Naphtho[2,1-b][1,5] and [1,2-f][1,4]oxazocines as selective NK1 antagonists

Article abstract of DOI:10.1016/j.bmc.2004.03.015

Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK₁ antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK₁ pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK₁ activity, was more NK₁ versus NK₂ selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK₁ antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK₁ pharmacophore model and present a further refinement of that model.

Full text of DOI:10.1016/j.bmc.2004.03.015

Bioorganic & Medicinal Chemistry 12 (2004) 2653–2669
Naphtho[2,1-b][1,5] and [1,2-f][1,4]oxazocines as selective
NK1 antagonists
Cyrus J. Ohnmacht,a,* Jeffrey S. Albert,a Peter R. Bernstein,a William L. Rumsey,b,ꢀ
Brian B. Masek,a,ꢁ Bruce T. Dembofsky,a Gerard M. Koether,a Donald W. Andisika
and David Aharonyb
aDepartment of Medicinal Chemistry, AstraZeneca Pharmaceuticals LP, PO Box 15437, Wilmington, DE 19850-5437, USA
bDepartment of Neuroscience, AstraZeneca Pharmaceuticals LP, PO Box 15437, Wilmington, DE 19850-5437, USA
Received 7 January 2004; revised 19 February 2004; accepted 8 March 2004
Available online 2 April 2004
Abstract—Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-
naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of
those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a
purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to
contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of
atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported
pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use
mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as
NK1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss
the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that
model.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of the rhodopsin-like family named NK1, NK2, and
NK3, respectively. The three mammalian tachykinins
are thought to be involved in numerous physiological
functions and have been linked from animal studies to
diseases and conditions such as asthma and COPD,
inflammatory bowel disorders, inflammatory pain,
cough, urinary disorders, and anxiety.3–9 Early clinical
studies with selective and mixed tachykinin antagonists
were conducted in those medical areas where the indi-
vidual or combined neuropeptide antagonists were
anticipated to be useful. However the outcome of these
clinical studies were often disappointing.10–16 Recent
evidence indicates that tachykinin antagonists are likely
to find application in conditions that lack an overt
inflammatory component such as emesis, depression/
anxiety, and urinary incontinence.17–21 Indeed, an NK1
antagonist, Emend (aprepitant), is now available to
prevent and control nausea and vomiting caused by
chemotherapy treatment.22
The term ‘tachykinin’ refers to a family of structurally
related mammalian neuropeptides1 sharing a common
C-terminus of Phe-X-Gly-Leu-Met-NH2. While it has
long been held that human tachykinins were limited to
only three [substance P (SP), neurokinin A (NKA), and
neurokinin B (NKB)] it should be noted that there has
been a recent report on the discovery of four additional
human tachykinins [named endokinins (EK)A-D to
reflect peripheral endocrine roles].2 SP, NKA, and NKB
are endogenous ligands at G protein-coupled receptors
Keywords: Tachykinin; NK1; Atropisomers; Antagonist.
* Corresponding author. Tel.: +1-302-886-2686; fax: +1-302-886-4989;
e-mail: cyrus.ohnmacht@astrazeneca.com
ꢀ
Present address: GlaxoSmithKline, 709 Swedeland Rd, UW2532,
PO Box 1539, King of Prussia, PA 19406-0939, USA.
ꢁ
Our interest in the tachykinin area began with a pro-
gram aimed at selective NK2 antagonists for use in
Present address: Optive Research, Inc., 7000 North Mopac Express-
way, Austin, TX 78731, USA.
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.03.015

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C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
asthma,23 progressed through a search for mixed NK1/
NK2 antagonists, also primarily aimed at asthma,24;25
and most recently to a search for an NK1 selective
antagonist aimed at depression.26 This selectivity pro-
gression is notable in that it was accomplished largely by
variation of the aryl amide moiety of a conserved core
structure (Fig. 1). Within this structural family, key
aspects that influence NK1 and NK2 affinity or selec-
tivity have been described in prior reports. Briefly, the
following observations were made; (1) the aryl amide
orientation is important,23 the s-cis isomer favors NK2
and the s-trans isomer favors NK1; (2) the nature of the
substitution in the ‘western region’ is important for NK2
binding, while changes are more broadly tolerated for
NK1 binding;27 and (3) the balance of NK1/NK2 selec-
tivity can be modulated by substitution at the naph-
thamide 2-position.28
Figure 2. Pharmacophore model showing the dichloroaryl and naph-
thamide regions in 3. Tethering linkage is shown as a dotted line.
Relaxed-eye stereoview, hydrogens omitted for clarity.
the amide carbonyl, the positioning of the amide car-
bonyl as a hydrogen bond acceptor, and an aryl–aryl
stacking interaction. Based on this model it seemed
possible that cyclization between the amide methyl and
naphthalene-2-moiety would enforce the desired con-
formation. This has led to the development of a series of
new, potent, non-atropisomeric NK1 antagonists and to
the further refinement of our pharmacophore model.
From these observations, a detailed NK1 pharmaco-
phore model was proposed, and we identified the potent,
orally active NK1 antagonist 3.28 This compound existed
as a mixture of four resolvable atropisomers (slowly
interconverting conformational isomers). Unfortu-
nately, this atropisomeric property leads to substantial
complications in its further development as a drug.
Subsequent efforts focused on modulating the rate of
atropisomer interconversion and led to the identification
of 4,26 which had a significantly slower interconversion
rate. However, we sought to eliminate all atropisomeric
properties.
2. Chemical synthesis
The cyclics used in the ‘ring sizing’ study were prepared
as indicated in Scheme 1. The six-membered ring system
was prepared by analogy to a literature method used in
the synthesis of 2,3-dihydro-4H-1,3-benzoxazin-4-
ones.29 The seven- and eight-membered rings (11b and
11c) were formed in good yields (71% and 54%,
respectively) by the action of sodium hydride on the
corresponding mesylates 10b and 10c.
This report describes our efforts to eliminate atropiso-
meric properties of compounds related to 2 and 3 by
adding a rigidifying tether. Based on structure–activity
relationships (SAR), modeling, and crystallographic
studies, a detailed pharmacophore model was proposed
for the NK1 binding of 3.26 As shown in Figure 2, the
pharmacophore model involves a trans arrangement of
The 1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-oxa-
zocines were prepared as indicated in Scheme 2. In this
series, a BOP-Cl facilitated amide ring closure strategy
proved to be most synthetically efficient. The ring clo-
sure yields in the preparation of 25a–e varied from 36%
to 62%.
Selectivity
1 (ZD7944) NK2
O
N
3. Results and discussion
O
S
O
3.1. Determination of appropriate ring size for the
cyclizing tether
N
2 (ZD6021) NK1/NK2
N
To eliminate atropisomeric properties we used 3 as a
starting point and surveyed six-, seven-, and eight-
membered rings to find the optimal length for a tether-
ing group to bridge between the amide N-methyl and the
naphthalene 2-position (Fig. 3). Based on prior work26
our pharmacophore model involved the following fea-
tures; (1) a nearly orthogonal arrangement of the amide
and naphthalene ring, (2) an aryl–aryl stacking inter-
action between the dichloroaryl and naphthalene rings,
and (3) a trans amide bond that positions the amide
carbonyl to act as a hydrogen bonding acceptor. We
anticipated that the seven and/or eight-membered ring
tether could be acceptable.
Western
region
N
Cl
Cl
O
Central
core
N
3 (ZD4974)
X = O
NK1
X
4
X = CH2
N
Benzamide region
Figure 1. Changes in the benzamide region of the molecule allow a
range of NK1 and NK2 selectivity.

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2655
R1
R2
O
O
R1
R3
R4
R2
O
R3
R4
HO
HO
N
N
H
OH
NH2
i
N
H
i
ii
R5
OH
O
OH
Me CN
Cl
Cl
Cl
Cl
Cl
Cl
Cl
18
Cl
5
Cl
Cl
19a-e
ii
20a-e, R5 = H
21a-e, R5 = Boc
6
iii
iv
Si
O
O
Si
O
O
R6
N
N
O
O
H
R5
CN
X
n
O
R
N
N
O
O
CN
O
R4
O
R4
CN
R1
R2
R3
Cl
R1
R2
R3
Cl
CN
Cl
Cl
Cl
Cl
vii
Cl
11b, n = 2
11c, n = 3
Cl
7, R = Me
8, R = H
vi
iii
22a-e, R5 = Boc, R6 = Me
23a-e, R5 = H, R6 = Me
25a-e, X = CH2
26a-e, X = O
iv
viii
9b, R = HO(CH2)2
9c, R = HO(CH2)3
10b, R = MsO(CH2)2
10c, R = MsO(CH2)3
v
v
vi
24a-e, R5 = H, R6 = H
to
13b, 13c
vii
ix
26
6
x
iii
Me
N
O
N
O
S
CN
O
O
Me
Me
HO
HO
N
H
N
O
R4
viii, ix
R1
O
R2
n
CN
R3
HO
N
O
to 13a
Cl
N
CN
CN
Cl
Substitution pattern
Cl
Cl
O
Cl
Cl
28 (a) R1, R2, R3, R4 = H
13a, n = 1
13b, n = 2
13c, n = 3
Cl
29 (b) R1 = CH3, R2, R3, R4 = H
30 (c) R2 = CH3, R1, R3, R4 = H
31 (d) R3 = CH3, R1, R2, R4 = H
32 (e) R4 = CH3, R1, R2, R3 = H
x
12
Cl
27
O
S
Scheme 2. (i) iPr2EtN, H2NCR1R2CR3R4OH, DMAP, Me2NCH2-
CH2CH2N@C@NEtÆHCl; (ii) LiAlH4, Et2O; (iii) O(CO2t-Bu)2,
Na2CO3, dioxane/H2O; (iv) NaH, methyl 2-(bromomethyl)-3-cyano-1-
naphthoate, 33, DMF, THF; (v) TFA, CH2Cl2; (vi) pyridine hydro-
chloride, 180 ꢁC; (vii) BOP-Cl, iPr2EtN, MeCN, (viii) O3, CH2Cl2,
ꢀ78 ꢁC, Me2S; (ix) Me2NHÆHCl, HOAc, NaBH3CN, MeOH; (x) 4-
[(S)-2-methylsulfinylphenyl]piperidine, HOAc, NaBH3CN, MeOH.
O
N
O
N
O
N
xi
n
n
O
O
CN
CN
Cl
Cl
Cl
Cl
15, n = 1
16, n = 2
17, n = 3
14a, n = 1
14b, n = 2
14c, n = 3
Scheme 1. (i) 3-Cyano-2-methoxy-1-naphthoyl chloride, NaOH,
CH2Cl2; (ii) tBuMe2SiCl, DMAP, Et3N, CH2Cl2; (iii) MgI2, benzene;
H2O; (iv) Cl(CH2)2-3OH, DMF, K2CO3; (v) MeSO2Cl, Et3N, CH2Cl2;
(vi) NaH, THF; (vii) 5% HF/MeCN; (viii) trioxane, HOAc, H2SO4,
CH2Cl2; (ix) 1 N NaOH, THF, MeOH, (x) oxalyl chloride, DMSO,
Et3N, CH2Cl2; (xi) 4-[(S)-2-methylsulfinylphenyl]piperidine, NaBH4,
HOAc, MeOH.
O
O
R
N
N
CN
CN
Cl
Cl
Cl
Find optimal ring size
Cl
The tethering rings did have a marked effect on the
conformational properties. Whereas 3 existed as a mix-
ture of four atropisomers (readily apparent by NMR
and HPLC), the eight-membered ring 17 exists as mix-
tures of two atropisomers, while the seven- and six-
membered rings, 16 and 15, respectively, appeared
(NMR and HPLC) to exist in only a single conforma-
tion.
Figure 3. Schematic representation of tether addition.
NK1 receptor than for the NK2 receptor (Table 1). This
was anticipated since cyclization locks the amide in the
trans configuration, and thus they cannot adopt the cis-
amide configuration that appears necessary for activity
at the NK2 receptor.23 Within the cyclics the NK1
binding affinity was similar for the seven- and eight-
membered rings, and significantly weaker for the six-
membered ring.
To evaluate NK1 antagonist activity, the cyclic ethers
15–17 were compared to the acyclic ether 3 in three
biological assays.26 The cyclized compounds had sig-
nificantly greater binding affinity for the cloned human

