Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine

Article abstract of DOI:10.1021/acs.orglett.5b02921

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi-Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.

Full text of DOI:10.1021/acs.orglett.5b02921

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor
Antagonist for Treating Migraine
Guanglin Luo,* Ling Chen, Charles M. Conway, Walter Kostich, John E. Macor, and Gene M. Dubowchik
Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
S
* Supporting Information
ABSTRACT: An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-
927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi−
Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral
center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered
heterocycles as exemplified by pyrazine and thiazole derivatives.
igraine is a painful, incapacitating disease that affects a
Mlarge portion (12%) of the adult population and imposes
a substantial economic burden on society (estimated to be $13
billion per year).1 Calcitonin gene-related peptide (CGRP) is
thought to play a causal role in migraine and may act via
multiple mechanisms including pain transmission, neurogenic
inflammation, and/or neurogenic vasodilation.2 As current
standard of care, the triptan class of 5-HT1B/1D receptor
agonists actively constrict the dilated cranial arteries associated
with a migraine and relieve migraine coincident with a
reduction in CGRP levels.3 However, triptans are also
associated with a number of unpleasant, and potentially
dangerous, cardiovascular side effects due to their nonselective
smooth muscle vasoconstriction.4 Because CGRP receptor
antagonists block cranial vessel dilation, they are devoid of
these undesirable cardiovascular effects of triptans and are
Figure 1. CGRP receptor antagonists.
emerging as new therapeutics for the effective treatment of
migraine.5
An oral CGRP receptor antagonist, telcagepant (MK-0974)6
(1, Figure 1), showed positive results in several phase II and
phase III trials but was discontinued following a migraine-
preventative study.7 A recent publication from our laboratory
disclosed the potent, oral CGRP receptor antagonist, BMS-
846372, containing a cyclohepta[b]pyridine core (2, Figure 1),
that was an attractive preclinical lead.8 Poor aqueous solubility
of 2 (<2 μg/mL) led us to install a primary amine in 3 (BMS-
927711/rimegepant, Figure 1), which had even better potency
and much improved aqueous solubility (50 μg/mL).9 In a
phase II clinical trial, compound 3 showed efficacy comparable
to sumatriptan (Imitrex, 100 mg), but without the significant
cardiovascular side effects associated with sumatriptan.10 We
wanted to further explore this core structure with other
heterocycles such as pyrazine 4a and thiazole 4b, keeping the
spatial relationship of the pyridine sp2 nitrogen, which is a
critical pharmacophore for CGRP receptor affinity (Figure 1).
Attempts to prepare 4a in a manner analogous to the
synthesis of 2 and 38,9,11 failed. Indeed, heterocycle-fused
cycloheptane ring systems are rare in the literature.12
A
retrosynthetic analysis of target 4 is shown in Scheme 1 using
the precedented carbamate formation from the alcohol
5.8,9,11,13 For the synthesis of 5, we envisioned a key Heck
cyclization at the position next to the heterocyclic nitrogen to
afford 6, which left a double bond for generation of the alcohol
through the ketone intermediate. The Heck substrate 7, a chiral
amine intermediate, could be generated in a diastereoselective
Received: October 8, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b02921
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Letter
obtained in 20% yield. However, higher reaction temperatures
intended to effect better conversion gave 14 as the main
product instead. For example, when the reaction was run at 100
°C for 20 h, 49% of 14 and only 13% of 6a were obtained.
Further optimization failed to improve the yield of 6a for
enough material to proceed.
Scheme 1. Retrosynthetic Analysis for 4
An alternative route for the Heck reaction to work is shown
in Scheme 3. Compound 13 was converted to the α,ß-
unsaturated ester 15 under standard reaction conditions with
Grubbs II catalyst.24 With the ester group in place, Heck
cyclization could be run at higher temperatures (160 °C under
microwave heating, 2 h) to effect the best conversion to the
desired 17 (major product in 54% yield) with a smaller amount
of the isomerized product 16 (24% yield). Ozonolysis of 17 led
to the ketone 18 in 66% yield. Reduction of 18 by NaBH4
afforded the two easily separable diastereomeric alcohols 5a and
19 in good yield. Coupling of 5a with compound 20 under the
previously reported conditions,11 followed by TFA-mediated
Boc removal, gave the desired carbamate 4a.
fashion from a chiral sulfinamide intermediate 9. The
counterpart anion nucleophile 8 could be generated from a
halogenated heterocycle. The sulfinamide 9 came from the α-
aryl aldehyde 10 which had to be prepared enantioselectively
and was expected to be prone to epimerization.
We also decided to prepare the corresponding urea analogue.
Thus, alcohol 19 was converted to the key intermediate amine
21 in 77% overall yield as shown in Scheme 4 through
Mitsunobu reaction with phthalimide, followed by treatment
with hydrazine. However, 21 failed to react with 20 or our
previous activated carbamate.8,13 In the end, the carbamoyl
chloride 24 was freshly prepared from 23, which was in turn
synthesized from 22 in three steps. Under these conditions,
formation of the urea proceeded smoothly in 61% yield. A
minor side product in which the SEM group transferred to the
oxygen was also generated in 13% yield.25 Removal of both Boc
and SEM groups by TFA afforded the urea analogue 25 in 55%
yield.
With this route successfully established, we applied it to the
synthesis of the thiazole analogue 4b as shown in Scheme 5.
Starting with 2,4-dibromothiazole, we hoped that the 2-Br
substituent could be retained to the end of the sequence as a
handle for further functionalization. However, the 2-Br
derivative of 27 was not well-behaved in the Heck cyclization.
Hence, 2-Br was removed in one pot by lithium−halogen
exchange after the lithiation of 2,4-dibromothiazole by LDA26
and addition of 9 to generate compound 7b as the major
diasteeromer. Removal of the sulfinyl group followed by Boc
protection afforded compound 26, which was converted to
acrylate 27 as described above. Under the conditions used for
the pyrazine 15, Heck cyclization yielded a majority of the
undesired endocyclic alkene 28 (2:1 over the desired isomer
29). For this synthesis, we discovered that the aldehyde 10 that
had been used to prepare 9 had partially epimerized during
One proven approach to establish a chiral aryl center is the
Hayashi−Miyaura Rh-catalyzed arylboronic acid addition to a
nitroalkene.14 In the asymmetric synthesis of 1, 2,3-
difluorophenylboronic acid was added successfully to an α-
unsubstituted nitroalkene with good diastereoselectivity.15 We
were able to apply the reported conditions15 to our synthesis of
12 as shown in Scheme 2. Nitroalkene 11 was prepared in 72%
yield from 5-pentenaldehyde with nitromethane using
tetramethylguanidine (TMG) as catalyst and followed by
addition of methansulfonyl chloride and triethylamine to effect
the elimination of nitro alcohol.15 Compound 12 was then
prepared in 96% yield using the reported conditions.15 The Nef
reaction16 was successfully optimized to convert the nitroalkane
to the desired aldehyde 10, which was directly used in the next
reaction without noticeable epimerization.17 Enantiomerically
pure (R)-(+)-2-methyl-2-propanesulfinamide reacted18 with 10
to afford 9 in 73% yield from 12 with good diastereomeric ratio
(>93:7 dr) as evidenced by 1H NMR. Diastereoselective
reaction of 9 with lithiated 2-bromopyrazine19 went smoothly
to afford mostly 7a in 62% yield (∼9:1 dr by H NMR ).
Several attempts at Heck cyclization of 7a under mild
conditions gave no product, while temperatures higher than
120 °C21 caused decomposition of the sulfinyl group.
Consequently, a protecting group swap with Boc was carried
out using HCl in dioxane22 and Boc anhydride, giving 13 in
92% yield. The minor diastereomer was easily removed by flash
column chromatography at this stage. With 13, a series of
conditions for Heck cyclization were screened. Under the
conditions shown in Scheme 2,23 the desired product 6a was
20 18b
1
Scheme 2. Enantioselective Synthesis of 13 and Attempted Heck Cyclization
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DOI: 10.1021/acs.orglett.5b02921
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Scheme 3. Heck Cyclization and Synthesis of 4a
Scheme 4. Synthesis of 25
Scheme 5. Asymmetric Synthesis of 4b
storage (∼25% wrong diastereomer in 9). Consequently,
compounds 7b, 26, 27, 28, and 29 each consisted of two
inseparable diastereomers in a 3:1 ratio, as evidenced by H
Scheme 6. Synthesis of 4c
1
NMR analysis.25 After ozonolysis of 29, the undesired minor
diastereomer was finally removed by flash column chromatog-
raphy from ketone 30 (58% yield plus 20% diasteromeric
ketone). After NaBH4 reduction, the desired major alcohol 5b
was obtained in 58% yield, which was carried on to 4b in good
yield. Using a recently reported trifluoromethylation reaction,27
we were able to convert 5b to 31 in 24% yield, which led to
analogue 4c as shown in Scheme 6.
Binding affinities for the new CGRP receptor antagonists
were determined by inhibition of 125I-CGRP binding to SK-N-
MC cell membranes, which endogenously express the
receptor.28 Binding data for compounds tested is shown in
Table 1. Urethanes 4a, 4b, and 4c all showed CGRP receptor
binding activities that were comparable to those of 2 (BMS-
846372) and rimegepant 3. The urea analogue 25, compared to
4a, had 10-fold lower potency, which, however, was comparable
to telcagepant 1. Further profiling of these new compounds
showed them to be inferior to 3 in terms of metabolic stability.
C
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(10) Marcus, R.; Goadsby, P. J.; Dodick, D.; Stock, D.; Manos, G.;
Fischer, T. Z. Cephalalgia 2014, 34, 114.
(11) Leahy, D. K.; Fan, Y.; Desai, L. V.; Chan, C.; Zhu, J.; Luo, G.;
Chen, L.; Hanson, R. L.; Sugiyama, M.; Rosner, T.; Cuniere, N.; Guo,
Z.; Hsiao, Y.; Gao, Q. Org. Lett. 2012, 14, 4938.
(12) The cycloheptapyrazine ring system exists in the natural product
dragmacidin E. See: (a) Capon, R. J.; Rooney, F.; Murray, L. M.;
Collins, E.; Sim, A. T. R.; Rostas, J. A. P.; Butler, M. S.; Carroll, A. R. J.
Nat. Prod. 1998, 61, 660. (b) Cutignano, A.; Bifulco, G.; Bruno, I.;
Casapullo, A.; Gomez-Paloma, L.; Riccio, R. Tetrahedron 2000, 56,
3743.
Table 1. hCGRP Ki Data
compd
hCGRP Ki (nM)
rimegepant
0.027 0.001
0.056 0.011
0.55 0.094
0.048 0.011
0.065 0.011
4a
25
4b
4c
In summary, we have developed a novel asymmetric
synthesis of select heterocyclic analogues of the CGRP receptor
antagonist rimegepant 3. These showed binding affinity against
the CGRP receptor that was comparable to the rimegepant.
Our approach to the novel core structures featured a 7-
membered ring intramolecular Heck cyclization in which the
critical location of the double bond was achieved by addition of
an ester group. The aryl chiral center was constructed by a
variant of the Hayashi−Miyaura reaction, and the amine chiral
center was obtained by Ellman chiral sulfinamide chemistry in a
diastereoselective reaction with nucleophiles generated by
lithiation of bromo heterocycles.
(13) Luo, G.; Chen, L.; Civiello, R.; Pin, S. S.; Xu, C.; Kostich, W.;
Kelley, M.; Conway, C. M.; Macor, J. E.; Dubowchik, G. M. Bioorg.
Med. Chem. Lett. 2012, 22, 2917.
(14) (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(b) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716.
(15) 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.
(16) (a) Nef, J. U. Liebigs Ann. Chem. 1894, 280, 263. (b) Noland, W.
E. Chem. Rev. 1955, 55, 137.
(17) The Nef reaction (steps 1 and 2) afforded, in addition to 10, the
dimethyl acetal as the major product which could be recovered after
the next sulfinamide reaction and deprotected by TFA in CHCl3/H2O
to generate 10. The best approach was to directly treat the crude Nef
reaction product with TFA and use the freshly prepared 10 in the
following sulfinamide reaction. On one occasion when 10 was left
under house vacuum overnight and used, it was found to be partially
epimerized as evidenced in compound 9 as a mixture of two
diastereomers. However, partially epimerized 10 could be used as
diastereomers could be separated at later stage. See the Supporting
Information for details.
(18) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278. (b) Cheng, L.; Liu, L.; Sui, Y.; Wang,
D.; Chen, Y. Tetrahedron: Asymmetry 2007, 18, 1833.
(19) Decrane, L.; Ple, N.; Turck, A. J. Heterocycl. Chem. 2005, 42,
509.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02921.
Experimental procedures and characterization of all
intermediates and products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*Phone: 203-677-6640. Fax: 203-677-7702. E-mail: guanglin.
luo@bms.com.
Notes
(20) Both racemic 9 and 7a were prepared for references. See the
Supporting Information for details.
(21) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8, 4775.
(22) (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12.
(b) Jiang, W.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C. W.;
Arellano, L. M.; White, N. S.; Tucci, F. C. J. Org. Chem. 2005, 70,
8924.
(23) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(24) Giguere, D.; Patnam, R.; Juarez-Ruiz, J. M.; Neault, M.; Roy, R.
Tetrahedron Lett. 2009, 50, 4254.
The authors declare no competing financial interest.
REFERENCES
■
(1) Hu, X. H.; Markson, L. E.; Lipton, R. B.; Stewart, W. F.; Berger,
M. L. Arch. Intern. Med. 1999, 159, 813.
(2) Durham, P. L. N. Engl. J. Med. 2004, 350, 1073.
(3) Goadsby, P. J.; Edvinsson, L. Ann. Neurol. 1993, 33, 48.
(4) Tfelt-Hansen, P.; De Vries, P.; Saxena, P. R. Drugs 2000, 60,
1259.
(5) Karsan, N.; Goadsby, P. J. Curr. Neurol. Neurosci. Rep. 2015, 15,
25.
(6) Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, J.
Z.; Kane, S. A.; Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston,
V. K.; Wong, B. K.; Miller-Stein, C. M.; Hershey, J. C.; Graham, S. L.;
Vacca, J. P.; Williams, T. M. J. Med. Chem. 2007, 50, 5564.
(7) (a) Hewitt, D. J.; Martin, V.; Lipton, R. B.; Brandes, J.; Ceesay,
P.; Gottwald, R.; Schaefer, E.; Lines, C.; Ho, T. W. Headache 2011, 51,
533. (b) Tfelt-Hansen, P. Headache 2011, 51, 118. (c) Merck recently
discontinued the development of telcagepant: http://www.
healthcentral.com/migraine/c/202/142294/telcagepant-merck.
(8) Luo, G.; Chen, L.; Conway, C. M.; Keavy, D.; Denton, R.;
Kostich, W.; Mercer, S.; Schartman, R.; Signor, L.; Lentz, K.;
Browning, M.; Macor, J. E.; Dubowchik, G. M. ACS Med. Chem.
Lett. 2012, 3, 337.
(25) See the Supporting Information for details.
(26) (a) Athmani, S.; Bruce, A.; Iddon, B. J. Chem. Soc., Perkin Trans.
1 1992, 215. (b) Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36,
9293.
(27) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.;
Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98.
(28) Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D.;
Davis, C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench,
P.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L.; Thalody, G.;
Widmann, K. A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. J. Med. Chem.
2008, 51, 4858.
(9) Luo, G.; Chen, L.; Conway, C. M.; Denton, R.; Keavy, D.; Signor,
L.; Kostich, W.; Lentz, K. A.; Santone, K. S.; Schartman, R.; Browning,
M.; Tong, G.; Houston, J. G.; Dubowchik, G. M.; Macor, J. E. J. Med.
Chem. 2012, 55, 10644.
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DOI: 10.1021/acs.orglett.5b02921
Org. Lett. XXXX, XXX, XXX−XXX