Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-14
2002-10-08
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S497000, C549S233000, C549S234000, C568S855000, C568S857000
Reexamination Certificate
active
06462207
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates, in general, to polyethylene glycol (“PEG”) derivatives and, in particular, to PEG derivatives containing a diene functionality which may be used in a Diels-Alder reaction to prepare an array of PEG adducts.
PEG is the focus of considerable attention in the biotechnical and biomedical communities. It has been approved by the United States Food and Drug Administration for internal consumption and has been used in a variety of applications including, for example, drug compounding, surface modification (to provide protein and cell rejecting surfaces), hydrogels for cell encapsulation, drug delivery and wound covering, modification of small-molecule pharmaceuticals, and liposomes and micelles for drug delivery. These and other applications for PEG are described in detail in the literature. See, for example, Zalipsky, S.,
Bioconjugate Chem
. 6, 150-165 (1995); Herman, et al., Journal of Bioactive and
Compatible Polymers
, 10, 145-187 (1995);
Poly
(ethylene glycol)
Chemistry. Biomedical and Biotechnical Applications
, J. M. Harris, Editor, Plenum, New York (1992); and Poly (
ethylene glycol
)
Chemistry and Biological Applications
, J. M. Harris and S. Zalipsky, editors, ACS Symposium Series: American Chemical Society: Washington, D.C. (1997).
For use in these various applications, an “activated” form of PEG, commonly referred to as a PEG derivative is used. Typically, PEG derivatives contain at least one electrophilic center available for reaction with nucleophilic centers of biomolecules (e.g., lysine, cysteine and like residues of proteins) or surfaces (e.g., aminated glass). For example, Royer describes the preparation of PEG acetaldehyde for attaching PEG to enzymes and other proteins in U.S. Pat. No. 4,002,531. Harris et al. describe the preparation of PEG propionaldehyde for linking or tethering molecules to organic or polymer surfaces in water in U.S. Pat. No. 5,252,714. Other PEG derivatives for these and other applications are described in S. Zalipsky, Advanced Drug Delivery Reviews, 16, 157 (1995); K. Nilsson and K. Mosbach, Methods in Enzymology, 104, 56 (1984); C. Delgado, G. E. Francis, and D. Fisher, in “Separations Using Aqueous Phase Systems,” D. Fisher and I. A. Sutherland, Eds., Plenum, London, 1989, pp. 211-213; M. B. Stark and J. K. Holmberg, Biotech. Bioeng., 34, 942 (1989); J. M. Harris and K. Yoshinaga, J. Bioact. Compat. Polym., 4, 281 (1989); H. Walter, D. E. Brooks, and D. Fisher (Editors), “Partitioning in Aqueous Two-Phase Systems,” Academic Press, Orlando, Fla., 1985; D. Fisher and I. A. Sutherland (Editors), “Separations Using Aqueous Phase Systems: Applications in Cell Biology and Biotechnology,” Plenum, London, 1989.
While a number of PEG derivatives have been identified and some are now commercially available, interest remains for new PEG derivatives that possess novel properties. In particular, there is an interest in new PEG derivatives which upon further chemical modification are useful in biomedical applications and permit the synthesis of new polymers (e.g., copolymers, homopolymers, and optically active polymers).
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of PEG derivatives which upon further chemical modification are useful in biomedical applications, permit the synthesis of new polymers (e.g., copolymers, homopolymers and optically active polymers), are optionally stable in water, selectively react with functional groups such as amines and thiols, are capable of efficiently linking or tethering molecules to organic or polymer surfaces in water by use of PEG derivatives, or may be used as intermediates in the preparation of compositions possessing such properties.
Briefly, therefore, the present invention is directed to a PEG derivative having the formula
X—(—CH
2
CH
2
O—)
n
—(—CH
2
CH
2
Y—)
m
—R
1
(1)
wherein
m is a cardinal number (that is, 0 or at least 1);
n is at least 1,
R
1
is a diene moiety selected independently from R
2
,
R
2
is a diene moiety selected independently from R
1
,
X is hydroxyl, —YR
2
, optionally substituted hydrocarbyloxy, or heteroaryloxy; and
Y is oxygen, sulfur or —NH—.
The present invention is further directed to a process for the preparation of a cyclic product. The process comprises reacting a PEG derivative containing a diene moiety with a dienophile in a Diels-Alder reaction.
Other objects will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, a class of PEG derivatives having a diene moiety have been discovered which, upon further chemical modification, are of interest in connection with various biotechnical and biomedical applications. In addition, some of these PEG derivatives permit the synthesis of new polymers (e.g., copolymers, homopolymers and optically active polymers).
The PEG derivatives of the present invention have the formula
X—(—CH
2
CH
2
O—)
n
—(—CH
2
CH
2
Y—)
m
—R
1
(1)
wherein m, n, R
1
, X and Y are as previously defined. In one embodiment, X is —YR
2
and R
1
and R
2
are the same diene moieties. For example, R
1
(and R
2
when present) may be a substituted or unsubstituted hydrocarbyl radical containing a conjugated diene. Alternatively, R
1
(and R
2
when present) may be a substituted or unsubstituted heterocyclic radical. In any event, R
1
(and R
2
when present) is preferably in, or capable of adopting a cisoid conformation. More preferably, R
1
(and R
2
when present) is
—(CH
2
)
t
CH═CH—CH═CR
3
R
4
(2)
wherein
p is at least 1;
R
3
and R
4
are independently hydrogen, alkyl or aryl;
R
5
and R
55
are independently alkyl, alkenyl, alkynyl, aryl or heteroatomic;
a is 0-2, preferably 0 or 1, more preferably 0;
b is 0-2, preferably 0 or 1, more preferably 0;
t is a natural number greater than zero;
v is 0-3, preferably 0 or 1, and more preferably 0; and
w is 0-4, preferably 0 or 1, and more preferably 0.
In one embodiment of the present invention, n is at least about 20, more preferably is at least about 30, and still more preferably about 30 to about 50. In general, it is preferred that n be less than 500, and more preferably less than about 200. In addition, m is preferably no greater than 5, more preferably no greater than 3, and still more preferably 0.
In general, therefore, in preferred PEG derivatives of the present invention n is at least about 20, m is 0-5, X is hydroxyl, alkoxy (such as methoxy) alkenyloxy, alkynyloxy, or aryloxy (such as benzyloxy), Y is oxygen (if m is at least 1), t is 1, and w is preferably 0. In one preferred embodiment of the present invention R
1
(and R
2
when present) is
—(CH
2
)
t
CH═CH—CH═CR
3
R
4
in the trans configuration, and R
3
and R
4
are preferably lower alkyl or hydrogen (more preferably hydrogen). In other preferred embodiments, R
1
(and R
2
when present) corresponds to one of structures 3 to 6, and R
5
(if present) or R
55
(if present) are/is preferably hydrogen or lower alkyl.
The PEG derivatives of the present invention advantageously serve as the diene in a Diels-Alder type cycloaddition reaction with a dienophile. The dienophile for this reaction is preferably a substituted or unsubstituted alkene, alkyne or heteroatomic. In general, dienophiles bearing electron-withdrawing groups such as carbonyl, carboxylate, sulfonyl, sulfonate, cyano, halogen, nitro, trihaloalkyl groups undergo the Diels-Alder reaction with facility. Preferred dienophiles include substituted alkenes such as acrolein, acrylic acid, benzoquinone, maleic anhydride, acrylonitrile, and vinyl ketones such as methylvinyl ketone. Preferred dienophiles also include substituted alkynes such as dicyanoacetylene and esters of acetylenedicarboxylic acid. Heteroatomic dienophiles are also preferred such as the iminourethanes and esters of azodicarboxylic acid.
Diels-Alder reactions are typically carried out in an organic solvent, typically an aprotic organic solvent such as tetrahydrofuran or toluene, o
Desai Rita
Rotman Alan L.
Senniger Powers Leavitt & Roedel
Southwest Missouri State University
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