Galeterone

TOK-001 is a multifunctional antiandrogen and CYP17 inhibitor (IC50=47 nM) in castration resistant prostate cancer (CRPC).

Galeterone is a 3-hydroxy steroid. It has a role as an androgen.|Galeterone has been used in trials studying the treatment of Prostate Cancer.|Galeterone is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling. Localized to the endoplasmic reticulum (ER), the cytochrome P450 enzyme CYP17 (P450C17 or CYP17A1) exhibits both 17alpha-hydroxylase and 17,20-lyase activities, and plays a key role in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.

The acetate 4 (1.3 g 3.02 mmol) was dissolved in methanol (20 mL) under an inert Ar atmosphere, and the resulting solution treated with 10percent methanolic KOH (8 mL). The mixture was stirred at room temperature for 1.5 h, and then concentrated under reduced pressure at approx. 40 [00151] 17-(lH-Benzimidazol-l-yl)-androsta-5, 16-dien-3-one (33): To a ice cold solution of 5 (0.05 g, 0.13 mmol) in dry DCM (3 mL) was added Dess-Martin periodinane (0.11 g, 0.26 mmol) and the mixture was stirred at ice cold temperature for 5 h. Then it was diluted with ether and was quenched with a mixture of saturated aqueous NaHC03/Na2S203 (1 :3). The organic layer was washed with brine and dried over Na2S04, then solvent was evaporated under vacuum and the crude product was purified by FCC [DCM/ethanol/TEA (30: 1 :0.05)] to give the title compound 33 (0.035 g, 70percent): mp 170-172 °C; IR (Neat) 2941, 1711, 1491, 1451, 1226, 751 cm'1; 1H NMR (500 MHz, CDCI3) delta 1.05 (s, 3 H, I8-CH3), 1.24 (s, 3 H, 19-CH3), 5.41 (t, 1 H, J = 2.5 Hz, 6-H), 5.99 (br, 1 H, 16-H), 7.30 (m, 2 H, aromatic-Hs), 7.49 (d, J = 6.9 Hz, 1 H, aromatic-H), 7.81 (m, 1 H, aromatic-H), and 7.96 (s, 1 H, 2'-H); 13C NMR (500 MHz, CDCI3) delta 209.9, 147.3, 143.5, 139.2, 134.8, 124.3, 123.5, 122.8, 122.6, 122.0, 120.5, 111.3, 56.0, 49.9, 49.7, 47.5, 37.74, 37.4, 37.0, 31.3, 31.1, 30.4, 19.3, 19.2, 16.8, 16.2. HRMS calcd 409.2250 (C26H3oON2.Na+), found 409.2258.3beta-Hydroxy-17-(lIT-benzimidazol-l-yl)androsta-5, 16-diene (5): The acetate 4 (1.3 g 3.02 mmol) was dissolved in methanol (20 mL) under an inert Ar atmosphere, and the resulting solution treated with 10percent methanolic KOH (8 mL). The mixture was stirred at room temperature for 1.5 h, and then concentrated under reduced pressure at approx. 40 0C to a volume of 10 mL. This solution was poured into ice water (300 mL), and the resulting white EPO The key intermediate in the synthesis of the 17-benzazoles, 3beta-acetoxy-17-chloro-16-formylandtrosta-5, 16-dine (2) was obtained by the routine procedure as previously described21'22 (Scheme 1). Treatment of Compound 2 with benzimidazole in the presence of K2CO3 in DMF at approx. 8O0C gave the desired 3beta-acetoxy-17-lH-benzimidazole (3) in near quantitative yield. Compound 3 was smoothly deformylated with 10percent palladium on activated charcoal in refluxing benzonitrile to give Compound 4 in 93percent yield, from which hydrolysis gave the required 3beta-hydroxy 17-benzimidazole (5). Modified Oppenauer oxidation of Compound 5 afforded the corresponding delta4-3-oxo analog (6).General procedure: [00130] General method C: Synthesis of 3/?-Hydroxy-17-(lH-heteroaryl-l-yl)- androsta-5, 16-diene (5, 16-22) and 3 ?-Hydoxy-17-(lH-benzimidazol-l-yl)-16- ((alkyl/arylamino)methyl)-androsta-5, 16-diene (25, 28 and 31): The acetate (15, 16b-22b, 24, 27, 30) (1 g) was dissolved in methanol (15 mL) under an inert Ar atmosphere, and the resulting solution was treated with 10percent methanolic KOH (5 mL). The mixture was stirred at room temperature, monitored by TLC. Reaction mixture concentrated under vacuum, ice water (100 mL) added, and the resulting white precipitate was filtered, washed with water and dried. FCC on a short silica gel column, eluting with petroleum ether/EtOAc (6:4) to obtain pure target compounds. Above listed final compounds were synthesized (using reactants, reagent and solvent ratio), isolated and purified by using this method unless otherwise stated. [00131] 3/?-Hydroxy-17-(lH-benzimidazol-l-yl)-androsta-5, 16-diene (5)24 Compound 5 prepared by following general method C, treating acetate solution of 15 (1 g 3.02 mmol) in methanol (15 mL) with 10percent methanolic KOH (5 mL) for 1.5 h. Purification by FCC over short column provided pure 5 with identical spectral and analytical data as we previously reported.In one embodiment, a solution of a compound of Formula iv in a solvent is prepared, and the solution is contacted with a base for a period of time sufficient to provide a compound of Formula v (i.e., Compound (1)). In some embodiments, the period of time is about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, or about 24 hours. In some embodiments, the time is from about 1 hour to about 24 hours. In some embodiments, the base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, a sodium phosphate, or a potassium phosphate. In some embodiments, the solvent comprises water, methanol, ethanol, 2-propanol, t-butanol, or mixtures thereof. In some embodiments, the solvent comprises methanol and the base comprises sodium methoxide. In some embodiments, the temperature is about 35 °C, about 50 °C, about 70°C, about 100 °C, or a temperature effective to sustain reflux conditions. In some embodiments, the temperature is from about 25 °C to about 100 °C. The compound of Formula v can be isolated from the reaction mixture and purified by any method known to one of skill in the art. Such methods include, but are not limited to, extraction. The isolated compound of Formula v may optionally be purified by any method known to one of skill in the art. Such methods include, but are not limited to, trituration.

Galeterone is an androgen receptor antagonist and CYP17A1 enzyme inhibitor.

Molecular Weight:388.5
XLogP3:5.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:388.251463648
Monoisotopic Mass:388.251463648
Topological Polar Surface Area:38
Heavy Atom Count:29
Complexity:743
Defined Atom Stereocenter Count:6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes