4,4-Disubstituted piperidine high-affinity NK1 antagonists: Structure- activity relationships and in vivo activity

Article abstract of DOI:10.1021/jm980376b

Previously reported studies from these laboratories described the design of a novel series of high-affinity NK₁ antagonists based on the 4,4- disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK₁ affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3,5-bis(trifluoromethyl)benzyl ether, 12 (hNK₁ IC₅₀ = 0.95 nM). Additional studies have shown that this class of NK₁ antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK₁ IC₅₀ = 5.3 nM) and sulfonyl (39) (hNK₁ IC₅₀ = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID₅₀ = 0.22 and 0.28 mg/kg, respectively).

Full text of DOI:10.1021/jm980376b

J . Med. Chem. 1998, 41, 4623-4635
4623
4,4-Disu bstitu ted P ip er id in e High -Affin ity NK1 An ta gon ists: Str u ctu r e-Activity
Rela tion sh ip s a n d in Vivo Activity
Graeme I. Stevenson,* Ian Huscroft, Angus M. MacLeod, Christopher J . Swain, Margaret A. Cascieri,§
Gary G. Chicchi,§ Michael I. Graham, Timothy Harrison, Fintan J . Kelleher, Marc Kurtz,§
Tamara Ladduwahetty, Kevin J . Merchant, J oseph M. Metzger,§ D. E. MacIntyre,§ Sharon Sadowski,§
Balbinder Sohal, and Andrew P. Owens
Department of Medicinal Chemistry, Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K., and Departments of Pharmacology, Molecular Pharmacology,
and Biochemistry, Merck Research Laboratories, Rahway, New J ersey 07065
Received J une 19, 1998
Previously reported studies from these laboratories described the design of a novel series of
high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further
structure-activity studies have now established that for high NK1 affinity the benzyl ether
side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the
3,5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 ) 0.95 nM). Additional studies have shown
that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine
nitrogen, including acyl (38) (hNK1 IC50 ) 5.3 nM) and sulfonyl (39) (hNK1 IC50 ) 5.7 nM)
derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were
selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing
excellent profiles (ID50 ) 0.22 and 0.28 mg/kg, respectively).
The discovery of CP-96,3451 (1) (Chart 1), the first
selective non-peptide NK1 antagonist, has led to an
intensive exploration of the pharmacology of the NK1
receptor. This quinuclidine-based compound has
spawned several classes of selective non-peptide sub-
stance P antagonists including the aminopiperidine-
based CP-99,9942 (2) and GR 2030403 (3), the (benzyloxy)-
piperidine-based L-733,0604 (4) and L-741,6715 (5), and
the related morpholine acetal L-742,6946 (6) as well as
more diverse structures such as L-732,1387 (7) and SR
1403338 (8). Together with the availability of the cloned
human NK1 receptor,9 these non-peptide ligands have
been used to define a putative pharmacophore for NK1
antagonists.2 Substance P and the NK1 receptor have
been implicated in neurogenic inflammation,10 trans-
mission of pain,11 vasodilation,12 airway smooth muscle
contraction,13 regulation of the immune response,14 and
dural inflammation in migraine15 and as a central
component of cytotoxin-induced emesis.16
Many of the early non-peptide NK1 antagonists suf-
fered from poor central nervous system (CNS) penetra-
tion,17 lack of oral activity, and unwanted affinity at
L-type calcium channels.4,18 With the establishment of
a working NK1 pharmacophore, the emphasis in the
field has now shifted toward the fine-tuning of in vivo
properties in order to exploit the undoubted benefits of
NK1 receptor blockade. In this paper we present our
efforts in this area utilizing the 4,4-disubstituted pip-
eridine class of NK1 antagonist.19
side chain of 2 can be replaced by a benzylic ether and
that further deletions can be made to afford an acyclic
series of NK1 antagonists based on phenylglycine21 (9)
(Figure 1). This type of system probably contains the
minimum elements required for binding to the human
NK1 receptor and is in good agreement with published
pharmacophore models. However, although ligands
such as 9 have modest affinity for the NK1 receptor (IC50
) 13.5 nM), with six freely rotatable bonds such a
flexible system probably suffers a loss in binding
through entropic factors. Studies from our laboratories
established that conformational restriction of 9 in a cis-
(2S,3S)-piperidine ring gave the high-affinity NK1 an-
tagonist 4 (hNK1 IC50 ) 1.0 nM4) (Figure 1).
An alternative conformationally restricted system
based on 9 can be achieved by introducing a piperidine
ring to produce a 2,2-geminally disubstituted system
(10) (Figure 1) in which the unsubstituted phenyl group
occupies an axial position.22 Modeling studies predicted
that aryl rings in both 4 and 10 could occupy similar
positions in space with respect to the basic nitrogen and
should therefore have similar affinities. This indeed
proved to be the case for 10 (hNK1 IC50 ) 1.0 nM),
suggesting that the piperidine ring had no specific
binding role at the NK1 receptor, other than as a
conformational support.
In an extension to this approach19 we then varied the
distance between the basic nitrogen and the diaryl ether
portion of the pharmacophore to give a 3,3-geminally
disubstituted piperidine system (11) (Figure 1) which
suffered a 20-fold loss in affinity compared to 4 and 10.
However the 4,4-disubstituted piperidine system 12
(Figure 1) retained affinity (hNK1 IC50 ) 0.95 nM)
comparable to 4 and 10. This compound does not fit
current NK1 pharmacophore models in that the basic
nitrogen lies outside the given distance constraints to
Simplification of 1 by conversion to 2 established the
cis-(2S,3S)-piperidine as a basic framework for high-
affinity NK1 antagonists. Furthermore, studies from
our laboratories20 have established that, with the ap-
propriate choice of aryl substituent, the benzylamine
§ Merck Research Laboratories, Rahway, NJ .
10.1021/jm980376b CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/09/1998

4624 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Stevenson et al.
F igu r e 1. Derivation of the 4,4-disubstituted piperidine system.
Ch a r t 1
the rest of the pharmacophore2 and it is achiral, in
contrast to the stereochemical requirements observed
in other series of NK1 antagonists.4 In a recent com-
munication19 we described the development and initial
studies on this type of NK1 antagonist; in this paper
we now present a full examination of the structure-
activity relationship (SAR) of 4,4-disubstituted piperi-
dine-based NK1 antagonists.
Ch em istr y
Compounds 12-24 were prepared from the amino
acid 26 by a one-pot reduction/protection sequence to
give the key intermediate alcohol 27. Deprotonation of
27 followed by treatment with the appropriate benzyl
bromide and subsequent deprotection afforded the final
compounds (Scheme 1).

