U.S. patent application number 13/285913 was filed with the patent office on 2012-02-23 for covalent modification of metal surfaces.
This patent application is currently assigned to INTEZYNE TECHNOLOGIES. Invention is credited to Kurt Breitenkamp, Rebecca Breitenkamp, Kevin N. Sill, Habib Skaff.
Application Number | 20120046757 13/285913 |
Document ID | / |
Family ID | 38895514 |
Filed Date | 2012-02-23 |
United States Patent
Application |
20120046757 |
Kind Code |
A1 |
Breitenkamp; Kurt ; et
al. |
February 23, 2012 |
COVALENT MODIFICATION OF METAL SURFACES
Abstract
The present invention provides modified metal surfaces, methods
of preparing the same, and intermediates thereto. These materials
are useful in a variety of applications including biomaterials.
Inventors: |
Breitenkamp; Kurt; (Tampa,
FL) ; Breitenkamp; Rebecca; (Tampa, FL) ;
Sill; Kevin N.; (Tampa, FL) ; Skaff; Habib;
(Tampa, FL) |
Assignee: |
INTEZYNE TECHNOLOGIES
Tampa
FL
|
Family ID: |
38895514 |
Appl. No.: |
13/285913 |
Filed: |
October 31, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11825791 |
Jul 9, 2007 |
8066824 |
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13285913 |
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60819200 |
Jul 7, 2006 |
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Current U.S.
Class: |
623/23.7 ;
528/399; 528/400; 562/23 |
Current CPC
Class: |
A61L 2400/18 20130101;
B82Y 30/00 20130101; C07D 498/02 20130101; B82Y 40/00 20130101;
A61L 31/022 20130101; A61L 31/14 20130101; A61F 2/82 20130101; B05D
3/142 20130101; B05D 2202/00 20130101; A61L 27/04 20130101; A61L
27/50 20130101; B05D 3/102 20130101; B05D 1/185 20130101 |
Class at
Publication: |
623/23.7 ;
528/400; 528/399; 562/23 |
International
Class: |
A61F 2/82 20060101
A61F002/82; C08G 65/34 20060101 C08G065/34; C07F 9/38 20060101
C07F009/38; C08G 65/28 20060101 C08G065/28 |
Claims
1.-15. (canceled)
16. A compound of formula II-e: ##STR00143## or a salt thereof,
wherein: W is --C(.dbd.O)OH, --C(.dbd.O)X, --P(.dbd.O)(OH).sub.2,
--P(.dbd.O)(X).sub.2, --P(.dbd.O)(R.sup.a)OH,
--P(.dbd.O)(R.sup.a)X, --Si(R.sup.a).sub.2OH,
--Si(OR.sup.a).sub.2OH, --Si(R.sup.a).sub.2X,
--Si(R.sup.a)(OH).sub.2, --Si(R.sup.a)X.sub.2,
--Si(OR.sup.a).sub.2X, or N.dbd.C.dbd.O; each X is independently
Cl, Br, or I; and each R.sup.a is hydrogen, an alkyl group, or an
aryl group; y is 1-2500; each R is independently hydrogen or an
optionally substituted aliphatic group; L.sup.1 is a valence bond
or a bivalent, saturated or unsaturated, straight or branched
C.sub.1-12 alkylene chain, wherein 0-6 methylene units of L.sup.1
are independently replaced by -Cy-, --O--, --NR--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein: each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and
L.sup.2 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of L.sup.2 are independently replaced by -Cy-,
--O--, --NR--, --S--, or --C(O)--, wherein: each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
17. An implantable device, wherein at least a portion of said
device is a covalently modified metal surface.
18. The implantable device according to claim 17, wherein said
device is PEGylated.
19. The implantable device according to claim 17, wherein said
device is selected from cardiovascular devices (e.g., implantable
venous catheters, venous ports, tunneled venous catheters, chronic
infusion lines or ports, including hepatic artery infusion
catheters, pacemaker wires, implantable defibrillators);
neurologic/neurosurgical devices (e.g., ventricular peritoneal
shunts, ventricular atrial shunts, nerve stimulator devices, dural
patches and implants to prevent epidural fibrosis post-laminectomy,
devices for continuous subarachnoid infusions); gastrointestinal
devices (e.g., chronic indwelling catheters, feeding tubes,
portosystemic shunts, shunts for ascites, peritoneal implants for
drug delivery, peritoneal dialysis catheters, implantable meshes
for hernias, suspensions or solid implants to prevent surgical
adhesions, including meshes); genitourinary devices (e.g., uterine
implants, including intrauterine devices (IUDs) and devices to
prevent endometrial hyperplasia, fallopian tubal implants,
including reversible sterilization devices, fallopian tubal stents,
artificial sphincters and periurethral implants for incontinence,
ureteric stents, chronic indwelling catheters, bladder
augmentations, or wraps or splints for vasovasostomy);
otolaryngology devices (e.g., ossicular implants, Eustachian tube
splints or stents for glue ear or chronic otitis as an alternative
to transtempanic drains); and orthopedic implants (e.g., cemented
orthopedic prostheses).
20. The implantable device according to claim 19, wherein said
device is a stent.
21. A method for expanding the lumen of a body passageway,
comprising inserting a stent into the passageway, the stent having
a generally tubular structure, at least a portion of the surface of
the structure being covalently modified according to the method of
claim 1, such that the passageway is expanded.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application Ser. No. 60/819,200, filed Jul. 7, 2006, the entirety
of which is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Modification of inorganic substrates with polymeric
materials has been utilized in a range of applications across
numerous scientific disciplines including analytical chemistry,
biology, and electronics. (Mansky, P., et al. Science 1997, 275,
1458-1460; Huang, Z. Langmuir, 1997, 13, 6480-6484. Granick, S. et.
al. J. Polym. Sci. B. 2003, 41, 2755-2793.) Inorganic substrates
can be coated with polymers or other molecules using a number of
currently available methods. One popular, simple method involves
the physical adsorbtion of a polymer to a substrate through coating
or other deposition techniques. Other methods utilize covalent or
ionic bonding between functionality on a polymer, or small
molecule, and functionality present on the substrate surface to
achieve modification. (Denes, A. R. et. al. J. Appl. Polym. Sci.
2001, 81, 3425-3438). While simple adsorption of polymers to metal
substrates has proven successful in many cases, this procedure does
not produce mechanically robust coatings with long-term stability.
Post-adsorption crosslinking (Dong, B. et. al.; J. Appl. Polym.
Sci., 2005, 97, 485-497.) of the polymer coating may increase the
toughness and short-term performance of the resulting film, but
such crosslinking can also result in cracking and flaking of the
polymer films over time, resulting in mechanical failure and a
dramatic reduction in film properties. The chemical attachment of
functional polymers to a metal substrate introduces a stable,
robust linkage between polymer chains and the metal substrate and
represents a more desirable scenario for many applications where
the long-term stability of the coating is required for optimal
performance. (Hara, H. et. al. Adv. Drug Del. Rev. 2006, 58,
377-388.) However, the methodologies to prepare covalent attachment
of polymers to metallic and non-metallic substrates has thus far
been limited to only a few examples of suitable substrates and
complimentary chemical functionalities. Such examples include the
near-covalent interaction between gold substrates and
thiol-functionalized molecules, covalent bonds formed between
silica and alcohol, silyl chloride, or silyl alcohol-functionalized
compounds, and covalent bonds formed between
hydrogen-functionalized silicon surfaces and alkene-substituted
molecules. (Mansky, P., et. al. Science 1997, 275, 1458-1460,
Pesek, J. J.; Matyska, M. T. Interface Science 1997, 5,
103-117.)
[0003] Accordingly, it would be advantageous to provide a method of
modifying metal surfaces to provide a metal substrate capable of
forming covalent bonds with appropriately functionalized polymers
or small molecule derivatives.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIG. 1 depicts a method for covalently modifying a metal
surface via dehydration reaction.
[0005] FIG. 2 depicts a method for covalently modifying a metal
surface via condensation reaction.
[0006] FIG. 3 depicts a method for covalently modifying a metal
surface via dehydration reaction.
[0007] FIG. 4 depicts a method for covalently modifying a metal
surface via condensation reaction.
[0008] FIG. 5 depicts a method for covalently modifying a metal
surface via dehydration reaction.
[0009] FIG. 6 depicts a method for covalently modifying a metal
surface via condensation reaction.
[0010] FIG. 7 depicts a method for covalently modifying a metal
surface via dehydration reaction.
[0011] FIG. 8 depicts a method for covalently modifying a metal
surface via condensation reaction.
[0012] FIG. 9 depicts a method for covalently modifying a metal
surface and crosslinking via dehydration reaction.
[0013] FIG. 10 depicts a method for covalently modifying a metal
surface via condensation reaction followed by crosslinking.
[0014] FIG. 11 depicts a method for PEGylating a metal surface via
dehydration reaction.
[0015] FIG. 12 depicts a method for PEGylating a metal surface via
condensation reaction.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
1. General Description of the Invention
[0016] The present invention provides methods for covalently
modifying a metal surface with a polymeric group or a small
molecule organic moiety. In order to covalently bond the polymeric
group or small molecule organic moiety to the metal surface, the
metal surface is treated to introduce hydroxyl groups. In certain
embodiments, the present invention provides a method for covalently
modifying a metal surface, comprising the steps of introducing
hydroxyl groups onto a metal substrate and covalently bonding a
polymer or small molecule organic moiety onto the resulting
hydrophilic metal surface.
2. Definitions
[0017] Compounds of this invention include those described
generally above, and are further illustrated by the embodiments,
sub-embodiments, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For
purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 75.sup.th Ed. Additionally,
general principles of organic chemistry are described in "Organic
Chemistry", Thomas Sorrell, University Science Books, Sausalito:
1999, and "March's Advanced Organic Chemistry", 5.sup.th Ed., Ed.:
Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,
the entire contents of which are hereby incorporated by
reference.
[0018] As used herein, the term "sequential polymerization", and
variations thereof, refers to the method where after a first
monomer (e.g. NCA or lactam) is incorporated into the polymer, thus
forming a "block", a second monomer (e.g. NCA or lactam) is added
to the reaction and the polymerization continues in a similar
fashion resulting in the formation of multi-block copolymers.
[0019] As used herein, the term "block copolymer" refers to a
polymer comprising two or more polymer portions. The term
"multi-block copolymer" refers to a polymer comprising at least
three separate polymer portions. These are also referred to as
triblock copolymers, tetrablock copolymers, etc. Such multi-block
copolymers may be of the format X-W-X', W-X-X', W-X-X'-X'' or
X'-X-W-X-X', wherein W is a certain synthetic polymer portion and
X, X', and X'' are differing polymer chains. In certain aspects,
the synthetic polymer is used as the center block which allows the
growth of multiple blocks symmetrically from center.
[0020] As used herein, the term "synthetic polymer" refers to a
polymer that is well known in the art and includes polystryrene,
polyalkylene oxides, polyacrylates, polyacrylamides, polyamines,
polyolefins, and derivatives thereof.
[0021] As used herein, the term "natural polymer" refers to a
polymer that is well known in the art and includes polysaccarides,
dextran, heparin, fibronectin, poly(amino acids), starch, amylose,
amylopectin, polypeptides, proteins, and derivatives thereof.
[0022] As used herein, the term "polymer" may refer to either a
natural polymer or synthetic polymer.
[0023] As used herein, the term "poly(amino acid)" or "amino acid
block" refers to a covalently linked amino acid chain wherein each
monomer is an amino acid unit. Such amino acid units include
natural and unnatural amino acids. In certain embodiments, each
amino acid unit is in the L-configuration. Such poly(amino acids)
include those having suitably protected functional groups. For
example, amino acid monomers may have hydroxyl or amino moieties
which are optionally protected by a suitable hydroxyl protecting
group or a suitable amine protecting group, as appropriate. Such
suitable hydroxyl protecting groups and suitable amine protecting
groups are described in more detail herein, infra. As used herein,
an amino acid block comprises one or more monomers or a set of two
or more monomers. In certain embodiments, an amino acid block
comprises one or more monomers such that the overall block is
hydrophilic. In other embodiments, an amino acid block comprises
one or more monomers such that the overall block is hydrophobic. In
still other embodiments, amino acid blocks of the present invention
include random amino acid blocks, ie blocks comprising a mixture of
amino acid residues.
[0024] As used herein, the phrase "natural amino acid side-chain
group" refers to the side-chain group of any of the 20 amino acids
naturally occurring in proteins. Such natural amino acids include
the nonpolar, or hydrophobic amino acids, glycine, alanine, valine,
leucine isoleucine, methionine, phenylalanine, tryptophan, and
proline. Cysteine is sometimes classified as nonpolar or
hydrophobic and other times as polar. Natural amino acids also
include polar, or hydrophilic amino acids, such as tyrosine,
serine, threonine, aspartic acid (also known as aspartate, when
charged), glutamic acid (also known as glutamate, when charged),
asparagine, and glutamine. Certain polar, or hydrophilic, amino
acids have charged side-chains. Such charged amino acids include
lysine, arginine, and histidine. One of ordinary skill in the art
would recognize that protection of a polar or hydrophilic amino
acid side-chain can render that amino acid nonpolar. For example, a
suitably protected tyrosine hydroxyl group can render that tyrosine
nonpolar and hydrophobic by virtue of protecting the hydroxyl
group.
[0025] As used herein, the phrase "unnatural amino acid side-chain
group" refers to amino acids not included in the list of 20 amino
acids naturally occurring in proteins, as described above. Such
amino acids include the D-isomer of any of the 20 naturally
occurring amino acids. Unnatural amino acids also include
homoserine, ornithine, and thyroxine. Other unnatural amino acids
side-chains are well know to one of ordinary skill in the art and
include unnatural aliphatic side chains. Other unnatural amino
acids include modified amino acids, including those that are
N-alkylated, cyclized, phosphorylated, acetylated, amidated,
azidylated, labelled, and the like.
[0026] As used herein, the phrase "living polymer chain-end" refers
to the terminus resulting from a polymerization reaction having
maintained chain-end reactivity after the completion of the
reaction.
[0027] As used herein, the term "termination" refers to attaching a
terminal group to a polymer chain-end by the reaction of a living
polymer with an appropriate compound. Alternatively, the term
"termination" may refer to attaching a terminal group to a hydroxyl
end, or derivative thereof, of the polymer chain.
[0028] As used herein, the term "polymerization terminator" is used
interchangeably with the term "polymerization terminating agent"
and refers to a compound for attaching a terminal group to a
polymer chain-end of a living polymer. Alternatively, the term
"polymerization terminator" may refer to a compound for attaching a
terminal group to a hydroxyl end, or derivative thereof, of the
polymer chain.
[0029] As used herein, the term "polymerization initiator" refers
to a compound, or anion thereof, which reacts with the desired
monomer in a manner which results in polymerization of that
monomer. In certain embodiments, the polymerization initiator is
the anion of a functional group which initiates the polymerization
of ethylene oxide. In other embodiments, the polymerization
initiator is the amine salt described herein.
[0030] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, refers to the replacement of hydrogen radicals
in a given structure with the radical of a specified substituent.
Unless otherwise indicated, an optionally substituted group may
have a substituent at each substitutable position of the group, and
when more than one position in any given structure may be
substituted with more than one substituent selected from a
specified group, the substituent may be either the same or
different at every position. Combinations of substituents
envisioned by this invention are preferably those that result in
the formation of stable or chemically feasible compounds.
[0031] The term "stable", as used herein, refers to compounds that
are not substantially altered when subjected to conditions to allow
for their production, detection, and preferably their recovery,
purification, and use for one or more of the purposes disclosed
herein. In some embodiments, a stable compound or chemically
feasible compound is one that is not substantially altered when
kept at a temperature of 40.degree. C. or less, in the absence of
moisture or other chemically reactive conditions, for at least a
week.
[0032] The term "aliphatic" or "aliphatic group", as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or bicyclic hydrocarbon that is completely saturated or
that contains one or more units of unsaturation, but which is not
aromatic (also referred to herein as "carbocycle" "cycloaliphatic"
or "cycloalkyl"), that has a single point of attachment to the rest
of the molecule. Unless otherwise specified, aliphatic groups
contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic
groups contain 1-10 aliphatic carbon atoms. In other embodiments,
aliphatic groups contain 1-8 aliphatic carbon atoms. In still other
embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms,
and in yet other embodiments aliphatic groups contain 1-4 aliphatic
carbon atoms. In some embodiments, "cycloaliphatic" (or
"carbocycle" or "cycloalkyl") refers to a monocyclic
C.sub.3-C.sub.8 hydrocarbon or bicyclic C.sub.8-C.sub.12
hydrocarbon that is completely saturated or that contains one or
more units of unsaturation, but which is not aromatic, that has a
single point of attachment to the rest of the molecule wherein any
individual ring in said bicyclic ring system has 3-7 members.
Suitable aliphatic groups include, but are not limited to, linear
or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl
groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0033] The term "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" as used herein means
non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in
which one or more ring members is an independently selected
heteroatom. In some embodiments, the "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" group has three to
fourteen ring members in which one or more ring members is a
heteroatom independently selected from oxygen, sulfur, nitrogen, or
phosphorus, and each ring in the system contains 3 to 7 ring
members.
[0034] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon (including, any oxidized form of
nitrogen, sulfur, phosphorus, or silicon; the quaternized form of
any basic nitrogen or; a substitutable nitrogen of a heterocyclic
ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl).
[0035] The term "unsaturated", as used herein, means that a moiety
has one or more units of unsaturation.
[0036] The term "alkoxy", or "thioalkyl", as used herein, refers to
an alkyl group, as previously defined, attached to the principal
carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl")
atom.
[0037] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means
alkyl, alkenyl or alkoxy, as the case may be, substituted with one
or more halogen atoms. The term "halogen" means F, Cl, Br, or
I.
[0038] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic,
bicyclic, and tricyclic ring systems having a total of five to
fourteen ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3 to 7 ring
members. The term "aryl" may be used interchangeably with the term
"aryl ring". The term "aryl" also refers to heteroaryl ring systems
as defined hereinbelow.
[0039] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
monocyclic, bicyclic, and tricyclic ring systems having a total of
five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or
more heteroatoms, and wherein each ring in the system contains 3 to
7 ring members. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic".
[0040] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy
and the like) group may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl or
heteroaryl group are selected from halogen; N.sub.3, CN, R.sup.o;
OR.sup.o; SR.sup.o; 1,2-methylene-dioxy; 1,2-ethylenedioxy; phenyl
(Ph) optionally substituted with R.sup.o; --O(Ph) optionally
substituted with R.sup.o; (CH.sub.2).sub.1-2(Ph), optionally
substituted with R.sup.o; CH.dbd.CH(Ph), optionally substituted
with R.sup.o; NO.sub.2; CN; N(R.sup.o).sub.2; NR.sup.oC(O)R.sup.o;
NR.sup.oC(O)N(R.sup.o).sub.2; NR.sup.oCO.sub.2R.sup.o;
--NR.sup.oNR.sup.oC(O)R.sup.o;
NR.sup.oNR.sup.oC(O)N(R.sup.o).sub.2;
NR.sup.oNR.sup.oCO.sub.2R.sup.o; C(O)C(O)R.sup.o;
C(O)CH.sub.2C(O)R.sup.o; CO.sub.2R.sup.o; C(O)R.sup.o;
C(O)N(R.sup.o).sub.2; OC(O)N(R.sup.o).sub.2; S(O).sub.2R.sup.o;
SO.sub.2N(R.sup.o).sub.2; S(O)R.sup.o;
NR.sup.oSO.sub.2N(R.sup.o).sub.2; NR.sup.oSO.sub.2R.sup.o;
C(.dbd.S)N(R.sup.o).sub.2; C(.dbd.NH)--N(R.sup.o).sub.2; or
(CH.sub.2).sub.0-2NHC(O)R.sup.o wherein each independent occurrence
of R.sup.o is selected from hydrogen, optionally substituted
C.sub.1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring, phenyl, O(Ph), or CH.sub.2(Ph), or,
notwithstanding the definition above, two independent occurrences
of R.sup.o, on the same substituent or different substituents,
taken together with the atom(s) to which each R.sup.o group is
bound, form a 3-8 membered cycloalkyl, heterocyclyl, aryl, or
heteroaryl ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic
group of R.sup.o are selected from N.sub.3, CN, NH.sub.2,
NH(C.sub.1-4aliphatic), N(C.sub.1-4aliphatic).sub.2, halogen,
C.sub.1-4aliphatic, OH, O(C.sub.1-4aliphatic), NO.sub.2, CN,
CO.sub.2H, CO.sub.2(C.sub.1-4aliphatic), O(haloC.sub.1-4aliphatic),
or haloC.sub.1-4aliphatic, wherein each of the foregoing
C.sub.1-4aliphatic groups of R.sup.o is unsubstituted.
[0041] An aliphatic or heteroaliphatic group or a non-aromatic
heterocyclic ring may contain one or more substituents. Suitable
substituents on the saturated carbon of an aliphatic or
heteroaliphatic group, or of a non-aromatic heterocyclic ring are
selected from those listed above for the unsaturated carbon of an
aryl or heteroaryl group and additionally include the following:
.dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2, .dbd.NNHC(O)R*,
.dbd.NNHCO.sub.2(alkyl), .dbd.NNHSO.sub.2(alkyl), or .dbd.NR*,
where each R* is independently selected from hydrogen or an
optionally substituted C.sub.1-6 aliphatic. Optional substituents
on the aliphatic group of R* are selected from NH.sub.2,
NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen,
C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN,
CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4
aliphatic), or halo(C.sub.1-4 aliphatic), wherein each of the
foregoing C.sub.1-4aliphatic groups of R* is unsubstituted.
[0042] Optional substituents on the nitrogen of a non-aromatic
heterocyclic ring are selected from R.sup.+, N(R.sup.+).sub.2,
C(O)R.sup.+, CO.sub.2R.sup.+, C(O)C(O)R.sup.+,
C(O)CH.sub.2C(O)R.sup.+, SO.sub.2R.sup.+, SO.sub.2N(R.sup.+).sub.2,
C(.dbd.S)N(R.sup.+).sub.2, C(.dbd.NH)--N(R.sup.+).sub.2, or
NR.sup.+SO.sub.2R.sup.+; wherein R.sup.+ is hydrogen, an optionally
substituted C.sub.1-6 aliphatic, optionally substituted phenyl,
optionally substituted O(Ph), optionally substituted CH.sub.2(Ph),
optionally substituted (CH.sub.2).sub.1-2(Ph); optionally
substituted CH.dbd.CH(Ph); or an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring having one to four heteroatoms
independently selected from oxygen, nitrogen, or sulfur, or,
notwithstanding the definition above, two independent occurrences
of R.sup.+, on the same substituent or different substituents,
taken together with the atom(s) to which each R.sup.+ group is
bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or
heteroaryl ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic
group or the phenyl ring of R.sup.+ are selected from NH.sub.2,
NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen,
C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN,
CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4
aliphatic), or halo(C.sub.1-4 aliphatic), wherein each of the
foregoing C.sub.1-4aliphatic groups of R.sup.+ is
unsubstituted.
[0043] As detailed above, in some embodiments, two independent
occurrences of R.sup.o (or R.sup.+, or any other variable similarly
defined herein), are taken together with the atom(s) to which each
variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl,
aryl, or heteroaryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Exemplary rings that are
formed when two independent occurrences of R.sup.o (or R.sup.+, or
any other variable similarly defined herein) are taken together
with the atom(s) to which each variable is bound include, but are
not limited to the following: a) two independent occurrences of
R.sup.o (or R.sup.+, or any other variable similarly defined
herein) that are bound to the same atom and are taken together with
that atom to form a ring, for example, N(R.sup.o).sub.2, where both
occurrences of R.sup.o are taken together with the nitrogen atom to
form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and
b) two independent occurrences of R.sup.o (or R.sup.+, or any other
variable similarly defined herein) that are bound to different
atoms and are taken together with both of those atoms to form a
ring, for example where a phenyl group is substituted with two
occurrences of OR.sup.o
##STR00001##
these two occurrences of R.sup.o are taken together with the oxygen
atoms to which they are bound to form a fused 6-membered oxygen
containing ring
##STR00002##
It will be appreciated that a variety of other rings can be formed
when two independent occurrences of R.sup.o (or R.sup.+, or any
other variable similarly defined herein) are taken together with
the atom(s) to which each variable is bound and that the examples
detailed above are not intended to be limiting.
[0044] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
[0045] As used herein, the term "detectable moiety" is used
interchangeably with the term "label" and relates to any moiety
capable of being detected, e.g., primary labels and secondary
labels. Primary labels, such as radioisotopes (e.g., .sup.32P,
.sup.33P, .sup.35S, or .sup.14C), mass-tags, and fluorescent labels
are signal generating reporter groups which can be detected without
further modifications.
[0046] The term "secondary label" as used herein refers to moieties
such as biotin and various protein antigens that require the
presence of a second intermediate for production of a detectable
signal. For biotin, the secondary intermediate may include
streptavidin-enzyme conjugates. For antigen labels, secondary
intermediates may include antibody-enzyme conjugates. Some
fluorescent groups act as secondary labels because they transfer
energy to another group in the process of nonradiative fluorescent
resonance energy transfer (FRET), and the second group produces the
detected signal.
[0047] The terms "fluorescent label", "fluorescent dye", and
"fluorophore" as used herein refer to moieties that absorb light
energy at a defined excitation wavelength and emit light energy at
a different wavelength. Examples of fluorescent labels include, but
are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor
488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor
594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA,
AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR,
BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589,
BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine
6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow,
Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl,
Dapoxyl, Dialkylaminocoumarin,
4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin,
Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD
700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue,
Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green
500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B,
Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green,
2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine
(TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas
Red-X.
[0048] The term "mass-tag" as used herein refers to any moiety that
is capable of being uniquely detected by virtue of its mass using
mass spectrometry (MS) detection techniques. Examples of mass-tags
include electrophore release tags such as
N-[3-[4'-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]ison-
ipecotic Acid,
4'-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methyl
acetophenone, and their derivatives. The synthesis and utility of
these mass-tags is described in U.S. Pat. Nos. 4,650,750,
4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020,
and 5,650,270. Other examples of mass-tags include, but are not
limited to, nucleotides, dideoxynucleotides, oligonucleotides of
varying length and base composition, oligopeptides,
oligosaccharides, and other synthetic polymers of varying length
and monomer composition. A large variety of organic molecules, both
neutral and charged (biomolecules or synthetic compounds) of an
appropriate mass range (100-2000 Daltons) may also be used as
mass-tags.
[0049] The term "metal substrate", as used herein refers to any
metallic material which may be modified to incorporate hydroxyl
groups to which a functionalized end-group of a polymeric or small
molecule organic group can be attached.
3. Description of Exemplary Embodiments
[0050] As described generally above, the present invention provides
a method for covalently modifying a metal substrate, comprising the
steps of introducing hydroxyl groups onto the metal substrate to
produce a hydrophilic metal surface and covalently bonding a
polymer or small molecule organic moiety onto the hydrophilic metal
surface. As used herein, the phrase "hydrophilic metal surface"
refers to a metal substrate onto which a plurality of hydroxyl
groups has been incorporated. One of ordinary skill in the art
would recognize that various metallic substrates are amenable to
methods of the present invention. In certain embodiments, the metal
substrate is any such substrate that comprises iron. In other
embodiments, the metal substrate comprises a stainless steel, a
cobalt alloy, or a titanium alloy. In still other embodiments, the
metal substrate comprises iron, iron alloys, steel, stainless
steel, austenitic stainless steel, Type 316 stainless steel,
ferritic stainless steel, martensitic stainless steel, duplex
stainless steel, cobalt, cobalt alloys, cobalt-chromium alloys,
stellite alloys, Vitallium.RTM., titanium, titanium alloys,
nickel-titanium alloys, nitinol, or super-alloys.
[0051] Hydrophilic metal surfaces can be prepared with the use of
oxygen and/or water plasmas. (Kim et. al. Surface and Coatings
Technology, 2003, 171, 312-316). It has been shown that hydroxyl
groups, in the form of Fe(OH).sub.2, are the source of this
hydrophilicity on the metal surface. (Suzuki et. al. Surface and
Coatings Technology 2005, 200, 284-287). This strategy extends to a
number of iron-based metals and alloys such as iron, iron alloys,
steel, stainless steel, austenitic stainless steel, Type 316
stainless steel, ferritic stainless steel, martensitic stainless
steel, and duplex stainless steel. Other suitable metal substrates
include cobalt, cobalt alloys, cobalt-chromium alloys, stellite
alloys, Vitallium.RTM., titanium, titanium alloys, nickel-titanium
alloys, nitinol, and super-alloys. The geometry of the metal
substrate includes, but is not limited to, flat surfaces, curved
surfaces, cylinders, spheres, wire mesh, and tubing.
[0052] Using chemical functionality on the surface of
plasma-treated metals, it would be advantageous to perform
additional chemical modification of the substrate through
dehydration or condensation reactions. Such reactions proceed on
the hydrophilic metal surface without the need for additional
reagents or catalysts. Chemical functionalities that undergo
dehydration reactions with the plasma-modified metal substrates
include, but are not limited to, phosphonic acids, silyl-alcohols
and carboxylic acids. (Raman, A.; Gawalt, E. S. Langmuir, 2007, 23,
2284-2288. Raman, A. et. al. Langmuir, 2006, 22, 6469-6472. Gao, W.
et al. Langmuir, 1996, 12, 6429-6435.) In addition, phosphonic
halides, acyl halides, and silyl-halides can undergo condensation
reactions with hydroxyl functionalized metal surfaces to afford the
desired modified metallic material.
[0053] In certain embodiments, the dehydration reaction is carried
out by first incubating the hydrophilic metal surface with the
suitable functional molecule in an aqueous or organic solution.
Without wishing to be bound by any particular theory, it is
believed that during incubation, hydrogen bonding promotes the
interaction of the functional molecule with the modified metal
surface. This hydrogen-bonded intermediate is then converted to a
covalent bond by subsequent dehydration. In certain embodiments,
the dehydration step is performed at reduced pressure and/or
elevated temperature. In other embodiments, the condensation
reaction of acid-halide or silyl halide functional molecules and
hydroxyl-functionalized metal substrates is performed using
anhydrous conditions in dry organic solvents, leading directly to
the desired covalently modified metal surface. One of ordinary
still in the art will appreciate that the covalent bond forming
reactions contemplated by the present invention are not limited to
dehydration and condensation reactions and include, for example,
addition reactions.
[0054] The introduction of hydroxyl groups onto a metal surface is
well known to one of ordinary skill in the art. One of ordinary
skill would recognize that there are multiple methods for
accomplishing the functionalization of a metal substrate. One such
method is the oxidation of iron atoms found in metal substrates.
Such oxidation is well known in the art and includes cold plasma
methods as described by, e.g., Suzuki, et al, Surface &
Coatings Technology, (2005) 284-287. In certain embodiments, the
metal substrate is oxidized with water vapor plasma.
[0055] As described generally above, the functionalized metal
surface is covalently bonded to a polymer or a small molecule
organic moiety. One of ordinary skill in the art would appreciate
that hydroxyl groups are covalently bonded to a variety of other
functional groups (e.g., with carboxylic acids to form esters
thereof) by condensation or dehydration reaction. All such
functional groups capable of covalently bonding to the hydroxyl
groups incorporated onto the metal surface are contemplated. In
certain embodiments, the polymer or small molecule organic moiety
comprises one or more functional groups capable of covalently
bonding to one or more hydroxyl groups incorporated onto the metal
surface. Exemplary functional groups include, but are not limited
to, phosphonic acids, silyl-alcohols, carboxylic acids, phosphonic
halides, acyl halides, and silyl-halides.
[0056] Polymeric groups for use in the present invention comprise
one or more functional groups capable of covalently bonding with
one or more hydroxyl groups incorporated onto the metal surface. It
will be appreciated that many such polymeric groups are amenable to
this reaction. These polymeric groups include natural or synthetic
polymers and copolymers. Exemplary polymers include
mono-functionalized PEG's, poly(amino acids), heterobifunctional
PEG's, branched PEG's, heterofunctionalized branched PEG's,
PEG-b-PAA-b-PAA block copolymer, PEG-b-PAA-b-PEG block copolymers,
PEG-b-polyester-b-PEG block copolymers, PEG-b-PAA block copolymers,
[where PAA refers to poly(amino acid)], dextran, heparin,
fibronectin, chitosan, amylose, amylopectin, glycogen, xanthan,
gellan, pullulun, cellulose, and cellulose acetate.
[0057] In certain embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula I:
R.sup.1--W I
wherein: [0058] R.sup.1 is a natural or synthetic polymer or
copolymer group or a small molecule organic group; [0059] W is
--C(.dbd.O)OH, --C(.dbd.O)X, --P(.dbd.O)(OH).sub.2,
--P(.dbd.O)(X).sub.2, --P(.dbd.O)(R.sup.a)OH,
--P(.dbd.O)(R.sup.a)X, --O--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2OH,
--Si(R.sup.a).sub.2OH, --Si(OR.sup.a).sub.2OH,
--Si(R.sup.a).sub.2X, --Si(R.sup.a)(OH).sub.2,
--Si(R.sup.a)X.sub.2, --Si(OR.sup.a).sub.2X, C(.dbd.O)H,
--N.dbd.C.dbd.S, --N.dbd.C.dbd.O, phenol, thiophenol, or an
epoxide; [0060] each X is independently Cl, Br, or I; and [0061]
each R.sup.a is hydrogen, an alkyl group, or an aryl group; [0062]
and (c) coupling the compound of formula I to one or more of the
hydroxyl groups on the metal surface.
[0063] As described generally above, the coupling step (c) can be
performed in the absence of reagents or catalysts by dehydration or
condensation. However, it is also contemplated that the coupling
step (c) can be performed in the presence of such reagents or
catalysts. For example, coupling step (c) may be performed in the
presence of a suitable base. Suitable bases include any of those
known to one of ordinary skill in the art for such coupling
reactions. Exemplary bases include, but are not limited to,
triethylamine, diisopropylamine, diisopropylethylamine,
dimethylaminopyridine, and the like.
[0064] One of ordinary skill in the art will appreciate that when W
is --C(.dbd.O)X, --P(.dbd.O)(X).sub.2, --P(.dbd.O)(R.sup.a)X,
--Si(R.sup.a).sub.2X, or --Si(OR.sup.a).sub.2X, then the coupling
at step (c) can occur by a condensation reaction. See FIGS. 2, 4,
6, 8, 10, and 12 which depict representative methods of the present
invention whereby coupling step (c) occurs by condensation
reaction.
[0065] Similarly, when W is --C(.dbd.O)OH, --P(.dbd.O)(OH).sub.2,
--P(.dbd.O)(R.sup.a)OH, --Si(R.sup.a).sub.2OH, or
--Si(OR.sup.a).sub.2OH, the coupling at step (c) can occur by a
dehydration reaction. See FIGS. 1, 3, 5, 7, 9, and 11 which depict
representative methods of the present invention whereby coupling
step (c) occurs by dehydration reaction.
[0066] In certain embodiments, the metal substrate comprises iron,
iron alloys, steel, stainless steel, austenitic stainless steel,
Type 316 stainless steel, ferritic stainless steel, martensitic
stainless steel, duplex stainless steel, cobalt, cobalt alloys,
cobalt-chromium alloys, stellite alloys, Vitallium.RTM., titanium,
titanium alloys, nickel-titanium alloys, nitinol, or
super-alloys.
