Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-08-14
2000-01-18
Moezie, F. T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514256, 514258, 514301, 514317, 514330, 514329, A61K 3809, A61K 31505, A61K 3144
Patent
active
060157895
DESCRIPTION:
BRIEF SUMMARY
This application is a .sctn.371 application of PCT/JP97/01459, filed Apr. 25, 1997.
TECHNICAL FIELD
1. Background of the Invention
The present invention relates to a pharmaceutical comprising a compound having luteinizing hormone releasing hormone activity in combination with a nonpeptide compound having luteinizing hormone releasing hormone antagonizing activity.
2. Background Art
Superactive peptide analogs of luteinizing hormone releasing hormone (hereinafter referred to sometimes as LH-RH) which is one of the hormones originating from the hypothalamus [Schally, A. V. et al., J. Biological Chemistry, 246, 7230-7236, 1971 and Burgus, R. et al., Proc. Natl. Acad. Sci. USA, 69, 278-282, 1972] are superagonists or agonists of LH-RH receptors and, if administered repeatedly, suppress the production and release of luteinizing hormone releasing hormone in the hypophysis to weaken the responsiveness of the testes and ovaries to luteinizing hormone releasing hormone and consequently reduce the secretion of testosterone and estrogen. It is, therefore, known that these compounds exhibit antitumor activity in cancers dependent on such hormones, for example carcinoma of the prostate, and actually they have been put to use clinically. These compounds are also used broadly as therapeutic drugs for endometriosis, hystereoma, and precocious puberty.
Reports are available on the combined use of a peptide LH-RH (super)agonist and a peptide LH-RH antagonist but there has been no report about the use of a nonpeptide LH-RH antagonist in combination with an LH-RH superagonist or agonist.
Since the above-mentioned peptide hormone analogs are either superagonists or agonists, they have been found to cause a transient exacervation (flare) of illness with elevation of serum testosterone and estrogen as the result of a pituitary-gonadotropic action (acute action) manifested immediately following initial dosing. In fact, it takes about 2-3 weeks for such a peptide superagonist or agonist to show a steady effect and, therefore, establishment of a prophylactic modality for preventing the progression and exacerbation of illness during this intervening period is a major goal of research.
Furthermore, in order that the action of such a peptide or nonpeptide (super)agonist may be amplified, the advent of a nonpeptide LH-RH antagonist compound that may be administered orally is being awaited.
3. Disclosure of Invention
The inventors of the present invention, taking into account the fact that thieno[2,3-b]pyridine derivatives and thieno[2,3-d]pyrimidine derivatives, both of which have excellent LH-RH antagonizing activity, can be administered orally and speculating that said superagonists or agonists might be safely administered if their effect be carefully modulated by controlling the dosage and administration interval, did much research and have completed the present invention.
SUMMARY OF THE INVENTION
The present invention relates to: releasing hormone activity in combination with a nonpeptide compound having luteinizing hormone releasing hormone antagonizing activity, luteinizing hormone releasing hormone activity is a peptide compound, natural hormone or an analog thereof, polypeptide of the formula: Phe; R.sub.3 is Gly or a D-amino acid residue which may optionally be substituted; R.sub.4 is Leu, Ile, or Nle; R.sub.5 is a group of the formula: Gly-NH--R.sub.6 wherein R.sub.6 is a hydrogen or an optionally substituted alkyl group, or a group of the formula: NH--R.sub.6 ' wherein R.sub.6 ' is a hydrogen, an alkyl group which may optionally be substituted with amino or hydroxy or ureido, compound selected from the group consisting of leuprorelin, gohadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin, and recirelin, luteinizing hormone releasing hormone activity is in a controlled release dosage form, dosage form is microcapsules, dosage form is a transnasal drug delivery system or an implant, a condensed cyclic compound containing at least a condensed bicyclic structure of an optionally substi
REFERENCES:
Th. Reissmann et al., "Development and applications of luteinizing hormone-releasing hormone antagonists in the treatment of infertility: an overview", Human Reproduction, vol. 10, No. 8, pp. 1974-1981, 1995.
J. Pinski et al., "Blockade of the LH response induced by the agonist D-Trp-6-LHRH in rats by a highly potent LH-RH antagonist SB-75", The Prostate, vol. 20, No. 3, pp. 213-224, 1992.
G. Emons et al., "The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers", Human Reproduction Update, vol. 9, No. 7, pp. 1364-1379, 1994.
Furuya Shuichi
Suzuki Nobuhiro
Moezie F. T.
Takeda Chemical Industries Ltd.
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