An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration

Article abstract of DOI:10.1021/jm0109558

1-(5-{[2R,3S)-2-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3- (4-fluorophenyl)morpholin-4-yl]methyl}-2H-1,2,3-triazol-4yl)-N,N- dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK₁ receptor antagonist with a lon

Full text of DOI:10.1021/jm0109558

4296
J . Med. Chem. 2001, 44, 4296-4299
An Or a lly Active, Wa ter -Solu ble Neu r ok in in -1 Recep tor An ta gon ist Su ita ble for
Both In tr a ven ou s a n d Or a l Clin ica l Ad m in istr a tion
Timothy Harrison,*,† Andrew P. Owens,† Brian J . Williams,† Christopher J . Swain,† Angela Williams,†
Emma J . Carlson,† Wayne Rycroft,† F. David Tattersall,† Margaret A. Cascieri,‡ Gary G. Chicchi,‡
Sharon Sadowski,‡ Nadia M. J . Rupniak,† and Richard J . Hargreaves†
The Neuroscience Research Centre, Merck, Sharp & Dohme, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.,
and Merck Research Laboratories, P.O. Box 2000, Rahway, New J ersey 07065
Received J une 14, 2001
1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpho-
lin-4-yl]methyl}-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high
affinity, orally active, h-NK1 receptor antagonist with a long central duration of action and a
solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-
4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal
rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly
effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.
In tr od u ction
The search for potent, non-peptide antagonists of the
human neurokinin-1 (h-NK1) receptor has been a long
standing objective of pharmaceutical research.1 It has
been demonstrated that 1 (CP-99,994), a selective h-NK1
antagonist, displays anti-emetic activity against a range
of emetogens, including those for which conventional
therapy might fail.2 Interest in this area has been
further stimulated recently by the disclosure that
blockade of central h-NK1 receptors provides a new and
distinct mechanism for antidepressant activity.3 A re-
cent report from these laboratories described the iden-
of a novel triazole synthesis developed by Banert.6 This
tification of 2 (MK-0869), a potent, orally active, mor-
allowed a wide range of amines to be efficiently screened
pholine acetal-based h-NK1 antagonist.4 Although this
as potential solubilizing groups.
compound displays an excellent in vivo profile, and is a
potent anti-emetic, the low aqueous solubility of 2 re-
Ch em istr y
quired development of a phosphorylated pro-drug for
The synthesis of the key morpholine acetal 4 has been
intravenous administration in order to allow maximum
described previously.4 Reaction of 4 with two equiva-
flexibility in clinical use.5 We therefore sought to develop
lents of 1,4-dichloro-2-butyne in the presence of K2CO3
an alternative to 2 which retained the excellent in vivo
afforded propargyl chloride 5 in 68% yield. The chloride
profile, including long duration of action and excellent
could be displaced with azide at room temperature in
CNS penetration, but which would be suitable for
98% yield by treatment with sodium azide in DMSO.
intravenous administration in humans without the need
Warming the propargylic azide 6 in dioxane with an
for pro-drug modification. We hereby report that 3
amine in a sealed tube provided triazoles 7. This
fulfills these requirements.
reaction has been shown to proceed via isomerization
of the propargylic azide to an allenic azide, followed by
Because the morpholine acetal core of 2 had been
optimized to provide compounds with excellent duration
cyclization to form a triazafulvene, and finally trapping
of action, we sought to keep this portion of the molecule
by the amine.6 The triazafulvene is a powerful electro-
intact and modify the pendant heterocyclic group.
phile, and a wide range of other nucleophiles (alcohols
Although substitution of the 3-oxo-1,2,4-triazol-5-yl
moiety with a range of heterocycles was investigated,
and thiols - results not shown) can be introduced at
the 5-position of the triazole by application of this
the 5-aminomethyl-substituted 1,2,3-triazol-4-yl group
reaction (Scheme 1).
proved to be optimal in terms of CNS penetration and
duration. We were able to construct the triazole moiety
in such a way that the amine substituent was intro-
duced at the end of the synthesis by taking advantage
P h a r m a cology
CNS P en etr a tion a n d Du r a tion of Action . CNS
penetration of NK1 antagonists is essential for their
anti-emetic and antidepressant activity in preclinical
assays.8 Central infusion of the selective NK1 receptor
agonist GR73632 in gerbils (a species with human-like
NK1 receptor pharmacology)9 elicits a vigorous, repeti-
* To whom correspondence should be addressed. Tel: 01279 440302.
