Chemical Properties
Pale Beige Solid
Uses
Bazedoxifene acetate has been used to study its efficacy in inhibiting the interleukin-6 (IL-6)/IL-6R/glycoprotein 130 pathway and its effects on medulloblastoma cells.
Uses
Bazedoxifene Acetate is a nonsteroidal selective estrogen receptor modulator (SERM). Bazedoxifene Acetate is used as an antiosteoporotic.
Biological Activity
bazedoxifene, a novel selective estrogen receptor modulator (serm), has been developed to have favorable effects on bone and the lipid profile while minimizing stimulation of uterine or breast tissues. two large phase iii
Biochem/physiol Actions
Bazedoxifene is a third generation nonsteroidal selective estrogen receptor modulator (SERM), used clinically to treat postmenopausal osteoporosis. Bazedoxifene binds to estrogen receptor-α with IC50 = 26 nM, similar to that of raloxifene, but lower affinity than 17-β estradiol. Bazedoxifene did not stimulate proliferation of MCF-7 cells, instead inhibited 17β -estradiol-induced proliferation with IC50 = 0.19 nM, exhibiting a desirable profile of agonist/antagonist activity.
Clinical Use
The selective estrogen receptor modulator bazedoxifene acetate was approved in Spain for the treatment
of osteoporosis in postmenopausal women. The drug was discovered by Wyeth (now Pfizer) and
licensed to Almirall. Clinical trials with bazedoxifene along with conjugated estrogens
demonstrated significant improvement in bone mineral density and prevented bone loss in
postmenopausal women without osteoporosis. It also reduces fracture risks among women with
postmenopausal osteroporosis.
Synthesis
Among many syntheses reported for this drug, the most
recent process scale synthesis (multi-kg scale) is highlighted and involves the union of azepane
ether 9 and indole 12. 4-Hydroxybenzyl alcohol (6) was converted in two steps to chloride 9 (the Scheme). The reaction of 6 with 2-chloroethyl azepane hydrochloride (7) in a biphasic mixture of sodium
hydroxide and toluene in the presence of tetrabutylammonium bromide (TBAB) gave the desired
intermediate alcohol 8 in 61% yield. Treatment of 8 with thionyl chloride (SOCl2) gave the requisite
chloride 9 in 61% yield. The reaction of 2-bromopropiophenone (10) with an excess of 4-benzyloxy
aniline hydrochloride (11) in the presence of triethylamine (TEA) in N,N-dimethylformamide (DMF) at
elevated temperatures resulted in indole 12 in 65% yield. Alkylation of 12 with benzylchloride 9 in the presence of sodium hydride (NaH) afforded N-alkylated compound 13. The benzyl ether functionalities
from compound 13 were removed via hydrogenolysis and subsequently subjected to acidic conditions,
providing diol 14 as the hydrochloride salt in 91% yield. The hydrochloride was then exchanged for the
acetate via free base preparation with 5% sodium bicarbonate or triethylamine, followed by treatment
with acetic acid giving bazedoxifene acetate (II) in 73¨C85% yield.