2656
C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
Table 1. Effect of ring size on biological activity
O
S
O
N
N
A
B
Cl
N
Cl
Compound
A-B (ring size)
Binding
pKi
RPA
GFT
% inhibd
a
b
c
NK1
NK2
pKb
3
See Figure 1
CH2O (6)
9.50 ꢁ 0.11
7.50 ꢁ 0.03
ND
22%e
93 ꢁ 4
ND
15
16
17
27
8.68f
6.32 ꢁ 0.44
8.71 ꢁ 0.10h
34%e
CH2CH2O (7)
CH2CH2CH2O (8)
CH2CH2OCH2 (8)
10.28g
9.96g
9.94f
6.42g
3 ꢁ 1
2 ꢁ 1
5 ꢁ 2
6.10g
ND
26%e
ND ¼ Not determined.
a hNK1-MEL, ligand ¼ 3H-SP.
b hNK2-MEL, ligand ¼ 3H-NKA.
c pKb of 15 determined at 1 lM; 16 at 0.1 lM.
d Inhibition of ASMSP-induced foot tapping response in gerbil; determined 4 h after oral dosing of antagonist at 10 lmol/kg; initiated by CNS
administration of ASMSP (100 pmol). Greater values indicate greater activity.
e Because these compounds displayed uncompetitive antagonism, potency is evaluated by monitoring the magnitude of the maximum tissue relax-
ation response (control response; ꢁ5%); lower values indicate greater activity. Agonist: ASMSP, antagonist concentration: 10 nM.
f n ¼ 2.
g n ¼ 1.
h Compound causes a 56% suppression of the maximum tissue relaxation response (ASMSP 1 lM) therefore, by definition, it does not behave as a
purely competitive antagonist. However, the affinity (pKb) for this compound could be determined at a 0.1 lM antagonist concentration where
suppression of the response was minimal.
In the in vitro rabbit pulmonary artery (RPA) assay,
only the activity seen with the eight-membered ring
compound 17 approached the potency of the acyclic 3.
As was noted in the earlier publication26 the more potent
NK1 antagonists of this series induce a suppression of
the maximal response to the selective NK1 agonist Ac-
[Arg(6), Sar(9), Met(O-2)(11)] Substance P(6-11)
(ASMSP). This behavior was suggested to be associated
with noncompetitive or partially competitive antago-
nism. A low concentration of 16 allowed a pKb deter-
mination for that compound. With 3 and 17 a pKb could
not be determined, however the relative antagonist
activity of the compounds could be estimated by
recording the maximum tissue relaxation response to
increasing agonist concentration following incubation of
the tissue with antagonist at 10 nM. A smaller number
(smaller percent of control, i.e. response in the absence
of antagonist) is indicative of higher antagonist affinity.
Thus 17 is seen as less active than 3 in the RPA screen.
In part to address this, we attempted to improve CNS
distribution by reducing molecular weight. These efforts
are also described below.
3.2. Elimination of atropisomeric properties by stereo-
specific substitution of the eight-membered ring system;
structural and biological effects
By further optimizing the tethering ring, we hoped to
stabilize the putative NK1 active conformation in order
to improve activity and completely eliminate atropiso-
meric properties. We speculated that it should be pos-
sible to stabilize and rigidify the conformation necessary
for NK1 receptor activity (relative to other possible
eight-membered ring conformers) by stereospecific
addition of a methyl group to one of the ring methyl-
enes. Such an approach has been successfully demon-
strated for a structurally unrelated series of cyclic NK1
antagonists.31 Additional study in the 17 series is hin-
dered synthetically by the lack of an appropriate chiral
pool of precursors. By moving the ether oxygen position
in the eight-membered ring of 17, the resulting ring
system (i.e. 27) was readily amenable to stereoselective
methyl substitution at each of the positions in the ethyl
portion of the ring. It was demonstrated that biological
activity was maintained after reversal of the methylene
and ether oxygen in the ring; NK1 antagonist affinity
and atropisomeric properties are very similar for 17 and
An intracerebroventricular (icv) injection of ASMSP to
gerbil induces a foot tapping response that can be
attenuated by prior treatment with a CNS-penetrant
NK1 antagonist. This can provide a convenient way to
assess CNS antagonist potency.30 Despite the high
affinity of 16, and 17 (Table 1) these compounds were
inactive in the GFT (gerbil foot tap) model (as is a
similarly substituted close analog 27, see text below). It
was not clear if this is due to metabolism or distribution.

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2657
proton in approximately the same 7:3 ratio (Table 2,
Fig. 5). The NMR signal corresponding to the minor
component (7.3 ppm) was in the normal region expected.
However, the H8 NMR signal corresponding to the
major component had a chemical shift of 6.6 ppm, which
was atypically upfield shifted. Similarly upfield shifted
H8 signals had been previously noted in the 3 atrop-
isomer mixture and with the NK1 preferring isomer of
4.27
O
O
CN
CN
N
N
N
N
O
R4
O
R1
R2
R3
Cl
Cl
28
Cl
Cl
Figure 4. Left: compound 28 lacks the piperidine substitution found in
27 and acyclic analogs 3 and 4. Right: methyl substitution at each of
the sites in the aminoethanol region (R1–R4) was explored.
One possible explanation for the unusually upfield-
shifted signal is that the conformation of the major
component adopts an edge-to-face aryl–aryl folded
geometry that places the H8 proton into the shielding
cone of the dichloroaryl ring. Such a folded geometry
has been hypothesized for structurally distinct NK1
antagonists32–37 and has been identified by molecular
modeling as being a critical part of the NK1 pharma-
cophore in the acyclic series.26
27 [both exist as a mixture of two atropisomers of ratio
6:4 (NMR, HPLC)]. Since compounds 17 and 27 had
similar biological activity, either could have served as a
starting point for further elaboration, however; we chose
to focus on the ring system from 27 because synthesis of
such analogs was more direct.
In a separate report, we describe that removal of the
piperidine region from acyclic compounds related to 3
leads to markedly reduced NK2 affinity, and retention of
NK1 affinity.27 This was also observed for the current
cyclic series where replacement of the aryl piperidine in
27 with a simple dimethyl amine group led to compound
28 (Fig. 4) with equivalent NK1 binding affinity (both
pKi ¼ 9:9). Compound 28 was thus used as the template
in our effort to stabilize the active NK1 conformation by
ring methylation.
Positioning of the ring methyl substituent in 28 sub-
stantially altered the conformational equilibrium among
the atropisomers. For example, 29 (Table 2) exists pre-
dominantly in a conformation that affords the NMR
upfield shifted naphthalene H8, while inversion of the
stereochemistry (affording 30) appears to reverse the
conformational bias.
Among the series of regioisomers, compound 32 had the
best combination of in vivo potency and conformational
properties (only a single conformational form was de-
tected by HPLC and NMR). It is evident that there is no
direct correlation between the atropisomer distribution
and antagonist potency. For example, 29 and 32 appear
to exist in the (putatively desired) folded conformation
as suggested from NMR (d H8 ¼ 6.3 and 6.7 ppm,
respectively); however, they differ significantly when
tested in the GFT model. Addition of the methyl sub-
stitution at any of the four positions moderately reduces
antagonist activity relative to 28. Therefore, we specu-
late that while methyl substitution can serve to stabilize
Individual substitution at each of the sites in the am-
inoethanol region (Fig. 4) was explored as a means to
stabilize the bioactive ring conformation. Such substi-
tution altered both the NK1 affinity and atropisomeric
properties (Table 2). The unsubstituted analog 28 dis-
plays the best NK1 binding affinity and potency in the
gerbil foot tap (GFT) in vivo assay. However, solutions
of this compound exist as a mixture of two atropisomers
in a ratio of approximately 7:3 (HPLC). NMR analysis
of this mixture showed two signals for the naphthyl H8
Table 2. Activity and atropisomers distribution of mono-methyl substituted 28 analogs
H8
O
Me
N
CN
Me
N
O
R4
R1
R2
R3
Cl
Cl
Compound
Methyl position
RPA
pKb
GFTa
% inhibition
H8
Shifted:unshiftedb
28
29
30
31
32
None
R1
9.10 ꢁ 0.03
8.63 ꢁ 0.13
8.64 ꢁ 0.09
8.29 ꢁ 0.15
8.34 ꢁ 0.02
38 ꢁ 11
3 ꢁ 1
68:32
>98:2
10:90
R2
8 ꢁ 3
R3
R4
23 ꢁ 13
63 ꢁ 23
31:68
>98:2
a % Inhibition, 30 lM/kg, 4 h post dose, [ASMSP] ¼ 100 pmol.
b NMR integration % atropisomer with H8 shifted upfield: % atropisomers with H8 unshifted.

2658
C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
0.15
0.10
0.05
0.00
H8A
(Obscured by
overlapping signals)
H 8B
9.0
8.5
8.0
7.5
7.0
6.5
6.0
Figure 5. NMR spectrum of the equilibrium mixture of 28 indicating position of H8 in the two atropisomeric forms.
the bioactive conformation of the ring system it also
adds destabilizing interactions with the receptor. As a
consequence, we regard 32 as an improved compound
for structural reasons, but sub-optimal as an NK1
antagonist.
phenyl ring such that a stacking interaction is no longer
possible. This is further consistent with NMR spec-
troscopy of the less active component, which shows the
naphthalene H8 in the expected, nonshifted region.
Modeling of 32 predicted that conformation A would be
favored by 3 kcal/mol. The remaining compounds (28–
31) showed essentially the same preferred conforma-
tions, but with different associated energies. Taken
together, these modeling data, which are consistent with
experimental results, suggest a detailed model for
the NK1 pharmacophore; the key elements of which are
the aryl–aryl folded geometry and the positioning of the
amide carbonyl as a hydrogen bond acceptor.
3.3. Pharmacophore model
Conformational features of the eight-membered ring
system were investigated by molecular modeling to
better understand the factors responsible for the
observed atropisomeric properties. For compound 28
two discrete low energy conformers were identified,
which were consistent with the population distribution
and spectral properties that were experimentally ob-
served.
This refined pharmacophore model, developed from the
cyclized derivates discussed here, corroborates our ear-
lier model developed through the analysis of the NK1-
preferential isomer of 4.26 In that earlier work, the
chemically diverse NK1 receptor antagonists TAK-63732
and MK-86938 overlaid well with the pharmacophore
model.26
Shown in Figure 6 are the two predicted low energy
conformers for the core region of 32. In conformation
‘A’, the phenyl and naphthyl groups are oriented with
an edge-to-face stacking interaction. Such a conforma-
tion would place the naphthalene H8 into the shielding
zone of the phenyl ring. This is consistent with the
previously presented NMR spectral data that show an
upfield shift of about 1 ppm for the H8 proton. In con-
formation ‘B’, the orientation of the eight-membered
ring positions the naphthalene away from the face of the
4. Conclusions
Through prior efforts we had developed a series of
2-substituted naphthamides as potent and selective NK1
antagonists; however these compounds contained two
bonds with restricted rotation. Therefore, compounds in
that series existed as a mixture of four slowly intercon-
verting conformational isomers (atropisomers). In this
report we demonstrated that by introducing a tethering
bridge, the resulting eight-membered cyclic ethers had a
conformational bias that reduced the number of atrop-
isomers to two, while retaining high affinity, selective
NK1 binding. Equilibration between the two atropi-
somers could be further controlled by methyl substitu-
tion of positions on the eight-membered ring. In this
cyclic series, the preferred methyl ring substitution is
that found in 32. This compound exists essentially as a
single atropisomer.
Molecular modeling of the eight-membered ring system
indicated two low energy conformers. In one proposed
conformer, the naphthyl ring participates in an aryl–aryl
Figure 6. Stereoview representation (relaxed eye) of two low energy
conformers of the right side fragment of 28.

