U.S. patent application number 15/868516 was filed with the patent office on 2018-05-17 for quaternary phosphonium coated surfaces and methods of making the same.
The applicant listed for this patent is Orthobond, Inc.. Invention is credited to Randy Clevenger, Se-Ho Kim.
Application Number | 20180134832 15/868516 |
Document ID | / |
Family ID | 55761686 |
Filed Date | 2018-05-17 |
United States Patent
Application |
20180134832 |
Kind Code |
A1 |
Clevenger; Randy ; et
al. |
May 17, 2018 |
QUATERNARY PHOSPHONIUM COATED SURFACES AND METHODS OF MAKING THE
SAME
Abstract
Disclosed herein is a composition comprising a substrate with
functionalized surface covalently bound to an anti-infective agent,
such as a quaternary phosphonium compound with anti-bacterial
activity against a broad range of bacteria, methods of synthesizing
an anti-infective composition, and its resultant antimicrobial
performance.
Inventors: |
Clevenger; Randy; (North
Plainfield, NJ) ; Kim; Se-Ho; (North Brunswick,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Orthobond, Inc. |
North Brunswick |
NJ |
US |
|
|
Family ID: |
55761686 |
Appl. No.: |
15/868516 |
Filed: |
January 11, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14922983 |
Oct 26, 2015 |
9868808 |
|
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15868516 |
|
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62068347 |
Oct 24, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C09D 5/14 20130101; C08F
292/00 20130101; C08F 230/02 20130101; C08F 230/02 20130101; C08F
2438/01 20130101; C08F 292/00 20130101 |
International
Class: |
C08F 292/00 20060101
C08F292/00; C08F 230/02 20060101 C08F230/02 |
Claims
1. A composition comprising a substrate comprising a functionalized
surface; and a quaternary phosphonium compound bonded to the
functionalized surface, wherein the quaternary phosphonium compound
has a radical of formula I ##STR00020## wherein X.sub.1, X.sub.2,
X.sub.3, and X.sub.4 are independently non-existent or
independently selected from O, S, NR.sub.5, .dbd.N--, PR.sub.6, and
.dbd.P--; and wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are independently selected from the group consisting of
hydrogen, alkyls, substituted alkyl, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl,
substituted cycloalkenyl, alkynyl, substituted alkynyl, haloalkyl,
hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, haloalkoxy, aryl,
substituted aryl, aryloxy, aralkyloxy, heteroaryl, substituted
heteroaryl, heterocycle, substituted heterocycle, amino,
alkylamino, dialkylamino, hydroxyalkylamino, (amino)alkyl,
(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl), carboxamido,
(carboxamido)alkyl, methacrylate, methacrylamide, sulfonamide,
alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,
mercaptoalkyl, carboxy, carboxyalkyl, ureido, guanidine,
(heterocyclo)alkyl, (heteroaryl)alkyl.
2. The composition of claim 1, wherein the functionalized surface
is natively functionalized or functionalized with a functionalizing
agent covalently bonded thereto.
3. The composition of claim 2, further comprising a linker, having
a proximal end and a distal end, wherein the linker is covalently
bonded on its proximal end to the natively functionalized surface,
and wherein the linker is covalently bonded on its distal end to
the quaternary phosphonium compound.
4. The composition of claim 2, further comprising a linker, having
a proximal and a distal end, wherein the linker is covalently
bonded on its proximal end to the functionalizing agent, and
wherein the linker is covalently bonded on its distal end to the
quaternary phosphonium compound.
5. The composition of claim 1, wherein the functionalized surface
is selected from the group consisting of metals, alloys, polymers,
plastics, ceramics, silicon, glass, composites, tissue and surfaces
with acidic protons.
6. The composition of claim 2, wherein the functionalized surface
is functionalized with a functionalizing agent selected from the
group consisting of phosphonic acids, phosphoric acids, carboxylic
acids, sulfonic acids, sulfinic acids, phosphonates, phosphonic
acid anhydrides, phosphoric acid esters, phosphorus pentoxides,
carboxylic acid esters, carboxylic anhydrides, sulfonates, sulfonic
acid anhydrides, sulfinic esters, sulfinic anhydrides, alcohols,
thiols, alkanes, alkenes, alkynes, and diazo compounds.
7. The composition of claim 1, wherein the quaternary phosphonium
compound has a structure ##STR00021## wherein n2 is between 1 and
50.
8. The composition of claim 4, wherein the linker has a structure
##STR00022## wherein n1 is between 1 and 100 and R' is
independently a hydrogen, or a quaternary phosphonium compound.
9. The composition of claim 4 having a structure ##STR00023##
wherein n1 is between 1 and 100.
10. A method for preparing a composition comprising attaching a
quaternary phosphonium compound to a functionalized surface of a
substrate, wherein the quaternary phosphonium compound has a
radical of formula I ##STR00024## wherein X.sub.1, X.sub.2,
X.sub.3, and X.sub.4 are independently non-existent or
independently selected from O, S, NR.sub.5, .dbd.N--, PR.sub.6, and
.dbd.P--; and wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are independently selected from the group consisting of
hydrogen, alkyls, substituted alkyl, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl,
substituted cycloalkenyl, alkynyl, substituted alkynyl, haloalkyl,
hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, haloalkoxy, aryl,
substituted aryl, aryloxy, aralkyloxy, heteroaryl, substituted
heteroaryl, heterocycle, substituted heterocycle, amino,
alkylamino, dialkylamino, hydroxyalkylamino, (amino)alkyl,
(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl), carboxamido,
(carboxamido)alkyl, methacrylate, methacrylamide, sulfonamide,
alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,
mercaptoalkyl, carboxy, carboxyalkyl, ureido, guanidine,
(heterocyclo)alkyl, and (heteroaryl)alkyl, and are linked to the
phosphorus through any one of oxygen, nitrogen, sulfur, carbon, and
phosphorus.
11. The method of claim 10, wherein attaching the quaternary
phosphonium compound to a functionalized surface comprises
covalently bonding a functionalizing agent to the surface; and
covalently bonding the quaternary phosphonium compound to the
functionalized surface.
12. The method of claim 10, wherein attaching a quaternary
phosphonium compound to a functionalized surface comprises
covalently binding a functionalizing agent to the surface;
activating the surface; polymerizing a linker, having a proximal
and a distal end, to form a covalent bond between the activated
functionalized surface and the proximal end of the linker; and
subsequently covalently binding the distal end of the linker to the
quaternary phosphonium compound.
13. The method of claim 10, wherein attaching a quaternary
phosphonium compound to a functionalized surface comprises
polymerizing a linker, having a proximal and a distal end, to form
a covalent bond between the quaternary phosphonium compound and the
distal end of the linker; and subsequently covalently binding the
proximal end of the linker to the functionalized surface.
14. The method of claim 10, wherein the functionalized surface is
selected from the group consisting of metals, alloys, polymers,
plastics, ceramics, silicon, glass, composites, tissue and surfaces
with acidic protons.
15. The method of claim 11, wherein the functionalizing agent is
selected from the group consisting of phosphonic acids, phosphoric
acids, carboxylic acids, sulfonic acids, sulfinic acids,
phosphonates, phosphonic acid anhydrides, phosphoric acid esters,
phosphorus pentoxides, carboxylic acid esters, carboxylic
anhydrides, sulfonates, sulfonic acid anhydrides, sulfinic esters,
sulfinic anhydrides, alcohols, thiols, alkanes, alkenes, alkynes,
and diazo compounds.
16. The method of claim 10, wherein the quaternary phosphonium
compound is a radical of ##STR00025## wherein n2 is between 1 and
50.
17. The method of claim 13, wherein the linker has a structure
##STR00026## wherein n1 is between 1 and 100 and R' is
independently a hydrogen, or a quaternary phosphonium compound.
18. The method of claim 12, wherein the composition has a structure
##STR00027## wherein n1 is between 1 and 100.
19. The composition of claim 1, wherein the quaternary phosphonium
compound is a radical of ##STR00028## wherein n3 is between 1 and
50.
20. The method of claim 10, wherein the quaternary phosphonium
compound is a radical of ##STR00029## wherein n3 is between 1 and
50.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 62/068,347, filed Oct. 24, 2014, the
entirety of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to surface attachment of
quaternary phosphonium compounds with anti-bacterial activity
against a broad range of bacteria. In particular, methods are
provided for attaching various substrate surfaces to quaternary
phosphonium compounds to obtain anti-bacterial activity.
BACKGROUND OF THE INVENTION
[0003] The need for control of infection is a vital concern for
many, from public health officials, hospital and school
administrators and the like, to private citizens. Typically,
control of infection can be achieved by the topical application of
disinfectants, antiseptics, antibacterials and the like to surfaces
likely to be contacted by infectious agents. Common disinfectants
include active chlorine such as hypochlorites, chloramines,
dichloroisocyanurate and trichloroisocyanurate, wet chlorine,
chlorine dioxide and the like, active oxygen, including peroxides,
such as peracetic acid, potassium persulfate, sodium perborate,
sodium percarbonate and urea perhydrate, iodine compounds such as
povidone iodide, iodine tincture, iodinated nonionic surfactants,
concentrated alcohols such as ethanol, n-propanol and isopropanol
and mixtures thereof; 2-phenoxyethanol and 1- and
2-phenoxypropanols, phenolic compounds, cresols, halogenated
phenols, such as hexachlorophene, triclosan, trichlorophenol,
tribromophenol, pentachlorophenol, Dibromol and salts thereof,
cationic surfactants, including quaternaryammonium cations such as
benzalkonium chloride, cetyl trimethylammonium bromide orchloride,
didecyldimethylammonium chloride, cetylpyridinium chloride,
benzethonium chloride and others, and non-quaternary compounds,
such as chlorhexidine, glucoprotamine, octenidine dihydrochloride
etc.); strong oxidizers, such as ozone and permanganate solutions;
heavy metals and their salts, such as colloidal silver, silver
nitrate, mercury chloride, phenylmercury salts, copper, copper
sulfate, copper oxide-chloride and the like, and strong acids
(phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic
acids) and alkalis (sodium, potassium, calcium hydroxides).
