INDENOISOQUINOLINE-RELEASABLE POLYMER CONJUGATES

• US 20090156629A1
• Filed: 06/08/2007
• Published: 06/18/2009
• Est. Priority Date: 06/09/2006
• Status: Abandoned Application

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Gao, Ying, Zhao, Hong
• Application Number:
  US12/301,346
• Publication Number:
  US 20090156629A1
• Time in Patent Office: Days
• US Class Current: 514/283
• 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: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention provides releasably-linked indenoisoquinoline polymer conjugates. Methods of making the conjugates and methods of treating mammals using the same are also disclosed.

Claims

1. A compound of Formula (I)

wherein

A is a capping group

R is a substantially non-antigenic water-soluble polymer;

and

L and L′

are independently selected releasable linkers.

2. The compound of claim 1, wherein the independently selected releasable linkers are of the Formula (II)

wherein

L₁ is a bifunctional linking moiety;

Y_1-4 are independently O, S, or NR₁₂;

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-, cyano-, carboxy-, C_1-6 carboxyalkyls and C_1-6 alkyl carbonyls;

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

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

(m) and (p) are independently zero a positive integer.

3. A compound of claim 1 having the Formula (III)

wherein

A is a capping group or

R is a substantially non-antigenic water-soluble polymer;

L₁ is a bifunctional linking moiety;

Y_1-4 are independently O, S, or NR₁₂;

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-, cyano-, carboxy-, C_1-6 carboxyalkyls and C_1-6 alkyl carbonyls;

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

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

(m) and (p) are independently zero a positive integer.

4. The compound of claim 3, wherein the capping group is selected from the group consisting of hydrogen, NH₂, OH, CO₂H, C_1-6 alkyl, C_1-6 alkoxy, and dialkyl acyl urea alkyls.

5. The compound of claim 3, wherein the capping group is CH₃ or OCH₃.

6. The compound of claim 3, wherein A is

7. A compound of claim 3 having the formula

8. A compound of claim 7 having the formula

9. A compound of claim 3, having the formula

10. The compound of claim 3, wherein R comprises a linear, terminally branched or multi-aimed polyalkylene oxide.

11. The compound of claim 3, wherein R is selected from the group consisting of —

C(═

Y₂₁)—

(CH₂)_n—

O—

(CH₂CH₂O)_x-A, and —

C(═

Y₂₁)—

Y₂₂—

(CH₂)_n—

O—

(CH₂CH₂O)_x-A

wherein

(n) is zero or a positive integer;

Y_21-22 are independently O, S or NR₁₂; and

(x) represents the degree of polymerization.

12. The compound of claim 10, wherein said polyalkylene oxide is a polyethylene glycol of the formula:

—

O—

(CH₂CH₂O)_x—

wherein x is an integer from about 10 to about 2,300.

13. The compound of claim 10, wherein the polyalkylene oxide has an average molecular weight from about 2,000 to about 100,000 Daltons.

14. The compound of claim 10, wherein the polyalkylene oxide residue has an average molecular weight of from about 10,000 to about 80,000 daltons.

15. The compound of claim 10, wherein the polyalkylene oxide has an average molecular weight from about 20,000 to about 60,000 Daltons.

16. The compound of claim 10, wherein the polyalkylene oxide has an average molecular weight of about 40,000 Daltons.

17. The compound of claim 3, wherein (m) and (p) are zero.

18. The compound of claim 3, wherein R₁, R₄, R₉ and R₁₀ are all hydrogen.

19. The compound of claim 3, wherein Y_1-4 are O.

20. A compound of claim 3, selected from the group consisting of:

wherein PEG has the formula;

—

(CH₂CH₂O)_x—

CH₂CH₂—

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

21. A compound of claim 3 is

wherein x Is an integer from about 10 to about 2300.

22. A pharmaceutically acceptable formulation containing an effective amount of a compound of claim 3 or salt thereof.

23. A method of treating cancers, comprising administering an effective amount of a compound of claim 3 to a patient in need thereof.

24. The method of claim 23, wherein the compound of claim 3 is

wherein x is an integer from about 10 to about 2300.

25. A method of preparing a compound of Formula (III), comprising;

(a) providing an activated polymer having the structure;

(b) reacting the activated polymer with a protected indenoisoquinoline having the structure;

(c) removing the protecting group from the resulting intermediate of step (b) to form the compound of Formula (III);

wherein

A is a capping group or

R is a substantially non-antigenic water-soluble polymer;

L₁ is a bifunctional linking moiety;

Y_1-4 are independently O, S, or NR₁₂;

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-, cyano-, carboxy-, C_1-6 carboxyalkyls and C_1-6 alkyl carbonyls;

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

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

(m) and (p) are independently zero or a positive integer;

B₁ is a leaving group; and

B₂ is a protecting group.