STRUCTURE-ACTIVITY STUDIES OF 2,3,4,4A,5,9B-HEXAHYDROINDENO[1,2-C]PYRIDINES AS ANTISPERMATOGENIC AGENTS FOR MALE CONTRACEPTION

Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-methyl-5-p-tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R(1) = ethyl, R(2) = R(3) = methyl, R(4) = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R(1) = ethyl, R(2) = methyl, R(3) = COOH, R(4) = H), ester (RTI-4587-056, 12b; R(1) = ethyl, R(2) = methyl, R(3) = COOMe, R(4) = H), formyl (RTI-4587-030, 12i; R(1) = ethyl, R2 = methyl, R(3) = CHO, R(4) = H), or hydroxymethyl (RTI-4587-055, 12g; R(1) = ethyl, R(2) = methyl, R(3) = CH2OH, R(4) = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.