However, many of these compounds are harmful to mammalian tissue.
Moreover, these compounds only have a short-term effect resulting
in a need to be reapplied constantly.
[0004] Antibiotics can be administered to stop infection in
individuals. However, such administration is not always effective.
Numerous medical applications, including orthopedic, trauma, spine
and general surgery applications, where the potential for infection
is a serious concern, are not amenable to simple application of
antiseptic or treatment with antibiotics. For example, infection
can be a devastating complication of a total joint arthroplasty
(TJA). While some infections may be treated by antibiotic
suppression alone, more aggressive therapies, such as two-stage
re-implantation, are often required. The treatment of
post-arthroplasty infections in 1999 cost over $200 million in the
US alone. Spangehl, M. J., et al., J Bone Joint Surg. Am., 1999,
81(5), 672-682. TJA infections occur when bacteria colonize the
surface of the implant. These species then form a resistant biofilm
on the implant surface, which nullifies the body's normal antibody
response.
[0005] External fixation devices provide temporary but necessary
rigid constraints to facilitate bone healing. However, patients
risk pin-tract infection at the site extending from the skin-pin
interface to within the bone tissue. Such complications can result
in sepsis and osteomyelitis, which could require sequestrectomy for
correction. Even the most stringent pin-handling and post-procedure
protocols have only a limited effect. Studies have shown that such
protocols do not reduce the chance of infection. Davies, R., et al.
J Bone Joint Surg. Br., 2005, 87-B, 716-719.
[0006] In minimally-invasive spine fusions, pedicle screws are
first implanted in the bone of the vertebrae, and then rods are
fixed into the heads of the screws to immobilize and stabilize the
affected segments. Screws and rods pass through the patient's skin
into the spine space via a cannulated channel. As in external
fixation, screws and rods are also prone to pin-tract infections;
due to the implants' pathway through the skin, the chance of
contacting and/or passing harmful bacteria is greatly
increased.
[0007] Catheters and shunts are placed in any number of body
cavities and vessels to facilitate the injection, drainage, or
exchange of fluids. Infections are common in catheter placements
and are largely dependent on how long the patient is catheterized.
For example, Kass reports an infection rate of virtually 100% for
patients with indwelling urethral catheters draining into an open
system for longer than 4 days. Kass, E. H., Trans. Assoc. Am.
Physicians, 1956, 69, 56-63.
[0008] Therefore, there is a need for substrates and materials with
anti-infective surfaces, such as medical devices including
implants, screws, rods, pins, catheters, stents, surgical tools and
the like which could prevent infections by proactively killing
bacteria that attempt to colonize the device surface both pre- and
post-operatively. Moreover, there is a need for anti-infective
surfaces that may be employed in locations particularly susceptible
to hosting infectious agents, such as public places, common areas
of buildings, fixtures and the like.
SUMMARY OF THE INVENTION
[0009] In some embodiments of the invention, a surface of interest
is functionalized in accordance with a suitable functionalization
method and an anti-infective agent is disposed on the
functionalized surface.
[0010] In some embodiments, the invention is directed to a
composition comprising a substrate comprising a functionalized
surface and a quaternary phosphonium compound covalently bound
directly to the functionalized surface.
[0011] In some embodiments the surface of the substrate is
functionalized with a functionalizing agent. In other embodiments
the surface of the substrate may be natively functionalized.
[0012] In some embodiments a linker, having a proximal and a distal
end, may be covalently bound on its proximal end to the
functionalized surface of the substrate, and may be covalently
bound on its distal end to a quaternary phosphonium compound.
[0013] In some embodiments a plurality of linkers may be covalently
bound on their proximal ends to the functionalized surface or to a
plurality of functionalizing agents, with each linker being
covalently bound on their distal end to a plurality of
anti-infective agents. In some embodiments, the anti-infective
agents may be all the same, for example, quaternary phosphonium
compounds. In other embodiments, the anti-infective agents may
vary, for example, various quaternary phosphonium compounds, or a
combination of quaternary phosphonium compounds with other
anti-infective agents. In some embodiments, the plurality of
functionalizing agents is independently identical or different. In
some embodiments, the plurality of linkers is independently
identical or different.
[0014] In some embodiments, the composition may take a form of an
antibacterial polymer brush comprising a surface and a thickness.
In some embodiments, varying antibacterial polymer brush thickness
may have varying antibacterial efficacy. In some embodiments, the
antibacterial polymer brush disrupts bacterial cells, thereby
maintaining antibacterial activity for prolonged duration without
being reapplied.
[0015] In some embodiments, the anti-infective agent may be a
quaternary phosphonium compound having the radical formula of
formula I:
##STR00001##
wherein X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are independently
non-existent or independently selected from O, S, NR.sub.5,
.dbd.N--, PR.sub.6, and .dbd.P--, and wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected
from the group consisting of hydrogen, alkyls, substituted alkyl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, alkenyl, substituted cycloalkenyl, alkynyl,
substituted alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,
heteroalkyl, haloalkoxy, aryl, substituted aryl, aryloxy,
aralkyloxy, heteroaryl, substituted heteroaryl, heterocycle,
substituted heterocycle, amino, alkylamino, dialkylamino,
hydroxyalkylamino, (amino)alkyl, (alkylamino)alkyl,
(dialkylamino)alkyl, (cyano)alkyl), carboxamido,
(carboxamido)alkyl, methacrylate, methacrylamide, sulfonamide,
alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,
mercaptoalkyl, carboxy, carboxyalkyl, ureido, guanidine,
(heterocyclo)alkyl, (heteroaryl)alkyl.
[0016] In some embodiments, one of R.sub.1, R.sub.2, R.sub.3, or
R.sub.4 may bind the quaternary phosphonium compound either
directly to the functionalized surface, functionalizing agent, or
to the distal end of a linker. In other embodiments, more than one
of R.sub.1, R.sub.2, R.sub.3, or R.sub.4 may bind the quaternary
phosphonium compound either directly to a functionalized surface,
to a functionalizing agent, or to the distal end of a linker. In
some embodiments, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 may be the
same. In other embodiments, some of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 may be the same and some may be different.
[0017] Virtually any surface which may be functionalized is
suitable for the inclusion of an anti-infective agent in accordance
with the disclosed embodiments. Examples of such surfaces include
but are not limited to metals, alloys, polymers, plastics,
ceramics, silicon, glass, composites, tissue and surfaces with
acidic protons.
[0018] Functionalization of substrates in accordance with the
present invention may be achieved in a variety of ways. For
example, the surfaces of the substrates can be functionalized by a
reaction with functionalizing agents such as phosphonic acids,
phosphoric acids, carboxylic acids, sulfonic acids, sulfinic acids,
phosphonates, phosphonic acid anhydrides, phosphoric acid esters,
phosphorus pentoxides, carboxylic acid esters, carboxylic
anhydrides, sulfonates, sulfonic acid anhydrides, sulfinic esters,
sulfinic anhydrides, alcohols, thiols, alkanes, alkenes, alkynes,
and diazo compounds. In some embodiments, the surfaces may be
naturally functionalized.
[0019] Anti-infective agents as discussed herein may include
bactericidal and bacteriostatic agents including disinfectants,
antiseptics and antibiotics. Not all bactericidal and
bacteriostatic agents may be used as antiseptics on mammalian
tissue as they may have adverse effects thereon. Some embodiments
of the present invention may involve uses without contact of an
anti-infective surface with mammalian tissue, such as interior
surfaces of plumbing fixtures, building materials, ductwork, clean
rooms, etc. In such applications certain anti-infective agents may
be used, such as disinfectants, which would not be appropriate for
use in applications in which contact with mammalian tissue was
contemplated or possible.
[0020] In other embodiments, the anti-infective composition of the
present invention may involve contact with mammalian tissue and may
comprise quaternary ammonium compounds such as choline and choline
derivatives, quaternary ammonium dendrimers, silver, copper, and
cationic species; silver and copper. In other embodiments
anti-infective agents may comprise quaternary phosphonium compounds
such as phosphonium methacrylate.
[0021] Devices made in accordance with the present disclosure
provide a multitude of clinical benefits. For example, in partially
external devices, anti-infective surfaces thereof may kill
bacterial species at the device-skin interface, thus preventing
pin-site infections. Devices including an anti-infective surface
may prevent the colonization by infectious species of implanted
surfaces, potentially reducing the incidence of deep infection,
especially in high-risk populations. In catheters and shunts with
anti-infective surfaces the potential for infection is minimized by
killing bacteria traveling up the intubated pathway into the
patient. Another example is in total hip arthroplasties;
anti-infective hip stems may kill bacterial species and inhibit
biofilm formation at the device-tissue interface, preventing the
bacterial colonization of the hip replacement, which can lead to
loosening due to infection and could require cost and painful hip
revision surgery. The anti-infective agent is highly stable under
physiological conditions. The anti-infective agent does not leach
from its material host, so there is no undesirable secondary
result. Due to its nanometer scale, the anti-infective agent does
not interfere with desired mechanical surface features that may be
critical to the function of device such as an implant. The
anti-infective agent is not visible to the naked eye and does not
obscure identifying features or product markings.
