RELEASABLE POLYMERIC CONJUGATES BASED ON ALIPHATIC BIODEGRADABLE LINKERS

• US 20080305070A1
• Filed: 07/25/2008
• Published: 12/11/2008
• Est. Priority Date: 08/13/2002
• Status: Active Grant

• Current Assignee: Belrose Pharma, Inc.
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: ZHAO, Hong, GREENWALD, Richard B., ADLER, Susan L.
• Granted Patent: US 8,192,743 B2
• Time in Patent Office: Days
• US Class Current: 424/78.19
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 277/16 Sulfur atoms
• CPC Class Codes: C07H 15/24 Condensed ring systems having three or more rings

Abstract

Activated polymeric bicine derivatives such as,

as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.

Claims

1. A compound comprising Formula (I):

wherein;

R₁ is selected from the group consisting of substantially non-antigenic polymer residues, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, aralkyls, and terminal branching groups;

Z and Z′

are the same or different and are independently selected from the group consisting of hydrophobic moieties, bifunctional linking moieties,

wherein L₅ is a bifunctional linker and Y₄ is O, S or NR₁₁, and combinations thereof;

Y_1-3 may be the same or different and are selected from the group consisting of O, S and NR₁₁;

L₁ and L₃ are independently selected bifunctional linkers;

R₃-R₁₁, R₂₄ and R₂₅ may be the same or different and are selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, 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;

L₂ is —

C(O)(CR₃₀R₃₁)Y₁₅(CR₃₂R₃₃)C(O)NR₃₅—

or —

C(O)(CR₃₀R₃₁)(CR₃₂R₃₃)C(O)NR₃₅—

wherein;

Y₁₅ is selected from the group consisting of O, S, NR₃₄ and CH₂, and

R_30-35 may be the same or different and are selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl and aryl;

A and A′

may be the same or different and are independently selected from the group consisting of alkyl groups, leaving groups, functional groups, diagnostic agents, targeting moieties, biologically active moieties, and OH;

a, g, and e are the same or different and are independently 0 or a positive integer from about 1 to about 5;

b, c, d and d′

are the same or different and are independently 0 or 1, and

m, n, n, o, and p are the same or different and are independently a positive integer from about 1 to about 6,

provided that (a+e) is equal to or greater than 1.

2. The compound of claim 1, wherein R₃-R₁₀, R_24-25 and R_30-34 are each hydrogen;

and Y₁₅ is O or NR₃₄.

3. The compound of claim 1, wherein a, b, c, d, d′

, g, m, n, o and p are each 1.

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

5. The compound of claim 1, wherein R₁ comprises a polyethylene glycol.

6. The compound of claim 1, wherein A is selected from the group consisting of an activating group, a targeting group and a biologically active moiety, and A′

is selected from the group consisting of an alkyl group, an activating group, a targeting group and a diagnostic agent.

7. The compound of claim 1 wherein R₁ further comprises a capping group J, selected from the group consisting of OH, NH₂, SH, CO₂H, C_1-6 alkyl moieties, and

8. A compound of claim 7, of the formula:

9. The compound of claim 1, wherein R₁ is selected from the group consisting of:

J-O—

(CH₂CH₂O)_x—

,

J-O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

J-O—

(CH₂CH₂O)_x—

CH₂CH₂NR₁₂—

,

J-O—

(C₂CH₂O)_x—

CH₂CH₂S—

,

—

OC(O)CH₂—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

—

NR₁₂CH₂CH₂—

O—

(CH₂CH₂O)_x—

CH₂CH₂NR₁₂— and

—

SCH₂CH₂—

O—

(CH₂CH₂O)_x—

CH₂CH₂S—

.

wherein;

x is the degree of polymerization;

R₁₂ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyl, C_2-6 alkynyl, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, 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; and

J is a capping group.

10. The compound of claim 1, wherein R₁ is selected from the group consisting of:

CH₃—

O—

(CH₂CH₂O)_x—

,

CH₃—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

CH₃—

O—

(CH₂CH₂O)_x—

CH₂CH₂NH— and

CH₃—

O—

(CH₂CH₂O)_x—

CH₂CH₂S—

wherein x is the degree of polymerization.

11. The compound of claim 1, wherein R₁ comprises a polymer residue of the formula

wherein:

x is the degree of polymerization.

12. The compound of claim 1 wherein L₁ and L₃ are independently selected the group consisting of:

—

NR₁₉(CR₁₄R₁₅)_tO—

,

—

NR₁₉(CR₁₄R₁₅)_t(CR₁₆CR₁₇O)_sNR₁₉—

,

—

O(CR₁₄R₁₅)_tNR₁₉—

,

—

O(CR₁₄R₁₅)_tO—

,

—

NR₁₉(CR₁₄R₁₅)_tCR₁₉—

,

—

NR₁₉(CR₁₄R₁₅)_t(CR₁₆CR₁₇O)_s—

,

—

NR₁₉(CR₁₆CR₁₇O)_t—

,

—

NR₁₉(CR₁₆CR₁₇O)_t(CR₁₄R₁₅)_sNR₁₉—

,

—

O(CR₁₆CR₁₇)_tNR₁₉—

wherein;

R₁₄-R₁₇ and R₁₉ are independently selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, 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;

R₁₈ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, 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, NO₂, haloalkyl and halogen; and

t and s are individually selected positive integers from about 1 to about 4.

