Terminally-branched polymeric linkers and polymeric conjugates containing the same

• US 6,395,266 B1
• Filed: 04/16/1999
• Issued: 05/28/2002
• 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: Greenwald, Richard B., Pendri, Annapurna, Martinez, Anthony J., Choe, Yun H.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Fubara, Blessing M.
• Application Number:
  US09/293,624
• Time in Patent Office: 1,138 Days
• Field of Search: 514/772.3,283,506,513,515,613,626 424/78.3
• 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_1-16 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.

which is optionally capped with a moiety of the formula:

Claims

1. A compound comprising 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 is

 

wherein B is a leaving 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, Cl_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, aralkyl., 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 non-antigenic polymer having a molecular weight of at least about 20,000 Daltons.

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

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

4. 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.

5. 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.

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

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

8. The compound of claim 7, wherein (n1) is 1 and (n2) is 2.

9. The compound of claim 1, wherein (m1) and (m2) are 1.

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

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

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

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

14. 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, amphotericin B, nystatin, doxorubicin, daunorubicin, maytansinie, vancomycin and erythromycin.

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

16. 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.

19. 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 1 wherein B is a residue of a biologically active moiety.

17. A method or preparing a polymeric transport system, comprising

a) reacting a compound of formula:

wherein J is

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 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;

Y₁ is O,S, or NR₉;

R_4-5 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 alkyls, 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 ), and (p2) are independently zero or a positive integer; and

(Z) is an electron withdrawing group;

with a compound of the formula;

 

wherein

B₂ is a leaving group which is capable of reacting with an unprotected amine;

Y₂is O,S, or NR₉;

q is independently zero or a positive integer;

R_2-3 are 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;

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); and

(R₁) is a polymeric residue; and

b) reacting the resultant compound with a sufficient amount of a biologically active moiety having a substitutable hydroxyl or amino group.

18. A method of preparing a polymeric transport system, comprising

a) reacting a sufficient amount of a biologically active moiety having a substitutable hydroxyl or amino group with a compound of the formula:

 

wherein B₃ is a cleavable protecting group;

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, 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;

Y₁ is O,S, or NR₉;

R_4-5 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), and (p2) are independently zero or a positive integer; and

(Z) is an electron withdrawing group;

with a biologically active moiety having a hydroxyl or amine group;

b) deprotecting the resultant intermediate by removing B₃; and

c) reacting the deprotected intermediate compound with a compound of the formula

 

wherein

B₂ is a leaving group which is capable of reacting with an unprotected amine;

Y₂ is O,S, or NR₉;

q is independently zero or a positive integer;

R_2-3 are 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;

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); and

(R₁) is a polymeric residue.