An efficient route to xanthine based A2A adenosine receptor antagonists and functional derivatives

Article abstract of DOI:10.1039/c003382k

A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A_2A adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

Full text of DOI:10.1039/c003382k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An efficient route to xanthine based A2A adenosine receptor antagonists and
functional derivatives†
Paul LaBeaume, Ma Dong, Michail Sitkovsky, Elizabeth V. Jones, Rhiannon Thomas, Sara Sadler,
Amy E. Kallmerten and Graham B. Jones*
Received 22nd February 2010, Accepted 24th June 2010
First published as an Advance Article on the web 23rd July 2010
DOI: 10.1039/c003382k
A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and
carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family
of A2A adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented
including a pro-drug variant, and application to related image contrast agents developed.
Nonetheless, using 0.6 equivalents of BDMS very high yields of
the product xanthines 5 are attainable, suggesting the BDMS is
regenerated during the cycle. Under closer scrutiny, DMSO, Me2S,
HBr and H2O can all be detected during the reaction. DMSO,
Introduction
Due to pathway interactions between A2A and D2 receptors,
antagonists of the adenosine receptor have become major targets
in CNS drug discovery.1 Lead compounds based on the xanthine
formed either directly through oxidative elimination from 2 with
skeleton, including the chlorostyryl caffeine CSC,2 the thienylated
BDMS or via attack of Me2S by in situ generated HOBr, can be
xanthine DMPTX,3 and the dimethoxystyryl xanthine KW-6002
reconverted to BDMS by reaction with HBr/Br2/H2O. Me2S and
have been investigated.4 Based on promising results obtained
HBr could in turn be released by BDMS in facilitating dehydro-
genation of aminal 4, either through collapse of an N-bromo inter-
mediate, or via bromide induced dehydrogenation, with the aminal
C–H departing as hydride to capture the bromonium ion of the
R
with co-administration of levodopa, KW-6002 (Istradefyllineꢀ),
is a clinical candidate for Parkinson’s disease.5 Several annula-
tion strategies have been explored in the construction of the
xanthine backbone, most commonly via disconnection to the
BDMS. Clearly, the intricacies of the process warrant further in-
corresponding amino-acylaminouracil,6 or closure of the 6-amino-
vestigation and thorough kinetic analysis, given the high efficiency
5-iminouracils, typically utilizing oxidative methods.7
of the method. The process proved amenable to a broad range
of substrates (Chart 1), and requires only trivial purification of
products 5.
Results and discussion
The utility of the bromo-substituted products for subsequent
transformations was readily demonstrated through Pd mediated
coupling to give analogs 7 and 9 (Scheme 2). Given the ease
of coupling we were motivated to investigate the potential for
in situ tandem ring closure and bromination, and after some
effort determined that utilization of 1.6 equivalents of the reagent
(0.5 for 4 h then and additional 1.1 eq. for 10 h) effected conversion
of p-methoxy benzaldehyde and salicylaldehyde into 10 and 11
respectively. The utility of the phenolic functionality was further
Given the importance of the xanthine class we became interested
in developing a one-pot method through direct coupling of
carboxaldehydes with readily available 5,6-diaminouracils 1 under
mild conditions.8
Under stoichiometric conditions, simple aldehydes coupled with
1 to produce high yields of xanthines 5 presumably via the imine
intermediate 3 and/or its aminal form 4 (Scheme 1).9 Attempts
to isolate presumed intermediates 2 and 4 were unsuccessful
but at 10 mol% BDMS substantial buildup of imine 3 occurs.
Scheme 1 BDMS accelerated condensation in synthesis of the xanthine
core
Department of Chemistry and Chemical Biology, Northeastern University,
Boston, MA., USA 02115. E-mail: gr.jones@neu.edu; Fax: (+)1 617
3738795
† Electronic supplementary information (ESI) available: Experimen-
tal procedures, structural proofs, NMR of the products. See DOI:
10.1039/c003382k
Scheme 2 Pd coupling and in situ dehydration-aryl bromination en route
to functionalized xanthines
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Chart 1 Xanthines accessible via BDMS route
Scheme 4 Fluorodenitration route to potential labeled PET imaging
agents
In addition to use in CNS disorders, KW-6002 has shown
promise as an antitumoral agent, but suffers from poor water
solubility in vivo.14 Accordingly we sought to synthesize a hy-
drophilic variant in the form of a prodrug, as the hydrophobic
xanthine core imparts A2A receptor affinity.15 After consideration,
a tetrapeptide substrate for the enzyme legumain was designed,
being the only asparaginyl endopeptidase of the mammalian
genome, and over expressed in neoplasms.16 Alkylation and O-
demethylation of substrate 21 allowed phenolic coupling of 23
with the boc protected tetra-peptide 24 (Scheme 5).17 A series of
enzymatic digests were examined on substrate 25, which gave clean
conversion to alanine conjugate 26 within 5 h. This promising
prodrug, which presumably does not cross the blood brain barrier
effectively is now the subject of extensive in vitro and in vivo
antitumoral assays.
Scheme 3 Application of BDMS methodology to synthesis of KW-6002.
demonstrated through conversion to 12 and 13, and the bromo
group through Suzuki coupling of 12 to produce 14 (Scheme 2).
Microwave accelerated conditions to expedite the ring closing
process were also investigated, 4-bromobenzaldehyde reacting
(CEM Discover, 150 W, 110 ◦C, 100 psi, CH3CN) to produce
the corresponding xanthine in 72% yield within 30 min. This
result bodes well for the application of the method for the rapid
production of libraries of xanthine derivatives under automated
conditions.10
In order to demonstrate the effectiveness of our approach, we
conducted a comparative synthesis of KW-6002 (18, Scheme 3)
from 1. As can easily be seen the direct route to key intermediate 17
is superior, and opens the prospect of targeted library design for the
class. Given the importance of the KW-6002 agents in modulating
CNS related pathways, methods to allow in vivo imaging will likely
become of significance. A route to a 11C labeled version has been
reported,11a and given its time-to-peak plasma concentration of
2–5 h,11b a suitably functionalized 18F labeled derivative would
presumably offer considerable utility in extended PET imaging
studies of this class of agent.11c
Conclusions
In summary, a direct route to the xanthine class of adenosine
receptor antagonists has been developed. The process is efficient,
scalable, and can be applied to versatile and diverse library
construction. In the case of aryl aldehyde substrates tandem in
situ bromination of the products is an effective adaptation of
the process, and promises to extend the versatility in the form of
heavily substituted xanthine derivatives. Potential use of xanthine
derived A2A antagonists for in vivo imaging and as antitumorals
may be facilitated by synthesis of derivatives bearing radiolabels
and enzyme substrates, using additional methodology outlined
herein.
To demonstrate proof-of-principle, nitrosubstituted xanthine 19
was N-methylated then subjected to microwave accelerated fluoro-
denitration using anhydrous TBAF giving appreciable quantities
of 20 in <10 min (Scheme 4).12
Given the half life of 18F (120 min), we expect cyclotron derived
18F variants of this process to be useful in preparation of agents
for direct PET imaging of KW-6002.13
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Scheme 5 Preparation and functionalization of xanthine prodrug conjugates.
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Representative experimental procedure
Synthesis of 8-(5-bromo-2-hydroxyphenyl)1,3-diethyl-1H-purine-
2,6(3H,7H)-dione
(Bromodimethyl)sulfonium bromide (0.879 g, 4.0 mmol) was
added (in two portions) to a mixture of p-methoxybenzaldehyde
(0.3053 g, 2.5 mmol) and 1,3,-diethyl-5,6-diaminouracil (0.495 g
2.5 mmol) in acetonitrile (5 mL). The reaction mixture was stirred
at room temperature for 14 h. The precipitate formed was collected
by vacuum filtration, washed with ethyl acetate and dried in vacuo.
The crude solid was purified by recrystallization from DMSO
and water to yield the title compound (0.66 g, 73%) as a white
solid m.p. 315–317 ◦C; TLC (dichloromethane–methanol = 19 : 1):
Rf 0.30; 1H NMR (500 MHz, d6-DMSO): d 13.80–14.20 (brs, 1H),
11.75–12.10 (brs, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.5,
2.5 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.08 (q, J = 7.5 Hz, 2H), 3.96
(q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.5 Hz,
3H); 13C NMR (125 MHz, d6-DMSO): d 156.6, 154.4, 150.7,
150.6, 148.1, 135.1, 129.7, 120.2, 118.0, 115.3, 111.3, 55.6, 39.2,
36.7, 13.9; HRMS (ESI) m/z calcd for C15H16BrN4O3 (M+H)+:
379.0406, found, 379.0401.
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4155–4157 | 4157
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