Antiaggregating and antithrombotic activities of new 1, 2, 3-triazolecarboxamides.

Article abstract of DOI:10.1002/ardp.200300837

Twenty five new triazolecarboxamides related to YC-1 were prepared and tested for their antiplatelet (in vitro) and antithrombotic (in vivo) activities. Five of them inhibited the aggregation of blood platelets (Born test, inducer collagen) with IC50 values between 90 and 130 microM. Nine compounds exhibited significant antithrombotic properties with an inhibition of thrombus formation between 11 and 7%. Only one compound (8c) showed both, in vitro and in vivo effects. In vitro, the most active compounds were 11c and 12d. They inhibit platelet aggregation with IC50 = 90 and 95 microM. In vivo, 10a showed the strongest inhibition of thrombus formation with 11% in arterioles (5% in venules) after a single oral dose of 60 mg/kg. With serotonin as inducer both, 11c and 12d, showed lower IC50 values namely 25 or 30 microM, respectively. Additional antiplatelet activities were found for 11c against adrenaline (IC50 = 25 microM) and for 12d against platelet activating factor (PAF) (IC50 = 15 microM) as inducer.

Full text of DOI:10.1002/ardp.200300837

156 Rehse et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Anke Cwiklicki*,
Klaus Rehse
Antiaggregating and Antithrombotic Activities
of new 1,2,3-Triazolecarboxamides
Institut für Pharmazie,
Freie Universität Berlin,
Berlin, Germany
Twenty five new triazolecarboxamides related to YC-1 were prepared and tested
for their antiplatelet (in vitro) and antithrombotic (in vivo) activities. Five of them
inhibited the aggregation of blood platelets (Born test, inducer collagen) with
IC50 values between 90 and 130 µM. Nine compounds exhibited significant
antithrombotic properties with an inhibition of thrombus formation between 11
and 7%. Only one compound (8c) showed both, in vitro and in vivo effects.
In vitro, the most active compounds were 11c and 12d. They inhibit platelet
aggregation with IC50 = 90 and 95 µM. In vivo, 10a showed the strongest inhi-
bition of thrombus formation with 11% in arterioles (5% in venules) after a single
oral dose of 60 mg/kg. With serotonin as inducer both, 11c and 12d, showed
lower IC50 values namely 25 or 30 µM, respectively. Additional antiplatelet activi-
ties were found for 11c against adrenaline (IC50 = 25 µM) and for 12d against
platelet activating factor (PAF) (IC50 = 15 µM) as inducer.
Keywords: YC-1; Triazolecarboxamides; Antiplatelet effects; Antithrombotic
properties
Received: August 20, 2003; Accepted November 25, 2003 [FP837]
DOI 10.1002/ardp.200300837
Introduction
The concentration of cyclic GMP in platelets is regu-
lated by soluble guanylate cyclase (sGC), which cata-
lyzes the synthesis of cyclic GMP from GTP, and cyclic
GMP phosphodiesterase, which degrades cyclic GMP
to 5Ј-GMP. Agents that elevate the cyclic GMP level
either by stimulating sGC or inhibiting cyclic GMP pho-
sphodiesterase are powerful inhibitors of platelet ag-
gregation. YC-1 activates sGC of human platelets by a
NO-independent mechanism and exerts its antiplatelet
effects through the sGC/cyclic GMP pathway. Surpris-
ingly, YC-1 not only activated sGC, but also affected
cyclic GMP metabolism, as it inhibits the activity of
phosphodiesterase (PDE) isoforms 1Ϫ5 [1].
Figure 1. Triazole derivatives related to YC 1.
Chemistry
Therefore, we synthesized new compounds related to
YC-1 (see Figure 1) in which the indazole heterocycle
was replaced by triazoles, primaryly by 1H-1,2,3-tri-
azoles. The benzyl residue at N-1 of indazole was
modified using phenyl-, alkyl- and arylalkyl groups.
The hydroxymethylfuryl residue of YC-1 was replaced
by various carboxamide functions and the importance
of the hydroxy group was investigated. Primarily, com-
pounds with an additional basic centre within the
amide function were investigated.
The most common method for the preparation of
1,2,3-triazoles is the 1,3-dipolar cycloaddition of az-
ides with acetylenes (Scheme 1) [2]. Most of the az-
ides were synthesized according to a procedure re-
ported previously [3]. Alkylazides were prepared from
corresponding iodides or bromides and sodium azide
with methylcarbitol and water as solvent [4]. Arylalkyl-
azides were prepared from the corresponding chlo-
rides or bromides via the reaction with sodium azide
in a mixture of carbitol and water as solvent. Phenyl
azide has been prepared following a combination of
the methods described by Noelting [5] and Lindsay [6].
Correspondence: Klaus Rehse, Institut für Pharmazie, Freie
Universität Berlin, Königin-Luise-Straße 2+4, D-14195 Berlin,
Germany. Phone: +49 30 838-53290/64, Fax: + 49 30 838-
53251; e-mail: Rehiwer@zedat.fu-berlin.de
* Part of the PhD thesis Anke Cwiklicki, FU Berlin, 2002.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Activities of new 1,2,3-Triazolecarboxamides 157
Scheme 1. Reaction between azides and acetylene
derivatives. R is alkyl, arylalkyl or phenyl.
Scheme 2. Triazolecarboxamides from 3 (8-11) and
6/7 (12/13). R is alkyl, arylalkyl or phenyl, X = O-CH2-
CH2-OH; NH-CH2-CH2-OH or CH2-N(CH3)2; Y = H or
CH3.
Azides 1 were reacted with ethyl propiolate (2) or ethyl
phenylpropiolate (5) in boiling ethanol to give the 1H-
1,2,3-triazoles 3/4 or 6/7 (Scheme 1). The products
1
were characterized by H-NMR spectroscopy. The re-
The triazolecarboxylates where reacted with various
amines in ethanol as solvent to give triazolecarboxam-
ides 8؊13 (Scheme 2).
action of azides with ethyl propiolate or ethyl phenyl-
propiolate is not regiospecific, i.e. mixtures are ob-
tained. TLC using a mixture of petroleum ether or hex-
ane with ethyl acetate (ratio 3:1) as eluent confirmed
the presence of two products. These products are the
isomeric triazole-4- and 5-carboxylates. The 1,4-iso-
Biology
1
mer (3) is identified by the H-NMR signal of the tri-
Inhibition of platelet aggregation in vitro
(Born test)
azole-H (H-5), which appears upfield of the corre-
sponding triazole-H (H-4) for the other isomer (4) [7].
For instance, in the 1-phenyl-1H-1,2,3-triazole-4-car-
boxylic acid ethylester 3d the proton in 5-position ap-
pears at 8.47 ppm. In the corresponding 1-phenyl-1H-
1,2,3-triazole 5-carboxylic acid the proton in 4-position
resonates at 9.49 ppm. The mixtures were separated
by column chromatography using silica gel as sorbent
and a petroleum ether/ethyl acetate mixture (3:1) as
eluent. First the 5-carboxylate (4d, 17%) and then the
4-carboxylate (3d, 83%) are obtained.
The platelet aggregation experiments were carried out
as already described [9]. The standard drug acetyl-
salicylic acid (asa) showed an IC50 = 175
20 µM.
