Methods for preparing conjugates

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Quick Facts

Patent No.: US 8,703,115
App. No.: 13/788,179
Granted: Apr 22, 2014
Kind: B2

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Abstract

The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a conjugate having a degradable linkage. 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 for delivering such compositions are also provided.

Claims (41)

1. A method for preparing a conjugate, wherein the method comprises: contacting 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,

with an amino group-containing active agent under conditions suitable to form a covalent attachment between the polymeric reagent and the amino group-containing active agent.

2. The method of claim 1 , wherein said contacting step is conducted using a molar excess of polymeric reagent.

3. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 2:1.

4. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 3:1.

5. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 4:1.

6. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 5:1.

7. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 6:1.

8. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 8:1.

9. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 10:1.

10. The method of claim 1 , wherein each of POLY 1 and POLY 2 is a poly(ethylene glycol).

11. The method of claim 10 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6,000 Daltons.

12. The method of claim 10 , 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.

13. The method 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—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)—.

14. The method of claim 1 , wherein R 1 is H and R 2 is H.

15. The method of claim 1 , wherein Y 1 is O and Y 2 is O.

16. The method of claim 1 , wherein the amino group-containing active agent is a polypeptide.

17. The method of claim 1 , wherein the conjugate corresponds to the following formula: