Novel 1,1,3-trioxo-2H,4H-thieno [3,4-e] [1,2,4] thiadiazine derivatives as non-nucleoside reverse transcriptase inhibitors that inhibit human immunodeficiency virus type 1 replication

Article abstract of DOI:10.1021/jm9802012

The 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) represent a recently discovered chemical class of non-nucleoside reverse transcriptase inhibitors that selectively block human immunodeficiency virus type 1 replication. In a search for a bett

Full text of DOI:10.1021/jm9802012

J . Med. Chem. 1998, 41, 4109-4117
4109
Novel 1,1,3-Tr ioxo-2H,4H-th ien o[3,4-e][1,2,4]th ia d ia zin e Der iva tives a s
Non -Nu cleosid e Rever se Tr a n scr ip ta se In h ibitor s Th a t In h ibit Hu m a n
Im m u n od eficien cy Vir u s Typ e 1 Rep lica tion
Esther Arranz,† J uan A. D´ıaz,† Simon T. Ingate,† Myriam Witvrouw,‡ Christophe Pannecouque,‡ J an Balzarini,‡
Erik De Clercq,‡ and Salvador Vega*,†
Instituto de Quı´mica Me´dica, CSIC, J uan de la Cierva, 3, 28006 Madrid, Spain, and Rega Institute for Medical Research,
Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received March 31, 1998
The 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) represent a recently discovered
chemical class of non-nucleoside reverse transcriptase inhibitors that selectively block human
immunodeficiency virus type 1 replication. In a search for a better understanding of their
mode of binding and with the aim of obtaining novel lead compounds, a second series of TTD
derivatives was synthesized and evaluated for antiviral activity. The design of the new
compounds was based on a variety of chemical modifications which were carried out in the
original prototype 20a (QM 96521). Substitution of a halogen at the meta position of the N-2
benzyl group resulted in an improvement of the antiviral activity by 1 order of magnitude.
Compounds bearing at the N-4 position a cyanomethyl, propargyl, or benzyl substituent were
found to be the most potent of the series. Modifying the thieno[3,4-e] ring fused to the 1,2,4-
thiadiazine moiety to other heterocyclic ring systems decreased the potency. The results
obtained in this investigation have provided new indications for the design of even more effective
TTDs.
In tr od u ction
HIV-1 activity. Thus, while unsubstituted compounds
at this position were inactive, the methyl, ethyl, and
n-propyl containing derivatives showed inhibition of
HIV-1 RT at sub-micromolar concentrations. The N-4
cyanomethyl derivative 20a , an intermediate in the
synthesis of amides (which were inactive), and the N-4
propargyl derivative 20d showed, in this order, the
highest activity. Why exactly the presence of the N-4
cyanomethyl moiety in 20a ensures anti-HIV-1 activity
relative to the ethyl or n-propyl substituents remains
to be elucidated, but may be due to steric or electronic
effects (i.e., the n-propyl group is not linear, the ethyl
group is smaller, and the cyano group has π-electrons).
The closely related benzo[1,2,4]thiadiazine derivative
with the same nitrogen substitutions as 20a was also
synthesized and was found to be inactive, thus demon-
strating the requirement of the thieno[3,4-e] fused
heterocycle for activity.
We have recently described the synthesis and biologi-
cal activity of a new family of inhibitors of the human
immunodeficiency virus type 1 (HIV-1),1 the 2,4-disub-
stituted 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadia-
zines (TTDs). These compounds, the prototype being
2-benzyl-4-cyanomethyl-2H,4H-thieno[3,4-e][1,2,4]thia-
diazine (20a , QM 96521), belong to the same group of
inhibitors as BHAP,2 PETT,3 R-APA,4 nevirapine,5 etc.,
which are known as non-nucleoside reverse tran-
scriptase inhibitors (NNRTIs).6,7 Like other NNRTIs,
the TTDs selectively inhibit HIV-1 replication at the
reverse transcription (RT) step. In our preceding pub-
lications we have described the discovery of the TTDs
and the development of 20a (QM 96521) as a lead for
further studies.1,8
We discovered that compounds in this series with a
benzyl moiety at N-2 showed RT inhibition, while
unsubstituted compounds or compounds bearing other
groups at this position (such as phenyl or alkyl substit-
uents) were completely devoid of activity. We also found
that alkylation of the N-4 position was essential for anti-
Molecular modeling and X-ray diffraction studies
carried out with these thieno[1,2,4]thiadiazines8 dem-
onstrated that the N-2 benzyl moiety allows the mol-
ecule to adopt the “butterfly” conformation which is
commonly encountered in the NNRTIs. Interestingly,
these investigations also demonstrated that the N-4
cyanomethyl substituent of 20a is on the same side of
the plane as the N-2 benzyl group, and consequently,
the overall conformation of this compound is very
similar to that of nevirapine.9
If HIV-1 was cultured in the presence of low concen-
trations of the TTD a resistant virus strain was gener-
ated with a unique amino acid change (V179D) in the
reverse transcriptase.8 In models of the binding of 20a
to HIV-1-RT, the N-4 substituent was found to be close
* To whom correspondence should be addressed.
† Instituto de Qu´ımica Me´dica, CSIC.
‡ Rega Institute for Medical Research, Katholieke Universiteit
Leuven.
S0022-2623(98)00201-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/15/1998

4110 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Arranz et al.
Sch em e 1a
F igu r e 1. Planned modifications to the lead compound.
to this amino acid, which may explain why the V179D
mutation leads to resistance.8
In the present paper we disclose the results of our
studies on a new series of TTDs. Our goal was to better
understand the mode of binding and to obtain com-
pounds with better activity and selectivity. The struc-
tural changes investigated are summarized in Figure
1. We have concentrated on four parts of the molecule:
(i) the nature of the heterocycle fused to the 1,2,4-
thiadiazine ring, (ii) the length of the methylene bridge
between the bicyclic system and the phenyl ring at N-2,
(iii) substitutions in the phenyl ring or changing the
phenyl to pyridines, and (iv) other substitutions at N-4.
We thought that a heterocycle attached to the 1,2,4-
thiadiazine ring would be important since the benzo
fused bicycles are inactive; we therefore synthesized
1,2,4-thiadiazines with the thieno[2,3-e], thieno[3,2-e],
and pyrazolo[4,3-e] modifications. With these new
derivatives we could investigate the effect of changing
the position and nature of the heteroatom on the HIV-1
inhibitory activity. We felt it necessary to study com-
pounds with either one or two methylene groups in the
bridge between the two π-electron containing systems
because the PETT compounds have two methylene
groups. Another obvious modification that we wished
to study was the introduction of substitutions at the
phenyl ring or its replacement for pyridine; halogenated
phenyl rings and pyridines are often found in other
NNRTIs such as R-APA, PETT, and TIBO. To gain
insight in the role that the cyanomethyl group may play
in the interaction of TTD derivatives with the HIV-1
RT, we also synthesized heterothiadiazines bearing
other π-electron containing substituents at the N-4
position, such as benzyl, substituted benzyl, allyl, and
propargyl groups; nevirapine, as is well known, bears
in its structure a cyclopropyl group which has a certain
π-character.10
a
Reagents: (i) R1NH2/THF; (ii) N2H4‚H2O/EtOH; (iii) 2 N HCl
or HNO3, NaNO2, H2O; (iv) ∆/toluene.
Sch em e 2a
a
Reagents: (i) benzylamine (2 equiv), THF; (ii) n-BuLi (1.2
equiv), THF, CO2; (iii) H3O+; (iv) DPPA, TEA, toluene, ∆.
Sch em e 3a
a
Reagents: (i) NaH (1 equiv), DMF, benzyl halides.
in the in the presence of potassium carbonate (K2CO3)
(Scheme 1) gave the corresponding sulfamoyl com-
pounds 2a -c. Treatment of 2a -c with hydrazine
hydrate in refluxing ethanol afforded the hydrazide
derivatives 3a -c, which were readily converted to the
acyl azides 4a -c by the action of nitrous acid. Heating
4a -c in refluxing dry toluene led to the desired thieno-
[3,4-e][1,2,4]thiadiazines 5a -c, by spontaneous ring
closure of the intermediate isocyanates formed in the
rearrangement of these acyl azides. Benzylthienothia-
diazine 8 (Scheme 2) was also synthesized from the
carboxylic acid 7 by a modification of the Curtius
reaction which involves the use of diphenylphosphoryl
azide (DPPA).14,15 Thus, reaction of 5-chloro-2-chloro-
sulfonylthiophene16 with benzylamine in THF afforded
the sulfamide 6, which was converted to the carboxylic
acid 7 by metalation at the 3-position with n-BuLi in
dry THF, followed by carbonation of the formed orga-
nolithium compound with powdered dry ice and subse-
Ch em istr y
For the synthesis of compounds 16-19 we designed
a procedure based on the methods previously described
for the preparation of the parent 1,1,3-trioxo-2H,4H-
hetero[1,2,4]thiadiazines and their first 2,4-substituted
derivatives.1,11 The procedure, which is outlined in
Schemes 1-4, consists of the cyclization of the sulfa-
moylheterocarboxylic derivatives 2a -c and 7 through
a typical Curtius reaction12,13 followed by alkylation of
the intermediate N-2 substituted thiadiazines thus
obtained, to give the target N-2,N-4 dialkyl hetero[1,2,4]-
thiadiazines.
Thus, reaction of methyl 4-chlorosulfonylthiophene-
3-carboxylate (1) with phenethylamine, 2-picolylamine,
and 3-picolylamine in dry tetrahydrofuran (THF) and

Novel TTD Derivatives That Inhibit HIV-1 Replication
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4111
Sch em e 4a
CH). When the EC50 and CC50 values of the chlorinated
derivatives 16e-h and 16k -n were compared with
those of their corresponding nonhalogenated analogues
20b and 20c, the presence of the o-, p-, and 2,6-
dichlorobenzyl substituents appeared to be deleterious.
This was particularly pronounced for the para-chlori-
nated analogues 16k and 16l which were completely
inactive. The N-2-(3-chlorobenzyl)-N-4-methyl analogue
16g was less active than 20b; however, the observed
improvement in the EC50 value of the N-4-ethyl deriva-
tive 16h with respect to 20c encouraged us to prepare
more N-2-(3-chlorobenzyl) bearing derivatives.
