Maris Veveris

Synthesis, vasodilating, antithrombotic and cardioprotective activity of pyridyl substituted 5-silyl(germyl)isoxazolines-2.

The reactions of [2+3] cycloaddition of pyridylnitrile oxides to vinyl- and allylgermanes proceed regioselectively and afford 5-Ge-substituted isoxazolines-2. We have synthesized 9 new pyridyl substituted 5-Si(Ge)-isoxazolines-2 and investigated their biological activity. The vasodilating, anticoagulant and cardioprotective activities of 5-Si(Ge) substituted isoxazolines-2 have been studied in vitro and in vivo. Substitution of the silicon atom for the germanium one leads to the significant increase in vasodilating, antithrombotic and cardioprotective activity. The insertion of the methylene group between Ge and the isoxazoline ring reduces the vasodilating activity. The most active isoxazoline - 3-(5‵-triethylgermyl-3‵-isoxazolinyl)pyridine hydrochloride protects the heart from rhythm disturbances and lethality during ischaemia-reperfusion.

Cardioprotective effects of N‐hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats

The potential for the N‐hydroxyguanidine compound PR5 (N‐(3,4‐dimethoxy‐2‐chlorobenzylideneamino)‐N′‐hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. Administration of 1–10 mg kg−1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg−1 of PR5, respectively). Administration of 3 mg kg−1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. Coronary occlusion/reperfusion (10–20 min) increased malondialdehyde (MDA) of rat hearts (0.88±0.13 for sham vs 1.45±0.12 nmol mg−1 protein for ischaemic; P<0.05). In rats where 3 mg kg−1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04±0.12; P<0.05 vs ischaemic). PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326±32 mg for controls vs 137±21 mg for animals treated with 3×3 mg kg−1 of PR5 (P<0.01). PR5 reduced the elevation of the ST‐segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. We conclude that the N‐hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life‐threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N‐hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.

Synthesis, vasodilating and antithrombotic activity of pyridyl‐substituted silylisoxazolines

3 - (2-Pyridyl) - 5 - phenyldimethylsilylisoxazoline, 3-(3-pyridyl) - 5 - phenyldimethylsilylisoxazoline and 3-(4-pyridyl) - 5 - phenyldimethylsilylisoxazoline were obtained by the [2+3] cycloaddition reaction of pyridyl nitrile oxides to phenyldimethylvinylsilane. The condensation of 3-pyridyl-substituted 5-triethoxysilylisoxazolines with triethanolamine afforded 3 - (2-pyridyl) - 5 - silatranylisoxazoline, 3 - (3 - pyridyl)-5-silatranylisoxazoline and 3-(4-pyridyl)-5-silatranylisoxazoline (12). In experiments in vivo and in vitro the vasodilating, antiarrhythmic and antithrombotic properties of pyridyl-substituted silylisoxazolines, their influence on the haemodynamic parameters in anaesthetized animals and their acute toxicity have been studied. It has been found that pyridyl-substituted silylisoxazolines possess vasodilating and antithrombotic properties. In experiments on the noradrenaline-preconstricted isolated rabbit ear artery, 3-(2-pyridyl)- and 3- (4- pyridyl) - 5 - phenyldimethylsilylisoxazoline exhibited pronounced vasodilating activity. 3 - (2 - Pyridyl) - and 3 - (3 - pyridyl) - 5 phenyldimethylsilylisoxazoline and 3-(2-pyridyl)-5-silatranylisoxazoline prolonged blood coagulation time

Synthesis of Silicon and Germanium Containing Heteroaromatic Sulfides as Cholesterol Level Lowering and Vasodilating Agents

Silicon and germanium containing heteroaromatic sulfides have been prepared using phase transfer catalytic (PTC) system thiol / Si or Ge containing alkyl halide / solid KOH / 18- crown-6 / toluene. The target sulfides were isolated in yields up to 92 %. It has been found that 2-{[dimethyl (β-triethylgermylethyl)-silylmethyl]thio}-1-methylimidazole and 2-{[dimethyl(β-triphenylsilylethyl) silyl-methyl]thio}benzothiazole are the most active cholesterol level lowering and vasodilating agents.

Silacyclic derivatives of heteroaromatic sulfides as selective cholesterol level lowering and vasodilating agents.

Silacyclic derivatives of heteroaromatic sulfides have been prepared by using phase transfer catalytic (PTC) system thiol / silacyclopropyl iodide / solid K2CO3 / 18-crown-6 / toluene. The target sulfides were isolated in yields up to 70 %. The S-derivatives of N-methylimidazolyl, benzoxazolyl and 1,3,4-triazolyl thiols selectively lowered the low density lipoprotein (LDL) level in mice with the high cholesterol diet in nutrition.

3 -(Hetarylthio ) -1 -propynyl (dimethylalkyl )silanes as selective cholesterol level lowering agents

3-(Hetarylthio)-1 -propynyl(dimethylalkyl)silanes selectively lowered the low-density lipoprotein (LDL) level in mice with a high cholesterol diet in nutrition. The quinoline derivatives were found to be the most active.

Synthesis and cholesterol level lowering activity of macrocyclic silicon containing benzimidazole sulfides

New silicon containing macrocyclic benzimidazole sulfides were synthesized using organometallic and phase transfer catalytic methods. These compounds were tested for cholesterol level lowering activity. It has been found that macrocycle 4 produced a high antiatherosclerotic activity protected increasing LDL cholesterol level. This compound has excellent atherosclerotic coefficient (0.074 ± 0.026).

Nitrogen-containing organosilicon compounds. CXXII. Synthesis and pharmacological studies of trialkylsilylalkylaminoethyl dicarboxylate methiodides

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