Caprolactams as potent CGRP receptor antagonists for the treatment of migraine

Article abstract of DOI:10.1016/j.bmcl.2007.06.062

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Replacements for the benzodiazepine core of an earlier lead structure 1 including 5-, 6-, and 7-membered lactams were explored. Within the 7-membered ring scaffold

Full text of DOI:10.1016/j.bmcl.2007.06.062

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4795–4798
Caprolactams as potent CGRP receptor antagonists
for the treatment of migraine
Anthony W. Shaw,a,* Daniel V. Paone,a Diem N. Nguyen,a Craig A. Stump,a
Christopher S. Burgey,a Scott D. Mosser,b Christopher A. Salvatore,b Ruth Z. Rutledge,b
Stefanie A. Kane,b Kenneth S. Koblan,b Samuel L. Graham,a
Joeseph P. Vaccaa and Theresa M. Williamsa
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA
bDepartment of Pain Research, Merck Research Laboratories, West Point, PA 19486, USA
Received 18 May 2007; revised 13 June 2007; accepted 18 June 2007
Available online 26 June 2007
Abstract—Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Replacements for the ben-
zodiazepine core of an earlier lead structure 1 including 5-, 6-, and 7-membered lactams were explored. Within the 7-membered ring
scaffold, phenyl substitution at various positions afforded the potent (3R)-amino-(6S)-phenyl caprolactam template. The phenylim-
idazolinone privileged structure gave additional potency enhancements, as 24 showed good potency in both CGRP binding
(Ki = 2 nM) and cAMP (IC50 = 4 nM) assays and was orally bioavailable in rats (27%).
Ó 2007 Elsevier Ltd. All rights reserved.
Migraines are episodic headache attacks usually lasting
4–72 h which can be accompanied by nausea and sensi-
tivity to light and sound.1 It is estimated that 13% of the
general population suffer from this condition.2 The cur-
rent gold standard for the treatment of migraine is the
class of 5-HT1B/1D agonists known as triptans. However,
these compounds are contraindicated in patients with
cardiovascular disease due to their direct vasoconstric-
tive effect.3 Development of a migraine drug that does
not cause direct vasoconstriction would have significant
therapeutic value.
of the triptan class of compounds without any cardio-
vascular side effects.7 Based on these studies our pro-
gram sought to identify potent, orally bioavailable,
non-peptide small molecule CGRP receptor antagonists
for the treatment of migraine.
Previously we have reported the identification and SAR
of a novel series of benzodiazepines as non-peptide
CGRP receptor antagonists.8 These compounds con-
sisted of an N-alkyl 3-aminobenzodiazepine linked
through a urea bond to a variety of GPCR privileged
structures. While compound 1 (Fig. 1) had good activity
in the CGRP binding assay (Ki = 55 nM), it suffered
from poor oral bioavailability (4% in rats). In general,
these benzodiazepine derivatives displayed poor phar-
macokinetic profiles. Thus we sought to replace the ben-
zodiazepine core with alternate scaffolds to improve
physicochemical properties and oral bioavailability.
Calcitonin gene-related peptide (CGRP) is a 37 amino
acid neuropeptide present in the CNS and periphery,4
with physiological functions that include nociception,
vasodilation, and neurogenic inflammation.5 Increased
levels of CGRP are observed during a migraine attack
and IV administration of CGRP can induce migraine
in migraineurs.6 In a clinical trial, infusion of a selective,
small molecule CGRP receptor antagonist demon-
strated relief of migraine headache pain similar to that
One strategy pursued was to successively remove the
two aryl groups in 1 to arrive at the 7-membered ring
core. To investigate the effect of the pendant phenyl
ring, fused caprolactam 2 was prepared. This compound
exhibited a substantial loss in potency9 compared to
benzodiazepine 1 in both the CGRP binding assay and
the cAMP cell-based functional assay.10 Further simpli-
fication by removal of the fused phenyl ring gave
Keywords: CGRP; CGRP receptor antagonist; Migraine;
Caprolactam.
*
Corresponding author. Tel.: +1 215 652 1097; fax: +1 215 652
7310; e-mail: Anthony_Shaw@merck.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.062

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A. W. Shaw et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4795–4798
9-fold less active then the cis enantiomers 13 in the
O
CGRP binding assay (Table 1). Separation of the
racemic cis mixture 13 showed that all the activity
was associated with just one of the enantiomers (14
and 15).13 Replacement of the N-t-butyl acetate group
with the cyclopropylmethyl group in 16 resulted in a
small improvement in potency and was utilized for
all subsequent SAR studies. Within the 6-phenyl
substituted analogs the racemic trans mixture 18 was
22-fold more active than the racemic cis mixture 17
in the CGRP binding assay. Interestingly, this repre-
sents a reversal in the more active configuration be-
tween the 6 and 7-substituted phenyl caprolactams,
possibly due to the phenyl ring occupying a pseudo-
equitorial site on the caprolactam ring for optimal po-
tency. After separation of the trans diastereomers (19
and 20), it was again found most of the CGRP bind-
ing affinity resided in one trans enantiomer (3R,6S) 20
with a Ki = 25 nM.13
N
NH
O
N
N
O
N
NH
1
human Ki = 55 nM
cAMP IC50 = 65 nM
O
O
N
N
NH
O
NH
O
3
2 (racemic)
human Ki = 3.7 μM
cAMP IC50 = 3.1 μM
human Ki = 7.8 μM
cAMP IC50 = 2.4 μM
Figure 1. Effect of phenyl group removal.
caprolactam 3, prepared from Boc-D-Lys.11 Although
another potency loss was observed, we were encouraged
that such a simplified structure as 3 retained activity in
both assays.
The synthesis of both the 6- and 7-substituted phenyl
caprolactams was carried out using a modification of
the procedure described by Yanagisawa.14 A representa-
tive synthesis of a 6-phenyl caprolactam is shown in
Scheme 1. Treatment of lactam 9 with sodium hydride
and cyclopropylmethyl bromide gave the N-alkylated
caprolactam selectively. Bromination with phosphorus
pentachloride and bromine was followed by displace-
ment with sodium azide to give 10 as a 3:1 trans/cis mix-
ture. The azide was hydrogenated with 10% palladium
on carbon to the primary amine which underwent
smooth urea formation with p-nitrophenyl chlorofor-
mate and the dihydroquinazolinone privileged structure
(8)15 to yield 11 as a mixture of four compounds which
were separated by chromatography.16
With the dramatic change to the 7-membered ring core,
we next explored different lactam ring sizes. The 5-, 6-,
and 7-membered analogs (4–7, Fig. 2) were prepared
and tested as individual enantiomers.11,12 The (R) enan-
tiomer 4 was found to be approximately 6-fold more ac-
tive than the (S) enantiomer 5. Additionally the (R)
enantiomer analogs of the 5-membered lactam 6 and
6-membered lactam 7 lost considerable potency relative
to the corresponding 7-membered compounds. We
therefore focused our subsequent efforts on the (3R)-
amino caprolactam template, attempting to build back
potency by reincorporating phenyl substitution around
the caprolactam ring.
The 5-phenyl substituted caprolactams required a
slightly different synthetic route (Scheme 2). Using the
Aube variation of the Schmidt rearrangement,17 4-phe-
nyl cyclohexanone 21 was treated with cyclopropylmeth-
yl azide and TiCl4 to give 22. Bromination followed by
displacement with azide and hydrogenation gave 23 as
a 1:1 mixture of cis and trans diastereomers.
Preparation of the various 7-phenyl caprolactam ster-
eoisomers revealed that the trans enantiomers 12 were
O
O
H
N
Due to sensitivity toward oxidative decomposition of
the benzylic methylene on the dihydroquinazolinone,18
alternate privileged structures19 were examined to im-
prove chemical stability. The most potent (3R,6S) phe-
nyl caprolactam was chosen as a screening template
and it was found that coupling with benzodiazepinone
A and triazolinone B gave compounds (25 and 26) that
were equipotent to the dihydroquinazolinone 20 (Table
2). Importantly, the derivatives were more stable relative
to compound 20. Utilization of phenylimidazolinone C
gave 24, which resulted in a 10-fold potency increase
in both CGRP binding (Ki = 2 nM) and cAMP
(IC50 = 4 nM) assays.
H
N
N
N
R
R
O
O
5
4
human Ki = 1.8 μM
human Ki = 11.1 μM
O
N
O
O
N
NH
R
R
N
H
O
7
6
human Ki = 46%@ 100 μM
human Ki = 63% @ 100 μM
Having established a correlation with the newer privi-
leged structures, the racemic 5-phenyl caprolactams
were coupled with triazolinone B (27 and 28) and found
to be substantially less active than the corresponding
6-phenyl caprolactams (Table 2). Interestingly, the
R =
N
N
NH
O
8
Figure 2. Effect of ring size and stereochemistry.

A. W. Shaw et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4795–4798
Table 1. Potencies of 6- and 7-substituted phenyl caprolactams
4797
R1
N
O
R2
R3
3
NH
O
6
N
N
O
NH
d
cAMP IC50 (nM)
Compound
R1
R2
R3
Stereoa
Kib,c (nM)
12
13
14
15
16
17
18
19
20
t-Butyl acetate
t-Butyl acetate
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
H
H
H
H
H
H
trans racemic
cis racemic
cis (3S,7S)
16950
1993
>10,000
934
—
2118
471
—
t-Butyl acetate
t-Butyl acetate
cis (3R,7R)
cis (3R,7R)
cis racemic
trans racemic
trans (3S,6R)
trans (3R,6S)
Cyclopropylmethyl
Cyclopropylmethyl
Cyclopropylmethyl
Cyclopropylmethyl
Cyclopropylmethyl
689
695
408
778
54
Phenyl
Phenyl
Phenyl
Phenyl
H
31
H
5828
25
6626
36
H
a Stereochemistry at aryl substituted position of caprolactam ring.
b Values are means of at least two determinations.
c Inhibition of [125I]-CGRP binding to native human CL–receptor/RAMP1 membranes.
d Inhibition of CGRP-stimulated cAMP production in native human E10 cells.
O
H
N
O
O
N
1. NaH, c-PrCH2Br
N
NH
O
N3
2. Br2, PCl5, I2 (cat.)
3. NaN3
N
N
N
NH
O
9
10
1
human Ki = 55 nM
cAMP IC50 = 65 nM
O
N
1. H2, Pd/C
NH
O
O
2. ClCO2C6H4NO2
privileged structure
N
N
N
O
O
NH
NH
O
NH
N
N
11
24
Scheme 1. 6-Phenyl caprolactam synthesis.
human Ki = 2 nM
cAMP IC50 = 4 nM
rat %F = 27
O
Figure 3. Evolution of caprolactam.
O
N
O
N
1. Br2, PCl5, I2 (cat.)
2. NaN3
N3
TiCl4
NH2
3. H2, Pd/C
availability in rats (F = 27%) with moderate clearance
(36 mL/min/kg).20
In conclusion, the 5-, 6-, and 7-substituted phenyl capro-
lactams were synthesized and examined as benzodiaze-
pine replacements, with the trans (3R)-amino-(6S)-
phenyl caprolactam scaffold consistently providing the
most activity in both the CGRP binding and cAMP as-
says. Replacement of the dihydroquinazolinone privi-
leged structure with the phenylimidazolinone provided
an additional 10-fold potency increase, resulting in 24
with Ki = 2 nM. A reduction in molecular weight was
achieved by removal of the fused phenyl group of the
benzodiazepine which may have contributed to an
increase in oral bioavailability (27%).21 With these
changes we have identified a new series of caprolactams
derived from benzodiazepine lead 1, which have paved
the way for a new series of orally bioavailable CGRP
receptor antagonists.
21
22
23
Scheme 2. 5-Phenyl caprolactam synthesis.
potency difference between the trans and cis diastereo-
mers was less dramatic at only 2-fold. Once again use
of the phenylimidazolinone privileged structure in-
creased potency 10-fold (29 and 30). Though potent
(Ki = 17 nM), the racemic trans diastereomers 30 are
still 9-fold less potent than 24. An even larger discrep-
ancy is seen in the cAMP assay, where 30 is approxi-
mately 35-fold less potent. Therefore, of the phenyl
caprolactams examined, we concluded that the 6-phenyl
caprolactam was the most favorable replacement for the
benzodiazepine core of 1 (Fig. 3). Compound 24 was
further characterized and found to have good oral bio-

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A. W. Shaw et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4795–4798
Table 2. Potencies of 5- and 6-substituted caprolactams with different GPCR privileged structures
O
N
O
O
O
NH
NH
NH
N
R3
=
N
N
3
NH
O
6
N
R3
R1
N
B
C
R2
R1
A
d
cAMP IC50 (nM)
Compound
R2
R3
Stereoa
Kib,c (nM)
25
26
24
27
28
29
30
Phenyl
Phenyl
Phenyl
H
H
H
H
A
B
C
B
B
C
C
trans (3R,6S)
trans (3R,6S)
trans (3R,6S)
cis racemic
29
29
32
45
2
4
Phenyl
Phenyl
Phenyl
Phenyl
544
266
35
3821
488
133
141
H
trans racemic
cis racemic
trans racemic
H
H
17
a Stereochemistry at aryl substituted position of caprolactam ring.
b Values are means of at least two determinations.
c Inhibition of [125I]-CGRP binding to native human CL–receptor/RAMP1 membranes.
d Inhibition of CGRP-stimulated cAMP production in native human E10 cells.
11. Amblard, M.; Daffix, I.; Berge, G.; Dodey, P.; Pruneau,
D.; Paquet, J.-L.; Luccarini, J.-M.; Belichard, P.; Marti-
nez, J. J. Med. Chem. 1999, 42, 4193.
12. For experimental details, see: Burgey, C. S.; Paone, D. V.;
Shaw, A. W.; Williams, T. M. WO 2004/091514.
13. The stereochemistry was assigned based upon the benzo-
diazepine (3R)-amino group being the preferred configu-
ration for CGRP binding (see reference 8).
Acknowledgments
We thank the West Point Department of Medicinal
Chemistry mass spectroscopy, analytical chemistry,
NMR analysis and animal dosing groups, as well as
the Department of Drug Metabolism for their
assistance.
14. Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.;
Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi, K.; Mats-
ushita, Y.; Hata, T. J. Med. Chem. 1988, 31, 422.
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