Coumarin and related aromatic-based polymeric prodrugs

• US 6,214,330 B1
• Filed: 07/13/1998
• Issued: 04/10/2001
• Est. Priority Date: 07/13/1998
• Status: Expired due to Term

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Choc, Yun H., Greenwald, Richard B., Pendri, Annapurna
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/114,860
• Time in Patent Office: 1,002 Days
• Field of Search: 549/283, 549/273, 549/263, 424/78.01, 424/78.02, 424/78.03, 424/78.04, 424/78.05, 424/78.06, 424/78.07, 424/78.08, 548/400, 548/401, 548/416
• US Class Current: 424/78.01
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• 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

The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of the formula:

wherein:

B is H, OH, OSiR₁₃, a residue of an amine-containing target moiety or a residue of a hydroxyl-containing target moiety,

G is

or CH₂;

Y_1-2 are independently O or S;

M is X or Q; where X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y₂);

R₁, R₄, R₇, R₈, R₉, R₁₀ and R₁₃ are independently one 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, C_1-6 heteroalkoxy, except that R₁ and R₄ can also be a cyano, nitro, carboxyl, acyl, substituted acyl, carboxyalkyl;

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

(m) is zero or one;

(n) is zero or a positive integer;

(p) is zero, one or two;

(q) is three or four; and

R₁₁ is a substantially non-antigenic polymer.

Claims

1. A compound of the formula:

wherein

B is H, OH, OSiR₁₃, a residue of an amine-containing target moiety or a residue of a hydroxyl-containing target moiety;

G is

or CH₂;

Y₁and Y₂ are independently O or S;

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 C(═

Y₂);

R₇, R₈, R₉, R₁₀ and R₁₃ are independently 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 cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl, C_1-6 alkoxy, phenoxy, C_1-6 heteroalkoxy;

R₁ and R₄ are independently 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 cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl, C_1-6 alkoxy, phenoxy, C_1-6 heteroalkoxy, cyano, nitro, carboxyl, acyl, substituted acyl, carboxyalkyl;

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

(m) is zero or one;

(n) is zero or a positive integer;

(p) is zero or one;

(q) is three or four; and

R₁₁ is a polymer residue.

2. The compound of claim 1, wherein the aromatic moiety formed by Ar is selected from the group consisting of:

wherein J is O, S, or NR₁, E and Z are independently CH, O, S or NR₁; and

R₂, R₃, R₅ and R₆ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, C_1-8 heteroalkyl, C_1-8 heteroalkoxy, substituted C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 substituted cycloalkyl, aralkyl, aryl, and aryl substituted with moieties selected from the group consisting of halo-, nitro- and cyano-;

carboxy-, carboxyalkyl, and alkyl carbonyl.

3. The compound of claim 1, wherein said substituted C_1-6 alkyl is selected from the group consisting of carboxyalkyl, aminoalkyl, dialkylaminoalkyl, hydroxyalkyl and mercaptoalkyl.

4. The compound of claim 1 wherein X is selected from the group consisting of O, NR₁₂,

S, SO and SO₂, where Y₃ is O or S and where R₁₂ 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 cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl and substituted C_1-6 heteroalkyl.

5. The compound of claim 1, wherein Q is selected from the group consisting of C_2-4 alkyl, cycloalkyl, aryl, aralkyl groups substituted with a member of the group consisting of NH, O, S, —

CH₂—

C(O)—

NH—

, and ortho-substituted phenyl.

6. The compound of claim 1, wherein R₁₁ is selected from the group consisting of —

C(═

Y)—

(CH₂)_n—

O—

(CH₂CH₂O)_x—

A, —

C(═

Y)—

Y—

(CH₂)_n—

O—

(CH₂CH₂O)_x—

A and —

C(═

Y)—

NR₁₂—

(CH₂)_n—

O—

(CH₂CH₂O)_x—

A, where

R₁ and R₄ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl and substituted C_1-6 alkyl;

(n) is zero or a positive integer;

Y is O or S;

A is a capping group; and

(x) represents the degree of polymerization.

9. The compound of claim 2, wherein the aromatic moiety formed by Ar is

10. The compound of claim 2, wherein the aromatic moiety formed by Ar is

11. The compound of claim 10, wherein R₂ and R₅ are C_1-6 alkyls.

12. The compound of claim 10, wherein R₂ and R₅ are methyl.

13. The compound of claim 10, wherein R₃ and R₆ are hydrogen.

14. The compound of claim 1, wherein R₁₁ further comprises a capping group A.

15. The compound of claim 14, wherein A is selected from the group consisting of hydrogen, CO₂H, C_1-6 alkyl moiety, dialkyl acyl urea alkyl and

wherein B′

is the same as B or another member of the group defined as B.

16. The compound of claim 1, wherein R₁ and R₄ are independently selected from the group consisting of hydrogen, CH₃ and CH₂CH₃.

17. The compound of claim 4, wherein X is selected from the group consisting

18. The compound of claim 1, wherein (n) is an integer from about 1 to about 12.

19. The compound of claim 18, wherein (n) is 1 or 2.

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

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

22. The compound of claim 1, wherein (q) is 3.

23. The compound of claim 1, wherein Y₂ are O.

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

25. The compound of claim 24, wherein said polyalkylene oxide comprises polyethylene glycol.

26. The compound of claim 1, wherein said polymer has a molecular weight of from about 2,000 to about 100,000.

27. The compound of claim 26, wherein said polymer has a molecular weight of from about 5,000 to about 40,000.

28. The compound of claim 1, wherein B is a leaving group selected from the group consisting of N-hydroxybenzotriazolyl, halogen, N-hydroxyphthalimidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thione or an acid activating group.

29. The compound of claim 1, wherein B is a residue of a member of the group consisting of anthracyclines, daunorubicin, doxorubicin, p-hydroxyaniline mustard, Ara-C, and gemcitabine.

30. The compound of claim 1, wherein B is a residue of an enzyme, protein, peptide or an amine-containing compound.

31. The compound of claim 1, wherein B includes a second polymeric transport system.

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

35. A method of treatment, comprising:

administering to a mammal in need of such treatment an effective amount of a compound of claim 1, wherein B is a residue of an amine-containing or hydroxyl-containing target moiety.

7. A method for preparing a polymeric prodrug comprising:

a. contacting an intermediate compound (III)

where M₂ is a cleavable or reversible protecting group;

B₂ is a leaving group;

G is

or CH₂;

Y₁ and Y₂ are independently O or S;

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 C(═

Y₂);

R₁ and R₄ are independently 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 cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl, C_1-6 alkoxy, phenoxy, C_1-6 heteroalkoxy, cyano, nitro, carboxyl, acyl, substituted acyl, carboxyalkyl;

R₇ and R₈ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_3-2 branched alkyl, C_3-8 cycloalkyl, C_1-6 substituted alkyl, C_3-8 substituted cycloalkyl, aryl substituted aryl, aralkyl, C_1-6 heteroalkyl and substituted C_1-6 heteroalkyl;

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

(n) is zero or a positive integer;

(p) is zero, one or two;

(q) is three or four;

with an acid to deprotect the intermediate compound (III); and

b. reacting the unprotected intermediate with an activated polymer.

33. The method of claim 7, further comprising the step of

c. reacting the resultant compound of step b with an amine-containing or hydroxyl-containing compound to form a conjugate.

34. The method of claim 33, further comprising reacting said conjugate with an activated polymer to from a polymeric hybrid transport system.

8. A method for preparing a polymeric prodrug comprising:

a. providing an intermediate compound (III)

where M₂ is a cleavable or reversible protecting group;

B₂ is a leaving group;

G is

or CH₂;

Y₁ and Y₂ are independently O or S;

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 C(═

Y₂);

R₁ and R₄ are independently 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 cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl, C_1-6 alkoxy, phenoxy, C_1-6 heteroalkoxy, cyano, nitro, carboxyl, acyl, substituted acyl, carboxyalkyl;

R₇, and R₈ are independently 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 cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl and substituted C_1-6 heteroalkyl;

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

(n) is zero or a positive integer;

(p) is zero, one or two;

(q) is 3 or 4 and

b. coupling the intermediate compound (III) to an amine-containing compound or a hydroxyl-containing compound to form a second intermediate;

c. deprotecting the second intermediate with an acid; and

d. reacting the unprotected second intermediate with an activated polymer.