Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

Article abstract of DOI:10.3762/bjoc.6.71

We report the synthesis of a novel analogue of Alogliptin via condensation of two key intermediates one of which is an aminopiperidine derivative bearing a spirocyclic ring on the piperidine moiety. Preparation of the aminopiperidine intermediate was carried out by constructing the cyclopropyl ring prior to assembling the piperidine ring.

Full text of DOI:10.3762/bjoc.6.71

Synthesis of a novel analogue of DPP-4 inhibitor
Alogliptin: Introduction of a spirocyclic moiety
on the piperidine ring
Arumugam Kodimuthali1,2, Padala Lakshmi Prasunamba2
and Manojit Pal*1,3
Preliminary Communication
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 71. doi:10.3762/bjoc.6.71
1New Drug Discovery, R&D Center, Matrix Laboratories Ltd, Anrich
Industrial Estate, Bollaram, Jinnaram Mandal, Medak District, Andra
Pradesh 502 325, India, 2Department of Chemistry, University
College of Science, Osmania University, Hyderabad 500 007, India
and 3Present address: Institute of Life Science, University of
Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra
Pradesh, India
Received: 24 April 2010
Accepted: 07 June 2010
Published: 01 July 2010
Associate Editor: J. A. Porco Jr
© 2010 Kodimuthali et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Manojit Pal* - manojitpal@rediffmail.com
* Corresponding author
Keywords:
Alogliptin; cyclopropyl ring; DPP-4; piperidine
Abstract
We report the synthesis of a novel analogue of Alogliptin via condensation of two key intermediates one of which is an amino-
piperidine derivative bearing a spirocyclic ring on the piperidine moiety. Preparation of the aminopiperidine intermediate was
carried out by constructing the cyclopropyl ring prior to assembling the piperidine ring.
Introduction
Inhibition of dipeptidyl peptidase-4 (DPP-4; CD26; E.C. nical use and Vildagliptin has been launched in Europe only.
3.4.14.5) by small molecules has emerged as one of the key Several other inhibitors are in various stages of development.
approaches for the treatment of type-2 diabetes [1-5]. DPP-4, a For example, Alogliptin or (2-[[6-[(3R)-3-amino-1-piperidinyl]-
member of the prolyl oligopeptidase family of serine protease, 3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-
cleaves the N-terminal dipeptide from peptides with proline or benzonitrile) (A, Figure 1), a potent (IC50 < 10 nM) and
alanine in the second position. A large number of DPP-4 inhibi- selective inhibitor (selectivity > 10,000 over DPP-8 and 9) is
tors have been reported in the literature [6,7] including NVP- currently being evaluated in phase 3 clinical trials [8-10]. This
LAF237 (Vildagliptin), MK-0431 (Sitagliptin) and BMS- compound was identified by replacing the quinazolinone moiety
477118 (Saxagliptin). Presently, Sitagliptin is available for cli- of another inhibitor B with a pyrimidine dione (Figure 1) [8].
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Beilstein J. Org. Chem. 2010, 6, No. 71.
Figure 1: Design of a new DPP-4 inhibitor (C) based on Alogliptin (A) and other inhibitors (B).
All these inhibitors that belong to the non-peptidomimetic class tions of the spiro derivative 9a. Preparation of 9a can be carried
contain an aminopiperidinyl moiety which interacts with the out following two strategies e.g. construction of cyclopropyl
DPP-4 enzyme through salt bridges. As part of our ongoing ring on piperidine moiety (Strategy 1) or vice versa (Strategy
drug discovery program we sought to prepare a novel DPP-4 2). While the use of first strategy for the preparation of 9a has
inhibitor of structure C (Figure 1) bearing a spirocyclic ring on been reported in the literature [11], application of other strategy
the piperidinyl moiety. Our aim was to study the effect of this is not common. Initially, we attempted to synthesize the com-
structurally modified piperidinyl moiety on the interaction of C pound 9a from N-Boc protected piperidone 9b (PG = Boc) by
with DPP-4 enzyme. To the best of our knowledge this type of the reported method [11] based on C-alkylation. Surprisingly,
Alogliptin analogue has not yet been explored. Herein we report introduction of a cyclopropyl group at the position α to the
an efficient synthesis of compound C starting from readily piperidine carbonyl group with 2-chloroethyl dimethyl sulph-
available starting materials and reagents.
onium iodide did not work well in our hands. Other methods,
e.g., the use of 1,2-dibromoethane in the presence of various
bases such as NaH, CH3ONa or KO t-Bu at different tempera-
tures was also examined but failed to afford the desired product.
This prompted us to develop an alternative but more effective
method based on strategy 2 (Figure 2) for the synthesis of com-
pound 9 (R = Boc). Apart from our own requirements, we noted
that substituted piperidine derivatives containing spirocyclic
ring have a wide range of therapeutic effects, namely, as
Angiotensin Converting Enzyme (ACE) inhibitors [11], anti-
bacterial agents [12-15], Janus kinase 3 (JAK3) inhibitors [16],
Calcitonin-Gene Related Peptide (CGRP) modulators [17] etc.
Our synthesis of compound 9 (R = Boc) is shown in Scheme 1.
Results and Discussion
A retro synthetic analysis of compound C indicates that the key
step would involve the condensation of two key intermediates,
i.e., the piperidinyl derivative 9 and the appropriately substi-
tuted 6-chloro uracil derivative 11 (Figure 2). The intermediate
9 in turn could be synthesized via functional group manipula-
Commercially available ethyl cyanoacetate and 1,2-dibromo-
ethane was used to construct the appropriately functionalized
cyclopropyl ring (step i, Scheme 1) via a conventional C–C
bond forming reaction. The reaction proceeded well to afford
the functionalized cyclopropane derivative 1 as a result of the
formation of two C–C bonds in a single step. Selective reduc-
tion of the cyano group of the resulting cyanoester 1 afforded
the corresponding amine 2 (step ii, Scheme 1) which on
Michael addition to methyl acrylate followed by N-protection
furnished the diester 4 (steps iii and iv, Scheme 1). The
N-protection step was necessary to avoid the undesirable par-
ticipation of the NH group in subsequent steps. A facile base
mediated intramolecular cyclization (Dieckmann reaction) [18]
of compound 4 provided the key piperidin-4-one ester 5 which
Figure 2: Strategy to prepare compound C (PG = protecting group).
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Beilstein J. Org. Chem. 2010, 6, No. 71.
Scheme 1: Reagents and conditions: (i) EtONa, BrCH2CH2Br, EtOH, reflux, 3.5 h (70% yield); (ii) Pd/C, MeOH, H2, RT, 4 h (93% yield); (iii)
CH2=CHCOOMe, THF, RT, 3 h (74% yield); (iv) ClCOOBn, TEA, DCM, 0–5 °C, 3 h (80% yield); (v) NaH, DMF, RT, 7 h (86% yield); (vi) NaCl, DMSO,
H2O, 110 °C, 7 h (76% yield); (vii) NH3 in EtOH, Ti(OPr)4, NaBH4, 12 h (67% yield); (viii) (Boc)2O, TEA, DCM, 0 °C, 2 h (70% yield); (ix) Pd/C, MeOH,
H2, RT, 4 h (85% yield).
on decarboxylation under Krapcho conditions [19] afforded the 1H NMR spectra of compound C indicated the presence of a
desired compound 6 (steps v and vi, Scheme 1). Reductive spiro cyclopropyl ring: the four cyclopropyl protons appeared as
amination of the ketone followed by Boc protection of the a series of four multiplets in the region δ 0.15–0.25, 0.30–0.40,
resulting amine 7 provided the compound 8 (steps vii and viii, 0.50–0.60 and 0.65–0.75, the vinylic proton of pyrimidine-2,4-
Scheme 1). Finally, deprotection of the secondary amine of dione moiety appeared as a singlet at δ 5.36, whilst two
compound 8 (step ix, Scheme 1) afforded the target interme- doublets at δ 5.11 and 5.23 were indicative of the benzylic
diate 9 which was used directly in the next step. It is worth methylene hydrogen atoms. This in conjunction with IR bands
noting that although a shorter synthesis of compound 6 or at 2230 and 1642 cm−1 for CN and amide carbonyl group,
similar derivative could be achieved starting from N-Boc respectively, characterized compound C.
protected piperidin-4-one [11,20], its preparation from ethyl
cyclopropanecarboxylate however, requires a longer synthetic Compound C was then tested for its ability to inhibit DPP-4
route or the tedious preparation of suitable starting materials enzyme in vitro at three concentrations, e.g., 1.0, 5.0 and 10.0
[21,22].
µM [24]. While significant inhibition of DPP-4 was observed at
these concentrations, compound C however, was found to be
With the piperidinyl intermediate 9 in hand, we then focused less potent than Alogliptin. Based on the interaction [8] of com-
our attention on the other intermediate 11, the preparation of pound B with the active site of DPP-4 (Figure 1) it was
which has been previously documented [23]. The reaction of predicted that (i) the cyanobenzyl group of compound C would
commercially available 6-chlorouracil with 2-(bromo- fill the S1 pocket (formed by V656, Y631, Y662, W659, Y666,
methyl)benzonitrile in the presence of NaH afforded the and V711) and interact with Arg125, (ii) the carbonyl at C-2
N-alkylated product 10 which on methylation with methyl would provide an important hydrogen bond to the backbone NH
iodide provided the target intermediate 11 (steps i and ii, of Tyr631 (Figure 3). Although the cyclopropyl ring could
Scheme 2). The chloro compound 11 was then reacted with the potentially occupy the nearby empty space to enhance the
amine 9 in the presence of NaHCO3 in a sealed tube to give the hydrophobic interactions with DPP-4, the required orientation
expected coupled product 12 (step iii, Scheme 2). Finally, of the aminopiperidine motif of C to form an effective salt
N-deprotection of compound 12 using trifluoroacetic acid bridge to Glu205/Gul206 was probably perturbed. This could be
(TFA) gave the target compound C as the TFA salt. The the reason for observed lower potency of C in comparison to
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Beilstein J. Org. Chem. 2010, 6, No. 71.
Scheme 2: Reagents and conditions: (i) NaH, LiBr, DMF - DMSO, 12 h (55% yield); (ii) NaH, LiBr, CH3I, DMF - THF, RT, 12 h (65% yield); (iii)
NaHCO3, DMSO, 100 °C, 2 h (40% yield); (iv) TFA, THF, RT, 2.5 h (85% yield).
Alogliptin in vitro. Nevertheless, to gain further insight we plan DPP-4 inhibitor Alogliptin. We believe that the present syn-
to conduct Structure-Activity-Relationship (SAR) studies for thesis could find application in the preparation of diverse
this class of compound that would eventually help to identify a aminopiperidine derivatives thereby facilitating the synthesis of
potential lead possessing favorable pharmacological properties. novel compounds of potential biological interest.
Supporting Information
Supporting Information File 1
Experimental procedures and spectral data
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-71-S1.pdf]
Acknowledgements
A. K. thanks the management of Matrix Laboratories Ltd,
Hyderabad, India for continuous support and encouragement.
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Figure 3: Predicted interactions of compound C with DPP-4.
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