Conjugates formed from polymer derivatives having particular atom arrangements
View Patent ↗Polymeric reagents are provided comprising a moiety of atoms arranged in a specific order, wherein the moiety is positioned between a water-soluble polymer and a reactive group. The polymeric reagents are useful for, among other things, forming polymer-active agent conjugates. Related methods, compositions, preparations, and so forth are also provided.
1. A conjugate of the following structure:
wherein:
POLY 1 is a water-soluble polymer selected from the group consisting of poly(alkylene glycols), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline and poly(N-acryloylmorpholine);
POLY 2 is a water-soluble polymer selected from the group consisting of poly(alkylene glycols), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline and poly(N-acryloylmorpholine);
(a) is 0, 1, 2 or 3;
(b) is 0, 1, 2 or 3;
(e) is 0, 1, 2 or 3;
(f 1 ) is 0, 1, 2 or 3;
(g 1 ) is 0, 1, 2 or 3;
(h) is 0, 1, 2 or 3;
(j) is 0, 1, 2 or 3;
Each R l is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl;
X 1 , when present, is a first spacer moiety;
X 2 , when present, is a second spacer moiety;
X 5 , when present, is a fifth spacer moiety;
X 6 , when present, is a sixth spacer moiety;
X 7 , when present, is a seven spacer moiety;
X 8 , when present, is an eight spacer moiety;
R 1 is a branching moiety selected from the group consisting of
wherein (p) is 1-10 and (q) is 1-10; and
Active Agent is a residue of a pharmacologically active agent.
2. The conjugate of claim 1 , wherein each R 1 is H.
3. The conjugate of claim 1 , wherein each water-soluble polymer is a poly(alkylene glycol).
4. The conjugate of claim 3 , wherein each poly(alkylene glycol) is a poly(ethylene glycol).
5. The conjugate of claim 4 , wherein each poly(ethylene glycol) is terminally capped with methoxy.
6. The conjugate of claim 4 , wherein each poly(ethylene glycol) has a molecular weight of from about 100 Daltons to about 100,000 Daltons.
7. The conjugate of claim 6 , wherein each poly(ethylene glycol) has a molecular weight of from about 1,000 Daltons to about 60,000 Daltons.
8. The conjugate of claim 7 , wherein each poly(ethylene glycol) has a molecular weight of from about 2,000 Daltons to about 50,000 Daltons.
9. The conjugate of claim 1 , has the following structure:
when the branching moiety R 5 is:
and,
wherein:
(m) is 2 to 4000;
(g 1 ) is 0, 1, 2 or 3;
(h) is 0, 1, 2 or 3;
(j) is 0 to 20;
(p) is 1;
(q) is 1; and
Active Agent is a residue of a pharmacologically active agent.
10. The conjugate of claim 9 , of the following structure:
(m) is 2 to 4000;
(g 1 ) is 0, 1, 2 or 3;
(c) is 1 to 10;
each R 2 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl;
each R 3 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl;
(j) is 0 to 20; and
Active Agent is a residue of a pharmacologically active agent.
11. The conjugate of claim 9 , wherein the pharmacologically active agent is selected from the group consisting of erythropoietin, granulocyte colony stimulating factor, interferon-α, human growth hormone, interferon-β, follicle stimulating hormone, Factor VIII, B-domain deleted Factor VIII, desmopressin and amdoxivir.
12. The conjugate of claim 9 , of the following structure:
wherein:
(m) is 2 to 4000;
(g 1 ) is 0, 1, 2 or 3;
(c) is 1 to 10;
each R 2 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl;
each R 3 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl;
(j) is 0 to 20; and
Active Agent is a residue of a pharmacologically active agent.
13. The conjugate of claim 12 , wherein the pharmacologically active agent is selected from the group consisting of erythropoietin, granulocyte colony stimulating factor, interferon-α, human growth hormone, interferon-β, follicle stimulating hormone, Factor VIII, B-domain deleted Factor VIII, desmopressin and amdoxivir.
14. The conjugate of claim 9 , of the following structure:
wherein:
(m) is 2 to 4000; and
Active Agent is a residue of a pharmacologically active agent.
15. The conjugate of claim 14 , wherein the pharmacologically active agent is selected from the group consisting of human growth hormone.
16. The conjugate of claim 1 , wherein the pharmacologically active agent is selected from the group consisting of erythropoietin, granulocyte-colony stimulating factor, interferon-α, human growth hormone, interferon-β, follicle stimulating hormone, Factor VIII, B-domain deleted Factor VIII, desmopressin and amdoxivir.
17. The conjugate of claim 1 , wherein each R 1 is H.
18. The conjugate of claim 1 , wherein each R 1 is an organic radical and is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl , alkynyl substituted alkynyl, aryl and substituted aryl.