Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs

Article abstract of DOI:10.1021/jm990617v

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl- 3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

Full text of DOI:10.1021/jm990617v

1234
J . Med. Chem. 2000, 43, 1234-1241
P h osp h or yla ted Mor p h olin e Aceta l Hu m a n Neu r ok in in -1 Recep tor An ta gon ists
a s Wa ter -Solu ble P r od r u gs
J effrey J . Hale,*,† Sander G. Mills,† Malcolm MacCoss,† Conrad P. Dorn,† Paul E. Finke,† Richard J . Budhu,†
Robert A. Reamer,† Su-Er W. Huskey,† Debra Luffer-Atlas,† Brian J . Dean,† Erin M. McGowan,†
William P. Feeney,† Shuet-Hing Lee Chiu,† Margaret A. Cascieri,† Gary G. Chicchi,† Marc M. Kurtz,†
Sharon Sadowski,† Elzbieta Ber,† F. David Tattersall,‡ Nadia M. J . Rupniak,‡ Angela R. Williams,‡
Wayne Rycroft,‡ Richard Hargreaves,‡ J oseph M. Metzger,† and D. Euan MacIntyre†
Merck Research Laboratories, P.O. Box 2000, Rahway, New J ersey 07065, and Merck, Sharp & Dohme,
Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received December 17, 1999
The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence
of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-
glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic
subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo
most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in
vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8
mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog.
Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but
it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the
guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of
2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical
candidate 2 suitable for intravenous administration in humans.
In tr od u ction
Emesis induced by radiation and/or chemotherapeutic
agents is a major side effect in the treatment of various
malignancies.1 The use of 5-hydroxytryptamine3 (5-HT3)
receptor antagonists has impacted cancer treatment in
a positive manner due to the efficacy these drugs have
in controlling the emesis that immediately follows the
administration of chemotherapeutic agents.2 Improving
the treatment of the second phase of chemotherapy-
induced emesis (delayed emesis) as well as identifying
agents that are efficacious against a wider variety of
emetogens remains the focus of current research.3
Recent disclosures of the effectiveness of human neu-
rokinin-1 receptor (hNK-1) or Substance P (SP) receptor
antagonists in controlling emesis in both preclinical4
and clinical5 settings indicate that compounds of this
class represent a potentially significant advance in the
treatment of chemotherapy-induced emesis and of nau-
sea and vomiting in general.
adverse effects in healthy male volunteers7 and highly
efficacious in the treatment of acute chemotherapy-
induced emesis when given in combination with gran-
isetron and dexamethasone, while being superior to
placebo in the prevention of delayed chemotherapy-
induced emesis.5a
The sparing water solubility of 2 (0.2 µg/mL in isotonic
saline) precludes its formulation in a vehicle acceptable
for intravenous administration in humans. Since the
availability of both an oral and an intravenous formula-
tion of 2 was deemed to be necessary in order to provide
maximum clinical flexibility with this compound, we
sought ways to overcome the solubility issues associated
with it. Pharmaceutically acceptable sulfonic acid salts8
(methane sulfonate, ethane disulfonate) of weakly basic
2 were prepared, but these salts dissociated in aqueous
media which resulted in the precipitation of the free
base from the acidic solution. The viability of preparing
a prodrug9 of 2 was therefore examined. Since a prodrug
of 2 would be used primarily for intravenous adminis-
tration, we hoped to identify an entity that had good
The details of our efforts to modify 1 (L-742,694)6
which resulted in the discovery of the potent, orally
bioavailable, CNS-penetrant hNK-1 antagonist 2 (L-
754,030, MK-0869) have been reported.4 This compound
has high affinity for the hNK-1 receptor (IC50 ) 90 (
50 pM for the displacement of [125I]-SP from hNK-1
expressed in CHO cells) and inhibits the actions of SP
in vivo after oral and intravenous dosing in animal
models of peripheral inflammation and emesis. In recent
clinical trials, 2 was well tolerated with no serious
* To whom correspondence should be addressed. Tel: 732-594-2916.
Fax: 732-594-5966. E-mail: jeffrey_hale@merck.com.
† Merck Research Laboratories.
‡ Merck Sharp & Dohme.
10.1021/jm990617v CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/25/2000

hNK-1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1235
Sch em e 1. Preparation of N2 Phosphoryl Derivatives of 1 and 2
water solubility, rapidly reverted to the parent while
releasing innocuous residues in vivo, and exhibited
sufficient chemical stability to allow for its routine
handing and storage. The recent example of the anti-
convulsant fosphenytoin10 highlights one successful
approach for introducing solubility-enhancing phos-
phate functionality into a bioactive nitrogenous hetero-
cycle,11 but we wished to avoid functionalized Mannich
adducts of 2 which would necessitate the release in vivo
of formaldehyde or other low molecular weight aliphatic
aldehydes. The simplest approach to introduce phos-
phate functionality into 2 would be the direct phospho-
rylation of the 1,2,4-triazol-3-one group, and we were
encouraged to pursue this as a prodrug strategy on
finding that the O-thiophosphorylation of some struc-
turally simple 1,2,4-triazol-3-ones had been reported.12
We wish to disclose herein our efforts toward the
preparation of chemically stable N-phosphoryl deriva-
tives of both 1 and 2, the details of their structure
determination, and the characterization of the N-
phosphoryl derivative of 2 as a prodrug in vitro and in
vivo.
sufficient stability to neutral or mildly acidic aqueous
solvents to allow for their purification using preparative
reverse-phase HPLC and were determined to be the N2
phosphoryl derivative 3 or 4 via a series of NMR
experiments (see below). Altering the base (sodium or
potassium bis(trimethylsilyl)amide, tert-butylmagne-
sium chloride, triethylamine) or the phosphorylating
agent (dibenzylphosphoryl chloride,14 dibenzylphospho-
ryl flouride,15 dibenzyl N,N-diethylphosphoramidite16)
did not improve the yield of 3 or 4 as compared to the
reaction of the lithium salt of 1 or 2 with TBPP; in many
cases the reaction mixtures contained the starting
material as the sole morpholine species.
