Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

Article abstract of DOI:10.1021/jm8016514

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy} -4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK1) receptor antagonist with a long ce

Full text of DOI:10.1021/jm8016514

J. Med. Chem. 2009, 52, 3039–3046
3039
Potent, Brain-Penetrant, Hydroisoindoline-Based Human Neurokinin-1 Receptor Antagonists
Jinlong Jiang,*,† Jaime L. Bunda,† Geoge A. Doss,† Gary G. Chicchi,‡ Marc M. Kurtz,‡ Kwei-Lan C. Tsao,‡ Xinchun Tong,§
Song Zheng,§ Alana Upthagrove,§ Koppara Samuel,§ Richard Tschirret-Guth,§ Sanjeev Kumar,§ Alan Wheeldon,|
Emma J. Carlson,| Richard Hargreaves, Donald Burns, Terence Hamill, Christine Ryan, Stephen M. Krause, WaiSi Eng,
Robert J. DeVita,† and Sander G. Mills†
Departments of Medicinal Chemistry, Immunology, and Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065, Merck
Sharp and Dohme-Neuroscience Research Center, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K., and Imaging Research,
Merck Research Laboratories, West Point, PennsylVania 19486
ReceiVed December 29, 2008
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-
cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK1)
receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug
interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides
90% NK1 receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent
than aprepitant, an NK1 antagonist marketed for the prevention of chemotherapy-induced and postoperative
nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing
five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate,
an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.
Introduction
Aprepitant has been shown to have a moderate inhibitory
effect as well as a possible inductive effect on cytochrome P450
(CYP-3A4).5 Thus, there was an interest in identifying an NK1
antagonist with a diminished potential to cause drug-drug
interactions, especially for conditions that require chronic
therapy. Identifying a preclinical candidate with minimal CYP-
3A4 inhibition and induction was one strategy to achieve this
goal. An alternative approach to reduce the adverse effects might
be to improve potency and brain penetration, thereby increasing
the central receptor occupancy at a lower systemic exposure
level of the NK1 antagonist to afford a larger window with
respect to CYP inhibition or induction.
Substance P is the most abundant neurokinin in the mam-
malian central nervous system (CNSa). The substance-P-preferring
neurokinin receptor (NK1) is highly expressed in brain regions that
are critical for mediation of a variety of biological effects.1 This
laboratory discovered the non-peptide NK1 antagonist aprepitant
(1) and has demonstrated that it had clinical antiemetic activity in
phase III studies. The FDA has approved acute dosing of aprepitant
for prevention of chemotherapy-induced nausea and vomiting
(CINV) and for prevention of postoperative nausea and vomiting
(PONV). Merck has also disclosed the results of a phase IIa study
in which aprepitant was shown to have efficacy in the treatment
of overactive bladder syndrome.2 NK1 receptor antagonists may
act like capsaicin by inhibiting sensorial input from the bladder to
the spinal cord, thus increasing the threshold to initiate micturi-
tion.3 Aprepitant has also been tested clinically as a therapy for
depression.4
CNS penetration of an NK1 antagonist has been suggested
to be essential for treatment of overactive bladder.2 PET studies
in rhesus have shown that aprepitant requires a plasma level of
as high as 900 nM (470 ng/ml) to achieve 90% receptor
occupancy in rhesus.6 Therefore, a more potent NK1 receptor
antagonist that provides a high receptor occupancy at a lower
drug level in plasma in rhesus PET studies would be highly
desirable. The results of the rhesus PET studies are assumed to
be correlated to the human NK1 receptor occupancy.
Modification of the compound properties may also provide
a way to improve tolerability. Many basic amine-based NK1
antagonists have previously been reported,7 but few nonbasic
ones were found in literature. Therefore, our efforts have focused
on nonbasic NK1 antagonists in the hope of improving brain
penetration and reducing off-target activities associated with
basic amine functionalities. Indeed, a neutral vinylogous amide-
based NK1 antagonist (2) recently disclosed by our group had
shown excellent potency, selectivity, pharmacokinetic profile,
and in vivo activity as compared to aprepitant.8 However,
compound 2 showed poor in vitro inositol 1-phosphate (IP-1)9
functional activity by Schild analysis and minimal improvement
of the drug exposure in plasma required to achieve more than
90% NK1 receptor occupancy in rhesus PET studies compared
to aprepitant.8 The limited potency of compound 2 in the rhesus
PET studies may have been related to a fast off-rate from the
NK1 receptor as evidenced by the poor in vitro IP-1 activity.
* To whom correspondence should be addressed. Address: Merck Research
Laboratories, P.O. Box 2000, RY121E-20, Rahway, NJ 07065. Phone: 732-
594-2119. Fax: 732-594-2535. E-mail: jinlong_jiang@merck.com.
†
Department of Medicinal Chemistry, Merck Research Laboratories.
Department of Immunology, Merck Research Laboratories.
Department of Drug Metabolism, Merck Research Laboratories.
Merck Sharp and Dohme-Neuroscience Research Center.
‡
§
|
Imaging Research, Merck Research Laboratories.
a Abbreviations: NK1, neurokinin-1; PET, position emission tomography;
CINV, chemotherapy-induced nausea and vomiting; PONV, postoperative
nausea and vomiting; CNS, central nervous system; IP-1, inositol 1-phos-
phate; CHO, Chinese hamster ovary.
10.1021/jm8016514 CCC: $40.75
2009 American Chemical Society
Published on Web 04/08/2009

3040 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Jiang et al.
Scheme 1
Scheme 2a
a Reagents: (a) EDC/DMAP, CH3NHOCH3-HCl/CH2Cl2, 20 °C; (b)
CH2dCHMgBr/THF-ether, 0 °C (80% yield for two steps); (c) t-BuOK,
TBSCl/THF, -78 to 20 °C (85%); (d) diethyl fumarate/xylene, 150-160
°C; (e) HF in CH3CN (2 M), 20 °C; (f) aq NaOH/CH3CN, 20 °C; (g) NaBH4/
MeOH, -78 to 20 °C; (h) silica gel separation, then ChiralPak AD column
(17.2% yield for five steps from step d to step h).
Our continued pursuit of nonbasic NK1 antagonists focused
on identifying a new core from which to attach heterocycles
with the potential to increase IP-1 activity, improve potency in
rhesus PET studies, and minimize drug-drug interaction
potential. Among our newly designed lead structures, hy-
droisoindolines 3 can be viewed as a new class of compounds
with a hybrid core derived from aprepitant 1 and compound 2.
We herein report the total synthesis of enantiomerically pure
hydroisoindolines 3 which afforded enhanced hNK1 antagonist
potency with the potential for fewer drug-drug interactions
compared to aprepitant.
Scheme 3a
Chemistry
Hydroisoindolines 3 represent a novel structural class of NK1
antagonists. Scheme 1 shows the retrosynthesis of the unsub-
stituted analogue 4 on the nitrogen. We envisioned that the
construction of the cyclohexanol core 7 might be accomplished
by a Diels-Alder condensation of diene 10 with trans-
dienophiles 9 and that the (R)-R-methyl bis(trifluoromethyl)-
benzyl ether could be installed by nucleophilic displacement
on (S)-trichloroacetimidate 8 with the cyclohexanol 7. Bis-
alkylation of an amine 6 with diol 5 via a bis-mesylate
intermediate would then provide the trans-fused pyrrolidine ring
in 4.
a Reagents: (a) cat. HBF4-Et2O/dichloromethane-cyclohexane (1:3), -5
to 0 °C (59%); (b) LiBH4/THF, 75 °C (95%); (c) MsCl, TEA, cat. DMAP/
CH2Cl2, -5 °C; (d) PhCH2NH2/EtOH, 150 °C (57% for two steps c and
d); (e) Pd(OH)2/C, H2, 45 psi/EtOH, 20 °C (90%).
two ketone isomers which were epimerized with sodium
hydroxide in acetonitrile for 10 min to give the trans-trans
racemic ketone 14 as the predominant product. Racemic 14 was
reduced with sodium borohydride at -78 to 20 °C to generate
about 4:1 mixture of the desired all-trans alcohol 7a and the
3,4-cis diastereomeric alcohol 7b. The desired enantiomer 7 was
separated from the mixture of 7a and 7b by chiral column
chromatography on a ChiralPak AD column (eluted with
heptane-isopropanol). The absolute configuration of the active
series was shown to be compound 7 by NMR analyses of
compound 17 (see Scheme 4).
The ether formation of a secondary alcohol with (1S)-1-[3,5-
bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroacetimidate (8)
has been documented in literature.10 SN2 reaction of the
enantiomerically pure alcohol 7 with 8 in the presence of a
catalytic amount of tetrafluorohydroboric acid gave ether 15 in
59% yield with generation of about 15% of the undesired more
polar (1S)-diastereomer (Scheme 3) which was readily removed
Diene 10 was prepared from commercially available 4-fluo-
rophenylacetic acid 11 (Scheme 2). Thus, treatment of 4-fluo-
rophenylacetic acid with N,O-dimethylhydroxylamine and EDC
followed by reaction with vinylmagnesium bromide gave R,ꢀ-
unsaturated ketone 12. Because of the instability of the R,ꢀ-
unsaturated ketone under basic conditions, it was required that
the Grignard reaction be quenched by pouring the reaction
mixture into a mixture of ice and 2 N hydrochloric acid to
prevent the decomposition of 12. The crude 12 was directly
treated with potassium tert-butoxide and tert-butyldimethylsilyl
chloride to give 10 in about 85% yield. The Diels-Alder
reaction of the crude 10 with diethyl fumarate was carried out
in xylenes in a 150-160 °C oil bath for 5 h to give adduct 13
1
as a mixture of the two phenyl isomers, as suggested by H
NMR of the crude 13 which showed multiplets of the olefinic
signals. Without purification, the silyl group in 13 was removed
with hydrogen fluoride in acetonitrile and gave a mixture of

Hydroisoindoline-Based Antagonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3041
Scheme 4a
Table 1. IC50 for Inhibition of Binding of 125I-Substance P to the hNK1
Receptor in Vitro without and with 50% Human Serum, Inhibition of
IP-1 Generation, and ID50 for Inhibition of GR73632-Induced Gerbil
Foot Tapping by hNK1 Antagonists
IC50, nM
ID50 (iv), mg/kg
IP-1 at 100 nM
hNK1 hNK1 binding with (% of substance P
compd binding 50% human serum response remaining) pretreatment pretreatment
1 h
24 h
4
0.15
0.06
0.255
0.09
0.11
0.525
0.10
0.13
7.3
9.5
17
9.8
7.8
73
44
5
17
18
19
20
21
22
23
0.08
0.46
54
58
40
79
9
11
22
0.13
0.18
0.20
0.30
4
equipotent hNK1 receptor affinity. However, an analogue with
an aromatic ring directly attached to the pyrrolidine nitrogen
atom as in compound 21 reduced the NK1 receptor affinity about
5-fold. The inclusion of 50% human serum to the binding media
decreased the affinity of most compounds in Table 1 by over
100-fold, suggesting that these compounds have high plasma
protein binding. Compound 17 also showed excellent selectivity
for hNK1 over the hNK2 and hNK3 receptors, with affinity values
of 2.4 µM for both receptors.12
NK1 antagonists inhibit substance-P-evoked IP-1 formation
in CHO cells stably expressing the recombinant human NK1
receptor and can decrease the maximal response to substance
P.9 The decrease in the maximal achievable substance P response
by compound 17 was concentration-dependent (Figure 1),
suggesting that it acts as a noncompetitive antagonist or that it
has a slow dissociation rate from the receptor. Table 1 shows
the IP-1 functional activity induced by 10 µM substance P in
the presence of 100 nM of test compounds. Although most
of the antagonists in Table 1 have similar hNK1 receptor binding
affinities, vinylogous amides 17, 22, and 23 showed the most
potent IP-1 functional blockade after substance P challenge up
to 10 µM, with less than 10% of the substance P response
remaining (i.e., insurmountable antagonism). Similar effects
were observed with aprepitant but with a somewhat attenuated
maximal response to substance P (about 11% of the maximal
substance P response remaining with 100 nM aprepitant versus
5% for compound 17 (Figure 2). In contrast, despite its high
hNK1 binding affinity, compound 2 demonstrated only modest
effects in this screen with 93% of the maximal substance P
response remaining. The poor in vitro receptor blockade of
a Reagents: (a) cyclic 1,3-diketone, cat. PTSA/toluene, 110 °C for 17,
22, and 23; (b) aq CH2O, NaBH3CN/MeOH, 0 °C for 18; (c) CH3NCO/
CH2Cl2, 20 °C for 19; (d) CH3COCl, TEA/CH2Cl2, 20 °C for 20; (e) 2-Cl-
pyrazine/EtOH, 120 °C for 21.
by silica gel column chromatography. Treatment of compound
15 with lithium borohydride in refluxing THF afforded alcohol
5, which was then converted into dimethanesulfonate by reaction
with methanesulfonyl chloride at 0 °C for 5 min. The crude
dimethylsulfonate was heated in a 150 °C oil bath with
benzylamine (3.0 equiv) to provide bicyclic amine 16. Finally,
the N-benzyl group of 16 was removed by hydrogenolysis to
give compound 4. Intermediate 4 was used to make various
N-substituted analogues including tertiary amine 18, urea 19,
acetamide 20, vinylogous amides 17, 22, 23, and N-aryl
analogue 21 using standard conditions (Scheme 4).
The final compounds and most intermediates were character-
1
ized by H NMR and LCMS. Compound 17 was thoroughly
studied by NMR with complete 1H and 13C NMR signal
assignments being obtained by using 1D and 2D NMR
techniques (COSY, NOESY, HSQC, and HMBC). The absolute
configuration was assigned on the basis of the known R-benzyl
chiral center adjacent to the ether oxygen, which was originally
obtained from commercially available (1S)-[3,5-bis(trifluorom-
ethyl)phenylethanol used in the preparation of imidate 8.10 The
compound exists as two distinct rotamers around the cyclo-
pentenone-pyrrolidine C-N bond in solution, the result of the
compound being a vinylogous amide.
Results and Discussion
In Vitro Biology. The in vitro human NK1 binding affinities
for compounds in Table 1 for biological data were determined
using Chinese hamster ovary (CHO) cells stably expressing the
recombinant hNK1 receptor.11 By use of standard competitive
radioligand binding techniques, the affinities of test compounds
were measured using [125I]substance P. All compounds in Table
1 have shown high hNK1 receptor binding affinities. The hNK1
receptor binding data for compounds 4, 18, 19, and 20 suggested
that a carbonyl group attached to the nitrogen increased the
receptor affinity, and basicity of compounds 4 and 18 has no
contribution to NK1 receptor binding. High affinity for the NK1
receptor was also seen with vinylogous amides, especially
compound 17, which had the highest affinity shown in Table
1. Vinylogous amide 23 with a six-membered ring or 22 with
an R-methyl substituted five-membered ring afforded nearly
Figure 1. Functional antagonism of substance-P-induced inositol
phosphate generation in CHO cells expressing human NK1 receptors
by compound 17. Substance P, at the indicated concentrations, was
incubated in the absence (squares) or presence of 0.3 nM (circles),
1 nM (triangles), 3 nM (inverted triangles), 10 nM (open squares),
30 nM (open circles), or 100 nM (open triangles) compound 17.

3042 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Jiang et al.
Figure 2. Comparison of the abilities of compounds 1 (aprepitant), 2,
and 17 to reduce the maximal achievable response of substance-P-
induced inositol phosphate generation in CHO cells expressing human
NK1 receptors. Substance P, at the indicated concentrations, was
incubated in the presence of 100 nM each of 1 (circles), 2 (triangles),
or 17 (squares).
Figure 3. NK1 receptor occupancy in rhesus brain determined by
PET for compounds 2 and 17 and aprepitant. All curves were fit to
a three-parameter Hill equation with the Hill coefficients equal to
∼0.9 for compound 2 and ∼1 for both compound 17 and aprepitant,
respectively.
compound 2 was likely due to a rapid off-rate from the hNK1
receptor (t1/2 of 13 min versus 154 min for aprepitant, data not
shown).
Table 2. Pharmacokinetics of Compound 17 after Intravenous and Oral
Administrationa
In Vivo Biology. In vivo activity of the targeted NK1 receptor
antagonists was assessed in gerbils, a species with NK1 receptor
pharmacology similar to that of human.13 In this study, icv
administration of the NK1 agonist GR7363213 (24) in gerbils
elicits a vigorous, repetitive hind foot tapping response, which
can be blocked by brain penetrant NK1 antagonists but not by
nonbrain penetrant antagonists.14 Therefore, this in vivo assay
provides a convenient measure of CNS penetration and antago-
nist efficacy. Selected compounds with both good hNK1 receptor
binding affinity and potent IP-1 activity were further evaluated
in the gerbil assay. All three vinylogous amides 17, 22, and 23
in Table 1 showed good in vivo activity inhibiting foot tapping
induced by the NK1 agonist 24 after iv administration. The ID50
values ranged from 0.08 to 0.18 mg/kg after 1 h and from 0.20
to 0.46 mg/kg after 24 h of pretreatment.
The data encouraged the further characterization of compound
17. Plasma IC50 values of 17 in the gerbil foot tapping assay
were 6.5 nM at 1 h and 6 nM at 24 h, which means that about
6 nM compound 17 in plasma can block 50% of NK1 agonist
24 induced gerbil foot tapping after single iv 1 and 24 h
pretreatments. Thus, low plasma levels of compound 17 were
able to drive and maintain complete inhibition of NK1 agonist
24-induced foot tapping. The results also indicate that this
compound has rapid and high brain penetration in the gerbil
with long central duration of action.
In rhesus monkey PET studies to determine brain NK1-
receptor occupancy,15 compound 17 showed good receptor
occupancy at low plasma concentration. Occupancy was deter-
mined by comparing NK1 PET ligand, [18F]SPARQ,15 binding
in the striatum before and after dosing with the test compound
to a plasma steady state level. The protocol used was designed
to minimize changes in occupancy during image acquisition by
minimizing changes in plasma level of the test compound during
the PET study. Thus, a steady state plasma concentration of
the compound was established using an iv bolus plus a matched
constant iv infusion of the compound prior to the bolus
administration of [18F]SPARQ with the test compound infusion
being continued for the entire PET imaging. Results from this
protocol are expected to be more predictive of occupancy results
in clinical studies after chronic oral dosing with NK1 antagonists
to plasma steady state levels. As shown in Figure 3, compound
17 achieved 90% receptor occupancy at a plasma steady state
concentration of 37 ng/mL (67 nM) and 50% occupancy at 5
species
pharmacokinetic
parameter
rat
dog
monkey
CLp ((mL/min)/kg)
Vdss (L/kg)
0.7
1.5
24
40
13
0.7
2.0
31
71
27
1
2.0
24
69
18
T1/2 (h)
F (%)
oral AUCnorm(0-∞) (µM·h per mg/kg)
a Pharmacokinetics were determined at doses of 1 mg/kg iv and 2 mg/
kg po in rats and at 0.5 mg/kg iv and 1 mg/kg po in dogs and monkeys.
Oral pharmacokinetics were determined using a solution formulation in
ethanol/PEG400/water (20:40:40, v/v/v).
ng/mL (9 nM). The plasma level necessary to achieve g90%
occupancy with aprepitant was 470 ng/mL (900 nM), while a
level of 51 ng/mL (96 nM) corresponded to 50% occupancy.
For compound 2, g 90% occupancy was achieved at 390 ng/
mL (780 nM), while a level of 31 ng/mL (62 nM) corresponded
to 50% occupancy (historical data).15
Pharmacokinetics. The pharmacokinetics of compound 17
in preclinical species was characterized by a low systemic
plasma clearance, extended plasma half-life, and good oral
bioavailability (see Table 2) in three species which indicate the
possibility for once daily dosing in man.
Ancillary Activity Profile. Compound 17 was a weak
reversible inhibitor of human CYP-3A4, 2C8, 2C9, 2C19, 2D6,
and 1A2 enzymes, the IC50 values of which were 39, 58, 30,
29, 35, and >100 µM, respectively. Compound 17 did not
significantly induce CYP-3A4 mRNA in three individual
preparations of human hepatocytes. These data suggested that
compound 17 should have minimal potential for drug-drug
interactions in humans. Although broad-based counterscreening
of compound 17 in more than 145 assays identified a number
of weak activities between 1 and 10 µM, no assays for which
IC50 < 1 µM were observed. Therefore, off-target activities were
more than 20000-fold less potent than hNK1 activity.
Conclusion
Hydroisoindoline-based compound 17 is a potent, nonbasic,
brain-penetrant hNK1 antagonist with a long duration of action.
It showed 10-fold greater potency in rhesus PET receptor
occupancy study relative to aprepitant. Compound 17 also
displayed a significantly improved CYP-3A4 inhibition and

Hydroisoindoline-Based Antagonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3043
in a 150-160 °C oil bath for 5 h. The solvent was evaporated under
induction profile compared to aprepitant. The rigid structure of
17 afforded appreciable stability toward human liver microsomal
incubation in vitro and imparted favorable in vitro and in vivo
properties relative to aprepitant. Compound 17 was chosen for
further development studies, the results of which will be
described in the future.
vacuum to give an oil which was used without further purification.
Racemic Diethyl (1S,2S,3R)-3-(4-Fluorophenyl)-4-oxocyclohex-
ane-1,2-dicarboxylate and Diethyl (1R,2R,3S)-3-(4-Fluorophenyl)-
4-oxocyclohexane-1,2-dicarboxylate (14). To a solution of inter-
mediate 13 in acetonitrile (30 mL) in a plastic reaction flask was
added a solution of HF in acetonitrile (2.5 M, 200 mL) at room
temperature. The resulting mixture was stirred at room temperature
for 24 h. The reaction mixture was added to a mixture of sodium
hydroxide (5.0 N, 125 mL) and ice (100 g), then stirred for 10
min. The resulting mixture was diluted with ether (300 mL), and
the organic layer was separated. The aqueous layer was saturated
with sodium chloride and extracted with an additional portion of
ether. The combined organic layers were washed with brine and
dried (MgSO4), and the solvent was evaporated under vacuum to
Experimental Section
General. Unless specified otherwise, all materials were purchased
1
from commercial sources and used as received. H and 13C NMR
spectra were recorded on Varian 500 or Varian 600. Purity of
compounds 17-19 and intermediate 4 for NK1 receptor binding
and gerbil foot tapping assays was determined by open access
LCMS analysis (Agllent 110 system, linear gradient program using
water-0.05%TFA as solvent A and acetonitrile-0.05% TFA as
solvent B; t ) 0 min, 10% B; t ) 7 min, 100% B; flow rate, 1
mL/min; UV detection, 220 nm) as g95% pure and was confirmed
by 1H NMR before the samples were sent for testing. The g99.5%
purity of PET sample of 17 was determined by an analytic group
in house. The 100% enantiopurity of compound 17 was confirmed
by chiral HPLC on four different chiral columns (Shimadzu system,
4.6 nm × 250 nm, hexane/isopropanol): ChiralCel OD, ChiralCel
OJ, CiralPak AS, and ChiralPak AD.
1
give the crude title compounds (40.8 g). H NMR (CDCl3, 500
MHz) δ 7.10 (2 H, m), 7.05 (2 H, m), 4.23-4.15 (2 H, m),
3.90-3.80 (3 H, m), 3.32 (1 H, td, J1 ) 13.0 Hz, J2 ) 4.0 Hz),
3.21 (1 H, t, J ) 12.9 Hz), 2.68 (2 H, m), 2.55 (1 H, m), 2.07 (1
H, m), 1.30 (3 H, t, J ) 7.2 Hz), 0.85 (3 H, t, J ) 7.2 Hz).
Mixture of All-trans-Racemic Diethyl 3-(4-Fluorophenyl)-4-
hydroxycyclohexane-1,2-dicarboxylate (7a) and 3,4-cis-Diethyl (3-
(4-Fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (7b). To
a solution of the crude intermediate (14, 40.2 g, 119.3 mmol) in
methanol (150 mL) was added NaBH4 powder (4.1 g, 108.5 mmol)
under nitrogen at -78 °C. The resulting mixture was stirred at -78
°C for 2 h. The cooling bath was removed, and the reaction mixture
was allowed to warm to room temperature, then stirred for 2 h.
The reaction was carefully quenched by the addition of 30 mL of
water and acidified with hydrochloric acid (2 N). The resulting
mixture was diluted with ether, and the organic layer was separated.
The aqueous layer was saturated with sodium chloride and extracted
with an additional portion of ether. The combined organic layers
were washed with brine and dried (MgSO4), and the solvent was
evaporated under vacuum. The residue was dissolved in ether,
washed with saturated aqueous NaHCO3 and brine, dried (MgSO4),
and concentrated under vacuum to give the crude title compounds
which were preliminarily purified by column chromatography (4:1
hexane/ethyl acetate) to afford a 21 g mixture for the chiral
separation.
1-(4-Fluorophenyl)but-3-en-2-one (12). To a solution of 4-fluo-
rophenylacetic acid 11 (16.7 g, 108.4 mmol) in dry methylene
chloride (200 mL) under nitrogen was added hydrogen chloride
salt of N,O-dimethylhydroxylamine (13.8 g, 141.5 mmol), triethy-
lamine (20 mL, 143.7 mmol), 4-dimethylaminopyridine (14.2 g,
119.3 mmol), and EDC (27 g, 140.6 mmol). The reaction mixture
was stirred at room temperature for 4 h. The mixture was washed
consecutively with hydrochloric acid (2 N), brine, saturated aqueous
sodium bicarbonate, and brine. The organic layer was dried
(MgSO4) and concentrated under vacuum to give a crude 2-(4-
fluorophenyl)-N-methoxy-N-methylacetamide (21 g),which was
1
used without further purification. H NMR (CDCl3, 500 MHz) δ
7.26 (2 H, m), 7.02 (2 H, m), 3.77 (2 H, s), 3.65 (3 H, s), 3.21 (3
H, s). To a solution of vinylmagnesium bromide (220 mL, 1.0 M)
in THF (100 mL) was added dropwise under nitrogen at 0 °C a
solution of 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide (21
g, 106.6 mmol) in ether (150 mL). The mixture was stirred at 0 °C
for 0.5 h, then poured slowly into a mixture of ice (150 g) and
hydrochloric acid (2 N, 300 mL). The resulting mixture was diluted
with ether (200 mL). The organic layer was separated, and the
aqueous was extracted with ether. The combined organic layers
were washed with brine and dried over MgSO4, and the solvent
was evaporated under vacuum to give the crude title compound
(14.2 g, 80% for two steps), which was used without further
purification. 1H NMR (CDCl3, 500 MHz) δ 7.19 (2 H, m), 7.02 (2
H, t, J ) 9.5 Hz), 6.42 (1 H, dd, J1 ) 14.2 Hz, J2 ) 11 Hz), 6.34
(1 H, d, J ) 14.2 Hz), 5.86 (1 H, d, J ) 11 Hz), 3.87 (2 H, s).
Diethyl (1S,2S,3R,4S)-3-(4-Fluorophenyl)-4-hydroxycyclohex-
ane-1,2-dicarboxylate (7). An amount of 21 g of the racemic mixture
of diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-
1,2-dicarboxylate and diethyl (1R,2R,3S,4R)-3-(4-fluorophenyl)-4-
hydroxycyclohexane-1,2-dicarboxylate was separated by preparative
chiral HPLC using ChiralPak AD column, eluting with heptanes/
i-PrOH (9/1) to afford 9.09 g (20.2% yield for four steps and 17.2%
for five steps from diene 10) of the desired first eluting isomer
diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-
1
1,2-dicarboxylate. H NMR (CDCl3, 500 MHz) δ 7.25 (2 H, m),
7.05 (2 H, t, J ) 8.2 Hz), 4.20-4.05 (2 H, m), 3.85-3.72 (3 H,
m), 2.85 (2 H, m), 2.70 (1 H, t, J ) 7.8 Hz), 2.25 (2 H, m), 1.70
(1 H, m), 1.60 (1 H, m), 1.25 (3 H, t, J ) 7.2 Hz), 0.85 (3 H, t, J
) 7.2 Hz).
1E and 1Z-tert-Butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}-
dimethylsilane (10). To a solution of potassium tert-butoxide (1.0
M in THF, 104 mL) in THF (100 mL) under nitrogen at -78 °C
was added a solution of 1-(4-fluorophenyl)but-3-en-2-one (12,
14.2 g, 86.6 mmol) and tert-butylchlorodimethylsilane (13.0 g, 86.6
mmol) in THF (100 mL). The reaction mixture was stirred at -78
°C for 6 h, then at room temperature for 6 h. The mixture was
quenched with water (50 mL) and diluted with hexanes (150 mL),
and the organic layer was separated. The organic layer was washed
with brine and dried (MgSO4), and the solvent was evaporated under
vacuum to give the crude title compounds (20.5 g, 85.1% as the
(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroetha-
nimidoate (8). To a solution of (1S)-1-[3,5-bis(trifluoromethyl)phe-
nyl]ethanol (25.8 g, 100 mmol) in ether (200 mL) under nitrogen
atmosphere was added DBU (3 mL, 20 mmol) at 0 °C. After the
mixture was stirred at 0 °C for 10 min, trichloroacetonitrile (15
mL, 150 mmol) was added dropwise over 15 min. The resulting
mixture was stirred at 0 °C for 2 h, during which time it became
deep-yellow in color. The volatiles were removed under vacuum
in a water bath (<35 °C) to give a pale-brown mobile liquid which
was purified by column chromatography on silica gel (3 in. × 10
in. pad) in two batches, eluting with hexanes/EtOAc (9/1) and then
hexanes/EtOAc (4/1). The product fractions were combined and
the solvent removed under vacuum to give 37.5 g (93.6% yield) of
the title compound as a pale-yellow oil. 1H NMR (CDCl3, 500 MHz)
δ 1.74 (3 H, d, J ) 6.5 Hz), 6.07 (1 H, q, J ) 6.5 Hz), 7.82 (1 H,
s), 7.86 (2 H, s), 8.40 (1 H, br s) ppm.
1
crude product), which were used without further purification. H
NMR (CDCl3, 500 MHz) δ 7.52 (2 H, m), 6.98 (2 H, m), 6.33 (1
H, dd, J1 ) 13.2 Hz, J2 ) 8.5 Hz), 5.97 (1 H, s), 5.52 (1 H, d, J
) 13.2 Hz), 5.17 (1 H, d, J ) 8.5 Hz).
Diethyl 4-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)cy-
clohex-4-ene-1,2-dicarboxylate (13). A solution of compound 10
(37 g, ∼80% pure, 133.1 mmol) and diethyl (2E)-but-2-enedioate
(18 g, 104.6 mmol) in xylenes (200 mL) under nitrogen was heated

3044 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Jiang et al.
Diethyl (1S,2S,3R,4S)-4-{(1R)-1-[3,5-Bis(trifluoromethyl)phe-
nyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate (15).
To a solution of the enantiomer 7 (9.09 g, 26.9 mmol)) and imidate
8 (21.5 g, 53.5 mmol) in cyclohexane/1,2-chloroethane (3/1, 250
mL) under nitrogen atmosphere at -5 °C was added HBF4 (54%
in ether, 0.51 mL, 3.58 mmol). The reaction mixture was stirred at
-5 to 0 °C for 24 h, then diluted with ether. The mixture was
washed with saturated aqueous NaHCO3. The organic layer was
dried (MgSO4), and the solvent was evaporated under vacuum. The
residue was purified by flash column chromatography on silica gel,
eluting with EtOAc/hexanes (1/4) to give 9.2 g (59.2% yield) of
1.57 (1 H, m), 1.33 (3 H, t, J ) 6..5 Hz), 1.30 (1 H, m). 13C NMR
(CDCl3, 125 MHz) δ 161.6 (d, J ) 245.6 Hz), 146.2, 137.1, 131.3
(q, J ) 32.7 Hz), 129.0, 128.7, 128.4, 127.1, 126.3, 123.2 (q, J )
272.5 Hz), 121.3, 115.2, 115.0, 81.0, 74.9, 61.3, 61.2, 58.1, 58.9,
53.2, 49.0, 44.2, 32.1, 26.6, 24.4. MS: (MH)+ 566.2238 (566.2294).
(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-
4-(4-fluorophenyl)octahydro-1H-isoindole (4). To a solution of
(3aR,4R,5S,7aS)-2-benzyl-5-{(1R)-1-[3,5-bis(trifluoromethyl)phe-
nyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (16) (0.5 g,
0.88 mmol) in EtOH (50 mL) was added Pd(OH)2C (0.2 g, 20%
by weight). The reaction mixture was hydrogenated at 50 psi for
16 h at room temperature. The catalyst was filtered and the solvent
of the filtrate was evaporated under vacuum to give the title
compound (0.38 g, 90% yield). 1H NMR (CDCl3, 500 MHz) δ 7.70
(1 H, s), 7.20 (2 H, s), 6.95 (2 H, m), 6.87 (2 H, t, J ) 8.5 Hz),
4.42 (1 H, q, J ) 6.5 Hz), 3.31 (2 H, m), 2.80 (1 H, m), 2.65 (1 H,
m), 2.50 (2 H, m), 2.40 (1 H, m), 2.05 (1 H, m), 1.77 (2 H, m),
1.53 (1 H, m), 1.31 (2 H, d, J ) 6.5 Hz). 13C NMR (CDCl3, 125
MHz) δ 161.7(d, J ) 245.6 Hz), 145.8, 136.0, 131.36 (q, J ) 33.6
Hz), 128.6, 126.2, 123.1 (q, J ) 272.5 Hz), 121.4, 115.4, 115.2,
80.2, 74.9, 52.4, 49.4, 48.9, 48.2, 43.8, 31.5, 25.5, 24.3. MS: (MH)+
476.1810 (476.1824).
1
the title compound. H NMR (CDCl3, 500 MHz) δ 7.70 (1 H, s),
7.20 (2 H, s), 7.00 (2 H, m), 6.85 (2 H, t, J ) 8.5 Hz), 4.43 (1 H,
q, J ) 6.0 Hz), 4.20-4.10 (2 H, m), 3.80-3.73 (2 H, m), 3.36 (1
H, m), 2.90-2.76 (2 H, m), 2.40 (1 H, m), 2.28 (1 H, m), 1.63-1.55
(2 H, m), 1.33 (3 H, d, J ) 6.0 Hz), 1.25 (3 H, t, J ) 7.2 Hz), 0.82
(3 H, t, J ) 7.2 Hz). Unreacted starting alcohol could be recovered
by flushing the column with EtOAc and reused in the above
reaction.
[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-
3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethano (5). To a solution
of diethyl (1S,2S,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phe-
nyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate (9.2
g, 15.9 mmol) in THF (100 mL) under nitrogen atmosphere at room
temperature was added LiBH4 powder (2 g, 112.4 mmol, excess).
The resulting mixture was heated at 75 °C for 2 h. The reaction
mixture was quenched by dropwise addition of water (30 mL). The
mixture was stirred for 0.5 h, and then hydrochloric acid (2 N, 100
mL) was carefully added. The mixture was diluted with ethyl acetate
(150 mL). The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate. The combined organic extracts
were dried over MgSO4, and the solvent was evaporated under
vacuum to give 7.5 g (95% yield) of the crude diol as an oil which
was used without further purification. 1H NMR (CDCl3, 500 MHz)
δ 7.70 (1 H, s), 7.20 (2 H, s), 7.00 (2 H, m), 6.87 (2 H, t, J ) 8.2
Hz), 4.20 (1 H, q, J ) 6.0 Hz), 3.78 (1 H, m), 3.67 (1 H, m), 3.52
(1 H, m), 3.30-3.20 (2 H, m), 2.58 (1 H, t, J ) 11.9 Hz), 2.32 (1
H, m), 1.87 (1 H, m), 1.65 (1 H, m), 1.58-1.35 (3 H, m), 1.30 (3
H, t, J ) 6.0 Hz).
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phe-
nyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindol-2-yl]cyclopent-
2-en-1-one (17). To a solution of amine 4 (0.73 g, 1.5 mmol) in
toluene (25 mL) was added cyclopentane-1,3-dione (0.18 g, 1.8
mmol) and p-toluenesulfonic acid (0.03 g, 0.15 mmol). The mixture
was heated at reflux for 2 h, and the reaction was monitored by
LCMS. The solvent was removed under vacuum, and the residue
was purified by preparative TLC, eluting with CHCl3/2 N NH3 in
MeOH (9/1) to afford 0.49 g (0.88 mmol, 57%) of the title
compound. The compound could be crystallized (mp ) 216.5-217.5
°C) from hexanes/EtOAc or hexanes/EtOH. 1H NMR (CD3CN, 600
MHz) δ 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2 H, m), 6.93 (2 H, t, J
) 8.2 Hz), 4.89, 4.48 (1 H, s), 4.47 (1 H, m), 3.71, 3.48 (1 H, m),
3.35 (1 H, m), 3.28-3.17 (1 H, m), 2.95 (1 H, m), 2.95, 2.81 (1 H,
m), 2.68 (2 H, m), 2.45 (2 H, m), 2.37 (2 H, m), 2.15 (1 H, m),
1.93 (2 H, m), 1.60 (1 H, m), 1.38 (1 H, m), 1.36 (3 H, t, J ) 6.0
Hz). 13C NMR(CD3CN, 150 Mz) 201.8, 175.3, 161.6 (d, JCF
)
243 Hz), 147.1, 137.60, 130.7 (q, JCF ) 33 Hz), 129.4, 126.9, 123.7
(q, JCF ) 272 Hz), 121.3, 114.9, 98.5, 80.5, 74.7, 54.2, 52.9, 52.5,
52.5, 51.2, 48.3, 43.5, 34.0, 31.7, 27.4, 25.6, 23.7, 11.9. MS: (MH)+
556.2081 (556.2087).
(3aR,4R,5S,7aS)-2-Benzyl-5-{(1R)-1-[3,5-bis(trifluoromethyl)phe-
nyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (16). To a
solution of [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phe-
nyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol (5,
2.82 g, 85% pure, 4.9 mmol) in methylene chloride (50 mL) cooled
to -5 °C in an ice/salt bath was added methanesulfonyl chloride
(1.0 mL), triethylamine (2.1 mL), and DMAP (44 mg). The reaction
mixture was stirred at -5 °C for 10 min, then quenched with
hydrochloric acid (2 N, 50 mL) at the same temperature. The
organic layer was separated, and the aqueous layer was extracted
with additional methylene chloride (50 mL). The combined organic
layers were washed with brine and dried (MgSO4), and the solvent
was evaporated under vacuum to give [(1S,2R,3R,4S)-4-{(1R)-1-
[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclo-
hexane-1,2-diyl]di(methylene) dimethanesulfonate as an oil which
was used without further purification. In a pressure tube was placed
a solution of crude [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluorom-
ethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(m-
ethylene) dimethanesulfonate (from 2.82 g of crude diol) in ethanol
(20 mL) and benzylamine (1.2 mL, excess). The pressure tube was
sealed and heated at 150 °C in an oil bath for 3 h. The mixture
was cooled to room temperature and was stirred with NaOH (2 N,
20 mL) for 5 min. The volatiles were removed under vacuum. The
residue was diluted with 100 mL of ethyl acetate, washed with
brine, dried over MgSO4, and the solvent was evaporated under
vacuum. The residue was purified by column chromatography on
silica gel, eluting with EtOAc to give 1.6 g (57.0% for two steps)
(4R,5S)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-(4-
fluorophenyl)-2-methyloctahydro-1H-isoindole (18). To a solution
of amine 4 (0.025 g, 0.055 mmol) and aqueous formaldehyde (0.008
mL, 37% aqueous, 0.107 mmol) in methanol was added potassium
acetate (15.5 mg, 0.158 mmol) and sodium cyanoborohydride (6.7
mg, 0.105 mmol) at 0 °C. The mixture was stirred at room
temperature for 0.5 h, diluted with ether, and washed with brine.
The organic layer was separated, dried over MgSO4, and concen-
trated. The mixture was purified by preparative TLC (ethyl acetate,
23 mg, 89%). 1H NMR (CDCl3, 500 MHz) δ 7.71 (1 H, s), 7.22 (2
H, s), 7.00 (2 H, m), 6.88 (2 H, t, J ) 8.5 Hz), 4.43 (1 H, q, J )
6.5 Hz), 3.33 (2 H, m), 2.78 (2 H, m), 2.66 (1 H, m), 2.64 (3 H, s),
2.55 (1 H, t, J ) 10.5 Hz), 2.42 (1 H, m), 2.08 (1 H, m), 2.00 (2
H, m), 1.58 (1 H, m), 1.37 (1 H, m), 1.33 (3 H, d, J ) 6.5 Hz). 13
C
NMR (CDCl3, 125 MHz) δ 161.8 (d, J ) 245.7 Hz), 145.8, 135.7,
131.3 (q, J ) 33.6 Hz), 128.6, 126.1, 123.1 (q, J ) 273.1 Hz),
121.4, 115.5, 115.4, 80.0, 75.0, 60.0, 58.8, 52.4, 48.7, 43.8, 43.1,
31.5, 25.7, 24.3. MS: (MH)+ 490.2000 (490.1981).
(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-
4-(4-fluorophenyl)-N-methyloctahydro-2H-isoindole-2-carboxam-
ide (19). To a solution of amine 4 (20 mg, 0.042 mmol) in methylene
chloride (2 mL) at room temperature was added several drops of
methyl isocyanate. The resulting mixture was stirred at room
temperature for 2 h. Several drops of NaOH (2 N) were added to
the reaction mixture. The organic layer was separated and dried
over MgSO4, and the solvent was removed under vacuum. The
residue was purified by preparative TLC, eluting with EtOAc (18
mg, 80%). 1H NMR (CDCl3, 500 MHz) δ 7.71 (1 H, s), 7.23 (2 H,
1
of the title compound. H NMR (CDCl3, 500 MHz) δ 7.70 (1 H,
s), 7.35-7.20 (5 H, m), 7.20 (2 H, s), 6.97 (2 H, m), 6.85 (2 H, t,
J ) 8.2 Hz), 4.42 (1 H, t, J ) 6.0 Hz), 3.75 (2 H, d, J ) 13.4 Hz),
3.50 (2 H, d, J ) 13.4 Hz), 3.30 (1 H, m), 2.96 (1 H, m), 2.52 (3
H, m), 2.19 (2 H, m), 1.98 (1 H, m), 1.97 (1 H, m), 1.86 (2 H, m),

Hydroisoindoline-Based Antagonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3045
s), 6.98 (2 H, m), 6.85 (2 H, m), 4.45 (1 H, m), 4.00 (1 H, m), 3.68
(1 H, m), 3.36 (1 H, m), 3.08 (1 H, m), 2.93 (1 H, m), 2.77 (3 H,
s), 2.76 (1 H, m), 2.55 (1 H, m), 2.45 (1 H, m), 2.10 (1 H, d, J )
12.5 Hz), 1.82 (2 H, m), 1.60 (1 H, m), 1.30 (1 H, m). 1.30 (3 H,
d, J ) 6.5 Hz). 13C NMR (CDCl3, 125 MHz) δ 162.7 (d, J ) 245.6
Hz),157.4, 146.0, 136.4, 131.1 (q, J ) 33.6 Hz), 128.7, 126.2, 124.3,
123.1 (q, J ) 272.5 Hz), 121.4, 115.4, 115.2, 80.4, 74.8, 52.8, 50.7,
49.4, 49.0, 43.7, 31.7, 27.3, 27.2, 26.1, 26.0, 24.4. MS: (MH)+
533.2047 (533.2039).
31.6, 31.6, 27.6, 27.4, 26.0, 25.0, 24.3, 22.0, 21.9. MS: (MH)+
570.2237 (570.2243).
Acknowledgment. The authors thank the Comparative
Medicine Group for dosing the animals used in pharmacokinetic
experiments, the Synthetic Services team for scale-up and large-
scale separation of the synthetic intermediates, and Deborah J.
Newton, Regina Wang, Jiffry Ismail, and Dylan Hartley in
Department of Drug Metabolism for obtaining CYP3A4 inhibi-
tion and CYP3A4 induction data of the compounds described
in this paper. Help from Paul Finke in the preparation of this
manuscript is also gratefully acknowledged.
