Diels-Alder reaction of 1,6-bis(trimethylsilyloxy)-2,4-hexadiene with α-substituted acrylates and 5 to 7-and 9 to 11-membered α-(methylene)lactones has been carried out to examine correlation of dienophile structure with endo/exo selectivity. While the conformationally flexible acrylates produced cycloadducts of endo/exo = 59:41 to 74:26, the 5 to 7-membered lactones with rigid s-cis conjugated system provided cycloadducts of endo/exo = 13:87 to 32:68 and the 9 to 11-membered lactones which can take both s-cis and s-trans conformation afforded endo/exo ratios of 37:63 to 57:43.

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The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC 50 ‫031؍‬ nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED 50 ‫؍‬ 7 mg/kg).Key words androgen receptor; pure antagonist; prostate cancer Chem. Pharm. Bull. 56(11) 1555-1561 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: tachibanakzt@chugai-pharm.co.jp Chart 1. Structures of AR AntagonistsIn the preparation of aminonitriles 8a-l by the coupling of corresponding amines 7 with acetone cyanohydrin 6, NEt 3 was used when the amine was HCl salt (Chart 2). Isothiocyanate 10, which was derived from 9 and thiophosgene, was coupled with compounds 8a-l in THF in the presence of NEt 3 under reflux to give 5-imino-2-thioxoimidazolidines 11a-h and 14a-d. The imino groups and terminal esters of compounds 11a-h were hydrolyzed successively to give methylene linker compounds 13a-h (Chart 3). Compound 14a, in which the protecting group of phenolic OH was the methoxymethyl group, was converted to phenol-terminal thiohydantoin 16a directly by heating in 6 N-HCl and dioxane. Compounds 14b-d, in which the hydroxyl groups were protected by the methyl group, were converted to compounds 15a-c under the same conditions followed by deprotection of the methyl group by BBr 3 . Alkylation of the hydroxyl groups of 16a-d followed by hydrolysis of the terminal esters gave phenyl-inserted derivatives 18a-d (Chart 4).The synthesized compounds were evaluated for their in vitro binding affinities and agonist/antagonist activities for AR using the same procedures as reported previously.11) The binding affinity for AR was determined by displacement of [ 3 H]-mibolerone with the test compound utilizing CHO-K1/hAR cells. The agonistic and antagonistic activities of the compounds for AR were determined by RGA using hARtransfected Hela cells. Antagonistic activity was determined by the IC 50 value, the concentration of a compound that inhibits the transcriptional activity of 0.1 nM of DHT by 50%.To determine agonistic activity, we calculated the value of EC 5 , the concentration of a compound-treated group in which the transcriptional activity is 5% of the transcriptional activity of 0.1 nM of DHT. The maximum transcriptional activity of each compound indicated as its efficacy (% of 0.1 nM of DHT). A "pure antagonist" was defined as having an EC 5 value greater than 10000 nM. First, we evaluated RU56187 (5) for its binding and transcriptional activities for AR in our assay systems to estimate the validity of the compound as a template (Table 1, Fig. 1). As shown in Fig. 1, it exhibited remarkable agonistic activity at concentration as low as 1 nM. Although it tended to show antagonistic activities at lower concentrations, its own agon...

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