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

a technology of synthesis and antagonists, applied in the field of intermediaries for the synthesis of lhrh antagonists, can solve the problems of high cost of the method of synthesis of lhrh analogs known in the art, and achieve the effect of improving yield and/or purity of the produ

Inactive Publication Date: 2005-06-09
POLYPEPTIDE LAB AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides a tripeptide intermediate for the synthesis of LHRH analogs that improves yield and purity. Additionally, the invention provides a process for the production of such a tripeptide intermediate and a process for coupling a tripeptide to a hepta- or hexapeptide."

Problems solved by technology

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

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0026] Boc-D-4ClPhe-OSu. Boc-D-4ClPhe-OH (299,75 g; 1,0 eq.) and HONSu (184,1 g; 1,6 eq.) are dissolved in 2-propanol (4,5 L). The mixture is cooled to 0° C. and DIC (164,1 g; 1.3 eq.) is added. The mixture is stirred for 16 h while warming to room temperature. The product is filtered of, washed with 2-propanol (1,5 L) and dried. Yield: 85%. HPLC purity: 98,8%.

example 2

[0027] Boc-D-4ClPhe-D-3Pal-OH. H-D-3Pal-OH, 2 HCl (251,1 g; 1,05 eq.) and Boc-D-4ClPhe-OSu (396,8 g; 1,0 eq.) are dissolved in DMSO (3,33 L) and NMM (318,8 g; 3,15 eq.) is added. The mixture is stirred for 16 h at room temperature. Water (17 L) is added and pH is adjusted to 4-4,5 which causes the product to precipitate. The mixture is filtered and the product is washed with water (3×5 L) to remove traces of DMSO, H-D-3Pal-OH and Boc-D-4ClPhe-OH. The product is dried. Yield: 80%. HPLC purity: 97,8%

example 3

[0028] Boc-D-2Nal-OSu. Boc-D-2Nal-OH (315,4 g; 1,0 eq.) is dissolved in 2-propanol (6,8 L) at −10° C. and IBC (157 g; 1,15 eq.) and NMM (116 g; 1,15 eq.) is added. After stirring for 5-10 min a mixture of HONSu (230,1 g; 2,0 eq.) in 2-propanol (1,4 L) is added. Additional NMM (10,1 g; 0,1 eq.) is added. After half an hour water (0,82 L) is added to dissolve precipitated NMM·HCl. The product is isolated by filtration, washed with 2-propanol (1 L), and dried. Yield.: 90%. HPLC purity: 98,3%.

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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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K5/08C07K5/087C07K7/23
CPCC07K1/02C07K7/23C07K5/0827C07K5/0804C07K5/08
Inventor RASMUSSENRASMUSSENWACHS, WOLFGANG O.HANSEN, STEFANFOMSGAARD, JENS
Owner POLYPEPTIDE LAB AS
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