John O. Gardner

Agents for alkylating steroid hormone receptors. I. Analogs derived from esters of 17α-hydroxyprogesterone

Abstract A method designed to selectively tag hormonal receptor sites is discussed. Acylation of 17 α -hydroxyprogesterone with the half acids, half esters of glutaric, adipic, and pimelic acids followed by selective hydrolyses afforded the ω -carboxybutanoate, the ω -carboxypentanoate, and the ω -carboxyhexanoate of 17 α -hydroxyprogesterone. These acids were converted via their acid chlorides to the 5-keto-6-diazohexanoate, the 6-keto-7-diazoheptanoate, and the 7-keto-8-diazooctanoate of 17 α -hydroxyprogesterone. The latter compounds were active in the Clauberg assay, but they appear not to have alkylated the Clauberg receptor.

Ring-d-bridged steroid analogs. IX. 19-nor-14α, 17α-ethano-16α-carbomethoxy-4-pregnene-3, 20-dione.☆

Abstract The synthesis of 19-nor-14α, 17α-ethano-16α-carbomethoxypregn-4-ene-3,20-dione (X) from 3β-acetoxy-14α, 17α-ethano-16α-carbomethoxy-pregn-5-ene-20-one (III) is described. In the Clauberg Assay (subcutaneous administration), 16α-carbomethoxypregn-4-ene-3,20-dione has been found to have approximately 3.5% the activity of progesterone. Introduction of a 14α, 17α-ethano bridge further reduces the activity by more than a factor of 4. In contrast to this, the 19-nor compound (X) appears to be at least 167% as active as progesterone and over 25X as active as 14α,17α-ethano-16α-carbotnethoxypregn-4-ene-3,20-dione (XII). The significance of these facts with respect to the possible mode of progesterone binding to the Clauberg receptor is discussed.

IMPROVED PREPARATION OF (R) AND (S)-3-AMINOQUINUCLIDINE DIHYDROCHLORIDE

Abstract An improved procedure for the synthesis of either (R) or (S)-3-aminoquinuclidine was developed. Key intermediate imine 2 was made in a one pot process using lithium oxide as the base and molecular sieves.