Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 20 4239
at C-4 was established by analysis of a H-15N HMBC
2D NMR experiment in which the N-7 atom of 3,
resonating at δ183 ppm showed a strong cross-peak with
the C-6 proton resonating at δ 8.23, while the parameter
of the experiment was optimized for a 8 Hz coupling
constant. Literature precedent indicates that 2J (HN)
for pyridine and quinoline derivatives is approximately
11 Hz, falling off to less than 0.3 Hz for coupling across
four bonds.18 The strength of the cross coupling in the
1H-15N HMBC 2D NMR experiment is consistent with
the methoxy substituent located at C-4 rather than C-2,
regiochemistry subsequently confirmed by single-crystal
X-ray analysis.19 The C-2 proton of 3 resonated as two
singlets at δ 8.09 and 8.15 that coalesced to a single
singlet when the DMSO-d6 solution was warmed to 120
°C, indicating that 3 exists as a pair of rotational
conformers at room temperature.
1
gp120 to the CD4 receptor. Bioorg. Med. Chem. Lett. 1993, 3,
2851-2856. (c) Chen, S.; Chrusciel, R. A.; Nakanishi, H.;
Raktabutr, A.; J ohnson, M. E.; Sato, A.; Weiner, D.; Hoxie, J .;
Uri Saragovi, H.; Greene, M. I.; Kahn, M. Design and synthesis
of a CD4 â-turn mimetic that inhibits human immunodeficiency
virus envelope glycoprotein gp120 binding and infection of
human lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 1992, 89,
5872-5876. (d) Zhang, J . L.; Choe, H.; Dezube, B. J .; Farzan,
M.; Sharma, P. L.; Zhou, X. C.; Chen, L. B.; Ono, M.; Gillies, S.;
Wu, Y.; Sodroski, J . G.; Crumpacker, C. S. The bis-azo compound
FP-21399 inhibits HIV-1 replication by preventing viral entry.
Virology 1998, 244, 530-541.
(6) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J .
Experimental and computational approaches to estimate solubil-
ity and permeability in drug discovery and development settings.
Adv. Drug Deliv. Rev. 1997, 23, 3-25.
(7) Snyder, D. W.; Bach, N. J .; Dillard, R. D.; Draheim, S. E.;
Carlson, D. G.; Fox, N.; Roehm, N. W.; Armstrong, C. T.; Chang,
C. H.; Hartley, L. W.; J ohnson, L. M.; Roman, C. R.; Smith, A.
C.; Song, M.; Fleisch, J . H. Pharmacology of LY315920/S-5920
[[3-(aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-
acetate,
a potent and selective secretory phospholipase A2
inhibitor: A new class of anti-inflammatory drugs, SPI. J .
Pharmacol. Exp. Ther. 1999, 288, 1117-1124.
The preparation of 2 was accomplished from 4-fluor-
oindole using a synthetic protocol similar to that used
to secure 7 but more convenient, taking advantage of
the enhanced reactivity of 4-fluoroindole toward oxalyl
chloride in Et2O, which allowed the corresponding acid
chloride to be realized in a single procedure. Exposure
of this acid chloride to N-benzoylpiperazine in the
(8) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.;
Lien, E. J . “Aromatic” substituent constants for structure-
activity correlations. J . Med. Chem. 1973, 16, 1207-1216.
(9) In addition to modifications of the indole moiety of 2, the
azaindole
3 incorporates a 2-(R)-methyl substituent in the
piperazine ring. The introduction of this methyl group can affect
potency and both physical and pharmacokinetic properties.
However, the role of 2-(R)-methyl moiety in modulating potency
has been found to be somewhat enigmatic, being dependent upon
the context and optimally able to provide an advantage of up to
1 order of magnitude. In the example at hand, the 2-(R)-methyl
group in 3 exerts a minimal effect on potency but exerts a
favorable effect on aqueous solubility.
i
presence of Pr2NEt in THF afforded 2.
