1. Field of Invention
The present invention relates to compounds as a progesterone receptor binding inhibotor and pharmaceutical compositions containing the same.
2. Background Art
In recent years, even in Japan, the number of patients suffering from breast cancer has increased, and it is foreseen that the number of the patients suffering from breast cancer would become largest among the malignant tumors in women in the 21st century. Ovariectomy has for the first time been used as endocrinotherapy for breast cancer. Thereafter, adrenalectomy and hypophysectomy have been reported to be useful as therapy for breast cancer in progress, and, since then, surgical endocrinotherapy has been mainly used and made progress. In the surgical endocrinotherapy, an organ involved in the secretion of estrogen is removed to regress estrogen dependent breast cancer. This, however, results in loss of not only estrogen but also life-sustaining hormones, including steroid hormones, posing many problems associated with the quality of life.
Non-steroidal anti-estrogen agents typified by Tamoxifen Citrate which appeared in the latter half of 1970s have extensively used clinically by virtue of high effect against breast cancer and much lower side effect than conventional androgen and estrogen. Then, they have replaced the surgical endocrinotherapy used as main therapy for breast cancer.
More recently, agents having a new mechanism of action, such as medroxyprogesterone acetate (MPA) ("NYUGAN NO RINSHO", vol. 1, 201-213 (1986)), aromatase inhibitor, luteinizing hormone-releasing hormone (LH-RH) agonist ("GAN TO KAGAKU RYOHO", 16, 2729 (1994)) have been developed, resulting in diversified endocrinotherapy for breast cancer.
Further, in recent years, the treatment of breast cancer with an antiprogesterone agent based on progesterone receptor has been actively attempted. For example, Mifepristone (RU38486) (Cancer Res.), 49, 2851-2856, 1989, Onapristone (ZK98299) (J. Steroid Biochem. Molecu. Biol., 41, 339-348, 1992) and the like are under development. These novel types of agents as a progesterone receptor binding inhibotor are expected to be useful for the treatment of not only breast cancer but also for endometriosis, hysteromyoma, meningioma and the like. Further, side effects, attributable to weak estrogenagonist action which are developed by prolonged administration of Tamoxifen Citrate, such as endometrioma, thrombosis, and hepatoma, and, in addition, cancer resistant to Tamoxifen Citrate, have been reported as a new problem. Since antiprogesterone agents are different from Tamoxifen Citrate in mechanism of action, they are expected as novel therapeutic agents which can avoid the above problems.
However, all of them have a steroidal skeleton. Thus, they have been pointed out to have side effect characteristic of steroid. Therefore, in order to overcome these problems, an agent having progesterone receptor binding inhibitory activity without the steroid skeleton has been desired in the art.
Some of the present inventors have previously succeeded in isolation of substance PF1092, which, despite a non-steroid skeleton, is a inhibitor against binding of progesterone to progesterone receptor, from a cultured mixture of a strain belonging to the genus Penicillium (Japanese Patent Laid-Open No. 253467/1996 and EP722940A, which are incorporated herein by reference).
The substance PF1092 is a ligularenolide type sesquiterpene having in its molecule an enol lactone ring structure. Many sesquiterpenes each having in its molecule an oxygen atom derived from a lactone ring structure or a furan ring structure are known in the art.
To the best of the present inventors' knowledge, no ligularenolide type skeleton containing a hetero atom, other than an oxygen atom, independently of natural and non-natural types are known in the art.
USPTO Backgrounds
USPTO Backgrounds