Modular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers

Article abstract of DOI:10.1016/j.bmcl.2013.03.114

A novel approach to the synthesis of substituted piperazines and their investigation as N-type calcium channel blockers is presented. A common scaffold exhibiting high activity as N-type blockers is N-substituted piperazine. Using recently developed titanium and zirconium catalysts, we describe the efficient and modular synthesis of 2,5-asymmetrically disubstituted piperazines from simple amines and alkynes. The method requires only three isolation/purification protocols and no protection/deprotection steps for the diastereoselective synthesis of 2,5-dialkylated piperazines in moderate to high yield. Screening of the synthesized piperazines for N-type channel blocking activity and selectivity shows the highest activity for a compound with a benzhydryl group on the nitrogen (position 1) and an unprotected alcohol-functionalized side chain.

Full text of DOI:10.1016/j.bmcl.2013.03.114

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3257–3261
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Modular, efficient synthesis of asymmetrically substituted piperazine
scaffolds as potent calcium channel blockers
Andrey Borzenko a, Hassan Pajouhesh b, Jerrie-Lynn Morrison b, Elizabeth Tringham b, Terrance P. Snutch c,
Laurel L. Schafer a,
⇑
a Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1
b Zalicus Pharmaceuticals Ltd, 301-2389 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
c Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of substituted piperazines and their investigation as N-type calcium
channel blockers is presented. A common scaffold exhibiting high activity as N-type blockers is N-substi-
tuted piperazine. Using recently developed titanium and zirconium catalysts, we describe the efficient
and modular synthesis of 2,5-asymmetrically disubstituted piperazines from simple amines and alkynes.
The method requires only three isolation/purification protocols and no protection/deprotection steps for
the diastereoselective synthesis of 2,5-dialkylated piperazines in moderate to high yield. Screening of the
synthesized piperazines for N-type channel blocking activity and selectivity shows the highest activity for
a compound with a benzhydryl group on the nitrogen (position 1) and an unprotected alcohol-function-
alized side chain.
Received 26 January 2013
Revised 23 March 2013
Accepted 27 March 2013
Available online 4 April 2013
Keywords:
N-type calcium channel
L-type calcium channel
Titanium catalysis
Zirconium catalysis
Substituted piperazines
Ó 2013 Elsevier Ltd. All rights reserved.
Voltage-gated calcium (Ca2+) channels play important physio-
logical roles ranging from the control of cellular excitability and
muscle contraction to the release of neurotransmitters and hor-
mones. Based upon biophysical and pharmacological criteria, there
are four distinct subtypes of high voltage-activated Ca2+ channels
(L-, N-, P/Q- and R-types) and a further class of low voltage-acti-
vated channels (called T-type).1 Of note concerning pain process-
ing, in the primary afferent nociceptive pathway N-type Ca2+
channels are located at a subset of terminals in the dorsal horn
of the spinal cord where they play a crucial role in the release of
pro-nociceptive neurotransmitters and neuropeptides.2 As such,
the N-type Ca2+ channel is particularly interesting as a clinical tar-
get and over the past two decades there has been considerable
interest in generating selective N-type channel blockers aimed at
the inhibition of spinal neurotransmitter release and the attenua-
Some of the most common scaffolds that have shown promise
for developing N-type channel blockers are N,N0-disubstituted
piperazines (Fig. 1).6 Piperazine itself as well as 2,5-dimethylpiper-
azine are symmetric, commercially available, inexpensive com-
pounds, which makes their synthetic elaboration for medicinal
chemistry attractive. Furthermore, by varying chemical and physi-
cal properties aimed at the N-type channel target, preferred com-
pounds have substituents on both nitrogens, which historically
has resulted in highly lipophilic compounds.7 More recent achieve-
ments have illustrated the favorable impact of asymmetrically
substituted 2-methylpiperazines.6c For example, Figure 2 shows a
compound that is active for N-type channel blockade and notably
more selective over the L-type Ca2+ channel and hERG potassium
channel than its unmethylated analog.6c These results illustrate
that without investigating the effect of varied substituents on the
piperazine scaffold, significant limitations remain in exploring
molecular and functional diversity within this class of promising
compounds.
2,5-Unsymmetrically disubstituted piperazines can be accessed
via reduction of related diketopiperazines, and several of such ami-
no acid derived products are presently commercially available.8
While well-established, their syntheses are typically achieved
using commercially available amino acids and their derivatives
(e.g., 2-aminoalcohols9 and 1,2-diamines10). Most of these syn-
thetic approaches result in substantial waste generation due to
requisite sequential protection/deprotection steps11 and/or the
tion of afferent pain signals.3
x-Conotoxin MVIIA and its synthetic
analog Ziconotide (PrialtÒ) were the first described selective
N-type Ca2+ channel blockers for pain intervention, although their
use clinically is restricted to intrathecal administration due to their
polypeptidic structure.4 There has been a subsequent concerted ef-
fort to design and synthesize small molecules that are selective for
the N-type Ca2+ channel in order to provide both state-dependent
blockade and oral availability.5
⇑
Corresponding author.
E-mail address: schafer@chem.ubc.ca (L.L. Schafer).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.114

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A. Borzenko et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3257–3261
efficient route into a variety of heterocycles.16 Most importantly,
R'
N
R'
N
R'
N
this catalyst is tolerant to a number of functional groups that
R'''
may be incorporated into aminoalkene substrates.17
N
N
N
By combining these two hydroamination technologies into an
efficient approach for the synthesis of 2,5-substituted piperazines,
we recently disclosed the facile preparation of a number of hetero-
cycles.17 Scheme 1 illustrates our synthetic approach. The first
three steps are conducted in a one-pot fashion to complete: (a) reg-
ioselective hydroamination in the presence of a titanium cata-
lyst,15a (b) the addition of trimethylsilyl cyanide to the imine18
and (c) substitution of the TMS group with a benzyl or benzhydryl
R''
R''
R''
Commonly used
piperazine scaffolds
This work
Figure 1. Comparison of piperazine scaffolds.
Target of this research
F
derivative. After the purification of the a-aminonitriles the second
O
O
N
N
reaction is the reduction of the cyano group to the primary
amine.19 Finally, to complete the piperazine core, intramolecular
and diastereoselective hydroamination of the N-containing amin-
oalkene is performed using zirconium catalyst B.16,17
(CH2)3
O
F
This efficient and modular approach toward the synthesis of cis-
unsymmetrically substituted pure piperazines provides the oppor-
tunity to prepare classes of previously undescribed compounds for
biological screening. Moreover, piperazines furnished from this
route contain an unsubstituted nitrogen, which may potentially re-
duce lipophilicity to result in Ca2+ channel blockers with more
favourable physiochemical characteristics. Alternatively, the
Figure 2. Lead compound of a previous generation of piperazines.6c
use of stoichiometric amino acid coupling reagents.12 Alterna-
tively, the Ugi reaction, an efficient multi-component coupling
reaction, can be used to rapidly assemble the precursor diketopi-
perazines. Unfortunately, the products of this reaction are mixtures
of diastereomers that require further purification.13 Here we show
that recently developed group 4 metal hydroamination catalysts
can be used for the atom-economic and diastereoselective synthe-
sis of 2-alkyl-5-methyl-substituted piperazines from simple, com-
mercially available alkyne and amine starting materials. By
unsubstituted nitrogen may be
functionalization.
a site for further selective
N-type and L-type Ca2+ channel blocking affinities were deter-
mined using HEK cells stably co-expressing either the rat brain
CaV2.2 N-type complex or the rat cardiac CaV1.2 L-type complex
together with the Kir2.3 potassium channel. A high-throughput
FLIPR assay was performed using the fluorescent Ca2+ indicator
dye, Fluo-4, and with each compound examined by an 8 point con-
combining a one-pot reaction to access the requisite
a-aminoni-
trile intermediates, followed by reduction and then catalytic ring
closure via hydroamination, such unsymmetrically substituted
piperazines can be prepared with only 3 isolation/purification pro-
tocols and no protection/deprotection steps.14 Most importantly,
the 2-alkyl substituent can be derived from a broad range of termi-
nal alkynes ensuring that this protocol is not limited to amino
acids. This modular synthetic approach from readily available
starting materials has allowed for the investigation of previously
unexplored piperazine scaffolds as N-type channel blockers.
We have been interested in the development of efficient early
transition metal hydroamination catalysts for applications in or-
ganic synthesis. The combination of low toxicity and low cost of
these reactive metals make them attractive for use in the prepara-
tion of pharmaceuticals. Our previous work resulted in the devel-
opment of a very efficient titanium bis(amidate) precatalyst A
(Scheme 1), exclusively providing aldimines from a variety of com-
mercially available terminal alkynes and amines.15
centration-dependent response profile (0.003–10 lM). Membrane
potential and channel state were controlled via altering the exter-
nal potassium ion concentration.14,20,21
Initial investigations focused on the use of phenylacetylene as a
starting material, which resulted in a benzyl group in the 2-posi-
tion of the piperazine core (Scheme 1, R1 = Ph). These benzylmeth-
ylpiperazines were screened against the N-type and L-type Ca2+
channels (Table 1). Overall, the N-type blocking affinities and
selectivity against the L-type channel of both N,N0-disubstituted
and N-monosubstituted piperazines were generally unfavorable,
with the best compound being the benzhydryl-N-monosubstituted
piperazine (compound 6).
Due to the low activity of the 2-benzylpiperazines we next took
advantage of our modular protocol to vary position 2 of the piper-
azine core, while comparing benzyl and benzhydryl groups as
N-substituents (Table 2). These changes could be easily achieved
with the method described here, starting from commercially avail-
able alkynes to easily introduce variable substituents into position
2 (Scheme 1). The screening focused on the N-monosubstituted
piperazines based upon the preferred profile of compound 6 and
indeed showed improved N-type blocking activity (e.g., compound
11) although selectivity against the L-type channel was only
modest.
This second step of our screening confirmed that changing the
substitution pattern from N,N0-disubstituted to N-monosubsti-
tuted and thus significantly varying the overall molecular geome-
try (Fig. 3) could potentially lead to more active compounds.
Furthermore, piperazines with a hydrogen bonding functionality
in position 2 (compounds 7 and 11) are the most active. Once
again, benzhydryl substituent (compounds 10 and 11) as compared
to the benzyl group (compounds 7–9) yields piperazines that are
more potent inhibitors.
Other recent investigations have led to the development of a
zirconium precatalyst
B with a tethered bis(ureate) ligand
(Scheme 1).16 Intramolecular diastereoselective Markovnikov
hydroamination of aminoalkenes with this catalyst provides an
N
O
N
NMe
O
2
Ph
Ti(NEt2)2
N
N
2
Zr NMe2
[Ti] cat
A
[Zr] cat
O
HNMe2
B
N
R2
N
R2
N
A
1) 5 mol% [Ti] cat.
2) TMSCN
R1
R1
4) LAH
R1
5) 10 mol%
[Zr] cat. B
3) R2Br, NaF
15-crown-5
H2N
CN
N
H
One-Pot Reaction
In a final series we examined N-benzhydryl piperazines with
the hydrogen bonding substituents at varying distances from the
piperazine core. This was easily achieved by using starting materi-
Scheme 1. General scheme for efficient and modular synthesis of 2,5-asymmetri-
cally substituted piperazines from simple alkynes and amines.

A. Borzenko et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3257–3261
3259
Table 1
N-type and L-type calcium channel blocking affinities for compounds 1–6
Structure
CH2Ph
N-type IC50
(l
M)
L-type IC50
10.0
(lM)
L/N ratio
1.2
Yielda (%)
HN
N
8.37
75
66
64
1
F
CH2Ph
N
O
S
F3C
N
10.0
10.0
10.0
ND
1.0
—
O
2
F
Ph
CH2Ph
N
Ph
N
O 3
F
CH2Ph
10.0
10.0
4.34
10.0
10.0
1.78
1.0
1.0
0.4
82
76
32
HN
N
Ph
4
CH2Ph
N
O
S
O
F3C
N
Ph
5
CH2Ph
Ph
N
HN
Ph
6
ND = not determined.
a
Overall isolated yield using alkyne as the limiting reagent.
Table 2
N-type and L-type calcium channel blocking affinities for compounds 7–11
Structure
N-type IC50
(l
M)
L-type IC50
3.34
(lM)
L/N ratio
0.7
Yielda (%)
21
Ph
TBSO
N
4.85
7
N
H
Ph
N
9.84
10.0
2.40
1.07
9.23
5.6
0.9
0.6
0.7
1.4
44
24
21
23
8
N
H
Ph
N
9
N
H
Ph
Ph
N
1.78
1.53
N
H
Ph
10
Ph
TBSO
N
11
N
H
a
Overall isolated yield using alkyne as the limiting reagent.
als of varying chain lengths in the protected alcohol alkyne starting
material. To verify that piperazines with a free N–H functionality
are preferred even when another hydrogen bonding site is incorpo-
rated in the compound, various N0-substituents were reevaluated.
As observed in Table 3, shortening the protected alcohol chain
as well as introduction of the substituent on the second nitrogen,
did not enhance the activity of any of the screened piperazine
derivatives over compound 11. However, it is noteworthy that in

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A. Borzenko et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3257–3261
R1
N
N
N
N
H
N,N´-disubstituted
N-monosubstituted
Figure 3. New direction in the development of substituted piperazines.
Table 3
N-type and L-type calcium channel blocking affinities for compounds 12–15
Structure
N-type IC50
(
lM)
L-type IC50
6.8
(lM)
L/N ratio
0.7
Yielda (%)
23
Ph
Ph
Ph
Ph
N
TBSO
10.0
12
13
N
H
N
N
TBSO
TBSO
2.6
4.7
5.1
8.2
2.0
1.7
1.0
18
20
19
Tos
Ph
Ph
N
14
N
Tos
Ph
Ph
TBSO
N
10.0
10.0
15
N
(p-F3CC6H4)O2S
Overall isolated yield using alkyne as the limiting reagent.
a
the case of a shorter protected alcohol chain (compounds 12 and
13) the N-substituent makes the piperazine a more potent N-type
channel blocking compound. Furthermore, it was noted that
changing the N0-substituent from a tosyl group to a fluorinated
derivative resulted in a reduction in N-type channel blocking activ-
ity (compounds 14 and 15).
Under the assay conditions employed, alcohol deprotection may
be a concern. Thus, in order to probe the difference between pro-
tected and deprotected alcohols, compounds 16 and 17 were pre-
pared and tested (Fig. 4). Deprotected alcohols are less lipophilic
and potentially may provide improved physiochemical properties
compared to previously synthesized substituted piperazines.6
Indeed, one of the TBS-deprotected piperazines (16, Fig. 4)
affinity, an approximate six-fold selectivity over the L-type channel
and a 12-fold state-dependent preference for the N-type channel
inactivated state over the N-type closed state (not shown).
In summary, a novel catalytic approach to the synthesis of
asymmetrically substituted piperazines has shown significant
synthetic potential. The method exhibits good substrate scope,
high yields and excellent diastereoselectivity allowing for the
generation of a focused library of potential Ca2+ channel block-
ers. The functional screening of a series of novel asymmetrically
substituted piperazines revealed (1-benzhydryl-5-methylpipera-
zin-2-yl)butan-1-ol (compound 16) to exhibit sub-micromolar
N-type channel blocking affinity, state-dependence and promis-
ing selectivity over the L-type Ca2+ channel. This contribution
highlights a modular synthetic approach for the efficient prepa-
ration of previously undescribed piperazines suitable for biolog-
ical screening.
showed sub-micromolar (IC50 = 0.85
lM) N-type channel blocking
Ph
Ph
Ph
N
Acknowledgments
HO
N
HO
The authors gratefully thank Zalicus Pharmaceuticals Ltd for
support in the biological screening assays. Work in the laboratory
of L.L.S. is supported by the Natural Sciences and Engineering
Research Council of Canada, and in the laboratory of T.P.S. by
an operating Grant from the Canadian Institutes of Health
Research /ce:grant-sponsor> (#10677). L.L.S. is a Canada Research
16
N
H
17
N
H
N-type IC50 = 0.85 µM
L-type IC50 = 5.40 µM
N-type IC50 = 9.60 µM
L-type IC50 = 10.0 µM
Figure 4. Deprotected alcohol substituted piperazines.

A. Borzenko et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3257–3261
3261
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Chair in Catalyst Development and T.P.S. a Canada Research Chair
in Biotechnology and Genomics-Neurobiology.
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Supplementary data
Supplementary data associated with this article can be found, in
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