Conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates

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Quick Facts

Patent No.: US 8,252,275
App. No.: 11/454,971
Granted: Aug 28, 2012
Kind: B2

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Abstract

The present invention provides conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates. The conjugates as well as the polymeric reagents used to form the conjugates include at least one of each the following: an aromatic moiety comprising an ionizable hydrogen atom, a spacer moiety, and a water-soluble polymer. Methods of making polymeric reagents and conjugates, as well as methods for administering conjugates and compositions, are also provided.

Claims (64)

1. A polymeric reagent of the following formula:

wherein:

POLY 1 is a first water-soluble polymer selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, and poly(N-acrylmorpholine);

POLY 2 is a second water-soluble polymer selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, and poly(N-acrylmorpholine);

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

2. The polymeric reagent of claim 1 , wherein each of POLY 1 and POLY 2 is a poly(alkylene glycol), wherein the poly(alkylene glycol) is a poly(ethylene glycol).

3. The polymeric reagent of claim 2 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6,000 Daltons.

4. The polymeric reagent of claim 2 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.

5. The polymeric reagent of claim 1 , wherein the first spacer moiety is selected from the group consisting of —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —NH—C(O)—, —NH—C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —NH—CH 2 —CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —C(O)—NH—(CH 2 CH 2 O) 1-3 —CH 2 —CH 2 —NH—, —C(O)—NH—CH 2 —CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —C(O)—NH—(CH 2 CH 2 O) 1-3 —CH 2 —CH 2 —NH—C(O)—, —NH—C(O)—CH 2 —, —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —O—, —O—CH 2 —C(O)—NH—, —CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —O—CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —O—, —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —O—, and —O—CH 2 —CH 2 —NH—C(O)—, and the second spacer moiety is selected from the group consisting of —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —NH—C(O)—, —NH—C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —NH—CH 2 —CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —C(O)—NH—(CH 2 CH 2 O) 1-3 —CH 2 —CH 2 —NH—, —C(O)—NH—CH 2 —CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —C(O)—NH—(CH 2 CH 2 O) 1-3 —CH 2 —CH 2 —NH—C(O)—, —NH—C(O)—CH 2 —, —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —O—, —O—CH 2 —C(O)—NH—, —CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —O—CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —O—, —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —O—, and —O—CH 2 —CH 2 —NH—C(O)—.

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

7. The polymeric reagent of claim 1 , wherein the functional group capable of reacting with an amino group of an active agent is selected from the group consisting of carbonates of N-succinimidyl, 1-benzotriazolyl, imidazole, imidazole, halides and phenolates.

8. The polymeric reagent of claim 1 , wherein the functional group capable of reacting with an amino group is a carbonate of N-succinimidyl.

9. The polymeric reagent of claim 1 , of the formula: