Triazolylbenzimidazolthiones and derivatives of the new 1,2,3-triazolo[1,5-a][1,3,5]benzotriazepine heterocycle

Article abstract of DOI:10.1002/jhet.5570390628

Four new triazolylbenzimidazolthione derivatives (2a-d), analogous to triazolylbenzimidazolone derivatives previously tested as activators of the BK_Ca potassium channels, were prepared and assayed without success. Some derivatives of a new tric

Full text of DOI:10.1002/jhet.5570390628

Nov-Dec 2002
Triazolylbenzimidazolthiones and Derivatives of the New
1,2,3-Triazolo[1,5-a][1,3,5]benzotriazepine Heterocycle
Giuliana Biagi, Irene Giorgi, Oreste Livi*, Antonio Nardi, and Valerio Scartoni
1293
Dipartimento di Scienze Farmaceutiche, Università di Pisa,
via Bonanno 6, 56126 Pisa, Italy
Received May 5, 2002
Four new triazolylbenzimidazolthione derivatives (2a-d), analogous to triazolylbenzimidazolone deriva-
tives previously tested as activators of the BKCa potassium channels, were prepared and assayed without
success. Some derivatives of a new tricyclic nitrogen heterocycle, 1,2,3-triazolo[1,5-a][1,3,5]benzo-
triazepine, bearing a carboxamido group in the 3 position, other substituents in the 8 position and a carbonyl
(5a-d) or thione (6a-c) or methylthio (7a-c) function in the 5 position were synthesised. The nucleophilic dis-
placement of the methylthio substituent with morpholine or cyclopentylamine provided the 5-amino-
substituted tricyclic derivatives 8a-d. Starting from the 1-(2-nitrophenyl)-4-cyano-5-amino-1,2,3-triazole
(9), the 3-cyano-triazolobenzotriazepin-5-one derivative 12 was also obtained. The majority of the new
compounds were tested towards the BKCa potassium channels, the benzodiazepine and adenosine A1 and
A2A receptors, but no remarkable activity was detected.
J. Heterocyclic Chem., 39, 1293(2002).
For some time we have been interested in the investiga-
the correlation with tricyclic structures having in vivo bio-
logical activity, like dibenzo[1,3]diazepines (excitant,
aggressant, motor stimulant and anticonvulsant activity) [7]
or 4-aryl-1,3-benzodiazepines (antihypertensive activity)
[8], we decided to employ some synthesis intermediates of
previous structures for the preparation of the new tricyclic
nitrogen heterocycle 1,2,3-triazolo[1,5-a][1,3,5]benzotria-
zepine, corresponding to the general structure A (Figure 1).
tion of compounds with potential activity towards potas-
sium channels [1]. In particular our attention was directed
to compounds active towards high conductance calcium
activated potassium channels (BK ), because of the cor-
Ca
relation of their structure with that of the reference benz-
imidazolone compounds NS 004 and NS 1619 [2-5].
The pharmacological experimentation of several 5-sub-
stituted-1-(triazol-5-yl)-benzotriazole and 5-substituted-1-
(triazol-5-yl)-benzimidazolone derivatives [3,4] had shown
that the benzotriazole compounds possessed an activity
higher than that of the benzimidazolone compounds.
However we decided on substituting the oxygen atom of
the benzimidazolone ring with a sulphur atom, to evaluate
the effect afforded to the biological properties. In fact the
change of the biological activity related to the structural
change induced by the passage from nitrogen (benzotria-
zole) to oxygen (benzimidazolone) to sulphur (benzimida-
zolthione) as acceptor sites of a hydrogen bond, could give
information about this pharmacophoric parameter.
In this case introduction of a sulphur atom in the 5 posi-
tion in the place of the oxygen, could also allow the prepa-
ration of further new derivatives, by the conversion to a
methylthio group, well available towards the nucleophilic
substitution. The synthesis of this new heterocycle
(Scheme 2), required the preparation of the 1-(2-nitro-
phenyl)-4-carboxamido-5-amino-1,2,3-triazoles 3a-d, by
ionic 1,3-dipolar cycloaddition reaction of the suitable
2-nitrophenylazide to cyanacetamide. This reaction had
to be carried out under mild conditions (low temperature)
to decrease the formation of the corresponding 4-carbox-
amido-5-(2-nitroanilino)-1,2,3-triazoles. These com-
pounds were really the main reaction products and came
from the Dimroth isomerization of 3, isomerization which
was aided by the alkaline medium and by the presence of a
nitro substituent [9]. Compounds 3a and 3b have previ-
ously been described in the literature [6] while 3c and 3d
were isolated in 30% and 11% yield respectively.