[0022] Devices in accordance with the present disclosure are not
limited to medical devices. For example, devices embodying the
present disclosures may include fixtures, structures, fittings,
barriers, and the like having anti-infective surfaces.
[0023] In some embodiments, the invention is directed to a method
of making an anti-infective composition, the method comprising
covalently binding an anti-infective agent to a functionalized
surface of a substrate.
[0024] In some embodiments, the method comprises covalently binding
a quaternary phosphonium compound either directly to a
functionalized surface, to a functionalizing agent, or to a distal
end of a linker which is covalently bonded to the functionalized
surface or to a functionalizing agent.
[0025] In some embodiments, a linker is initially covalently bound
on its proximal end to a functionalized surface and an
anti-infective agent, such as a quaternary phosphonium compound, is
subsequently covalently bound to the linker's distal end. In other
embodiments, a linker is initially covalently bound on its distal
end to an anti-infective agent, such as a quaternary ammonium
compound, and is subsequently covalently bound on its proximal end
to the functionalized surface.
[0026] In some embodiments, the anti-infective agent, e.g.
quaternary phosphonium compound, may be activated before covalently
binding it to a functionalized surface, a functionalizing agent, or
a linker's distal end. In some embodiments, the functionalized
surface may be activated before covalently binding it to a linker's
proximal end or to an anti-infective agent.
[0027] In some embodiments, the covalent binding may be performed
through surface initiated atom transfer radical polymerization.
[0028] In some embodiments, after the linker is covalently bound on
one of its ends, either on the proximal end to the functionalized
surface or on the distal end to the anti-infective agent, it is
polymerized pursuant to predetermined parameters, such as time and
amount of monomer, thereby obtaining a polymer brush structure with
a desired surface and thickness. In some embodiments, after
polymerization of the linker is complete, the unbound end of the
linker (either distal or proximal) is covalently bound to either
the functionalized surface or the anti-infective agent. In some
embodiments, varying polymer brush thickness may result in varying
antimicrobial activity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The above and other features of the present disclosure,
their nature, and various advantages will become more apparent upon
consideration of the following detailed description, taken in
conjunction with the accompanying drawings, in which:
[0030] FIG. 1 depicts a schematic of an anti-infective agent bound
to a surface in accordance with at least one embodiment of the
present disclosure.
[0031] FIG. 2 depicts a flow chart illustrating a method of
preparing an anti-infective composition according to an embodiment
of the invention.
[0032] FIG. 3 depicts a flow chart illustrating a method of
preparing an anti-infective composition according to another
embodiment of the invention.
[0033] FIG. 4 depicts a scheme illustrating a method of preparing a
particular anti-infective composition pursuant to example 1.
[0034] FIG. 5 depicts the anti-bacterial efficacy of two
anti-infective compositions prepared pursuant to some embodiments
of the invention immediately after the compositions were prepared
(t=0).
[0035] FIG. 6 depicts the anti-bacterial efficacy of two
anti-infective compositions prepared pursuant to some embodiments
of the invention one year after the compositions were prepared (t=1
year).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0036] For the purpose of the present disclosure, the term "alkyl"
as used by itself or as part of another group refers to a linear or
branched chain aliphatic hydrocarbon containing one to twelve
carbon atoms (i.e., C.sub.1-12 alkyl) or the number of carbon atoms
designated (i.e., a C.sub.1 alkyl such as methyl, a C.sub.2 alkyl
such as ethyl, a C.sub.3 alkyl such as propyl or isopropyl, etc.).
In one embodiment, the alkyl group is chosen from a linear chain
C.sub.1-10 alkyl group. In another embodiment, the alkyl group is
chosen from a branched chain C.sub.1-10 alkyl group. In another
embodiment, the alkyl group is chosen from a linear chain C.sub.1-6
alkyl group. In another embodiment, the alkyl group is chosen from
a branched chain C.sub.1-6 alkyl group. In another embodiment, the
alkyl group is chosen from a linear chain C.sub.1-4 alkyl group. In
another embodiment, the alkyl group is chosen from a branched chain
C.sub.1-4 alkyl group. In another embodiment, the alkyl group is
chosen from a linear or branched chain C.sub.2-4 alkyl group.
Non-limiting exemplary C.sub.1-10 alkyl groups include methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl,
3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.
Non-limiting exemplary C.sub.1-4 alkyl groups include methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and
iso-butyl.
[0037] For the purpose of the present disclosure, the term
"optionally substituted alkyl" as used by itself or as part of
another group means that the alkyl as defined above is either
unsubstituted or substituted with one, two, or three substituents
independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy,
alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl,
and the like. In one embodiment, the optionally substituted alkyl
is substituted with two substituents. In another embodiment, the
optionally substituted alkyl is substituted with one substituent.
Non-limiting exemplary optionally substituted alkyl groups include
--CH.sub.2CH.sub.2NO.sub.2, --CH.sub.2CH.sub.2CO.sub.2H,
--CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --CH.sub.2CH.sub.2COPh,
--CH.sub.2C.sub.6H.sub.11, and the like.
[0038] For the purpose of the present disclosure, the term
"cycloalkyl" as used by itself or as part of another group refers
to saturated and partially unsaturated (containing one or two
double bonds) cyclic aliphatic hydrocarbons containing one to three
rings having from three to twelve carbon atoms (i.e., C.sub.3-12
cycloalkyl) or the number of carbons designated. In one embodiment,
the cycloalkyl group has two rings. In one embodiment, the
cycloalkyl group has one ring. In another embodiment, the
cycloalkyl group is chosen from a C.sub.3-8 cycloalkyl group. In
another embodiment, the cycloalkyl group is chosen from a C.sub.3-6
cycloalkyl group. Non-limiting exemplary cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and the
like.
[0039] For the purpose of the present disclosure, the term
"optionally substituted cycloalkyl" as used by itself or as part of
another group means that the cycloalkyl as defined above is either
unsubstituted or substituted with one, two, or three substituents
independently chosen from halo, nitro, cyano, hydroxy, amino,
alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,
haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,
sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,
alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,
(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl,
mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one
embodiment, the optionally substituted cycloalkyl is substituted
with two substituents. In another embodiment, the optionally
substituted cycloalkyl is substituted with one substituent.
Non-limiting exemplary optionally substituted cycloalkyl groups
include:
##STR00002##
[0040] For the purpose of the present disclosure, the term
"cycloalkenyl" as used by itself or part of another group refers to
a partially unsaturated cycloalkyl group as defined above. In one
embodiment, the cycloalkenyl has one carbon-to-carbon double bond.
In another embodiment, the cycloalkenyl group is chosen from a
C.sub.4-8 cycloalkenyl group. Exemplary cycloalkenyl groups include
cyclopentenyl, cyclohexenyl, and the like.
[0041] For the purpose of the present disclosure, the term
"optionally substituted cycloalkenyl" as used by itself or as part
of another group means that the cycloalkenyl as defined above is
either unsubstituted or substituted with one, two, or three
substituents independently chosen from halo, nitro, cyano, hydroxy,
amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,
dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,
carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,
alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,
carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,
hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,
(cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,
(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the
optionally substituted cycloalkenyl is substituted with two
substituents. In another embodiment, the optionally substituted
cycloalkenyl is substituted with one substituent. In another
embodiment, the cycloalkenyl is unsubstituted.
[0042] For the purpose of the present disclosure, the term
"alkenyl" as used by itself or as part of another group refers to
an alkyl group as defined above containing one, two or three
carbon-to-carbon double bonds. In one embodiment, the alkenyl group
is chosen from a C.sub.2-6 alkenyl group. In another embodiment,
the alkenyl group is chosen from a C.sub.2-4 alkenyl group.
Non-limiting exemplary alkenyl groups include ethenyl, propenyl,
isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
[0043] For the purpose of the present disclosure, the term
"optionally substituted alkenyl" as used herein by itself or as
part of another group means the alkenyl as defined above is either
unsubstituted or substituted with one, two or three substituents
independently chosen from halo, nitro, cyano, hydroxy, amino,
alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,
haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,
sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
[0044] For the purpose of the present disclosure, the term
"alkynyl" as used by itself or as part of another group refers to
an alkyl group as defined above containing one to three
carbon-to-carbon triple bonds. In one embodiment, the alkynyl has
one carbon-to-carbon triple bond. In one embodiment, the alkynyl
group is chosen from a C.sub.2-6 alkynyl group. In another
embodiment, the alkynyl group is chosen from a C.sub.2-4 alkynyl
group. Non-limiting exemplary alkynyl groups include ethynyl,
propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
[0045] For the purpose of the present disclosure, the term
"optionally substituted alkynyl" as used herein by itself or as
part of another group means the alkynyl as defined above is either
unsubstituted or substituted with one, two or three substituents
independently chosen from halo, nitro, cyano, hydroxy, amino,
alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,
haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,
sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
[0046] For the purpose of the present disclosure, the term
"haloalkyl" as used by itself or as part of another group refers to
an alkyl group substituted by one or more fluorine, chlorine,
bromine and/or iodine atoms. In one embodiment, the alkyl group is
substituted by one, two, or three fluorine and/or chlorine atoms.
In another embodiment, the haloalkyl group is chosen from a
C.sub.1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups
include fluoromethyl, difluoromethyl, trifluoromethyl,
pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl,
and trichloromethyl groups.
[0047] For the purpose of the present disclosure, the term
"hydroxyalkyl" as used by itself or as part of another group refers
to an alkyl group substituted with one or more, e.g., one, two, or
three, hydroxy groups. In one embodiment, the hydroxyalkyl group is
a monohydroxyalkyl group, i.e., substituted with one hydroxy group.
In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl
group, i.e., substituted with two hydroxy groups. In another
embodiment, the hydroxyalkyl group is chosen from a C.sub.1-4
hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups
include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl
groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,
2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,
2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.
[0048] For the purpose of the present disclosure, the term "alkoxy"
as used by itself or as part of another group refers to an
optionally substituted alkyl, optionally substituted cycloalkyl,
optionally substituted alkenyl, optionally substituted
cycloalkenyl, optionally substituted alkynyl or optionally
substituted alkynyl attached to a terminal oxygen atom. In one
embodiment, the alkoxy group is chosen from a C.sub.1-4 alkoxy
group. In another embodiment, the alkoxy group is chosen from a
C.sub.1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy,
ethoxy, and tert-butoxy.
[0049] For the purpose of the present disclosure, the term
"alkoxyalkyl" as used by itself or as part of another group refers
to an alkyl group substituted with an alkoxy group. Non-limiting
exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl,
methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl,
ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl,
propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl,
isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
[0050] For the purpose of the present disclosure, the term
"heteroalkyl" as used by itself or part of another group refers to
a stable linear or branched chain hydrocarbon radical containing 1
to 10 carbon atoms and at least two heteroatoms, which can be the
same or different, selected from O, N, or S, wherein: 1) the
nitrogen atom(s) and sulfur atom(s) can optionally be oxidized;
and/or 2) the nitrogen atom(s) can optionally be quaternized. The
heteroatoms can be placed at any interior position of the
heteroalkyl group or at a position at which the heteroalkyl group
is attached to the remainder of the molecule. In one embodiment,
the heteroalkyl group contains two oxygen atoms. Non-limiting
exemplary heteroalkyl groups include
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2, --OCH.sub.2CH.sub.2NH.sub.2,
and --NHCH.sub.2CH.sub.2N(H)CH.sub.3.
[0051] For the purpose of the present disclosure, the term
"haloalkoxy" as used by itself or as part of another group refers
to a haloalkyl attached to a terminal oxygen atom. Non-limiting
exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy,
trifluoromethoxy, and 2,2,2-trifluoroethoxy.
[0052] For the purpose of the present disclosure, the term "aryl"
as used by itself or as part of another group refers to a
monocyclic or bicyclic aromatic ring system having from six to
fourteen carbon atoms (i.e., C.sub.6-14 aryl). Non-limiting
exemplary aryl groups include phenyl (abbreviated as "Ph"),
naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl,
biphenylenyl, and fluorenyl groups. In one embodiment, the aryl
group is chosen from phenyl or naphthyl.
[0053] For the purpose of the present disclosure, the term
"optionally substituted aryl" as used herein by itself or as part
of another group means that the aryl as defined above is either
unsubstituted or substituted with one to five substituents
independently chosen from halo, nitro, cyano, hydroxy, amino,
alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,
haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,
sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,
alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,
(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl,
mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one
embodiment, the optionally substituted aryl is an optionally
substituted phenyl. In one embodiment, the optionally substituted
phenyl has four substituents. In another embodiment, the optionally
substituted phenyl has three substituents. In another embodiment,
the optionally substituted phenyl has two substituents. In another
embodiment, the optionally substituted phenyl has one substituent.
Non-limiting exemplary substituted aryl groups include
2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl,
2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl,
3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl,
2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl,
3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl
3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,
2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The term
optionally substituted aryl is meant to include groups having fused
optionally substituted cycloalkyl and fused optionally substituted
heterocyclo rings. Examples include:
##STR00003##
[0054] For the purpose of the present disclosure, the term
"aryloxy" as used by itself or as part of another group refers to
an optionally substituted aryl attached to a terminal oxygen atom.
A non-limiting exemplary aryloxy group is PhO--.
[0055] For the purpose of the present disclosure, the term
"aralkyloxy" as used by itself or as part of another group refers
to an aralkyl group attached to a terminal oxygen atom. A
non-limiting exemplary aralkyloxy group is PhCH.sub.2O--.
[0056] For the purpose of the present disclosure, the term
"heteroaryl" or "heteroaromatic" refers to monocyclic and bicyclic
aromatic ring systems having 5 to 14 ring atoms (i.e., C.sub.5-14
heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from
oxygen, nitrogen and sulfur. In one embodiment, the heteroaryl has
three heteroatoms. In another embodiment, the heteroaryl has two
heteroatoms. In another embodiment, the heteroaryl has one
heteroatom. In one embodiment, the heteroaryl is a C.sub.5
heteroaryl. In another embodiment, the heteroaryl is a C.sub.6
heteroaryl. Non-limiting exemplary heteroaryl groups include
thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl,
chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl,
3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl,
4aH-carbazolyl, carbazolyl, 3-carbolinyl, phenanthridinyl,
acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl,
isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and
phenoxazinyl. In one embodiment, the heteroaryl is chosen from
thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and
3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl),
imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl
(e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl),
pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl),
pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,
and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl,
and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl,
isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl,
oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl,
isoxazol-4-yl, and isoxazol-5-yl). The term "heteroaryl" is also
meant to include possible N-oxides. Exemplary N-oxides include
pyridyl N-oxide, and the like.
[0057] For the purpose of the present disclosure, the term
"optionally substituted heteroaryl" as used by itself or as part of
another group means that the heteroaryl as defined above is either
unsubstituted or substituted with one to four substituents, e.g.,
one or two substituents, independently chosen from halo, nitro,
cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,
hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,
carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,
alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,
carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,
hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,
(cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,
(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the
optionally substituted heteroaryl has one substituent. In one
embodiment, the optionally substituted is an optionally substituted
pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or
nitrogen atom can be substituted. In another embodiment, the
optionally substituted heteroaryl is an optionally substituted
indole.
[0058] For the purpose of the present disclosure, the term
"heterocycle" or "heterocyclo" as used by itself or as part of
another group refers to saturated and partially unsaturated (e.g.,
containing one or two double bonds) cyclic groups containing one,
two, or three rings having from three to fourteen ring members
(i.e., a 3- to 14-membered heterocyclo) and at least one
heteroatom. Each heteroatom is independently selected from the
group consisting of oxygen, sulfur, including sulfoxide and
sulfone, and/or nitrogen atoms, which can be quaternized. The term
"heterocyclo" is meant to include cyclic ureido groups such as
2-imidazolidinone and cyclic amide groups such as .rho.3-lactam,
.gamma.-lactam, .delta.-lactam and .epsilon.-lactam. The term
"heterocyclo" is also meant to include groups having fused
optionally substituted aryl groups, e.g., indolinyl. In one
embodiment, the heterocyclo group is chosen from a 5- or 6-membered
cyclic group containing one ring and one or two oxygen and/or
nitrogen atoms. The heterocyclo can be optionally linked to the
rest of the molecule through a carbon or nitrogen atom.
Non-limiting exemplary heterocyclo groups include
2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl,
pyrrolidinyl, and indolinyl.
[0059] For the purpose of the present disclosure, the term
"optionally substituted heterocyclo" as used herein by itself or
part of another group means the heterocyclo as defined above is
either unsubstituted or substituted with one to four substituents
independently selected from halo, nitro, cyano, hydroxy, amino,
alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,
haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,
sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,
alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,
(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl,
mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, and the like.
Substitution may occur on any available carbon or nitrogen atom,
and may form a spirocycle. Non-limiting exemplary optionally
substituted heterocyclo groups include:
##STR00004##
[0060] For the purpose of the present disclosure, the term "amino"
as used by itself or as part of another group refers to
--NH.sub.2.
[0061] For the purpose of the present disclosure, the term
"alkylamino" as used by itself or as part of another group refers
to --NHR.sup.15, wherein R.sup.15 is alkyl.
[0062] For the purpose of the present disclosure, the term
"dialkylamino" as used by itself or as part of another group refers
to --NR.sup.16aR.sup.16b, wherein R.sup.16a and R.sup.16b are each
independently alkyl or R.sup.16a and R.sup.16b are taken together
to form a 3- to 8-membered optionally substituted heterocyclo.
[0063] For the purpose of the present disclosure, the term
"hydroxyalkylamino" as used by itself or as part of another group
refers to --NHR.sup.17, wherein R.sup.17 is hydroxyalkyl.
[0064] For the purpose of the present disclosure, the term
"(amino)alkyl" as used by itself or as part of another group refers
to an alkyl group substituted with an amino group. Non-limiting
exemplary amino alkyl groups include --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, and the like.
[0065] For the purpose of the present disclosure, the term
"(alkylamino)alkyl" as used by itself or as part of another group
refers alkyl group substituted an alkylamino group. A non-limiting
exemplary (alkylamino)alkyl group is
--CH.sub.2CH.sub.2N(H)CH.sub.3.
[0066] For the purpose of the present disclosure, the term
"(dialkylamino)alkyl" as used by itself or as part of another group
refers to an alkyl group substituted by a dialkylamino group. A
non-limiting exemplary (dialkylamino)alkyl group is
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2.
[0067] For the purpose of the present disclosure, the term
"(cyano)alkyl" as used by itself or as part of another group refers
to an alkyl group substituted with one or more cyano, e.g., --CN,
groups. Non-limiting exemplary (cyano)alkyl groups include
--CH.sub.2CH.sub.2CN, --CH.sub.2CH.sub.2CH.sub.2CN, and
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN.
[0068] For the purpose of the present disclosure, the term
"carboxamido" as used by itself or as part of another group refers
to a radical of formula --C(.dbd.O)NR.sup.24aR.sup.24b, wherein
R.sup.24a and R.sup.24b are each independently hydrogen, optionally
substituted alkyl, optionally substituted aryl, or optionally
substituted heteroaryl, or R.sup.24a and R.sup.24b taken together
with the nitrogen to which they are attached from a 3- to
8-membered heterocyclo group. In one embodiment, R.sup.24a and
R.sup.24b are each independently hydrogen or optionally substituted
alkyl. Non-limiting exemplary carboxamido groups include
--CONH.sub.2, --CON(H)CH.sub.3, --CON(CH.sub.3).sub.2, and
--CON(H)Ph.
[0069] For the purpose of the present disclosure, the term
"(carboxamido)alkyl" as used by itself or as part of another group
refers to an alkyl group with a carboxamido group. Non-limiting
exemplary (carboxamido)alkyl groups include --CH.sub.2CONH.sub.2,
--C(H)CH.sub.3--CONH.sub.2, and --CH.sub.2CON(H)CH.sub.3.
[0070] For the purpose of the present disclosure, the term
"methacrylate" as used by itself or as part of another group refers
to the radical of formula
##STR00005##
wherein R.sup.28 is independently hydrogen, or alkyl, or
substituted alkyl, or cycloalkyl, or substituted cycloalkyl,
cycloalkenyl, or substituted cycloalkenyl, or alkenyl, or
substituted cycloalkenyl, or alkynyl, substituted alkynyl, or
haloalkyl, or hydroxyalkyl, or alkoxy, or alkoxyalkyl, or
heteroalkyl, or haloalkoxy, or aryl, or substituted aryl, or
aryloxy, or aralkyloxy, or heteroaryl, or substituted heteroaryl,
or heterocycle, or substituted heterocycle, or amino, or
alkylamino, or dialkylamino, or hydroxyalkylamino, or (amino)alkyl,
or (alkylamino)alkyl, or (dialkylamino)alkyl, or (cyano)alkyl), or
carboxamido, or (carboxamido)alkyl, or sulfonamide, or
alkylcarbonyl, or arylcarbonyl, or alkylsulfonyl, or arylsulfonyl,
or mercaptoalkyl, or carboxy, or carboxyalkyl, or ureido, or
guanidine, or (heterocyclo)alkyl, or (heteroaryl)alkyl.
[0071] For the purpose of the present disclosure, the term
"methacrylamide" as used by itself or as part of another group
refers to the radical of formula
##STR00006##
wherein R.sup.27a and R.sup.27b are independently hydrogen, or
alkyl, or substituted alkyl, or cycloalkyl, or substituted
cycloalkyl, cycloalkenyl, or substituted cycloalkenyl, or alkenyl,
or substituted cycloalkenyl, or alkynyl, substituted alkynyl, or
haloalkyl, or hydroxyalkyl, or alkoxy, or alkoxyalkyl, or
heteroalkyl, or haloalkoxy, or aryl, or substituted aryl, or
aryloxy, or aralkyloxy, or heteroaryl, or substituted heteroaryl,
or heterocycle, or substituted heterocycle, or amino, or
alkylamino, or dialkylamino, or hydroxyalkylamino, or (amino)alkyl,
or (alkylamino)alkyl, or (dialkylamino)alkyl, or (cyano)alkyl), or
carboxamido, or (carboxamido)alkyl, or sulfonamide, or
alkylcarbonyl, or arylcarbonyl, or alkylsulfonyl, or arylsulfonyl,
or mercaptoalkyl, or carboxy, or carboxyalkyl, or ureido, or
guanidine, or (heterocyclo)alkyl, or (heteroaryl)alkyl.
[0072] For the purpose of the present disclosure, the term
"sulfonamido" as used by itself or as part of another group refers
to a radical of the formula --SO.sub.2NR.sup.23aR.sup.23b, wherein
R.sup.23a and R.sup.23b are each independently hydrogen, optionally
substituted alkyl, or optionally substituted aryl, or R.sup.23a and
R.sup.23b taken together with the nitrogen to which they are
attached from a 3- to 8-membered heterocyclo group. Non-limiting
exemplary sulfonamido groups include --SO.sub.2NH.sub.2,
--SO.sub.2N(H)CH.sub.3, and --SO.sub.2N(H)Ph.
[0073] For the purpose of the present disclosure, the term
"alkylcarbonyl" as used by itself or as part of another group
refers to a carbonyl group, i.e., --C(.dbd.O)--, substituted by an
alkyl group. A non-limiting exemplary alkylcarbonyl group is
--COCH.sub.3.
[0074] For the purpose of the present disclosure, the term
"arylcarbonyl" as used by itself or as part of another group refers
to a carbonyl group, i.e., --C(.dbd.O)--, substituted by an
optionally substituted aryl group. A non-limiting exemplary
arylcarbonyl group is --COPh.
[0075] For the purpose of the present disclosure, the term
"alkylsulfonyl" as used by itself or as part of another group
refers to a sulfonyl group, i.e., --SO.sub.2--, substituted by any
of the above-mentioned optionally substituted alkyl groups. A
non-limiting exemplary alkylsulfonyl group is
--SO.sub.2CH.sub.3.
[0076] For the purpose of the present disclosure, the term
"arylsulfonyl" as used by itself or as part of another group refers
to a sulfonyl group, i.e., --SO.sub.2--, substituted by any of the
above-mentioned optionally substituted aryl groups. A non-limiting
exemplary arylsulfonyl group is --SO.sub.2Ph.
[0077] For the purpose of the present disclosure, the term
"mercaptoalkyl" as used by itself or as part of another group
refers to any of the above-mentioned alkyl groups substituted by a
--SH group.
[0078] For the purpose of the present disclosure, the term
"carboxy" as used by itself or as part of another group refers to a
radical of the formula --COOH.
[0079] For the purpose of the present disclosure, the term
"carboxyalkyl" as used by itself or as part of another group refers
to any of the above-mentioned alkyl groups substituted with a
--COOH. A non-limiting exemplary carboxyalkyl group is
--CH.sub.2CO.sub.2H.
[0080] For the purpose of the present disclosure, the term
"aralkyl" as used by itself or as part of another group refers to
an alkyl group substituted with one, two, or three optionally
substituted aryl groups. In one embodiment, the aralkyl group is a
C.sub.1-4 alkyl substituted with one optionally substituted aryl
group. Non-limiting exemplary aralkyl groups include benzyl,
phenethyl, --CHPh.sub.2, and --CH(4-FPh).sub.2.
[0081] For the purpose of the present disclosure, the term "ureido"
as used by itself or as part of another group refers to a radical
of the formula --NR.sup.22aC(.dbd.O)NR.sup.22bR.sup.22c, wherein
R.sup.22a is hydrogen, alkyl, or optionally substituted aryl, and
R.sup.22b and R.sup.22c are each independently hydrogen, alkyl, or
optionally substituted aryl, or R.sup.22b and R.sup.22c taken
together with the nitrogen to which they are attached form a 4- to
8-membered heterocyclo group. Non-limiting exemplary ureido groups
include --NHC(C.dbd.O)NH.sub.2 and --NHC(C.dbd.O)NHCH.sub.3.
[0082] For the purpose of the present disclosure, the term
"guanidino" as used by itself or as part of another group refers to
a radical of the formula
--NR.sup.25aC(.dbd.NR.sup.26)NR.sup.25bR.sup.25c, wherein
R.sup.25a, R.sup.25b and R.sup.25c are each independently hydrogen,
alkyl, or optionally substituted aryl, and R.sup.26 is hydrogen,
alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or
sulfonamido. Non-limiting exemplary guanidino groups include
--NHC(C.dbd.NH)NH.sub.2, --NHC(C.dbd.NCN)NH.sub.2,
--NHC(C.dbd.NH)NHCH.sub.3, and the like.
[0083] For the purpose of the present disclosure, the term
"(heterocyclo)alkyl" as used by itself or as part of another group
refers to an alkyl group substituted with one, two, or three
optionally substituted heterocyclo groups. In one embodiment, the
(heterocyclo)alkyl is a (C.sub.1-4)alkyl substituted with one
optionally substituted heterocyclo group. Non-limiting exemplary
(heterocyclo)alkyl groups include:
##STR00007##
[0084] For the purpose of the present disclosure, the term
"(heteroaryl)alkyl" as used by itself or as part of another group
refers to an alkyl group substituted with one, two, or three
optionally substituted heteroaryl groups. In one embodiment, the
(heteroaryl)alkyl group is a (C.sub.1-4)alkyl substituted with one
optionally substituted heteroaryl group. Non-limiting exemplary
(heteroaryl)alkyl groups include:
##STR00008##
[0085] The present disclosure encompasses any of the compounds
disclosed herein which are isotopically-labelled (i.e.,
radiolabeled) by having one or more atoms replaced by an atom
having a different atomic mass or mass number. Examples of isotopes
that can be incorporated into the disclosed compounds include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively, e.g.,
.sup.3H, .sup.11C, and .sup.14C. Isotopically-labeled compounds can
be prepared by methods known in the art.
[0086] Some of the compounds disclosed herein may contain one or
more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The present
disclosure is meant to encompass the use of all such possible
forms, as well as their racemic and resolved forms and mixtures
thereof. The individual enantiomers can be separated according to
methods known in the art in view of the present disclosure. When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended that they include both E and Z geometric
isomers. All tautomers are intended to be encompassed by the
present disclosure as well.
