Leiomyomas are the most common non-cancerous tumor in women of childbearing age. Uterine leiomyomas (or fibroids) are considered to be benign tumors of muscle and connective tissue that develop within or are attached to, the uterine wall. It is estimated from ultrasound examination that over 70% of women will develop fibroids by the time they reach menopause. (Baird et al., Am J. Obstet. Gynecol. 2005; 188: 100-107; and Cramer et al. Am. J. Clin Pathol. 1990; 90: 435-438.) While not all women are symptomatic to warrant therapy, a significant number of women experience moderate to severe symptoms including abnormal uterine bleeding, pelvic pressure and pain, and reproductive dysfunction.
Current treatment therapies include surgical intervention, such as, hysterectomies and myomectomies. Less invasive procedures include: uterine artery embolization and thermoablative coagulation. Medical therapies include hormone treatment. Currently the only FDA approved hormone treatment is the use of a GnRH (gonadotropin-releasing hormone) agonist preoperatively with iron. (Walker and Stewart, Science, 2005; 308; 1589-1592.) The GnRH agonist therapy is often limited to 1-3 months because of measurable bone loss which leads to osteoporosis with long term use. Further, the GnRH agonist treated myomas often return to pre-treatment size within weeks of therapy cessation. Consequently, this treatment is often used to reduce the size of the myoma and allow the woman to prepare for its eventual surgical removal. (Stewart, Lancet, 2001; 357; 293-298.)
These options have undesirable consequences for women who wish to conceive at a later time. Obviously, a hysterectomy would prohibit subsequent conception, and the other surgical options also present risks, including uterine rupture and recurrent fibroids. Medical treatment can also cause significant side effects. For example, GnRH agonists produce an environment in the body that is very similar to that of menopause, with associated side effects like hot Rashes, vaginal dryness, and, as noted above, loss of bone density. These and other problems highlight the continuing need to treat and ameliorate the gynecological disorders such as myomas in general, more specifically but not exclusively, leiomyomas, and endometriosis, and their attendant symptoms.
As further background, the following references describe indole or indoline structures and their therapeutic use.
Merce et al. in WO 2005/013976 disclose indole-6 sulfonamide derivatives of the following formula substituted as described therein:
which are stated to be useful as 5-HT-6 modulators.
Hsieh et al. in U.S. Pat. No. 6,933,316 disclose indole compounds of the formula below and substituted as described therein:
which are stated to exhibit anti-cancer activities and function by targeting microtubule polymerization/depolymerization.
The above references either do not described efficacious treatment of abnormal tissue growth or compounds useful as progesterone receptor ligands. Further, the described compounds exhibit one or more undesirable characteristics including low bioavailability, low progesterone binding affinity, non specific binding to hormone receptors in general, i.e., absence of progesterone receptor (PR) specific binding, and no or low efficacious treatment of tumors, in general, and more specifically no or low efficacious treatment of myomas, leiomyomas, and endometriosis. Consequently, a significant need remains for effective compounds and treatment method(s) for tumors, gynecological disorders, and related sequelae. The present invention addresses these needs.