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New NO-Donors with Antithrombotic and Vasodilating Activities Part 14 134-Triazol-1-oles.

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New NO-Donors with Antithrombotic and Vasodilating Activities, Part 14
Klaus Rehse”, Daniela Piechocki, Markus Schober, Heike Scheffler, Nora Reitner, and E. Unsolda)
lnstitut fiir Phartnazie I dcr Freien Univer\itiit Berlin. Kiinigin-Luise-Str. 2+4, D-I4195 Berlin. Germany
Gesellschaft fur Strahlenschutz- und Umweltforschung, Neuherberg
Key Words: 1,3,4-Triazol-l-oles; antithrombotic e8ect.s; blood pressure; azodioxime; platelet aggregation; nitric oxide
Recently we reported on the antithrombotic and vasodilating activities of nitrolic acids”’ (e.g. 6 in Scheme 1). These
are oximes which are “activated” by an electron withdrawing
substituent, namely a nitro group. We were able to show that
these compounds release nitrosohydrogen both from the hydroxyimino and from the nitro group. We were now interested
in seeing whether oximes with electron withdrawing substituents other than a nitro group could also form nitrosohydrogen, which is known to be prone to oxidation to nitric oxide.
We recognized that in 1882 V. Meyerc2Ihad already reported
the reduction of ethylnitrolic acid with N d H g yields an
azodioxime (7, trivial name: azaurolic acid). This is known
to release N 2 0 readily in the solid stateL2]as well as in
solutionr3’. Therefore formation of nitrosohydrogen must
have primarily occurred. On the other hand, the so-called
“leukazone” is obtained. The correct structure determined by
Armandr4]is 2,s-dimethyl-1,3,4-triazolole (Scheme 1, coinpound 5). For 7 and - surprisingly - for 5 we found antithrombotic properties (see below). We argued that the activity of 5
could also be related to the formation of an NO species. This
prompted us to study the title compounds more systematically.
Chemical access to type 5 compounds via ethylnitrolic acid
6 and azaurolic acid 7 is unique. We therefore used the more
general method of Becker et al.r51(Scheme 1) who reacted
the iminothers 1 with benzhydrazides to type 3 compounds.
Arch. Piinmi. Phrrrm. Metl. Cheriz.
Scheme 1: Synthesis of 1,3,4-triam- l-ole\
Exchange of the imino group by hydroxylamine gave the
oximes 4 which can be cyclized in aqueous alkaline to the
1,3,6triazoles 5. The synthesis of 5g which bears no substituent in 5-position is better performed with the ortho ester of
formic acidr6’(8) as starting material. The substituents were
chosen according to their electron donating or withdrawing
properties. As the synthesis of all compounds has already
been reported we have only summarized new and characteristic spectral data in Table 1. Most striking was the high
intensity of the molecular ion formed in the mass spectrometer after electron impact. Mostly this ion is the base peak,
0 VCH Verlagsgesellschaft mhH, D-6945 I Weinheim, 1996
0365-6233/96/1111-0511 $5.00 + .25/0
Table 1: Characteristic rpectral data of I .3,4-triazololes (5).
Rehse and co-workers
=8 ppm or from the position of the hydroxyl
proton (=I2 ppm) which also reflects the acidic
nature of this group.
a. Born T[>d7'
Platelet aggregation in platelet rich human
plasma was induced by collagen. As expected
only the azodioxime 7 inhibited the platelet
aggregation. An IC5o = 15 ymol/L was determined (acetylsalicylic acid: 175 ymol/L).
b. Tlzmrnbosis Model'"
Briefly the formation of thrombi in mesenteric
vessels of rats is induced by the beam of
Table 2: Antithrombotic properties of I .3,4-triazol- 1-ales 2 h after p.0. administration of
laser via a microscope (35 mW, 50
60 mg/kg of each compound to rats. Statistics: Man-Whitney U test.
ms). The number of exposures ("shots") necessary to form a thrombus of defined size is
counted. From the average shot number the
percentage of inhibition of thrombosis is calculated. The results are compiled in Table 2.
