2(S)-((3,5-bis(trifluoromethyl)benzyl)-oxy)-3(S)-phenyl-4-((3-oxo-2,2,4- triazol-5-yl)methyl)rnorpholine (1): A potent, orally active, morpholine-based human neurokinin-1 receptor antagonist

Full text of DOI:10.1021/jm950654w

1760
J . Med. Chem. 1996, 39, 1760 1762
2(S)-((3,5-Bis(tr iflu or om eth yl)ben zyl)-
oxy)-3(S)-p h en yl-4-((3-oxo-1,2,4-tr ia zol-
5-yl)m eth yl)m or p h olin e (1): A P oten t,
Or a lly Active, Mor p h olin e-Ba sed Hu m a n
Neu r ok in in -1 Recep tor An ta gon ist
J effrey J . Hale,* Sander G. Mills, Malcolm MacCoss,
Shrenik K. Shah, Hongbo Qi, David J . Mathre,
Margaret A. Cascieri, Sharon Sadowski,
Catherine D. Strader,† D. Euan MacIntyre, and
J oseph M. Metzger
when small heterocycles are linked to the piperidine
nitrogen by a methylene spacer, subnanomolar antago-
nists with good oral activity can be identified.11b These
observations prompted us to execute a study of potential
human NK-1 receptor antagonists featuring the weakly
basic morpholine core which employs a side-chain ether
linkage established to have activity as well as potency-
enhancing substituents on the morpholine nitrogen.11b
The synthesis of 2-alkoxy-3-phenylmorpholines (which
are known in other contexts12) has not been the subject
of any systematic study. The chemistry that was
developed to diastereoselectively prepare either of the
2,3-disubstituted morpholine core structures is shown
in Scheme 1. Partial reduction of 3(S)-phenyl-2-mor-
pholinone (5; prepared from N-benzyl-(S)-phenylgly-
cine13 using a modification of the literature procedure14)
could be carried out with a variety of reducing agents
(DIBALH, Red-Al, L-Selectride) to afford lactol 6 which
was obtained as an 8:1 trans/cis mixture of C2 epimers.
Attempts to convert 6 to a morpholine having the
desired 2,3-cis configuration were unsuccessful as con-
ventional alkylation,15 glycosidation,16 or acetal ex-
change12 conditions afforded mainly the 2,3-trans-
morpholine. A control experiment was carried out in
which the reaction of 5 with 1.1 equiv of L-Selectride
at 78 °C was quenched with acetic anhydride. This
afforded the 2,3-cis-acyl acetal 7 as the major product
and showed that isomerization of the 2,3-cis-lactol
alkoxide was minimized in the absence of moisture at
low temperature. Alkylation of the L-Selectride reduc-
tion intermediate proved to be more difficult than
acylation but was possible using 3,5-bis(trifluorometh-
yl)benzyl trifluoromethanesulfonate (8); this gave 9 as
the major product. Catalytic reduction of 9 afforded
morpholine 10, which has 2(S),3(S) stereochemistry,
making it configurationally analogous to 3.
Merck Research Laboratories, Rahway, New J ersey 07065
Received September 1, 1995
The pharmacologic actions of the mammalian tachy-
kinin substance P (SP) have been implicated in the
pathogenesis of a variety of inflammatory diseases,
including migraine,1 rheumatoid arthritis,2 asthma,3
and inflammatory bowel disease.4 This profile has
stimulated a great deal of interest in the identification
of antagonists of the neurokinin-1 (NK-1) receptor (to
which SP preferentially binds5), since the clinical ap-
plication of such compounds could result in substantial
therapeutic advantages over existing treatment modali-
ties. Since the disclosure6 of the first nonpeptide human
NK-1 receptor antagonist, CP-96,345 (2), numerous
reports of antagonists encompassing a variety of struc-
ture types have appeared in the literature.7 We wish
to report herein our initial efforts toward the prepara-
tion and characterization of a series of novel, orally
active, morpholine-based human NK-1 antagonists ex-
emplified by 1 (2(S)-((3,5-bis(trifluoromethyl)benzyl)-
oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)mor-
pholine, L-742,694).
The affinity of the quinuclidine 2 for the L-type
calcium channel has been implicated as a possible
source of the antinociceptive and antiinflammatory
activities of compounds in this structure class.8 Struc-
tural changes in several classes of compounds, including
the piperidine amines9 (such as CP-99,994, 3) and
piperidine ethers10 (such as L-733,060, 4), that were
aimed at lowering basicity have been reported to reduce
this nonspecific interaction. Substitution on the nitrogen
of the piperidine ethers with electron-withdrawing
groups such as CH2CO2Me and CH2CONH2 led to
compounds with minimal basicity and markedly de-
creased L-type calcium channel affinity in which affinity
for the human NK-1 receptor was maintained at nano-
molar levels.11a Recently, it has been demonstrated that
The 2,3-trans-morpholine diastereomer was prepared
via a Williamson etherification15 of lactol 6 to afford 11
as the sole product in excellent yield. Catalytic reduc-
tion of 11 gave morpholine 12. The enantiomers of
compounds 10 and 12 (13 and 14, respectively) were
prepared starting from N-benzyl-(R)-phenylglycine.
