Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-08-22
2002-04-02
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S173000, C540S029000, C552S553000, C552S595000, C552S610000
Reexamination Certificate
active
06365582
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new thiol esters of S-substituted 11&bgr;-benzaldoxime-estra-4,9-diene-carboxylic acid of the general formula I
and to their pharmaceutically acceptable salts, to a method for their synthesis and to pharmaceutical preparations containing these compounds.
2. Description of the Related Art
The EP-A-0 648 778 and the EP-A-0 648 779 disclose esters, carboxylate esters and urethanes of 11&bgr;-benzaldoxime-estra-4,9-dienes. The compounds described therein have anti-progestational activity.
Anti-progestogens are steroids which, like progesterone and other progestational substances, have a high affinity for the progesterone receptor. However, they are different from these in that they do not lead to the typical physiological effects, which are brought about by the progesterone receptor. Instead, progesterone is displaced from its bonding to the receptor and its activity is inhibited. From the scientific literature, it is known that, aside from the displacement of progesterone from its binding site, malfunctions of the gene-regulatory receptor function play a decisive role here.
(Klein-Hitpass, L., Cato, A. C. B, Henderson, D., Ryffel, U.: Nucleic Acid Res. 19 (1991), 1227-1234; Horwitz, K. B.: Endocrine Rev. 13 (1992) 146); McDonnell D. P.: Trends Endocrinol. Metab. 6 (1995) 133-138).
With respect to the last-mentioned aspect, known antagonists, for example ZK 98299=onapristone (DE-A-35 04 421) and RU 486=mifepristone (EP-A-0 057 115) differ at the molecular level (type I/type II antagonists) and indeed in that in the case of type I antagonists (e.g. onapristone), the hormone receptor complex no longer binds to the hormone-responsible elements or binds in a labile manner, whereas with type II (e.g. Ru 486) this is still the case (Klein-Hitpass et al.). Antigestagens which still allow receptor binding to DNA can have progesterone-like actions, while in the case of disturbance of the DNA binding of the receptor this is not possible.
Modulation of gene-regulatory activity of individual progesterone antagonists can also take place by mechanisms which initially start from the receptor protein. Various studies have demonstrated that the gene-regulatory activity of antagonist-receptor complexes is stimulated by cyclic AMP. In the presence of high concentrations of c-AMP in the tissue, activation of the antagonist-receptor complexes manifests itself; at low concentrations the receptor remains inhibited with respect to gene-regulatory activity. The occurrence of corresponding phenomena is apparently also substance-specific. The production of high c-AMP concentrations (in vitro) leads to partial agonistic action in some antigestagens; in other substances corresponding effects are, however, not caused by c-AMP (Sartorius, C A., Tung, L., Takmoto, G S., Horwitz, K B.: J Biol. Chem 268 (1993) 9262-9266; Sobek, L., Kaufmann, G., Schubert, G., and Oettel, M., 79th Annual Meeting of the Endocrine Society 1997, 3-452, 549).
Differences at the molecular level are also expressed in the pharmacodynamic behavior of progesterone antagonists. This can be demonstrated in the very different pharmacodynamic behavior of substances which are very well characterized in vivo and in vitro, such as onapristone and mifepristone (RU 486) [Elger, W., W., Neff, G., Beier, S., Fähnrich, M., Grundel, M. et al. in Current Concepts in Fertility Regulation and Reproduction, ed. Puri, C. P. and Van Look, P. F. H. (1994) 303-328.
Progesterone plays a crucial role in the control of the organ systems involved in reproductive processes. This applies to the morphological metaplastic processes in the genital tract and in the mammary gland, the regulation of hormones of the anterior pituitary lobe and of the genital organs or the inhibition and activation of parturition. These functions react with different sensitivity to progesterone. Processes which take place at very low progesterone levels deserve particular consideration with respect to the pharmacology of the antigestagens. “Pure” progesterone antagonists of type I can bring about effects which can be achieved with no [sic] dose using partial agonistic antagonists. This generally ought to be the case when the threshold for the respective effect is low, that is below the partial agonistic activity of a progesterone antagonist. Conversely, there is the possibility that under the influence of progesterone antagonists of type II, effects are observed which are caused not by the inhibition, but by the activation of the progesterone receptor. At an identical dose of this antagonist, the functions of progesterone are inhabited which proceed at high tissue concentrations.
An example of the first-mentioned case is the prostaglandin secretion of the uterus in the guinea pig during its menstrual cycle. This is stimulated toward the end of the cycle by very low progesterone levels. Only pure progesterone antagonists of type I are able to inhibit the progesterone secretion of the uterus in guinea pigs to such an extent that the reformation of the corpus luteum is completely inhibited (Elger, W., Neef, G., Beier, S., Fähnrich, M., Grundel, M., et al. in Current Concepts in fertility Regulation and Reproduction, ed. Puri, C. P. and Van Look, P. F. H. 1994 303-328). Partial agonistic substances inhibits this process little or not at all.
In the human, the progesterone antagonist RU 486 has various effects on reproductive functions which are relevant to use in therapy. This substance inhibits the action of progesterone to such an extent that when used during pregnancy the induction of an abortion occurs. This abortion- or labor-inducing property is considerably increased by simultaneous or sequential treatment with a prostaglandin (Van Look, P. F. A.; Bygdeman, M.: Oxf. Rev. Reprod. Biol. 11 (1989), 1-60; Elger, W., Neef, G., Beier, S., Fähnrich, M., Grundel, M. et al. In Current Concepts in Fertility Regulation and Reproduction, ed. Puri, C. P. and Van Look, P. F. H. 1994 303-328). Corresponding effects can be adequately explained on the basis of the pregnancy-regulating function of progesterone in pregnancy.
In addition, RU 486 and other antigestagens have effects in which the mechanism of the withdrawal of progesterone is not so clearly confirmed. This relates primarily to effects in the menstrual cycle in phases in which the progesterone levels in the blood are very low. Here, two phenomena are to be mentioned in particular, the inhibition of ovulation (Croxatto, H. B., Salvatierra; A. M.; Croxatto, H. D.; Fuentealba, A.: Hum. Reprod. 8 (1993), 201-207) and the inhibition of the estrogen-induced proliferation of the genital epithelia, in particular those of the endometrium (Wolf, J. P., Hsiu, J. G., Anderson, T. L., Ulmann, A., Baulieeu, E. E. and Hodgen, G. D.: Fertility & Sterility 52 (1989) 1055-1060). Corresponding effects are of central importance for the use of the antigestagens, in particular for antiovulatory strategies in fertility control, the reversible induction of amenorrhea, for example in the therapy of endometriosis and for the suppression of undesired estrogenic effects in the endometrium in the course of a substitution therapy with estrogens in the menopause. The coupling of the abortive and labor-inducing action with the progesterone-agonistic and in particular the antiovulatory and proliferation-inhibiting properties is of advantage for the therapeutic use of type I antagonists such as RU 486.
SUMMARY OF THE INVENTION
The object of the present invention is therefore to make available compounds which overcome the disadvantages outlined above.
The object is achieved by making available compounds of the general formula I
according to Claim 1 and their pharmaceutically acceptable salts and also a process for their preparation. Pharmnaceutical compositions are further made available which contain a compound of the general formula I or its pharmaceutically acceptable salt.
The present invention thus relates to S-substituted 11&bgr;-benzaldoxime estra-4,9-die
Elger Walter
Kaufmann Guenther
Ring Sven
Schneider Birgit
Schubert Gerd
Badio Barbara P.
Jenapharm GmbH & Co. KG
Striker Michael J.
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