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US 2007/0166276 A1Published application
Releasable polymeric conjugates based on aliphatic biodegradable linkers
OwnerHong Zhao, Richard Greenwald +1inventors
InventorsHong Zhao, Richard Greenwald, Susan Adler
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Abstract
Activated polymeric bicine derivatives such as Formula (I), as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.
Claims34
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 among moieties actively transported into a target cell, hydrophobic moieties, bifunctional linking moieties 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, C1-6alkyls, 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 among leaving groups, functional groups, biologically active moieties 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.
14 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 among moieties actively transported into a target cell, hydrophobic moieties, bifunctional linking moieties 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 L2 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;
- with an amino-containing, biologically active agent under conditions sufficient to form
- wherein A2 is a residue of an amine containing biologically active agent.
12 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.