Compounds 16i and 16j were 10-fold more active than
their unsubstituted counterparts 20a and 20d , with
selectivity indices ranging from >3800 to 376, respec-
tively, thus demonstrating that the presence of a
chlorine atom at this position results in a marked
improvement in the anti-HIV-1 activity of these com-
pounds. Replacement of the chlorine atom by other
halogens led to the meta-brominated compound 16o,
which was as active as 16i, and the fluorine substituted
16p , which was the most active compound (EC50 ) 0.05
µM) of the series. Although the 3,5-difluorobenzyl
containing compound 16q is 3 times more active than
20a , it is not as potent as 16p . This seems to suggest
that one substituent in the phenyl ring of the N-2 benzyl
group is optimal for maximal anti-HIV-1 activity, but
more studies are required to prove this hypothesis.
a
Reagents: (i) NaH (1.2 equiv), DMF, R2X.
quent acidification. Cyclization of compound 7 with
DPPA in the presence of triethylamine in dry toluene
afforded the required benzylthienothiadiazine 8 (38%),
with the concomitant formation of 2-benzyl-5-chloro-
1,1,3-trioxo-2,3-dihydrothieno[3,2-d]isothiazole (9) (26%).
Monosubstituted heterothiadiazines 13a -g, 14, and
15 (Scheme 3) were achieved by alkylation of 1,1,3-
trioxo-2H,4H-thieno[3,4-e]-, 1,1,3-trioxo-2H,4H-thieno-
[2,3-e]-, and 6-methyl-1,1,3-trioxo-2H,4H-pyrazolo[4,3-
e][1,2,4]thiadiazines11 (10-12) with a variety of benzyl
halides in the presence of sodium hydride (NaH) and
N,N-dimethylformamide (DMF), following a recently
reported method.1 Finally the target heterothiadiazines
16-19 (Scheme 4) were synthesized by alkylation at N-4
of 2-substituted compounds 5, 8, and 13-15 with alkyl
halides also using the NaH/DMF system. The struc-
tures of all newly synthesized compounds were estab-
lished on the basis of analytical and NMR data.
The effect of the halogen atom in the meta position
is as yet not clear and may be due to steric, lipophilic,
or perhaps electrostatic interactions within the NNRTI
binding site. To clarify this point, we produced the
picoline substituted analogues 16u -x, since the nitro-
gen atom in the pyridine ring of these compounds would
impart electrostatic interactions rather than steric or
lipophilic ones. The 2-picolyl derivatives 16u and 16v
were less active than their respective benzyl analogues
20c and 20a . Surprisingly, 16w was 6 times more
active than the related compound 20e. We are as yet
uncertain as to why this should be so, but it may be
due to subtle differences in the binding of 20e and 16w
relative to 20a brought about by the presence of the
larger N-4 benzyl group in the former compounds. The
3-picolyl derivative 16x was found to be 4 times as
potent as its prototype 20a , which supports the argu-
ment for a favorable electrostatic interaction between
the N-2 substituent of the TTDs and RT. The N-2
phenylethyl substitution in 16r -t gave rise to com-
pounds with much less activity than their benzylated
counterparts.
Biologica l Resu lts a n d Discu ssion
In our previous publications dealing with the first
generation of TTD derivatives we have shown that
active compounds require the presence of both an N-2
benzyl group and alkyl substituent at the N-4 position.1,8
The earliest compounds in this family that exhibited
inhibition of HIV possessed the methyl, ethyl, or propyl
groups at N-4. Marked improvements in the activity
of these compounds were observed with the N-4 cya-
nomethyl, propargyl, and benzyl derivatives, whereas
the allyl and cyanoethyl bearing analogues were less
potent. In the present work we have synthesized a
second series of compounds 16-19 in order to better
understand how the TTDs interact with the NNRTI
binding site and to begin to optimize the structure of
these inhibitors. The results are presented in Table 1.
The synthesis and antiviral activity of the TTD deriva-
tives 20 have been reported previously;1 their EC50 and
CC50 values were included for comparative purposes.
We first studied the effect of the introduction of
halogens in the phenyl ring of the N-2 benzyl substitu-
ent of the lead compound 20a . Such a modification had
been demonstrated in other NNRTIs to lead to an
improvement in their potencies.3,4,17 Thus, we synthe-
sized the TTD analogues 16e-q which all bear haloge-
nated benzyl moieties and differ in their N-4 substitu-
tions (initially limited to Me, Et, CH2CtN, and CH2Ct
We were also interested in understanding the role
played by the thiophene ring of the thieno[3,4-e][1,2,4]-
thiadiazine bicyclic system. We have observed that the
benzo fused bicycle containing TTD-like compounds
were inactive, and thus we wished to investigate the
effect of other heterocycles attached to the 1,2,4-thia-
diazine. In Table 1, we include the results obtained for
the thieno[2,3-e] (17), 6-methylpyrazolo[3,4-e] (18), and
6-chlorothieno[3,2-e] (19) fused TTD analogues. In
general, such modifications in the TTD bicyclic nucleus
resulted in less active molecules; this is easier to see in
the compounds of series 17 which are all less active than
the thieno[3,4-e] analogues. The analysis of the inhibi-
tory effects brought about by the other ring systems

4112 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Arranz et al.
Ta ble 1. Anti-HIV-1 Activity and Cytotoxicity of 2,4-Disubstituted 1,1,3-Trioxo-2H,4H-hetero[1,2,4]thiadiazines 16-19
HIV-1 (IIIB)
compd no.
X
Y
Z
R1
R2
EC50 (µM)a
CC50 (µM)b
SI
16a
16b
16c
16d
16e
16f
16g
16h
16i
16j
16k
16l
16m
16n
16o
16p
16q
16r
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
S
S
S
S
S
CH
CH
CH
CH
CH
CH
CH
CH
CH
Bn
Bn
Bn
Bn
2-Cl-benzyl
3-Cl-benzyl
4-Cl-benzyl
CH2CO2Et
Me
Et
Me
Et
CH2CN
CH2CtCH
Me
Et
Me
0.10
0.8
1.4
>119.0
>119.0
18.6
129.6
446.3
605.3
>729
>700.6
>340
65.7
417
273
527.5
74.1
68.6
>1190
>149
13
7.4
18
<1
83
2-Cl-benzyl
2-Cl-benzyl
3-Cl-benzyl
3-Cl-benzyl
3-Cl-benzyl
3-Cl-benzyl
4-Cl-benzyl
4-Cl-benzyl
2,6-di-Cl-benzyl
2,6-di-Cl-benzyl
3-Br-benzyl
3-F-benzyl
3,5-di-F-benzyl
phenethyl
phenethyl
phenethyl
2-picolyl
2-picolyl
2-picolyl
3-picolyl
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
>446.3
7.3
7.6
2.1
0.09
0.1
>96
>334
>3778
657
<1
>417
>273
>527.5
>74.1
0.09
0.05
0.3
<1
<1
Et
<1
CH2CN
CH2CN
CH2CN
Et
CH2CN
Bn
Et
CH2CN
Bn
CH2CN
Me
Et
n-Pr
CH2CN
Bn
762
1872
340
38
93.6
102.0
330.0
40.3
226.0
>387.0
>374
166.0
>150.0
>811.0
374
403.0
219.0
>650
498.5
320.6
152.0
>119.0
502.7
527.9
>775.0
>376
>650
683
8.6
3.6
10.9
41.4
1.1
16s
16t
11
21
>9
>340
415
>750
1
18
>1
73
16u
16v
16w
16x
17a
17b
17c
17d
17e
0.4
0.2
>811
20.5
>403
3.0
CH
CH
CH
CH
CH
NCH3
NCH3
CCl
CCl
S
8.3
>78
18a
18b
19a
Me
Et
CH2CN
Bn
CH2CN
Me
>498.5
>320.6
24.5
4.5
<1
N
S
S
CH
CH
CH
CH
CH
<1
6
19b
20a c
20bc
20cc
20d c
20ec
Nevirapine
AZT
>26
559
196
>310
>376
>296
22,767
50,587
0.9
2.7
2.5
1.0
2.2
0.03
0.0007
S
S
S
S
Et
CH2CtCH
Bn
Bn
35.6
a
EC50: dose of compound required to achieve 50% protection of MT-4 cells from HIV-1 induced cytopathogenicity, as determined by
the MIT method. CC50: dosage required to reduce the viability of mock-infected cells by 50%, as determined by the MTT method. c The
b
synthesis and antiviral properties of these compounds were previously described.1 All data represent mean values for at least two separate
experiments.
(compounds 18 and 19) is complicated by the presence
of the N-methyl group in 18 (these compounds are not
active and are noncytotoxic) and the 6-chloro group in
19. These negative results suggest that there may be
limited space around this part of the TTD molecule
when bound to the RT.
Since earlier studies on the TTDs revealed that the
N-4 benzyl derivative 20e was fairly potent, it appeared
of interest to verify if halogenation of this benzyl group
would increase the activity of these analogues. Deriva-
tives 16a , 16b, and 16c, bearing o-, m- and p-chloroben-
zyl substituents at N-4, respectively, were more effective
than their prototype 20e; compounds 16b and 16c,
however, were less selective. The o-Cl substituted
derivative 16a , with an EC50 value of 0.10 µM and a
selectivity index of >1190, was one of the most active
TTDs of this series, and this makes it another lead
compound for the synthesis of further TTD analogues.
In conclusion, we have described the synthesis and
structuresactivity relationships of a second generation
of TTD analogues, which showed improved potency as
inhibitors of the human immunodeficiency virus type 1
[HIV-1(IIIB)] replication in MT-4 cells. We have dem-
onstrated that the introduction of a meta-halogenated
benzyl substituent at the N-2 position resulted in
compounds which exhibit a 10-fold increase in their
ability to inhibit the HIV-1 reverse transcriptase with
respect to the nonhalogenated lead compound (in the
order F > Cl ≈ Br). The presence of the halogen
probably improves the binding of the TTDs to RT via a
favorable electrostatic interaction, since a similar al-
though less marked effect is also observed with the N-2
substituted picolyl derivatives. The fact that the most
active TTDs bear a cyanomethyl, propargyl, or benzyl
group at their N-4 position points to the importance of
the presence of π-electron containing substituents at

Novel TTD Derivatives That Inhibit HIV-1 Replication
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4113
4-[N -(2-P i c o ly l)s u lfa m o y l]t h i o p h e n e -3-c a r b o h y -
d r a zid e (3b). Yield: 90%; mp 173-174 °C (EtOH). IR (KBr,
cm-1): 3405, 3342, 3220 (NH); 1660 (CdO); 1327, 1160 (SO2).
