A. Kojima et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5311–5316
5315
3-(R3)-substituted propiolic acid esters by a method similar to
that used for the conversion of 5a to 2a or 2o. Compound 21
was prepared from aminopyridinium salt of 5a and ethyl 4,4-
bis(ethoxy)but-2-ynoate followed by O-acetylation. After depro-
tection of the acetal group of 21, the resulting aldehyde was re-
acted with DAST to give 22. Hydroxylation of 22 followed by
decarboxylation gave 23, which was converted to 4a by the
same method as used for conversion of 8a to 2a. Reaction of
N-aminopyridinium salt of 5a and ethyl 4-(tetrahydropyran-2-
yloxy)but-2-ynoate gave 24 and 25. After oxidation of 24 to car-
boxylic acid 26, which was converted to amide 27, the THP
group of 27 was removed and then oxidation of the alcohol gave
4n. Compound 4n was reacted with methylmagnesium bromide
to afford 4j, which was oxidized to give4m. Treatment of 4n
with hydroxylamine gave 4o, which was reacted with trifluoro-
acetic anhydride to give 4p. Oxidation of 4n with silver nitrate
gave 4r. Removal of the THP group of 26 followed by treatment
with methyl iodide in the presence of silver oxide gave 28.
Hydroxylation of 28 afforded the carboxylic acid, which was con-
verted to 4k or 4l by the same method as used for conversion of
10 to 2a or 2o. Treatment of 25 with 3,4-dihydro-2H-pyran in
the presence of a catalytic amount of p-toluenesulfonic acid gave
24 and 29. Compound 29 was converted to 30 in a three-step se-
quence of reaction, that is oxidation, oximation and dehydroxy-
lation. After removal of the THP group of 30, the resulting
alcohol was converted to 4q by a method similar to that used
for the conversion of 8a to 2o.
tory activity compared with 2a. From the above results, an
electron-withdrawing group is suitable for the in vitro activity.
On the other hand, their N-oxides (4c, 4e and 4g) showed great-
er potency than 4b, 4d and 4f, respectively. A cyclopropyl analog
(4h) showed PDE4 inhibitory activity almost equal to that of 2a.
Surprisingly, 4h and the N-oxide 4i exhibited excellent in vivo
effects via oral administration in the LPS model. The 2-hydroxy-
ethyl-(4j) and methoxymethyl-(4k, 4l) analogs exhibited reduction
of activity. Acetyl-(4m), formyl-(4n), oxime-(4o) and cyano-(4p)
analogs showed good PDE4 inhibitory activity, but they were less
effective via oral administration in the LPS model than 2a. On the
other hand, the activity of the carboxylic acid analog (4r) was
remarkably decreased.
The binding model of 2a docked into the catalytic pocket of
PDE4 is shown in Figure 2. As expected initially, nitrogen atom of
1-position of the pyrazolopyridine part interacted with the distal
Gln residue of the Q-pocket, and the pyridine ring of 2a fit to the
M-pocket at an appropriate position.
Our structure–activity relationship studies with compound
series related to KCA-1490 revealed that the PDE3-inhibitory activ-
ity is heavily dependent on the presence of the 5-methyldihydro-
pyridazinone, as described in the previous report.2c Therefore,
the PDE3-inhibitory activity of KCA1490 may remarkably
decreased, and the PDE4 inhibitory activity of 2a may increased
by the replacement of the pyridazinone group to the pyridylamino-
carbonyl group.
In conclusion, we have presented the design, synthesis, and
evaluation of pyrazolo[1,5-a]pyridine derivatives as selective
PDE4 inhibitors derived from the structure of KCA-1490, a dual
PDE3/4 inhibitor. Our investigation revealed that 2a and 4h were
selective PDE4 inhibitors with anti-inflammatory activity in ani-
mal models. We are currently assessing the toxicity of these
compounds in comparison with that of roflumilast.
The inhibitory activities observed for R2, the substituent at the
2-position of pyrazolopyridine of 2a are shown in Table 3.
Compound 4a, which has a difluoromethyl group, showed high
PDE4 inhibitory activity, but it was less effective via oral adminis-
tration at the LPS model than 2a. The hydrogen-(4b), ethyl-(4d)
and isopropyl-(4f) analogs of 2a exhibited decreased PDE4 inhibi-
OH
N
OAc
N
OAc
N
OH
N
CO2Et
OEt
CO2Et
a
b
c
CHF2
CHF2
N
N
N
OEt
OMe
5a
OMe
OMe
22
OMe
23
d, e, f
21
4a
4m
g, c
k
4j
4p
N
OH
O
OH
j
m
Cl
Cl
HN
O
d, e
h
i, d
l
4n
4r
4o
N
N
N
N
OR
OTHP
n
N
OMe
OMe
N
OTHP
24
: R = THP
26
27
25: R = H
OMe
i, o
q
OTHP
OTHP
O
OMe
d, l, m
i, d-f
p, f
4q
4k, 4l
CN
N
N
N
N
N
N
OH
OMe
OMe
OMe
OMe
29
30
28
Scheme 3. Reagents and conditions: (a) (1) MSH, CH2Cl2, 0 °C, to rt, (2) ethyl 4,4-bis(ethoxy)but-2-ynoate, K2CO3, DMF, rt, (3) Ac2O, pyridine, rt; (b) (1) cat. TsOHÁH2O,
acetone, H2O, 70 °C, (2) DAST, CH2Cl2, 0 °C to rt; (c) (1) 10% KOH, EtOH, refl., (2) o-dichlorobenzene, 150 °C; (d) MnO2, CHCl3, 50 °C; (e) NaClO2, NaH2PO4, 2-methyl-2-butene,
t-BuOH, H2O, rt; (f) (1) 4-nitrophenol, EDCI, DMAP, CH2Cl2, rt, (2) 4-amino-3,5-dichloropyridine or 4-amino-3,5-dichloropyridine N-oxide/NaH, DMF, rt; (g) (1) MSH, CH2Cl2
0 °C to rt, (2) ethyl 4-(tetrahydropyran-2-yloxy)but-2-ynoate, K2CO3, DMF, rt; (h) (1) TBTU, iPr2NEt, CH2Cl2, rt, (2) 4-amino-3,5-dichloropyridine/RedAlÒ, toluene, 100 °C; (i)
cat. TsOHÁH2O, MeOH, rt; (j) MeMgBr, THF, À78 °C to rt; (k) Dess–Martin periodinane, CH2Cl2, 0 °C to rt; (1) HONH2ÁHCl, AcONa, MeOH, rt; (m) TFAA, Et3N, CH2Cl2, rt; (n)
AgNO3, NaOH, H2O, rt, (o) Mel, Ag2O, DMF, rt; (p) 10% KOH, EtOH, rt; (q) 3,4-dihydro-2H-pyran, cat. TsOHÁH2O, DMF, rt, from 25.