[0067] In other embodiments, R.sup.1 is a synthetic polymer such as
linear homopolymers, branched homopolymers, block copolymers,
branched block copolymers, star polymers, star copolymers, graft
copolymers, hyperbranched copolymers, and dendrimers. In still
other embodiments, R.sup.1 is a natural polymer such as
oligopeptides, proteins, polynucleic acids (e.g. DNA and RNA),
oligosaccharides, and polysaccharides. According to another aspect
of the present invention, R.sup.1 is poly(ethylene glycol) (PEG), a
heterobifunctional PEG, a branched PEG, heterofunctionalized
branched PEG's, PEG-b-PAA-b-PAA block copolymer, PEG-b-PAA-b-PEG
block copolymers, PEG-b-polyester-b-PEG block copolymers, PEG-b-PAA
block copolymers, [where PAA refers to poly(amino acid)], dextran,
heparin, fibronectin, chitosan, amylose, amylopectin, glycogen,
xanthan, gellan, pullulun, cellulose, and cellulose acetate.
[0068] In certain embodiments, R.sup.1 is a small molecule organic
group. In other embodiments, R.sup.1 is selected from
monosaccharides (e.g., glucose, galactose, fructose) and
disaccharides (e.g., sucrose, lactose, maltose),
phosphorylcholines, phosoplipids, cyclodextrans, and small molecule
drugs.
[0069] In other embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) providing a metal surface having a plurality of hydroxyl
groups; (b) providing a compound of formula I:
R.sup.1--W I
wherein: [0070] R.sup.1 is a natural or synthetic polymer or
copolymer group or a small molecule organic group; [0071] W is
--C(.dbd.O)OH, --C(.dbd.O)X, --P(.dbd.O)(OH).sub.2,
--P(.dbd.O)(X).sub.2, --P(.dbd.O)(R.sup.a)OH,
--P(.dbd.O)(R.sup.a)X, --O--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2OH,
--Si(R.sup.a).sub.2OH, --Si(OR.sup.a).sub.2OH,
--Si(R.sup.a).sub.2X, --Si(R.sup.a)(OH).sub.2,
--Si(R.sup.a)X.sub.2, --Si(OR.sup.a).sub.2X, C(.dbd.O)H,
--N.dbd.C.dbd.S, --N.dbd.C.dbd.O, phenol, thiophenol, or an
epoxide; [0072] each X is independently Cl, Br, or I; and [0073]
each R.sup.a is hydrogen, an alkyl group, or an aryl group; [0074]
and (c) coupling the compound of formula I to one or more of the
hydroxyl groups on the metal surface.
Polymer Groups
[0075] As defined generally above, R.sup.1 is a natural or
synthetic polymer or copolymer group or a small molecule organic
group. In certain embodiments, R.sup.1 is a poly(alkylene oxide)
group or a branched poly(alkylene oxide). In other embodiments,
R.sup.1 is a poly(ethylene glycol) group ("PEG"). PEG's are well
known to one of ordinary skill in the art and include those
described in detail in International Patent Application publication
number WO2006/047419, U.S. Provisional Patent Application Ser. No.
60/795,412, filed Apr. 27, 2006, and U.S. Provisional Patent
Application Ser. No. 60/795,374, filed Apr. 27, 2006, the entirety
of each of which is hereby incorporated herein by reference.
According to another aspect of the present invention, R.sup.1 is a
group of formula II:
##STR00003##
or a salt thereof, wherein: [0076] y is 0-2500; [0077] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a small
molecule drug, a 9-30 membered crown ether, a mono-protected amine,
a di-protected amine, a protected aldehyde, a protected hydroxyl, a
protected carboxylic acid, a protected thiol, or an optionally
substituted group selected from aliphatic, a 3-8 membered
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10 membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety; [0078] each X'
is independently halogen; [0079] each R is independently hydrogen
or an optionally substituted aliphatic group; [0080] L.sup.1 is a
valence bond or a bivalent, saturated or unsaturated, straight or
branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units of
L.sup.1 are independently replaced by -Cy-, --O--, --NR--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein: [0081] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; and [0082] L.sup.2 is a valence bond or a bivalent,
saturated or unsaturated, straight or branched C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein:
[0083] each -Cy- is independently an optionally substituted 3-8
membered bivalent, saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an optionally substituted 8-10 membered
bivalent saturated, partially unsaturated, or aryl bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0084] As defined generally above, the y group of formula II is
0-2500. In certain embodiments, the y group of formula II is 0. In
certain embodiments, the present invention provides compounds of
formula II, as described above, wherein y is about 225. In other
embodiments, y is about 10 to about 40. In other embodiments, y is
about 40 to about 60. In still other embodiments, y is about 90 to
about 150. In still other embodiments, y is about 200 to about 250.
In other embodiments, y is about 300 to about 375. In other
embodiments, y is about 400 to about 500. In still other
embodiments, y is about 650 to about 750. In still other
embodiments, y is about 1 to about 10.
[0085] In certain embodiments, R.sup.2 is optionally substituted
aliphatic. In other embodiments, R.sup.2 is an unsubstituted
aliphatic. In some embodiments, said R.sup.2 moiety is an
optionally substituted alkyl group. In other embodiments, said
R.sup.2 moiety is an optionally substituted alkynyl or alkenyl
group. Such groups include methyl, t-butyl, 5-norbornene-2-yl,
octane-5-yl, --C.ident.CH, --CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2C.ident.CH, and
--CH.sub.2CH.sub.2CH.sub.2C.ident.CH. When said R.sup.2 moiety is a
substituted aliphatic group, suitable substituents on R.sup.2
include any of CN, N.sub.3, NO.sub.2, --CO.sub.2H, --SH,
--NH.sub.2, --C(O)H, --NHC(O)R.sup.o, --NHC(S)R.sup.o,
--NHC(O)NR.sup.o.sub.2, --NHC(S)NR.sup.o.sub.2, --NHC(O)OR.sup.o,
--NHNHC(O)R.sup.o, --NHNHC(O)NR.sup.o.sub.2, --NHNHC(O)OR.sup.o,
--C(O)R.sup.o, --C(S)R.sup.o, --C(O)OR.sup.o, --C(O)SR.sup.o,
--C(O)OSiR.sup.o.sub.3, --OC(O)R.sup.o, SC(S)SR.sup.o,
--SC(O)R.sup.o, --C(O)N(R.sup.o).sub.2, --C(S)N(R.sup.o).sub.2,
--C(S)SR.sup.o, --SC(S)SR.sup.o, --OC(O)N(R.sup.o).sub.2,
--C(O)NHN(R.sup.o).sub.2, --C(O)N(OR.sup.o)R.sup.o,
--C(O)C(O)R.sup.o, --C(O)CH.sub.2C(O)R.sup.o,
--C(NOR.sup.o)R.sup.o, --SSR.sup.o, --S(O).sub.2R.sup.o,
--S(O).sub.2OR.sup.o, --OS(O).sub.2R.sup.o,
--S(O).sub.2N(R.sup.o).sub.2, --S(O)R.sup.o,
--N(R.sup.o)S(O).sub.2N(R.sup.o).sub.2,
--N(R.sup.o)S(O).sub.2R.sup.o, --N(OR.sup.o)R.sup.o,
--C(NH)N(R.sup.o).sub.2, --P(O).sub.2R.sup.o,
--P(O)(R.sup.o).sub.2, --OP(O)(R.sup.o).sub.2, or
--OP(O)(OR.sup.o).sub.2, wherein each R.sup.o is as defined
herein.
[0086] In other embodiments, R.sup.2 is an aliphatic group
optionally substituted with any of Cl, Br, I, F, --NH2, --OH, --SH,
--CO.sub.2H, --C(O)H, --C(O)(C.sub.1-6 aliphatic),
--NHC(O)(C.sub.1-6 aliphatic), --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-6 aliphatic), --NHC(S)NH--, --NHC(S)N(C.sub.1-6
aliphatic).sub.2, --NHC(O)O(C.sub.1-6 aliphatic), --NHNH.sub.2,
--NHNHC(O)(C.sub.1-6 aliphatic), --NHNHC(O)NH.sub.2,
--NHNHC(O)NH(C.sub.1-6 aliphatic), --NHNHC(O)O(C.sub.1-6
aliphatic), --C(O)NH.sub.2, --C(O)NH(C.sub.1-6 aliphatic).sub.2,
--C(O)NHNH.sub.2, --C(S)N(C.sub.1-6 aliphatic).sub.2,
--OC(O)NH(C.sub.1-6 aliphatic), --C(O)C(O)(C.sub.1-6 aliphatic),
--C(O)CH.sub.2C(O)(C.sub.1-6 aliphatic), --S(O).sub.2(C.sub.1-6
aliphatic), --S(O).sub.2O(C.sub.1-6 aliphatic),
--OS(O).sub.2(C.sub.1-6 aliphatic), --S(O).sub.2NH(C.sub.1-6
aliphatic), --S(O)(C.sub.1-6 aliphatic), --NHS(O).sub.2NH(C.sub.1-6
aliphatic), --NHS(O).sub.2(C.sub.1-6 aliphatic),
--P(O).sub.2(C.sub.1-6 aliphatic), --P(O)(C.sub.1-6
aliphatic).sub.2, --OP(O)(C.sub.1-6 aliphatic).sub.2, or
--OP(O)(OC.sub.1-6 aliphatic).sub.2.
[0087] In certain embodiments, the R.sup.2 group of formula II is a
group suitable for Click chemistry. Click reactions tend to involve
high-energy ("spring-loaded") reagents with well-defined reaction
coordinates, that give rise to selective bond-forming events of
wide scope. Examples include nucleophilic trapping of strained-ring
electrophiles (epoxide, aziridines, aziridinium ions, episulfonium
ions), certain carbonyl reactivity (e.g., the reaction between
aldehydes and hydrazines or hydroxylamines), and several
cycloaddition reactions. The azide-alkyne 1,3-dipolar cycloaddition
is one such reaction. Click chemistry is known in the art and one
of ordinary skill in the art would recognize that certain R.sup.2
moieties of the present invention are suitable for Click
chemistry.
[0088] According to one embodiment, the R.sup.2 group of formula II
is an azide-containing group. According to another embodiment, the
R.sup.2 group of formula II is an alkyne-containing group. In
certain embodiments, the R.sup.2 group of formula II has a terminal
alkyne moiety. According to another embodiment, the R.sup.2 group
of formula II is an aldehyde-containing group. In certain
embodiments, the R.sup.2 group of formula II has a terminal
hydrazine moiety. In other embodiments, the R.sup.2 group of
formula II has a terminal oxyamine moiety. In still other
embodiments, the R.sup.2 group of formula II is a
epoxide-containing group. In certain other embodiments, the R.sup.2
group of formula II has a terminal maleimide moiety.
[0089] In other embodiments, R.sup.2 is an optionally substituted
3-8 membered saturated, partially unsaturated, or aryl ring having
0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10 membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. In certain embodiments, R.sup.2 is an
optionally substituted 5-7 membered saturated or partially
unsaturated ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. In other embodiments, R.sup.2 is an
optionally substituted phenyl ring or a 5-6 membered heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0090] In certain embodiments, the R.sup.2 group of formula II is
an optionally substituted aryl group. Examples include optionally
substituted phenyl, optionally substituted pyridyl, optionally
substituted naphthyl, optionally substituted pyrenyl, optionally
substituted triazole, optionally substituted imidazole, optionally
substituted phthalimide, optionally substituted tetrazole,
optionally substituted furan, and optionally substituted pyran.
When said R.sup.2 moiety is a substituted aryl group, suitable
substituents on R.sup.2 include any of R.sup.o, CN, N.sub.3,
NO.sub.2, --CH.sub.3, --CH.sub.2N.sub.3, t-butyl,
5-norbornene-2-yl, octane-5-yl, --CH.dbd.CH.sub.2,
--CH.sub.2C.ident.CH, --CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2CH.sub.2C.ident.CH, Cl, Br, I, F, --NH.sub.2,
--OH, --SH, --CO.sub.2H, --C(O)H, --CH.sub.2NH.sub.2, --CH.sub.2OH,
--CH.sub.2SH, --CH.sub.2CO.sub.2H, --CH.sub.2C(O)H,
--C(O)(C.sub.1-6 aliphatic), --NHC(O)(C.sub.1-6 aliphatic),
--NHC(O)NH--, --NHC(O)NH(C.sub.1-6 aliphatic), --NHC(S)NH.sub.2,
--NHC(S)N(C.sub.1-6 aliphatic).sub.2, --NHC(O)O(C.sub.1-6
aliphatic), --NHNH.sub.2, --NHNHC(O)(C.sub.1-6 aliphatic),
--NHNHC(O)NH.sub.2, --NHNHC(O)NH(C.sub.1-6 aliphatic),
--NHNHC(O)O(C.sub.1-6 aliphatic), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-6 aliphatic).sub.2, --C(O)NHNH.sub.2,
--C(S)N(C.sub.1-6 aliphatic).sub.2, --OC(O)NH(C.sub.1-6 aliphatic),
--C(O)C(O)(C.sub.1-6 aliphatic), --C(O)CH.sub.2C(O)(C.sub.1-6
aliphatic), --S(O).sub.2(C.sub.1-6 aliphatic),
--S(O).sub.2O(C.sub.1-6 aliphatic), --OS(O).sub.2(C.sub.1-6
aliphatic), --S(O).sub.2NH(C.sub.1-6 aliphatic), --S(O)(C.sub.1-6
aliphatic), --NHS(O).sub.2NH(C.sub.1-6 aliphatic),
--NHS(O).sub.2(C.sub.1-6 aliphatic), --P(O).sub.2(C.sub.1-6
aliphatic), --P(O)(C.sub.1-6 aliphatic).sub.2, --OP(O)(C.sub.1-6
aliphatic).sub.2, or --OP(O)(OC.sub.1-6 aliphatic).sub.2.
[0091] Suitable substitutents on R.sup.2 further include
bis-(4-ethynyl-benzyl)-amino, dipropargylamino,
di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino,
propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy,
2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl,
2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl,
bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, and [1,3]dioxan-2-yl.
[0092] In other embodiments, R.sup.2 is hydrogen.
[0093] According to one embodiment, R.sup.2 is methyl.
[0094] In certain embodiments, R.sup.2 is N.sub.3.
[0095] In other embodiments, R.sup.2 is an epoxide ring.
[0096] In certain embodiments, the R.sup.2 group of formula II is a
crown ether. Examples of such crown ethers include 12-crown-4,
15-crown-5, and 18-crown-6.
[0097] In still other embodiments, R.sup.2 is a detectable moiety.
Detectable moieties are known in the art and include those
described herein. According to one aspect of the invention, the
R.sup.2 group of formula II is a fluorescent moiety. Such
fluorescent moieties are well known in the art and include
coumarins, quinolones, benzoisoquinolones, hostasol, and Rhodamine
dyes, to name but a few. Exemplary fluorescent moieties of R.sup.2
include anthracen-9-yl, pyren-4-yl, 9-H-carbazol-9-yl, the
carboxylate of rhodamine B, and the carboxylate of coumarin 343. In
certain embodiments, R.sup.2 is a detectable moiety selected
from:
##STR00004## ##STR00005##
[0098] In certain embodiments, R.sup.2 is --P(O)(OR).sub.2, or
--P(O)(halogen).sub.2. According to one aspect, the present
invention provides a compound of formula II, wherein R.sup.2 is
--P(O)(OH).sub.2. According to another aspect, the present
invention provides a compound of formula II, wherein R.sup.2 is
--P(O)(Cl).sub.2. One of ordinary skill in the art would recognize
that when R.sup.2 is --P(O)(OR).sub.2, or --P(O)(halogen).sub.2,
the R.sup.2 group is also capable of forming a covalent bond with
the hydrophilic metal surface thus forming a "looped"
attachment.
[0099] As defined generally above, the L.sup.1 group of formula II
is a valence bond or a bivalent, saturated or unsaturated, straight
or branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units
of L.sup.1 are independently replaced by -Cy-, --O--, --NR--,
--S--, --OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0100] In certain embodiments, L.sup.1 is a valence bond. In other
embodiments, L.sup.1 is a bivalent, saturated C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.1 are independently
replaced by -Cy-, --O--, --NH--, --S--, --OC(O)--, --C(O)O--,
--C(O)--, --C(O)NH--, or --NHC(O)--, wherein each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. In still other embodiments, L.sup.1 is a bivalent,
saturated C.sub.1-6 alkylene chain, wherein 0-3 methylene units of
L.sup.1 are independently replaced by -Cy-, --O--, --NH--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --C(O)NH--, or --NHC(O)--.
[0101] In certain embodiments, L.sup.1 is -Cy- (i.e. a C.sub.1
alkylene chain wherein the methylene unit is replaced by -Cy-),
wherein -Cy- is an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. According to one aspect of the present invention, -Cy- is
an optionally substituted bivalent aryl group. According to another
aspect of the present invention, -Cy- is an optionally substituted
bivalent phenyl group. In other embodiments, -Cy- is an optionally
substituted 5-8 membered bivalent, saturated carbocyclic ring. In
still other embodiments, -Cy- is an optionally substituted 5-8
membered bivalent, saturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Exemplary -Cy- groups include bivalent rings selected from
phenyl, pyridyl, pyrimidinyl, cyclohexyl, cyclopentyl, or
cyclopropyl.
[0102] In certain embodiments, the L.sup.1 group of formula II is
--O--, --S--, --NH--, or --C(O)O--. In other embodiments, the
L.sup.1 group of formula II is -Cy-, --C(O)--, --C(O)NH--,
--NHC(O)--, --NH--O--, or --O-Cy-CH.sub.2NH--O--. In still other
embodiments, the L.sup.1 group of formula II is any of
--OCH.sub.2--, --OCH.sub.2C(O)--, --OCH.sub.2CH.sub.2C(O)--,
--OCH.sub.2CH.sub.2O--, --OCH.sub.2CH.sub.2S--,
--OCH.sub.2CH.sub.2C(O)O--, --OCH.sub.2CH.sub.2NH--,
--OCH.sub.2CH.sub.2NHC(O)--, --OCH.sub.2CH.sub.2C(O)NH--, and
--NHC(O)CH.sub.2CH.sub.2C(O)O--. According to another aspect, the
L.sup.1 group of formula II is any of
--OCH.sub.2CH.sub.2NHC(O)CH.sub.2CH.sub.2C(O)O--,
--OCH.sub.2CH.sub.2NHC(O)CH.sub.2OCH.sub.2C(O)O--,
--OCH.sub.2CH.sub.2NHC(O)CH.sub.2OCH.sub.2C(O)NH--,
--CH.sub.2C(O)NH--, --CH.sub.2C(O)NHNH--, or
--OCH.sub.2CH.sub.2NHNH--.