1H NMR (DMSO-d6, δ): 9.93 (bs, 1H, NH); 8.42 (dd, 1H, J 6′5′
) 4.5 Hz, J ) 1.0 Hz, pyridine H-6′); 8.18 (d, 1H, J ) 3.2 Hz,
thiophene); 8.02 (d, 1H, J ) 3.2 Hz, thiophene); 7.69 (dt, 1H,
J 4′5′ ) 7.8 Hz, J ) 1.8 Hz, pyridine H-4′); 7.63 (bs, 1H, NH);
7.35 (d, 1H, J 3′4′ ) 7.8 Hz, pyridine H-3′); 7.23 (ddd, 1H, J 5′4′
) 7.8 Hz, J 5′6′ ) 4.5 Hz, J 5′3′ ) 1.0 Hz, H-5′); 4.13 (s, 2H, CH2).
Anal. (C11H12N4O3S2) C, H, N, S.
this nitrogen. Halogenated benzyl moieties at N-4 are
responsible for the observed increase in the activity of
these derivatives relative to their nonhalogenated par-
ent compound. The work reported here generated the
new lead compounds 16a (QM 96625), 16i (QM 96539),
and 16p (QM 96639) which are now subject of further
optimization in our laboratory.
Exp er im en ta l Section
4-[N -(3-P i c o ly l)s u lfa m o y l]t h i o p h e n e -3-c a r b o h y -
d r a zid e (3c). Yield: 72%; mp 142-144 °C (EtOH). IR (KBr,
cm-1): 3335, 3260 (NH); 1665 (CdO); 1327, 1150 (SO2). 1H
NMR (DMSO-d6, δ): 9.91 (bs, 1H, NH); 8.42-8.39 (m, 2H,
pyridine, H-2′, H-6′); 8.15 (d, 1H, J ) 3.2 Hz, thiophene); 8.00
(d, 1H, J ) 3.2 Hz, thiophene); 7.70 (bs, 1H, NH); 7.64 (dt,
1H, J ) 7.8 Hz, J ) 2.0 Hz, pyridine, H-4′); 7.26 (dd, 1H, J )
7.8 Hz, J ) 4.7 Hz, pyridine H-5′); 4.58 (bs, 2H, NH2); 4.13 (s,
2H, CH2). Anal. (C11H12N4O3S2) C, H, N, S.
Ch em ica l P r oced u r es. Melting points were determined
on a Gallenkamp capillary apparatus and are uncorrected.
Elemental analyses were performed with a Heraeus CHN-
RAPID instrument at the Centro Nacional de Qu´ımica Or-
ga´nica, CSIC, Madrid. Analytical results which are only
indicated by symbols were found within (0.4% of the theoreti-
cal values. 1H NMR spectra (300 MHz) were recorded on a
Varian XL-300 spectrometer in the indicated solvent. Chemi-
cal shifts are expressed in δ units from tetramethylsilane
(TMS) as an internal standard. IR spectra were measured
with a Shimadzu IR-435 spectrometer. Silica gel/TLC cards
(Fluka, silica gel-precoated aluminum cards with fluorescent
indicator 254 nm) were used for thin-layer chromatography
(TLC). Developed plates were visualized by UV light. Flash
column chromatography was performed on columns packed
with silica gel 60 (230-400 mesh) (Merck).
Gen er a l P r oced u r e for th e P r ep a r a tion of Der iva tives
2a -c. Exa m p le: 4-(N-P h en eth ylsu lfa m oyl)th iop h en e-3-
m eth yl Ca r boxyla te (2a ). To a mixture of 1 (5.0 g, 20 mmol),
K2CO3 (1.44 g, 10 mmol), and THF (25 mL) was added
dropwise a solution of 2-phenylethylamine (2.42 g, 2.9 mL, 20
mmol) in the same solvent, maintaining the temperature below
10 °C. The reaction mixture was stirred at 5 °C for 1 h, and
then it was refluxed for 6 h. The solvent was evaporated, and
the residue was purified by column chromatography using
hexane/AcOEt 3:1 as eluent to give 2a (75%) as an oil. IR (film,
cm-1): 3300 (NH); 1722 (CdO); 1335, 1165 (SO2); 1250 (C-
O). 1H NMR (DMSO-d6, δ): 8.43 (d, 1H, J ) 3.3 Hz,
thiophene); 8.25 (d, 1H, J ) 3.3 Hz, thiophene); 7.28-7.06 (m,
5H, benzene); 6.82 (t, 1H, J ) 5.7 Hz, NH); 3.76 (s, 3H, CH3);
3.12 (dt, 2H, J ) 5.7 Hz, J ) 7.2 Hz, CH2N); 2.96 (t, 2H, J )
7.2 Hz, CH2). Anal. (C14H15NO4S2) C, H, N, S.
Gen er a l P r oced u r e for th e P r ep a r a tion of Der iva tives
4a -b. Exa m p le: 4-(N-P h en eth ylsu lfa m oyl)th iop h en e-3-
ca r boxy a zid e (4a ). To a suspension of 3a (0.5 g, 1.5 mmol)
in 2 N hydrochloric acid (6 mL) and acetic acid (5 mL) was
added dropwise a solution of sodium nitrite (0.2 g, 2.9 mmol)
in water (0.5 mL), maintaining the temperature below 10 °C.
The reaction mixture was stirred at this temperature for 2 h,
and the precipitate was filtered off, washed with water, and
dried to yield 4a (0.43 g, 83%). The compound was pure
enough to be used as such in the following step. IR (KBr,
cm-1): 3250 (NH); 2160, 1215 (N3); 1677 (CdO); 1322, 1160
(SO2).
4-[N-(2-P icolyl)su lfa m oyl]th iop h en e-3-ca r boxy Azid e
(4b). Yield: 76%. IR (KBr, cm-1): 3260 (NH); 2150, 1210 (N3);
1673 (CdO); 1325, 1150 (SO2).
Gen er a l P r oced u r e for th e P r ep a r a tion of Der iva tives
5a -c. Exa m p le: 2-(2-P h en yleth yl)-1,1,3-tr ioxo-2H,4H-
th ien o[3,4-e][1,2,4]th ia d ia zin e (5a ). A solution of com-
pound 4a (0.5 g, 1.4 mmol) in dry toluene (25 mL) was refluxed
for 5 h. The precipitate was filtered and recrystallized from
Et2O-Ligroin to give 5a (70%) as white crystals; mp 136-
138 °C. IR (KBr, cm-1): 1695 (CdO); 1337, 1167 (SO2). 1H
NMR (DMSO-d6, δ): 11.26 (bs, 1H, NH); 8.56 (d, 1H, J ) 3.1
Hz, thiophene); 7.26-7.17 (m, 5H, benzene); 7.01 (d, 1H, J )
3.1 Hz, thiophene); 3.92 (t, 2H, J ) 7.6 Hz, CH2N); 2.90 (t,
2H, J ) 7.6 Hz, CH2). EI-MS, m/z: 308 (M+). Anal.
(C13H12N2O3S2) C, H, N, S.
4-[N-(2-P icolyl)su lfa m oyl]th iop h en e-3-m eth yl Ca r box-
yla te (2b). Yield: 67%. mp 72-74 °C (EtOH). IR (KBr,
cm-1): 3242 (NH); 1720 (CdO); 1335, 1170 (SO2); 1250 (C-
O). 1H NMR (DMSO-d6, δ): 12.00-9.00 (bs, 1H, NH); 8.38
(d, 1H, J ) 3.4 Hz, thiophene); 8.20 (d, 1H, J ) 3.4 Hz,
thiophene); 7.67 (dt, 1H, J 4′6′ ) 1.8 Hz, J 4′3′ ) 7.7 Hz, pyridine
H-4′); 7.49 (dd, 1H, J 6′5′ ) 4.8 Hz, J 6′4′ ) 1.7 Hz, pyridine H-6′);
2-P i c o ly l-1,1,3-t r i o x o -2H ,4H -t h i e n o [3,4-e][1,2,4]-
th ia d ia zin e (5b). Yield: 85%; mp 210-212 °C (EtOH). IR
(KBr, cm-1): 1705 (CdO); 1335, 1170 (SO2). 1H NMR (DMSO-
d6, δ): 8.59 (d, 1H, J ) 3.2 Hz, thiophene); 8.46 (ddd, 1H, J )
4.8 Hz, J ) 1.7 Hz, J ) 1.0 Hz, pyridine H-3′); 7.75 (dt, 1H, J
) 7.7 Hz, J ) 1.7 Hz, pyridine H-5′); 7.29 (d, 1H, J ) 7.9 Hz,
pyridine H-6′); 7.25 (ddd, 1H, J ) 7.4 Hz, J ) 4.8 Hz, J ) 1.0
Hz, pyridine H-4′); 7.06 (d, 1H, J ) 3.2 Hz, thiophene); 5.02
(s, 2H, CH2). EI-MS, m/z: 295 (M+). Anal. (C11H9N3O3S2) C,
H, N, S.
7.28 (d, 1H, J 3′4′ ) 7.7 Hz, pyridine H-3′); 7.19 (dd, 1H, J 5′6′
)
4.8 Hz, J 5′4′ ) 7.3 Hz, pyridine H-5′); 4.22 (s, 2H, CH2); 3.83
(s, 3H, CH3). Anal. (C12H12N2O4S2) C, H, N, S.
4-[N-(3-P icolyl)su lfa m oyl]th iop h en e-3-m eth yl Ca r box-
yla te (2c). Yield: 50%; mp 108-110 °C (EtOH-H2O). IR
(KBr, cm-1): 3290 (NH); 1717 (CdO); 1255 (C-O); 1330, 1152
(SO2). 1H NMR (DMSO-d6, δ): 8.39 (m, 2H, pyridine, H-2′,
H-6′); 8.35 (d, 1H, J ) 3.4 Hz, thiophene); 8.19 (d, 1H,
thiophene); 7.60 (dt, 1H, J ) 7.9 Hz, J ) 2.0 Hz, pyridine,
H-4′); 7.54 (bs, 1H, NH); 7.24 (dd, 1H, J ) 7.9 Hz, J ) 4.8 Hz,
pyridine, H-5′); 4.18 (s, 2H, CH2); 3.82 (s, 3H, CH3). Anal.