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2659
edge to face stacking interaction. This is consistent with
experimental results that indicate an atypically upfield-
shifted position for the naphthalene H8 proton in the
NK1 active atropisomer. Additionally such aryl–aryl
stacking interactions have been proposed as key ele-
ments in structurally unrelated NK1 antagonists. Based
on these observations, we have proposed an NK1
pharmacophore model that involves an aryl–aryl
stacking interaction and the amide carbonyl as a
hydrogen bond acceptor.
moved in vacuo and the residue set under vacuum pump
pressure for 2 h. The crude 3-cyano-2-methoxy-1-naph-
thalenecarbonyl chloride in dichloromethane (10 mL)
was added to a rapidly stirred, cooled (0 ꢁC) mixture
of (S)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine42 (5)
(0.518 g, 2.22 mmol) in dichloromethane (20 mL) and
10% NaOH (2.67 mL). The stirred reaction was allowed
to warm in the ice bath to room temperature overnight,
partitioned between additional dichloromethane and
water, the organic phase separated, washed with water,
dried (Na2SO4) and the solvent removed in vacuo. The
crude material was purified by gradient chromatography
(0.5%, 2.0%, 5.0% MeOH/dichloromethane) to give 6
(0.95 g, 97%) as a white solid. 1H NMR (300 MHz,
CDCl3) d 8.16 (s, 1H), 7.82 (d, 1H), 7.65–7.32 (m, 5H),
7.14 (dd, 1H), 6.18 (t, 1H), 3.98 (s, 3H), 3.8–3.68 (m,
3H), 3.54 (m, 1H) 3.18 (m, 1H), 2.05 (m, 1H), 1.77 (m,
1H), MS APCI, m=z ¼ 443 (MþH).
5. Experimental
5.1. Biological studies
The cloning, heterologous expression and scale-up
growth of MEL cells transfected with either the NK1 or
NK2 receptor were conducted as previously described
for the human NK2 receptor.39;40 Functional pharma-
cology studies, RPA and GFT, were carried out as
previously described.25;26
5.5. N-[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(3,4-di-
chlorophenyl)butyl]-3-cyano-2-methoxy-1-naphthamide
(7)
5.2. Molecular modeling
To a stirred solution of 3-cyano-N-[(2S)-2-(3,4-dichloro-
phenyl)-4-hydroxybutyl]-2-methoxy-1-naphthamide (6)
(5.51 g, 12.46 mmol) and dichloromethane (100 mL) was
Molecular mechanics computations were performed in
vacuo, using the AESOP41 force field with full geometry
optimization of all conformations examined and results
were visualized using the in-house molecular graphics
program ENIGMA.
successively
added
tert-butyldimethylsilylchloride
(2.82 g, 18.69 mmol), 4-dimethylaminopyridine (0.076 g,
0.623 mmol), and triethylamine (2.78 mL, 19.94 mmol)
and the reaction mixture stirred at room temperature
overnight. The mixture was partitioned between addi-
tional dichloromethane and water, the organic layer was
collected, washed with water and dried (Na2SO4). The
crude product was purified by gradient chromatography
(eluting with 70%, 50% hexane/Et2O) to yield the title
compound (6.48 g, 94%) as a white solid. 1H NMR
(300 MHz, CDCl3) d 8.2 (s, 1H), 7.82 (d, 1H), 7.62–7.36
(m, 5H), 7.16 (dd, 1H), 6.14 (t, 1H), 4.01 (s, 3H), 3.88–
3.78 (m, 2H), 3.64 (m, 1H), 3.47 (m, 1H), 3.20 (m, 1H),
2.03 (m, 1H), 1.84 (m, 1H), 0.86 (s, 9H), 0.016 (s, 6H).
MS APCI, m=z ¼ 557 (MþH).
5.3. Chemistry
1H NMR spectra were obtained at 300 MHz using a
Bruker DPX 300 spectrometer in CDCl3 and were ref-
erenced to TMS unless otherwise noted. Unit mass
spectral data were obtained on a Micromass platform
LCZ equipped with APCI. Accurate mass measure-
ments were obtained on a Micromass GCT TOF mass
spectrometer. Silica gel chromatography was performed
ꢀ
with ICN silica 32–63, 60 A. Thin-layer chromatography
was done on silica gel 60 F-254 (0.25 mm thickness)
plates, and visualization was accomplished with UV
light. Elemental analyses (C, H, N) were performed by
MicroAnalysis, Wilmington, DE. All materials obtained
commercially were used without further purification.
For compounds containing derivatives of 2-substituted-
5.6. N-[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(3,4-di-
chlorophenyl)butyl]-3-cyano-2-hydroxy-1-naphthamide
(8)
A three-neck flask containing a magnetic stirrer and
magnesium chips (0.68 g, 27.96 mmol) was flame dried
and allowed to cool to room temperature under nitro-
gen. After the addition of diethyl ether (30 mL), benzene
(15 mL), and iodine (3.55 g, 13.98 mmol), the reaction
mixture was heated at reflux for 2 h. After cooling to
room temperature the solution was transferred by can-
nula to a flask containing 7 (6.48 g, 11.65 mmol) in
108 mL benzene. Heating under reflux was continued for
1 h, the mixture allowed to cool to room temperature
then 1 N HCl and dichloromethane were introduced and
the mixture stirred for 15 min. The collected organic
phase was washed twice with water, dried (Na2SO4)
filtered and concentrated. The crude product was puri-
fied by gradient chromatography (eluting with 2%, 5%,
1
1-naphthoic acids, H NMR spectra and HPLC chro-
matograms are complex because these compounds exist
as a mixture of slowly interconverting atropisomers; and
1
in these cases H NMR integrations are not reported.
5.4. 3-Cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxy-
butyl]-2-methoxy-1-naphthamide (6)
To a stirred solution of 3-cyano-2-methoxy-1-naphthoic
acid28 (0.506 g, 2.22 mmol) and dichloromethane
(28 mL) was added oxalyl chloride (0.24 mL, 2.78 mmol)
and two drops of dimethylformamide. After 2 h at room
temperature toluene (10 mL) was added, the solvent re-

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C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
10% MeOH/dichloromethane) to give the title com-
1
pound (5.57 g, 88%) as a light yellow solid. H NMR
(300 MHz, CDCl3) d 11.91 (br s, 1H), 8.15 (s, 1H), 7.77
(m, 1H), 7.45–7.13 (m, 6H), 6.28 (m, 1H), 3.96 (m, 1H),
3.62–3.25 (m, 4H), 1.99 (m, 1H), 1.84 (m, 1H), 0.70 (s,
9H), 0.011 (s, 6H). MS APCI, m=z ¼ 543 (MþH).
utively with two portions of 0.5 N HCl and two portions
of saturated sodium bicarbonate, dried (Na2SO4), fil-
tered, and the solvent removed in vacuo. Flash chro-
matography (70% diethyl ether/hexane) returned the
1
title compound 10b (0.454 g, 82%) as a white solid. H
NMR (300 MHz, CDCl3) d 8.24 (s, 1H), 7.88–7.85 (m,
1H), 7.65–7.55 (m, 2H), 7.53–7.40 (m, 3H), 7.21–7.17
(dd, 1H), 6.21 (t, 1H), 4.58–4.55 (m, 2H), 4.50–4.47 (m,
2H), 3.94–3.81 (m, 2H), 3.69–3.64 (m, 1H), 3.53–3.47
(m, 1H), 3.21–3.19 (m, 1H), 3.16 (s, 3H), 2.04–2.00 (m,
1H), 1.88–1.83 (m, 1H), 0.85 (s, 9H), 0.01 (s, 6H). MS
APCI, m=z ¼ 665 (MþH).
5.7. N-[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(3,4-di-
chlorophenyl)butyl]-3-cyano-2-(2-hydroxyethoxy)-1-
naphthamide (9b)
A stirred mixture of 8 (1.50 g, 2.76 mmol), DMF
(15.0 mL), K2CO3 (0.574 g, 4.15 mmol) and 2-bromo-
ethanol (0.22 mL, 3.1 mmol) was heated in a 100 ꢁC oil
bath for 4 h. After cooling to room temperature di-
chloromethane, water, and saturated NH4 Cl were ad-
ded and the mixture stirred for 30 min. After further
dilution with water the organic layer was collected,
washed twice with water, dried (Na2SO4), filtered, and
the solvent removed in vacuo. Purification by column
chromatography (5%, 10%, 50% diethyl ether/dichloro-
methane) gave the title compound (0.49 g, 30% yield) as
5.10. 2-{[1-({[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-
(3,4-dichlorophenyl)butyl]amino}carbonyl)-3-cyano-2-
naphthyl]oxy}propyl methanesulfonate (10c)
Compound 9c (0.592 g, 0.986 mmol) and triethylamine
(0.21 mL, 1.50 mmol) was reacted with methanesulfonyl
chloride (0.086 mL, 1.10 mmol) as described above to
yield, after gradient chromatography (60%, 80% diethyl
1
ether/hexane), 10c (0.647g, 97%) as a white solid. H
1
a white solid. H NMR (300 MHz, CDCl3) d 8.20 (s,
NMR (300 MHz, CDCl3) d 8.19 (s, 1H), 7.83–7.80 (m,
1H), 7.59–7.52 (m, 2H), 7.43–7.41 (m, 2H), 7.36 (m, 1H),
7.16–7.13 (dd, 1H), 6.10 (t, 3H), 4.50 (t, 2H), 4.30 (t,
2H), 3.90–3.80 (m, 2H), 3.65–3.59 (m, 1H), 3.46–3.42
(m, 1H), 3.14 (m, 1H), 3.07 (s, 3H), 2.27–2.19 (m, 2H),
2.01–1.96 (m, 1H), 1.83–1.79 (m, 1H), 0.83 (s, 9H),
ꢀ0.057 (s, 6H). MS APCI, m=z ¼ 679 (MþH).
1H), 7.83 (dd, 1H, J ¼ 7 Hz, J ¼ 2 Hz), 7.51–7.55 (m,
2H), 7.43 (d, 1H, J ¼ 8 Hz), 7.39–7.44 (m, 1H), 7.37 (d,
1H, J ¼ 2 Hz), 7.15 (dd, 1H, J ¼ 8 Hz, J ¼ 2 Hz), 6.26
(t, 1H, J ¼ 6 Hz), 3.43–3.46 (m, 2H), 3.73–3.91 (m, 5H),
3.61–3.68 (m, 1H), 3.41–3.49 (m, 1H), 3.13–3.23 (m,
1H), 1.97–2.08 (m, 1H), 1.76–1.86 (m, 1H), 0.83 (s, 9H),
ꢀ0.02 (s, 3H), ꢀ0.04 (s, 3H). MS APCI, m=z ¼ 587
(MþH).
5.11. 2-[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(3,4-di-
chlorophenyl)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-
f][1,4]oxazepine-6-carbonitrile (11b)
5.8. N-[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(3,4-di-
chlorophenyl)butyl]-3-cyano-2-(3-hydroxypropoxy)-1-
naphthamide (9c)
To a stirred solution of 10b (0.24 g, 0.36 mmol) and
tetrahydrofuran (THF) (12.0 mL) was added 95% NaH
(0.010 g, 0.38 mmol) and the mixture refluxed for 40 min.
After quenching with NH4Cl, the mixture was parti-
tioned between dichloromethane and water, the organic
phase was collected, washed twice with water, dried
(Na2SO4), filtered, and concentrated. Purification by
gradient chromatography (80%, 60%, 20% hexane/Et2O)
gave the title compound (0.23 g, 71%) as a white solid.
1H NMR (300 MHz, CDCl3) d 8.25 (s, 1H), 7.91–7.82
(m, 2H), 7.64 (t, 1H), 7.54 (t, 1H), 7.39 (m, 2H), 7.16
(dd, 1H), 4.43 (m, 2H), 3.96 (m, 2H), 3.64 (m, 1H), 3.46–
3.27 (m, 4H), 2.04 (m, 1H), 1.87 (m, 1H), 0.89 (s, 9H),
0.011 (s, 6H). MS APCI, m=z ¼ 569 (MþH).
The procedure described for 9b substituting 3-bromo-1-
propanol (0.28 mL, 3.1 mmol) for 2-bromoethanol, gave
1
the title compound (0.59 g, 36%) as a white solid. H
NMR (300 MHz, CDCl3) d 8.18 (s, 1H), 7.80–7.84 (m,
1H), 7.49–7.57 (m, 2H), 7.43 (d, 1H, J ¼ 8:3 Hz), 7.36–
7.40 (m, 2H), 7.15 (dd, 1H, J ¼ 8:3 Hz, J ¼ 2:3 Hz), 6.17
(t, 1H, J ¼ 5:7 Hz), 4.25–4.37 (m, 2H), 3.47–3.95 (m,
4H), 3.60–3.67 (m, 1H), 3.40–3.47 (m, 1H), 3.11–3.21
(m, 1H), 2.58 (t, 1H, J ¼ 6 Hz), 1.95–2.06 (m, 3H), 1.74–
1.85 (m, 1H), 0.83 (s, 9H), ꢀ0.03 (s, 3H), ꢀ0.04 (s, 3H).
MS APCI, m=z ¼ 601 (MþH).
5.9. 2-{[1-({[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-
(3,4-dichlorophenyl)butyl]amino}carbonyl)-3-cyano-2-
naphthyl]oxy}ethyl methanesulfonate (10b)
5.12. 2-[(2S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(3,4-di-
chlorophenyl)butyl]-1-oxo-2,3,4,5-tetrahydro-1H-naph-
tho[2,1-b][1,5]oxazocine-7-carbonitrile (11c)
A
stirred cooled (0 ꢁC) solution of 9b (0.487 g,
0.831 mmol), triethylamine (0.177 mL, 1.27 mmol), and
dichloromethane (10 mL) was treated dropwise with
methanesulfonyl chloride (0.072 mL, 0.931 mmol) and
the mixture kept in the ice bath and allowed to slowly
warm to room temperature overnight. The mixture was
portioned between additional dichloromethane and
water, the organic layer was collected, washed consec-
Reaction of 10c (0.890 g, 1.31 mmol) in THF (36.0 mL)
with 90% NaH (0.035 g, 1.39 mmol) as described above
for 10b gave, after gradient chromatography (80%, 60%
1
hexane/Et2O), 11c (0.411 g, 54%) as a white solid. H
NMR (300 MHz, CDCl3) d 8.19–8.12 (m, 1H), 7.70 (m,
1H), 7.54–7.34 (m, 4H), 7.24 (m, 1H), 6.64 (m, 1H),
4.88–4.59 (m, 2H), 4.19 (m, 1H), 3.62 (m, 1H), 3.49–3.07

