WO2011056545A2 - Liquides ioniques antimicrobiens - Google Patents

Liquides ioniques antimicrobiens Download PDF

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WO2011056545A2
WO2011056545A2 PCT/US2010/054048 US2010054048W WO2011056545A2 WO 2011056545 A2 WO2011056545 A2 WO 2011056545A2 US 2010054048 W US2010054048 W US 2010054048W WO 2011056545 A2 WO2011056545 A2 WO 2011056545A2
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linear
certain embodiments
ionic liquid
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WO2011056545A3 (fr
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Mark W. Grinstaff
Michel Wathier
George A. O'toole
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Boston University
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Boston University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • VRE Enterococcus
  • Fungi are also important pathogens. Invasive fungal infections pose a serious threat to individuals with underlying medical issues such as HIV. As is the case with bacteria, fungal resistance to frontline antifungal compounds, such as azoles, is also a significant problem. Furthermore, some current antifungals have limitations in regards to their systemic use or their activity versus pathogens such as Aspergillus. Thus, the need to develop new antifungal compounds is also urgent. The increasing concern about resistance is reflected in such documents as the Public Health Action Plan to combat Antimicrobial Resistance issued by the CDC. Despite the pressing need for new antimicrobial compounds, there are few new broad spectrum and Gram-negative-targeted compounds in the pipeline.
  • compositions, formulations, and use of ionic liquids as antimicrobial agent e.g. as antibacterial and/or antifungal agents.
  • the ionic liquids can be paired with one or more singly charge species or with one or more multi-charged species.
  • the method involves the use of one or more ionic liquids as an antimicrobial agent.
  • the one or more ionic liquids may be used in combination with one or more non-ionic liquid antimicrobial agents.
  • the ionic liquids can be delivery to a patient via oral, iv, ip, or topical treatment.
  • Another aspect of the invention relates to the use of the ionic liquids to coat the surface of a medical implant or device and thus prevent a microbial infection and/or biofilm formation.
  • Figure 1 depicts a table of ionic liquids.
  • Figure 2 depicts a scheme showing one approach to the synthesis of an ionic liquid.
  • Figure 3 depicts a scheme showing one approach to the synthesis of an ionic liquid.
  • Figure 4 depicts additional [A] multi-cationic and [B] multi-anionic architectures of the invention.
  • Figure 5 depicts selected approaches to forming cationic and anionic components of the invention.
  • Figures 6A-6C depicts cytotoxicity test results of Dex C-10- and PBS-treated corneas in mouse keratitis model.
  • Figures 7A-7C shows the efficacy of Dex C-10 against P. aeruginosa in mouse keratitis mo del .
  • Figure 8 shows the efficacy of Dex C-10 against S. Aureus in an interperitoneal mouse model.
  • Figure 9 shows the efficacy of Dex C-10 against P. aeruginosa in an interperitoneal mouse model.
  • the ionic liquids disclosed herein can find various applications in the
  • the ionic liquids of the present invention can be used in the treatment of microbial infections.
  • one aspect of the present invention relates to methods which generally include administration of an effective amount of an ionic liquid, or a pharmaceutical composition thereof, to an individual in need thereof.
  • the ionic liquids can also be used with medical devices to prevent implant infections. They can also be used in non-medical applications for example in marine applications to prevent biofouling of ships, boats, or
  • the ionic liquids are multicationic or
  • Ionic liquids are "salt-like" materials that are liquid at relatively low temperatures, e.g., less than 400 °C.
  • Ionic liquids are typically composed of a mono-cationic organic compound, such as a compound based on the structure of a imidazolium, pyridinium, pyrrolidinium, phosphonium, ammonium or sulfonium, and an inorganic or organic anion, such as a alkyl sulfate, tosylate, methansulfonate, hexafluorophosphate, tetrafluoroborate, halide, or carboxylic acid.
  • a mono-cationic organic compound such as a compound based on the structure of a imidazolium, pyridinium, pyrrolidinium, phosphonium, ammonium or sulfonium
  • an inorganic or organic anion such as a alkyl sulfate, tosylate, methansulfonate, hexafluorophosphate, tetrafluoroborate, halide, or carboxylic acid.
  • the prototypical ionic liquid of l-ethyl-3-methylimidazolium ethyl sulfate has a melting point of less than -20 °C; whereas, sodium chloride has a melting point of 801 °C.
  • the strong ionic interaction between these mono-cations and mono-anions results in low vapor pressure, non-flammable materials with high thermal, mechanical, and electrochemical stability. More recently, a dicationic organic compound with two mono- anions has been reported.
  • Ionic liquids have found uses in a wide range of applications including, but not limited to, lubricants, MADLI-TOF matrices, protein crystallization matrices, solvents for heterogeneous catalysis, solvents for homogeneous catalysis, solvent for organic synthesis, solvents for desulfurization, liquid crystals, thermal fluids, fuel cells, sensors, metal finishers, materials for gas separations, distillation fluids, extraction mediums, and membrane technology.
  • the phosphonium based ionic liquids such as tetradecyl(tributyl)phosphonium chloride, see Figure 3, are of wide-spread interest for applications given their favorable material properties such as low vapor pressure and high thermal, mechanical, and electrochemical stability.
  • These ionic liquids are prepared by nucleophilic addition of tertiary phosphines to haloalkanes ( Figure 3, eqn. 1) and as such a number of mono and di- substituted alkyl compounds have been prepared of that general structure ⁇ Green Chemistry
  • the ionic liquid described below can have compositions that possess single cation and single anion as well as multi-cationic and multi-anionic centers, such as those described in International Patent Application Publication No. WO 07/124397 to Grinstaff et al. ; hereby incorporated by reference in its entirety.
  • the ionic liquids of the invention include a plurality of organic cations that contain independently for each occurrence a heterocycle selected from the group consisting of azathiozoles, pyrazoles, thiazoles, isothiazoles, oxothiazoles, oxazines, oxazo lines, oxazoboroles, dithioazoles, triazoles, selenozoles, oxaphopholes, pyrroles, boroles, furans, thiophenes, phospholes, pentazoles, indoles, indolines, oxazoles, isoozazoles, isotriazoles, tetrazoles, benzofurans, dibenzofurans, benzothiophenes, dibenzothiophenes, thiadiazoles, pyrimidines, pyrazines, pyridazines, piperazines, pipidines, morpholenes,
  • Acyclic organic cations are also included in the invention; for example, amines such as amidines, imines, guanidines, phosphines such as phosphinimines, arsines, stibines, ethers, thioethers, and selenoethers.
  • amines such as amidines, imines, guanidines
  • phosphines such as phosphinimines, arsines, stibines, ethers, thioethers, and selenoethers.
  • the ionic liquids of the invention include a plurality of organic and inorganic anions that contain independently for each occurrence a carboxylic acid, sulfonic acid, tetrafluoroborate, hexafluorophosphate, bis- trifluoromethane-sulfonimide, and derivatives thereof.
  • Additional anionic species of the invention include borates, phosphates, nitrates, sulfates, triflates, antimonates,
  • One aspect of the invention relates to the ionic liquids formed via the ionic liquid reagents as described herein.
  • one aspect of the invention relates to an ionic liquid comprising an anionic component and a cationic component, wherein:
  • said anionic component is Y or X-[Y] m ;
  • n 1100 inclusive
  • X is selected from the group consisting of linear or branched alkanes, linear or branched alkenes, linear or branched alkynes, monocyclic or polycyclic aromatics, monocyclic or polycyclic heteroaromatics, linear or branched polysilanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyalkylene oxides, linear or branched polysiloxanes, linear or branched polyacrylates, linear or branched polyacetals, linear or branched acrylics, linear or branched cellulosics, linear or branched polyethers, linear or branched halogenated polyethers, linear or branched halocarbons, linear or branched polyamides, linear or branched polycarbonates, linear or branched polyethylenes, linear or branched polypropylenes, linear or branched polystyrenes, and linear or branched polyurethanes
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafiuoroborates, hexafluorophosphates,
  • bis-trifluoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is W-[Z] n ;
  • n 1-100 inclusive
  • W is absent, or selected from the group consisting of linear or branched alkanes, linear or branched alkenes, linear or branched alkynes, monocyclic or polycyclic aromatics, monocyclic or polycyclic heteroaromatics, linear or branched polysilanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyalkylene oxides, linear or branched polysiloxanes, linear or branched polyacrylates, linear or branched polyacetals, linear or branched acrylics, linear or branched cellulosics, linear or branched polyethers, linear or branched halogenated polyethers, linear or branched halocarbons, linear or branched polyamides, linear or branched polycarbonates, linear or branched polyethylenes, linear or branched polypropylenes, linear or branched polystyrenes, and linear or branched polyurethan
  • R-N- provided that at least one Z is selected from the group consisting of R
  • R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formyl, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate,
  • R is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate, thioisocyanate, azide, acyl azide, hydrazine
  • R is a bond to W; and at least one R is alkylene-R -R .
  • the present invention relates to the aforementioned ionic liquid, wherein said anionic component is Y.
  • the present invention relates to the aforementioned ionic liquid, wherein Y is selected from the group consisting of [CH3CO2] “1 , [CI] “1 , [CIO4] “1 , [Br] 1 , [PFe] 1 , [BF4] “1 , [B(CN) 4 ] 1 , [AICL,] "1 , [AI2CI7] “1 , [CuClz] "1 , [Cu 2 Cl 3 ] [ZnCl 3 ] [ZnCU] 2 ,
  • the present invention relates to the aforementioned ionic liquid, wherein said anionic component is X-[Y] m .
  • the present invention relates to the aforementioned ionic liquid, wherein Y is selected, independently for each occurrence, from the group consisting of -[SO,] "1 , -[S0 4 ]- 2 , -[SbFs] 1 , -[N(CN)] 1 , -[CF 2 S(0) 2 NS(0) 2 CF 3 ] 1 , -[PF5] 1 , - [BiCN ⁇ and - BF,]- 1 .
  • the present invention relates to the aforementioned ionic liquid, wherein Y is -[C0 2 ] _1 .
  • the present invention relates to the aforementioned ionic liquid, wherein m is 2-20 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein m is 2-10 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, where m is 2, 3 or 4.
  • the present invention relates to the aforementioned ionic liquid, wherein X is selected, independently for each occurrence, from the group consisting of linear or branched alkanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyethers, linear or branched polyacrylic acids, linear or branched polyamides, and polyether triamines, or a combination thereof.
  • the present invention relates to the aforementioned ionic liquid, wherein X is A, AO(AO) p A, or ANH(ANH) P A; A is, independently for each occurrence, -(CQ 2 ) P -; Q is, independently for each occurrence, hydrogen or methyl; and p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein X is C(R')(A) 3 , C(R)[(AO) p A] 3 , C(R)[(ANH) P A] 3 , N(A-) 3 , N[(AO) p A] 3 , or N[(ANH) P A] 3 ;
  • A is, independently for each occurrence, -(0(3 ⁇ 4) ⁇ -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive; and
  • R' is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehy
  • the present invention relates to the aforementioned ionic liquid, wherein X is C(ACH 2 ) 4 , C[(AO) p A] 4 , C[(ANH) P A] 4 , (A) 2 N(AO) p AN(A) 2 , or (A) 2 N(ANH) P AN(A) 2 ;
  • A is, independently for each occurrence, -(CQ 2 ) P -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein W is selected, independently for each occurrence, from the group consisting of linear or branched alkanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyethers, linear or branched polyacrylic acids, linear or branched polyamides, polyether triamines, or a combination thereof.
