Hydrolysable polymeric FMOC-linker
View Patent ↗The invention relates to Fmoc (9-fluorenyl-methoxycarbonyl)-based polymeric conjugates. These conjugates are useful for extending the in-vivo circulation of protein and peptide drugs.
1. A compound of the formula 1
wherein Z a leaving group and at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y;
Y is a radical containing a semi-synthetic carbohydrate biopolymer, which is bound to a N-succinimidyl moiety;
at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is optionally bound to radical X;
X is —SO 3 —R 3 ;
R 3 is independently selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl and (C 1 -C 8 )-alkyl-R 4 ; and
R 4 is a polymer.
2. The compound according to claim 1 , wherein Z is an N-succinimidyl ester;
Y is:
POLYMER is a semi-synthetic carbohydrate biopolymer;
R 1 is at each occurrence independently a (C 1 -C 8 )-alkyl;
R 2 is independently selected from the group consisting of —C(O)NR—, —C(O)NR(C 1 -C 8 )-alkyl-NR—, —NRC(O)— and —NRC(O)-(C 1 -C 8 )-alkyl-NR; and
R is independently either hydrogen or (C 1 -C 8 )-alkyl.
3. The compound according to claim 2 , wherein R 2 is either —C(O)NR— or —NRC(O)— and wherein R is independently either hydrogen or (C 1 -C 8 )-alkyl.
4. The compound according to claim 3 , wherein said POLYMER is bound via a thioether linkage.
5. The compound according to claim 1 , wherein said semi-synthetic carbohydrate biopolymer is a polysaccharide.
6. The compound according to claim 5 , wherein said polysaccharide is polysialic acid (PSA).
7. The compound according to claim 5 , wherein said polysaccharide comprises at least 3 units of a monosaccharide.
8. A compound according to claim 1 , wherein said compound is selected from the group consisting of I, II, III, IV, V, VI, VII, VIII, IX, X and XI:
9. A conjugate comprising a compound of formula 1 and a protein or peptide drug, the compound of formula 1 having a structure
wherein Z a leaving group and at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y;
Y is a radical containing a semi-synthetic carbohydrate biopolymer, which is bound to a N-succinimidyl moiety;
at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is optionally bound to radical X;
R 3 is independently selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl and (C 1 -C 8 )-alkyl-R 4 ; and
R 4 is a polymer.