17α-Halogenated PROGESTERONES: ORALLY-ACTIVE PROGESTINS

Abstract

170-Chloroprogesterone, 60-fluoro -170-brornoprogesterone, l-dehydro-6a-fluoro-170-brornoprogestero~le, and 60-chloro-170-bromoprogesterone have been synthesized. These compounds have been found to be orally-active progestins without androgenic properties.In recent years, considerable effort has been devoted to the search for orally-active progestational agents to substitute for the natural hormone, progesterone. The newer synthetic progestogeils ~vhich have acquired prominence because of their oral activity fall into two classes: 19-ilorsteroids such as 19-norprogesterone (1) and 17a-ethynyl-19-ilortestosterone (2) and its A5('0)-isomer (3), and derivatives of progesterone containing a 17a-acetoxy substituent (4-7).I t has been shown recently that l'ia-bromoprogesteroile (8) is an orally-active progestogen (9), indicating that substituents other than acetoxyl a t C-17 can enhance the very wealc oral activity of progesterone. It was clearly of interest to prepare other 17a-halogenated progesterones, and to determine whether modifications in structure which enhance the activity of 17a-acetoxyprogesterone, such as the introduction of a Ga-halo substituent and a A'-double bond (4, 5), would have a similar effect on the comparatively wealc oral activity of 17a-broil~oprogesterone.In this paper, we record the synthesis and preliminary biological evaluation of 17a-chloroprogesteroi~e and of the Ga-fluoro-, I-dehydro-Ga-fluoro-, and Ga-chloroderivatives of 17a-bro~l~oprogesterone. I r a -ChloroprogesteronePregnenolone acetate (I) \\.as brominated a t a low temperature, and the 5,G-dibromide I1 jvas allowed to react with chlorine in acetic acid. The resulting mixture of 17-and 21-chloro derivatives (111) was treated with sodium iodide in acetone which regenerated the 5,G-double bond and replaced chlorine a t C-21 with iodine. Finallj., the iodine a t C-21 was ren~oved by reduction with aqueous sodium bisulphite solution (10) and 17a-chloropregnenolone acetate (IV, R = Ac) was isolated after chromatographic purification. The a-configuration of the chlorine was inferred from the general preference for "back-side" attack and from the fact that bromiilation of 20-lcetones has been clearly shown to result in the fornlation of 17a-broino derivatives (11).Acid-catalyzed hydrolysis of IV ( R = Ac) yielded 17a-chloropregnei~olone (IV, R = H), which, without purification, was oxidized with chromic acid in acetone (12).T h e shift of the double bond into conjugation with the carbonyl group to yield 17a-chloroprogesterone (V) was completed by treatment of the crude oxidation product with oxalic acid (13).Ga-Halo-1 7a-bromoprogesterones2 17a-Bromopregileilolone acetate (VI) (8, 10) was coilverted to a 6-fluoro derivative by conveiltional means (14). Epoxidation of VI with nlonoperphthalic acid gave a mixture of 50,GP-and 5a,Ga-epoxides, VII and VIII. T h e epoxides were separated by chromatog- 'Manzcscript received M a y 9 , 1960.

Synthesis of halogenated pregnanes, mechanistic probes of steroid hydroxylases CYP17A1 and CYP21A2

“…Using procedures described in sections 2.2.19–2.2.21, hydrolysis of acetate 34 gave 11 (15 mg, 80%), and oxidation/isomerization of 11 gave 2 [19] (10 mg, 67%, 2 steps). 1 H NMR of compound 11 (400 MHz, CDCl 3 ) δ 5.37-5.35 (m, 1H), 3.57-3.50 (m, 1H), 3.01 (ddd, J 1 = 15.4, J 2 = 11.5, J 3 = 2.9 Hz, 1H), 2.32 (s, 3H), 2.32-2.15 (m, 2H), 2.06-1.93 (m, 3H), 1.92-1.80 (m, 4H), 1.79-1.74 (m, 1H), 1.72-1.64 (m, 2H), 1.60-1.37 (m, 3H), 1.15-1.02 (m, 2H), 1.01 (s, 3H), 0.74 (s, 3H).…”

Synthesis and Evaluation of Some Alkoxy-, Chloro-, and Acyloxy-Conjugated Styryl Ketones Against P-388 Lymphocytic Leukemia and an Examination of the Metabolism and Toxicological Effects of l-(m-Ethoxymethyloxyphenyl)-l-nonen-3-one in Rats

“…In an attempt to prepare the dibromo analog of XVc, the required intermediate ketone, 1,2-dibromo-4-methyl-l-phenyl-3-hexanone (XVIb), was prepared by a literature method (45) to give the desired product as colorless needles (mp 97.5', 64% yield).…”

The Synthesis of 17β-Amino-17-isoprogesterone

“…(39) G. Drefahl and D. Martin, Chem. Ber., 98, 2497(1960; A. Kasahara, Nippon Kagaku Zasaki, 80, 416 (1959).…”