Trimethyl lock based tetrapartate prodrugs

• US 6,624,142 B2
• Filed: 05/09/2001
• Issued: 09/23/2003
• Est. Priority Date: 12/30/1997
• 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:
  US09/852,335
• Publication Number:
  US 20020006898A1
• Time in Patent Office: 867 Days
• Field of Search: 424/1.11, 424/9.1, 424/85.1, 424/94.3, 514/2, 514/15, 514/16, 514/17, 514/18, 514/19, 514/34, 514/49, 514/241, 514/247, 514/269, 514/291, 514/296, 514/345, 514/372, 514/380, 514/404, 514/422, 514/423, 514/424, 514/445, 514/473, 514/480, 514/490, 514/529, 514/546, 514/551, 514/564, 514/646, 514/656, 530/328, 530/329, 530/330, 530/331, 530/345, 530/408, 530/409, 530/410, 435/188, 525/50, 525/54.1, 525/403, 534/10, 536/6.4, 536/28.5, 544/180, 544/239, 544/298, 546/82, 546/110, 546/279.1, 546/290, 546/300, 546/301, 548/213, 548/243, 548/364.1, 548/370.1, 548/370.4, 548/518, 548/556, 549/66, 549/479, 560/129.155, 560/157, 560/170, 562/449
• 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
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/48 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms

Abstract

The invention is directed primarily to compounds of Formula I:

wherein:

R₁ is a

polymeric residue;

L₁ is a bifunctional linking group;

Y₁ and Y₂ are independently O, S or NR₇;

R_2-7 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, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy;

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

Z is selected from the group consisting of:

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

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

(y) is a positive integer greater than or equal to 1.

Methods of making and using the same are also disclosed.

Claims

1. A compound of Formula I:

wherein;

R₁ is a mono- or bivalent polymer residue,

L₁ is a bifunctional linking group;

Y₁ and Y₂ are independently O, S or NR₇;

R_2-7 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, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy;

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

Z is selected from the group consisting of;

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

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

(y) is a positive integer greater than or equal to 1.

2. The compound of claim 1, wherein y is 1 or 2.

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(═

NR₁₂), wherein R₁₂ is selected from the same group as R₂.

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 residue ranges in size from 2 to about 10 amino acid residues.

7. The compound of claim 6 wherein the peptide residue 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 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-hydroxyphthalimidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thione, and combinations thereof.

13. The compound of claim 1, wherein Y₁ and Y₂ are both O.

14. The compound of claim 1, wherein R₁ comprises a polyalkylene oxide residue.

15. The compound of claim 14, wherein said polyalkylene oxide residue comprises polyethylene glycol.

16. 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.

17. 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.

19. The compound of claim 1, wherein Ar is

wherein

R₂, R₉, R₁₀ and R₁₁ 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, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy.

20. The compound of claim 19 wherein R₂ is CH₃.

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

22. A compound of claim 21 wherein each polyethylene glycol (PEG) residue has a number average molecular weight of from about 20,000 to 40,000 daltons.

23. 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 the cell, together with a carrier acceptable for in vivo administration to an animal in need thereof.

26. 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.

27. 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 L₁* is the remainder of L₁, after hydrolysis of the polymeric residue (R₁); and

Formula (I-i) subsequently spontaneously hydrolyzes to Formula (I-ii)

 

and Formula I-(iii) Z—

[D]y;

and Z—

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

18. A compound of Formula (I):

wherein;

R₁ is a mono- or bivalent polymer residue,

L₁ is a bifunctional linking group;

Y₁ and Y₂ are independently O, S or NR₇;

R_2-7 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, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy;

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

Z is selected from the group consisting of;

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

Ar is selected from the group consisting of

 

wherein

R₂, R₉, R₁₀ and R₁₁ 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, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy;

Z₁ and Z₂ are independently CR₂₃ or NR₂₄; and

Z₃ is O, S or NR₂₅ where R_23-25 are selected from the same group as that which defines R₂ or a cyano, intro, carboxyl, acyl, substituted acyl or carboxyalkyl;

and (y) is a positive integer greater than or equal to 1.

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

with a compound of formula;

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

with at least one biologically active material;

wherein

R₁ is a polymeric residue;

L₁ is a bifunctional linking group;

Y₁ and Y₂ are independently O, S or NR₇;

R_2-7 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, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy;

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;

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

La is a leaving group for Formula IV wherein Z is covalently linked thereto.