Tomoo Nakazawa

Relaxant Action of Azulene‐1‐carboxamidine Derivative N1, N1‐dimethyl‐N2‐(2‐pyridylmethyl)‐5‐isopropyl‐3,8‐dimethylazulene‐1‐carboxamidine (HNS‐32) in Pig Coronary Artery

HNS-32 (N1N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3,8-dimethylazulene-1-carbox-amidine) (CAS 186086-10-2) is a newly synthesized compound with an azulene structure within the molecule. The coronary relaxant action of HNS-32 was investigated pharmaco-mechanically on isolated pig coronary artery. The effects of HNS-32 were compared with diltiazem, a Ca2+-channel blocker. HNS-32 inhibited sustained contractions evoked by high KCl, prostaglandin F2α, a thromboxane A2 mimetic (U46619) and endothelin-1 in a concentration-dependent manner. The potency of HNS-32 to inhibit these contractions was 5- to 40-times lower than diltiazem. HNS-32 also diminished phasic contractions induced by acetylcholine, histamine and 5-hydroxytryptamine. Addition of excess Ca2+ counteracted HNS-32-induced inhibition of high KCl-induced contraction only by approximately 10% whereas it restored diltiazem-induced inhibition by about 50%. Suppression of the contractile response to a phorbol ester (phorbol 12,13-dibutyrate) by HNS-32 was approximately 40%. HNS-32 prevents coronary contractions produced by a wide variety of spasmogens. Although inhibitions of L-type Ca2+ channels and protein kinase C may be partly responsible for HNS-32 action, some direct action on the contractile systems seems to be involved in the coronary relaxation by HNS-32.

Voltammetric behavior and electronic molecular structures of several azulenylketones

Abstract The formation of the radical and/or ion species of five azulenylketones, 1-benzoylazulene 4 , 1-benzoyl-5-isopropyl-3, 8-dimethyl-azulene 5 , di-1-azulenyl ketone 6 , 3,8-dimethyl-5-isopropyl-1-azulenyl 1-azulenyl ketone 7 , bis(3,8-dimethyl-5-isopropyl-1-azulenyl) ketone 8 , was studied with cyclic voltammetry. The cathodic peak potentials of the formation of the anion radicals of 4, 6 and 7 almost coincided with each other and those of 5 and 8 also coincided with each other. The cathodic peak potentials of the formation of the dianions of 6, 7 and 8 were nearly equal to those of the corresponding azulenes, azulene 1 and guaiazulene 2 , respectively. All the peak potentials of the azulene compounds measured shifted negatively when the azulene rings were substituted by alkyl groups. These results and the energy calculation with MOPAC led to the conclusions (A) that the two azulene rings are not coplanar for the anion radicals and dianions of the di-1-azulenylketones; (B) that the anion radical generated at the carbonyl group is electronically stabilized by one azulene ring having lower LUMO or one of the rings when two azulene rings are identical; (C) that the formation of the dianion, the one-electron injection into the anion radical, occurs at another azulene ring; and (D) that the electronic inductive effect of alkyl groups on the azulene ring destabilizes the anion radical and dianion species of the ketones and stabilizes the cation species of the ketones qualitatively.

The reactions of 4,5-dehydrotropone with 4-phenyloxazols

Abstract 4,5-Dehydrotropone reacted with 4-phenyl-, 5-methyl-4-phenyl-, and 2,5-dimethyl-4-phenyloxazol to give, involving facile loss of benzonitrile from the corresponding Diels-Alder adducts, furo-[3,4-d]tropone and its 1-methyl and 1,3-dimethyl derivative, respectively. Protonation of furo[3,4-d]-tropones yielded delocalized 6-hydroxy-3-oxaazulenium ions.