The purified major reaction products (3 and 4) slowly
decomposed at room temperature, so they were im-
mediately converted to phosphate salts 5 and 6. Cata-
lytic hydrogenation of 3 or 4 was carried out in the
presence of 2 molar equiv of a metal bicarbonate or an
amine to directly provide the desired crude phosphate
salt. After filtration of the catalyst and concentration
of the filtrate, 5 or 6 was extracted into water and
lyophilized, which served to remove the minor amounts
(∼10%) of the parent compound 1 or 2 that invariably
formed during the hydrogenation. Phosphate salts
prepared in this manner were determined to contain
only the product and residual 1 or 2 (<1%) as the sole
organic components. Various salt forms of 5 and 6 were
prepared in this manner; salt forms were also intercon-
verted using ion exchange chromatography.17
Ch em istr y
Treatment of a solution of the lithium salt of 1 or 2
in THF at 0 °C with tetrabenzyl pyrophosphate (TB-
PP)13 afforded mixtures of the starting materials and
two products (Scheme 1). Under these conditions, ap-
proximately 60% of 1 or 2 was converted to the products,
and the product ratio ranged from 5:1 to 10:1. The
products of these reactions were stable to aqueous
workup conditions (saturated aqueous NaHCO3 solu-
tion), but they were found to decompose on exposure to
silica gel during column chromatography which initially
hindered the separation and purification of reaction
mixtures. The major reaction products did exhibit
Further experimentation provided an indication as to
the possible identity of the side product formed during
the phosphorylation reaction and led to reaction condi-
tions that circumvented the need for the HPLC purifica-
tion of 3 and 4. If a mixture of 1 or 2 and TBPP in THF
at 0 °C was treated with 1 equiv of a nonnucleophilic
base such as sodium bis(trimethylsilyl)amide (NaH-

1236 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Hale et al.
Sch em e 2. Potential Pathway for the Formation and Consumption of Byproduct 7 during the Dibenzyl
Phosphorylation Reaction
MDS), the reaction profile observed was the same as
that seen when the preformed lithium salt of the 3-oxo-
1,2,4-triazole was treated with TBPP. The addition of
excess TBPP to the reaction mixture did not affect the
amounts of the other reaction components present,
indicating that the base had been consumed. However,
the addition of excess NaHMDS served to consume
residual 1 or 2, TBPP, and the byproduct that was
detected in the reactions using 1 equiv of base. If 2.2-
2.5 equiv of NaHMDS was gradually added to a mixture
of 1 or 2 and a slight excess of TBPP in THF at 0 °C,
the phosphate diester 3 or 4 was observed to be the
major organic species present with residual starting
material (∼5%) being the other major component. After
aqueous workup, the crude diester 3 or 4 was subjected
to the hydrogenation and extraction/lyophilization pro-
tocol that was previously employed with diester that
was obtained after HPLC purification to afford the
phosphate salts 5 and 6.
The dibenzylphosphorylation 1 and 2 is regioselective,
and this selectivity presumably arises from the equili-
bration of any of the dibenzylphosphorylated 3-oxo-1,2,4-
triazole species that are formed to the N2 isomer via
intermolecular dibenzylphosphoryl transfer and/or in-
tramolecular dibenzylphosphoryl 1,3-shifts (Scheme 2).
If the product (3 or 4) of the phosphorylation reaction
is more acidic than the starting material (1 or 2), 2
molar equiv of base are required for the phosphorylation
reaction to proceed to completion under equilibration
conditions. Consumption of the byproduct as excess base
added to the reaction mixture is noteworthy. While
attempts to isolate the byproduct in pure form by HPLC
were unsuccessful, examination of reaction mixtures by
HPLC-MS provided insights regarding its identity.
Analysis of the components in an aliquot removed from
the phosphorylation reaction of 1 or 2 after 1 molar
equiv of NaHMDS had been added revealed that the
byproduct was not a phosphate dibenzyl ester isomeric
to 3 or 4 or a bis(dibenzylphosphoryl) species but rather
a product (7) that results from the displacement of one
of the benzyloxy groups from the TBPP (Scheme 2). As
the reaction proceeds, both the desired product (3 or 4)
and 7 can consume excess base (NaHMDS, sodium
benzyloxide, or the sodium salt of 1 or 2). While the
sodium salt of 3 or 4 is presumably stable, 7 can
potentially isomerize under basic conditions to an
intermediate (8) which can eliminate benzyl phosphite
to give 9 and provide the product (3 or 4) at equilibri-
um.18
Monobasic and dibasic salts of 5 and 6 were prepared
with the goals of identifying a crystalline derivative that
would further aid in their purification and impart solid
state stability to these compounds. While none of the
salts that were prepared were crystalline, qualitative
examination of the lyophilized solids afforded useful
information regarding their solid state stability. The
degradation of the monobasic salts to 1 or 2 and
inorganic phosphate was found to occur more rapidly
than with the dibasic salts. The degradation of salts
with metal counterions (Na, K) was found to be more
rapid than for salts derived from amine bases. The
lyophilized salts of 5 or 6 with three pharmaceutically
acceptable amine bases8 (choline, tris(hydroxymethyl)-
methylamine, N-methyl-D-glucamine) were found to be
appreciably stable. While the bis(choline) and bis(tris-
(hydroxymethyl)methylamine) salts were hygroscopic,
the bis(N-methyl-D-glucamine salts (10 and 11) were
tractable solids which made this the salt form of choice.
Degradation of 10 and 11 occurred at a rate of less than
0.1% per day under ambient conditions, and samples
of these salts showed no detectable degradation after
storage for 6 months at -20 °C. As expected, 11 showed
greatly enhanced aqueous solubility (12 mg/mL in
isotonic saline) as compared to 2. The optimized prepa-
ration of 10 and 11 is shown in Scheme 3.
