Syntheses and gastric acid antisecretory properties of the H2-receptor antagonist. N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d]isot hiazol-3-amine 1,1-dioxide and related derivatives.

The synthesis and gastric acid antisecretory properties of several N-substituted thieno[3,4-d]isothiazol-3-amine 1,1-dioxides and analogues are described. Two of the more potent compounds, N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide (6a) and N-[4-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide, showed greater potencies as H2-receptor antagonists (in vitro) than ranitidine. They also had potent gastric acid antisecretory activities in vivo, inhibiting basal acid secretion in the rat, histamine-stimulated acid secretion in the dog, and food-stimulated acid secretion in the dog. These were selected for further pharmacological evaluation.

Synthesis and antibacterial activity of C-3' isothiazolyl and related cephalosporins.

The synthesis of C-3' isothiazolyl and related cephalosporins is presented. The compounds exhibit activity against a variety of Gram-positive and Gram-negative organisms.

Structural modification of H2-receptor antagonists provide post-H2-receptor gastric antisecretory activity.

Structural analogues (e.g., Wy-46,499) of a known H2-antagonist (Wy-45,662) were found to inhibit acid secretion in the pylorus ligated rat and to block forskolin and DBcAMP-stimulated [14C]amino-pyrine (AP) uptake by rat isolated gastric mucosal cell preparations. Wy-45,662 (N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno [3,4- d]isothiazol-3-amine 1, 1-dioxide), a very potent histamine H2-antagonist and antisecretory agent in the rat (ED50 approximately equal to 0.3 mg/kg), had no effect in vitro at 1 microM on forskolin-induced [14C]AP uptake while 10 nM Wy-45,662 completely suppressed histamine-stimulated [14C]AP uptake. In contrast, the N-benzylated form of Wy-45,662, Wy-46,499, dose-dependently (1 X 10(-7) -3 X 10(-6)M) suppressed forskolin-stimulated [14C]AP uptake while retaining modest antisecretory activity (ED50 approximately equal to 8 mg/kg) in vivo. Wy-46,499's modest antisecretory activity was thus attributable to inhibition via a post-histamine H2-receptor mechanism.

Synthesis of (+)-11-deoxy-15-ethynyl prostaglandins.

This article describes the preparation of (+)-11-deoxy-15-ethynyl prostaglandins (1 & 16). The key step involves a conjugate addition of the substituted 1-lithio-1-oct-1-ene (2) to the cyclopentenone (3 & 12) to furnish 11-deoxy-prostaglandin skeleton in a simple fashion. Of particular interest in this synthesis is the preparation of alkyl side chain (7) which was achieved in an efficient three-step synthesis starting from the readily available beta-iodo vinyl ketone (4).

Synthesis of arylnaphthalenyl derivatives: inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a reductase.

Trans-tetrahydro-4-hydroxy-6-[1-aryl-7-naphthalenyl]-2H-pyran-2-ones of general structure 4 were prepared and tested for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. In contrast to previously described biphenyl lactones (2) containing an ethenyl linkage, linkage of the pyranone ring to the aryl moiety in these compounds is via a rigid aromatic ring system, which still allows free rotation of the aryl rings. The imposed conformational constraint is compatible with activity, since members of the series had activity in range 1-20 microM (IC50 values).