  • the present invention relates to the aforementioned ionic liquid, wherein W is A, AO(AO) p A, or ANH(ANH) P A; A is, independently for each occurrence, -(CQ 2 ) P -; Q is, independently for each occurrence, hydrogen or methyl; and p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein W is C(R')(A) 3 , C(R)[(AO) p A] 3 , C(R)[(ANH) P A] 3 , N(A) 3 , N[(AO) p A] 3 , or N[(ANH) P A] 3 ;
  • A is, independently for each occurrence, -(0(3 ⁇ 4) ⁇ -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40
  • R' is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, iso
  • the present invention relates to the aforementioned ionic liquid, wherein W is C(ACH 2 ) 4 , C[(AO) p A] 4 , C[(ANH) p A] 4 , (A) 2 N(AO) p AN(A) 2 , or (A) 2 N(ANH) P AN(A) 2 ;
  • A is, independently for each occurrence, -(CQ 2 ) P -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein X and W are the same.
  • the present invention relates to the aforementioned ionic liquid, wherein n is 2-20 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein n is 2-10 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, where n is 2, 3, or 4.
  • the present invention relates to the aforementioned ionic liquid, wherein Z is selected, independently for each occurrence, from the group consisting
  • the present invention relates to the aforementioned ionic liquid, wherein Z is selected, independently
  • the present invention relates to the aforementioned ionic liquid, wherein R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl or alkylene-R B -R c .
  • R is alkyl, aralkyl, aryl, heteroaryl or a macromolecule.
  • R c is alkyl.
  • R c is aralkyl.
  • R is an enzyme.
  • R is an enzyme with one or more pendant amines, thiols and/or alcohols.
  • R is an enzyme.
  • R c is an enzyme with one or more pendant amines.
  • the present invention relates to the aforementioned ionic liquid, wherein R c is lysozyme.
  • the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ]k-; wherein k is 10- 30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -,
  • Another aspect of the invention relates to an ionic liquid comprising an anionic component and a cationic component, wherein:
  • said anionic component is Y;
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafluoroborates, hexafluorophosphates,
  • said cationic component is Z
  • Z is selected, independently for each occurrence, from the group consisting of
  • R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succimmidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate,
  • R B is oxo, arylene, heteroarylene or heterocyclylene
  • R c is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succimmidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate, thioisocyanate, azide, acyl azide, hydra
  • the present invention relates to the aforementioned ionic liquid, wherein said anionic component is Y.
  • the present invention relates to the aforementioned ionic liquid, wherein Y is selected from the group consisting of [CH 3 CO 2 ] “1 , [CI] “1 , [CIO 4 ] “1 , [Br] ⁇ [I] "1 , [SO4] “2 , [CH3SO3] "1 , [SbF 6 ]- ⁇ [N(CN) 2 ]- ⁇ [CF 3 S(0)2NS(0) 2 CF 3 ]- 1 , [PF 6 ] ⁇ [BF4] 1 , [B(CN) 4 ]- 1 , [AICI 4 ]- 1 , [A Clv]- 1 , [CuCl 2 ] _1 , [CujClj]- 1 , [ZnCy 1 , [ZnCU] "2 ,
  • the present invention relates to the aforementioned ionic liquid, wherein Z is selected, independently for each occurrence, from the group consisting
  • the present invention relates to the aforementioned ionic liquid, wherein Z is R- %P-R
  • the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ]k-; wherein k is 10- 30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CFI 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and
  • Another aspect of the invention relates to an ionic liquid comprising an anionic component and a cationic component, wherein:
  • said anionic component is Y;
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafluoroborates, hexafluorophosphates,
  • bis-trifluoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is Z
  • R 1 is alkyl
  • R 2 is alkyl
  • R 3 is alkyl
  • R 4 is alkylene-R 5 ; alcohol, CN, and
  • R 6 is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate, thioisocyanate, azide, acyl azide, hydrazin
  • the present invention relates to the aforementioned ionic liquid, wherein Y is selected from the group consisting of [CH3CO2] “1 , [CI] "1 , [CIO4] “1 , [Br]
  • the present invention relates to the aforementioned ionic liquid, wherein R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein R 1 is butyl or hexyl.
  • the present invention relates to the aforementioned ionic liquid, wherein R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein R 2 is butyl or hexyl.
  • the present invention relates to the aforementioned ionic liquid, wherein R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein R 3 is butyl or hexyl.
  • the present invention relates to the aforementioned ionic liquid, wherein R 4 is selected from the group consisting of -[CH2]kR-5; wherein k is 1 -30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein R 4 is selected from the group consisting of -[CH 2 ] k R 5 ; wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid, wherein alkylene is selected from the group consisting of -[CH 2 ] k R 5 ; wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned ionic liquid, wherein R 4 is -CH 2 R 5 , -CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 CH 2 R 5 ,
  • the present invention relates to the aforementioned ionic liquid, wherein R 4 is -CH 2 CH 2 CH 2 R 5 .
  • the present invention relates to the aforementioned ionic
  • the present invention relates to
  • present invention relates to the aforementioned ionic liquid, wherein R In certain embodiments, the present invention relates to
  • the present invention relates to the aforementioned ionic
  • the present invention relates to a liquid, wherein R is .
  • the present invention relates to the aforementioned ionic liquid, wherein R 6 is alkyl, aralkyl or aryl.
  • the present invention relates to the aforementioned ionic
  • the present invention relates to the aforementioned ionic liquid, wherein the ionic liquid reagent is
  • an ionic liquid is a small molecule compound that can be easily coupled to another small molecule or macromolecule (such as an enzyme) to afford an ionic liquid or ionic viscoelastic.
  • the reaction between the ionic liquid and the small molecule or macromolecule is well-defined and high yielding (e.g. greater than about 60%); is thermodynamically favored; can be performed in one-step; and
  • B3806550.2 - 19 - Atty. Docket No. BUX-008.25 comprises an ionic liquid which is stable enough to be stored (and shipped) prior to use. As such the type of coupling chemistry that can be used for the ionic liquid are limited.
  • One example of coupling chemistry which can be used with ionic liquids is click chemistry as described in Kolb et al. (Angew. Chem. Int. Ed. Engl. 2001, 40, 2004-2021).
  • One example of a click chemistry reaction is the Azide-Alkyne Huisgen Cycloaddition, which is a 1 ,3-dipolar cycloaddition between an azide and a terminal or internal alkyne to give a 1 ,2,3-triazole.
  • an ionic liquid bearing a terminal alkyne (phosphonium (trihexyl) pentyne) was reacted with an azide-containing small molecule ((S)-3-azidopropane-l,2- diol) to form a triazole-containing ionic liquid.
  • ionic liquids One example of coupling chemistry which can be used with ionic liquids is amide bond formation, such as via an active N-hydroxysuccinimide (NHS) ester or acyl chloride.
  • NHS N-hydroxysuccinimide
  • the ionic liquid can possess one or more electrophilic groups (e.g., NHS, acyl chloride, isocynate) for coupling with a nucleophilic small molecule or macromolecule.
  • NHS activated esters are stable enough to be purified and stored for future reactions facilitating wide-spread use of NHS activated ester "reagents" by many types of scientists. The success of this reaction is exemplified through its application in
  • an ionic liquid bearing an NHS activate ester (Figure 4; 2, IL-OSu) was prepared and reacted with a series of electronically and structurally different nucleophiles including alkyl, benzyl, and aromatic amines, an alkyl thiol, and lysozyme.
  • Figure 4 1, IL-OSu
  • nucleophiles including alkyl, benzyl, and aromatic amines, an alkyl thiol, and lysozyme.
  • the general coupling procedure involved dissolving compound 2 (1.2 eq.) in dry dichloromethane followed by the addition of triethylamine (1.2 eq.) and the appropriate amine or thiol nucleophile (1 eq.) under nitrogen. The mixture was stirred for 12 hrs at room temperature, concentrated, dried and analyzed by NMR and HR-mass spectrometry. The primary alkyl and benzyl amines reacted with 2 in good to high yield (greater than about 80%). As expected, a lowering of the amine pKa either through para substitution of benzyl amine with fluorine or the use of aniline instead of benzyl amine reduced the coupling yield.
  • the reaction was not limited to amines, an alkyl thiol reacted readily with 2 in high yield to afford the thioester linkage and the
  • One aspect of the invention relates to a method of preparing an ionic liquid comprising the step of:
  • the ionic liquid reagent comprises an anionic component and a cationic component; said anionic component is Y or X-[Y] m ;
  • n 1100 inclusive
  • X is selected from the group consisting of linear or branched alkanes, linear or branched alkenes, linear or branched alkynes, monocyclic or polycyclic aromatics, monocyclic or polycyclic heteroaromatics, linear or branched polysilanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyalkylene oxides, linear or branched polysiloxanes, linear or branched polyacrylates, linear or branched polyacetals, linear or branched acrylics, linear or branched cellulosics, linear or branched polyethers, linear or branched halogenated polyethers, linear or branched halocarbons, linear or branched polyamides, linear or branched polycarbonates, linear or branched polyethylenes, linear or branched polypropylenes, linear or branched polystyrenes, and linear or branched polyurethanes
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafiuoroborates, hexafluorophosphates,
  • bis-trifluoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is W-[Z] n ;
  • n 1-100 inclusive
  • Z is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl,
  • R-N- provided that at least one Z is selected from the group consisting of R
  • R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate,
  • R A comprises at least one electrophile, nucleophile, dipolarophile, 1,3-dipole, diene or dieneophile;
  • R is a bond to W; and at least one R is alkylene-R A .
  • the present invention relates to the aforementioned method, wherein said anionic component is Y.
  • the present invention relates to the aforementioned method wherein Y is selected from the group consisting of [CH3CO2] “1 , [CI] “1 , [Br] “1 , [I] “1 , [S0 4 r 2 , [CH3SO3] “1 , [BF 4 ] _1 ,
  • the present invention relates to the aforementioned method, wherein said anionic component is X-[Y] m .
  • the present invention relates to the aforementioned method, wherein Y is selected, independently for each occurrence, from the group consisting of -[CO2]- 1 , -[SO3]- 1 , -[S0 4 ]- 2 , -[SbFs] "1 , -[N(CN)]- 1 , -[PF5] "1 , - [BiCN ⁇ . and -tBFaT 1 .
  • the present invention relates to the aforementioned method, wherein Y is -[C0 2 ] _1 .
  • the present invention relates to the aforementioned method, wherein m is 2-20 inclusive. In certain embodiments, the present invention relates to the aforementioned method, wherein m is 2-10 inclusive In certain embodiments, the present invention relates to the aforementioned method, where m is 2, 3 or 4.
  • the present invention relates to the aforementioned method, wherein X is selected, independently for each occurrence, from the group consisting of linear or branched alkanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyethers, linear or branched polyacrylic acids, linear or branched polyamides, and polyether triamines, or a combination thereof.
  • the present invention relates to the aforementioned method, wherein X is A, AO(AO) p A, or ANH(ANH)pA; A is, independently for each occurrence, -(CQ 2 )p-; Q is, independently for each occurrence, hydrogen or methyl; and p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned method, wherein X is C(R')(A) 3 , C(R')[(AO) p A] 3 , C(R')[(ANH) P A] 3 , N(A-) 3 , N[(AO) p A] 3 , or
  • A is, independently for each occurrence, -(CQ2) P -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive; and
  • R' is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxy
  • the present invention relates to the aforementioned method, wherein X is C(ACH 2 ) 4 , C[(AO) p A] 4 , C[(ANH)pA] 4 , (A) 2 N(AO) p AN(A) 2 , or
  • the present invention relates to the aforementioned method, wherein W is selected, independently for each occurrence, from the group consisting of linear or branched alkanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyethers, linear or branched polyacrylic acids, linear or branched polyamides, polyether triamines, or a combination thereof.
  • the present invention relates to the aforementioned method, wherein W is A, AO(AO) p A, or ANH(ANH) p A; A is, independently for each occurrence, -(CQ 2 ) P -; Q is, independently for each occurrence, hydrogen or methyl; and p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned method, wherein W is C(R)(A) 3 , C(R)[(AO) p A] 3 , C(R)[(ANH) P A] 3 , N(A) 3 , N[(AO) p A] 3 , or N[(ANH) P A] 3 ;
  • A is, independently for each occurrence, -(CQ 2 ) P -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive; and
  • R is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide
  • the present invention relates to the aforementioned method, wherein W is C(ACH 2 ) 4 , C[(AO) p A] 4 , C[(ANH)pA] 4 , (A) 2 N(AO) p AN(A) 2 , or
  • the present invention relates to the aforementioned method, wherein X and W are the same.
  • the present invention relates to the aforementioned method, wherein n is 2-20 inclusive. In certain embodiments, the present invention relates to the aforementioned method, wherein n is 2-10 inclusive In certain embodiments, the present invention relates to the aforementioned method, where n is 2, 3, or 4.
  • the present invention relates to the aforementioned method, wherein Z is selected, independently for each occurrence, from the group consisting of
  • CH(OAH)(AOH), -AH)Ph, and -Si(OH)(AH) A is, independently for each occurrence,
  • the present invention relates to the aforementioned method, wherein Z is selected, independently for each occurrence, hydrogen or methyl; and r is, independently for each occurrence, 0-40 inclusive.
  • Z is selected, independently for each occurrence, hydrogen or methyl
  • the present invention relates to the aforementioned method, wherein R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl or alkylene-R A .
  • the present invention relates to the aforementioned method, wherein R A is an electrophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is a carboxyl-containing electrophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an N-hydroxysuccinimide (NHS) ester, acyl chloride or isocynate. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an N- hydroxysuccinimide (NHS) ester.
  • NHS N-hydroxysuccinimide
  • the present invention relates to the aforementioned method, wherein R A is a nucleophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an amine or thiol. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an alkyl amine. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an alkyl thiol. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aralkyl amine. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aralkyl thiol. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aryl amine. In certain embodiments, the present invention relates to the aforementioned method, wherein R is an aryl thiol.
  • the present invention relates to the aforementioned method, wherein R A is an enzyme. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an enzyme with one or more pendant amines. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is lysozyme.
  • the present invention relates to the aforementioned method, wherein R A is a dipolarophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is alkynyl.
  • the present invention relates to the aforementioned method, wherein R A is a 1,3-dipole. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is azidyl. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is acyl azidyl.
  • the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -[CH 2 ] k -; wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the
  • alkylene is selected from the group consisting of -[CH 2 ]k-; wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -,
  • Another aspect of the invention relates to a method of preparing an ionic liquid comprising the step of:
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafluoroborates, hexafluorophosphates,
  • bis-trifluoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is Z
  • Z is selected, independently for each occurrence, from the group consisting of
  • ⁇ is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate,
  • R A comprises at least one electrophile, nucleophile, dipolarophile, 1,3-dipole, diene or dieneophile;
  • At least one R is alkylene-R A .
  • the present invention relates to the aforementioned method, wherein said anionic component is Y.
  • the present invention relates to the aforementioned method, wherein Y is selected from the group consisting of [CH 3 CO 2 ] “1 , [CI] “1 , [Br] “1 , [I] “1 , [S0 4 ] “2 , [CH 3 SO 3 ] “1 , [CF 3 S(0) 2 NS(0) 2 CF 3 ] 1 , [PFe] 1 , [BF 4 ] "1 ,
  • the present invention relates to the aforementioned method, wherein Z is selected, independently for each occurrence, from the group consisting of
  • the present invention relates to the aforementioned method, wherein R is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl or alkylene-R A .
  • the present invention relates to the aforementioned method, wherein R A is an electrophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is a carboxyl-containing electrophile. In certain
  • the present invention relates to the aforementioned method, wherein R A is an N-hydroxysuccinimide (NHS) ester, acyl chloride or isocynate. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an N- hydroxysuccinimide (NHS) ester.
  • the present invention relates to the aforementioned method, wherein R A is a nucleophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an amine or thiol. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an alkyl amine. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an alkyl thiol. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aralkyl amine. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aralkyl thiol. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aryl amine. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an aryl thiol.
  • the present invention relates to the aforementioned method, wherein R A is an enzyme. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is an enzyme with one or more pendant amines, thiols and/or alcohols. In certain embodiments, the present invention relates to the
  • R A is an enzyme with one or more pendant amines.
  • the present invention relates to the aforementioned method, wherein R A is lysozyme.
  • the present invention relates to the aforementioned method, wherein R A is a dipolarophile. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is alkynyl.
  • the present invention relates to the aforementioned method, wherein R A is a 1,3-dipole. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is azidyl. In certain embodiments, the present invention relates to the aforementioned method, wherein R A is acyl azidyl.
  • the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -[CH 2 ] k -; wherein k is 1-30
  • the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the
  • alkylene is selected from the group consisting of -[CH 2 ] k -; wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -,
  • Another aspect of the invention relates to a method of preparing an ionic liquid comprising the step of:
  • the ionic liquid reagent comprises an anionic component and a cationic component; said anionic component is Y;
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafiuoroborates, hexafluorophosphates,
  • bis-trifiuoromethane-sulfonimides borates, phosphates, nitrates, sulfates, trifiates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is Z
  • R is alkyl
  • R 2 is alkyl
  • R 3 is alkyl
  • R 4 is alkylene-R 5 ;
  • R 6 is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate, thioisocyanate, azide, acyl azide, hydrazin
  • the present invention relates to the aforementioned method, wherein Y is selected from the group consisting of [CH 3 CO 2 ] “1 , [CI] “1 , [CIO 4 ] “1 , [Br] “1 , [I] "1 , [S0 4 ] “2 , [CH3S03] “1 , [SbF 6 ] “ ⁇ [N(CN) 2 ]- ⁇ [CF 3 S(0) 2 NS(0) 2 CF 3 ]- 1 , [PF 6 ] ⁇ [BF4] "1 ,
  • the present invention relates to the aforementioned method, wherein R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned method, wherein R 1 is butyl or hexyl.
  • the present invention relates to the aforementioned method, wherein R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned method, wherein R 2 is butyl or hexyl.
  • the present invention relates to the aforementioned method, wherein R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned method, wherein R 3 is butyl or hexyl.
  • the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -[CH 2 ] k R 5 ; wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned method, wherein alkylene is selected from the group consisting of -[CH 2 ] k R 5 ; wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the
  • alkylene is selected from the group consisting of - [CH 2 ] k R 5 ; wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned method, wherein R 4 is -CH 2 R 5 , -CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 CH 2 R 5 ,
  • the present invention relates to the aforementioned method, wherein R 4 is -CH 2 CH 2 CH 2 R 5 .
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • ionic liquid reagent is or
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the second chemical group is an amine. In certain embodiments, the present invention relates to the aforementioned method and the attendant definitions, wherein the second chemical group is a thiol.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the ionic liquid reagent is reacted with a small molecule. In certain embodiments, the present invention relates to the aforementioned method and the attendant definitions, wherein the ionic liquid reagent is reacted with a small molecule; and the small molecule is an alkyl amine, aryl amine, aralkyl amine, alkyl thiol, aryl thiol or aralkyl thiol.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the ionic liquid reagent is reacted with a
  • the present invention relates to the
  • the ionic liquid reagent is reacted with a macromolecule; and the macromolecule is an enzyme.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the ionic liquid reagent is reacted with a macromolecule; and the macromolecule is lysozyme.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the reaction is acid-catalyzed or base-catalyzed.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the reaction is selected from the group consisting of SN2 displacement reactions, 1 ,2- or 1 ,4-addition reactions, 1 ,3-dipolar cycloaddition reactions, Diels- Alder reactions, condensation reactions (such as esterification and amidation), acylation reactions, ring-forming reactions, and metathesis reactions.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the reaction is a condensation reaction.
  • the present invention relates to the aforementioned method and the attendant definitions, wherein the reaction is a 1 ,3-dipolar cycloaddition.
  • ionic liquid reagents as used in the methods described above.