Thus starting from the suitable 5-(2-aminoanilino)-1,2,3-
triazoles 1a-d (Scheme 1), previously described in the liter-
ature [6,2], by reaction with carbon disulphide in ethanolic
solution in the presence of sodium ethoxide at 50 °C for
several hours, the corresponding benzimidazolthione deriv-
atives 2a-d were obtained in good yield. In addition, by
Reduction of the nitro to amino group by catalytic
hydrogenation on Pd/C or Ni-Raney (for the chloroderiva-

1294
G. Biagi, I. Giorgi, O. Livi, A. Nardi, and V. Scartoni
Vol. 39
tive 3d ), working at a temperature < 30 °C for the isola-
tion of compounds, provided the corresponding deriva-
tives 4a-d in high yield. In this case also, compounds 4a
and 4b have previously been described in the literature [6].
The amino derivatives 4a-d in pyridine solution reacted
with phosgene in toluene solution at room temperature
overnight, to give the expected tricyclic triazolobenzotri-
azepine compounds 5a-d. Compound 5a was isolated in
62.5% yield, probably due to the greater solubility of 4a in
pyridine, but compounds 5b, 5c and 5d were obtained in
45%, 48% and 32% yield respectively.
derivatives 8a and 8b were obtained in high yield; simi-
larly on heating 7b and 7c with cyclopentylamine, the
derivatives 8c and 8d were isolated.
In order to change the carboxamido substituent on the
1,2,3-triazole ring for a nitrile group (Scheme 4), reaction
of 2-nitrophenylazide [10] to malononitrile, carried out at
temperature < -5 °C, gave the 1-(2-nitrophenyl)-4-cyano-
5-amino-1H-1,2,3-triazole (9) in 86% yield. On heating 9
under reflux in toluene solution for 2 hours, Dimroth iso-
merization [9] was induced and the 4-cyano-5-(2-
nitroanilino)-1,2,3-triazole (10) was characterized for
comparison purposes. The nitro derivative 9 underwent a
catalytic hydrogenation to give the corresponding amino-
triazole 11 which was isolated in 40% yield after chro-
matography working at a temperature < 30 °C. Finally,
the diamino derivative 11 in pyridine solution reacted with
excess phosgene (added as triphosgene in toluene solution)
at room temperature overnight to give the expected
triazolobenzotriazepine derivative 12, isolated by silica gel
column chromatography, in 79% yield.
Similarly, the same diamino derivatives 4a-c in ethano-
lic solution in the presence of sodium ethoxide, reacted
with excess carbon disulphide at 50 °C for 20-30 hours to
give the corresponding tricyclic compounds 6a-c, bearing
a sulphur atom in the 5 position, in 72%, 38% and 53%
yield respectively. The 5-methylthio derivatives 7a-c,
useful synthetic intermediates, were obtained in high yield
treating the corresponding thione/thiole derivatives 6a-c in
2.5% sodium hydroxide solution with methyl iodide at
room temperature.
The structures of all the new prepared compounds were
assigned upon the basis of known reaction mechanisms
and our previous evidence concerning triazolylbenzotria-
zole [6] and triazolylbenzimidazolone [11] derivatives and
were confirmed by analytical and spectroscopic methods
The preparation of the derivatives 8a-d with aliphatic
amines is shown in Scheme 3.
1
(mass spectra in Table 1 and H-nmr spectra in Table 2).
In addition, as a further structure confirmation and a better
13
characterization, the C-nmr spectra in DMSO-d of com-
6
pounds 2c, 5a and 6b are reported: 2c: d 171.0 (CS), 160.0
(CONH ), 138.5(C4’), 136.5 (C5’), 132.9 (C7a), 132.1
2
(C3a), 127.8 (C5), 122.6 (C6), 110.9 (C4), 109.6 (C7); 5a: d
162.8 (CONH ), 155.9 (CO), 137.6 (C3), 130.1 (C8), 129.6
2
(C3a), 125.8 (C6a), 125.8 (C10a), 124.9 (C9), 121.9 (C7),
121.7 (C10);6b: d 182.4 (CS), 162.3 (CONH ), 139.4 (C8),
2
136.2 (C3), 127.8 (C3a), 126.0 (C9), 125.0 (C10a), 123.5
Thus on heating 7a and 7b in excess morpholine at the
refluxing temperature for 3 hours, the 5-morpholino
(C6a), 122.0 (C7), 120.6 (C10), 20.1 (CH ).
