Schering Corporation

Elliot L Shapiro

Michael J Green

Ho-Jane Shue

Richard W Draper

Thomas L Popper

Arthur S Watnick

Margaret A Gentles

Lawrence E Finkenor

This invention relates to novel 3,20-dioxo-1,4-pregnadiene-17.alpha.-ol 17-aromatic heterocyclic carboxylates, to pharmaceutical formulations thereof, and their use in the treatment and control of inflammatory conditions.

3,20-Dioxo-1,4-pregnadiene-17.alpha.-ol 17-aromatic heterocycle

Disclosed is an improved process for the synthesis of 6-bromo-17,21-dihydroxy-3,11,20-trioxo-1,4,-pregnadienes 17,21-diesters. In particular, this invention relates to the conversion of 17,21-dihydroxy-3,11,20-trioxo-1,4-pregnadienes 17,21-diesters to 6-borom-17,21-dihyroxy-3,11,20-trioxo-1,4-pregnadienes-17-21-diesters via bromination under ionic conditions, e.g. bromine in acetic acid.

Process for the synthesis of 6-bromo-17,21-dihydroxy

3-Oxo-6-unsubstituted-7.alpha.-halogeno-4-dehydro steroids, wherein said halogen is chlorine, bromine or iodine, are prepared by reaction of a 3-oxo-6,7-di-unsubstituted-4,6-bis-dehydro steroid with at least an equimolar quantity of the corresponding hydrogen halide in a non-reactive organic solvent at temperatures no higher than about 30.degree. C, and then are isolated by removal of said solvent and any excess acid at temperatures no higher than about 25.degree. C without subjecting said 3-oxo-6-unsubstituted-7.alpha.-halogeno-4-dehydro steroid to a basic medium. A preferred species of this process is that wherein the starting steroid is a 3,20-dioxo-9-unsubstituted-11-oxygenated-1,4,6-pregnatriene-17,21-diol or ester thereof, preferably a 17,21-di-lower alkanoate or a 17-benzoate 21-lower alkanoate ester thereof, whereby is prepared in good yields a 3,20-dioxo-7.alpha.-halogeno-1,4-pregnadiene-17.alpha.,21-diol or ester thereof, useful as topical anti-inflammatory agents. Also described are novel 3,20-dioxo-7.alpha.-halogeno-4-pregnene-17.alpha.,21-diols and esters thereof having anti-inflammatory activity as well as 3-oxo-7.alpha.-halogeno-17.alpha.-4-pregnene-21,17.beta.-carbolactone aldosterone antagonists.

Process for the preparation of 7.alpha.-halogeno-3-oxo-4-dehydro

Steroidal 6-azido-4,6-pregnadieno[3,2-c]pyrazoles having glucocorticoid activity are prepared by treating a 6-unsubstituted-4,6-pregnadieno[3,2-c]pyrazole with a halogen azide followed by treatment of the thereby formed 6-azido-7-halogeno-6,7-dihydro-4-pregnene[3,2-c]pyrazole with a dehydrohalogenating agent. Other methods of preparing these compounds are described, including the process of treating a 6-azido-17.alpha.,20; 20,21-bismethylenedioxy-4,6-pregnadiene-3-one with an alkyl formate in the presence of base followed by treatment of the resulting 2-hydroxymethylene derivative with a hydrazine or, alternatively, by converting said 2-hydroxymethylene to a 2-alkoxymethylene derivative followed by treatment thereof with a hydrazine. Preferred compounds include 6-azido-11.beta.,17.alpha.,21-trihydroxy-20-keto-4,6-pregnadieno[3,2-c]pyr azoles, particularly 2'-phenyl-9.alpha.-fluoro(and 9.alpha.-chloro)-16-methyl-derivatives thereof which possess potent anti-inflammatory activity. Of interest is 2'-phenyl-6-azido-9.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alph a.-methyl-20-keto-4,6-pregnadieno[3,2-c]pyrazole.

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Cedar Grove, NJ, United States of America

Elliot L Shapiro