Experimental antiulcer drugs. 1. Indole-1-alkanamides and pyrrole-1-alkanamides.

The synthesis and gastric antisecretory activity of a series of indole-1-alkanamides and pyrrole-1-alkanamides are presented. A marked elevation of the pH of the gastric secretions of the rat was observed after oral administration of 100 mg/kg of 2,3-dimethylindole-1-acetamide (2), -1-propionamide (8), and -1-butyramide (13). Replacement of either methyl group by a hydrogen atom or an ethyl radical resulted in greatly diminished activity. In the acetamide and propionamide series the 3-hydroxymethyl-2-methyl (14 and 15) derivatives exhibited activity but only when administered by the subcutaneous route. 2,3-Dimethylindole (18) was active and 2,3,4,5-tetramethylpyrrole-1-acetamide was moderately active. A number of the activ compounds were tested in the mouse mydriasis test for anticholinergic activity and found to be inactive. They were also found to be inactive in blocking histamine-induced acid secretion in the dog.

Metabolism of arildone, an antiviral agent, in laboratory animals.

After arildone administration, four compounds were identified in the excreta of laboratory animals: unchanged drug, arildone; the O-desmethyl metabolite, 4-[6-(2-chloro-4-hydroxy)phenoxy]hexyl-3,5-heptanedione; the sulfate ester of 2-chloro-4-methoxyphenol; and a labile conjugate of chlorohydroquinone, tentatively characterized as the sulfate ester. The concentrations of each of these were determined in the urine and/or plasma of rats, dogs, and mice after administration of 14C-arildone.

Metabolism of amrinone in animals.

The biotransformation of 14C-amrinone was studied in rats, dogs, and monkeys by automated gradient high-performance liquid chromatography. The major pathways of metabolism elucidated are: A) glucuronidation at the primary amino nitrogen atom and/or the enolized oxygen atom of the pyridone ring; B) addition of glutathione at the pyridone 2-position and ultimate hydrolysis of this compound to the 2-S-cysteinyl metabolite; C) formation of the primary amino N-acetyl derivative and subsequent oxidation of this to the corresponding N-glycolate. In each species studied, urine was the primary route of elimination and unchanged amrinone was the major urinary excretion product, the other known pathways being: rat, A and C; dog, A and B; monkey, A.

The disposition of quinfamide in the rat.

The disposition of quinfamide 1-(dichloroacetyl)-6-(2-furoyloxy)-1, 2, 3, 4-tetrahydroquinoline, an enteric anti-amoebic agent, was studied in the rat. A peak blood level equivalent to 2.3 micrograms/ml of quinfamide was observed at 7 hr following a 20 mg/kg oral dose. Urinary recovery of radioactivity was much higher (84%) following intravenous than oral (48%) administration. Drug levels, in all of the tissues examined. were low. The major pathways of quinfamide metabolism in the rat involve hydrolysis of one or both ester groups, acetylation of the de-acylated product to 1-acetyl-1, 2, 3, 4-tetrahydro-6-quinolinol, oxidation of this to the 1-glycolyl metabolite, and aromatization to 6-hydroxyquinoline.

A gas chromatography-mass fragmentographic method for the assay of ajmaline and its monochloroacetyl ester.

A gas chromatograph-mass fragmentography method for simultaneous assay of 17-monochloroacetyl-ajmaline (MCAA) and its hydrolysis product, ajmaline, is described. Recovery of both compounds from whole blood averaged 71%. About 5% of MCAA was hydrolyzed during the assay procedure. The method was accurate and precise to within a few percent. It was suitable for assays of blood levels in the dog after an i.v. dose of 2 mg/kg or an oral dose of 5 mg/kg.