[0103] As defined generally above, the R.sup.2 group of formula II
is, inter alia, a mono-protected amine, a di-protected amine, a
protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, or a protected thiol. Protected hydroxyl groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, the entirety
of which is incorporated herein by reference. Examples of suitably
protected hydroxyl groups further include, but are not limited to,
esters, carbonates, sulfonates allyl ethers, ethers, silyl ethers,
alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of
suitable esters include formates, acetates, proprionates,
pentanoates, crotonates, and benzoates. Specific examples of
suitable esters include formate, benzoyl formate, chloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate,
4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate),
crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate,
2,4,6-trimethylbenzoate. Examples of suitable carbonates include
9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl,
2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and
p-nitrobenzyl carbonate. Examples of suitable silyl ethers include
trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, triisopropylsilyl ether, and other
trialkylsilyl ethers. Examples of suitable alkyl ethers include
methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl,
t-butyl, and allyl ether, or derivatives thereof. Alkoxyalkyl
ethers include acetals such as methoxymethyl, methylthiomethyl,
(2-methoxyethoxy)methyl, benzyloxymethyl,
beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether.
Examples of suitable arylalkyl ethers include benzyl,
p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl,
p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2-
and 4-picolyl ethers.
[0104] Protected amines are well known in the art and include those
described in detail in Greene (1999). Suitable mono-protected
amines further include, but are not limited to, aralkylamines,
carbamates, allyl amines, amides, and the like. Examples of
suitable mono-protected amino moieties include
t-butyloxycarbonylamino (--NHBOC), ethyloxycarbonylamino,
methyloxycarbonylamino, trichloroethyloxycarbonylamino,
allyloxycarbonylamino (--NHAlloc), benzyloxocarbonyl amino
(--NHCBZ), allylamino, benzylamino (--NHBn),
fluorenylmethylcarbonyl (--NHFmoc), formamido, acetamido,
chloroacetamido, dichloroacetamido, trichloroacetamido,
phenylacetamido, trifluoroacetamido, benzamido,
t-butyldiphenylsilyl, and the like. Suitable di-protected amines
include amines that are substituted with two substituents
independently selected from those described above as mono-protected
amines, and further include cyclic imides, such as phthalimide,
maleimide, succinimide, and the like. Suitable di-protected amines
also include pyrroles and the like,
2,2,5,5-tetramethyl-[1,2,5]azadisilolidine and the like, and
azide.
[0105] Protected aldehydes are well known in the art and include
those described in detail in Greene (1999). Suitable protected
aldehydes further include, but are not limited to, acyclic acetals,
cyclic acetals, hydrazones, imines, and the like. Examples of such
groups include dimethyl acetal, diethyl acetal, diisopropyl acetal,
dibenzyl acetal, bis(2-nitrobenzyl)acetal, 1,3-dioxanes,
1,3-dioxolanes, semicarbazones, and derivatives thereof.
[0106] Protected carboxylic acids are well known in the art and
include those described in detail in Greene (1999). Suitable
protected carboxylic acids further include, but are not limited to,
optionally substituted C.sub.1-6 aliphatic esters, optionally
substituted aryl esters, silyl esters, activated esters, amides,
hydrazides, and the like. Examples of such ester groups include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and
phenyl ester, wherein each group is optionally substituted.
Additional suitable protected carboxylic acids include oxazolines
and ortho esters.
[0107] Protected thiols are well known in the art and include those
described in detail in Greene (1999). Suitable protected thiols
further include, but are not limited to, disulfides, thioethers,
silyl thioethers, thioesters, thiocarbonates, and thiocarbamates,
and the like. Examples of such groups include, but are not limited
to, alkyl thioethers, benzyl and substituted benzyl thioethers,
triphenylmethyl thioethers, and trichloroethoxycarbonyl thioester,
to name but a few.
[0108] As defined generally above, the L.sup.2 group of formula II
is L.sup.2 is a valence bond or a bivalent, saturated or
unsaturated, straight or branched C.sub.1-12 alkylene chain,
wherein 0-6 methylene units of L.sup.2 are independently replaced
by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0109] In certain embodiments, L.sup.2 is a valence bond. In other
embodiments, L.sup.2 is a bivalent, saturated C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, or --O--, --NH--, wherein each -Cy- is
independently an optionally substituted 5-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. In still other embodiments, L.sup.2 is a bivalent,
saturated C.sub.1-6 alkylene chain, wherein 0-2 methylene units of
L.sup.2 are independently replaced by -Cy-.
[0110] In certain embodiments, L.sup.2 is -Cy- (i.e., a C.sub.1
alkylene chain wherein the methylene unit is replaced by -Cy-),
wherein -Cy- is an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. According to one aspect of the present invention, -Cy- is
an optionally substituted bivalent aryl group. According to another
aspect of the present invention, -Cy- is an optionally substituted
bivalent phenyl group. In other embodiments, -Cy- is an optionally
substituted 5-8 membered bivalent, saturated carbocyclic ring. In
still other embodiments, -Cy- is an optionally substituted 5-8
membered bivalent, saturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Exemplary -Cy- groups include bivalent rings selected from
phenyl, pyridyl, pyrimidinyl, cyclohexyl, cyclopentyl, or
cyclopropyl.
[0111] In certain embodiments, the L.sup.2 group of formula II is
--O--, --S--, --NH--, or --C(O)--. In still other embodiments, the
L.sup.2 group of formula II is any of --OCH.sub.2--,
--OCH.sub.2C(O)--, --OCH.sub.2CH.sub.2C(O)--,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2CH.sub.2S--. In other
embodiments, the L.sup.2 group of formula II is
--OC(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2--,
--NHC(O)CH.sub.2CH.sub.2--, --NHC(O)CH.sub.2CH.sub.2CH.sub.2--,
--OC(O)CH.sub.2CH.sub.2CH.sub.2--, --O-Cy-, --O-Cy-CH.sub.2--,
--O-Cy-NH--, --O-Cy-S--, --O-Cy-C(O)--, or --O-Cy-C(O)O-Cy-.
[0112] In certain embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula II-a:
##STR00006##
or a salt thereof, wherein: [0113] W is --C(.dbd.O)OH,
--C(.dbd.O)X, --P(.dbd.O)(OH).sub.2, --P(.dbd.O)(X).sub.2,
--P(.dbd.O)(R.sup.a)OH, --P(.dbd.O)(R.sup.a)X,
--O--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2OH, --Si(R.sup.a).sub.2OH,
--Si(OR.sup.a).sub.2OH, --Si(R.sup.a).sub.2X,
--Si(R.sup.a)(OH).sub.2, --Si(R.sup.a)X.sub.2,
--Si(OR.sup.a).sub.2X, C(.dbd.O)H, --N.dbd.C.dbd.S,
--N.dbd.C.dbd.O, phenol, thiophenol, or an epoxide; [0114] each X
is independently Cl, Br, or I; and [0115] each R.sup.a is hydrogen,
an alkyl group, or an aryl group; [0116] y is 0-2500; [0117]
R.sup.2 is hydrogen, halogen, NO.sub.2, CN, N.sub.3,
--N.dbd.C.dbd.O, --C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2,
--P(O)(X').sub.2, a 9-30 membered crown ether, a mono-protected
amine, a di-protected amine, a protected aldehyde, a protected
hydroxyl, a protected carboxylic acid, a protected thiol, or an
optionally substituted group selected from aliphatic, a 3-8
membered saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10 membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety; [0118] each X'
is independently halogen; [0119] each R is independently hydrogen
or an optionally substituted aliphatic group; [0120] L.sup.1 is a
valence bond or a bivalent, saturated or unsaturated, straight or
branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units of
L.sup.1 are independently replaced by -Cy-, --O--, --NR--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein: [0121] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; and [0122] L.sup.2 is a valence bond or a bivalent,
saturated or unsaturated, straight or branched C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein:
[0123] each -Cy- is independently an optionally substituted 3-8
membered bivalent, saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an optionally substituted 8-10 membered
bivalent saturated, partially unsaturated, or aryl bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur. [0124] and (c) coupling the compound of formula
II-a to one or more of the hydroxyl groups on the metal
surface.
[0125] Each of the R.sup.2, L.sup.1, y, and L.sup.2 groups of
formula II-a are as described in classes and subclasses for
compounds of formula II, both singly and in combination.
[0126] In other embodiments, the present invention provides a
compound of formula II-a':
##STR00007##
or a salt thereof, wherein: [0127] W is --Si(R.sup.a).sub.2OH,
--Si(OR.sup.a).sub.2OH, --Si(R.sup.a).sub.2X,
--Si(R.sup.a)(OH).sub.2, --Si(R.sup.a)X.sub.2, or
--Si(OR.sup.a).sub.2X; [0128] each X is independently Cl, Br, or I;
and [0129] each R.sup.a is hydrogen, an alkyl group, or an aryl
group; [0130] y is 0-2500; [0131] R.sup.2 is hydrogen, halogen,
NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O, --C(R).dbd.NN(R).sub.2,
--P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30 membered crown ether, a
mono-protected amine, a di-protected amine, a protected aldehyde, a
protected hydroxyl, a protected carboxylic acid, a protected thiol,
or an optionally substituted group selected from aliphatic, a 3-8
membered saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10 membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety; [0132] each X'
is independently halogen; [0133] each R is independently hydrogen
or an optionally substituted aliphatic group; [0134] L.sup.1 is a
valence bond or a bivalent, saturated or unsaturated, straight or
branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units of
L.sup.1 are independently replaced by -Cy-, --O--, --NR--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein: [0135] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; and [0136] L.sup.2 is a valence bond or a bivalent,
saturated or unsaturated, straight or branched C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein:
[0137] each -Cy- is independently an optionally substituted 3-8
membered bivalent, saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an optionally substituted 8-10 membered
bivalent saturated, partially unsaturated, or aryl bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0138] Each of the R.sup.2, L.sup.1, y, and L.sup.2 groups of
formula II-a' are as described in classes and subclasses for
compounds of formula II, both singly and in combination.
[0139] In other embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula II-b:
##STR00008##
or a salt thereof, wherein: [0140] y is 10-2500; [0141] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30
membered crown ether, a mono-protected amine, a di-protected amine,
a protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, a protected thiol, or an optionally substituted group
selected from aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an 8-10 membered
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a detectable moiety; [0142] each X' is independently
halogen; [0143] each R is independently hydrogen or an optionally
substituted aliphatic group; [0144] L.sup.1 is a valence bond or a
bivalent, saturated or unsaturated, straight or branched C.sub.1-12
alkylene chain, wherein 0-6 methylene units of L.sup.1 are
independently replaced by -Cy-, --O--, --NR--, --S--, --OC(O)--,
--C(O)O--, --C(O)--, --SO--, --SO.sub.2--, --NRSO.sub.2--,
--SO.sub.2NR--, --NRC(O)--, --C(O)NR--, --OC(O)NR--, or
--NRC(O)O--, wherein: [0145] each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0146]
L.sup.2 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of L.sup.2 are independently replaced by -Cy-,
--O--, --NR--, --S--, or --C(O)--, wherein: [0147] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. [0148] and (c) coupling the compound of formula II-b to one
or more of the hydroxyl groups on the metal surface by dehydration
reaction.
[0149] Each of the R.sup.2, L.sup.1, y, and L.sup.2 groups of
formula II-b are as described in classes and subclasses for
compounds of formula II, both singly and in combination.
[0150] In other embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula II-c:
##STR00009##
or a salt thereof, wherein: [0151] y is 10-2500; [0152] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30
membered crown ether, a mono-protected amine, a di-protected amine,
a protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, a protected thiol, or an optionally substituted group
selected from aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an 8-10 membered
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a detectable moiety; [0153] each X' is independently
halogen; [0154] each R is independently hydrogen or an optionally
substituted aliphatic group; [0155] L.sup.1 is a valence bond or a
bivalent, saturated or unsaturated, straight or branched C.sub.1-12
alkylene chain, wherein 0-6 methylene units of L.sup.1 are
independently replaced by -Cy-, --O--, --NR--, --S--, --OC(O)--,
--C(O)O--, --C(O)--, --SO--, --SO.sub.2--, --NRSO.sub.2--,
--SO.sub.2NR--, --NRC(O)--, --C(O)NR--, --OC(O)NR--, or
--NRC(O)O--, wherein: [0156] each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0157]
L.sup.2 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of L.sup.2 are independently replaced by -Cy-,
--O--, --NR--, --S--, or --C(O)--, wherein: [0158] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. [0159] and (c) coupling the compound of formula II-c to one
or more of the hydroxyl groups on the metal surface by condensation
reaction.
[0160] Each of the R.sup.2, y, and L.sup.2 groups of formula II-c
are as described in classes and subclasses for compounds of formula
II, both singly and in combination.
[0161] In certain embodiments, the R.sup.1 group of formula I is a
group of formula II-d:
##STR00010##
or a salt thereof, wherein: [0162] y is 0-2500; [0163] each R is
independently hydrogen or an optionally substituted aliphatic
group; [0164] L.sup.1 is a valence bond or a bivalent, saturated or
unsaturated, straight or branched C.sub.1-12 alkylene chain,
wherein 0-6 methylene units of L.sup.1 are independently replaced
by -Cy-, --O--, --NR--, --S--, --OC(O)--, --C(O)O--, --C(O)--,
--SO--, --SO.sub.2--, --NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--,
--C(O)NR--, --OC(O)NR--, or --NRC(O)O--, wherein: [0165] each -Cy-
is independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; and [0166] L.sup.2 is a valence bond or a bivalent,
saturated or unsaturated, straight or branched C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein:
[0167] each -Cy- is independently an optionally substituted 3-8
membered bivalent, saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an optionally substituted 8-10 membered
bivalent saturated, partially unsaturated, or aryl bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0168] Each of the L.sup.1, y, and L.sup.2 groups of formula II-d
are as described in classes and subclasses for compounds of formula
II, both singly and in combination.
[0169] In certain embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula II-e:
##STR00011##
or a salt thereof, wherein: [0170] W is --C(.dbd.O)OH,
--C(.dbd.O)X, --P(.dbd.O)(OH).sub.2, --P(.dbd.O)(X).sub.2,
--P(.dbd.O)(R.sup.a)OH, --P(.dbd.O)(R.sup.a)X,
--O--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2OH, --Si(R.sup.a).sub.2OH,
--Si(OR.sup.a).sub.2OH, --Si(R.sup.a).sub.2X,
--Si(R.sup.a)(OH).sub.2, --Si(R.sup.a)X.sub.2,
--Si(OR.sup.a).sub.2X, C(.dbd.O)H, --N.dbd.C.dbd.S,
--N.dbd.C.dbd.O, phenol, thiophenol, or an epoxide; [0171] each X
is independently Cl, Br, or I; and [0172] each R.sup.a is hydrogen,
an alkyl group, or an aryl group; [0173] y is 0-2500; [0174] each R
is independently hydrogen or an optionally substituted aliphatic
group; [0175] L.sup.1 is a valence bond or a bivalent, saturated or
unsaturated, straight or branched C.sub.1-12 alkylene chain,
wherein 0-6 methylene units of L.sup.1 are independently replaced
by -Cy-, --O--, --NR--, --S--, --OC(O)--, --C(O)O--, --C(O)--,
--SO--, --SO.sub.2--, --NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--,
--C(O)NR--, --OC(O)NR--, or --NRC(O)O--, wherein: [0176] each -Cy-
is independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; and [0177] L.sup.2 is a valence bond or a bivalent,
saturated or unsaturated, straight or branched C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein:
[0178] each -Cy- is independently an optionally substituted 3-8
membered bivalent, saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an optionally substituted 8-10 membered
bivalent saturated, partially unsaturated, or aryl bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, [0179] and (c) coupling the compound of formula
II-e to one or more of the hydroxyl groups on the metal
surface.
[0180] Each of the L.sup.1, y, W, and L.sup.2 groups of formula
II-e are as described in classes and subclasses for compounds of
formulae I and II, both singly and in combination.
[0181] In other embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula II-e; and
(c) coupling the compound of formula II-e to one or more of the
hydroxyl groups on the metal surface, further comprising the step
of coupling the azide-terminal end to a suitable group via Click
chemistry.
[0182] In other embodiments, the present invention provides a
compound of formula II-e':
##STR00012##
or a salt thereof, wherein: [0183] W is --Si(R.sup.a).sub.2OH,
--Si(OR.sup.a).sub.2OH, --Si(R.sup.a).sub.2X,
--Si(R.sup.a)(OH).sub.2, --Si(R.sup.a)X.sub.2, or
--Si(OR.sup.a).sub.2X; [0184] each X is independently Cl, Br, or I;
and [0185] each R.sup.a is hydrogen, an alkyl group, or an aryl
group; [0186] y is 0-2500; [0187] each R is independently hydrogen
or an optionally substituted aliphatic group; [0188] L.sup.1 is a
valence bond or a bivalent, saturated or unsaturated, straight or
branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units of
L.sup.1 are independently replaced by -Cy-, --O--, --NR--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein: [0189] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; and [0190] L.sup.2 is a valence bond or a bivalent,
saturated or unsaturated, straight or branched C.sub.1-12 alkylene
chain, wherein 0-6 methylene units of L.sup.2 are independently
replaced by -Cy-, --O--, --NR--, --S--, or --C(O)--, wherein:
[0191] each -Cy- is independently an optionally substituted 3-8
membered bivalent, saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an optionally substituted 8-10 membered
bivalent saturated, partially unsaturated, or aryl bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0192] Each of the L.sup.1, y, W, and L.sup.2 groups of formula
II-e' are as described in classes and subclasses for compounds of
formulae I and II, both singly and in combination.
[0193] In other embodiments, the R.sup.1 group of formula I is a
copolymer group. Multiblock copolymers of the present invention are
prepared by methods known to one of ordinary skill in the art and
those described in detail in U.S. patent application Ser. No.
11/325,020 filed Jan. 4, 2006, the entirety of which is hereby
incorporated herein by reference. According to another aspect,
R.sup.1 is a block copolymer group of formula III:
##STR00013##
wherein: [0194] y is 1-2500; [0195] m is 1 to 1000; [0196] m' is 0
to 1000; [0197] R.sup.x and R.sup.y are each independently a
natural or unnatural amino acid side-chain group, wherein R.sup.x
and R.sup.y are different from each other; [0198] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30
membered crown ether, a mono-protected amine, a di-protected amine,
a protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, a protected thiol, or an optionally substituted group
selected from aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an 8-10 membered
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a detectable moiety; [0199] each X' is independently
halogen; [0200] each R is independently hydrogen or an optionally
substituted aliphatic group; [0201] L.sup.1 is a valence bond or a
bivalent, saturated or unsaturated, straight or branched C.sub.1-12
alkylene chain, wherein 0-6 methylene units of L.sup.1 are
independently replaced by -Cy-, --O--, --NR--, --S--, --OC(O)--,
--C(O)O--, --C(O)--, --SO--, --SO.sub.2--, --NRSO.sub.2--,
--SO.sub.2NR--, --NRC(O)--, --C(O)NR--, --OC(O)NR--, or
--NRC(O)O--, wherein: [0202] each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0203] Q
is a valence bond or a bivalent, saturated or unsaturated, straight
or branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units
of Q are independently replaced by -Cy-, --O--, --NH--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NHSO.sub.2--, --SO.sub.2NH--, --NHC(O)--, --C(O)NH--,
--OC(O)NH--, or --NHC(O)O--, wherein: [0204] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0205]
L.sup.3 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of Q are independently replaced by -Cy-, --O--,
--NH--, --S--, or --C(O)--, wherein: [0206] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0207] In certain embodiments, the m' group of formula III is
1-1000. In certain embodiments, the m' group of formula III is 0.
In other embodiments, m' is 1-1000. According to other embodiments,
m and m' are independently 10 to 100 repeat units. In still other
embodiments, m is 1-20 repeat units and m' is 10-50 repeat
units.
[0208] As defined generally above, the Q group of formula III is a
valence bond or a bivalent, saturated or unsaturated, straight or
branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units of
Q are independently replaced by -Cy-, --O--, --NH--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NHSO.sub.2--, --SO.sub.2NH--, --NHC(O)--, --C(O)NH--,
--OC(O)NH--, or --NHC(O)O--, wherein -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In certain
embodiments, Q is a valence bond. In other embodiments, Q is a
bivalent, saturated C.sub.1-12 alkylene chain, wherein 0-6
methylene units of Q are independently replaced by -Cy-, --O--,
--NH--, --S--, --OC(O)--, --C(O)O--, or --C(O)--, wherein -Cy- is
an optionally substituted 5-8 membered bivalent, saturated,
partially unsaturated, or aryl ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or an
optionally substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0209] In certain embodiments, Q is -Cy- (i.e. a C.sub.1 alkylene
chain wherein the methylene unit is replaced by -Cy-), wherein -Cy-
is an optionally substituted 5-8 membered bivalent, saturated,
partially unsaturated, or aryl ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. According
to one aspect of the present invention, -Cy- is an optionally
substituted bivalent aryl group. According to another aspect of the
present invention, -Cy- is an optionally substituted bivalent
phenyl group. In other embodiments, -Cy- is an optionally
substituted 5-8 membered bivalent, saturated carbocyclic ring. In
still other embodiments, -Cy- is an optionally substituted 5-8
membered bivalent, saturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Exemplary -Cy- groups include bivalent rings selected from
phenyl, pyridyl, pyrimidinyl, cyclohexyl, cyclopentyl, or
cyclopropyl.
[0210] In certain embodiments, R.sup.x is a crosslinkable amino
acid side-chain group and R.sup.y is a hydrophobic amino acid
side-chain group. Such crosslinkable amino acid side-chain groups
include tyrosine, serine, cysteine, threonine, aspartic acid (also
known as aspartate, when charged), glutamic acid (also known as
glutamate, when charged), asparagine, histidine, lysine, arginine,
and glutamine. Such hydrophobic amino acid side-chain groups
include a suitably protected tyrosine side-chain, a suitably
protected serine side-chain, a suitably protected threonine
side-chain, phenylalanine, alanine, valine, leucine, tryptophan,
proline, benzyl and alkyl glutamates, or benzyl and alkyl
aspartates or mixtures thereof. In other embodiments, R.sup.y is an
ionic amino acid side-chain group. Such ionic amino acid side chain
groups includes a lysine side-chain, arginine side-chain, or a
suitably protected lysine or arginine side-chain, an aspartic acid
side chain, glutamic acid side-chain, or a suitably protected
aspartic acid or glutamic acid side-chain. One of ordinary skill in
the art would recognize that protection of a polar or hydrophilic
amino acid side-chain can render that amino acid nonpolar. For
example, a suitably protected tyrosine hydroxyl group can render
that tyrosine nonpolar and hydrophobic by virtue of protecting the
hydroxyl group. Suitable protecting groups for the hydroxyl, amino,
and thiol, and carboylate functional groups of R.sup.x and R.sup.y
are as described herein.
[0211] In other embodiments, R.sup.y comprises a mixture of
hydrophobic and hydrophilic amino acid side-chain groups such that
the overall poly(amino acid) block comprising R.sup.y is
hydrophobic. Such mixtures of amino acid side-chain groups include
phenylalanine/tyrosine, phenalanine/serine, leucine/tyrosine, and
the like. According to another embodiment, R.sup.y is a hydrophobic
amino acid side-chain group selected from phenylalanine, alanine,
or leucine, and one or more of tyrosine, serine, or threonine.
[0212] As defined above, R.sup.x is a natural or unnatural amino
acid side-chain group capable of forming cross-links. It will be
appreciated that a variety of amino acid side-chain functional
groups are capable of such cross-linking, including, but not
limited to, carboxylate, hydroxyl, thiol, and amino groups.
Examples of R.sup.x moieties having functional groups capable of
forming cross-links include a glutamic acid side-chain,
--CH.sub.2C(O)CH, an aspartic acid side-chain,
--CH.sub.2CH.sub.2C(O)OH, a cystein side-chain, --CH.sub.2SH, a
serine side-chain, --CH.sub.2OH, an aldehyde containing side-chain,
--CH.sub.2C(O)H, a lysine side-chain, --(CH.sub.2).sub.4NH.sub.2,
an arginine side-chain, --(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, a
histidine side-chain, --CH.sub.2-imidazol-4-yl.
[0213] In certain embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula III-a:
##STR00014##
wherein: [0214] W is --C(.dbd.O)OH, --C(.dbd.O)X,
--P(.dbd.O)(OH).sub.2, --P(.dbd.O)(X).sub.2,
--P(.dbd.O)(R.sup.a)OH, --P(.dbd.O)(R.sup.a)X,
--O--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2OH, --Si(R.sup.a).sub.2OH,
--Si(OR.sup.a).sub.2OH, --Si(R.sup.a).sub.2X,
--Si(R.sup.a)(OH).sub.2, --Si(R.sup.a)X.sub.2,
--Si(OR.sup.a).sub.2X, C(.dbd.O)H, --N.dbd.C.dbd.S,
--N.dbd.C.dbd.O, phenol, thiophenol, or an epoxide; [0215] each X
is independently Cl, Br, or I; and [0216] each R.sup.a is hydrogen,
an alkyl group, or an aryl group; [0217] y is 1-2500; [0218] m is 1
to 1000; [0219] m' is 0 to 1000; [0220] R.sup.x and R.sup.y are
each independently a natural or unnatural amino acid side-chain
group, wherein R.sup.x and R.sup.y are different from each other;
[0221] R.sup.2 is hydrogen, halogen, NO.sub.2, CN, N.sub.3,
--N.dbd.C.dbd.O, --C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2,
--P(O)(X').sub.2, a 9-30 membered crown ether, a mono-protected
amine, a di-protected amine, a protected aldehyde, a protected
hydroxyl, a protected carboxylic acid, a protected thiol, or an
optionally substituted group selected from aliphatic, a 3-8
membered saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10 membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety; [0222] each X'
is independently halogen; [0223] each R is independently hydrogen
or an optionally substituted aliphatic group; [0224] L.sup.1 is a
valence bond or a bivalent, saturated or unsaturated, straight or
branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units of
L.sup.1 are independently replaced by -Cy-, --O--, --NR--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--, --C(O)NR--,
--OC(O)NR--, or --NRC(O)O--, wherein: [0225] each -Cy- is
independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; [0226] Q is a valence bond or a bivalent, saturated or
unsaturated, straight or branched C.sub.1-12 alkylene chain,
wherein 0-6 methylene units of Q are independently replaced by
-Cy-, --O--, --NH--, --S--, --OC(O)--, --C(O)O--, --C(O)--, --SO--,
--SO.sub.2--, --NHSO.sub.2--, --SO.sub.2NH--, --NHC(O)--,
--C(O)NH--, --OC(O)NH--, or --NHC(O)O--, wherein: [0227] -Cy- is an
optionally substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0228]
L.sup.3 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of Q are independently replaced by -Cy-, --O--,
--NH--, --S--, or --C(O)--, wherein: [0229] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0230] and
(c) coupling the compound of formula III-a to one or more of the
hydroxyl groups on the metal surface.
[0231] Each of the R.sup.2, L.sup.1, y, m, m', Q, R.sup.x, R.sup.y,
and L.sup.3 groups of formula III-a are as described in classes and
subclasses for compounds of formulae II and III, both singly and in
combination.
[0232] In certain embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula III-b:
##STR00015##
wherein: [0233] y is 1-2500; [0234] m is 1 to 1000; [0235] m' is 0
to 1000; [0236] R.sup.x and R.sup.y are each independently a
natural or unnatural amino acid side-chain group, wherein R.sup.x
and R.sup.y are different from each other; [0237] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30
membered crown ether, a mono-protected amine, a di-protected amine,
a protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, a protected thiol, or an optionally substituted group
selected from aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an 8-10 membered
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a detectable moiety; [0238] each X' is independently
halogen; [0239] each R is independently hydrogen or an optionally
substituted aliphatic group; [0240] L.sup.1 is a valence bond or a
bivalent, saturated or unsaturated, straight or branched C.sub.1-12
alkylene chain, wherein 0-6 methylene units of L.sup.1 are
independently replaced by -Cy-, --O--, --NR--, --S--, --OC(O)--,
--C(O)O--, --C(O)--, --SO--, --SO.sub.2--, --NRSO.sub.2--,
--SO.sub.2NR--, --NRC(O)--, --C(O)NR--, --OC(O)NR--, or
--NRC(O)O--, wherein: [0241] each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0242] Q
is a valence bond or a bivalent, saturated or unsaturated, straight
or branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units
of Q are independently replaced by -Cy-, --O--, --NH--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NHSO.sub.2--, --SO.sub.2NH--, --NHC(O)--, --C(O)NH--,
--OC(O)NH--, or --NHC(O)O--, wherein: [0243] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0244]
L.sup.3 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of Q are independently replaced by -Cy-, --O--,
--NH--, --S--, or --C(O)--, wherein: [0245] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0246] and
(c) coupling the compound of formula III-b to one or more of the
hydroxyl groups on the metal surface by dehydration reaction.
[0247] Each of the R.sup.2, L.sup.1, y, m, m', Q, R.sup.x, R.sup.y,
and L.sup.3 groups of formula III-b are as described in classes and
subclasses for compounds of formula III, both singly and in
combination.
[0248] In certain embodiments, the present invention provides a
method for preparing a covalently modified metal surface,
comprising the steps of:
(a) modifying a metal substrate to incorporate thereon a plurality
of hydroxyl groups; (b) providing a compound of formula III-c:
##STR00016##
wherein: [0249] y is 10-2500; [0250] m is 1 to 1000; [0251] m' is 0
to 1000; [0252] R.sup.x and R.sup.y are each independently a
natural or unnatural amino acid side-chain group, wherein R.sup.x
and R.sup.y are different from each other; [0253] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30
membered crown ether, a mono-protected amine, a di-protected amine,
a protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, a protected thiol, or an optionally substituted group
selected from aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an 8-10 membered
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a detectable moiety; [0254] each X' is independently
halogen; [0255] each R is independently hydrogen or an optionally
substituted aliphatic group; [0256] L.sup.1 is a valence bond or a
bivalent, saturated or unsaturated, straight or branched C.sub.1-12
alkylene chain, wherein 0-6 methylene units of L.sup.1 are
independently replaced by -Cy-, --O--, --NR--, --S--, --OC(O)--,
--C(O)O--, --C(O)--, --SO--, --SO.sub.2--, --NRSO.sub.2--,
--SO.sub.2NR--, --NRC(O)--, --C(O)NR--, --OC(O)NR--, or
--NRC(O)O--, wherein: [0257] each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0258] Q
is a valence bond or a bivalent, saturated or unsaturated, straight
or branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units
of Q are independently replaced by -Cy-, --O--, --NH--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NHSO.sub.2--, --SO.sub.2NH--, --NHC(O)--, --C(O)NH--,
--OC(O)NH--, or --NHC(O)O--, wherein: [0259] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0260]
L.sup.3 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of Q are independently replaced by -Cy-, --O--,
--NH--, --S--, or --C(O)--, wherein: [0261] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0262] and
(c) coupling the compound of formula III-c to one or more of the
hydroxyl groups on the metal surface by dehydration reaction.
[0263] Each of the R.sup.2, L.sup.1, y, m, m', Q, R.sup.x, R.sup.y,
and L.sup.3 groups of formula III-c are as described in classes and
subclasses for compounds of formula III, both singly and in
combination.
[0264] In other embodiments, R.sup.1 is a block copolymer group of
formula IV:
##STR00017##
wherein: [0265] y is 10-2500; [0266] m is 1 to 1000; [0267] m' is 0
to 1000; [0268] R.sup.x and R.sup.y are each independently a
natural or unnatural amino acid side-chain group, wherein R.sup.x
and R.sup.y are different from each other; [0269] R.sup.2 is
hydrogen, halogen, NO.sub.2, CN, N.sub.3, --N.dbd.C.dbd.O,
--C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2, --P(O)(X').sub.2, a 9-30
membered crown ether, a mono-protected amine, a di-protected amine,
a protected aldehyde, a protected hydroxyl, a protected carboxylic
acid, a protected thiol, or an optionally substituted group
selected from aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an 8-10 membered
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a detectable moiety; [0270] each X' is independently
halogen; [0271] each R is independently hydrogen or an optionally
substituted aliphatic group; [0272] L.sup.1 is a valence bond or a
bivalent, saturated or unsaturated, straight or branched C.sub.1-12
alkylene chain, wherein 0-6 methylene units of L.sup.1 are
independently replaced by -Cy-, --O--, --NR--, --S--, --OC(O)--,
--C(O)O--, --C(O)--, --SO--, --SO.sub.2--, --NRSO.sub.2--,
--SO.sub.2NR--, --NRC(O)--, --C(O)NR--, --OC(O)NR--, or
--NRC(O)O--, wherein: [0273] each -Cy- is independently an
optionally substituted 3-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0274] Q
is a valence bond or a bivalent, saturated or unsaturated, straight
or branched C.sub.1-12 alkylene chain, wherein 0-6 methylene units
of Q are independently replaced by -Cy-, --O--, --NH--, --S--,
--OC(O)--, --C(O)O--, --C(O)--, --SO--, --SO.sub.2--,
--NHSO.sub.2--, --SO.sub.2NH--, --NHC(O)--, --C(O)NH--,
--OC(O)NH--, or --NHC(O)O--, wherein: [0275] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and [0276]
L.sup.2 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of Q are independently replaced by -Cy-, --O--,
--NH--, --S--, or --C(O)--, wherein: [0277] -Cy- is an optionally
substituted 5-8 membered bivalent, saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an optionally
substituted 8-10 membered bivalent saturated, partially
unsaturated, or aryl bicyclic ring having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0278]
R.sup.2a is a mono-protected amine, a di-protected amine,
--NHR.sup.3, --N(R.sup.3).sub.2, --NHC(O)R.sup.3,
--NR.sup.3C(O)R.sup.3, --NHC(O)NHR.sup.3, --NHC(O)N(R.sup.3).sub.2,
--NR.sup.3C(O)NHR.sup.3, --NR.sup.3C(O)N(R.sup.3).sub.2,
--NHC(O)OR.sup.3, --NR.sup.3C(O)OR.sup.3, --NHSO.sub.2R.sup.3, or
--NR.sup.3SO.sub.2R.sup.3; and [0279] each R.sup.3 is independently
an optionally substituted group selected from aliphatic, a 5-8
membered saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10-membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety, or: [0280] two
R.sup.3 on the same nitrogen atom are taken together with said
nitrogen atom to form an optionally substituted 4-7 membered
saturated, partially unsaturated, or aryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0281] Each of the R.sup.2, L.sup.1, y, m, m', Q, R.sup.x, R.sup.y,
and L.sup.2 groups of formula IV are as described in classes and
subclasses for compounds of formulae II and III, both singly and in
combination.
[0282] As defined generally above, the R.sup.2a group of formula IV
is a mono-protected amine, a di-protected amine, --NHR.sup.3,
--N(R.sup.3).sub.2, --NHC(O)R.sup.3, --NR.sup.3C(O)R.sup.3,
--NHC(O)NHR.sup.3, --NHC(O)N(R.sup.3).sub.2,
--NR.sup.3C(O)NHR.sup.3, --NR.sup.3C(O)N(R.sup.3).sub.2,
--NHC(O)OR.sup.3, --NR.sup.3C(O)OR.sup.3, --NHSO.sub.2R.sup.3, or
--NR.sup.3SO.sub.2R.sup.3, wherein each R.sup.3 is independently an
optionally substituted group selected from aliphatic, a 5-8
membered saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10-membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety, or two R.sup.3
on the same nitrogen atom are taken together with said nitrogen
atom to form an optionally substituted 4-7 membered saturated,
partially unsaturated, or aryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0283] In certain embodiments, the R.sup.2a group of formula IV is
--NHR.sup.3 or --N(R.sup.3).sub.2 wherein each R.sup.3 is an
optionally substituted aliphatic group. One exemplary R.sup.3 group
is 5-norbornen-2-yl-methyl. According to yet another aspect of the
present invention, the R.sup.2a group of formula IV is --NHR.sup.3
wherein R.sup.3 is a C.sub.1-6 aliphatic group substituted with
N.sub.3. Examples include --CH.sub.2N.sub.3. In some embodiments,
R.sup.3 is an optionally substituted C.sub.1-6 alkyl group.
Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl,
2-(tetrahydropyran-2-yloxy)ethyl, pyridin-2-yldisulfanylmethyl,
methyldisulfanylmethyl, (4-acetylenylphenyl)methyl,
3-(methoxycarbonyl)-prop-2-ynyl, methoxycarbonylmethyl,
2-(N-methyl-N-(4-acetylenylphenyl)carbonylamino)-ethyl,
2-phthalimidoethyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl,
4-iodobenzyl, 4-propargyloxybenzyl, 2-nitrobenzyl,
4-(bis-4-acetylenylbenzyl)aminomethyl-benzyl,
4-propargyloxy-benzyl, 4-dipropargylamino-benzyl,
4-(2-propargyloxy-ethyldisulfanyl)benzyl, 2-propargyloxy-ethyl,
2-propargyldisulfanyl-ethyl, 4-propargyloxy-butyl,
2-(N-methyl-N-propargylamino)ethyl, and
2-(2-dipropargylaminoethoxy)-ethyl. In other embodiments, R.sup.3
is an optionally substituted C.sub.2-6 alkenyl group. Examples
include vinyl, allyl, crotyl, 2-propenyl, and but-3-enyl. When
R.sup.3 group is a substituted aliphatic group, suitable
substituents on R.sup.3 include N.sub.3, CN, and halogen. In
certain embodiments, R.sup.3 is --CH.sub.2CN, --CH.sub.2CH.sub.2CN,
--CH.sub.2CH(OCH.sub.3).sub.2, 4-(bisbenzyloxymethyl)phenylmethyl,
and the like.
[0284] According to another aspect of the present invention, the
R.sup.2a group of formula IV is --NHR.sup.3 wherein R.sup.3 is an
optionally substituted C.sub.2-6 alkynyl group. Examples include
--CC.ident.CH, --CH.sub.2C.ident.CH, --CH.sub.2C.ident.CCH.sub.3,
and --CH.sub.2CH.sub.2C.ident.CH.
[0285] In certain embodiments, the R.sup.2a group of formula IV is
--NHR.sup.3 wherein R.sup.3 is an optionally substituted
5-8-membered aryl ring. In certain embodiments, R.sup.3 is
optionally substituted phenyl or optionally substituted pyridyl.
Examples include phenyl, 4-t-butoxycarbonylaminophenyl,
4-azidomethylphenyl, 4-propargyloxyphenyl, 2-pyridyl, 3-pyridyl,
and 4-pyridyl. In certain embodiments, R.sup.2a is
4-t-butoxycarbonylaminophenylamino, 4-azidomethylphenamino, or
4-propargyloxyphenylamino.
[0286] In certain embodiments, the R.sup.2a group of formula IV is
--NHR.sup.3 wherein R.sup.3 is an optionally substituted phenyl
ring. Suitable substituents on the R.sup.3 phenyl ring include
halogen; --(CH.sub.2).sub.0-4R.sup.o; --(CH.sub.2).sub.0-4OR.sup.o;
--(CH.sub.2).sub.0-4CH(OR.sup.o).sub.2;
--(CH.sub.2).sub.0-4SR.sup.o; --(CH.sub.2).sub.0-4Ph, which may be
substituted with R.sup.o; --(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph
which may be substituted with R.sup.o; --CH.dbd.CHPh, which may be
substituted with R.sup.o; --NO.sub.2; --CN; --N.sub.3;
--(CH.sub.2).sub.0-4N(R.sup.o).sub.2;
--(CH.sub.2).sub.0-4N(R.sup.o)C(O)R.sup.o; --N(R.sup.o)C(S)R.sup.o;
--(CH.sub.2).sub.0-4N(R.sup.o)C(O)NR.sup.o.sub.2;
--N(R.sup.o)C(S)NR.sup.o.sub.2;
--(CH.sub.2).sub.0-4N(R.sup.o)C(O)OR.sup.o;
--N(R.sup.o)N(R.sup.o)C(O)R.sup.o;
--N(R.sup.o)N(R.sup.o)C(O)NR.sup.o.sub.2;
--N(R.sup.o)N(R.sup.o)C(O)OR.sup.o;
--(CH.sub.2).sub.0-4C(O)R.sup.o; --C(S)R.sup.o;
--(CH.sub.2).sub.0-4C(O)OR.sup.o; --(CH.sub.2).sub.0-4C(O)SR.sup.o;
--(CH.sub.2).sub.0-4C(O)OSiR.sup.o.sub.3;
--(CH.sub.2).sub.0-4OC(O)R.sup.o; --(CH.sub.2).sub.0-4SC(O)R.sup.o;
--(CH.sub.2).sub.0-4C(O)NR.sup.o.sub.2; --C(S)NR.sup.o.sub.2;
--(CH.sub.2).sub.0-4OC(O)NR.sup.o.sub.2; --C(O)N(OR.sup.o)R.sup.o;
--C(O)C(O)R.sup.o; --C(O)CH.sub.2C(O)R.sup.o;
--C(NOR.sup.o)R.sup.o; --(CH.sub.2).sub.0-4SSR.sup.o;
--(CH.sub.2).sub.0-4S(O).sub.2R.sup.o;
--(CH.sub.2).sub.0-4S(O).sub.2OR.sup.o;
--(CH.sub.2).sub.0-4O(O).sub.2R.sup.o; --S(O).sub.2NR.sup.o.sub.2;
--(CH.sub.2).sub.0-4(O)R.sup.o;
--N(R.sup.o)S(O).sub.2NR.sup.o.sub.2;
--N(R.sup.o)S(O).sub.2R.sup.o; --N(OR.sup.o)R.sup.o;
--C(NH)NR.sup.o.sub.2; --P(O).sub.2R.sup.o; --P(O)R.sup.o.sub.2;
--OP(O)R.sup.o.sub.2; SiR.sup.o.sub.3; wherein each independent
occurrence of R.sup.o is as defined herein supra. In other
embodiments, the R.sup.2a group of formula IV is --NHR.sup.3
wherein R.sup.3 is phenyl substituted with one or more optionally
substituted C.sub.1-6 aliphatic groups. In still other embodiments,
R.sup.3 is phenyl substituted with vinyl, allyl, acetylenyl,
--CH.sub.2N.sub.3, --CH.sub.2CH.sub.2N.sub.3,
--CH.sub.2C.ident.CCH.sub.3, or --CH.sub.2C.ident.CH.
[0287] In certain embodiments, the R.sup.2a group of formula IV is
--NHR.sup.3 wherein R.sup.3 is phenyl substituted with N.sub.3,
N(R.sup.o).sub.2, CO.sub.2R.sup.o, or C(O)R.sup.o wherein each
R.sup.o is independently as defined herein supra.
[0288] In certain embodiments, the R.sup.2a group of formula IV is
--N(R.sup.3).sub.2 wherein each R.sup.3 is independently an
optionally substituted group selected from aliphatic, phenyl,
naphthyl, a 5-6 membered aryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 8-10
membered bicyclic aryl ring having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a detectable
moiety.
[0289] In other embodiments, the R.sup.2a group of formula IV is
--N(R.sup.3).sub.2 wherein the two R.sup.3 groups are taken
together with said nitrogen atom to form an optionally substituted
4-7 membered saturated, partially unsaturated, or aryl ring having
1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. According to another embodiment, the two R.sup.3 groups are
taken together to form a 5-6-membered saturated or partially
unsaturated ring having one nitrogen wherein said ring is
substituted with one or two oxo groups. Such R.sup.2a groups
include, but are not limited to, phthalimide, maleimide and
succinimide.
[0290] In certain embodiments, the R.sup.2a group of formula IV is
a mono-protected or di-protected amino group. In certain
embodiments R.sup.2a is a mono-protected amine. In certain
embodiments R.sup.2a is a mono-protected amine selected from
aralkylamines, carbamates, allyl amines, or amides. Examplary
mono-protected amino moieties include t-butyloxycarbonylamino,
ethyloxycarbonylamino, methyloxycarbonylamino,
trichloroethyloxy-carbonylamino, allyloxycarbonylamino,
benzyloxocarbonylamino, allylamino, benzylamino,
fluorenylmethylcarbonyl, formamido, acetamido, chloroacetamido,
dichloroacetamido, trichloroacetamido, phenylacetamido,
trifluoroacetamido, benzamido, and t-butyldiphenylsilylamino. In
other embodiments R.sup.2a is a di-protected amine. Exemplary
di-protected amino moieties include di-benzylamino, di-allylamino,
phthalimide, maleimido, succinimido, pyrrolo,
2,2,5,5-tetramethyl-[1,2,5]azadisilolidino, and azido. In certain
embodiments, the R.sup.2a moiety is phthalimido. In other
embodiments, the R.sup.2a moiety is mono- or di-benzylamino or
mono- or di-allylamino.
[0291] In certain embodiments, the R.sup.2a group of formula IV
comprises a group suitable for Click chemistry. One of ordinary
skill in the art would recognize that certain R.sup.2a groups of
the present invention are suitable for Click chemistry.
[0292] Compounds of formula IV having R.sup.2a groups comprising
groups suitable for Click chemistry are useful for conjugating said
compounds to biological systems such as proteins, viruses, and
cells, to name but a few. Thus, another embodiment of the present
invention provides a method of conjugating the R.sup.2a group of a
compound of formula IV to a macromolecule via Click chemistry. Yet
another embodiment of the present invention provides a
macromolecule conjugated to a compound of formula IV via the
R.sup.2a group.
[0293] According to one embodiment, the R.sup.2a group of formula
IV is an azide-containing group. According to another embodiment,
the R.sup.2a group of formula IV is an alkyne-containing group.
[0294] In certain embodiments, the R.sup.2a group of formula IV has
a terminal alkyne moiety. In other embodiments, the R.sup.2a group
of formula IV is an alkyne-containing moiety having an electron
withdrawing group. Accordingly, in such embodiments, the R.sup.2a
group of formula IV is
##STR00018##
wherein E is an electron withdrawing group and y is 0-6. Such
electron withdrawing groups are known to one of ordinary skill in
the art. In certain embodiments, E is an ester. In other
embodiments, the R.sup.2a group of formula IV is
##STR00019##
wherein E is an electron withdrawing group, such as a --C(O)O--
group and y is 0-6.
[0295] According to another embodiment, the present invention
provides compounds of formula IV, as described above, wherein said
compounds have a polydispersity index ("PDI") of about 1.0 to about
1.2. According to another embodiment, the present invention
provides compounds of formula IV, as described above, wherein said
compound has a polydispersity index ("PDI") of about 1.03 to about
1.15. According to yet another embodiment, the present invention
provides compounds of formula IV, as described above, wherein said
compound has a polydispersity index ("PDI") of about 1.10 to about
1.12. According to other embodiments, the present invention
provides compounds of formula IV having a PDI of less than about
1.10.
[0296] In certain embodiments, the present invention provides
compounds of formula IV, as described above, wherein n is about
225. In other embodiments, n is about 200 to about 300. In still
other embodiments, n is about 200 to about 250. In still other
embodiments, n is about 100 to about 150. In still other
embodiments, n is about 400 to about 500.
[0297] Exemplary R.sup.2a groups of formula IV are set forth in
Table 1, below.
TABLE-US-00001 TABLE 1 Representative R.sup.2a Groups ##STR00020##
i ##STR00021## ii ##STR00022## iii ##STR00023## iv ##STR00024## v
##STR00025## vi ##STR00026## vii ##STR00027## viii ##STR00028## ix
##STR00029## x ##STR00030## x ##STR00031## xi ##STR00032## xii
##STR00033## xiii ##STR00034## xiv ##STR00035## xv ##STR00036## xvi
##STR00037## xvii ##STR00038## xviii ##STR00039## xix ##STR00040##
xx ##STR00041## xxi ##STR00042## xxii ##STR00043## xxiii
##STR00044## xxiv ##STR00045## xxv ##STR00046## xxvi ##STR00047##
xxvii ##STR00048## xxviii ##STR00049## xxix ##STR00050## xxx
##STR00051## xxxi ##STR00052## xxxii ##STR00053## xxxiii
##STR00054## xxxiv ##STR00055## xxxv ##STR00056## xxxvi
##STR00057## xxxvii ##STR00058## xxxviii ##STR00059## xxxix
##STR00060## xl ##STR00061## xli ##STR00062## xlii ##STR00063##
xliii ##STR00064## xliv ##STR00065## xlv ##STR00066## xlvi
##STR00067## xlvii
[0298] In certain embodiments, the R.sup.2a group of formula IV is
selected from any of those R.sup.2a groups depicted in Table 1,
supra. In other embodiments, the R.sup.2a group of formula IV is
group v, viii, xvi, xix, xxii, xxx, xxxi, xxxii, xxxiii, xxxiv,
xxxv, xxxvi, xxxvii, or xlii. In yet other embodiments, the
R.sup.2a group of formula IV is xv, xviii, xx, xxi, xxxviii, or
xxxix.
Small Molecule Organic Groups
[0299] As defined generally above, R.sup.1 is, inter alia, a small
molecule organic group. In certain embodiments, R.sup.1 is selected
from monosaccharides (e.g., glucose, galactose, or fructose)
disaccharides (e.g., sucrose, lactose, or maltose),
phosphorylcholines, phosoplipids, cyclodextran, small molecule
drugs, optionally substituted aliphatic groups, optionally
substituted cyclic groups, detectable moieties, and the like.
[0300] In certain embodiments, R.sup.1 is a group of formula V:
##STR00068## [0301] R.sup.4 is hydrogen, halogen, NO.sub.2, CN,
N.sub.3, --N.dbd.C.dbd.O, --C(R).dbd.NN(R).sub.2, --P(O)(OR).sub.2,
--P(O)(X'').sub.2, a 9-30 membered crown ether, a small molecule
drug, or an optionally substituted group selected from aliphatic, a
3-8 membered saturated, partially unsaturated, or aryl ring having
0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an 8-10 membered saturated, partially unsaturated, or aryl
bicyclic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a detectable moiety; [0302] each
X'' is independently halogen; [0303] each R is independently
hydrogen or an optionally substituted aliphatic group; [0304]
L.sup.4 is a valence bond or a bivalent, saturated or unsaturated,
straight or branched C.sub.1-12 alkylene chain, wherein 0-6
methylene units of L.sup.4 are independently replaced by -Cy-,
--O--, --NR--, --S--, --OC(O)--, --C(O)O--, --C(O)--, --SO--,
--SO.sub.2--, --NRSO.sub.2--, --SO.sub.2NR--, --NRC(O)--,
--C(O)NR--, --OC(O)NR--, or --NRC(O)O--, wherein: [0305] each -Cy-
is independently an optionally substituted 3-8 membered bivalent,
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an optionally substituted 8-10 membered bivalent
saturated, partially unsaturated, or aryl bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0306] In other embodiments, the R.sup.1 group of formula I or the
R.sup.4 group of formula V is a small molecule drug. For formula I,
it is contemplated that the small molecule drug is either bonded
directly to W or through a linker group L.sup.5, wherein L.sup.5 is
as defined for the L.sup.2 group of formula II and in classes and
subclasses described for L.sup.2 herein. In certain embodiments,
the linker group L.sup.4 or L.sup.5 is a hydrolytically cleavable
linker group. It will be appreciated that when the R.sup.1 group of
formula I or the R.sup.4 group of formula V is a small molecule
drug and the corresponding L.sup.4 or L.sup.5 linker group is a
hydrolytically cleavable linker group, then the small molecule drug
can be slowly released by the metal surface covalently modified
therewith, upon, for example, implantation into a patient. Such
hydrolytically cleavable linker groups are well known to one or
ordinary skill in the art.
[0307] In certain embodiments, the small molecule drug is a member
of the taxane family of anti-tubulin agents. In other embodiments,
the small molecule drug is paclitaxel. In still other embodiments,
the small molecule drug is docetaxel. In certain embodiments, the
small molecule drug is a member of the anthracyline family of
cytotoxic agents. In other embodiments, the small molecule drug is
doxorubicin. In still other embodiments, the small molecule drug is
daunorubicin. In still other embodiments, the small molecule drug
is epirubicin.
[0308] In other embodiments, the R.sup.1 group of formula I or the
R.sup.4 group of formula V is an antithrombogenic oligopeptide.
Such antithrombogenic oligopeptide are well known in the art and
include sequences such as Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and/or
Cys-(D)Phe-Pro-Arg.
[0309] It will also be appreciated that the R.sup.2 group of
formula II can be an antithromobgenic oligopeptide, such as those
name above, attached to PEG via a hydrolytically stable
linkage.
[0310] In other embodiments, the R.sup.1 group of formula I or the
R.sup.4 group of formula V is a cell-binding oligopeptide.
Cell-binding oligopeptides are well known in the art and include
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5 integrin
binding peptide sequences such as those containing the Arg-Gly-Asp
(RGD) and Asn-Gly-Arg (NGR) oligopeptide sequences. In one
embodiment, the R.sup.1 group of formula I or the R.sup.4 group of
formula V is the cell-binding oligopeptide GRGDS. In another
embodiment, the oligopeptide sequence is a cyclic RGD sequence such
as c(RGDfK).
[0311] It will also be appreciated that the R.sup.2 group of
formula II can be a cell-binding oligopeptide, such as those name
above, attached to PEG via a hydrolytically stable linkage.
[0312] It will also be appreciated that when the R.sup.2 group of
formula II is a small molecule drug attached to the PEG via a
hydrolytically cleavable linker group, then that small molecule
drug is slowly released by the metal surface covalently modified
therewith leaving the PEGylated metal surface. In certain
embodiments, the small molecule drug connected to PEG via a
hydrolytically cleavable linker is a member of the taxane family of
anti-tubulin agents. In other embodiments, the small molecule drug
connected to PEG via a hydrolytically cleavable linker is
paclitaxel. In still other embodiments, the small molecule drug
connected to PEG via a hydrolytically cleavable linker is
docetaxel.
[0313] It will also be appreciated that when the polymers of
formula III are used for surface modification, a hydrophobic small
molecule drug can be encapsulated in the hydrophobic region of
polymer layer. Such encapsulated small molecule drugs can be slowly
released by the diffusion from the polymer layer. In certain
embodiments, the encapsulated small molecule drug is a member of
the taxane family of anti-tubulin agents. In other embodiments, the
encapsulated small molecule drug is paclitaxel. In still other
embodiments, the encapsulated small molecule drug is docetaxel.
[0314] When the polymers of formula III are used for surface
modification and encapsulation of a hydrophobic small molecule
drug, the R.sup.x groups of the polymer layer may be optionally
crosslinked to control the diffusion of the encapsulated drug. Such
crosslinking chemistry is well known in the art and includes such
methods described in detail in United States patent application
publication number US20060240092, the entirety of which is hereby
incorporated herein by reference. Such encapsulated small molecule
drugs can be released in a controlled fashion over longer time
periods compared to release by diffusion alone. In certain
embodiments, the encapsulated small molecule drug is a member of
the taxane family of anti-tubulin agents. In other embodiments, the
encapsulated small molecule drug is paclitaxel. In still other
embodiments, the encapsulated small molecule drug is docetaxel.
[0315] Small molecule drugs suitable as R.sup.1, R.sup.2, and
R.sup.4 groups of the present compounds include, but are not
limited to, those having a functional group, or can be modified to
include a functional group, suitable for covalently linking to one
or more hydroxyl groups incorporated onto the metal substrate. As
described herein, such drugs can be linked directly or via a
hydrolytically cleavable linker. Such drugs include, without
limitation, chemotherapeutic agents or other anti-proliferative
agents including alkylating drugs (mechlorethamine, chlorambucil,
Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites
(Methotrexate), purine antagonists and pyrimidine antagonists
(6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine),
spindle poisons (Vinblastine, Vincristine, Vinorelbine,
Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),
antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas
(Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin),
enzymes (Asparaginase), angiogenesis inhibitors (Avastin) and
hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol),
Gleevec, dexamethasone, and cyclophosphamide. For a more
comprehensive discussion of updated cancer therapies see,
http://www.nci.nih.gov/, a list of the FDA approved oncology drugs
at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck
Manual, Seventeenth Ed. 1999, the entire contents of which are
hereby incorporated by reference.
[0316] In other embodiments, the chemotherapeutic agent is
Exemestance (aromasin), Camptosar (irinotecan), Ellence
(epirubicin), Femara (Letrozole), Gleevac (imatinib mesylate),
Lentaron (formestane), Cytadren/Orimeten (aminoglutethimide),
Temodar, Proscar (finasteride), Viadur (leuprolide), Nexavar
(Sorafenib), Kytril (Granisetron), Taxotere (Docetaxel), Taxol
(paclitaxel), Kytril (Granisetron), Vesanoid (tretinoin) (retin A),
XELODA (Capecitabine), Arimidex (Anastrozole), Casodex/Cosudex
(Bicalutamide), Faslodex (Fulvestrant), Iressa (Gefitinib),
Nolvadex, Istubal, Valodex (tamoxifen citrate), Tomudex
(Raltitrexed), Zoladex (goserelin acetate), Leustatin (Cladribine),
Velcade (bortezomib), Mylotarg (gemtuzumab ozogamicin), Alimta
(pemetrexed), Gemzar (gemcitabine hydrochloride), Rituxan
(rituximab), Revlimid (lenalidomide), Thalomid (thalidomide),
Alkeran (melphalan), and derivatives thereof.
[0317] Other exemplary small molecule drugs include analgesics,
anti-inflammatory agents, antihelminthics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anti-fungal
agents, anti-gout agents, anti-hypertensive agents, anti-malarials,
anti-migraine agents, anti-muscarinic agents, anti-neoplastic
agents, erectile dysfunction improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine receptor antagonists, keratolyptics, lipid regulating
agents, anti-anginal agents, Cox-2 inhibitors, leukotriene
inhibitors, macrolides, muscle relaxants, nutritional agents, opiod
analgesics, protease inhibitors, sex hormones, stimulants, muscle
relaxants, anti-osteoporosis agents, anti-obesity agents, cognition
enhancers, anti-urinary incontinence agents, anti-benign prostate
hypertrophy agents, essential fatty acids, non-essential fatty
acids, and mixtures thereof.
[0318] Other examples of small molecule drugs include treatments
for Alzheimer's Disease such as Aricept.RTM. and Excelon.RTM.;
treatments for Parkinson's Disease such as L-DOPA/carbidopa,
entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating Multiple
Sclerosis (MS) such as beta interferon (e.g., Avonex.RTM. and
Rebif.RTM.), Copaxone.RTM., and mitoxantrone; treatments for asthma
such as albuterol and Singulair.RTM.; agents for treating
schizophrenia such as zyprexa, risperdal, seroquel, and
haloperidol; anti-inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive agents such
as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil,
interferons, corticosteroids, cyclophosphamide, azathioprine, and
sulfasalazine; neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion
channel blockers, riluzole, and anti-Parkinsonian agents; agents
for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth factors; and agents for treating
immunodeficiency disorders such as gamma globulin.
[0319] In other embodiments, the R.sup.1 group of formula I or the
R.sup.4 group of formula V is a small molecule
blood-compatibilizing agent. Such blood-compatibilizing agents are
well known in the art and include phosphorylchoine and
phosphorylcholine derivatives.
[0320] It will also be appreciated that the R.sup.2 group of
formula II can be a small molecule blood-compatibilizing agent
attached to the PEG via a hydrolytically stable linkage. In certain
embodiments, the R.sup.2 group is phosphorylchoine or a
phosphorylcholine derivative.
[0321] Exemplary R.sup.1 groups are set forth in Table 2,
below.
TABLE-US-00002 TABLE 2 Representative R.sup.1 Groups ##STR00069## i
##STR00070## ii ##STR00071## iii ##STR00072## iv ##STR00073## v
##STR00074## vi ##STR00075## vii ##STR00076## viii ##STR00077## ix
##STR00078## x ##STR00079## xi ##STR00080## xii ##STR00081## xiii
##STR00082## xiv ##STR00083## xv ##STR00084## xvi ##STR00085## xvii
##STR00086## xviii ##STR00087## xix ##STR00088## xx ##STR00089##
xxi ##STR00090## xxii ##STR00091## xxiii ##STR00092## xxiv
##STR00093## xxv ##STR00094## xxvi ##STR00095## xxvii ##STR00096##
xxviii ##STR00097## xxix ##STR00098## xxx ##STR00099## xxxi
##STR00100## xxxii ##STR00101## xxxiii ##STR00102## xxxiv
##STR00103## xxxv ##STR00104## xxxvi ##STR00105## xxxvii
##STR00106## xxxviii ##STR00107## xxxix ##STR00108## xxxx
##STR00109## xxxxi ##STR00110## xxxxii ##STR00111## xxxxiii
##STR00112## xxxxiv ##STR00113## xxxxv wherein each y, m, and m' is
as defined above and described herein.
[0322] Additional exemplary R.sup.1 groups are set forth in Table
3, below.
TABLE-US-00003 TABLE 3 Representative R.sup.1 Groups ##STR00114##
xii ##STR00115## xiii ##STR00116## xiv ##STR00117## xv ##STR00118##
xvi ##STR00119## xvii ##STR00120## xviii ##STR00121## xix
##STR00122## xx ##STR00123## xxi ##STR00124## xxii wherein each y
is as defined above and described herein.
[0323] Exemplary R.sup.a groups are set forth in Table 4,
below.
TABLE-US-00004 TABLE 4 Exemplary R.sup.a Groups ##STR00125## a - -
- -CH.sub.3 b ##STR00126## c ##STR00127## d ##STR00128## e
[0324] Exemplary R.sup.2 groups are set forth in Table 5,
below.
TABLE-US-00005 TABLE 5 Exemplary R2 Groups ##STR00129## a
##STR00130## b ##STR00131## c ##STR00132## d ##STR00133## e
##STR00134## f ##STR00135## g ##STR00136## h ##STR00137## i
##STR00138## j ##STR00139## k ##STR00140## l - - - -CH.sub.3 m
4. General Methods for Providing Compounds of the Present
Invention
[0325] Multiblock copolymers of the present invention are prepared
by methods known to one of ordinary skill in the art and those
described in detail in U.S. patent application Ser. No. 11/325,020
filed Jan. 4, 2006, the entirety of which is hereby incorporated
herein by reference. Generally, such multiblock copolymers are
prepared by sequentially polymerizing one or more cyclic amino acid
monomers onto a hydrophilic polymer having a terminal amine salt
wherein said polymerization is initiated by said amine salt. In
certain embodiments, said polymerization occurs by ring-opening
polymerization of the cyclic amino acid monomers. In other
embodiments, the cyclic amino acid monomer is an amino acid NCA,
lactam, or imide.
##STR00141##
[0326] Scheme 1 above depicts a general method for preparing
multiblock polymers of the R.sup.1 group of formula I of the
present invention. A macroinitiator of formula A is treated with a
first amino acid NCA to form a compound of formula B having a first
amino acid block. The second amino acid NCA is added to the living
polymer of formula B to form a compound of formula III-a having two
differing amino acid blocks. Each of the R.sup.2, L.sup.1, A, y, Q,
R.sup.x, R.sup.y, m, and m' groups depicted in Scheme 1 are as
defined and described in classes and subclasses, singly and in
combination, herein.
##STR00142##
[0327] Scheme 2 above shows one exemplary method for preparing the
bifunctional PEGs used to prepare the multiblock copolymers of the
present invention. As described in United States patent application
publication number US20060142506, suitably protected PEG-amines may
be formed by terminating the living polymer chain end of a PEG with
a terminating agent that contains a suitably protected amine. The
suitably protected amine may then be deprotected to generate a PEG
that is terminated with a free amine that may subsequently be
converted into the corresponding PEG-amine salt macroinitiator. In
certain embodiments, the PEG-amine salt macroinitiator of the
present invention is prepared directly from a suitably protected
PEG-amine by deprotecting said protected amine with an acid.
Accordingly, in other embodiments, the terminating agent has
suitably protected amino group wherein the protecting group is
acid-labile.
[0328] Alternatively, suitable synthetic polymers having a terminal
amine salt may be prepared from synthetic polymers that contain
terminal functional groups that may be converted to amine salts by
known synthetic routes. In certain embodiments, the conversion of
the terminal functional groups to the amine salts is conducted in a
single synthetic step. In other embodiments, the conversion of the
terminal functional groups to the amine salts is achieved by way of
a multi-step sequence. Functional group transformations that afford
amines, amine salts, or protected amines are well known in the art
and include those described in Larock, R. C., "Comprehensive
Organic Transformations," John Wiley & Sons, New York,
1999.
[0329] At step (a), the polymerization initiator is treated with a
suitable base to form D. A variety of bases are suitable for the
reaction at step (a). Such bases include, but are not limited to,
potassium naphthalenide, diphenylmethyl potassium, triphenylmethyl
potassium, and potassium hydride. At step (b), the resulting anion
is treated with ethylene oxide to form the polymer E. Polymer E can
be transformed at step (d) to a compound of formula A directly by
terminating the living polymer chain-end of E with a suitable
polymerization terminator to afford a compound of formula A.
Alternatively, polymer E may be quenched at step (c) to form the
hydroxyl compound F. Compound F is then derivatized to afford a
compound of formula A by methods known in the art, including those
described herein. Each of the R.sup.2, L.sup.1, A, y, and Q groups
depicted in Scheme 2 are as defined and described in classes and
subclasses, singly and in combination, herein.
[0330] Although certain exemplary embodiments are depicted and
described above and herein, it will be appreciated that compounds
of the invention can be prepared according to the methods described
generally above using appropriate starting materials by methods
generally available to one of ordinary skill in the art. Additional
embodiments are exemplified in more detail herein.
5. Uses
[0331] The modified metal surfaces in accordance with the present
invention are useful for a multitude of uses. In certain
embodiments, the covalently modified metal surfaces are useful in
any application where metal is typically coated in a non-covalent
fashion. Such applications include coated implantable medical
devices. Such implantable devices include prostheses, artificial
valves, vascular grafts, stents, catheters, and the like. These,
and other such devices, are described in more detail below. In
certain embodiments, the implantable device is a cardiovascular
device, a neurosurgical device, a gastrointestinal device, a
genitourinary device, a phthalmologic implant, an otolaryngology
device, a plastic surgery implant, or an orthopedic implant.
[0332] Certain disorders are associated with the tissue trauma
resulting from a medical procedure, such as angioplasty, or from
the implantation of a medical device. For example, restenosis is a
re-narrowing or blockage of an artery at the same site where
treatment, such as an angioplasty or stent procedure, has already
taken place. One cause of restenosis is tissue growth at the site
of treatment characterized by a proliferation of the smooth muscle
cells that normally line blood vessels.
[0333] Recent developments in the ongoing battle to reduce
restenosis include the drug-eluting stent which has a medication
coated on it to reduce the proliferation of cells that can cause
restenosis. There is a continuing need to develop stents and other
implantable devices coated with anti-proliferative agents
advantageous for treating or preventing disorders associated with
tissue trauma caused by implantable devices.
[0334] According to another aspect, the present invention provides
a method for treating or preventing disorders associated with
tissue trauma caused by implantable devices wherein said method
comprises providing an implantable device, wherein at least a
portion of said implantable device is a covalently modified metal
surface in accordance with the present invention, and implanting
said device in a patient. Said method is useful for treating or
preventing, for example, restenosis of blood vessels subject to
traumas such as angioplasty and stenting.
[0335] In other embodiments, the present invention provides an
implantable device, wherein at least a portion of said device is a
covalently modified metal surface. In still other embodiments, the
present invention provides a PEGylated implantable device, wherein
at least a portion of said device is a metal surface comprising PEG
covalently bonded thereto.
[0336] Vascular stents, for example, have been used to overcome
restenosis (re-narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk clot
formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a composition
comprising an anti-proliferative compound. Such coatings and the
general preparation of coated implantable devices are described in
U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings
are typically biocompatible polymeric materials such as a hydrogel
polymer, polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and mixtures
thereof. However, none of these coatings is covalently bonded to
the device.
[0337] As described generally herein, one method of treating
restenosis is to coat an implantable device with an
anti-proliferative compound. Although the present invention
contemplates covalently modified metal surfaces which incorporate
small molecule drugs, one of ordinary skill in the art will
appreciate that the present invention also contemplates covalently
modified metal surfaces which do not incorporate small molecule
drugs. Without wishing to be bound by any particular theory, it is
believed that the "stealth" properties of PEG are particularly
suited for implantable devices having at least a portion which is a
metal surface covalently modified with PEG or a functionalized PEG.
It is believed that the PEG itself will not induce restenosis, or
other tissue injury caused by an implantable device, thereby
negating the need for incorporation of an anti-proliferative or
other small molecule drug. Thus, the present invention also
provides an implantable device covalently modified in accordance
with the present invention. In certain embodiments, the implantable
device is covalently modified by a functionalized PEG. In other
embodiments, the implantable device is covalently modified by a
functionalized PEG of formula II as defined above and in classes
and subclasses described herein.
[0338] As discussed above, the present devices are useful for
treating or preventing restenosis of blood vessels subject to
traumas such as angioplasty and stenting. For example, it is
contemplated that such implanted medical devices include as
tubings, shunts, catheters, artificial implants, pins, electrical
implants such as pacemakers, and especially for arterial or venous
stents, including balloon-expandable stents.
[0339] In certain embodiments, methods of the present invention are
used for coating stents, or a metallic substrate to be made into a
stent. A stent is typically an open tubular structure that has a
pattern (or patterns) of apertures extending from the outer surface
of the stent to the lumen. It is commonplace to make stents of
biocompatible metallic materials, with the patterns cut on the
surface with a laser machine. The stent can be electro-polished to
minimize surface irregularities since these irregularities can
trigger an adverse biological response. However, stents may still
stimulate foreign body reactions that result in thrombosis or
restenosis. To avoid these complications, a variety of stent
coatings and compositions have been proposed to reduce the
incidence of these complications or other complications and restore
tissue function by itself or by delivering therapeutic compound to
the lumen. For example, compounds having antiproliferative and
anti-inflammatory activities have been evaluated as stent coatings,
and have shown promise in preventing restenosis (See, for example,
Presbitero P. et al., "Drug eluting stents do they make the
difference?", Minerva Cardioangiol, 2002, 50(5):431-442; Ruygrok P.
N. et al., "Rapamycin in cardiovascular medicine", Intern. Med. J.,
2003, 33(3):103-109; and Marx S. O. et al., "Bench to bedside: the
development of rapamycin and its application to stent restenosis",
Circulation, 2001, 104(8):852-855).
[0340] In certain embodiments, the present invention provides a
stent, having at least a portion which is a covalently modified
metal surface, for insertion into an artery or vein following
balloon angioplasty. According to one aspect, the present invention
provides a method of inhibiting arterial restenosis or arterial
occlusion following vascular trauma comprising insertion into a
subject in need thereof, a stent, having at least a portion which
is a covalently modified metal surface. In the practice of the
method, the subject may be a coronary bypass, vascular surgery,
organ transplant or coronary or any other arterial angioplasty
patient, for example.
[0341] In another aspect, the invention encompasses implants and
surgical or medical devices, including stents and grafts, having at
least a portion which is a covalently modified metal surface. In
certain embodiments, the devices include compounds which inhibit
smooth muscle cell proliferation. Representative examples of
implants and surgical or medical devices contemplated by the
present invention include cardiovascular devices (e.g., implantable
venous catheters, venous ports, tunneled venous catheters, chronic
infusion lines or ports, including hepatic artery infusion
catheters, pacemaker wires, implantable defibrillators);
neurologic/neurosurgical devices (e.g., ventricular peritoneal
shunts, ventricular atrial shunts, nerve stimulator devices, dural
patches and implants to prevent epidural fibrosis post-laminectomy,
devices for continuous subarachnoid infusions); gastrointestinal
devices (e.g., chronic indwelling catheters, feeding tubes,
portosystemic shunts, shunts for ascites, peritoneal implants for
drug delivery, peritoneal dialysis catheters, implantable meshes
for hernias, suspensions or solid implants to prevent surgical
adhesions, including meshes); genitourinary devices (e.g., uterine
implants, including intrauterine devices (IUDs) and devices to
prevent endometrial hyperplasia, fallopian tubal implants,
including reversible sterilization devices, fallopian tubal stents,
artificial sphincters and periurethral implants for incontinence,
ureteric stents, chronic indwelling catheters, bladder
augmentations, or wraps or splints for vasovasostomy);
otolaryngology devices (e.g., ossicular implants, Eustachian tube
splints or stents for glue ear or chronic otitis as an alternative
to transtempanic drains); and orthopedic implants (e.g., cemented
orthopedic prostheses).
[0342] In other embodiments of the invention, the implant or device
contemplated by the present invention provides a uniform,
predictable, prolonged release of the therapeutic agent, or
composition thereof, into the tissue surrounding the implant or
device once it has been deployed. For vascular stents, in addition
to the above properties, the composition should not render the
stent thrombogenic (causing blood clots to form), or cause
significant turbulence in blood flow (more than the stent itself
would be expected to cause if it was uncoated). In certain
embodiments, said therapeutic agent is an anti-proliferative
compound. In still other embodiments, said therapeutic agent is
Paclitaxel.
[0343] In the case of stents, a wide variety of stents may be
covalently modified in accordance with the present invention
including esophageal stents, gastrointestinal stents, vascular
stents, biliary stents, colonic stents, pancreatic stents, ureteric
and urethral stents, lacrimal stents, Eustachian tube stents,
fallopian tube stents and tracheal/bronchial stents (See, for
example, U.S. Pat. No. 6,515,016, the entire contents of which are
incorporated herein by reference). Stents may be readily obtained
from commercial sources, or constructed in accordance with
well-known techniques. Representative examples of stents include
those described in U.S. Pat. No. 4,768,523, entitled "Hydrogel
Adhesive"; U.S. Pat. No. 4,776,337, entitled "Expandable
Intraluminal Graft, and Method and Apparatus for Implanting and
Expandable Intraluminal Graft"; U.S. Pat. No. 5,041,126 entitled
"Endovascular Stent and Delivery System"; U.S. Pat. No. 5,052,998
entitled "Indwelling Stent and Method of Use"; U.S. Pat. No.
5,064,435 entitled "Self-Expanding Prosthesis Having Stable Axial
Length"; U.S. Pat. No. 5,147,370, entitled "Nitinol Stent for
Hollow Body Conduits"; U.S. Pat. No. 5,176,626, entitled
"Indwelling Stent"; U.S. Pat. No. 6,344,028 entitled "Replenishable
Stent and Delivery System"; and U.S. Pat. No. 5,328,471, entitled
"Method and Apparatus for Treatment of Focal Disease in Hollow
Tubular Organs and Other Tissue Lumens."
[0344] As discussed above, the stent covalently modified in
accordance with the present invention may be used to eliminate a
vascular obstruction and prevent restenosis or reduce the rate of
restenosis. Within other aspects of the present invention, such
stents are provided for expanding the lumen of a body passageway.
Specifically, a stent having a generally tubular structure, and at
least a portion which is covalently modified metal, may be inserted
into the passageway, such that the passageway is expanded. In
certain embodiments, the stent may be used to eliminate a biliary,
gastrointestinal, esophageal, tracheal/bronchial, urethral or
vascular obstruction.
[0345] In other embodiments, methods are provided for preventing
restenosis, comprising inserting a stent into an obstructed blood
vessel, the stent having a generally tubular structure, at least a
portion of the surface of the structure being covalently modified
in accordance with the present invention, such that the obstruction
is eliminated and smooth muscle cell proliferation is prevented or
inhibited.
[0346] Within other aspects of the present invention, methods are
provided for expanding the lumen of a body passageway, comprising
inserting a stent into the passageway, the stent having a generally
tubular structure, at least a portion of the surface of the
structure being covalently modified in accordance with the present
invention, such that the passageway is expanded. In certain
embodiments, the lumen of a body passageway is expanded in order to
eliminate a biliary, gastrointestinal, esophageal,
tracheal/bronchial, urethral and/or vascular obstruction.
[0347] In certain embodiments, methods are provided for eliminating
biliary obstructions, comprising inserting a biliary stent into a
biliary passageway, the stent having a generally tubular structure,
at least a portion of the surface of the structure being covalently
modified in accordance with the present invention, such that the
biliary obstruction is eliminated. For example, tumor overgrowth of
the common bile duct results in progressive cholestatic jaundice
which is incompatible with life. Generally, the biliary system
which drains bile from the liver into the duodenum is most often
obstructed by (1) a tumor composed of bile duct cells
(cholangiocarcinoma), (2) a tumor which invades the bile duct
(e.g., pancreatic carcinoma), or (3) a tumor which exerts extrinsic
pressure and compresses the bile duct (e.g., enlarged lymph nodes).
Both primary biliary tumors, as well as other tumors which cause
compression of the biliary tree may be treated utilizing stents,
implants and other surgical or medical devices, at least a portion
of which is metal which is covalently modified in accordance with
the present invention.
[0348] One example of primary biliary tumors are adenocarcinomas
(which are also called Klatskin tumors when found at the
bifurcation of the common hepatic duct). These tumors are also
referred to as biliary carcinomas, choledocholangiocarcinomas, or
adenocarcinomas of the biliary system. Benign tumors which affect
the bile duct (e.g., adenoma of the biliary system), and, in rare
cases, squamous cell carcinomas of the bile duct and
adenocarcinomas of the gallbladder, may also cause compression of
the biliary tree and therefore, result in biliary obstruction.
Compression of the biliary tree is most commonly due to tumors of
the liver and pancreas which compress and therefore obstruct the
ducts. Most of the tumors from the pancreas arise from cells of the
pancreatic ducts. This is a highly fatal form of cancer (5% of all
cancer deaths; 26,000 new cases per year in the U.S.) with an
average of 6 months survival and a 1 year survival rate of only
10%. When these tumors are located in the head of the pancreas they
frequently cause biliary obstruction, and this detracts
significantly from the quality of life of the patient. While all
types of pancreatic tumors are generally referred to as "carcinoma
of the pancreas" there are histologic subtypes including:
adenocarcinoma, adenosquamous carcinoma, cystadenocarcinoma, and
acinar cell carcinoma. Hepatic tumors, as discussed above, may also
cause compression of the biliary tree, and therefore cause
obstruction of the biliary ducts.
[0349] A biliary stent is first inserted into a biliary passageway
in one of several ways: from the top end by inserting a needle
through the abdominal wall and through the liver (a percutaneous
transhepatic cholangiogram or "PTC"); from the bottom end by
cannulating the bile duct through an endoscope inserted through the
mouth, stomach, and duodenum (an endoscopic retrograde
cholangiogram or "ERCP"); or by direct incision during a surgical
procedure. A preinsertion examination, PTC, ERCP, or direct
visualization at the time of surgery is optionally performed to
determine the appropriate position for stent insertion. A guidewire
is then advanced through the lesion, and over this a delivery
catheter is passed to allow the stent to be inserted in its
collapsed form. If the diagnostic exam was a PTC, the guidewire and
delivery catheter is inserted via the abdominal wall, while if the
original exam was an ERCP the stent may be placed via the mouth.
The stent is then positioned under radiologic, endoscopic, or
direct visual control taking particular care to place it precisely
across the narrowing in the bile duct. The delivery catheter is
then removed leaving the stent standing as a scaffolding which
holds the bile duct open. A further cholangiogram may be performed
to document that the stent is appropriately positioned.
[0350] In certain embodiments, methods are provided for eliminating
esophageal obstructions, comprising inserting an esophageal stent
into an esophagus, the stent having a generally tubular structure,
at least a portion of the surface of the structure being covalently
modified in accordance with the present invention, such that the
esophageal obstruction is eliminated. For example, the esophagus is
the hollow tube which transports food and liquids from the mouth to
the stomach. Cancer of the esophagus or invasion by cancer arising
in adjacent organs (e.g., cancer of the stomach or lung) results in
the inability to swallow food or saliva. In certain embodiments, a
pre-insertion examination, usually a barium swallow or endoscopy is
performed in order to determine the appropriate position for stent
insertion. A catheter or endoscope may then be positioned through
the mouth, and a guidewire is advanced through the blockage. A
stent delivery catheter is passed over the guidewire under
radiologic or endoscopic control, and a stent is placed precisely
across the narrowing in the esophagus. A post-insertion
examination, usually a barium swallow x-ray, may be utilized to
confirm appropriate positioning.
[0351] In certain embodiments, methods are provided for eliminating
colonic obstructions, comprising inserting a colonic stent into a
colon, the stent having a generally tubular structure, at least a
portion of the surface of the structure being covalently modified
in accordance with the present invention, such that the colonic
obstruction is eliminated. For example, the colon is the hollow
tube which transports digested food and waste materials from the
small intestines to the anus. Cancer of the rectum and/or colon or
invasion by cancer arising in adjacent organs (e.g., cancer of the
uterus, ovary, bladder) results in the inability to eliminate feces
from the bowel. In certain embodiments, a pre-insertion
examination, usually a barium enema or colonoscopy is performed in
order to determine the appropriate position for stent insertion. A
catheter or endoscope may then be positioned through the anus, and
a guidewire is advanced through the blockage. A stent delivery
catheter is passed over the guidewire under radiologic or
endoscopic control, and a stent is placed precisely across the
narrowing in the colon or rectum. A post-insertion examination,
usually a barium enema x-ray, may be utilized to confirm
appropriate positioning.
[0352] In certain embodiments, methods are provided for eliminating
tracheal/bronchial obstructions, comprising inserting a
tracheal/bronchial stent into a trachea or bronchi, the stent
having a generally tubular structure, at least a portion of the
surface of the structure being covalently modified in accordance
with the present invention, such that the tracheal/bronchial
obstruction is eliminated. For example, the trachea and bronchi are
tubes which carry air from the mouth and nose to the lungs.
Blockage of the trachea by cancer, invasion by cancer arising in
adjacent organs (e.g., cancer of the lung), or collapse of the
trachea or bronchi due to chondromalacia (weakening of the
cartilage rings) results in inability to breathe. In certain
embodiments, a pre-insertion examination, usually an endoscopy, is
performed in order to determine the appropriate position for stent
insertion. A catheter or endoscope is then positioned through the
mouth, and a guidewire advanced through the blockage. A delivery
catheter is then passed over the guidewire in order to allow a
collapsed stent to be inserted. The stent is placed under
radiologic or endoscopic control in order to place it precisely
across the narrowing. The delivery catheter may then be removed
leaving the stent standing as a scaffold on its own. A
post-insertion examination, usually a bronchoscopy may be utilized
to confirm appropriate positioning.
[0353] In certain embodiments, methods are provided for eliminating
urethral obstructions, comprising inserting a urethral stent into a
urethra, the stent having a generally tubular structure, at least a
portion of the surface of the structure being covalently modified
in accordance with the present invention, such that the urethral
obstruction is eliminated. For example, the urethra is the tube
which drains the bladder through the penis. Extrinsic narrowing of
the urethra as it passes through the prostate, due to hypertrophy
of the prostate, occurs in virtually every man over the age of 60
and causes progressive difficulty with urination. In certain
embodiments, a pre-insertion examination, usually an endoscopy or
urethrogram is first performed in order to determine the
appropriate position for stent insertion, which is above the
external urinary sphincter at the lower end, and close to flush
with the bladder neck at the upper end. An endoscope or catheter is
then positioned through the penile opening and a guidewire advanced
into the bladder. A delivery catheter is then passed over the
guidewire in order to allow stent insertion. The delivery catheter
is then removed, and the stent expanded into place. A
post-insertion examination, usually endoscopy or retrograde
urethrogram, may be utilized to confirm appropriate position.
[0354] In certain embodiments, methods are provided for eliminating
vascular obstructions, comprising inserting a vascular stent into a
blood vessel, the stent having a generally tubular structure, at
least a portion of the surface of the structure being covalently
modified in accordance with the present invention, such that the
vascular obstruction is eliminated. For example, stents may be
placed in a wide array of blood vessels, both arteries and veins,
to prevent recurrent stenosis at the site of failed angioplasties,
to treat narrowings that would likely fail if treated with
angioplasty, and to treat post-surgical narrowings (e.g., dialysis
graft stenosis). Suitable sites include, but are not limited to,
the iliac, renal, and coronary arteries, the superior vena cava,
and in dialysis grafts. In certain embodiments, angiography is
first performed in order to localize the site for placement of the
stent. This is typically accomplished by injecting radiopaque
contrast through a catheter inserted into an artery or vein as an
x-ray is taken. A catheter may then be inserted either
percutaneously or by surgery into the femoral artery, brachial
artery, femoral vein, or brachial vein, and advanced into the
appropriate blood vessel by steering it through the vascular system
under fluoroscopic guidance. A stent may then be positioned across
the vascular stenosis. A post-insertion angiogram may also be
utilized in order to confirm appropriate positioning.
[0355] Compositions comprising one or more therapeutic agents can
be coated on a device according to the present invention, which is
then implanted to provide localized delivery of the therapeutic
agent or agents contained therein. In certain embodiments, said
therapeutic agent is an anti-proliferative compound. In still other
embodiments, said therapeutic agent is Paclitaxel. General methods
for delivering the therapeutic agent or agents contained within the
coating on said device to targeted areas of the body have been
described, for example, in U.S. Pat. No. 5,651,986. Such localized
delivery is useful for, among other things, inhibiting the growth
of a tumor. This method avoids the systemic levels of the
chemotherapeutic agent or agents often associated with toxicity.
The localized delivery of the therapeutic agent is achieved by
implanting a device, coated with a composition of the present
invention, proximally to the tumor. The therapeutic agent is
typically released from the device by diffusion, degradation of the
matrix, or a combination thereof. Thus, another aspect of the
present invention relates to a method for inhibiting growth of a
tumor, in a patient in need thereof, comprising implanting a
device, coated with a composition as described herein, for
administering localized delivery of the therapeutic agent.
EXAMPLES
Preparation of Bifunctional PEGs and Multiblock Copolymers of the
Present Invention
[0356] As described generally above, multiblock copolymers of the
present invention are prepared using the heterobifunctional PEGs
described herein and in United States patent application
publication number US20060142506, the entirety of which is hereby
incorporated herein by reference. The preparation of multiblock
polymers in accordance with the present invention is accomplished
by methods known in the art, including those described in detail in
United States patent application publication number US20060172914,
the entirety of which is hereby incorporated herein by
reference.
Example 1
[0357] A coupon of 316 stainless steel is placed in an oxidation
reactor and treated with a 1.3.times.10.sup.16 m.sup.-3 and 3 eV
water vapor plasma at 100.degree. C. for a period of 24 hours. The
metal substrate is placed in an aqueous solution containing 5 wt %
phosphonic acid functionalized poly(ethylene glycol) for one hour.
The substrate is removed from the PEG solution and dried under
vacuum at 160.degree. C. for 24 hours to give the desired
PEG-functionalized stainless steel. See FIG. 11.
Example 2
[0358] A 1/2''.times.1/2''.times.1/8'' 316 L stainless steel coupon
was cleaned with an argon plasma process (250 mtorr Ar.sub.2,
100.degree. C., 4000 watts for 15 minutes at a flow of 2.5 slm).
The freshly cleaned coupon was then exposed to an oxygen plasma
treatment (250 mtorr O.sub.2, 100.degree. C., 4000 watts for 15
minutes flow of 2.5 slm). Contact angle was found to be
8.degree..
Example 3
[0359] A coupon of 316 stainless steel is placed in an oxidation
reactor and treated with a 1.3.times.10.sup.16 m.sup.-3 and 3 eV
water vapor plasma at 100.degree. C. for a period of 24 hours. The
metal substrate is placed in a vacuum flask and the system
evacuated. The flask is backfilled with Argon and an anhydrous
solution containing 5 wt % phosphonic chloride functionalized
poly(ethylene glycol) in tetrahydrofuran is added. After sixteen
hours, the substrate is removed from the PEG solution and dried
under vacuum at 60.degree. C. for 24 hours to give the desired
PEG-functionalized stainless steel. See FIG. 12.
Example 4
[0360] An oxygen plasma treated coupon was placed in an aqueous
solution containing 10 wt % THP-PEG-Phosphonic acid (5,000 g/mol).
The coupon was allowed to remain in the PEG solution for 2 hours at
which point it was removed for the PEG solution and placed in a
pyrex dish. The coupon was heated to 160.degree. C. under vacuum
for 12 hours. The coupon was allowed to cool to room temperature at
which point is was washed with methylene chloride and acetone and
subsequently dried with a paper towel. Contact angle was found to
be 18.degree..
Example 5
[0361] An oxygen plasma treated coupon was placed in an aqueous
solution containing 10 wt % dibenzylamine-PEG-Phosphonic acid
(8,000 g/mol). The coupon was allowed to remain in the PEG solution
for 2 hours at which point it was removed for the PEG solution and
placed in a pyrex dish. The coupon was heated to 160.degree. C.
under vacuum for 12 hours. The coupon was allowed to cool to room
temperature at which point is was washed with methylene chloride
and acetone and subsequently dried with a paper towel. Contact
angle was found to be 49.degree..
* * * * *
References