Terminally-branched polymeric linkers and polymeric conjugates containing the same

• US 20020183259A1
• Filed: 02/19/2002
• Published: 12/05/2002
• Est. Priority Date: 02/20/2001
• Status: Abandoned Application

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Greenwald, Richard B., Choe, Yun Hwang
• Application Number:
  US10/078,730
• Publication Number:
  US 20020183259A1
• Time in Patent Office: Days
• US Class Current: 514/19
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• 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: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

Terminally-branched polymeric prodrug platforms capable of high degrees of loading are disclosed. In preferred aspects of the invention, the prodrug platform releases multiple parent compounds after each branch holding the active agent undergoes a benzyl elimination reaction. Methods of preparing the prodrugs and using the same in the treatment of mammals are also disclosed. In one preferred aspect, polymeric conjugates such as

are provided.

Claims

1. A compound comprising the formula:

2. The compound of claim 1, wherein R, further comprises a capping group A, selected from the group consisting of hydrogen, NH₂, OH, CO₂H, C_1-6 moieties and

3. A compound of claim 2, comprising the formula:

4. The compound of claim 1, wherein said terminal branching group comprises the formula:

5. The compound of claim 3, Y₁ is O.

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

7. The compound of claim 6, wherein R₁ comprises a polyethylene glycol residue.

8. The compound of claim 3, wherein R₁ comprises a polyethylene glycol residue.

9. The compound of claim 6, wherein R₁ is selected from the group consisting of

—

C(═

Y₈)—

(CH₂)<sub>f—

O—

(CH2</sub>CH₂O)_x—

A, —

C(═

Y₈)—

Y₉—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

A, —

C(═

Y8)—

NR₂₀—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

A, —

(CR₂₁R₂₂)_e—

O—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

A, —

NR₂₀—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

A, —

C(═

Y₈)—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

(CH₂)_f—

C(═

Y₈)—

, —

C(═

Y₈)—

Y₉—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

(CH₂)_f—

Y₉—

C(═

Y₈)—

, —

C(═

Y₈)—

NR₂₀—

(CH₂)<sub>f—

O—

(CH2</sub>CH₂O)_x—

(CH₂)_f—

NR₂₀—

C(═

Y₈)—

, —

(CR₂₁R₂₂)_e—

O—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

(CH₂)_f—

O—

(CR₂₁R₂₂)_e—

, and —

NR₂₀—

(CH₂)_f—

O—

(CH₂CH₂O)_x—

(CH₂)_f—

NR₂₀—

wherein;

Y₈ and Y₉ are independently O, S or NR₂₀;

x is the degree of polymerization;

R₂₀, R₂₁ and R₂₂ are independently selected from among H, 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;

e and f are independently zero, one or two; and

A is a capping group.

10. The compound of claim 9, wherein R₁ comprises —

O—

(CH₂CH₂O)_x and x is a positive integer so that the weight average molecular weight is at least about 20,000.

11. The compound of claim 3, wherein R₁ has a weight average molecular weight of from about 20,000 to about 100,000.

12. The compound of claim 3, wherein R₁ has a weight average molecular weight of from about 25,000 to about 60,000.

13. A compound of claim 3, comprising the formula

14. The compound of claim 13, wherein D₁ is

15. The compound of claim 13, wherein D₁ is

16. The compound of claim 1, wherein L₁ is (CH₂CH₂O)₂.

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

—

CH₂—

, —

CH(CH₃)—

, —

CH₂C(O)NHCH(CH₃)—

, —

(CH₂)₂—

, —

CH₂ C(O)NHCH₂—

, —

(CH₂)₂—

NH—

, —

(CH₂)₂—

NH—

C(O)(CH₂)₂NH— and

—

CH₂C(O)NHCH(CH₂CH(CH₃)₂)—

.

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

19. A compound of claim 18, wherein B is a residue of a member of the group consisting of:

daunorubicin, doxorubicin;

p-aminoaniline mustard, melphalan, Ara-C (cytosine arabinoside), leucine-Ara-C, and gemcitabine

20. A method of treatment, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1, wherein D₁ is a residue of a biologically active moiety.

21. A method of treatment, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 18.

22. A method of preparing a polymer conjugate, comprising:

reacting a compound of the formula (VIII);

wherein (v) and (t) are independently 0 or a positive integer up to about 6;

L₁ and L₂ are independently selected bifunctional linkers;

Y_4-7 are independently selected from the group consisting of O, S and NR₁₄;

R_11-14 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;

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

B′

₁ is a residue of a hydroxyl- or an amine-containing moiety;

with a compound of the formula (IX);

wherein

E₅ is

E_6-8 are independently H, E₅ or

wherein

D₃ and D₄ are independently OH, a leaving group which is capable of reacting with an unprotected amine or hydroxyl or a terminal branching group;

R₁ is a polymeric residue;

Y₁ is O, S or NR₄;

M is O, S or NR₅;

(n) and (p) are independently 0 or a positive integer;

Y_2-3 are independently O, S or NR₁₀; and

R_2-10 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;

under conditions sufficient to cause a polymeric conjugate to be formed.