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In this study novel substituted 6-benzyl-thieno[2,3-b][1,4]thiazines with an urea moiety were synthesized. Structural modifications of the amino side chain were carried out with the aim of finding tissue specific compounds. The effects on papillary muscles, right atria, aortic strips, and terminal ilea were investigated. Compounds 10c and 10d showed the most potent negative inotropic effect. The calcium antagonism of all derivatives occurred in a non-competitive manner, which may indicate that they also have potassium channel opening activities.

KT-362 is an antiarrhythmic and antihypertensive agent with vasodilating activity. Since it carries a homoveratryl group in the side chain, an obvious relation exists to the verapamil-type calcium antagonists. Replacement of the fused aromatic moiety in KT-362 with thiophene provided 8-[N-[2-(3,4-dimethoxyphenyl) ethyl]-beta-alanyl]-5,6,7,8-tetrahydrothieno[3,2-b][1,4] thiazepine (1). Compound 1 shows a negative chronotropic activity in spontaneously beating right atria (IC50 = 23 microM, n = 7), and a negative inotropic effect in papillary muscles (IC50 = 2.7 microM, n = 7) and left atria (IC50 = 4 microM, n = 6) of the guinea-pig heart. The decrease of contractility in papillary muscles could be antagonized by increasing the extracellular calcium concentration. Compound 1 was found to affect high (IC50: 70 +/- 5 microM) and low (IC50: 129 +/- 34 microM) voltage-activated calcium channel currents as well as voltage-activated sodium channel currents (IC50: 80 +/- 13 microM) in chick dorsal root ganglion neurons. In addition nicotine-induced currents were potently inhibited (IC50: 6 +/- 0.7 microM) in bovine chromaffin cells.

Ausgehend vom Ester 5 wird uber mehrere Stufen 4-[3-[2-(3,4-Dimethoxyphenyl)-ethylamino]-propanoyl]-2-ethyl-4,5,6,7-tetrahydrothieno[2,3-b]-[1,4]thiazepin (3) aufgebaut, eine thienoanaloge Verbindung zum Calciumkanalblocker KT-362. Es wird uber die Ca2+-antagonistische Wirkung dieses Thiazepinderivats berichtet. Synthesis and Ca2+Antagonistic Activity of a Thieno-KT-362 Analogue The thienoanalog of the calcium antagonist KT-362, compound 3, was prepared from ester 5 and the Ca2+ antagonistic activity was evaluated in isolated ring segments of rat aorta.

2-Vinylbenzoxazole (3) is obtained by condensation of acrylic acid with 2-aminophenol in a mixture of phosphorus pentoxide/methansulfonic acid. Interaction of 3 with N-, O-, and C-nucleophiles yields 2-substituted 2-ethyl-benzoxazoles. Compounds 8a, 8b and 8e show analgetic activity in mice. Moreover, fungicide, insecticide and nematocide activity of some compounds is found.

A series of thienothiazines was synthesized and tested for their ability to inhibit P-glycoprotein, which is responsible for multidrug resistance in tumor cells. Highest activity was found for compounds with a homoveratryl side chain, which is also present in other modulators of multidrug resistance, such as verapamil. Although for several classes of MDR-modulators lipophilicity was shown to be a major determinant for high activity, no satisfactory correlation was obtained for the set of thienothiazines (r = 0.35). However, the use of molar refractivity as descriptor yields a good correlation with biological activity. This gives renewed evidence for the importance of molar refractivity and indicates that, in addition to lipophilicity, polar interactions also play an important role in ligand/receptor interaction.

Durch Lithiierung von 1 und nachfolgende Umsetzung mit D2O bzw. CH3I wird die Methylgruppe an C-2 unter Bildung der Verbindungen 2 und 3 substituiert. Die Verwendung von Carbonylverbindungen als elektrophile Reaktionspartner ermoglicht die Darstellung der anellierten Oxazinderivate 7 und 8. Studies on the Chemistry of 1,4-Oxazines, XIX: Synthesis of Pyrano[4,3-b]-1,4-oxazines by Reaction of a Lithiated Oxazincarboxylate with Carbonyl Compounds Lithiation of 1 and subsequent reaction with D2O as well as CH3I yields compounds 2 and 3 by substitution of the methyl group in position 2. Carbonyl compounds as electrophilic agents lead to the anellated oxazine derivatives 7 and 8, respectively.