C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens, in vitro biological activities, pharmacokinetics and antitumor activity
Described are steroidal C-17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines. Methods for their synthesis are also described, which include methods having a step of nucleophilic vinylic “addition-elimination” substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene or analogs thereof and benzoazole or pyrimidinoazole nucleophiles and methods having a palladium catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3β-ol or analogs thereof with tributylstannyl diazines. The compounds are potent inhibitors of human CYP17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds are useful for the treatment of human prostate cancer.
1. A pharmaceutical composition comprising a compound of formula:
or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for oral, parenteral, enteral, intraperitoneal, topical, transdermal, ophthalmic, nasal, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, or intrathecal administration.
3. A method of treating prostate cancer comprising administering to a patient in need thereof the pharmaceutical composition of claim 1 .
4. A method of treating prostate cancer comprising administering to a patient in need thereof a compound of formula:
or a pharmaceutically acceptable salt thereof.
5. A method of reducing androgen receptor activity in a human or non-human subject, the method comprising administering to a human or non-human subject in need thereof a compound of formula:
or a pharmaceutically acceptable salt thereof,
so as to reduce androgen receptor activity in the human or non-human subject.
6. A method of inhibiting CYP17 activity in a human or non-human subject, the method comprising administering to a human or non-human subject in need thereof a compound of formula:
or a pharmaceutically acceptable salt thereof,
so as to inhibit CYP17 activity in the human or non-human subject.