Prostate cancer has become the most common cancer among men, and the second leading cause of male cancer deaths in the United States.1) Testosterone and 5a-dihydrotestosterone are androgens that are required for the development of both the normal prostate and prostate cancer.
2)Androgens act through the androgen receptor (AR), which belongs to the steroid-receptor superfamily of ligand-dependent transcription factors.3,4) Both steroidal and nonsteroidal antiandrogens are available, and these molecules are of clinical utility as chemotherapeutic agents for prostate cancer (Fig. 1). 5,6) Cyproterone acetate (CPA: 1) is a typical steroidal AR antagonist.7) It was one of the earliest of these drugs to be administered orally, but CPA shows agonistic activity and overlapping effects with other hormonal systems, leading to a range of unpleasant side effects. A number of nonsteroidal AR antagonists have been reported in the literature [8][9][10][11][12][13][14][15][16][17] and three of these, flutamide (2), [18][19][20] nilutamide (3) 21) and bicalutamide (4) [22][23][24][25] (Fig. 1), are pure antiandrogens used in the treatment of prostate cancer. 26) However, these nonsteroidal AR antagonists exhibit adverse effects such as mastodynia, gynaecomastia and hepatotoxicity [18][19][20][21][22][23][24][25] ; and therefore potent AR antagonists with fewer adverse effects are highly desirable. Moreover, flutamide therapy requires administration three times each day, and bicalutamide is taken once a day. Therefore, from a quality of life perspective, it would be desirable for new generation AR antagonists to have a longer duration of action, at least equal to that of bicalutamide.In a previous paper, 27) we reported a new series of N-arylpiperazine derivatives as potent nonsteroidal AR antagonists. Among these derivatives, YM-92088 (5) was shown to be a more potent than bicalutamide as an in vitro AR antagonist (4). However, the in vivo antiandrogenic activity of 5 was lower than that of bicalutamide. Hence, to find AR antagonists with greater oral potency, we have conducted further modification of 5, and in this paper we describe the results of our studies on the synthesis and pharmacological evaluation of a series of N-arylpiperazine-1-carboxamide derivatives as AR antagonists.
ChemistryCompounds selected for biological evaluation were prepared as described in Charts 1-4. All synthesized compounds were characterized by 1 H-NMR, mass spectrometry and elemental analysis.As shown in Chart 1, compounds 7-12 and 19 were prepared in good yields by ipso substitution of 4-fluoro-2-(trifluoromethyl)benzonitrile (6) with the corresponding cyclic amines and, in the case of compound 9, by subsequent deprotection of the Boc group. Treatment of 7-12 with 4-fluorophenyl isocyanate afforded the urea derivatives 13-18a. The amide derivative (20) was obtained from compound 19 by hydrolysis followed by conventional amidation. Compound 22 was obtained by coupling N-Boc piperidinone with 4-bromo-2-(trifluoromethyl)benzonitrile, which was prepar...