[Thiophene as a structural element of physiologically active substances. 20. Thiophene analogs of the leukotriene D4 antagonist Ro 23-3544]. / Thiophen als Strukturelement physiologisch aktiver Substanzen, 20. Mitt. Ein Thiophenanalogon des Leukotrien D4 Antagonisten Ro 23-3544.

The synthesis of 6-Acetyl-7-[[5-(5-acetyl-4-hydroxy-3-propyl-2-thienyl- oxy)pentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (1), a thiophene analogue of the leukotriene antagonist Ro 23-3544, is described. Compound 1 shows almost no effect on leukotriene D4 induced broncho-constriction on anesthesized guinea pigs.

[Thiophene as a structural element of physiologically active compounds. 19. The synthesis of substituted (6H-thieno[2,3-b]pyrrol-4-yl)phenylmethanones]. / Thiophen als Strukturelement physiologisch aktiver Substanzen, 19. Mitt. Die Synthese von substituierten (6H-Thieno[2,3-b]pyrrol-4-yl)-phenylmethanonen.

The synthesis of 4-Methoxyphenyl-[5-methyl-6-(2-(4-morpholinyl)-ethyl)-6H-thieno[2,3- b]pyrrol-4-yl)phenylmethanone (1), a thiophene analogue of the analgesic Pravadoline B, is described. Starting with the acetylprotected thienylhydrazine 2b compound 7 was obtained in a Fischer-analogue cyclication in two steps. Use of the BOC-protected thienylhydrazine 2a yielded the pyrazol 5. Alkylation of 7 with N-(2-Chloroethyl)morpholine gave the target compound 1. In the acetylcholine-writhing-test in mice as well as in the acetic acid-writhing-test in rats 1 showed a significant lower antinociceptive activity than Pravadolin (B).

Overview of the pharmacological properties, pharmacokinetics and animal safety assessment of lornoxicam.

Lornoxicam is a new, highly potent antirheumatic agent which is an oxicam derivative. Although highly potent as a cyclo-oxygenase inhibitor, the compound does not cause inhibition of 5-lipoxygenase and does not appear to shunt arachidonic acid through this cascade. This powerful inhibition of cyclo-oxygenase has manifested itself as highly potent analgesic and anti-inflammatory effects in animal studies and also prevented the bone destruction which normally occurs in the adjuvant polyarthritic rat. To explain this finding, studies have demonstrated that lornoxicam inhibits polymorphonuclear (PMN)-leukocyte migration; inhibits the release of superoxide from human PMN-leukocytes; inhibits the release of platelet derived growth factor (PDGF) from human platelets and stimulates the synthesis of proteoglycans in cartilage in tissue culture. Lornoxicam is well absorbed and has a plasma t1/2 in man of 4 hours which is distinctly different from other oxicams. It is metabolized in animals and in man to the 5'-hydroxy-metabolite which is inactive in pharmacological tests. In vitro and in vivo animal safety studies have demonstrated both subchronically and chronically that lornoxicam manifests no unusual toxicity, is not a mutagen nor is it tumorigenic and causes no fetal teratogenicity in reproduction studies.

Effects of long-term administration of propyldazine on blood pressure and counter-regulatory systems in conscious hypertensive dogs.

The counter-regulatory effects in response to blood pressure reduction by propyldazine were studied in conscious dogs with bilateral cellophane perinephritis hypertension. During a 22-day period of chronic treatment, the initial increase in heart rate, plasma renin activity, angiotensin II, aldosterone, and vasopressin, which indicate counter-regulation to the drug induced decrease in blood pressure, vanished. On the fifth day of treatment another, presumably cellular mechanism, had taken over the restitution of blood pressure and thereby led to tolerance towards the action of further propyldazine administration. Seven days after the end of chronic treatment a renewed propyldazine administration did not produce the same effects as obtained with the first administration; after 28 days the hypotensive effect of propyldazine was identical to the one observed before treatment.