Diazepinones, their production and use

Details Diazepinones, their production and use Diazepinones, their production and use

1996-06-25

1999-02-02

Berch, Mark L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540495, C07D40306, A61K 3155

Patent

active

058665676

DESCRIPTION:

BRIEF SUMMARY
This application is a national stage application under 35 U.S.C. .sctn. 371 of Pct application No. JP96/01463.


TECHNICAL FIELD

The present invention relates to novel diazepinone compounds and salts having excellent gonadotropin releasing hormone (GnRH) receptor antagonist activity, processes for producing them, and use.


BACKGROUND ART

GnRH is a decapeptide, a peptide consisting of 10 amino acids, which is produced in the hypothalamus and modulates the secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH), etc. via receptors supposedly present in the anterior lobe of the pituitary gland to thereby exhibit multi-pronged physiological activity inclusive of induction of ovulation. Therefore, selective antagonists and agonists specific for such receptors modulate the activities of GnRH hormones produced in the hypothalamus and control secretion of the anterior pituitary hormones such as LH and FSH. As a consequence, the secretion of estrogen in women and of testosterone in men is suppressed. Therefore, these agonists and antagonists can be expected to be clinically useful for the prevention or treatment of gonadotropin-dependent diseases.
Since the discovery of GnRH in 1971, leuprolerin acetate and many other peptides have been synthesized in anticipation of their utility as agonists or antagonists of GnRH. Leuprolerin acetate, which is 20-50 times as active as native GnRH, causes the so-called receptor down-regulation on repeated administration to diminish the release of gonadotropins in the pituitary gland, reduce the response of the testes to gonadotropins to cut down on the production of testosterone to the castrated level, and reduce the productivity of estrogen in the ovaries. As a consequence, the compound exhibits antitumoral efficacy in cancers dependent on such hormones, typically prostate cancer. In fact, leuprolerin acetate is in broad use clinically as a therapeutic agent for prostate cancer, endometriosis, and precocious puberty. It has also been demonstrated that the compound is effective in the treatment of hysteromyoma and breast cancer as well.
However, these GnRH agonists are not well absorbed after oral administration because of their peptide structures, thus imposing restrictions on the dosage form. Moreover, these compounds show a burst of agonist activity following commencement of therapy, elevating blood steroid hormone levels and, hence, causing transient exacerbations, e.g. of bone ache, before the onset of expected therapeutic effects.
Meanwhile, as a tricyclic compound, JP-A-54 135788 discloses that a compound of the formula: ##STR2## wherein X represents halogen, lower alkyl or lower alkoxy; n is 1 or 2; R.sup.1 and R.sup.2 may be the same or different and each represents H or lower alkyl; either one of the two bonds represented by dotted lines is a double bond but, when R.sup.2 is lower alkyl, it is bound to the nitrogen atom not forming a double bond; and where X and R.sup.1 represent H and n is equal to 1, R.sup.2 is lower alkyl, has anxiolytic and analgesic actions. Furthermore, WO94/17075 discloses that a compound of the formula: ##STR3## wherein n is 0 or 1, X typically represents .dbd.CH, Z represents nitrogen which may be substituted typically by alkyl; W typically represents C.dbd.0; R.sup.1 and R.sub.2 each typically represents hydrogen, benzyl or C.sub.2-6 alkylacyl; R.sub.8, R.sub.9 and R.sub.4 each typically represents hydrogen, is useful as an antiviral agent.
However, none of the compounds ever discovered are medicinally useful GnRH receptor antagonists and the development of a therapeutically useful compound having improved GnRH receptor antagonist activity with a low risk of side effect has been awaited.


DISCLOSURE OF INVENTION
referred to briefly as compound (I)! having a basal structure of 1,5-benzodiazepine and, in the 1-position thereof, a substituent comprising an aromatic or heteroaromatic ring substituted by a substituted amino group having a defined chemical structure as represented by the following formula (I), as well as a salt

REFERENCES:
patent: 4678784 (1987-07-01), Ho

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