0.25H2O) C, H, N.
1
0.517%, EtOH). Anal. (C40H51N5O4S‚0.5H2O) C, H, N. H NMR
data of the chiral compounds were identical with those of 5d.
Receptor Binding Assays. The binding activities were deter-
mined according to the protocol previously reported.20 Binding
assays for other chemokine receptors were carried out in a similar
manner using the following ligands: [125I]-RANTES for CCR1,
[
125I]-MCP-1 for CCR2b, [125I]-eotaxin for CCR3, [125I]-TARC for
CCR4, and [125I]-MIP-3â for CCR7.
HIV-1 Envelope-Mediated Membrane Fusion Assay. COS-7
cells were maintained in Dulbecco’s modified Eagle medium (D-
MEM), supplemented with 10% fetal bovine serum (FBS) and
antibiotics (100 U/mL penicillin G and 100 µg/mL streptomycin).
MOLT-4/CCR5/Luc+ cells, a lymphoblastoid 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, antibiotics,
and 500 µg/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 mammalian cells. Expression
vectors encoding Tat, Rev, and envelope were mixed at a ratio of
5:1:3 and cotransfected into COS-7 cells using Lipofectamine 2000
(Invitrogen). 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 concentrations of the test compounds
were added to the wells. The cell suspension was incubated at 37
°C. The mixture of D-MEM and RPMI 1640 medium supplemented
with 10% FBS and antibiotics was used as medium for membrane
8-{4-[2-(Butoxy)ethoxy]phenyl}-1-propyl-N-(4-{[(4-propyl-
4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxamide (5c). To a solution of 20a (0.70 g,
1.05 mmol) in CH2Cl2 (10 mL) was added a solution of 70%
mCPBA (0.39 g, 1.58 mmol) in CH2Cl2 (10 mL) at -78 °C. After
being stirred at -78 °C for 1 h, aqueous Na2S2O3 was added to the
mixture, and the mixture was stirred at room temperature for 0.5
h. 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 f EtOAc/EtOH ) 19:
1) and recrystallization from EtOAc-i-Pr2O to give 579 mg (81%)
1
of 5c as yellow crystals, mp 167-170 °C. H NMR (300 MHz,
CDCl3) δ 0.88-1.02 (9H, m), 1.34-1.46 (2H, m), 1.52-1.76 (8H,
m), 2.53-2.63 (2H, m), 3.15-3.24 (2H, m), 3.47-3.58 (4H, m),
3.62-3.82 (4H, m), 3.98 (1H, d, J ) 14.1 Hz), 4.12-4.16 (3H,
m), 6.78 (1H, d, J ) 9.0 Hz), 6.93-6.96 (3H, m), 7.33-7.39 (6H,

CCR5 Antagonists as Ani-HIV-1 Agents
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2047
fusion. After an overnight incubation, Luc-Screen (Tropix) was
added to each well, and the mixtures were incubated at room
temperature for 10 min. The luciferase activity was measured with
a luminometer (Wallac 1420 ARVOsx).
Shiki for the membrane fusion assay and anti-HIV-1 assay; Mr.
Atsutoshi Furuta for the pharmacokinetic analysis; and Mr.
Mitsutaka Tanaka for optical resolution by HPLC. We also thank
Dr. Kiminori Tomimatsu and his group for the synthesis of
intermediate 19.
Antiviral Assay in MOLT-4/CCR5 cells. RPMI 1640 medium
supplemented with 10% FBS and antibiotics was used in viral
replication assay. MOLT-4/CCR5 cells were inoculated with 5000
CCID50 of R5 HIV-1 BaL per 1 × 106 cells and incubated for 6 h.
The cells were washed to remove unadsorbed viral particles and
seeded into a 96-well plate (5 × 105 cells/well) with culture medium
containing various concentrations of test compounds. On day 3 after
infection, the cells were subcultured at 1:5 with culture medium
containing the same concentration of the test compounds. On day
5 after infection, the culture supernatants were collected and
determined for their p24 antigen levels by a p24 antigen ELISA
kit (ZeptoMetrix).
Antiviral Assay in PBMCs. PHA-stimulated PBMCs were
inoculated with 11- 55 ng of p24 of HIV-1 clinical isolates (KK,
CTV, HKW, HNK, HTN, HHA) per 4 × 106 cells and incubated
for 4 h. The cells were washed with culture medium to remove
unadsorbed viral particles and seeded into a 96-well plate (2 ×
105 cells/ well) with culture medium containing various concentra-
tions of test compounds. On day 4 after infection, the cells were
subcultured at 1:2 with culture medium containing the same
concentration of the test compounds. On day 7 after infection, the
culture supernatants were collected and determined for their p24
antigen levels by an ELISA kit.
Supporting Information Available: Elemental analysis results
for compounds 12a, 16a-c,f,g, 17, 20a,b, and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
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JM0509703