(C12H12N2O4S2) C, H, N, S.
Gen er a l P r oced u r e for th e P r ep a r a tion of Der iva tives
3a -c. Exa m p le: 4-(N-P h en eth ylsu lfa m oyl)th iop h en e-3-
ca r boh yd r a zid e (3a ). A mixture of compound 2a (5 g, 15
mmol) and hydrazine hydrate (98%) (2.06 g, 2 mL, 40 mmol)
in ethanol (11 mL) was refluxed for 1 h. The precipitate
formed was filtered off, washed with ice cold ethanol, and
purified by recrystallization to yield 3a (3.20 g, 64%); mp 152-
154 °C (MeOH). IR (KBr, cm-1): 3330, 3290 (NH); 1660 (Cd
O); 1332, 1175 (SO2). 1H NMR (DMSO-d6, δ): 9.94 (bs, 1H,
NH); 8.25 (d, 1H, J ) 3.1 Hz, thiophene); 8.05 (d, 1H, J ) 3.1
Hz, thiophene); 7.21-7.13 (m, 6H, benzene and NH); 4.60 (bs,
2H, NH2); 3.05 (t, 2H, J ) 7.3 Hz, CH2); 2.70 (t, 2H, J ) 7.3
Hz, CH2). Anal. (C13H15N3O3S2) C, H, N, S.
2-(3-P icolyl)-1,1,3-t r ioxo-2H ,4H -t h ie n o[3,4-e][1,2,4]-
th ia d ia zin e (5c). To a solution of compound 3c (0.64 g, 2.0
mmol) in 2 N nitric acid (7 mL) was added dropwise a solution
of sodium nitrite (0.27 g) in water (0.5 mL), maintaining the
temperature below 10 °C. The reaction mixture was stirred
at this temperature for 2 h, and then it was extracted three
times with toluene. The organic extracts were combined,
washed with water, and dried. The solution was filtered and
refluxed for 5 h. The solvent was evaporated at reduced
pressure, and the residue was recrystallized to yield 5c (51%);
mp 192-194 °C (acetonitrile). IR (KBr, cm-1): 1695 (CdO);
1340, 1180 (SO2). 1H NMR (DMSO-d6, δ): 11.40 (bs, 1H, NH);
8.64 (d, 1H, J ) 3.2 Hz, thiophene); 8.56 (d, 1H, J 2′4′ ) 2.0 Hz,
pyridine H-2′); 8.48 (dd, 1H, J 6′5′ ) 4.9 Hz, J 6′4′ ) 1.5 Hz,
pyridine H-6′); 7.73 (dt, 1H, J 4′3′ ) 7.8 Hz, J 4′2′ ) J 4′6′ ) 1.9
Hz, pyridine H-4′); 7.37 (dd, 1H, J 4′5′ ) 7.8 Hz, J 5′6′ ) 4.9 Hz,

4114 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Arranz et al.
pyridine H-5′); 7.05 (d, 1H, J ) 3.2 Hz, thiophene); 4.96 (s,
2H, CH2). EI-MS, m/z: 295 (M+). Anal. (C11H9N3O3S2) C, H,
N, S.
2-(m -Ch lor ob en zyl)-1,1,3-t r ioxo-2H ,4H -t h ien o[3,4-e]-
[1,2,4]th ia d ia zin e (13b). The thiadiazine 10 reacted with
3-chlorobenzyl bromide for 18 h. The residue was chromato-
graphed (hexane/ethyl acetate 2:1). Yield: 55%; white solid
mp 196-198 °C (acetonitrile). IR (KBr, cm-1): 3190 (NH);
1695 (CdO); 1345, 1185 (SO2). 1H NMR (DMSO-d6, δ): 11.38
(bs, 1H, NH); 8.63 (d, 1H, J ) 3.2 Hz, thiophene); 7.37-7.29
(m, 4H, benzene); 7.05 (d, 1H, J ) 3.2 Hz, thiophene); 4.92 (s,
2H, CH2). EI-MS, m/z: 328 (M+). Anal. (C12H9ClN2O3S2) C,
H, N, S.
2-(p-Ch lor oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o[3,4-e][1,2,4]-
th ia d ia zin e (13c). The thiadiazine 10 reacted with 4-chlo-
robenzyl chloride for 24 h. The residue was chromatographed
(hexane/ethyl acetate 3:1). Yield: 61%; white solid mp 164-
166 °C (EtOH). IR (KBr, cm-1): 3190 (NH); 1695 (CdO); 1345,
1170 (SO2). 1H NMR (DMSO-d6, δ): 11.38 (bs, 1H, NH); 8.62
(d, 1H, J ) 3.3 Hz, thiophene); 7.41-7.30 (d, 4H, benzene);
7.03 (d, 1H, J ) 3.3 Hz, thiophene); 4.90 (s, 2H, CH2). EI-
MS, m/z: 328 (M+). Anal. (C12H9ClN2O3S2) C, H, N, S.
2-(2,6-Dich lor oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o[3,4-e]-
[1,2,4]th ia d ia zin e (13d ). The thiadiazine 10 reacted with
2,6-dichlorobenzyl bromide for 48 h. Yield: 53%; white solid
mp 211-213 °C (EtOH). IR (KBr, cm-1): 3200 (NH); 1695
(CdO); 1340, 1180 (SO2). 1H NMR (DMSO-d6, δ): 11.33 (bs,
1H, NH); 8.45 (d, 1H, J ) 3.1 Hz, thiophene); 7.43-7.28 (m,
3H, benzene); 7.02 (d, 1H, J ) 3.1 Hz, thiophene); 5.21 (s, 2H,
CH2). EI-MS, m/z: 362 (M+). Anal. (C12H8Cl2N2O3S2) C, H,
N, S.
2-(m -Br om ob en zyl)-1,1,3-t r ioxo-2H ,4H -t h ien o[3,4-e]-
[1,2,4]th ia d ia zin e (13e). The thiadiazine 10 reacted with
3-bromobenzyl bromide for 24 h. The residue was chromato-
graphed (dichloromethane). Yield: 48%; white solid mp 182-
184 °C (EtOH). IR (KBr, cm-1): 1695 (CdO); 1345, 1182 (SO2).
1H NMR (DMSO-d6, δ): 11.50 (bs, 1H, NH); 8.73 (d, 1H, J )
3.2 Hz, thiophene); 7.51-7.28 (m, 4H, benzene); 7.05 (d, 1H,
J ) 3.2 Hz, thiophene); 4.91 (s, 2H, CH2). EI-MS, m/z: 374
(M+ + 2). Anal. (C12H9BrN2O3S2) C, H, N, S.
2-(m -F lu or ob en zyl)-1,1,3-t r ioxo-2H ,4H -t h ien o[3,4-e]-
[1,2,4]th ia d ia zin e (13f). The thiadiazine 10 reacted with
3-fluorobenzyl bromide for 24 h. The residue was chromato-
graphed (hexane/ethyl acetate 5:1). Yield: 44%; white solid
mp 175-177 °C (EtOH). IR (KBr, cm-1): 1700 (CdO); 1340,
1182 (SO2). 1H NMR (DMSO-d6, δ): 11.50 (bs, 1H, NH); 8.62
(d, 1H, J ) 3.2 Hz, thiophene); 7.41-7.34 (m, 1H, benzene);
7.18-7-07 (m, 3H, benzene); 7.05 (d, 1H, J ) 3.2 Hz,
thiophene); 4.94 (s, 2H, CH2). EI-MS, m/z: 312 (M+). Anal.
(C12H9FN2O3S2) C, H, N, S.
2-(3,5-Diflu or oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o[3,4-e]-
[1,2,4]th ia d ia zin e (13 g). The thiadiazine 10 reacted with
3,5-difluorobenzyl bromide for 24 h. The residue was chro-
matographed (hexane/ethyl acetate 5:1). Yield: 54%; white
solid mp 182-184 °C. IR (KBr, cm-1): 1695 (CdO); 1352, 1183
(SO2). 1H NMR (DMSO-d6, δ): 11.00 (bs, 1H, NH); 8.66 (d,
1H, J ) 3.2 Hz, thiophene); 7.17-7.02 (m, 4H, thiophene and
aromatic); 4.96 (s, 2H, CH2). EI-MS, m/z: 330 (M+). Anal.
(C12H8F2N2O3S2) C, H, N, S.
2-B e n z y l-1,1,3-t r i o x o -2H ,4H -t h i e n o [2,3-e][1,2,4]-
t h ia d ia zin e (14) a n d 2,4-Dib en zyl-1,1,3-t r ioxo-2H ,4H -
th ien o[2,3-e][1,2,4]th ia d ia zin e (17e). The thiadiazine 11
reacted with benzyl bromide for 24 h. Purification of the
residue by column chromatography (hexane/AcOEt 3:1) gave
from the faster eluting fractions compound 17e (7.5%); mp
125-127 °C. IR (KBr, cm-1): 1695 (CdO); 1335, 1172 (SO2).
1H NMR (DMSO-d6, δ): 7.42-7.25 (m, 12H, thiophene and
benzene); 5.18 (s, 2H, CH2); 5.04 (s, 2H, CH2). From the slower
moving fractions the 2-benzyl derivative 14 (50%) was ob-
tained; mp 167-169 °C (EtOH-H2O). IR (KBr, cm-1): 1675
(CdO); 1320, 1155 (SO2). 1H NMR (DMSO-d6, δ): 7.39-7.20
(m, 7H, thiophene and benzene); 4.93 (s, 2H, CH2). EI-MS,
m/z: 395 (M+ + 1). Anal. (C12H10N2O3S2) C, H, N, S.
2-Ben zyl-6-m eth yl-1,1,3-tr ioxo-2H,4H-p yr a zolo[4,3-e]-
[1,2,4]th ia d ia zin e (15). The thiadiazine 12 reacted with
benzyl bromide for 24 h to give 15 (38%) as a white solid; mp
209-211 °C (AcOEt). IR (KBr, cm-1): 3200 (NH); 1685 (Cd
2-(N-Ben zylsu lfa m oyl)-5-ch lor ot h iop h en e (6). To a
solution of 5-chloro-2-chlorosulfonylthiophene (6.0 g, 30 mmol)
in THF (10 mL) was added a solution of benzylamine (6.30
mL, 60 mmol) in THF (3 mL), maintaining the temperature
below 10 °C. The reaction mixture was stirred at room
temperature for 1 h, and then it was refluxed for 30 min. After
cooling, the precipitate was filtered and washed with ethyl
ether. The filtrate was washed with 2 N HCl and water, and
the organic layer was dried (Na2SO4) and concentrated in
vacuo. Recrystallization of the residue gave 6 (6.97 g, 88%)
as a white solid; mp 81-83 °C (EtOH-H2O). IR (KBr, cm-1):
3290, 3270 (NH); 1330, 1155 (SO2). 1H NMR (DMSO-d6, δ):
8.51 (bs, 1H, exchange with D2O, NH); 7.44 (d, 1H, J ) 4.0
Hz, thiophene); 7,27 (m, 5H, benzene); 7.20 (d, 1H, J ) 4.0
Hz, thiophene); 4.10 (s, 2H, CH2). Anal. (C11H10ClNO2S2) C,
H, N, S.
2-(N-Ben zylsu lfa m oyl)-5-ch lor oth iop h en e-3-ca r boxy-
lic Acid (7). To a solution of 6 (1.0 g, 3.5 mmol) in dry THF
(10 mL), under N2 and at -60 °C, was added dropwise n-BuLi
(2.5 M solution in hexane) (3.47 mL, 8.7 mmol). The reaction
mixture was stirred at -30 °C for 90 min and then was poured
over solid CO2. After the mixture was stirred for 2 h, the
solvent was evaporated, and the residue was treated with
water and acidified with 35% HCl. The mixture was extracted
with ethyl ether, and the organic layer was separated, washed
with water, and dried (Na2SO4). Removal of the solvent
furnished 7 (1.0 g, 88%) which was recrystallized from toluene;
mp 152-154 °C. IR (KBr, cm-1): 3350 (NH); 1720, 1700 (Cd
O); 1335, 1157 (SO2). 1H NMR (DMSO-d6, δ): 16.00-10.00
(bs, 1H, exchange with D2O, CO2H); 8.05 (t, 1H, J ) 5.5 Hz,
exchange with D2O, NH); 7.37 (s, 1H, thiophene); 7.21 (s, 5H,
benzene; 4.21 (d, 2H, J ) 5.5 Hz, CH2). Anal. (C12H10ClNO4S2)
C, H, N, S.
2-Ben zyl-6-ch lor o-1,1,3-tr ioxo-2H,4H-th ien o[3,2-e][1,2,4]-
th ia d ia zin e (8) a n d 2-Ben zyl-5-ch lor o-1,1,3-tr ioxo-2,3-
d ih yd r o-th ien o[3,2-d ]isoth ia zole (9). To a suspension of
7 (0.50 g, 1.5 mmol) and diphenylphosphoryl azide (DPPA)
(0.21 mL, 1.5 mmol) in dry toluene (15 mL) was added
triethylamine (0.21 mL (1.5 mmol). The reaction mixture was
stirred at 80 °C for 24 h. The solvent was evaporated in vacuo,
and the oily residue was purified by column chromatography
(hexane/AcOEt 6:1). The faster moving fractions gave the
thienosaccharine 9 (0.12 g, 26%; mp 164-166 °C). IR (KBr,
cm-1): 1737 (CdO); 1340, 1180 (SO2). 1H NMR (DMSO-d6,
δ): 7.76 (s, 1H, thiophene); 7.37-7.31 (m, 5H, benzene); 4.85
(s, 2H, CH2). The slower moving fractions gave the thienothi-
adiazine 8 (38%) which was recrystallized from EtOH-H2O;
mp 187-189 °C. IR (KBr, cm-1): 3230 (NH); 1680 (CdO);
1345, 1185 (SO2). 1H NMR (DMSO-d6, δ): 11.20 (bs, 1H, NH);
7.38-7.24 (m, 5H, benzene); 6.99 (s, 1H, thiophene); 4.96 (s,
2H, CH2). EI-MS, m/z: 329 (M++1). Anal. (C12H9ClN2O3S2)
C, H, N, S.
Gen er a l Meth od for th e Syn th esis of th e 2-Su bstitu ted
1,1,3-Tr ioxo-2H,4H-h eter o[1,2,4]th ia d ia zin e (13-15). To
a solution of the previously described 1,1,3-trioxo-2H,4H-
hetero[1,2,4]thiadiazine11 10-12 (1 equiv) in dry DMF, under
N2, was added slowly sodium hydride (60% dispersion in
mineral oil) (1 equiv), maintaining the temperature below 10
°C. After 15 min, the appropriate alkyl halide (1 equiv) was
added, and the reaction mixture was stirred at 5-60 °C for
15-48 h. After cooling, the solvent was evaporated to dryness
at reduced pressure, and the crude residue was purified by
column chromatography or by recrystallization.
2-(o-Ch lor oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o[3,4-e][1,2,4]-
th ia d ia zin e (13a ). The thiadiazine 10 reacted with 2-chlo-
robenzyl chloride for 18 h. Yield: 51%; white solid mp 188-
190 °C (EtOH). IR (KBr, cm-1): 1695 (CdO); 1330, 1175 (SO2).
1H NMR (DMSO-d6, δ): 11.40 (bs, 1H, NH); 8.65 (d, 1H, J )
3.2 Hz, thiophene); 7.49-7.17 (m, 4H, benzene); 7.09 (d, 1H,
J ) 3.2 Hz, thiophene); 5.00 (s, 2H, CH2). EI-MS, m/z: 328
(M+). Anal. (C12H9ClN2O3S2) C, H, N, S.

Novel TTD Derivatives That Inhibit HIV-1 Replication
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4115
O); 1325, 1165 (SO2). 1H NMR (DMSO-d6, δ): 11.00 (bs, 1H,
NH); 7.76 (s, 1H, pyrazole); 7.36-7.21 (m, 5H, benzene); 4.91
(s, 2H, CH2); 3.96 (s, 3H, CH3). EI-MS, m/z: 292 (M+). Anal.
(C12H12N4O3S) C, H, N, S.
190 °C (acetonitrile). IR (KBr, cm-1): 1683 (CdO); 1337, 1192
(SO2). 1H NMR (DMSO-d6, δ): 8.72 (d, 1H, J ) 3.2 Hz,
thiophene); 7.41 (d, 1H, J ) 3.2 Hz, thiophene); 7.38-7.31 (m,
4H, benzene); 4.95 (s, 2H, CH2); 3.39 (s, 3H, CH3). Anal.
(C13H11ClN2O3S2) C, H, N, S.
Gen er a l P r oced u r e for th e Syn th esis of 2,4-Disu bsti-
tu ted 1,1,3-Tr ioxo-2H,4H-h eter o[1,2,4]th ia d ia zin es (16-
19). To a solution of the corresponding 2-substituted het-
erothiadiazine (1 equiv) in dry DMF, under N2, was added
slowly sodium hydride (60% dispersion in mineral oil, 1.0-
1.5 equiv) maintaining the temperature below 10 °C. After
15 min, the appropriate alkyl halide (1.0-1.2 equiv) was
added, and the reaction mixture was stirred for 30-40 h at
50-60 °C. The solvent was evaporated to dryness, and the
crude material was filtered, washed with water, dried, and
chromatographed or recrystallized from a suitable solvent.
2-Ben zyl-4-(2-ch lor oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16a ). This compound was obtained
(80%) from reaction of 2-benzyl-1,1,3-trioxo-2H,4H-thieno[3,4-
e][1,2,4]thiadiazine1 with 2-chlorobenzyl chloride. The crude
material was chromatographed (hexane/dichloromethane 2:1);
mp 156-158 °C. IR (KBr, cm-1): 1697 (CdO); 1343, 1172
(SO2). 1H NMR (DMSO-d6, δ): 8.73 (d, 1H, J ) 3.1 Hz,
thiophene); 7.51 (dd, 1H, J ) 7.7 Hz, benzene); 7.34-7.22 (m,
8H, thiophene and benzene); 6.98 (d, 1H, J ) 7.6 Hz, benzene);
5.23 (s, 2H, CH2); 5.00 (s, 2H, CH2). Anal. (C19H15ClN2O3S2)
C, H, N, S.
2-Ben zyl-4-(3-ch lor oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16b). This compound was obtained
(75%) from reaction of 2-benzyl-1,1,3-trioxo-2H,4H-thieno[3,4-
e][1,2,4]thiadiazine1 with 3-chlorobenzyl bromide. The crude
material was chromatographed (hexane/dichloromethane 2:1);
mp 148-150 °C. IR (KBr, cm-1): 1693 (CdO); 1345, 1167
(SO2). 1H NMR (DMSO-d6, δ): 8.71 (d, 1H, J ) 3.2 Hz,
thiophene); 7.38-7.17 (m, 10H, thiophene and benzene); 5.21
(s, 2H, CH2); 5.01 (s, 2H, CH2). Anal. (C19H15ClN2O3S2) C, H,
N, S.
2-Ben zyl-4-(4-ch lor oben zyl)-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16c). This compound was obtained
(78%) from reaction of 2-benzyl-1,1,3-trioxo-2H,4H-thieno[3,4-
e][1,2,4]thiadiazine1 with 4-chlorobenzyl chloride. The crude
material was chromatographed (hexane/AcOEt 1:1); mp 135-
137 °C. IR (KBr, cm-1): 1692 (CdO); 1345, 1167 (SO2). 1H
NMR (DMSO-d6, δ): 8.70 (d, 1H, J ) 3.1 Hz, thiophene); 7.41-
7.23 (m, 10H, thiophene CH and benzene); 5.19 (s, 2H, CH2);
5.00 (s, 2H, CH2). Anal. (C19H15ClN2O3S2) C, H, N, S.