This percentage of deviation from the mean is typical
for these antiplatelet experiments. The results of the
Born test are given in column 4 of all three Tables 1,
2 and 3.
The compounds 10d, 11c, 12c, and 12d with one vol-
uminous substituent on the N-1 of the triazole or with
an alkyl or cycloalkyl substituent at N-1 and a phe-
nylgroup at the triazole C-5 combined with a basic
moiety within the amide function showed antiaggregat-
ing effects (IC50 = 90Ϫ125 µM). The lipophilicity of
these substituents plays a major role. On the other
hand, compound 8c with 4-methylbenzyl substituent at
the N-1 of the triazole without a basic portion in the
amide function showed some antiaggregating activity
(IC50 = 130 µM). The introduction of the basic NH in-
stead of the O-moiety in 9f lead to an antiaggregating
compound 10d with IC50 = 100 µM. Similiarly appears
the change from 9f to 11c (see Table 1). There are no
significant results for the compounds 10d and 11c in
vivo. An additional phenyl-substituent in triazole C-5 of
11a results in compound 12d with IC50 = 95 µM. The
same effect is observed by variation of 10a to 12c.
The hydroxy group is not essential for the antiplatelet
activity. The compounds 11c and 12d were tested in
vitro (Born test) with other inducers (ADP, adrenaline,
In general, the reaction of azides with ethyl propiolate
(2) resulted in the 1,4-isomer (3) as the major product
(83Ϫ100%), whereas the reaction with ethyl phenyl-
propiolate (5) afforded mixtures with the two isomers
in approximately equal portions [8] (6/7). The isomeric
products were separated by column chromatography
too, using a silica gel and also a petroleum ether/ethyl
acetate mixture. The compound appearing first in the
eluent was claimed by Buckle et al. [8] to be the 5-car-
boxylate.
An unambiguous assignment can be made via the 1H-
NMR signal of N-CH2 group in 1-position of the tria-
zole. If the ester function is vicinal, i.e. in 5-position,
its anisotropic effect causes a downfield shift to 5.94
ppm (7c, CDCl3). A vicinal phenyl group (i.e. ester in
4-position) results in an upfield signal at 5.35 ppm (6c,
CDCl3). The same is true for 6d (4.40 ppm, CDCl3)
and 7d (4.96 ppm).
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158 Rehse et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Table 1. In vitro (Born test, inducer collagen) antiplatelet and in vivo antithrombotic properties of triazolecarbox-
amides 8Ϫ11. Statistics: Wilcoxon Man Whitney U test, n. s. = not significant.
Inhibition of thrombus
formation
Born test
venules
arterioles
Cpd.
8a
8b
8c
8d
9a
9b
9c
9d
R
X
OH
OH
OH
IC50 (µmol/L)
> 300
> 300
130
%
sx (α)
n.s.
n.s.
n.s.
n.s.
%
sx (α)
n.s.
1 (0,05)
1 (0,05)
3 (0,01)
cyclohexyl
benzyl
4-methylbenzyl
benzyl
4
7
7
OCH3
> 300
> 300
> 300
> 300
> 300
> 300
> 300
> 300
> 300
> 300
100
heptyl
cyclohexyl
benzyl
O-CH2-CH2-OH
O-CH2-CH2-OH
O-CH2-CH2-OH
O-CH2-CH2-OH
O-CH2-CH2-OH
O-CH2-CH2-OH
NH-CH2-CH2-OH
NH-CH2-CH2-OH
NH-CH2-CH2-OH
NH-CH2-CH2-OH
NH-CH2-CH2-OH
CH2-N(CH3)2
CH2-N(CH3)2
CH2-N(CH3)2
not tested
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
4-methylbenzyl
4-fluorbenzyl
biphenylmethyl
heptyl
10 1 (0,002)
9
9e
9f
1 (0,02)
n.s.
n.s.
10a
10b
10c
10d
10e
11a
11b
11c
5
4
2 (0,05)
1 (0,05)
n.s.
n.s.
1 (0,1)
11 2 (0,002)
7
benzyl
1 (0,01)
n.s.
n.s.
4-methylbenzyl
biphenylmethyl
phenyl
cyclohexyl
benzyl
biphenylmethyl
> 300
> 300
> 300
90
3
10 1 (0,002)
not tested
n.s.
n.s.
9
2 (0,01)
n.s.
Table 2. In vitro (Born test, inducer collagen) antiplatelet and in vivo antithrombotic properties of triazolecarbox-
amides 12. Statistics: Wilcoxon Man Whitney U test, n. s. = not significant.
Inhibition of thrombus
formation
Born test
venules
sx (α)
arterioles
% sx (α)
Cpd.
12a
R
X
OH
IC50 (µmol/L)
> 300
%
benzyl
n.s.
n.s.
12b
phenylethyl
heptyl
O-CH2-CH2-OH
NH-CH2-CH2-OH
> 300
125
n.s.
n.s.
not tested
12c
12d
12e
cyclohexyl
biphenylmethyl
CH2-N(CH3)2
CH2-N(CH3)2
95
250
n.s.
not tested
n.s.
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Activities of new 1,2,3-Triazolecarboxamides 159
Table 3. In vitro (Born test, inducer collagen) antiplatelet and in vivo antithrombotic properties of triazolecarbox-
amides 13. Statistics: Wilcoxon Man Whitney U test, n. s. = not significant.
Inhibition of thrombus
formation
Born test
venules
arterioles
Cpd.
13a
13b
R
X
OH
IC50 (µmol/L)
> 300
%
sx (α)
n. s.
1 (0,1)
%
8
9
sx (α)
1 (0,1)
1 (0,1)
benzyl
phenylethyl
O-CH2-CH2-OH
> 300
3
Table 4. In vitro antiplatelet properties of compounds
11c and 12d with different inducers of the platelet
aggregation.
fect in arterioles (7%). Compounds with voluminous
substituents like biphenylmethyl at the triazole N-1
showed no activity in vivo. Among the isomeric amides
12 and 13 (a/b), only the 5-carboxylates exhibited
antithrombotic properties, whereas the 4-carboxylates
are without activity.
Compd.
IC50 (µmol/L)
Collagen ADP Serotonin Adrenaline PAF
11c
12d
90
95
200
80
25
30
25
145
250
15
Activation of sGC and inhibition of phospho-
diesterases
The activation of soluble guanylate cyclase (sGC) was
determined as described previously [10]. Compounds
8, 9a, 10d, 11a, 12a, and 12b were tested in concen-
trations of 10 and 100 µM and exhibited no activity.
PAF (platelet activating factor), and serotonin). The re-
sults are shown in Table 4. Obviously, 11c is most ac-
tive against serotonin and adrenaline. Compound 12d
has its peak activity against PAF with an IC50 = 15 µM.
The inhibition of PDE 1, 2, 3, 5, and 9 was as deter-
mined in c-GMP-SPA-test. Compounds 8, 9a, 10d,
11a, 12a, and 12b showed no activity in a concen-
tration of 10 µM. These observations strongly suggest
a mechanism for the antiplatelet effects different from
YC-1.
Inhibition of thrombus formation in vivo
(laser-thrombosis model)
The influence of the test compounds on the formation
of thrombi was assayed in a laser-thrombosis model
[9]. The results are compiled in the last column of
Tables 1, 2 and 3 each. In general, triazolecarbox-
amides selected for Table 1 exhibit a moderate
(Յ11%) inhibition of thrombus formation in arterioles.
The effects in venules are weaker. This is not surpris-
ing, because it is more difficult to inhibit the formation
of thrombi in venules. The reason is that the blood flow
in venules is much slower than in arterioles, and there-
fore, thrombus formation is easier induced, but harder
to inhibit.
Acknowledgments
We thank J.-P. Stasch and E. Bischoff, Institute of
Cardiovascular Research, Bayer AG, Wuppertal, Ger-
many, for testing the compounds on sGC activation
and PDE inhibition.
Experimental
Chemistry
In the triazolecarboxamides the results present a
mixed picture. Nearly all antithrombotic compounds
are without basic centre in the amide moiety. Surpris-
ingly, 8c with a 4-methylbenzyl-substituent at the N-1
of the triazole and missing a basic center in the amide
The full set of data is given in the PhD thesis Anke Cwiklicki,
FU Berlin 2002.
Mp (uncorr.), Linström. Ϫ Elemental analysis: Elementar
Vario EL. Ϫ IR: ATI Mattson Genesis Serie FTIR Ϫ NMR:
Bruker Advance DPX 400, (Bruker, Rheinstetten, Germany).
function showed both, antiaggregating activity (IC50
=
Ϫ
EI-MS: CH-7A-Varian MAT (70 eV), (Varian,
130 µM) and a small but significant antithrombotic ef-
Braunschweig, Germany).
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160 Rehse et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Procedure for the synthesis of phenylazide (1)
1-Heptyl-5-phenyl-1H-1,2,3-triazole-4-carboxylicacidethyl-
ester (6a)
6.2 g (0.07 mol) aniline was suspended in 50 mL of water.
After addition of 25 g conc. H2SO4 the mixture was stirred
while cooling with ice-water and a solution of 5.25 g NaNO2
in 31 mL water was added dropwise. 100 mL of hexane were
added, followed by dropwise addition of a solution of 4.6 g
NaN3 in water. After stirring for 3 h, the organic phase was
separated, dried with anhydrous Na2SO4, filtered and the
solvent removed in vacuo. Yellow liquid, yield 7.0 g (96%). Ϫ
Anal. C6H5N3. Ϫ 1H-NMR ([D6]DMSO): δ = (ppm) 7.12 (m,
2H), 7.20 (m, 1H), 7.42 (m, 2H).
from 2.6 g (18.4 mmol) azidoheptane and 3-phenylpropi-
olicacidethylester. Crystals, yield 3.0 g (52%). Ϫ Anal.
C18H25N3O2. Ϫ 1H-NMR ([D6]DMSO): δ (ppm) = 0.80 (t, 3H,
CH2CH3), 1.08Ϫ1.24 (m, 11H, (CH2)4, OCH2CH3), 1.62 (m,
2H, CH2CH2CH2N),4.14 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.23
(t, 2H, J = 7.0 Hz, CH2N), 7.49 (m, 2H, ph-H), 7.54 (m, 3H,
ph-H)
1-Cyclohexyl-5-phenyl-1H-1,2,3-triazole-4-carboxylicacid-
ethylester (6b)
General procedure for the synthesis of 1H-1,2,3-triazolecar-
boxylicacidesters
from 1g (8 mmol) azidocyclohexane and 3-phenylpropiolic-
acidethylester. Crystals, yield 1.3
g (56%). Ϫ Anal.
C17H21N3O2. Ϫ 1H-NMR ([D6]DMSO): δ (ppm) = 1.07 (t, J =
7.1 Hz, 3H, CH3), 1.20 (m, 3H, CH, CH2), 1.59 (m, 1H, CH),
1.78 (m, 2H, CH2), 1.94 (m, 4H, (CH2)4), 4.00 (m, 1H,
CH2CHCH2), 4.12 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.47 (m,
2H, ph-H), 7.56 (m, 3H, ph-H).
To 10 mmol of the azide in 50 mL ethanol, 10 mmol of the
alkine are added. The mixture is refluxed for at least 8 h (TLC
monitoring). Then the solvent is removed in vacuo. The resi-
due is recrystallized from petrolether/methanol.
1-Benzyl-5(and-4)-phenyl-1H-1,2,3-triazole-4(and-5)-car-
boxylicacidethylester (6c/7c)
1-Heptyl-1H-1,2,3-triazole-4-carboxylicacidethylester (3a)
from 1 g (7.1 mmol) azidoheptane and ethylpriolate. Crystals,
yield 0.9 g (53%). Ϫ Anal. C12H21N3O2. Ϫ 1H-NMR (CDCl3):
δ (ppm) = 0.88 (t, J = 7.0 Hz, 3H, CH2CH3), 1.28 (m, 4H),
1.32 (m, 4H) 1.42 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.93 (m, 2H,
NCH2CH2), 4.41 (m, 4H, NCH2, OCH2), 8.05 (s, 1H, tr-H).
from 1.5 g (10 mmol) azidomethylbenzene and 3-phenylpro-
piolicacidethylester. Powder, yield 2.8 g (91%), mixture of iso-
mers (45% 7c/55% 6c). Ϫ Anal. C18H17N3O2. Ϫ 1H-NMR
(CDCl3): δ (ppm) = 1.17 (t, J = 7.2 Hz, 3H, OCH2CH3 7c),
1.25 (t, J = 7.2 Hz, 3H, OCH2CH3 6c), 5.43 (s, 2H, CH2N,
6c), 5.94 (s, 2H, CH2N, 7c), 6.99 (m, 2H, aromat., 2 ϫ 4-ph-
H), 7.18Ϫ7.51 (m, 16H, aromat., 4 ϫ 4 ph-H, 6c+7c), 7.25
(m, 4H, 2 ϫ OCH2CH3, 6c+7c), 7.71 (m, 2H, 2 ϫ 4-ph-H).
1-Cyclohexyl-1H-1,2,3-triazole-4-carboxylicacidethylester
(3b)
1-Phenylethyl-5(and-4)-phenyl-1H-1,2,3-triazole-4(and-5)-
carbxylicacidethylester (6d/7d)
from 0.44 g (3.5 mmol) azidocyclohexane and ethylpropi-
olate, Crystals, yield 0.5 g (65%). Ϫ Anal. C11H17N3O2. Ϫ 1H-
NMR ([D6]DMSO): δ (ppm) = 1.25 (m, 1H, CH), 1.30 (t, J =
7.1 Hz, 3H, CH3), 1.66 (m, 1H, CH), 1.82 (m, 4H, (CH2)2),
2.06 (m, 2H, CH2), 4.30 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.54
(m, 1H), 8.82 (s, 1H, tr-H).
from 0.85 g (5.8 mmol) azidoethylbenzene and 3-phenylpro-
piolicacidethaclester. Crystals and oil, yield 1.3 g (70%) Ϫ
Column chromatography gave 6d 40% and 7d 60%. Ϫ Anal.
C
19H19N3O2. Ϫ 1H-NMR (CDCl3) 6d: δ (ppm) = 1.24 (t, J =
7.1 Hz, 3H, OCH2CH3), 3.16 (t, J = 7.2 Hz, 2H, CH2CH2N),
4.27 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.40 (t, J = 7.2 Hz, 2H,
CH2N), 6.88 (m, 2H, ph-H), 6.95 (m, 2H, ph-H), 7.21 (m, 3H,
ph-H), 7.38-7.48 (m, 3H, ph-H). Ϫ 1H-NMR (CDCl3) 7d: δ
(ppm) = 1.23 (t, J = 7.2 Hz, 3H, OCH2CH3) 3.24 (t, J = 7.8
Hz, 2H, CH2CH2N), 4.27 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.96
(t, J = 7.8 Hz, 2H, CH2N), 7.20-7.33 (m, 5H, ph-H), 7.42 (m,
3H, ph-H), 7.69 (m, 2H, ph-H).
1-(4-Phenyl)-benzyl-1H-1,2,3-triazole-4-carboxylicacidethyl-
ester (3c)
from 0.5 g (2.4 mmol) azido-4-phenylbenzene and ethylpropi-
olate. Powder, mp 148°C, yield 0.65 g (88%). Ϫ Anal.
C18H17N3O2. Ϫ IR (KBr): ν = 1724 cmϪ1 (C=O), 1226 (CϪO),
743 (aromatic). Ϫ 1H-NMR ([D6]DMSO): δ (ppm) = 1.30 (t,
J = 7.1 Hz, 3H, CH3), 4.30 (q, J = 7.1 Hz, 2H, CH3CH2O),
5.70 (s, 2H, CH2N), 7.37 (m, 1H, 4Ј-ph-H), 7.45 (m, 4H, ph-
H), 7.66 (m, 4H, ph-H), 8.90 (s, 1H, tr-H). Ϫ MS (70 eV):
m/z (%) = 307 (11) [M+•], 278 (3) [M+•C2H5], 167 (100)
[M+•ϪN3].
General procedure for the synthesis of the type 8 carbox-
amides
The ester and a three- to fivefold amount of the amine are
heated in methanol to 50°C (DC control with hexane/ethyl-
acetate 3:1). After about 24 h the solvent is removed in vacuo
and the carboxamide precipitated with water. In case no pre-
cipitate forms, the mixture should be extracted with trichloro-
methane, dried over Na2SO4, filtered, and concentrated. At
5°C the carboxamides often crystallized; if not, the crystalli-
zation is induced by a suitable amount of petrolic ether or di-
isopropylether.
1-Phenyl-1H-1,2,3-triazole-4-(and-5-)carboxylicacidethyl-
ester (3d/4d)
from 2.4 g (0.02 mol) azidobenzene and ethylpropiolate.
Powder, mixture of isomers, yield 3.0 g (69%). Column chro-
matography (hexane/ethylacetate 3:1) gave 2.5 g (83%) 3d
(crystals, mp 86°C) and 0.5 g (17%) 4d (yellow oil). Ϫ Anal.
C11H11N3O2. Ϫ 1H-NMR ([D6]DMSO) 3d: δ (ppm) = 1.35 (t,
J = 7.1 Hz, 3H, CH3), 4.37 (q, J = 7.1 Hz, 2H, OCH2CH3),
7.54 (m, 1H, 4-ph-H), 7.62 (m, 2H, ph-H), 7.99 (m, 2H, ph-
H), 9.49 (s, 1H, tr-H). Ϫ 1H-NMR ([D6] DMSO) 4d: δ (ppm) =
1.17 (t, J = 7.1 Hz, 3H, CH3), 4.22 (q, J = 7.1 Hz, 2H,
OCH2CH3), 7.59 (m, 5H, ph-H),8.47 (s, 1H, tr-H).
1-Cyclohexyl-1H-1,2,3-triazole-N-(2-hydroxyethyl)-4-
carboxamide (8a)
from 0.45 g (2 mmol) 3b. Crystals, mp 135°C, yield 0.3 g
(62%). Ϫ Anal. C11H18N4O2. Ϫ IR (KBr): ν = 3427 cmϪ1 (OH),
1648 (C=O), 1576 (C=N), 1053 (C=C). Ϫ 1H-NMR (CDCl3):
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Activities of new 1,2,3-Triazolecarboxamides 161
δ (ppm) = 1.31 (m, 2H, CH2), 1.46 (m, 2H, CH2), 1.74 (m, 2H,
CH2), 1.95 (m, 2H, CH2), 2.23 (m, 2H, CH2), 3.63 (m, 2H,
CH2CH2OH), 3.83 (m, 2H, CH2CH2OH), 4.48 (m, 1H, CHN),
7.52 (s, br, 1H, NH), 8.07 (s, 1H, tr-H). Ϫ MS (70 eV): m/z
(%) = 237 (<1) [M+•ϪH]+, 220 (11) [M+•ϪH2O]+, 208 (100)
[M+•ϪCH2O]+, 207 (89) [M+•ϪCH2OH]+, 195 (30), 178 (82)
[RϪCsϵO]+, 125 (92) [C6H11N3]+, 96 (63), 83 (54) [C6H11]+,
55 (78) [C4H7]+, 41 (65) [C3H5]+.
(ppm) = 1.30 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.77 (m, 2H,
CH2), 1.95 (m, 2H, CH2), 2.22 (m, 2H, CH2), 2.90 (t, J = 5.1
Hz, 1H, OH, D2O ex.), 3.62 (m, 4H, CH2OCH2), 3.75 (m, 4H,
NHCH2, CH2OH), 4.47 (m, 1H, CHN), 7.52 (s, br., 1H, NH),
8.06 (s, 1H, tr-H) Ϫ MS (70 eV): m/z (%) = 282 (<1) [M+•],
221 (27), 207 (87) [M•+ϪCH2O(CH2)2OH]+, 178 (76)
[RCϵO]+, 125 (100) [C6H11N3]+, 96 (55).
1-Phenylmethyl-1H-[1,2,3-triazole-N-[2-(2-hydroxyethoxy)-
1-Benzyl-1H-1,2,3-triazole-N-(2-hydroxyethyl)-4-car-
boxamide (8b)
ethyl]-4-carboxamide (9c)
from 0.5 g (2.2 mmol) 1-phenylmethyl-1H-1,2,3-triazole-4-
carboxylicacidethylester. Crystals, mp 115°C, yield 0.35 g
(55%). Ϫ Anal. C14H18N4O3. Ϫ IR(KBr): ν = 3327 cmϪ1
from 0.5 g (2.2 mmol) 1-benzyl-1H-1,2,3-triazole-4-carboxyl-
icacidethylester. Crystals, mp 124°C (C2H5OH/H2O), yield
0.3 g (56%). Ϫ Anal. C12H14N4O2. IR (KBr): ν = 3416 cmϪ1
(OH); 3106 (NH); 1654 (C=O); 1576 (C=N); 1051 (C=C); 719
(aromat.). Ϫ 1H-NMR (CDCl3): δ (ppm) = 2.56 (s, br, -OH,
D2O ex.), 3.62 (q, J = 5.3 Hz, 2H, CH2CH2OH) 3.81 (t, J =
4.5 Hz, 2H, CH2CH2OH) 5.55 (s, 2H, CH2N), 7.28 (m, 2H,
ph-H), 7.39 (m, 3H, ph-H), 7.52 (s, br, 1H, NH, D2O ex.), 7.96
(OH); 1650 (C=O); 1578 (C=N); 1055 (C=C).
Ϫ
1H-NMR ([D6]DMSO):
δ
(ppm) 3.39-3.52 (m, 8H,
=
HN(CH2)2O(CH2)2OH), 4.60 (s, br., 1H, OH, D2O ex.), 5.65
(s, 2H, phCH2N), 7.35 (m, 5H, ph-H), 8.43 (t, J = 5.7 Hz, 1H,
O=CϪNH, D2O ex.), 8.62 (s, 1H, tr-H) Ϫ MS (70 eV):
m/z (%) = 291 (<1) [M+H]+•, 260 (6) [M+•ϪCH2OH]+, 229 (10)
[M+-OCH2CH2OH]+, 215 (21), 186 (31) [RCϪO]+, 91 (100)
[C7H7]+.
(s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 228 (3) [M+•ϪH2O]+•
216 (29), 186 (29) [M+•ϪNH(CH2)2OH]+, 91 (100) [C7H7]+.
,
1-(4-Methylphenylmethyl)-1H-1,2,3-triazole-N-(2-hydroxy-
ethyl)-4-carboxamide (8c)
1-(4-Methylbenzyl)-1H-1,2,3-triazole-N-[2-(2-hydroxyethoxy)-
ethyl]-4-carboxamide (9d)
from 0.45 g (1.8 mmol) 1-(4-methylphenyl)-1H-1,2,3-triazole-
4-carboxylicacidethylester. Crystals, mp 151°C, yield 0.3 g
(64%) Ϫ Anal. C13H16N4O2. Ϫ IR (KBr): ν = 3275 cmϪ1 (OH);
1666 (C=O); 1578 (C=N); 1063 (C=C). Ϫ 1H-NMR (CDCl3):
δ (ppm) = 2.36 (s, 3H, CH3), 2.60 (s, br., 1H, OH, D2O ex.),
3.61 (m, 2H, CH2OH), 3.82 (t, J = 5 Hz, 2H, NCH2), 5.50 (s,
2H, CH2N), 7.18 (m, 4H), 7.52 (s, br, 1H, NH, D2O ex.), 7.93
(s, 1H, tr-H).MS (70 eV): m/z (%) = 261(<1) [M+H]+, 230 (18),
[M+•ϪCH2OH]+, 105 (100) [CH3-C6H4-CH2]+, 77 (13), 31 (6)
[H2C=OH]+.
from 0.45 g (1.8 mmol) 1-(4-methylbenzyl)-1H-1,2,3-triazole-
4-carboxylicacidethylester. Crystals, mp 129°C, yield 0.3 g
(55%). Ϫ Anal. C15H20N4O3. Ϫ IR (KBr): ν = 3327 (OH)
cmϪ1; 1652 (C=O); 1578 (C=N); 1053 (C=O). Ϫ 1H-NMR
(CDCl3): δ (ppm) = 2.36 (s, 3H, CH3), 3.61 (m, 2H, OCH2),
3.65 (m, 4H, HNCH2, OCH2), 3.75 (m, 2H, CH2OH), 5.50 (s,
2H, CH2N), 7.18 (m, 4H, ph-H), 7.50 (s, 1H, NH), 7.92 (s, 1H,
tr-H). Ϫ MS (70 eV): m/z (%) = 304 (<1) [M+], 105 (100)
[CH3C7H6]+.
1-(4-Fluorobenzyl)-1H-1,2,3-triazole-N-[2-(2-hydroxyethoxy)-
1-Benzyl-1H[1,2,3]-triazole-N-(2-methoxyethyl)-4-car-
boxamide (8d)
ethyl]-4-carboxamide (9e)
from 0.45 g (1.8 mmol) 1-(4-fluorobenzyl)-1H-1,2,3-triazole-
4-carboxylicacidethylester. Crystals, mp 157°C, yield 0.34 g
(61%) Ϫ Anal. C14H17FN4O3. Ϫ IR (KBr): ν = 3314 cmϪ1
(OH): 1654 (C=O): 1579 (C=N): 1058 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 3.41 (m, 4H, CH2OCH2), 3.49 (m, 4H,
2 x CH2), 4.59 (t, J = 5.4 Hz, 1H, OH), 5.64 (s, 2H, CH2N),
7.22 (m, 2H, ph-H), 7.42 (m, 2H, ph-H), 8.42 (t, J = 5.5 Hz,
1H, O=C-NH), 8.63 (s, 1H, tr-H) Ϫ MS (70 eV): m/z (%) =
308 (<1) [M+•], 233 (11), 204 (14), 109 (100).
from 0.45 g (1.9 mmol) 1-benzyl-1H-1,2,3-triazole-4-carboxyl-
icacidethylester. Crystals, mp 138°C, yield 0.35 g (71%) Ϫ
Anal. C13H16N4O2. Ϫ IR (KBr): ν = 3311 (NH) cmϪ1; 1580
1
(C=N); 1055 (C=O). Ϫ H-NMR ([D6]DMSO): δ (ppm) = 3.25
(s, 3H, OCH3), 3.42 (m, 4H, CH2CH2OCH3), 5.64 (s, 2H,
phCH2N), 7.38 (m, 5H, ph-H), 8.40 (t, J = 5.7 Hz, 1H, O=C-
NH), 8.62 (s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 260 (3)
[M+•], 228 (24), 215 (19), 186 (32), 91 (100).
1-Heptyl-1H-[1,2,3]-triazole-N-[2-(2-hydroxyethoxy)-ethyl]-4-
carboxamide (9a)
1-(4-Phenylbenzyl)-1H-1,2,3-triazole-N-[2-(2-hydroxy-
ethoxy)-ethyl]-4-carboxamide (9f)
from 0.45 g (1.9 mmol) 3a. Crystals, mp 72-74°C, yield 0.26
g (46%) Ϫ Anal. C14H26N4O3. Ϫ IR (KBr): ν = 3433 cmϪ1
(OH): 1648 (C=O): 1576 (C=N): 1050 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 1.24 (m, 8H, (CH2)4), 0.85 (t, J = 6.9
Hz, 3H, CH3), 1.83 (m, 2H, CH2CH2CH2), 3.42 (m, 4H,
CH2OCH2), 3.50 (m, 4H, NHCH2, CH2OH), 4.39 (t, J = 7.0
Hz, 2H, CH2N), 4.59 (t, J = 5.4 Hz, 1H, OH, D2O ex.), 8.37
(t, J = 5.7 Hz, 1H, O=C-NH, D2O ex.), 8.56 (s, 1H, tr-H) Ϫ
MS (70 eV): m/z (%) = 298 [M+•], 236 (32), 223 (93)
[M+•ϪCH2O(CH2)2OH]+, 194 (100) [RCϵO]+, 57 (66).
from 0.35 g (1.1 mmol) 3c. Crystals, mp 178°C, yield 0.25 g
(60%). Ϫ Anal. C20H22N4O3. Ϫ IR (KBr): ν = 3400 cmϪ1
(OH); 1648 (C=O); 1574 (C=N); 1067 (C=O). Ϫ 1H-NMR
(CDCl3): δ (ppm) = 3.62 (m, 2H, HNCH2), 3.67 (m, 4H,
CH2OCH2), 3.76 (m, 2H, CH2OH), 5.59 (s, 2H, CH2N), 7.37
(m, 2H, ph-H), 7.45 (m, 2H, ph-H), 7.57 (m, 5H, ph-H), 8.00
(s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 366 (<1) [M+•], 167
(100).
1-Heptyl-1H-1,2,3-triazole-N-[2-(2-hydroxyethylamino)-ethyl]-
4-carboxamide (10a)
1-Cyclohexyl-1H-[1,2,3]-triazole-N-[2-(2-hydroxyethoxy)-
ethyl]-4-carboxamide (9b)
from 0.5 g (2.1 mmol) 3a. Crystals, mp 107Ϫ110 °C, yield 0.4
g (64%) Ϫ Anal. C14H27N5O2. Ϫ IR (KBr): ν = 3340 (OH)
cmϪ1; 1648 (C=O); 1576 (C=N); 1069 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 0.88 (m, 3H, CH3), 1.27 (m, 4H,
(CH2)2), 1.86 (quint, J = 7.1 Hz, 2H, CH2CH2CH2), 2.61 (t,
from 0.5 g (2.2 mmol) 3b. Crystals, mp 65°C, yield 0.35 g
(56%) Ϫ Anal. C13H22N4O3. Ϫ IR: ν = 3317 cmϪ1 (OH); 1658
(C=O); 1575 (C=N); 1060 (C=C). Ϫ 1H-NMR (CDCl3): δ
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162 Rehse et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
J = 5.7 Hz, 2H, CH2NH), 2.70 (t, J = 6.4 Hz, 2H, HNCH2),
3.35 (m, 2H, O=C-HNCH2), 3.46 (t, J = 5.7 Hz, CH2OH), 4.41
(t, J = 7.0 Hz, 2H, CH2CH2N), 8.39 (t, J = 5,7 Hz, 1H, O=C-
NH, D2O ex.), 8.58 (s, 1H, tr-H) Ϫ MS (70 eV): m/z (%) =
297 (<1) [M+•], 87 (40), 74 (100).
1-Cyclohexyl-1H-[1,2,3]-triazole-N-(3-dimethylaminopropyl)-
4-carboxamide (11a)
from 0.45 g (2 mmol) 3b. Crystals, mp 125°C, yield 0.4 g
(72%). Ϫ Anal. C14H25N5O. Ϫ IR (KBr): ν = 3433 cmϪ1; 1658
(C=O); 1573 (C=N); 1057 (C=C). Ϫ 1H-NMR ([D6]DMSO): δ
(ppm) = 1.22 (m, 1H, HCH), 1.41 (m, 2H, CH2), 1.63 (m, 3H,
HCH, CH2), 1.77 (m, 2H, CH2), 2.07 (m, 2H, CH2), 2.12 (s,
6H, N(CH3)2), 2.23 (m, 2H, CH2N(CH3)2), 3.26 (m, 2H,
HNCH2), 4.51 (m, 1H, CHN), 8.53 (t, J = 5.8 Hz, 1H, O=C-
NH), 8.57 (s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 279 (5)
[M+•], 58 (100) [CH2=N+(CH3)2].
1-Benzyl-1H-1,2,3-triazole-N-[2-(2-hydroxyethylamino)-
ethyl]-4-carboxamide (10b)
from 0.45 g (1.9 mmol) 1-benzyl-1H-1,2,3-triazole-4-carboxyl-
icacidethylester. Crystals, mp 136-138°C (CHCl3/petrolic
ether), yield 0.3 g (54%). Ϫ Anal. C14H19N5O2. Ϫ IR (KBr):
ν = 3339 cmϪ1 (OH); 1649 (C=O); 1577 (C=N): 1068 (C=C).
1H-NMR ([D6]DMSO): δ (ppm) = 2.58 (t, J = 5.8 Hz, 2H,
1-Phenylmethyl-1H-1,2,3-triazole-N-(3-dimethylamino-
propyl)-4-carboxamide (11b)
Ϫ
NHCH2), 2.66 (t, J = 6.5 Hz, 2H, CHNH), 3.32 (2H, O=C-
NHCH2), 3.43 (m, 2H, CH2OH), 5.65 (s, 2H, CH2N), 7.35 (m,
3H, ph-H), 7.39 (m, 2H, ph-H), 8.39 (s, br., 1H, NH, D2O ex.),
8.60 (s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 290 (1) [M+H]+,
271 (8) [M+•ϪH2O]+•, 258 (21) [M+•ϪCH2OH]+, 187 (9) [R-
CsϵO]+, 159 (20) [C6H5CH2Tr]+, 91 (74), 87 (71), 74 (100)
[CH2NH(CH2)2OH]+, 30 (22) [CH2NH2]+.
from 0.45 g (1.9 mmol) 1-phenylmethyl-1H-1,2,3-triazole-4-
carboxylicacidethylester. Crystals, mp 140°C, yield 0.39 g
(71%). Ϫ Anal. C15H21N5O. Ϫ IR (KBr): ν = 3325 (NH) cmϪ1
;
1648 (C=O); 1577 (C=N); 1048 (C=C).
Ϫ
1H-NMR
([D6]DMSO): δ (ppm) = 1.62 (dt, J = 7.0/7.0 Hz, 2H,
CH2CH2CH2), 2.11 (s, 6H, N(CH3)2), 2.22 (t, J = 7.0 Hz, 2H,
CH2N(CH3)2), 3.26 (m, 2H, HNCH2), 5.64 (s, 2H, phCH2N),
7.37 (m, 5H, ph-H), 8.57 (m, 1H, O=C-NH, D2O ex.), 8.60 (s,
1H, tr-H). Ϫ MS (70 eV): m/z (%) = 287 (4) [M+•], 91 (17), 58
(100) [CH2=N+(CH3)2].
1-(4-Methylbenzyl)-1H-1,2,3-triazole-N-[2-(2-hydroxy-
ethylamino)-ethyl]-4-carboxamide (10c)
from 0.5 g (2 mmol) 1-(4-methylbenzyl)-1H-1,2,3-triazole-4-
carboxylicacidethylester. Column chromatography: eluent
CHCl3 / CH3OH (1:2). Crystals, mp 132°C, yield 0.25 g
(41%). Ϫ Anal. C15H21N5O2. Ϫ IR (KBr): ν = 3345 cmϪ1
(OH); 1648 (C=O); 1577 (C=N); 1068 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 2.57 (t, J = 5.7 Hz, 2H, CH2NH), 2.66
(t, J = 6.4 Hz, 2H, HNCH2), 3.30 (O=C-HNCH2), 3.41 (m, 2H,
CH2OH), 4.43 (m, 1H, OH, D2O ex.), 5.58 (s, 2H, CH2N), 7.19
(“d”, J = 7,9 Hz, 2H, ph-H), 7.23 (“d”, J = 7,9 Hz, 2H, ph-H),
8.37 (t, J = 5.3 Hz, 1H, O=C-NH, D2O ex.), 8.57 (s, 1H, tr-H).
