Search for no donors. Part I. 3-Quinuclidone oximes

Abstract

Identification of the "endothelial relaxation factor" as the endogenic NO formed from L-arginine in the vascular endothelium [1] has stimulated the search for new generation of cardiovascular drugs [2][3][4][5]. At present, it has been established that biochemical synthesis of NO proceeds by different pathways. Exogenic organic nitrates (nitroglycerin, nitrosorbid, and other classical vasodilators) are subject to reduction [6], as well as the new NO precursors such as N-nitropyrazoles [7] and furoxanes [8]. On the contrary, L-arginine -the main NO source in the organism -is oxidized by the enzyme NO-synthase (NOS) to . NOS is also capable of forming NO from [3-mercaptoethylguanidine [9,10]. Study of the weU-known vasodilator molsidomin showed that this agent generates NO by reaction with atmospheric oxygen [3]. It was found that 1,2-diazetine-l,2-dioxides form NO upon thermolysis and/or hydrolysis [I1]. Muller et al. [12] reported on the use of (+)-3-(E)-4ethyl-2[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK 409) as the NO donor in solutions at pH -7.5, but failed t o establish a group (oxime, nitro, or both) acting as the source of NO [12]. Recently we have demonstrated that 3-quinuclidone oximes may serve as the source of NO and activate the soluble guanylate cyclase [13]. The purpose of this work was to extend the group of oximes and study their hypotensive activity.The NO precursors were obtained on the basis of both well-known (Va/VIa, Vb/VIb, Ve/VIe, Vi/VIi) [14], (Vc/VIc, Vd/VId, VIIb] [13], and newly synthesized (VfiVlfVh/VIh) 2-arylmethylene-3-quinuclidone oximes and their hydrogenated analogs IXb and IXe. The compact rind framework structure of quinuclidine (1-azabicyclo[2.2.2]octane) provides spatial fixation of the substituents and sufficiently high solubility of hydrochlorides, while the double bond in position 2 sometimes allows us to obtain the (Z/E) isomer

Oximes, amidoximes and hydroxamic acids as nitric oxide donors

“…differential polarography according to the previously described protocol. [1][2] Under these conditions oximes 1 do not generate NO, which is in sharp contrast with our earlier finding that (E)-2-[(2'-hydroxyphenyl)methylene]-and 2-[(2'-hydroxyphenyl)methyl]quinuclidin-3-one gave NO in 17% and 10% yields, respectively. A possible explanation for this difference may lie in the fact that the rigid structure of the quinuclidine derivatives allows for intramolecular interaction of the 2'-OH group and the oxime fragment, which is impossible for syn-oxime 1c.…”

“…The most active NO donors containing a 2-HO-phenyl group proximal to the oxime fragment activated soluble guanylate cyclase; 4-HO-isomers, 2-MeO-and 4-MeO-derivatives as well as the oxime of quinuclidin-3-one were much less active. [1][2] The aim of this work is an investigation of the factors affecting the ability of the oxime group to serve as NO precursor, with special attention given to the influence of its conjugation with heteroatoms (O, N) and aromatic rings. For this purpose three series of compounds: oximes RCH=NOH 1 and 2, hydroxamic acids RC(=O)NOH 3 and amidoximes RC(NH 2 )=NOH 4 were chosen.…”

Captodative aminoalkenes

“…318 Phenylhydrazine reacts analogously to primary amines to produce phenylhydrazone. 290 The reactions of hydroxylamines with the arylmethylidenequinuclidinones 151 bearing a substituent at the double bond afforded oximes 167, 298,319,320 whereas the reaction of the unsubstituted methylidenequinuclidin-3-one 151 (R 1 = H) with hydroxylamine gave rise to oxime 168, which was isolated as dihydrochloride. 321 It was assumed that this reaction proceeded through the intermediate formation of 4a-hydroxyisoxazolidino [4,5-b]quinuclidine 169.…”

“…When subjected to platinum-or palladium-catalysed hydrogenation, methylidene-and arylmethylidenequinuclidinones were transformed into saturated ketones 173. 288,291,292,298,305 The corresponding allylic alcohols 174 were selectively obtained with the use of NaBH 4 . 288,308,324,325 Stereospecific reduction of both functional groups in the benzylidenequinuclidinone 151 (R = Ph) with lithium aluminium hydride afforded benzylquinuclidinol trans-175 (R = Ph).…”