a process for the preparation of strontium ranelate
REVIEW OF LITERATURE
a process for the preparation of strontium ranelate or its hydrate by reacting a tetra ester
compound of formula I: where in R, R1, R2, and R3 is independently a linear or branched C1-C6
alkyl group or a substituted or unsubstituted C3-C12 cyclic group, in the presence of a lithium
base and in a solvent with an inorganic acid salt of strontium [31].
N
COOR
COOR 3
COOR 1 N
S
COOR 2
Formula: I
2.2 European patent 0415850 reported Strontium ranelate had prepared by heating at
reflux the ranelic acid with NaOH in an aqueous alcoholic medium & then distilling of the
ethanol & most of the water to isolate the tetra sodium salt form of the ranelate was precipitated,
now then the salt was reacted with Strontium Chloride in water to yield Strontium Ranelate
which is isolated by filtration. The yield obtained by this process is < 70% [32].
O +
O Na
OH N -
O N N
-
NaOH SrCl 2 O OC
O
HO + - O 2+
NaO Sr -
N COO
S N -
OH S - O OC N 2+
O O + S Sr
HO O + - Na -
Na O COO
O
O
2.3 Vaysee-ludot et al., 2009 reported that the preparation of strontium ranelate by reacting
ranelic acid and tetra hydro furan in a clean round bottom flask and then made to react with
aqueous solution of NaOH by stirring for 4-6 hours then of aqueous solution of SrCl2 and water
were added and stirred for 20 hours at 20-25oC and strontium ranelate was filtered out. The yield
obtained by this method was 93.8% [33].
+
O Na
-
O N
N
SrCl 2 -
O OC
+ - O
NaO 2+
Sr -
N TETRA HYDRO FURAN COO
S - -
O + O OC N 2+
O + - S Sr
Na O Na
-
COO
O
2.4 Vaysee-ludot et al., 2009 reported that the preparation of strontium ranelate by reacting
ranelic acid and acetone in a clean round bottom flask and then made to react with aqueous
solution of NaOH by stirring for 4-6 hours then of aqueous solution of SrCl2 and water were
added and stirred for 20 hours at 20-25oC and strontium ranelate was filtered out. The yield
obtained by this method was92.6% [34].
+
O Na
-
O N
N
SrCl 2 -
O OC
+ - O
NaO 2+
Sr -
N Acetone COO
S - -
O + O OC N 2+
O + - S Sr
Na O Na
-
COO
O
2.5 Vaysee-ludot et al., 2009 reported that the preparation of strontium ranelate by reacting
ranelic acid and Iso Propanol in a clean round bottom flask and then made to react with aqueous
solution of NaOH by stirring for 4-6 hours then of aqueous solution of SrCl2 and water were
added and stirred for 20 hours at 20-25oC and strontium ranelate was filtered out. The yield
obtained by this method was 94.8% [35].
+
O Na
-
O N
N
SrCl 2 -
O OC
+ - O
NaO 2+
Sr -
N ISO PROPANOL COO
S - -
O + O OC N 2+
O + - S Sr
Na O Na
-
COO
O
2.6 Vaysee-ludot et al., 2009 reported that the preparation of strontium ranelate by reacting
ranelic acid and Tetra hydro furan in a clean round bottom flask and then made to react with
aqueous solution of KOH by stirring for 4-6 hours then of aqueous solution of SrCl2 and water
were added and stirred for 20 hours at 20-25oC and strontium ranelate was filtered out. The yield
obtained by this method was 94% [36].
O +
O K
OH N -
O N
Tetra Hydro Furan N
-
KOH SrCl 2 O OC
O
HO + - O 2+
K O Sr -
N COO
S N -
OH S - O OC N 2+
O O + S Sr
HO O + - K -
K O COO
O
O
2.7 Lucile et al., 2007 reported that the Methyl 5-amino-4-cyano-3-(2-Methoxy-oxo ethyl)-2-
thiophene-carboxylate was prepared by using Dimethyl-3-oxo glutarate and malononitrle,
Sulphur. In that reaction Catalyst was used as Morpholine. Then K2CO3, Adogen464 & methyl
Bromo acetate added to stirr for 4-5 Hours to form Ranelic acid. Now took the dry Ranelic acid
and Strontium Hydroxide, water add to stirred and finaly heat to reflux and continue refluxing
whilst hot, washed the cake with bioling water and dry the powder. The yeild obtained is 96%
and the purity is 98% [37].