Substituted Piperidine High-Affinity NK1 Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4625
Sch em e 1a
minutes postchallenge the animals were euthanized
using CO2 gas, and a 1-mL heparinized blood sample
was obtained via cardiac puncture. Cell-free plasma
was prepared by centrifugation (8000g, 5 min, 20 °C)
and a portion (100 mL) stored for analysis. The vena
cava and aorta were transected to exsanguinate the
animal prior to removal of the esophagus. The tissues
were place in tared vials, dried (65 °C, 24 h), and
reweighed. Dried tissue samples and an aliquot (100
mL) of plasma from each animal were extracted/
incubated in formamide (1 mL, 65 °C, 24 h). The extent
of plasma extravasation was assessed by comparing the
absorption (OD650 nm) of the formamide extracts of tissue
to that of cell-free plasma from the same animal.
a
Reagents: (i) LiAlH4, THF; (ii) BOC2O, THF, H2O; (iii) NaH
(60%), DMF, ArCH2Br; (iv) HCl, Et2O.
The N-alkyl derivatives 28-30 were prepared by
reductive amination of the appropriate aldehyde (Scheme
2). The oxadiazole (31) and thiazole (32) derivatives
were prepared by direct alkylation using the com-
mercially available heteroarylmethyl chlorides (Scheme
2). Alkylation using methyl bromoacetate afforded 33
(Scheme 2).
Resu lts a n d Discu ssion
The methylene-linked triazole 34 and the correspond-
ing triazolone 35 were prepared by alkylation using the
appropriate imidrazone 36 or 37, followed by thermally
induced cyclization to give the desired products 34 and
35 (Scheme 3).
The acetamide (38) and sulfonamide (39) analogues
were prepared via acylation with the appropriate acid
chloride (Scheme 4). Compounds 40-48 were prepared
by coupling 12 to the appropriate acid under standard
amide bond formation conditions using bis(2-oxo-3-
oxazolidinyl)phosphinic chloride/Et3N (Scheme 4).
The compounds bearing an amino-based linking group
(48 and 49) were derived from the commercially avail-
able nitrile 50 by reduction/protection to give the amine
51, followed by alkylation to give 48 and 49 (Scheme
5).
Treatment of methyl 3,5-bis(trifluoromethyl)benzoate
(52) with the anion of dimethyl methylphosphonate
afforded dimethyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-
ketoethylphosphonate (53), which when combined with
the aldehyde 54, obtained via reduction of 50, gave the
R,â-unsaturated ketone 55. Complete reduction to the
alcohol 56 followed by activation as the phenyl thiono-
carbonate and treatment with AIBN/tributyltin hydride
gave the n-propyl-linked derivative 57, (Scheme 6).
The preliminary study of this class of NK1 antagonist
established the 4,4-disubstituted piperidine system as
a suitable framework for high NK1 affinity.19 A brief
exploration of the substitution type and pattern of the
benzyl ether side chain established that the nature of
this moiety was a critical determinant of the level of
binding achieved. In common with other benzyl ether-
based NK1 antagonists, the 3,5-bis(trifluoromethyl)-
benzyl side chain provided a compound with subnano-
molar receptor affinity (12, IC50 ) 0.95 nM). We
therefore decided that in extending this series we should
begin by examining the scope for substitution on the
benzyl ether side chain.
The simple unsubstituted benzyl ether 13 (Table 1)
provides a baseline for this study; with an IC50 of 1.133
µM, it illustrates how much binding energy is gained
from the 3,5-bis(trifluoromethyl) substitution. The 3,5-
bis(trifluoromethyl) function (12) affords a highly lipo-
philic but electron-deficient aryl ring. Deletion of one
of the trifluoromethyl groups (14) results in a 50-fold
loss in affinity, as does changing to the 2-trifluoromethyl
(15), while the 4-trifluoromethyl (16) results in complete
loss in affinity. This confirms that both substituents
are required for high-affinity binding. Replacement of
the trifluoromethyl groups with chlorine (17) results in
a 4-fold loss in affinity, with the equivalent dimethyl
derivative (18) being 9-fold less active. Given that there
is a larger difference in the electronic effects of methyl
and chlorine with respect to trifluoromethyl than there
is in their respective lipophilic parameters, these results
would suggest that lipophilicity is predominant. This
was confirmed by maintaining one substituent as meth-
yl while the other was increased in bulk to tBu or bromo
(19 and 20), both of which had similar affinity to 12.
Monosubstituted benzyl ethers with a large lipophilic
substituent in the meta position such as the iodo (21),
tBu (22), and trifluoromethoxy (23) analogues suffer a
significant loss in binding affinity compared to 12. The
overall conclusion from this study is that the benzyl
ether side chain requires at least one meta substituent,
but for high NK1 affinity it must be 3,5-disubstituted
and preferably highly lipophilic.
Biology
A stable CHO cell line expressing the human NK1
receptor was used to determine the binding affinity of
the compounds prepared in this study. [125I]Tyr8 sub-
stance P (0.1 nM) was used as the radioligand. Inhibi-
tion of substance P-induced accumulation of inositol
phosphate in CHO cells expressing the hNK1 receptor
was assayed as previously described.23
In Vivo Stu d ies. Male Hartley guinea pigs (VAF,
∼400-600 g of body weight) were anesthetized by
intramuscular injection with ketamine (30 mg/kg) plus
xylazine (6 mg/kg). Test compounds were administered
at 1.0 mg/kg in ethanol (5%):Cremophor (5%):saline
(90%). After 10 min, Evans blue dye (25 mg/mL solution
in saline, containing 50 mmol/mL heparin) was filtered
through a 0.22-µm disk filter and 0.5 mL injected
intravenously via a saphenous vein. Twenty minutes
postinjection of Evans blue dye, animals were chal-
lenged intravenously by injection of resiniferatoxin (7.0
nmol administered over 30 s) via the penile vein. Ten
These gross observations can be interpreted as fol-
lows: Unlike other classes of NK1 antagonists, the 4,4-
disubstituted piperidines have three freely rotatable
bonds in the linking chain and are relatively flexible
molecules. Solution NMR studies confirm the axial

4626 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Stevenson et al.
Sch em e 2a
a
Reagents: (i) RCHO, NaCNBH3, MeOH, AcOH; (ii) RCH2Br, Et3N, DCM.
Sch em e 3a
a
Reagents: (i) K2CO3, DMF; (ii) DMF 140 °C.
Sch em e 4a
lapse.24 It would appear that this is best provided by
inclusion of the 3,5-bis(trifluoromethyl)benzyl ether side
chain (12).
Currently most NK1 antagonists conform to a simple
pharmacophore consisting of two aryl rings separated
by a four-atom link containing a putative H bond donor/
acceptor residing within a specific distance to a basic
nitrogen and some degree of enantioselective binding.2,4
This pharmacophore is based on the observed SAR of
the cis-(2S,3S)-piperidine-based NK1 antagonists at both
the wild type and selective mutant human NK1 recep-
tors.25 The 4,4-disubstituted piperidine type NK1 an-
tagonist cannot display enantioselective binding; how-
ever it is likely that the role of the two aryl rings is
consistent with the established models. Having estab-
lished that the SAR of the benzyl ether in this series
resembled that in other benzyl ether-derived NK1
antagonists, we now proceeded to explore the role of the
basic nitrogen.
a
Reagents: (i) CH3COCl or CH3SO2Cl, Et3N, DCM; (ii) RCO2H,
BOPCl, Et3N, DCM.
orientation of the phenyl ring, placing the more flexible
benzyl ether side chain equatorial. No definitive con-
formation of this side chain has been observed in these
studies. Structural studies on other classes of NK1
antagonists have indicated that some degree of interac-
tion of their respective aryl rings is beneficial to high-
affinity binding.2 In general this is maintained by a
relatively well-defined rigid conformation via specific
stereochemistry and hindered rotation. Consequently
various different aryl substitutions such as those used
in the cis-(2S,3S)-piperidine benzyl ether series (as
exemplified by 4) have been utilized to achieve sub-
nanomolar affinities. Indeed the SAR of the benzyl
ether function in the 4,4-disubstituted piperidines fol-
lows this general trend; however, due to the flexibility
of the side chain, any interaction of the two aryl rings
must be driven by the electrostatic characteristics of the
rings themselves, perhaps aided by hydrophobic col-
In previous piperidine-based NK1 antagonist series
(such as 2 and 4), significant affinity for L-type calcium
channels has been observed, a feature which can be
avoided by decreasing the pKa of the piperidine nitrogen
via N-substitution with electron-withdrawing groups.
We were encouraged to find that 12, although having a
more basic piperidine nitrogen (pKa ) 9.8) than 1 (pKa
) 8.92), showed only weak affinity for L-type calcium
channels (IC50 ) 4.3 µM). Retention of a basic piperi-

