Chemistry Reference
In-Depth Information
Table 4.10 Mouse and rat iv and oral pharmacokinetics of PQIP and AQIP.
a
Compound
PQIP
AQIP
Route of administration
Species
Mouse
Rat
Mouse
Rat
Dose (mg kg
1
)
iv
10
5
5
1
T
1/2
(h)
5
20
5.1
19.9
V
ss
(L kg
1
)
8
21
10.0
14.0
Cl (mLmin
1
kg
1
)
19
16
24
10
Dose (mg kg
1
)
Oral
25
20
25
50
C
max
(mM)
2.2
1.35
3.4
1.6
C
24h
(mM)
1.04
0.74
0.4
0.9
T
1/2
(h)
23.6
28.7
N/A
N/A
AUC
0
N
(ng hmL
1
)
34546
28705
25582
37429
%F
100
100
100
38
a
Cl
¼
clearance, V
ss
¼
volume of distribution at steady state, t
1/2
¼
elimination half-life, C
max
¼
maximum measured plasma concentration, C
24h
¼
plasma concentration at 24 h, AUC
0
N
¼
area
under the concentration-tme curve extrapolated to infinity, N/A
¼
not available, %F
¼
oral
bioavailability.
N
NH
2
N
MW 421.51
PSA 89.3 Å2
cLogP 3.73
N
N
CH
3
H
O
Figure 4.6
OSI-906.
4.7 Synthesis of OSI-906
The linear synthesis of OSI-906 (Scheme 4.4) began with the treatment of
commercially available 7-methylquinoline (20) with phenyllithium, followed by
refluxing with sulfur in methanol to afford 7-methyl-2-phenylquinoline (21).
Oxidation of the 7-methyl group with selenium dioxide afforded 2-phenylqui-
noline-7-carbaldehyde (22) in 42% over three steps. Directed ortho-metallation
of 2-chloropyrazine with a preformed solution of LiTMP followed by
quenching with aldehyde 22 afforded alcohol 23 in 76% yield. Conversion of
alcohol 23 to its respective chloride by treatment with thionyl chloride, fol-
lowed by reaction with potassium phthalimide and then subsequent hydrazine-
mediated phthalimide deprotection, afforded the desired amine 24 in 72% over
three steps. Coupling of 3-methylenecyclobutanecarboxylic acid with amine 24
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