Fax: 01279 440390. E-mail: timothy_harrison@merck.com.
† Merck, Sharp & Dohme, Essex, U.K.
‡ Merck Research Laboratories, Rahway, NJ .
10.1021/jm0109558 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/20/2001

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4297
Sch em e 1
Ta ble 1. IC50 for Inhibition of Binding of 125I-substance P to
the h-NK1 Receptor in vitro7 and ID50 for Inhibition of
GR73632-induced Gerbil Foot Tapping10 by h-NK1 Antagonists
expressed in CHO cells.7 Compound 3 showed excellent
selectivity (>3000-fold) with respect to both h-NK2 and
h-NK3 receptors. Further counterscreening demon-
strated that 3 had >3000-fold selectivity versus 100
receptors, ion-channels, and enzymes (data not shown).
Compound 3 is a stable, non-hygroscopic hydrochloride
salt. The solubility of 3 in water is >100 mg/mL at room
temperature.
immediate
24 h
pretreatment pretreatment
NR1R2 in
compound compound 7 (nM ( SD)
h-NK1 IC50
ID50
ID50
(mg/kg iv)a
(mg/kg iv)a
8
9
3
10
11
12
NH2
0.25 ( 0.10
0.29 ( 0.15
0.19 ( 0.08
0.35 ( 0.05
0.19 ( 0.02
5.3
3.1
0.2
1.0
0.4
0.4
0.4
NHMe
NMe2‚HCl
NiPr2
azetidine
pyrrolidine 0.21 ( 0.04
- 0.09 ( 0.06
0.3
An ti-Em etic Activity in F er r ets. In addition to
inhibiting the retching and vomiting induced by cyto-
toxic chemotherapeutic agents such as cisplatin, the
NK1 receptor antagonist CP-99,994 has also been shown
to be effective against the emesis produced by centrally
acting drugs such as morphine and apomorphine2 which
is resistant to treatment with 5-HT3 receptor antago-
nists.11 This action may be of value in the control of
emesis associated with the use of opiate analgesics in
situations such as post-operative pain. NK1 Receptor
antagonists may thus provide broader anti-emetic pro-
tection than 5-HT3 receptor antagonists. The effects of
3 against cisplatin-induced emesis in the ferret were
therefore examined. Compound 3 (0.1-3 mg/kg iv)
inhibited retching and vomiting in a dose-dependent
manner over the 4 h observation period after cisplatin
administration (Figure 1). The anti-emetic effect ob-
served was significant even at the lowest dose tested
(0.1 mg/kg iv) with protection being complete at doses
g 1 mg/kg iv. After orally dosing a solution of 3 in water,
marked inhibition of retching and vomiting was ob-
served; this was virtually complete at doses of 1 and 3
mg/kg (Figure 1). The ID90 (inhibitory dose giving g 90%
inhibition of retching) for 3 was 0.1 mg/kg intravenously
and 1.0 mg/kg orally.
MK-0869
0.3
a
Test compounds were administered iv as a solution in aqueous
acid followed by GR73632 challenge icv at the time indicated.
tive hindfoot tapping response, which can be blocked
by brain penetrant (but not by non brain penetrant)
antagonists.10 This assay thus provides a convenient
measure of CNS penetration, and can be used to give
an indication of the central duration of action of
antagonists by treating with test compounds prior to
the agonist challenge (Table 1).
