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 treatment 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 obtained by palladium-catalysed coupling reaction of diethyl(3-pyridyl)-borane with 4-bromobenzoic acid derivatives, followed by alpha-oxidation of the 1-methyl-pyridinium salt and subsequent separation of the regioisomers. Catalytic 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 hydrogenation of the alkene obtained by Wittig reaction of 5-formyl-1,2-dihydro-1-methyl-2(1H)-pyridone with (2-phenylethyl)triphenylphosphonium bromide, respectively. The phenyl ring was functionalized by Friedel-Crafts reaction, haloform cleavage to give the acid, formation of the acid chloride, and subsequent treatment with the appropriate amines. Again, catalytic hydrogenation of the pyridones (5, 6) led to the piperidones (7, 8). The 5 alpha-reductase inhibitory properties were determined using rat ventral prostate, as well as human BPH tissue as enzyme source, 1 beta-2 beta-[3H]testosterone as substrate and a HPLC procedure for the separation of dihydrotestosterone (DHT). Tested at a concentration of 100 microM, the inhibition values of 1-8 ranged from 0-79%. Significant differences were observed between rat and human enzyme. The most active compound was ethyl 4-(1-methyl-2-oxopiperid-5-yl)benzoate 3c (68%) for the human enzyme and N,N-bis(1-methylethyl)-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl) propyl] benzamide 6a (79%) for the rat enzyme.
Hartmann
R W
RW
Pharmazeutische und Medizinische Chemie, Universität des Saarlandes, Saarbrücken, Germany.
Reichert
M
M
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010881:Piperidones / Q000138:chemical synthesis* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000201:enzymology; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000201:enzymology; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism
C411246:4-(1-methyl-2-oxopiperid-5-yl)benzoate; D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D010881:Piperidones; D011728:Pyridones; D013739:Testosterone