ABSTRACT
The synthesis of 1,3-disubstituted 2,4,5,6-tetrahydro-4,6,6-trimethyl-2-phenylcyclopenta[c]pyrrole-4-carboxamides is reported. The derivatives included R1 = R3 = H, R1 = CH2OH with R3 = H (16) or CH3, R1 = CH3 with R3 = CH2OH (17), and R1 = R3 = CH2OH. The monohydroxymethyl derivatives were as active as the parent cyclopentapyrrole, where R1 = R3 = CH3 (1), when administered orally in the pyloric ligated rat. The compounds lacking one or both CH3 groups at C-1 or C-3 were much less active. Compounds 16 and 17 inhibited histamine-induced gastric acid secretion in the dog.
Subject(s)
Anti-Ulcer Agents/chemical synthesis , Cyclopentanes/chemical synthesis , Pyrroles/chemical synthesis , Animals , Cyclopentanes/pharmacology , Dogs , Gastric Juice/metabolism , Haplorhini , Hematologic Diseases/chemically induced , Mice , Pyrroles/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Condensation of a 1-substituted 2,5-dimethylpyrrole 6 with 2 mol of 2-amino-2-methylpropionitrile in hot acetic acid yielded a 2-substituted 2,4,5,6-tetrahydro-1,3,4,5,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile (4). Hydrolysis of the nitriles to the amides gave a group of compounds which were active as antisecretory agents in the pyloric-ligated rat. Outstanding in this respect was the 2-phenyl derivative 5b, the most active compound in the series. It did not possess anticholinergic properties. In contrast to the indoles and pyrroles reported earlier, 5b demonstrated marked activity in blocking gastric acid secretion in the histamine-stimulated dog.
Subject(s)
Anti-Ulcer Agents/chemical synthesis , Pyrroles/chemical synthesis , Animals , Depression, Chemical , Dogs , Gastric Juice/metabolism , Guinea Pigs , Heart Rate/drug effects , In Vitro Techniques , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Pyrroles/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
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.
