WO2011056168A1 - Procédés et compositions antimicrobiens - Google Patents

Procédés et compositions antimicrobiens Download PDF

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Publication number
WO2011056168A1
WO2011056168A1 PCT/US2009/063152 US2009063152W WO2011056168A1 WO 2011056168 A1 WO2011056168 A1 WO 2011056168A1 US 2009063152 W US2009063152 W US 2009063152W WO 2011056168 A1 WO2011056168 A1 WO 2011056168A1
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optionally substituted
compounds
compound
contemplated
null
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PCT/US2009/063152
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English (en)
Inventor
Dusan Miljkovic
Esmir Gunic
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Biosyb Pharmaceuticals
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Priority to PCT/US2009/063152 priority Critical patent/WO2011056168A1/fr
Publication of WO2011056168A1 publication Critical patent/WO2011056168A1/fr

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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
    • A61K31/69—Boron compounds
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the field of the invention is antimicrobial compositions and methods.
  • Antibiotic resistance has become an increasingly significant problem and is frequently observed only a few years following introduction of the antibiotic. Indeed, most common bacterial strains with clinical relevance have already developed resistance against one or another antibiotic, however, have retained sensitivity to other antibiotics. Unfortunately, few bacterial strains are now resistant to most common antibiotics and treatment of infections with those strains has become a major public health concern.
  • unusual antibiotics include those that include boron, which are typically formed by certain fungi (e.g. , by streptomycetes).
  • boromycin see e.g., U.S. Pat. No. 3,864,479
  • aplasmomycin J Antibiot 1 977 30(9):714-719
  • Similar to boromycin is tartrolone (J Antibiot 1995 Jan;48( l ):26-30.) and borophycin (J. Org.
  • caustic silver, silver salts, and silver nitrate solutions can be used to arrest the spread of infection in wounds due to the antimicrobial effect of silver ions.
  • a relatively commonly used compound is silver sulfadiazine for burn victims.
  • various other complexed silver compounds have been known to exhibit antimicrobial action including silver cotton and silver alginates (Polym. Adv. Technol. 2007; 18: 620-628).
  • Silver ion compounds tend to exhibit potent antimicrobial activity, and will in almost all cases not lead to resistance in a microorganism. However, most silver ion compositions will eventually produce a redox reaction in the tissue and consequently lead to various adverse effects.
  • the silver ion release rate may be controlled by a carrier (e.g. , SILVASORBTM (polyacrylate hydrophilic matrix with ionic silver by Medline Industries, Inc.)).
  • a carrier e.g. , SILVASORBTM (polyacrylate hydrophilic matrix with ionic silver by Medline Industries, Inc.)
  • SILVASORBTM polyacrylate hydrophilic matrix with ionic silver by Medline Industries, Inc.
  • compositions will most preferably comprise a hydrophobic compound that includes a tetrahedral or trigonal boron-ligand structure, wherein the compound is preferably an internal salt or forms a salt with a cation, most typically with an antimicrobially active cation.
  • contemplated tetrahedral or trigonal boron-ligand structures may be used as a delivery system for various antimicrobially active cations.
  • method of treating a microbial infection comprises a step of administering a compound in a pharmaceutical composition, wherein the compound is preferably hydrophobic and has a structure according to Formula I
  • Z ⁇ , Z2, Z3, and Z4 are independently selected from the group consisting of O, S, and NR7; wherein Ri and R2 are independently null, O, S, NRg, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, or optionally substituted alkynyl; m and n are independently an integer between 1 and 3 ; wherein R3, R4, R5, R6, R7, and Rs are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or optionally substituted aryl; wherein Me+ is a metal cation or null where one of Ri, R2, R3, R4, R5, Re, R7, and Rs
  • Zi, Z 2 , Z3, and Z4 in the compounds according to Formula I will be O, and/or that at least one of Rj and R 2 are null.
  • at least one of Ri and R 2 in such compounds are null, and/or that at least one of R3, R4, R5, and R6 are optionally H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl.
  • at least one of R3, R4, R5, and 6 is covalently coupled to at least another one of R3, R4, R5, and R6.
  • Me+ is an antimicrobially active cation (e.g. , Ag+ or a cation comprising a quaternary ammonium ion).
  • particularly preferred compounds will have a structure according to
  • R3, R4, R5, and R 3 ⁇ 4 are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkoxy, or optionally substituted alkyl; and wherein at least one of R3, R4, R5, and R6 has at least 5 carbon atoms.
  • compounds according to Formula II will include those in which two of R3, R4, R5, and Re are H, and in which another two of R3, R4, R5, and Re are optionally substituted acyl, each having between 6 and 20 carbon atoms.
  • R3, R4, R5, and R6 will be selected such that the compound has a solubility in water of less than 10 mg/ml, and more typically less than 1 mg/ml.
  • contemplated herein will be formulated into pharmaceutical compositions for treatment of a microbial infection, and most typically a bacterial (e.g., multi-drug resistant Staphylococcus aureus) or viral infection.
  • contemplated pharmaceutical compositions will be formulated for topical delivery.
  • Figure 1 depicts exemplary compounds according to the inventive subject matter. Detailed Description
  • contemplated antimicrobial compounds will include those in which boron is bound to one or more ligands to so form a trigonal or tetragonal boron-ligand structure that is negatively charged, and wherein the negative charge is compensated with a cation, which is most preferably a cation with antimicrobial activity.
  • inventive compounds will exhibit significant antimicrobial action that is at least in part attributable to the (most likely sterically strained) trigonal or tetragonal boron ligand, and/or further exhibits additional antimicrobial action that is at least in part attributable to the cation (e.g., Ag+ ion).
  • the antimicrobial effect may be considered a multi-strike effect, possibly having two distinct targets and/or mechanism of action.
  • contemplated compounds are hydrophobic compounds (i. e., have solubility in water at pH 7.0 and 20 °C of less than 10 mg/ml) and will have a negative net charge that is compensated with an antimicrobially active cation.
  • contemplated compounds will include antimicrobially active hydrophobic compounds with a tetrahedral or trigonal boron- ligand structure, wherein the compound is an internal salt or forms a salt with a cation. Most typically, the cation has antimicrobial activity (e.g. , silver or includes quaternary ammonium compound). Viewed from a different perspective, contemplated compounds will include a tetrahedral or trigonal boron-ligand structure and a cation having antimicrobial activity.
  • the tetrahedral boron-ligand structure will include four oxygen atoms, and/or comprise two bidentate ligands, while the cation having antimicrobial activity is preferably a Ag+ ion or a cation with a quaternary ammonium group.
  • the antimicrobially active compound has a structure according to Formula I Me+
  • Zi , Z 2 , Z3, and Z4 are independently selected from the group consisting of O, Se, S, and NR5; wherein R, , R 2 , R3, R4, and R 5 are independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, or optionally substituted aryl; wherein optionally at least one of Ri , R2, R3, R 4 , and R5 is covalently coupled to another one of Ri, R 2 , R3, R 4 , and R5; and wherein Me+ is a metal cation; most preferably, Zi, Z 2 , Z3, and Z 4 , and Ri , R 2 , R3, R 4 , and R5 are selected such that the compound has a partitioning coefficient
  • Z ⁇ , Z 2 , Z3, and Z 4 are independently selected from the group consisting of O, S, and NR7; wherein Ri and R 2 are independently null, O, S, NRs, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, or optionally substituted alkynyl; m and n are independently an integer between 1 and 3 ; wherein R3, R 4 , R 5 , R6, R7, and R8 are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or optionally substituted aryl; wherein Me+ is a metal cation or null where one of Ri, R 2 , R3, R4,
  • R3, R4, R5, and R6 has between 3 and 24 carbon atoms and is independently optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, or H, wherein such pattern of substitution advantageously imparts hydrophobicicty into the compound.
  • At least one (and more preferably at least two, or even all of) Zi, Z 2 , Z3, and Z4 are O, and that m and n are 0 and Ri and R2 are null.
  • R4 and Re are H, and/or Me+ is Ag. Therefore, especially preferred compounds include a tetrahedral boron-ligand structure that comprises an optionally substituted boron-monoacylglycerol diester. [0032] Consequently, especially preferred compounds will have a structure according to Formula III
  • R 3 , R4, R 5 , and R 6 are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkoxy, or optionally substituted alkyl; and wherein at least one of R3, R4, R5, and R6 has at least 5 carbon atoms.
  • R3, R4, R5, and R6 in compounds according to Formula III are H, and that another two of R 3 , R4, R 5 , and R6 are optionally substituted acyl, each having between 6 and 20 carbon atoms.
  • R3, R4, R5, and R6 are selected such that the compound has a solubility in water of less than 10 mg/ml, and most typically less than 1 mg/ml.
  • suitable compounds will also include all known compounds with antibacterial activity that have reactive groups suitable for formation of a trigonal or tetragonal boron ligand structure. Most typically, such reactive groups will be hydroxyl groups and/or thiol groups.
  • particularly preferred naturally occurring compounds include various flavanoid compounds, and especially catechins (e.g., green tea catechin such as epigallocatechin, epicatechin, etc.), numerous 'mycins' (e.g., antibacterial compounds that are produced by fungi, such as bleomycin, streptomycin, etc.), terpenoids, etc.
  • catechins e.g., green tea catechin such as epigallocatechin, epicatechin, etc.
  • numerous 'mycins' e.g., antibacterial compounds that are produced by fungi, such as bleomycin, streptomycin, etc.
  • terpenoids e.g., terpenoids
  • Further contemplated (typically synthetic) compounds include antibiotics that target bacterial cell wall synthesis (e.g., beta-lactam compounds, including penicillin-type antibiotics or cephalosporin-type compounds), that target the cell membrane (e.g., polymixins), or that interfere with essential bacterial enzymes (e.g
  • antibiotics targeting bacterial protein synthesis e.g., aminoglycosides, macrolides, tetracyclines
  • cyclic lipopeptides, glycylcyclines, and oxazolidinones are also contemplated.
  • Such compounds are most preferably reacted with a boron-containig compound (e.g., boric acid) to form with one or more reactive groups the corresponding trigonal or tetragonal boron-ligand structure.
  • boron-containig compound e.g., boric acid
  • alkyl refers to any linear, branched, or cyclic (cycloalkyl) hydrocarbon in which all carbon-carbon bonds are single bonds.
  • substituted alkyl refers to any alkyl that further comprises a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -NH 2 , - OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(0)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH 3 + ), halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -NH 2 , - OH, -SH, -NC, etc.
  • electrophilic groups e.g
  • acyl refers to any organic radical (e.g., RCO-; RCS- for thioacyl; RCNR'- for aminoacyl) that can be formed by removing a hydroxyl group from the corresponding organic carboxylic acid.
  • alkoxy refers to any alkyl (optionally comprising a double or triple bond) with a terminal O radical. For example, CH3CH20 is considered an alkoxy compound under the scope of this definition.
  • alkenyl refers to any linear, branched, or cyclic alkyl with at least one carbon-carbon double bond
  • substituted alkenyl refers to any alkenyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • alkynyl refers to any linear, branched, or cyclic alkyl or alkenyl with at least one carbon- carbon triple bond.
  • substituted alkynyl refers to any alkynyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • aryl refers to any aromatic cyclic alkenyl or alkynyl.
  • substituted aryl refers to any aryl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • alkaryl is employed where the aryl is further covalently bound to an alkyl, alkenyl, or alkynyl.
  • heteroalkyl refers to any linear, branched, or cyclic hydrocarbon comprising at least one bond in which a carbon atom is covalently bound to a non-carbon atom (e.g., nitrogen atom, sulfur atom, phosphorus atom, etc.).
  • a non-carbon atom e.g., nitrogen atom, sulfur atom, phosphorus atom, etc.
  • Especially preferred heteroalkyls include heterocyclic compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom.
  • heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine). Further contemplated heterocylces may be fused (i. e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle" as used herein.
  • fused heterocycles include a 5-membered ring fused to a 6- membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine).
  • a 6-membered ring e.g., purine, pyrrolo[2,3-d]pyrimidine
  • a 6-membered ring fused to another 6-membered or higher ring e.g., pyrido[4,5-d]pyrimidine, benzodiazepine
  • substituted as used herein also refers to a replacement of a chemical group or substituent (typically H or OH) with a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -N3 ⁇ 4, -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(0)OR [with R being any organic radical], C(X)OH [with X being O, S, NR], etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH 3 + ), halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -N3 ⁇ 4, -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(0)OR [with R
  • substituted includes nucleophilic (e.g., -NH 2 , -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(0)OR [with R being any organic radical], C(X)OH [with X being O, S, NR], etc.), polar groups (e.g. , -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH 3 + ), halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(0)OR [with R being any organic radical], C(X)OH [with X being O, S, NR], etc.
  • polar groups e.g. , -OH
  • contemplated compounds will also include all prodrug forms, wherein the prodrug form may be activated/converted to the active form in one or more than one step, and wherein the activation/conversion of the prodrug into the active form may occur intracellularly or extracellularly (in a single step or multiple steps).
  • Especially contemplated prodrug forms include those that confer a particular specificity towards a infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs" by Kenneth B. Sloan (Marcel Dekker; ISBN: 0824786297), and "Design of Prodrugs” by Hans Bundgaard (ASIN: 044480675X) which are incorporated by reference herein.
  • suitable prodrug forms of contemplated compounds may be formed for various purposes, including reduction of toxicity, increasing specificity towards a particular microorganism, etc.
  • acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to pro- drug forms to facilitate delivery of active compounds to a target site within the host organism or patient.
  • One of ordinary skill in the art will also take advantage of favorable
  • compositions for treatment of a microbial infection are contemplated in which the composition includes one or more of contemplated antimicrobially active compounds and a pharmaceutically acceptable carrier. While numerous routes of administration are deemed suitable, it is generally preferred contemplated compositions are formulated for topical delivery. However, in further contemplated aspects, pharmaceutical compositions presented herein may also be formulated for oral or parenteral delivery.
  • compositions with contemplated compounds may be effective for the treatment of numerous infectious diseases, and particularly bacterial, fungal, and viral infections.
  • compositions according to the inventive subject matter will comprise a therapeutically effective amount of contemplated compounds (or pharmaceutically acceptable salt, hydrate, or prodrug thereof), and a pharmaceutically acceptable carrier.
  • compositions are formulated for treatment of bacterial infection, and most typically a topical bacterial infection, including those common with burn wounds, ulcerative disorders, diabetes, and skin infections with Staphylococcus (and especially multi-drug resistant Staphylococcus aureus [MRSA]).
  • contemplated compositions may also be formulated for treatment of a topical viral infection, a topical infection with a protozoan, or a topical fungal infection.
  • compositions may be formulated for treatment of various systemic or organ-specific infections ⁇ e.g., bacterial or viral encephalitis, sepsis, protozoan infection such as Plasmodium falciparum, etc.).
  • contemplated compounds are included in a composition that is formulated with one or more non-toxic pharmaceutically acceptable carriers.
  • pharmaceutical compositions according to the inventive subject matter may be administered to humans and other animals using various routes, including orally, rectally, parenteral ly, intraperitoneally, vaginally, or topically.
  • contemplated compositions will be formulated for topical delivery and all known topical formulations are deemed suitable for use herein.
  • especially preferred topical formulations include creams, lotions, balms, foams, liquids, powders, and pharmaceutically inactive polymeric carriers that allow coating of an area of skin with the carrier that comprises contemplated compounds. Therefore, formulations will typically include oil-in-water emulsions, water-in-oil emulsions, suspensions, hydrophobic carriers (and especially those comprising oils, waxes, and lipids), and liposome formulations.
  • topical formulations are described in “Topical Drug Delivery Formulations” by (Informa HealthCare; ISBN: 082478183X) or in “Cosmetic Formulation of Skin Care Products” by Zoe Diana Draelos and Lauren A. Thaman (Informa HealthCare; ISBN: 0849339685).
  • contemplated topical formulations may administered under occlusion, or may be administered using iontophoretic methods or electroporation.
  • suitable pharmaceutical compositions for injection preferably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, emulsions, or suspensions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, oils, and injectable organic esters (e.g., ethyl oleate).
  • Contemplated compositions may also contain various inactive ingredients, including preservatives, wetting agents, emulsifying agents, and/or dispersing agents. Sterility may be ensured by inclusion of antibacterial and/or antifungal agents (e.g., paraben, phenol sorbic acid, chlorobutanol, etc.). Where appropriate, osmotically active agents may be included (e.g., sugars, sodium chloride, etc.).
  • antibacterial and/or antifungal agents e.g., paraben, phenol sorbic acid, chlorobutanol, etc.
  • osmotically active agents may be included (e.g., sugars, sodium chloride, etc.).
  • contemplated compositions may be formulated into solid dosage forms for oral administration, and may therefore be capsules, tablets, pills, powders, and granules.
  • contemplated compound are mixed with at least one of a pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate), a filler or extender (e.g., starch, lactose, sucrose, glucose, mannitol, or silicic acid), a binder (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, etc.), a humectant (e.g., glycerol), a disintegrating agent (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, or sodium carbonate), a solution retarding agent (e.g., paraffin), an absorption accelerator (e.g.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Contemplated compositions may further be formulated to release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Contemplated compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art (e.g., water, or other solvent, solubilizing agents), emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide), oils (and in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions may also include adjuvants such as wetting
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions in liposome form may further contain stabilizers, preservatives, excipients, etc.
  • Preferred lipids for liposome formation include phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • contemplated compounds in pharmaceutical compositions may be varied to obtain an amount of contemplated compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.
  • the selected dosage level will depend upon various factors, including the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical histoiy of the patient being treated.
  • dosage levels of about 0.01 mg to about 500 mg, more preferably of about 0.5 mg to about 50 mg of contemplated compound per kilogram of body weight per day are administered (topical or otherwise) to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. , two to four separate doses per day.
  • contemplated pharmaceutical compositions may also include additional pharmaceutically active compounds, and especially contemplated additional pharmaceutically active compounds include antibacterial and antiviral agents, which may act, for example, on cell division, cell wall synthesis, DNA replication, host cell cycle, or bacterial and/or host cell metabolism.
  • suitable active agents include immunologically active agents ⁇ e.g. , anti-inflammatory agents, immunosuppressants, steroids, or interferons (alpha, beta, or gamma) and fragments thereof.
  • additional pharmaceutically active compounds may be included in the same pharmaceutical composition, or may be administered separately, and a person of ordinary skill in the art will readily determine schedule and route of suitable co-administration of the additional pharmaceutically active compounds.
  • contemplated compounds may be administered alone or in combination with other agents for the treatment of various diseases or conditions.
  • Combination therapies according to the present invention comprise the administration of at least one compound of the present invention or a functional derivative thereof and at least one other
  • the active ingredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this may occur simultaneously or separately in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • a method of treating an infectious disease in a mammal will comprise a step of administering an effective amount of contemplated pharmaceutical compositions, which is preferably used to treat a (e.g. , topical) bacterial infection or a viral infection.
  • the bacterial infection is an infection with a multi-drug resistant Staphylococcus aureus.
  • the herpesviridae family e.g. , simplex virus, herpes virus
  • the adenoviridae family e.g. , adenovirus
  • paramyxoviridae family e.g. , measles or mumps virus
  • the orthomyxoviridae family e.g. , influenza virus
  • the coronaviridae family e.g., coronavirus, SARS virus
  • the picornaviridae family e.g., enterovirus, poliovirus, etc.
  • the flaviviridae e.g. , HCV, west nile virus.
  • Most typically, use against such viruses is by topical and/or oral administration, however, parenteral administration is also deemed appropriate.
  • contemplated that the compounds according to the inventive subject matter may be effective against gram positive bacteria and/or gram-negative bacteria. Therefore, contemplated bacterial infections include those with various Bacilli (e.g.