Regioisom er Deter m in a tion
The diester 4 was sufficiently stable to allow for its
1
characterization by H and 13C NMR spectroscopy, and
these experiments provided the key data for the deter-
mination of the regiochemical outcome of the diben-
zylphosphorylation reaction (Figure 1). The 13C spec-
trum of 4 in d6-DMSO solution showed 13C-31P coupling
to both C3 and C5. The magnitude of these couplings
(13.2 and 11.9 Hz, respectively) is consistent with each
of the carbon atoms of the 3-oxo-1,2,4-triazole ring being
two or three atoms removed from the phosphorus atom,
which indicated that one of the nitrogen atoms and not
the oxygen atom of the heterocycle had been diben-
zylphosphorylated. Examination of the 13C NMR spectra

hNK-1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1237
Sch em e 3. Optimized Preparation of 10 and 11
in d6-DMSO solution of partially deuterated 2 and 4 was
used to confirm the assignment of the chemical shifts
for the two carbons of the 3-oxo-1,2,4-triazole ring of 2
and to determine which nitrogen atom of the heterocycle
of 2 had been phosphorylated.19 Since proton exchange
is slow in DMSO, adding sufficient D2O to 50% deuter-
ate the 3-oxo-1,2,4-triazole ring nitrogens of 2 allowed
for the observation of two secondary isotope shifts of
0.13 ppm each for the 156.2 ppm signal, indicating that
it corresponds to a carbon between two nitrogens and
therefore must correlate to C3. A secondary isotope shift
of 0.12 ppm and a tertiary isotope shift of 0.04 ppm were
observed for the 143.8 ppm signal, indicating that this
resonance must be due to C5. A similar deuterium
isotope experiment with 4 revealed isotope shifts to C3
of 0.14 ppm and to C5 of 0.13 ppm, which is only
consistent with N2, and not N1 or N4, of the 3-oxo-1,2,4-
triazole being the ring nitrogen atom that had been
dibenzylphosphorylated. It was therefore reasoned that
4 is the correct structure for the product of the diben-
zylphosphorylation reaction.
Con ver sion of 11 to 2 in Vitr o a n d in Vivo
A series of experiments were carried out to examine
the stability of 11 in plasma and hepatic subcellular
fractions in vitro and to demonstrate that the metabolic
conversion of 11 to 2 occurs in vivo.20 Control incuba-
tions of 11 at concentrations ranging from 1 µg/mL to
25 µg/mL in fresh, heparinized rat and dog blood at 0
°C in the presence of vanadate were first carried out to
establish that 11 was stable in plasma in the absence
of alkaline phosphatase and that the conversion of 11
to 2 ex vivo was low. Similar incubations of 11 at a
concentration of 10 µg/mL in the absence of vanadate
in rat, dog, and human blood (Table 1) indicated that
appreciable conversion to 2 occurred in rat blood (t1/2
=
30 min), but was much slower in dog blood (t1/2 > 300
min). Compound 11 was very stable in human blood
with only about 10% conversion detected after 2 h. Since
metabolic conversion of 11 to 2 could also occur in liver,
the stability of 11 in human hepatic subcellular fractions
was then examined (Table 2). The rate of conversion of
11 to 2 in human liver microsomes was rapid with only
3% of 11 remaining after 15 min. The rate of conversion
in the cytosolic fraction was slower but still appreciable,
with almost 70% conversion of 11 to 2 after 120 min.
Similar results were obtained with dog hepatic subcel-
lular fractions (data not shown). On the basis of these
results, it was concluded that 11 could indeed function
as a prodrug of 2 in vivo in all three species examined
and that the metabolic conversion of 11 to 2 would be
expected to occur primarily during hepatic circulation
in humans.
F igu r e 1. 13C NMR data for the determination of the
regiochemistry of 4.

1238 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Hale et al.
Ta ble 1. Concentrations (µM) of 11 and 2 in Plasma after Incubation in Rat, Dog, and Human Blooda
rat
dog
human
time
(min)
11
2
11
2
11
2
0
15
30
60
120
23 ( 0.5
18 ( 0.5
13 ( 1.0
6.4 ( 0.5
1.9 ( 0.1
0.6 ( 0.05
5.8 ( 0.3
8.0 ( 0.4
11 ( 0.5
15 ( 0.9
26 ( 0.7
26 ( 1.1
25 ( 0.3
24 ( 0.6
20 ( 1.1
1.2 ( 0.1
1.8 ( 0.05
2.4 ( 0.05
3.9 ( 0.2
6.0 ( 0.5
26 ( 0.9
27 ( 0.8
26 ( 0.4
26 ( 0.9
26 ( 0.7
0.8 ( 0.05
1.0 ( 0.1
1.1 ( 0.1
1.4 ( 0.1
2.3 ( 0.4
a
Incubation of 11 (16.3 µM, 3 samples/data point) in fresh, heparinized blood at 37 °C for the specified time was followed by treatment
with vanadate (5 mM) at 4 °C to minimize ex vivo conversion of 11 to 2. Plasma samples were obtained by centrifugation at 4 °C, subjected
to solid-phase extraction, and analyzed for 11 and 2 by LC/MS/MS.
Ta ble 2. Conversion of 11 to 2 in Human Hepatic Subcellular
Ta ble 5. Comparison of the hNK-1 Affinities and
Pharmacology of 2 and 11
Fractionsa
microsomal
cytosolic
2
11
time
(min)
11 (µM)
2 (µM)
11 (µM)
2 (µM)
Receptor Bindinga
hNK-1 IC50 (nM)
0.09 ( 0.05
1.2 ( 1.2b
0
15
30
60
120
8 ( 0.3
0.2 ( 0.05
blqb
0.6 ( 0.1
5.3 ( 0.1
5.2 ( 0.3
5.1 ( 0.2
5.1 ( 0.1
7.5 ( 0.1
6.8 ( 0.2
6.1 ( 0.1
4.5 ( 0.2
2.4 ( 0.2
0.1 ( 0.05
0.9 ( 0.05
1.7 ( 0.1
2.8 ( 0.1
4.4 ( 0.1
Inhibition of SP-Mediated Vascular Leakage in the
Guinea Pig (SYVAL)c
blqb
ID50 (po, mg/kg, 1 h before RTX)
ID50 (iv, mg/kg, 1 h before RTX)
ID50 (po, mg/kg, 24 h before RTX)
0.012
0.002
0.5
0.016
0.006
0.9
blqa
a
Incubation of 11 (8.1 µM, 3 samples/data point) in human
hepatic microsomal or cytosolic fractions at 37 °C for the specified
time was followed by solid-phase extraction and analysis for 11
Inhibition of Cisplatin-Induced Retching and
Vomiting in the Ferretd
b
mean retches, 0.1 mg/kg, iv
mean retches, 0.3 mg/kg, iv
mean retches, 1.0 mg/kg, iv
control
mean vomits, 0.1 mg/kg, iv
mean vomits, 0.3 mg/kg, iv
mean vomits, 1.0 mg/kg, iv
control
90 ( 26
115 ( 29
26 ( 5
2 ( 2
164 ( 41
16 ( 3
4 ( 1
1 ( 1
20 ( 5
0.8
and 2 by LC/MS/MS. Below limit of quantitation.
