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US 2002/0161052 A1Published application
Terminally-branched polymeric linkers and polymeric conjugates containing the same
OwnerYun Hwang Choe, Richard B. Greenwaldinventors
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Abstract
Terminally-branched polymeric prodrug platforms capable of high degrees of loading are disclosed. In preferred aspects of the invention, the prodrug platform releases multiple parent compounds after each branch holding the active agent undergoes a benzyl elimination reaction. Methods of preparing the prodrugs and using the same in the treatment of mammals are also disclosed. In one preferred aspect, polymeric conjugates such as 1 are provided
Claims24
A compound comprising the formula:
- 34
- wherein:
- R1 is a polymeric residue;
- Y1 is O, S or NR4;
- M is O, S or NR5;
- E1 is
- 35
- E2-4 are independently H, E1 or
- 36
- (a) is zero or one;
- (m) is zero or a positive integer;
- (n) and (p) are independently 0 or a positive integer;
- Y2-3 are independently O, S or NR10;
- R2-1are 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;
- D1 and D2 are independently OH,
- 37
- or a terminal branching group;
- wherein (v) and (t) are independently 0 or a positive integer up to about 6;
- J is NR12 or
- 38
- L1 and L2 are independently selected bifunctional linkers;
- Y4-7 are independently selected from the group consisting of O, S and NR14;
- R11-14 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 heteroakoxy;
- Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
- B1 and B2 are independently selected from the group consisting of leaving groups, OH, residues of hydroxyl-containing moieties or amine-containing moieties.
22 more elements
A method of preparing a polymer conjugate, comprising:
- reacting a compound of the formula (VIII):
- 54
- wherein
- (v) and (t) are independently 0 or a positive integer up to about 6;
- J is NR12 or
- 55
- L1 and L2 are independently selected bifunctional linkers;
- Y4-5 are independently selected from the group consisting of O, S and NR17;
- R11-17 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 cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 hetero-alkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
- Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
- and
- B′1 is a residue of a hydroxyl- or an amine-containing moiety;
- with a compound of the formula (IX):
- 56
- wherein
- E5 is
- 57
- E6-8 are independently H, E5 or
- 58
- D3 and D4 are independently OH, a leaving group which is capable of reacting with an unprotected amine or hydroxyl or a terminal branching group;
- R1 is a polymeric residue;
- Y1 is O, S or NR4;
- Mis O, S or NR5;
- (a) is zero or one;
- (m) is 0 or a positive integer;
- (n) and (p) are independently 0 or a positive integer;
- Y2-3 are independently O, S or NR10;
- and
- R2-10 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;
- under conditions sufficient to cause a polymeric conjugate to be formed.
27 more elements
Dependencies are inferred from the claim text.