O
O
CH3 CH3 N
-
O O O OC
2+
Sr -
Morpholine - COO
O K2 CO3 , Andogen 464 NaOH,H 2 O, O OC N
S 2+
+ Methyl Bromo Acetate Sr(OH) 2 -
Sr
N COO
CH3 OH
N
2.8 B.V.shiva et al., 2007 reported that a mixture of tetrahydrofuran and 5-(bis-
ethoxycarbonylmethyl-amino)-4-cyano-3-methoxycarbonylmethyl-thiophene-2-carboxylic acid
ethyl ester and 1200 ml 10% aq. solution of lithium hydroxide monohydrate was stirred at room
temperature for about 3 to 4 hours in a round bottom flask. The reaction mass was filtered off to
remove any insoluble material. The clear filtrate was further distilled below 55°C to get oily
residue to which 250 ml of toluene was added and further distilled below 55°C to remove water
traces if any to get oily residue. Next, a mixture of methanol and ethyl acetate (2.5 liters; 1:1
mixture) was added to the oily residue and the reaction mass was stirred at 55°C to get a free
solid. The reaction mass was cooled under stirring at room temperature and a precipitate of the
lithium salt was formed. The precipitated solid of the lithium salt was filtered off and washed
with a mixture of methanol and ethyl acetate (250 ml; 1:1) to form a wet cake. The wet cake was
dried to yield 240 grams of the lithium salt [38].
N
+ O-OC
Li
-
+ O-OC
COO +
Li N Li
S
-
COO +
Li
2.9 Strontium Ranelate activity effect on the Serum insulin like Growth factor.
Ibrahim Gulhan.sibel Bilgilli et al., 2008 reported that the investigated the effects of
strontium Ranelate on Serum insulin like growth Factor-1, leptin and osteocalcin levels in
osteoporotic post menopausal woman. In this study they discussed the growing interest of bone
in agents which stimulates bone formation, such as growth hormone and insulin like growth
factor-1, which play an important role on metabolism, being essential for the development and
growth of the skeleton and for the maintenance of bone mass. Insulin like Growth factor-1 is a
7.6kDa, 70 amino acids residue peptide that mediates the action of growth hormone. Finally
Strontium ranelate increases the serum insulin growth factor-1 levels in osteoporotic post
menopausal women [39].
2.10 Strontium ranelate effect on the Gonadal steroids.
R P. Radzki et al., 2009 reported that the studies were aimed at determinatning of the
effect of strontium ranelate (SR) on the mineralization processes and selected parameters of
oxidative stress in orchidectomized rats during the development of osteopenia. Male Wistar rats
were sham-operated (SHO) and orchidectomized (ORX). ORX animals were divided into control
(ORX-C) and gavaged with SR (ORX-SR), at a dose of 900mg/kg/b.w. After 60 days the
animals were scanned for determination of bone mineral density (BMD) of the whole
skeleton.Isolated femora were examined by DEXA and pQCT. Tomographic measurements were
performed for a total slice and separately for the cortical and trabecular parts of the distal end of
the femora. The intensity of lipid peroxidation (ILP) and total antioxidant capacity (TAC) in
blood serum were measured. SR treatment increased vBMD and BMC of total, trabecular and
cortical bone in ORX rats compared to ORX-C and SHO rats. SR increased ILP by 21.3%, as
compared to SHO. SR improved densitometric and geometric parameters of femora by
orchidectomized rats what prevented degradation of bone tissue [40].
2.11 The Biological role of Strontium.
S.Pors Nielsen et al., 2004 reported that the review summarized old and more recent
literature on the biological role of the bone-seeking trace metal strontium (Sr). It covers areas of
chemistry, nutrition, toxicity, and transport across biological membranes, homeostasis, general
physiology, calcium–strontium interactions, and particularly the role of strontium in bone. The
promoting action of strontium on calcium uptake into bone at moderate strontium
supplementation, and the rachitogenic action of strontium at higher dietary strontium levels are
emphasized. The literature is summarized of the novel antiosteoporotic drug strontium ranelate,
which appears to act by a combination of reduced bone resorption and increased uptake of
calcium into bone [41].
2.12 Strontium Ranelate effect on the Nuclear Factor-κB Ligand
Axelle Caudrillier et al., 2010 reported that a new method for preparing salts of
metal cations and organic acids, especially divalent salts of alkaline earth metal ions from group
II of the periodic system and carboxylic acids. The method comprising the use of a high
temperature (about 90° or more) and, optionally. high pressure, in order to obtain a higher yield,
purity and faster reaction speed than obtained with known synthesis methods. It is Used as a
dominant-negative form of the calcium-sensing receptor (CaR) and a small interfering RNA
approach, They provided evidences that the inhibition of osteoclast differentiation by Sr2+ is
mediated by stimulation of the CaR [42].
2.13 Strontium Ranelate effect on the Calcium-sensing Receptor
Anne S. Hurtel-Lemaire et al., 2009 reported that the Stimulation of the CaR, Sr2+
induces mature osteoclast apoptosis in an IP3-independent but PLC-dependent Manner-DN-CaR
transfection of mature rabbit osteoclasts partially but significantly inhibited Sr2+ induced
Osteoclast apoptosis. DN-CaR-transfected osteoclast apoptosis was reduced by about 36%
compared with that observed in β-galactosidase transfected cells cultured for 48 h in the presence
of 20 mM Sr2+. Notably, because wild type CaR homodimers would be unaffected by the DN-
CaR or because of non-CaR action(s) of the Sr2+ [43].
2.14 Strontium ranelate effect on the extracellular calcium-sensing receptor.
Coulombe et al., 2004 reported that the extracellular calcium-sensing receptor (CaSR) is
activated by divalent cations and may also mediate some of the effects of strontium ranelate, a
new drug for the prevention and treatment of post-menopausal osteoporosis. Here, They showed
that the maximal effect of Sr(2+) was comparable to that observed for Ca(2+) for both the cloned
rat CaSR expressed in Chinese hamster ovary [CHO(CaSR)] cells and the mouse CaSR
constitutively expressed in AtT-20 cells as measured by the accumulation of [(3)H]inositol
phosphates (IP) resulting from CaSR activation [44].
2.15 Strontium Ranelate effect on the Cation Sensing Receptor
Naibedya Chattopadhyay et al., 2007 reported that the Strontium ranelate has several
beneficial effects on bone and reduces the risk of vertebral and hip fractures in women with
postmenopausal osteoporosis. We investigated whether Sr2+ acts via a cell surface calcium-
sensing receptor (CaR) in HEK293 cells stably transfected with the bovine CaR (HEK-CaR) and
rat primary osteoblasts (POBs) expressing the CaR endogenously. Elevating Ca2+ or
Sr2+ concentration-dependently activated the CaR in HEK-CaR but not in non-transfected cells,
but the potency of Sr2+ varied depending on the biological response tested and reported [45].
2.16Strontium Ranelate effect on the WNT signalling pathway.
Mark S. Rybchyn et al, 2011 reported that the Sclerostin was an important regulator of
bone homeostasis and canonical Wnt signalling is a key regulator of osteogenesis. Strontium
ranelate is a treatment for osteoporosis that has been shown to reduce fracture risk, in part, by
increasing bone formation. Here we show that exposure of human osteoblasts in primary culture
to strontium, increased mineralization and decreased the expression of sclerostin, an
osteocytespecific secreted protein that acts as a negative regulator of bone formation by
inhibiting canonical Wnt signalling [46].
2.17 Strontium Ranelate effect on the MAPK pathway.
Fan yang et al., 2011 reported that the Strontium-containing hydroxyapatite was also
demonstrated to stimulate the osteoblast activity and inhibit the osteoclast activity. However, the
molecular mechanisms of strontium underlying such beneficial effects were still not fully
understood. In this study, they investigated the effects of strontium on the osteogenic
differentiation of human mesenchymal stem cells (MSCs) and its related mechanism; its
osteogenic potential was also evaluated using a calvarial defect model in rats. They found that
strontium could enhance the osteogenic differentiation of the MSCs, with upregulated
extracellular matrix (ECM) gene expression and activated Wnt/β-catenin pathway. After
transplanting the collagen-strontium-substituted hydroxyapatite scaffold into the bone defect
region, histology and computed tomography scanning revealed that in vivo bone formation was
significantly enhanced [47].
2.18 Strontium Ranelate effect on the NFAT pathway.
Fromigué O et al., 2010 reported that the antiosteoporotic treatment strontium ranelate
(SrRan) was shown to increase bone mass and strength by dissociating bone resorption and bone
formation. To identify the molecular mechanisms of action of SrRan on osteoblasts, they
investigated its effects on calcineurin-NFAT (nuclear factor of activated T cells) signaling, an
important calcium sensitive pathway controlling bone formation. Using murine MC3T3-E1 and
primary murine osteoblasts, they demonstrate that SrRan induces NFATc1 nuclear translocation,
as shown by immunocytochemical and Western blot analyses. Molecular analysis showed that
SrRan increased NFATc1 transactivation in osteoblasts, an effect that was fully abrogated by the
calcineurin inhibitors cyclosporin A or FK506, confirming that SrRan activates NFATc1
signaling in osteoblasts [48].
2.19 Strontium ranelate effect on the Alkaline Phosphatase.
Ray Sahelian et al., 2008 reported that the Strontium was used in the treatment of
osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as
isotope. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited
disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline
phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites-two for zinc,
one for magnesium, and one for calcium ion-that can be substituted by strontium. This has
functional implications because calcineurin inhibitors blunted the enhanced osteoblast replication
and expression of the osteoblast phenotypic markers Runx2, alkaline phosphatase, and type I
collagen induced by SrRan [49].
2.20 Strontium ranelate effect on the Bone Morphogenetic Protein Pathway.
I.R. Garrett et al., 2007 reported that the bone morphogenetic proteins (BMPs) clearly
played a central role in both bone cartilage formation and repair. Recent research into the
regulation of the BMP pathway had led to the discovery of a number of small molecular weight
compounds as candidate bone anabolic agents. These agents used in a new wave of more
innovative and versatile treatments for osteoporosis as well as orthopedic and dental indications
[50]
.
2.21 Strontium ranelate compare with PTH hormone.
Bjoern Habermann et al.,2006 reported that the treatment of strontium ranelate led to a
significant increase in callus resistance compared to the ovariectomized (OVX) control rats,
whereas both PTH 1-34 and strontium ranelate increased the bone volume/tissue volume ratio of
the callus [51].