5 ( 3
0 ( 0
Ta ble 3. Average AUC Measurements of 2 after Intravenous
Administration of 11 and 2 in the Rat
100 ( 24
13 ( 4
1 ( 1
dose of 11 (mg/kg)
AUC of 2 (ng‚h/mL)
dose of 2 (mg/kg)
1
8
25
570 ( 120 6300 ( 1400 22000 ( 1200
0 ( 0
13 ( 4
0.3
2
5
AUC of 2 (mg‚h/mL) 2700 ( 340 6400 ( 1200
ID90 (iv, mg/kg)
a
Displacement of [125I]-SP from the human NK-1 receptor
expressed in CHO cells. Data are reported as the mean ( SD for
Ta ble 4. Average AUC Measurements of 2 after Intravenous
Administration of 11 and 2 in the Dog
b
2 (n ) 13) and 11 (n ) 8). See ref 24. c Comound 2 or 11 was
administered either po or iv followed by resiniferatoxin (RTX)
dose of 11 (mg/kg)
AUC of 2 (ng‚h/mL)
dose of 2 (mg/kg)
0.5
1100 ( 300
0.5
2
32
challenge at the time indicated. Dose-response data were deter-
8900 ( 1500 370000 ( 55000
d
mined for n ) 2-11 animals/data point. The antiemetic activity
2
of 2 and 11 in ferrets (n ) 4) during a 4 h observation period after
administration of cisplatin (10 mg/kg, iv). Control animals (n )
4-6) were pretreated with vehicle (PEG 300 for 2, water for 11).
AUC of 2 (mg‚h/mL) 3800 ( 1100 38000 ( 8000
The conversion of 11 to 2 in vivo after intravenous
administration in rats and dogs was demonstrated.
Three doses of 11 (1, 8, and 25 mg/kg of body mass) were
administered in the rat (Table 3). A near proportional
increase in the AUC of 2 was seen after the 8 mg/kg
dose as compared to the 1 mg/kg dose, and an additional
4-fold increase in the AUC of 2 was seen after the 25
mg/kg dose. Concentrations of 11 in these experiments
fell below the limits of quantitation by HPLC-MS/MS
within 5 min at the two lower doses and by 1 h at the
higher dose. In separate experiments, the kinetics of 2
in the rat after intravenous administration were found
to be linear with near proportional increases in the AUC
at doses of 0.2, 2, and 5 mg/kg of body mass (0.2 mg/kg
data not shown). After 1 and 8 mg/kg doses of 11, the
resulting exposure of 2 was found to be quantitatively
proportional to the dose of 11 within experimental error.
Conversion of 11 to 2 in dogs after intravenous
administration (0.5, 2.0, and 32.0 mg/kg of body mass)
was also found to be rapid with the plasma concentra-
tion of 11 being below the limits of detection within 15
min at all three doses tested. The exposure of 2 after
the administration of the 0.5 mg/kg dose of 11 was found
to be quantitatively proportional within experimental
error (Table 4). Calculations at higher doses were
complicated by the nonlinear kinetics exhibited by 2
which suggests that elimination of 2 might be saturated
at doses greater or equal to 2 mg/kg of body mass in
the dog.
F u n ction a l Ch a r a cter iza tion of 11
A series of experiments in preclinical assays that
involve peripheral and central NK-1 blockade was
carried out to establish that 11 was functionally equiva-
lent in vivo to the parent hNK-1 antagonist 2 (Table
5). The observed increase in vascular permeability in
the guinea pig after the systemic administration of
resiniferatoxin (RTX) is mediated by SP, and the result-
ing peripheral inflammation can be inhibited by NK-1
receptor antagonists.4 Comparison of the activities of 2
and 11 in an assay based on this phenomenon (SY-
VAL21) indicates that the two compounds are potent
inhibitors of this SP-mediated response when admin-
istered both 1 h and 24 h after RTX challenge. Correct-
ing for the fact that the molecular weight of 11 is
roughly twice that of 2, these compounds are equipotent
on a molar basis at the time points tested in this assay.
Retching and vomiting in the ferret can be elicited by a
variety of emetogens (cisplatin, morphine, apomorphne,
copper sulfate) and attenuated by the preadministration
of CNS-penetrant hNK-1 receptor antagonists.22 The

hNK-1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1239
resulting mixture was stirred cold for 5 min. TBPP (4.20 g,
7.9 mmol) was added to the reaction mixture as a solid in one
portion. The cooling bath was removed, and the resulting
mixture was stirred at room temperature for 45 min. The
reaction was quenched with 200 mL of saturated NaHCO3 and
extracted with 2 × 300 mL of ether. The ether extracts were
combined, dried, and concentrated in vacuo. HPLC (Zorbax
Rx-C8, 4.6 × 250 mm column, 65:35 v/v CH3CN/H2O, 1.5 mL/
min, 210 nm) indicated that the reaction workup was a
mixture of 2 (17%, t ) 3.6 min), TBPP (33%, t ) 6.8 min), 4
(44%, t ) 10.8 min), and 7 (5%, t ) 12.9 min).
The mixture obtained from the reaction workup was divided
into three equal parts, and each portion was purified on a
Waters PrepLC System 500A equipped with two 47 × 300 mm
Waters Preppak Cartridges containing 300 Å 15-20 µm,
Bondapak C8 reverse-phase packing material using 2:1 v/v
CH3CN/H2O as the eluant (prepacked columns: Waters Part
No. WATO38572). Fractions from the individual runs were
assayed using the analytical HPLC system described above;
fractions containing pure 2 were pooled and concentrated in
vacuo to remove the CH3CN. The resulting cloudy aqueous
mixture was diluted with an equal volume of saturated NaCl
and extracted with 3 × 250 mL of ether. The ether extracts
were combined, dried, and concentrated in vacuo. A total of
1.70 g (39%) of 4 was obtained as an oil from the three
chromatographic runs: 1H NMR (CDCl3, 500 MHz, ppm) δ 1.43
(d, J ) 6.0, 3H), 2.50 (dt, J ) 3.5, 11.5, 1H), 2.81 (d, J ) 11.5,
1H), 2.91 (d, J ) 14.5, 1H), 3.46 (d, J ) 2.0, 1H), 3.49 (d, J )
14.5, 1H), 3.62-3.65 (m, 1H), 4.22 (dt, J ) 2.0, 11.5, 1H), 4.31
(d, J ) 2.0, 1H), 4.87 (q, J ) 6.0, 1H), 5.19-5.30 (m, 4H), 7.08-
7.38 (16H), 7.64 (s, 1H), 9.96 (br s, 1H); 13C NMR (CDCl3, 125
MHz, ppm) δ 24.4, 50.5, 52.5, 59.1, 68.6, 70.4 (app d, J ) 5.5),
72.3, 95.1, 115.7 (d, J ) 21.1), 121.5, 125.1 (q, J ) 270.9), 126.2,
128.2, 128.5, 128.7, 130.7 (d, J ) 8.2), 131.6 (q, J ) 33.0), 131.8,
145.2, 147.9 (d, J ) 11.0), 155.7 (d, J ) 11.9), 162.8 (d, J )
247.1); ESI-MS 795 (M + H, 100%).
