Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1984-05-04
1985-11-12
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514800, 2601125LH, A61K 3700, C07C10352
Patent
active
045528640
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to new gonadoliberin derivatives and a process for their preparation. More particularly, the invention concerns new gonadoliberin derivatives of the formula (I) alkyl moiety, includes a process for the preparation of said nona- or decapeptide derivatives and pharmaceutical or veterinary compositions containing them.
The abbreviations used in the above formula and hereinbelow correspond to the generally accepted nomenclature of the chemistry of peptides [see e.g. J. Biol. Chem. 241, 527 (1966)]. In the specification the following further abbreviations will be used:
BACKGROUND OF THE INVENTION
Gonadoliberin (also referred to as gonadotropin releasing hormone, Gn-RH, luteinizing and folliculus stimulating hormone, releasing hormone, LH(FSH-RH) and its known derivatives are capable of releasing the luteinizing and folliculus stimulating hormones (LH and FSH).
It is known in the art [M. Monahan et al., Biochemistry 12, 4616-4620 (1973)] that those gonadoliberin derivatives in which glycine in the 6-position is replaced by certain D-amino acids have a surplus effect related to gonadoliberin. This increase in the activity is most expressed in case of the compounds which contain D-tryptophane or D-tert.butyl-serine in the 6-position (J. Sandow et al., Control of Ovulation, Butterworths, London, 1978, pp. 49-70).
According to Nestor et al.[J. Med. Chem. 25, 795-801 (1982), U.S. Pat. No. 4,234,571] by replacing the glycine in the 6-position of gonadoliberin by D-amino acids having a highly lipophilic side-chain also effective gonadoliberin analogues can be prepared.
It is further known that the biological activity of gonadoliberin can further be increased by replacing the glycine-amide group in the 10-position with amide groups containing aliphatic carbon chain [M. Fujino et al., J.Med.Chem. 16, 1144-1147 (1973)].
According to Coy, D. H., Labrie, F., Savary, M., Coy, E. J., Schally, A. V. Biochem. Biophys. Res. Commun. 67, 576-582 (1975), potent gonadoliberin derivatives can be obtained also by replacing the 6-glycine in gonadoliberin or in a corresponding amide by a D-phenylalanyl group.
The invention relates to new gonadoliberin derivatives which show a better biological activity than their known analogues.
According to another aspect of the invention we provide a process for the preparation of the new nona- and decapeptide derivatives of the formula (I) (X and Y are as defined above), by which in place of the 6-glycine group other amino acids can be incorporated with a good yield, without racemization.
SUMMARY OF THE INVENTION
The invention is based on the surprising finding that the compounds which contain a D-thyroxyl, D-thyronyl or D-4-chlorophenyl-alanyl group in place of the 6-glycine group of gonadoliberin have a better biological activity and can easily be prepared.
We have further found that the activity of these new gonadoliberin derivatives can be increased further by replacing the glycine-amide group in the 10-position by an --NH--C.sub.1-4 -alkyl group.
According to the invention the new nona- or decapeptide derivatives of the formula (I) salts and complexes thereof are prepared by condensing a pentapeptide azide of the formula (II) or decapeptide amide obtained into an acid addition salt thereof by reacting it with a suitable acid, or if desired, deliberating the free base from an acid addition salt obtained with a base, and if desired, converting a nona- or decapeptide-amide obtained into a metal complex thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The D-Thy.sup.6 -gonadoliberin derivatives are preferably prepared by reducing the D-Thx.sup.6 -gonadoliberin derivatives. The reduction is preferably carried out with hydrogen. If the reduction is performed with tritium gas, in the presence of a catalyst, from D-Thx.sup.6 -gonadoliberin D-Thy.sup.6 -gonadoliberin specifically labelled with tritium is obtained. These gonadoliberin derivatives which show a high specific radioactivity can excellently be used in various tests and as diagnostics.
Th
REFERENCES:
patent: 3888836 (1975-06-01), Veber et al.
patent: 4024248 (1977-05-01), Konig et al.
patent: 4382922 (1983-05-01), Rivier et al.
patent: 4410514 (1983-10-01), Vale, Jr. et al.
Biochem. And Biophys. Res. Commun., 60, (1974), 406-412.
Antoni Ferenc
Erchegyi Judit
Horvath Aniko
Keri Gyorgi
Mezo Imre
Dubno Herbert
Phillips Delbert R.
Reanal Finomvegyszergyar
Ross Karl F.
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