a. Field of the Invention
This invention relates to the decapeptide (pyro)Glu-His-Trp-Ser-Tyr-D-Phe-Leu-Arg-Pro-Gly-NH.sub.2, salts thereof and intermediates for the synthesis thereof.
The decapeptide of this invention also is called L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L- leucyl-L-arginyl-L-prolylglycinamide and may be designated by the abbreviation [D-Phe.sup.6 ]-LH-RH.
b. Background of the Invention
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are both gonadotrophic hormones elaborated by the pituitary gland of humans and of animals. LH together with FSH stimulates the release of estrogens from the maturing follicles in the ovary and induces the process of ovulation in the female. In the male, LH stimulates the interstitial cells and is for that reason also called interstitial cell stimulating hormone (ICSH). FSH induces maturation of the follicles in the ovary and together with LH, plays an important role in the cyclic phenomena in the female. FSH promotes the development of germinal cells in the testes of the male. Both LH and FSH are released from the pituitary gland by the action of LH- and FSH-releasing hormone, and there is good evidence that said releasing hormone is elaborated in the hypothalamus and reaches the pituitary gland by a neurohumoral pathway, see e.g., A. V. Schally, et al., Recent Progress in Hormone Research, 24, 497 (1968).
The natural LH- and FSH-releasing hormone has been isolated from pig hypothalami and its constitution elucidated by A. V. Schally, et al., Biochem. Biophys. Res. Commun., 43, 393 and 1334 (1971), who proposed the decapeptide structure (pyro)-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2.
This constitution has been confirmed by snythesis; for example, see H. Matsuo, et al., Biochem. Biophys. Res. Comm., 45, 822 (1971) and R. Geiger et al., ibid, 45, 767 (1971).
Hereinafter the natural LH- and FSH-releasing hormone is called LH-RH.
Because of the importance of LH-RH to both diagnostic and therapeutic medicine, considerable interest has been shown in the preparation of new compounds having improved properties over the natural hormone. One approach to this goal has been the replacement of an amino acid residue of LH-RH with another amino acid. Although in a few instances decapeptides containing such a replacement have been found to be more active than LH-RH, for example, [D-Ala.sup.6 ]-LH-RH, A. Arimura, et al., Endocrinology, 95, 1174 (1974) and [D-Leu.sup.6 ]-LH-RH, J. A. Vilchez-Martinez, et al., Biochem. Biophys. Res. Commun., 59, 1226 (1974), for the most part the replacement containing decapeptides have been less active.
Now it has been found that the replacement of the glycyl moiety in position 6 of LH-RH with D-phenylalanine gives a compound that is much more active and longer acting than LH-RH. Such attributes of the present decapeptide have practical significance: the lesser minimum effective dose reducing side effects as well as the cost for the preparation of the compound and the longer acting property reducing the need for frequent administration.
USPTO Backgrounds
USPTO Backgrounds