Analysis by chiral HPLC showed that all four diaster-
eomers had 98.0% ee.
† Current address: Schering Plough Research Institute, 2015 Gal-
loping Hill Rd., Kenilworth, NJ 07033.
0022-2623/96/1839-1760$12.00/0 © 1996 American Chemical Society

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1761
Ta ble 1. Human NK-1 Receptor Binding
Sch em e 1a
compd
R
IC50 (nM)a
0.4 0.1
0.5 0.1
0.87 0.51 (n 7)
2.4 2.2
376 105
287 58
59 19
1.6 1.1
66 14
1.1 0.4
0.13 0.04
0.09 0.03 (n 6)
2
3
4
10
12
13
14
15
16
17
19
1
CO2CH3
CO2H
CONH2
1,2,4-triazolyl
3-oxo-1,2,4-triazolyl
20
21
22
21
116 34
19
2
3
a
Displacement of 125I-labeled SP from the human NK-1 receptor
a
Reagents: (a) DIBALH, CH2Cl2/toluene, 78 °C (94%); (b)
expressed in CHO cells. Data are reported as the mean SD for
L-Selectride, THF, 78 °C, then 8, 50 °C (73%); (c) 3,5-
bis(trifluoromethyl)benzyl bromide, NaH, cat. Bu4N I , THF, 0
°C to room temperature (93%); (d) H2, 10% Pd/C, 95% EtOH; (e)
ammonium formate, 10% Pd/C, MeOH/H2O, 65 °C.
n
3 determinations unless otherwise noted.
Ta ble 2. L-Type Calcium Channel Binding and SPIDER
Ca2 channel
SPIDER
compd
(IC50, µM)a
(ID50, mpk)b
Sch em e 2a
3
1
4
11
1
4
1.6
0.009
a
Inhibition of [3H]diltiazem binding to the L-type calcium
channel in rabbit skeletal muscle. Data are reported as the mean
SD for n 2 determinations. b SP-induced dermal inflammation
(SPIDER) assay in the guinea pig. Antagonist was administered
po followed by SP challenge id after 1 h. Dose response data was
determined for n
5 12 animals/data point.
decreased human NK-1 binding affinity. A more dra-
matic increase in potency occurred when the carboxa-
mide was replaced by either a 1,2,4-triazole (19) or a
3-oxo-1,2,4-triazole (1), the latter being 25 times more
potent than the parent morpholine 10. Interestingly,
a more modest increase was seen with the isomers of 1
(20 22) as compared to their corresponding parent
morpholines. These results nicely parallel observations
with the piperidine ethers.11
Screening of 1 against cloned human NK-2 and NK-3
receptors expressed in CHO cells using [125I]neurokinin
A and [125I]Bolton-Hunter-labeled eledoisin as radioli-
gands, respectively, was also carried out.20 The mea-
a
See text and Supporting Information for details.
Several N-substituted derivatives of morpholine 10
were prepared (Scheme 2). Carboxylic ester 15 and
carboxamide 17 were prepared by N,N-diisopropylethyl-
amine-mediated alkylation of 10 with methyl bromoac-
etate and iodoacetamide, respectively, while saponifica-
tion of 15 afforded carboxylic acid 16. Heterocyclic
carboxamide replacements were introduced by alkylat-
ing 10 with either N-formyl- or N-(methoxycarbonyl)-
2-chloroacetamidrazone17 followed by thermal ring clo-
sure to afford the corresponding 1,2,4-triazole (19) and
1,2,4-triazol-3-one (1) derivatives. The three stereoiso-
mers of 1 were also prepared from the appropriate
intermediate morpholine (12 f 20, 13 f 21, 14 f 22)
and obtained with high enantiomeric purity (g99.8% ee)
after recrystallization.18
sured binding constants (human NK-2, IC50
7 µM;
human NK-3, IC50 150 nM) indicate that 1 is highly
selective for the human NK-1 receptor. Measurement
of the inhibition of [3H]diltiazem binding to the L-type
calcium channel in rabbit skeletal muscle21 by 1 showed
it to have about a 3-fold lower affinity than 3 (Table 2).
