Terminally-branched polymeric linkers and polymeric conjugates containing the same

• US 6,638,499 B2
• Filed: 02/06/2002
• Issued: 10/28/2003
• Est. Priority Date: 04/17/1998
• Status: Expired due to Fees

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Pendri, Annapurna, Choe, Yun H., Greenwald, Richard B., Martinez, Anthony J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US10/067,930
• Publication Number:
  US 20020103259A1
• Time in Patent Office: 629 Days
• Field of Search: 424/78.3, 514/772.3, 514/283, 514/506, 514/513, 514/515, 514/613, 514/626
• US Class Current: 424/78.3
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 15/252 Naphthacene radicals, e.g. daunomycins, adriamycins
• CPC Class Codes: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G

Abstract

The present invention is directed to polymeric-prodrug transport forms of the formula:

wherein:

E_1-4 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, C_1-6 heteroalkoxy,

and at least one of E_1-4 includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or

wherein J₁ is the same as J, or another member of the group defining J and E₅ is the same as E_1-4, or another member of the group defining E_1-4,

Y_1-2 are independently O, S or NR₉;

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

R_2-5 and R_7-9 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 heteroakoxy;

(m1) and (m2) are independently zero or one;

(n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer,

Z is an electron withdrawing group; and

R₁ is a polymeric residue.

which is optionally capped with a moiety of the formula:

Claims

1. A compound comprising the formula:

E₄ is 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 substituwd 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_1-3 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, C_1-6 heteroalkoxy, and at least one of E_1-3 is

wherein B is a (caving group, OH. a residue of a hydroxyl-containing moiety, a residue of an amine-containing moiety or

wherein J₁ is the same as J, or another member of the group defining J and E₅ is the same as E_1-4, or another member of the group defining E_1-4;

Y_1-2 are independently O, S or NR₉;

M is a heteroatom selected from either X or Q;

wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═

Y₂);

R_2-5 and R_7-9 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,

(m1) and (m2) are independently zero or one;

(n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer;

Z is an electron withdrawing group; and

R₁ is a polymeric residue of a substantially ron-antigenic polymer having a molecular weight of at least about 20,000 Daltons.

2. A compound of claim 1, having a formula selected from the group consisting of:

wherein (x) represents the degree of polymerization and “

Drug”

represents a residue of a hydroxyl- or amine-containing biologically active compound which has undergone a substitution reaction which results in the attachment of the biologically active moiety to the branched polymer.

3. The compound of claim 1, wherein Y₁ and Y₂ are oxygen.

4. The compound of claim 1, wherein R_2-5, R₇ and R₈ are hydrogen.

5. The compound of claim 1, wherein X is selected from the group consisting of O, S, SO, SO₂, C(Y₃) and NR₆, wherein Y₃ is selected from the group consisting of O, S and R₉, and R₆ is 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.

6. The compound of claim 1, wherein Q is selected from the group consisting of C_2-4 alkyls, cycloalkyls, aryls, aralkyl groups substituted with a member of the group consisting of NH, O, S, —

CH₂—

C(O)—

NH—

, and ortho-substituted phenyls.

7. The compound of claim 1, wherein (p1) and (p2) are 1.

8. The compound of claim 1, wherein (n1) and (n2) are individually 1 or 2.

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

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

11. The compound of claim 10, wherein said polyalkylene oxide residue comprises polyethylene glycol.

12. The compound of claim 1, wherein said polymeric residue has a molecular weight of from about 20,000 to about 40,000.

13. The compound of claim 1, wherein B is a residue of a member of the group consisting of Ara-C, camptothecin, camptothecin analogs, paclitaxel, taxoteres, gemcitabine, podophyllotoxin, fluconazole, ciclopirox, amphoteracin B, nystatin, doxorubicin, daunorubicin, maytansine, vancomycin and erythromycin.

14. A method of treating a mammal with prodrugs, comprising:

administering to a mammal in need of such treatment an effective amount of a composition of claim 2.