Ϫ MS (70 eV): m/z (%) = 304 (<1) [M+H]+, 272 (14), 105
(100), 87 (50), 74 (85).
1-(4-Phenylbenzyl)-1H-1,2,3-triazole-N-(3-dimethylamino-
propyl)-4-carboxamide (11c)
from 0.5 g (1.6 mmol) 3c. Crystals, mp 190°C, yield 0.36 g
(62%). Ϫ Anal. C21H25N5O. Ϫ IR (KBr): ν = 3327 (NH) cmϪ1
;
1648 (C=O); 1575 (C=N); 1046 (C=C).
Ϫ
1H-NMR
([D6]DMSO): δ (ppm) = 1.62 (tt, J = 7.0/7.0 Hz, 2H,
CH2CH2CH2), 2.11 (s, 6H, N(CH3)2), 2.23 (t, J = 7.0 Hz, 2H,
CH2N(CH3)2), 3.26 (q, J = 6.6 Hz, HNCH2), 5.69 (s, 2H,
phCH2N), 7.37 (m, 1H, ph-H), 7.45 (m, 4H, ph-H), 7.66 (m,
4H, ph-H), 8.58 (t, J = 5.8 Hz, 1H, O=C-NH, D2O ex.), 8.64
(s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 363 (5) [M+•], 167
(17), 58 (100) [CH2=N+(CH3)2].
1-(4-Phenylbenzyl)-1H-1,2,3-triazole-N-[2-(2-hydroxyethyl-
amino)-ethyl]-4-carboxamide (10d)
1-Benzyl-5-phenyl-1H-1,2,3-triazole-N-(2-hydroxyethyl)-4-
carboxamide (12a)
from 0.35 g (1.1 mmol) 3c. Crystals, mp 187-189°C, yield 0.2
g (50%). Ϫ Anal. C20H23N5O2. Ϫ IR (KBr): ν = 3331 (OH)
cmϪ1; 1650 (C=O); 1574 (C=N); 1067 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 2.60 (t, J = 5.7 Hz, 2H, CH2NH), 2.69
(t, J = 6.4 Hz, 2H, HNCH2), 3.33 (m, 2H, O=C-NHCH2), 3.43
(m, 2H, CH2OH), 4.45 (s, br., 1H, OH, D2O ex.), 5.69 (s, 2H,
CH2N), 7.37 (m, 4H, ph-H), 7.46 (m, 4H, ph-H), 7.66 (m, 4H,
ph-H), 8.39 (t, J = 5.6 Hz, 1H, O=C-NH, D2O ex.), 8.65 (s,
1H, tr-H). Ϫ MS (70 eV): m/z (%) = 364 (<1) [M+•], 167 (100),
87 (51), 74 (91).
from 6c/7c. Ϫ Anal. C18H18N4O2. Ϫ IR (KBr): ν = 3549 cmϪ1
(OH); 1622 (C=O). Ϫ 1H-NMR (CDCl3): δ (ppm) = 3.57 (q,
2H, CH2CH2OH), 3.79 (t, 2H, CH2CH2OH), 5.43 (s, 2H,
CH2N), 7.01 (m, 4H, ph-H), 7.45 (m, 6H, ph-H), 7.64 (s, 1H,
O=C-NH). Ϫ MS (70 eV): m/z (%) = 322 (1) [M+], 304 (2)
[M+•-H2O]+•, 292 (17) [M+•-CH2O]+•, 291 (12) [M+•-CH2OH]+,
262 (25) [RϪCϵO]+, 91 (100) [C7H7]+.
1-Phenylethyl-5-phenyl-1H-[1,2,3]-triazole-N-[2-(2-hydroxy-
ethoxy)-ethyl]-4-carboxamide (12b)
1-Phenyl-1H-1,2,3-triazole-N-[2-(2-hydroxyethylamino)-
ethyl]-4-carboxamide (10e)
from 0.5 g (1.6 mmol) 6d. Yellow oil, yield 0.3 g (50%). Ϫ
Anal. C21H24N4O3. Ϫ IR (film): ν = 3413 cmϪ1 (OH); 1668
(C=O); 1572 (C=N); 1070 (C=C). Ϫ 1H-NMR ([D6]DMSO): δ
(ppm) = 3.00 (t, J = 7.0 Hz, 2H, CH2CH2N), 3.30 (2H, CH2O),
3.41 (m, 2H, CH2O), 3.48 (m, 4H, CH2OH, CH2NH), 4.49 (t,
J = 7.1 Hz, 2H, CH2N), 4.59 (t, J = 5.5 Hz, 1H, OH, D2O ex.),
6.91 (m, 2H, ph-H), 7.19 (m, 5H, ph-H), 7.47 (m, 3H, ph-H),
8.36 (t, J = 5.8 Hz, 1H, O=C-NH). Ϫ MS (70 eV): m/z (%) =
381 (2) [M+H]+, 380 (2) [M+•], 350 (9) [M+•-CH2O]+•, 335 (17),
319 (13) [M+-O(CH2)2OH]+, 306 (23), 277 (45) [RCϵO]+, 105
(100) [C8H9]+, 91 (8) [C7H7]+, 45 (16) [CH3-O+=CH2].
from 0.45 g (2.1 mmol) 3d. Crystals, mp 140°C, yield 0.3 g
(53%). Ϫ Anal. C13H17N5O2. Ϫ IR (KBr): ν = 3431 (OH)
cmϪ1; 1652 (C=O); 1578 (C=N); 1061 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 2.60 (t, J = 5.8 Hz, 2H, HNCH2), 2.71
(t, J = 6.5 Hz, 2H, CH2NH), 3.38 (t, J = 6.2 Hz, 2H, O=
CHNCH2), 3.45 (t, J = 5.8 Hz, 2H, CH2OH) 4.45 (s, br., 1H,
OH, D2O ex.), 7.53 (t, J = 7.4 Hz, 1H, 4-ph-H), 7.62 (m, 2H,
3-, 5-ph-H), 7.98 (m, 2H, 2-, 6-ph-H), 8.53 (t, J = 5.6 Hz, 1H,
O=C-NH), 9.26 (s, 1H, tr-H). Ϫ MS (70 eV): m/z (%) = 257
(2) [M+•ϪH2O]+•, 87 (37), 74 (100).
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163
Activities of new 1,2,3-Triazolecarboxamides 163
1-Heptyl-5-phenyl-1H-1,2,3-triazole-N-[2-(2-hydroxyethyl-
amino)-ethyl]-4-carboxamide (12c)
3468 cmϪ1 (OH); 1641 (C=O); 1561 (C=N); 1069 (C=C). Ϫ
1H-NMR (CDCl3): δ (ppm) = 3.39 (dt, J = 6.5/6.5 Hz, 2H,
CH2CH2OH), 3.57 (t, J = 6.5 Hz, 2H, CH2CH2OH), 5.89 (s,
2H, CH2N), 7.32 (m, 5H, ph-H), 7.45 (m, 3H, ph-H), 7.66 (m,
2H, ph-H). Ϫ MS (70 eV): m/z (%) = 322 (<1) [M+], 262 (<1)
[R-CϵO]+, 116 (7), 91 (100) [C6H5CH2]+.
from 0.6 g (1.9 mmol) 6a. Crystals, mp 50Ϫ52°C, yield 0.42
g (59%). Ϫ Anal. C20H31N5O2. Ϫ IR (KBr): ν = 3439 cmϪ1
(OH); 1662 (C=O); 1570 (C=N); 1065 (C=C). Ϫ 1H-NMR
([D6]DMSO): δ (ppm) = 0.80 (s, 3H, CH3), 1.09 (m, 6H,
ᮀCH2ᮀ3), 1.17 (m, 2H, CH2) 1.61 (t, J = 6.8 Hz, 2H,
CH2CH2N), 2.57 (m, 2H, CH2NH), 2.64 (t, J = 6.5 Hz, 2H,
NHCH2), 3.30 (NHCH2), 3.42 (m, 2H, CH2OH), 4.23 (t, J =
7.1 Hz, 2H, CH2CH2N), 7.48 (m, 5H, ph-H), 8.32 (t, J = 5.7
Hz, 1H, O=C-NH, D2O ex.). Ϫ MS (70 eV): m/z (%) = 373
(1) [M+•], 342 (28), 300 (77), 287 (100), 270 (20) [RCϵO]+,
159 (55), 117 (29), 87 (69), 74 (98) [CH2=NH+(CH2)2OH].
1-Phenylethyl-4-phenyl-1H-1,2,3-triazole-N-[2-(2-hydroxy-
ethoxy)-ethyl]-5-carboxamide (13b)
from 0.5 g (1.6 mmol)7d. Oil, yield 0.3 g (50%). Ϫ Anal.
C21H24N4O3. Ϫ IR (film): ν = 3554 (OH) cmϪ1; 1640 (C=O).
Ϫ 1H-NMR (CDCl3): δ = 3.26 (t, J = 7.6 Hz,2H, phCH2CH2N)
3.40 (m, 2H, CH2O), 3.46 (m, 4H, OCH2, HNCH2), 3.54 (m,
2H, CH2OH), 4.92 (t, J = 7.6 Hz, 2H, PhCH2CH2N), 6.02 (s,
br., 1H, O=C-NH), 7.22 (m, 3H, ph-H), 7.29 (m, 2H, ph-H),
7.47 (m, 3H, ph-H) 7.65 (m, 2H, ph-H). Ϫ MS (70 eV): m/z
(%) = 380 (13) [M+•], 105 (100).
1-Cyclohexyl-5-phenyl-1H-1,2,3-triazole-N-(3-dimethyl-
aminopropyl)-4-carboxamide (12d)
from 0.5 g (1.7 mmol) 6b. Crystals, mp 105°C, yield 0.45 g
(74%). υ Anal. C20H29N5O. Ϫ IR (KBr): ν = 3327 (OH) cmϪ1
;
1666 (C=O); 1569 (C=N); 1042 (C=C).
Ϫ
1H-NMR
References
([D6]DMSO): δ (ppm) = 1.21 (m, 3H, CHCH2), 1.58 (m, 1H,
CH), 1.58 (tt, J = 6.9/6.9 Hz, 2H, CH2CH2CH2), 1.77 (m, 2H,
CH2), 1.90 (m, 4H, CH2CH2), 2.10 (s, 6H, N(CH3)2), 2.20 (t,
J = 7.0 Hz, 2H, CH2CH2N(CH3)2), 3.19 (q, J = 6.5 Hz, 2H,
NHCH2CH2), 4.00 (m, 1H, CH), 7.43 (m, 2H, ph-H), 7.52 (m,
3H, ph-H), 8.52 (t, J = 5.7 Hz, 1H, C=O-NH, D2O ex.). MS
(70 eV): m/z (%) = 355 (9) [M+], 58 (100) [CH2=N+(CH3)2].
[1] J. Galle, U. Zabel, U. Hübner, A. Hatzelmann, B.
Wagner, C. Wanner, H. H. H. W. Schmidt, Br. J. Pharma-
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[2] S. T. Abu-Orabi, M. A. Atfah, I. Jibril, F. M. Mari’i, A. A.
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[3] E. Lieber, T. S. Chao, C. N. R. Rao, J. Org. Chem. 1957,
22, 238Ϫ240.
1-Biphenyl-5-phenyl-1H-1,2,3-triazole-N-(3-dimethylamino-
propyl)-4-carboxamide (12e)
[4] K. Satyanarayana, K. Rehse, Arch. Pharm. Pharm. Med.
Chem. 1998, 331, 207Ϫ210.
from 0.5 g (1.3 mmol) 1-biphenyl-5-phenyl-1H-1,2,3-triazole-
4-carboxylicacidethylester. Crystals, mp 105°C, yield 0.28g
(49%). Ϫ Anal. C27H29N5O. Ϫ IR (KBr): ν = 3329 (NH) cmϪ1
;
[5] E. Nölting, O. Michel, Ber. Dtsch. Chem. Ges. 1893,
26, 86Ϫ92.
1664 (C=O); 1570 (C=N). Ϫ 1H-NMR ([D6]DMSO): δ (ppm) =
1.60 (tt, J = 7.0/7.0 Hz, 2H, CH2CH2CH2), 2.10 (s, 6H,
N(CH3)2), 2.21 (t, J = 7.0 Hz, 2H, CH2N), 3.20 (q, J = 6.6 Hz,
2H, HNCH2), 5.54 (s, 2H, phCH2N),7.03 (m, 1H, 4Ј-ph-H),
7.41 (m, 4H, ph-H), 7.60 (m, 4H, ph-H), 8.60 (t, J = 5.8 Hz,
1H, O=C-NH). Ϫ MS (70 eV): m/z (%) = 439 (15) [M+], 167
(36), 58 (100) [CH2=N+(CH3)2].
[6] R. O. Lindsay, C. F. H. Allen, Org. Synth. Coll. Vol.3,
1955, 710Ϫ711.
[7] L. Bertelli, G. Biagi, I. Giorgi, C. Manera, O. Livi, V. Scar-
toni, L. Betti, G. Gianniccini, L. Trincavelli, P. L. Barili,
Eur. J. Med. Chem., 1998, 33, 113Ϫ122.
[8] D. R. Buckle, C. J. M. Rockell, J. Chem. Soc. Perkin
Trans. 1, 1982, 627Ϫ630.
1-Benzyl-4-phenyl-1H-1,2,3-triazole-N-(2-hydroxyethyl)-5-
carboxamide (13a)
[9] K. Rehse, F. Brehme, Arch. Pharm. Pharm. Med. Chem.
2000, 333, 157Ϫ161.
from 1.5 g (4.9 mmol) 6c/7c mixture of isomers (1:1) Separ-
ation from 1-benzyl-5-phenyl-1H-1,2,3-triazole-N-(2-hydroxy-
ethyl)-4-carboxamide by column chromatography on sil-
icagel: eluent CHCl3/C2H5OH (3:1). Crystals, mp 123/140°C,
yield 0.25 g (32%). Ϫ Anal. C18H18N4O2. Ϫ IR (KBr): ν =
[10] M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H.
Schröder, R. Gerzer, J.-P. Stasch, J. Mol. Med. 1999,
77, 14Ϫ23.
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