The unique structure of 1 prompted an examination
of some of its physicochemical properties. The pKa of
Binding affinities were determined by measuring the
displacement of 125I-labeled SP from the human NK-1
receptor stably expressed in CHO cells19 (Table 1). Data
for the four possible N-unsubstituted morpholine iso-
mers 10 and 12 14 confirmed that the 2(S),3(S) ster-
eochemistry is preferred. Modest enhancement in
potency was seen in the compounds N-alkylated with
neutral, electron-withdrawing head groups (15 and 17),
while introduction of a carboxylic acid (16) substantially
the morpholine nitrogen of 1 was determined to be
3
in 1:1 (v/v) methanol/water. Coupled with the potency
of 1, this shows that the strategy, employed by oth-
ers,11,22 of minimizing the pKa of basic NK-1 antagonists
in order to lessen L-type calcium channel binding can
be extended to this family of compounds. (The pKa’s of
the benzyl and piperidine amines of 3 in 1:1 (v/v)
methanol/water were 4.0 and 8.7, respectively.) The

1762 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Communications to the Editor
P. A.; Snider, R. M.; Desai, M. C.; Rosen, T.; Bryce, D. K.; Longo,
K. P.; Reynolds, L. S.; Robinson, G.; Schmidt, A. W.; Siok, C.;
Heym, J . Pharmacology of CP-99,994; a Nonpeptide Antagonist
of the Tachykinin Neurokinin-1 Receptor. J . Pharmacol. Exp.
Ther. 1993, 267, 472 479.
stability of 1 toward acid was also examined. Incuba-
tion of 1 in simulated gastric fluid23 at 37 °C for 4 h
resulted in no acetal hydrolysis (no generation of 3,5-
bis(trifluoromethyl)benzyl alcohol occurred) or isomer-
ization to a 2,3-trans diastereomer.24 This stability, an
obviously desirable property of a compound that would
be administered po, was further evidenced by the high
oral potency of 1 in the SP-induced plasma extravasa-
tion (SPIDER) assay25 (Table 2). The ID50 of 1 in this
assay is 170 times less than that of 3; this marked
difference may be attributed at least in part to the poor
oral bioavailability of 3.26
In conclusion, the morpholine compounds described
herein represent a novel class of human NK-1 receptor
antagonists. Further, 1 is a potent, orally active
member of this class that should prove to be an
important tool in the study of neurokinin pharmacology.
Elaboration on the synthetic chemistry required for the
preparation of these compounds and detailed structure
activity studies will be the subject of future reports.
(10) Harrison, T.; Williams, B. J .; Swain, C. J .; Ball, R. G. Piperidine-
Ether Based hNK1 Antagonists 1: Determination of the Relative
and Absolute Stereochemical Requirements. Bioorg. Med. Chem.
Lett. 1994, 4, 2545 2550.
(11) (a) Harrison, T.; Owens, A. P.; Williams, B. J .; Swain, C. J .;
Baker, R.; Hutson, P. H.; Sadowski, S.; Cascieri, M. A. Piperi-
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212. (b) 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.; Shep-
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greaves, R. J . N-Heteroaryl-2-Phenyl-3-Benzyloxypiperidines: A
Novel Class of Potent, Orally Active Human NK-1 Antagonists.
Manuscript submitted to J . Med. Chem.
(12) Rekka, A.; Kourounakis, P. Synthesis, Physicochemical Proper-
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Methyl-Morpholines. Eur. J . Med. Chem. 1989, 24, 179 185.
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Ack n ow led gm en t. We would like to thank Ian
Cottrell and Michael Ashwood for synthetic assistance,
Derek Von Langen for helpful HPLC discussions, J ames
Pivnichny and Dorothy Levorse for technical assistance,
and Amy Bernick for providing mass spectral data.
(15) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Nouvelle Meth-
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(17) Yanagisawa, I.; Hirata, Y.; Ishii, Y. Histamine H2 Receptor
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(18) The stereochemical purity was determined by supercritical fluid
chromatography (SFC) using a novel two-column (achiral and
chiral column in series) approach. For details, see the Support-
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Markides, K. E. J . Chromatogr. A 1994, 666, 381 394.
(19) 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 Radio-
iodinated Antagonist to the Human Neurokinin-1 Receptor.
Mol. Pharmacol. 1992, 42, 458 465.
Su p p or tin g In for m a tion Ava ila ble: Full descriptions of
the preparation of compounds 1 and 5 22, the chiral HPLC
assays used to determine the enantiomeric excess of com-
pounds 1, 5, 10, 12 14, and 20 22, the assays used to
determine the pKa and acid stability of 1, and the dose
response data from the SPIDER assay of 1 and 3 (13 pages).
Ordering information is given on any current masthead page.
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J M950654W