Optimization of azepanone calcitonin gene-related peptide (CGRP) receptor antagonists: Development of novel spiropiperidines

Article abstract of DOI:10.1016/j.bmcl.2009.09.066

Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism.

Full text of DOI:10.1016/j.bmcl.2009.09.066

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6368–6372
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Optimization of azepanone calcitonin gene-related peptide (CGRP) receptor
antagonists: Development of novel spiropiperidines
a
a
b
b
Christopher S. Burgey a, , Craig M. Potteiger , James Z. Deng , Scott D. Mosser , Christopher A. Salvatore ,
*
Sean Yu c, Shane Roller c, Stefanie A. Kane b, Joseph P. Vacca a, Theresa M. Williams a
a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
b Department of Pain and Migraine Research, Merck Research Laboratories, West Point, PA 19486, USA
c Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good
potency and have reduced potential for metabolism.
Received 20 August 2009
Revised 16 September 2009
Accepted 17 September 2009
Available online 22 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
CGRP
CGRP receptor antagonists
Migraine
Calcitonin gene-related peptide
Within the field of antimigraine therapy, the development of
novel drugs with enhanced safety profiles and/or improved efficacy
is a current major focus. The triptan class of 5-HT1B/1D receptor
agonists represents the current standard of treatment for a mi-
graine attack; however, these compounds are contraindicated in
patients with cardiovascular disease.1 Calcitonin gene-related pep-
tide (CGRP) has been proposed to be a key neuropeptide in the
pathogenesis of migraine headache, engendering hope for the
development of receptor antagonists as therapeutics devoid of
the cardiovascular effects associated with current migraine
treatments.2
We have undertaken a research program aimed at identifying
small-molecule CGRP receptor antagonists suitable for oral admin-
istration during a migraine attack.3 A recent report from these lab-
oratories detailed the identification of a series of potent, orally
bioavailable, small-molecule, azepanone-based CGRP receptor
antagonists.4 A development candidate was selected from this ser-
ies (Fig. 1, telcagepant, MK-0974) and this compound has recently
demonstrated efficacy similar to a triptan in a phase 3 migraine
clinical trial; importantly, overall adverse event rates were compa-
rable to placebo and lower than the triptan positive comparator.5
Research efforts have continued within the azepanone series,
focusing on the identification of compounds with improved
profiles. One area targeted for optimization was the elimination/
modification of areas of the lead molecule known to be susceptible
to oxidative metabolism (i.e., metabolic soft-spots). The primary
site of metabolism is the piperidine-based ‘privileged structure’.
For example, telcagepant undergoes N-oxidation to afford 1 and
N-dealkylation to produce hydroxypiperidine 2. These pathways
are manifested in the low oral bioavailability in rhesus, primarily
due to intestinal first-pass metabolism (Fig. 1).6
O
NH
F3C
O
N
N
N
H
N
F
N
F
O
Ki = 0.8 nM
cAMP IC50 = 2 nM
+50% HS IC50 = 11 nM
telcagepant
(MK-0974)
metabolism
O
NH
O
OH
N
N
N
N
1
2
Ki = 66 nM
Ki = 5000 nM
* Corresponding author.
E-mail address: christopher_burgey@merck.com (C.S. Burgey).
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.066

C. S. Burgey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6368–6372
6369
O
required to maintain CGRP potency, namely a cyclic amide such
as pyridinone 6 (Table 1: Ki = 100 nM). Preparation of the analo-
gous pyridazinone led to a 10-fold improvement in potency (7:
Ki = 10 nM). In an attempt to further improve potency, lipophilic
groups were installed at the 6-position of the pyridazinone. A small
methyl group enhances potency modestly, while the larger phenyl
group reduces binding affinity. These results suggest that the key
HBA (X = N) that occupies the ‘aza binding’ site of the CGRP recep-
tor can be incorporated into the same ring system as the key cyclic
amide.7 Of additional note is the relatively modest in vitro efficacy
shift (ꢀ2-fold) of these pyridazinones in the presence of 50% HS.
While these compounds were designed to circumvent the
N-dealkylation process observed with the parent piperidine-
azabenzimidazolone, the PK was not improved. For example,
analog 8 exhibits low to moderate plasma clearance and bioavail-
ability in rats (Cl = 9.8 mL/min/kg; F = 15%).
Modification of the piperidine-based privileged structure
according to pathway B (Chart 1) offered an alternative strategy
designed to overcome the metabolic susceptibility via formation
of spirocycles. Previous work from our group has shown that a
hydantoin can be incorporated at the piperidine C4-position to de-
liver potent CGRP receptor antagonists7 and spirocyclization of this
heterocycle similarly afforded potent compounds (Table 2, exam-
ple 10). Both N-methylation to 11 and preparation of the oxazolid-
inedione 12 led to significant losses of CGRP affinity. The
spirosuccinimide 13 retains the good potency of the hydantoin,
with both of these analogs exhibiting nominal shift in the presence
of human serum. Deletion of the distal carbonyl group to give
spiropyrrolidinone 14 illustrates the minimal structural motif to
retain good potency. The two glutarimide isomers, 15 and 16,
demonstrate that a 5-member ring is optimal.
NH
O
N
N
X
A
NH
n
N
X
4
n
B
O
3
n
X = HBA or Ar
n = 0 - 2
NH
X
N
5
Chart 1.
Guided by this data, in combination with the proposed pharma-
cophore 3,7 two general strategies for attenuation of metabolism
were outlined. In the first (Chart 1, A), elimination of the N-dealky-
lation pathway could be achieved by replacement of the C4pip–Nhet
bond with an C4pip–Chet (sp2) bond; alternatively, a similar result
could also be achieved by spirocyclization of the two ring systems
(Chart 1, B). In the design of specific analogs we were cognizant
that an H-bond acceptor would likely be required to confer good
potency (X = HBA) and if it were to be a nitrogen (X = N) then the
N-oxidation pathway would not be circumvented.
All compounds prepared were tested in the CGRP receptor com-
petitive [125I]-CGRP radioligand binding assay (Ki). Selected com-
pounds were subsequently tested for their functional ability to
inhibit CGRP-stimulated cAMP production in whole cells (cAMP
IC50); this assay could also be conducted in 50% human serum
(+HS) to estimate the impact of plasma protein binding on
in vitro efficacy.8
According to strategy A (Chart 1) the piperidine-based privi-
leged structure was pared back to the basic pharmacophore
As Chart 1 illustrates, the potency of the amide pharmacophore
can also be improved by strategic introduction of an aryl group
(X = Ar). Examples 17 and 18 demonstrate that a pendant aryl
group, preferring a trajectory from a sp2 carbon, can access this
type of interaction within the spiropiperidine motif (Table 2).
Fusion of the aryl group into a bicyclic system represented by quino-
lone 19 leads to a significant loss in affinity. Moving the spirocyclic
ring junction b to the carbonyl, as in benzoxazinone 20, confers a
substantial potency gain. Notably, significant in vitro cAMP efficacy
shifts are observed in the presence of human serum.
Table 1
4-Substituted piperidine SAR
F3C
O
N
F
H
N
R
F
O
Within the 4-substituted piperidines it has been shown that
proper placement of a single nitrogen within the bicyclic ring sys-
tem can produce an 100-fold improvement in CGRP binding
affinity (‘aza binding site’).7 Furthermore, the resultant azacycles
attenuate plasma protein binding and, accordingly, demonstrate
minimal in vitro efficacy shift in the presence of human serum.
Production of the azabenzoxazinone 21 demonstrates that this
binding motif is also accessible within the spirocyclic piperidines
(Table 2). The naphthyridinone 22 is slightly less potent, while
the azaoxindole 23 is equipotent. Notably, these compounds do
not shift to an appreciable extent in the cAMP assay with added
serum.