  • Bacillus anthracis Bordetella pertussis, Borrelia burgdorferi, various Brucelli (e.g., Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, etc ), Campylobacter jejuni, various Chalmydiae (e.g., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis), various clostridial infections (e.g., Clostridium botidinum, Clostridium difficile, Clostridium perfringens,
  • contemplated compounds and compositions were even effective against multi-drug resistant Staphylococcus aureus.
  • Further suitable uses include those in which contemplated compounds and compositions are employed in the treatment or prevention of parasitic infections and infestations, typically with protozoa (e.g., malaria), amoebae, or microsporidiae.
  • the inventors also contemplate a method of delivering a Ag+ ion to a tissue.
  • a method of delivering a Ag+ ion to a tissue will include a step of binding the Ag+ ion to a (preferably lipophilic) tetrahedral boron-ligand structure to thereby form an Ag-containing compound, and a further step of administering the (lipophilic) Ag-containing compound to the tissue.
  • the silver ions in contemplated compounds did not produce visible stains ⁇ i. e. , Ag+ reduction to elemental Ag) upon prolonged storage and even topical application to skin.
  • the lipophilic ligand(s) and/or the lipophilic carrier-solvent significantly decreases the one-electron reduction of the Ag+ ion into the elemental metallic Ag°. Such decrease may be a consequence of the low dielectric constant of the whole formulation media (thus inhibiting the acceptance of an electron), since so far Ag + salts used in medicine have been mainly hydrophilic water soluble and/or dispersible salts. In these known cases, a photochemical reduction takes place, whereupon a photon liberates an electron into a high dielectric constant media which in turn enhances the deposition of elemental silver.
  • antimicrobial cations include Sn2+, and various quaternary ammonium compounds (e.g., 3-(p-nitrophen- oxy-carbonyl)-propyldimethyldodecylammonium bromide, phenoxycarbonylmethyldimethyl- tetradecylammonium bromide, etc., and those disclosed in U.S. Pat. No. 3,882, 166.
  • boron-containing reagents suitable for use herein include boric acid, metallic borates, and various borate esters (e.g., tri-methyl-, tri-ethyl-, or tri-alkyl-borates).
  • lipophilic organic reagents for the formation of the boron-ligand structure include mono-O-acyl, mono-O-alkyl, and mono-O- cycloalkyl derivatives of glycerol (wherein the position of the monoacyl, monoalkyl, monocycloalkyl or other substituent may be at the O- l or 0-2 atom of the glycerol moiety).
  • suitable alternative lipophilic reagents include acylated or alkylated (e.g., mono-, di-, tri-or higher) derivatives of a polyol (e.g., erythritol, xylitol, sorbitol, mannitol, glycol, polyethylene glycol, branched polyols, etc.) in which the position of the substituent may be variable.
  • a polyol e.g., erythritol, xylitol, sorbitol, mannitol, glycol, polyethylene glycol, branched polyols, etc.
  • at least two free hydroxyl group will be in positions 1,2- or 1 ,3- with respect to each other.
  • Still further preferred lipophilic reagents include all vicinal 1 ,2- or 1 ,3-diol compounds with at least two lipophilic substituents proximal to the diol-function.
  • the oxygen atom(s) may be replaced with any other suitable heteroatom that is capable of binding binds boron (e.g., nitrogen, sulfur, selenium, etc.)
  • the general procedure typically comprises a step of heating and mixing the lipophilic reagent(s) with the boron-containing compound(s) for a time sufficient to allow reaction to occur (or better to complete). Most typically the reaction mixture will at such point become homogenous.
  • reaction is complete upon disappearance of the solid phase (which may be accompanied by formation of a homogenous liquid phase when constant removal of water vapor is carried out, preferably in vacuum using a cold trap).
  • suitable reaction temperatures and other conditions will depend on the specific reagents; however, temperatures between about 50 to 150 °C are generally sufficient. It should further be appreciated that the reaction can be catalyzed using suitable catalysts.
  • the organic ligand will be provided in stoichiometric quantities relative to the boron-containing compound, however, may also be in molar excess. Such excess lipophilic reagent may then serve as the lipophilic phase of the future final formulation.