2-(S)-(1-(R)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth oxy)-3-
(S)-(4-flu or o)p h en yl-4-(1-p h osp h or yl-3-oxo-4H,-1,2,4-tr i-
a zol-5-yl)m eth ylm or p h olin e, Dip ota ssiu m Sa lt (6, M )
K). A solution of 2.61 g (3.3 mmol) of 4 in 75 mL of MeOH
was treated with a solution of 660 mg (6.6 mmol) of KHCO3
in 10 mL of H2O. Then 10% Pd/C (250 mg) was added, and
the resulting mixture was hydrogenated at 40 psi for 3 h. The
mixture was filtered through Celite; the reaction flask and
filter cake were rinsed well with MeOH (∼750 mL). The filtrate
was concentrated in vacuo. The residue was dissolved in 250
mL of H2O; attempted extraction of the aqueous solution with
400 mL of ether resulted in the formation of an emulsion. The
emulsion was transferred into 50 mL centrifuge tubes; cen-
trifugation at 3000 rpm for 15 min effected separation of the
layers. The organic layers were drawn off, the aqueous layers
were combined and filtered, and the filtrate was lyophilized
to afford 1.95 g (86%) of 6 (M ) K) as an amorphous solid: 1H
NMR (D2O, 500 MHz, ppm) δ 1.48 (d, J ) 6.5, 3H), 2.61 (app
t, J ) 10.5, 1H), 2.95-2.97 (m, 2H), 3.57 (app s, 1H), 3.63 (d,
J ) 14.5, 1H), 3.76 (d, J ) 10.5, 1H), 4.24 (app t, J ) 11.0,
1H), 4.47 (app s, 1H), 4.87 (q, J ) 6.5, 1H, peak partially
obscured by HOD), 7.04 (br t, J ) 8.0, 2H), 7.31-7.35 (m, 2H),
7.38 (s, 2H), 7.84 (s, 1H); 13C NMR (CD3OD, 125 MHz, ppm) δ
24.7, 52.3, 53.4, 60.5, 70.6. 73.7, 97.2, 116.1 (d, J ) 21.9), 122.3,
124.6 (q, J ) 271.0), 127.8, 132.2, 132.7 (q, J ) 33.0), 134.3,
145.2 (d, J ) 11.0), 147.6, 159.0 (d, J ) 10.2), 164.0 (d, J )
244.4).
2-(S)-(1-(R)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth oxy)-3-
(S)-(4-flu or o)p h en yl-4-(1-p h osp h or yl-3-oxo-4H,-1,2,4-tr i-
a zol-5-yl)m eth ylm or p h olin e, Bis(N-m eth yl-D-glu ca m in e)
Sa lt (11). A solution of 2.00 g (3.7 mmol) of 2 and 2.80 g (5.2
mmol) of TBPP in 50 mL of THF was cooled to 0 °C. A 1.0 M
solution of NaHMDS in THF (9.4 mL, 9.4 mmol) was added
to the cooled reaction mixture using a syringe pump at a rate
of 1 equiv/h maintaining the internal temperature at 0 °C.
After the addition of the NaHMDS solution, the reaction was
stirred at 0 °C for 15 min and quenched with 100 mL of
saturated NaHCO3. The quenched mixture was extracted with
emetic response due to the chemotherapeutic agent
cisplatin is suppressed in the ferret by both 2 and 11;
again these compounds are equipotent on a molar basis
after correcting for the difference in molecular weight.23
The binding affinity of 2 and 11 to hNK-1 was
determined by measuring the displacement of [125I]SP
from the hNK-1 receptor stably expressed in CHO cells
(Table 5).24 Compound 11 was found to have good
affinity for the hNK-1 receptor (IC50 ) 1.2 nM), but it
is still 10 times less potent than 2 in the same assay.25
The oral activity of 11 in SYVAL probably arises from
the conversion of this compound to 2 in the guinea pig
stomach. However, based on the observations regarding
the conversion of 11 to 2 in rats and dogs in vitro and
in vivo (see preceding section), the efficacy of 11 after
intravenous administration almost certainly arises from
its metabolic conversion to 2 in vivo. The supposition
that 11 is functionally equivalent to 2 is further sup-
ported by the ability of this compound to suppress
cisplatin-induced emesis in the ferret. Compound 11
would be expected to be negatively charged and poorly
brain penetrant at physiologic pH; conversion of 11 to
the CNS-penetrant 2 must be occurring since the
requirement that SP receptor antagonists traverse the
blood-brain barrier in order to elicit this response is well
established.22
Con clu sion
The sparing water solubility of the orally active,
human NK-1 receptor antagonist 2 necessitated the
identification of a method to deliver this compound
intravenously in a manner suitable for clinical use. An
unprecedented prodrug strategy was undertaken, and
the N-phosphoryl derivative of 2 was targeted as an
entity with the potential to be metabolically converted
in vivo to 2. An efficient sequence to effect a regiose-
lective dibenzylphosphorylation of 2 with tetrabenzyl
pyrophosphate giving 4 followed by catalytic hydrogena-
tion in the presence N-methyl-D-glucamine to directly
afford the phosphate salt 11 was established. A series
of experiments were carried out to demonstrate that 11
is metabolically converted to 2 both in vitro and in vivo
in rats and dogs and that 11 is functionally equivalent
in vivo in assays of SP-mediated events to 2. The data
presented herein supported the further evaluation of 11
as a prodrug of 2 in a clinical setting. The reports that
have appeared describing the favorable tolerability
profile of 11 in humans26 and the efficacy of 11 in the
treatment chemotherapy-induced emesis27 serve to fur-
ther demonstrate the viability of this prodrug strategy
for the intravenous delivery of 2.
