Synthesis of high molecular weight non-peptidic polymer...

Details Synthesis of high molecular weight non-peptidic polymer... Synthesis of high molecular weight non-peptidic polymer...

2001-12-18

2004-08-10

Acquah, Samuel A. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S054200, C525S398000, C525S399000, C525S400000, C525S437000, C525S535000, C525S539000, C525S540000, C514S002600, C514S023000, C514S04400A, C514S054000, C514S103000, C514S476000, C514S506000, C514S553000, C514S580000

Reexamination Certificate

active

06774180

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to derivatives of poly(ethylene glycol) and related polymers and methods for their synthesis. More particularly, the invention relates to high molecular weight derivatives and methods of producing high molecular weight derivatives.
BACKGROUND OF THE INVENTION
Covalent attachment of the hydrophilic polymer poly(ethylene glycol), abbreviated PEG, also known as poly(ethylene oxide), abbreviated PEO, to molecules and surfaces is of considerable utility in biotechnology and medicine. In its most common form, PEG is a linear polymer terminated at each end with hydroxyl groups:
HO—CH
2
CH
2
O—(CH
2
CH
2
O)
n
—CH
2
CH
2
—OH
The above polymer, &agr;, &ohgr;-dihydroxypoly(ethylene glycol), can be represented in brief form as HO-PEG-OH where it is understood that the -PEG- symbol represents the following structural unit:
—CH
2
CH
2
O—(CH
2
CH
2
O)
n
—CH
2
CH
2
—
where n typically ranges from about 3 to about 4000.
PEG is commonly used as methoxy-PEG-OH, or mPEG in brief, in which one terminus is the relatively inert methoxy group, while the other terminus is a hydroxyl group that is subject to ready chemical modification. The structure of mPEG is given below.
CH
3
O—(CH
2
CH
2
O)
n
—CH
2
CH
2
—OH
The copolymers of ethylene oxide and propylene oxide are closely related to PEG in their chemistry, and they can be substituted for PEG in many of its applications.
HO—CH
2
CHRO(CH
2
CHRO)
n
CH
2
CH
2
—OH
where R═H or alkyl, such as CH
3
.
PEG is also commonly used in multi-arm forms in which linear PEGs are attached to a central core:
R(—O-PEG-OH)
n
where R is a core derived from, for example, pentaerythritol or glycerol oligomers. PEGs can also be prepared with degradable linkages in the backbone.
PEG is a polymer having the properties of solubility in water and in many organic solvents, lack of toxicity, and lack of immunogenicity. One use of PEG is to covalently attach the polymer to insoluble molecules to make the resulting PEG-molecule “conjugate” soluble. For example, it has been shown that the water-insoluble drug paclitaxel, when coupled to PEG, becomes water-soluble. Greenwald, et al.,
J. Org. Chem.,
60:331-336 (1995).
To couple PEG to a molecule, such as a protein, it is often necessary to “activate” the PEG to prepare a derivative of the PEG having a functional group at the terminus. The functional group can react with certain moieties on the protein, such as an amino group, thus forming a PEG-protein conjugate. Many activated derivatives of PEG have been described. An example of such an activated derivative is the succinimidyl succinate “active ester”:
CH
3
O-PEG-O
2
C—CH
2
CH
2
—CO
2
—NS
where NS=
Hereinafter, the succinimidyl active ester moiety will be represented as —CO
2
—NS. Such activated PEGs can also be prepared from the above described multi-arm forms or from branch forms such as:
(PEG-O-CO—NH)
2
LYS-NS
as described in Harris, et al., U.S. Pat. No. 5,932,462, which is incorporated by reference herein in its entirety. Functional groups can be attached to the terminus of PEG by direct conversion of the starting hydroxyl to other forms or by attachment of organic spacer groups to the hydroxyl group. For example, the succinate PEG above is prepared by attachment of succinic anhydride to PEG. Similarly one can react glutaric anhydride to prepare PEG glutarate, PEG-O
2
C—CH
2
CH
2
CH
2
—CO
2
H. Even larger aliphatic spacers can be added. As described in Okamoto, et al.,
Eur. Polym. J.,
19, 341-346 (1983), PEG can be converted to a PEG amine by reacting PEG-OH with ONC—(CH
2
)
6
—NCO and then converting the remaining isocyanate to amine product PEG-O
2
CNH—(CH
2
)
6
—NH
2
.
As applications of PEG chemistry have become more sophisticated, there has been an increasing need for high molecular weight, high purity PEG derivatives. The synthesis of these compounds is complicated by the difficulty in removing polymeric impurities that accumulate during multi-step preparations. Small molecule impurities are normally easily removed by simple procedures such as precipitation. However, high molecular weight polymeric side-products are generally quite difficult to remove and require utilization of time-consuming and expensive chromatographic techniques. There remains a need in the art for improved methods of preparing high molecular weight PEG derivatives.
SUMMARY OF THE INVENTION
The invention includes high molecular weight activated polymer derivatives and methods for making them. A small, difunctional oligo(ethylene glycol) (“OEG”) derivative or similar oligomer or small polymer is covalently linked to a large poly(ethylene glycol) polymer (“PEG”) derivative or similar polymer. In this way, most of the chemical transformations can be conducted on the oligomeric or small polymeric compound. Large polymeric impurities are more difficult to separate from the desired product than are smaller ones, and the products of these reactions involving these polymers typically include unreacted reagents, difunctional components that can result in cross linking, partially reacted components, and other polymeric impurities. The invention avoids these impurities by reducing the number of reactions needed to create the large polymer.
Thus, as shown below, one can make a complicated polymeric compound in one step by reacting a complicated oligomer, for example, Y′—OEG-Y, where Y and Y′ are active moieties, with a simple high molecular weight polymeric compound, for example, mPEG-Z, where Z reacts with one of Y or Y′, to make a new linking group X between the larger PEG and the smaller PEG. In this way, polymeric impurities do not accumulate. Y and Y′ can be the same or different, but should be chosen so that the two moieties are compatible and will not react with each other.
In a typical reaction for producing a high molecular weight monofunctional large molecule, a monomethoxy poly(ethylene glycol) is reacted with a smaller PEG polymer, in which the functional group Z on the monofunctional larger PEG polymer reacts with the functional group Y′ on the heterobifunctional smaller polymer. The high molecular weight product retains the active group Y. The reactants are linked by a group X formed by the reaction of the Z and Y′ moieties. This reaction can be illustrated as follows:
mPEG-Z+Y′-OEG-Y→mPEG-X-OEG-Y
For example, an mPEG-propionic acid of molecular weight 32,000 which is a compound typically made in several steps from mPEG-OH, can be prepared in a single step by reacting an activated MPEG carbonate 30,000 that has been prepared in one step from mPEG-OH, with &agr;-amino-&ohgr;-propionic acid of molecular weight 2000. Most of the chemical transformations can be performed on the small, inexpensive, more readily purified PEG 2000.
Monofunctional, homobifunctional, and heterobifunctional large molecules can be prepared by the practice of the invention, although not necessarily all with equivalent results. Reactions that tend to introduce complications in the larger polymeric component of the product molecule may reduce the effectiveness of the method if impurities are increased with multiple reaction steps.
In a somewhat more generalized embodiment, showing a poly(ethylene glycol) polymer with greater specificity, the structure of the products of the invention can be described as follows:
R—(OCH
2
CH
2
)
n
—X—(CH
2
CH
2
—O)
m
—Y
The above structure is prepared by reacting R—(OCH
2
CH
2
)
n
—Z with Y′—(CH
2
CH
2
—O)
m
—Y, where Z is a group reactive with Y′ and neither Y nor R is reactive with Z or Y′. R can be a capping moiety, including various alkyl moieties, typically methoxy as attached to PEG. R can also be a reactive group or a protected reactive group Y″ in which the reactive group can be deprotected and available for reaction at some later desired time. Y and Y′ can be the same if Y′ has been a protected group or a different group that does not participate in the reactions used to create the product molecule. Functional groups include, but are not lim

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