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US 2008/0076792 A1Published application
Heterobifunctional Polymeric Bioconjugates
AssigneeEnzon Pharmaceuticals, Inc.
InventorsRichard GREENWALD, Hong ZHAO
Life of this patent
Estimating the term…
Abstract
Heterobifunctional polymeric prodrug platforms for delivering biologically active compounds, including proteins, monoclonal antibodies and the like are disclosed. One preferred compound is Methods of making and using the compounds and conjugates described herein are also provided.
Claims25
A compound of the formula:
- wherein:
- X1-X6 are independently O, S or NR1;
- R44 and R44′ are independently selected polyalkylene oxides;
- R1 is selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, aralkyls, and C3-8 substituted cycloalkyls;
- R40-43 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6heteroalkoxy;
- y, p, y′ and p′ are independently zero or a positive integer;
- n and n′ are independently 0 or a positive integer;
- a and b are independently zero or a positive integer, provided that a+b is greater than or equal to 2;
- z is a positive integer;
- D10 and D11 are independently selected from the group consisting of OH, halogens, targeting agents, drugs, enzymes, proteins, therapeutically active compounds, dyes, chelating agents, isotope labeled compounds or together form a terminal group of the formula:
- Y7-9 are independently selected from the group consisting of O, S or NR1″;
- R1″ is hydrogen or methyl;
- R9-18 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- L3-4 are independently selected bifunctional linkers;
- Q is selected from among moieties actively transported into a target cell, hydrophobic moieties, bifunctional linking moieties and combinations thereof;
- l, k, m and o are independently positive integers;
- j and h are independently zero or a positive integer;
- g, i and q are independently zero or one;
- and
- B′ is selected from the group consisting of leaving groups, activating groups, OH, biologically active moieties and diagnostic agents.
17 more elements
A method of making a polymeric conjugate comprising:
- a) reacting a compound of formula (i)
- wherein:
- A1 is an activating group;
- T is a protecting group;
- X1, X3 and X5 are independently O, S or NR1;
- R44 is a polyalkylene oxide;
- R1 is selected from hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, aralkyls, and C3-8 substituted cycloalkyls;
- R40-41 are independently selected, from the group consisting of hydrogen, C1-6 alkyls, C3-12, branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 hetero-alkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- n is 1 or a positive integer;
- y is zero or a positive integer;
- t is a positive integer;
- and
- p is zero or one;
- with a compound of the formula (II):
- wherein:
- X2, X4 and X6 are independently O, S or NR1;
- R44′ is a polyalkylene oxide;
- R1 is selected from hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, aralkyls, and C3-8 substituted cycloalkyls;
- R42-43 are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- n′ is a positive integer;
- y′ is zero or a positive integer;
- t′ is a positive integer;
- and
- p′ is zero or one;
- under sufficient conditions to form a compound of formula (iii):
22 more elements
A method of treating a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I):
- wherein:
- X1-X6 are independently O, S or NR1;
- R44 and R44′ are independently selected polyalkylene oxides;
- R1 is selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, aralkyls, and C3-8 substituted cycloalkyls;
- R40-43 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- y, p, y′ and p′ are independently zero or a positive integer;
- n and n′ are independently 0 or a positive integer;
- a and b are independently zero or a positive integer, provided that a+b is greater than or equal to 2;
- z is a positive integer;
- and
- D1 and D2 are independently selected from the group consisting B, leaving groups, activating groups, and terminal groups,
- wherein
- B is selected from the group consisting of biologically active moieties, diagnostic agents and OH;
- said leaving groups are selected from the group, consisting of halogens, activated carbonates, carbonyl imidazole, cyclic imide thiones, isocyanates, N-hydroxysuccinimidyl, para-nitrophenol, N-hydroxyphtalimide, N-hydroxybenzotriazolyl, imidazole, and tosylates;
- and,
- said terminal groups are selected from the group consisting of:
- wherein:
- Y1-6 are independently selected from the group consisting of O, S or NR1′;
- R1′ is selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, aralkyls, and C3-8 substituted cycloalkyls;
- R2-8 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- Ar is a moiety which forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
- L1-2 are independently selected bifunctional linkers;
- e and f′ are independently selected positive integers;
- c, c′ and e′ are independently zero or a positive integer;
- d, f and d′ are independently zero or one;
- and
- B′ is selected from the group consisting of leaving groups, activating groups, OH, biologically active moieties and diagnostic agents wherein said leaving groups are selected from the group consisting of halogens, activated carbonates, carbonyl imidazole, cyclic imide thiones, isocyanates, N-hydroxysuccinimidyl, para-nitrophenol, N-hydroxyphtalimide, N-hydroxy-benzotriazolyl, imidazole, and tosylates,
- provided that n and n′ are positive integers when both a and b are positive integers;
- and
- wherein at least one of D1 and D2 is B and B is a residue of a biologically active moiety.
27 more elements
Dependencies are inferred from the claim text.