Obviously compound 5a shows the strongest
antithrombotic effect both in arterioles and in
venules. Compound 5b has the same electron
density in the triazole ring. This is demonstrated by the position of the methyl group in
the 'H-NMR spectrum, which is at 2.25 ppm in
5a and at 2.26 ppm in 5b. As 5b is more
lipophilic than 5a and should therefore be absorbed even better than 5a from the gastrointestinal tract, the space consuming properties of
the benzyl group of 5b should be responsible
for this drop in activity. The same conclusion
Table 3: lntluencc of 5a (60 mg/kg) p a , on blood pressure and heart rate in spontaneously might be drawn from the results obtained with
5c-5e. There is observed a decay in activity
hypertensive rats (statihtics: Man-Whitney U tmt)
with growing space requirement of the substituent. Comparison of 5c with 5f shows that the
electron withdrawing properties of the phenyl
group in principle are not unfavorable. Comparison of compound 5g with 5a supports the
idea that one space consuming substituent is
sufficient for a decrease in activity.
The azodioxime 7 in the same dose inhibited
thrombus formation i n arterioles by 24 k 3
(p 5 0.002) 9% and in venules by 18 f 6 0, 5
0.02) %.
Arch. Pharm.
Cllrin 329. 51 1-513 (1996)
1,3,4-Triazol- 1-ole
d. NO Formation from 5a
The combination of antithrombotic and vasodilating properties together with the chemical structure of 5a gives rise to
the assumption that they are caused by NO formation in vivo.
As this is difficult to prove by in vivo or ex vivo experiments
we used a cytochrome P450 analogous model[91reaction, to
investigate whether at least in principle NO formation at
either redox state seems possible by metabolic processes for
instance in the liver. Briefly, the system 02/cytochrome P450
was mimicked b the pair iodosobenzene (as its trifluoroacetate)/ FeIX-tetraphenylporphyrin. However, neither
the formation of nitrosohydrogen (as N 2 0 , GC, ECD)['O1 nor
NO' [91 (Chemiluminescence) could be detected.
The same result was obtained when liver microsomes [ I l l
were used to mimic the metabolism of 5a. To obtain a high
concentration of cytochrome P450 in the microsomes the
rabbits were pretreated with dexamethasone. For the detection of NO the hernoglobid02 assay was used'12]. This
system is able to convert NO to nitrate and methemoglobin.
The latter can be detected spectroscopically at 401 nm. Thus
the question whether the antithrombotic effects of type 5
compounds are due to the in vivo formation of nitric oxide
remains open.
Experimental Part
I , 1'-Azo-bis-ethanoneOximelll(7)
From 3.0 g (29 mmol) 1-nitro-ethanonoxime with 3 % NdHg. Orange
crystals, mp 140"C., yield 0.2 g (10 %).-Anal. CdHgN402.- IR (KBr): 1634
cm-' (C=NOH), 1468 (N=N).- 'H-NMR ([DhlDMSO): 6 = 2.02 (s, 6H,
CH3), 12.6 (s, 2H, OH).- + FAB-MS (DMSO/glycerol):m/z (%) = 145 (53)
[(M+H)+], 114 (69) [M+-NO], 42 (100) [(CH3C+=NH].
K. Rehse, M. Herpel, D. Piechocki, Arch. Pharm. (Weinheim), 1996,
329, 83-86.
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H. Wieland, Justus Liebigs Ann. Chem. 1907,353, 65-105.
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H.G.O. Becker, G. Gormar, H.-J. Timpe, J. Prakt. Chem. 1970, 312,
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S.M. McElvain, J.W. Nelson, J. Am. Chem. Soc. 1942,64, 1825-1827.
K. Rehse, U. Siemann, Arch. Pharm. (Weinheim),1981,314,627-630.
K. Rehse, A. Kesselhut, V. Schein, M. Kampfe, B. Rose, E. Unsold,
Arch. Pharm. (Weinheim), 1981,314, 627-630.
H.-J. Duchstein, S. Riederer, Arch. Pharm. (Weinheim), 1995, 328,
[lo] K. Rehse, M. Herpel, D. Piechocki, Arch. Pharm. Pharm. Med. Chem.
[ l I] B. Clement, M.-H. Schultze-Mosgau, H. Wohlers, Biochem. Pharmucol. 1993,46, 2249-2267.
[ 121 M. Feelich, D. Kubitzek, J. Werringloer in Nitric Oxide Research, Ed.
M. Feelisch, J. Stamler pp 455478, J. Wiley and Sons, Chichester, New
York, Brisbane, Toronto, Singapore, 1996.
Received: August 28, 1996 [FP147]
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Arch. Phurm.Phann. Med. Chem. 329,511-513 (1996)
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134, part, vasodilating, triazole, oles, antithrombotic, donor, activities, new
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