  • GMO Glycerol-Mono-Oleate
  • BA Boric Acid
  • reaction product can be used as such for creating the suitable lipid formulations, or it can be further treated as follows:
  • the Na-salt of GMO-complexed BA (from above) is cooled to RT and mixed with about 50 mL of distilled water, and Trimethyl Cethyl Ammonium Chloride (3.43 g: 10 mM) dissolved in about 50 mL of distilled water is added. In formed emulsion solid NaCl is added to saturate water layer. Upon short standing a clear oily layer separated that represents almost pure Tetralkyl ammonium salt of GMO-Complexed-BA.
  • Figure 1 depicts exemplary compounds BO to B9 made by the above procedure in which Ri, R2, R3 and R 4 are independently H or saturated alkyls (C I -24), unsaturated alkyls (CI -24), branched saturated alkyls (C I -24), C 1 -C24 alkynyl, C 1 -C24 substituted alkyl, Cl - C24 substituted alkenyl with 1 -6 double bonds, C 1 -C24 substituted alkynyl, branched unsaturated alkyls (C1 -C24), cyclic saturated alkyls (CI -24), amino acids, alkyl esters of amino acids, etc., wherein each of the above may be optionally substituted.
  • Me+ is preferably an inorganic cation (and especially Ag+ or Sn2+), or an organic cation, most preferably with antimicrobial activity (typically comprising a quaternary ammonium group).
  • MIC Minimum Inhibitory Concentration evaluation of selected test products was performed using a modification of the Macrodilution Broth Method outlined in CLSI Document M7-A7, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Seventh Edition. A duplicate series of eleven two-fold dilutions of each test product were prepared using the appropriate nutrient broth medium. Each series of product dilutions was challenged, in duplicate, versus six different microorganism strains. Following incubation, the Minimum Inhibitory Concentrations (MIC) of each product were determined visually and documented.
  • the Minimum Inhibitory Concentration (MIC) of Test Product #2, AGFB (Lot Number 1001 -87), was determined to be 1 :64 (6.56 mcg/mL) versus Escherichia coli (ATCC # 1 1229), 1 :32 (13.13 meg /mL) versus Staphylococcus aureus aureus (ATCC #6538), Staphylococcus aureus aureus MRSA (ATCC #700698; MRSA Methicillin-Resistant Staphylococcus aureus), and Trichophyton mentagrophytes (ATCC #9533), and to be ⁇ 1 :8 (52.50 meg /mL) versus Streptococcus pneumoniae (ATCC #6305).
  • the Minimum Inhibitory Concentration was determined to be ⁇ 1 :2 (>210.00 meg /mL) versus Candida albicans (ATCC # 10231).

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Abstract

La présente invention concerne des composés, compositions et procédés antimicrobiens basés sur un composé hydrophobe comprenant une structure de ligand du bore tétraédrique ou rhomboédrique dans laquelle le composé est de préférence un sel interne ou forme un sel avec un cation actif sur le plan antimicrobien.
PCT/US2009/063152 2009-11-03 2009-11-03 Procédés et compositions antimicrobiens WO2011056168A1 (fr)

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WO2018017911A1 (fr) * 2016-07-22 2018-01-25 The Lubrizol Corporation Composés borates tétraédriques aliphatiques pour compositions lubrifiantes

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US20040110724A1 (en) * 2002-12-04 2004-06-10 Dusan Miljkovic Enzyme inhibitors and methods therefor
WO2006117077A1 (fr) * 2005-05-03 2006-11-09 Dsm Ip Assets B.V. Derives aryle de la curcumine, de la demethoxycurcumine, de la bisdemethoxycurcumine ou de la curcumine-isoxazolide et utilisation de ceux-ci comme additifs dans des aliments pour animaux
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018017911A1 (fr) * 2016-07-22 2018-01-25 The Lubrizol Corporation Composés borates tétraédriques aliphatiques pour compositions lubrifiantes
US10774283B2 (en) 2016-07-22 2020-09-15 The Lubrizol Corporation Aliphatic tetrahedral borate compounds for fully formulated lubricating compositions
US11459520B2 (en) 2016-07-22 2022-10-04 The Lubrizol Corporation Aliphatic tetrahedral borate compounds for lubricating compositions

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