Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-11
2004-12-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S235800, C514S252010, C514S270000, C514S272000, C514S274000, C544S123000, C544S295000, C544S299000, C544S300000, C544S301000, C544S302000, C544S304000
Reexamination Certificate
active
06833372
ABSTRACT:
TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION
This invention relates generally to compounds that affect the action of human gonadotropin-releasing hormone (GnRH). More particularly, it relates to certain non-peptide GnRH antagonists or agonists and to their preparation. These non-peptide GnRH agents have advantageous physical, chemical, and biological properties, and are useful medicaments for diseases or conditions mediated by modulation of the pituitary-gonadal axis. The invention also relates to methods for treating individuals needing therapeutic regulation of GnRH—i.e., methods for treating diseases and conditions mediated by GnRH regulation—involving the administration of such GnRH agents.
BACKGROUND OF THE INVENTION
Gonadotropin-Releasing Hormone (GnRH), also known as luteinizing hormone-releasing hormone (LH-RH), plays a central role in the biology of reproduction. Various analogs have been used for an increasing number of clinical indications. The GnRH decapeptide (pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
or p-EHWSYGLRPG-NH
2
) is produced in neurons of the medial basal hypothalamus from a larger precursor by enzymatic processing. The decapeptide is released in a pulsatile manner into the pituitary portal circulation system where GnRH interacts with high-affinity receptors (7-Transmembrane G-Protein Coupled Receptors) in the anterior pituitary gland located at the base of the brain. In the pituitary, GnRH triggers the release of two gonadotropic hormones (gonadotropins): luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In testes and ovaries, LH stimulates the production of testosterone and estradiol, respectively. FSH stimulates follicle growth in women and sperm formation in men. When correctly functioning, the pulse-timed release and concentration levels of GnRH are critical for the maintenance of gonadal steroidogenesis and for normal functions of reproduction related to growth and sexual development.
The pituitary response to GnRH varies greatly throughout life. GnRH and the, gonadotropins first appear in the fetus at about ten weeks of gestation. The sensitivity to GnRH declines, after a brief rise during the first three months after birth, until the onset of puberty. Before puberty, the FSH response to GnRH is greater than that of LH. Once puberty begins, sensitivity to GnRH increases, and pulsatile LH secretion ensues. Later in puberty and throughout the reproductive years, pulsatile release of GnRH occurs throughout the day, with LH responsiveness being greater than that of FSH. Pulsatile GnRH release results in pulsatile LH and FSH release from the pituitary and, hence, testosterone and estradiol release from the gonads. After menopause, FSH and LH-concentrations rise, and post-menopausal FSH levels are higher than those of LH.
Chronic administration of GnRH agonists and antagonists to animals or to man results in decreased circulating levels of both LH and FSH. GnRH agonists are compounds that mimic endogenous GnRH to stimulate receptors on the pituitary gland, resulting in release of LH and FSH. After a transient rise in gonadal hormone production or “flare” response, chronic administration of GnRH agonists results in a down-regulation of GnRH receptors. GnRH receptor down-regulation and desensitization of the pituitary results in a decrease of circulating levels of LH and FSH. In spite of the symptom-exacerbating hormonal flare experienced, GnRH agonists have been the treatment of choice for sex-steroid-dependent pathophysiologies. For example GnRH agonists have been used to reduce testosterone production, thereby reducing prostate volume in benign prostatic hyperplasia (BPH) and slowing tumor growth in prostate cancer. These compounds have also been used to treat breast and ovarian cancers.
Recently, GnRH antagonists have become available for clinical evaluation GnRH antagonists have an immediate effect on the pituitary without the observed flare associated with agonists. Use of GnRH antagonists (e.g., decapeptides) has been reported in the literature for treatment of breast, ovarian, and prostatic cancers. Other uses of antagonists, like agonists, include endometriosis (including endometriosis with pain), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), prostatic hypertrophy, amenorrhea (e.g., secondary amenorrhea), uterine fibroids, and precocious puberty. These agents may also be useful in the symptomatic relief of premenstrual syndrome (PMS), pregnancy regulation, infertility remedy, or menstruation regulation. Furthermore, antagonists may be useful to regulate the secretion of gonadotropins in male mammals to arrest spermatogenesis (e.g., as male contraceptives), and for treatment of male sex offenders. Importantly, GnRH antagonists (and agonists) have found utility in treatments where a reversible suppression of the pituitary-gonadal axis is desired and in the treatment of sleep disorders (e.g., apnea.)
For over fifty years, androgen deprivation has been the most effective systematic therapy for the treatment of metastatic carcinoma of the prostate. The rationale is simple—the prostate gland requires androgens for proper growth, maintenance, and function. Yet, prostate cancer and benign prostate hyperplasia are common in men and develop in an environment of continuous androgen exposure. Thus, utilizing a GnRH antagonist to interrupt the pituitary-gonadal axis reduces androgen production and results in tumor growth modulation. Furthermore, GnRH antagonists may have a direct effect on tumor growth by blocking receptors on the tumor cells. For those cancer types that respond both to sex hormones and to GnRH directly, antagonists should be effective in slowing tumor growth by these two mechanisms. Since GnRH receptors are present on many prostate and breast cancer cells, it has recently been speculated that GnRH antagonists may also be effective in treating non-hormone-dependent tumors. Recent literature examples indicate that GnRH receptors are present on a number of cancer cell lines, including:
prostate cancer: GnRH agonists exert both in vitro, and in vivo, a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines [Montagnani et al.,
Arch. Ital. Urol. Androl
., 69(4), 257-263 (1997); Jungwirth et al., “GnRH Antagonist Inhibit the Growth of Androgen-Independent PC-3 Prostate Cancer in Nude Mice,”
Prostate
, 32(3), 164-172 (1997)];
ovarian cancer: The demonstration of GnRH receptors in human ovarian cancers provides a rationale for the use of therapeutic approaches based on GnRH analogues in this malignancy [Srkalovic et al.,
Int. J. Oncol
., 12(3), 489-498 (1998)].
breast cancer: Breast cancer is the most common type of cancer in women over the age of forty and is the leading cause of cancer-related death in women. Systematic endocrine intervention represents a major treatment option for the management of advanced breast cancer, especially with estrogen-dependent cancers. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer [Kottler et al.,
Int. J. Cancer
, 71(4), 595-599 (1997)].
GnRH agents may also be useful in treating cancer through generation of thymus re-growth and therefore induction of the development of new T-cells. See Norwood Abbey press release dated Mar. 5, 2001, “Norwood Abbey Announces Breakthrough In Immunology.” These white blood cells, which develop in the thymus gland, are a fundamental component of the immune system's involvement in a range of diseases, including viral infections, transplant organ rejection, cancer, and autoimmune diseases. Thus, for example, since the human immunodeficiency virus (HIV) preferentially infects and destroys T-cells, GnRH agents may be useful for treating HIV infection or acquired immune deficiency syndrome (AIDS). Additionally, GnRH agents may be useful in combating infection in tissue-transplant patients where immunos
Anderson Mark B.
Christie Lance C.
Feng Jun
Hong Yufeng
Li Haitao
Hutchinson Keith D.
Pfizer Inc.
Raymond Richard L.
Richardson Peter C.
Zielinski Bryan C.
LandOfFree
Non-peptide GnRH agents, Pharmaceutical compositions, and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Non-peptide GnRH agents, Pharmaceutical compositions, and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Non-peptide GnRH agents, Pharmaceutical compositions, and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3307064