3

Nov-Dec 2002
New 1,2,3-Triazolo[1,5-a][1,3,5]benzotriazepine Heterocycle
1295
Table 1
Chemical and Physical Properties of the Prepared Compounds
Comp.
Solvent
Yield
%
Crystall.
M.p. (°C)
Formula
Analyses C, H, N
Calcd./ Found %
Mass m/z
(%)
+
M
Base
2a
2b
2c
2d
3c
3d
4c
4d
5a
5b
5c
5d
6a
6b
6c
7a
7b
7c
8a
8b
8c
8d
9
62
76
60
69
30
11
94
96
62
45
48
32
72
38
53
85
89
89
91
79
92
90
86
94
40
79
H O
270-272 dec.
273-274 dec.
268-271
282-284 dec.
271-273
305-308
196-198
185-187
229-231
258-261
270-272
279-281
259-261
261-263
258-260
285-287
286-288
280 dec.
285-287
326-328
308-310
313-315
C
C
C
H N OS
46.15, 3.10, 32.29
46.48, 3.05, 32.46
48.17, 3.67, 30.64
48.50, 3.70, 30.95
40.75, 2.39, 28.52
41.05, 2.50, 28.89
49.76, 3.25, 32.24
49.77, 3.23, 32.25
43.17, 3.62, 30.21
43.51, 3.73, 30.53
38.25, 2.50, 29.73
38.43, 2.46, 29.78
48.38, 4.87, 33.85
48.70, 4.94, 34.17
42.78, 3.59, 33.26
43.08, 3.48, 33.59
49.18, 3.30, 34.41
48.82, 3.13, 34.39
51.16, 3.90, 32.54
51.49, 3.97, 33.34
48.18, 3.68, 30.64
48.30, 3.70, 31.00
43.10, 2.53, 30.16
42.79, 2.74, 30.52
46.15, 3.10, 32.29
46.07, 3.12, 32.62
48.17, 3.67, 30.64
48.28, 3.70, 30.60
45.51, 3.47, 28.95
45.19, 3.65, 28.61
48.17, 3.67, 30.64
48.51, 3.58, 30.87
49.99, 4.19, 29.15
49.88, 3.99, 29.22
47.36, 3.97, 27.62
47.05, 3.91, 27.63
53.67, 4.83, 31.29
53.93, 4.93, 30.96
55.04, 5.23, 29.95
54.79, 5.05, 29.65
59.06, 5.89, 30.16
59.13, 6.12, 29.88
56.30, 5.61, 28.72
56.30, 5.68, 29.05
46.96, 2.63, 36.51
47.08, 2.81, 36.85
46.96, 2.63, 36.51
47.25, 2.70, 36.83
53.99, 4.03, 41.98
54.23, 4.22, 42.29
53.10, 2.67, 37.15
53.41, 2.85, 36.88
260 (41.82) 44
2
10 8 6
H O
H N OS
11 10 6
274 (9.47)
294 (7.21)
44
44
2
H O
H N OSCl
7 6
2
10
H O
C H N S
217 (93.70) 39
278 (7.98) 44
282 (5.40) 140
2
9 7 5
EtOAc/Petr.Eth.
[a]
EtOAc/Petr.Eth.
[a]
C H N O
10 10 6 4
C H N O Cl
9 7 6 3
Acetone/Petr.Eth.
C
H
N O
6 2
248 (2.44)
252 (4.28)
44
44
10 12
EtOAc/Petr.Eth.
C H N OCl
9
9 6
DMF/H O
C
H N O
8 6 2
244 (47.30) 118
258 (17.78) 44
274 (72.19) 174
278 (15.63) 44
2
10
DMF/H O
C H N O
11 10 6 2
2
DMF/H O
C
C
C
C
C
H N O
2
11 10 6 3
DMF
H N O Cl
7 6 2
10
10
DMF/H O
H N OS
260 (1.62)
274 (7.26)
290 (3.53)
44
44
44
2
8 6
DMF
H N OS
11 10 6
DMF/H O
H N O S
11 10 6 2
2
H O
C
C
C
C
C
C
C
H N OS
274 (3.42) 150
288 (15.11) 44
304 (25.27) 44
313 (51.63) 44
327 (44.01) 255
325 (74:57) 158
341 (18.51) 41
2
11 10 6
H O
H N OS
12 12 6
2
H O
H N O S
12 12 6 2
2
EtOH/H O
H N O
14 15 7
2
2
2
EtOH/H O
H N O
15 17 7
2
EtOH
EtOH
H N O
16 19 7
H
N O
7
16 19
2
Acetone/Petr.Eth. [a] 132-134
C H N O
230 (100)
230 (1.54)
200 (8.22)
230
53
9
6
6
2
2
10
11
12
EtOAc/Hexane
186-188
133-135
C H N O
9
6
6
6
EtOAc/Petr.Eth.
[a]
DMF/H O
C H N
53
9
8
295-298
[b]
C
H N O
226 (29.89) 118
2
10
6 6
[a] crystallized by solution at room temperature, beginning precipitation with petroleum ether and cooling at –20 °C; [b] at 240-245
°C the amorphous solid changed to white needles.
The uv data of the tricyclic derivative 12 are also
The ir spectra of the benzimidazolthiones 2a-d and of
the tricyclic compounds 5a-d and 6a-c show the expected
bands corresponding to NH and CO groups: Compounds
reported as an example of absorbance of these structures:
-5
l
= 221nm, log e = 4.520 (c 2.78 10 M, isopropanol).
max

1296
G. Biagi, I. Giorgi, O. Livi, A. Nardi, and V. Scartoni
Vol. 39
Table 2
1
H-NMR Spectra in DMSO-d (d)
6
2a
2b
2c
2d
3c
3d
4c
4d
5a
5b
5c
5d
6a
6b
6c
7a
7b
7c
8a
8b
8c
8d
9
13.10 (s, 1H, NH); 7.89 and 7.53 (2s, 2H, NH ); 7.25-6.80 (m, 4H, Ar)
2
7.86 and 7.54 (2s, 2H, NH ); 7.05-6.68 (m, 3H, Ar); 2.36 (s, 3H, Me)
2
13.17 (brs, 1H, NH); 12.41 (brs, 1H, NH); 7.89 and 7.53 (2s, 2H, NH ); 7.27-6.81 (m, 3H, Ar)
2
8.52 (s, 1H, NH); 7.38-7.10 (m, 5H, Ar and Triaz.)
7.81-7.46(m, 3H, Ar); 7.58 and 7.20 (2s, 2H, NH ); 6.48 (s, 2H, NH ); 3.94 (s, 3H, Me)
2
2
8.43 (d, 1H, Ar); 8.06 (dd, 1H, Ar); 7.84 (d, 1H, Ar); 7.62 and 7.23 (2 brs, 2H, NH ); 6.62 (s, 2H, NH )
2
2
7.52 and 7.13 (2s, 2H, NH ); 6.98-6.22 (m, 3H, Ar); 5.95 (s, 2H, NH ); 5.13 (s, 2H, NH ); 3.72 (s, 3H, Me)
2
2
2
7.54 and 7.14 (2 brs, 2H, NH ); 7.09-6.63 (m, 3H, Ar); 6.13 (s, 2H, NH ); 5.48 (s, 2H, NH )
2
2
2
9.84 (s, 1H, NH); 8.93 (s, 1H, NH); 8.17 and 7.77 (2s, 2H, NH ); 7.92-7.22 (m, 3H, Ar)
2
11.00 (s, 1H, NH); 9.76 (s, 1H, NH); 8.87 and 8.15 (2s, 2H, NH ); 7.78-7.03 (m, 3H, Ar); 2.31 (s, 3H, Me)
2
9.74 (s, 1H, NH); 8.90 (s, 1H, NH); 8.13 (s, 1H, NH ); 7.84-6.80 (m, 4H, Ar and NH ); 3.78 (s, 3H, Me)
2
2
9.92 (s, 1H, NH); 9.04 (s, 1H, NH); 8.17 and 7.76 (2s, 2H, NH ); 7.94-7.29 (m, 4H, Ar)
2
11.20 (s, 1H, NH); 10.06 (s, 1H, NH); 8.27 and 7.94 (2s, 2H, NH ); 7.89-7.28 (m, 4H, Ar)
2
11.11 (s, 1H, NH); 10.01 (s, 1H, NH); 8.24 and 7.85 (2s, 2H, NH ); 7.81-7.08 (m, 3H, Ar); 2.29 (s, 3H, Me)
2
11.07 (s, 1H, NH); 10.03 (s, 1H, NH); 8.21 (s, 1H, NH ); 7.85-6.80 (m, 4H, Ar and NH ); 3.77 (s, 3H, Me)
2
2
11.19 and 10.05 (2s, 1H, NH); 8.26 (s, 1H, NH ); 7.93-7.25 (m, 5H, Ar and NH ); 2.50 (s, 3H, Me)
2
2
9.70 (s, 1H, NH); 7.66-6.78 (m, 5H, Ar and NH ); 2.50 (s, 3H, Me); 2.23 (s, 3H, Me)
2
9.76 (brs, 1H, NH); 7.70-6.59 (m, 5H, Ar and NH ); 3.74 (s, 3H, Me); 2.51 (s, 3H, Me)
2
8.70 (brs, 1H, NH); 7.76 (d, 1H, Ar); 7.43-7.10 (m, 5H, Ar and NH ); 3.67-3.52 (m, 8H, Morph)
2
8.68 (brs, 1H, NH); 7.76-6.95 (m, 5H, Ar and NH ); 3.68-3.50 (m, 8H, Morph); 2.30 (s, 3H, Me)
2
7.72 and 7.33 (2s, 2H, NH ); 7.66-6.70 (m, 3H, Ar); 7.29 (brs, 1H, NH); 4.02 (brs, 1H, NH); 2.27 (s, 3H, Me); 1.93-1.47 (m, 9H, Cyclop)
2
7.72 and 7.34 (2s, 2H, NH ); 7.70-6.45 (m, 3H, Ar); 7.24 (brs, 1H, NH); 4.00 (brs, 1H, NH); 3.77 (s, 3H, Me); 1.94-1.44 (m, 9H, Cyclop)
2
8.32-7.78 (m, 4H, Ar); 7.35 (s, 2H, NH )
2
10
11
12
9.86 (s, 1H, NH); 8.17-7.07 (m, 5H, Ar and NH)
7.28-6.61 (m, 4H, Ar); 6.85 (s, 2H, NH ); 5.26 (s, 2H, NH )
2
2
11.06 (s, 1H, NH); 9.73 (s, 1H, NH); 7.87-7.23 (m, 4H, Ar)
-1
EXPERIMENTAL
2a-d: NH signals at 3450-3170 cm and CONH signal at
2
-1
1676-1650 cm ; Compounds 5a-d: NH signals at 3360-
3250 cm and clear carbonyl signals for NHCONH at
Melting points were determined on a Kofler hot-stage and are
uncorrected. IR spectra in nujol mulls were recorded on a Mattson
Genesis series FTIR spectrometer. UV spectrum was obtained on a
Perkin-Elmer Lambda 15 UV/VIS spectrophotometer in iso-
propanol. 1H-NMR and 13C-NMR spectra were recorded with a
Varian Gemini 200 spectrometer in d units, using TMS as internal
standard. Mass spectra were performed with a Hewlett Packard
MS/System 5988 A. Elemental analyses (C,H,N) were within ±
0.4% of theoretical values and were performed on a Carlo Erba
Elemental Analyzer Mod. 1106 apparatus. TLC data were obtained
with Merck silica gel 60 F254 aluminum sheets. Petroleum ether
corresponds to fraction boiling at 40-60 °C. Phosgene, azides and
carbon disulphide are very toxic and dangerous reagents which
requires an appropriate personal protection.
-1
-1
-1
1747-1733 cm and for CONH at 1680-1668 cm ;
2
-1
Compounds 6a-c : NH signals at 3390-3170 cm and
-1
CONH signal at 1666-1661 cm .
2
Finally, a chemical confirmation of the new 1,2,3-tria-
zolo[1,5-a][1,3,5]benzotriazepine structure was achieved
by the following reactions. The 1-benzyl-4-carboxamido-
5-amino-1H-1,2,3-triazole [12] was reacted either with
phosgene or thiophosgene under the previously employed
reaction conditions, which did not induce Dimroth isomer-
ization, but no azapurine derivative was isolated. Thus the
involvement of the carboxamido group in the cyclization
could be excluded; the only effect of the reagent was the
partial dehydration of the carboxamido to cyano group.