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2661
(m, 5H), 2.20–1.83 (m, 4H), 0.88 (s, 9H), 0.11 (s, 6H).
MS APCI, m=z ¼ 583 (MþH).
36 mL CH3CN) and the mixture stirred at room tem-
perature for 40 min. The reaction was quenched by the
addition of dichloromethane, water, and solid NaHCO3
until pH ¼ 6–7 was obtained. The organic phase was
collected, washed twice with water, dried (Na2SO4),
filtered, and concentrated to yield 13b (0.175 g, 97%) as a
white solid. 1H NMR (300 MHZ, CDCl3) d 8.25 (s, 1H),
7.97 (d, 1H), 7.84 (d, 1H), 7.65 (t, 1H), 7.54 (t, 1H), 7.41
(m, 2H), 7.17 (dd, 1H), 4.39 (m, 2H), 4.07 (m, 1H), 3.89–
3.69 (m, 2H), 3.55 (m, 1H), 3.37–3.29 (m, 3H), 2.11–1.91
(m, 2H), 1.74 (t, 1H). MS APCI m=z ¼ 455 (MþH).
5.13. 3-Cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxy-
butyl]-2-hydroxy-1-naphthamide (12)
Using the procedure described in the preparation of 8, 6
(0.95 g, 2.15 mmol) was converted to the title compound;
light yellow solid (0.82 g, 89%). 1H NMR (300 MHz,
CDCl3) d 11.89 (s, 1H), 8.15 (s, 1H), 7.82–7.76 (m, 1H),
7.55–7.26 (m, 5H), 7.16 (dd, 1H), 6.42 (t, 1H), 4.05–3.97
(m, 1H), 3.76–3.48 (m, 3H), 3.31–3.25 (m, 1H), 2.09–
1.83 (m, 2H), 1.70–1.58 (m, 1H). MS APCI, m=z ¼ 429
(MþH).
5.16. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-1-
oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b][1,5]oxazocine-
7-carbonitrile (13c)
5.14. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-1-
oxo-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-5-carbo-
nitrile (13a)
Compound 11c (0.411 g, 0.706 mmol) was reacted as
above with 5% HF/CH3CN (7 mL 50% HF/63 mL
CH3CN) to yield 13c (0.316 g, 95%) as a white solid. No
1
purification was required. H NMR (300 MHz, CDCl3)
This compound was prepared by modification of a
synthetic method reported by Finkelstein and Chiang.29
A stirred solution of 12 (0.82 g, 1.9 mmol) in acetic acid
(19.2 mL) was treated successively with chloroform
(24 mL) and trioxane (0.112 g, 1.24 mmol). The reaction
was cooled to 5 ꢁC and concentrated sulfuric acid
(1.0 mL) was added dropwise during which time the
mixture became light red in color. The mixture was
stirred at room temperature overnight and then parti-
tioned between dichloromethane and a large volume of
water. The organic phase was collected, washed twice
with water, dried (Na2SO4), and the solvent removed in
vacuo. Gradient column chromatography (0.5%, 2%,
5% methanol/dichloromethane) returned a white foam
(0.77 g), which was shown (1H NMR and MS) to consist
of a mixture of the alcohol acetates of 12 and 13a.
d 8.21–8.10 (m, 1H), 8.01–7.34 (m, 5H), 7.25 (m, 1H),
6.65 (m, 1H), 4.83–4.58 (m, 2H), 4.20–4.13 (m, 1H), 3.69
(m, 1H), 3.50–2.72 (m, 5H), 2.17–1.80 (m, 4H), 1.45 (m,
1H). MS APCI, m=z ¼ 469 (MþH).
5.17. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-1-oxo-
2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-5-carbonitrile
(14a)
To a stirred ꢀ78 ꢁC solution of oxalyl chloride
(0.082 mL, 0.94 mmol) and dichloromethane (8 mL) was
added a solution of dimethyl sulfoxide (0.134 mL,
1.56 mmol) in dichloromethane (4 mL). After stirring for
5 min a solution of 13a (0.276 g, 0.627 mmol) in dichlo-
romethane (8 mL) was added. After stirring for 15 min,
triethylamine (0.53 mL, 3.76 mmol) was added. The
mixture was stirred an addition 15 min in the bath, the
bath removed and stirring continued at ambient tem-
perature for an additional 2 h. The reaction mixture was
partitioned between dichloromethane and a large vol-
ume of water, the organic phase collected, washed with
additional water, the organic phase dried (Na2SO4), and
concentrated. Gradient chromatography (1%, 20%, 50%
Et2O/dichloromethane) yielded 0.228 g, (83%) of the title
compound as a white solid. 1H NMR (300 MHz,
CDCl3) d 9.75 (s, 1H), 9.13 (d, 1H), 8.35 (s, 1H), 8.02–
7.74 (m, 2H), 7.58–7.53 (m, 1H), 7.43–7.35 (m, 2H), 7.15
(dd, 1H), 5.11–5.02 (m, 2H), 3.98–3.91 (m, 1H), 3.74–
3.66 (m, 2H), 3.06–2.82 (m, 2H). MS APCI, m=z ¼ 439
(MþH).
A stirred solution of the above acetate mixture and THF
(18 mL) was treated with water (7 mL) and 1 N-NaOH
(3.2 mL). Methanol (ꢂ3 mL) was added give a clear
solution. After 2.75 h at room temperature the mixture
was partitioned between dichloromethane and water,
the organic collected and combined with an additional
washing of the aqueous layer with dichloromethane. The
organics were dried (Na2SO4) and the solvent removed
in vacuo. Gradient column chromatography (2%, 3%
5% methanol/dichloromethane) gave the title material as
a white solid (0.28 g, 33%). 1H NMR (300 MHz, CDCl3)
d 9.17 (d, 1H), 8.22 (s, 1H), 8.0–7.73 (m, 2H), 7.57–7.52
(m, 1H), 7.45–7.26 (m, 2H), 7.14 (dd, 1H), 5.07 (d, 1H),
4.92 (d, 1H), 4.11 (dd, 1H), 3.73–3.66 (m, 1H), 3.62–3.50
(m, 2H), 3.35–3.27 (m, 1H), 2.08–2.03 (m, 1H), 1.92–
1.85 (m, 1H), 1.72 (t, 1H). MS APCI, m=z ¼ 441
(MþH).
5.18. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-1-oxo-
1,2,3,4-tetrahydronaphtho[1,2-f][1,4]oxazepine-6-carbo-
nitrile (14b)
5.15. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-1-
oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]oxazepine-6-
carbonitrile (13b)
Using the standard Swern oxidizing conditions de-
scribed in the preparation of 14a, 13b (0.175 g,
0.385 mmol) was converted to 0.148 g (84%) of the title
compound as a white solid. 1H NMR (300 MHz,
CDCl3) d 9.80 (s, 1H), 8.26 (s, 1H), 7.93–7.83 (m, 2H),
A solution of 11b (0.23 g, 0.397 mmol) in CH3CN (5 mL)
was added to stirred 5% HF/CH3CN (4 mL 50% HF/

