3554
D. G. Brown et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3553–3556
The synthesis of these analogues is shown below in
Scheme 1. Commercially available pyridyl ketones 3
were converted to tert-butoxy hydrazones 4 in the pres-
ence of catalytic acid.4 Alternatively, non- commercially
available ketones were prepared according to the pro-
cedure of Sheldrake which employs alkylation of a ketal
carbon and subsequent deprotection.5 The hydrazones
were then reduced using catalytic hydrogenation to give
the hydrazines 5. Hydrazines 5 were coupled with acid
amide 66 using carbodiimides to give the intermediate
hydrazine amides 7. The final cyclization was accom-
plished with methanesulfonic acid yielding 2a–t as the
methanesulfonic acid salts.
quite high.8 The low yield was a result of the difficulty of
separating the final material from excess t-butyl carba-
zate. Unfortunately, when the amount of t-butyl carba-
zate was reduced from five equivalents to one
equivalent, the enantioselectivity dropped off rather
precipitously. Using only one equivalent led to nearly
racemic material. These results suggest a competitive
SN1 pathway can occur when the concentration of car-
bazate is low. As an alternative, the racemic hydrazine
can be separated by preparatory chiral HPLC. Coupling
of the chiral hydrazines was accomplished using EDCI
in refluxing CH2Cl2 as outlined in Scheme 1 to give rise
to 2c (Table 1). The opposite enantiomer (R)-13 was
prepared in an analogous fashion to give 2d beginning
with the (S)-alcohol 10 also obtained from the chiral
resolution described above (Scheme 3).
We were also interested in the pyridyl N-oxide deriva-
tives of these compounds. In theory, these compounds
may possess better water solubility than the parent
compounds. The N-oxide analogue of 1 is readily pre-
pared by dissolving 1 in methanolic choline hydroxide
solution, followed by the addition of m-CPBA to give
8a, or correspondingly 8b Scheme 2.
Biological and physical data of these compounds are
shown in Table 1. From the data, it is apparent that
affinity at the glycine site decreased with increasing
substitution on the a-carbon.9 In this regard, the chiral
analogues 2c and 2d represent an interesting compar-
ison. The (S)-isomer 2c was reasonably potent, whereas
the (R)-isomer was absent of activity. The pyridyl N-
oxides 8a and 8b were less potent that the unoxidized
analogues (1 and 2n) with a 5- to 10-fold decrease in
binding affinity being observed.
Chiral analogues of 2 were prepared with greater than
98% enantiomeric purity. The chiral acetate 11 served
as a good starting point and was prepared by enyzmatic
resolution of 1-(2-pyridyl)ethanol 9 using Novozyme-
435.7 The acetate was then hydrolyzed and converted to
mesylate 12. The mesylate was displaced with t-butyl-
carbazate to give the desired chiral hydrazine (S)-13.
Although the yield was low, the enantioselectivity was
Despite the drop-off in binding affinity, the drug-like
physical properties of these a-branched compounds
appeared to improve over the unsubstituted counterparts.
For example, all of the unsubstituted analogues (R=H
for 2a, 2k, 1, 8a) possessed poor Caco-2 permeabilities
(A>B<10 Â 10À7). In the 2- and 4-pyridyl series, sub-
stitution of alkyl groups on the a-carbon resulted in
improved Caco-2 permeability. In these two series small
aliphatic substitution (e.g., R=Me) led in some cases to
30-fold improvements in Caco-2 permeabilities (e.g., 2c,
2n) with only 2- to 3-fold loss in binding activity. The
Caco-2 improvements were not seen in the 3-pyridyl series
when R=Me, but did improve with R=Et (2l vs 2m).
However, the ethyl substituted compound was devoid of
binding activity. These improvements in cellular perme-
ability may be due to the increase of hydrophobicity at
the a-carbon. The N-oxide 8a showed little change in
Caco-2 permeability over the parent compound 1.
In general, solubilities of the substituted analogues were
also improved from the lead compound 1. The
improved solubility may be due to distortion of the
planar conformation, resulting in potentially weaker
crystal packing forces. In some cases, this can be sup-
ported by a corresponding lowering of melting points
between the a-alkyl substituted and unsubstituted ana-
logues.10 For example, compound 1 has a melting point
range between 277 and 278 ꢀC as the methanesulfonate
salt. The a-methyl analogue 2n has a melting point
range between 245 and 247 ꢀC for the same salt form.
Similar observations are seen with 2a and 2k and their
corresponding a-alkyl analogues.
Scheme 1. Reagents and conditions: (a) t-BocNHNH2, THF, HCl
(cat.), 60–95%; (b) 10% Pd/C, MeOH, H2, 40 psi, 18 h, 35–98%; (c) 5,
CMC or EDCI, THF or CH2Cl2, DMAP (cat.), 15–78%; (d)
CH3SO3H, THF, rt, 30–85%.
Scheme 2. Reagents and conditions: (a) choline hydroxide, MeOH;
m-CPBA, 20%.
It is also apparent that the improvement in drug-like
physical properties paralleled an improvement in oral
Brown, Dean G.
