No abstract

The synthesis of 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (Tröger's base) from p-toluidine and of two Tröger's base analogs from other anilines by reaction with hexamethylenetetramine in trifluoroacetic acid is described. 2,3,6,7-Tetrahydro-9-methyl-2,6-di-p-tolyl-1H,5H-pyrimido[5,6,1-ij] quinazoline is formed as a secondary product in the reaction of p-toluidine and hexamethylenetetramine. One of the Tröger's base analogs, 2,8-bis(3'-pyridylmethyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]d iazocine (5), is an effective inhibitor of the enzyme, thromboxane A2 (TxA2) synthase, with an ED50 of 30 ng/mL in a specified in vitro assay. Three analogs having substituents on the bridging methylene group of the bicyclic nucleus of the Tröger's base structure were prepared, but all were considerably less active than the aforementioned compound in the inhibition assay. The structures of these inhibitors of TxA2 synthase fall outside the classical structure-activity relationship that has been established for this class of enzyme inhibitors.

No abstract

No abstract

No abstract

Di- and triaminopyrimidine 3-oxides (e.g., 2,4-diamino-6-piperidinylpyrimidine 3-oxide and 2,4-diamino-6-(diallylamino)triazine 3-oxide) react with sources of sulfur trioxide, such as sulfur trioxide trimethylamine or chlorosulfuryl chloride, to yield the corresponding heterocyclic O-sulfates. These sulfates are inner salts with unusual physical properties. The structure of the O-sulfate of 2,4-diamino-6-piperidinylpyrimidine 3-oxide was confirmed by X-ray. These O-sulfates are hypotensives. They apparently act by direct vasodilation.

No abstract

The activity of angiotensin-converting enzyme in hindlegs and kidneys was compared in anesthetized dogs. Intra-arterial injections of angiotensin I or angiotensin II to one kidney or one hindleg caused dose-dependent decreases in blood flow in that vascular bed. An inhibitor of angiotensin-converting enzyme activity did not affect the vasoconstrictor activity of angiotensin II but substantially reduced that of angiotensin I. The reduction in vasoconstrictor activity of angiotensin I during enzyme inhibition was used to calculate conversion of angiotensin I to angiotensin II. There was 40% conversion in hindleg but only 2.1% in kidney. After intra-arterial injection of angiotensin I, bioassay of angiotensin II in the renal or iliac venous blood indicated that 60-90% of freshly formed angiotensin II was inactivated before leaving the kidney or hindleg. The results show that converting enzyme activity is much greater in hindlegs than in kidneys and that the endogenously formed angiotensin II following intra-arterial injection of angiotensin I is destroyed to the same extent as intra-arterially injected angiotensin II. Intra-arterial infusion of the enzyme inhibitor increased hindleg blood flow in half of the dogs; renal blood flow increased in only one dog. The inhibitor did not affect vascular responses produced by norepinephrine, histamine, vasopressin, or prostaglandin F 2α but the effects of bradykinin were potentiated.