DOUBLE-ACYLATED GLP-1 DERIVATIVES

摘要

The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1 (7-37), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37), wherein the first K residue is designated K 37 , and the second K residue is designated K 26 , which derivative comprises two albumin binding moieties attached to K 26 and K 37 , respectively, wherein the albumin binding moiety comprises a protracting moiety selected from:
€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 1:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-(CH 2 ) x -CO-*
€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 2:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 6 H 4 -O-(CH 2 ) y -CO-*
€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 3:€ƒ€ƒ€ƒ€ƒ€ƒR 1 -C 6 H 4 -(CH 2 ) z -CO-*
€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 4:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 4 SH 2 -(CH 2 ) w -CO-*
in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, R 1 is a group having a molar mass not higher than 150 Da, and w is an integer in the range of 6-18; with the proviso that when the protracting moiety is Chem. 1, the albumin binding moiety further comprises a linker of formula Chem. 5: *-NH-(CH 2 ) 2 -(O-(CH 2 ) 2 ) k -O-(CH 2 ) n -CO-*, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.