Tetrahydroindolizinone NK1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.01.120

A new class of potent NK₁ receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK₁ receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK₁ binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P₄₅₀ inhibition and hPXR induction profiles.

Full text of DOI:10.1016/j.bmcl.2010.01.120

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2354–2358
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Tetrahydroindolizinone NK1 antagonists
a
a
b
b
d
Jianming Bao a, , Huagang Lu , Gregori J. Morriello , Emma J. Carlson , Alan Wheeldon , Gary G. Chicchi ,
*
Marc M. Kurtz d, Kwei-Lan C. Tsao d, Song Zheng c, Xinchun Tong c, Sander G. Mills a, Robert J. DeVita a
a Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
b Department In Vivo Neuroscience, Merck Research Laboratories, Rahway, NJ 07065, USA
c Department Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA
d Department Immunology and Rheumatology, Merck Research Laboratories, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified.
This series of compounds demonstrated improved functional activities as compared to previously iden-
tified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is
discussed in detail. A number of compounds displayed high NK1 receptor occupancy at both 1 h and
24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other
NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction
profiles.
Received 15 December 2009
Revised 20 January 2010
Accepted 21 January 2010
Available online 1 February 2010
Keywords:
Tetrahydroindolizinone
NK1
Ó 2010 Elsevier Ltd. All rights reserved.
Antagonists
Gerbil foot tapping
IP1
The neurokinin-1 receptor (NK1) is present in high concentra-
tions in central and peripheral nerve systems.1 Through the studies
of the physiological effect of the ligand substance P, the NK1 recep-
tor has been selected as a therapeutic target for treatment of che-
motherapy-induced nausea and vomiting (CINV), post-operative
nausea and vomiting (PONV),2,3 urinary incontinence4 and other
disorders. Aprepitant (Emend™)5 is currently the only NK1 antago-
nist on market, and it is approved for the treatment of CINV and
PONV. In our NK1 antagonist backup program, we focused our
efforts on the discovery of efficacious compounds that are orally
bioavailable and brain-penetrating with minimum potential for
drug–drug interactions.
aldehyde, which was further oxidized to carboxylic acid 3 with Na-
ClO2. One carbon homologation of acid 3 with diazomethane and
AgOBz provided ester 5. Ester 5 was partially reduced to aldehyde
6 by DIBAL-H. Addition of the anion of t-BuOAc to aldehyde 6 affor-
ded aldol product 7, which upon deprotection by HCl and intramo-
lecular EDC coupling provided hexahydroindolizinone 8 (Scheme
1). Oxidation of alcohol 8 to ketone 9 was achieved with PCC-alu-
mina in 63% yield. The enolate of ketone 9 reacted with 2-[N,N-
bis(trifluoromethanesulfonyl)amino]-5-chloropyridine to provide
vinyl triflate 10. Compounds 11–29 and 37 were prepared from
intermediate 10 by the Suzuki coupling reaction. Compounds 38
and 40 were prepared from triflate 10 by Stille coupling reactions.
Compounds 39 and 41 were prepared from olefenic compounds 38
and 40, respectively by selective hydrogenation (25 psi H2, 10%
Previously, we have disclosed a novel class of NK1 antagonists
based on the 5,5-fused pyrrolidine core (1) (Fig. 1).6,7a These com-
pounds displayed sub-nanomolar NK1 affinity,8 moderate func-
tional activity,9 and had good efficacy in the gerbil foot tapping
model.10 We have designed and synthesized a new class of NK1
antagonist with a 6,5-fused tetrahydroindolizinone core (1a) in or-
der to expand the scope of this class of compounds, to improve
functional activity and to minimize potential P450 inhibition and
hPXR induction issues. Herein, the initial SAR results at the 7-posi-
tion of this fused system are presented.
CF3
CF3
CF3
CF3
O
O
O
O
N
N
R1
The tetrahydroindolizinone derivatives7b were synthesized as
illustrated in Scheme 1. The intermediate 27a was oxidized to its
R2
R7
F
F
1a
1
* Corresponding author. Tel.: +1 732 594 6650; fax: +1 732 594 5350.
E-mail address: bao_jianming@merck.com (J. Bao).
Figure 1. Structure of 5,5-fused pyrrolidine NK1 antagonists 1 and proposed 6,5-
fused tetrahydroindolizinone 1a.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.120

J. Bao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2354–2358
2355
Pd–C in MeOH). Alkene 33 was prepared from 8 through formation
of its mesylate followed by elimination of MsOH under basic
condition.
Lactone compounds 34 and 35 were prepared according to
Scheme 2. Palladium catalyzed coupling reaction of 10 with diol
10a provided lactol 10b, which was oxidized with Ag2CO3 to afford
lactones 34 and 35.11
which reacts with amidoximes to afford 30–32 (Scheme 2).12 Di-
rect displacement of OTf of 10 with 4-OH piperidine provided 36.
Biological results for compounds with b-aromatic substituents
are shown in Table 1. With a few exceptions (12–14, 20, 27 and
32), most of the analogs in Table 1 displayed potent sub-nanomolar
NK1 binding affinities. In presence of 50% human serum, their NK1
binding activities varied widely. Polar compounds had smaller ser-
um shifts (16 vs 17, 20 vs 21 and 22 vs 23). A significant improve-
ment in IP-1 functional activity was observed for these 6,5-fused
Oxadiazoles 30–32 were prepared by palladium catalyzed reac-
tion of 10 with CO to generate an acyl-palladium intermediate,
CF3
CF3
c, d
e
a, b
O
Boc
N
Boc
N
Boc
N
Boc
HO
N
HOOC
O
F
CO2Me
F
F
CHN2
3
F
4
2
5
f, g
O
O
Boc
N
N
Boc
N
N
k
i, j
h
F
OH
F
HO
F
CHO
F
O
9
t-BuO2C
8
6
7
l, m
CF3
O
CF3
N
n or o
O
O
O
N
N
p, q
8
F
TfO
F
10
F
R
33
11-29, 37 (Suzuki coupling)
38 and 40 (Stille Coupling)
Scheme 1. Synthesis of 11–29, 33, 37–38 and 40. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, À78 °C, 15 min, then Et3N, À78 °C 15 min; (b) NaClO2, t-BuOH, rt, 16 h,
100%, two steps; (c) i-BuOCOCl, Et3N, THF, 0 °C, 1 h; (d) CH2N2, THF, 0 °C to rt, 2 h, 68%, two steps; (e) AgOBz, Et3N, MeOH, rt, 16 h, 77%; (f) DIBAL-H, CH2Cl2, À78 °C, 1.5 h; (g)
MeOH, À78 °C to rt; (h) LHMDS/t-butyl acetate, THF, À78 to 30 °C, 3 h, 87%, two steps); (i) HCl, 1,4-dioxane, rt, 2 h; (j) EDC, DMAP, CH2Cl2, 75%, two steps; (k) PCC-alumina,
CH2Cl2, rt, 18 h, 63%; (l) KHMDS, THF, À78 °C, 0.5 h; (m) 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine, THF, À78 °C, 1.5 h, 99%, two steps; (n) Suzuki
coupling, Pd(PPh3)4, boronic acid, toluene, water, 120 °C, 18 h; (o) Stille coupling, Pd(PPh3)4, vinyl tin reagent, dioxane, 108 °C, 18 h; (p) MsCl, Et3N, CH2Cl2, 0 °C to rt, 1 h,
100%; (q) piperidine, toluene, 64 °C, 18 h, 73%.
O
O
O
O
N
N
N
a
b
OH
OH
+
F
F
F
TfO
34-35
10a
10
10b
O
O
HO
NOH
c
R
NH2
d
O
O
N
N
N
F
O
N
F
N
R
36
HO
30-32
Scheme 2. Synthesis of 30–32 and 34–36. Reagents and conditions: (a) Pd(OAc)2, n-Bu4NCl, DMF, 70 °C, 3 h; (b) Ag2CO3-Celite, toluene, 80 °C, 24 h, 78%; (c) 4-
hydroxypiperidine, THF, 80 °C, 1 h, 100%; (d) Pd(PPh3)4, CO, toluene, 95 °C, 16 h, 65–73%, two steps.

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J. Bao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2354–2358
Table 1
Activities of compounds with b-aromatic substituents
CF3
CF3
O
O
N
R
F
Compd
R
NK1
+50 %HS
IP-1b
Gerbil FTc
Compd
R
NK1
+50 %HS
IP-1
Gerbil FT
a
IC50 (nM)
%SPRR
% Inhibition
IC50 (nM)
%SPRR
% Inhibition
33
11
H
0.013
0.93
0.53
89.5
48
17
22
23
0.18
0.15
8.5
2.3
9
25
42
N
N+
Ph
—
—
11
O-
N
CN
F
12
1.8
53
3
24
0.16
4
84
98
N
NH
N
13
14
2
100
54
7
—
—
25
26
0.15
0.13
7.7
5.4
55
14
82
94
N
N
NHSO2Me
OH
1.0
11
N
N
Ph
15
16
0.39
0.14
23
3
4
—
27
28
1.9
66
3
—
—
O
N
N
8.1
100
0.11
6.4
31
N+ O-
O
N
17
0.10
2.1
11
100
29
0.11
5.6
59
—
F
N
O
18
19
20
0.11
0.51
1.1
11.7
34
7
96
85
—
30
31
32
0.15
0.40
1.7
5.1
27
72
35
32
21
—
—
—
N
N
Et
N
12
5
N
N
N
O
N
OMe
iPr
44
N
O
O
21
0.27
3.9
17
0
NH
a
Displacement of [125I] labelled substance P from the cloned hNK1 receptor expressed in CHO cells. Data are mean (n = 3).8
IP-1 assay: Measures the response of inositol phosphate generation to substance P (10 lM) and is reported as the percent of substance P response remaining (SPRR) at
b
100 nM NK1 antagonist concentration.9
c
Inhibition of GR73632 induced foot tapping in gerbils@ 3 mg/kg iv at 24 h.10
compounds with b-substituents compared with unsubstituted
compound 33. In general, the IP-1 functional activity of these
6,5-fused compounds was also significantly better than that of
the 5,5-fused pyrrolidine compounds previously disclosed (IP-1:
28–90%).7a A majority of these compounds had IP-1 activities be-
low 20% substance P response remaining (SPRR) at 100 nM antag-
onist concentration. Among compounds with a six-membered ring
substituents at the 7-position, compared to compound 11, a substi-
tuent at the 4-position of the phenyl group had a positive impact
on the IP-1 activity (11 vs 12–16). Compounds with a pyridyl sub-
stituent also had improved IP-1 activities compared to compound
11. Except compounds 26 and 27, compounds with a five-mem-
bered ring substituent were less potent than compounds with a
six-membered ring substituents in the IP-1 assay. The NK1 binding
affinity and the functional activity did not always directly correlate
(for example, compound 12 had weaker NK1 binding activity and
excellent IP-1 activity). There was also no correlation between
the polarity of a compound and its IP-1 functional activity (25 vs
26 and 27).
Some of the compounds with potent NK1 binding and functional
activity were also tested in the gerbil foot tapping assay10, which
measured how effective the compound blocked the NK1 receptor
at 24 h in the gerbil brain (Table 1). Data from this assay also pro-
vided an indication of the duration of parent or active metabolites,
and an indication of brain penetration. Compounds 16 and 17 dem-
onstrated complete inhibition of gerbil foot tapping at 24 h at an iv
dose of 3 mg/kg.
The SAR learned from Table 1 was applied in the design of com-
pounds with non-aromatic b substituents at the 7-position and
data are presented in Table 2. These compounds all have a polar

J. Bao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2354–2358
2357
Table 2
Table 4
Activities of compounds with b non-aromatic substituents
Pharmacokinetic profile of 40
CF3
t1/2 (h) Vd (L/kg) Clp (mL/mg/kg) nAUC (po) (
l
M h kg/mg) F (%)
5.3
44
Rat 2.8
Dog 8.8
7.2
11
33
17
0.05
0.69
CF3
O
O
N
Table 5
P450 inhibition and hPXR induction data for compound 40
R
F
IP-1b
%
Gerbil FTc
Cyp 2C9
36.5
Cyp 2D6
35.7
Cyp 3A4
>50
PXR
>30
Compd
R
NK1
+50 %HS
a
IC50 (lM)
IC50 (nM)
% Inhibition
O
O
fast
34
35
0.066
1.4
2.4
5
5
98d
96d
O isomer
At 1 h, the IC50 values in plasma and brain are 0.57 and 6.9 nM,
respectively indicating that low plasma and brain concentrations
drive efficacy in gerbil and a high b/p ratio.
slow
isomer
0.11
O
Compound 40 was evaluated for PK properties in rat and dog
(Table 4). In rat, it showed high clearance (33 mL/min/kg), very
low oral AUC (0.05), desirable plasma half-life (2.8 h) and poor oral
bioavailability. However, in dog, the PK profile improved with
moderate clearance (11 mL/min/kg), better oral AUC (0.69), good
half-life, and improved oral bioavailability.
Compound 40 had a low affinity for cytochrome P450 enzymes
and a reduced potential for induction as measured by a hPXR
induction assay (Table 5), which indicated that compound 40
may have reduced liability for drug–drug interactions.
N
OH
OH
36
37
38
39
40
41
0.16
0.18
0.18
0.09
0.18
0.041
11
4
82
13
8
—
O
9.6
3.2
1.9
0.21
14
3
—
100d
100
91
O
N
N
2
4
In summary, a new class of NK1 receptor antagonists based on a
tetrahydroindolizinone core with substitutions at the 7-position
has been identified. These 6,5-fused pyrrolidine NK1 antagonists
generally had sub-nanomolar NK1 binding affinities and excellent
functional IP-1 activities. Many of these analogs have potent
in vivo efficacy in the gerbil model at 24 h. Compound 40 had
excellent efficacy in the gerbil foot tapping model at both 1 h
and 24 h. It also had a clean profile in human P450 inhibition and
PXR induction assays, thus reducing the potential for drug–drug
interactions.
a
Displacement of [125I] labelled substance P from the cloned hNK1 receptor
expressed in CHO cells. Data are mean (n = 3).8
b
IP-1 assay9: Measure the response of inositol phosphate generation to sub-
stance P (10 lM) and reported as the percent of substance P response remaining
(SPRR) at 100 nM NK1 antagonist concentration x.
c
Inhibition of GR73632 induced foot tapping in gerbils@ 3 mg/kg iv at 24 h.10
1 h at 1 mg/kg.
d
group at the far side of the attachment to reduce serum shifts. All
of them exhibited sub-nanomolar binding potency on the NK1
receptor. They had lower shifts in affinity in the presence of human
serum as compared to the compounds with b-aromatic substitu-
ents, probably due to higher polarity. Importantly, all of them
had excellent functional activities. In the gerbil foot tapping assay,
all tested compounds displayed potent efficacy at 1 h or 24 h. Com-
pound 40 was prepared initially as an intermediate for compound
41. The t-Bu group of compound 41 was used to block possible
metabolism of the piperidine group. It was surprising to find that
compound 40 is more potent than 41 in the gerbil foot tapping as-
say despite the fact that compound 41 is about fourfold (ninefold
with human serum) more potent than compound 40 in the binding
assay.
Acknowledgments
The authors wish to thank the Synthetic Services Group for
scale-up of synthetic intermediate 2.
References and notes
1. Duffy, R. A. Expert Opin. Emerg. Drugs 2004, 9, 9.
2. Tattersall, F. D.; Rycroft, W.; Cumberbatch, M. Neuropharmacology 2000, 39,
652.
3. Rupniak, N. M.; 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. Eur. J.
Pharmacol. Med. Chem. 1997, 326, 201.
4. Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg. Med. Chem. 2005, 13, 5717.
5. 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.; Williams, A.; Rycroft, W.; Hargreaves, R. J.; MacIntyre, D. E. J.
Med. Chem. 1998, 41, 4607.
Given its single dose potency in the gerbil foot tapping assay,
compound 40 was titrated to have an ID50 = 0.05 mg/kg at 1 h
and an ID50 = 0.49 mg/kg at 24 h (Table 3). These data indicate that
compound 40 was one of the most potent compounds in this assay.
6. Morriello, G. J.; Devita, R. J.; Mills, S. G.; Young, J. R.; Lin, P.; Doss, G.; Chicchi, G.
G.; DeMartino, J.; Kurtz, M.; Tsao, K. C.; Carlson, E.; Townson, K.; Wheeldon, A.;
Boyce, S.; Collinson, N.; Rupniak, N.; Moore, S. Bioorg. Med. Chem. 2008, 16,
2156.
7. (a) Morriello, G. J.; Mills, S. G.; Johnson, T.; Reibarkh, M.; Chicchi, G.; DeMartino,
J.; Kurtz, M.; Davies, P.; Tsao, K. C.; Carlson, E.; Townson, K.; Tattersall, F. D.;
Wheeldon, A.; Boyce, S.; Collinson, N.; Rupniak, N.; Moore, S.; Devita, R. J.
Bioorg. Med. Chem. Lett. 2010, 20, 2007; (b) For detailed procedures for
synthesis of the compounds in this Letter: Bao, J.; Devita, R. J.; Mills, S. G.;
Morriello, G. J. WO 2007136570.
Table 3
In vivo activity of compound 40 in Gerbila
Time (h)
ID50
ID50 (at 1 mpk, iv)
Plasma
Brain
1
24
0.05
0.49
0.57
—
6.9
—
8. NK1 binding assay: Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal, A.;
Swain, C. J.; Seward, E. M.; Frances, B.; Burns, D.; Strader, C. D. Mol. Pharmacol.
1992, 42, 458.
a
Plasma drug levels determined by LC–MS following protein precipitation.

2358
J. Bao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2354–2358
9. Young, J. R.; Eid, R.; Turner, C.; DeVita, R. J.; Kurtz, M. M.; Tsao, K. C.; Chicchi, G.
G.; Wheeldon, A.; Carlson, E.; Mills, S. G. Bioorg. Med. Chem. Lett. 2007, 17, 5310.
10. Rupniak, N. M. J.; Tattersall, F. D.; Williams, A. R.; Rycroft, W.; Carlson, E.;
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. Eur. J.
Pharmacol. 1997, 326, 201.
11. Arcadi, A.; Bernocchi, E.; Cacchi, S.; Marinelli, F. Tetrahedron 1991, 47, 1525.
12. Young, J.; Devita, R. Tetrahedron Lett. 1998, 39, 3931.