Classifications

• • 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
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
  • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
  • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
  • A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
  • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
  • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
  • A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
  • A01N55/08—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur containing boron
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
  • A61P31/02—Local antiseptics
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics

Definitions

• This invention is related to the use of a volatile antimicrobial compound against pathogens affecting humans comprising contacting infected areas with an atmosphere containing an effective amount of a volatile antimicrobial compound in gaseous form.
• the volatile antimicrobial compounds provided include certain oxaborole compounds, for example benzoxaboroles. Delivery systems are provided to take advantage of the volatile nature of these antimicrobial compounds. The method and use disclosed can be combined with other volatile compounds.
• a method of using a volatile antimicrobial compound against pathogens including human pathogens comprises contacting areas infected by the pathogens with an atmosphere containing an effective amount of the volatile antimicrobial compound in gaseous form, the volatile antimicrobial compound having a structure of formula (I), (II), or (III):
• the method provided further comprises impregnating, microencapsulating, or coating a material for releasing the volatile antimicrobial compound in a gaseous form.
• the matrix comprises a slow release mechanism.
• the matrix comprises an absorbent material.
• the matrix comprises a fabric.
• the absorbent material or fabric comprises materials made of cellulose, glass, polymer, nylon, or plastic fibers.
• the volatile antimicrobial compound has a structure of
• the method provided further comprises impregnating, microencapsulating, or coating a material for releasing the volatile antimicrobial compound in a gaseous form.
• the matrix comprises a slow release mechanism.
• the matrix comprises an absorbent material.
• the matrix comprises a fabric.
• the absorbent material or fabric comprises materials made of cellulose, glass, polymer, nylon, or plastic fibers.
• the volatile antimicrobial compound has a structure of
• B is boron
• a method of using a volatile antimicrobial compound against pathogens including human pathogens comprises contacting areas infected by the pathogens with an atmosphere containing an effective amount of the volatile antimicrobial compound in gaseous form, the volatile antimicrobial compound having a structure of formula (VIII):
• the method provided further comprises impregnating, microencapsulating, or coating a material for releasing the volatile antimicrobial compound in a gaseous form.
• the matrix comprises a slow release mechanism.
• the matrix comprises an absorbent material.
• the matrix comprises a fabric.
• the absorbent material or fabric comprises materials made of cellulose, glass, polymer, nylon, or plastic fibers.
• step (b) heating the mixture from step (a) to evaporate the organic solvent and render the volatile antimicrobial compound into its gaseous form;
• volatile compounds based on a discovery that benzoxaborole compounds have volatility at room temperature, a cold storage temperature (for example 1 °C to 10 °C), or a human body temperature.
• the invention is related to the unique application of volatile fungicidal and anti-microbial compounds to control human diseases. Delivery of the active ingredient may depend on impregnating a matrix which will release the active ingredient in a volatile form slowly over time in the vicinity of the infected area.
• alkyl refers to an unsubstituted or substituted, hydrocarbon group and can include straight, branched, cyclic, saturated and/or unsaturated features.
• the alkyl moiety may be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety, typically, the alkyl moiety is a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
• the alkyl moiety may be cyclic, the alkyl moiety typically is acyclic group.
• substituted refers to groups which may be used to replace another group on a molecule.
• aromatic refers to a cyclic or polycyclic moiety having a conjugated unsaturated (4 ⁇ +2) ⁇ electron system (where n is a positive integer), sometimes referred to as a delocalized ⁇ electron system.
• heterocycloalkynyl aromatic, heteroaromatic or any combination thereof.
• a non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, anthryl, azulenyl; and a non-fused bi-aryl group includes biphenyl.
• heteroaryl groups include, but are not limited to, acridinyl, benzo[l,3]dioxole, benzimidazolyl, benzindazolyl, benzoisooxazolyl, benzokisazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,
• a leaving group can be HC(0)-COOH or RC(0)-COOH, wherein R is a Ci-C 6 alkyl or substituted Ci-C 6 alkyl.
• R 22 and R 23 are independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted alkanoyl;
• the volatile antimicrobial compound of the invention has the structure of formula (IV):
• the volatile antimicrobial compound of the invention has the structure of formula (IX):
• B is boron
• the volatile antimicrobial compound has a structure of
• R b is halogen, substituted or unsubstituted alkyl, C(0)R 12 , C(0)OR 12 , OR 12 ,
• the volatile antimicrobial compound of the invention is selected from:
• R is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
• R b is selected from fluorine and chlorine. In another embodiment, R b is selected from OR 26 and NR 27 R 28 . In another embodiment when R b is OR 26 , R 26 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
• the volatile antimicrobial compound of the invention has the structure of formula (A):
• G is a substituted or unsubstituted C 1-18 -alkylene, arylalkylene, arylene, or heterocyclic moiety; and pharmaceutically acceptable salts thereof.
• the - L A - G - L B - portion of formula (A) comprises asymmetrical functional groups (i.e., asymmetrical bridges).
• the - L A - G - L B - portion of formula (A) comprises one hydroxyl group and one amine group.
• the - L A - G - L B - portion of formula (A) comprises an amino alcohol.
• G is a substituted or unsubstituted C 1-8 -alkylene.
• G is a substituted or unsubstituted C 1-4 -alkylene.
• G is selected from -CH 2 -, -CH 2 -CH 2 -, and -CH 2 -CH 2 -CH 2 -.
• At least one of R A and R B is selected from formula (B),
• R 9 is CN, C(0)NR n R 12 , or C(0)OR 3 wherein R 3 is hydrogen, substituted alkyl, or unsubstituted alkyl,
• R 9 is CN and R 10 is R b
• At least one of R A and R B has a structure selected from:
• At least one of R A and R B has a structure selected from:
• At least one of R A and R B has a structure selected from:
• R 9 is -CONR'R 2 and R 10 is R b
• R and R are independently selected from substituted or unsubstituted alkyl.
• R b is NR 21 R 22 ,
• each of A 1 , A 2 , D 1 , and D 2 is independently hydrogen, substituted or unsubstituted CMS -alkyl, arylalkyl, aryl, or heterocyclic; or A 1 and D 1 , or A 2 and D 2 together form a 5, 6, or 7-membered fused ring which is substituted or unsubstituted;
• each of R 13 , R 16 , R 17 , R 18 , and R 19 is independently hydrogen, substituted or unsubstituted Ci_6 -alkyl, nitrile, nitro, aryl or aryl alkyl; or R 16 and R 17 , or R 18 and R 19 together form an alicyclic ring which is substituted or unsubstituted;
• the method provided comprises
• the contacting comprises applying the volatile antimicrobial compound to the surface of a material or absorbing or imbedding it into a material by ways selected from the group consisting of spray, mist, drench, or direct gaseous treatment, and combinations thereof.
• the gas treatment is released from the group consisting of release from a sachet, release from a synthetic or natural film, fibrous material, and/or release from a liner or powder and combinations thereof.
• Compound B (2-(hydroxymethyl)phenylboronic acid cyclic monoester, a des- fluoro analogue of Compound A), is evaluated in a similar manner. The compound is applied to the Whatman filter paper at rates from 0.5 mg to 0.0039 mg/disk. Results show that Compound B inhibits 100% Botrytis cinerea at a rate of 0.0078 mg/disk.
• MIC minimum inhibitory concentration
• compounds are diluted in acetone, and the appropriate amount of compound is added to the disks in a dose dependent manner to achieve a final headspace concentration of 1142.9 to 0.6 mg/L.
• the acetone is permitted to evaporate for 5 minutes.
• the headspace around the inoculum is then sealed inside the well by the film with the adhering disk containing the fungicide by inverting the plates over the treated disks and sealing to prevent any of the chemical from flaking from the disk and falling onto the inoculated agar.
• Compound A is then introduced into the cabinet containing the clamshell by using the sublimation device set at 180 °C to achieve a final headspace concentration of 0.1 mg/L and equilibrated at 1 °C for 0.5 or 1 hour.
• Volatile assay 12-well (6.5 mL volume per well) microtiter plates are used. A 3- mL volume of half strength PDA is added to each well. After cooling, 1 of 1 x 10 5 spores per mL of Botrytis cinerea or Penicillium expansum suspension is spotted to the center of the agar. A Whatman #1 filter disk (Cat. No. 1001-0155) is placed, in duplicate, on the underside of a polyethylene PCR plate sealing film. Test compounds are mixed with acetone and the mixtures are added to disks in a dose dependent manner to achieve a final headspace concentration of 35.7 to 0.03 mg/L. The acetone is permitted to evaporate for 5 minutes.
• the headspace around the inoculum is then sealed inside the well by the film with the adhering disk containing the fungicide. Plates are inverted, placed over the treated disks, and sealed to prevent any of the chemical from flaking from the disk and falling onto the inoculated agar. After 3 days of incubation at 23 °C, cultures are evaluated for percent growth relative to the acetone only control.
• Table 16 demonstrates the unexpected volatility of Compound A to control Penicillium expansum on apples and pears, as well as Penicillium digitatum on oranges. Volatile application of Compound A results in excellent inhibition of browning and sporulation, whereas all other active ingredients result in no or little inhibition. However, contact application of Compound A does not provide good inhibition of browning and sporulation as compared to other fungicides, demonstrating that the volatile application is important for the fungicidal activity of Compound A.
• Itraconazole > 50 > 50 > 50 > 50 n.d. not determined.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Plant Pathology (AREA)
• Dentistry (AREA)
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• Zoology (AREA)
• Agronomy & Crop Science (AREA)
• Pest Control & Pesticides (AREA)
• Wood Science & Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dermatology (AREA)
• Gynecology & Obstetrics (AREA)
• Reproductive Health (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 2015
  • 2015-04-20 EP EP15720174.0A patent/EP3148551B1/en not_active Not-in-force
  • 2015-04-20 JP JP2016567600A patent/JP6682454B2/ja not_active Expired - Fee Related
  • 2015-04-20 AU AU2015259744A patent/AU2015259744B2/en not_active Ceased
  • 2015-04-20 CA CA2954803A patent/CA2954803A1/en not_active Abandoned
  • 2015-04-20 WO PCT/US2015/026639 patent/WO2015175157A1/en not_active Ceased
  • 2015-04-20 KR KR1020167034164A patent/KR20170007347A/ko not_active Ceased
  • 2015-04-20 MX MX2016014853A patent/MX382705B/es unknown
  • 2015-04-20 SG SG11201609020VA patent/SG11201609020VA/en unknown
  • 2015-04-20 CN CN201580026228.0A patent/CN106413720B/zh not_active Expired - Fee Related
  • 2015-05-08 TW TW104114734A patent/TW201622730A/zh unknown
  • 2015-05-08 UY UY0001036116A patent/UY36116A/es not_active Application Discontinuation
  • 2015-05-11 BR BR102015010681A patent/BR102015010681A2/pt not_active Application Discontinuation
  • 2015-05-12 AR ARP150101457A patent/AR100407A1/es unknown
• 2016
  • 2016-11-09 CL CL2016002850A patent/CL2016002850A1/es unknown
  • 2016-12-09 ZA ZA2016/08517A patent/ZA201608517B/en unknown

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