Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-02-27
2004-09-21
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S718000, C560S231000, C568S663000, C568S715000, C552S626000
Reexamination Certificate
active
06794409
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the use of a new principle for
(a) improving pregnancy potential with ER&bgr;-agonists in connection with in vivo treatment and in connection with in vitro fertilisation (IVF) and embryo transfer treatment and
(b) inhibiting pregnancy potential with ER&bgr;-antagonists.
More specificially, the application relates to
(a) improvement of pregnancy potential of oocytes and preimplantational embryos by improvement and stimulation of ovarian folliculogenesis and
(b) inhibition of pregnancy potential by inhibiting folliculogenesis, ovulation and preimplantational development of ovulated oocytes.
This present invention relates further to new compounds as pharmaceutical active ingredients, which have in vitro a higher affinity to estrogen receptor preparations of rat prostates than to estrogen receptor preparations of rat uteri and exert a contraceptive action in vivo by their preferential action on the ovary, to their production, their therapeutic application and pharmaceutical forms for dispensing that contain the new compounds.
The chemical compounds are novel, steroidal, tissue-selective antiestrogens.
BACKGROUND OF THE INVENTION
Follicular growth refers to the development of an ovarian follicle from the primordial to antral follicle. Patients suffering from ovarian infertility, e.g. polycystic ovarian syndrom patients, have a disordered folliculogenesis and the numbers of primary and secondary follicles are about twice those observed in the normal ovary (Hughesden (1982), Obstet Gynecol Survey 37:59-77). Therefore, it may be concluded that follicular growth is often impaired in infertility patients.
There is evidence that most, if not all, of the steps from primordial to early antral follicles are gonadotropin-independent but it is not yet clear which of the many candidates among the paracrine and autocrine factors which have been identified in preantral follicles are the most important for early follicular growth (Elvin et al. (1999), Mol Cell Endocrinol 13:1035-1048; McNatty et al. (1999), J Reprod Fertil Suppl 54:3-16). Gonadotropins are mainly involved for the late steps of folliculogenesis, e.g. the transition from an early antral follicle to an ovulatory follicle.
Couples seeking infertility treatment will often be subject to different in vivo and in vitro treatment regimes. In vitro and vivo infertility (IVF) treatment regimens often consists of ovulation induction by pretreatment with exogenous gonadotrophins, mainly follicle stimulating hormone (FSH) and antiestrogens (White et al. (1996), J Clin Endocrinol Metab 81:3821-3824). The in vitro treatment protocol then involves retrieving the oocytes from the preovulatory, antral follicles of the ovaries in order to be matured and/or fertilised in vitro. After fertilisation and preimplantational embryo development, one to three embryos are retransfered in the woman's uterus in order to get a successful pregnancy. IVF is now an established treatment, which has been performed on a large scale for more than 20 years.
The protocols used for administration of exogenous gonadotropins are numerous and not without risks and disadvantages. The major disadvantages includes the risk of achieving ovarian hyperstimulation syndrome (OHSS) which in severe cases may be life threatening, the economic costs to the couple, side effects from the gonadotropin preparations including weight gain, bloating, nausea, vomiting, and the unknown long-term cancer risk.
One way to alleviate the risks, side effects, and economic disadvantages of controlled ovarian stimulation protocols would be to properly mature and stimulate follicular growth of ovarian infertility patients in vivo with a suitable agent before exogenous gonadotropin treatment starts. This approach would imply that the women are without gonadotropin stimulation or receive a minimal exogenous gonadotropin stimulation.
On the other hand contraceptive methods involving the administration of chemical substances are widely practiced among women who desire to limit pregnancies. Among the presently used chemical methods of fertility control, the most important are those which act by means of the following:
(a) suppression of ovulation through inhibition of gonadotropin release (inhibition of the endocrine principle),
(b) alteration of the female reproductive tract to prevent migration of sperm to the site of fertilisation,
(c) blocking the implantation of the zygote (nidation),
(d) spermicidal action or
(e) an abortifacient.
The oral contraceptives, consisting of an estrogen combined with a progestin or a progestin alone, are the most prominent chemical contraceptive agents. The contraceptives of the combined type act primarily by suppressing ovulation by negative feedback to prevent gonadotropin release by the pituitary. Although the oral contraceptives are highly effective, their use is associated with unpleasant side effects, such as nausea, depression, weight gain and headache, and an increased long-time risk of severe disease, such as thromboembolism, stroke, hepatic adenoma, gall bladder disease, hypertension and bleeding irregularities, indicating that an effective contraceptive principle without sides effects is presently not available. Therefore a need exists in medicine for new contraceptive methods.
An ideal contraceptive compound acting on the ovarian follicle would be an agent that does not modify the endocrine pituitary—ovarian communication system but selectively interrupt folliculogenesis, e.g. the paracrine interplay between the granulosa cell and the oocyte, leading
(a) to an impairment of the follicular programm and an ovulated oocyte that is uncapable to get fertilised or
(b) to an impairment of the follicular programm and an inhibition of ovulation,
Follicular growth is the development of an ovarian follicle from the primordial stage to the large antral follicle that is ready to burst. Only an optimally built-up antral follicle has the potential to ovulate a mature egg cell. Patients with ovarian infertility, e.g., PCOS (=polycystic ovarian syndrome) patients, have a disrupted folliculogenesis associated with hormonal and ovulation disorders as well as insufficiently matured egg cells (Franks et al. (2000) Mol Cell Endocrinol 163:49-52).
There are always more indications that the early stages of folliculogenesis, i.e., the development steps from the primordial follicle to the early antral follicle, are gonadotrophin-independent, but it is still not conclusively explained which of the identified autocrine or paracrine factors (Elvin et al. (1999). Mol Cell Endocrinol 13:1035-1048; McNatty et al. (1999), J Reprod Fertil Suppl 54; 3-16) are the most important in early folliculogenesis. Gonadotrophins, such as, e.g., FSH (follicle-stimulating hormone), however, are mainly involved in the late steps of folliculogenesis, i.e., the development from the early antral follicle to the large ovulatory follicle. Additional modulators of folliculogenesis are also discussed in the late folliculogenesis, however (Elvin et al. (1999), Mol Cell Endocrinol 13:1035-1048).
Until recently, only a single type of estrogen receptor (ER) has thought to exist and mediate the genomic effects of 17&bgr;-estradiol in mammalian tissues. However, the cloning of a gene encoding a second type of ER, termed ER&bgr; has prompted a reevaluation of estrogen actions (Kuiper et al (1996), Proc Natl Acad Sci 93:5925-5930). Whereas transcripts encoding the classical ER (now referred to as ER&agr;) are detected in nearly all tissues assayed from both sexes in animal models, the highest expression of ER&bgr; mRNA can be observed in the ovary (Couse et al. (1997), Endocrinology 138:4613-4612). Because ER&agr; and ER&bgr; have different tissue distributions, especially regarding the ovary, differences in ligand interaction or activity with the two ERs could translate into important differences in their biological actions at the tissue level. After the successful generation of ER&agr; and ER&bgr; knockout mice (Couse et al. (1999), Endocrine Reviews 20:358-41
Fritzemeier Karl-Heinrich
Hegele-Hartung Christa
Kosemund Dirk
Mueller Gerd
Peters Olaf
Badio Barbara P.
Millen White Zelano & Branigan P.C.
Schering AG
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