Synthesis and evaluation of quinoxalinones as HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1016/S0960-894X(00)00321-8

A series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h and 6k) and N-carboalkoxy (6m-6y) substituted compounds displayed activity comparable or better than Efavirenz and GW420867X. (C) 2000 Dupont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00321-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1729±1731
Synthesis and Evaluation of Quinoxalinones as HIV-1 Reverse
Transcriptase Inhibitors
Mona Patel,* Robert J. McHugh, Jr., Beverly C. Cordova, Ronald M. Klabe,
Susan Erickson-Viitanen, George L. Trainor and James D. Rodgers
DuPont Pharmaceuticals Company, Experimental Station, E500/4803, PO Box 80500, Wilmington, DE 19880-0500, USA
Received 18 April 2000; accepted 31 May 2000
AbstractÐA series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The
N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h, and 6k) and N-carboalkoxy (6m±6y) substituted compounds displayed activity
comparable or better than Efavirenz and GW420867X. # 2000 Dupont Pharmaceuticals Company. Published by Elsevier Science
Ltd. All rights reserved.
Non-nucleoside HIV-1 reverse transcriptase inhibitors
(NNRTIs) play an integral role in combination therapy
for the treatment of AIDS. Efavirenz,1 a potent NNRTI,
is an essential component of a very e€ective combination
therapy when administered with AZT and 3TC. However,
as with all current HIV therapies, the development of
drug-resistant strains of the virus is of major concern. In
our attempts to ®nd second generation analogues that may
e€ectively treat NNRTI therapy failures, we prepared
hybrid compounds containing structural features from
both Efavirenz and the Glaxo Wellcome clinical candidate
GW420867X.2 The hybrids synthesized combine the qua-
ternary carbon bearing the tri¯uoromethyl and cyclopro-
pylacetylene groups of Efavirenz with the quinoxaline
core of GW420867X (Fig. 1).
of substitutents at the N-4 position either by (a) alkylation
with alkyl halides (tBuOK, THF) or (b) acylation or sul-
fonylation (nBuLi, THF/chloroformates/acid chlorides/
sulfonyl chlorides) provided the fully substituted quinox-
alinones (5). Removal of the SEM protecting group by
treatment with boron tri¯uoride in dichloromethane
provided quinoxalinones (6) in moderate yields as shown
in Scheme 1.4
To improve upon the overall yield so as to facilitate the
scale up of (6m) for pharmacokinetic studies, an alternate
route for the preparation of (6m) was developed (Scheme
2). Quinoxalinone (2) was converted to quinoxaline (7)
Chemistry
Commercially available ortho-phenylenediamines (1) were
treated with hexa¯uoropropylene oxide (HFPO) under
basic conditions to provide the corresponding quinox-
alinones (2).3 4-Substituted phenylenediamines gave mix-
tures of 6- and 7-substituted quinoxalinones, which were
separated via chromatography. Protection of 2 with
SEM-Cl (DIPEA, DMF) provided the N-SEM protected
compounds (3). Addition of lithium cyclopropylacetylide
to imines (3) resulted in the formation of 3,3-disubstituted
quinoxalinones (4) in good yields. Introduction of a variety
*Corresponding author. Tel.: +1-302-695-1233; fax: +1-302-695-8344;
e-mail: mona.patel@dupontpharma.com
Figure 1.
0960-894X/00/$ - see front matter # 2000 Dupont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00321-8

1730
M. Patel et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1729±1731
by treatment with silver carbonate and p-methoxybenzyl
chloride. Quinoxaline (7) was treated with lithium cyclo-
propylacetylide and the resulting anion was quenched
with ethyl chloroformate to provide the fully substituted
quinoxaline (8) in good yield. Removal of the PMB pro-
tecting group was carried out under acidic conditions,
providing 6m in a substantially improved overall yield of
27% versus 1.5% by the earlier route (Scheme 2).4
were of special interest as they bore the 6-F susbtitution
present in GW420867X and were more potent in the cell
based assay. Amides (6z, 6aa, and 6bb) bearing isopropyl,
cyclopropyl and phenyl groups were prepared. Groups
larger than isobutyl were not tolerated as side chains in
both the carbamate (6p and 6q) and amide (6bb) series.
Derivatisation of the N-4 position to a sulfonamide (6cc±
6ee) was clearly detrimental to antiviral activity. Sub-
stitutions at the C-6 position of the quinoxalinones
(X=Cl, F, OMe) did not appear to in¯uence the potency
of the compound. Although the 6-F and 6-Cl substituted
carbamates (6t±6y) were very potent compounds, they
were highly protein bound resulting in a 33- to 50-fold
loss in IC90 values in the protein binding shift assay,5
and therefore were not considered for pharmacokinetic
studies. Comparatively, 6-H substituted carbamate (6m)
showed low protein binding (18-fold loss in IC90 value)
and a good resistance pro®le (K103N=30 nM; L100I=75
nM), and was selected for pharmacokinetic studies.
Compound 6m was resolved by chiral HPLC and the
Results and Discussion
A variety of alkyl groups were introduced at the N-4
position of quinoxalinones to provide compounds 6a±6l.
This substitution pattern resulted in compounds compar-
able in activity in both the enzyme inhibition and whole
cell antiviral assays to GW420867X. Next, we introduced
acyl groups at the N-4 position of the quinoxalinones.
Carbamates (6m±6o and 6r±6y) were the most potent
compounds prepared in this series. Compounds 6w±6y
Scheme 1. Reagents and conditions: (a) HFPO, NaHCO3, ether, 25 ꢀC, 3 h, 15±90%; (b) SEMCl, DIPEA, DMF, 25 ꢀC, 14 h, 13±90%; (c) nBuLi,
cyclopropylacetylene, THF, 78 ꢀC to 25 ꢀC, 0.3 h, 45±92%; (d) RX, tBuOK, DMF, 25 ꢀC, 14 h, 21±70%; or ClCO2R, nBuLi, THF, 78 ꢀC to
25 ꢀC, 1 h, 34±92%; or ClCOR, nBuLi, THF, 78 ꢀC to 25 ꢀC, 1 h, 60±69%; or ClSO2R, nBuLi, THF, 78 ꢀC to 25 ꢀC, 1 h, 16±34%; (e) BF3ꢁ Et2O,
DCM, 0 ꢀC to 25 ꢀC, 1.5 h; 15% NaOH, MeOH, 25 ꢀC, 0.6 h, 3±87%.
Scheme 2. Reagents and conditions: (a) PMBCl, Ag2CO3, DMF, 25 ꢀC, 14 h, 46%; (b) nBuLi, cyclopropylacetylene, THF, 78 ꢀC to 25 ꢀC, 1 h;
NaI, 25 ꢀC, 0.6 h; ClCO2Et, THF, 25 ꢀC, 0.6 h, 85%; (c) HCl in ether, 25 ꢀC, 0.6 h, 70%.

M. Patel et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1729±1731
Table 1. Antiviral activity of 3,3-disubstituted quinoxalinones
1731
In summary, although we were able to prepare potent
compounds bearing tri¯uoromethyl and cyclopropyl-
acetylene groups at the C-3 carbon of quinoxalinones,
high protein binding (6t±6y) and a poor pharmacokinetic
pro®le (6m*) precluded further development of this class
of compounds (Table 1).
Compound
X
R
IC50 (nM)6a IC90 (nM)6b
References and Notes
Efavirenz7
Ð
Ð
H
H
H
H
H
F
Ð
Ð
48
179
253
601
1818
1807
340
124
263
329
404
650
109
123
118
108
169
1142
672
147
504
127
160
315
121
130
183
127
160
2
11
17
22
21
53
32
21
23
27
52
85
19
29
9
15
GW620867X7
1. (a) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.;
Lumma, W. C.; Lyle, T. A.; Hu€, J. R. et al., Antimicrob.
Agents Chemother. 1995, 39, 2602. (b) Patel, M.; Ko, S. S.;
McHugh, R. J.; Markwalder, J. A.; Srivastava, A. S.; Cor-
dova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Trainor, G.
L.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1999, 9, 2805. (c)
Patel, M.; McHugh, R. J.; Cordova, B. C.; Klabe, R. M.;
Erickson-Viitanen, S.; Trainor, G. L.; Ko, S. S. Bioorg. Med.
Chem. Lett. 1999, 9, 3221.
2. Kleim, J.-P.; Bender, R.; Billhardt, U. M.; Meischner, C.;
Reiss, G.; Rosner, M.; Winkler, I.; Paessens, A. Antimicrob.
Agents Chemother. 1993, 37, 1659.
3. Ishikawa, N.; Sasaki, S. Bull. Chem. Soc. Jpn. 1977, 50,
2164.
4. All compounds provided satisfactory spectral data (1H
NMR, 19F NMR, CIMS/ESIMS, and HRMS/peak match)
and were homogeneous by TLC.
6a
6b
6c
6d
6e
Cyclopropylmethyl
Allyl
Benzyl
Propargyl
Cyclopropylethyl
Allyl
Cyclopropylmethyl
Cyclopropylmethyl
Isobutyl
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
F
Cl
Cl
Cl
Allyl
OMe Cyclopropylmethyl
OMe
H
H
H
H
H
H
H
Cl
Cl
Cl
F
Allyl
COOEt
COOiPr
COOC(CH2)Me
COOiBu
COOnBu
COOCH2CHCH2
COOMe
COOEt
11
158
105
30
44
11
19
15
8
6s
6t
5. The protein binding shift assay is a measure of the increase
in IC90 values due to the binding of the compound to human
serum proteins (HSA and AAG) in plasma, resulting in lower
free drug concentrations.
6u
6v
6w
6x
6y
6z
6aa
6bb
6cc
6dd
6ee
COOiPr
COOC(CH2)Me
COOEt
COOiPr
COOC(CH2)Me
CYcyclopropylmethyl
CIiPr
6. (a) All compounds were assayed for enzyme inhibitory
activity (IC50) according to the protocol described in: Sardana,
V. V.; Emini, E. A.; Gotlib, L.; Graham, D. J.; Lineberger, D.
W.; Long, D. W.; Schlabach, A. J.; Wolfgang, J. A.; Condra,
J. H. J. Biol. Chem. 1992, 267, 17526 using a template primer
poly (rA) oligo (dT)12 18. (b) All compounds were assayed for
whole cell based antiviral activity (IC90) according to the pro-
tocol described in: Bacheler, L. T.; Paul, M.; Jadhav, P. K.;
Otto, M.; Miller, J. Antiviral Chem. Chemother. 1994, 5, 111.
7. The data presented for Efavirenz and HBY1293/GW867
re¯ect values determined for a single enantiomer, whereas the
data shown for 6a±6ee are that of racemic mixtures. The bio-
logical evaluation of each enantiomer of Efavirenz and other
quinoxalinones had determined that only the S enantiomer
was active.
F
F
9
8
11
H
H
H
H
H
H
19
COPh
SO2Et
SO2iPr
SO2nPr
>5000
>5000
>5000
>5000
>1000
>1000
>1000
>1000
active enantiomer 6m* (IC50=45 nM; IC90=4.8 nM)
was subjected to oral pharmacokinetic studies in rhesus
monkeys. Unfortunately, poor bioavailability of 6m*,
was observed and no further studies have been planned.