Novel bronchodilators: Synthesis, transamination reactions, and pharmacology of a series of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides

Article abstract of DOI:10.1021/jm000970x

The synthesis, pharmacological evaluation, and structure - activity relationships of a new class of bronchodilator agents, derivatives of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides are described. The compounds were prepared by reaction of 3,4,5-triamino-1,2,6-thiadiazine 1,1-dioxide with suitable 1,2-dicarbonyl compounds or α-hydroxyiminoketones and subsequent N-alkylation. A transamination procedure for synthesizing derivatives with different substituents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine derivatives were screened for tracheal relaxing activity in vitro, and the active compounds were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by the 4-amino-1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.

Full text of DOI:10.1021/jm000970x

J . Med. Chem. 2000, 43, 4219-4227
4219
Novel Br on ch od ila tor s: Syn th esis, Tr a n sa m in a tion Rea ction s, a n d
P h a r m a cology of a Ser ies of P yr a zin o[2,3-c][1,2,6]th ia d ia zin e 2,2-Dioxid es
Nuria Campillo, Concepcio´n Garc´ıa, Pilar Goya, Ibon Alkorta, and J uan A. Pa´ez*
Instituto de Quı´mica Me´dica CSIC, J uan de la Cierva 3, 28006 Madrid, Spain
Received April 26, 2000
The synthesis, pharmacological evaluation, and structure-activity relationships of a new class
of bronchodilator agents, derivatives of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides are
described. The compounds were prepared by reaction of 3,4,5-triamino-1,2,6-thiadiazine 1,1-
dioxide with suitable 1,2-dicarbonyl compounds or R-hydroxyiminoketones and subsequent
N-alkylation. A transamination procedure for synthesizing derivatives with different substit-
uents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine
derivatives were screened for tracheal relaxing activity in vitro, and the active compounds
were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline.
Among the compounds studied, the most interesting properties were displayed by the 4-amino-
1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.
Asthma and chronic obstructive pulmonary disease
(COPD) are characterized by chronic obstruction of the
flow of air through the airways. COPD involves chronic
bronchitis or emphysema and its irreversible nature
contrasts with the reversible condition of asthma.1-5
Asthma is an extremely common disorder, responsible
for more pediatric hospital admissions than any other
single illness, and COPD represents now the fourth to
fifth most common cause of death.
ides may comprise three steps involving ring formation
between the 3,4,5-triamino-1,2,6-thiadiazine 1,1-dioxide
124 and suitable 1,2-dicarbonyl compounds or R-hy-
droxyiminoketones, subsequent introduction of the sub-
stituent at the N-1 position, and transamination of the
amino group at the 4-position.
The new pyrazino[2,3-c][1,2,6]thiadiazine derivatives
prepared for this work are gathered in Table 1. In the
first step, formation of the heterocyclic system, different
methods can be used depending on the kind of substitu-
tion desired at the 6- and 7-positions. In the case of 6,7
symmetrically disubstituted derivatives, the synthesis
can be achieved from o-diaminothiadiazines and 1,2-
dicarbonyl compounds.16
Although different,1,2 the pharmacological treatment
of both diseases is similar because the inflammatory/
bronchospastic component is the amenable aspect to
therapy, and thus â2-adrenoreceptor agonists, anticho-
linergics, and theophylline, among other drugs, can be
used with different degrees of efficacy.6-11 Corticoster-
oids are the mainstay of nonbronchodilator therapy for
asthma; however, their utility in COPD is less clear.
At present, therapies for COPD are not very effective,
and all these medications have well-established un-
wanted secondary effects, and so new therapeutic ap-
proaches for the treatment of these lung diseases still
represent an important challenge in medicinal chem-
istry.1,2,12-13
Within this context, we wish to report a novel class
of bronchodilator agents not related structurally to any
of the bronchodilators known, which shows interesting
tracheal relaxing properties (comparable to theophyl-
line) and which are derived from the pyrazino[2,3-c]-
[1,2,6]thiadiazine 2,2-dioxide system.14,15 This hetero-
cycle first reported by our group,16 has been the subject
of our research in relation to its particular structural
features,17-20 and we have also described the diuretic
properties of some particular derivatives21 and the
ability to inhibit platelet aggregation of some aryl
substituted compounds.22,23
When the dicarbonyl compound used to build the
pyrazino moiety has different substituents, the two
possible isomers at positions 6 and 7 can be formed. The
selectivity is specially high when one of the substituents
of the dicarbonyl compound is a methyl group, and in
this case, 6-methyl derivatives are obtained.21 However,
from R-hydroxyiminoketones it is possible to selectively
obtain the 6- or 7-substituted derivatives depending on
whether the substituent is linked to the carbonyl or the
hydroxyimino function, respectively.
Thus, the synthesis of N(1)H-pyrazinothiadiazines
2-4 was carried out starting from 1,24 and dicarbonyl
compounds such as 1,2-cycloheptanedione,25 4-methyl-
2,3-pentanedione, or 2,3-heptanedione (Scheme 1). In
the reaction of 1 with 2-oxobutanaldehyde,26 the selec-
tivity is high and only 7-ethyl derivative 5 is obtained.
The 7-unsubstituted pyrazinothiadiazines were synthe-
sized from R-hydroxyiminoketones, and thus, 6-methyl,
6-ethyl, 6-propyl, 6-isopropyl, and 6-tert-butyl deriva-
tives 6-10 were prepared by reaction of 1 and the
corresponding R-hydroxyiminoketones obtained from the
â-oxoesters using the Freon method.27 Compounds
11-16 were synthesized following previously pub-
lished procedures16,17,23 and were used as starting com-
pounds to prepare other N-substituted derivatives in
this work.
Ch em istr y
The general synthetic route for the formation of
substituted pyrazino[2,3-c][1,2,6]thiadiazine 2,2-diox-
* To whom correspondence should be addressed. Fax: 91 5644853.
E-mail: juan@suricata.iqm.csic.es.
10.1021/jm000970x CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

4220 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Campillo et al.