In summary, optimization of a structurally elemen-
tary and effective inhibitor of HIV attachment (1) into
a compound (3) with improved antiviral potency, at-
tractive pharmaceutical and pharmacokinetic proper-
ties, and a safety profile appropriate for more advanced
studies has been accomplished. These indole-based
compounds represent the basic pharmacophore of a new
class of HIV-1 inhibitor that are the first small mol-
ecules able to effectively and potently interfere with the
interaction of the HIV surface protein gp120 and the
primary host cell receptor CD4, the initial step of HIV
entry. As such, they add to the emerging repertoire of
HIV-1 inhibiting compounds that interfere with the
viral entry process, providing an effective complement
to the CCR5 and CXR4 coreceptor antagonists and
enfuvirtide, the gp41 fusion inhibitor. A more detailed
analysis of the profile of 3 as an inhibitor of HIV-1
clinical isolates will be presented in due course.21
(10) Kwong, P. D.; Wyatt, R.; Robinson, J .; Sweet, R. W.; Sodroski,
J .; Hendrickson, W. A. Structure of an HIV gp120 envelope
glycoprotein in complex with the CD4 receptor and a neutral-
izing human antibody. Nature 1998, 393, 648-659.
(11) (a) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J .; Meanwell, N. A.;
Kadow, J . F.; Wang, T. An effective procedure for the acylation
of azaindoles at C-3. J . Org. Chem. 2002, 67, 6226-6227. (b)
Yeung, K.-S.; Farkas, M. E.; Qiu, Z.; Yang, Z. Friedel-Crafts
acylation of indoles in acidic imidazolium chloroaluminate ionic
liquid at room temperature. Tetrahedron Lett. 2002, 43, 5793-
5795.
(12) An alternative approach relied upon the reaction of the zinc salt
of 4, generated by treatment with MeMgI and subsequent
exchange with ZnCl2, in CH2Cl2 with methyl chlorooxoacetate.
(13) Li, H.; J iang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Good, M.
3-(Diet h oxyph osph or yloxy)-1,2,3-ben zot r ia zin -4(3H )-on e
(DEPBT): A new coupling reagent with remarkable resistance
to racemization. Org. Lett. 1999, 1, 91-93.
(14) Wang, T.; Zhang, Z.; Meanwell, N. A. A one-pot procedure for
the regioselective preparation of mono-benzoylated derivatives
of unsymmetrical piperazines. J . Org. Chem. 2000, 65, 4740-
4742.
(15) Harada, N.; Kawaguchi, T.; Inoue, I.; Ohashi, M.; Oda, K.;
Hashiyama, T.; Tsujihara, K. Synthesis and antitumor activity
of quaternary salts of 2-(2′-oxoalkoxy)-9-hydroxyellipticines.
Chem. Pharm. Bull. 1997, 45, 134-137.
(16) Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.; Crifantini,
M.; Martelli, S. Synthesis of 4-amino-1-â-D-ribofuranosyl-1H-
pyrrolo[2,3-b]pyridine (1-Deazatubercidin) as a potential anti-
tumor agent. J . Med. Chem. 1982, 25, 1258-1261.
(17) Fanghaenel, E.; Hucke, A.; Lochter, T. H.; Baumeister, U.;
Hartungm, H. Ring transformation of 1,1-dioxo-1,3-thiazine-6-
carbaldehydes with nitrogen nucleophiles to substituted pyri-
dine-3-sulfonanilides. Synthesis 1996, 1375-1379.
(18) Levy, G. C.; Lichter, R. L. Nitrogen-15 Nuclear Magnetic
Resonance Spectroscopy; Wiley-Interscience: New York, 1979;
Chapter 4, pp 115 and 117.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and analytical data for the preparation of compounds 2,
3, and 5-9. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Proc. Natl. Acad. Sci. U.S.A., in press.
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