TARGETED POLYMERIC PRODRUGS CONTAINING MULTIFUNCTIONAL LINKERS

• US 20100233190A1
• Filed: 03/12/2009
• Published: 09/16/2010
• Est. Priority Date: 09/15/2006
• Status: Active Grant

• Current Assignee: Belrose Pharma, Inc.
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Reddy, Pasanna, ZHAO, Hong, RUBIO, Maria Belen
• Granted Patent: US 8,367,065 B2
• Time in Patent Office: Days
• US Class Current: 424/179.100
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: C07D 207/416 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 207/448 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The present invention provides single chain antibody-directed polymeric prodrugs containing multifunctional linkers. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.

Claims

1. A compound of the Formula (I)

2. The compound of claim 1, wherein L₂ is selected from the group consisting of:

3. The compound of claim 2, wherein L₂ is selected from the group consisting of:

4. A compound of claim 2, selected from the group consisting of:

5. A compound of claim 4, selected from the group consisting of:

6. The compound of claim 1, wherein the biologically active moiety is selected from the group consisting of —

NH₂ containing moieties, —

OH containing moieties and —

SH containing moieties.

7. The compound of claim 1, wherein the biologically active moiety is selected from the group consisting of pharmaceutically active compounds, enzymes, proteins, oligonucleotides, antibodies, monoclonal antibodies, single chain antibodies and peptides.

8. The compound of claim 7, wherein the pharmaceutically active compounds are selected from the group consisting of DNA topoisomerase inhibitors, microtubule inhibiting drugs, DNA damaging agents, antimetabolites, nucleoside analogs and anticancer drugs.

9. The compound of claim 1, wherein the biologically active moiety is an oligonucleotide.

10. The compound of claim 9, wherein the oligonucleotide is selected from the group consisting of antisense oligonucleotides, locked nucleic acids (LNA), short interfering RNA (siRNA), microRNA (miRNA), aptamers, peptide nucleic acid (PNA), and phosphorodiamidate morpholino oligonucleotides (PMO).

11. The compound of claim 9, wherein the oligonucleotide is selected from the group consisting of antisense bcl-2 oligonucleotides, antisense HIF-1a oligonucleotides, and antisense Survivin oligonucleotides.

12. The compound of claim 1, wherein the targeting agent is selected from the group consisting of monoclonal antibodies, single chain antibodies, cell adhesion peptides, cell penetrating peptides, receptor ligands, targeting carbohydrate molecules or lectins and oligonucleotide.

13. The compound of claim 1, wherein the targeting agent is selected from the group consisting of RGD peptide, selectin, TAT, penetratin, (Arg)₉ and folic acid.

14. The compound of claim 1, wherein the releasable linker is selected from the group consisting of benzyl elimination-based linkers, trialkyl lock-based linkers, bicine-based linkers, acid-labile linkers, lysosomally cleavable peptides and capthepsin B cleavable peptides.

15. The compound of claim 1, wherein the releasable linkers are independently selected from the group consisting of:

16. The compound of claim 1, wherein the permanent linkers are independently selected from the group consisting of:

17. The compound of claim 1, wherein L₁ and L₃ are independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide.

18. The compound of claim 1, wherein R₁ comprises a linear, terminally branched or multi-armed polyalkylene oxide.

19. The compound of claim 18, wherein the polyalkylene oxide is selected from the group consisting of polyethylene glycol and polypropylene glycol.

20. The compound of claim 18, wherein the polyalkylene oxide is selected from the group consisting of

—

Y₂₁—

(CH₂CH₂O)_n—

CH₂CH₂Y₂₁—

,

—

Y₂₁—

(CH₂CH₂O)_n—

CH₂C(═

Y₂₂)—

Y₂₁—

,

—

Y₂₁—

C(═

Y₂₂)—

(CH₂)_a2—

Y₂₃—

(CH₂CH₂O)_n—

CH₂CH₂—

Y₂₃—

(CH₂)_a2—

C(═

Y₂₂)—

Y₂₁— and

—

Y₂₁—

(CR₅₁R₅₂)_a2—

Y₂₃—

(CH₂)_b2—

O—

(CH₂CH₂O)_n—

(CH₂)_b2—

Y₂₃—

(CR₅₁R₅₂)_a2—

Y₂₁—

,

wherein;

Y₂₁ and Y₂₃ are independently O, S, SO, SO₂, NR₅₃ or a bond;

Y₂₂ is O, S, or NR₅₃;

R_51-53 are independently selected from the group for R₂;

(a2) and (b2) are independently zero or a positive integer; and

(n) is an integer from about 10 to about 2300.

21. The compound of claim 18 wherein the polyalkylene oxide is a polyethylene glycol of the formula, —

O—

(CH₂CH₂O)_n—

wherein (n) is an integer from about 10 to about 2,300.

22. The compound of claim 1, wherein R₁ has an average molecular weight from about 2,000 to about 100,000 daltons.

23. The compound of claim 1, wherein R₁ has an average molecular weight of from about 5,000 to about 60,000 daltons.

24. The compound of claim 1, wherein R₁ has an average molecular weight from about 5,000 to about 25,000 daltons or from about 20,000 to about 45,000 daltons.

25. A compound of claim 1, selected from the group consisting of:

26. A compound of claim 1, selected from the group consisting of:

29. A method of treating a mammal, comprising administering an effective amount of a compound of Formula (I) of claim 1 to a patient in need thereof.

30. A method of administering polynucleotides to mammalian cells, comprising delivering an effective amount of a compound of Formula (I) of claim 1 to a cell requiring such treatment.

27. A method of preparing a polymeric conjugate containing a multifunctional linker comprising:

reacting a compound of Formula (IIIa);

28. The method of claim 27 further comprising:

reacting the compound of Formula (IIIc);