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O
O
O
a
b
OH
CO
2
Et
O
O
O
CHO
H
H
CO
2
Et
O
O
OH
14
S
15
O
O
16
O
O
O
BzO
c
F
d
e
O
H
BzO
F
CO
2
Et
OH
18
17
NH
2
NHBz
N
N
f
N
N
O
O
BzO
HO
O
O
BzO
HO
F
F
19
PSI-6130
Scheme 11.2
Reagents: (a) Ph
3
PC(Me)CO
2
Et, DCM, -40 1C; then KMnO
4
, acetone,
0 1C; (b) SOCl
2
, TEA, DCM, 0 1C; then aq. NaOCl, TEMPO,
NaHCO
3
, MeCN, 0 1C; (c) TEAF, dioxane, 100 1C; then (MeO)
2
CMe
2
,
conc. HCl, dioxane, RT; (d) EtOH, conc. HCl, RT; then BzCl, pyridine,
RT; (e) Li(OBu
t
)
3
AlH, THF, -20 1C; then Ac
2
O, DMAP, -20 1C; then
silylayed N
4
-Bz-cytosine (prepared from N-benzoylcytosine, NH
4
SO
4
,
hexamethyldisilazane, reflux), SnCl
4
, PhCl, RT to 65 1C; (f) NH
3
,
MeOH, RT.
420% and was subsequently used to produce multikilogram quantities of
PSI-6130.
24
11.3 The Prodrug RG7128
11.3.1 From PSI-6130 to RG7128
PSI-6130 was progressed into clinical studies after demonstrating an excep-
tional safety profile in preclinical toxicology assessments. In the Phase I single
ascending dosing study to assess safety, tolerability, and PK, PSI-6130 was
given orally at doses of 500, 1500, and 3000mg QD as a solution in grape juice.
The compound was well tolerated at all doses, and no adverse events were
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