Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2002-08-13
2003-12-30
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C514S177000, C514S179000
Reexamination Certificate
active
06670493
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the use of glucocorticoid receptor antagonists for the prevention and treatment of diseases of the male reproductive system, as well as to glucocorticoid receptor antagonists, which are particularly suitable for this purpose.
It is well known that physical and/or mental stress, age as well as exogenous factors, such as drugs and excessive consumption of alcohol, can lead to sexual dysfunctions and hypogonadism in men. According to presently existing understanding, these diseases are caused by a decreased androgen production, especially by a decreased testosterone production.
Various attempts were made to treat the above diseases. However, the drugs used either were not sufficiently effective or showed serious side effects, which harmed the patients more than they healed them or were not suitable for other reasons.
There is therefore an appreciable demand for new compounds to prevent and/or treat the diseases above.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to be able to prevent and treat the symptoms, caused by a decreased androgen production. It is furthermore an object of the present invention to make available compounds, which can be used advantageously for the treatment and/or prevention of diseases, which are caused by a decreased androgen production.
Pursuant to the invention, the aforementioned objective is accomplished by the use of glucocorticoid receptor antagonists. Within the meaning of the present invention, glucocorticoid receptor antagonists are understood to be drugs, which inhibit the action of glucocorticoids by binding to glucocorticoid receptors.
The present invention is based on the surprising realization that, when glucocorticoid receptor antagonists are administered, the androgen production, which previously was decreased by the excess of glucocorticoid, is increased.
If for example Leydig cells (cells from the testes, which produce male sex hormones) are stimulated with human chorion gonadotropin (hCG), there is an increase in testosterone production due to these cells. If now the cells are incubated with hCG and a glucocorticoid, such as dexamethasone (a ligand for the glucocorticoid receptor (GR)), a significant decrease in testosterone production can be observed. It has now been found that the decrease in testosterone production is prevented by the glucocorticoid, if the latter is administered together with a glucocorticoid receptor antagonists in such an experiment. This effect was observed not only in cells, but also in experimental animals.
In experimental animals, stress or an increased glucocorticoid blood level cause an inhibition of the secretory activity of the endocrine system of the male gonads, which is documented by a decreased serum testosterone level. At the same time, an inhibition of (decrease in) male sexual activity is observed. These symptoms are characteristic, for instance, of hypogonadism and are observed in other syndromes, such as stress and, in particular, chronic stress.
Glucocorticoid receptor antagonists, which may be natural or synthetic compounds, occupy the glucocorticoid receptor and, in doing so, displace the natural (endogenous) ligand of the glucocorticoid receptor, the glucocorticoids, so that, by a selective antagonization of the glucocorticoid receptor, the transfer of chemical signals over this receptor, at the very least, is reduced, but may even also be prevented almost completely. By the displacement of the glucocorticoids by glucocorticoid receptor antagonists, the excessive occupation of glucocorticoid receptors by glucocorticoids is antagonized.
This reduction in or prevention of the occupation of the glucocorticoid receptors by glucocorticoids may be desirable especially if the glucocorticoid level in the body is increased. Such an increase can be caused, for example, by (i) physical or mental stress, (ii) a pathological increase in the secretory activity of the adrenal cortex, (iii) alcohol and drug misuse and withdrawal, (iv) exogenous administration of medicinal drugs, such as cortisol, for the treatment of chronic diseases and (v) aging.
If the realizations and experimental results, described above, are combined, they lead to the assumption, without being definitive, that the excessive secretion of glucocorticoids results in an excessive occupation of glucocorticoid receptors in endocrine cells of the male gonad and/or in the relevant regions of the central nervous system. This can cause disorders of the male reproductive system due to a decrease in the production of male sex hormones (androgens, especially testosterone), an impairment of the responsiveness of the endocrine system of the male gonads for the stimulating effect of gonadotropin, an impairment of the neuronal responsiveness to sexual stimuli and, consequently, an erectile dysfunction. These symptoms are described generally by the expression “hypogonadism in males”, which includes a plurality of somatic and endocrine dysfunctions. In the sense of the present invention, “hypogonadism” does not include the consequences of the surgical removal (gonadectomy) or of the congenital defects (agenesia) of the male gonads.
Especially the hypogonadism in males, especially the hypogonadotropic hypogonadism, sexual dysfunctions in males and infertility can be treated and/or prevented particularly well by administering glucocorticoid receptor antagonists, the excessive occupation of the glucocorticoid receptors by glucocorticoid receptor antagonists in the organism, especially in the organs responsible for reproduction and/or in neuronal circuits, which are responsible for its control, being reduced or prevented.
There are two mechanisms, by means of which the interaction between glucocorticoids and glucocorticoid receptors can proceed. The type 1 mechanism is distinguished by an interaction between the glucocorticoid receptor and special DNA sequences. On the other hand, the interaction between glucocorticoid receptors and other transcription factors, in the absence of specific DNA binding, participates possibly over a direct protein—protein intraction in the type 2 mechanism.
In a preferred embodiment, the glucocorticoid receptor antagonist, which is used pursuant to the invention, antagonizes the type I transcription induction of the glucocorticoid receptor gene. A particularly good therapeutic effect is noted in the treatment of the aforementioned diseases when glucocorticoid receptor antagonists are used. It is well known that glucocorticoid play an important role in the immune system. Since the glucocorticoid-induced immune suppression takes place exclusively by the type 2 mechanism of the glucocorticoid receptor action, glucocorticoid receptor antagonists are preferred, which antagonize the type 1 transcription induction of the glucocorticoid receptor gene, since by these means no negative effects on the immune system can be detected.
In a preferred embodiment, the glucocorticoid receptor essentially does not antagonize the type 2 transcription inhibition. When glucocorticoid receptor antagonists with this property were used pursuant to the invention, it was not possible to detect any side effects, especially side effects on the immune system. In this connection, the expression “essentially does not antagonize” means that possible antagonizing can be detected only insofar as non-physiological or pathological effects were not observed.
Preferably, the glucocorticoid receptor antagonist employed for the inventive use, essentially do not bind to other steroid receptors. In this connection, the expression “essentially do not bind” means that only sufficient glucocorticoid receptor antagonist binds to other steroid receptors as glucocorticoid receptors, so that no effects, brought about by the other receptors, can be noted or existing physiological effects are eliminated. Examples of other steroid receptors are the mineral corticoid receptors, estrogen, progesterone receptors and androgen receptors. Due to this high selectivity of the glucocorticoid receptor antago
Patchev Vladimir
Schubert Gerd
Sobek Lothar
Jenapharm GmbH & Co. KG
Kumar Shailendra
LandOfFree
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