The reaction of 1-(2-aminophenyl)-4-carboxamido-5-
amino-1H-1,2,3-triazole (4a) with excess phosgene under
prolonged reaction times did not provide the tricyclic
derivative 5a, but the tricyclic cyanoderivative 12, involv-
ing the cyclization between the two amino groups and the
dehydration of the carboxamido group.
1-(1,2,3-Triazol-5-yl)-benzimidazolthiones (2a-d).
To a stirred solution of sodium ethoxide, prepared from
sodium (0.043 g, 1.87 mmol) in 16 mL of absolute ethanol, 1.70
mmoles of the appropriate 5-(2-aminoanilino)-1,2,3-triazoles
(1a, 1b, 1c or 1d) [6,2] and 10 mL of carbon disulphide were
added and the mixture was heated at 50 °C for 18 hours under
stirring. After ~ 1 hour the solution colour changed from brown
to yellow. The solvent was evaporated in vacuo, the residue was
treated with water and the resulting solution was acidified with
10% hydrochloric acid to precipitate the title compounds which
were collected by filtration and washed with water (Table 1).
Several compounds were tested to evaluate their activity
towards potassium channels (2a,b,c, d; 5a,c; 6a,c; 12), A
and A adenosine receptors (2b,d; 5b,d; 6a,b,d; 12; 7b,c;
1
2A
8a,b) and benzodiazepine receptors (2b,d; 5b,d; 6a,b,d;
12), but no remarkable activity was detected.
1-(2-Nitro-4-substituted-phenyl)-4-carboxamido-5-amino-1H-
1,2,3-triazoles (3c and 3d).
The experimental procedures are reported in our
previous papers : [5], [13] and [13] respectively.
To a stirred solution of sodium ethoxide, prepared from sodium
(1.20 g, 52 mmol) in 80 mL of absolute ethanol, cyanacetamide (

Nov-Dec 2002
New 1,2,3-Triazolo[1,5-a][1,3,5]benzotriazepine Heterocycle
1297
tion were added and the mixture was stirred at room temperature
for a night. Water was added and stirring continued for 2 hours,
the precipitate was collected by filtration, washed and purified by
extraction with a little methanol then recrystallized (Table 1).
4.37 g, 52 mmol) was added. After ~15 minutes the suspension
was cooled into an ice-salt bath at -10 °C and a solution of 43.8
mmoles of the appropriate azide (2-nitro-4-methoxy-phenylazide
[14] or 2-nitro-4-chloro-phenylazide [15]) in 120 mL of absolute
ethanol was added drop by drop, keeping the temperature < -5 °C.
The reaction mixture was stirred for 1 hour into the ice-bath, then
overnight at room temperature. Water was added to precipitate the
title compounds which were collected by filtration and washed with
water (Table 1). The ethanolic-aqueous filtrate was concentrated in
vacuo, treated with 10% sodium hydroxide and heated to boiling for
~ 10 minutes. By cooling ~ 15-30 % of the 2-nitro-4-substituted-
phenyl derivative precipitated and was filtered off. From the fil-
trate, by acidification to pH 2 with 36% hydrochloric acid, the cor-
responding Dimroth isomer precipitated: 4-carboxamido-5-(2-nitro-
4-methoxy-anilino)-1,2,3-triazole [2] in 23% yield or 4-carboxam-
ido-5-(2-nitro-4-chloro-anilino)-1,2,3-triazole [2] in 53% yield.
8-Substituted-3-carboxamido-1,2,3-triazolo[1,5-a][1,3,5]benzo-
triazepin-5-thiones (6a-c).
To a stirred solution of sodium ethoxide, prepared from sodium
(0.046 g, 2.00 mmol) in 20 mL of absolute ethanol, 2.00 mmoles
of the suitable diamino derivative (4a, 4b or 4c) and 20 mL of car-
bon disulphide were added and the mixture was heated at 50 °C
under stirring for 30 hours. The reaction mixture was evaporated
in vacuo, the residue was treated with water and the resulting solu-
tion was acidified with 10% hydrochloric acid to precipitate the
title compounds which were collected by filtration and washed
with water then recrystallized (Table 1).
1-(2-Amino-4-methoxyphenyl)-4-carboxamido-5-amino-1H-
1,2,3-triazole (4c).
