438
C. Genicot et al. / Bioorg. Med. Chem. Lett. 13 (2003) 437–442
(Fig. 2). In addition to its modest affinity for the NK1
receptor, absorption issues were anticipated due to the
poor aqueous solubility (s: 0.6 mg/mL, pH: 7.4) and high
lipophilicity (log D >5.0) of the compound. Sequential
removal of the benzyl and trimethoxybenzyl groups on
the piperazine ring led to 7, a molecule with a much
better affinity for the NK1 receptor and lower lipophili-
city (log D: 2.40). These results bear out the currently
established pharmacophoric model consisting of two
aromatic rings, a hydrogen bond acceptor and a nitro-
gen atom.7 However, the presence of the second nitro-
gen of the piperazine greatly improved solubility (s:
0.2 mg/mL for 7) and gave us the opportunity to further
modulate the physicochemical and ADME properties of
the molecule (vide infra).
(Scheme 3). Homogeneous hydrogenation with Wilk-
inson’s catalyst and deprotection of the nitrogen affor-
ded the expected products as a mixture of two
diastereoisomers that were separated by chromato-
graphy. Absolute configuration of the second chiral
center was determined by X-ray diffraction analysis on
the hydrochloride salt of 59a (Fig. 3).
Biology
As can be seen in Table 1, introduction of substituents
other than CF3 on the distal aromatic ring led to a loss
of affinity for the NK1 receptor. The drop was moderate
when chlorine or bromine atoms were used instead of
CF3 and was much more severe when fluorine or alkyl
groups (Me, tBu) were introduced instead of CF3.
Attempts to modify the position of the substituents was
unconvincing, for example when the CF3 groups were
shifted to the 2,5-position, a 100-fold loss of affinity was
observed (21). Hence, CF3 substituents in 3,5-position
appear to be optimal for high affinity.
Chemistry
Preparation of the benzyloxyphenethylpiperazines (9–
23) started from 2-phenyl-2-piperazinylethanol (8)
which was easily obtained by reaction of the N-pro-
tected piperazine with bromophenylacetate followed by
reduction of the ester (Scheme 1). Enantiomerically pure
8 was obtained by gently heating the N-protected
piperazine with the chiral styrene epoxide in ethanol.
The nucleophilic attack on the epoxide gave a mixture
of two regioisomers that were readily separated by
chromatography. Synthesis of substituted-phenyl or
heteroarylpiperazinylether (24–39) relies on the recently
reported arylboronic acid Mannich reaction.8 This ele-
gant three-component coupling reaction provided a
straightforward access to alcohol intermediates by sim-
ply stirring at room temperature in methylene chloride
the commercially available arylboronic acid, the N-Boc
piperazine and the hydroxyacetaldehyde. Alkylation of
the alcohols with benzyl bromides under standard con-
ditions followed by cleavage of the carbamate group
gave the target compounds 24.
Introduction of substituents in the para position of the
proximal phenyl was detrimental to the interaction with
the NK1 receptor (Table 2). Surprisingly, even a fluorine
Substituents on the basic nitrogen were introduced
through alkylation or acylation with the appropriate
reagents. Compounds bearing either a carboxylic acid
or a tetrazole were prepared from the corresponding
amide or nitrile following experimental procedures
described in the literature (Scheme 2). The Williamson
reaction could not be used for the preparation of the
a-methylsubstitutedbenzylethers (58–61) since rapid
decomposition of the benzylbromides took place.
Therefore condensation of the (R) or (S) alcohol 8 with
benzoic acid and methylenation of the resulting ester
with dimethyltitanocene9 yielded the enol ethers
Scheme 1. (i) K2CO3, DMF, rt, 84%; (ii) LAH, THF, ꢀ10ꢁC, 93%;
(iii) EtOH, reflux, 92%; (iv) NaH, NaI, THF, rt; (v) KOH, EtOH, 80 ꢁC;
(vi) CH2Cl2, 50ꢁC; (vii) NaH, NaI, THF, rt; (viii) KOH, EtOH, 80ꢁC.
Figure 2.