  • one aspect of the invention relates to an ionic liquid reagent comprising an anionic component and a cationic component, wherein:
  • said anionic component is Y or X-[Y] m ;
  • m 1 - 100 inclusive
  • X is selected from the group consisting of linear or branched alkanes, linear or branched alkenes, linear or branched alkynes, monocyclic or polycyclic aromatics, monocyclic or polycyclic heteroaromatics, linear or branched polysilanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyalkylene oxides, linear or branched polysiloxanes, linear or branched polyacrylates, linear or branched polyacetals, linear or branched acrylics, linear or branched cellulosics, linear or branched polyethers, linear or branched halogenated polyethers, linear or branched halocarbons, linear or branched polyamides, linear or branched polycarbonates, linear or branched polyethylenes, linear or branched polypropylenes, linear or branched polystyrenes, and linear or branched polyurethanes
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafluoroborates, hexafluorophosphates,
  • bis-trifluoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is W-[Z] N ;
  • n is 1-100 inclusive;
  • W is absent, or selected from the group consisting of linear or branched alkanes, linear or branched alkenes, linear or branched alkynes, monocyclic or polycyclic aromatics, monocyclic or polycyclic heteroaromatics, linear or branched polysilanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyalkylene oxides, linear or branched polysiloxanes, linear or branched polyacrylates, linear or branched polyacetals, linear or branched acrylics, linear or branched cellulosics, linear or branched polyethers, linear or branched halogenated polyethers, linear or branched halocarbons, linear or branched polyamides, linear or branched polycarbonates, linear or branched polyethylenes, linear or branched polypropylenes, linear or branched polystyrenes, and linear or branched polyurethan
  • Z is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate, thioisocyanate,
  • R-N-R provided that at least one Z is selected from the group consisting of R ,
  • R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate,
  • R A comprises at least one electrophile, nucleophile, dipolarophile, 1,3-dipole, diene or dieneophile;
  • R is a bond to W; and at least one R is alkylene-R A .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein said anionic component is Y.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Y is selected from the group consisting of [CH 3 CO 2 ] "1 , [CI] “1 , [CIO4] “1 , [Br] “1 , [I] "1 , [SO4] “2 , [CH3SO3] "1 , [SbFg] 1 , [NCC ⁇ ] 1 , [CFsS ⁇ NSCO ⁇ CFs] 1 , [PF 6 ]- ⁇ [BF4] "1 , [B(CN) 4 ]- ⁇ [AICI4]- 1 , [Alffl- 1 , [CuCy 1 , [C112CI3]- 1 , [ZnCy 1 , [ZnCl 4 ]- 2 , [Z ⁇ Cls]- 1 , [FeC ] "1 , [FeCU] "1 , ⁇ Cl,] "1 , [T1CI5]
  • the present invention relates to the aforementioned ionic liquid reagent, wherein said anionic component is X-[Y] m .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Y is selected, independently for each occurrence, from the group consisting of -[C02]- 1 , -[SO3] "1 , -[S0 4 ] "2 , -[SbFj] "1 , -[N(CN)] 1 , -[CFzSCO ⁇ NSCO ⁇ ] 1 , -[PF 5 ] "1 , -[BCC ⁇ ] 1 , and -[BF 3 ] "1 .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Y is -[CO2] "1 .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein m is 2-20 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein m is 2-10 inclusive In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, where m is 2, 3 or 4.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein X is selected, independently for each occurrence, from the group consisting of linear or branched alkanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyethers, linear or branched
  • the present invention relates to the aforementioned ionic liquid reagent, wherein X is A, AO(AO) p A, or ANH(ANH) P A; A is, independently for each occurrence, -(CQ 2 ) P -; Q is, independently for each occurrence, hydrogen or methyl; and p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein X is C(R')(A) 3 , C(R')[(AO)pA] 3 , C(R')[(ANH) P A] 3 , N(A-) 3 , N[(AO) p A] 3 , or N[(ANH) P A] 3 ;
  • A is, independently for each occurrence, -(C h ;
  • Q i s ' independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive; and
  • R' is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, al
  • the present invention relates to the aforementioned ionic liquid reagent, wherein X is C(ACH 2 ) 4 , C[(AO)pA] 4 , C[(ANH) P A] 4 , (A) 2 N(AO) p AN(A) 2 , or (A) 2 N(ANH) P AN(A) 2 ; A is, independently for each occurrence, -(CQ 2 ) P -; Q is,
  • the present invention relates to the aforementioned ionic liquid reagent, wherein W is selected, independently for each occurrence, from the group consisting of linear or branched alkanes, linear or branched polyethylene glycols, linear or branched poly(propylene glycol), linear or branched polyethers, linear or branched polyacrylic acids, linear or branched polyamides, polyether triamines, or a combination thereof.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein W is C(R')(A) 3 , C(R')[(AO) p A] 3 , C(R')[(ANH) P A] 3 , N(A) 3 , N[(AO) p A] 3 , or N[(ANH) P A] 3 ;
  • A is, independently for each occurrence, -(CQ 2 ) P -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive; and
  • R' is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, alde
  • the present invention relates to the aforementioned ionic liquid reagent, wherein W is C(ACH 2 ) , C[(AO) p A] 4 , C[(ANH) P A] 4 , (A) 2 N(AO) p AN(A) 2 , or (A) 2 N(ANH) P AN(A) 2 ;
  • A is, independently for each occurrence, -(CQ 2 ) P -;
  • Q is, independently for each occurrence, hydrogen or methyl;
  • p is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein X and W are the same.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein n is 2-20 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein n is 2- 10 inclusive In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, where n is 2, 3, or 4.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Z is selected, independently for each occurrence, from the group
  • A is, independently for each occurrence, -(0 ⁇ 3 ⁇ 4) ⁇ -;
  • Q is, independently for each occurrence, hydrogen or methyl; and
  • r is, independently for each occurrence, 0-40 inclusive.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Z is selected,
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl or alkylene-R A .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an electrophile. In certain embodiments, the present invention
  • B3806550.2 - 43 - Atty. Docket No. BUX-008.25 relates to the aforementioned ionic liquid reagent, wherein R A is a carboxyl-containing electrophile.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an N-hydroxysuccinimide (NHS) ester, acyl chloride or isocynate.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an N-hydroxysuccinimide (NHS) ester.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a nucleophile. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an amine or thiol. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an alkyl amine. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an alkyl thiol. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aralkyl amine. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aralkyl thiol. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aralkyl thiol.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aryl amine. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aryl thiol.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an enzyme. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an enzyme with one or more pendant amines, thiols and/or alcohols. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an enzyme with one or more pendant amines. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is lysozyme.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a dipolarophile. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is alkynyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a 1,3-dipole. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is azidyl. In certain embodiments,
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is acyl azidyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ]k-; wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CI3 ⁇ 4] k -; wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and
  • Another aspect of the invention relates to an ionic liquid reagent comprising an anionic component and a cationic component, wherein:
  • said anionic component is Y;
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafluoroborates, hexafluorophosphates,
  • bis-trifiuoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is Z
  • Z is selected, independently for each occurrence, from the group consisting of
  • R is a bond to W or is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate,
  • At least one R is alkylene-R A .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein said anionic component is Y.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Y is selected from the group consisting of [CH 3 CO2] “1 , [CI] “1 , [CIO4] “1 , [Br!
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Z is selected, independently for each occurrence, from the group
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl or alkylene-R A .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an electrophile. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a carboxyl-containing electrophile. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an N-hydroxysuccinimide (NHS) ester, acyl chloride or isocynate. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an N-hydroxysuccinimide (NHS) ester.
  • NHS N-hydroxysuccinimide
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a nucleophile. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an amine or thiol. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an alkyl amine. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an alkyl thiol. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aralkyl amine. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aralkyl thiol. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aralkyl thiol.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aryl amine. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an aryl thiol.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an enzyme. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an enzyme with one or more pendant amines, thiols and/or alcohols. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is an enzyme with one or more pendant amines. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is lysozyme.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a dipolarophile. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is alkynyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R A is a 1,3-dipole. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is azidyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R A is acyl azidyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ] k -; wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CI3 ⁇ 4] k -; wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and
  • Another aspect of the invention relates to an ionic liquid reagent comprising an anionic component and a cationic component, wherein:
  • said anionic component is Y;
  • Y is selected, independently for each occurrence, from the group consisting of carboxylic acids, sulfonic acids, tetrafluoroborates, hexafluorophosphates,
  • bis-trifluoromethane-sulfonimides borates, phosphates, nitrates, sulfates, triflates, antimonates, phosphoniums, carboranes, poly-oxo metallates, and metalloboranes;
  • said cationic component is Z
  • R is alkyl
  • R 2 is alkyl
  • R 3 is alkyl
  • R 4 is alkylene-R 5 ;
  • R 6 is hydrogen, alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, nitro, cyano, isocyano, isocyanate, thioisocyanate, azide, acyl azide, hydrazin
  • the present invention relates to the aforementioned ionic liquid reagent, wherein Y is selected from the group consisting of [CH 3 CO2] "1 , [CI] “1 , [CIO4]- 1 , [Br] “1 , [I] "1 , [SO4]- 2 , [CH3SO3]- 1 , [SbFs] 1 , [NCC ⁇ ] 1 , [CFsS ⁇ NS ⁇ CFs] 1 , [PFe] "1 , [BF4] "1 , [A1CU] “1 , [AI2CI7]- 1 , [CuCy 1 , [CuzCy 1 , [ZnCla] "1 , [ZnC ] “2 ,
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R 1 is butyl or hexyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R 2 is butyl or hexyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein R 3 is butyl or hexyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 1-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 10-30 inclusive. In certain embodiments, the present invention relates to the aforementioned ionic liquid reagent, wherein alkylene is selected from the group consisting of -[CH 2 ] k S wherein k is 20-30 inclusive.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R 4 is -CH 2 R 5 , -CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 CH 2 R 5 , -CH 2 CH 2 CH 2 CH 2 R "! , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 R "! , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 R "! , -CH2CH2CH2CH2CH2CH2R 5 , or -CHzCHzCHzCHzCHjCHzCHzCHaR 5 .
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R 4 is -CH 2 CH 2 CH 2 R 5 .
  • the present invention relates to the aforementioned ionic
  • liquid reagent wherein R 5 is 0 ; and R 6 is succinimidyl.
  • the present invention relates to the aforementioned ionic liquid reagent, wherein R 5 is ⁇ N
  • the present invention relates to the aforementioned ionic
  • the present invention relates to the aforementioned ionic liquid reagent, wherein the ionic liquid reagent is
  • One aspect of the invention relates to a method of treating or preventing a microbial infection comprising the step of administering an effective amount of any of the aforementioned ionic liquids, or a pharmaceutical composition thereof, to a patient in need thereof.
  • any one or more of the aforementioned ionic liquids, or a pharmaceutical composition thereof will generally be administered to a patient in need thereof in such amounts and for such a time as is necessary or sufficient to achieve at least one desired result.
  • the desired result may vary depending on the condition to be treated, the extent of an infection, the amount of ionic liquid(s) given, and the number of
  • one or more of the aforementioned ionic liquids may be administered to a patient suffering from a bacterial
  • one or more of the aforementioned ionic liquids may be administered to the eye of a patient prior to (prophylactic), during, or after undergoing surgery (e.g., cataract surgery) in such amounts that it kills or prevents the growth of the bacteria.
  • one or more the aforementioned ionic liquids may be administered to the skin of a patient undergoing a surgical or cosmetic procedure in such amounts and for such a time that it kills or prevents the growth of the bacteria.
  • the aforementioned ionic liquid used is multicationic (i.e. the cationic portion of the ionic liquid comprises multiple positive charges). In certain embodiments, the aforementioned ionic liquid used is multianionic (i.e. the anionic portion of the ionic liquid comprises multiple negative charges).
  • a treatment according to the present invention may consist of a single dose or a plurality of doses over a period of time. Administration may be one or multiple times daily, weekly (or at some other multiple day interval) or on an intermittent schedule.
  • the exact amount of an inventive ionic liquid(s), or a pharmaceutical composition thereof, to be administered will vary from subject to subject and will depend on several factors (as outlined herein).
  • any of the aforementioned ionic liquids, or pharmaceutical compositions thereof, may be administered using any route of administration effective for achieving the desired effect. Administration can be applied topically, locally or systemically. Methods of local administration include, but are not limited to, dermal, intradermal, intramuscular, intraperitoneal, subcutaneous, ocular, and intra-articular routes.
