# US 8,541,608 B2 · Method for preparing a polymer conjugate

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- Number: US 8,541,608 B2
- Document ID: US8541608B2
- Status: Granted
- Kind: B2
- Application number: 13/680,764
- Filed: 2012-11-19
- Published: 2013-03-28
- Granted: 2013-09-24
- Earliest claimed: 2006-11-30
- Assignees: Nektar Therapeutics
- Applicants: Nektar Therapeutics
- Inventors: Wen Zhang
- Web page: https://patentgrep.com/patent/US8541608B2

## CPC

- C08G 65/33344: {containing carbamate group}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- C07D 491/147: the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein is a straightforward and efficient method for covalently attaching a polyethylene glycol polymer to a taxane. The method involves, among other things, a step of reacting a taxame with a polyethylene glycol polymer comprising a functional group reactive with a functional group within said taxane in the presence of a coupling reagent and DPTS. The result of the reacting step is the formation of a polyethylene glycol-taxane conjugate.

## Claims

### Claim 1

A method for covalently attaching a polyethylene glycol polymer to a taxane, said method comprising the step of:
reacting a taxane with a polyethylene glycol comprising a functional group reactive with a functional group within said taxane in the presence of a coupling reagent and 4-(dimethylamino)-pyridinium-p-toluenesulfonate (DPTS), under conditions effective to promote reaction between said taxane and said polyethylene glycol to thereby faun a polyethylene glycol-taxane conjugate
wherein said polyethylene glycol comprises the following structure:
and wherein each n is from about 5 to about 400.

### Claim 2 (depends on 1)

The method of claim 1, wherein said coupling reagent is a carbodiimide.

### Claim 3 (depends on 2)

The method of claim 2, wherein said coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-tert-butyl-N′-methylcarbodiimide (TBMC), and N-tert-butyl-N′-ethylcarbodiimide (TBEC).

### Claim 4 (depends on 1)

The method of claim 1, wherein said coupling reagent is N,N′-diisopropylcarbodiimide.

### Claim 5 (depends on 1, 2, 3, 4)

The method of any one of claims 1 to 4, wherein said reacting step is carried out in an organic solvent selected from the group consisting of dichloromethane, chloroform, acetonitrile and tetrahydrofuran.

### Claim 6 (depends on 5)

The method of claim 5, wherein said reacting step is carried out at a temperature ranging from 0° C. to 100° C.

### Claim 7 (depends on 6)

The method of claim 6, wherein said reacting step is carried out at room temperature.

### Claim 8 (depends on 1, 2, 3, 4)

The method of any one of claims 1-4, wherein the amount of DPTS in said reacting step ranges from about 0.05 to 0.75 equivalents relative to said functional group within said taxane.

### Claim 9 (depends on 8)

The method of claim 8, wherein the amount of DPTS in said reacting step ranges from about 0.10 to 0.60 equivalents relative to said functional group within said taxane.

### Claim 10 (depends on 1, 2, 3, 4)

The method of any one of claims 1-4, wherein the amount of said coupling reagent ranges from about 1.25 to 5 equivalents relative to said functional group within said taxane.

### Claim 11 (depends on 1, 2, 3, 4)

The method of any one of claims 1-4, wherein said functional group within the polyethylene glycol is selected from the group consisting of amino, hydroxyl, and carboxyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein said functional group within the taxane is hydroxyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein said taxane possesses more than one of said first functional groups.

### Claim 14 (depends on 1, 2, 3, 4)

The method of any one of claims 1-4, wherein said reaction results in formation of an ester bond.

### Claim 15 (depends on 1)

The method of claim 1, wherein said polyethylene glycol-taxane conjugate has said polyethylene glycol covalently attached, via an ester linkgage, to a single hydroxyl site on said taxane.

### Claim 16 (depends on 1)

The method of claim 1, wherein said polyethylene glycol is:
and wherein each n is from about 5 to about 400.

### Claim 17 (depends on 1)

The method of claim 1, wherein said reacting step forms a polyethylene glycol-taxane conjugate possessing an average number of taxane molecules per conjugate ranging from about 2.1 to 3.75.

### Claim 18 (depends on 17)

The method of claim 17, wherein said reacting step forms a polyethylene-taxane conjugate possessing an average number of taxane molecules per conjugate ranging from about 2.3 to 3.2.