Structural optimization affording 2-(R)-(1-(R)-3,5- bis(trifluoromethyl)phenylethoxy)-3'-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4- triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist

Article abstract of DOI:10.1021/jm980299k

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3,5- bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phe

Full text of DOI:10.1021/jm980299k

J . Med. Chem. 1998, 41, 4607-4614
4607
Str u ctu r a l Op tim iza tion Affor d in g
2-(R)-(1-(R)-3,5-Bis(tr iflu or om eth yl)p h en yleth oxy)-3-(S)-(4-flu or o)p h en yl-4-
(3-oxo-1,2,4-tr ia zol-5-yl)m eth ylm or p h olin e, a P oten t, Or a lly Active, Lon g-Actin g
Mor p h olin e Aceta l Hu m a n NK-1 Recep tor An ta gon ist
J effrey J . Hale,*,† Sander G. Mills,† Malcolm MacCoss,† Paul E. Finke,† Margaret A. Cascieri,†
Sharon Sadowski,† Elzbieta Ber,† Gary G. Chicchi,† Marc Kurtz,† J oseph Metzger,† George Eiermann,†
Nancy N. Tsou,† F. David Tattersall,‡ Nadia M. J . Rupniak,‡ Angela R. Williams,‡ Wayne Rycroft,‡
Richard Hargreaves,‡ and D. Euan MacIntyre†
Merck Research Laboratories, P.O. Box 2000, Rahway, New J ersey 07065, and Neuroscience Research Centre,
Merck, Sharp & Dohme, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received May 13, 1998
Structural modifications requiring novel synthetic chemistry were made to the morpholine
acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery
of 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-
5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor
antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably
expressed in CHO cells (IC50 ) 0.09 ( 0.06 nM) and by the measurement of the rates of
association (k1 ) 2.8 ( 1.1 × 108 M-1 min-1) and dissociation (k-1 ) 0.0054 ( 0.003 min-1) of
17 from hNK-1 expressed in Sf9 membranes which yields Kd ) 19 ( 12 pM and a t1/2 for receptor
occupancy equal to 154 ( 75 min. Inflammation in the guinea pig induced by a resiniferatoxin
challenge (with NK-1 receptor activation mediating the subsequent increase in vascular
permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17
(IC50 (1 h) ) 0.008 mg/kg; IC90 (24 h) ) 1.8 mg/kg), indicating that this compound has good
oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is
also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1
agonist-induced foot tapping response in gerbils (IC50 (4 h) ) 0.04 ( 0.006 mg/kg; IC50 (24 h)
) 0.33 ( 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge.
The activity of 17 at extended time points in these preclinical animal models sets it apart
from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and
could prove to be an advantage in the treatment of chronic disorders related to the actions of
Substance P. In part on the basis of these data, 17 has been identified as a potential clinical
candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and
various psychiatric disorders.
In tr od u ction
The central and peripheral actions of the mammalian
tachykinin Substance P (SP) have been associated with
numerous inflammatory conditions including migraine,1
rheumatoid arthritis,2 asthma,3 and inflammatory bowel
disease4 as well as mediation of the emetic reflex5 and
the modulation of central nervous system (CNS) disor-
ders such as Parkinson’s disease6 and anxiety.7 This
profile has stimulated a search for potent, nonpeptide
out independently by groups at Pfizer and Glaxo-
Wellcome, has resulted in the discovery of CP 122,72111
antagonists of the human neurokinin-1 (hNK-1) receptor
to which SP preferentially binds.8 This search has
further intensified in recent years due in part to the
demonstration that a selective hNK-1 antagonist (CP
99,994, 1) exhibits antiemetic activity in mammals
against a broad spectrum of emetogens.9 This property
of 1 coupled with its reported modest oral bioavailabil-
ity10 serves to further emphasize the clinical utility of
a hNK-1 receptor antagonist exhibiting a favorable
pharmacokinetic profile. The modification of 1, carried
(2) and GR 205,17112 (3), both of which are reported to
† Merck Research Laboratories.
‡ Merck, Sharp & Dohme.
exhibit enhanced potency and oral activity in animal
10.1021/jm980299k CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/02/1998

4608 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Hale et al.
models of SP-induced inflammation and emesis.13 The
first report of the prevention of chemotherapy-induced
emesis in humans by an hNK-1 receptor antagonist (2)
has appeared.14
Sch em e 1
Our efforts to target a series of potent, orally active
hNK-1 antagonists based on a morpholine acetal core
and exemplified by 4 were recently disclosed;15 the
biochemical characterization16 and the antiemetic activ-
ity17 of this compound have been subsequently docu-
mented. The continuation of work in this area focused
on identifying the features of 4 that could be considered
to be potential metabolic liabilities and making struc-
tural changes to 4 that would lessen their effect while
not compromising the pharmacologic profile initially
observed with this class of compounds. Specifically, it
was reasoned that debenzylation of 4, via either a
hydrolytic or oxidative pathway, would be slowed by
substituting one of the benzylic hydrogens with a methyl
group.18 While oxidative metabolism of the electron-poor
3,5-bis(CF3)-substituted phenyl ring of 4 seemed to be
unlikely, such a process seemed possible with the phenyl
ring at C3 of the morpholine. Substituting the para
position of this phenyl ring (the most likely point for
metabolism) with a fluorine atom would serve to block
metabolism and slow oxidation at other positions of the
ring. Metabolism of the (3-oxo-1,2,4-triazol-5-yl)methyl
functionality of 4 or dealkylation of the morpholine
nitrogen also seemed possible, but we chose to maintain
this structural feature as the structure-activity rela-
tionship of pendant heterocycles that was developed for
the closely related piperidine ether hNK-1 antagonists19
indicated that this feature exhibited appreciable stabil-
ity in vitro toward rat liver microsomal incubation and
optimally imparted favorable in vivo properties to these
molecules. We report herein the novel synthetic chem-
istry employed to prepare the compounds targetted as
the result of our reasoning and the resulting optimiza-
tion of these morpholine acetal compounds which af-
forded hNK-1 antagonists exhibiting high potency and
enhanced duration of action in vivo as compared to
compounds 1-4.
analogous strategy for the preparation of compounds
with R-methyl substitution on the C2 benzyl ether was
not effective. The secondary triflate (6) required for this
reaction was readily obtained and handled, but it could
not be used in the reduction/alkylation sequence. There
was no direct alkylation by 6 of the intermediate
obtained during L-Selectride reduction of 5 under the
previously employed reaction conditions; the only prod-
uct seen was 7 which results from the reaction of 6 with
the THF solvent and the subsequent alkylation of the
“L-Selectride alkoxide” by the resulting oxonium ion.
A different strategy that takes advantage of the facile
acylation of the morpholinone “L-Selectride alkoxide”
met with more success (Scheme 2). Morpholinone 5 was
again reacted with L-Selectride in THF at -78 °C, and
the reaction was quenched with 3,5-bis(trifluoromethyl)-
benzoyl chloride to afford acyl acetal 8 in 79% yield. This
compound was first reacted with Tebbe reagent20 to
provide the stable enol ether 9 in 15% yield which has
the carbon skeleton of the desired C2 R-methyl benzyl
ether compounds, albeit in the wrong oxidation state.
The low yield for the acyl acetal to enol ether conversion
was attributed to the Lewis acidity of the Tebbe reagent
and was improved to 69% by employing dimethyl
titanocene;21 this reagent generates an analogous tita-
nium ylide under neutral conditions. Catalytic hydro-
genation of 9 to give 10 and 11 was first carried out
stepwise: the enol ether double bond was reduced in
the presence of rhodium on alumina or rhodium on
carbon (affording a 2:1 mixture of R-methyl diastereo-
mers), and the primary N-benzyl group was reduced in
the presence of palladium on carbon. It was subse-
quently found that concomitant reduction of the double
bond and the N-benzyl substituent was possible by
carrying out the hydrogenation of 9 in the presence of
palladium on carbon catalyst; this resulted in an
increased diastereoselection (8:1) favoring the formation
of 10 which has the R-(R)-methyl stereochemistry.22
Both 10 and 11 were converted to the corresponding
methylene-linked 3-oxo-1,2,4-triazol-5-yl derivatives, 12
and 13, using conditions previously reported.15
Ch em istr y
The key step in the preparation of morpholine acetal
hNK-1 antagonists such as 4 was a reduction/alkylation
sequence in which 3-(S)-phenyl-4-benzyl-2-morpholi-
none (5) was first treated with lithium tri-sec-butyl-
borohydride (L-Selectride) in THF at -78 °C and the
resulting intermediate was reacted at low temperature
with 3,5-bis(trifluoromethyl)benzyl triflate (Scheme 1).15
This reaction afforded an intermediate morpholine
acetal in which the substituents at C2 and C3 of the
morpholine are in the preferred cis configuration. An
Compounds 14 and 15 were also prepared from 5 by

Discovery of a Potent hNK-1 Receptor Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4609
Ta ble 1. hNK-1 Receptor Binding
Sch em e 2
compd
hNK-1 IC50 (nM)a
1
(()-2
3
4
12
13
14
15
16
0.5 ( 0.1
0.14 ( 0.06
0.08 ( 0.05
0.09 ( 0.03 (n ) 6)
0.88 ( 0.03
0.09 ( 0.03
0.10 ( 0.02
0.27 ( 0.03
0.07 ( 0.05
17
0.09 ( 0.06 (n ) 7)
a
Displacement of 125I-labeled SP from the human NK-1 receptor
expressed in CHO cells. Data are reported as the mean ( SD for
n ) 3 determinations unless otherwise noted.
the hNK-1 receptor, [125I]neurokinin A from the human
NK-2 receptor, and [125I]Bolton-Hunter-labeled eledoisin
from the human NK-3 receptor, all stably expressed in
CHO cells.25 The ability of test compounds to inhibit
[3H]diltiazem binding to the L-type calcium channel in
rabbit skeletal muscle26 was also determined.
The data obtained for hNK-1 receptor binding are
shown in Table 1. The hNK-1 binding affinities for 12
and 13 indicate that the R-(R) stereochemistry is
required for methyl-substituted C2 benzyl ethers to
avoid a significant loss of affinity. Replacement of one
of the trifluoromethyl groups in the C2 benzyl ether with
a fluorine (14) afforded another compound that was
equipotent to 4, while removal of the trifluoromethyl
group (15) led to a 3-fold decrease in receptor affinity.
Substitution of the phenyl ring at C3 of 4 with a fluorine
atom at its 4-position gave 16, which has the highest
affinity of this series. High affinity for the hNK-1
receptor was also seen in 17 (which incorporates the
R-(R)-methyl group of 12 and the fluorine substitution
of 16), demonstrating that both structural changes could
be made to 4 without a deleterious effect on this
property. The most potent morpholine compounds (4,
12, 14, 16, 17) had hNK-1 receptor affinity comparable
to that of the piperdine compounds 2 and 3. All of the
new compounds prepared had hNK-2 IC50 > 1 µM,
simply substituting the appropriate benzoyl chloride in
the reduction/acylation step. Compounds 16 and 17,
which have a fluorine atom at the 4-position of the C3
phenyl ring, were prepared from (S)-(4-fluoro)phenyl-
glycine23 using the methods previously described15 or
the methods described above. The preparation of [3H]-
17 used for a portion of its in vitro functional charac-
terization required the modification of the synthetic
chemistry described above and will be detailed else-
where.24
hNK-3 IC50 > 100 nM, and L-type Ca2+ channel IC50
1 µM.
>
These initial observations prompted the further char-
acterization of 17. As was previously reported for 4,16
preincubation (15 min at 37 °C) of CHO cells expressing
hNK-1 receptors with increasing concentrations of 17
increases the apparent EC50 for SP stimulation of
inositol phosphate synthesis and decreases the maximal
stimulation observed (Figure 1). Thus, 17 produces an
insurmountable antagonism of SP in this test system.
These data suggest that 17 is a noncompetetive or
pseudo-irreversible hNK-1 antagonist. In addition, the
level of inositol phosphate synthesis in the absence of
added SP is higher in CHO cells expressing the hNK-1
receptor than the levels in null CHO cells that do not
express the receptor (Figure 2). Inositol phosphate
synthesis is partially inhibited by 17 in CHO cells
expressing the hNK-1 receptor, but not in null CHO
cells, although this effect has proven to be variable
depending on the lot of serum utilized to support the
growth of these cells (Figure 2). These data suggest that
the high levels of heterologous expression of the hNK-1
receptor result in a population of receptors that are
activated in the absence of agonist and that 17 attenu-
In Vitr o Bioch em istr y
The binding affinities of test compounds were deter-
mined by measuring the displacement of [125I]SP from

4610 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Hale et al.
F igu r e 3. Dissociation of [3H]-17 from the hNK-1 receptor at
22 °C. The ligand (1.2 nM) was incubated with hNK-1
expressed in baculovirus-infected Sf9 cells until equilibrium,
and dissociation was initiated with addition of 100-fold excess
of unlabeled ligand. Data shown are the average of two
experiments.
F igu r e 1. Inhibition of SP-induced inositol-1-phosphate (IP1)
synthesis in hNK-1/CHO cells by 17. SP was incubated in the
absence (-b-) or presence of 0.3 (-O-) or 1 nM (-9-) 17 added
15 min before addition of SP.
Ta ble 2. Inhibition of Resiniferatoxin-Induced Systemic
Vascular Leakage in Guinea Pig (SYVAL)
compd
ID50 (po, 1 h, mg/kg)a
ID90 (po, 24 h, mg/kg)a
(()-2
3
0.010
0.007
0.006
0.010
0.008
0.008
>10b
>10c
5.4
4
13
16
17
2.3
2.3
1.8
a
Antagonist was administered po followed by resiniferatoxin
challenge at the time indicated. Dose-response data was deter-
b
mined for n ) 4-12 animals/data point. 12 ( 25% inhibition at
10 mg/kg. c 33 ( 14% inhibition at 10 mg/kg.
constants for the association of [3H]-17 with the hNK-1
receptor at 22 °C at 4.7, 7.8, and 22.3 nM are 1.7, 2.6,
and 3.4 min-1, respectively, and the calculated rate of
association (k1) from these data is 2.8 ( 1.1 × 108 M-1
min-1. Calculation of the Kd from the ratio of k-1/k1
gives a value of 19 ( 12 pM, which likely represents
the true affinity of 17 for the hNK-1 receptor.
F igu r e 2. Effect of 17 on inositol phosphate synthesis in CHO
cells in the absence (-O-) or presence (-b-) of transfected hNK-1
receptor. Mean data ( SEM are shown for two determinations
for two independent experiments.
ates this activation. This suggests that 17 is an inverse
agonist of the hNK-1 receptor in this system and shows
similar pharmacological activity to that observed with
some other antagonists of G protein-coupled receptors.27
Similar observations have been made using 1 and 3,
suggesting that this property is not unique to 17 (data
not shown). In addition, the enantiomers of these
compounds are much less active as inverse agaonists,
consistent with their poorer affinity for the hNK-1
receptor. It should be noted that the relevance of this
inverse agonist activity as observed in test systems with
highly overexpressed receptors to the activity of the
compounds in vivo in tissues expressing physiological
levels of receptors is unclear.
Saturation binding analysis with increasing concen-
trations of [3H]-17 demonstrates that the ligand specif-
ically binds to the hNK-1 receptor expressed in Sf9
membranes16 with Kd ) 0.2 nM (data not shown). [3H]-
17 dissociates from the hNK-1 receptor with simple
monophasic kinetics with a rate of dissociation (k-1) of
0.0054 ( 0.003 min-1 (n ) 3) and t1/2 for receptor
occupancy of 154 ( 75 min (Figure 3, n ) 2). The rate
In Vivo P h a r m a cology
Intravenous administration of resiniferatoxin induces
a dose-dependent vascular leakage in the esophagus,
trachea, and bladder of guinea pigs. This response
results from the neuropeptide liberation from capsaicin-
sensitive nerve fibers that is induced by resiniferatoxin
(with SP mediating the increase in vascular perme-
ability) and is inhibited by the systemic administration
of hNK-1 receptor antagonists. This provides a ready
method for examining the ability of a test compound to
prevent NK-1-mediated inflammation in the periphery
and, when the compound is administered po, an indica-
tion of its oral bioavailability. The results of the assay
(SYVAL28) based on these phenomena for the series of
compounds described herein are shown in Table 2.
Piperidines (()-2 and 3 and the morpholines 4, 13, 16,
and 17 were all potent inhibitors of this response (ID50
e 0.1 mpk, po) when given 1 h prior to resiniferatoxin
challenge. Differences in potency were seen in the
morpholine compounds when these were administered

Discovery of a Potent hNK-1 Receptor Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4611
Ta ble 3. Inhibition of GR 73632-Induced Foot Tapping in
Gerbils
piperidine compounds as it was greater than 16 times
more potent than (()-2 and 33 times more potent than
(()-3 at this time point. This result indicates that while
the piperidine compounds (()-2 or (()-3 quickly pen-
etrate the CNS, they also clear from the CNS and/or
dissociate from central NK-1 receptors more rapidly
than does 17.
ID50 (iv, mg/kg)a
compd
t ) 0 h
t ) 4 h
t ) 24 h
(()-2
(()-3
4
13
16
0.03
0.04
0.85
0.16
0.30
0.36
0.24
0.02
ndc
0.04
0.07
0.04
5.37
>10b
2.88
1.11
1.24
0.33
Preclinical studies have demonstrated that the retch-
ing and vomiting induced by emetogens such as cis-
platin, apomorphine, and morphine can be attenuated
by the preadministration of an NK-1 receptor antag-
onist.9-12 The fact that 5-HT3 receptor antagonists,
which are currently used in the treatment of chemo-
therapy-induced emesis, are ineffective against centrally
acting emetogens (apomorphine, morphine) and the
gastric irritant copper sulfate29 suggests that NK-1
receptor antagonists may provide protection against a
broader spectrum of emetogens than do the existing
therapies. The antiemetic action of 17 against cisplatin,
apomorphine, and morphine is shown in Table 3.
Suppression of emesis by 17 was seen on cisplatin,
apomorphine, and morphine challenge at doses that
compare favorably to the effective doses reported for 211a
and 3.12 In addition, 17 was found to be 10 times more
potent than 4 (ID90 ) 3.0 mg/kg, iv) in inhibiting
cisplatin-induced emesis, indicating again that the
structural changes made to 4 resulting in 17 are
pharmacologically favorable.
17
a
Test compounds were administered iv followed by GR 73632
challenge icv at the time indicated. ID50 data was calculated by
nonlinear least-squares regression analysis of mean data. Between
3 and 9 animals received one dose of each test compound or vehicle.
b
47 ( 12% inhibtion at 10 mg/kg. c Not determined.
24 h prior to challenge, with 17 being 3 times more
potent than 4. The duration of action of the series of
morpholine compounds in this assay greatly differs from
that of either piperidine compound; both (()-2 and 3
are essentially inactive at the 24 h time point. These
results indicate that all of the compounds tested have
appreciable oral bioavailability and that the piperidine
compounds are metabolized and/or excreted at a rate
higher than that of the morpholine compounds. The
trend in increasing potency seen in the morpholine
series could be attributed to the enhanced metabolic
stability afforded by the structural changes that were
made in modifying 4 to 17.
Foot tapping in gerbils can be induced by the central
infusion of an NK-1-selective agonist (GR 73632).17 This
readily quantifiable response can be inhibited by the
systemic adminstration of brain penetrant NK-1 an-
tagonists and therefore provides a convenient assay for
CNS penetration. The activity in such an assay of
several of the compounds described herein is shown in
Table 3. The piperidines (()-2 and (()-3 are potent
inhibitors of the foot tapping response when dosed
immediately prior to NK-1 agonist challenge; (()-3
maintains this activity when administered 4 h before
GR 73632 challenge. The morpholines 4, 13, 16, and
17 are less potent on immediate pretreatment but have
comparable potency to (()-3 at 4 h, indicating that they
penetrate the CNS more slowly than do either (()-2 or
(()-3. Two observations are notable regarding the data
that were obtained when the test compounds were
administered 24 h prior to GR 73632 challenge. First,
the trend in the duration of action of the morpholine
compounds 4, 13, 16, and 17 that was observed for
perpheral NK-1 blockade (SYVAL, see preceding para-
graph) is even more distinct in this assay of central
NK-1 blockade. The most active morpholine (17) is 9
times more potent than the least active morpholine (4),
indicating that the structural modifications made to 4
are pharmacodynamically beneficial. Second, 17 exhib-
its a central duration of action superior to either of the
Con clu sion
Structural modifications requiring novel synthetic
chemistry were made to the morpholine hNK-1 receptor
antagonist L-742,694 (4), and this has resulted in the
discovery of L-754,030 (17). This compound is a potent
inverse agonist of the hNK-1 receptor in the in vitro
systems described herein and antagonizes the effects
of SP in a pseudo-irreversible or noncompetitive man-
ner. Kinetic analysis of the rates of association and
dissociation of 17 from the hNK-1 receptor are consis-
tent with the hypothesis that 17 is a competitive
antagonist that can behave as a pseudo-irreversible
antagonist under some conditions due to its slow rate
of dissociation from the receptor. The actions of SP are
potently antagonized by 17 in a dose-dependent manner
in vivo in both the periphery and the CNS, and this
compound exhibits antiemetic activity comparable to the
piperidine hNK-1 receptor antagonists 2 and 3. The
observed enhanced duration of action of 17 as compared
to piperidines 2 and 3 and the morpholine hNK-1
antagonist 4 sets it apart from these compounds; this
property could be advantageous if an hNK-1 antagonist
proves to be useful in the treatment of disorders related
to the sustained actions of SP. The data presented
herein support the further evaluation of 17 as a
potential clinical candidate for the treatment of pain,30
Ta ble 4. Antiemetic Actions of 17 in the Ferreta
emetogen
dose of 17
retches
vomits
control retches
control vomits
cisplatin, 10 mg/kg, iv
cisplatin, 10 mg/kg, iv
apomorphine, 0.25 mg/kg, sc
morphine, 0.5 mg/kg, sc
3.0 mg/kg, po
0.3 mg/kg, iv
3.0 mg/kg, po
3.0 mg/kg, po
2.8 ( 1.7
5.3 ( 3.3
4.1 ( 1.8
6.0 ( 3.0
0.5 ( 0.3
1.0 ( 0.7
0.7 ( 0.4
0.5 ( 0.3
154.8 ( 14.5
100.0 ( 24.4
28.3 ( 6.5
22.3 ( 2.1
12.7 ( 3.8
3.3 ( 0.8
5.5 ( 1.1
44.7 ( 7.3
a
17 was adminstered iv or po followed by emetogen challenge after 3 min (iv experiment) or 60 min (po experiments). Drug vehicle
(control) was PEG 300 (iv experiment) or 0.5% Methocel (po experiment). Between 4 and 7 animals received one dose of 17 or drug
vehicle.

4612 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Hale et al.
migraine, chemotherapy-induced emesis,31 and psychi-
atric disorders.
2-(R)-(1-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth en yloxy)-
3-(S)-p h en yl-4-ben zylm or p h olin e (9). A solution of 2.50
g (4.9 mmol) of 8 in 75 mL of THF was treated with 75.0 mL
of 1.0 M dimethyl titanocene21 solution in toluene, and the
resulting mixture was stirred in an oil bath set at 85 °C for
18 h. The reaction mixture was cooled and concentrated.
Flash chromatography on 150 g of silica gel using 3:1 v/v
hexanes/CH2Cl2 as the eluant afforded 1.71 g (69%) of 9 as a
solid. An analytical sample was obtained by recrystallization
Exp er im en ta l Section
Gen er a l. See Supporting Information for general experi-
mental details.
(()-1-(3,5-Bis(t r iflu or om et h yl)p h en yl)et h ylt r iflu or o-
m eth ylsu lfon a te (6). A solution of 5.00 g (19.5 mmol) of 3,5-
bis(trifluoromethyl)acetophenone in 100 mL of MeOH at 0 °C
was treated with 400 mg (10.6 mmol) of NaBH4. The resulting
mixture was stirred cold for 15 min, the reaction was quenched
with 25 mL of 2.0 N HCl, and the MeOH was removed in
vacuo. The resulting aqueous mixture was partitioned be-
tween 250 mL of ether and 25 mL of 2.0 N HCl, and the layers
were separated. The organic layer was washed with 100 mL
of saturated NaHCO3 and 100 mL of saturated NaCl, dried,
and concentrated. The resulting solid was recrystallized from
50 mL of hexanes at -78 °C to afford 4.70 g (93%) of (()-1-
(3,5-bis(trifluoromethyl)phenyl)ethanol: 1H NMR (200 MHz)
1.55 (d, J ) 6.5, 3H), 2.11 (br s, 1H), 5.05 (q, J ) 6.5, 1H),
7.79 (s, 1H), 7.84 (s, 2H).
A solution of 2.58 g (10.0 mmol) of (()-1-(3,5-bis(trifluoro-
methyl)phenyl)ethanol and 2.57 g (12.5 mmol) of 4-methyl-
2,6-di-tert-butylpyridine in 30 mL of CCl4 was treated with
1.85 mL (11.0 mmol) of trifluoromethanesulfonic anhydride,
and the resulting mixture was stirred at room temperature
for 45 min. The mixture was filtered using a Schlenk ap-
paratus, and the filtrate was concentrated. The residue was
redissolved in 10 mL of CH2Cl2 and used immediately. 1H
NMR (200 MHz) of the crude triflate revealed that it was an
8:1 mixture of 6 (6.03, J ) 6.5, -CH(CH3)-OSO2CF3) and
diastereomeric symmetrical benzyl ethers (4.36, J ) 6.8 and
4.60, J ) 6.6, ArCH(CH3)OCH(CH3)Ar).
2-(R)-(4-(1-(RS)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth ox-
yl)bu tyloxy)-3-(S)-p h en yl-4-ben zylm or p h olin e (7). A so-
lution of 1.00 g (3.7 mmol) of 515 in 15 mL of THF at -78 °C
was treated with 4.20 mL of 1.0 M L-Selectride in THF. The
resulting mixture was stirred cold for 1 h and then was treated
with a solution of 6 in 10 mL of CH2Cl2. The reaction was
stirred at -78 °C for 2 h and at -50 °C for 20 h, quenched
with 50 mL of saturated NaHCO3, and extracted with 100 mL
of ether. The organics were separated, washed with 50 mL of
0.5 N KHSO4 and 50 mL of saturated NaCl, dried, and
concentrated. Flash chromatography on 50 g of silica gel using
20:1 v/v and then 10:1 v/v hexanes/CH2Cl2 afforded 890 mg
(41%) of 7 as a 3:2 mixture of inseparable diastereomers: 1H
NMR (400 MHz) 1.39 (d, J ) 6.5) and 1.45 (d, J ) 6.5),
diastereomeric -OCH(CH3)Ar; 4.54 (d, J ) 2.7) and 4.57 (J )
2.7), diastereomeric -O-CH-O-; FAB-MS 582 (M + H).
i
from PrOH, mp 112-114 °C: [R] ) +105.4 (c ) 1.0); 1H NMR
(400 MHz) 2.42 (dt, J ) 3.6, 12.0, 1H), 2.87-2.91 (m, 1H), 2.92
and 4.00 (ABq, J ) 13.6, 1H), 3.62-3.66 (m, 1H), 3.73 (d, J )
2.8, 1H), 4.09 (dt, J ) 2.4, 12.0, 1H); 4.75 (d, J ) 3.2, 1H),
4.79 (d, J ) 3.2, 1H), 5.36 (d, J ) 2.8, 1H), 7.24-7.42 (m, 8H),
7.63 (app d, J ) 7.2, 2H), 7.79 (s, 1H), 7.91 (s, 2H); FAB-MS
508(M + H). Anal. (C27H23F6NO2) C, H, N, F.
2-(R)-(1-(R)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth oxy)-3-
(S)-p h en ylm or p h olin e (10) a n d 2-(R)-(1-(S)-(3,5-Bis(tr i-
flu or om et h yl)p h en yl)et h oxy)-3-(S)-p h en ylm or p h olin e
(11). A mixture of 1.50 g (2.9 mmol) of 9 and 750 mg of 10%
palladium on carbon in 25 mL of 3:1 v/v EtOAc/iPrOH was
stirred under an atmosphere of H2 for 48 h. The catalyst was
filtered onto a pad of Celite; the reaction flask and filter cake
were rinsed well with EtOAc (∼500 mL). The filtrate was
concentrated. Flash chromatography on 60 g of silica gel using
2:1 v/v hexanes/ether as the eluant afforded 106 mg (9%) of
11 as an oil; further elution with 3:2 v/v ether/hexanes afforded
899 mg (75%) of 10 as an oil. For 10: 1H NMR (400 MHz)
1.46 (d, J ) 6.4, 3H), 1.92 (br s, 1H), 3.13 (dd, J ) 12.0, 3.2,
1H), 3.24 (dt, J ) 3.2, 12.0, 1H), 3.61-3.64 (m, 1H), 4.04 (d, J
) 2.4, 1H), 4.14 (dt, J ) 2.8, 12.0), 4.48 (d, J ) 2.4, 1H), 4.90
(q, J ) 6.4, 1H), 7.21-7.33 (m, 7H), 7.64 (s, 1H); NH3/CI-MS
420 (M + H). Anal. (C20H19F6NO2) C, H, N, F. For 11: 1H
NMR (400 MHz) 1.14 (d, J ) 6.4, 3H), 1.82 (br s, 1H), 3.04
(dd, J ) 12.0, 2.8, 1H), 3.19 (dt, J ) 3.6, 12.4, 1H), 3.44-3.48
(m, 1H), 3.83 (dt, J ) 2.4, 12.0, 1H), 4.12 (d, J ) 2.4, 1H), 4.69
(q, J ) 6.4, 1H), 4.91 (d, J ) 2.4, 1H), 7.29-7.42 (m, 5H), 7.72
(s, 2H), 7.76 (s, 1H).
2-(R)-(1-(R)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth oxy)-3-
(S )-p h e n yl-4-(3-oxo-1,2,4-t r ia zol-5-yl)m e t h ylm or p h o-
lin e (12). A solution of 945 mg (2.3 mmol) of 10, 447 mg (2.7
mmol) of N-methoxycarbonyl-2-chloroacetamidrazone,32 and
0.78 mL of DIEA in 17 mL of MeCN was stirred at room
temperature for 20 h. The mixture was concentrated, the
residue was partitioned between 50 mL of CH2Cl2 and 25 mL
of H2O, and the layers were separated. The organic layer was
dried and concentrated. Flash chromatography on 50 g of
silica gel using 50:1:0.1 v/v/v CH2Cl2/MeOH/H2O as the eluant
afforded 1.12 g (91%) of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-
phenyl)ethoxy)-3-(S)-phenyl-4-(2-N-(methoxycarbonyl)aceta-
midrazono)morpholine (10a ) as a solid, mp ) 91-94 °C: [R]
2-(R)-(3,5-Bis(tr iflu or om eth yl)ben zoyloxy)-3-(S)-p h en -
yl-4-ben zylm or p h olin e (8). A solution of 2.67 g (10.0 mmol)
of 515 in 40 mL of THF at -78 °C was treated with 12.5 mL of
1.0 M L-Selectride solution in THF, maintaining the internal
temperature below -70 °C. The resulting solution was stirred
cold for 45 min and then was charged with 3.60 mL (20.0
mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The result-
ing yellow mixture was stirred cold for 30 min and then
quenched with 50 mL of saturated NaHCO3. The quenched
mixture was partitioned between 300 mL of ether and 50 mL
of water, the layers were separated, and the organic layer was
dried. The aqueous layer was extracted with 300 mL of ether;
the extract was dried and combined with the original organic
layer. The combined organics were concentrated. Flash
chromatography on 250 g of silica gel using 20:1 v/v and then
10:1 v/v hexanes/ether as the eluant gave 4.74 g of impure 8
1
) +62.0 (c ) 0.9); H NMR (400 MHz) 1.46 (d, J ) 6.5, 3H),
2.50 (dt, J ) 3.5, 12.0, 1H), 2.55 and 3.35 (ABq, J ) 14.0, 2H),
2.95 (app d, J ) 12.0, 1H), 3.46 (d, J ) 2.5, 1H), 3.65-3.68
(m, 1H), 3.78 (s, 3H), 4.25 (dt, J ) 2.5, 12.0, 1H), 4.37 (d, J )
2.5, 1H), 4.86 (q, J ) 6.5, 1H), 5.35 (br s, 2H), 7.15 (s, 2H),
7.29-7.35 (m, 5H), 7.61 (s, 1H), NH3/CI-MS 549 (M + H).
A suspension of 1.01 g (1.8 mmol) of 10a in 15 mL of xylenes
was heated at reflux for 2 h. The mixture was cooled and
concentrated. Flash chromatography on 50 g of silica gel using
40:1:0.1 v/v/v CH2Cl2/MeOH/H2O as the eluants afforded 781
mg of impure 12. Recrystallization from 50 mL of 10:1 v/v
hexanes/EtOAc afforded 710 mg (76%) of pure 12, mp ) 220-
1
221 °C: [R] ) +44.5 (c ) 1.0); H NMR (400 MHz) 1.47 (d, J
) 6.8, 3H), 2.01-2.05 (m, 2H), 2.55 (dt, J ) 3.6, 12.0, 1H),
2.91 and 3.69 (ABq, J ) 10.8, 2H), 2.95-2.98 (m, 1H), 3.49 (d,
J ) 2.4, 1H), 3.63-3.67 (m, 1H), 4.29 (dt, J ) 2.4, 10.0), 4.38
(d, J ) 2.4, 1H), 4.88 (q, J ) 6.8, 1H), 7.14 (s, 2H), 7.33-7.40
(m, 5H), 7.62 (s, 1H), 9.91 (br s, 1H), 10.16 (br s, 1H); FAB-
MS 517 (M + H). Anal. (C23H22F6N4O3) C, H, N, F.
i
as an oil. Crystallization from 100 mL of cold PrOH (0 °C)
afforded 4.04 g (79%) of 8 as a solid, mp ) 104-105 °C: [R] )
1
+130.3 (c ) 1.0); H NMR (200 MHz) 2.50 (dt, J ) 3.4, 12.0,
1H), 2.94-3.00 (m, 1H), 2.99 and 4.00 (ABq, J ) 13.6, 2H),
3.72-3.79 (m, 1H), 3.82 (d, J ) 2.6, 1H), 4.20 (dt, J ) 2.4,
12.0, 1H), 6.22 (d, J ) 2.6, 1H), 7.22-7.37 (m, 8H), 7.58 (app
d, J ) 6.8, 2H), 8.07 (s, 1H), 8.47 (s, 2H); FAB-MS 510 (M +
H). Anal. (C26H21F6NO3) C, H, N, F.
2-(R)-(1-(S)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth oxy)-3-
(S )-p h e n yl-4-(3-oxo-1,2,4-t r ia zol-5-yl)m e t h ylm or p h o-
lin e (13). The title compound was prepared in 32% yield from
11 using a procedure analogous to that described to prepare

Discovery of a Potent hNK-1 Receptor Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4613
12: 1H NMR (400 MHz) 1.09 (d, J ) 6.4, 3H), 2.47-2.53 (m,
1H), 2.83 (app d, J ) 11.6, 1H), 2.95 (d, J ) 14.0, 1H), 3.51-
3.65 (m, 3H), 4.01 (app t, J ) 11.6, 1H), 4.60, (q, J ) 6.4, 1H),
4.84 (d, J ) 2.4, 1H), 7.33-7.51 (m, 5H), 7.74 (s, 2H), 7.76 (s,
1H), 9.51 (br s, 1H), 10.00 (br s, 1H); FAB-MS 517 (M + H).
The following compounds were prepared using procedures
described in the Supporting Information or procedures analo-
gous to those above or in ref 15.
to resiniferatoxin challenge. ID50 values were calculated by
nonlinear least-squares regression analysis of the mean data.
In h ib it ion of GR 73,632-In d u ced F oot Ta p p in g in
Ger bils. Male or female Mongolian gerbils (35-70 g) were
anaesthetized by inhalation of an isoflurane/oxygen mixture
to permit exposure of the jugular vein through a skin incision
in the neck using a blunt dissection to clear surrounding
salivary gland and connective tissues. Test compound or
vehicle was administered intravenously using an injection
volume of 5 mL/kg. The wound was closed, and a second skin
incision was made in the midline of the scalp to expose the
skull. GR 73,632 was infused directly in the cerebral ventri-
cules (3 pmol in 5 mL icv) by vertical insertion of a cuffed 27-
gauge needle to a depth of 4.5 mm below bregma. The scalp
incision was closed and the animal allowed to recover from
the anaesthesia in a clear Perspex observation box (25 cm ×
20 cm × 20 cm). The duration of hind foot tapping was then
recorded continuously for 5 min using a stopclock. The time
lapse from induction to recovery of anaesthesia, with interven-
ing iv and icv injections, was 3-4 min per animal. ID50 values
were calculated by nonlinear least-squares regression analysis
of the mean data.
(R)-(1-(R)-(3-Flu or o-3-(tr iflu or om eth yl)ph en yl)eth oxy)-
3-(S)-p h en yl-4-(3-oxo-1,2,4-t r ia zol-5-yl)m et h ylm or p h o-
lin e (14): 1H NMR (400 MHz) 1.40 (d, J ) 6.3, 3H), 2.54 (app
t, J ) 11.0, 1H), 2.87 (app d, J ) 12.2, 1H), 2.94 (app d, J )
14.0, 1H), 3.46-3.48 (m, 1H), 3.63 (app t, J ) 14.0, 2H), 4.24
(app t, J ) 10.8, 1H), 4.25 (app t, J ) 11.0, 1H), 4.35 (d, J )
1.5, 1H), 4.75 (q, J ) 6.3, 1H), 6.62 (d, J ) 6.7, 1H), 6.78 (s,
1H), 7.01 (d, J ) 8.4, 1H), 7.24 (d, J ) 3.9, 1H), 7.35 (app s,
4H), 9.61 (br s, 1H), 9.89 (br s). Anal. (C22H21F4N4O3) C, H,
N, F.
(R)-(1-(R)-(3-(Tr iflu or om et h yl)p h en yl)et h oxy)-3-(S)-
p h en yl-4-(3-oxo-1,2,4-tr ia zol-5-yl)m eth ylm or p h olin e (15):
1H NMR (400 MHz) 1.40 (d, J ) 6.8, 3H), 2.53 (app t, J )
11.2, 1H), 2.86 (app d, J ) 12.2, 1H), 2.94 (app d, J ) 14.3,
1H), 3.43-3.45 (m, 1H), 3.63 (d, J ) 14.0, 2H), 4.24 (app t, J
) 10.8, 1H), 4.27 (app t, J ) 11.5, 1H), 4.34 (d, J ) 2.1, 1H),
4.76 (q, J ) 6.8, 1H), 6.63 (d, J ) 7.7, 1H), 7.06 (t, J ) 7.6,
1H), 7.25-7.45 (m, 6H), 9.63 (br s, 1H), 9.74 (br s). Anal.
(C22H22F3N4O3) C, H, N, F.
In h ibition of Em esis by 17 in th e F er r et. Male ferrets
(1.0-2.0 kg) were used in all studies. For intravenous studies,
ferrets under halothane anaesthesia were dosed with 17 (0.3
mg/kg) or drug vehicle followed 3 min later by cisplatin (10
mg/kg iv). For oral studies, ferrets were dosed with 17 (3.0
mg/kg) or drug vehicle followed 60 min later by cisplatin (10
mg/kg iv, under halothane anaesthesia), apomorphine (0.5 mg/
kg sc), or morphine (0.5 mg/kg sc). The animals dosed with
cisplatin were observed for the next 240 min for retching and
vomiting behavior, following which they were humanely killed.
Animals that were used in the apomorphine and morphine
experiments were observed for retching and vomiting for 30
min after injection of these emetogens and inspected daily for
any clinical abnormality. No adverse effects of the drug
treatments were observed following these experiments.
2-(S)-(3,5-Bis(tr iflu or om eth yl)ben zyloxy)-3-(S)-(4-flu o-
r o)p h en yl-4-(3-oxo-1,2,4-t r ia zol-5-yl)m et h ylm or p h olin e
(16): 1H NMR (400 MHz) 2.55 (dt, J ) 3.6, 12.0, 1H), 2.91 (d,
J ) 11.6, 1H), 2.93 and 3.59 (ABq, J ) 14.4, 2H), 3.57 (d, J )
2.8, 1H), 3.67-3.70 (m, 1H), 4.18 (dt, J ) 2.4, 11.6, 1H), 4.48
and 4.84 (ABq, J ) 13.6, 2H), 4.65 (d, J ) 2.8, 1H), 7.07 (t, J
) 8.4, 2H), 7.41 (s, 2H), 7.45-7.48 (m, 2H), 7.68 (s, 1H), 10.04
(br s, 1H), 10.69 (br s, 1H); FAB-MS 521 (M + H). Anal.
(C22H19F7N4O3) C, H, N, F.
(R)-(1-(R)-(3,5-Bis(t r iflu or om et h yl)p h en yl)et h oxy)-3-
(S)-(flu or o)p h en yl-4-(3-oxo-1,2,4-tr ia zol-5-yl)m eth ylm or -
p h olin e (17): mp ) 244-245 °C; [R] ) +68.1 (c ) 0.6, MeOH);
1H NMR (CDCl3 + CD3OD, 500 MHz) 1.48 (d, J ) 6.8, 3H),
2.52 (app t, J ) 10.4, 1H), 2.85-2.88 (m, 2H), 3.47 (d, J ) 2.8,
1H), 3.63 (d, J ) 14.4, 1H), 3.70 (dd, J ) 2.0, 11.6, 1H), 4.24
(app t, J ) 10.8, 1H), 4.35 (d, J ) 2.8, 1H), 4.91 (q, J ) 6.8,
1H), 7.07 (app t, J ) 8.4, 2H), 7.15 (s, 2H), 7.37-7.40 (m, 2H),
7.65 (s, 1H); FAB-MS 535 (M + H). Anal. (C23H21F7N4O3) C,
H, N, F.
Ack n ow led gm en t. We thank Ms. Amy Bernick for
providing mass spectral data.
Su p p or tin g In for m a tion Ava ila ble: Full descriptions of
the preparation and characterization of the intermediates used
to prepare 16 and 17 and crystallographic data for 17 (13
pages). Ordering information is given on any current mast-
head page.
Sen sor otoxin -In d u ced System ic Va scu la r Lea k in th e
Gu in ea P ig (SYVAL). Male Dunkin Hartley guinea pigs
(400-600 g) were anaesthetized by intramuscular injection
with Ketamine (30 mg/kg) plus xylazine (6 mg/kg). Evans Blue
dye (25 mg/mL solution in saline, containing 100 units/mL of
heparin) was filtered through a 0.22 µm disk filter and injected
intravenously via a saphenous vein. The animals were chal-
lenged intravenously by injection of capsaicin or resiniferatoxin
(400 µL/kg administered over 30 s) via the penile vein 10 min
postinjection of the Evans Blue dye. At 10 min post resin-
iferatoxin challenge, the animals were euthanized using CO2
gas, a midline incision was performed, and 1 mL of heparinized
blood sample was obtained by venepunture from the vena cava.
Cell-free plasma was prepared by centrifugation (8000 rpm, 5
min, 20 °C), and a portion (100 mL) was removed and stored
for analyses. The bladder was then removed, and the vena
cava and aorta were transected to exsanguinate the animal
prior to the removal of the trachea and the esophagus. The
tissues were placed in tared vials, dried in an oven (24 h, 65
°C), and reweighed. Dried tissue samples and an aliquot (100
mL) of plasma from the animal were extracted/incubated in
formamide (1 mL, 65 °C, 24 h). The extent of plasma
extravasation (expressed as mg plasma/g dry weight tisuue)
was assessed by comparing in a plate-reading spectrophotom-
eter the absorption (OD620-650) of the formamide extracts of
tissue to that of cell-free plasma from the same animal. Test
compounds were administered ip, iv, or orally at 1 or 24 h prior
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(22) Single-crystal X-ray analysis of 17 determined the relative
configuration to be 2-(S), 3-(R), R-(R). Since 17 is derived from
10, the stereochemical outcome of the hydrogenation of 9 is as
described in the text. Crystal structure details: C
23H21F7N4O3;
Mr ) 534.438; orthorhombic space group P212121; a ) 7.770(3),
b ) 43.031(2), c ) 7.403(3) Å; V ) 2475(2) Å3; Z ) 4; F(000) )
1096; T ) 294 K. Data were collected on an AFC5 diffactometer
to a θ limit of 72.68° using Cu KR radiation. There are 2755
unique reflections with 1339 observed at the I g 2σ(I) level. The
structure was solved by direct methods (SHELXS), and refined
(SHELXL) using full-matrix least-squares on F2 using 323
parameters and all 2755 reflections. Final agreement statistics
are R ) 0.105, wR ) 0.284, S ) 1.25, (∆/σ)max ) 0.03. The atomic
coordinates for this structure have been deposited with the
Cambridge Crystallographic Data Centre and further crystal-
lographic details are available in the Supporting Information.
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