New nonsteroidal steroid 5 alpha-reductase inhibitors. Syntheses and structure-activity studies on carboxamide phenylalkyl-substituted pyridones and piperidones

In the search for nonsteroidal inhibitors of 5 alpha-reductase for the trea tment of benign prostatic hyperplasia (BPH), we synthesized diisopropyl (1a -8a) and tert-butyl (1b-8b) benzamides, as well as ethyl benzoates (1c, 3c) , which were substituted in 4 position via variable alkyl spacer (n = 0: 1- 4, n = 1: 5, 7 and n = 3: 6, 8) with a 1-methyl-2-pyridone (1, 2, 5, 6) or a 1-methyl-2-piperidone (3, 4. 7, 8) moiety mimicking steroidal ring A. The directly connected benzamides (1a-4a, 1b-4b) and benzoates (1c, 3c) were o btained by palladium-catalysed coupling reaction of diethyl(3-pyridyl)-bora ne with 4-bromobenzoic acid derivatives, followed by alpha-oxidation of the 1-methyl-pyridinium salt and subsequent separation of the regioisomers. Ca talytic hydrogenation of the pyridones (1, 2) led to the piperidones (3, 4) . The preparation of the benzamides with a methylene (5, 7) and a propylene spacer (6, 8), respectively, started with the reduction of the keto group of 5-benzoyl-1,2-dihydro-1-methyl-2(1H)-pyridone and catalytic hydrogenatio n of the alkene obtained by Wittig reaction of 5-formyl-1,2-dihydro-1-methy l-2(1H)-pyridone with (2-phenylethyl)triphenylphosphonium bromide, respecti vely. The phenyl ring was functionalized by Friedel-Crafts reaction, halofo rm cleavage to give the acid, formation of the acid chloride, and subsequen t treatment with the appropriate amines. Again, catalytic hydrogenation of the pyridones (5, 6) led to the piperidones (7, 8). The 5 alpha-reductase i nhibitory properties were determined using rat ventral prostate, as well as human BPH tissue as enzyme source, 1 beta-2 beta-[H-3] testosterone as sub strate and a HPLC procedure for the separation of dihydrotestosterone (DHT) . Tested at a concentration of 100 mu M, the inhibition values of 1-8 range d from 0-79%. significant differences were observed between rat and human e nzyme. The most active compound was ethyl 4-(1-methyl-2-oxopiperid-5-yl)ben zoate 3c (68%) for the human enzyme and N,N-bis(1-methylethyl)-4-[3-(1,2-di hydro-1-methyl-2-oxopyrid-5-yl)propyl]benzamide 6a (79%) for the rat enzyme .