cisapride Thus one possible target for CRPC treatment

Thus one possible target for CRPC treatment is the enzyme 17,20-lyase, which plays a crucial role in androgen biosynthesis. This is because inhibition of 17,20-lyase would be expected to decrease serum androgen levels secreted not only by the testes but also by the adrenal glands.7, 8, 9 In recent years, several groups have reported the development of steroidal and non-steroidal inhibitors of 17,20-lyase,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 such as YM-116 and abiraterone acetate, which have been evaluated in clinical studies, and we have also disclosed the design of 17,20-lyase inhibitors such as compounds 1a and 1b (Kaku et al., manuscript in preparation), as shown in Figure 1. We have previously reported that the introduction of a small alkoxy group such as methoxy or ethoxy group at the 6-position of the naphthalene ring of these compounds slightly increased 17,20-lyase inhibition. Moreover, docking studies of 1a using a homology model for human 17,20-lyase suggested that the methoxy group at the 6-position on the naphthalene ring might form a hydrogen bond with threonine 101 (Thr101) in the active site of the enzyme. Unfortunately, cisapride 1a was found to also be a potent inhibitor of CYP3A4, with an IC50 value of less than 1000nM, as shown in Table 1. Therefore, we continued further modification of this series of compounds, aiming to improve the selectivity for 17,20-lyase over CYP3A4. In this report, we discuss the synthesis and structure–activity relationships (SAR) of novel naphthylmethylimidazole derivatives and related compounds as 17,20-lyase inhibitors. Additionally, asymmetric synthesis of the selected compound using the chiral α-hydroxy ketone was achieved and is described in detail.
Chemistry The synthesis of ketone 6 is outlined in Scheme 1. As reported previously, conversion of 6-bromo-2-naphthol to dibromide 2 was achieved by treatment with triphenylphosphine (PPh3) and bromine at 70–300°C. Treating dibromide 2 with a sub-stoichiometric amount of n-butyllithium (n-BuLi) in tetrahydrofuran (THF) followed by the addition of ketone 3, gave bromide 4 in high yield. Sequential treatment of bromide 4 with n-BuLi generated the lithium dianion, to which Weinreb’s amide was added at −78°C to give a moderate yield of ketone 5. Finally, removal of the trityl group with pyridine hydrochloride in methanol (MeOH) provided the targeted ketone 6. The syntheses of 10a and 10b are shown in Scheme 2. Conversion of bromide 4 into 7 was performed by Buchwald’s method using tris(dibenzylideneactone)dipalladium (Pd2(dba)2), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), sodium tert-butoxide (tert-BuONa) and benzophenonimine, to provide good yields of 7. The resulting imine 7 was deprotected to give 8, which was then treated with acetic anhydride or phenyl chloroformate, followed by methylamine hydrochloride to yield 9a and 9b, respectively. Subsequent deprotections of 9a and 9b were performed by treatment with pyridine hydrochloride to give 10a and 10b, respectively. The syntheses of the trisubstituted naphthalene derivatives 11b–d are shown in Scheme 3. 6-Bromo-2-naphthol was chlorinated at the 1-position with sulfuryl chloride to give a moderate yield of 11b. After Wolff–Kishner reduction of 1-formyl-2-naphthol, 12 was treated with bromine to give 6-brominated 11c in high yield. Trimethoxyborane-catalyzed reduction of 13 with lithium borohydride gave alcohol 14. The alcohol 14 was successively oxidized with manganese dioxide (MnO2) to produce 15 in high yield (in two steps). After Wolff–Kishner reduction of the aldehyde 15, conversion of the methoxy group of 16 with BBr3 was carried out to give a high yield of phenol 11d. The syntheses of 22 and 24a–24h are shown in Scheme 4. Phenols 11a–d were protected with tert-butyldimethylsilyl chloride (TBSCl), the resulting silyl ethers were treated with n-BuLi at −78°C, followed by addition of ketone 3 to produce excellent yields of 18a–d, respectively. Removal of the tert-butyldimethylsilyl (TBS) group with tetrabutylammonium fluoride (TBAF) provided phenols 19a–d, which were allowed to react with trifluoromethansulfonic anhydride (Tf2O) to give 20a–d, respectively. Methoxycarbonylation of 20a–d using palladium(II) acetate (Pd(OAc)2) and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in MeOH and N,N-dimethylformamide (DMF) under CO atmosphere gave the corresponding esters, which underwent hydrolysis, followed by treatment with diphenylphosphoryl azide (DPPA) and ammonium bicarbonate or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI·HCl) and alkylamine to provide carbamoyl derivatives 23a–h in good yield. Deprotections of 21a and 23a–h were performed according to a similar method as described for 6 to give the desired compounds 22 and 24a–h, respectively.