Biodegradable high molecular weight polymeric linkers and their conjugates

• US 6,251,382 B1
• Filed: 04/15/1999
• Issued: 06/26/2001
• Est. Priority Date: 04/17/1998
• Status: Active Grant

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Greenwald, Richard B., Pendri, Annapurna, Martinez, Anthony J., Choe, Yun H.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US09/293,557
• Time in Patent Office: 803 Days
• Field of Search: 424/486, 424/78.17, 514/2, 525/54.1, 560/159
• US Class Current: 424/78.17
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

Polymeric compounds of the formula:

(D)_n—M—(R₁)_m  (I)

wherein

(m) and (n) independently selected positive integers, preferably from about 1 to about 6 each;

D is a residue of a biologically active moiety;

M is a multifunctional linker/spacer moiety; and

R₁ is a polymer residue are disclosed. Methods of preparing the same and methods of treatment using the same are also included as part of the present invention.

Claims

1. A polymer conjugate of the formula:

wherein;

D is a biologically active compound having an available hydroxyl group which undergoes a substitution reaction,

R₁ is a polymer residues;

R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R_9′

, R_10′

, R_11′

, and R_12′

are independently selected from hydrogen, C_1-6 substituted cycloalkyls, aryls, substituted aqyls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phonoxy and C_1-6 hoteroakoxy;

p is a positive integer;

m and n are independently selected positive integers; and

Y, Y₂, Y₃, Y′

, Y_2′

and Y_3′

are independently selected from O, S, NR₂.

2. The compound of claim 1 wherein D is a member of the group consisting of anti-tumor agents, cardiovascular agents, anti-neoplastics, anti-infectives, anti-fungals, anti-anxiety agents, gastrointestinal agents, central nervous system-activating agents, analgesics, fertility or contraceptive agents, anti-inflammatory agents, steroidal agents, anti-urecemic agents, cardiovascular agents, vasodilating agents and vasoconstricting agents.

3. The compound of claim 1, wherein Y, Y_2-3, Y′

and Y<sub>2′

-3′</sub>

are each oxygen.

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

5. The compound of claim 4, wherein said polyalkylene oxide residue comprises polyethylene glycol.

6. The compound of claim 4, wherein said polyalkylene oxide residue has a molecular weight of from about 2,000 to about 100,000.

7. The compound of claim 6, wherein said polyalkylene oxide residue has a molecular weight of from about 5,000 to about 50,000.

8. The compound of claim 7, wherein said polyalkylene oxide residue has a molecular weight of from about 20,000 to about 40,000.

9. The compound of claim 1, wherein m and n are each 1.

10. The compound of claim 1, wherein p is 3.

11. The compound of claim 1, herein R_1-7, R_9-12 and R_9′

-12′

are each individually H.

12. A method of preparing a polymer conjugate of the formula:

wherein;

D is a biologically active compound having an available hydroxyl group which undergoes a substitution reaction,

R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R_9′

, R_10′

, R_11′

, and R_12′

are independently selected from hydrogen, C_1-6 subftutd cycloalkyb, aryls, substituted arylsB ualkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phonoxy and C_1-6 hoteroakoxy;

p is a positive integer;

m and n are independently selected positive integers;

Y, Y₂, Y₃, Y′

, Y_2′

and Y_3′

are independently selected from O, S, NR₂; and

R₁ is a polymer residue;

wherein the method comprises;

(a) reacting a biologically active compound, bearing a hydroxyl group, with a partially blocked multifunctional mioety for a time and under conditions effective to form a covalent bond between said biologically active compound and said partially blocked multifunctional moiety;

(b) deblocking the product of step (a) to form a deblocked intermediate;

(c) reacting the deblocked intermediate with an activated polymer for a time and under conditions effective to form the polymer conjugate of claim 1; and

(d) isolating the polymer conjugate of claim 1.

13. A method of preparing a polymer conjugate of the formula:

wherein;

D is a biologically active mioety;

R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R_9′

, R_10′

, R_11′

and R_12′

are independently selected from hydrogen, C_1-6 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 salkoxy, phenoxy and C_1-6 hoteroakoxy;

p is a positive integer;

m and n are independently selected positive integers;

Y, Y₂, Y₃, Y′

, Y_2′

and Y_3′

are independently selected from O, S, NR₂; and

R₁ is a polymer residue;

wherein the method comprises;

(a) reacting multifunctional moiety with an activated polymer for a time and under conditions effective to form a covalent bond between aid multifunctional moiety and said polymer;

(b) reacting a biologically active compound, bearing a hydroxyl group, with the product of step (a) for a time and under conditions effective to form the polymer conjugate of claim 1; and

(c) isolating the polymer conjugate of claim 1.