Granted Patent B2

US 7,887,789 · App. 10/851,691 · Granted Feb 15, 2011

Abstract

Claims (45)

1. A polymeric reagent of the following structure

wherein:

POLY 1 is a linear, water-soluble homopolymer selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyols);

POLY 2 is a linear, water-soluble homopolymer selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyols);

(a) is 0, 1, 2 or 3;

(b) is 0, 1, 2 or 3;

(e) is 0, 1, 2 or 3;

(f) is 0, 1, 2 or 3;

(g′) is 0, 1, 2 or 3;

(h) is 0, 1, 2 or 3;

(j) is 0 to 20;

each R 1 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 of a linear chain of from one to twenty atoms in length wherein the first spacer moiety is composed of one or more atoms each independently selected from the group consisting of carbon, nitrogen, oxygen, sulfur and hydrogen;

X 2 , when present, is a second spacer moiety of a linear chain of from one to twenty atoms in length wherein the second spacer moiety is composed of one or more atoms each independently selected from the group consisting of carbon, nitrogen, oxygen, sulfur and hydrogen;

X 5 , when present, is a fifth spacer moiety of a linear chain of from one to twenty atoms in length wherein the fifth spacer moiety is composed of one or more atoms each independently selected from the group consisting of carbon, nitrogen, oxygen, sulfur and hydrogen;

X 6 , when present, is a sixth spacer moiety of a linear chain of from one to twenty atoms in length wherein the sixth spacer moiety is composed of one or more atoms each independently selected from the group consisting of carbon, nitrogen, oxygen, sulfur and hydrogen;

X 7 , when present, is a seventh spacer moiety of a linear chain of from one to twenty atoms in length wherein the seventh spacer moiety is composed of one or more atoms each independently selected from the group consisting of carbon, nitrogen, oxygen, sulfur and hydrogen;

X 8 , when present, is an eighth spacer moiety of a linear chain of from one to twenty atoms in length wherein the eighth spacer moiety is composed of one or more atoms each independently selected from the group consisting of carbon, nitrogen, oxygen, sulfur and hydrogen;

R 5 is a three-way branching moiety selected from the group consisting of

wherein (p) is 1-8 and (q) is 1-8; and

Z is a reactive group suitable for reaction with an electrophile or a nucleophile of a biologically active agent.

2. The polymeric reagent of claim 1 , wherein each R 1 is H.

3. The polymeric reagent of claim 2 , wherein each R 1 is an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl.

4. The polymeric reagent of claim 2 , wherein each R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tent-butyl, n-pentyl, isopentyl, neopentyl, tort-pentyl, and piperidonyl.

5. The polymeric reagent of claim 1 , wherein each water-soluble polymer is a poly(alkylene oxide).

6. The polymeric reagent of claim 5 , wherein each poly(alkylene oxide) is a poly(ethylene glycol).

7. The polymeric reagent of claim 6 , wherein each poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting hydroxyl and alkoxy.

8. The polymeric reagent of claim 6 , wherein each poly(ethylene glycol) is terminally capped with methoxy.

9. The polymeric reagent of claim 7 , wherein each poly(ethylene glycol) has a molecular weight of from about 100 Daltons to about 100,000 Daltons.

10. The polymeric reagent of claim 9 , wherein each poly(ethylene glycol) has a molecular weight of from about 1,000 Daltons to about 60,000 Daltons.

11. The polymeric reagent of claim 10 , wherein each poly(ethylene glycol) has a molecular weight of from about 2,000 Daltons to about 50,000 Daltons.

12. The polymeric reagent of claim 1 , wherein each nitrogen atom of each

moiety is linked to the water-soluble polymer through a direct covalent bond.

13. The polymeric reagent of claim 1 , wherein each nitrogen atom of each

moiety is linked to the water-soluble polymer through a first spacer moiety.

14. The polymeric reagent of claim 1 , wherein the reactive group is selected from the group consisting of hydroxyl, ester, orthoester, carbonate, acetal, aldehyde, aldehyde hydrate, ketone, vinyl ketone, ketone hydrate, thione, monothiohydrate, dithiohydrate, hemiketal, monothioketal hemiketal, dithiohemiketal, ketal, dithioketal, alkenyl, acrylate, methacrylate, acrylamide, sulfone, amine, hydrazide, thiol, disulfide, thiol hydrate, carboxylic acid, isocyanate, isothiocyanate, maleimide, succinimide, benzotriazole , vinylsulfone, chloroethylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, thiosulfonate, tresylate, silane, —(CH 2 ) r CO 2 H, —(CH 2 ) r′ —CO 2 NS, —(CH 2 ) r′ CO 2 Bt, —(CH 2 ) r CH(OR) 2 , —(CH 2 ) r CHO, —(CH 2 ) 2 —NH 2 , —(CH 2 ) r M, —(CH 2 ) r —S—SO 2 —R, where r is 1-5, r′ is 0-5, R is aryl or alkyl, NS is N-succinimidyl, Bt is 1-benzotriazolyl, and M is N-maleimidyl, and protected and activated forms of any of the foregoing.

15. The polymeric reagent of claim 1 , comprising a structure of:

wherein (m) is 2 to 4000, and (f) is 0 to 6 and (n) is 0 to 20.

16. The polymeric reagent of claim 15 , wherein (f) is 2 to 4 and (n) is 0 to 4.

17. The polymeric reagent of claim 1 , comprising a structure selected from the group consisting of:

wherein each (m) is 2 to 4000.

18. The polymeric reagent of claim 1 , comprising a structure selected from the group consisting of

19. The polymeric reagent of claim 1 , comprising a structure selected from the group consisting of

20. The polymeric reagent of claim 1 , comprising a structure selected from the group consisting of

wherein each (m) is 2 to 4000 and each (n) 0 to 20.

Assignments (6)