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US 7,087,229 B2Granted
Releasable polymeric conjugates based on aliphatic biodegradable linkers
AssigneeEnzon Pharmaceuticals, Inc.
InventorsHong Zhao, Richard B. Greenwald
Life of this patent
Estimating the term…
Abstract
Activated polymeric bicine derivatives such as, as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.
Claims32
A compound comprising the Formula (I):
- wherein:
- R1 and R2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C1-6 alkyls, C2-6 alkenyl, C2-6 alkynyl, aralkyls, and terminal branching groups;
- Z is selected from the group consisting of hydrophobics moieties, bifunctional linking moieties,
- wherein L3 is a bifunctional linker and Y4 is O, S or NR11, and combinations thereof;
- Y1-3 may be the same or different and are selected from among O, S or NR11;
- L1 and L2 may be the same or different bifunctional linkers;
- R3–R11, R24and R25 may be the same or different and are selected from the group consisting of hydrogen, C1-6 alkyls, C2-6 alkenyl, C2-6 alkynyl, C3-19 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C2-6 substituted alkenyls, C2-6 substituted alkynyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- L3 and L4 may be the same or different and are selected from:
- —C(O)(CR30R31)Y15(CR32R33)C(O)— or
- —C(O)(CR30R31)(CR32R33)C(O)—
- wherein:
- Y15 is selected from O, S, NR34 or CH2, and
- R30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl;
- A is selected from the group consisting of bioligically active proteins, leaving groups, functional groups, and OH;
- a, b, c, d, and e are independently 0 or 1
- m, n, o, and p are independently positive integers,
- f and g are 0 or 1, provided that
- at least one of (f+a) or (g+c) is equal to 2.
15 more elements
A method of preparing a polymer conjugate, comprising reacting a compound of the formula:
- wherein:
- A1 is a leaving group;
- R1 and R2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C1-6 alkyls, C2-6 alkenyl, C2-6 alkynyl, aralkyls, and terminal branching groups, provided both R1 and R2 are not H;
- Z is selected from hydrophobic moieties, bifunctional linking moieties,
- wherein L3 is a bifunctional linker and Y4 is O, S or NR11, and combinations thereof;
- Y1-3 may be the same or different and are selected from among O, S or NR11;
- L1 and L2 may be the same or different bifunctional linkers;
- R3–R11, R24 and R25 may be the same or different and are selected from the group consisting of hydrogen, C1-6 alkyls, C2-6 alkenyl, C2-6 alkynyl, C3-19 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C2-6 substituted alkenyls, C2-6 substituted alkynyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- L3 and L4 may be the same or different and are selected from:
- —C(O)(CR30R31)Y15(CR32R33)C(O)— or
- —C(O)(CR30R31)(CR32R33)C(O)—
- wherein:
- Y15 is selected from O, S, NR34 or CH2, and
- R30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl;
- wherein a, b, c, d, and e are independently 0 or 1 m, n, o, and p are independantly positive integers, f and g are 0 or 1, provided that at least one of (f+a) or (g+c) is equal to 2;
- with a biologically active protein under conditions sufficient to form
- wherein A2 is a residue of a biologically active agent.
14 more elements
A method of preparing a bicine-based polymer transport system, comprising:
- a) reacting a blocked bifunctional linker with an anhydride to form an extended blocked bifunctional spacer of the formula:
- b) attaching the blocked bifunctional spacer to each hydroxyl of an acid protected bicine molecule;
- c) deblocking the resultant intermediate and reacting it with an activated polymer under basic coupling conditions, and
- d) deprotecting the bicine acid and thereafter activating the acid with a suitable activating group under coupling conditions.
1 more element
Dependencies are inferred from the claim text.