It can be seen that a range of amines (primary,
secondary, and tertiary) could be introduced at the
5-position of the heterocycle without significant re-
duction of the h-NK1 IC50. However, potency in the
gerbil foot-tapping model, which provides a measure of
brain NK1 receptor occupancy, increased in the order
primary<secondary<tertiary amine. Both acyclic and
cyclic tertiary amines provided compounds with excel-
lent CNS activity, although potency in the gerbil assay
decreased as the lipophilicity of the amine increased
(compare 3 and 10). Compound 3, which had the highest
potency of the compounds tested after immediate pre-
treatment, also had excellent duration in this test (ID50
0.3 mg/kg iv following 24 h pretreatment). On the basis
of this excellent duration of activity and a favorable
pharmacokinetic profile in rat, dog, and Rhesus monkey,
3 was selected for further profiling.
In Vitr o P h a r m a cology of 3. Compound 3 inhibits
the binding of 125I-substance P to the h-NK1 receptor
with an IC50 of 0.19 ( 0.08 nM.7 The Kd calculated from
these data is 119 ( 18 pM. In the presence of 1% human
serum albumin, 3 inhibits binding of 125I-substance P
to the h-NK1 receptor with IC50 of 0.5 nM, suggesting
the compound has low affinity for serum proteins. The
binding affinities of 3 at h-NK2 and h-NK3 receptors
were determined by displacement of 125I-neurokinin A
from the h-NK2 receptor and 125I-[iodo-histidyl-methyl-
Phe7] neurokinin B from the h-NK3 receptor, all stably
In h ibition of Neon a ta l Voca liza tion in Gu in ea
P igs. The ability of centrally acting NK1 receptor
antagonists and established antidepressant drugs to
inhibit separation-induced vocalizations in guinea pig
pups suggested an antidepressant-like preclinical profile
of NK1 receptor antagonists, which was subsequently
confirmed in clinical trials.3 Compound 3 caused a dose-
dependent inhibition of neonatal vocalization with an
ID50 of 0.2 mg/kg po given 4 h before maternal separa-
tion (Figure 2).
Con clu sion
Compound 3 is a potent, water soluble, highly brain-
penetrant h-NK1 antagonist with a long central duration
of action which is suitable for both oral and intravenous
clinical administration. The amino-methyl triazole unit,
which confers excellent water solubility to 3, was

4298 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Brief Articles
and concentrated to leave an oil. Purification by chromatog-
raphy on silica gel using hexanes-ethyl acetate (successively
with 19:1, 9:1, 6:1, and 4:1, followed by 100% ethyl acetate)
as eluant provided, in order of elution, 5 (4.1 g, 68%) as a clear,
colorless oil: 1H NMR (250 MHz, CDCl3) δ 1.41 (3H, d, J )
6.6 Hz), 2.80 (1H, app. t, J ) 10.8 Hz), 2.87 (1H, td, J ) 3.5,
11.7 Hz), 3.22 (2H, t, J ) 1.9 Hz), 3.52 (1H, d, J ) 2.8 Hz),
3.68 (1H, dd, J ) 1.4, 11.1 Hz), 4.00 (2H, t, J ) 1.9 Hz), 4.22-
4.32 (2H, m), 4.81 (1H, q, J ) 6.6 Hz), 6.96 (2H, t, J ) 8.7
Hz), 7.10 (2H, s), 7.31 (2H, br s), 7.56 (1H, s), m/z (CI+) 524
(M+H, 100%); the 1,4-bis(morpholino)-2-butynyl dimer (0.45
g, 8.5%); and recovered starting material (0.65 g, 13%).
(2R,3S)-4-(4-Azid ob u t -2-yn yl)-2-({(1R)-1-[3,5-b is(t r i-
flu or om eth yl)p h en yl]eth yl}oxy)-3-(4-flu or op h en yl)m or -
p h olin e, 6. Sodium azide (0.562 g, 8.65 mmol) was added to
a stirred solution of 5 (4.0 g, 7.67 mmol) in dry dimethyl
sulfoxide (17 mL) and the reaction mixture was stirred at 23
°C for 20 h. The mixture was then partitioned between
saturated aqueous NH4Cl solution (200 mL) and ethyl acetate
(80 mL). The layers were separated, and the aqueous phase
was extracted with ethyl acetate (3 × 50 mL). The combined
organic phases were washed with H2O (1 × 80 mL). then dried
(MgSO4) and concentrated (bath temp < 35 °C) to afford 6 (3.9
g, 98%) as a clear, colorless oil which was used without further
purification (purification could be performed if necessary by
chromatography on silica eluting with 20% ethyl acetate in
F igu r e 1. Effect of 3 (0.1-3 mg/kg iv and po) on the retching
and vomiting response to cisplatin (10 mg/kg iv) in the ferret.