Substituted Piperidine High-Affinity NK1 Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4627
Sch em e 5a
a
Reagents: (i) BOC2O, Et3N, DCM; (ii) LiAlH4, THF; (iii) BzBr, Et3N, DCM; (iv) HCl, Et2O.
Sch em e 6a
a
Reagents: (i) dimethyl methylphosphonate, NaH, DMF; (ii) DIBAL-H, BOC2O; (iii) K2CO3, DMF; (iv) H2, Pd/C; (v) NaBH4; (vi) PhOCSCl,
DMAP, DCM; (vii) AlBN, Bu3Sn, toluene; (viii) HCl, Et2O.
dine nitrogen in this system therefore offered greater
scope for substitution.
ring and side chain nitrogens will be protonated (2,
pKaN-1 ) 8.92, pKaN-2 ) 4.98). Any decrease in pKa
N-1
caused by the introduction of an electron-withdrawing
group or by acylation of the piperidine nitrogen would,
however, allow protonation of the side chain nitrogen,
removing H bond acceptor capacity, resulting in reduced
affinity. Second, acylation of the cis-(2S,3S)-piperidine-
based system would by virtue of A1-3 strain invert the
piperidine ring, placing the 2-phenyl group in an axial
position, an effect which is likely to lower affinity by
limiting the possibilities for interaction between the two
aryl rings. Similar observations have been made in the
cis-(2S,3S)-piperidine-based NK1 antagonists.18c In com-
pounds such as 12 there is no second nitrogen, and the
lack of any C-2 substituent means that there is no A1-3
strain to be relieved on acylation; consequently there
is no change in conformation or affinity.
The simple N-methyl derivative 28 is equipotent with
12 (Table 2). Increasing the size of the N-alkyl group
does cause a decrease in affinity, but with some degree
of steric tolerance (29-30). A variety of heterocycles
such as oxadiazole (31), thiazole (32), triazole (34), and
triazolone (35) can be incorporated without significant
losses in NK1 affinity. The ester derivative 33 also
retains affinity.
The net effect of these electron-withdrawing groups
will be to reduce the pKa of the piperidine nitrogen. The
fact that this did not adversely affect the NK1 affinity
raised the question of whether a basic nitrogen was
required at all. To examine this the simple acyl (38)
and sulfonyl (39) derivatives (Table 3) were prepared
and, remarkably, were found to have retained good
affinity compared to 12. There are two relevant factors
which need to be taken into account to explain this
observation. First, in the cis-(2S,3S)-piperidine-based
NK1 antagonists (e.g., 2) the C-3 benzylic amino group
is directly attached to the piperidine ring. For this
reason it is unlikely that at physiological pH both the
If a second, basic nitrogen is introduced into the acyl
side chain (40), then sub nanomolar affinity is regained.
Displacement by an ethyl linker (41) maintains high
affinity, while extension to a propyl linker (42) results
in a slight loss in affinity. As can be seen from
compound 43, the basic center can itself be incorporated

4628 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Ta ble 1. Benzyl Ether Substitutions
Stevenson et al.
a
Displacement of [125I]-labeled substance P from the cloned receptor expressed in CHO cells (n ) 3).
into a saturated ring, with no significant loss in affinity,
or it can be incorporated in a heterocyclic system (44-
47).
The conclusions that can be drawn from this study
are that a highly basic center is not required for binding
in this class of NK1 antagonist and that the area of the
molecule around the piperidine nitrogen may not inter-
act with the receptor, given the wide tolerability to
substituent size and character.
One of the distinguishing features of the 4,4-disub-
stituted piperidine NK1 antagonists described here is
the flexible portion of the molecule linking the benzyl
ether to the phenylpiperidine ring. On the basis of
current NK1 pharmacophores,2 the ether link in the side
chain should behave as a hydrogen bond acceptor.
However in the case of the 4,4-disubstituted piperidine
system, it must also allow or induce any aryl-aryl
interactions.
If the 3,5-bis(trifluoromethyl)benzyloxy side chain of
12 is replaced by the 2-methoxybenzylamino group
found in 1 and 2 to give 48, the resulting compound has
poor affinity for the NK1 receptor (31% @ 1 µM). This
is a significant departure from the observed SAR of the
cis-(2S,3S)-piperidine-based series where the O- for
N-substitution provided equipotent compounds (al-
though it should be noted that 2-methoxybenzyl ether
side chain in the quinuclidine type NK1 antagonist has
poor NK1 affinity26). The explanation for this may lie
in the fact that in compounds such as 2 the benzylic
amino group is directly attached to the piperidine/
quinuclidine ring (see above). In the case of 48 the
benzylic nitrogen is not directly attached to the piperi-
N-1
dine ring and is consequently more basic (48, pKa
10.6, pKa
)
N-2
) 8.2). If at physiological pH both the
piperidine and side chain nitrogens protonate, the
benzylic nitrogen will no longer be able to act as a
hydrogen bond acceptor. A secondary factor may be that
ortho substituents are not well-tolerated in this system
(Table 1). To examine the effect of the pKa of the side
chain nitrogen, the 3,5-bis(trifluoromethyl)benzylamino
compound 49 was prepared. The inductive effect of the
trifluoromethyl groups now decreases the electron den-
sity at the nitrogen (49, pKaN-1 ) 10.13, pKaN-2 ) 5.92),
and it will therefore be less likely to protonate at
physiological pH. This would indeed appear to be the
case as 49 (IC50 ) 12.6 nM), although less active than
12 (IC50 ) 0.95 nM), did recover most of the lost affinity.
Mutagenesis studies using 48 and 49 have also lent
weight to this theory.24 In the case where Lys106 has
been mutated to Glu106, 48 shows a large increase in
NK1 affinity from >100 to 30 nM, indicating that the
protonated form of 48 develops a more favorable inter-
action between ligand and receptor. The NK1 affinity
of 49 is however decreased by this same mutation (from
8.0 to 47 nM).
The compound bearing an all-carbon linking side
chain (57) shows a 200-fold loss in affinity (IC50 ) 180
nM), and this is to be expected from the loss of a