Ta ble 1. Physicochemical Data for 4-aminopyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides 2-10, 17-32, and 38-48
R1
R2
R3
R4
mp (°C)
recryst solv
formula
anal.a
b
2
3
4
5
6
7
8
9
CH2(CH)3CH2
H
H
H
H
H
H
H
H
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NHEt
280
-
C10H13N5O2S
C9H13N5O2S
C10H15N5O2S
C7H9N5O2S
C6H7N5O2S
C7H9N5O2S
C8H11N5O2S
C8H11N5O2S
C9H13N5O2S
C11H15N5O2S
C11H17N5O2S
C11H17N5O2S
C9H13N5O2S
C8H11N5O2S
C9H13N5O2S
C10H15N5O2S
C10H15N5O2S
C11H17N5O2S
C7H9N5O2S
C12H11N5O2S
C13H13N5O2S
C7H9N5O2S
C10H13N5O4S
C9H13N5O3S
C9H11N5O4S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N
Me
Me
H
Me
Et
i-Pr
Bu
Et
H
257-259
211-213
190-192
282-284
169-170
184-186
212-214
285-287
267-269
164-166
149-151
168-170
171-173
172-174
114-116
150-152
171-73
214
EtOH/water
water/MeOH
acetic ac/water
water
water
water
H
Pr
H
i-Pr
t-Bu
H
H
water
10
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
38
39
40
41
42
43
44
45
46
47
48
H
water/MeOH
water/MeOH
water/MeOH
water/MeOH
water/EtOH
water/EtOH
water/MeOH
MeOH/water
MeOH/water
water/MeOH
water/EtOH
EtOH/water
EtOH/water
water
EtOH/water
water
-
EtOH/water
EtOH/water
EtOH
EtOH/water
EtOH
CH2(CH)3CH2
Me
Et
Me
Et
Et
Et
Et
Et
Et
Me
Me
Me
Et
CH2COOEt
CH2CH2OH
CH2COOH
Et
Me
Me
Et
Et
Et
Me
Me
H
Me
Et
i-Pr
Bu
Et
H
H
Pr
H
i-Pr
t-Bu
Me
H
Ph
H
H
H
H
Ph
Me
H
295
246-247
207-209
208-210
171-172
292
227-229
172-174
278
Me
Me
Me
Ph
H
H
Me
Me
H
Ph
Ph
Ph
H
C15H17N5O2S
NH(CH2)2NH2
NHNH2
NHCH2Ph
NHCH2Ph
NHEt
NHCH2-2py
NHCH2CH2OH
NHNH2
NH(CH2)2NMe2
N-pyrrolidinyl
C14H16N6O2S
C12H12N6O2S
C20H19N5O2S
C15H17N5O2S
H
H
C, H, N
155
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N
C, H, N, S
C, H, N, S
C, H, N, S
C, H, N, S
Me
Me
Me
Me
Me
Me
Ph
193-194
166-168
214-216
181-182
170-172
127
H
EtOH/water
water/EtOH
water/MeOH
water/MeOH
EtOH/water
EtOH
C10H15N5O2S
Me
Et
Et
Et
Me
Me
Et
Et
Et
Me
C14H16N6O2S
C12H19N5O3S
C10H6N6O2S
C14H24N6O2S
245-247
C17H19N5O2S
a
b
Elemental analyses were within (0.4 of the calculated values for the formulas given. Purified by chromatography on silica gel
using hexane/acetone/acetic acid (12/4/1) as eluent.
Sch em e 1
ate or triethylamine as base. Thus, reaction of N(1)H-
pyrazino[2,3-c][1,2,6]thiadiazine derivatives 2-10 in
acetone and triethylamine as base, with methyl or ethyl
iodide, afforded the corresponding methyl or ethyl
derivatives 17-25, respectively.
Derivatives 26-28 were obtained by reaction of
compounds 6, 12,17 and 1622 with methyl iodide in
acetone, and potassium carbonate. Treatment of com-
pounds 1116 and 6 with ethyl iodide or ethyl bromoac-
etate in the presence of triethylamine, afforded the
corresponding derivatives 29 and 30, respectively.
On the other hand, the preparation of compound 31
was carried out by reaction of 1316 with 2-bromoethanol
(Scheme 2). The carboxymethyl derivative 32 was
obtained by hydrolysis of 1-ethoxycarbonylmethyl de-
rivative 33.21 Finally, compounds 34-37 were prepared
from 12-15 according to previously reported proce-
dures21 (Scheme 2).
For the modification of the 4-position of the hetero-
cyclic system, in principle alkylation at the exocyclic
amino group with alkyl halides in basic medium is
possible.28 Following this method, the 4-ethylamino
derivative 38 was prepared from the reaction of 4-amino-
6-phenyl compound 37 with ethyl iodide and potassium
The N(1)-substituted compounds 17-32 described in
this work are gathered in Table 1 and Scheme 2.
Substitution at position 1 from the corresponding N(1)H-
pyrazinothiadiazines 2,2-dioxides can be performed with
alkyl halides in acetone using either potassium carbon-

Synthesis of Novel Bronchodilators
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4221
Sch em e 2
Sch em e 3
The alkylamino derivatives of the pyrazinothiadiaz-
ines synthesized are shown in Scheme 3. Thus, different
4-substituted derivatives 39-47 were obtained from 21,
27, and 34-36 by reaction with primary amines such
as benzylamine, ethylenediamine, ethanolamine, N,N-
dimethylethylenediamine, 2-picolylamine, and hydra-
zine in methanol. This method can also be used with
secondary amines, like pyrrolidine, and so it was pos-
sible to obtain the pyrrolidinyl derivative 48 from
compound 28.
The structures of all the new compounds synthesized
have been established on the basis of their analytical
and spectroscopic data. The 13C NMR chemical shifts
are gathered in Table 2. The positions of the 6- and
7-substituents were established according to the long-
range coupling constants and chemical shifts of the C-7
and C-6 carbons.
P h a r m a cologica l Resu lts
The N1-substituted compounds synthesized in this
work 17-26, 29-32, and 38-48, together with deriva-
tives 33-37 and 49-6821-23 previously available, were
screened for tracheal relaxing activity in vitro29 on
guinea pig trachea, and the results obtained are gath-
ered in Table 3.
On the basis of the corresponding tracheal relaxing
screening results, selected compounds were further
evaluated as bronchodilator agents in vivo30 in com-
parison to theophylline. Finally, the most promising
compound was subjected to toxicity studies.
The results obtained for the tracheal relaxing activity
of pyrazino[2,3-c][1,2,6]thiadiazine compounds and theo-
phylline are shown in Table 3. Derivatives with a
percentage of tracheal tone inhibition more than 50%
at concentrations of 30 µg/mL, similar to theophylline,
were considered with pharmacological activity signifi-
cance.
In the tracheal relax assay (Table 3), the activity of
the 4-NH2 derivatives was similar to the corresponding
4-amino substituted compounds when the group at the
4-position is hydrazino or alkylamino except in the case
of the 4-(ethylamino)-6-phenyl derivative 38, which
carbonate (Scheme 3). However, in this procedure it is
very difficult, in some cases, to prevent the formation
of mixtures of mono and dialkyl products.
Therefore, a different approach to the preparation of
4-amino substituted pyrazino[2,3-c][1,2,6]thiadiazines
has been developed and consists of a transamination
reaction, described here for the first time. Thus, reaction
of the N1-substituted 4-aminopyrazinothiadiazines with
an excess of the corresponding amine in alcoholic
medium yielded the 4-amino-substituted derivatives.

4222 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Campillo et al.
Ta ble 2. 13C NMR Spectral Data (δ, DMSO-d6) for Componds
2-1 17-32, and 38-48
The bronchoconstriction in guinea pigs was deter-
mined by the Konzett and Rossler test30 using histamine
as spasmogen. The activity of pyrazino[2,3-c][1,2,6]-
thiadiazine derivatives in relation to theophylline was
studied at 25 and 100 mg/kg (the evaluation method is
described in the Experimental Section). In Figure 1 are
gathered those derivatives which had a significant
activity at 25 mg/kg or 100 mg/kg (p < 0.05). All
derivatives showed interesting bronchodilator properties
although the 1-ethyl-6-methylpyrazino[2,3-c][1,2,6]-
thiadiazine 2,2-dioxide 21 is clearly the most interesting
compound, with an activity 30% higher than theophyl-
line at 100 mg/kg.
Finally, toxicological studies have also been carried
out, and thus, LD50 values have been determined in
mouse and rat and are shown in Figure 2. The values
obtained for the LD50 in these animal species indicate
that 21 is, in both cases, less toxic than theophylline,
being the LD50 of compound 21 3.6 times higher in
mouse and 7.7 times higher in rat. (Figure 2). This may
represent an advantage over theophylline since it can
eventually result in a better therapeutic index.
C-4
C-7
C-8a
C-6
C-4a
other signals
2
3
4
5
6
7
8
9
158.8 163.7 146.8 151.4 118.2 37.3, 36.3, 31.2, 26.0, 25.6
158.8 165.5 147.3 144.5 118.8 20.5, 31.4, 20.9
158.8 161.3 147.1 145.4 118.7 20.5, 33.9, 29.1 21.9, 13.5
158.7 163.6 148.7 137.2 120.2 28.1, 12.7
158.8 148.7 149.5 144.0 120.3 20.2
158.7 148.2 147.4 151.5 121.1 27.0, 13.0
158.6 148.4 147.4 150.2 121.3 35.6, 21.8, 13.4
158.7 147.3 147.4 154.9 121.0 32.5, 21.9
10 158.7 145.8 147.0 156.9 120.0 35.9, 29.4
17 158.7 163.3 146.8 150.2 119.2 27.6, 37.5, 35.9, 31.1, 25.8,
25.5
18 158.5 164.8 146.6 143.5 119.6 37.5, 31.3, 20.8, 20.1, 13.7
19 158.7 160.8 147.1 144.5 119.6 33.9, 28.5, 27.8, 21.8, 20.2,
13.7
20 158.6 163.3 148.0 136.2 120.9 37.6, 28.2, 13.8, 12.4
21 158.7 148.5 146.9 145.9 122.2 37.7, 20.2, 13.9
22 158.6 147.8 146.9 150.4 122.2 37.6, 26.8, 13.8, 13.0
23 158.8 148.4 147.2 149.7 122.5 38.0, 35.7, 22.1, 14.1, 13.8
24 158.7 147.0 147.0 154.0 122.1 37.4, 32.4, 21.9, 13.9
25 158.6 145.5 155.9 146.5 121.5 37.6, 35.8, 29.4, 13.8
26 158.5 148.4 147.5 145.9 122.3 28.1, 20.1
27 157.9 154.2 148.3 133.3 121.6 134.3, 131.0, 128.7, 127.4,
27.6
28 158.6 156.7 147.1 145.6 120.4 136.8, 129.3, 128.7, 128.2,
23.67, 28.0
29 158.4 148.7 148.6 136.7 123.6 37.7, 12.8
30 158.4 148.3 146.8 146.5 122.2 167.3, 61.0, 43.0, 20.2, 13.9
31 159.0 158.3 146.9 145.3 119.8 58.4, 43.6, 22.6, 20.8
32 158.7 158.2 146.4 145.8 119.7 168.9, 22.5, 20.8, 42.7
38 156.4 145.4 147.1 143.6 122.5 134.5, 129.7, 128.8, 126.6,
37.9, 35.9, 13.9, 13.7
Con clu sion s
From a synthetic point of view, new derivatives of
pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide have been
prepared, and the transamination procedure to obtain
4-aminosubstituted derivatives within this series is
reported here for the first time.
Regarding their activity, several compounds have
shown interesting results in tracheal relaxation screen-
ing in vitro, and bronchodilator properties, comparable
to theophylline, in guinea pigs in vivo.
From these, 4-amino-1-ethyl-6-methylpyrazino[2,3-c]-
[1,2,6]thiadiazine 2,2-dioxide (21) emerges as a promis-
ing candidate. The inhibition of the bronchoconstriction
induced by other spasmogens (histamine, methacholline,
arachidonic acid, or PAF) in vivo and the ability of
compound 21 to relax human bronchus and to inhibit
human bronchial phosphodiesterase activity have been
published elsewhere.31 All these findings, together with
its LD50 values here determined suggest that pyra-
zino[2,3-c][1,2,6]thiadiazine 2,2-dioxide 21 can be re-
garded as a new bronchodilator agent useful for lung
diseases.
39 154.2 155.6 148.2 133.6 122.4 134.5, 131.0, 129.2, 127.7,
44.1, 40.0, 28.0
40 151.2 153.3 148.0 133.5 122.7 134.6, 131.2, 129.1, 127.5,
28.1
41 154.1 155.5 148.0 134.4 121.8 133.5, 128.9, 128.2, 127.5,
131.2, 128.9, 127.4,
43.9, 37.4, 13.5
42 156.0 148.3 146.6 145.8 122.3 43.9, 37.7, 20.0, 13.7
43 155.6 148.1 146.5 145.7 122.4 37.6, 35.8, 22.0, 13.6, 13.7
44 156.3 158.0 146.8 144.9 119.9 156.1, 148.8, 136.6, 122.3,
121.3, 45.5, 27.8,
22.5, 20.5
45 156.3 161.5 146.3 144.5 119.6 58.4, 43.4, 37.6, 27.5, 20.3,
13.9, 10.7
46 152.5 160.5 145.9 144.1 119.8 37.4, 27.3, 20.1, 10.7, 13.8
47 156.1 161.5 146.3 144.5 119.5 56.8, 45.1, 38.6, 37.6, 27.5,
20.3, 13.9, 10.7
48 154.4 154.8 148.5 144.9 123.9 137.5, 128.8, 128.7, 128.5,
51.9, 51.0, 28.7, 27.0,
23.5, 23.4
shows a lower MIC (10 µg/mL) than the corresponding
unsubstituted 4-amino derivative 37.
Regarding substituents at 1-position, the tracheal
relaxant activity increases by the presence of a methyl
group (35, 52; MIC ) 3 µg/mL), except for 1-ethyl-6-
methyl derivative 21, which shows activity at 30 µg/
mL while the corresponding methyl compound 26 is
devoid of activity (Table 3). This 1-ethyl compound 21,
as will be shown later, is the most interesting derivative
concerning its bronchodilator properties in vivo.
The influence of the substitution at 6- and 7-posi-
tions depends on the group attached to the other
position without being possible to establish general
structure-activity relationships. Thus, in the 7H- and
7-methyl series, the 6-ethyl group shows a higher
activity, while in the 7-ethyl and 7-phenyl series it is
the 6H group, and in the 7-phenyl series the 6H or 6-Me
groups.
Exp er im en ta l Section
Chemistry. Gen er a l. Melting points were determined with
a Reichert-J ung Thermovar micro melting point apparatus and
are uncorrected. 1H NMR spectra (200 or 300 MHz) and 13C
NMR spectra (75 MHz) were recorded on a Gemini or Varian
XL-300 spectrometer and are reported in ppm on the δ scale.
The signal of the solvent was used as reference. Elemental
analyses were performed on a Heraeus CHN-O-Rapid ana-
lyzer. Column chromatography was carried out on silica gel
(Merck, particle size 70-230 mesh). The 1,2-cycloheptanedi-
one25 and the ethylglyoxal26 were prepared from cyclohep-
tanone and butanaldehyde with selenium dioxide, respectively,
following described procedures. In the case of the R-hydroxy-
iminoketones, the syntesized compounds were obtained from
â-oxoesters by means of Freon’s method.27
4-Am in o-1,6,7,8,9,10-h exa h yd r ocycloh ep ta [b]p yr a zin o-
[2,3-c][1,2,6]th ia d ia zin e 2,2-Dioxid e (2). To a suspension
of 1 (1.30 g, 7.3 mmol) in acetic acid (60 mL, 80 °C) and
concentrated hydrochloric acid (0.2 mL) was added 1,2-
cycloheptanedione (0.95 g, 7.3 mmol). After heating the
mixture at 80 °C for 5 h, the precipitate was filtered, washed
The compounds which showed a similar or higher
activity in comparison to theophylline were further
evaluated in guinea pigs to determine their bronchodi-
lator activity in vivo.

Synthesis of Novel Bronchodilators
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4223
Ta ble 3. Relaxant Tracheal Activity in Vitro of Pyrazino[2,3-c]-1,2,6-thiadiazine 2,2-Dioxides 17-26 and 29-68a
tracheal
relaxation
MICc
R1
CH2-(CH2)3CH2
i-Pr
R2
R3
R4
%inhibitionb
17
18
19
20
21
22
23
24
25
26
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
theophylline
Me
Et
Me
Et
Et
Et
Et
Et
Et
Me
Et
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NHEt
88
55
64
80
67
72
90
57
86
45
13
20
59
13
15
95
92
0
10
30
10
30
30
10
10
30
30
d
d
d
30
d
d
3
3
d
d
10
d
10
d
d
30
d
d
30
d
d
d
d
10
d
30
3
30
30
d
Me
Me
H
Bu
Et
Me
Et
H
H
Pr
H
i-Pr
t-Bu
Me
H
H
H
H
H
Me
Me
Me
Me
H
Me
Me
Ph
Ph
H
H
CH2COOEt
CH2CH2OH
CH2COOH
CH2COOEt
Me
Me
Me
Ph
Me
Et
H
H
Ph
Ph
Ph
H
H
Me
Et
Et
Et
Et
Me
Et
Et
Et
Me
Me
Et
Et
Et
20
74
6
NH(CH2)2NH2
NHNH2
NHCH2Ph
NHCH2Ph
NHEt
NHCH2-2-Py
NHCH2CH2OH
NHNH2
NH(CH2)2NMe2
N-pyrrolidinyl
NH2
H
H
81
20
27
63
31
41
72
34
10
22
42
72
33
58
95
75
51
34
100
95
0
Me
Me
Me
Me
Me
Me
Ph
H
Me
Et
Et
Et
Me
H
Me
Me
Et
H
H
Me
Ph
Me
Me
Et
Et
Et
Pr
NH2
NH2
NH2
NH2
NH2
NHMe
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
CH2COOEt
Et
Me
Me
Me
Me
Me
Me
Me
Et
Pr
Me
Et
Pr
Et
Et
Et
Et
Et
Et
Me
Et
Et
Me
Et
Ph
Me
Et
3
10
d
Et
i-Pr
(CH2)2-
Ph
Ph
Ph
Cl
i-Pr
(CH2)2-
H
Me
Ph
Ph
Me
Ph
0
d
82
56
93
24
86
88
63
60
10
30
30
d
30
10
30
30
Br
Br
NH2
NH2
Et
a
The evaluation method is described in the Experimental Section. Test compound inhibition by more than 50% was considered of
b
pharmacological significance. The compounds were assayed in duplicate for each concentration. Percentage of inhibition at 30 µg/mL of
test compound. c Results expressed as the lowest concentration (µg/mL) required to obtain a inhibitory response by more than 50%.
d
Compounds devoid of tracheal relaxing activity at 30 µg/mL.
with water, and recrystallized from the appropriate solvent
(see Table 1) to give 2 (1.12 g, 57%). 1H NMR (200 MHz,
DMSO-d6): δ 11.94 (br s, 1H, NH), 8.57 (br s, 1H, NH2), 8.32
(br s, 1H, NH2), 3.00 (t, 4H, 2CH2), 1.85 (m, 2H, CH2), 1.67
(m, 4H, 2CH2).
4-Am in o-7-isopr opyl-6-m eth yl-1H-pyr azin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (3). To a suspension of 1 (2.00 g,
11.3 mmol) in acetic acid (60 mL, 80 °C) was added 4-methyl-
2,3-pentanedione (1.59 g, 12.4 mmol). After heating the
mixture at 80 °C for 6 h, the precipitate was filtered, washed
with water, and recrystallized from the appropriate solvent
(see Table 1) to give 3 (1.53 g, 53%). 1H NMR (200 MHz,
DMSO-d6): δ 11.91 (br s, 1H, NH), 8.50 (br s, 1H, NH2), 8.35
(br s, 1H, NH2), 3.28 (m, 1H, CH), 2.54 (s, 2H, CH3), 1.07 (d,
6H, 2CH3).
8.5 mmol) in acetic acid (50 mL, 80 °C) was added 2,3-
heptanedione (1.19 g, 9.3 mmol). After heating the mixture at
80 °C for 6 h, the precipitate was filtered, washed with water,
and recrystallized from the appropriate solvent (see Table 1)
to give 4 (1.64 g, 73%). 1H NMR (200 MHz, DMSO-d6): δ 11.87
(br s, 1H, NH), 8.44 (br s, 1H, NH2), 8.29 (br s, 1H, NH2), 2.79
(t, 2H, (C-6)-CH2), 2.51 (s, 3H, (C-7)-CH3), 1.64 (m, 2H, CH2),
1.37 (m, 2H, CH2), 0.91 (t, 3H, CH3).
4-Am in o-7-et h yl-1H -p yr a zin o[2,3-c][1,2,6]t h ia d ia zin e
2,2-Dioxid e (5). To a suspension of 1 (5.00 g, 28.2 mmol) in
water (100 mL), ethanol (66 mL), and concentrated hydrochlo-
ric acid (0.5 mL) was added ethylglyoxal (3.00 g, 35.0 mmol).
The reaction mixture was stirred at room temperature for 4
days and then evaporated to dryness. The residue was purified
by chromatography on silica gel using dichloromethane/
methanol (15/1) as eluent and recrystallized from the ap-
propriate solvent (see Table 1) to yield 5 (0.98 g, 16%). 1H NMR
4-Am in o-7-b u t yl-6-m et h yl-1H -p yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (4). To a suspension of 1 (1.50 g,

4224 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Campillo et al.
F igu r e 1. Comparison of bronchodilatory effect of selected compounds versus theophylline in the model of bronchospasm induced
by histamine in guinea pig. The activity is expressed as the percentage of the inhibitory response vs theophylline (see Experimental
Section). The relation values are means of 5-6 experiments (p < 0.05).
8.42 (br s, 1H, NH2), 2.73 (t, 2H, CH2), 1.74 (m, 2H, CH2), 0.87
(t, 3H, CH3).
4-Am in o-6-isop r op yl-1H -p yr a zin o[2,3-c][1,2,6]t h ia -
d ia zin e 2,2-Dioxid e (9). From 1 (1.00 g, 5.6 mmol), methanol
(40 mL), concentrated hydrochloric acid (0.15 mL), and 1-hy-
droxyimino-3-methyl-2-butanone (1.31 g, 11.3 mmol). Reaction
time 5 h. Yield 9 (0.96 g, 71%). 1H NMR (300 MHz, DMSO-
d6): δ 12.08 (br s, 1H, NH), 8.61 (br s, 1H, NH2), 8.56 (s, 1H,
7-H), 8.38 (br s, 1H, NH2), 3.10 (m, 1H, CH), 1.25 (d, 6H, 2CH3).
4-Am in o-6-t er t -b u t yl-1H -p yr a zin o[2,3-c][1,2,6]t h ia -
d ia zin e 2,2-Dioxid e (10). From 1 (1.00 g, 5.6 mmol), metha-
nol (40 mL), concentrated hydrochloric acid (0.15 mL), and
1-hydroxyimino-3-dimethyl-2-butanone (1.53 g, 11.3 mmol).
Reaction time 5 h. Yield 10 (1.07 g, 75%). 1H NMR (300 MHz,
DMSO-d6): δ 12.10 (br s, 1H, NH), 8.72 (s, 1H, 7-H), 8.63 (br
s, 1H, NH2), 8.35 (br s, 1H, NH2), 1.35 (s, 9H, 3CH3).
Gen er a l P r oced u r e for th e Syn th esis of N-1-Alk yl-
p yr a zin o[2,3-c][1,2,6]th ia d ia zin e 2,2-Dioxid es (17-31). To
the corresponding 4-amino-1H-pyrazino[2,3-c][1,2,6]thiadiazine
F igu r e 2. LD50 values (mg/kg) of 21 in mouse or rat in
2,2-dioxide derivative in acetone, and either potassium carbon-
comparison to theophylline.
ate or triethylamine was added the alkyl halide. The reaction
mixture was stirred at room temperature or heated at reflux
and then evaporated to dryness, and diluted hydrochloric acid
was added to the residue. The precipitate was filtered and
recrystallized from the appropriate solvent (Table 1).
(200 MHz, DMSO-d6): δ 12.11 (br s, 1H, NH), 8.53 (br s, 2H,
NH2), 8.31 (s, 1H, CH), 2.82 (q, 2H, CH2), 1.23 (t, 3H, CH3).
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
6-10 fr om 3,4,5-Tr ia m in o-2H-1,2,6-th ia d ia zin e 1,1-Diox-
4-Am in o-1-m eth yl-6,7,8,9-tetr a h yd r o-10H-cycloh ep ta -
id e. To a suspension of 1 in methanol and concentrated
[b]pyr azin o[2,3-c][1,2,6]th iadiazin e 2,2-Dioxide (17). From
hydrochloric acid was added the corresponding R-hydroxyimino
2 (0.60 g, 2.2 mmol), acetone (25 mL), triethylamine (0.3 mL,
compound, and the mixture heated at reflux. The reaction
2.3 mmol), and methyl iodide (0.5 mL, 8.0 mmol). Reaction
mixture was evaporated to dryness, and water was added to
the residue. The precipitate was filtered, washed with
water, and recrystallized from the appropriate solvent (see
Table 1).
1
time 7 days at room temperature. Yield 17 (0.40 g, 63%). H
NMR (200 MHz, DMSO-d6) δ: 8.73 (br s, 1H, NH2), 8.59 (br s,
1H, NH2), 3.33 (s, 3H, CH3), 3.04-3.00 (m, 4H, 2CH2), 1.82
(m, 2H, CH2), 1.66 (m, 4H, 2CH2).
4-Am in o-6-m e t h yl-1H -p yr a zin o[2,3-c][1,2,6]t h ia d i-
a zin e 2,2-Dioxid e (6). From 1 (20.00 g, 112.8 mmol), metha-
nol (800 mL), concentrated hydrochloric acid (2 mL), and
pyruvaldoxime (18.00 g, 206.7 mmol). Reaction time 24 h. Yield
6 (21.70 g, 91%). H NMR (200 MHz, DMSO-d6): δ 12.05 (br
s, 1H, NH), 8.58 (br s, 1H, NH2), 8.51 (s, 1H, 7-H), 8.44 (br s,
1H, NH2), 2.49 (s, 3H, CH3).
4-Am in o-6-et h yl-1H -p yr a zin o[2,3-c][1,2,6]t h ia d ia zin e
2,2-Dioxid e (7). From 1 (1.50 g, 8.4 mmol), methanol (60 mL),
concentrated hydrochloric acid (0.2 mL), and 1-hydroxyimino-
2-butanone (1.75 g, 16.6 mmol). Reaction time 5 h. Yield 7 (0.79
g, 42%). 1H NMR (200 MHz, DMSO-d6): δ 12.06 (br s, 1H,
NH), 8.61 (br s, 1H, NH2), 8.56 (s, 1H, 7-H), 8.55 (br s, 1H,
NH2), 2.80 (q, 2H, CH2), 1.25 (t, 3H, CH3).
4-Am i n o -6-p r o p y l-1H -p y r a z i n o [2,3-c ][1,2,6]t h i a -
d ia zin e 2,2-Dioxid e (8). From 1 (1.00 g, 5.6 mmol), methanol
(40 mL), concentrated hydrochloric acid (0.15 mL), and 1-hy-
droxyimino-2-pentanone (1.31 g, 11.3 mmol). Reaction time 5
h. Yield 8 (1.08 g, 80%). 1H NMR (200 MHz, DMSO-d6): δ
12.10 (br s, 1H, NH), 8.62 (br s, 1H, NH2), 8.52 (s, 1H, 7-H),
4-Am in o-1-eth yl-7-isop r op yl-6-m eth ylp yr a zin o[2,3-c]-
[1,2,6]th ia d ia zin e 2,2-Dioxid e (18). From 3 (1.00 g, 3.9
mmol), acetone (30 mL), triethylamine (0.5 mL, 6.2 mmol), and
ethyl iodide (0.4 mL, 4.7 mmol). Reaction time 4 days (heated
1
1
at reflux). Yield 18 (0.79 g, 71%). H NMR (200 MHz, DMSO-
d6): δ 8.65 (br s, 1H, NH2), 8.49 (br s, 1H, NH2), 4.01 (q, 2H,
N-CH2), 3.28 (m, 1H, CH), 2.55 (s, 3H, CH3), 1.32-1.19 (m,
9H, 3CH3).
4-Am in o-7-b u t yl-1,6-d im e t h ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (19). From 4 (1.00 g, 3.7 mmol),
acetone (30 mL), triethylamine (0.6 mL, 4,3 mmol), and methyl
iodide (0.7 mL, 11.2 mmol). Reaction time 24 h at room
temperature. Yield 19 (0.65 g, 62%). 1H NMR (300 MHz,
DMSO-d6): δ 8.72 (br s, 1H, NH2), 8.58 (br s, 1H, NH2), 3.35
(s, 3H, N-CH3), 2.85 (t, 2H, C7-CH2), 2.52 (s, 3H, C6-CH3),
1.70 (q, 2H, CH2), 1.38 (m, 2H, CH2), 0.92 (t, 3H, CH3).
4-Am in o-1,7-dieth ylpyr azin o[2,3-c][1,2,6]th iadiazin e 2,2-
Dioxid e (20). From 5 (1.00 g, 4.4 mmol), acetone (25 mL),
triethylamine (0.6 mL, 4.6 mmol), and ethyl iodide (0.7 mL,
11.2 mmol). Reaction time 6 days at room temperature. Yield

Synthesis of Novel Bronchodilators
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4225
1
20 (0.58 g, 56%). H NMR (200 MHz, DMSO-d6): δ 8.79 (br s,
4-Am in o-1-[(eth oxycar bon yl)m eth yl]-6-m eth ylpyr azin o-
[2,3-c][1,2,6]th ia d ia zin e 2,2-Dioxid e (30). From 6 (2.50 g,
11.7 mmol), acetone (100 mL), triethylamine (1.7 mL, 12,2
mmol), and ethyl bromoacetate (1.4 mL, 12.8 mmol). Reaction
1H, NH2), 8.66 (s, 1H, CH), 8.61 (br s, 1H, NH2), 4.02 (q, 2H,
CH2), 2.87 (q, 2H, CH2), 1.28 (t, 6H, 2CH3).
4-Am i n o -1-e t h y l-6-m e t h y lp y r a z i n o [2,3-c ][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (21). From 6 (5.20 g, 24.4 mmol),
acetone (725 mL), potassium carbonate (1.68 g, 12.2 mmol),
and ethyl iodide, (3.0 mL, 37.5 mmol). Reaction time 20 days
at room temperature. Yield 21 (4.30 g, 73%).
1
time 2 days at room temperature. Yield 30 (1.25 g, 36%). H
NMR (200 MHz, DMSO-d6): δ 8.95 (br s, 1H, NH2), 8.82 (br s,
1H, NH2), 8.61 (s, 1H, CH), 4.69 (s, 2H, N-CH2), 4.10 (q, 2H,
O-CH2), 2.55 (s, 3H, CH3), 1.61 (t, 3H, CH3).
From 6 (0.50 g, 2.3 mmol), acetone (60 mL), triethylamine
(0.4 mL, 2.9 mmol), and ethyl iodide (0.4 mL, 5.0 mmol).
Reaction time 8 h (heated at reflux). Yield (0.31 g, 54%). 1H
NMR (200 MHz, DMSO-d6): δ 8.70 (br s, 2H, NH2), 8.63 (s,
1H, 7-H), 4.02 (q, 2H, CH2), 2.53 (s, 3H, CH3), 1.27 (t, 3H, CH3).
4-Am in o-1,6-dieth ylpyr azin o[2,3-c][1,2,6]th iadiazin e 2,2-
Dioxid e (22). From 7 (0.79 g, 3.4 mmol), acetone (30 mL),
triethylamine (0.5 mL, 3.6 mmol), and ethyl iodide (0.4 mL,
5.0 mmol). Reaction time 15 days at room temperature. Yield
4-Am in o-1-(2-h yd r oxyeth yl)-6,7-d im eth ylp yr a zin o[2,3-
c][1,2,6]th ia d ia zin e 2,2-Dioxid e (31). From 13, (2.00 g, 8.8
mmol), acetone (200 mL), potassium carbonate (0.60 g, 4.4
mmol), tetrabutylammonium iodide (1.65 g, 4.0 mmol), and
2-bromoethanol (0.8 mL, 11.2 mmol). Reaction time 7 days at
room temperature. Yield 31 (0.74 g, 31%). 1H NMR (200 MHz,
DMSO-d6): δ 8.67 (br s, 1H, NH2), 8.52 (br s, 1H, NH2), 4.88
(t, 1H, OH), 4.04 (s, 2H, CH2), 3.62 (q, 2H, CH2), 3.31 (s, 3H,
CH3), 2.55 (s, 3H, CH3).
4-Am in o-1-ca r boxym eth yl-6,7-d im eth ylp yr a zin o[2,3-c]-
[1,2,6]th ia d ia zin e 2,2-Dioxid e (32). A solution of 37 (0.80
g, 2.5 mmol) in 2 N hydrochloric acid (70 mL) was heated 70
°C for 5 h. Then, the precipitate was filtered to give 32 (0.42
g, 58%). 1H NMR (200 MHz, DMSO-d6): δ 8.77 (br s, 1H, NH2),
8.63 (br s, 1H, NH2), 4.58 (s, 2H, CH2), 2.52 (s, 3H, CH3), 2.51
(s, 3H, CH3).
1
22 (0.57 g, 60%). H NMR (200 MHz, DMSO-d6): δ 8.80 (br s,
1H, NH2), 8.66 (s, 1H, 7-H), 8.62 (br s, 1H, NH2), 4.03 (q, 2H,
CH2), 2.83 (q, 2H, CH2), 1.28 (t, 6H, 2CH3).
4-Am i n o -1-e t h y l-6-p r o p y lp y r a z i n o [2,3-c ][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (23). From 8 (0.60 g, 2.4 mmol),
acetone (20 mL), triethylamine (0.4 mL, 2.9 mmol), and ethyl
iodide (0.3 mL, 3.7 mmol). Reaction time 15 days at 4 °C. Yield
1
23 (0.28 g, 46%). H NMR (200 MHz, DMSO-d6): δ 8.79 (br s,
1-Eth yl-4-(eth yla m in o)-6-p h en ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (38). From 37 (1.00 g, 3.6 mmol),
potassium carbonate (0.25 g, 1.8 mmol), acetone (50 mL), and
ethyl iodide (0.6 mL, 7.5 mmol). Reaction time 5 days (heated
1H, NH2), 8.64 (s, 1H, 7-H), 8.61 (br s, 1H, NH2), 4.03 (q, 2H,
N-CH2), 2.78 (t, 2H, CH2), 1.75 (m, 2H, CH2), 1.27 (t, 3H, CH3),
0.91 (t, 3H, CH3).
1
4-Am in o-1-e t h yl-6-isop r op ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (24). From 9 (1.50 g, 6.2 mmol),
acetone (100 mL), triethylamine (0.9 mL, 6.4 mmol), and ethyl
iodide (0.7 mL, 8.7 mmol). Reaction time 6 days at room
temperature. Yield 24 (0.93 g, 56%). 1H NMR (200 MHz,
DMSO-d6): δ 8.82 (br s, 1H, NH2), 8.67 (s, 1H, 7-H), 8.59 (br
s, 1H, NH2), 4.02 (q, 2H, CH2), 3.13 (sep, 1H, CH), 1.29-1.27
(m, 9H, 3CH3).
4-Am in o-6-t er t -b u t yl-1-e t h ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (25). From 10 (0.82 g, 3.2 mmol),
acetone (35 mL), triethylamine (0.5 mL, 3.6 mmol), and ethyl
iodide (0.6 mL, 7.5 mmol). Reaction time 5 days at room
temperature. Yield 25 (0.56 g, 61%). 1H NMR (200 MHz,
DMSO-d6): δ 8.83 (br s, 2H, NH2, 7-H, 8.56 (br s, 1H, NH2),
4.03 (q, 2H, CH2), 1.37 (s, 9H, 3CH3), 1.28 (t, 3H, CH3).
4 -A m i n o -1 , 6 -d i m e t h y l p y r a z i n o [ 2 , 3 -c ] [ 1 , 2 , 6 ] -
th ia d ia zin e 2,2-Dioxid e (26). From 6 (1.50 g, 7.0 mmol),
acetone (50 mL), potassium carbonate (0.50 g, 3.6 mmol), and
methyl iodide (2.0 mL, 32.1 mmol). Reaction time 10 h at room
temperature. Yield 26 (0.65 g, 41%). 1H NMR (300 MHz,
DMSO-d6): δ 8.84 (br s, 1H, NH2), 8.71 (br s, 1H, NH2), 8.63
(s, 1H, CH), 3.34 (s, 3H, CH3), 2.52 (s, 3H, CH3).
4-Am in o -1-m e t h y l-7-p h e n y lp y r a zin o [2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (27). From 12, (3.00 g, 11.0 mmol),
acetone (180 mL), potassium carbonate (0.75 g, 5.5 mmol), and
methyl iodide (4.0 mL, 64.2 mmol). Reaction time 5 days at
room temperature. Yield 27 (2.26 g, 76%). 1H NMR (200 MHz,
DMSO-d6): δ 9.03 (s, 1H, CH), 8.90 (br s, 1H, NH2), 8.88 (br
s, 1H, NH2), 8.32-8.27 (m, 2H, Ph), 7.60-7.57 (m, 3H, Ph),
3.48 (s, 3H, CH3).
4-Am in o-1,7-d im et h yl-6-p h en ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (28). From 16 (2.00 g, 6.9 mmol),
acetone (80 mL), potassium bicarbonate (0.75 g, 7.6 mmol),
and methyl iodide (3.0 mL, 48.2 mmol). Reaction time 24 h at
room temperature. Yield 28 (1.71 g, 82%). 1H NMR (200 MHz,
DMSO-d6): δ 8.77 (br s, 1H, NH2), 8.59 (br s, 1H, NH2), 7.74-
7.49 (m, 5H, Ph), 4.07 (s, 3H, CH3), 2.63 (s, 3H, CH3).
