The present invention relates to progesterone receptor modulators.
Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors”. The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist.
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of ER agonists, alternatively they may be used in conjunction with PR antagonists. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
U.S. Pat. No. 6,407,101, which is hereby incorporated by reference, describes the preparation of cyclocarbamate derivatives, which are useful as progesterone receptor modulators. These cyclocarbamate derivatives, including, e.g., 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzoxazin-6-yl)-1-methyl-1H-2-cyano-pyrrole, are prepared by thionation of the corresponding benzoxazin-2-one (Scheme 1).

What is needed in the art are alternate compounds that are effective as progesterone receptor modulators.