N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: A novel class of potent orally active human NK1 antagonists

Article abstract of DOI:10.1021/jm9506534

The preparation of a series of N-heteroarylpiperidine ether-based human NK₁ antagonists is described. Two of the compounds (3-[{(2S,3S)-3-(((3,5- bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino}methyl ]-1,2,4- triazole (11) and 5-[{(2S,3S)-3-(((3,5- bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino}methyl ]-3-oxo- 1,2,4-triazolone (12)), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.

Full text of DOI:10.1021/jm9506534

J . Med. Chem. 1996, 39, 2907-2914
2907
N-Heter oa r yl-2-p h en yl-3-(ben zyloxy)p ip er id in es: A Novel Cla ss of P oten t Or a lly
Active Hu m a n NK1 An ta gon ists
T. Ladduwahetty,* R. Baker, M. A. Cascieri,† M. S. Chambers, K. Haworth, L. E. Keown, D. E. MacIntyre,†
J . M. Metzger,† S. Owen, W. Rycroft, S. Sadowski,† E. M. Seward, S. L. Shepheard, C. J . Swain, F. D. Tattersall,
A. P. Watt, D. W. Williamson, and R. J . Hargreaves
Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road,
Harlow, Essex CM20 2QR, U.K., and Merck Research Laboratories, Rahway, New J ersey 07065
Received September 1, 1995X
The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is
described. Two of the compounds (3-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-
2-phenylpiperidino}methyl]-1,2,4-triazole (11) and 5-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)-
phenyl)methyl)oxy)-2-phenylpiperidino}methyl]-3-oxo-1,2,4-triazolone (12)), in particular, are
orally bioavailable and exhibited significant improvements in potency, both in vitro and in
vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a
selected number of compounds from this series show the triazolone heterocycle to be
considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in
a number of assays that may be predictive of the clinical utility of substance P antagonists.
Substance P (SP) is a member of the tachykinin
peptide family that acts primarily through the NK1
receptor. There is considerable evidence to show that
this undecapeptide is implicated in a number of both
central and peripheral functions, clearly suggesting the
possible clinical potential of a SP antagonist. For
instance, it has been reported that SP is involved in
nociception, particularly in the presence of peripheral
inflammation,1,2 suggesting a role for NK1 antagonists
as non-opioid analgesics or as agents for the treatment
of rheumatoid arthritis.3 Furthermore, experimental
Having recognized that the primary carboxamide moiety
evidence shows that the stimulation of the trigeminal
nerve leads to the release of neuropeptides4a causing
inflammation of the dura mater, which can be blocked
by NK1 antagonists thus indicating their possible role
in the treatment of migraine.4b,c More recently it has
been suggested that centrally active NK1 antagonists
may have a role in controlling the emesis induced by a
variety of cytotoxic agents.5
could potentially be a liability with regards to the in
vivo pharmacokinetics of 1, we embarked on a program
to replace it with a series of 5-membered heterocycles.
We report herein the culmination of this program, with
the synthesis and in vitro and in vivo profiles of a novel
orally active NK1 antagonist 12 (L-741,671) displaying
high affinity and selectivity with excellent in vivo
activity.
Several factors preclude a number of SP antagonists
that have been disclosed so far from being of clinical
utility. For instance CP-99,994, one of the first non-
peptide NK1 antagonists to be reported in the literature,
suffers from poor oral bioavailability.10 The lack of
central nervous system (CNS) penetration7 and, in some
cases, activity at L-type calcium channels8 are other
concerns regarding currently existing antagonists. The
recent disclosure by Armour et al. of GR203040, a
potent, orally active 5-triazolyl analogue of CP-99,994,
is a testament to the fact that making some discerning
structural changes to existing leads can in fact overcome
some of these problems.10
In earlier work we had identified a series of quinu-
clidine-6e and piperidine9a-based benzyl ethers that led
to the identification of 1, a high-affinity NK1 antagonist
that is also devoid of any activity at the L-type calcium
channel (hNK1 IC50 1.3 nM, Ca2+ IC50 > 30 mM).9b We
attribute this reduction in calicum channel affinity to
the reduced pKa of the piperidine nitrogen in 1.6j
Ch em istr y
The syntheses of the isomeric imidazole analogues are
as shown in Scheme 1. Commercially available 4-(hy-
droxymethyl)imidazole and 2-imidazolecarboxaldehyde
were converted to their corresponding mesylates and
alkylated with the parent piperidine 29c to furnish the
N-protected derivatives 7a and 8a . Protection of the
imidazole nitrogen as the electron-withdrawing sulfona-
mide significantly enhanced the yield of the alkylation.
Removal of the sulfonamide to give the parent imida-
zoles 7 and 8 was accomplished under acidic conditions.
The triazole 11 and triazolone 12 (Scheme 2) were
† Merck Research Laboratories, NJ .
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
S0022-2623(95)00653-4 CCC: $12.00 © 1996 American Chemical Society

2908 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Ladduwahetty et al.
Sch em e 1a
Sch em e 3a
a
(a) NaBH4, methanol; (b) TsCl, pyridine; (c) 2, Et3N, DMF, 60
°C.
Sch em e 4a
a
(a) p-Toluenesulfonyl chloride, Et3N; (b) NaBH4, methanol; (c)
MsCl, pyridine; (d) 2, K2CO3, DMF; (e) HCl.
Sch em e 2a
a
(a) 2-Furoyl chloride, Et3N, CH2Cl2; (b) BH3-DMS, THF,
reflux.
In Vitr o Biology
The results (Table 1) indicate that while substitution
of the carboxamide in 1 (hNK1 IC50 1.3 nM) by a
lipophilic heterocycle such as furan (3, 30 nM) has a
deleterious effect on the binding to the NK1 receptor,
this loss in affinity can be regained by the addition of
polar atoms into the heterocyclic ring. The oxazole
analogue 4 (1.0 nM) and the oxadiazole 15 (0.97 nM),
the latter being a heterocycle that has previously been
established as a stable replacement for a carboxamide
in vivo,12 have the same affinity for the NK1 receptor
as the carboxamide. The isomeric imidazoles 7 (0.9 nM)
and 8 (0.53 nM) also have a similar affinity for the NK1
receptor although their affinity for the Ca2+ channel is
significantly greater than that of those analogues that
contain neutral heterocycles. Thus the relationship
between Ca2+ channel and basicity9b in this region of
the molecule is once again confirmed.6j However moving
to the triazole analogue 11 (0.22 nM) gave a significant
increase in affinity over 1, while the triazolone 12 (0.05
nM) afforded a 25-fold increase. Polar heteroatoms are
most beneficial to this region of the receptor since
replacement of the polar carbonyl group in the triaz-
olone with the more lipophilic thiocarbonyl, as in 14 (0.8
nM), leads to some loss in affinity. However, inclusion
of a negatively charged polar group such as the tetra-
zole, as in 17 (43 nM), results in a significant loss in
affinity for the NK1 receptor.
Two of the compounds, the triazolone 12 and the
triazole 11, were fully evaluated and shown to display
high affinity for the NK1 receptor while retaining
excellent selectivity over other neurokinin receptors
(NK2, NK3 > 1000 nM). In addition, the reduced
basicity of the piperidine nitrogen in L-741,671 (pKa
5.3)13 results in the complete abolition of binding to the
calcium channel (IC50 > 10 000 nM). Both compounds
have also been screened against a variety of G-protein-
linked receptors and ion channels and no significant
interactions identified.
a
(a) 2, K2CO3, DMF; (b) DMF, 140 °C.
prepared by cyclization of the intermediates 9 and 10
obtained by alkylation of the parent piperidine with the
corresponding (chloromethyl)amidrazone. The other
heterocyclic analogues were synthesized by direct alky-
lation of 2 with the tosylate of the requisite heterocycle
(Scheme 3), reduction of the amide formed by acylation
of 2 with the heterocyclic carboxylic acid chloride
(Scheme 4), or using established methodology involving
easily accessible intermediates such as the hydrazide
13 for 14 and 15 (Scheme 5) and nitrile 16 for 17
(Scheme 6).

Novel, Orally Active Human NK1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2909
Sch em e 5a
Sch em e 6a
a
(a) K2CO3, DMF, bromoacetonitrile; (b) NaN3, Et3N‚HCl,
N-methyl-2-pyrrolidone.
In Vivo Biology
The in vivo properties of 11 and 12 were explored in
three different assays intended to evaluate their thera-
peutic potential in the treatment of inflammation,
migraine, and emesis (Table 2). The SP-induced dermal
extravasation (SPIDER) assay measures the extent of
vascular leakage of Evans blue dye in the guinea pig
after the oral administration of a test compound.14 Both
compounds are extremely potent in this assay with 12
showing >40-fold increase in potency over CP-99,994.
This increase is greater than that predicted by compar-
ing the in vitro affinities of the two compounds and
therefore can only be attributed to the more favorable
pharmacokinetic profile of 12. The presence of the
heterocycle also improves oral activity in the piperidine
ether series since comparison with 1 shows 12 to have
a >20-fold increase in potency.
The stimulation of the trigeminal nerve leads to the
release of neuropeptides causing inflammation of the
dura mater.4 The extent of leakage can be assessed by
use of the plasma marker [125I]bovine serum albumin.
This extravasation in rats can be blocked by 12 in a dose
dependent manner, with an ID50 of 28 µg/kg iv, while
the triazole 11 showes an even greater potency at 8 µg/
kg iv. Thus both compounds display greater potency
than CP-99,994 in this migraine model.15
a
(a) K2CO3, ethyl bromoacetate, DMF; (b) NH2NH2, EtOH,
reflux; (c) KOCN, HCl (conctd), reflux; (d) NaOH (2 N), reflux;
(e) pentafluorophenyl formate, 50 °C; (f) SOCl2, Et3N, PhCH3,
90 °C.
In Vitr o Meta bolism /P h a r m a cok in etics
Examining a selected number of the heterocyclic
analogues in rat liver microsomes (Table 3) suggests
that the stability of the compounds vary considerably
depending on the heterocyclic substituent. Hence,
while the oxazole 4 is unstable to rat liver microsomes,
most of the compound being degraded in 15 min, the
imidazole 8 is more stable, 18% of the compound
remaining 24 h after incubation. The triazole 11
appears to be even more stable, while the triazolone 12
is more stable still, with 84% of the compound remain-
ing after 24 h.
The effects of the NK1 antagonist 12 were assessed
against the emesis induced by the cytotoxic chemothera-
Prompted by the promising results of the rat microso-
mal study of 11 and 12, their full pharmacokinetic
profiles were evaluated (Table 4). Thus 12 displays
excellent oral bioavailability in rat (46%), the result of
a relatively high clearance being compensated for by a
high volume of distribution. The triazole 11 also shows
a respectable oral bioavailability of 18% in rat, even
though the more favorable clearance rate relative to 12
is counterbalanced by a lower volume of distribution.
Furthermore the triazolone 12 has also been shown to
be orally bioavailable in rhesus monkey (24%), display-
ing an excellent profile that includes a low clearance
(2.3 mL/kg/min) and a half-life of 2.7 h.
peutic agent cisplatin (10 mg/kg iv) in the ferret.5
A
dose dependent inhibition of emesis was observed (ID90
1.0 mg/kg iv), with a dose of 3 mg/kg iv giving complete
blockade for the 4 h observation period.
Con clu sion
Examining a series of 5-membered heterocycles as a
stable replacements for the carboxamide in 1 has
culminated in the synthesis of the triazole and triaz-
olone analogues 11 and 12, where the latter shows a
25-fold increase in in vitro affinity over the initial lead.
Furthermore evaluation of a number of heterocyclic

2910 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Ta ble 1. In Vitro Binding Affinities
Ladduwahetty et al.
a
Displacement of [125I]Tyr8 SP from the cloned human NK1 receptor expressed in CHO cells. Data reported as the mean ( SD for n
) 3 unless otherwise noted. Displacement of [3H]dilitiazam from the rabbit skeletal muscle calcium channel.
b
Ta ble 2. In Vivo Properties
Ta ble 3. Microsomal Incubation Analysisa
rat trigeminal
modelb ID50
(mg/kg iv)
ferret
time
SPIDERa ID50
(mg/kg po)
emesisc ID90
(mg/kg iv)
compd
15 min
0.05
1 h
4 h
24 h
compd
4
8
11
12
1
0.8
0.4
0.037
1.6
NT
NT
NT
1.0
0.72
0.87
1.04
0.55
0.61
0.90
0.18
0.33
0.84
11
12
0.008
0.028
0.0524c
CP-99,994
3.05a
a
Degradation of compound in incubations at 25 µM with normal
a
Inhibition of SP-induced dermal extravasation in the guinea
pig. Antagonist was administered po followed by SP challenge id
after 1 h. Dose-response data were determined for n ) 5-12
rat liver microsomes (n ) 1 determinations). Substrate concentra-
tions are shown relative to an initial concentration of 1.0. P-450
concentration was 1.45 nM/mg of microsomal protein.
b
animals/data point. Inhibition of plasma extravasation produced
in the dura mater of the rat after iv administration of test
compound, n ) 8-10. c Effects of the test compound on the
wretching and vomiting response in ferrets induced by cisplatin
(10 mg/kg iv, n ) 6-8).
displays good bioavailability in two species, rat and
rhesus monkey. The triazolone 12 therefore represents
a novel class of potent, orally active NK1 antagonists.
In addition 12 has also been shown to be active in a
number of animal models that display the therapeutic
potential of antagonists at the NK1 receptor. The
analogues in rat liver microsomes shows 12 to be the
most stable. This is borne out by the fact that 12

Novel, Orally Active Human NK1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2911
Ta ble 4. Pharmacokineticsa
3-(((3,5-Bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpip-
eridine hydrochloride (1 g) was liberated from the hydrochloride
salt by partitioning between ethyl acetate and 2 M sodium
hydroxide. The organic phase was washed successively with
water and saturated brine, dried (MgSO4), and evaporated in
vacuo. To a solution of the residual oil in tetrahydrofuran (20
mL) were added triethylamine (0.4 mL) and methyl bromoac-
etate (400 mg), and the solution was heated at reflux under
an atmosphere of nitrogen for 16 h. To the cooled solution
were added ethyl acetate and water, and the organic phase
was washed further with water and dried (MgSO4). After the
solvent had been removed in vacuo, the residue was chro-
matographed on silica gel eluting with ethyl acetate/petroleum
ether (3:10). The product was recrystallized from diethyl
ether/petroleum ether to give the title compound (76%): mp
81-83 °C; MS (CI+) m/ z 476 (M + H)+. Anal. (C23H23F6-
NO3‚0.1H2O) C, H, N.
compd
F (%)
C1 (mL/kg/min)
VD (L/kg)
Rat Pharmacokinetics
11
12
18
46
44
73
2.6
6.5
Rhesus Pharmacokinetics
23.7 2.4
12
0.55
a
F ) bioavailability, C1 ) plasma clearance after iv dosing; iv
and po dosing at 3 mg/kg.
distinct advantage of the triazolone heterocycle for both
the in vitro and in vivo potencies of the piperidine ether
series is currently being taken advantage of in other
classes of SP-antagonists.
Exp er im en ta l Section
(2S,3S)-3-(((3,5-Bis(t r iflu or om et h yl)p h en yl)m et h yl)-
oxy)-1-((ca r b oxyh yd r a zid o)m et h yl)-2-p h en ylp ip er id in -
iu m Hyd r och lor id e (13). Hydrazine hydrate (3.0 mL) was
added to a solution of (2S,3S)-3-(((3,5-bis-(trifluoromethyl)-
phenyl)methyl)oxy)-1-(carbomethoxymethyl)-2-phenylpiperi-
dine (2.95 g) in ethanol (80 mL). The solution was heated at
reflux for 18 h, after which the ethanol was removed in vacuo.
The residue was extracted into ethyl acetate, and the organic
layer was washed with brine, dried (MgSO4), and concentrated
to give the title compound (2.79 g). This was dissolved in
methanol (5 mL), and a methanolic solution of hydrogen
chloride was added. Methanol was removed in vacuo, and the
salt was recrystallized from diethyl ether to give the hydro-
chloride salt (91%): 1H NMR (360 MHz, DMSO) δ 1.77-1.93
(2H, m, CH2), 2.08-2.21 (1H, m, CH2), 2.22-2.35 (1H, m, CH2),
3.56 (1H, d, NCHHCH2), 3.64 (1H, d, J ) 16.5 Hz, NCHHCO),
3.77 (1H, d, NCHHCH2), 3.92 (1H, d, J ) 16.5 Hz, NCHHCO),
3.96 (1H, brs, CHO), 4.37 (1H, d, J ) 13.0 Hz, OCHH), 4.83
(1H, d, J ) 13.0 Hz, OCHH), 4.95 (1H, s, CHPh), 7.36-7.46
(3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH),
7.97 (1H, s, ArH); MS (CI)+ m/ z 475.
Melting points were determined with a Bu¨chi capillary
melting point apparatus and are uncorrected. NMR spectra
were recorded at 250 or 360 MHz on Bruker AM360 and
AC250 instruments, respectively. The term “dried” refers to
drying of an organic phase over anhydrous magnesium sulfate
and then filtering, and organic solvents were evaporated on a
Bu¨chi rotary evaporator at reduced pressure. Column chro-
matography was carried out on silica gel (Merck art. 7734).
Elemental analyses were determined by Butterworth Labo-
ratories Ltd., Teddington, England.
(()-cis-{3-(((3,5-Bis(t r iflu or om et h yl)p h en yl)m et h yl)-
oxy)-2-ph en ylpiper idin o}m eth yl]fu r an (3). (()-cis-3-(((3,5-
Bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidine hy-
drochloride salt9c (400 mg) and triethylamine (300 mg) were
dissolved in dichloromethane, and the mixture was stirred for
10 min at 0 °C. 2-Furoyl chloride (155 mg) was added to the
solution, and the reaction mixture was stirred for 15 min. The
reaction was partitioned between ethyl acetate (50 mL) and
water (20 mL). The organic layer was then washed with brine,
separated, dried (MgSO4), and concentrated in vacuo. The
residue was purified by chromatography on silica gel using
20% ethyl acetate in petroleum ether, affording a clear oil: 420
4-[{(2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)ph en yl)m eth yl)-
oxy)-2-p h en ylp ip er id in o}m eth yl]oxa zole (4). (a ) 4-(Hy-
d r oxym eth yl)-1,3-oxa zole. 1,3-Oxazole-4-carboxaldehyde16
(0.38 g) was dissolved in anhydrous methanol and stirred
under nitrogen; sodium borohydride (0.074 g) was added
carefully. After 1 h no starting material was present by TLC
using 50% ethyl acetate in hexane as eluent. The methanol
was removed by rotary evaporator (water bath temperature
40 °C). The residue was purified by chromatography on silica
gel eluting with 100% diethyl ether. This afforded the alcohol
(0.27 g) as a white solid: 1H NMR (360 MHz, CDCl3) δ 2.93
(OH), 4.63 (2H, s, CH2OH), 7.64 (1H, s, oxazole-H), 7.90 (1H,
s, oxazole-H).
1
mg (85%); H NMR (360 MHz, DMSO-d6) δ 1.6-1.8 (2H, m,
CH2), 1.9-2.1 (2H, m, CH2), 2.99 (1H, mc, CHHN), 4.02 (1H,
q, J ) 5.0 Hz, CHO), 4.0-4.2 (1H, m, CHHN), 4.78 (1H, d, J
) 13.0 Hz, OCHH), 4.86 (1H, d, J ) 13.0 Hz, OCHH), 5.95
(1H, s, CHPh), 6.62 (1H, s, furan-H), 6.99 (1H, s, furan-H),
7.25-7.36 (3H, m, ArH), 7.51-7.54 (2H, m, ArH), 7.83 (1H, s,
furan-H), 7.90 (2H, s, ArH), 7.99 (1H, s, ArH); MS (CI+) m/ z
498 (M+ + 1, 20).
The (()-cis-3-(((3,5-Bis(trifluoromethyl)phenyl)methyl)oxy)-
1-(2-furoyl)-2-phenylpiperidine (340 mg) prepared as above
was dissolved in tetrahydrofuran. To this solution was added
borane-dimethyl sulfide complex (0.18 mL of 10 M solution),
and the resulting solution was heated at reflux for 8 h. The
mixture was cooled, methanol was added to quench excess
borane, and the solvents were removed in vacuo. The residue
was dissolved in methanol (10 mL), and potassium carbonate
was added (238 mg). This mixture was heated at reflux for 1
h; the methanol was removed in vacuo, and the residue was
dispersed between ethyl acetate and brine. The ethyl acetate
layer was dried (MgSO4) and evaporated. The residue was
purified by chromatography on silica gel using 10% ethyl
acetate in petroleum ether. The product was recrystallized
from ether/hexane to yield a white solid (60 mg, 20%): mp
103-104 °C; 1H NMR (360 MHz, CDCl3) δ 1.4-1.5 (2H, m,
CH2CH2), 1.8-1.9 (1H, m, CHHCH2N), 2.1-2.2 (2H, m,
CHHCH2N, CHHN), 2.95-3.0 (1H, m, CHHN), 3.11-3.15 (1H,
d, J ) 15.0 Hz, NCHH-furan), 3.38 (1H, s, NCHCHO), 3.54-
3.58 (1H, d, J ) 15.0 Hz, NCHH-furan), 3.56 (1H, s, NCH-
CHO), 4.02-4.06 (1H, d, J ) 13.0 Hz, OCHH-), 4.59-4.62 (1H,
d, J ) 13.0 Hz, OCHH-), 6.08-6.09 (1H, m, furan-H), 6.35-
6.36 (1H, m, furan-H), 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H,
m, ArH), 7.55 (1H, s, furan-H), 7.68 (2H, s, ArH), 7.93 (1H, s,
ArH); MS (CI+) m/ z 485 (M+ + 1, 100). Anal. (C25H23NF6O)
C, H, N.
(b) 4-(Hydroxymethyl)-1,3-oxazole (0.13 g) was dissolved in
anhydrous dichloromethane (4 mL) under an atmosphere of
nitrogen. Triethylamine (0.19 mL) and p-toluenesulfonyl
chloride (0.13 g) were added to the reaction mixture which was
stirred for 1 h at room temperature. A further portion of
p-toluenesulfonyl chloride (0.13 g) and a catalytic amount of
(dimethylamino)pyridine were added to the mixture. (2S,3S)-
3-(((3,5-Bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperi-
dine (1.2 g, free base) was dissolved in dimethylformamide (5
mL) and added to the reaction mixture followed by triethyl-
lamine (0.19 mL). The reaction mixture was heated at 60 °C
for 2 h, and the resulting mixture was diluted with water (50
mL) and extracted with dichloromethane (3 × 20 mL). The
combined organic layers were dried (MgSO4) and concentrated
in vacuo to afford a yellow oil. This was purified by chroma-
tography on silica gel using a gradient elution of 30-60% ether
in hexane to afford the title compound as a white solid (5%
yield). This was recrystallized from ether/hexane: mp 102-
104 °C; 1H NMR (360 MHz, CDCl3) δ 1.46-1.64 (1H, m, NCH2-
CH2CHH), 1.7-1.87 (1H, m, NCH2CH2CHH), 1.96-2.20 (2H,
m, NCH2CH2), 2.32-2.48 (1H, m, NCHH), 3.20-3.46 (3H, m,
NCHH, NCHH-oxazole, CHOCH2Ar), 3.55 (1H, brs, CHPh),
3.68 (1H, d, J ) 14.5 Hz, NCHH-oxazole), 4.01 (1H, d, J )
11.5 Hz, OCHHAr), 4.46 (1H, d, J ) 11.5 Hz, OCHHAr), 7.24-
(2S,3S)-3-(((3,5-Bis(t r iflu or om et h yl)p h en yl)m et h yl)-
oxy)-1-(car bom eth oxym eth yl)-2ph en ylpiper idin e. (2S,3S)-

2912 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Ladduwahetty et al.
7.58 (8H, m, ArH), 7.70 (1H, s, ArH), 7.80 (1H, s, ArH); MS
(CI+) 458 (M+ + 1, 100).
m, CHH), 2.04-2.21 (2H, m, CH2), 3.07-3.23 (1H, m, NCHH),
3.41-3.51 (1H, m, NCHH), 3.66 (1H, s, CHO), 4.09 (1H, d, J
) 13.0 Hz, OCHH), 4.25 (1H, d, J ) 15.5 Hz, CH-imidazole),
4.30 (1H, s, CHPh), 4.39 (1H, d, J ) 15.5 Hz, CHH-imidazole),
4.55 (1H, d, J ) 13.0 Hz, OCHH), 7.1-7.2 (3H, m, ArH), 7.2-
7.3 (2H, m, ArH), 7.38 (2H, s, imidazole-H), 7.48 (2H, s, ArH),
7.51 (1H, s, ArH); MS (CI+) m/ z (M+ + 1, 25). Anal.
(C24H23F6N3O‚2HCl‚H2O) C, H, N.
4-[{2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)p h en yl)m eth yl)-
oxy)-2-ph en ylpiper idin o}m eth yl]im idazole Dih ydr och lo-
r id e (8). This was prepared following the procedure described
for 7 using (2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)-
oxy)-2-phenylpiperidine hydrochloride salt and 4-(hydroxy-
methyl)imidazole (Aldrich) as starting materials. This af-
forded the title compound as a white crystalline compound
(26% overall yield): mp 206-210 °C; 1H NMR (360 MHz, D2O)
δ 1.73 (1H, m, NCH2CH2CHH), 1.94-2.06 (1H, m, NCH2CH2-
CHH), 2.22-2.40 (2H, m, NCH2CH2), 3.33 (1H, mc, NCHH),
3.70-3.81 (1H, m, NCHH), 3.97 (1H, brs, CHO), 4.30 (1H, d,
J ) 12.5 Hz, OCHH), 4.42 (2H, s, NCH2-imidazole), 4.50 (1H,
s, NCHPh), 4.75 (1H, d, J ) 12.5 Hz, OCHH), 7.48 (6H, brs,
ArH, imidazole-H), 7.74 (2H, s, ArH), 7.95 (1H, s, ArH), 8.80
(1H, s, imidazole-H); MS (CI+) m/ z 484 (M+ + 1). Anal.
(C24H23F6N3O‚2HCl‚H2) C, H, N.
2-[{(2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)ph en yl)m eth yl)-
oxy)-2-p h en ylp ip er id in o}m eth yl]-1-(p-tolylsu lfon yl)im i-
d a zole Dih yd r och lor id e (7). (a ) N-(p -Tolylsu lfon yl)-
im id a zole-2-ca r boxa ld eh yd e. Imidazole-2-carboxaldehyde
(1.92 g) was suspended in dichloromethane (20 mL). p-
Toluenesulfonyl chloride (3.8 g) and triethylamine (2.8 mL)
were added to the mixture which was stirred at room tem-
perature for 12 h. The resulting slurry was diluted with water,
and the organic layer was washed with brine, dried (MgSO4),
and filtered. The dichloromethane layer was concentrated in
vacuo, and the residue was purified by column chromatography
on silica gel using 50% ethyl acetate in hexane as eluent. This
afforded the product as a yellow oil which crystallized on
standing: 1H NMR (360 MHz, CDCl3) δ 2.44 (3H, s, ArCH3),
7.31 (1H, d, J ) 1.5 Hz, imidazole-H), 7.37 (2H, d, J ) 8.0 Hz,
ArH), 7.83 (1H, d, J ) 1.5 Hz, imidazole-H), 8.00 (2H, d, J )
8.0 Hz, ArH), 9.78 (1H, s, CHO); MS (CI+) m/ z 251 (M+ + 1).
(b) 2-(Hydr oxym eth yl)-1-(p-tolylsu lfon yl)im idazole. The
aldehyde from above (3 g) was dissolved in methanol (15 mL),
and sodium borohydride (114 mg) was added portionwise. This
solution was stirred for 10 min. Methanol was removed in
vacuo, and the residue was dispersed between ethyl acetate
and water. The organic layer was separated, dried (MgSO4),
and filtered, and the solvent was removed in vacuo to afford a
crystalline solid: 1H NMR (250 MHz, CDCl3) δ 2.42 (3H, s,
ArCH3), 4.84 (2H, s, CH2O), 7.00 (1H, d, J ) 1.5 Hz, imidazole-
H), 7.36 (2H, d, J ) 8.0 Hz, ArH), 7.40 (1H, d, J ) 1.5 Hz,
imidazole-H), 7.84 (2H, d, J ) 8.0 Hz, ArH).
(c) (N-(p-Tolylsu lfon yl)im id a zol-2-yl)m eth yl Meth a n e-
su lfon a te. The alcohol described in part b above (12.6 mg)
was dissolved in dichloromethane (2.5 mL) and triethylamine
(0.07 mL). This solution was cooled to 0 °C. Methanesulfonyl
chloride (0.04 mL) was added to the solution dropwise. After
stirring for 10 min the solution was diluted with water, and
the organic layer was separated, dried (MgSO4), and filtered
and the solvent removed in vacuo to yield a white solid which
was used in the following reaction without further purification
(69% from 2-imidazolecarboxaldehyde): 1H NMR (250 MHz,
CDCl3) δ 2.44 (3H, s, ArH), 2.94 (3H, s, SO2CH3), 5.51 (2H, s,
CH2SO2), 7.08 (1H, d, J ) 1.5 Hz, imidazole-H), 7.40 (2H, d, J
) 8.0 Hz, ArH), 7.49 (1H, d, J ) 1.5 Hz, imidazole-H), 7.92
(2H, d, J ) 8.0 Hz, ArH).
(d) (N-(p-Tolylsulfonyl)imidazol-2-yl)methyl methanesulfonate
(1.6 g) was added to a suspension of (2S,3S)-3-(((3,5-bis-
(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidine hy-
drochloride salt (2.47 g) and potassium carbonate (800 mg) in
dimethylformamide (10 mL), and the resulting mixture was
heated at 100 °C for 2 h. The mixture was cooled, diluted with
water (100 mL), and extracted with ethyl acetate (3 × 20 mL).
The organic extracts were combined, washed with brine, dried
(MgSO4), and concentrated in vacuo. This afforded a colorless
oil which was purified by column chromatography on silica
gel using 25-30% ethyl acetate in hexane. This afforded the
product as a white crystalline solid which was recrystallized
from dichloromethane/petroleum ether: 50% yield; mp 125-
126 °C; 1H NMR (360 MHz, DMSO-d6) δ 1.4-1.5 (1H, m,
NCH2CH2CHH), 1.5-1.67 (1H, m, NCH2CH2CHH), 1.8-2.0
(1H, m, NCH2CHH), 2.06-2.1 (1H, m, NCH2CHH), 2.35 (3H,
s, CH3), 2.4 (1H, mc, NCHH), 2.7-2.86 (1H, m, NCHH), 3.50
(1H, d, J ) 14.0 Hz, CHH-imidazole), 3.56 (1H, brs, CHO),
3.76 (1H, d, J ) 1.5 Hz, CHPh), 4.08 (1H, d, J ) 14.0 Hz, CHH-
imidazole), 4.09 (1H, d, J ) 12.0 Hz, OCHH), 4.48 (1H, d, J )
12.0 Hz, OCHH), 6.96 (1H, d, J ) 1.0 Hz, imidazole-H), 7.12
(2H, d, J ) 8.5 Hz, ArH), 7.2-7.3 (3H, m, ArH), 7.34 (1H, d,
J ) 1.0 Hz, imidazole-H), 7.46-7.58 (2H, m, ArH), 7.60 (2H,
s, ArH), 7.71 (1H, ArH), 7.79 (2H, d, J ) 8.5 Hz, ArH); MS
(CI+) m/ z 638 (M+ + 1). Anal. (C31H29F6N3O3S) C, H, N.
The white solid was dissolved in dichloromethane, and
ethereal hydrogen chloride was added. The resulting solution
was stirred for 30 min, whereupon the title compound crystal-
lized from solution. This was removed by filtration and
recrystallized from ethyl acetate/methanol to afford the title
compound (75% yield) as a white crystalline solid: 1H NMR
(360 MHz, D2O) δ 1.61-1.74 (1H, m, CHH), 1.76-1.88 (1H,
3-[{(2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)ph en yl)m eth yl)-
oxy)-2-p h en ylp ip er id in o}m eth yl]-1,2,4-tr ia zole Dih yd r o-
ch lor id e (11). (2S,3S)-3-(((3,5-Bis(trifluoromethyl)phenyl)-
methyl)oxy)-2-phenylpiperidine hydrochloride salt (1.0 g),
anhydrous potassium carbonate (0.94 g), and N-formyl-2-
chloroacetamidohydrazone (0.46 g)11 were heated to 60 °C in
anhydrous dimethylformamide for 3 h followed by heating at
130 °C for 12 h. The reaction mixture was cooled, diluted with
ethyl acetate (100 mL), and washed with water (3 × 20 mL).
The ethyl acetate layer was dried (MgSO4), filtered, and
evaporated to give a brown oil. This was purified on silica gel
using ethyl acetate in petroleum ether (70:30) as eluent. This
afforded the product as a white solid: 81% yield; mp (free base)
1
209-210 °C; H NMR (250 MHz, CDCl3) δ 1.6 (2H, m, CH2),
1.95-2.24 (2H, m, CH2), 2.34 (1H, m, NCHH), 3.06 (1H, m,
NCHH), 3.44 (1H, d, NCHH-triazole), 3.5 (1H, brs, N-CHH-
triazole), 3.6 (1H, brs, NCHPh), 3.8 (1H, d, CHO), 4.04 (1H, d,
OCHH-Ar), 4.50 (1H, d, OCHHAr), 7.3 (3H, m, ArH), 7.44 (2H,
m, ArH), 7.5 (2H, s, ArH), 7.7 (1H, s, ArH), 7.9 (1H, s, triazole-
H); MS (CI+) m/ z 485 (M+ + 1, 35). The free base was treated
with ethereal chloride to afford the product as a white
crystalline solid. Anal. (C23H22F6N4O‚2HCl) C, H, N.
5-[{2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)p h en yl)m eth yl)-
oxy)-2-ph en ylpiper idin o}m eth yl]-2,3-dih ydr o-(4H)-3-oxo-
1,2,4-tr ia zole Hyd r och lor id e (12). (a ) N-Ca r bom eth oxy-
2-ch lor oa ceta m id r a zon e. Sodium methoxide (0.032 g) was
added to a solution of chloroacetonitrile (1.26 mL) in anhydrous
methanol (15 mL) at 0 °C. The reaction mixture was stirred
at room temperature for 0.5 h and then neutralized with acetic
acid (0.034 mL). Methyl hydrazinocarboxylate (1.76 g) was
added and the reaction mixture stirred at room temperature
for 0.5 h. The solution was concentrated in vacuo to give the
title compound as an orange solid: MS (CI)+ m/ z 166.
(b) (2S,3S)-3-(((3,5-Bis(trifluoromethyl)phenyl)oxy)-2-phen-
ylpiperidine hydrochloride salt (0.50 g) was stirred with
N-carbomethoxy-2-chloroacetamidrazone (0.19 g) and potas-
sium carbonate (0.47 g) in dimethylformamide (10 mL) at 70
°C for 18 h. The reaction mixture was then stirred at 140 °C
for 1 h. After cooling, the material was partitioned between
ethyl acetate and water. The organic layer was washed with
water, dried (MgSO4), filtered, and concentrated. The residue
was purified by chromatography on silica gel using 5%
methanol in ethyl acetate as eluent. The product was recrys-
tallized from ethyl acetate/petroleum ether to give the title
compound as a white crystalline solid (75%). This was
converted to the hydrochloride salt by treating with ethereal
HCl to afford a white crystalline solid: mp 168-172 °C;
1H NMR (360 MHz, DMSO) δ 1.85 (2H, m, CH2) 2.0 (1H, m,
CH), 3.29 (1H, t, NCH), 3.65 (1H, d, NCH), 3.90 (2H, m, CH2-
triazole, NCHPh), 4.30 (1H, d, OCHHAr), 4.73 (1H, s, CHO),
4.79 (1H, d, OCHHAr); MS (CI)+ m/ z ((M + 1)+, 18). Anal.
(C23H24N4O2.5F6Cl) C, H, N.

Novel, Orally Active Human NK1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2913
5-[{(2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)ph en yl)m eth yl)-
oxy)-2-p h e n ylp ip e r id in o}m e t h yl]-2,3-d ih yd r o-(4H )-3-
th ioxo-1,2,4-tr ia zole Hyd r och lor id e (14). (2S,3S)-3-(((3,5-
Bis (t r iflu or om et h yl)p h en yl)m et h yl)oxy)-1-[(ca r boxy-
hydrazido)methyl]-2-phenylpiperidinium hydrochloride (0.230
g), potassium thiocyanate (0.45 g), and concentrated hydro-
chloric acid (2.3 mL) in water (12 mL) were heated under reflux
for 2 h. After cooling, solid sodium hydroxide was added until
pH ) 8, and the aqueous layer was extracted with ethyl
acetate. The organic layer was dried (MgSO4), filtered, and
evaporated to give the crude semicarbazide which was heated
at reflux in 2 N sodium hydroxide solution (10 mL) for 2 h.
After cooling the solution was acidified to pH ) 5-6 and the
product extracted into ethyl acetate. The organic layer was
dried (MgSO4), filtered, and evaporated. The crude triazole
was chromatographed on silica gel eluting with 40% ethyl
acetate/60-80 petroleum ether to give the title compound
(65%) as a white solid: 1H NMR (250 MHz, CDCl3) δ 1.6 (2H,
m, CH2), 1.9-2.3 (3H, m, CH2, NCHH), 2.95 (1H, brd, NCHH),
3.16 (1H, d, N-CHH-Het), 3.20 (1H, brs, CHO), 3.6 (1H, brs,
NCHPh), 3.78 (1H, d, N-CHH-Het), 4.1 (1H, d, CHH-Ar), 4.58
(1H, d, CHH-Ar), 7.32 (5H, m, ArH), 7.5 (2H, s, Ar-H), 7.78
(1H, s, ArH); MS (FAB) m/ z (M+ + 1, 80). This was treated
with ethereal hydrogen chloride to yield the crystalline hydro-
chloride: mp 154-157 °C. Found: C, 46.59; H, 4.52; N, 9.26;
Cl, 5.84. Anal. (C23H22F6N4OS‚HCl‚2H2O) C, H, N.
3-[{(2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)ph en yl)m eth yl)-
oxy)-2-p h en ylp ip er id in o}m eth yl]-1,2,4-oxa d ia zole (15). A
solution of pentafluorophenyl formate17 (178 mg, 0.84 mmol)
in chloroform (1 mL) was added to a stirred solution of the
hydrazide (0.160 mg), in chloroform (6 mL) at 25 °C under N2.
The reaction mixture was heated to 50 °C for a period of 5 h.
The solvent was evaporated and the residue partitioned
between EtOAc (20 mL) and water (20 mL). The organic layer
was washed further with 5% NaHCO3 and water (15 mL),
dried (MgSO4), and evaporated. The residue was chromato-
graphed on silica gel eluting with EtOAc and then 5% MeOH/
CH2Cl2 to give the N-formylhydrazide (124 mg, 59%) which
was redissolved in anhydrous toluene (12 mL) and cooled to 0
°C. Triethylamine (91 mL, 0.66 mmol) was added followed
by thionyl chloride (24 mL). The resulting white solid was
filtered and the filtrate heated at 90 °C for 1 h. Another
aliquot of triethylamine (45 mL) was added followed by thionyl
chloride (12 mL); another aliquot of triethylamine (4 mL) was
added followed by thionyl chloride (2 mL) and the reaction
d, J ) 17.5 Hz, NCHHCN), 4.09 (1H, s, CHPh), 4.35 (1H, d, J
) 13.0 Hz, OCHH), 4.73 (1H, d, J ) 13.0 Hz, OCHH), 7.4 (3H,
mc, ArH), 7.69-7.73 (5H, m, ArH); MS (CI+) m/ z 443 (M+
1, 30). Anal. (C22H18F6N2O‚HCl) C, H, N.
+
5-[{(2S,3S)-3-(((3,5-Bis(tr iflu or om eth yl)ph en yl)m eth yl)-
oxy)-2-p h en ylp ip er id in o}m eth yl]tetr a zole (17). The ni-
trile 16 (1.0 g), triethylamine hydrochloride (467 mg), and
sodium azide (441 mg) were dissolved in 1-methyl-2-pyrroli-
dinone (5 mL), and the reaction mixture was heated at reflux
under nitrogen for 2 h. The mixture was then cooled, diluted
with ice/water (80 mL), and acidified to pH ) 2 with metha-
nolic hydrogen chloride. This precipitated the product as a
white solid, which was purified on silica gel using a gradient
elution of methanol in dichloromethane (0-5%). The product
was recrystallized from ethyl/hexane (675 mg, 56%): mp 114-
1
115 °C; H NMR (360 MHz, DMSO-d6) δ 1.59-1.65 (2H, m,
NCH2CH2CH2), 2.02-2.22 (2H, m, NCH2CH2), 2.39-2.46 (1H,
m, CHHN), 2.98-3.02 (1H, m, CHHN), 3.62 (1H, s, NCHCHO),
3.66 (1H, s, NCHCHO), 3.70-3.74 (1H, d, J ) 15.5 Hz, NCHH-
tetrazole), 4.05-4.10 (1H, d, J ) 15.5 Hz, NCHH-tetrazole),
4.08-4.12 (1H, d, J ) 12.0 Hz, OCHH), 4.51-4.54 (1H, d, J )
12.0 Hz, OCHH), 5.30 (1H, s, NH), 7.30-7.35 (3H, m, ArH),
7.45-7.47 (2H, m, ArH), 7.51 (2H, s, ArH), 7.74 (1H, s, ArH);
MS (CI+) m/ z 486 (M+ + 1, 85). Anal. (C22H21F6N5O‚0.5H2O)
C, H, N.
P h a r m a cok in etic Eva lu a tion of 3-[{(2S,3S)-3-(((3,5-Bis-
(t r i flu o r o m e t h y l)p h e n y l)m e t h y l)o x y )-2-p h e n y lp i -
p er id in o}m eth yl]-1,2,4-tr ia zole Dih yd r och lor id e (11) in
Ra t. The compound was administered at 3 mg/kg iv and po
in rat. The vehicle used for both the iv and po formulations
was 1 mM HCl. The animals were sampled for plasma up to
8 h postdose (3 rats/time point). The pharmacokinetic pha-
rameters were calculated using standard equations using the
following set of data presented here as a mean ( SEM.
concentrations of 11 in plasma (mg/mL)
time (h)
iv
po
0.0833
1763.5 ( 107.2
825.5 ( 102.7
581.0 ( 16.0
303.6 ( 8.7
71.3 ( 5.9
13.2 ( 1.4
<10
40.1 ( 11.3
116.1 ( 35.3
35.1 ( 13.1
33.7 ( 9.3
36.9 ( 3.1
11.2 ( 1.7
<10
0.25
0.5
1
2
4
6
8
<10
mixture heated for
a further 45 min. The solvent was
evaporated in vacuo and the residue partitioned between ethyl
acetate (30 mL) and water (30 mL). The organic layer was
washed with water and brine, dried over MgSO4, and evapo-
rated. The residue was chromatographed on silica gel eluting
with 2:1 petroleum ether/ethyl acetate followed by 1:1 petro-
leum ether/ethyl acetate to afford the desired product as a
white solid (110 mg, 77%): 1H NMR (360 MHz, CDCl3) δ 8.27
(s, 1H), 7.65 (s, 1H), 7.42-7.45 (m, 4H), 7.19-7.30 (m, 3H),
4.42 (d, 1H), 3.96 (d, 1H), 3.88 (d, 1H), 3.64 (d, 1H), 3.52 (s,
2H), 3.07 (brd, 1H), 2.37 (dd, 1H), 2.09 (d, 1H), 1.97 (dd, 1H),
1.49 (m, 2H). Anal. (C23H21F6N3O2) C, H, N.
