Methods for preparing polymeric reagents
View Patent ↗The present invention provides among other things methods for preparing polymeric reagents, wherein the method comprises (a) providing an aromatic moiety bearing a hydroxy group, a first amino group and a second amino group; (b) reacting a functional group reagent with the hydroxy group to result in a hydroxy group bearing a functional group capable of reacting with an amino group of an active agent and resulting in a hydrolyzable carbamate; and (c) reacting a plurality of poly(alkylene glycol) water-soluble polymers bearing a reactive group with the first amino group and second amino group to result in (i) a first amino group bearing a water-soluble polymer through a spacer moiety, and (ii) a second amino group bearing a second water-soluble polymer through a spacer moiety.
1. A method for preparing a polymeric reagent, comprising
(a) providing an aromatic moiety bearing a hydroxy group, a first amino group and a second amino group and having the following structure,
(b) protecting the first amino group and second amino group;
(c) reacting a functional group reagent with the hydroxy group to result in a hydroxy group bearing a functional group capable of reacting with an amino group of an active agent and resulting in a hydrolyzable carbamate;
(d) deprotecting the first amino group and second amino group; and
(e) reacting a plurality of poly(alkylene glycol) water-soluble polymers bearing a reactive group with the first amino group and second amino group to result in (i) a first amino group bearing a water-soluble polymer through a spacer moiety, and (ii) a second amino group bearing a second water-soluble polymer through a spacer moiety,
wherein the polymeric reagent has the following structure:
and
POLY 1 is a first poly(alkylene glycol),
POLY 2 is a second poly(alkylene glycol):
X 1 is a first spacer moiety; and
X 2 is a second spacer moiety.
2. The method of claim 1 , wherein each of POLY 1 and POLY 2 is a poly(ethylene glycol).
3. The method 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 method 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 method of claim 1 , wherein the first spacer moiety is selected from the group consisting of —NH—C(O)—, —NH—C(O)—CH 2 —, —NH—C(O)—CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —C(O)—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —NH—CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —NH—C(O)—CH 2 —O—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, and —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —O—, and the second spacer moiety is selected from the group consisting of —NH—C(O)—, —NH—C(O)—CH 2 —, —NH—C(O)—CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —NH—C(O)—CH 2 —CH 2 —C(O)—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —NH—C(O)—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)—, —NH—C(O)—CH 2 —O—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, and —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —O—.
6. The method of claim 1 , wherein the polymeric reagent corresponds to the following formula:
wherein each (n) is from 4 to 1500.
7. The method of claim 1 , wherein the conjugate corresponds to the following formula:
wherein each (n) is from 4 to 1500.