  • effective doses may be calculated according to the body weight, body surface area, or organ size of the subject to be treated. Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials.
  • the dosage to be administered can be determined from studies using animal models for the particular type of condition to be treated, and/or from animal or human data obtained from agents which are known to exhibit similar pharmacological activities.
  • the final dosage regimen will be determined by the attending surgeon or physician, considering various factors which modify the action of active agent, e.g., the agent's specific activity, the agent's specific half-life in vivo, the severity of the condition and the responsiveness of
  • compositions according to the present invention are prepared so that a dosage unit contains between about 0.01 mg and about 250 mg of the aforementioned ionic liquid. In certain embodiments, compositions according to the present invention are prepared so that a dosage unit contains between about 0.01 mg and about 0.1 mg of the aforementioned ionic liquid. In certain embodiments, compositions according to the present invention are prepared so that a dosage unit contains between about 0.1 mg and about 1 mg of the aforementioned ionic liquid. In certain embodiments, compositions according to the present invention are prepared so that a dosage unit contains between about 1 mg and about 100 mg of the aforementioned ionic liquid. In certain embodiments, compositions according to the present invention are prepared so that a dosage unit contains between about 100 mg and about 250 mg of the aforementioned ionic liquid.
  • methods of treatment of the present invention can be employed in combination with additional therapies (i.e., a treatment according to the present invention can be administered concurrently with, prior to, or subsequently to one or more desired therapeutics or medical procedures).
  • additional therapies i.e., a treatment according to the present invention can be administered concurrently with, prior to, or subsequently to one or more desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in such a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • an ionic liquid(s) of the present invention is administered as an antibiotic to a patient suffering from a bacterial infection
  • the patient may further receive a non-steroidal or steroidal anti-inflammatory drug, antibiotics, antimicrobials, and/or may undergo other therapies.
  • an ionic liquid(s) of the present invention may be administered in combination with another aqueous soluble polymer, e.g., PEG, PEO, PAA
  • an ionic liquid(s) is administered as part of a surgical or clinical procedure.
  • a polymer used as an antibiotic or antifungal can be administered during an ocular surgery, cosmetic, orthopedic, thoracic, cardiovascular surgery.
  • methods of treatment of the present invention include administration of one or more the aforementioned ionic liquid(s) per se or in the form of a pharmaceutical composition.
  • a pharmaceutical composition will generally comprise an effective amount of at least one of the aforementioned ionic liquids and at least one pharmaceutically acceptable carrier or excipient.
  • compositions of the present invention may be formulated according to general pharmaceutical practice (see, for example, "Remington's Pharmaceutical Sciences” and “Encyclopedia of Pharmaceutical Technology", J. Swarbrick, and J.C. Boylan (Eds.), Marcel Dekker, Inc: New York, 1988).
  • the optimal pharmaceutical formulation can be varied depending upon the route of administration and desired dosage. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered compounds.
  • Formulation will preferably produce liquid or semi-liquid (e.g., gel) pharmaceutical compositions.
  • compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete unit of the aforementioned ionic liquid(s) for the patient to be treated. Each unit contains a predetermined quantity of active material calculated to produce the desired effect. It will be understood, however, that the total dosage of the composition will be decided by the attending physician within the scope of sound medical judgment.
  • Formulation of pharmaceutical compositions of the present invention will mainly depend on the form of administration chosen.
  • injectable formulations e.g., solutions, dispersions, suspensions, emulsions
  • a joint e.g., knee
  • intervertebral disc e.g., the urinary system, or the vocal cord.
  • Injectable formulations can also be used for certain reconstruction or cosmetic procedures. Other procedures may alternatively use gels, lotions, creams, ointments, plasters, bandages, sheets, foams, films, sponges, dressings, or bioadsorbable patches that can be applied to the area in need of treatment.
  • Physiologically acceptable carriers, vehicles, and/or excipients for use with pharmaceutical compositions of the present invention can be routinely selected for a particular use by those skilled in the art. These include, but are not limited to, solvents, buffering agents, inert diluents or fillers, suspending agents, dispersing or wetting agents, preservatives, stabilizers, chelating agents, emulsifying agents, anti-foaming agents, ointment bases, penetration enhancers, humectants, emollients, and skin protecting agents.
  • solvents examples include water, Ringer's solution, U.S.P., isotonic sodium chloride solution, alcohols, vegetable, marine and mineral oils, polyethylene glycols, propylene glycols, glycerol, and liquid polyalkylsiloxanes.
  • Inert diluents or fillers may be sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate.
  • buffering agents examples include citric acid, acetic acid, lactic acid,
  • Suitable suspending agents include, for example, naturally-occurring gums (e.g., acacia, arabic, xanthan, and tragacanth gum), celluloses (e.g., carboxymethyl-, hydroxyethyl-, hydroxypropyl-, and
  • hydroxypropylmethylcellulose hydroxypropylmethylcellulose
  • alginates alginates
  • chitosans examples of dispersing or wetting agents are naturally-occurring phosphatides (e.g., lecithin or soybean lecithin),
  • condensation products of ethylene oxide with fatty acids or with long chain aliphatic alcohols e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate.
  • Preservatives may be added to a pharmaceutical composition of the present invention to prevent microbial contamination that can affect the stability of the formulation and cause infection in the patient.
  • Suitable examples of preservatives include parabens (such as methyl-, ethyl-, propyl-, p-hydroxy-benzoate, butyl-, isobutyl- and isopropyl- paraben), potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDM hydantoin, iodopropylnyl butylcarbamate, benzalconium chloride, cetrimide, and benzylalcohol.
  • Examples of chelating agents include sodium EDTA and citric acid.
  • emulsifying agents are naturally-occurring gums, naturally-occurring phosphatides (e.g., soybean lecithin, sorbitan mono-oleate derivatives), sorbitan esters, monoglycerides, fatty alcohols, and fatty acid esters (e.g., triglycerides of fatty acids).
  • Anti-foaming agents usually facilitate manufacture, they dissipate foam by destabilizing the air-liquid interface and allow liquid to drain away from air pockets. Examples of anti- foaming agents include simethicone, dimethicone, ethanol, and ether.
  • gel bases or viscosity-increasing agents are liquid paraffin, polyethylene, fatty oils, colloidal silica or aluminum, glycerol, propylene glycol, carboxyvinyl polymers, magnesium-aluminum silicates, hydrophilic polymers (such as, for example, starch or cellulose derivatives), water-swellable hydrocolloids, carragenans, hyaluronates, and alginates.
  • Ointment bases suitable for use in the pharmaceutical compositions of the present invention may be hydrophobic or hydrophilic; and specific examples include paraffin, lanolin, liquid polyalkylsiloxanes, cetanol, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids, polyethylene glycols, and condensation products between sorbitan esters of fatty acids, ethylene oxide (e.g., polyoxyethylene sorbitan monooleate), and polysorbates.
  • specific examples include paraffin, lanolin, liquid polyalkylsiloxanes, cetanol, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids, polyethylene glycols, and condensation products between sorbitan esters of fatty acids, ethylene oxide (e.g., polyoxyethylene sorbitan monooleate), and polysorbates.
  • humectants examples include ethanol, isopropanol glycerin, propylene glycol, sorbitol, lactic acid, and urea.
  • Suitable emollients include cholesterol and glycerol.
  • Examples of skin protectants include vitamin E, allatoin, glycerin, zinc oxide, vitamins, and sunscreen agents.
  • compositions of the present invention may, alternatively or additionally, comprise other types of excipients including, thickening agents, bioadhesive polymers, and permeation enhancing agents.
  • Thickening agents are generally used to increase viscosity and improve bioadhesive properties of pharmaceutical compositions.
  • thickening agents include, but are not limited to, celluloses, polyethylene glycol, polyethylene oxide, naturally occurring gums, gelatin, karaya, pectin, alginic acid, and povidone.
  • a thickening agent is selected for its thioxotropic properties (i.e., has a viscosity that is decreased by shaking or stirring). The presence of such as an agent in a pharmaceutical composition allows the viscosity of the composition to be reduced at the time of
  • Permeation enhancing agents are vehicles containing specific agents that affect the delivery of active components through the skin. Permeation enhancing agents are generally divided into two classes: solvents and surface active compounds (amphiphilic molecules). Examples of solvent permeation enhancing agents include alcohols (e.g., ethyl alcohol, isopropyl alcohol), dimethyl formamide, dimethyl sulfoxide, 1 dodecylazocyloheptan-2- one, N-decyl-methylsulfoxide, lactic acid, N,N-diethyl-m-toluamide, N-methyl pyrrolidone, nonane, oleic acid, petrolatum, polyethylene glycol, propylene glycol, salicylic acid, urea, terpenes, and trichloroethanol.
  • solvent permeation enhancing agents include alcohols (e.g., ethyl alcohol, isopropyl alcohol), dimethyl formamide, dimethyl sulfoxide, 1 dodecyl
  • the surfactant permeation enhancing agent in the present inventive pharmaceutical compositions may be nonionic, amphoteric, cationic, anionic, or zwitterionic.
  • Suitable nonioinic surfactants include poly(oxyethylene)-poly(oxypropylene) block copolymers, commercially known as poloxamers; ethoxylated hydrogenated castor oils; polysorbates, such as Tween 20 or Tween 80.
  • Amphoteric surfactants include quaternized imidazole derivatives, cationic surfactants include cetypyridinium chloride, cationic surfactants include "soap" (fatty acid), alkylsulfonic acid salts (the main component of synthetic detergent, such as linear alkyl benzene sulfonate (LAS)), fatty alcohol sulfate (the main component of shampoo or old neutral detergents), and zwitterionic surfactants include the betaines and sulfobetaines.
  • Injectable or topical formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, GAMA irradiation sterilization, E-Beam irradiation sterilization or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • composition comprising compounds of the present invention is preferably prepared in the form of an emulsion, a gel, an ointment, a foam, a band-aid, a cream of a mixed-phase and amphiphilic, respectively emulsion system (oil/water-water/oil-mixed-phase), a liposome or transferosome.
  • emulsion system oil/water-water/oil-mixed-phase
  • liposome or transferosome emulsion system
  • the composition is prepared in form of a cream, especially basis cream DAC (Deutsche Arzneiffen Codex) Basiscreme.
  • compositions which can be topically applied are powders, pastes or solutions.
  • Pastes often comprise as a base component lipophilic and hydrophilic additives with high solid content to provide consistency.
  • the powders, in particular topically applied powders can comprise for the increase the dispersity as well as the fluidity and the slideability as well as for the prevention of agglomerates, starches like wheat or rice starch, flame dispersion silicon dioxide and/or silica. These additives can also function as diluent.
  • compositions of the present invention comprising an ionic liquid are prepared as an ointment, a gel, a band-aid, an emulsion, a lotion, a foam, a cream of mixed-phase or amphiphilic emulsion systems (oil- water/water-oil mixed phase), a liposome, a transferosome, a paste, or a powder.
  • compositions of the present invention are for example sodium alginate as gel-forming agent for the production of a suitable base or cellulose derivatives like, e.g. guar or xanthane gum, inorganic gel-forming agents like, e.g. aluminium hydroxide or betonite (so called thixotrope gel-forming agent), polyacrylic acid derivatives,
  • polyvinylpyrrolidone microcrystalline cellulose or carboxymethyl cellulose.
  • biocompatible polyoxameres can be used which form a thermoreversible gel.
  • phospholipids or amphiphilic low or high molecular weight compounds can be considered.
  • the gels can either be hydrogels based on water or hydrophobic organogels, for example, on the basis of mixtures of lower and higher molecular weight paraffin carbohydrates and Vaseline.
  • Skin soothing and/or anti-inflammation additives known to someone of skill in the art like, for example, synthetically produced substances and/or abstracts and/or substances from medicinal plants in particular bisobolol and panthenol can also be added to the composition.
  • coloring agents like, for example, yellow and/or red ferrous oxide and/or titanium dioxide for the adjustment of color and/or fragrances can be added to the composition.
  • compositions usable according to the present invention can comprise emulsifying agents.
  • emulsifying agents are neutral, anionic or cationic tensides, for
  • polyoxyethylene sorbitans e.g. lanette-types, woolwax, lanoline or other synthetic products, which are suitable for the production of oil/water and/or water/oil emulsions.
  • Hydrophilic organogels can be prepared, for example, on the basis of high molecular weight polyethylene glycols. This gel-type formulations are washable.
  • Employed as lipids in the form of fatty and/or oily and/or waxy components for the preparation of ointments, crimes or emulsions are Vaseline, natural and/or synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, e.g.
  • osmotically effective acids and bases e.g. hydrochloric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, further buffer-systems like, e.g. citrate, phosphate, Tris buffer, or
  • triethanolamine triethanolamine. Furthermore the stability can be improved by the addition of preservatives like, e.g. methyl or propylene benzoate (parabene) or sorbic acid.
  • preservatives like, e.g. methyl or propylene benzoate (parabene) or sorbic acid.
  • the aforementioned ionic liquid(s) is(are) the only active ingredient(s) in an inventive pharmaceutical composition.
  • the pharmaceutical composition further comprises one or more bioactive agents.
  • a bioactive agent may be associated with the ionic liquid.
  • a bioactive agent may be added to the composition of polymer and does not form any associations with the polymer.
  • bioactive agents as component(s) of an inventive pharmaceutical composition
  • selection of one or more bioactive agents as component(s) of an inventive pharmaceutical composition will be based on the intended purpose of the pharmaceutical composition (e.g., use in viscosupplementation in the treatment of joints, use as viscoelastics in cataract surgery, use as tissue space fillers for cosmetic procedures, treatment of urinary incontinence or treatment of vocal cord problems, or use as anti-adhesives for wound care).
  • the amount of bioactive agent present in a pharmaceutical composition will be the ordinary dosage required to obtain the desired result through local
  • bioactive agents examples include, but are not limited to, analgesics, anesthetics, pain-relieving agents, antimicrobial agents, antibacterial agents, antiviral agents, antifungal agents, antibiotics, anti-inflammatory agents, antioxidants, antiseptic agents, antipruritic agents, immunostimulating agents, and dermatological agents. Specific examples of suitable bioactive agents are provided and discussed below.
  • Anti-infective agents for use in pharmaceutical compositions of the present invention are compounds, molecules or drugs which, when administered locally, have an anti-infective activity (i.e., they can decrease the risk of infection; prevent infection; or inhibit, suppress, combat or otherwise treat infection).
  • Anti-infective agents include, but are not limited to, antiseptics, antimicrobial agents, antibiotics, antibacterial agents, antiviral agents, antifungal agents, anti-protozoan agents, and immunostimulating agents.
  • Antibiotics and other antimicrobial agents may be selected from the group consisting of bacitracin; the cephalosporins (such as cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, ceforanide, cefoxitin, cefuroxime, cefoperazone, cefotaxime, cefotetan, ceftazidime, ceftizoxime, ceftriaxone, and meropenem); cycloserine; fosfomycin, the penicillins (such as amdinocillin, ampicillin, amoxicillin, azlocillin, bacamipicillin, benzathine penicillin G, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, methicillin, mezlocillin, nafcillin, oxacillin
  • monobactams such as aztreonam
  • chloramphenicol clindamycin
  • cycloheximide fucidin
  • lincomycin puromycin
  • rifampicin other streptomycins
  • the macrolides such as erythromycin and oleandomycin
  • the fluoroquinolones actinomycin; ethambutol; 5- fluorocytosine; griseofulvin; rifamycins; the sulfonamides (such as sulfacytine,
  • sulfadiazine sulfisoxazole, sulfamethoxazole, sulfamethizole, and sulfapyridine); and trimethoprim.
  • antibacterial agents include, but are not limited to, bismuth containing compounds (such as bismuth aluminate, bismuth subcitrate, bismuth subgalate, and bismuth subsalicylate); nitrofurans (such as nitrofurazone, nitrofurantoin, and furazolidone);
  • bismuth containing compounds such as bismuth aluminate, bismuth subcitrate, bismuth subgalate, and bismuth subsalicylate
  • nitrofurans such as nitrofurazone, nitrofurantoin, and furazolidone
  • metronidazole metronidazole
  • tinidazole tinidazole
  • nimorazole nimorazole
  • benzoic acid metronidazole
  • Antiseptic agents may be selected from the group consisting of benzalkonium chloride, chlorhexidine, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol, and cetylpyridinium chloride.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • ionic liquid or "IL” as used herein means a salt or hydrate thereof with a melting point less than about 300 °C.
  • the ionic liquid has a melting point of less than about 200 °C.
  • the ionic liquid has a melting point of less than about 150 °C.
  • the ionic liquid has a melting point of less than about 100 °C.
  • the ionic liquid has a melting point of less than about 50 °C.
  • the ionic liquid has a melting point of less than about room temperature.
  • the ionic liquids of the present invention may comprise one or more compounds.
  • the ionic liquid may be a pure compound or may be a mixture of compounds. Each compound comprises an anion or a mixture of anions; and a cation or a mixture of cations.
  • Ionic liquids when used herein, includes both ionic liquids as described above as well as “ionic viscoelastics".
  • viscoelastic material is a liquid (or solid) with both viscous and elastic properties.
  • a viscoelastic liquid will deform and flow under the influence of an applied shear stress, but when the stress is removed the liquid will slowly recover from some of the deformation.
  • nucleophile is recognized in the art, and means a chemical moiety having a reactive pair of electrons.
  • nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
  • Illustrative anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite.
  • Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable
  • nucleophiles may also be a suitable nucleophile when reduction of the substrate is desired. Further examples of nucleophiles can be found in Figure 1.
  • electrospentative is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above.
  • Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like.
  • Non-cyclic electrophiles include sulfates, sulfonates (e.g., tosylates), chlorides, bromides, iodides, and the like. Further examples of electrophiles can be found in Figure 1.
  • electrophilic atom refers to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.
  • iene refers to hydrocarbons which contain two carbon-carbon double bonds.
  • dienophile refers to a substituted alkene which can combine with a diene in a Diels-Alder reaction to form a six-membered ring.
  • a 1,3-dipolar cycloaddition is the reaction between a 1,3-dipole and a dipolarophile, most of which are substituted alkenes or alkynes, to form a five-membered ring.
  • Examples of 1 ,3-dipolar cycloadditions include the azide-alkyne cycloadditions (azides and alkynes); diazo-alkene cycloadditions (diazo compounds and alkenes); nitrone-alkene (nitrones and alkenes).
  • a "1 ,3-dipole" is a type of organic compound with a three-atom pi-electron system containing 4 electrons delocalized over three atoms.
  • 1,3-dipoles include, azides, ozone, nitro compounds, diazo compounds, azoxide compounds, carbonyl oxides, nitrile oxides, nitrous oxide, nitrones, azomethine imine, nitrilimines, carbonyl imines, azomethine ylide. nitrile ylide and carbonyl ylide.
  • an element means one element or more than one element.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl), branched-chain alkyl groups (e.g., i-propyl, i-butyl, t-butyl), cycloalkyl (alicyclic) groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl
  • branched-chain alkyl groups e.g.,
  • Ci_6 alkyl means a straight or branched alkyl chain containing from 1 to 6 carbon atoms; examples of such group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, 3 -methyl-butyl, hexyl and 2,3-dimethylbutyl and like.
  • Ci_ alkyl means a straight or branched
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • alkylene is art-recognized, and as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a hydrocarbon compound, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.
  • linear saturated Ci_i 0 alkylene groups include, but are not limited to, -(CH 2 ) n - where n is an integer from 1 to 10, for example, - CH 2 - (methylene), -CH 2 CH 2 - (ethylene), -CH 2 CH 2 CH 2 - (propylene), -CH 2 CH 2 CH 2 CH 2 - (butylene), -CH 2 CH 2 CH 2 CH 2 CH 2 - (pentylene) and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - (hexylene).
  • Ci_i 0 alkylene groups examples include, but are not limited to, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 CH 2 -, - CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, and - CH 2 CH(CH 2 CH 3 )CH 2 -.
  • alicyclic saturated Ci_ioalkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-l,3-ylene), and cyclohexylene (e.g., cyclohex- 1 ,4-ylene).
  • Ci_ioalkylene groups examples include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-l,3-ylene), and cyclohexenylene (e.g., 2-cyclohexen- 1 ,4-ylene, 3- cyclohexen-l,2-ylene, and 2,5-cyclohexadien-l,4-ylene).
  • cyclopentenylene e.g., 4-cyclopenten-l,3-ylene
  • cyclohexenylene e.g., 2-cyclohexen- 1 ,4-ylene, 3- cyclohexen-l,2-ylene, and 2,5-cyclohexadien-l,4-ylene.
  • arylene is art-recognized, and as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of an aromatic ring, as defined below for aryl (the corresponding monodentate moiety).
  • aralkylene “heteroarylene,” and
  • aralkylene encompass aryl groups substituted with two alkyl radicals, as well as bidentate moieties wherein one or both of the radicals are on the aryl ring. Arylene, aralkylene, heteroarylene are all subsets of alkylene.
  • halo designates -F, -CI, -Br or -I.
  • haloalkyl refers to alkyl as defined above substituted with one are more halogen, where the halogen is a fluorine, chlorine, bromine or iodine atom.
  • perhaloalkyl as used herein as a group or a part of a group refers to a straight or branched carbon chain containing the specified number of carbon atoms and the requisite number of halogens so that the resulting group is fully saturated.
  • Ci_6 perhaloalkyl means a straight or branched alkyl chain containing from 1 to 6 carbon atoms and from 3 to 13 halogens; examples of such group include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl and like.
  • Ci_4 perfluoroalkyl means a straight or branched alkyl chain containing from 1 to 4 carbon atoms and 3 to 9 fluorine atoms.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (as defined below).
  • heteroarylkyl is art-recognized and refers to an alkyl group substituted with an heteroaryl group (as defined below).
  • carbonyl is art-recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an -0-, -S- or -N(R ), and R represents a
  • R 200 represents a group permitted by the rules of valence, such as hydrogen, alkyl, alkenyl, alkynyl, aryl, and heteroaryl, and R 106 represents
  • oxime is art-recognized and refers to a radical that can be represented by the general formula:
  • amino is art-recognized and as used herein refers to radicals of both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R , R and R each independently represent hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -(CH2)bR 2 °°, wherein b and R 200 are defined above.
  • amino also includes "acylamino,” which refers to a radical that represented by the general formula:
  • R 101 is as defined above, and R 104 represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH 2 ) b R 20 °, wherein b and R 200 are defined above.
  • phthalimidyl refers to a radical that can be represented by the general formula:
  • R 115 and R 116 are hydrogen or taken together with the carbons to which they are bound represents alkylene, arylene, heteroarylene or cycloalkylene.
  • R 115 and R 116 are hydrogen, the moiety is referred to herein as "succinimidyl.”
  • R 115 and R 116 taken together with the carbons to which they are bound, are phenyl, the moiety is referred to herein as "isoindolinyl-l,3-dione.”
  • anhydridyl refers to a radical that can be represented by the general formula:
  • hydroxyl means -OH.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an
  • alkoxy radicals as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-l-oxy and 2- methylprop-2-oxy.
  • aryloxy “heteroaryloxy”, “aralkyloxy” and
  • heteroaryoaralkyloxy are likewise defined.
  • nitro means -N0 2 .
  • cyano means -C ⁇ N.
  • isocyano means "-N ⁇ C”.
  • azide means "-N-N ⁇ N".
  • hydrazine refers to a radical that can be represented by the general formula:
  • R 101 , R 102 and R 103 are as defined above.
  • alkylthio refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an sulfur atom (i.e., an alkyl sulfenyl group).
  • arylthio refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an sulfur atom (i.e., an alkyl sulfenyl group).
  • arylthio refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an sulfur atom (i.e., an alkyl sulfenyl group).
  • aralkylthio and “heteroaralkylthio” are likewise defined.
  • sulfoxido refers to a radical that can be represented by the general formula:
  • R 112 represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH2)bR 200 , wherein b and R 200 are defined above.
  • sulfonyl refers to a radical that can be represented by the general formula:
  • R 111 represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH 2 ) b R wherein b and R 200 are defined above.
  • R 109 represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH 2 ) b R 2 wherein b and R 200 are defined above.
  • oxysulfonyl is art-recognized and includes a radical that can be represented by the general formula:
  • R 107 is an electron pair, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH 2 ) b R 200 , wherein b and R 200 are defined above.
  • sulfonylamino is art-recognized and includes a radical that can be represented by the general formula:
  • R 108 and R 109 independently represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH 2 )bR 200 , wherein b and R 200 are defined above.
  • sulfamoyl is art-recognized and includes a radical that can be represented by the general formula:
  • R 110 independently for each occurrence represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or -(CH 2 )bR 200 , wherein b and R 200 are defined above.
  • carbocyclyl is art-recognized and refers to univalent radical formed by removing a hydrogen atom from an benzene, napthalene, antracene or cycloalkane. Each of the rings of the carbocyclyl may be substituted with any of the radicals described herein.
  • polycyclyl is art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may be substituted with any of the radicals described herein.
  • aryl refer to 5 to 10-membered mono-, bi- or tri-cyclic radicals (i.e., a univalent radical formed by removing a hydrogen atom from a benzene, napthalene or antracene).
  • the aryl radical can be substituted at one or more ring positions with any of the radicals described herein.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.
  • heteroaryl refer to 5 to 10-membered mono-, bi- or tri-cyclic radicals which contain carbon atoms, hydrogen atoms, and one to four heteroatoms (i.e., a univalent radical formed by removing a hydrogen atom from a heteroaromatic compound).
  • heteroaryl rings have less aromatic character than their all- carbon counter parts.
  • a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • the heteroaryl radical can be substituted at one or more ring positions with any of the radicals described herein.
  • heterocyclyl refers to 3 to 10-membered radical ring structures which contain one to four heteroatoms (i.e., univalent radicals formed by removing a hydrogen atom from a ring of a heterocyclic compound).
  • Heterocyclic compounds include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,
  • heterocyclyl radicals which are not heteroaryl radicals.
  • silyl H 3 Si-
  • hydrocarbyl ⁇ Si- hydrocarbyl derivatives of the silyl (H 3 Si-) group (i.e., (hydrocarbyl ⁇ Si-), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g. ethyl, phenyl.
  • the hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2- (trimethylsilyl)ethoxy]methyl (SEM).
  • TMS trimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TIPS triisopropylsilyl
  • SEM [2- (trimethylsilyl)ethoxy]methyl
  • substituted is contemplated to include all permissible number and types of substituents of organic compounds (e.g., monosubstituted,
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described hereinabove (such as alkyl, halo, haloalkyl, perhaloalkyl, aralkyl, alkenyl, alkynyl, carbonyl, ester, carboxyl, carboxylic acid, formy, thiocarbonyl, thioester, thiocarboxylic acid, thioformyl, ketone, aldehyde, acyl halide, thiocarbonyl, oxime, amino, acylamino, amido, carbamoyl, imidyl, phthalimidyl, succinimidyl, maleimidyl, isoindolinyl-l,3-dione, anhydridyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, oxo, nitro, cyano, isocyano, isocyanate,
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and
  • nonafluorobutanesulfonyl groups are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Small molecule is an art-recognized term. In certain embodiments, this term refers to a molecule which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.
  • macromolecule refers to the four conventional biopolymers (nucleic acids, proteins, carbohydrates, and lipids), as well as non-polymeric molecules with large molecular mass such as macrocycles. Macromolecules are synthesized through the process of polymerization, during which monomers are assembled into macromolecules. An example of a macromolecule is an enzyme.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and ⁇ -enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • microorganism refers to disease causing or contributing bacteria (including Gram-negative and Gram-positive organisms, such as Staphylococci sps. ⁇ e.g. Staphylococcus aureus, Staphylococcus epidermis), Enterococcus sp. (E.
  • antibiotics and antifungals are examples of antimicrobial agents.
  • Gram-positive bacteria' is an art recognized term for bacteria characterized by having as part of their cell wall structure peptidoglycan as well as polysaccharides and/or teichoic acids and are characterized by their blue-violet color reaction in the Gram-staining procedure.
  • Gram-positive bacteria include: Actinomyces spp., Bacillus anthracis, Bifidobacterium spp., Clostridium botulinum, Clostridium perfringens, Clostridium spp., Clostridium tetani, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus faecalis, Enterococcus faecium, Erysipelothrix rhusiopathiae, Eubacterium spp., Gardnerella vaginalis, Gemella morbillorum, Leuconostoc spp., Mycobacterium abcessus, Mycobacterium avium complex, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium haemophilium,
  • Mycobacterium kansasii Mycobacterium leprae, Mycobacterium marinum, Mycobacterium scrofulaceum, Mycobacterium smegmatis, Mycobacterium terrae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Nocardia spp., Peptococcus niger,
  • Peptostreptococcus spp. Proprionibacterium spp., Staphylococcus aureus, Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdanensis, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Staphylococcus schleiferi, Staphylococcus similans, Staphylococcus warneri, Staphylococcus xylosus, Streptococcus agalactiae (group B streptococcus), Streptococcus anginosus, Streptococcus bovis, Streptococcus canis, Streptococcus equi, Streptococcus miller
  • Gram-negative bacteria is an art recognized term for bacteria characterized by the presence of a double membrane surrounding each bacterial cell.
  • Gram-negative bacteria include Acinetobacter calcoaceticus, Actinobacillus actinomycetemcomitans, Aeromonas hydrophila, Alcaligenes xylosoxidans, Bacteroides, Bacteroides fragilis, Bartonella bacilliformis, Bordetella spp., Borrelia burgdorferi, Branhamella catarrhalis, Brucella spp., Campylobacter spp., Chalmydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Chromobacterium violaceum, Citrobacter spp., Eikenella corrodens, Enterobacter aerogenes, Escherichia coli, Flavobacterium meningosepticum, Fusobacterium spp., Haemophilus influenzae, Haemophilus spp., Helicobacter pylori, Klebsiella spp.,
  • Medical device refers to a non-naturally occurring object that may be, is or has been inserted or implanted in a subject or applied to a surface of a subject.
  • Medical devices can be made of a variety of biocompatible materials, including: metals, ceramics, polymers, gels and fluids not normally found within the human body.
  • polymers useful in fabricating medical devices include such polymers as silicones, rubbers, latex, plastics, polyanhydrides, polyesters, polyorthoesters, polyamides, polyacrylonitrile, polyurethanes, polyethylene, polytetrafluoroethylene, polyethylenetetraphthalate and polyphazenes.
  • Medical devices can also be fabricated using certain naturally-occurring materials or treated naturally-occurring materials.
  • a heart valve can be fabricated by combining a treated porcine heart valve with an affixation apparatus using artificial materials.
  • Medical devices can include any combination of artificial materials, combinations selected because of the particular characteristics of the components.
  • a hip implant can include a combination of a metallic shaft to bear the weight, a ceramic artificial joint and a polymeric glue to affix the structure to the surrounding bone.
  • An implantable device is one intended to be completely imbedded in the body without any structure left outside the body
  • An insertable device is one that is partially imbedded in the body but has a part intended to be external (e.g. a catheter or a drain). Medical devices can be intended for short-term or long-term residence where they are positioned. A hip implant is intended for several decades of use, for example. By contrast, a tissue expander may only be needed for a few months, and is removed thereafter. Insertable devices tend to remain in place for shorter times than implantable devices, in part because they come into more contact with microorganisms that can colonize them.
  • Implant is any object intended for placement in a human body that is not a living tissue.
  • Implants include naturally derived objects that have been processed so that their living tissues have been devitalized.
  • bone grafts can be processed so that their living cells are removed, but so that their shape is retained to serve as a template for ingrowth of bone from a host.
  • naturally occurring coral can be processed to yield hydroxyapatite preparations that can be applied to the body for certain orthopedic and dental therapies.
  • An implant can also be an article comprising artificial components.
  • the term "implant" can be applied to the entire spectrum of medical devices intended for placement in a human body.
  • Trihexylphosphine (19.14 g, 94.7 mmol) and 1,10-dichlorodecane (10 g, 47.4 mmol) were mixed together and heated to 140 °C for 24 hours. Next, the mixture was placed under vacuum at 140 °C to remove any volatile components. A clear colorless liquid was obtained in 99% yield.
  • Trihexylphosphine (8.3 g, 29 mmol) and 1 -chlorodecane (5.22 g, 29.6 mmol) were mixed together and heated to 140 °C for 24 hours. Next, the mixture was placed under vacuum at 140 °C to remove any volatile components. A clear colorless liquid was obtained in 99% yield.