[0087] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms in space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0088] The term "chiral center" refers to a carbon atom to which
four different groups are attached.
[0089] The terms "enantiomer" and "enantiomeric" refer to a
molecule that cannot be superimposed on its mirror image and hence
is optically active wherein the enantiomer rotates the plane of
polarized light in one direction and its mirror image compound
rotates the plane of polarized light in the opposite direction.
[0090] The term "racemic" refers to a mixture of equal parts of
enantiomers and which mixture is optically inactive.
[0091] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule.
[0092] The term "about," as used herein in connection with a
measured quantity, refers to the normal variations in that measured
quantity, as expected by the skilled artisan making the measurement
and exercising a level of care commensurate with the objective of
measurement and the precision of the measuring equipment.
[0093] The term "distal," as used herein refers to the direction of
the substrate's surface.
[0094] The term "proximal," as used herein refers to the direction
of the anti-infective agent.
[0095] The term "independently," as used herein in connection with
a radical, a molecule, an atom, or any other use is not dependent
from anything else. Non-limiting examples is "X.sub.1, X.sub.2,
X.sub.3, and X.sub.4 are independently non-existent or
independently selected from," meaning that X.sub.1 can exist, not
exist, or be selected from any of the molecules listed, regardless
of whether either of X.sub.2, X.sub.3, and X.sub.4 exist, do not
exist, or selected from any of the molecules listed, regardless of
whether X.sub.1, X.sub.2, X.sub.3, and X.sub.4 may be all the same,
whether X.sub.1, X.sub.2, X.sub.3, and X.sub.4 may all vary, or
whether some of X.sub.1, X.sub.2, X.sub.3, and X.sub.4 may be the
same and some may vary.
[0096] The term "radical," as used herein refers to the molecule
presented absent a hydrogen, thereby making the molecule available
to covalently bind to another molecule, for example to form a brush
polymer (in which the molecule structure represents the monomer
unit for the brush polymer).
[0097] In general, in one or more embodiments, the invention is
directed to a composition comprising a functionalized surface of a
substrate which is covalently bound to a durable anti-infective
agent, such as a quaternary phosphonium compound. In other
embodiments, the invention is directed to methods of preparing an
anti-infective composition by attaching a durable anti-infective
agent, such as a quaternary phosphonium compound to a
functionalized surface.
Anti-Infective Composition
[0098] Now referring to FIG. 1, substrate's surface 10, in
accordance with the present disclosure, is functionalized with a
functionalizing layer 20, either natively occurring on the surface
or obtained through a functionalizing agent, and an anti-infective
agent 30.
[0099] Substrates in accordance with the present invention include
but are not limited to any device(s) specific to an application by
an orthopedic, cardiovascular, plastic, dermatologic, general,
maxillofacial or neuro surgeon or physician including, but not
limited to, cardiovascular or vascular implant device such as
stents, replacement heart valves, replacement heart valve
components, leaflets, sewing cuffs, orifices, annuloplasty rings,
pacemakers, pacemaker polymer mesh bags, pacemaker leads, pacing
wires, intracardiac patches/pledgets, vascular patches, vascular
grafts, intravascular catheters, and defibrillators; tissue
scaffolds; non-woven meshes, woven meshes, and foams; orthopedic
implant devices including orthopedic trauma implants, joint
implants, spinal implants, plates, screws, rods, plugs, cages,
pins, nails, wires, cables, anchors, scaffolds, artificial joints
selected from hand joints, wrist joints, elbow joints, shoulder
joints, spine joints, hip joints, knee joints and ankle joints;
bone replacement, bone fixation cerclage and dental and
maxillofacial implants; spine implant devices including
intervertebral cages, pedicle screws, rods, connectors,
cross-links, cables, spacers, facet replacement devices, facet
augmentation devices, interspinous process decompression devices,
interspinous spacers, vertebral augmentation devices, wires,
plates, spine arthroplasty devices, facet fixation devices, bone
anchors, soft tissue anchors, hooks, spacing cages, and cement
restricting cages; diagnostic implants, biosensors, glucose
monitoring devices, external fixation devices, external fixation
implants, dental implants, maxillofacial implants, external facial
fracture fixation devices and implants, contact lenses, intraocular
implants, keratoprostheses; neurosurgical devices and implants
selected from shunts and coils; general surgical devices and
implants selected from drainage catheters, shunts, tapes, meshes,
ropes, cables, wires, sutures, skin and tissue staples, bone
anchors, soft tissue anchors, bum sheets, and vascular patches; and
temporary/non-permanent implants. Specifically, such devices
include an anti-infective agent to counter infective agents.
[0100] Surface 10 may be virtually any material which is amenable
to either being natively functionalized or to reacting with a
functionalizing agent to form a functionalizing layer 20. Examples
of such materials include metals, alloys, polymers, plastics,
ceramics, silicon, glass, composites, tissue and surfaces with
acidic protons, such as --OH or --NH groups.
[0101] Metal surfaces which may be employed include titanium and
its alloys, stainless steels, cobalt chrome alloys, aluminum,
nickel, molybdenum, tantalum, zirconium, hafnium, vanadium, tin,
magnesium, manganese, niobium, and alloys containing them; and the
like.
[0102] Polymer surfaces which may be employed include but not
limited to synthetic and/or natural polymer molecules such as:
polyamides, polyurethanes, polyureas, polyesters, polyketones,
polyimides, polysulfides, polysulfoxides, polysulfones,
polythiophenes, polypyridines, polypyrrols, polyethers,
polysiloxanes, polysaccharides, fluoropolymers, amides, imides,
polypeptides, polyethylene, polystyrene, polypropylene, liquid
crystal polymers, thermoplastics, bismalimidtriazine (BT) resins,
benzocyclobutene polymers, Ajinomoto Buildup Films (ABF), low
Coefficient of Thermal Expansion (CTE) films of glass and epoxies,
aramides, polyfluoroolefins, epoxies, silicones or composites
containing these polymers.
[0103] Functionalizing layer 20 may be any layer suitable for a
particular application. In some embodiments, functionalization
layer 20 may be native functionalization of the surface. In other
embodiments, functionalization layer 20 may be obtained through a
functionalizing agent or a plurality of functionalizing agents. In
yet other embodiments, functionalization layer 20 may be obtained
through a combination of native functionalization and due to a
functionalizing agent or a plurality of functionalizing agents. In
some embodiments the plurality functionalizing agents may be all
identical, all different, or some identical and some different.
Such functionalized surfaces can be used to covalently bond
subsequent material, such as a linker, a plurality of linkers,
layers of anti-infective agent or a plurality of anti-infective
agents.
[0104] Functionalization of substrate surfaces in accordance with
the present invention may be achieved in a variety of ways. For
example, it is possible to functionalize the surface of a polymer
with an oxide, alkoxide or mixed oxide-alkoxide layer using an
alkoxide precursor. In one embodiment, the polymer surface may be
coated with a continuous oxide adhesion layer, i.e., a layer that
is formed by a matrix of individual spread molecules that are
chemically bonded and linked to each other, as opposed to
individual molecules sparsely covering the surface. In this
embodiment metal alkoxide molecules are bonded together on at least
a portion of a polymer surface to form a continuous layer and then
converted to an oxide functionalizing layer. In some embodiments,
the functionalized surface is coated with a self assembled
monolayer (SAM) of functionalizing agent covalently bound to the
functionalized surface.
[0105] It is further possible to form an adherent coating layer
that may be further functionalized with adherent species by heating
a self-assembled layer of a functionalized phosphonic acid on the
native oxide surface of a substrate. This process, described in
detail in U.S. Patent Application Publication 2004/0023048, the
entirety of which is incorporated herein by reference, provides on
the native oxide surface of a material a multi-segmented,
phosphorous-based coating layer having a difunctional
organophosphonic acid-based segment bonded to the native oxide
surface of the material and a linking segment bonded to the
organophosphonic acid-based segment. In accordance with this
process, a phosphorous-based coating layer may be provided having a
plurality of functionalized organophosphonate moieties bonded to
the native oxide surface of a substrate by a phosphonate bond and a
plurality of one or more anti-infective coating moieties, each
coating moiety being bonded to the functional group of at least one
functionalized organophosphonate moiety. When bonded by means of a
metal complex, the metal complex is further characterized by being
derived from a metal reagent, preferably a metal alkoxide
reagent.
[0106] The surfaces of the substrates can be further functionalized
by a reaction with functionalizing agents such as phosphonic acids,
phosphoric acids, carboxylic acids, sulfonic acids, sulfinic acids,
phosphonates, phosphonic acid anhydrides, phosphoric acid esters,
phosphorus pentoxides, carboxylic acid esters, carboxylic
anhydrides, sulfonates, sulfonic acid anhydrides, sulfinic esters,
sulfinic anhydrides, alcohols, thiols, alkanes, alkenes, alkynes,
and diazo compounds. In some embodiments, a single functionalizing
agent is reacted to functionalize the surface. In other
embodiments, a plurality of functionalizing agents are reacted to
functionalize the surface.
[0107] It is yet further possible to covalently bond the
anti-infective agent to a functionalizing agent before covalently
bonding said functionalized anti-infective agent to a natively
functionalized surface, a functionalizing agent bound to a surface,
or a linker's distal end. In some embodiments, it is possible to
covalently bond a plurality of anti-infective agents to a plurality
of functionalizing agents before covalently bonding said plurality
of anti-infective agents to a natively functionalized surface,
plurality of functionalizing agents bound to the surface, or a
plurality of linker's distal ends. In some embodiments, the
plurality of anti-infective agents (e.g. quaternary phosphonium
compound) may be all identical, all different, or some identical
and some different.