8-Substituted-3-carboxamido-5-methylthio-1,2,3-triazolo[1,5-a]-
[1,3,5] benzotriazepines (7a-c).
To a suspension of 3c (1.00 g, 3.57 mmol) in 200 mL of acetic
acid, 0.100 g of 10% Pd/C were added and the mixture was
hydrogenated at room temperature and pressure. The catalyst
was filtered off, washed with acetic acid and the combined
filtrates were evaporated in vacuo keeping the temperature < 30
°C. The solid residue was treated with 5% sodium hydrogen car-
bonate and the insoluble material, consisting of 4c, was collected
by filtration and washed with water (Table 1).
A suspension of 0.600 mmoles of the suitable triazolo-benzo-
triazepin-thione (6a, 6b or 6c) in 15 mL of 2.5% sodium hydrox-
ide was stirred for 10-15 minutes, 0.045 mL (0.720 mmol) of
iodomethane were added and stirring was continued at room tem-
perature for 30 minutes. The title compounds precipitated and
were collected by filtration then recrystallized (Table 1).
8-Substituted-3-carboxamido-1,2,3-triazolo[1,5-a][1,3,5]benzotri-
azepine-5-morpholino or Cyclopentylamino Derivatives (8a-d).
1-(2-Amino-4-chlorophenyl)-4-carboxamido-5-amino-1H-1,2,3-
triazole (4d).
A solution of 0.50 mmoles of the suitable methylthio deriva-
tive (7a,7b or 7c) in 6 mL of the appropriate amine (morpholine
or cyclopentylamine) was heated under reflux for 3 hours. The
title compounds precipitated by cooling. However the reaction
mixture was evaporatedin vacuo and the residue was treated with
water and collected by filtration then recrystallized (Table 1).
To a solution of 3d (1.25 g, 4.40 mmol) in 160 mL of
methanol, ~ 3 g of Ni-Raney as suspension in water were added
and the mixture was hydrogenated at room temperature and pres-
sure. The catalyst was filtered off, washed with methanol and
the combined filtrates were evaporatedin vacuo keeping the tem-
perature < 30 °C. The solid residue consisted of 4d (Table 1).
1-(2-Nitrophenyl)-4-cyano-5-amino-1H-1,2,3-triazole (9).
A stirred solution of sodium ethoxide, prepared from sodium
(0.340 g, 0.015 mmol) in 30 mL of absolute ethanol, was cooled
at -10 °C into an ice-salt bath. Under stirring a solution of
2-nitrophenylazide (2.00 g , 12.19 mmol) and malononitrile
(0.805 g, 12.19 mmol) in 50 mL of absolute ethanol was
dropped very slowly, keeping the temperature < -5 °C. After
1 hour the ice bath was removed and stirring was continued for
1 hour. Water was added until the triazole 9 precipitated as a
solid which was collected by filtration and washed with water
then recrystallized (Table 1).
3-Carboxamido-1,2,3-triazolo[1,5-a][1,3,5]benzotriazepin-5-one
(5a).
To a solution of 4a (0.590 g, 2.70 mmol) in 8 mL of anhydrous
pyridine, 2.15 mL (~ 4.0 mmol) of 20% phosgene in toluene solu-
tion were added and the mixture was stirred at room temperature
for 20 hours. Water was added and stirring continued for 2-3
hours, then the solution was acidified with 10% hydrochloric acid
(pH 3) to precipitate the crude title compound which was collected
by filtration, washed and dried. The solid could be purified by
extraction with boiling toluene then recrystallized (Table 1).
4-Cyano-5-(2-nitroanilino)-1,2,3-triazole (10).
8-Substituted-3-carboxamido-1,2,3-triazolo[1,5-a][1,3,5]benzo-
triazepin-5-ones (5b and 5c).
A solution of 0.100 g (0.43 mmol) of 9 in 10 mL of toluene
was heated under reflux for 2 hours. The white colour changed
to yellow. By cooling, the title compound precipitated; it was
recovered by filtration and recrystallized (Table 1).
To a solution of 5.0 mmoles of the suitable diamino derivative
(4b or 4c) in 38 mL of anhydrous pyridine, a solution of 0.600 g
(~ 6.0 mmol) of triphosgene in 10 mL of toluene was added and
the mixture was stirred at room temperature for a night. Water
was added to precipitate the title compounds and stirring was
continued for 2-3 hours, then the solid was collected by filtration,
washed and dried (Table 1).