13. The compound of claim 1 wherein L₂ is selected from the group consisting of:

—

C(O)CR₃₀R₃₀OCR₃₂R₃₃C(O)NR₃₅—

,

—

C(O)CR₃₀R₃₁NR₃₄CR₃₂R₃₃C(O)NR₃₅—

,

—

C(O)CR₃₀R₃₁SCR₃₂R₃₃C(O)NR₃₅— and

—

C(O)(CR₃₀R₃₁)_n′

C(O)NR₃₅—

wherein;

R_30-34 are independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 heteroalkyl and aryl; and

n′

is a positive integer from about 1 to about 3.

14. A compound of claim 1, wherein R₁ is selected from the group consisting of:

wherein;

(q) is an integer of from about 1 to about 5;

Z″

is O, NR₁₃, S, SO or SO₂

where R₁₃ is H, C_1-8 alkyl, C_1-8 branched alkyl, C_1-8 substituted alkyl, aryl or aralkyl;

(h) is 0 or 1; and

(k) is a positive integer from about 1 to about 6.

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

wherein A₁ is a leaving group.

16. The compound of claim 1, wherein A is a leaving group selected from the group consisting of

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

wherein;

Y₆ and Y₇ are independently O, S or NR₄₆;

L₆ is a bifunctional linker selected from the same group as that which defines L₁;

L₈ is a bifunctional linker selected from the same group as that which defines L₂;

R₄₀-R₄₆ may be the same or different and are selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, 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;

j, j′

, i and i′

are each independently 0 or a positive integer;

l and l′

are independently 0 or 1;

u, r, v and w are independently selected positive integers; and

R₅₀ is selected from the group consisting of substantially non-antigenic polymer residues, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, aralkyls, and

wherein;

L₇ is a bifunctional linker selected from the same group as that which defines L₁;

L₉ is a bifunctional linker selected from the same group as that which defines L₂; and

R₆₀ is selected from the group consisting of substantially non-antigenic polymer residues, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, and aralkyls.

18. A compound of claim 17, comprising the structure:

19. A compound of claim 18, comprising the structure:

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

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

wherein;

and

x is the degree of polymerization.

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

wherein

A and A′

are independently leaving groups;

and

x is the degree of polymerization.

25. A method of treatment, comprising administering to a mammal in need thereof, an effective amount of a compound of claim 1, wherein A′

is an alkyl group and A is a residue of a biologically active agent.

23. A method of preparing a polymer conjugate, comprising reacting a compound of the formula:

wherein;

A₁ is a leaving group;

A′

is selected from the group consisting of alkyl groups, leaving groups, functional groups, diagnostic agents, targeting moeities and OH;

R₁ is selected from the group consisting of substantially non-antigenic polymer residues, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, aralkyls, and terminal branching groups;

Z and Z′

are the same or different and are independently selected from the group consisting of hydrophobic moieties, bifunctional linking moieties,

wherein L₅ is a bifunctional linker and Y₄ is O, S or NR₁₁, and combinations thereof;

Y_1-3 are the same or different and are selected from the group consisting of O, S and NR₁₁;

L₁ and L₃ are independently selected bifunctional linkers;

R₃-R₁₁, R₂₄ and R₂₅ are the same or different and are selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, 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;

L₂ is —

C(O)(CR₃₀R₃₁)Y₁₅(CR₃₂R₃₃)C(O)NR₃₅—

or —

C(O)(CR₃₀R₃₁)(CR₃₂R₃₃)C(O)NR₃₅—

wherein;

Y₁₅ is selected from the group consisting of O, S, NR₃₄ and CH₂, and

R_30-35 are the same or different and are selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl and aryl;

a, g, and e are the same or different and are independently 0 or a positive integer;

b, c, d and d′

are independently 0 or 1;

m, n, o, and p are independently positive integers;

provided that (a+e) is equal to or greater than 1;

with a biologically active agent under conditions sufficient to form

wherein A₂ is a residue of a biologically active agent.

24. A method of preparing a bicine-based polymer transport system, comprising:

1) reacting one equivalent of an extended blocked bifunctional linker with one equivalent of an acid protected bicine moiety to form an intermediate of the formula;

where tBu is a protecting group;

2) reacting the intermediate above with an acylating agent to form an intermediate;

3) deblocking the resultant intermediate above and reacting it with an activated polymer under basic coupling conditions; and

4) deprotecting the bicine acid and thereafter activating the acid with a suitable activating group under coupling conditions.