Substituted Piperidine High-Affinity NK1 Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4629
Ta ble 2. N-Alkyl Substituents
a
Displacement of [125I]-labeled substance P from the cloned receptor expressed in CHO cells (n ) 3).
hydrogen-bonding interaction. By mutating the recep-
tor so that Gln165 is replaced by Ala, the observed
affinity of 57 is now 70 nM, whereas the affinity of 12
drops to 55 nM. This represents a loss in binding
energy of around 2.5 kcal, which is again consistent with
a hydrogen bond. The conclusion reached from this
study of the side chain is that, as expected, it must
contain a hydrogen bond acceptor, preferably an ether
oxygen, but alternatively a weakly basic nitrogen is
tolerated.
In Vivo Stu d ies. Initial examination of 12 in vivo
showed it to be poorly orally bioavailable. We therefore
carried out pharmacokinetic studies on a range of
N-substituted compounds to establish possible candi-
dates for in vivo screening.
Compounds (32) and (43) were tested in vivo using
the resiniferatoxin-induced vascular leakage model of
NK1 antagonist activity.27 The respective results are
displayed in Figure 2. Both 32, (ID50 ) 0.28 mg/kg) and
43 (ID50 ) 0.22 mg/kg) have a rapid onset of action. The
effect of the relatively long plasma half-life of 43
manifests itself as a long and flat tail off of the
inhibitory effect which is still significant 24 h after
dosing. Compound 32 has a rapid onset of action and
still shows significant inhibition at 16 h, after which
the effect tails off.
Con clu sion
We have developed a series of high-affinity NK1
antagonists based on
a 4-phenyl,4-arylmethyloxy-
Compounds were selected for this study on the basis
of high NK1 affinity and low affinity at L-type calcium
channels. Using these criteria 32 and 43 were selected,
and their respective pharmacokinetic profiles in rats
were determined. The results of these studies are
represented in Table 5.
Compound 32 shows good oral bioavailability, with a
relatively low plasma clearance rate. The magnitude
of peak plasma concentration and the time in which it
is reached were acceptable for in vivo studies of the type
intended. Compound 43 was found to have a marginally
superior pharmacokinetic profile to 32 with respect to
half-life and higher oral bioavailability. However this
has been attained at the cost of a much higher volume
of distribution and a slower rise to a lower maximum
plasma concentration.
methyl-substituted piperidine ring. This class of NK1
antagonist challenges currently accepted models of the
NK1 pharmacophore with respect to stereochemistry
and the absolute requirement for a basic nitrogen.
Compounds such as 32 and 43 have good oral bioavail-
ability and pharmacokinetics and display excellent
activity and extended duration of action in an in vivo
model of substance P-induced extravasation. Further
details of the in vivo properties of this class of NK1
antagonist will be reported in due course.
Exp er im en ta l Section
Melting points were determined with a Bu¨chi capillary
melting point apparatus and are uncorrected. NMR spectra
were recorded at 360 MHz on a Bruker AM360 instrument.
The term “dried” refers to drying of an organic phase over

4630 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Ta ble 3. N-Acyl Subtituents
Stevenson et al.
a
Displacement of [125I]-labeled substance P from the cloned receptor expressed in CHO cells (n ) 3).
Ta ble 4. Alternative Linkers
a
Displacement of [125I]-labeled substance P from the cloned receptor expressed in CHO cells (n ) 3). b 31% and 25% @ 0.1 µM. *C22H23NF6
requires 415.1734, found 415.1750.
anhydrous magnesium sulfate and then filtering, and organic
solvents were evaporated on a Bu¨chi rotary evaporator at
reduced pressure. Column chromatography was carried out
on silica gel (Merck Art 7734). Elemental analyses were
determined by Butterworth Laboratories Ltd., Teddington,
England.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
12-24.
1-(ter t-Bu t oxyca r b on yl)-4-p h en yl-4-(h yd r oxy-
m eth yl)p ip er id in e (27). A solution of lithium aluminum
hydride (4.02 g, 106 mmol) in dry THF (106 mL) was added
dropwise to a stirred solution of 4-phenyl-4-carboxypiperidine
tosylate (26) (20.0 g, 52.9 mmol) in dry THF (100 mL) at 0 °C.

Substituted Piperidine High-Affinity NK1 Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4631
Ta ble 5. Pharmacokinetic Studies
a
Study carried out in male rats, equal doses administered orally and iv. * Oral dosing.
F igu r e 2. Time-dependent inhibition of resiniferotoxin-induced esophageal plasma extravasation by 32 and 43 at 1 mg/kg po.
After the addition was complete the reaction mixture was
warmed to reflux for 90 min and then allowed to cool to room
temperature. The reaction was then quenched by addition of
aqueous 2 N sodium hydroxide (6.4 mL) followed by water (8.0
mL) which resulted in the formation of a white granular
precipitate. A second portion of NaOH (2.1 g, 52.5 mmol) in
water (25 mL) was added followed by a solution of di-tert-butyl
dicarbonate (11.56 g, 53 mmol) in dichloromethane (65 mL).
The resulting mixture was stirred at 25 °C for 18 h. After
this time the reaction mixture was filtered through a pad of
sodium sulfate, which was subsequently washed with dichlo-
romethane (3 × 100 mL). The filtrate was washed with water
(100 mL) and brine (100 mL), the organic layer separated,
dried over MgSO4, and filtered, and solvent removed under
reduced pressure to afford a clear oil which crystallized on
standing. Recrystallization from ether/n-hexane gave 27 as
white needles: mp 91-94 °C; 1H NMR (CDCl3) δ 1.43 (9H, s),
1.64 (1H, brs), 1.75 (2H, td, J ) 11.0, 10.0 Hz), 2.17 (2H, m),
3.05 (2H, td, J ) 11.0, 1.0 Hz), 3.55 (2H, s), 3.73 (2H, m), 7.24-
4-P h en yl-4-[3,5-bis(tr iflu or om eth yl)ben zyloxym eth yl]-
p ip er id in e Hyd r och lor id e (12). Sodium hydride (120 mg,
60% dispersion in mineral oil, 3.0 mmol) was added to a stirred
solution of 27 (760 mg, 2.6 mmol) and 3,5-bis(trifluoromethyl)-
benzyl bromide (801 mg, 2.61 mmol) in dry dimethylformamide
(5.0 mL). The resulting solution was stirred overnight at room
temperature, poured into water (100 mL), and extracted into
ethyl acetate (50 mL). The organic layer was separated,
washed with water (3 × 50 mL) and then brine (2 × 50 mL),
dried over MgSO4, and filtered and the solvent removed under
reduced pressure to afford a yellow oil. Purification by flash
chromatography (silica gel, 15% EtOAc/n-Hex) afforded 12 as
a clear oil (900 mg, 66%): 1H NMR (CDCl3) δ 1.46 (9H, s),
1.86 (2H, td, J ) 10.0, 1.0 Hz), 2.21 (2H, m), 3.03 (2H, td, J )
10.0, 1.0 Hz), 3.45 (2H, s), 3.76 (2H, m), 4.43 (2H, s), 7.24 (2H,
m), 7.33 (3H, m), 7.54 (2H, s), 7.73 (1H, s); MS m/e (CI+) 518
(M + H)+.
The recovered product (900 mg, 1.77 mmol) was dissolved
in dry diethyl ether (50 mL) and a stream of dry hydrogen
chloride gas passed through the solution for 30 min. The
solution was stirred for a further 2.5 h at room temperature,
7.41 (5H, m); MS m/e (CI+) 292 (M + H)+; HRMS calcd C17H25
-
NO3 291.1834, found 291.1851.

4632 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Stevenson et al.
at which point the solvent was removed under reduced
pressure to afford a white solid. Recrystallization from ethyl
acetate afforded 12 as a white powder (760 mg, 94%): mp 139-
141 °C; 1H NMR (DMSO-d6) δ 2.08 (2H, m), 2.19 (2H, m), 2.73
(2H, m), 3.21 (2H, m), 3.49 (2H, s), 4.58 (2H, s), 7.27 (5H, m),
7.77 (2H, s), 7.98 (1H, s), 9.7 (2H, brs); MS m/e (CI+) 418 (M
+ H)+. Anal. (C21H21NOF6‚HCl) C, H, N.
Meth yl 2-[4-P h en yl-4-(3,5-bis(tr iflu or om eth yl)ben zyl-
oxym eth yl)p ip er id in e]a ceta te Hyd r och lor id e (33). Po-
tassium carbonate (1.38 g, 10.0 mmol) was added to a stirred
solution of 12 (4.47 g, 8.7 mmol) and methyl bromoacetate (1.5
g, 9.8 mmol) in dry DMF (25 mL) and the resulting mixture
stirred at room temperature for 18 h. After this time the
reaction was diluted with water (100 mL), extracted into ethyl
acetate (50 mL), dried over MgSO4, and filtered and the solvent
removed under reduced pressure. The residual solid was
purified by flash chromatography (silica gel, 30% EtOAc/n-
Hex) to give a white solid. The recovered product was
redissolved in dry ether and treated with ethereal HCl followed
by removal of solvent under reduced pressure to give a white
solid. Recrystallization form 2-propanol afforded 33 as a white
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
28-30. 1-Met h yl-4-p h en yl-4-[3,5-b is(t r iflu or om et h yl)-
b en zyloxym et h yl]p ip er id in e p -Tolu en esu lfon a t e (28).
Sodium cyanoborohydride (147 mg, 2.82 mmol) was added to
a stirred suspension of 12 (533 mg, 1.83 mmol) and formal-
dehyde (175 mg, 0.5 mL, 37%, 5.83 mmol) in dry methanol
containing acetic acid (1.0 mL, 16.6 mmol). The resulting
solution was stirred for 18 h at room temperature. After this
time the solvent was removed under reduced pressure and the
residual oil taken up in water and basified to pH 10. The
aqueous solution was extracted into ethyl acetate, separated,
and dried over MgSO4. Filtration and removal of solvent gave
a yellow oil. Chromatography (silica gel, 5% MeOH/DCM)
afforded a clear oil (473 mg). The recovered oil was treated
with a solution of p-toluenesulfonic acid monohydrate (207 mg)
to afford the salt. Recrystallization from ethyl acetate gave
1
powder (2.23 g, 48%): mp 63-65 °C; H NMR (DMSO-d6) δ
2.04-2.11 (2H, m), 2.29-2.42 (4H, m), 2.81 (2H, m), 3.19 (2H,
s), 3.48 (2H, s), 3.69 (3H, s), 4.42 (2H, s), 7.21-7.36 (5H, m),
7.52 (2H, s), 7.72 (1H, s), 9.78 (1H, brs); MS m/e (CI+) 490 (M
+ H)+. Anal. (C24H25NO3F6‚HCl) C, H, N.
4-[3,5-Bis(tr iflu or om eth yl)ben zyloxym eth yl]-4-p h en yl-
1-(4H-[1,2,4]tr ia zol-3-ylm eth yl)p ip er id in e Dih yd r och lo-
r id e (34). Potassium carbonate (608 mg, 4.4 mmol) was added
to a suspension of 12 (500 mg, 1.1 mmol) and N-formamido-
2-(chloromethyl)acetamidine (36) (382 mg, 2.8 mmol) in DMF
(20 mL). The solution was warmed to 60 °C for 2 h and then
to 140 °C for a further 1 h. The reaction was cooled to room
temperature, diluted with water (100 mL), and extracted into
ethyl acetate (50 mL). The organic layers were separated,
washed with water (50 mL) and then brine (50 mL), and dried
over MgSO4, and the solvent was removed under reduced
pressure. The residual oil was purified by flash chromatog-
raphy (silica gel, 10% MeOH/DCM) and the recovered product
treated with excess ethereal hydrogen chloride followed by
removal of solvent under reduced pressure to give the hydro-
chloride salt. Recrystallization from 2-propanol gave 34 as a
white powder (400 mg, 63%): mp 119-120 °C. H NMR
(DMSO-d6) δ 2.16 (2H, m), 2.49-2.56 (2H, m), 2.77 (2H, m),
3.37 (2H, s), 3.42-3.46 (2H, m), 4.33 (2H, s), 4.57 (2H, m),
7.26-7.44 (5H, m), 7.75 (2H, s), 7.98 (1H, s), 8.59 (1H, s), 8.62
(1H, brs), 10.01 (2H, brs); MS m/e (CI+) 499 (M + H)+. Anal.
(C24H24N4OF6‚2HCl) C, H, N.
1
the 28 as a white powder (580 mg, 52%): mp 89-91 °C; H
NMR (DMSO-d6) δ 2.01 (2H, m), 2.21 (2H, m), 2.55 (2H, m),
2.67 (3H, s), 2.71 (2H, m), 3.37 (2H, s), 4.56 (2H, s), 7.30-7.48
(5H, m), 7.70 (2H, s), 7.99 (1H, s), 9.01 (1H, brs); MS m/e (CI+)
432 (M + H)+; HRMS calcd C22H23NOF6 432.1684, found
432.1664. Anal. (C22H23NOF6‚C7H8SO3) C, H, N.
4-[3,5-Bis(tr iflu or om eth yl)ben zyloxym eth yl]-1-([1,2,4]-
oxa d ia zol-3-ylm et h yl)-4-p h en ylp ip er id in e H yd r och lo-
r id e (31). 3-(Chloromethyl)[1,2,4]oxadiazole (130 mg, 1.1
mmol) was added to a stirred solution of 12 (500 mg, 1.1 mmol)
and diisopropylamine (426 mg, 3.3 mmol) in dry CH3CN (20
mL). After 18 h at room temperature the solvent was removed
under reduced pressure and the residue partitioned between
water (50 mL) and ethyl acetate (50 mL). The organic layer
was separated, washed with aqueous NaHCO3 (20 mL), water
(20 mL), and brine (20 mL), dried over MgSO4, and filtered
and the solvent removed under reduced pressure. The product
was purified by flash chromatography (silica gel, 5% MeOH/
DCM) to give a white solid (489 mg, 88%). The recovered
product was taken up in ether (20 mL) and treated with
ethereal HCl. The solvent was removed under reduced pres-
sure and the residue recrystallized from 2-propanol to give 31
as white needles (512 mg, 86%): mp 90-91 °C; 1H NMR
(DMSO-d6) δ 2.15 (4H, brm), 2.50 (2H, m), 2.51 (1H, m), 2.85
(1H, m), 3.37 (2H, m), 3.49 (2H, m), 4.58 (2H, brs), 7.39-7.45
(5H, m), 7.78 (2H, s), 7.97 (1H, s), 9.89 (1H, s), 11.00 (1H, brs);
MS m/e (CI+), 500 (M + H)+. Anal. (C24H23N3O2F6‚HCl) C,
H, N.
5-[4-(3,5-Bis(tr iflu or om eth yl)ben zyloxym eth yl)-4-ph en -
ylp ip er id in -1-ylm eth yl]-2,4-d ih yd r o-[1,2,4]tr ia zol-3-on e
(35). N-(Methoxycarbonyl)(chloromethyl)imidrazone (37) (7.1
g, 40.3 mmol) was added to a stirred suspension of 12 (15.0 g,
33.1 mmol) and K2CO3 (11.12 g, 80.6 mmol) in dry DMF (100
mL) and the resulting solution stirred for 24 h at room
temperature. The reaction mixture was diluted with water
(400 mL) and the resulting mixture extracted into ethyl acetate
(400 mL). The organic extract was washed exhaustively with
water (5 × 100 mL) and brine (200 mL), dried over MgSO4,
and filtered and the solvent removed under reduced pressure
to afford a yellow solid. The recovered solid was redissolved
in dry toluene and warmed to reflux for 30 min. The solvent
was removed under reduced pressure and the residue purified
by chromatography (silica gel, 15% EtOAc/n-Hex) to give the
product as a white powder (16.3 g, 95%). The recovered
product was taken up in dry ether and HCl gas passed through
the solution. Filtration afforded 35 as a white powder on
4-[3,5-Bis(tr iflu or om eth yl)ben zyloxym eth yl]-1-(2-m eth -
ylth ia zol-5-ylm eth yl)-4-p h en ylp ip er id in e Dih yd r och lo-
r id e (32). 5-(Chloromethyl)-2-methylthiazole (202 mg, 1.1
mmol) was added to a stirred solution of 12 (500 mg, 1.1 mmol)
and diisopropylamine (426 mg, 3.3 mmol) in dry CH3CN (20
mL). After 18 h at room temperature the solvent was removed
under reduced pressure and the residue partitioned between
water (50 mL) and ethyl acetate (50 mL). The organic layer
was separated, washed with aqueous NaHCO3 (20 mL), water
(20 mL), and brine (20 mL), dried over MgSO4, and filtered
and the solvent removed under reduced pressure. The product
was purified by flash chromatography (silica gel, 10% MeOH/
DCM) to give a white solid (470 mg, 80%). The recovered
product was taken up in ether (20 mL) and treated with
ethereal HCl. The solvent was removed under reduced pres-
sure and the residue recrystallized from ether to give 32 as
white needles (490 mg, 78%): mp 110-113 °C; 1H NMR
(DMSO-d6) δ 2.19 (3H, m), 2.37 (1H, m), 2.59 (3H, s) 2.74 (2H,
m), 3.29 (2H, m), 3.37 (2H, s), 4.25 (2H, d, J ) 1.0 Hz), 4.55
(2H, s) 7.24-7.44 (5H, m), 7.70 (1H, s), 7.73 (2H, s), 7.96 (1H,
s), 11.00 (2H, brs); MS m/e (CI+) 529 (M + H)+. Anal.
(C26H26N2OSF6‚2HCl) C, H, N.
1
stirring (17.1 g, 94%): mp 159-160 °C; H NMR (DMSO-d6)
δ 2.1 (2H, m), 2.23 (2H, m), 2.61 (2H, m), 2.93 (2H, m), 3.36
(2H, s), 3.80 (1H, d, J ) 15.0 Hz), 4.1 (1H, d, J ) 15.0 Hz), 4.2
(2H, s), 7.1-7.25 (5H, m), 7.76 (2H, s), 7.89 (1H, brs), 8.34
(1H, s), 8.88 (1H, s), 9.02 (1H, brs); MS m/e (CI+) 515 (M +
H)+. Anal. (C24H24N4O2F6‚HCl) C, H, N.
1-Acet yl-4-p h en yl-4-(3,5-b is(t r iflu or om et h yl)b en zyl-
oxym eth yl)p ip er id in e (38). Acetyl chloride (86 mg, 1.1
mmol) was added to a stirred solution of 12 (500 mg, 0.94
mmol) and triethylamine (310 mL, 4.22 mmol) in dry DCM at
0 °C. The resulting solution was allowed to warm to room
temperature overnight. The reaction mixture was diluted with
water (50 mL) and the organic layer separated. The aqueous
layer was extracted further with dichloromethane (2 × 50 mL),
the combined organic extracts were washed with 1 N aqueous

Substituted Piperidine High-Affinity NK1 Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4633
sodium hydroxide solution, dried over MgSO4, and filtered, and
the solvent was removed under reduced pressure to afford a
clear oil which solidified on standing. Recrystallization from
hexane/ether afforded 38 as white needles (389 mg, 89%): mp
64-65 °C; 1H NMR (DMSO-d6) δ 1.70-1.80 (1H, m), 1.81-
1.91 (1H, m), 1.97 (3H, s), 2.04-2.22 (2H, brm m), 2.90-2.99
(1H, m), 3.09-3.19 (1H, m), 3.51 (2H, s), 3.55-3.63 (1H, m),
3.80-3.89 (1H, m), 4.55 (2H, s), 7.20-7.45 (5H, m), 7.75 (2H,
m), 7.21-7.39 (5H, m); MS m/e (CI+) 291 (M + H)+; HRMS
calcd C17H26N2O2 290.1994, found 290.2012.
Com p ou n d s 48 a n d 49 P r ep a r ed by th e F ollow in g
P r oced u r e. 4-P h en yl-4-[3,5-bis(tr iflu or om eth yl)ben zyl-
a m in om eth yl]p ip er id in e Dih yd r och lor id e (49). A solu-
tion of 3,5-bis(trifluoromethyl)benzyl bromide (2.59 g, 8.48
mmol) in dry DCM was added dropwise to a chilled solution
of 51 (2.46 g, 8.48 mmol) in dry DCM. The reaction was
allowed to warm to room temperature, stirred for 2 h, and
diluted with water (50 mL) and the organic layer separated
and dried over MgSO4. Filtration and removal of solvent
under reduced pressure afforded a yellow oil, which was
further purified by MPLC (SiO2/EtOAc/n-Hex, 1:1). The
recovered product was treated with HCl/Et2O for 18 h. The
solvent was removed under reduced pressure and the product
recrystallized from EtOAc to give 49 (2.1 g, 54%): mp 210-
215 °C; 1H NMR (DMSO-d6) δ 2.08 (2H, m), 2.40 (2H, m), 2.49
(2H, s), 2.76 (2H, m), 3.22 (2H, m), 4.20 (2H, m), 7.34-7.45
(5H, m), 7.84 (2H, brs), 8.13 (1H, s), 8.23 (2H, s), 9.01 (2H,
brs); MS m/e (CI+) 417 (M + H)+. Anal. (C21H22N2F6‚2HCl)
C, H, N.
s), 7.96 (1H, s); MS m/e (CI+) 460 (M + H)+. Anal. (C23H23
-
NO2F6) C, H, N.
1-(Meth ylsu lfon yl)-4-p h en yl-4-(3,5-bis(tr iflu or om eth -
yl)ben zyloxym eth yl)piper idin e (39). Methanesulfonyl chlo-
ride (125 mg, 1.1 mmol) was added to a stirred solution of 12
(500 mg, 0.94 mmol) and triethylamine (310 mL, 4.22 mmol)
in dry DCM at 0 °C. The resulting solution was allowed to
warm to room temperature overnight. The reaction mixture
was diluted with water (50 mL) and the organic layer
separated. The aqueous layer was extracted further with
dichloromethane (2 × 50 mL), the combined organic extracts
were washed with 1 N aqueous sodium hydroxide solution,
dried over MgSO4, and filtered, and the solvent was removed
under reduced pressure to afford a clear oil which solidified
on standing. Recrystallization from ethyl acetate/n-hexane
afforded 39 as white needles (410 mg, 87%): mp 102-104 °C;
1H NMR (DMSO-d6) δ 1.97-2.08 (2H, m), 2.36-2.46 (2H, m),
2.66 (3H, s), 2.80-2.90 (2H, m), 3.44 (2H, s), 3.55-3.64 (2H,
m), 4.44 (2H, s), 7.24-7.44 (5H, m), 7.52 (2H, s), 7.73 (1H, s);
MS m/e (CI+) 496 (M + H)+. Anal. (C22H23NOF6S) C, H, N.
4-P h e n yl-4-(2-m e t h oxyb e n zyla m in om e t h yl)p ip e r i-
d in e d ih yd r och lor id e (48): prepared analogously to 49; mp
178-180 °C; 1H NMR (DMSO-d6) δ 2.14 (2H, m), 2.37 (2H,
m), 2.69 (2H, s), 2.78 (2H, m), 3.19 (2H, s), 3.33 (2H, s), 3.57
(3H, s), 6.91 (1H, d, J ) 6.0 Hz), 6.96 (1H, t, J ) 6.0, 1.0 Hz),
7.25 (1H, d, J ) 6.0 Hz), 7.37 (1H, t, J ) 6.0, 1.0 Hz), 7.41-
7.73 (5H, m), 9.30 (2H, brs); MS m/e (CI+) 311 (M + H)+. Anal.
(C20H27N2O‚2HCl) C, H, N.
Com p ou n d s 40-47 P r ep a r ed by th e F ollow in g P r oce-
d u r e. 1-[4-(3,5-Bis(tr iflu or om eth yl)ben zyloxym eth yl)-4-
ph en ylpiper idin -1-yl]-2-pyr r olidin eacetam ide p-Tolu en e-
su lfon a te (43). Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
(1.6 g, 6.29 mmol) was added to a stirred solution of 12 (2.85
g, 6.3 mmol), 2-(N-pyrrolidino)acetic acid hydrochloride (1.04
g, 6.3 mmol), and triethylamine (2.54 g, 25.2 mmol) in DCM
(20 mL). After 18 h the reaction was washed with water (50
mL) and brine (50 mL), the organic layers were separated,
dried over MgSO4 and filtered, and the solvent was removed
under reduced pressure. The residue was purified by chro-
matography (grade III alumina, 0-2% MeOH/DCM). The
recovered product was treated with p-toluenesulfonate mono-
hydrate (720 mg) to afford the salt. Recrystallization from
2-propanol afforded 43 as white needles (1.4 g, 42%): mp 121-
122 °C; 1H NMR (DMSO-d6) δ 1.8-1.97 (6H, m), 2.1-2.23 (2H,
m), 2.6 (4H, m), 2.9-3.05 (1H, m), 3.08 (1H, m), 3.14 (1H, d,
J ) 12 Hz), 3.20 (1H, d, J ) 12 Hz), 3.26 (2H, s), 3.88 (1H, dt,
J ) 10, 4 Hz), 4.21 (1H, dt, J ) 10, 4 Hz), 4.22 (2H, s), 7.2-
7.4 (5H, m), 7.56 (2H, s), 7.78 (1H, s) MS m/e (CI+) 529 (M +
H)+. Anal. (C27H30N2O2F6‚C7H8SO3) C, H, N.
4-P h en yl-4-(am in om eth yl)-1-(ter t-bu toxycar bon yl)piper -
id in e (51). Di-tert-butyl dicarbonate (20 g, 91.7 mmol) was
added to a stirred solution of 4-phenyl-4-cyano piperidine
hydrochloride (50) (20.0 g, 90.09 mmol) and triethylamine (9.5
g, 94.05 mmol) in dry DCM (100 mL). The resulting solution
was stirred overnight at room temperature. The reaction
mixture was then washed with water (2 × 100 mL) and the
organic layer separated and dried over MgSO4. Filtration and
removal of solvent under reduced pressure afforded a white
solid. Recrystallization from hexane gave N-(tert-butoxycar-
bonyl)-4-phenyl-4-cyanopiperidine as white needles (25.62 g,
99%): mp 64 °C; 1H NMR (CDCl3) δ 1.46 (9H, s), 1.90 (2H,
m), 2.04 (2H, m), 3.20 (2H, m), 4.26 (2H, m), 7.26-7.49 (5H,
m); MS m/e (CI+) 287 (M + H)+.
Dim et h yl 2-(3,5-Bis(t r iflu or om et h yl)p h en yl)-2-k et o-
eth ylp h osp h on a te (53). n-Butyllithium (165 mL of a 2.5 M
solution in hexane, 410 mmol) was added dropwise to a
solution of dimethyl methylphosphonate (50.1 g, 403 mmol)
in dry THF (500 mL) stirring under a dry nitrogen atmosphere
at -78 °C. After 1 h, methyl 3,5-bis(trifluoromethyl)benzoate
(52) (18.7 g, 68.75 mmol) in dry THF (50 mL) was added slowly
over a period of 30 min and stirred for a further 30 min. The
reaction was then quenched with aqueous 5 N hydrochloric
acid (500 mL) and the THF removed under reduced pressure.
The residual liquid was extracted with ethyl acetate (2 × 100
mL), the organic layer separated, dried over MgSO4, and
filtered, and the solvent removed under reduced pressure. The
residue was distilled under high vacuum to give 53 (bp 160-
162 °C @ 1 mmHg): 1H NMR (DMSO-d6) δ 3.66 (3H, s), 3.69
(3H, s), 3.89 (2H, d, J ) 21.0 Hz), 8.45 (1H, s), 8.50 (2H, s);
MS m/e (CI+) 365 (M + H)+.
N-(ter t-Bu toxyca r bon yl)-4-p h en ylp ip er id in e-4-ca r box-
a ld eh yd e (54). A solution of 50 (5.0 g, 17.4 mmol) in dry
toluene (100 mL) at -78 °C was treated with a solution of
DIBAL-H (27.7 mL, 1.0 mol) in toluene. The reaction was
maintained at -78 °C for 2 h, at which time it was quenched
by slow addition of a saturated aqueous solution of NH4Cl (20
mL) and allowed to warm to room temperature. The reaction
mixture was poured into water (100 mL) and extracted into
ethyl acetate. The organic layers were separated, dried over
MgSO4, and filtered, and solvent was removed to give a yellow
oil. Chromatography on silica gel (20% EtOAc in hexane)
afforded 54 as a clear oil (2.1 g, 41%): 1H NMR (CDCL3) δ
1.45 (9H, s), 1.95 (2H, m), 2.07 (2H, m), 3.12 (2H, m), 3.85
(2H, m), 7.26-7.40 (5H, m), 9.40 (1H, s); MS m/e (CI+) 290 (M
+ H)+; HRMS calcd C17H23NO3 289.1678 (290.1756 M + H+),
found 290.1764.
4-(3-(3′,5′-Bis(t r iflu or om et h yl)p h en yl)-3-k et op r op yl)-
4-p h en yl-N-(ter t-b u t oxyca r b on yl)p ip er id in e (55). So-
dium hydride (800 mg, 60% dispersion in mineral oil, 20.0
mmol) was added to a solution of 53 (4.6 g, 15.9 mmol) and 54
(5.8 g, 15.9 mmol) in dry DMF (100 mL). After 1 h 2-propanol
(50 mL) was added, and after a further 1 h the solvents were
removed under reduced pressure. The residue was purified
by flash chromatography (EtOAc/n-Hex, 1:9) to afford the
intermediate R,â-unsaturated ketone as a clear oil (6.2 g,
73%): 1H NMR (CDCl3) δ 1.46 (9H, s), 1.86-2.10 (2H, m),
2.30-2.46 (2H, m), 3.04-3.20 (2H, m), 3.84-3.98 (2H, m), 6.61
The recovered product was taken up in 15% acetic acid/
ethanol (300 mL) and hydrogenated at 50 psi over platinum
dioxide (0.5 g) for 18 h. The catalyst was filtered off and the
solvent removed under reduced pressure. The residue was
partitioned between ethyl acetate (100 mL) and aqueous 2 N
sodium hydroxide (100 mL) solution. The organic extract was
separated, dried over MgSO4, and filtered and the solvent
removed under reduced pressure to afford 51 as a clear oil (23.2
g, 80%): 1H NMR (CDCl3) δ 1.45 (9H, s), 1.67 (2H, m), 2.20
(2H, m), 2.75 (2H, s), 3.05 (2H, m), 3.50 (2H, brs), 3.71 (2H,

