Tetrapartate prodrugs

• US 20010031873A1
• Filed: 01/12/2001
• Published: 10/18/2001
• Est. Priority Date: 12/17/1997
• Status: Active Grant

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Zhao, Hong, Greenwald, Richard B.
• Granted Patent: US 6,720,306 B2
• Time in Patent Office: Days
• US Class Current: 546/290
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A compound of Formula I, providing tetrapartate prodrugs is provided

wherein:

L₁ is a bifunctional linking moiety;

D is a moiety that is a leaving group, or a residue of a compound to be delivered into a cell;

Z is covalently linked to [D]_y, wherein Z is selected from the group consisting of:

a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof,

Y₁, Y₂, Y₃ and Y₄ are each independently O, S, or NR₁₂;

R₁₁ is a mono- or divalent polymer residue;

R₁, R₄, R₉, R₁₀ and R₁₂ are independently selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-12 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls and substituted C_1-6 heteroalkyls;

R₂, R₃, R₅ and R₆ are independently selected from the group consisting of hydrogen, C_1-6 alkyls, C_1-6 alkoxy, phenoxy, C_1-8 heteroalkyls, C_1-8 heteroalkoxy, substituted C_1-6 alkyls, C_3-8 cycloalkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro- and cyano-, carboxy-, C_1-6 carboxyalkyls and C_1-6 alkylcarbonyls;

Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;

(m), (r), (s), (t), and (u) are independently zero or one;

(p) is zero or a positive integer; and (y) is 1 or 2;

together with methods of preparing and using these new tetrapartate prodrugs.

Claims

1. A compound of Formula I:

2. The compound of

claim 1

, wherein L₁ is selected from the group consisting of:

3. The compound of

claim 1

wherein when y is 2, each of the two D moieties is the same or different.

4. The compound of

claim 1

wherein Z is selected from the group consisting of an amino acid residue, a sugar residue, a fatty acid residue, a peptide residue, a C_6-18 alkyl, a substituted aryl, a heteroaryl, —

C(═

O), —

C(═

S), and —

C(═

NR₁₆), wherein R₁₆ is selected from the same group as R₁₂.

5. The compound of

claim 4

wherein the amino acid residue is selected from the group consisting of alanine, valine, leucine, isoleucine, glycine, serine, threonine, methionine, cysteine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine and proline.

6. The compound of

claim 4

wherein the peptide ranges in size from about 2 to about 10 amino acid residues.

7. The compound of

claim 6

wherein the peptide is Gly-Phe-Leu-Gly or Gly-Phe-Leu.

8. The compound of

claim 1

wherein each D moiety is independently a residue of an active biological material, or H.

9. The compound of

claim 1

wherein each D moiety is independently a residue of an anticancer agent, an anticancer prodrug, a detectable tag, and combinations thereof.

10. The compound of

claim 9

wherein the anticancer agent or anticancer prodrug comprises an anthracycline compound or a topoisomerase I inhibitor.

11. The compound of

claim 9

wherein the anticancer agent or anticancer prodrug is selected from the group consisting of daunorubicin, doxorubicin, p-aminoaniline mustard, melphalan, cytosine arabinoside, gemcitabine, and combinations thereof.

12. The compound of

claim 1

wherein at least one D moiety is a leaving group selected from the group consisting of as N-hydroxybenzotriazolyl, halogen, N-hydroxy-phthal-imidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thione, and combinations thereof.

13. The compound of

claim 1

wherein Ar is selected from the group consisting of,

14. The compound of

claim 1

, wherein

15. The compound of

claim 14

, wherein said amino acid residue is selected from the group consisting of naturally occurring and non-naturally occurring amino acid residues.

16. The compound of

claim 1

, wherein (p) is one.

17. The compound of

claim 2

, wherein X is selected from the group consisting of O, NR₁₂,

18. The compound of

claim 17

, wherein X is selected from the group consisting of O and NR₁₂.

19. The compound of

claim 2

, wherein Q is selected from the group consisting of C_2-4 alkyls, cycloalkyls, aryls, and aralkyl groups substituted with a member of the group consisting of NH, O, S, —

CH₂—

C(O)—

N(H)—

, and ortho-substituted phenyls.

20. The compound of

claim 2

, wherein (n) is 1 or 2.

21. The compound of

claim 1

, wherein (m) is 0.

22. The compound of

claim 1

, wherein Y₁, Y₂, Y₃ and Y₄ are O.

23. The compound of

claim 1

, wherein R₁₁ comprises a polyalkylene oxide residue.

24. The compound of

claim 23

, wherein said polyalkylene oxide residue comprises polyethylene glycol.

25. The compound of

claim 1

wherein said polymer residue has a number average molecular weight of from about 2,000 to about 100,000 daltons.

26. The compound of

claim 1

, wherein said polymer residue has a number average molecular weight of from about 20,000 to about 40,000 daltons.

27. The compound of

claim 13

, wherein Ar is

28. The compound of

claim 1

that is selected from the group consisting of:

29. The compound of

claim 28

wherein the polyethylene glycol (PEG) has a number average molecular weight of from about 20,000 to about 40,000 daltons.

30. A composition comprising a pharmaceutically or diagnostically effective amount of the compound of

claim 1

, where D is a residue of a compound to be delivered into a cell, together with a carrier acceptable for in vivo administration to an animal in need thereof.

33. A method of treating a disease or disorder in an animal, that comprises administering a pharmaceutically acceptable composition comprising an effective amount of a compound of

claim 1

, where D is a moiety that is a leaving group, or a residue of a compound to be delivered into a cell;

to an animal in need thereof.

34. A method of delivering a biologically active material D into a cell in need of treatment therewith, comprising the process of administering a compound of

claim 1

to an animal comprising said cell, wherein Formula I is hydrolyzed in vivo extracellularly to yield:

31. A method of preparing a tetrapartate prodrug comprising reacting a compound of formula:

32. A method of preparing a tetrapartate prodrug comprising reacting a compound of formula