[0108] Such functionalized surfaces can be used to covalently bond
subsequent material or layers thereof on the surface, which in the
present invention includes anti-infective agents, or linkers bound
to anti-infective agents. A plurality of one or more anti-infective
agents may be covalently bonded to the functionalized surface, the
functionalizing agents on the surface (which may vary), and the
linkers covalently bound to the surface (which may vary).
[0109] Anti-infective agents 30 that may be employed may include
bactericidal and bacteriostatic agents including disinfectants,
antiseptics and antibiotics. Disinfectants include active chlorine
such as hypochlorites, chloramines, dichloroisocyanurate and
trichloroisocyanurate, wet chlorine, chlorine dioxide and the like,
active oxygen, including peroxides, such as peracetic acid,
potassium persulfate, sodium perborate, sodium percarbonate and
urea perhydrate, iodine compounds such as iodpovidone, iodine
tincture, iodinated nonionic surfactants, concentrated alcohols
such as ethanol, n-propanol and isopropanol and mixtures thereof;
2-phenoxyethanol and 1- and 2-phenoxypropanols, phenolic compounds,
cresols, halogenated phenols, such as hexachlorophene, triclosan,
trichlorophenol, tribromophenol, pentachlorophenol, Dibromol and
salts thereof, cationic surfactants, including quaternary ammonium
cations such as benzalkonium chloride, cetyl trimethylammonium
bromide or chloride, didecyldimethylammonium chloride,
cetylpyridinium chloride, benzethonium chloride and others, and
non-quaternary compounds, such as chlorhexidine, glucoprotamine,
octenidine dihydrochloride etc.); strong oxidizers, such as ozone
and permanganate solutions; heavy metals and their salts, such as
colloidal silver, silver nitrate, mercury chloride, phenylmercury
salts, copper, copper sulfate, copper oxide-chloride and the like,
and strong acids (phosphoric, nitric, sulfuric, amidosulfuric,
toluenesulfonic acids) and alkalis (sodium, potassium, calcium
hydroxides).
[0110] Organic anti-infective moieties that may be added to a
functionalizing layer include quaternary ammonium alkylamines,
quaternary ammonium alkanols, usinic acid; cationic peptides such
as cecropins neutrophil defensins, polyphemusin, gramicidins,
thionins, histone-derived compounds, beta-hairpin, hemoglobin,
lactoferrin; anionic peptides such as neuropeptide precursors,
aromatic dipeptides, hemocyanin derivatives; other antimicrobial
peptides such as bacteriacins, cathelicidin, thrombocidin, and
histanins; antibodies, antibiotics, including tetracyclines,
amphenicols, penicillins, cephalosporins, monobactams, carbapenems,
sulfanomides, trimethoprim, macrolides, streptomycins, quinolones,
glycopeptides, polymyxins, lincosamides, streptogramins, imidazole
derivatives, nitrofuran derivatives; steroids; chlorhexidine;
phenol compounds including triclosan; epoxides; polymers and/or
polypeptides which have anti-infective properties.
[0111] Inorganic anti-infective coating layers that may be bonded
include silver, copper, zinc oxides, titanium oxides, zeolites,
silicates, calcium hydroxide, iodine, sodium hypochlorite,
sulfites, and sulfates.
[0112] Other anti-infective moieties include, quaternary
phosphonium compounds, such as
Triethyl(12-(methacryloyloxy)dodecyl)phosphonium bromide,
quaternary ammonium compounds, such as benzethonium chloride,
cetrimonium bromide, cetrimonium chloride,
dimethyldioctadecylammonium chloride, tetramethylammonium
hydroxide; quaternary ammonium alkyl dendrimers, silver, copper,
cationic species such as benzalkonium chloride, Bronidox; and
alkylated choline.
[0113] In some embodiments the anti-infective agent used is a
quaternary phosphonium compound comprising the radical of formula
I:
##STR00009##
wherein X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are independently
non-existent or independently selected from O, S, NR.sub.5,
.dbd.N--, PR.sub.6, and .dbd.P--; and wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected
from the group consisting of hydrogen, alkyls, substituted alkyl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, alkenyl, substituted cycloalkenyl, alkynyl,
substituted alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,
heteroalkyl, haloalkoxy, aryl, substituted aryl, aryloxy,
aralkyloxy, heteroaryl, substituted heteroaryl, heterocycle,
substituted heterocycle, amino, alkylamino, dialkylamino,
hydroxyalkylamino, (amino)alkyl, (alkylamino)alkyl,
(dialkylamino)alkyl, (cyano)alkyl), carboxamido,
(carboxamido)alkyl, methacrylate, methacrylamide, sulfonamide,
alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,
mercaptoalkyl, carboxy, carboxyalkyl, ureido, guanidine,
(heterocyclo)alkyl, (heteroaryl)alkyl.
[0114] In some embodiments, one of R.sub.1, R.sub.2, R.sub.3, or
R.sub.4 may bind the quaternary phosphonium compound either
directly to the functionalized surface, functionalizing agent, or
to the distal end of a linker. In other embodiments, more than one
of R.sub.1, R.sub.2, R.sub.3, or R.sub.4 may bind the quaternary
phosphonium compound either directly to a functionalized surface,
to a functionalizing agent, or to the distal end of a linker. In
some embodiments, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 may be the
same. In other embodiments, some of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 may be the same and some may be different.
[0115] In some embodiments, the anti-infective agent used is the
radical of the following structure or the monomer of the following
structure:
##STR00010##
wherein n2 is between 1 and 50.
[0116] In one embodiment, the anti-infective agent used is the
radical of the following structure or the monomer of the following
structure:
##STR00011##
[0117] In some embodiments, the anti-infective agent use is the
radical of the following structure or the monomer of the following
structure:
##STR00012##
wherein n3 is between 1 and 50.
[0118] In one embodiment, the anti-infective agent used is the
radical of the following structure or the monomer of the following
structure:
##STR00013##
[0119] Not all bactericidal and bacteriostatic agents may be used
as antiseptics on mammalian tissue as they may have adverse effects
thereon. It will be apparent to those skilled in the art that some
embodiments of the present invention may apply to uses that do not
involve contact of an anti-infective surface with mammalian tissue,
such as the fabric used for surgical barriers and the interior
surfaces of plumbing fixtures, building materials, ductwork, clean
rooms, etc. In such applications certain anti-infective agents may
be used, such as disinfectants, which would not be appropriate for
use in applications in which contact with mammalian tissue would be
contemplated or possible.
[0120] In some embodiments anti-infective agents used in
applications which involve possible contact with mammalian tissue
include but are not limited to quaternary phosphonium compounds
such as phosphonium methacrylate, quaternary ammonium compounds
such as choline and choline derivatives, quaternary ammonium
dendrimers, silver, copper, and cationic species. Quaternary
ammonium compounds ("quats") with long alkyl chains show proven
biocidal properties by disruption of cell walls. Nakagawa, Y., et
al., Appl. Environ. Microbial., 1984, 47:3, 513-518, incorporated
by reference herein in its entirety.
[0121] In certain embodiments, a linker, having a proximal end and
a distal end, may be present between the anti-infective agent and
the functionalized surface. In some embodiments, the linker may be
covalently bound to the anti-infective agent on its distal end. In
some embodiments, the linker may be covalently bound on its
proximal end to the functionalized surface, or a functionalizing
agent.
[0122] In some embodiments, a plurality of linkers, each having a
distal and a proximal end, may be covalently bound on their
proximal end to a plurality of functionalizing agents or directly
to a natively functionalized surface. In some embodiments, a second
amount of the plurality of functionalizing agents may remain not
bound to the plurality of linkers.
[0123] In some embodiments, a plurality of anti-infective agents
(such as a quaternary phosphonium compound) may be covalently bound
to a plurality of linkers (which are either directly bound to the
functionalized surface or are bound to a functionalizing agent). In
some embodiments, a second plurality of anti-infective agents (such
as a quaternary phosphonium compound) may be covalently bound to
the second plurality of functionalizing agents (which previously
were not bound to a plurality of linkers).
[0124] In certain embodiments, the plurality of linkers may be all
identical, all different, or some identical and some different. In
certain embodiments, the plurality of functionalizing agents may be
all identical, all different, or some identical and some different.
In certain embodiments, the plurality of anti-infective agents may
be all identical, all different, or some identical and some
different.
[0125] In some embodiments, the linker may be a radical of the
following:
##STR00014##
Wherein n1 is between 1 and 100 and R' is independently a hydrogen,
or an anti-infective agent (such as a quaternary phosphonium
compound).
[0126] In certain embodiments, the composition of the present
invention has the structure
##STR00015##
wherein n1 is between 1 and 100.
[0127] In certain embodiments, the anti-infective material may be
bound to the linker's distal end or to the functionalized surface
in a pattern or in a micropattern.
Method for Making an Anti-Infective Composition
[0128] Now referring to FIG. 2 illustrating a method 200 for making
an anti-infective composition according to an embodiment of the
invention. In one embodiment, the method comprises attaching an
anti-infective agent, such as a quaternary phosphonium compound, to
a functionalized surface, which is functionalized either natively
or with a functionalizing agent, in accordance with the methods
described hereinabove.
[0129] In some embodiments, attaching a quaternary phosphonium
compound to a functionalized surface comprises: introducing a
functionalized surface pursuant to block 202 (functionalized either
natively or with a functionalizing agent, in accordance with the
methods described hereinabove), optionally activating the
functionalized surface (not shown), polymerizing a linker, having a
proximal and a distal end, to form a covalent bond between the
activated functionalized surface and the proximal end of the linker
pursuant to block 204, and subsequently covalently binding the
distal end of the linker to the quaternary phosphonium compound
anti-infective agent (which may be functionalized and/or activated)
pursuant to block 206.