4634 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Stevenson et al.
ceptor. J . Pharmacol. Exp. Ther. 1993, 267, 472-479. (d) Lowe,
J . A., III. Nonpeptide tachykinin antagonists: Medicinal Chem-
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545. (e) Boks, G. J .; Tollenaere, J . P.; Kroon, J . Possible ligand
receptor interactions for NK1 antagonists as observed in their
crystal structures. Bioorg. Med. Chem. 1997, 5 (3), 535-547.
(3) Ward, P.; Armour, D. R.; Bays, D. E.; Evans, B.; Giblin, G. M.
P.; Heron, N.; Hubbard, T.; Liang, K.; Middlemiss, D.; Mordaunt,
J .; Naylor, A.; Pegg, N. A.; Vinader, V.; Watson, S. P.; Bountra,
C.; Evans, D. C. Discovery of an Orally Bioavailable NK-1
Receptor Antagonist, (2S, 3S)-(2-Methoxy-5-tetrazol-1-ylbenzyl)-
(2-phenylpiperidin-3-yl)amine (GR203040), with Potent Anti-
emetic Activity. J . Med. Chem. 1995, 38, 4985-4992.
(4) Harrison, T.; Williams, B. J .; Swain, C. J .; Ball, R. G. Piperidine
ether based hNK1 Antagonists: Determination of the Relative
and Absolute Stereochemical Requirements. Bioorg. Med. Chem.
Lett. 1994, 4 (21), 2545-2550.
(5) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.;
Haworth, K.; Keown, L.; MacIntyre, D. E.; Metzger, J . M.; Owen,
S.; Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard, S.;
Swain, C. J .; Tattersall, F. D.; Williamson, D.; Hargreaves, R.
(1H, d, J ) 8.7 Hz), 7.15 (1H, d, J ) 8.7 Hz), 7.21-7.48 (5H,
m), 7.99 (1H, s), 8.10 (2H, s).
The recovered ketone (6.2 g, 11.7 mmol) was dissolved in
ethanol (50 mL) and hydrogenated at 50 psi over 10% Pd/C
(1.0 g) for 16 h. The catalyst was filtered off and the solvent
removed under reduced pressure to afford 55 as a clear oil (6.1
g, 98%). A portion of the recovered product (100 mg, 0.19
mmol) was treated with ethereal hydrogen chloride for 16 h
and then concentrated under reduced pressure to give a white
solid. Recrystallization from ethyl acetate gave the hydro-
chloride salt as white needles (79 mg, 88%): mp 54-55 °C;
1H NMR (DMSO-d6) δ 1.96-2.03 (4H, brm), 2.35 (2H, m),
2.79-2.84 (4H, brm), 3.18 (2H, m), 7.21 (1H, m), 7.34-7.42
(4H, m), 8.29 (2H, s), 8.36 (1H, s), 9.03 (2H, brs); MS m/e (CI+)
430 (M + H)+. Anal. (C22H21NOF6‚HCl) C, H, N.
(()-4-(3-(3′,5′-Bis(tr iflu or om eth yl)p h en yl)-3-h yd r oxy-
pr opyl)-N-(ter t-bu toxycar bon yl)-4-ph en ylpiper idin e (56).
Sodium borohydride (0.3 g. 7.89 mmol) was added to 55 (1.5
g, 3.49 mmol) in methanol (20 mL). After 1 h the reaction
mixture was poured into water and extracted into ethyl
acetate. The organic layers were separated, dried over MgSO4,
and filtered, and the solvent was removed under reduced
pressure. The residue was purified by chromatography (silica
gel, 25% EtOAc/n-Hex) to give 56 (1.2 g, 64%): 1H NMR
(CDCl3) δ 1.43 (9H, s), 1.47-1.73 (2H, m), 2.04-2.17 (4H, m),
2.43 (1H, brs), 3.02-3.24 (4H, m), 3.58-3.66 (2H, m), 4.56-
4.58 (1H, m), 7.19-7.34 (5H, m), 7.61 (2H, s), 7.74 (1H, s); MS
m/e (CI+) 532 (M + H)+; HRMS calcd C27H31NO3F6 531.2208,
found 531.2230.
4-(3-(3′,5′-Bis(tr iflu or om eth yl)p h en yl)p r op yl)-4-p h en -
ylp ip er id in e Hyd r och lor id e (57). Phenyl chlorothioformate
(0.43 g, 2.5 mmol)) was added to a stirred solution of 56 (0.7
g, 1.62 mmol) and 4-(dimethylamino)pyridine (0.32 g, 2.62
mmol) in dichloromethane (50 mL) at 0 °C. The solution was
allowed to warm to 20 °C and stirred for 16 h. The mixture
was diluted with ethyl acetate and washed successively with
a 10% aqueous solution of citric acid (20 mL), water (20 mL),
aqueous sodium bicarbonate solution (50 mL), and brine (50
mL). The solution was dried over MgSO4 and the solvent
removed under reduced pressure. The residue was dissolved
in toluene (25 mL) which was purged with nitrogen gas, R,R-
azoisobutyronitrile (0.49 g, 2.98 mmol) and tributyltin hydride
(0.58 g, 1.99 mmol) were added, and the solution was heated
under reflux for 5 h, cooled to room temperature, and concen-
trated under reduced pressure. The residue was purified by
chromatography (silica gel, 10% EtOAc/n-Hex) and then
treated with ethereal hydrogen chloride for 16 h. The solvent
was removed under reduced pressure and the residue crystal-
lized from ethyl acetate to give 57 (290 mg, 39%): 1H NMR
(DMSO-d6) δ 1.22-1.32 (2H, m), 1.54-1.64 (2H, m), 1.83-1.94
(2H, m), 2.26-2.34 (2H, m), 2.62 (2H, t, J ) 7.5 Hz), 2.72 (2H,
t, J ) 10.0 Hz), 3.08-3.18 (2H, m), 7.21-7.37 (5H, m), 7.76
(2H, s), 7.86 (1H, s), 8.74 (2H, brs); MS m/e (CI+) 416 (M +
H)+; HRMS calcd C22H23NF6 415.1734, found 415.1750. Anal.
(C22H23NF6‚HCl) C, H; N: calcd, 3.10; found, 2.38.
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