Synthesis of carbon‐14 and tritiated steroidal 5α‐reductase inhibitors

Abstract

Summary17P-[N-( 1 , l -Dimethylethyl)carbamoyl]androsta-3,5-diene-4-~~C-3-carboxylic acid ([14C]SK&F 105657) was prepared via a three-step sequence (t-butyl amidation, triflation and carbomethoxylation) starting from androst-4-en-3-one-4-14C-1 7p-carboxylic acid. Its A-ring aromatic analog 17P-[N-(1,1 -dimethylethyl)carbamoyl]estra-1,3,5-(1 O)-triene-3-carboxylic acid (SK&F 105656) was labeled with tritium by means of iridium-mediated exchange methodology.Key Words: 5a-Reductase inhibitors, ring-labeled steroids, iridium-mediated tritium exchange, and 3H NMR. I n t r o d u c t i o nRecent efforts in searching for improved therapeutic agents to treat benign prostatic hyperplasia (BPH) in the aging male population led to the discovery of a series of unsaturated 3-carboxysteroids.1 ,2 These compounds bind to the enzyme human prostatic steroid 5a-reductase via a novel enzyme-NADP+-inhibitor ternary complex, and inhibit the biosynthesis of 5 a -d i h y d r o t e s t o~t e r o n e . 3~4 The latter, though it is essential for normal prostatic growth to reach puberty, also brings about the undesired effect of organ enlargement at a later age, causing, among other physiological symptoms, the indicative blockage of the urinary tract. Suppression of 5a-dihydrotestosterone synthesis would shrink prostate size and provide a potential cure for BPH.1,2 Being potent inhibitors of normal substrate binding to the human prostatic 5a-reductase, SK&F 105657 (1) and the A-ring aromatic analog SK&F 105656 (2), both with a 17P-t-butylcarboxamide, were targeted for further investigation. Experiments designed to profile their

Meta‐substituent effects on organoiridium‐catalyzed ortho‐hydrogen isotope exchange

“…These graphs are immediately informative in several ways: First, it is clear that in all three series, substrates with meta-CH 3 and -CF 3 undergo exchange at C2 much slower than at C6, and CF 3 has a stronger effect than CH 3 . This behavior is consistent with expectations based on steric factors alone.…”

“…Examination of the slopes of the curves from both substituents at early reaction stages shows that the rate of C6 deuteration is at least an order of magnitude faster than C2 deuteration. Second, within each class of substrate, those with metasubstituents possessing electron lone pairs either undergo labeling at C2 faster than at C6, or the labeling at C2 is less retarded relative to that at C6 compared with those substituted with CH 3 and CF 3 . This suggests the influence of a meta-effect opposing the steric effect.…”

“…Three substrate classes, typical of those commonly used as model substrates for HDE, were used: acetophenones, N,N-dimethylbenzamides and acetanilides. The meta-substituents included F, Cl, Br, I, CH 3 (or for acetophenone 3,4-dimethyl), CF 3 , OCH 3 , OH (for acetophenone and acetanilide) and OCF 3 (acetophenone only). In most cases, results from multiple experiments with the same substrate-catalyst combination were combined in order to give an adequate number of data points, as the rapid rate of exchange often permitted the acquisition of only a limited number of NMR measurements on a single sample.…”

“…For the last, the report of the Crabtree group that the hydrogens of the methyl group of 8-methylquinoline and the N3-methyl group of caffeine are rapidly exchanged with deuterium gas in the presence of [Ir(H) 2 (acetone) 2 (PPh 3 ) 2 ]BF 4 1 inspired us 2,3 and others 4 to investigate this and related iridium complexes for their ability to catalyze regioselective isotopic exchange labeling of compounds from deuterium or tritium gas sources. Since then, a variety of complexes have been found to be effective in different compound types, and organoiridium-catalyzed heteroatom-directed hydrogen isotope exchange (HDE) has become a commonly used method for the preparation of a wide variety of tritium-and deuterium-labeled compounds, especially for use as tracers in the life sciences.…”

“…Their potency in facilitating C2 exchange increases in the order IoBroOCH 3 (OCF 3 )ECloOHEF. Where tested, OCF 3 is only slightly less potent than OCH 3 . The effects of OH and F substituents are so strong that, as indicated by the slopes of the curves at early reaction stages, the rates of C2 deuteration are faster than those at C6 by at least an order of magnitude in the acetophenone and dimethylbenzamide series, and by a factor of at least five in the acetanilide series.…”