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C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
7.64 (t, 1H), 7.54 (t, 1H), 7.43 (m, 2H), 7.18 (dd, 1H),
4.42 (m, 2H), 3.95 (m, 2H), 3.75 (m, 1H), 3.40 (m, 2H),
3.10–2.90 (m, 2H). MS APCI, m=z ¼ 453 (MþH).
2.72 (m, 1H), 2.68 (s, 3H), 2.27 (m, 2H), 2.07–1.61 (m,
8H). MS APCI, m=z ¼ 660 (MþH). Anal. Calcd for
C36H35Cl2N3O3SÆ1.0C6H8O7Æ2.0H2O: C, 56.75; H, 5.33;
N, 4.72. Found: C, 56.50; H, 5.26; N, 4.43.
5.19. 2[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-1-oxo-
2,3,4,5-tetrahydro-1H-naphtho[2,1-b][1,5]oxazocine-7-
carbonitrile (14c)
5.22. 2-((2S)-2-(3,4-Dichlorophenyl)-4-4-[2-(methyl-
sulfinyl)phenyl]piperidin-1-ylbutyl)-1-oxo-2,3,4,5-tetrahy-
dro-1H-naphtho[2,1-b][1,5]oxazocine-7-carbonitrile (17)
Using the standard Swern oxidizing conditions de-
scribed in the preparation of 14a, 13c (0.271 g,
0.580 mmol) was converted to 0.261 g (96%) of 14c as a
4-[(S)-2-methylsulfinyl-phenyl]-piperidine (0.134 g, 0.560
mmol) was reacted with 14c (0.261 g, 0.560 mmol) in the
presence of sodium cyanoborohydride under the stan-
dard reductive amination conditions described in the
preparation of 15 to yield 17 (0.271 g, 72%) as a white
1
white solid. H NMR (300 MHz, CDCl3) 9.79 (m, 1H),
8.28–8.25 (m, 1H), 7.98–7.37 (m, 5H), 7.25 (m, 1H), 6.68
(m, 1H), 4.82–4.57 (m, 2H), 4.22–4.15 (m, 1H), 3.92–
3.36 (m, 3H), 3.17–2.88 (m, 3H), 2.19–1.97 (m, 2H). MS
APCI, m=z ¼ 467 (MþH).
1
solid, which was converted to the citrate salt. H NMR
(300 MHz, CDCl3) d 8.20–8.14 (m, 1H), 7.98 (m, 1H),
7.81–7.70 (m, 1H), 7.53–7.33 (m, 7H), 7.25 (m, 1H), 6.72
(m, 1H), 4.83–4.58 (m, 2H), 4.17 (m, 1H), 3.60–
3.32 (m, 2H), 3.14–2.91 (m, 3H), 2.79 (m, 1H), 2.68
(s, 3H), 2.33–2.26 (m, 2H), 2.19–1.63 (m, 11H). MS
APCI, m=z ¼ 674 (MþH). Anal. Calcd for
C37H37Cl2N3O3SÆ1.0C6H8O7Æ1.8H2O: C, 57.43; H, 5.44;
N, 4.67. Found: C, 57.43; H, 5.36; N, 4.49.
5.20. 2-((2S)-2-(3,4-Dichlorophenyl)-4-{4-[2-(methylsul-
finyl)phenyl]piperidin-1-yl}butyl)-1-oxo-2,3-dihydro-1H-
naphtho[1,2-e][1,3]oxazine-5-carbonitrile (15)
To a stirred solution of 4-[(S)-2-methylsulfinylphenyl]-
piperidine43 (0.108 g, 0.427 mmol) and MeOH (10 mL)
was added acetic acid (0.03 mL, 0.470 mmol) and a
solution of 14b (0.187 g, 0.427 mmol) in MeOH (18 mL).
The mixture was stirred for 30 min then a solution of
sodium cyanoborohydride (0.030 g, 0.47 mmol) in
MeOH (2 mL) was added and stirring was continued
overnight. The mixture was quenched with saturated
NaHCO3 and partitioned between dichloromethane and
water. The organic phase was collected, consecutively
washed with saturated aqueous NaHCO3 and water,
dried (Na2SO4), and the solvent removed in vacuo. The
crude product was purified by gradient chromatography
(2%, 3%, 5% MeOH/dichloromethane) to yield the title
compound (0.260 g, 94%) as a white solid that was con-
verted to the citrate salt. 1H NMR (300 MHz, CDCl3) d
9.19 (d, 1H), 8.29 (s, 1H), 7.99–7.96 (m, 1H), 7.85–7.74
(m, 2H), 7.58–7.55 (m, 1H), 7.46–7.26 (m, 5H), 7.13 (dd,
1H), 5.09 (d, 1H), 4.91 (d, 1H), 4.12–4.05 (m, 1H), 3.58–
3.51 (m, 1H), 3.23–3.17 (m, 1H), 3.01–2.90 (m, 2H),
2.73–2.70 (m, 1H), 2.67 (s, 3H), 2.31–2.21 (m, 2H), 2.09–
1.59 (m, 8H). MS APCI, m=z ¼ 646 (MþH). Anal. Calcd
for C35H33Cl2N3O3SÆ1.0C6H8O7Æ1.2H2O: C, 57.23; H,
5.08; N 4.88. Found: C, 57.10; H, 5.12; N, 4.67.
5.23. (2S)-2-(3,4-Dichlorophenyl)-N-(2-hydroxy-
ethyl)pent-4-enamide (19a)
A solution of (2S)-2-(3,4-dichlorophenyl)pent-4-enoic
acid44 (18, 2.0 g, 8.2 mmol), diisopropylethyl amine
(1.56 mL, 9.0 mmol), ethanolamine (0.59 mL, 9.8 mmol),
and 4-dimethylaminopyridine (1.0 g, 8.2 mmol) in
dichloromethane (32 mL) was cooled to 5 ꢁC and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (1.65 g, 8.6 mmol) was added. The cooling bath was
removed and reaction stirred for 50 min, then heated
briefly to reflux. After cooling, additional ethanolamine
(0.3 mL, 5.0 mmol) was added and stirring continued
for 10 min. The mixture was concentrated, diluted
with ethyl acetate; washed with 1 N HCl, then satu-
rated aqueous sodium carbonate, and brine, dried
(MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by chromatography
(30–80% ethyl acetate/hexanes) to afford the title
1
compound (1.0 g, 39%) as an oil. H NMR (300 MHz,
CDCl3) 7.40 (m, 2H), 7.18 (m, 1H), 5.93 (br s, 1H),
5.68 (m, 1H), 5.05 (m, 2H), 3.64 (m, 2H), 3.40 (m, 3H),
2.84 (m, 1H), 2.48 (m, 1H). MS APCI, m=z ¼ 288
(MþH).
5.21. 2-((2S)-2-(3,4-Dichlorophenyl)-4-4-[(S)-2-(methyl-
sulfinyl)phenyl]piperidin-1-ylbutyl)-1-oxo-1,2,3,4-tetrahy-
dronaphtho[1,2-f][1,4] oxazepine-6-carbonitrile (16)
19b–e were prepared analogously to 19a, using the
appropriate methyl substituted ethanolamine.
4-[(S)-2-methylsulfinyl-phenyl]-piperidine (0.078 g, 0.326
mmol) was reacted with 14b (0.148 g, 0.326 mmol) in the
presence of sodium cyanoborohydride under the
standard reductive amination conditions described in
the preparation of 15 to yield 16 (0.271 g, 72%) as a
5.24. (2S)-2-(3,4-Dichlorophenyl)-N-[(1R)-2-hydroxy-1-
methylethyl]pent-4-enamide (19b)
1
white solid that was converted to the citrate salt. H
Solid (88%). 1H NMR (300 MHz, CDCl3) d 7.42 (d, 1H),
7.40 (d, 1H), 7.18 (m, 1H), 5.69 (m, 2H), 5.06 (m, 2H),
4.04 (m, 1H), 3.65 (m, 1H), 3.53 (m, 1H), 3.30 (t, 1H),
2.83 (m, 1H), 2.46 (m, 2H), 1.10 (d, 3H). MS APCI,
m=z ¼ 302 (MþH).
NMR (300 MHz, CDCl3) d 8.25 (s, 1H), 8.0 (m, 2H),
7.84 (d, 1H), 7.66 (t, 1H), 7.56 (t, 1H), 7.48–7.35 (m,
5H), 7.17 (dd, 1H), 4.43–4.30 (m, 2H), 4.4 (m, 1H), 3.84
(m, 1H), 3.30 (m, 2H), 3.18 (m, 1H), 3.04–2.91 (m, 2H),

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2663
5.25. (2S)-2-(3,4-Dichlorophenyl)-N-[(1S)-2-hydroxy-1-
methylethyl]pent-4-enamide (19c)
2.44 (m, 1H), 2.31 (m, 1H), 0.99 (d, 3H). MS APCI,
m=z ¼ 288 (MþH).
Solid (81%) 1H NMR (300 MHz, CDCl3) d 7.43 (d, 1H),
7.40 (d, 1H), 7.19 (m, 1H), 5.68 (m, 2H), 5.05 (m, 2H),
4.04 (m, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 3.31 (t, 1H),
2.82 (m, 1H), 2.47 (m, 1H), 2.31 (t, 1H), 1.16 (d, 3H).
MS APCI, m=z ¼ 302 (MþH).
5.31. (2S)-1-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-
yl]amino}propan-2-ol (20d)
Oil (91%). 1H NMR ((300 MHz, CDCl3) d 7.29 (d, 1H),
7.27 (d, 1H), 7.03 (dd, 1H), 5.63 (m, 1H), 4.99 (m, 1H),
2.92–2.61 (m, 4H), 2.34 (m, 3H), 1.10 (d, 3H). MS
APCI, m=z ¼ 288 (MþH).
5.26. (2S)-2-(3,4-Dichlorophenyl)-N-[(2S)-2-hydroxy-
propyl]pent-4-enamide (19d)
5.32. (2R)-1-[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-
yl]aminopropan-2-ol (20e)
1
Oil (82%). H NMR (300 MHz, CDCl3) d 7.40 (m, 2H),
7.18 (dd, 1H), 6.19 (br s, 1H), 5.68 (m, 1H), 5.06 (m,
1H), 3.87 (m, 1H), 3.01 (m, 1H), 2.83 (m, 1H), 2.47 (m,
1H), 1.12 (d, 3H). MS APCI, m=z ¼ 302 (MþH). MS
APCI, m=z ¼ 302 (MþH).
Colorless oil (85%). The free-base reduction product was
used in the next reaction without additional purification.
1H NMR (300 MHz, DMSO-d6) d 7.52 (d, 1H,
J ¼ 8:3 Hz), 7.46 (s, 1H), 7.21 (dd, 1H, J ¼ 1:7, 8.3 Hz),
5.62 (m, 1H), 4.91 (m, 2H), 4.29 (br, 1H), 3.58 (m, 1H),
3.29 (s, 1H), 2.84 (m, 1H), 2.71 (m, 2H), 2.43 (m, 1H),
2.37 (d, 2H, J ¼ 5:7 Hz), 2.26 (m, 1H), 0.98 (d, 3H,
J ¼ 6:1 Hz). 13C NMR (75 MHz, DMSO-d6) d 145.72,
136.91, 131.04, 130.54, 130.30, 128.78, 128.64, 116.72,
65.42, 57.49, 54.74, 44.81, 37.89, 21.82. MS APCI,
m=z ¼ 288 (MþH). An analytical sample was prepared
by treating a dichloromethane solution of the title
compound with a slight excess of ethereal HCl at room
temperature. The hydrochloride salt of the title com-
pound was isolated as a white solid. Anal. Calcd for
C14H19Cl2NO 1.0 HCl: C 51.79, H 6.21, N 4.31. Found:
C 51.41, H 5.86, N 4.18.
5.27. (2S)-2-(3,4-Dichlorophenyl)-N-[(2R)-2-hydroxy-
propyl]pent-4-enamide (19e)
Oil (98%). 1H NMR (300 MHz, CDCl3) d 7.44–7.38 (m,
2H), 7.21–7.15 (m, 1H), 5.90 (br, 1H), 5.76–5.60 (m,
1H), 5.12–4.97 (m, 2H), 3.92–3.80 (m, 1H), 3.44–3.31
(m, 2H), 3.17–3.06 (m, 1H), 2.91–2.78 (m, 1H), 2.54–
2.41 (m, 1H), 2.12 (br, 1H), 1.15 (d, 3H, J ¼ 6:1 Hz). MS
APCI, m=z ¼ 302 (MþH).
5.28. 2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-yl]-
amino}ethanol (20a)
To a solution of 19a (1.5 g, 5.2 mmol) in diethyl ether
(105 mL) was added 13 mL of a 1 M solution of lithium
aluminum hydride in THF. The mixture was heated
under reflux for 3 h. After cooling, 10 mL of saturated
aqueous sodium sulfate was cautiously added and the
suspension stirred for 0.5 h. Solid sodium sulfate (10 g)
was added and the suspension stirred for 0.5 h, filtered
through Celite, rinsed with ethyl acetate, concentrated
under reduced pressure, and purified by passing through
a plug of silica gel with 3–7% methanol/dichloromethane
5.33. tert-Butyl [(2S)-2-(3,4-dichlorophenyl)pent-4-en-1-
yl](2-hydroxyethyl)carbamate (21a)
To a solution of compound 20a (1.25 g, 4.6 mmol) in
dioxane (10 mL), water (10 mL), and sodium carbonate
(0.51 g, 4.8 mmol) was cooled to 0 ꢁC and di-tert-butyl-
dicarbonate (1.04 g, 4.8 mmol) was slowly added as a
solution in dioxane (5 mL). After 1 h the mixture was
diluted with ethyl acetate, washed with water, and brine,
dried (MgSO4); filtered and concentrated under reduced
pressure. The resulting residue was passed through a
plug of silica to afford 1.4 g (81%) of the title compound
as an oil.1H NMR (300 MHz, CDCl3) d 7.37 (d, 1H),
7.26 (d, 1H), 7.00 (m, 1H), 5.62 (m, 1H), 5.00 (m, 2H),
3.71–2.94 (m, 7H), 2.34 (m, 2H), 1.41 (s, 9H).
1
to afford the title compound (1.25 g, 88%) as an oil. H
NMR (300 MHz, CDCl3) d 7.39 (d, 1H), 7.26 (d, 1H),
7.03 (dd, 1H), 5.64 (m, 1H), 4.98 (m, 2H), 3.55 (t, 2H),
2.71–2.94 (m, 5H), 2.26–2.51 (m, 2H). MS APCI,
m=z ¼ 274 (MþH).
20b–e were prepared analogously to 20a:
21b–e were prepared analogously to 21a:
5.29. (2R)-2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-
yl]amino}propan-1-ol (20b)
5.34. tert-Butyl [(2S)-2-(3,4-dichlorophenyl)pent-4-en-1-
yl][(1R)-2-hydroxy-1-methylethyl]carbamate (21b)
Oil (quant.). 1H NMR (300 MHz, CDCl3) d 7.38 (d,
1H), 7.28 (d, 1H), 7.03 (m, 1H), 5.64 (m, 1H), 4.98 (m,
2H), 3.49 (m, 1H), 3.14 (m, 1H), 2.79 (m, 4H), 2.36 (m,
2H), 0.97 (d, 3H). MS APCI, m=z ¼ 288 (MþH).
1
Oil (99%). H NMR (300 MHz, CDCl3) d 7.37 (d, 1H),
7.28 (d, 1H), 7.02 (m, 1H), 5.60 (m, 1H), 4.98 (m, 2H),
3.45 (m, 5H), 2.98 (s, 1H), 2.35 (m, 2H), 1.40 (s, 9H),
1.11 (d, 3H). MS APCI, m=z ¼ 288 (MꢀBocþH).
5.30. (2S)-2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-
yl]amino}propan-1-ol (20c)
5.35. tert-Butyl [(2S)-2-(3,4-dichlorophenyl)pent-4-en-1-
yl][(1 S)-2-hydroxy-1-methylethyl]carbamate (21c)
1
Oil (61%). H NMR (300 MHz, CDCl3) d 7.38 (d, 1H),
7.27 (d, 1H), 7.03 (m, 1H), 5.64 (m, 1H), 4.99 (m, 2H),
3.50 (m, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.73 (m, 3H),
1
Oil (96%). H NMR (300 MHz, CDCl3) d 7.37 (d, 1H),
7.27 (d, 1H), 7.01 (m, 1H), 5.62 (m, 1H), 4.98 (m, 2H),

2664
C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
3.52 (m, 5H), 3.14 (m, 1H), 2.97 (s, 1H), 2.36 (m, 2H),
1.43 (s, 9H), 1.03 (s, 3H). MS APCI, m=z ¼ 410 (MþNa).
5.42. Methyl 2-[((1R)-2-{(tert-butoxycarbonyl)[(2S)-2-
(3,4-dichlorophenyl)pent-4-en-1-yl]amino}-1-methyl-
ethoxy)methyl]-3-cyano-1-naphthoate (22e)
5.36. tert-Butyl [(2S)-2-(3,4-dichlorophenyl)pent-4-en-1-
yl][(2S)-2-hydroxypropyl]carbamate (21d)
Purification by flash chromatography (4:1 hexanes–ethyl
acetate) afforded the title compound as a colorless oil
(77%). 1H NMR (300 MHz, CDCl3, conformational
isomers evident) d 8.32 (1H), 7.90 (2H), 7.67 (2H), 7.26
(2H), 6.96 (1H), 5.54 (1H), 4.98–4.81 (3H), 4.71 (1H),
4.04 (3H), 3.91–3.54 (2H), 3.35–2.85 (3H), 2.81–2.60
(1H), 2.29 (2H), 1.45–1.28 (9H), 1.11 (3H). MS APCI,
m=z ¼ 511 (MꢀBocþH).
1
Oil (59%). H NMR (300 MHz, CDCl3) d 7.37 (d, 1H),
7.26 (d, 1H), 7.00 (m, 1H), 5.61 (m, 1H), 4.97 (m, 1H),
3.38 (m, 1H), 2.37 (m, 1H), 1.39 (s, 9H), 1.10 (d, 3H).
MS APCI, m=z ¼ 288 (MꢀBocþH).
5.37. tert-Butyl [(2S)-2-(3,4-dichlorophenyl)pent-4-en-1-
yl][(2R)-2-hydroxypropyl]carbamate (21e)
5.43. Methyl 3-cyano-2-[(2-{[(2S)-2-(3,4-dichlorophenyl)-
pent-4-en-1-yl]amino}ethoxy)methyl]-1-naphthoate (23a)
ethyl acetate), (82%). 1H NMR (300 MHz, CDCl3) d
7.36 (d, 1H, J ¼ 8:3 Hz), 7.25 (s, 1H), 7.00 (m, 1H),
5.69–5.55 (m, 1H), 5.04–4.93 (m, 2H), 3.86 (m, 1H), 3.53
(br, 1H), 3.32 (m, 1H), 3.03 (m, 3H), 2.35 (m, 2H), 1.41
(s, 9H), 1.08 (d, 3H, J ¼ 6:6 Hz). MS APCI, m=z ¼ 388
(MþH).
A solution of crude 22a and trifluoroacetic acid (10 mL)
was stirred in dichloromethane (10 mL), heated under
reflux for 20 min, concentrated, diluted with dichlo-
romethane, concentrated again, then purified by flash
chromatography (1–5% methanol/dichloromethane) to
afford 23a (1.5 g, 81%) as a foam solid. 1H NMR
(300 MHz, CDCl3) d 8.34 (s, 1H), 7.95 (d, 1H), 7.76 (m,
3H), 7.31 (d, 1H), 7.24 (d, 1H), 7.05 (dd, 1H), 5.55 (m,
1H), 4.98 (m, 2H), 4.76 (d, 2H), 4.03 (s, 3H), 3.83 (t,
2H), 3.42–3.12 (m, 5H), 2.38 (m, 2H). MS APCI,
m=z ¼ 497 (MþH).
5.38. Methyl 2-[(2-{(tert-butoxycarbonyl) [(2S)-2-(3,4-
dichlorophenyl)pent-4-en-1-yl]amino}ethoxy)methyl]-3-
cyano-1-naphthoate (22a)
A mixture of 21a (1.4 g, 3.7 mmol)), 33 (1.36 g, 4.5 mmol),
and sodium hydride (0.18 g of 60% dispersion in mineral
oil, 4.5 mmol) in dimethylformamide (6 mL) and tetra-
hydrofuran (6 mL) was stirred overnight. Additional
sodium hydride (30 mg of 60% dispersion in mineral oil,
0.75 mmol) was added and the reaction heated at 50 ꢁC
for 0.25 h, then at 60 ꢁC for 0.25 h. The mixture was
cooled, diluted with ethyl acetate, washed with water
(twice), and brine, dried (MgSO4), filtered, concentrated
under reduced pressure to afford 22a, which was used
without further characterization or purification.
23b–e were prepared analogously to 23a:
5.44. Methyl 3-cyano-2-{[((2R)-2-{[(2S)-2-(3,4-dichloro-
phenyl)pent-4-en-1-yl]amino}propyl)oxy]methyl}-1-naph-
thoate (23b)
1
(11% from 21b). H NMR (300 MHz, CDCl3) d 8.36 (s,
1H), 7.97 (d, 1H), 7.76 (m, 3H), 7.30 (d, 1H), 7.15 (d,
1H), 7.00 (m, 1H), 5.54 (m, 1H), 4.99 (m, 2H), 4.75 (s,
2H), 4.04 (s, 3H), 3.71 (m, 2H), 3.56 (s, 1H), 3.29 (m,
2H), 3.11 (m, 1H), 2.38 (m, 2H), 1.34 (d, 3H). MS APCI,
m=z ¼ 511.
22b–e were prepared analogously to 22a:
5.39. Methyl 2-{[((2R)-2-(tert-butoxycarbonyl)[(2S)-2-
(3,4-dichlorophenyl)pent-4-en-1-yl]aminopropyl)oxy]-
methyl}-3-cyano-1-naphthoate (22b)
5.45. Methyl 3-cyano-2-{[((2S)-2-[(2S)-2-(3,4-dichloro-
phenyl)pent-4-en-1-yl]aminopropyl)oxy]methyl}-1-naph-
thoate (23c)
Used without further characterization or purification.
Oil (74% from 21c). 1H NMR (400 MHz, CDCl3) d 9.79
(s), 8.36 (s), 7.97 (d), 7.77 (m), 7.27 (d), 7.07 (m), 6.63 (s),
5.55 (m), 4.99 (m), 4.76 (m), 4.05 (s), 3.71 (m), 3.52 (s),
3.40 (s), 3.06 (m), 2.36 (m), 1.35 (d). MS APCI,
m=z ¼ 511 (MþH).
5.40. Methyl 2-{[((2S)-2-{(tert-butoxycarbonyl)[(2S)-2-
(3,4-dichlorophenyl)pent-4-en-1-yl]amino}propyl)oxy]-
methyl}-3-cyano-1-naphthoate (22c)
Used without further characterization or purification.
5.41. Methyl 2-[((1S)-2-{(tert-butoxycarbonyl)[(2S)-2-
(3,4-dichlorophenyl)pent-4-en-1-yl]amino}-1-methyl-
ethoxy)methyl]-3-cyano-1-naphthoate (22d)
5.46. Methyl 3-cyano-2-[((1S)-2-{[(2S)-2-(3,4-dichloro-
phenyl)pent-4-en-1-yl]amino}-1-methylethoxy)methyl]-
1-naphthoate (23d)
Oil (65%). 1H NMR (300 MHz, CDCl3, 52 ꢁC) d 8.32 (s,
1H), 7.90 (m, 2H), 7.68 (m, 2H), 7.25 (m, 2H), 6.95 (dd,
1H), 5.52 (m, 1H), 4.85 (m, 3H), 4.70 (m, 1H), 4.03 (m,
3H), 3.82 (m, 1H), 3.65 (m, 2H), 3.48 (m, 1H), 3.09 (m,
2H), 2.93 (m, 1H), 2.30 (m, 2H), 1.32 (s, 9H), 1.16 (m,
3H). MS APCI, m=z ¼ 511 (MꢀBocþH).
Solid (72%). (300 MHz, CDCl3) d 8.28 (s, 1H), 7.87 (dd,
2H), 7.67 (m, 2H), 7.24 (m, 2H), 6.98 (d, 1H), 5.60 (m,
1H), 4.90 (m, 2H), 4.69 (d, 1H), 4.00 (s, 3H), 3.72 (m,
1H), 3.46 (s, 3H), 2.79 (m, 2H), 2.62 (m, 2H), 2.40 (m,
1H), 2.45 (m, 1H), 1.19 (d, 3H). MS APCI, m=z ¼ 511
(MþH).