P h a r m a cok in etic Eva lu a tion of 5-[{(2S,3S)-3-(((3,5-Bis-
(tr iflu or om eth yl)p h en yl)m eth yl)oxy)p h en ylp ip er id in o}-
m eth yl]-2,3-d ih yd r o-(4H)-3-oxo-1,2,4-tr ia zole Hyd r och lo-
r id e (12) in Ra t. Sixty-six male SD rats were given a 3 mg/
kg dose of 12 by either iv or oral route (33 rats/route). The
compound was administered intravenously as a solution (3 mg/
mL) in propylene glycol/water (48/52, v/v) and orally as a
solution (3 mg/mL) in PEG 400. Three rats from each dose
group were used per data point. The pharmacokinetic param-
eters were calculated using standard equations using the
following data presented as the mean ( SEM.
(2S,3S)-3-(((3,5-Bis(t r iflu or om et h yl)p h en yl)m et h yl)-
oxy)-1-(cya n om eth yl)-2-p h en ylp ip er id in iu m Hyd r och lo-
r id e (16). (2S,3S)-3-(((3,5-Bis(trifluoromethyl)phenyl)methyl)-
oxy)-2-phenylpiperidine hydrochloride salt (5 g), potassium
carbonate (1.7 g), and bromoacetonitrile (0.87 mL) were
suspended in dimethylformamide (15 mL), and the mixture
was stirred under nitrogen at 60 °C for 3 h. The mixture was
cooled, diluted with water (200 mL), and extracted with ethyl
acetate (2 × 50 mL). The organic extracts were washed with
brine, dried (MgSO4), and evaporated, affording a brown oil.
This was purified on silica gel using ethyl acetate in petroleum
ether (10%) as eluent. This afforded the product as a colorless
oil (2.5, 83%). A 100 mg sample of material was converted to
the hydrochloride salt by dissolution in ethereal hydrogen
chloride and recrystallization from ether/hexane (60 mg,
60%): mp 133-134 °C; 1H NMR (360 MHz, CDCl3) δ 1.75 (2H,
mc, CHH), 1.90 (2H, mc, CHH), 2.31 (1H, mc, CHH), 2.71 (1H,
mc, CHH), 3.19 (1H, mc, CHHN), 3.72 (1H, mc, CHHN), 3.81
(1H, d, J ) 17.5 Hz, NCHHCN), 3.86 (1H, s, CHO), 4.02 (1H,
concentrations of 12 in plasma (mg/mL)
time (h)
iv
po
0.083
0.25
0.5
1.0
2.0
3.0
4.0
5.0
6.0
599 ( 162
244 ( 21
291 ( 41
203 ( 15
135 ( 45
52 ( 6
30 ( 9
21 ( 9
9 ( 1
11 ( 5
29 ( 23
70 ( 30
45 ( 9
94 ( 15
65 ( 17
41 ( 11
25 ( 4
12 ( 3
<5
7.0
8.0
<5
<5
<5
P h a r m a cok in etics Eva lu a tion of 5-[{(2S,3S)-3-(((3,5-
B i s (t r i fl u o r o m e t h y l )p h e n y l )m e t h y l )o x y )p h e n y l -
p ip er id in o}m et h yl]-2,3-d ih yd r o-(4H )-3-oxo-1,2,4-t r ia z-
ole Hyd r och lor id e (12) in Rh esu s Mon k ey. Four Rhesus

2914 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Ladduwahetty et al.
clidine-Based NK-1 Antagonists 1:3-Benzyloxy-1-azabicyclo-
[2.2.2]octanes. Bioorg. Med. Chem. Lett. 1993, 3, 1361-1366.
(f) Garret, C.; Carrutte, A.; Fardin, V.; Moussaoui, S.; Peyronel,
J . F.; Blanchard, J .-C.; Laduron, P. M. Pharmacological proper-
ties of a Potent and Selective Nonpeptide Substance P Antago-
nist. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 10208-10212. (g)
Ouray-Donat, F.; Lefevre, I. A.; Guathier, T.; Emonds-Alt, X.;
Le Fur, G.; Soubrie, P. SR 140,333 A Novel and Potent Non-
peptide Antagonist of the NK1 receptor. Neuropeptides 1993,
24, 233. (h) MacLeod, A. M.; Merchant, K. J .; Brookfield, F.;
Lewis, R.; Kelleher, F.; Stevenson, G.; Owens, A.; Swain, C. J .;
Baker, R.; Cascieri, M. A.; Sadowski, S.; Ber, E.; MacIntyre, D.
E.; Metzger, J .; Ball, R. N-Acyl Tryptophan Benzyl Esters:
Potent Substance P Antagonists. J . Med. Chem. 1993, 36,
2044-2045. (i) Mills, S.; Wu, M. T.; MacCoss, M.; Budhu, R.;
Dorn, C. P.; Cascieri, M. A.; Sadowski, S.; Strader, C.; Greenlee,
W. J . 1,4-Diacylpiperazine-2-(S)-[(N-aminoalkyl)-carboxamides]
as Novel Potent Substance P Receptor Antagonists. Bioorg. Med.
Chem. Lett. 1993, 3, 2707. (j) Williams, B. J .; Teall, M.;
McKenna, J .; Harrison, T.; Swain, C. J .; Cascieri, M. A.;
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1994, 4, 1903-1908.
monkeys were dosed (at 3 mg/kg in propylene glycol) intrave-
nously and orally (n ) 2 for each data point). The pharma-
cokinetic parameters were calculated using standard equations
using the data shown below presented as the mean ( SEM.
concentrations of 12 in plasma (µg/mL)
time (h)
iv
po
0.167
0.5
1.0
2.0
4.0
5.24 ( 0.11
5.02 ( 0.59
3.66 ( 0.20
3.08 ( 0.63
1.98 ( 0.58
1.22 ( 0.41
0.72 ( 0.18
0.02 ( 0.02
0.05 ( 0.01
0.08 ( 0.004
0.15 ( 0.04
0.52 ( 0.03
0.58 ( 0.02
0.50 ( 0.02
6.0
8.0
Ack n ow led gm en t. The authors would like to thank
D. O’Connor for the results of the rat liver microsome
study and S. Patel for Ca2+ binding results.
(7) Rupniak, N. M. J .; Tattersall, F. D.; Rycroft, W.; Carlson, E.;
Webb, J . K.; Williams, A. R.; Hargreaves, R. J . Prediction of the
Anti-Emetic Activity of NK1 Antagonists in Ferrets by Their
Ability to Inhibit GR73632 Induced Foot Tapping in Gerbils. For
submission to Eur. J . Pharmacol.
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