(4R,5S)-2-Acetyl-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-
4-(4-fluorophenyl)octahydro-1H-isoindole (20). To a solution of
amine 4 (50 mg, 0.105 mmol) in dichloromethane were added acetyl
chloride (0.015 mL, 0.21mmol), trimethylamine (0.032 mL, 0.23
mmol), and a catalytic amount of DMAP. The solution was stirred
at room temperature for 0.5 h and washed with 2 N hydrochloric
acid and brine. The organic layer was dried over MgSO4, and the
solvent was removed under vacuum. The residue was purified by
preparative TLC (1:1 ethyl acetate/hexane, 45 mg, 83%). 1H NMR
(CDCl3, 500 MHz) δ 7.70 (1 H, s), 7.23 (2 H, s), 6.98 (2 H, m),
6.89 (2 H, m), 4.46 (1 H, m), 3.88, 3.66 (1 H, m), 3.37, 2.78 (1 H,
m), 3.36 (1 H, m), 3.10 (1 H, m), 2.55 (1 H, m), 2.42 (1 H, m),
2.10 (1 H, m), 2.01, 1.88 (3 H, two singlets), 11.88 (1 H, m), 1.62
(1 H, m), 1.34 (3 H, d, J ) 6.9 Hz), 1.34 (1 H, m). 13C NMR
(CDCl3, 125 MHz) δ 169.7 169.5, 163.7 (d, J ) 245.6 Hz), 145.9,
136.2, 136.1, 131.4 (q, J ) 33.5 Hz), 128.7, 126.1, 123.1 (q, J )
272.5 Hz), 121.4, 115.6, 115.3, 80.2, 80.1, 74.8, 52.7, 52.5, 51.3,
50.5, 49.5, 49.1, 48.0, 44.2, 42.8, 31.6, 26.0, 24.3, 21.9. MS: (MH)+
518.1933 (518.1930).
Supporting Information Available: Complete 1H and 13C
NMR signal assignments of compound 17 by using 1D and 2D
NMR techniques (COSY, NOESY, HSQC, and HMBC); 1H and
13C NMR spectra of compound 4. This material is available free
of charge via the Internet at http://pubs.acs.org.
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(CDCl3, 500 MHz) δ 7.98 (1 H, s), 7.77 (2 H, s), 7.76 (1 H, s),
7.30 (1 H, s), 7.05 (2 H, m), 6.90 (2 H, m), 4.47 (1 H, q, J ) 6.5
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(9) Rupniak, N. M. J.; Carlson, E. J.; Shepheard, S.; Bentley, G.; Williams,
A. R.; Hill, A.; Swain, C.; Mills, S. G.; Salvo, J. D.; Kiilburn, R.;
Cascieri, M. A.; Kurts, M. M.; Tsao, K.-L.; Gould, S. L.; Chicchi,
G. G. Comparison the Functional Blockade of Rat Substance P (NK1)
Receptors by GR205171, RP67580, SR140333 and NKP-608. Neu-
ropharmacology 2003, 45, 231–241.
(10) Kuethe, J. T.; Marcoux, J.-F.; Wong, A.; Wu, J.; Hillier, M. C.;
Dormer, P. G.; Davies, I. W.; Hughes, D. L. Setereoselective
Preparation of a Cyclopentane-Based NK1 Receptor Antagonist
Bearing Unsymmetrically Substituted Sec-Sec Ether. J. Org. Chem.
2006, 71, 7378–7390.
(11) Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal, A.; Swain,
C. J.; Seward, E. M.; Frances, B.; Burns, D.; Strader, C. D.
Characterization of the Binding of a Potent, Selective, Radioiodinated
Antagonist to Human Neurokinin-1 Receptor. Mol. Pharmacol. 1992,
42, 458–463.
3-[(4R,5S)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-
(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-2-methylcyclopent-2-
en-1-one (22). 22 was prepared in 53% yield following the procedure
1
for compound 17. H NMR (CDCl3, 500 MHz) δ 7.70 (1 H, s),
7.23 (1 H, s), 7.00 (2 H, m), 6.90 (2 H, m), 4.47 (1 H, q, J ) 6.5
Hz), 3.37 (2 H, m), 2.55 (1 H, m), 2.50-2.13 (5 H, m), 2.15 (1 H,
m), 1.95-1.70 (5 H, m), 1.60 (1 H, m), 1.20 (1 H, m), 1.18 (3 H,
d, J ) 6.9 Hz). 13C NMR (CDCl3, 125 MHz) δ 203.2, 170.8, 161.7
(d, J ) 245.7 Hz), 145.9, 136.1, 131.3 (q, J ) 33.7 Hz), 130.9,
128.6, 128.4, 126.1, 123.1 (q, J ) 272.5 Hz), 121.4, 115.4, 115.3,
107.3, 80.2, 74.8, 54.3, 53.1, 52.5, 32.6, 31.5, 27.6, 26.0, 25.9, 24.3,
8.8. MS: (MH)+ 570.2235 (570.2243).
3-[(4R,5S)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-
(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclohex-2-en-1-one (23).
23 was prepared in 45% yield following the procedure for
1
compound 17. H NMR (CDCl3, 500 MHz) δ 7.70 (1 H, s), 7.29,
7.24 (2 H, two singlets), 6.98 (2 H, m), 6.93 (1 H, m), 5.0, 4.81 (1
H, m), 4.45 (1 H, m), 3.70, 3.47 (1 H, two multiples), 3.36 (1 H,
m), 3.15, 3.08 (1 H, two multiples), 2.92 (1 H, m), 2.87, 2.70 (1
H, two multiples), 2.55 (1 H, m), 2.30-2.50 (3 H, m), 2.15 (3 H,
m), 2.12 (1 H, m), 2.00-1.90 (4 H, m), 1.60 (1 H, m), 1.35 (1 H,
m), 1.34 (3 H, d, J ) 6.8 Hz). 13C NMR (CDCl3, 125 MHz) δ
1916.2, 196.0, 163.6, 163.3, 161.7 (d, J ) 245.6 Hz), 145.9, 136.1,
135.9, 131.4 (q, J ) 33.6 Hz), 128.5, 126.4, 126.2, 123.1 (q, J )
272.5 Hz), 121.4, 115.5, 115.3, 98.4, 98.3, 98.2, 80.2, 79.9, 74.9,
74.8, 52.8, 52.7, 52.6, 52.0, 51.7, 48.5, 48.2, 43.6, 43.0, 35.8, 35.7,
(12) Results for hNK2 and hNK3 binding assays were obtained by MSD
Pharma Services-Discovery.

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Jiang et al.
(13) Beresford, I. J. M.; Birch, P. J.; Hagan, R. M.; Ireland, S. J.
Investigation into Species Variants in Tachykinin NK1 Receptors by
Use of the Non-Peptide Antagonist, CP-96,345. Br. J. Pharmacol.
1991, 104, 292–293.
(14) Rupniak, N. M. J.; Williams, A. R. Differential Inhibition of Foot
Tapping and Chromodacryyorrhoea in Gerbils by CNS Penetrant and
Non-Penetrant Tachykinin NK1 Receptor Antagonists. Eur. J. Pha-
macol 1994, 265, 179–183.
(15) Unpublished results obtained by Merck Resarch Laboratories, Imaging
Research WP44C-2, West Point, PA 19486. The results were obtained
in rhesus macaques using the PET tracer [18F]SPARQ as described
in the following: Burns, H. D.; Hamill, T. G.; Gibson, R. E. U.S.
Patent 6,241,964, 2001.
JM8016514