Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-04-17
2001-08-14
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S015800
Reexamination Certificate
active
06274573
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a therapeutic agent of uterine leiomyoma, having less adverse effects such as the reduction of bone density, wherein the agent can be used singly or can be used in combination with GnRH agonists and wherein the agent can be administered for a long term.
BACKGROUND ART
Dienogest is the International Nonproprietary Name (INN) of a known compound with the following structure (17 &agr;-cyanomethyl-17&bgr;-hydroxy-estra-4, 9(10) -dien-3-one) represented by the following formula (1).
The properties of the compound and a method for synthesizing the compound are generally described by Shubert, et al., Natural Products Chemistry 1984, Elsevier Science Publishers eds., 1985, pp.143-158.
Dienogest has been known to have progestational activity. In Germany, a combined drug of dienogest with ethinylestradiol has been introduced as an oral contraceptive into market. Additionally, the clinical development of dienogest as a therapeutic agent of endometriosis is ongoing (Kohler et al., Archives of Gynecology and Obstetrics, Vol.254, pp.594-595, 1993), and experimental reports have been issued to demonstrate the carcinostatic action of dienogest on uterine cancer and breast cancer (Katsuki et al., Japanese Patent Laid-open No. Hei 7-188026; Katsuki, et al., Cancer, Vol.79, pp.169-176, 1997). However, no report has been published yet to indicate the therapeutic effectivity of dienogest on uterine leiomyoma.
It is said that uterine leiomyoma is present in 20 to 40% of females above 30 years old, and uterine leiomyoma is one of diseases found the most frequently in the field of obstetrics and gynecology. Uterine leiomyoma is clearly different from endometriosis and uterine cancer in view of that uterine leiomyoma is a benign tumor of smooth muscle. Uterine leiomyoma develops mainly during reproductive ages and stops its growth or reduces its tumor size after menopause or castration. And, a hormone therapy with gonadotropin releasing hormone (GnRH) agonists typically including buserelin acetate has been indicated widely to treat uterine leiomyoma.
Although GnRH agonists have therapeutic effects on uterine leiomyoma, the decrease of bone minerals as well as adverse effects such as climacteric disorders occur at a high frequency, because of the reduction of blood estrogen level due to the main action mechanism of the agents. Because of these risks, the period of dosing GnRH agonists is generally limited not to exceed 6 months.
Moreover, a rebound phenomenon has been known that the uterine leiomyoma will restore the size before the therapy if the administration of GnRH agonists is discontinued (Freidman et al., Fertility and Sterility, Vol.49, pp.404-409, 1988).
In order to treat concomitant symptoms of uterine leiomyoma, an attempt was made in the past to use progestins typically including medroxyprogesterone acetate. However, the ability of progestins when administered singly for the treatment of uterine leiomyoma is now doubtful. When a progestin agent was administered to a patient with uterine leiomyoma, for example, the increase in number of mitotic cells in uterine leiomyoma tissues was observed (Kawaguchi et al., American Journal of Obstetrics and Gynecology, Vol.160, pp.637-641, 1988; Fujii et al., Molecule & Cell Biology, pp.46-57, 1997). It is suggested that progesterone has an critical role in the pathogenesis of uterine leiomyoma, on the basis of the findings that oral contraceptives cause the increase in the size of uterine leiomyoma and that uterine leiomyoma increases its size during pregnancy, i.e., a state of a high progesterone level in blood.
For the purpose of preventing the adverse effects of GnRH agonists as described above, a number of sex hormonal agents have been tried and used in combination. However, estrogenic agents are not appropriate because of their risks due to the direct stimulating action on leiomyoma tissues. In addition, there are number of reports showing that the attempts to use a GnRH agonist plus medroxyprogesterone (MPA) in combination were effective to reduce the adverse effects of the GnRH agonist such as hot flush and bone mineral loss, but that such trials often resulted in the enlargement of the size of leiomyoma lesion in compared to that of the treatment with the GnRH agonist alone. In other words, it is said that progestins contradict the therapeutic effect of GnRH agonists on uterine leiomyoma (Freidman et al., supra.; Carr et al., Journal of Clinical Endocrinology Metabolism, Vol.76, pp.1217-1223, 1993; Rein et al., American Journal of Obstetrics and Gynecology, Vol.172, pp.14-18, 1995).
Furthermore, it has been reported that the administration of RU-486, an anti-progestin could reduce the volume of uterine leiomyoma and the agent was therefore effective (Murphy et al., Journal of Clinical Endocrinology, Vol.76, pp.513-517, 1993; Yen et al., U.S. Pat. No. 5,468,741), so that the development of a therapeutic agent of uterine leiomyoma on the concept of anti-progestin is now under way (Murphy et al., supra; Hodogen et al., Published Japanese translation of PCT international publication for patent application No. Hei 9-508418). In recent years, accordingly, it is believed that progestins serve as a growth promoting factor for uterine leiomyoma (Rein et al., supra; Fujii et al., supra) and that the agents work adversely in the medical treatment of uterine leiomyoma. In these circumstances, dienogest has not been applied to treat uterine leiomyoma.
DISCLOSURE OF THE INVENTION
As has been described above, GnRH agonists are widely used currently for the treatment of uterine leiomyoma, but because of higher frequencies of the occurrence of adverse effects such as bone resorption action or climacteric disorders, the dosing period of the agonists is limited. Additionally, the rebound phenomenon after the stopping of the dosing is a serious problem. Hence, the development of a therapeutic agent with no such adverse effect or no such problem is demanded. Furthermore, the development of a novel pharmaceutical agent has also been desired, which never eliminates the therapeutic effect of GnRH agonists on uterine leiomyoma even if used as an agent in combination with GnRH agonists or never cause a regrowth of the uterine leiomyoma after the treatment with the GnRH agonists and at least reduces the adverse effects of the GnRH agonists. The present invention can overcome at least one of these problems.
In the circumstances mentioned above, the present inventors have made investigations to search an agent effective for uterine leiomyoma and simultaneously with less adverse effects or problems of the GnRH agonists. Quite unexpectedly, the inventors have found that dienogest has an ability to fulfill those requirements.
Dienogest has an action to reduce the volume of human uterine leiomyoma tissues. Still further, dienogest generally never affects the level of bone minerals, unlike GnRH agonists and the rebound phenomenon after the stopping of the dosing is remarkably prohibited. Based on these findings, the inventors have continued their investigations. Consequently, the invention has been achieved.
Dienogest as the effective ingredient of the therapeutic agent of uterine leiomyoma in accordance with the present invention is a compound with a structure represented by the formula (I) as described above and can form a solvate with various solvents pharmaceutically acceptable, such as water, ethanol, glycerol and acetic acid.
A first aspect of the present invention is a therapeutic agent of uterine leiomyoma, containing dienogest or a solvate thereof as the effective ingredient. Furthermore, it is a therapeutic agent of uterine leiomyoma that contains dienogest or a solvate thereof as the effective ingredient and by which the rebound phenomenon after the stopping of the dosing is prohibited.
A second aspect of the present invention is a therapeutic agent of uterine leiomyoma, for use in combination with other therapeutic agents of uterine leiomyoma. Other therapeutic agents in combination with the therapeutic agent of uter
Katsuki Yukio
Shimora Minoru
Birch & Stewart Kolasch & Birch, LLP
Mochida Pharmaceutical Co. Ltd.
Patten Patricia D
Weber Jon P.
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