Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production

Abstract

The novel tripeptides Ac-D-2Nal-D-4ClPhe-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-3Pal-OH are intermediates useful in the synthesis of LHRH analogs by coupling with suitable heptapeptides, in particular with the heptapeptides P1-Ser(P2)-NMeTyr(P3)-D-Lys(Nic)-Leu-Lys(iPr, P4)-Pro-D-AlaNH2 and P1-Ser(P2)-NMeTyr(P3)-D-Asn-Leu-Lys(iPr, P4)-Pro-D-AlaNH2.

Description

FIELD OF THE INVENTION [0001] The present invention relates to intermediates for the synthesis of LHRH antagonists, to a process for the production of these intermediates and to a process for the production of LHRH antagonists. BACKGROUND OF THE INVENTION [0002] The luteinizing hormone-releasing hormone, LHRH, controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). LHRH antagonists are compounds capable of blocking the secretion of FSH and LH. They are generally nona- and decapeptides (but may be shorter or longer) comprising part of or the entire structure of LHRH in which one or several amino acids have been exchanged for other natural amino acids and / or amino acids not found in nature. [0003] Synthetic LHRH antagonists may be used for contraception and in the treatment of benign hyperplasia of the prostate gland, hormonal-dependent tumors of the breast and ovaries, dysmenorrhea, endometriosis, and other conditions. These synthetic LHRH antagonis...

AI Technical Summary

Benefits of technology

[0006] It is thus an object of the invention to provide a tripeptide intermediate for the 3+7 and 3+6 synthesis of LHRH analogs in which the yield and / or purity of the product is improved.

[0024] A particular advantage with the method of the invention is that a cheaper starting material, H-D-Pal-OH.2HCl, can be used instead of the ester H-Pal-OR.2HCl; the protective group of the starting material need not be removed. Therefore the synthesis of the invention is one step shorter and avoids that material is lost in the additional step. Another advantage is that the formation of impurities in the saponification step is avoided. The formation of such impurities is well known. For instance, the basic conditions at the ester hydrolysis step cause partial racemization of D-Pal. The other prior-art alternative of removing the ester group by catalytic hydrogenation (in the case of allyl or benzyl ester groups) risks to cause a loss of Cl from 4ClPhe producing Phe. While allyl groups may be removed by still other reagents the full removal is difficult to control.

Problems solved by technology

Moreover, the methods for the synthesis of LHRH analogs known in the art are quite costly.