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H. H. Gu et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1323–1326
biological evaluation of a new class of inhibitors of
IMPDH, based on the diamide backbones I and II (Fig. 1).
0.052 mM (IMPDH II). With R3 fixed as H, other lipo-
philic residues were examined at the R4 position. Ana-
logues with R4 as benzyl Ie, cyclohexyl If, n-propyl Ig,
and iso-propyl Ih were all inactive when tested at the 10
mM concentration. In contrast, the t-butyl analogue Ii,
displayed an IC50 of 0.010 mM. Assessment of Ib and Ij,
both bearing methyl substitution at R3, demonstrated
the necessity for substitution with hydrogen to achieve
high potency. The R4 phenyl of Ia may be effectively
substituted. Compound Ic, functionalized with a carba-
mate side chain from VX-497, displayed an IC50 value
of 0.030 mM.
The synthesis of diamide analogues 8 and 9 is shown in
Scheme 1. The 3-methoxy-4-(5-oxazolyl)-aniline 5 was
prepared from 2-methoxy-4-nitro-toluene 1 on a multi-
gram scale utilizing a synthetic procedure described by
Vertex.10 Acylation of 5 with ethyl oxalyl chloride gave
the corresponding oxalamic acid ethyl ester, which was
hydrolyzed to generate the oxalamic acid 6. In a similar
synthetic sequence, the malonamic acid 7 was prepared
utilizing ethyl malonyl chloride as the acylating agent.
Amides 8 and 9 were synthesized from 6 and 7, respec-
tively, by treatment with the corresponding amine and
utilizing BOP as the coupling agent.11 The syntheses of
anilines 12 and 16, described in Scheme 2, were pre-
pared according to literature procedures.10,12 Com-
pound Ic was prepared from compound 6 utilizing [(3-
aminophenyl)methyl] carbamic acid [(3S)-tetrahydro-3-
furanyl] ester B under the standard BOP-coupling con-
ditions.13 Compounds Iq and Ir were prepared from
4-(5-oxazolyl)-aniline and 12, respectively, utilizing the
reaction sequence for the conversion of 5 to 8.
In general, analogues where R4 has a quaternary center
at the site of attachment retain potency. Compound Io,
featuring a carboxylic acid moiety, is the exception in
this group. Notably, when the gem-dimethyl residues of
R4 were fashioned into a cyclopentane ring giving Il,
potency was maintained. We found that small structural
changes to the 3-methoxy-4-(5-oxazolyl)-aniline moiety
led to significant changes in potency. Where replace-
ment of the methoxy residue with a bromide (Is) or
chloride (It) moiety was tolerated, removal of the
methoxy residue (Iq) was not. Similarly, utilizing
4-methyl-5-oxazolyl aniline as a replacement for 5 giv-
ing Ir, led to a significant loss in potency.
The structure–activity relationships for the inhibition of
IMPDH type II catalytic activity are summarized in
Table 1. In the ethanediamide series I, several lipophilic
residues were examined in the R3 and R4 positions.
Compound Ia (R4=Ph) displayed an IC50 value of
Propanediamide analogue IIa with phenyl as the R4
residue displayed potent inhibitory activity against
Scheme 1. Reagents and conditions: (a) HOAc, Ac2O, concd H2SO4, CrO3, 0–10 ꢁC (51%); (b) concd HCl, dioxane, reflux (91%); (c) TosMIC,
K2CO3, MeOH, reflux (84%); (d) 40 psi H2, Pd/C, EtOH, (95%); (e) ClCOCOOEt, Et3N, CH2Cl2 (95%); (f) NaOH, EtOH (90%); (g) ClCOCH2-
COOEt, Et3N, CH2Cl2 (100%); (h) NaOH, EtOH (96%); (i) BOP, NMM, DMF, HN-R3R4 (85–99%).
Scheme 2. Reagentsꢁand conditions: (a) Me-TosMIC, K2CO3, MeOH, reflux (79%); (b) 40 psi H2, Pd/C, EtOH, (95%); (c) HOAc, Ac2O, concd
reflux (95%).
.
H2SO4, CrO3, 0–10 C (28%); (d) concd HCl, dioxane, reflux (99%); (e) TosMIC, K2CO3, MeOH, reflux (95%); (f) SnCl2 2H2O, EtOH/EtOH,