Bars represent means ( SEM (n ) 4). *p<0.05 compared with
vehicle treatment, ANOVA followed by Dunnett’s t-test.
1
petroleum ethers (bp 60-80 °C)). H NMR (360 MHz, CDCl3)
δ 1.48 (3H, d, J ) 6.6 Hz), 2.87 (1H, app t, J ) 10.2 Hz), 2.98
(1H, td, J ) 3.6, 11.7 Hz), 3.35 (2H, t, J ) 1.9 Hz), 3.61 (1H,
d, J ) 2.8 Hz), 3.72 (1H, dq, J ) 1.4, 10.0 Hz), 3.92 (2H, t, J
) 1.9 Hz), 4.30-4.40 (2H, m), 4.89 (1H, q, J ) 6.6 Hz), 7.03
(2H, t, J ) 8.7 Hz), 7.17 (2H, s), 7.27 (2H, br s), 7.63 (1H, s).
1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(tr iflu or om eth yl)ph en yl]-
et h yl}oxy)-3-(4-flu or op h en yl)m or p h olin -4-yl]m et h yl}-
2H-1,2,3-tr ia zol-4-yl)-N,N-d im eth ylm eth a n a m in e h yd r o-
ch lor id e, 3. A solution of 6 (3.2 g, 6.0 mmol) in dry dioxane
(15 mL) was added to dimethylamine (ca 10 mL) which had
been condensed at -78 °C under N2 in a screw-top sealed tube.
The tube was sealed and allowed to warm to room temperature
followed by heating at 80-90 °C (bath temperature) with
stirring for 20 h. After the tube was cooled to 5 °C, it was
opened, and the volatiles were removed in vacuo to leave a
foam. This residue was purified by column chromatography
(CH2Cl2/MeOH/NH3, 95:5:0.2 then 90:10:0.2) to provide the
free-base of 3 (3.0 g, 87%) as a white foam. 1H NMR (360 MHz,
CDCl3) δ 1.44 (3H, d, J ) 6.6 Hz, CH3CH), 2.23 (6H, s,
(CH3)2N), 2.56 (1H, app. t, J ) 11.9 Hz, NCHHCH2O), 2.90
(1H, d, J ) 11.9 Hz, NCHHCH2O), 3.24 (1H, d, J ) 13.9 Hz,
O(CH2)2NCHH), 3.42 (1H, d, J ) 13.7 Hz, Me2NCHH), 3.45
(1H, d, J ) 2.7 Hz, NCHAr), 3.51 (1H, d, J ) 13.7 Hz, Me2-
NCHH), 3.61 (1H, d, J ) 11.4 Hz, OCHH), 3.78 (1H, d, J )
13.9 Hz, O(CH2)2NCHH), 4.22 (1H, app. t, J ) 11.4 Hz,
OCHH), 4.32 (1H, d, J ) 2.7 Hz, OCHO), 4.85 (1H, q, J ) 6.6
Hz, CHCH3), 7.05 (2H, t, J ) 8.6 Hz, HCdC(F)dCH), 7.16 (2H,
s, (CF3)CdCH-CdCH-C(CF3)), 7.47 (2H, br s, HCdC-CH)),
7.64 (1H, s, (CF3)CdCH-C(CF3)). 13C NMR (90.5 MHz, CDCl3)
δ 24.4 (CH3), 45.0 (2 × CH3), 48.9 (CH2), 52.0 (CH2), 52.3 (CH2),
59.5 (CH2), 69.3 (CH), 72.3 (CH), 95.6 (OCHO), 115.13 (d, 2J CF
F igu r e 2. Effect of 3 (0.1-1 mg/kg po) on neonatal vocaliza-
tion in guinea pigs. Values are means ( SEM (n ) 4-6).
constructed using a novel triazole synthesis developed
by Banert.6 Compound 3 is highly effective in pre-
clinical tests that are relevant to clinical efficacy in
emesis and depression.
Exp er im en ta l Section
Ch em istr y. Merck Kieselgel 60 F254 precoated silica plates
for TLC were obtained from BDH, Poole, Dorset, U.K. Column
chromatography was carried out on Fluka Kieselgel 60 0.035-
0.070 mm. Infrared (IR) spectra were recorded in the range
4000-600 cm-1 using a Nicolet 205 FTIR spectrometer. 1H and
13C NMR spectra were recorded using Bruker (AC250, AM360,
and AM400 MHz) spectrometers. Solvents are indicated in the
text, and tetramethylsilane was used as the internal reference.
Mass spectra were recorded using a VG Quattro mass spec-
trometer.
(2R,3S)-2-({(1R)-1-[3,5-Bis(t r iflu or om et h yl)p h en yl]-
e t h yl}oxy)-4-(4-ch lor ob u t -2-yn yl)-3-(4-flu or op h e n yl)-
m or p h olin e, 5. A solution of cis (2R,3S)-2-({(1R)-1-[3,5 Bis-
(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpho-
line 44 (5 g, 11.5 mmol) in dry N,N-dimethylformamide (20
mL) was added dropwise during 20 min to a stirred mixture
of 1,4-dichloro-2-butyne (2.2 mL, 23 mmol) and K2CO3 (4.8 g,
34.5 mmol) in dry N,N-dimethylformamide (20 mL) main-
tained at 50-60 °C (bath temperature). The reaction mixture
was stirred at 50-60 °C for 2 h, then cooled to 23 °C, diluted
with H2O (400 mL), and extracted with ethyl acetate (3 × 150
mL). The combined organic extracts were washed with H2O
(1 × 100 mL) and brine (1 × 100 mL), and then dried (MgSO4)
1
3
21.4 Hz), 123.02 (q, J CF3 272.7 Hz), 126.2, 131.0 (d, J CF
2
4
8.0 Hz), 131.586 (q, J CF 33.2 Hz), 132.93 (d, J CF 3.3 Hz),
139.94, 140.91, 145.52, 162.64 (d, 1J CF 247.5 Hz). m/z (CI+) 576
(M+H). IR (film) v 3150 (br), 1618 (w), 1520 (m), 1285 (s), 1145
(s), 1075 (s), 1035 (m), 765 (s) cm-1
.
HCl Salt Formation. The free base of 3 (3 g, 5.2 mmol) was
dissolved in dry diethyl ether (30 mL), and HCl in MeOH (1
M solution, 5.2 mL, 5.2 mmol) was added. The solution was
concentrated in vacuo to a partial foam, then redissolved in
dry diethyl ether (ca. 50 mL). The product which crystallized
was isolated by filtration then washed with dry diethyl ether
and dried in vacuo at 60 °C to provide the HCl salt 3 (2.5 g,
79%) as a crystalline, white solid, mp 194-198 °C, [R]22
+
D
65.0 (c ) 0.5, H2O). A further batch (0.3 g) crystallized from
the mother liquors on standing overnight. Anal. (C26H29F7N5O2-
Cl) C, H, N.

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4299
1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(tr iflu or om eth yl)ph en yl]-
et h yl}oxy)-3-(4-flu or op h en yl)m or p h olin -4-yl]m et h yl}-
Ack n ow led gm en t. The authors thank Dr. Richard
Herbert and Steve Thomas for their expert assistance
with acquisition and interpretation of spectral data, and
Marc Kurtz for his assistance in providing h-NK1 IC50
data.
2H-1,2,3-tr ia zol-4-yl)m eth a n a m in e, 8. Prepared from
6
following the procedure described for the preparation of 3 in
15% yield.1H NMR (400 MHz, CDCl3) δ 1.45 (3H, d, J )6.2 Hz,
CH3CH), 2.45 (1H, t, J ) 10.4 Hz, NCHHCH2O), 2.79 (1H, d,
J ) 11.4 Hz, NHHCH2O), 3.10 (1H, d, J ) 13.6 Hz, O(CH2)2-
NCHH), 3.44 (1H, s, NCHAr), 3.62 (1H, d, J ) 10.5 Hz,
OCHHCH2N), 3.76 (1H, d, J ) 13.6 Hz, O(CH2)2NCHH), 3.95
(2H, app. t, J ) 15.9 Hz, CH2NH2), 4.16 (1H, t, J ) 11.1 Hz,
OCHHCH2N), 4.32 (3H, m, NH2 and OCHO), 4.89 (1H, q, J )
6.2 Hz, CH3CHAr), 7.08 (2H, t, J ) 7.8 Hz, ArH), 7.20 (2H, s,
ArH) 7.49 (2H, m ArH), 7.63 (1H, s, ArH). Anal. (C24H24F7N5O2)
C, H, N.
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(8) 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.
(9) Beresford, I. J . M.; Birch, P. J .; Hagan, R. M.; Ireland, S. J .
Investigation into Species Variants in Tachykinin NK-1 Recep-
tors by Use of the Non-Peptide Antagonist, CP-96,345. Brit. J .
Pharmacol. 1991, 104, 292.
(10) Rupniak, N. M. J .; Williams, A. R. Differential Inhibition of Foot
Tapping and Chromodacryorrhoea in Gerbils by CNS Penetrant
and Non-Penetrant Tachykinin NK-1 Receptor Antagonists. Eur.
J . Pharmacol. 1994, 265, 179.
1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(tr iflu or om eth yl)ph en yl]-
et h yl}oxy)-3-(4-flu or op h en yl)m or p h olin -4-yl]m et h yl}-
2H-1,2,3-tr ia zol-4-yl)-N-m eth ylm eth a n a m in e, 9. Prepared
from 6 following the procedure described for the preparation
of 3 in 77% yield.1H NMR (360 MHz, CDCl3) δ 1.46 (3H, d, J
) 6.6 Hz, CH3CHAr), 2.44 (1H, td, J ) 12.1 Hz and 3.5 Hz,
NCHHCH2O), 2.53 (3H, s, CH3), 2.74 (1H, d, J ) 11.6 Hz,
NCHHCH2O), 3.10 (1H, d, J ) 13.5 Hz, O(CH2)2NHH), 3.4 (1H,
d, J ) 2.6 Hz, NCHAr), 3.61 (1H, d, J ) 11.7 Hz, OCHH),
3.76 (1H, d, J ) 13.6 Hz, O(CH2)2NCHH), 3.78 (1H, d, J )
13.8 Hz, CHHNHMe), 3.86 (1H, d, J ) 13.7 Hz, CHHNHMe),
4.16 (1H, t, J ) 11.7 Hz, OCHH), 4.32 (1H, d, J ) 2.6 Hz,
OCHO), 4.89 (1H, q, J ) 6.6 Hz, CHCH3), 5.30 (1H, vbs, NH),
7.08 (2H, d, J ) 8.7 Hz, ArH), 7.20 (2H, s, ArH), 7.47 (2H, m,
ArH), 7.64 (1H, s, ArH). Anal. (C25H26F7N5O2.0.5 H2O) C, H,
N.
1-[(5-{[(2R ,3S )-2-({(1R )-1-[3,5-Bis(t r iflu or om e t h yl)-
p h en yl]et h yl}oxy)-3-(4-flu or op h en yl)m or p h olin -4-yl]-
m e t h yl}-2H -1,2,3-t r ia zol-4-yl)]-N -isop r op ylp r op a n -2-
a m in e, 10. Prepared from 6 following the procedure described
for the preparation of 3 in 54% yield. 1H NMR (360 MHz,
CDCl3) δ 1.00 (12H, d, J ) 1.8 Hz, 2 × CH3CHCH3), 1.44 (3H,
d, J ) 6.6 Hz, CH3CHAr), 2.64 (1H, dt, J ) 3.5, 12.0 Hz,
NCHHCH2O), 2.93-3.03 (3H, m, 2 × CH3CHCH3, NCH-
HCH2O), 3.30 (1H, d, J ) 14.1 Hz, O(CH2)2NCHH), 3.48 (1H,
d, J ) 2.8 Hz, NCHAr), 3.51-3.76 (4H, m, O(CH2)2NCHH,
Triaz. CH2N, OCHH), 4.24 (1H, dt, J ) 2.4, 11.6 Hz, OCHH),
4.33 (1H, d, J ) 2.8 Hz, OCHO), 4.87 (1H, q, J ) 6.5 Hz,
CHCH3), 7.02-7.07 (2H, m, ArH), 7.17 (2H, s, ArH), 7.47 (2H,
vbs, ArH), 7.63 (1H, s, ArH). Anal. (C30H37F7N5O2Cl) C, H, N.
