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US 8,299,089 B2Granted
Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
AssigneeEnzon Pharmaceuticals, Inc.
InventorsHong Zhao, Maria Belen Rubio, Dechun Wu, Puja Sapra
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Abstract
A four arm-polyethylene glycol-7-ethyl-10-hydroxycamptothecin conjugate, such as, is disclosed. Methods of making the conjugates and methods of treating mammals using the same are also disclosed.
Claims23
A compound of Formula (I)
- wherein
- R1, R2, R3 and R4 are independently OH or (L)m-D;
- L is a bifunctional linker;
- D is a camptothecin or a camptothecin analog;
- m is 0 or a positive integer from 1 to 10;
- and
- n is from about 114 to about 227;
- provided that R1, R2, R3 and R4 are not all OH.
5 more elements
A method of preparing a multi-arm polymeric prodrug, comprising:
- (a) providing one equivalent of a camptothecin or camptothecin analog containing an available 20-hydroxyl group and one or more equivalents of a bifunctional linker containing an available carboxylic acid group;
- (b) reacting the two reactants under conditions effective to form a camptothecin-bifunctional linker intermediate having an available amine group;
- and
- (c) reacting one or more equivalents per active site of the resulting intermediate and one equivalent of an activated polymer of the formula (I),
- wherein the formula (I) is
- under conditions effective to form the multi-arm polymeric prodrug having the structure of
- wherein
- R1, R2, R3 and R4 are independently OH or (L)m-D;
- L is a bifunctional linker;
- D is a camptothecin or a camptothecin analog;
- m is 0 or a positive integer from 1 to 10;
- and
- n is from about 114 to about 227;
- provided that R1, R2, R3 and R4 are not all OH.
11 more elements
A method of preparing a multi-arm polymeric prodrug, comprising:
- (a) reacting one equivalent of a camptothecin or camptothecin analog containing an available 20-hydroxyl group
- with one or more equivalents of a bifunctional linker containing an available carboxylic acid group under conditions effective to form a camptothecin-bifunctional linker intermediate having an available amine group;
- and
- (b) reacting one or more equivalents per active site of the resulting intermediate from step (a)
- with one equivalent of an activated polymer of the formula (I),
- wherein the formula (I) is
- under conditions effective to form the multi-arm polymeric prodrug having the structure of
- wherein
- R1, R2, R3 and R4 are independently OH or (L)m-D;
- L is a bifunctional linker;
- D is camptothecin or a camptothecin analog;
- m is 0 or a positive integer from 1 to 10;
- and
- n is from about 114 to about 227;
- provided that R1, R2, R3 and R4 are not all OH.
12 more elements
Dependencies are inferred from the claim text.