These spiropiperidine-based CGRP receptor antagonists retain
the favorable rat PK properties inherent in the azabenzimidazoles
(21 F = 37%; 22 F = 26%; 23 F = 35%); furthermore, they show re-
duced propensity for metabolism on the terminal ring of the spiro-
cyclic system. For example 21 shows no evidence of oxidation on
the azabenzoxazinone ring in the presence of human, rat, and rhe-
sus liver microsomes.
b
c
Compds
R
Kia
(nM)
cAMP IC50
(nM)
+HS IC50
(nM)
O
NH
6
100
10
—
—
N
O
O
NH
N
7
8
44
13
112
21
N
N
NH
N
6.6
O
NH
N
N
9
240
—
—
The chemistry to access these piperidines, which were con-
verted to the final ureas using previously disclosed methods,9 is
highlighted below (Schemes 1–4).10
The general route to the pyridazinones is delineated in Scheme
1: piperidinyl-4-acetate 24 is alkylated with allylic bromides to de-
liver 25 and serves to install the C6 lipophilic group. Oxidative
a
Values are means of two experiments; inhibition of [125I]-CGRP binding against
the CGRP receptor (recombinant human CLR/RAMP1).
b
Inhibition of CGRP-stimulated cAMP production in cells.
Inhibition of CGRP-stimulated cAMP production in the presence of 50% human
c
serum.

6370
C. S. Burgey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6368–6372
Table 2
Spiropiperidine SAR
Table 2 (continued)
b
c
Compds
R
Kia
(nM)
cAMP IC50
(nM)
+HS IC50
(nM)
F3C
O
O
N
F
H
N
R
F
N
N
NH
N
22
3.5
1.7
11
11
O
b
c
O
Compds
R
Kia
(nM)
cAMP IC50
(nM)
+HS IC50
(nM)
NH
23
3.3
11
N
O
NH
a
Values are means of two experiments; inhibition of [125I]-CGRP binding against
10
46
94
—
122
—
N
N
N
the CGRP receptor (recombinant human CLR/RAMP1).
O
H
b
Inhibition of CGRP-stimulated cAMP production in cells.
Inhibition of CGRP-stimulated cAMP production in the presence of 50% human
c
O
serum.
NH
11
12
510
N
O
cleavage to ketone 26 is followed by ring closure with hydrazine to
deliver 27. Formal dehydrogenation to the pyridazinone is fol-
lowed by deprotection to give piperidine 28.
The synthesis of the spiroazabenzoxazinone can be accom-
plished according to Scheme 2. Ortho metalation11 of Boc protected
2-amino-6-chloropyridine12 30 and addition of the resultant anion
O
NH
8900
—
—
N
N
O
O
O
NH
13
14
15
41
55
—
95
—
O
R
O
Br
Cbz
140
340
Cbz
NH
N
O
LiHMDS
N
O
N
N
N
OEt
Cbz
OEt
THF, -78 oC
50 - 80%
R
O
24
25
NH
O
—
—
O
N
O
NaIO4
cat. OsO4
H2NNH2
OEt
AcOH, 50 oC
70 - 90%
16
17
390
30
—
—
NH
THF/H2O
R
60 - 100%
26
O
O
O
Cbz
N
O
NH
HN
O
R
1) CuCl2, MeCN, 90 o
C
N
23
871
N
NH
N
NH
N
2) H2, 10% Pd/C, EtOH
~ 50%
27
28
R
O
R = H, Me, Ph
NH
N
N
N
18
19
380
120
—
692
—
Scheme 1.
O
NH
O
1249
NHBoc
NH2
N
n-BuLi
TMEDA, THF
NaHMDS, THF
N
Boc2O
80%
CbzN
O
Cl
Cl
O
NH
50%
20
21
46
60
792
13
29
30
O
O
O
O
HN
NH
N
CbzN
NH
N
Pd/C, H2, EtOH
O
O
N
NH
N
1.1
2.7
32
31
Cl
Scheme 2.

C. S. Burgey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6368–6372
6371
O
two-stage deprotection with concomitant double bond reduction
gives the desired spironaphthyridinone 40.
Ph3P
O
CO2Me
DBU
Cbz
N
O
Cbz
N
The synthesis of the spiroazaoxindole is shown in Scheme 4.
Alkylation of the SEM-protected 7-azaindole 41 with cis-1,4-di-
chloro-2-butene affords the spirocyclopentene 42. Removal of the
SEM protecting group followed by osmium tetroxide catalyzed
dihydroxylation provides the diol intermediate 44. Periodate oxi-
dative cleavage of the diol, followed by a double reductive amina-
tion affords the spiropiperidine 45.17
DMF
50%
Benzene
85%
34
33
NH2
N
Br
O
O
O
NH
AlMe3
Cbz
N
Cbz
N
N
DCE, 55oC
55%
Br
In summary, utilizing the previously proposed pharmacophore,
two general strategies were outlined for attenuation of metabolism
of the piperidine-based privileged structure within the azepanone
series of CGRP receptor antagonists. Several novel piperidine-based
privileged structures have been developed that maintain compara-
ble potency to the phase 3 clinical compound telcagepant and have
the potential for reduced metabolism. The incorporation of these
novel spirocyclic privileged structures into newer non-azepanone
templates to deliver second-generation CGRP receptor antagonists
with differentiated profiles will be reported in the future.
35
36
Cy2MeN
Pd[P(t-Bu)3]2
NaH
SEM-Cl
O
SEM
N
Cbz
N
N
Dioxane, 50 o
75%
C
THF, 0oC
60%
Br
37
O
N
N
O
1. TFA
2.
Cbz
N
SEM
Cbz
N
NH
NH2
H2N
N
39
38
Acknowledgments
DCM
95%
We thank the mass spectroscopy, and NMR analysis groups for
their valuable assistance.
O
H2, 10% Pd/C
HN
NH
EtOH
80%
N
References and notes
40
Scheme 3.
1. Wackenfors, A.; Jarvius, M.; Ingemansson, R.; Edvinsson, L.; Malmsjo, M. J.
Cardiovasc. Pharmacol. 2004, 45, 476.
2. Durham, P. L.; Russo, A. F. Pharmacol. Ther. 2002, 94, 77; Edvinsson, L. Exp. Opin.
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Lesko, L. N. Engl. J. Med. 2004, 350, 1104; Petersen, K. A.; Birk, S.; Lassen, L. H.;
Krusse, C.; Jonassen, O.; Lesko, L.; Olesen, J. Cephalalgia 2004, 25, 139.
3. Williams, T. M.; Burgey, C. S.; Salvatore, C. A. Prog. Med. Chem. 2009, 47, 1.
4. Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, Z. J.; Kane, S. A.;
Koblan, K. S.; Salvatore, C. A.; Hershey, J. C.; Wong, B.; Roller, S. G.; Miller-Stein,
C.; Graham, S. L.; Vacca, J. P.; Williams, T. M. J. Med. Chem. 2007, 50, 5564;
Salvatore, C. A.; Hershey, J. C.; Corcoran, H. A.; Fay, J. F.; Johnston, V. K.; Moore,
E. L.; Mosser, S. D.; Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Graham, S. L.; Vacca,
J. P.; Williams, T. M.; Koblan, K. S.; Kane, S. A. JPET 2008, 324, 416; Burgey, C. S.;
Paone, D. V.; Shaw, A. W.; Deng, J. Z.; Nguyen, D. N.; Potteiger, C. M.; Graham, S.
L.; Vacca, J. P.; Williams, T. M. Org. Lett. 2008, 10, 3235.
to N-benxyloxycarbonyl-4-piperidinone, gives, after in situ cyliza-
tion, product 31.13 Final deprotection and dechlorination under
standard hydrogenolysis conditions gives the piperidine 32.
The synthesis of spironaphthyridinone 40 is summarized in
Scheme 3. Olefination of the 4-ketopiperidine 33 gives the
a
b,
,b-unsaturated ester 34, which can be isomerized to the
c
-unsaturated ester 35 under basic conditions (Scheme 3).14
Trimethylaluminum mediated amidation with 2-amino-3-bromo-
pyridine followed by amide alkylation gives the SEM protected
product 37.15 The key palladium-mediated spirocyclization can
5. Ho, T. W.; Mannix, L.; Fan, X.; Assaid, C.; Furtek, C.; Jones, C.; Lines, C.; Rapoport,
A. Neurology 2008, 70, 1305; Ho, T. W.; Ferrari, M. D.; Dodick, D. W., et al Lancet
2008, 372, 2115.
be effected through the Fu modification of the Heck reaction.16
A
6. Roller, S.; Cui, D.; Laspina, C.; Miller-Stein, C.; Rowe, J.; Wong, B.;
Prueksaritanont, T. Xenobiotica 2009, 39, 33.
7. Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.; Quigley, A. G.; Norton, B.
R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan,
K. S.; Vacca, J. P.; Graham, S. L.; Williams, T. M. Bioorg. Med. Chem. Lett. 2006, 16,
5052.
8. For the details of these assays, see: Bell, I. M.; Graham, S. L.; Williams, T. M.;
Stump, C. A. WO 2004/087649.
9. Williams, T. M.; Stump, C. A.; Nguyen, D. N.; Quigley, A. G.; Bell, I. M.; Gallichio,
S. N.; Zartman, C. B.; Wan, B.-L.; Kunapuli, P.; Kane, S. A.; Koblan, K. S.; Mallee, J.
J.; Mosser, S. D.; Rutledge, R. Z.; Salvatore, C.; Graham, S. L.; Vacca, J. P. Bioorg.
Med. Chem. Lett. 2006, 16, 2595.
10. For the details of the chemistry, see: Burgey, C. S.; Deng, Z. J.; Potteiger, C.;
Williams, T. M. WO 2006/041830 A2.; Burgey, C. S.; Paone, D. V.; Shaw, A. W.;
Nguyen, D. N.; Deng, Z. J.; Vacca, J. P.; Selnick, H. G.; Williams, T. M.; Potteiger,
C. WO 2006/044504 A2.
O
O
Cs2CO3
DMF
SEM
TFA,
DCM
N
SEM
N
N
Cl
Cl
N
77%
80%
41
42
HO
O
O
OsO4, DCM
NMe3
NH
N
NH
N
HO
O
11. Davies, A. J.; Brands, K. M. J.; Cowden, C. J.; Dolling, U.-H.; Lieberman, D. R.
Tetrahedron Lett. 2004, 45, 1721.
12. Ortho metalation/cyclization attempts without the chlorine group were
unsuccessful.
43
44
13. In situ cyclization via the use of a carbamate protecting group were essential,
as attempted deprotection of amides led to dehydration: for example,
O
1) NaIO4,
EtOH, H2O
HN
NH
N
2) 50 psi H2,
NH4OH, Pd/C
O
N
O
N
Cbz
acid
or
base
OH HN
N
HN
40% for 3 steps
45
N
Cbz
Scheme 4.

6372
C. S. Burgey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6368–6372
17. Coe, J. W. Org. Lett. 2000, 26, 4205; attempts to make this target by a Heck
spirocyclization led instead to the 6-endo-trig byproduct v.
14. Wu, J.; Wu, H.; Wei, S.; Dai, W.-M. Tetrahedron Lett. 2004, 45, 4401. Produced a
4: 1 mixture of product: SM.
15. Attempts to affect the desired cyclization from i instead produced 5-exo-trig
product ii.
O
O
O
SEM
N
CbzN
NSEM
CbzN
CbzN
N
NSEM
N
Pd(OAc)2
O
O
SEM
N
Cy2MeN
Pd[P(t-Bu)3]2
SEM
N
N
Br
iii
N
EtN3, PPh3
60%
Cbz
N
Cbz
N
N
iv
v
Br
Dioxane
50 o
C
6-endo-trig
Undesired product only
ii
i
16. Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.