(2R,3S)-4-{[5-(Azetid in -1-ylm eth yl)-2H-1,2,3-tr ia zol-4-
yl]m et h yl}-2-({(1R)-1-[3,5-b is(t r iflu or om et h yl)p h en yl]-
eth yl}oxy)-3-(4-flu or op h en yl)m or p h olin e, 11. Prepared
from 6 following the procedure described for the preparation
1
of 3 in 50% yield. H NMR(250 MHz, CDCl3) δ 1.45 (3H, d, J
) 6.6 Hz, CH3), 2.07-2.19 (2H, m, CH2CH2CH2), 2.56 (1H, dt,
J ) 3.5, 12.0 Hz, NCHHCH2O), 2.88 (1H, m, NCHHCH2O),
3.18-3.45 (6H, m, CH2CH2CH2, O(CH2)2NCHH, NCHAr),
3.60-3.80 (4H, m, O(CH2)2NCHH, Triaz. CH2N, OCHH), 4.17-
4.25 (1H, m, OCHH), 4.33 (1H, d, J ) 2.8 Hz, OCHO), 4.87
(1H, m, CHCH3), 7.04-7.09 (2H, m, ArH), 7.16 (2H, s, ArH),
7.50 (2H, m, ArH), 7.64 (1H, s, ArH). Anal. (C27H28F7N5O2‚
0.5H2O) C, H, N.
(2R,3S)-2-({(1R)-1-[3,5-Bis(t r iflu or om et h yl)p h en yl]-
e t h yl}oxy)-3-(4-flu or op h e n yl)-4-{[5-(p yr r olid in -1-yl-
m eth yl)-2H-1,2,3-tr ia zol-4-yl]m eth yl}m or p h olin e, 12. Pre-
pared from
6 following the procedure described for the
1
preparation of 3 in 80% yield. H NMR (360 MHz, DMSO-d6)
δ 1.44 (3H, d, J ) 6.6 Hz, CH3CHAr), 1.80 (4H, br s,
NCH2CH2CH2CH2N), 2.51-2.60 (5H, m, NCHHCH2O and
NCH2CH2CH2CH2N), 2.90 (1H, d, J ) 11.7 Hz, NCHHCH2O),
3.23 (1H, d, J ) 13.9 Hz, O(CH2)2NCHH), 3.45 (1H, d, J ) 2.7
Hz, NCHAr), 3.58-3.63 (2H, d, J ) 13.6 Hz and m, (CH2)4-
NCHH and OCHHCH2N), 3.69 (1H, d, J ) 13.6 Hz, (CH2)4-
NCHH), 3.79 (1H,d, J ) 14.0 Hz, O(CH2)2NCHH), 4.22 (1H,
td, J ) 2.1 and 11.5 Hz, OCHHCH2N), 4.30 (1H, d, J ) 2.8
Hz, OCHO), 4.86 (1H, q, J ) 6.6 Hz, CH3CHAr), 7.16 (2H, s,
ArH), 7.48 (2H, m, ArH), 7.64 (1H, s, ArH). Anal. (C28H30F7N5O2)
C, H, N.
(11) Andrews, P. L.; Bhandari, P. The 5-Hydroxytryptamine Receptor
Antagonists as Antiemetics: Preclinical Evaluation and Mech-
anism of Action. Eur. J . Cancer. 1993, 29A (Suppl. 1), S11-S16.
J M0109558