  • the material formed from mixing (CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 ) 3 P -CioH 2 o- P + (CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 3 ,2Cr with polyacrylic acid (240,000 Mw at 25% in water) can be pulled to form a fiber-like material.
  • tri-n-butyl(carboxypropyl)phosphonium chloride (1.0 eq) was dissolved in dry DCM then 1.1 eq NHS (525 mg, 4.56 mmol), 1.1 eq DCC (939 mg, 4.56 mmol) and a catalytic amount of HOBT were successively added. The mixture was allowed to stir at room temperature for 10 hrs. DCU was filtered and the filtrate was added drop-wise to a cold ether solution. The oily residue obtained was collected, redissolved in DCM and the previous operation was repeated three times to afford tri-n-butyl[carboxy(N- hydroxysuccinimide)propyl]phosphonium chloride (1.50 g, 86%).
  • the nucleophile e.g. an amine or thiol
  • TEA e.g. 1, 2-butanediol
  • 1.2 eq of the ionic liquid reagent are successively added.
  • the mixture is allowed to stir for 12 hrs then the yields are determined by ! H NMR (CDC1 3 ).
  • Trihexylphosphine (30 mmol) and 5-chloro-l-pentyne (30 mmol) were mixed together and heated to 100 °C for one week under nitrogen. Next, the mixture was placed under vacuum at 140 °C to remove any volatile components. The solution was rinsed with hexane. A clear colorless liquid was obtained in greater than about 90% yield and the trihexylphosphonium alkyne salt was characterized by NMR.
  • overnight TSB-grown cultures were diluted 1/100 into fresh TSB to a bacterial population of ⁇ 10 7 colony forming units (CFU)/ml and exposed to the diphosphonium dichlorides at concentrations over a wide range (0.00032 - 5 mg/mL; 5 -fold serial dilutions) for ⁇ 16 hrs at 37 °C without shaking.
  • the minimal inhibitory concentration (MIC) of the diphosphonium dichloride was similar or identical to the MBC (data not shown). These data clearly establish that diphosphonium dichlorides have antimicrobial activity, and the antimicrobial activity varies with the structure and chemical properties of the compounds.
  • aMBC minimal bacteriocidal concentration, measured in TSB medium after ⁇ 16 hrs of exposure to antibiotics. Starting inoculum ⁇ 1 x 10 7 CFU/imL
  • Di-Hex C IO exhibited activity versus two different clinical isolates of the Gram-negative organisms Klebsiella that was similar to its activity versus Gram- positive organisms.
  • Di-Hex C I O also demonstrated weak activity versus P. aeruginosa PA14, a well-known virulent laboratory strain.
  • Example 11 Kinetics of killing by the ILs.
  • a key property of any antimicrobial agent is that it should have minimal cytotoxic activity in the concentration range for which it displays antimicrobial activity.
  • the cytotoxicity of the diphosphonium dichlorides was tested versus epithelial cells. In studies using a cell line of lung epithelial origin, no apparent cytoxicity (i.e., equivalent to vehicle control) was observed after exposure to 0.6 mM of Di-Hex CIO after 24 hrs of incubation (not shown).
  • the IL were attached to a surface using one of two methods.
  • electrostatic interactions were used to assemble the IL on a Ti or Stainless Steel Surface. Both of these metals have an overall negative charge on their surface and thus the multicationic IL will adhere to the surface.
  • the IL are modified to contain one or more thiol linkages and the thiol linkage is used to attached the IL to a gold surface.
  • Example 15 ⁇ Ionic liquid Dex CIO has low micromolar activity versus clinical bacterial strains, include antibiotic-resistant isolates
  • Di-Hex CIO showed broad activity versus these clinical isolates, as well as activity versus P. aeruginosa.
  • this compound has a MBC for C. albicans on par with that observed for Staphylococcus spp.
  • these data indicate that Di-Hex CIO has broad-spectrum activity versus bacteria, and may also be effective versus fungi.
  • Example 16 Ionic liquid Dex CIO shows rapid bacterial killing
  • a desired feature of an antimicrobial agent is the ability to rapidly kill bacteria.
  • We assayed the kinetics of killing for Dex CIO against S. aureus and E. coli at t 0 (before addition of the antibiotic), then at 15 min, 30 min and 1 hr, 2 hr, 4 hr, 8 hr and 24 hr after addition of the compound.
  • Di-Hex CIO can kill S. aureus with an exposure time of less than 10 min at a concentration of, while 30 minutes is required to kill E. coli.
  • this IL can rapid result in bacterial cell death.
  • Example 17 Ionic liquid Dex CIO shows no obvious cytotoxicity in mouse corneas
  • IL As a first step to assess the efficacy of IL in vivo, we tested whether application to the eye resulted in any gross cytotoxicity.
  • Example 18 Ionic liquid Dex CIO protects against Pseudomonas aeruginosa infection in a mouse model of keratitis
  • mice were anesthetized and positioned under an operating microscope. Three scratches were made in the corneal epithelium with a 25 gauge needle with the bevel positioned up.
  • 5 of the bacterial suspension of overnight- grown bacteria was resuspended at the desired bacterial concentration ( ⁇ 10 5 CFU/5 ⁇ ) and was used as inoculum.
  • viable bacteria were determined from a small aliquot of the suspension by plating.
  • a score of 0 or 1 is assigned (0, intact corneal epithelium; 1, non-intact corneal epithelium).
  • scores ranging from 0-2 are assigned (0, no opacity; 1, partial opacity for 50% of the lesion; 2, partial opacity for 100% of the lesion).
  • the animals were sacrificed, and treated eyes were either: i) enucleated for pathologic examination to test for cytotoxicity via histopathological study or ii) homogenized to determine bacterial burden by viable plating.

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Abstract

Certains aspects de la présente invention concernent des compositions, des préparations, et l'utilisation de liquides ioniques comme agents antimicrobiens (par ex. comme agents antibactériens et/ou antifongiques). Dans certains modes de réalisation, les liquides ioniques peuvent être associés à une ou plusieurs espèce(s) à charge unique ou avec une ou plusieurs espèce(s) à plusieurs charges.
PCT/US2010/054048 2009-10-26 2010-10-26 Liquides ioniques antimicrobiens Ceased WO2011056545A2 (fr)

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WO2015066647A3 (fr) * 2013-11-03 2015-06-18 The Regents Of The University Of California Liquides ioniques pour administration transdermique de médicaments
US10828265B2 (en) 2016-12-09 2020-11-10 The Regents Of The University Of California Formulations of propranolol and analogs as an amorphous melt or ionic liquid for transdermal drug delivery
US10912834B2 (en) 2016-08-29 2021-02-09 The Regents Of The University Of California Topical formulations based on ionic species for skin treatment
US11781106B1 (en) * 2021-03-01 2023-10-10 United States Of America As Represented By The Secretary Of The Air Force Intracellular non-genetic modification of microorganisms using protein ionic liquids
CN117717892A (zh) * 2024-02-08 2024-03-19 四川益能康生环保科技有限公司 一种用于吸收二氧化硫的复合型脱硫剂及其制备工艺
US11945973B2 (en) 2019-05-15 2024-04-02 The Hong Kong University Of Science And Technology Ionic liquid-based coating and method of making articles coated with the same
US11986562B2 (en) 2016-10-18 2024-05-21 Marquette University Composite materials containing structural polymers and photoreactive nitric oxide releasing agents and uses thereof for wound dressings
EP4171761A4 (fr) * 2020-06-26 2024-07-24 Cage Bio Inc. Compositions désinfectantes contenant un liquide ionique
US12208069B2 (en) 2017-06-01 2025-01-28 Arizona Board Of Regents On Behalf Of Northern Arizona University Antibiofilm formulations
US12239948B2 (en) 2019-06-17 2025-03-04 Marquette University Materials based on natural pollen grains and uses thereof

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DK1212385T3 (en) * 1999-09-07 2016-04-04 Akzo Nobel Surface Chem Quaternary ammonium salts as thickeners for aqueous systems
US20040077519A1 (en) * 2002-06-28 2004-04-22 The Procter & Gamble Co. Ionic liquid based products and method of using the same
US20070225191A1 (en) * 2006-03-27 2007-09-27 The Procter & Gamble Company Methods for modifying bioplymers in ionic liquids
ATE501636T1 (de) * 2006-06-14 2011-04-15 Basf Se Antimikrobielle zusammensetzungen

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US11786597B2 (en) 2013-11-03 2023-10-17 The Regents Of The University Of California Ionic liquids for transdermal drug delivery
KR102286115B1 (ko) * 2013-11-03 2021-08-04 더 리전츠 오브 더 유니버시티 오브 캘리포니아 경피 약물 전달용 이온성 액체
JP2016535781A (ja) * 2013-11-03 2016-11-17 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 経皮薬物送達のためのイオン性液体
JP2019073561A (ja) * 2013-11-03 2019-05-16 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 経皮薬物送達のためのイオン性液体
US10449254B2 (en) 2013-11-03 2019-10-22 The Regents Of The University Of California Ionic liquids for transdermal drug delivery
WO2015066647A3 (fr) * 2013-11-03 2015-06-18 The Regents Of The University Of California Liquides ioniques pour administration transdermique de médicaments
KR20160097202A (ko) * 2013-11-03 2016-08-17 더 리전츠 오브 더 유니버시티 오브 캘리포니아 경피 약물 전달용 이온성 액체
US10912834B2 (en) 2016-08-29 2021-02-09 The Regents Of The University Of California Topical formulations based on ionic species for skin treatment
US11986562B2 (en) 2016-10-18 2024-05-21 Marquette University Composite materials containing structural polymers and photoreactive nitric oxide releasing agents and uses thereof for wound dressings
US10828265B2 (en) 2016-12-09 2020-11-10 The Regents Of The University Of California Formulations of propranolol and analogs as an amorphous melt or ionic liquid for transdermal drug delivery
US12208069B2 (en) 2017-06-01 2025-01-28 Arizona Board Of Regents On Behalf Of Northern Arizona University Antibiofilm formulations
US11945973B2 (en) 2019-05-15 2024-04-02 The Hong Kong University Of Science And Technology Ionic liquid-based coating and method of making articles coated with the same
US12239948B2 (en) 2019-06-17 2025-03-04 Marquette University Materials based on natural pollen grains and uses thereof
EP4171761A4 (fr) * 2020-06-26 2024-07-24 Cage Bio Inc. Compositions désinfectantes contenant un liquide ionique
US11781106B1 (en) * 2021-03-01 2023-10-10 United States Of America As Represented By The Secretary Of The Air Force Intracellular non-genetic modification of microorganisms using protein ionic liquids
CN117717892B (zh) * 2024-02-08 2024-04-30 四川益能康生环保科技有限公司 一种用于吸收二氧化硫的复合型脱硫剂及其制备工艺
CN117717892A (zh) * 2024-02-08 2024-03-19 四川益能康生环保科技有限公司 一种用于吸收二氧化硫的复合型脱硫剂及其制备工艺

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