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The synthesis of 3-pyridyl-substituted tetralones is presented. The alterations in the corticoid hormonal pattern caused by inhibitors of the 11/3-and 17«-hydroxylase enzyme systems and the gonadal inhibition by 17a-hydroxylase inhibitors are discussed. The biological activity of compounds VII and IX is being further investigated.Although the chemistry of pinacolone type compounds has been the subject of intensive research for many years, it has not been until the past decade that such ketones have been evaluated pharmacologically. In this connection the following two isomeric pairs of pinacolones, all of which possess unusual biological activity, have been studied in our laboratories.1,2 Ill, It = 3-Pyridyl, (mepyrapone3) IV, It = 3-PyridylIn the course of our continued search for adrenal cortical inhibitors, a number of compounds were found which altered the hormonal pattern in the adrenal effluent of the dog in a fashion different from the established changes in the hormonal output as evoked by mepyrapone. These substances are classified as inhibitors of the 17ahydroxylase system4 and their chemistry and biological activity serve as the subject matter of this report.Chemistry.-Our most potent 17 -hydroxylase inhibitors were found in a series of pyridyl-substituted tetralones, the synthesis of which is outlined in Scheme 1.In cyclization of the mría-substituted acid (VI, R = m-Cl) ring closure occurred in the ortho and para positions relative to the chlorine atom. The lower melting form constituted the major fraction and was assigned structure VIII.A strong band at 863 emu1 in the infrared absorption spectrum, indicative of 1.2,4-aromatic substitution, served to confirm this assignment. The structure of the higher melt-: 1)

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Complete or partial inhibition of adrenal corticoid secretion has become an important goal of the medical and biological sciences. The progress in both qualitative and quantitative assay methods for steroid hormones enables the biochemist to measure alterations in the hormonal balance. Consequently, it seems to be feasible to search for compounds which may induce selective reversible or even irreversible changes in the hormonal pattern.An extensive study has been made by chemists in producing alterations in the structure of the natural hormones in an effort to obtain compounds with a narrower spectrum of biological activity and a high intensity of the desired specific action. With regard to the corticoid hormones, most of these chemical changes were aimed at producing a high glucocorticoid activity. It should be noted here that one important feature of the evaluation of such " tailor-made ' hormones is their ability to diminish adrenocorticoid production via suppression of pituitary ACTH output.

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