Bisphosphonate prodrugs: synthesis of new aromatic and aliphatic
1-hydroxy-1,1-bisphosphonate partial esters
Maelle Monteil,
a
Erwann Guenin,
a
Evelyne Migianu,
a
Didier Lutomski
b
and Marc Lecouvey
a,
*
a
Laboratoire de Chimie Structurale Biomole
´
culaire BIOMOCETI (UMR 7033-CNRS), UFR S.M.B.H. Universite
´
Paris 13. 74,
Rue Marcel Cachin, F-93017 Bobigny Cedex, France
b
Laboratoire de Biochimie des Prote
´
ines et Prote
´
omique EA 3408, UFR S.M.B.H. Universite
´
Paris 13. 74, Rue Marcel Cachin,
F-93017 Bobigny Cedex, France
Received 8 March 2005; revised 16 May 2005; accepted 18 May 2005
Available online 15 June 2005
Abstract—Methods for the preparation of various 1-hydroxy-1,1-bisphosphonate partial esters were developed. They were obtained from
(alkyl or phenyl) bis(trimethylsilyl) phosphite and aromatic or aliphatic acid chlorides, followed by methanolysis.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
1-Hydroxymethylene-1,1-bisphosphonic acids (HMBP) are
an important class of drugs used clinically in the treatment
of bone diseases involving excessive bone destruction or
resorption such as Paget’s disease, osteoporosis and bone
metastases.
1,2
They are also routinely used as
99
Tc
complexes in skeletal scintigraphy. They are structural
analogues of natural pyrophosphates containing a P–C–P
backbone and so are stable to enzymatic hydrolysis. More
recently, bisphosphonates have been used for treatment of
metastatic cancer. It has been shown that these compounds
were able to inhibit bone metastases proliferation in prostate
or breast cancer.
3–5
They also inhibit experimental
angiogenesis in vitro and in vivo.
2,6–8
In addition, HMBP
have also activity against several trypanosomatid and
apicomplexan parasites.
9,10
Unfortunately, the bio-availability of HBMP’s is very poor
because of their strong hydrophilicity and their negative
charges due to their high ionization at physiological pH
values. These properties characterize poor cell membrane
permeability. Moreover, they also have powerful complexa-
tion properties towards calcium and other divalent metal
cations decreasing their gastro-intestinal absorption. As
such, only 3–7% of the drug is metabolized.
11
As the side
chain of HMBP is responsible for most of the activity, the
modification of some of the phosphonic acid functions
should be a satisfying way to increase lipophilicity.
Masking groups for the negative charge, introduced as
phosphonoester, could be an interesting approach for a
prodrug strategy. Few studies about the design of bispho-
sphonate prodrugs have been reported in the literature.
12–14
Only a few reports with phosphonoesters prodrugs
15,16
but such
a modification is widely used in phosphate chemistry.
17,18
Synthesis of 1-hydroxymethylene-1,1-bisphosphonate is
usually achieved from condensation of a trialkylphosphite
on an acid chloride leading to an a-ketophosphonate which
then reacts with a dialkyl phosphite.
19–21
Different
improvements of this method were proposed. Burgada et
al.
22–24
described a one pot reaction between acid halides
and a mixture of trialkyl and dialkyl phosphites and Ruel et
al.
25
used anions of dialkyl phosphites to obtain directly the
bisphosphonate tetraesters, at low temperature. The main
drawback of these techniques are the thermal and basic
instability of bisphosphonate tetraesters that promote their
phosphonate–phosphate isomerisation.
26
Moreover the
regioselective dealkylation to obtain partial esters is difficult
and does not occur in good yield. Our group recently
proposed a very mild and one-pot synthesis to obtain
bisphosphonate methyl esters from bis(trimethylsilyl)-
methyl phosphite and acyl chloride.
27
Herein, we will present the extension of this synthesis to
various 1-hydroxymethylene-1,1-bisphosphonate diesters
using several alkyl or aryl substituents.
2. Results and discussion
Alkyl or arylbis(trimethylsilyl) phosphites 2 were obtained
Tetrahedron 61 (2005) 7528–7537
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.053
Keywords: Bisphosphonate; Arbusov reaction.
*
Corresponding author. Tel.: C33 0 148387709; fax: C33 0 0148387625;
e-mail: m.lecouvey@smbh.univ-paris13.fr