Tetrapartate prodrugs

• US 6,720,306 B2
• Filed: 01/12/2001
• Issued: 04/13/2004
• Est. Priority Date: 12/17/1997
• Status: Expired due to Fees

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Zhao, Hong, Greenwald, Richard B.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/758,993
• Publication Number:
  US 20010031873A1
• Time in Patent Office: 1,187 Days
• Field of Search: 560/157, 560/158, 560/159, 560/160, 560/165, 560/179, 560/186, 560/187, 526/332, 528/421, 558/273, 562/449, 536/4.1, 536/6.4, 536/168, 536/172, 536/181, 536/28.5, 514/2, 514/13, 514/18, 514/84, 514/49, 514/347, 514/345, 514/351, 514/353, 514/434, 514/425, 514/426, 514/432, 514/445, 514/497, 514/457, 514/460, 514/471, 514/472, 514/473, 514/480, 514/512, 514/547, 514/564, 424/35.1, 424/35.2, 424/83.4, 424/94.3, 530/336, 530/330, 530/331, 530/345, 530/351, 530/403, 530/409, 530/410, 435/188
• US Class Current: 514/1.3
• 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:

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 hetoroalkyls;

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-, 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;

wherein Z[D]_y is capable of crossing the membrane of the target cell and is capable of being hydrolyzed therein to release D.

2. The compound of claim 1, wherein L₁ is selected from the group consisting of:

wherein;

M is X or Q;

where X is an electron withdrawing group;

Q is a moiety containing a free electron pair positioned three to six atoms from

(a) and (n) are independently zero or a positive integer;

(b) is zero or one;

(g) is a positive integer;

(q) is three or four;

R₇, R₈, R₁₄, R₁₅ and R₁₈ are independently selected from the group which defines R₉; and

Y₅ and Y₆ are independently O, S, or NR₁₂.

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 2 to about 10 amino acid residues.

7. The compound of claim 6 wherein the peptide is Gly-Phe-Leu-Gly (SEQ ID NO:

1) or Gly-Phe-Leu.

8. The compound of claim 1 wherein each D moiety is independently a residue of an active biological material.

9. The compound of claim 1 wherein at least one D moiety is a leaving group selected from the group consisting of N-hydroxybenzotriazolyl, halogen, N-hydroxyphthal-imidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thione, and combinations thereof.

10. The compound of claim 1 wherein Ar is selected from the group consisting of

wherein J is selected from the group consisting of O, S, and N—

R₁₉, B and Z are independently CR₁₉ or N—

R₁₉ and R₁₉ is selected from the group consisting of hydrogen, C_1-6 alkyl, C_3-12 branched alkyl, C_3-8 cycloalkyl, C_1-6 substituted alkyl, C_3-8 substituted cyoloalkyl, aryls, substituted aryl, aralkyl, C_1-6 heteroalkyl, and substituted C_1-6 heteroalkyls.

11. The compound of claim 1, wherein

comprises an amino acid residue.

12. The compound of claim 11, wherein said amino acid residue is selected from the group consisting of naturally occurring and non-naturally occurring amino acid residues.

13. The compound of claim 1, wherein (p) is one.

14. The compound of claim 2, wherein X is selected from the group consisting of O and NR₁₂.

15. 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.

16. The compound of claim 2, wherein (n) is 1 or 2.

17. The compound of claim 1, wherein (m) is 0.

18. The compound of claim 1, wherein Y₁, Y₂, Y₃ and Y₄ are O.

19. The compound of claim 1, wherein R₁₁ comprises a polyalkylene oxide residue.

20. The compound of claim 19, wherein said polyalkylene oxide residue comprises polyethylene glycol.

21. The compound of claim 1 wherein said polymer residue has a number average molecular weight of from about 2000 to about 100,000 daltons.

22. 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.

23. The compound of claim 10, wherein Ar is

wherein r and t are both 1, R₂ and R₆ are independently H or methyl.

24. The compound of claim 1 that is selected from the group consisting of:

25. The compound of claim 24 wherein the polyethylene glycol (PEG) has a number average molecular weight of from about 20,000 to about 40,000 daltons.

26. 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.

27. 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 residue of a compound to be delivered into a cell;

to an animal in need thereof.

28. 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:

wherein Y* is the remainder of Y₂, and is independently selected from the group consisting of HO—

, HS—

, or HNR₁₂;

and Formula I-(i) then spontaneously hydrolyzes to

and CO₂, and a compound of Formula I-(iii) Z—

[D]_y is released;

wherein Y** is the remainder of Y*, and is independently selected from the group consisting of O, S, or NR₁₂; and

Z—

[D]_y crosses the membrane of the cell, and is hydrolyzed therein to release D.

29. The compound of claim 2, wherein X is selected from the group consisting of O, NR₁₂,

S, SO and SO₂ where R₁₇ is 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.

30. A compound of Formula I:

wherein;

L₁ is a bifunctional linking moiety;

each D moiety is independently a residue of an anticancer agent, an anticancer prodrug, a detectable tag, or combinations thereof;

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, 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 cyoloalkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C_1-6 carboxyalkyls and C_1-6 alkylcarbonyls;

Ar is a moiety which when included in Formula (V) 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;

31. The compound of claim 30 wherein the anticancer agent or anticancer prodrug comprises an anthracycline compound or a topoisomerase T inhibitor.

32. The compound of claim 30 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.

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

with a compound of formula;

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

with at least one biologically active material;

wherein

L₁ is a bifunctional linking moiety;

La is a leaving group for Formula V;

Z is covalently linked to La and 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;

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 cyoloalkyls, 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,

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

R₁₁ is a monovalent or divalent polymer residue

wherein after the reaction Z is covalently linked to the at least one biologically active material.

35. A compound of Formula I:

wherein;

L₁ —

C(═

Y₃) comprises an amino acid residue;

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 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 cyoloalkyls, 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-, 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; and

(p) is zero or a positive integer; and

(y) is 1 or 2.