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species was attenuated for 16 compared to 4; 16 showed only a 3-
fold difference, whereas triazole 4 displayed 10-fold lower activity
at rP2X7. This greater potency for the tetrazole compared to the tri-
azole in the benzylamino variation parallels the greater potency for
tetrazole versus triazole seen previously with the directly attached
benzyl group,20 and shown here in the comparison of compound 2
with compound 3. The in vitro potencies of the three ortho-meth-
ylphenyl-substituted tetrazoles 3, 16, and 17 show no significant
differences at either rat or human receptors. From a synthetic
chemistry perspective, however, the method to prepare the ben-
zylaminotetrazoles was more amenable to analog generation. This
allowed a more expansive exploration of the SAR trends on the
right-hand aromatic group in this series compared with com-
pounds like 1 and 3.19
In summary, we have discovered a novel series of N-benzyl-
1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives that are
potent P2X7 receptor antagonists. This structural variation shows
improved rat potency over the corresponding triazole core (e.g.,
4), but similar P2X7 potency compared to the earlier tetrazole 3.
Convenient synthetic methodology allowed extensive SAR studies
to be conducted on the right-hand side of the molecule. This work
revealed the preferred substitution patterns for the N-benzylamine
moiety: 2-substituted and 2,3-disubstituted phenyl groups pro-
duced potent P2X7 receptor antagonists. Analogs 12 and 38 are
particularly interesting because of their high potency and narrow
species difference. These studies also revealed opportunities to
substitute in the ortho -position of the right-hand phenyl with
much larger and potentially water-solubilizing groups (e.g., 24
and 25). The results of studies with more diverse substitution in
the ortho-position will be reported in due course.
22. Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237.
23. Representative procedure for the preparation of aminotetrazoles 12–51. A
solution of amine 6 (0.74 mmol) in anhydrous THF (10 mL) was treated drop
wise with isothiocyanate 5 (0.74 mmol). The solution was stirred at room
temperature for 6 h and then mercuric chloride or mercuric acetate
(0.74 mmol) was added followed by sodium azide (2.21 mmol, 3.0 equiv).
The reaction was stirred at room temperature for 8 h. The black mixture was
filtered through a pad of Celite, washed with THF and concentrated under
reduced pressure. The residue was purified by reversed phase HPLC on a
Waters Nova-PakÒ HR C18 6um 60 Å Prep-PakÒ cartridge column
(40 mm ꢀ 100 mm) using
a
gradient of 0–70% acetonitrile:10 mM
ammonium acetate over 8 min (10 min run time) at a flow rate of 70 mL/
min) to yield the aminotetrazoles 12–51.
References and notes
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