2-Ben zyl-4-(eth oxycar bon ylm eth yl)-1,1,3-tr ioxo-2H,4H-
th ien o[3,4-e][1,2,4]th ia d ia zin e (16d ). This compound was
obtained (78%) from reaction of 2-benzyl-1,1,3-trioxo-2H,4H-
thieno[3,4-e][1,2,4]thiadiazine1 with ethyl bromoacetate. The
crude material was chromatographed (dichloromethane); mp
129-131 °C. IR (KBr, cm-1): 1762 (CdO); 1692 (CdO); 1345,
1175 (SO2); 1200 (C-O). 1H NMR (DMSO-d6, δ): 8.72 (d, 1H,
J ) 3.2 Hz, thiophene); 7.45 (d, 1H, J ) 3.2 Hz, thiophene);
7.30 (m, 5H, benzene); 4.97 (s, 2H, CH2); 4.73 (s, 2H, CH2);
4.12 (q, 2H, J ) 7.1 Hz, CH2O); 1.16 (t, 2H, J ) 7.1 Hz, CH3).
Anal. (C16H16N2O5S2) C, H, N, S.
2-(3-Ch lor oben zyl)-4-eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16h ). This compound was obtained
(92%) from reaction of 13b with ethyl iodide; mp 132-134 °C
(acetonitrile). IR (KBr, cm-1): 1670 (CdO); 1340, 1195 (SO2).
1H NMR (DMSO-d6, δ): 8.72 (d, 1H, J ) 3.1 Hz, thiophene);
7.52 (d, 1H, J ) 3.1 Hz, thiophene); 7.37-7.28 (m, 4H,
benzene); 4.95 (s, 2H, CH2); 3.95 (q, 2H, J ) 7.0 Hz, CH2);
1.19 (t, 3H, J ) 7.0 Hz, CH3). Anal. (C14H13ClN2O3S2) C, H,
N, S.
2-(3-Ch lor oben zyl)-4-cya n om eth yl-1,1,3-tr ioxo-2H,4H-
th ien o[3,4-e][1,2,4]th ia d ia zin e (16i). This compound was
obtained (80%) from reaction of 13b with 2-chloroacetonitrile.
The crude material was chromatographed (hexane/AcOEt 3:1);
mp 188-190 °C. IR (KBr, cm-1): 1695 (CdO); 1345, 1175
(SO2). 1H NMR (DMSO-d6, δ): 8.82 (d, 1H, J ) 3.1 Hz,
thiophene); 7.64 (d, 1H, J ) 3.1 Hz, thiophene); 7.43-7.33 (m,
4H, benzene); 5.15 (s, 2H, CH2); 5.00 (s, 2H, CH2). Anal.
(C14H10ClN3O3S2) C, H, N, S.
2-(3-Ch lor ob e n zyl)-4-p r op a r gyl-1,1,3-t r ioxo-2H ,4H -
th ien o[3,4-e][1,2,4]th ia d ia zin e (16j). This compound was
obtained (88%) from reaction of 13b with propargyl bromide.
The crude material was chromatographed (hexane/dichlo-
romethane 2:1); mp 137-139 °C. IR (KBr, cm-1): 3300; 1690
(CdO); 1330, 1145 (SO2). 1H NMR (DMSO-d6, δ): 8.74 (d, 1H,
J ) 3.1 Hz, thiophene); 7.48 (d, 1H, J ) 3.1 Hz, thiophene);
7.38-7.29 (m, 4H, benzene); 4.97 (s, 2H, CH2); 4.74 (d, 2H, J
) 2.4 Hz, CH2); 3.34 (t, 1H, J ) 2.4 Hz, tCH). Anal. (C15H11
ClN2O3S2) C, H, N, S.
-
2-(4-Ch lor oben zyl)-4-m eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16k ). This compound was obtained
(90%) from reaction of 13c with methyl iodide; mp 179-180
°C (acetonitrile). IR (KBr, cm-1): 1685 (CdO); 1337, 1195
(SO2). 1H NMR (DMSO-d6, δ): 8.71 (d, 1H, J ) 3.3 Hz,
thiophene); 7.41-7.32 (m, 5H, benzene and thiophene); 4.93
(s, 2H, CH2); 3.36 (s, 3H, CH3). Anal. (C13H11ClN2O3S2) C, H,
N, S.
2-(4-Ch lor oben zyl)-4-eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16l). This compound was obtained
(90%) from reaction of 13c with ethyl iodide; mp 188-190 °C
(acetonitrile). IR (KBr, cm-1): 1692 (CdO); 1320, 1190 (SO2).
1H NMR (DMSO-d6, δ): 8.70 (d, 1H, J ) 3.1 Hz, thiophene);
7.51 (d, 1H, J ) 3.1 Hz, thiophene); 7.42-7.31 (d, 4H, benzene);
4.93 (s, 2H, CH2); 3.94 (q, 2H, J ) 6.9 Hz, CH2); 1.18 (t, 3H, J
) 6.9 Hz, CH3). Anal. (C14H13ClN2O3S2) C, H, N, S.
2-(2,6-Dich lor ob en zyl)-4-m et h yl-1,1,3-t r ioxo-2H ,4H -
th ien o[3,4-e][1,2,4]th ia d ia zin e (16m ). This compound was
obtained (90%) from reaction of 13d with methyl iodide; mp
270-272 °C (acetonitrile). IR (KBr, cm-1): 1695 (CdO); 1345,
1190 (SO2). 1H NMR (DMSO-d6, δ): 8.56 (d, 1H, J ) 3.1 Hz,
thiophene); 7.43-7.31 (m, 4H, benzene and thiophene); 5.22
(s, 2H, CH2); 3.39 (s, 3H, CH3). Anal. (C13H10Cl2N2O3S2) C,
H, N, S.
2-(2,6-Dich lor oben zyl)-4-eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16n ). This compound was obtained
(93%) from reaction of 13d with ethyl iodide; mp 184-186 °C
(acetonitrile). IR (KBr, cm-1): 1692 (CdO); 1345, 1175 (SO2).
1H NMR (DMSO-d6, δ): 8.52 (d, 1H, J ) 3.1 Hz, thiophene);
7.49 (d, 1H, J ) 3.1 Hz, thiophene); 7.43-7.27 (m, 3H,
benzene); 5.25 (s, 2H, CH2); 3.95 (q, 2H, J ) 7.0 Hz, CH2);
1.17 (s, 3H, J ) 7.0 Hz, CH3). Anal. (C14H12Cl2N2O3S2) C, H,
N, S.
2-(2-Ch lor oben zyl)-4-m eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16e). This compound was obtained
(80%) from reaction of 13a with methyl iodide; mp 198-200
°C (MeOH). IR (KBr, cm-1):: 1685 (CdO); 1340, 1193 (SO2).
1H NMR (DMSO-d6, δ): 8.73 (d, 1H, J ) 3.1 Hz, thiophene);
7.46-7.23 (m, 5H, thiophene and benzene); 5.03 (s, 2H, CH2);
3.41 (s, 3H, CH3). Anal. (C13H11ClN2O3S2) C, H, N, S.
2-(2-Ch lor oben zyl)-4-eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16f). This compound was obtained
(87%) from reaction of 13a with ethyl iodide; mp 138-140 °C
1
(MeOH). IR (KBr, cm-1):: 1680 (CdO); 1340, 1190 (SO2). H
NMR (DMSO-d6, δ): 8.70 (d, 1H, J ) 3.2 Hz, thiophene); 7.54
(d, 1H, J ) 3.2 Hz, thiophene); 7.48-7.17 (m, 4H, benzene);
5.04 (s, 2H, CH2); 3.97 (q, 2H, J ) 7.1 Hz, CH2); 1.21 (t, 3H, J
) 7.1 Hz, CH3). Anal. (C14H13ClN2O3S2) C, H, N, S.
2-(3-Ch lor oben zyl)-4-m eth yl-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16 g). This compound was ob-
tained (90%) from reaction of 13b with methyl iodide; mp 188-
2-(3-Br om oben zyl)-4-cya n om eth yl-1,1,3-tr ioxo-2H,4H-
th ien o[3,4-e][1,2,4]th ia d ia zin e (16o). This compound was
obtained (72%) from reaction of 13e with 2-chloroacetonitrile.
The crude material was chromatographed (dichloromethane);
mp 182-184 °C. IR (KBr, cm-1): 1692 (CdO); 1335, 1170
(SO2). 1H NMR (DMSO-d6, δ): 8.82 (d, 1H, J ) 3.1 Hz,
thiophene); 7.65 (d, 1H, J ) 3.1 Hz, thiophene); 7.58-7.33 (m,

4116 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Arranz et al.
4H, benzene); 5.15 (s, 2H, CH2); 5.00 (s, 2H, CH2). Anal.
(C14H10BrN3O3S2) C, H, N, S.
4-Ben zyl-2-picolyl-1,1,3-tr ioxo-2H,4H-th ien o[3,4-e][1,2,4]-
th ia d ia zin e (16w ). This compound was obtained (63%) from
reaction of 5b with benzyl bromide; mp 125-127 °C (MeOH).
IR (KBr, cm-1): 1680 (CdO); 1330, 1165 (SO2). 1H NMR
(DMSO-d6, δ): 8.67 (d, 1H, J ) 3.2 Hz, thiophene); 8.49 (ddd,
1H, J ) 4.8 Hz, J ) 1.8 Hz, J ) 0.9 Hz, pyridine H-3′); 7.78
(dt, 1H, J ) 7.7 Hz, J ) 1.8 Hz, pyridine H-5′); 7.34-7.24 (m,
8H, thiophene, benzene, and pyridine H-6′and H-4′); 5.21 (s,
2H, CH2); 5.13 (s, 2H, CH2). Anal. (C18H15N3O3S2) C, H, N,
S.
4-Cya n om eth yl-2-(3-p icolyl)-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16x). This compound was obtained
(66%) from reaction of 5c with 2-chloroacetonitrile. The crude
material was chromatographed (dichloromethane/EtOH 100:
1); mp 151-153 °C. IR (KBr, cm-1): 1698 (CdO); 1347, 1165
(SO2). 1H NMR (DMSO-d6, δ): 8.80 (d, 1H, J ) 3.1 Hz,
thiophene); 8.60 (d, 1H, J 2′4′ ) 1.9 Hz, pyridine H-2′); 8.50 (dd,
1H, J 6′4′ ) 1.6 Hz, J 6′5′ ) 4.7 Hz, pyridine H-6′); 7.77 (ddd, 1H,
J 4′5′ ) 7.8 Hz, J 4′2′ ) 1.9 Hz, J 4′6′ ) 1.6 Hz, pyridine H-4′); 7.63
(d, 1H, J ) 3.1 Hz, thiophene); 7.39 (dd, 1H, J 5′4′ ) 7.8 Hz,
J 5′6′ ) 4.7 Hz, pyridine H-5′); 5.14 (s, 2H, CH2); 5.03 (s, 2H,
CH2). Anal. (C13H10N4O3S2) C, H, N, S.
