PRODRUGS COMPRISING AN INSULIN LINKER CONJUGATE

摘要

The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof comprising an insulin linker conjugate D-L, wherein D represents the insulin moiety; and -L is a non-biologically active linker moiety -L1 represented by formula (I),;;wherein the dashed line indicates the attachment to one of the amino groups of the insulin by forming an amide bond. The invention further relates to pharmaceutical compositions comprising said prodrugs as well as their use as a medicament for treating or preventing diseases or disorders which can be treated by insulin.

主权项

1. A prodrug comprising:
a hydrogel (Z) with a backbone moieties of formula C-(A-Hyp)4, wherein:
each A is independently selected from the formula —(CH2)n1(OCH2CH2)nX′—, wherein:
n1 is 1 or 2;n is an integer ranging from 5 to 50; andX′ is an amide linkage linking A and Hyp;each Hyp is independently selected from hyperbranched polypeptides comprising lysine;the backbone moieties are crosslinked by poly(ethylene glycol)-based crosslinker moieties, comprising m ethylene glycol units, wherein m is an integer ranging from 10-70, and terminated by at least two hydrolytically degradable bonds; a linker L2 connected to the backbone moiety, wherein:
L2 is a single chemical bond or is a C1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from —O— and C(O)N(R3aa) optionally substituted with one or more groups independently selected from OH and C(O)N(R3aaR3aaa), wherein R3aa and R3aaa are independently selected from the group consisting of H and C1-4 alkyl; andL2 is attached to Z via a terminal group selected from the group consisting of wherein L2 is attached to the sulfur atom in structure X and Z is attached to the nitrogen atom in structure X or L2 is attached to the nitrogen atom in structure XI and Z is attached to the sulfur atom in structure XI; and an insulin-linker conjugate D-L1, wherein:
D is insulin; andL1 is:wherein:
the dashed line indicates the point of attachment of L1 to one of the amino groups of insulin through an amide bond;X is N(R3)R1a is selected from the group consisting of H, NH(R2b), N(R2b)C(O)R4 and
C1-4 alkyl;R1, R2, R2a, R2b, R3, and R4 are independently selected from the group consisting of H and C1-4 alkyl, and optionally substituted with L2Z; andL1 is substituted with one L2-Z provided that the hydrogen marked with the asterisk in formula (I) is not replaced;or a pharmaceutically acceptable salt thereof, wherein said prodrug is in the form of microparticles.