[0130] In other embodiments, as illustrated in FIG. 3 by method
300, the order may vary. For example, attaching a quaternary
phosphonium compound to a functionalized surface may comprise:
polymerizing a linker, having a proximal and a distal end, to form
a covalent bond between the anti-infective agent (e.g., quaternary
phosphonium compound) and the distal end of the linker pursuant to
block 302, introducing a functionalized surface pursuant to block
304 (functionalized either natively or with a functionalizing
agent, in accordance with the methods described hereinabove),
optionally activating the functionalized surface (not shown), and
subsequently covalently binding the proximal end of the linker to
the functionalized surface pursuant to block 306.
[0131] In yet other embodiments, attaching a quaternary phosphonium
compound to a functionalized surface may comprise: polymerizing a
linker, having a proximal and a distal end, to form a covalent bond
between the quaternary phosphonium compound and the distal end of
the linker; and simultaneously covalently binding the proximal end
of the linker to the functionalized surface.
[0132] In some embodiments, covalently bonding the linker may
comprise using Surface-Initiated Atom Transfer Radical
Polymerization (SI ATRP). In some embodiments polymerizing through
SI ATRP comprises: introducing an anti-infective agent (e.g.,
quaternary phosphonium compound), introducing an initiator (e.g.,
alkyl halide initiator), introducing a transition metal complex
(e.g., CuBr), introducing a ligand (e.g.,
N,N,N',N'',N'''-pentamethyldiethylenetriamine), and polymerizing
for a predetermined time to obtain a desired polymer brush
thickness.
[0133] In some embodiments, the ratio of the components in the
polymerization step is 2:1:1.4 of monomer:metalcomplex:ligand. In
some embodiments, the polymer brush thickness effects the
antibacterial efficacy. In some embodiments, the composition
disclosed herein shows greater than 99% reduction in a variety of
bacteria for prolonged duration.
[0134] It is believed that one of ordinary skill in the art can,
using the preceding description and the following illustrative
examples, make and utilize the compounds and articles of the
present invention and practice the claimed methods. The following
examples are given to illustrate the present invention. It should
be understood that the invention is not to be limited to the
specific conditions or details described in these examples.
Example 1: Synthesis of Antibacterial Polymer Brushes Via
Surface-Initiated Atom Transfer Radical Polymerization
(SI-ATRP)
[0135] Referring to FIG. 4, glass bead-blasted Ti-alloy
(Ti.sub.6V.sub.aAl) coupons 1 were cleaned and contacted with
phosphonoundecanol (PUL) in a 15 mM solution of PUL in ethanol,
thereby covalently binding the PUL to the titanium alloy, and
forming a Self Assembled Monolayer (SAM) of PUL on the titanium
alloy surface as illustrated by numeral 2. Step a is also referred
to, in some embodiments of the invention, as covalently binding a
functionalizing agent to the surface, where the functionalizing
agent in this instance is PUL.
[0136] The terminal hydroxyl group of the functionalizing agents 2
(PUL) were esterified with .alpha.-bromoisobutyryl bromide in
dichloromethane to form the composition illustrated by numeral 3.
Step b is also referred to, in some embodiments of the invention,
as activating the surface, thereby preparing it for subsequent
SI-ATRP of the linker (i.e. covalently binding the linker on its
proximal end to the surface) and ultimately of the anti-infective
(i.e. covalently binding the anti-infective agent to the linker on
its distal end).
[0137] The SI-ATRP of the anti-infective agent, quaternary
phosphonium compound phosphonium methaceylate illustrated by
numeral 4, was performed in water in the presence of CuBr and a
ligand N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDETA). The
ratio employed was [monomer]:[Cu]:[PMDETA]=2:1.0:1.4. However, one
of ordinary skill in the art will appreciate that the
polymerization time and amount of monomer used may vary to control
the thickness of the polymer brushes and the resulting
antibacterial properties of polymer brush surfaces. Step c is also
referred to, in some embodiments of the invention, as polymerizing
a linker onto the activated functionalized surface and covalently
binding the quaternary phosphonium compound to the linker.
[0138] FIG. 5 illustrates the prolonged antibacterial performance
of the composition prepared according to embodiments of the
invention. A composition comprising a radical of the quaternary
phosphonium compound of the following structure:
##STR00016##
have shown a 99.5% killing of S. aureus and a 98% of E. coli.
Additionally, a composition comprising a radical of the quaternary
phosphonium compound of the following structure:
##STR00017##
have shown a 98.9% killing of S. aureus and a 99% of E. coli.
[0139] The antibacterial activity and efficacy was shown to be
maintained even after aging the composition for one year as 6
illustrated in FIG. 6. Test coupons were placed in a modified ASTM
E2149 efficacy study using S. aureus (ATCC#29213) with an inoculum
level of 10.sup.6Colony Forming Units (CFU) per ml. After a 24 hour
exposure, the coupons were evaluated relative to untreated samples
for CFU/ml reduction from bacteria recovered directly from the
sample surface, and showed >95% killing at the surface for both
treatments. Specifically, a 95.2% killing was observed at the
titanium surface treated with the quaternary organophosphonate
compound of the following structure:
##STR00018##
No reduction in antibacterial efficacy was observed outside of the
margin of error of the experiment. In changes in the antibacterial
efficacy are likely due to variability in the treatment and the
essay rather that real reduction in efficacy over time.
Additionally, a 99.8% killing was observed at the titanium surface
treated with the quaternary organophosphonate compound of the
following structure:
##STR00019##
Similarly to the previous compound, no reduction in antibacterial
efficacy was observed outside of the margin of error of the
experiment. In changes in the antibacterial efficacy are likely due
to variability in the treatment and the essay rather that real
reduction in efficacy over time.
Example 2: Synthesis of a Quaternary Phosphonium Compound
Phosphonium Methacrylate
[0140] A 100 mL pressure tube was charged successively with
acetonitrile (18 mL), triethylphosphine (2.05 mL, 17.3 mmol) and
12-bromo-1-dodecanol (4.00 g, 15.1 mmol). The mixture was heated at
90.degree. C. for 2 days and concentrated in vacuum. The residue
was dissolved in dichloromethane (10 mL). The solution was added
drop-wise into ether (150 mL) with stirring to precipitate the
product. After stirring for an additional one hour, the
precipitates were collected by filtration, washed with ethanol, and
air-dried to afford the target compound, i.e.
Triethyl(12-hydroxydodecyl)phosphonium bromide (4.4 g, 65%).
[0141] To a solution of triethyl(12-hydroxydodecyl)phosphonium
bromide (4.00 g, 10.4 mmol) in chloroform (50 mL) was slowly added
methacryloyl chloride (1.07 mL, 11.0 mmol) at 0.degree. C. and the
mixture was stirred at room temperature for three days. Upon
completion, the mixture was diluted with dichloromethane. Sodium
carbonate (5 g) was added to the mixture. After stirring for 30
min, the mixture was filtered and concentrated in vacuum. The
residual oil was then passed through a fritted glass filter to
afford the product, i.e.
Triethyl(12-(methacryloyloxy)dodecyl)phosphonium bromide (4.7 g,
quantitative).
[0142] For simplicity of explanation, the embodiments of the
methods of this disclosure are depicted and described as a series
of acts. However, acts in accordance with this disclosure can occur
in various orders and/or concurrently, and with other acts not
presented and described herein. Furthermore, not all illustrated
acts may be required to implement the methods in accordance with
the disclosed subject matter. In addition, those skilled in the art
will understand and appreciate that the methods could alternatively
be represented as a series of interrelated states via a state
diagram or events.
[0143] In the foregoing description, numerous specific details are
set forth, such as specific materials, dimensions, processes
parameters, etc., to provide a thorough understanding of the
present invention. The particular features, structures, materials,
or characteristics may be combined in any suitable manner in one or
more embodiments. The words "example" or "exemplary" are used
herein to mean serving as an example, instance, or illustration.
Any aspect or design described herein as "example" or "exemplary"
is not necessarily to be construed as preferred or advantageous
over other aspects or designs. Rather, use of the words "example"
or "exemplary" is intended to present concepts in a concrete
fashion. As used in this application, the term "or" is intended to
mean an inclusive "or" rather than an exclusive "or". That is,
unless specified otherwise, or clear from context, "X includes A or
B" is intended to mean any of the natural inclusive permutations.
That is, if X includes A; X includes B; or X includes both A and B,
then "X includes A or B" is satisfied under any of the foregoing
instances. In addition, the articles "a" and "an" as used in this
application and the appended claims should generally be construed
to mean "one or more" unless specified otherwise or clear from
context to be directed to a singular form. Reference throughout
this specification to "an embodiment", "certain embodiments", or
"one embodiment" means that a particular feature, structure, or
characteristic described in connection with the embodiment is
included in at least one embodiment. Thus, the appearances of the
phrase "an embodiment", "certain embodiments", or "one embodiment"
in various places throughout this specification are not necessarily
all referring to the same embodiment.
[0144] Although certain presently preferred embodiments of the
invention have been specifically described herein, it will be
apparent to those skilled in the art to which the invention
pertains that variations and modifications of the various
embodiments shown and described herein may be made without
departing from the spirit and scope of the invention. Accordingly,
it is intended that the invention be limited only to the extent
required by the appended claims and the applicable rules of law.
All references cited herein are incorporated fully by
reference.
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