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US 2019/0375892 A1Published application
Methods for preparing polymeric reagents and compositions of polymeric reagents
AssigneeNektar Therapeutics
InventorsAntoni Kozlowski, Jon McKannan, Samuel P. McManus
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Abstract
Methods for preparing active carbonate esters of water-soluble polymers are provided. Also provided are other methods related to the active carbonate esters of water-soluble polymers, as well as corresponding compositions.
Claims35
A synthetic method comprising:
- (a) combining a composition comprising an aprotic solvent and an amine-terminated or hydroxy-terminated, water-soluble polymer with a composition comprising an activated carbonate reagent, optionally in the presence of a catalyst or acid-neutralizing base, wherein the composition comprising the activated carbonate reagent is added such that there is an excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated, water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent;
- and
- (b) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent, wherein the composition comprising a reactive molecule is added such that substantially all of the unreacted activated carbonate reagent is substantially consumed.
A synthetic method comprising:
- (a) combining a composition comprising an aprotic solvent and a hydroxy-terminated, water-soluble polymer having the following structure:
- CH3O—(CH2CH2O)n—CH2CH2—OH
- wherein (n) is an integer from 2 to about 4000, with a composition comprising di(1-benzotriazolyl) carbonate, wherein the composition comprising the di(1-benzotriazolyl) carbonate is added such that there is an excess of the di(1-benzotriazolyl) carbonate relative to the hydroxy-terminated, water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer having the following structure:
- wherein (n) is an integer from 2 to about 4000, and unreacted di(1-benzotriazolyl) carbonate;
- (b) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of a water-soluble polymer and unreacted di(1-benzotriazolyl) carbonate, wherein the composition comprising the reactive compound is added such that substantially all of the unreacted di(1-benzotriazolyl) carbonate is substantially consumed.
2 more elements
A synthetic method comprising:
- (a) combining a composition comprising an aprotic solvent and a hydroxy-terminated, water-soluble polymer having the following structure:
- CH3O—(CH2CH2O)n—CH2CH2—OH
- wherein (n) is an integer from 2 to about 4000, with a composition comprising disuccinimidyl carbonate, wherein the composition comprising the disuccinimidyl carbonate is added such that there is an excess of the disuccinimidyl carbonate relative to the hydroxy-terminated, water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer having the following structure:
- wherein (n) is an integer from 2 to about 4000, and unreacted disuccinimidyl carbonate;
- (b) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of the water-soluble polymer and unreacted disuccinimidyl carbonate, wherein the composition comprising the reactive molecule is added such that substantially all of the unreacted disuccinimidyl carbonate is substantially consumed.
2 more elements
A synthetic method comprising:
- (a) combining a composition comprising an aprotic solvent and a hydroxy-terminated, water-soluble polymer having the following structure:
- CH3O—(CH2CH2O)n—CH2CH2—OH
- wherein (n) is an integer from 2 to about 4000, with a composition comprising p-nitrophenyl chloroformate, wherein the composition comprising the p-nitrophenyl chloroformate is added such that there is an excess of the p-nitrophenyl chloroformate relative to the hydroxy-terminated, water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer having the following structure:
- wherein (n) is an integer from 2 to about 4000, and unreacted p-nitrophenyl chloroformate;
- (b) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of water-soluble polymer and unreacted p-nitrophenyl chloroformate, wherein the composition comprising the reactive molecule is added such that substantially all of the unreacted p-nitrophenyl chloroformate is substantially consumed.
2 more elements
A synthetic method comprising
- reacting an active carbonate ester of a water-soluble polymer prepared by
- (i) combining a composition comprising an aprotic solvent and an amine-terminated or hydroxy-terminated, water-soluble polymer with a composition comprising an activated carbonate reagent, optionally in the presence of a catalyst or acid-neutralizing base, wherein the composition comprising the activated carbonate reagent is added such that there is an excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated, water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent;
- and
- (ii) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent, wherein the composition comprising a reactive molecule is added such that substantially all of the unreacted activated carbonate reagent is substantially consumed,
- with an active agent under conjugation conditions to thereby result in a water-soluble polymer-active agent conjugate.
2 more elements
A synthetic method comprising:
- reacting a polymeric reagent prepared by
- (a) combining a composition comprising an aprotic solvent and an amine-terminated or hydroxy-terminated, water-soluble polymer with a composition comprising an activated carbonate reagent, optionally in the presence of a catalyst or acid-neutralizing base, wherein the composition comprising the activated carbonate reagent is added such that there is an excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated, water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent;
- (b) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent, wherein the composition comprising a reactive molecule is added such that substantially all of the unreacted activated carbonate reagent is substantially consumed;
- and
- (c) reacting the active carbonate ester of the water-soluble polymer in one or more reactions to form a polymeric reagent
- with an active agent under conjugation conditions to thereby result in a water-soluble polymer-active agent conjugate.
3 more elements
Dependencies are inferred from the claim text.