4-Am in o-1-et h ylp yr a zin o[2,3-c][1,2,6]t h ia d ia zin e 2,2-
Dioxid e (29). From 11 (1.00 g, 5.0 mmol), acetone (55 mL),
triethylamine (0.7 mL, 5.0 mmol), and ethyl iodide (0.7 mL,
8.7 mmol). Reaction time 5 days at room temperature. To the
reaction mixture was added dichloromethane, and the organic
layer was separated, evaporated to dryness, and recrystallized
from water to yield 29 (0.57 g, 50%). 1H NMR (200 MHz,
DMSO-d6): δ 8.83 (br s, 2H, NH2), 8.72 (d, 1H, CH), 8.42 (d,
1H, CH), 4.04 (q, 2H, CH2), 1.28 (t, 3H, CH3).
at reflux). Yield 38 (0.72 g, 60%). H NMR (200 MHz, DMSO-
d6): δ 9.46 (t, 1H, NH), 9.39 (s, 1H, CH), 8.34-7.49 (m, 5H,
Ph), 4.09 (q, 2H, CH2), 3.48 (q, 2H, CH2), 1.34 (t, 3H, CH3),
1.22 (t, 3H, CH3).
Tr a n sa m in a tion . Gen er a l P r oced u r e for th e Syn th esis
of Com p ou n d s 39-48. To a solution of the N-1-substituted
pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide in methanol, the
correspondig amine was added. The reaction mixture was
stirred at room temperature or heated at reflux and evaporated
to dryness, and water was added to the residue. The precipitate
was filtered and recrystallized from the appropriate solvent
(see Table 1).
4-[(2-Am in oeth yl)a m in o]-1-m eth yl-7-p h en ylp yr a zin o-
[2,3-c][1,2,6]th ia d ia zin e 2,2-Dioxid e (39). From 27 (1.00 g,
3.4 mmol), methanol (45 mL), and ethylendiamine (0.6 mL,
34.4 mmol). Reaction time 6 h (heated at reflux). Yield 39 (0.67
g, 56%). 1H NMR (200 MHz, DMSO-d6): δ 9.04 (s, 1H, CH),
8.32-7.58 (m, 5H, Ph), 3.49 (s, 3H, CH3), 3.41 (m, 2H, CH2),
2.78 (t, 2H, CH2).
4-Hyd r a zin o-1-m eth yl-7-p h en ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (40). From 27 (1.00 g, 3.4 mmol),
methanol (90 mL), and hydrazine hydrate (1.5 mL, 30.7 mmol).
Reaction time 20 h at room temperature. Yield 40 (0.51 g,
48%). 1H NMR (200 MHz, DMSO-d6): δ 8.95 (s, 1H, CH), 8.26-
7.53 (m, 5H, Ph), 3.44 (s, 3H, N-CH3).
4-Ben zyla m in o-1-eth yl-7-p h en ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (41). From 34 (0.60 g, 1.98 mmol),
methanol (35 mL), and benzylamine (2.0 mL, 18.3 mmol).
Reaction time 5 days (heated at reflux). Yield 41 (0.53 g, 68%).
1H NMR (200 MHz, DMSO-d6): δ 9.96 (br s, 1H, NH), 9.05 (s,
1H, CH), 8.30-8.26 (m, 2H, Ph), 7.62-7.59 (m, 3H, Ph), 7.36-
7.25 (m, 5H, Ph), 4.62 (s, 2H, CH2), 4.15 (q, 2H, CH2), 1.38 (t,
3H, CH3).
4-Ben zyla m in o-1-eth yl-6-m eth ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (42). From 21 (0.80 g, 3.3 mmol),
methanol (30 mL), and benzylamine (3.0 mL, 27.5 mmol).
Reaction time 62 h (heated at reflux). Yield 42 (0.44 g, 40%).
1H NMR (200 MHz, DMSO-d6): δ 9.77 (t, 1H, NH), 8.65 (s,
1H, CH), 7.35-7.25 (m, 5H, Ph), 4.60 (d, 2H, NH-CH2), 4.02
(q, 2H, CH2), 2.55 (s, 3H, C6-CH3), 1.27 (t, 3H, CH3).
1-Eth yl-4-(eth yla m in o)-6-m eth ylp yr a zin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (43). From 21 (0.90 g, 3.7 mmol),
methanol (40 mL), and ethylamine (2 mL, 35.3 mmol). Reac-
tion time 48 h (heated at reflux). Yield 43 (0.82 g, 81%). 1H
NMR (200 MHz, DMSO-d6): δ 9.25 (t, 1H, NH), 8.62 (s, 1H,

4226 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Campillo et al.
CH), 4.01 (q, 2H, CH2), 3.41 (q, 2H, CH2), 2.54 (s, 3H, C6-
Ack n ow led gm en t. We are grateful to E. Carrasco
and M. Grau from Prodesfarma S. A., Barcelona, Spain,
for biological assays.
CH3), 1.27 (t, 3H, CH3), 1.16 (t, 3H, CH3).
1,6,7-Tr im eth yl-4-(2-picolylam in o)pyr azin o[2,3-c][1,2,6]-
th ia d ia zin e 2,2-Dioxid e (44). From 35 (1.00 g, 4.1 mmol),
ethanol (50 mL), and 2-picolylamine (3.0 mL, 29.1 mmol)
Reaction time 62 h (heated at reflux). Yield 44 (0.87 g, 65%).
1H NMR (300 MHz, DMSO-d6): δ 9.63 (br s, 1H, NH), 8.53
(dd, 1H, py), 7.77 (m, 1H, py), 7.27-7.35 (m, 2H, py), 4.72 (s,
2H, CH2), 3.36 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.55 (s, 3H,
CH3).
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Refer en ces
1,7-Dieth yl-4-[(2-h yd r oxy)eth yla m in o]-6-m eth ylpyr a zi-
n o[2,3-c][1,2,6]th ia d ia zin e 2,2-Dioxid e (45). From 36 (1.50
g, 5.6 mmol), methanol (50 mL), and ethanolamine (3.0 mL,
49.7 mmol). Reaction time 28 h (heated at reflux). Yield 45
(1.70 g, 97%). 1H NMR (200 MHz, DMSO-d6): δ 8.88 (br s,
1H, NH), 4.90 (t, 1H, OH), 4.04 (q, 2H, CH2), 3.59 (q, 2H, CH2),
3.45 (t, 2H, CH2), 2.90 (t, 2H, CH2), 2.54 (s, 3H, CH3), 1.30 (s,
3H, CH3), 1.26 (t, 3H, CH3).
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1
g, 88%). H NMR (300 MHz, DMSO-d6): δ 4.01 (q, 2H, CH2),
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1
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Synthesis of Novel Bronchodilators
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