Exp er im en ta l Section
Gen er a l. General experimental details have been previ-
ously described.6 Compounds 1,6 2,4 and tetrabenzyl pyrophos-
phate13b (TBPP) were prepared according to the published
procedures. The protocols for the examination of the metabolic
conversion in vitro and in vivo of 11 to 2 in rats and dogs,20
the inhibition of resiniferatoxin-induced systemic vascular
leakage in the guinea pig,4 and the attenuation of cisplatin-
induced emesis in the ferret22 are described elsewhere.
2-(S)-(1-(R)-(3,5-Bis(tr iflu or om eth yl)p h en yl)eth oxy)-3-
(S)-(4-flu or o)p h en yl-4-(1-d iben zylp h osp h or yl-3-oxo-4H,-
1,2,4-tr ia zol-5-yl)m eth ylm or p h olin e (4). A solution of 3.00
g (5.6 mmol) of 2 in 120 mL of THF at 0 °C was treated with
3.90 mL of 1.6 M n-butyllithium solution in hexanes. The

1240 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Hale et al.
(5) (a) Navari, R., M.; Reinhart, R. R.; Gralla, R. J .; Kris, M. G.;
Hesketh, P. J .; Khojasteh, A.; Kindler, H.; Grote, T. H.; Pen-
drgras, K.; Grunberg, S. M.; Carides, A. D.; Gertz, B. J . for the
L-754,030 Antiemetic Trials Group. Reduction of Cisplatin-
Induced Emesis by a Selective Neurokinin-1 Receptor Antago-
nist. N. Engl. J . Med. 1999, 340, 190-195. (b) Hesketh, P. J .;
Gralla, R. J .; Webb, R. T.; Ueno, W.; Silberman, S. Randomised
Phase II Study of the Neurokinin-1 Antagonist CJ 11,974 for
the Control of Cisplatin-Induced Emesis. Proc. Am. Soc. Clin.
Oncol. 1998, 17, A19. (c) Gesztesi, Z. S.; Song, D.; White, P. F.
Comparison of a New NK-1 Antagonist (CP 122,721) to On-
dansetron in the Prevention of Post-Operative Nausea and
Vomiting. Anesth. Anal. 1998, 86, A1780. (d) Diemunch, P.,
Schoeffler, P., Bryssine, B., Muller, L.; Lees, J .; McQuade, B.;
Spraggs, C. Anti-Emetic Activity of the NK-1 Antagonist GR
205171 in the Treatment of PONV Following Major Gynaeco-
logical Surgery. Anesth. Anal. 1998, 86, S436. (e) Kris, M. G.;
Radford, J . E.; Pizzo, B. A.; Inabinet, R.; Hesketh, A.; Hesketh,
P. J . Use of an NK-1 Receptor Antagonist to Prevent Delayed
Emesis After Cisplatin. J . Natl. Cancer Inst. 1997, 89, 817-
818.
(6) Hale, J . J .; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre,
D. J .; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre,
D. E.; Metzger, J . M. 2-(S)-((3,5-Bis(trifluoromethyl)benzyl)oxy)-
3-(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl) morpholine: A
Potent, Orally Active, Morpholine-Based Human Neurokinin-1
Receptor Antagonist. J . Med. Chem. 1996, 39, 1760-1762.
(7) Newby, D. E.; Sciberras, D. G.; Ferro, C. J .; Mendel, C. M.; Gertz,
B. J .; Majumdar, A.; Lowry, R. C., Webb, D. J . Antagonism of
Substance P-Induced Forearm Vasodilation by the Neurokinin
Type I Receptor Antagonist L-754,030. Presented at the British
Pharmacological Society Autumn Meeting, Edinburgh, Scotland,
September 1-4, 1997; Abstract XX.
300 mL of ether; the ether extract was washed with 100 mL
of 0.5 N KHSO4, 100 mL of saturated NaHCO3, and 100 mL
of saturated NaCl, dried, and concentrated in vacuo. HPLC
(Zorbax Rx-C8, 4.6 × 250 mm column, 50/50 v/v to 100/0 v/v
gradient CH3CN/H2O over 25 min, 1.5 mL/min, 210 nm)
indicated that the reaction workup was a mixture of 2 (3%, t
) 6.3 min), TBPP (1%, t ) 10.7 min), and 4 (90%, t ) 13.0
min).
A solution of the crude 4 in 50 mL of MeOH, a solution of
1.45 g (7.4 mmol) of N-methyl-D-glucamine in 10 mL of H2O,
and 200 mg of 10% Pd/C were combined, and the resulting
mixture was hydrogenated at 40 psi for 2 h. The reaction
mixture was filtered through a pad of Celite; the reaction flask
and filter cake were rinsed well with MeOH (400 mL). The
filtrate was concentrated in vacuo. The crude product was
i
dissolved in 25 mL of MeOH; 125 mL of PrOH was added to
the solution, and the resulting mixture was aged at room
temperature for 30 min. The solid that had precipitated was
filtered, washed with 75 mL of iPrOH and 75 mL of ether, and
dried. The solid was partitioned between 150 mL of ether and
150 mL of water; an emulsion formed on mixing of the layers.
The emulsion was transferred into 50 mL centrifuge tubes;
centrifugation at 3000 rpm for 15 min caused separation of
the layers. The organic layers were drawn off, the aqueous
layers were combined and filtered, and the filtrate was
lyophilized to afford 3.40 g (86%) of 11 as an amorphous
solid: 1H NMR (CD3OD, 500 MHz, ppm) δ 1.43 (d, J ) 6.6,
3H), 2.72 (s, 6H), 2.84 (d, J ) 13.9, 1H), 2.94 (d, J ) 10.3,
1H), 3.12-3.30 (m, 4H), 3.42-3.83 (m, 14H), 4.19-4.25 (m,
3H), 4.35 (d, J ) 2.2, 1H), 7.04 (t, J ) 8.5, 2H), 7.30 (s, 2H),
7.52 (br s, 2H), 7.70 (s, 1H); 13C NMR (CD3OD, 125 MHz, ppm)
δ 24.7, 34.4, 52.3, 53.1, 53.5, 60.5, 64.7, 69.9, 70.4, 72.0, 72.4,
72.6, 73.6, 97.1, 116.2 (d, J ) 21.9), 122.3, 124.5 (q J ) 271.0),
127.7, 132.3, 132.7 (q, J ) 33.8), 134.8, 145.9, 147.5, 158.9,
163.9 (d, J ) 245.3); ESI-MS 615 (M + H, 100%); HPLC
(Zorbax Rx-C8, 4.6 × 250 mm column, 25/75 v/v to 90/10 v/v
gradient CH3CN/H2O over 15 min, then hold 9 min, 1.5 mL/
min, 210 nm) t ) 9.0 min. Anal. (C37H56F7N6O16P/4H2O) C, H,
N, F, P.
(8) (a) Gould, P. L. Salt Selection for Basic Drugs. Int. J . Pharm.
1986, 33, 201-217. (b) Berge, S. M.; Bighley, L. D.; Monkhouse,
D. C. Pharmaceutical Salts. J . Pharm. Sci. 1977, 66, 1-19.
(9) (a) Fleisher, D.; Bong, R.; Stewart, B. H. Improved Oral Drug
Delivery: Solubility Limitations Overcome by the Use of Pro-
drugs. Adv. Drug Delivery Rev. 1996, 19, 115-130. (b) Balant,
L. P.; Doekler, E.; Buri, P. Prodrugs for the Improvement of Drug
Adsorption Via Different Routes of Administration. Eur. J . Drug
Metab. Pharm. 1990, 15, 143-153.
(10) Stella, V. J . A Case for Prodrugs: Fosphenytoin. Adv. Drug
Delivery Rev. 1996, 19, 311-330.
(11) For other examples, see: (a) Murdock, K. C.; Lee, V. J .; Citarella,
R. V.; Durr, F. E.; Nicolau, G.; Kohlbrenner, M. N-Phosphoryl
Derivatives of Bisantrene. Antitumor Prodrugs with Enhanced
Solubility and Reduced Potential for Toxicity. J . Med. Chem.
1993, 36, 2098-2101. (b) Varia, S. A.; Schuller, S.; Sloan, K. B.;
Stella, V. J . Phenytoin Prodrugs III: Water Soluble Prodrugs
for Oral and/or Parenteral Use. J . Pharm. Sci. 1984, 73, 1068-
1073.
2-(S)-((3,5-Bis(tr iflu or om eth yl)ben zyloxy)-3-(S)-p h en -
yl-4-(1-p h osp h or yl-3-oxo-4H ,-1,2,4-t r ia zol-5-yl)m et h yl-
m or p h olin e, Bis(N-m eth yl-D-glu ca m in e) Sa lt (10). The
title compound was prepared in 63% yield from 1 using
procedures analogous to those described for 11: 1H NMR (CD3-
OD, 500 MHz, ppm) δ 2.51 (app t, J ) 9.5, 1H), 2.69 (s, 6H),
2.88-2.91 (2H), 3.08-3.17 (4H), 3.54 (d, J ) 10.0, 1H), 3.60-
3.81 (14H), 4.13-4.17 (3H), 4.48 (d, J ) 8.5, 1H), 4.75 (d, J )
2.0, 1H), 4.82 (d, J ) 8.5), 7.28-7.37 (3H), 7.55-7.59 (2H),
7.57 (s, 2H), 7.77 (s, 1H); ESI-MS 583 (M + H, 100%); HPLC
(Zorbax Rx-C8, 4.6 × 250 mm column, 25/75 v/v to 90/10 v/v
gradient CH3CN/H2O over 15 min, then hold 9 min, 1.5 mL/
min, 210 nm) t ) 8.8 min. Anal. (C36H55F6N6O16P /6H2O) C,
H, N; F: calcd, 10.55; found, 9.32; P: calcd, 2.87, found, 3.51.
(12) (a) Hoffmann, H.; Hammann, I.; Stendel, W. Insecticidal and
Acaricidal O-Triazolylthiophosphoric(phosphinic) Acid Esters.
Ger. Offen. 2,403,711, 1975. (b) Boehner, B.; Meyer, W.; Dawes,
D. Triazolyl Phosphorodithioates. Ger. Offen. 2,352,140, 1974.
(13) (a) Watanbe, Y.; Nakahira, H.; Bunya, M.; Ozahi, S. An Efficient
Method for Phosphorylation of Inositol Derivatives. Tetrahedron
Lett. 1987, 28, 4179-4180. (b) Khorana, H. G.; Todd, A. R.
Studies on Phosphorylation. Part XI. The Reaction Between
Carbodiimides and Acid Esters of Phosphoric Acid. A New
Method for the Preparation of Pyrophosphates. J . Chem. Soc.
1953, 2257-2260.
(14) Macher, I. A Convenient Synthesis of 2-Deoxy-2[(R)-3-Hydroxy-
tetradecanamido]-3-O-[(R)-Hydroxydecanoyl]-a-D-Glucopyanose-
1-Phosphate. Carbohydrate Res. 1987, 162, 79-84.
(15) Watanabe, Y.; Hyodo, N.; Ozaki, S. Dibenzyl Phosphorfluoridate,
A New Phosphorylating Agent. Tetrahedron Lett. 1988, 29,
5763-5764.
(16) Perich, J . W.; J ohns, R. B. Synthesis of Casein-Related Peptides
and Phosphopeptides. The Efficient Global ‘Phosphite-Triester’
Phosphorylation of Protected Serine Derivatives and Peptides
by Using Dibenzyl or Di-tert-Butyl N, N.-Diethylphosphoramid-
ite. Aust. J . Chem. 1990, 43, 1623-1632.
(17) Ion exchange chromatography was carried out using Amber-
chrom CG-161, a nonfunctionalized polystyrene/divinylbenzene
resin.
(18) Difficulties were encountered in obtaining fractions of pure 7
during the preparative reverse-phase HPLC purification of 3 or
4. The observed relative lability of 7 as compared to 3 or 4 also
hindered attempts to isolate it in pure form. Subjection of 7 to
treatment with NaHMDS both in the presence and absence of
TBPP would serve to demonstrate that it is converted to the 3
or 4.
(19) Upfield shifts in the NMR spectrum are observable on substitut-
ing an atom with its heavier isotope due to the resulting
shortened bond distance and lower ground state potential
Refer en ces
(1) Tavorath, R.; Hesketh, P. J . Drug Treament of Chemotherapy-
Induced Delayed Emesis. Drugs 1996, 52, 639-648.
(2) (a) Roila, F.; The Italian Group for Antiemetic Research.
Dexamethazone, Granisetron, or Both for the Prevention of
Nauseas and Vomiting During Chemotherapy for Cancer, N.
Engl. J . Med. 1995, 332, 1-5. (b) Andrews, P. L. R.; Rapeport,
W. G.; Sanger, G. J . Neuropharmacology of Emesis Induced by
Anti-Cancer Therapy. Trends Pharmacol. Sci. 1988, 9, 334-341.
(3) Bountra, C.; Gale, J . D.; Gardner, C. J .; J ordan, C. C.; Kilpatrick,
G. J .; Twissel, D. J .; Ward, P. Towards Understanding the
Aetiology and Pathophysiology of the Emetic Reflex: Novel
Approaches to Antiemetic Drugs. Oncology 1996, 53, 102-109.
(4) Hale, J . J .; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M.
A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J .;
Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. J . M.;
Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E.
Structural Optimization Affording 2-(R)-(1-(R)-(3,5-Bis(trifluo-
romethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-
triazol-5-yl)methyl morpholine, a Potent, Orally Active, Long-
Acting Morpholine Acetal Human NK-1 Receptor Antagonist.
J . Med. Chem. 1998, 41, 4607-4614 and references therein.

hNK-1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1241
energy. The resulting lower paramagnetic shielding results in
the observed upfield shift. For applications involving carbohy-
drates and peptides, see: (a) Otter, A.; Liu, X.; Kotovych, G.
Hydrogen-Deuterium Isotope Effects in 13C NMR Experiments
of Peptides. J . Magn. Reson. 1990, 86, 657-662. (b) Davies, D.
B.; Christofides, J . C. Secondary Isotope Multiplet NMR Spec-
troscopy of Partially Labeled Entities. Carbon-13 SIMPLE NMR
of Carbohydrates. J . Am. Chem. Soc. 1983, 105, 5099-5105. (c)
Davies, D. B.; Christofides, J . C. A Method to Assign 13C NMR
Signals of Compounds with Exchangeable Hydrogen Atoms
Using Two and Three Bond Isotope Effects: Cellobiose. J . Chem.
Soc., Chem. Commun. 1983, 324-326. For a general treatment
of this phenomenon, see: Breitmaier, E.; Voelter, W. Carbon-
13 NMR Spectroscopy; VCH Publishers: New York, 1987; pp
109-117.
Antagonist MK 0869 (L-754,030) and Its Water Soluble Phos-
phoryl Prodrug, L-758, 298, Inhibit Acute and Delayed Cisplatin-
Induced Emesis in Ferrets. Neuropharmacology 1999, in press.
(24) Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal, A.;
Swain, S.; Seward, E.; Frances, B.; Burns, D.; Strader, C. D.;
Characterization of the Binding of a Potent, Selective Radioio-
dinated Antagonist to the Human Neurokinin-1 Receptor. Mol.
Pharmacol. 1992, 42, 458-465.
(25) Variations in the measured IC50 values for 11 have been
attributed to the moderate instability of 11 in the vehicle(s) used
in the hNK-1 binding assay. Correcting for the minor quantity
(<5%) of 2 present in samples of 11 afforded IC50 values in the
1.0-1.5 nM range.
(26) (a) Newby, D. E.; Sciberras, D. G.; Ferro, C. J .; Gertz, B. J .;
Sommerville, D.; Majumdar, A.; Lowry, R. C.; Webb, D. J .
Substance P-Induced Vasodilation is Mediated by the Neuro-
(20) Huskey, S.-E. W.; Luffer-Atlas, D.; Dean, B. J .; McGowan, E.
M.; Feeney, W. P. Chiu, S.-H. L. Substance P Receptor Antago-
nist. I. Conversion of Phosphoramidate Prodrug L-758,298 to
L-754,030 Following Intravenous Administration in Rats and
Dogs. Drug Metab. Dispos. 1999, 27, 1367-1373.
kinin Type
I Receptor But Does Not Contribute to Basal
Vascular Tone in Man. Br. J . Clin. Pharmacol. 1999, 48, 336-
344. (b) Norman, B.; Panebianco, D.; Block, G. A. A Placebo-
Controlled, In-Clinic Study to Explore the Preliminary Safety
and Efficacy of Intravenous L-758,298 (A Prodrug of the NK-1
Receptor Antagonist L-754,030) in the Acute Treatment of
Migraine. Cephalalgia 1998, 18, P42, 407.
(21) Acronym for Resiniferatoxin-Induced SYstemic VAscular Leak-
age.
(22) Rupniak, N. M. J .; Tattersall, F. D.; Williams, A. R.; Rycroft,
W.; Carlson, E. J .; Cascieri, M. A.; Sadowski, S.; Ber, E.; Hale,
J . J .; Mills, S. G.; MacCoss, M.; Seward, E.; Huscroft, I.; Owen,
S.; Swain, C. J .; Hill, R. G.; Hargreaves, R. J . In Vitro and In
Vivo Predictors of the Anti-Emetic Activity of Tachykinin NK-1
Receptor Antagonists. Eur. J . Pharmacol. 1997, 326, 201-209.
(23) Tattersall, F. D.; Rycroft, W.; Cumberbatch, M.; Mason, G.; Tye,
S.; Williamson, D. J .; Hale, J . J .; Mills, S. G.; Finke, P. E.;
MacCoss, M.; Sadowski, S.; Ber, E.; Cascier, M. A.; Hill, R. G.;
MacIntyre, D. E.; Hargreaves, R. J . The Novel NK-1 Receptor
(27) Van Belle, S.; Cocquyt, V., De Smet, M.; Decramer, M.; O-Brien,
M.; Schellens, J .; Reinhardt, R. R.; Gertz, B. J . Comparison of a
Neurokinin-1 Antagonist, L-758,298, to Ondansetron in the
Prevention of Cisplatin-Induced Emesis. Presented at the 34th
Annual Meeting of the American Society of Clinical Oncology,
Los Angeles, CA, May 16-19, 1998, Abstract No. 198.
J M990617V