Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Polymer from ethylenic monomers only
Reexamination Certificate
2001-08-20
2004-01-20
Wang, Shengjun (Department: 1619)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Polymer from ethylenic monomers only
C424S078310, C514S772400, C514S773000, C526S303100, C526S307300
Reexamination Certificate
active
06680051
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally the field of chemistry. More particularly, the invention relates to polymers containing amino acids and processes of making such polymers.
BACKGROUND
Polymers containing amino acid-based moieties are of interest for several reasons including their potential biological compatibility and biodegradability. Moreover, chiral amino acid-based polymers can have induced crystallinity, a property allowing such polymers to form higher ordered structures that exhibit enhanced solubility characteristics. These properties make such polymers ideal candidates for a variety of biomaterial applications, e.g., for drug delivery systems, biomimetic systems, biodegradable macromolecules, other biomaterials, and as chiral purification media. See, Birchall et al., Polymer 2001, 42, 375-389; Langer, R. Acc. Chem. Res. 2000, 33, 94-101; and Sanda, F. and Endo, T. Macromol. Chem. Phys. 1999, 200, 2651-2661.
Recently, Endo and coworkers have reported the synthesis of several branched and linear polymer systems containing amino acid moieties using acrylamide substrates (Sanda et al., J. Polym. Sci., Part A: Polym. Chem. 1997, 35, 2619-2629; and Murata et al., Macromolecules 1996, 29, 5535-5538); by the radical polyaddition of dithiols with diolefins (Koyama et al., Macromolecules 1998, 31, 1495-1500); as well as by the polycondensation of diols from amino alcohols and dicarboxylic acids (Koyama et al., J. Polym. Sci., Part A: Polym Chem. 1997, 35, 345-352). Circular dichroism showed that several of these polymers formed higher ordered structures. Koyama et al., Macromolecules 1998, 31, 1495-1500. In addition to the foregoing, Maynard and Grubbs have produced polymers containing amino acid moieties via the ring-opening metathesis polymerization (ROMP) of oligopeptide-substituted norbornenes, and have also copolymerized these monomers with penta(ethyleneoxide) substituted norbonenes to form water-soluble polymers. Maynard et al., Macromolecules 2000, 33, 6239-6248; Maynard, H. D. and Grubbs, R. H. Macromolecules 1999, 32, 6917-6924; and Maynard et al., J. Am. Chem. Soc. 2001, 123, 1275-1279.
Each of the foregoing methods has certain advantages and disadvantages for the production of particular types of amino acid-containing polymers. Thus, additional methods of making such polymers would advance the field. Methods that can be used with a wide range of different monomers and those that yield polymers in the form of strong films (e.g., so that they can fashioned into rigid devices) and/or with the amino acid moieties arranged in a regular pattern (e.g., for chiral separations) would be especially advantageous.
SUMMARY
What has been discovered is a new acyclic diene metathesis (ADMET) chemistry-based method of making polymers incorporating amino acids or polypeptides. In a first variation of this method, the amino acid or polypeptide moieties are incorporated within the backbone of the polymer to yield a linear copolymer (a linear functionalized polymer). In a second variation of this method, the amino acid or polypeptide moieties are covalently bonded to the backbone of the polymer to yield a branched polymer. Functionalized polymers prepared by this method could be used to produce a broad range of commercially important products such as chromatography reagents (e.g., for use in separatory reagents), biomimetics, biodegradable synthetic polymers, and drug delivery agents.
For example, branched functionalized polymers could be used as tissue culture substrates. Such polymers could also be used in an implantable medical device to modify the physiological response to the device. In another application, by incorporating only one chiral species (L or D; or R or S) of an amino acid onto the polymer backbone, the polymer could also be used to resolve enantiomers in a racemic mixture or to identify ligands that preferably interact with one chiral species.
Linear copolymers made from both amino acid-based monomers and hydrocarbon-based monomers could be used to make materials that biodegrade more quickly than conventional carbon-based linear polymers (e.g., polyethylene). Such materials could be fashioned into films for use in packaging, bags, and the like, that would quickly be degraded (e.g., by chemical or microorganism-mediated processes) in landfills. Similarly, such materials could be fashioned into medical implants designed to slowly degrade within a body. For example, the material could be impregnated with a drug for sustained release. It might also be fashioned into a scaffolding for applications in tissue engineering. In addition, drugs having improved pharmacodynamics could be made by incorporating biologically active oligopeptides within such polymers (e.g., to reduce the rate of degradation of the oligopeptide).
Accordingly, the invention features a method of making an amino acid-containing polymer. The method includes the steps of: (a) providing a monomer having the structure:
wherein y is an integer greater or equal to 1, n is an integer greater than 1, m is an integer greater than 2, x is an integer greater than or equal to 1, R is a moiety comprising a hydrogen atom and a carbon atom, and R
1
is any protecting group or H;
(b) forming a reaction mixture by contacting the monmer with an agent capable of catalyzing the polymerization of the monomer into a polymer having the structure of:
wherein Z is an integer greater than 1;
(c) placing the reaction mixture under conditions that result in the formation of the polymer in reaction mixture.
In preferred variations of the method, the catalyst is a ruthenium-based catalyst (e.g., Ru*; see below). In other variations, n is an integer selected from 2, 3, 4, 5, 6, 7, 8, and 9; and m is an integer selected from 2, 3, 4, 5, 6, 7, 8, and 9. In certain embodiments of the invention n is equal to m. In other embodiments, n is not equal to m.
In various embodiments, R includes a moiety selected from: CH
3
; CH(CH
3
)
2
; and CH
2
CH(CH
3
)
2
. For example, R can include an amino acid side chain moiety, the amino acid being selected from the group consisting of: arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, and tyrosine. R can also include a polypeptide.
The step (c) of placing the reaction mixture under conditions that result in the formation of the polymer in reaction mixture can include applying a vacuum force to the reaction mixture; flowing an inert gas over the reaction mixture; adding heat to the reaction mixture; or adding a solvent to the reaction mixture. The method of the invention can also include a step (d) of hydrogenating the polymer.
In another aspect the invention features a polymer having the structure of: polymer A, polymer B, polymer C, polymer D, polymer E, polymer F, or polymer G, wherein z is an integer greater than 1, y is an integer greater or equal to 1, n is an integer greater than 1, m is an integer greater than 2, x is an integer greater than or equal to 1, R is a moiety comprising a hydrogen atom and a carbon atom, and R
1
is any protecting group or H.
In various embodiments, R includes a moiety selected from: CH
3
; CH(CH
3
)
2
; and CH
2
CH(CH
3
)
2
. For example, R can include an amino acid side chain moiety, the amino acid being selected from the group consisting of: arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, and tyrosine. R can also include a polypeptide.
In certain embodiments of the invention, the polymer is fashioned into a thin film. The polymer can also be a chiral polyolefin.
By the term “polypeptide” is meant any peptide-linked chain of amino acids, regardless of length.
Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those
Gomez Fernando J.
Hopkins Timothy E.
Pawlow James H.
Wagener Kenneth B.
Akerman & Senterfitt
Kim Stanley A.
University of Florida
Wang Shengjun
LandOfFree
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