Acid-catalyzed ethanolysis of di-l-azulenyl ketones

Abstract Substituted di-l-azulenyl ketones composed of 3,8-dimethtyl-5-isopropyl-l-azulenyl and/or 4,6,8-trimethyl-l-azulenyl group were refluxed in ethanol in the presence of p -toluenesulfonic acid to give substituted azulenes and ethyl azulene-l-carboxylates derived from the cleavage of either of C-CO bonds of di-l-azulenyl ketones. The facility and the product distributions of the ethanolysis were affected markedly by the substituents.

Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats

HNS-32 (N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091 ± 225 to 656 ± 116 and 286 ± 69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183 ± 33 to 28 ± 9 and 4 ± 2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936 ± 159 beats/30 min (p < 0.05), 39 ± 22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126 ± 34 to 37 ± 12 and 3 ± 2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16 ± 9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399 ± 14 to 350 ± 8 and 299 ± 10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.

A theoretical explanation of charge-transfer bands of bridged tropylium cations and their concentration-dependent MCD spectra

Abstract The weak broad longest-wavelength bands observed in absorption and MCD spectra of bridged tropylium cations are interpreted, with the aid of molecular orbital computations, as due to charge-transfer transitions from the remote chromophores to the tropylium moiety incorporated in the rigid bicyclo[2,2,2]-octane system. The MCD spectra change their profile on dilution.

Synthesis and intramolecular charge-transfer interaction of o-tropyliobiphenyl tetrafluoroborates

Abstract A series of o-tropyliobiphenyl tetradfluoroborates has been synthesized. Evidences are presented to show that exhibit strong intramolecular charge-transfer interaction between tropylium ion and remote aryl ring. The structure of was determined by single crystal X-ray diffraction study.

Further evidence for the intramolecular charge-transfer interaction between tropylium ion and remote benzene rings in 9,10-dihydro-9,10-(1,2-tropylio)anthracene tetrafluoroborate and its methyl derivatives

A series of 9,10-dihydro-9,10-(1,2-tropylio)anthracene tetrafluoroborates has been prepared. The intramolecular charge-transfer interactions in were confirmed by their UV spectra and pKR+ values. As a model compound 1,2,3,4-tetrahydro-1,4-(1,2-tropylio)naphthalene tetrafluoroborate (5)_was also examined.

Effects of HNS-32, a Novel Antiarrhythmic Agent, on Guinea-Pig Myocardium

The electrophysiological and mechanical effects of HNS-32, a novel azulene-1-carboxamidine derivative with antiarrhythmic activity, were studied in isolated guinea-pig myocardial preparations. HNS-32 (10^–6–10^–4 mol/l) concentration-dependently decreased the maximum rate of rise (V_max) of action potential in isolated papillary muscle; the potency was the same or slightly higher than that of disopyramide. At 10^–4 mol/l, HNS-32 also shortened the action potential duration (APD) and depolarized the resting membrane potential; these effects were similar to those of 10^–5 mol/l verapamil. HNS-32 (10^–7–10^–4 mol/l), as well as verapamil (10^–8–10^–5 mol/l) and disopyramide (10^–6–10^–3 mol/l), had concentration-dependent negative chronotropic and negative inotropic effects on isolated right atrial and right ventricular papillary muscle preparations, respectively. The concentration-response relationship for the positive chronotropic effect of isoproterenol was not affected by HNS-32 (10^–5 mol/l). In isolated ventricular myocytes, HNS-32 (10^–6–10^–4 mol/l) concentration-dependently inhibited the peak amplitude of the L-type Ca²⁺ current. These results suggest that NHS-32 has V_max reducing activity on myocardial tissue, which may be responsible for antiarrhythmic effect. The drug may also have additional effect on the Ca²⁺ channel at higher concentrations.

Tropone and 8,8-dicyanoheptafulvene incorporated in bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane ring systems

Das in situ aus dem entsprechenden Aminocycloheptatriazolon erhaltene Dehydro-tropon (I) liefert mit Cyclopentadien (IIa) und Cyclohexadien (IIb) die Addukte (III), die in Trifluoressigsaure die Kationen (IV) geben.