Pseudonitroles and Their Dimeric Azodioxides

Abstract

Thirteen geminally substituted nitro‐nitroso compounds (pseudonitroles) have been synthesized, four of them for the first time. In the solid state the pseudonitroles are dimerized to azodioxides. This is proved by IR spectroscopy, with the dimeric N‐O valence vibration being observed between 1293 and 1306 cm–1. Only 1,3‐diphenyl‐2‐nitro‐2‐nitrosopropane is monomeric even when solid. This is backed by its blue color and an IR band at 1574 cm–1. When dissolved in chloroform these azodioxides dissociate completely to the blue monomers (λmax ?po 650 nm). Eight pseudonitroles inhibited the aggregation of blood platelets half‐maximally at concentrations below 10 μM (Born test, collagen). When administered orally to rats (60 mg/kg) the thrombus formation in mesenteric arterioles and venules was inhibited up to 25 percent (k: 1‐nitro‐1‐nitrosocyclohexane). When kept in aqueous media at 37°C nitric oxide and its reduced form, i.e. nitrosohydrogen, are released. This suggests that the above biological effects arise from an NO dependent mechanism. The lack of influence on the blood pressure of spontaneously hypertensive rats, however, strongly suggests that an enzyme supported rather than a thermal formation of NO occurs in vivo.

Nitrosation Products of Hexamethylenetetramine

“…This again [13] shows that it is possible in NO donors to separate the antithrombotic properties from hypotonous effects. The reason might be that endothelial and/or smooth muscle cells are not able to transform 2 to nitric oxide while the metabolic potential of liver cells is sufficient for this process so that blood platelets can still be influenced.…”

Pseudonitrosites and Other Azodioxides with Vicinal Electron Acceptors

“…Six of the pseudonitrosites (2c-h) were prepared for the first time. The substituents R 1 were chosen on the basis of previous experience concerning suitable lipophilia and (platelet) membrane affinity. The compounds form colorless crystals and hence are type 2 azodioxides.…”

“…Type 6 compounds which are very unstable could not be tested as we were unable to obtain a sufficient amount for the blood pressure experiments. The pseudonitrosites are to our knowledge the second class of NO donors where the desired antithrombotic effect could be separated from the unwanted hypotonous properties [1] . This result suggests that the endothelium at least of SHR is not able to convert pseudonitrosites to nitric oxide.…”

“…(n = 5) (n = 5) Ethanol 0.9 ± 0.05 not detected (n = 5) - -------------------------------- 1) The full set of data is given in the PhD thesis of M. Herpel, FU Berlin 1997.…”

“…Recently we reported on antithrombotic azodioxides (I) which were activated by electron acceptors geminal to the nitroso group [1,2] . The rationale was that the acceptor X should decrease the electron density of the C-NO bond and thereby make those compounds prone to the release of nitric oxide.…”