ABSTRACT
A novel series of acidic cycloalkanoindoles comprising tetrahydrocarbazole-, cyclopentindole-, and cycloheptindole-1-acetic acids has been synthesized via the Fischer indolization between a phenylhydrazine and a 1-alkyl-2-oxocycloalkaneacetic acid ester. These compounds were evaluated, orally, for their capacities to decrease estabished adjuvant arthritis in rats. The most active compound of the series was 1-ethyl-8-n-propyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid (AY-24 873),which had an ED50 of 1.1 +/- 0.2 mg/kg. AY-24 873 was also studied orally in rats for its effect on the acute inflammatory response in the carrageenin paw edema test. It was found that AY-24 873 was about ten times more active against the chromic than against the acute models of inflammation used.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Carbazoles/chemical synthesis , Indoles/chemical synthesis , Animals , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Carbazoles/adverse effects , Carbazoles/therapeutic use , Cycloheptanes/adverse effects , Cycloheptanes/chemical synthesis , Cycloheptanes/therapeutic use , Cyclopentanes/chemical synthesis , Cyclopentanes/therapeutic use , Edema/drug therapy , Indoles/adverse effects , Indoles/therapeutic use , Rats , Stomach Ulcer/chemically induced , Structure-Activity RelationshipABSTRACT
The synthesis and antiinflammatory activities of a series of 23 novel 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-alkanoic acids are described and some relationships between structure and activity are discussed. One of these compounds, 1,3,4,9-tetrahydro-1-propylpyrano[3,4-b]indole-1-acetic acid (prodolic acid, USAN), has been selected for further studies.