1-(2-Aminophenyl)-4-cyano-5-amino-1H-1,2,3-triazole (11).
To a solution of the nitrophenyltriazole 9 (0.375 g, 1.30 mmol)
in 10 mL of methanol, 10% Pd/C (0.030 g) was added and the
mixture was hydrogenated at room temperature and pressure.
The catalyst was filtered off, repeatedly washed with methanol
and the combined filtrates were evaporated in vacuo keeping the
temperature < 30 °C. The crude residue (0.260 g) was purified
by absorption on silica gel and flash-chromatography through a
8-Chloro-3-carboxamido-1,2,3-triazolo[1,5-a][1,3,5]benzotri-
azepin-5-one (5d).
To a solution of 4d (1.00 g, 3.96 mmol) in 20 mL of anhydrous
pyridine, 3.2 mL (~ 6.0 mmol) of 20% phosgene in toluene solu-

1298
G. Biagi, I. Giorgi, O. Livi, A. Nardi, and V. Scartoni
Vol. 39
[4] G. Biagi, V. Calderone, I. Giorgi, O. Livi, V. Scartoni, B.
Baragatti and E. Martinotti, Farmaco, 56, 841 (2001).
[5] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, P. L. Barili, V.
Calderone and E. Martinotti, Farmaco, 56, 827 (2001).
[6] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, S. Velo and P. L.
Barili, J. Heterocyclic Chem., 33, 1847 (1996).
[7] W. E. Kreighbaum and H. C. Scarborough, J. Med. Chem.,
7, 310 (1964).
[8] L. L. Setescak, F. W. Dekow, J. M. Kitzen and L. L.
Martin, J. Med. Chem., 27, 401 (1984).
silica gel column, eluting with ethyl acetate/petroleum ether
2:1.(Table 1).
3 Cyano-1,2,3-triazolo[1,5-a][1,3,5]benzotriazepin-5-one (12).
To a solution of 11 (0.200 g, 1.00 mmol) in 5 mL of anhydrous
pyridine, a solution of triphosgene (0.100 g, 1.0 mmol) in 5 mL
of toluene was added and the mixture was stirred at room temper-
ature for a night. Water was added to precipitate the title com-
pound and stirring was continued for 3 hours, then the solid was
collected by filtration and washed with water. The crude residue
(0.220 g) was purified by absorption on silica gel and flash-chro-
matography through a silica gel column, eluting with ethyl
acetate/petroleum ether 4:5 (Table 1).
[9] T. L. Gilchrist and G. E. Gymer in Advances in
Heterocyclic Chemistry, Vol. 16, A. R. Katritzky and A. J. Boulton,
eds, Academic Press, New York, 1974, pp 78-80.
[10] P. A. S. Smith and J. K. Boyer in Organic Syntheses, Vol.
31, R. S. Schreiber, ed, Wiley & Sons, New York, 1951, pp 14-16.
[11] L. Bertelli, G. Biagi, V. Calderone, I. Giorgi, O. Livi, V.
Scartoni and P. L. Barili, J. Heterocyclic Chem., 37, 1169 (2000).
[12] A. Albert, J. Chem. Soc. Perkin Trans., 1, 2659 (1973).
[13] L. Bertelli, G. Biagi, I. Giorgi, C. Manera, O. Livi, V.
Scartoni, L. Betti, G. Giannaccini, L. Trincavelli and P. L. Barili, Eur.
J. Med. Chem., 33, 113 (1998).
REFERENCES AND NOTES
[1] N.S. Cook, Potassium channels: structure, classification,
function and therapeutic potential, Ellis Horwood Limited,
Southampton, UK, 1990.
[2] G. Biagi, V. Calderone, I. Giorgi, O. Livi, V. Scartoni, B.
Baragatti and E. Martinotti, Eur. J. Med. Chem., 35, 715 (2000).
[3] B. Baragatti, G. Biagi, V. Calderone, I. Giorgi, O. Livi, E.
Martinotti and V. Scartoni,Eur. J. Med. Chem., 35, 949 (2000).
[14] L. K. Dyall and J. E. Kemp, Aust. J. Chem., 20, 1395
(1967).
[15] L. K. Dyall, Aust. J. Chem., 39, 89 (1986).