4-Cya n om eth yl-2-(3-flu or oben zyl)-1,1,3-tr ioxo-2H,4H-
th ien o[3,4-e][1,2,4]th ia d ia zin e (16p ). This compound was
obtained (65%) from reaction of 13f with 2-chloroacetonitrile.
The crude material was chromatographed (hexane/dichlo-
romethane 1:2); mp 152-153 °C. IR (KBr, cm-1): 1692 (Cd
O); 1335, 1170 (SO2). 1H NMR (DMSO-d6, δ): 8.79 (d, 1H, J
) 3.1 Hz, thiophene); 7.63 (d, 1H, J ) 3.1 Hz, thiophene);
7.44-7.36 (m, 1H, benzene); 7.21-7.12 (m, 3H, benzene); 5.14
(s, 2H, CH2); 5.01 (s, 2H, CH2). Anal. (C14H10FN3O3S2) C, H,
N, S.
4-Cya n om e t h yl-2-(3,5-d iflu or ob e n zyl)-1,1,3-t r ioxo-
2H,4H-th ien o[3,4-e][1,2,4]th ia d ia zin e (16q). This com-
pound was obtained (79%) from reaction of 13g with 2-chlo-
roacetonitrile The crude material was chromatographed (hexane/
dichloromethane 1:2); mp 117-119 °C. IR (KBr, cm-1): 1690
(CdO); 1335, 1175 (SO2). 1H NMR (DMSO-d6, δ): 8.80 (d, 1H,
J ) 3.1 Hz, thiophene); 7.64 (d, 1H, J ) 3.1 Hz, thiophene);
7.22-7.04 (m, 3H, benzene); 5.14 (s, 2H, CH2); 5.02 (s, 2H,
CH2). Anal. (C14H9F2N3O3S2) C, H, N, S.
4-E t h yl-2-(2-p h en ylet h yl)-1,1,3-t r ioxo-2H ,4H -t h ien o-
[3,4-e][1,2,4]th ia d ia zin e (16r ). This compound was obtained
(80%) from reaction of 5a with ethyl iodide. The crude
material was chromatographed (dichloromethane); mp 97-98
°C. IR (KBr, cm-1): 1665 (CdO); 1335, 1180 (SO2). 1H NMR
(DMSO-d6, δ): 8.62 (d, 1H, J ) 3.2 Hz, thiophene); 7.45 (d,
1H, J ) 3.2 Hz, thiophene); 7.24-7.11 (m, 5H, benzene); 4.00-
3.32 (m, 4H, 2CH2); 2.89 (t, 2H, J ) 7.7 Hz, CH2); 1.16 (t, 3H,
J ) 6.8 Hz, CH3). Anal. (C15H16N2O3S2) C, H, N, S.
4-Cya n om et h yl-2-(2-p h en ylet h yl)-1,1,3-t r ioxo-2H ,4H -
th ien o[3,4-e][1,2,4]th ia d ia zin e (16s). This compound was
obtained (89%) from reaction of 5a with 2-chloroacetonitrile.
The crude material was chromatographed (dichloromethane);
mp 144-146 °C. IR (KBr, cm-1): 1692 (CdO); 1335, 1165
(SO2). 1H NMR (DMSO-d6, δ): 8.68 (d, 1H, J ) 3.0 Hz,
thiophene); 7.58 (d, 1H, J ) 3.0 Hz, thiophene); 7.24-7.13 (m,
5H, benzene); 5.11 (s, 2H, CH2); 3.99 (t, 2H, J ) 7.7 Hz, CH2);
2.91 (t, 2H, J ) 7.7 Hz, CH2). Anal. (C15H13N3O3S2) C, H, N,
S.
4-Ben zyl-2-(2-p h en yleth yl)-1,1,3-tr ioxo-2H,4H-th ien o-
[3,4-e][1,2,4]th ia d ia zin e (16t). This compound was obtained
(85%) from reaction of 5a with benzyl bromide. The crude
material was chromatographed (hexane/AcOEt 6:1); mp 102-
103 °C. IR (KBr, cm-1): 1677 (CdO); 1325, 1165 (SO2). 1H
NMR (DMSO-d6, δ): 8.61 (d, 1H, J ) 3.3 Hz, thiophene); 7.33-
7.15 (m, 11H, benzene and thiophene); 5.17 (s, 2H, CH2); 4.03
(t, 2H, J ) 7.8 Hz, CH2); 2.95 (t, 2H, J ) 7.8 Hz, CH2). Anal.
(C20H18N2O3S2) C, H, N, S.
4-Eth yl-2-p icolyl-1,1,3-tr ioxo-2H,4H-th ien o[3,4-e][1,2,4]-
th ia d ia zin e (16u ). This compound was obtained (71%) from
reaction of 5b with ethyl iodide. The crude material was
chromatographed (dichloromethane/ethanol 50:1); mp 132-
134 °C. IR (KBr, cm-1): 1675 (CdO); 1337, 1165 (SO2). 1H
NMR (DMSO-d6, δ): 8.67 (d, 1H, J ) 3.1 Hz, thiophene); 8.45
(ddd, 1H, J ) 4.9 Hz, J ) 1.7 Hz, J ) 0.9 Hz, pyridine H-3′),
7.76 (dt, 1H, J ) 7.7 Hz, J ) 1.7 Hz, pyridine H-5′); 7.53 (d,
1H, J ) 3.1 Hz, thiophene); 7.29 (d, 1H, J ) 7.7 Hz, pyridine
H-6′); 7.27-7.24 (ddd, 1H, J ) 7.6 Hz, J ) 4.9 Hz, J ) 0.9 Hz,
pyridine, H-4′); 5.05 (s, 2H, CH2); 3.97 (q, 2H, J ) 7.0 Hz, CH2);
1.21 (t, 3H, J ) 7.0 Hz, CH3). Anal. (C13H13N3O3S2) C, H, N,
S.
4-Cya n om eth yl-2-p icolyl-1,1,3-tr ioxo-2H,4H-th ien o[3,4-
e][1,2,4]th ia d ia zin e (16v). This compound was obtained
(66%) from reaction of 5b with 2-chloroacetonitrile. The crude
material was chromatographed (dichloromethane/ethanol 50:
1); mp 167-168 °C. IR (KBr, cm-1): 2320 (CN); 1693 (CdO);
1347, 1167 (SO2). 1H NMR (DMSO-d6, δ): 8.74 (d, 1H, J )
3.1 Hz, thiophene); 8.44 (ddd, J ) 4.8 Hz, J ) 1.8 Hz, J ) 1.0
Hz, pyridine H-3′); 7.77 (dt, 1H, J ) 7.7 Hz, J ) 1.8 Hz,
pyridine H-5′); 7.63 (d, 1H, J ) 3.1 Hz, thiophene); 7.35 (d,
1H, J ) 7.9 Hz, pyridine H-6′); 7.27 (ddd, 1H, J ) 7.5 Hz, J )
4.8 Hz, pyridine H-4′); 5.14 (s, 2H, CH2); 5.10 (s, 2H, CH2).
Anal. (C13H10N4O3S2) C, H, N, S.
2-Ben zyl-4-m eth yl-1,1,3-tr ioxo-2H,4H-th ien o[2,3-e][1,2,4]-
th ia d ia zin e (17a ). This compound was obtained (92%) from
reaction of 14 with methyl iodide; mp 156-158 °C (EtOH). IR
(KBr, cm-1): 1682 (CdO); 1325, 1145 (SO2). 1H NMR (DMSO-
d6, δ): 7.45 (d, 2H, thiophene); 7.34-7.20 (m, 5H, benzene);
4.95 (s, 2H, CH2); 3.44 (s, 3H, CH3). Anal. (C13H12N2O3S2) C,
H, N, S.
2-Ben zyl-4-eth yl-1,1,3-tr ioxo-2H,4H-th ien o[2,3-e][1,2,4]-
th ia d ia zin e (17b). This compound was obtained (92%) from
reaction of 14 with ethyl iodide; mp 116-117 °C (EtOH). IR
(KBr, cm-1): 1690 (CdO); 1322, 1140 (SO2). 1H NMR (DMSO-
d6, δ): 7.45 (d, 2H, thiophene); 7.34-7.28 (m, 5H, benzene);
4.97 (s, 2H, CH2); 3.93 (q, 2H, J ) 7.1 Hz, CH2); 1.23 (t, 3H, J
) 7.1 Hz, CH3). Anal. (C14H14N2O3S2) C, H, N, S.
2-Ben zyl-4-(n -p r op yl)-1,1,3-tr ioxo-2H,4H-th ien o[2,3-e]-
[1,2,4]th ia d ia zin e (17c). This compound was obtained (90%)
from reaction of 14 with n-propyl bromide; mp 139-140 °C
(EtOH). IR (KBr, cm-1): 1692 (CdO); 1325 (SO2). 1H NMR
(DMSO-d6, δ): 7.45 (d, 2H, thiophene); 7.34-7.28 (m, 5H,
benzene); 4.97 (s, 2H, CH2); 3.88 (t, 2H, J ) 7.2 Hz, CH2); 1.67
(m, 2H, CH2);0.85 (t, 3H, J )7.2 Hz, CH3). Anal. (C15H16N2O3S2)
C, H, N, S.
2-Ben zyl-4-cya n om eth yl-1,1,3-tr ioxo-2H,4H-th ien o[2,3-
e][1,2,4]th ia d ia zin e (17d ). This compound was obtained
(75%) from reaction of 14 with 2-chloroacetonitrile; mp 140-
142 °C (EtOH). IR (KBr, cm-1): 1705 (CdO); 1335, 1180 (SO2).
1H NMR (DMSO-d6, δ): 7.56 (d, 1H, J ) 5.7 Hz, thiophene);
7.51 (d, 1H, J ) 5.7 Hz, thiophene); 7.38-7.28 (m, 5H,
benzene); 5.18 (s, 2H, CH2); 5.01 (s, 2H, CH2). Anal.
(C14H11N3O3S2) C, H, N, S.
2-Ben zyl-4,6-d im eth yl-1,1,3-tr ioxo-2H,4H-p yr a zolo[4,3-
e][1,2,4]th ia d ia zin e (18a ). This compound was obtained
(86%) from reaction of 15 with methyl iodide; mp 147-149 °C
(AcOEt-hexane). IR (KBr, cm-1): 1695 (CdO); 1360, 1180
(SO2). 1H NMR (DMSO-d6, δ): 8.10 (s, 1H, pyrazole); 7.34-
7.25 (m, 5H, benzene); 4.95 (s, 2H, CH2); 4.00 (s, 3H, CH3);
3.30 (s, 3H, CH3). Anal. (C13H14N4O3S) C, H, N, S.
2-Ben zyl-4-eth yl-6-m eth yl-1,1,3-tr ioxo-2H,4H-p yr a zolo-
[4,3-e][1,2,4]th ia d ia zin e (18b). This compound was obtained
(80%) from reaction of 15 with ethyl iodide; mp 132-134 °C
(AcOEt-hexane). IR (KBr, cm-1): 1680 (CdO); 1322, 1180
(SO2). 1H NMR (DMSO-d6, δ): 8.19 (s, 1H, pyrazole); 7.30 (s,
5H, benzene); 4.95 (s, 2H, CH2); 3.99 (s, 3H, CH3); 3.79 (q, 2H,
J
) 7.0 Hz, CH2); 1.14 (t, 3H, J ) 7.0 Hz, CH3). Anal.
(C14H16N4O3S) C, H, N, S.
2-Ben zyl-6-ch lor o-4-cya n om et h yl-1,1,3-t r ioxo-2H ,4H -
th ien o[3,2-e][1,2,4]th ia d ia zin e (19a ). This compound was
obtained (66%) from reaction of 8 with 2-chloroacetonitrile; mp
143-145 °C (MeOH). IR (KBr, cm-1): 1695 (CdO); 1355, 1175
(SO2). 1H NMR (DMSO-d6, δ): 7.79 (s, 1H, thiophene); 7.37-
7.35 (m, 5H, benzene); 5.14 (s, 2H, CH2); 5.02 (s, 2H, CH2).
Anal. (C14H10ClN3O3S2) C, H, N, S.

Novel TTD Derivatives That Inhibit HIV-1 Replication
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4117
(5) Merluzzi, V. J .; Hargrave, K. D.; Labadia, M.; Grozinger, K.;
Skoog, M.; Wu, J . C.; Shih, C.-K.; Eckner, K.; Hattox, S.; Adams,
J .; Rosenthal, A. S.; Faanes, R.; Eckner, R. J .; Koup, R. A.;
Sullivan, J . L. Inhibition of HIV-1 replication by a nonnucleoside
reverse transcriptase inhibitor. Science 1990, 250, 1411-1413.
(6) De Clercq, E. What can be expected from nonnucleoside reverse
transcriptase inhibitors (NNRTIs) in the treatment of human
immunodeficiency virus type 1 (HIV-1) infections? Rev. Med.
Virol. 1996, 6, 97-117.
(7) De Clercq, E. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) for the treatment of human immunodeficiency virus
type 1 (HIV-1) infections: strategies to overcome drug resistance
development. Med. Res. Rev. 1996, 16, 125-157.
(8) Witvrouw, M.; Arranz, M. E.; Pannecouque, C.; Declercq, R.;
J onckheere, H.; Schmit, J .-C.; Vandamme, A.-M.; D´ıaz, J . A.;
Ingate, S. T.; Desmyter, J .; Esnouf, R.; Van Meervelt, L.; Vega,
S.; Balzarini, J .; De Clercq, E. 1,1,3-Trioxo-2H,4H-thieno[3,4-e]-
[1,2,4]thiadiazines (TTD) derivatives: A new class of nonnucleo-
side HIV-1 reverse transcriptase inhibitors (NNRTIs) with anti-
HIV-1 activity. Antimicrob. Agents Chemother. 1998, 42, 618-
623.
(9) Ren, J .; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.;
Keeling, J .; Darby, G.; J ones, Y.; Stuart, D.; Stammers, D. High-
resolution structures of HIV-1 RT from four RT-inhibitor
complexes. Nature Struct. Biol. 1995, 2, 293-302.
6-Ch lor o-2,4-d iben zyl-1,1,3-tr ioxo-2H,4H-th ien o[3,2-e]-
[1,2,4]th ia d ia zin e (19b). This compound was obtained (78%)
from reaction of 8 with benzyl bromide; mp 132-133 °C
(MeOH). IR (KBr, cm-1): 1677 (CdO); 1340, 1185 (SO2). 1H
NMR (DMSO-d6, δ): 7.56 (s, 1H, thiophene); 7.39-7.18 (m,
10H, benzene); 5.25 (s, 2H, CH2); 5.05 (s, 2H, CH2). Anal.
(C19H15ClN2O3S2) C, H, N, S.
Ack n ow led gm en t. The financial support of this
work by the Comisio´n Interministerial de Ciencia y
Tecnolog´ıa (CICYT), Madrid, Spain (research grant SAF
96-0111), is gratefully acknowledged. We thank the
Consejer´ıa de Educacio´n y Cultura de la Comunidad de
Madrid for a graduate fellowship and the Sociedad
Espan˜ola de Qu´ımica Terape´utica for a Scientific Award
to E.A. We also thank the Biomedical Research Program
of the European Commission for supporting this col-
laborative work. We want to acknowledge Kristien
Erven for excellent technical assistance with the anti-
HIV assays, J uan J . Bustos for preparation of the
starting materials, and Francisco Caballero for editorial
assistance.
(10) Weigert, F. J .; Roberts, J . D. Nuclear Magnetic resonance
spectroscopy. Carbon-carbon coupling in cyclopropane deriva-
tives. J . Am. Chem. Soc. 1967, 89, 5962-5963.
Refer en ces
(11) Arranz, M. E.; Vega, S.; D´ıaz, J . A. Synthesis of hetero[1,2,4]-
thiadiazine 1,1-dioxides. Heterocycles 1997, 45, 1767-1774.
(12) Banthorpe, D. V. Rearrangements involving azido groups. In The
Chemistry of Azido Group; Patai, S., Ed.; Interscience Publish-
ers: London, 1971; pp 397-440.
(13) Shioiri, T. Degradation reactions. In Comprehensive Organic
Synthesis, Selectivity, Strategy and Efficiency in Modern Organic
Chemistry, 1st ed.; Trost, M. T., Fleming, I., Winterfeldt, E., Eds.;
Pergamon Press Inc.: London, 1991; pp 795-827.
(14) Shoiri, T.; Ninomiya, K.; Yamada, S. Diphenylphosphoryl azide.
A new convenient reagent for a modified Curtius raction and
for the peptide synthesis. J . Am. Chem. Soc. 1972, 94, 6203-
6205.
(15) Ninomiya, Shoiri, T.; K.; Yamada, S. Phosphorus in organic
synthesis. Diphenylphosphorazidate (DPPA). A new convenient
reagent for modified Curtius ractions. Tetrahedron, 1974, 30,
2151-2157.
(16) Unterhalt, B.; Moghaddam, S. 2,3-Dihydro-3-oxo-thienoisothia-
zol-1,1-dioxide und ihre 3-thioxo-verbindungen. Pharmazie 1994,
49, 115-117.
(17) Pauwels, R.; Andries, K.; Debyser, Z.; Kukla, M. J .; Schols, D.;
Breslin, H. J .; Woestenborghs, R.; Desmyter, J .; J anssen, M. A.
C.; De Clercq, E. J anssen, P. A. J . New tetraimidazo[4,5,1-jk]-
[1,4]benzodiazepin-2(1H)-one and -thione derivatives are potent
inhibitors of human immunodeficiency virus type 1 replication
and are synergistic with 2′,3′-dideoxynucleoside analogues.
Antimicrob. Agents Chemother. 1994, 38, 2863-2870.
(1) Arranz, M. E.; D´ıaz, J . A.; Ingate, S. T.; Witvrouw, M.; Pan-
necouque, C.; Balzarini, J .; De Clercq, Vega, S. Synthesis and
anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]-
thiadiazines (TTD): A new family of HIV-1 specific nonnucleo-
side reverse transcriptase inhibitors. J . Med. Chem. submitted
for publication.
(2) Romero, D. L.; Busso, M.; Tan, C.-K.; Reusser, F.; Palmer, J .
R.; Poppe, S. M.; Aristoff, P. A.; Downey, K. M.; So, A. G.;
Resnick, L.; Tarpley, W. G. Nonnucleoside reverse transcriptase
inhibitors that potently and specifically block human immuno-
deficiency virus type 1 replication. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 8806-8810.
(3) Ahgren, C.; Backro, K.; Bell, F. W.; Cantrell, A. S.; Clemens,
M.; Colacino, J . M.; Deeter, J . B.; Engelhardt, J . A.; Hogberg,
M.; J askunas, S. R.; J ohansson, N. G.; J ordan, C. L.; Kasher, J .
S.; Kinnick, M. D.; Lind, P.; Lopez, C.; Morin, J . M.; Muesing,
M. A.; Noreen, R.; Oberg, B.; Paget, C. J .; Palkowitz, J . A.;
Parrish, C. A.; Pranc, P.; Rippy, M. K.; Rydergard, C.; Sahlberg,
C.; Swanson, S.; Ternansky, R. J .; Unge, T.; Vasileff, R. T.;
Vrang, L.; West, S. J .; Zhang, H.; Zhou, X.-X. The PETT series,
a new class of potent nonnucleoside inhibitors of human immu-
nodeficiency virus type 1 reverse transcriptase. Antimicrob.
Agents Chemother. 1995, 39, 1329-1335.
(4) Pauwels, R.; Andries, K.; Debyser, Z.; Van Daele, P.; Schols, D.;
Stoffels, P.; De Vreese, K.; Woestenborghs, R.; Vandamme, A.-
M.; J anssen, C. G. M.; Anne´, J .; Cauwenberg, G.; Desmyter, J .;
Heykants, J .; J anssen, M. A. C.; De Clercq, E. J anssen, P. A. J .
Potent highly selective human immunodeficiency virus type 1
(HIV-1) inhibition by
derivatives targeted at HIV-1 reverse transcriptase. Proc. Natl.
Acad. Sci. U.S.A. 1993, 90, 1711-1715.
a series of R-anilinophenylacetamide
J M9802012