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2665
5.47. Methyl 3-cyano-2-[((1R)-2-{[(2S)-2-(3,4-dichloro-
phenyl)pent-4-en-1-yl]amino}-1-methylethoxy)methyl]-
1-naphthoate (23e)
2H), 3.29 (m), 2.47 (m), 2.28 (m, 1H), 1.21 (d, 3H). MS
APCI, m=z ¼ 497 (MþH).
Compound 22e (15.80 g, 25.84 mmol) was dissolved in
9:1 (v/v) dichloromethane–trifluoroacetic acid at 0 ꢁC
under N2. After 30 min the solution was allowed to
warm to ambient temperature and stirred an additional
2 h. The solvent was evaporated and the residue parti-
tioned between ethyl acetate and saturated aqueous so-
dium bicarbonate. The organic phase was separated,
dried (Na2 SO4), filtered and evaporated to afford
5.51. 3-Cyano-2-[((1S)-2-{[(2S)-2-(3,4-dichlorophenyl)-
pent-4-en-1-yl]amino}-1-methylethoxy)methyl]-1-naph-
thoic acid hydrochloride (24d)
Solid (62%). (300 MHz, CDCl3) d 7.92 (s, 1H), 7.78 (d,
1H), 7.71–7.52 (m, 3H), 7.37 (s, 1H), 7.24 (d, 1H), 7.06
(dd, 1H), 5.30 (d, 2H), 4.99 (m, 4H), 4.65 (d, 1H), 4.30
(m, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 3.13 (d, 1H), 2.86
(t, 1H), 2.56 (m, 1H), 2.35 (m, 1H), 1.34 (d, 3H). MS
APCI, m=z ¼ 497 (MþH).
1
12.78 g (97%) of the title compound as a yellow oil. H
NMR (300 MHz, CDCl3) d 8.32 (s, 1H), 7.94 (d, 1H,
J ¼ 7:9 Hz), 7.82 (d, 1H, J ¼ 7:9 Hz), 7.70 (m, 2H), 7.25
(m, 1H), 7.16 (d, 1H, J ¼ 8:3 Hz), 6.99 (dd, 1H,
J ¼ 2:2; 8:3 Hz), 5.56 (m, 1H), 5.00–4.80 (m, 4H), 4.62
(d, 1H, J ¼ 10:9 Hz), 4.03 (s, 3H), 3.89 (br, 1H), 3.14–
2.86 (m, 4H), 2.81–2.71 (m, 1H), 2.48–2.23 (m, 2H), 1.27
(d, 3H, J ¼ 6:1 Hz). MS APCI, m=z ¼ 511 (MþH).
5.52. 3-Cyano-2-[((1R)-2-{[(2S)-2-(3,4-dichlorophenyl)-
pent-4-en-1-yl]amino}-1-methylethoxy)methyl]-1-naph-
thoic acid hydrochloride (24e)
1
Tan solid (88%). H NMR (300 MHz, CDCl3) d 10.75
(br, 1H), 8.23 (s, 1H), 7.90 (m, 2H), 7.66 (m, 2H), 7.23
(m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 6.68 (br, 2H), 5.54
(m, 1H), 5.02 (m, 3H), 4.71 (m, 1H), 4.25 (m, 1H), 3.34–
2.82 (m, 5H), 2.57–2.32 (m, 2H), 1.38 (d, 3H,
J ¼ 6:1 Hz). MS APCI, m=z ¼ 497 (MþH).
5.48. 3-Cyano-2-[(2-{[(2S)-2-(3,4-dichlorophenyl)pent-4-
en-1-yl]amino}ethoxy)methyl]-1-naphthoic acid hydro-
chloride (24a)
A mixture of 23a (1.5 g, 3.0 mmol) and pyridine hydro-
chloride (3.5 g, 30 mmol) was heated with stirring in a
pre-heated 180 ꢁC oil bath for 15 min. The cooled resi-
due was partitioned between ethyl acetate and water,
washed with 0.5 N HCl and brine, dried (MgSO4), fil-
tered, concentrated under reduced pressure, and diluted
with diethyl ether to afford a precipitate, which was
collected to afford 24a (1.1 g, 70%) as a tan solid.1H
NMR (300 MHz, CDCl3) d 9.11 (br s, 1H), 8.17 (s, 1H),
7.98 (d, 1H), 7.82 (d, 1H), 7.73 (t, 1H), 7.62 (t, 1H), 7.40
(d, 1H), 7.27 (d, 1H), 7.11 (dd, 1H), 5.61 (m, 1H), 5.05
(m, 2H), 4.97 (s, 2H), 4.03 (m, 2H), 3.40 (m, 2H), 3.20
(m, 3H), 2.48 (m, 2H). MS APCI, m=z ¼ 483 (MþH).
5.53. 2-[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-yl]-1-oxo-
1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocine-7-
carbonitrile (25a)
A solution of 24a (0.78 g, 1.7 mmol), N,N-diisopropyl-
ethylamine (0.54 mL, 3.1 mmol) and bis-(2-oxo-3-oxa-
zolidinyl)-phosphinic chloride (0.40 g, 1.57 mmol) in
acetonitrile (40 mL) was stirred for 1 h. Additional di-
isopropylethylamine (0.14 mL, 0.80 mmol) and bis-(2-
oxo-3-oxazolidinyl)-phosphinic
chloride
(0.10 g,
0.39 mmol) were added and the mixture stirred for 0.5 h,
concentrated, diluted with ethyl acetate; washed with
0.5 N HCl, and brine, dried (MgSO4), filtered, concen-
trated, and purified by flash chromatography (20–30%
ethyl acetate/hexanes) to afford 0.41 g (53%) of the title
compound as a foam solid. 1H NMR (300 MHz, CDCl3)
d 8.29 (s), 8.23 (s), 8.04 (d), 7.91 (d), 7.80 (m), 7.66 (t),
7.50 (m), 7.37 (m), 7.28 (m), 7.13 (dd), 6.69 (d), 5.67 (m),
5.11–4.74 (m), 4.62 (m), 4.02–3.68 (m), 3.49–2.98 (m),
2.64–2.43 (m). MS APCI, m=z ¼ 465 (MþH).
24b–e were prepared analogously to 24a:
5.49. 3-Cyano-2-{[((2R)-2-{[(2S)-2-(3,4-dichlorophenyl)-
pent-4-en-1-yl]amino}propyl)oxy]methyl}-1-naphthoic
acid hydrochloride (24b)
Solid (68%) 1H NMR (300 MHz, CDCl3) d 9.31 (s, 1H),
8.30 (s, 1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.71 (m, 2H),
7.56 (s), 7.27 (d, 1H), 7.10 (d, 1H), 7.04 (m, 1H), 5.60 (m,
1H), 4.99 (m, 4H), 3.87 (m, 2H), 3.50 (m, 1H), 3.23 (m,
2H), 2.43 (m, 2H), 2.09 (m, 1H), 1.40 (d, 3H). MS APCI,
m=z ¼ 497 (MþH).
25b–e were prepared analogously to 25a:
5.54. (3R)-2-[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-yl]-
3-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-
oxazocine-7-carbonitrile (25b)
5.50. 3-Cyano-2-{[((2S)-2-[(2S)-2-(3,4-dichlorophenyl)-
pent-4-en-1-yl]aminopropyl)oxy]methyl}-1-naphthoic acid
hydrochloride (24c)
Solid (36%). 1H NMR (300 MHz, CDCl3) d 8.16 (s, 1H),
7.79 (d, 1H), 7.54 (m, 2H), 7.41 (m, 3H), 6.53 (d, 1H),
5.69 (m, 1H), 5.39 (m, 1H), 5.07 (m, 2H), 4.86 (m, 1H),
4.61 (m, 1H), 3.99 (m, 1H), 3.76 (m, 1H), 3.47 (m, 1H),
3.07 (m, 2H), 2.49 (m, 2H), 1.21 (d, 3H). MS APCI,
m=z ¼ 479 (MþH).
Solid (49%). 1H NMR (300 MHz, DMSO) d 8.76 (s,
1H), 8.16 (d, 1H), 7.96 (d, 1H), 7.81 (m, 2H), 7.53 (m,
2H), 7.26 (m, 1H), 5.53 (m, 1H), 4.86 (m, 4H), 3.66 (d,

2666
C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
5.55. (3S)-2-[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-yl]-
3-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-
oxazocine-7-carbonitrile (25c)
5.59. 2-(2R)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-
3-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-
f][1,4]oxazocine-7-carbonitrile (26b)
1
(49%). H NMR (300 MHz, CDCl3) d 8.22 (s), 7.97 (d),
Solid (71%). 1H NMR (300 MHz, CDCl3) d 9.79 (s, 1H),
8.16 (s, 1H), 7.79 (d, 1H), 7.53 (m, 3H), 7.40 (m, 2H),
6.49 (d, 1H), 5.11 (q, 2H), 4.55 (m, 1H), 3.98 (m, 1H),
3.76 (t, 1H), 3.60 (m, 1H), 3.47 (m, 1H), 3.20 (m, 1H),
2.97 (m, 2H), 1.31 (d, 3H). MS APCI, m=z ¼ 481
(MþH).
7.88 (d), 7.76 (t), 7.63 (t), 7.52 (m), 7.40 (m), 7.14 (m),
6.56 (d), 5.73 (m), 5.36 (d), 5.06 (m), 4.85 (d), 4.15
(m), 3.84 (m), 3.53 (m), 2.93 (m), 2.69 (m), 2.52 (m),
0.93 (d), 0.61 (d), 0.42 (d). MS APCI, m=z ¼ 479
(MþH).
5.60. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-3,3-di-
methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-
oxazocine-7-carbonitrile (26c)
5.56. (4S)-2-[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-yl]-
4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-
oxazocine-7-carbonitrile (25d)
1
Solid (64%). H NMR (300 MHz, CDCl3) d 9.81 (s),
Solid (57%). 1H NMR (300 MHz, CDCl3) d 8.31 (s, 1H),
8.09 (d, 1H), 7.92 (d, 1H), 7.77 (t, 1H), 7.65 (t, 1H), 7.38
(m, 2H), 7.14 (dd, 1H), 5.72 (m, 1H), 5.30 (s, 1H), 5.11
(m, 1H), 5.04 (m, 2H), 4.57 (m, 2H), 3.89 (m, 1H), 3.45
(m, 1H), 3.07 (m, 2H), 2.51 (m, 2H), 1.01 (d, 3H). MS
APCI, m=z ¼ 479 (MþH).
8.24 (s), 7.96 (d), 7.90 (d), 7.78 (t), 7.65 (t), 7.48 (d), 7.41
(d), 7.19 (m), 6.51 (d), 5.34 (d), 5.22 (d), 4.87 (d), 4.43
(d), 4.15 (m), 3.92 (m), 3.63 (t), 3.44 (m), 3.32 (d), 3.06
(m), 0.71 (d), 0.45 (d). MS APCI, m=z ¼ 481 (MþH).
5.61. (3R,4S)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-
3,4-dimethyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-
f][1,4]oxazocine-7-carbonitrile (26d)
5.57. (4R)-2-[(2S)-2-(3,4-Dichlorophenyl)pent-4-en-1-yl]-
4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-
oxazocine-7-carbonitrile (25e)
Solid (67%). 1H NMR (300 MHz, CDCl3) d 9.78 (s, 1H),
9.00 (d, 1H), 8.32 (s, 1H), 8.09 (t, 1H), 7.92 (d, 1H), 7.77
(m, 1H), 7.67 (m, 1H), 7.41 (m, 2H), 5.12 (d, 1H), 4.56
(m, 2H), 3.90 (m, 1H), 3.45 (d, 2H), 3.09 (m, 3H), 1.05
(m, 3H). MS APCI, m=z ¼ 481 (MþH).
Purification by flash chromatography (100:1, dichlo-
romethane–methanol) afforded the title compound as a
1
colorless oil (58%). H NMR (300 MHz, CDCl3) d 8.25
(s, 1H), 7.82 (d, 1H, J ¼ 7:4 Hz), 7.60–7.47 (m, 3H), 7.37
(m, 1H), 7.26 (m, 1H), 6.71 (d, 1H, J ¼ 8:3 Hz), 5.66
(m, 1H), 5.19–4.86 (m, 4H), 4.57 (d, 1H, J ¼ 13:5 Hz),
3.96 (m, 1H), 3.22–3.00 (m, 4H), 2.50 (t, 2H,
J ¼ 7:0 Hz), 1.17 (d, 3H, J ¼ 6:6 Hz). MS APCI, m=z ¼
479 (MþH); Anal. Calcd for C27H24Cl2N2O2Æ1.0H2O: C,
65.20; H, 5.27; N, 5.63. Found: C, 65.23; H, 4.88; N,
5.61.
5.62. (3R,4R)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-
3,4- dimethyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-
f][1,4]oxazocine-7-carbonitrile (26e)
Colorless oil (47%). 1H NMR (300 MHz, CDCl3) d 9.79
(s, 1H), 8.26 (s, 1H), 7.83 (d, 1H, J ¼ 8:3 Hz), 7.61–7.46
(m, 3H), 7.42 (d, 1H, J ¼ 2:2 Hz), 7.28 (m, 1H), 6.68 (d,
1H, J ¼ 8:3 Hz), 5.16 (d, 1H, J ¼ 14:0 Hz), 4.90 (m,
1H), 4.55 (d, 1H, J ¼ 14:0 Hz), 3.96 (m, 1H), 3.75–3.57
(m, 1H), 3.18 (m, 3H), 2.95 (d, 2H, J ¼ 7:0 Hz), 1.21 (d,
3H, J ¼ 6:6 Hz). 13C NMR (75 MHz, CDCl3) d 199.15,
168.54, 140.92, 136.81, 133.28, 132.74, 132.34, 132.01,
131.57, 131.26, 130.82, 130.69, 130.36, 128.32, 128.26,
127.93, 125.78, 117.3, 110.02, 73.78, 66.79, 53.07, 47.92,
47.8, 36.28, 20.02. MS APCI, m=z ¼ 481 (MþH).
5.58. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-1-oxo-
1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocine-7-
carbonitrile (26a)
A stream of ozone was passed through a solution of 25a
(0.40 g, 0.89 mmol) in methanol (10 mL) and dichlo-
romethane (20 mL) at ꢀ78 ꢁC for 5 min when the blue
solution color persisted. Stirring was continued for
10 min then nitrogen was bubbled through for 5 min.
The reaction was warmed to ꢀ30 ꢁC and dimethyl
sulfide (0.32 mL, 4.4 mmol) was added. The mixture was
warmed to room temperature, stirred 1.5 h, concen-
trated, and purified by chromatography using 50–60%
ethyl acetate/hexanes to afford the product (0.30 g, 75%)
as a foam solid. 1H NMR (300 MHz, CDCl3) d 9.79 (d),
8.31 (s), 8.23 (s), 8.03 (d), 7.92 (d), 7.80 (m), 7.67 (t),
7.59–7.37 (m), 7.28 (m), 7.19 (dd), 6.66 (d), 5.08–4.74
(m), 4.61 (m), 4.05–3.01 (m), 2.96 (d), 2.76 (m). MS
APCI, m=z ¼ 467 (MþH).
5.63. 2-((2S)-2-(3,4-Dichlorophenyl)-4-4-[2-(methylsulfin-
yl)phenyl]piperidin-1-ylbutyl)-1-oxo-1,3,4,6-tetrahydro-
2H-naphtho[1,2-f][1,4]oxazocine-7-carbonitrile (27)
A solution of 26a (50 mg, 0.11 mmol), 4-[(S)-2-methyl-
sulfinylphenyl]-piperidine43 (30 mg, 0.13 mmol), and
acetic acid (0.012 mL) was stirred in methanol (2 mL) for
0.5 h. Sodium cyanoborohydride (12 mg, 0.19 mmol)
was added as a solution in methanol (1 mL) in three
portions over 10 min., stirred 2 h, then concentrated
under reduced pressure. The residue was diluted with
ethyl acetate, washed with water and brine, dried
26b–e were prepared analogously to 26a:

C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
2667
(MgSO4), filtered, concentrated, and purified by flash
chromatography to afford the product (50 mg, 69%) as a
solid, which was converted to the citrate salt. H NMR
(300 MHz, DMSO-d6) d 8.68 (s), 8.62 (s), 8.09 (d),
8.01 (d), 7.94–7.36 (m), 6.47 (d), 4.87 (m), 4.72 (t),
4.00 (t), 3.90–3.64 (m), 3.51–1.75 (m). MS APCI, m=z ¼
674 (MþH). HRMS (CI) m=z calculated for
C37H37Cl2N3O3S (MþH) 674.2011, found: 674.2009.
5.66. (3S)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-(dimethyl-
amino)butyl]-3-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naph-
tho[1,2-f][1,4]oxazocine-7-carbonitrile trifluoroacetate
(30)
1
1
Oil (95%). H NMR (300 MHz, DMSO) d 9.46 (s), 8.67
(s), 8.62 (s), 8.08 (d), 8.03 (d), 7.90 (d), 7.82 (t), 7.71 (t),
7.64 (d), 7.43 (m), 6.37 (d), 5.30 (d), 5.01 (d), 4.84 (d),
4.35 (d), 3.68 (m), 3.20 (m), 2.80 (t), 2.15 (m), 0.45 (d),
0.23 (d). MS APCI, m=z ¼ 510 (MþH). HRMS (CI) m=z
calculated for C28H29Cl2N3O2 (MþH) 510.1710, found
510.1733.
5.64. 2-[(2S)-2-(3,4-Dichlorophenyl)-4-(dimethylamino)-
butyl]-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-
oxazocine-7-carbonitrile (28)
A solution of 26a (0.10 g, 0.021 mmol), triethylamine
(0.034 mL, 0.038 mmol), and dimethylamine hydro-
chloride (23 mg, 0.28 mmol) was dissolved in 2 mL of
methanol. Acetic acid was added dropwise until the pH
was between 4 and 5. After stirring for 1.5 h a solution
of sodium cyanoborohydride (23 mg, 0.37 mmol) in
methanol (1 mL) was added in three portions over
10 min and the reaction was allowed to stir for 3 h. The
mixture was concentrated; diluted with ethyl acetate,
washed with water and brine, dried (MgSO4); filtered,
concentrated, and purified by flash chromatography (6–
10% methanol/dichloromethane). An ethyl acetate
solution of the product containing trace amount of tri-
ethylamine was washed with water and brine; dried
(MgSO4), filtered, and concentrated under reduced
pressure to afford the title compound (80 mg, 75%) as an
oil. This material was converted to the citrate salt by
combining with an equimolar amount of citric acid in
5.67. (4S)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-(dimethyl-
amino)butyl]-4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-
naphtho[1,2-f][1,4]oxazocine-7-carbonitrile (31).
Oil (21%)
1H NMR (300 MHz, DMSO) d 8.33 (s, 1H), 8.03 (d, 1H),
7.93 (d, 1H), 7.77 (t, 1H), 7.67 (t, 1H), 7.43 (m, 2H), 7.21
(dd, 1H), 5.15 (d, 1H), 4.53 (m, 2H), 3.87 (m, 1H), 3.46
(m, 1H), 3.08 (m, 2H), 2.84 (m, 3H), 2.31 (m, 2H), 2.13
(br s, 6H), 1.02 (d, 3h). MS APCI, m=z ¼ 510 (MþH).
5.68. (4R)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-(dimethyl-
amino)butyl]-4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-
naphtho[1,2-f][1,4]oxazocine-7-carbonitrile (32)
Compound 26e (160 mg, 0.333 mmol) was dissolved in
THF (1 mL) and dimethylamine (2 M solution in THF,
416 lL, 0.832 mmol) was added. The mixture was di-
luted with methanol (3 mL) and stirred for 10 min.
Sodium cyanoborohydride (50 mg, 0.796 mmol) was
added and the reaction was stirred for 2 h at ambient
temperature. The reaction mixture evaporated and the
residue purified by preparative HPLC [Phenomenex
LUNA C-18(2), 250 · 21.2 mm (10l) column eluting
with acetonitrile–water gradient containing 0.1% TFA
(40–70% acetonitrile over 20 min.)]. Fractions contain-
ing product were pooled and partially concentrated to
remove the acetonitrile. The residual aqueous solution
was made basic by addition of 10% aqueous sodium
carbonate, and the solution extracted with ethyl acetate
(3x). The organic extracts were dried (Na2SO4), filtered,
and evaporated to afford 73 mg (0.143 mmol, 43% yield)
1
methanol, then drying. H NMR (300 MHz, DMSO-d6)
d 8.68 (s), 8.62 (s), 8.09 (d), 8.01 (d), 7.90 (d), 7.82–7.59
(m), 7.40 (m), 6.44 (d), 4.87 (m), 4.71 (t), 4.32 (dd), 3.99
(t), 3.89–3.64 (m), 3.42–2.94 (m), 2.83–2.55 (m), 2.10.
MS APCI, m=z ¼ 496 (MþH). HRMS (CI) m=z calcu-
lated for C27H27Cl2N3O2 (MþH) 496.1559, found:
496.1553.
29, 30, 31, and 32 were prepared analogously to 28.
They were purified by reverse phase HPLC on a Phe-
nomenex LUNA C-18(2), 250 · 21.2 mm (10l) column
eluting with acetonitrile–water gradient containing 0.1%
TFA (40–70% acetonitrile over 20 min) and several were
isolated as the trifluoroacetate salt by concentration of
the appropriate fractions.
1
of the title compound as a white foamy solid. H NMR
(300 MHz, CDCl3) d 8.24 (s, 1H), 7.81 (m, 1H), 7.59–
7.45 (m, 3H), 7.39 (m, 1H), 7.29–7.24 (m, 1H), 6.74
(d, 1H, J ¼ 8:2 Hz), 5.15 (d, 1H, J ¼ 14:2 Hz), 4.91
(t, 1H, J ¼ 14:2 Hz), 4.56 (d, 1H, J ¼ 14:2 Hz), 3.96
(m, 1H), 3.21–3.03 (m, 4H), 2.19 (m, 8H), 1.96–1.75
(m, 2H), 1.17 (d, 3H, J ¼ 6:1 Hz); 13C NMR (75 MHz,
CDCl3) d 168.69, 142.35, 137.05, 133.97, 132.87,
132.58, 132.36, 131.67, 131.37, 131.27, 131.16,
131.00, 130.62, 129.20, 128.57, 128.37, 126.26,
117.72, 110.39, 74.03, 67.15, 57.36, 53.47, 49.17,
45.76, 40.99, 32.13, 20.45. MS APCI, m=z ¼ 510
(MþH). Anal. Calcd for C27H27Cl2N3O2Æ1.0H2O: C,
63.64; H, 5.91; N, 7.95. Found: C, 63.96; H, 5.58; N,
8.03.
5.65. (3R)-2-[(2S)-2-(3,4-Dichlorophenyl)-4-(dimethyl-
amino)butyl]-3-methyl-1-oxo-1,3,4,6-tetrahydro-2H-
naphtho[1,2-f][1,4]oxazocine-7-carbonitrile trifluoroace-
tate (29)
1
Gum (quant.) H NMR (300 MHz, DMSO) d 9.46 (s,
1H), 8.54 (s, 1H), 7.98 (d, 1H), 7.73 (m, 2H), 7.61 (t,
1H), 7.51 (d, 1H), 7.33 (t, 1H), 6.31 (d, 1H), 5.07 (q, 2H),
4.48 (t, 1H), 3.92 (m, 1H), 3.73 (t, 1H), 3.57 (m, 1H),
3.10 (m, 3H), 2.75 (t, 7H), 2.09 (m, 2H), 1.16 (d, 3H).
MS APCI, m=z ¼ 510 (MþH). Anal. Calcd for
C28H29Cl2N3O2Æ1.5 C2HF3O2: C, 54.64; H, 4.51; N, 6.17.
Found: C, 54.86; H, 4.25; N, 6.21.

2668
C. J. Ohnmacht et al. / Bioorg. Med. Chem. 12 (2004) 2653–2669
17. Gale, J. D.; O’Neill, B. T.; Humphrey, J. M. Expert Opin.
Ther. Patents 2001, 11, 1837.
5.69. Methyl 2-(bromomethyl)-3-cyano-1-naphthoate (33)
A solution of methyl-3-cyano-2-methyl-1-naphthoate26
(4.8 g, 21.3 mmol), N-bromosuccinimide (15.2 g,
85.4 mmol), and 2,20-azobis(2-methylisobutyronitrile)
(0.35 g, 2.1 mmol) in carbon tetrachloride (85 mL) was
heated under reflux for 3 h. The cooled mixture was
diluted with dichloromethane and water and the excess
N-bromosuccinimide quenched by adding sodium thio-
sulfate pentahydrate (15.2 g, 61.2 mmol) and stirring for
0.5 h. The layers were separated and the organic washed
with water and brine, dried (MgSO4), filtered; and
concentrated under reduced pressure. The crude mate-
rial was then passed through a plug of silica gel using
40–60% dichloromethane/hexanes as eluant to afford the
18. Stout, S. C.; Owens, M. J.; Nemeroff, C. B. Annu. Rev.
Pharmacol. Toxicol. 2001, 41, 877.
19. Rupniak, N. M. J.; Kramer, M. S. Trends Pharmacol. Sci.
1999, 20, 485.
20. Andersson, K. E. Exp. Physiol. 1999, 84, 195.
21. Bain, E. E.; Candilis, P. J. Expert Opin. Ther. Patents
2000, 10, 389.
22. Anon Med. Lett. Drugs Ther. 2003, 45, 62.
23. Shenvi, A. B.; Aharony, D.; Brown, F. J.; Buckner, C. K.;
Campbell, J. B.; Dedinas, R. F.; Gero, T. W.; Green, R.
C.; Jacobs, R. T.; Kusner, E. J.; Miller, S. C.; Ohnmacht,
C.; Palmer, W.; Smith, R.; Steelman, G.; Ulatowski, T.;
Veale, C.; Walsh, S. In Abstracts of Papers, Part 1, 214th
National Meeting of the American Chemical Society, Las
Vegas, NV, 1–7 September 1997; p MEDI 264.
24. Bernstein, P. R.; Aharony, D.; Albert, J. S.; Andisik, D.;
Barthlow, H. G.; Bialecki, R.; Davenport, T.; Dedinas, R.
F.; Dembofsky, B. T.; Koether, G.; Kosmider, B. J.;
Kirkland, K.; Ohnmacht, C. J.; Potts, W.; Rumsey, W. L.;
Shen, L.; Shenvi, A.; Sherwood, S.; Stollman, D.; Russell,
K. Bioorg. Med. Chem. Lett. 2001, 11, 2769.
1
title compound as a white solid (5.2 g, 80%). H NMR
(300 MHz, CDCl3) d 8.33 (s, 1H), 7.90 (m, 2H), 7.69 (m,
2H), 4.82 (s, 2H), 4.13 (s, 3H). MS APCI, m=z ¼ 304
(Mþ).
25. Rumsey, W. L.; Aharony, D.; Bialecki, R. A.; Abbott, B.
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Acknowledgements
We gratefully acknowledge Herbert G. Barthlow and
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