WO2002026061A1 - Agent anti-microbien - Google Patents

Agent anti-microbien Download PDF

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Publication number
WO2002026061A1
WO2002026061A1 PCT/GB2001/004330 GB0104330W WO0226061A1 WO 2002026061 A1 WO2002026061 A1 WO 2002026061A1 GB 0104330 W GB0104330 W GB 0104330W WO 0226061 A1 WO0226061 A1 WO 0226061A1
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WO
WIPO (PCT)
Prior art keywords
hydrocarbyl group
group
compound
formula
ascopyrone
Prior art date
Application number
PCT/GB2001/004330
Other languages
English (en)
Inventor
Dieter Elsser
Andrew John Morgan
Linda Valerie Thomas
Shukun Yu
Original Assignee
Danisco A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0023686A external-priority patent/GB0023686D0/en
Priority claimed from GB0023687A external-priority patent/GB0023687D0/en
Application filed by Danisco A/S filed Critical Danisco A/S
Priority to CA002423139A priority Critical patent/CA2423139A1/fr
Priority to EP01970015A priority patent/EP1322189A1/fr
Priority to AU2001290135A priority patent/AU2001290135A1/en
Priority to GB0302415A priority patent/GB2381456B/en
Priority to NZ523687A priority patent/NZ523687A/en
Priority to JP2002529896A priority patent/JP2004509908A/ja
Publication of WO2002026061A1 publication Critical patent/WO2002026061A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3544—Organic compounds containing hetero rings
    • 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
    • A01N43/14—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 six-membered rings
    • A01N43/16—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 six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3562—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances

Definitions

  • the present invention relates to antimicrobial agents. More specifically, the invention relates to the antimicrobial activity of a series of anhydrofructose derivatives.
  • Listeria monocytogenes is one example of an organism which can contaminate certain foodstuffs and which exhibits resistance to many physical and chemical treatments.
  • Listeria monocytogenes is a gram-positive bacillus that causes serious infection, mainly in immunocompromised patients and newborn infants. Meningitis and bacteremia are the most frequent manifestations of listeriosis.
  • Bacillus cereus is another common cause of food poisoning. Two distinct clinical syndromes have been identified, the first having a short incubation period of about 4 hours, the second having an incubation period of about 17 hours. B. cereus food poisoning is initiated when the spore forms survive cooking and the contaminated food is allowed to reach temperatures that permit germination of the spore and elaboration of an enterotoxin.
  • Salmonella of which there are over two thousand different strains, is a further cause of food poisoning in humans.
  • Salmonella is a genus of rod-shaped Gram-negative Enterobacteriaceae that inhabit the intestine and cause infections such as gastroenteritis and typhoid. If invasive, they can cause enteric fevers (for example, typhoid caused by Salmonella typhi, or paratyphoid fever caused by Salmonella paratyphi).
  • Other strains of Salmonella are associated with food poisoning (usually Salmonella Typhimurium, Salmonella panama or Salmonella Enteritidis, the latter notorious for the contamination of poultry) and occasionally septicaemia in non-intestinal tissues.
  • Salmonella cannot propagate at pH values below 4.5. As a consequence, mildly acid products such as fine food and non-fermented meat products are especially susceptible to attack by Salmonella.
  • nitrite is often used as a preservative.
  • the addition of nitrite is restricted for toxological reasons (due to its acute toxicity, together with the dangers associated with nitrosamine formation).
  • Salmonella is only inhibited at concentrations of nitrite beyond 1 ,000 ppm, which are far beyond legal limits.
  • bacteriocins are unable to inhibit Salmonella in food, whereas benzoic acid is unsuitable because the inhibitory effect can only be observed in acid products.
  • phytogenic ingredients or “natural substances”
  • oil extracts from different spices has also been tested, but again the concentrations required for achieving the inhibitory effect on Salmonella were too high and the sensorical influence on the food was too strong.
  • the present invention seeks to alleviate the problems associated with prior art chemical substances and to provide new antimicrobial compositions based on anhydrofructose derivatives.
  • the invention seeks to provide antimicrobial agents that are suitable for use in foodstuffs/feed.
  • the invention provides an antimicrobial composition comprising a cyclic compound having Formula I,
  • a second aspect of the invention provides a process for preventing and/or inhibiting the growth of, and/or killing, microorganisms in a material, the process comprising the step of contacting the material with a cyclic compound having Formula I,
  • the invention relates to the use of a compound having Formula I,
  • ester group it is meant a group of the formula X- C(O)0-Y wherein X and Y are hydrocarbyl groups.
  • the material is a foodstuff or feed.
  • the present invention relates to antimicrobial substances that are suitable for use in foodstuffs and/or feed to inhibit food poisoning and spoiling bacteria contained therein.
  • the material is a home product, a body care product or a cosmetic product, for example, a body lotion.
  • antimicrobial refers to a substance that kills or prevents or inhibits the growth or reproduction of microorganisms. Antimicrobials are generally classified according to the type of microorganism they are effective against. For example, antibacterial substances are effective against bacteria, antifungal substances are effective against fungi, including yeast, and antiviral substances are effective against viruses. Certain antimicrobials can be used internally, for example antibiotic medications, whereas other antimicrobials are for external use only, such as antiseptics.
  • hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents.
  • substituents may include halo-, alkoxy-, nitro-, hydroxy, carboxyl, epoxy, acrylic, hydrocarbon, N-acyl, or cyclic group etc.
  • substituents may include halo-, alkoxy-, nitro-, hydroxy, carboxyl, epoxy, acrylic, hydrocarbon, N-acyl, or cyclic group etc.
  • a combination of substituents may form a cyclic group.
  • the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other.
  • at least two of the carbons may be linked via a suitable element or group.
  • the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen.
  • the cyclic compound of the invention is a compound having Formula II
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined hereinabove.
  • the cyclic compound is a compound having Formula III
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined hereinabove.
  • said cyclic compound is of Formula IN,
  • said cyclic compound is of formula N,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined hereinabove.
  • R 3 is selected from a substituent comprising an -OH group and -OC(O)R ⁇ wherein R' is a H or a hydrocarbyl group. Even more preferably, R 3 is -OC(O)R', wherein R' is a H or a hydrocarbyl group. Even more preferably, R 3 is -OC(O)R', wherein R' is a hydrocarbyl group.
  • R is -OC(O)R', wherein R' is R" group.
  • R' and/or R" is a branched or unbranched, substituted or unsubstituted alkyl group.
  • R' and/or R" is (CH 2 ) P CH 3 , wherein p is from 1 to 24.
  • R' and/or R" is a C 8 alkyl group.
  • R' and/or R" is a C 12 alkyl group.
  • R' and/or R" is a C 16 or a C 18 alkyl group.
  • R is of the formula -(CH 2 ) n -OC(O)- (CH 2 ) P CH 3 , wherein n and p are each independently from 1 to 24.
  • R 3 is of the formula -(CH 2 ) n -OC(O)-(CH 2 ) 7 CH 3 , wherein n is from 1 to 24, preferably from 1 to 20, preferably from 1 to 10, preferably from 1 to 5, or preferably 1, 2, or 3.
  • R 3 is of the formula -(CH 2 ) n -OC(O)-(CH 2 ) ⁇ CH 3 , wherein n is from 1 to 24, preferably from 1 to 20, preferably from 1 to 10, preferably from 1 to 5, or preferably 1, 2, or 3.
  • R 4 and R 5 represent a bond with an adjacent atom on the ring of the cyclic compound.
  • the compound is esterified anhydrofructose wherein at least one OH group of anhydrofructose is esterified to form a -OC(O)R'" group, wherein R'" is a hydrocarbyl group.
  • R" ' is a branched or unbranched, substituted or unsubstituted alkyl group.
  • R'" is (CH 2 ) P CH 3 , wherein p is from 1 to 24,
  • R'" is a C 8 alkyl group.
  • R'" is a C 12 alkyl group.
  • R'" is a C 16 or a C 18 alkyl group
  • the cyclic compound is of the formula:
  • cyclic compound is of the formula:
  • the cyclic compound is selected from the following:
  • the cyclic compound is selected from the following:
  • the compound of the invention is a derivative of Ascopyrone P, Ascopyrone M, Ascopyrone T, Ascopyrone T l5 Ascopyrone T 2 , Ascopyrone T 3 , and mixtures thereof.
  • the compound of the invention is selected from esterfied Ascopyrone P, esterfied Ascopyrone M, esterfied Ascopyrone T, esterfied Ascopyrone T 1? esterfied Ascopyrone T 2 , esterfied Ascopyrone T 3 , and mixtures thereof.
  • Ascopyrone is a known compound, i 1978 and 1981, a group of American scientists prepared Ascopyrone P by pyrolysis of amylopectin, amylose and cellulose at the Wood Chemistry laboratory in Montana, with the intention of using Ascopyrone P as a starting material for organic synthesis [Shafizadeh, F., Furneaux R.H., Stevenson, T.T., and Cochran, T.G., l,5-Anhydro-4-deoxy-D-g/ , cero-hex-l-en-3-ulose and other pyrolysis products of cellulose, Carbohydr. Res.
  • Ascopyrone P and Ascopyrone T can be produced enzymatically from 1,5-anhydro-D- fructose using cell-free extract prepared from the fungi of the order Pezizales, such as Plicaria leiocarpa and Anthracobia melaloma, and the order of Tuberales, such as, Tuber melanosporum.
  • Ascopyrone T ⁇ is the dihydrate form of Ascopyrone T
  • Ascopyrone T 2 and T 3 are the tautomeric monohydrate forms of Ascopyrone T.
  • Ascopyrone M can be produced from 1,5-anhydro-D-fructose by EDTA-sensitive dehydratases isolated from the fungi Morels, such as Morchella vulgaris, Gyromitres, pezizes, such as Peziza echinospora.
  • Ascopyrone M, P and T can also be produced chemically by treating 1,5-anhydro-D- fructose with alkali under mild conditions [Studies on the degradation of some pentoses and of 1,5-anhydro-D-fructose, the product of the starch-degrading enzyme a-l,4-glucan lyase; Thesis, Ahmad, T., The Swedish University of Agricultural Sciences, Sweden, 1995].
  • the compound of the present invention is prepared by chemical means, it may be prepared in accordance with one of the following methods:
  • Ascopyrone P may be produced by treating 1,5-anhydro-D-fructose with non-aqueous acid at elevated temperature, for example at 70 °C.
  • Ascopyrones for example, Ascopyrone P, T and M
  • Ascopyrone P, T and M may be produced from 1,5- anhydro-D-fructose by alkaline treatment according to Ahmad, T., 1995.
  • the compound of the present invention is prepared by enzymatic means as disclosed in M.-A. Baute et al, [Phytochemistry, 33 (1993): 41-45).
  • ascopyrones such as, Ascopyrone P, T and M
  • the compound is selected from the following:
  • the cyclic compound having formula I has an antimicrobial effect against gram positive bacteria and yeasts.
  • the cyclic compound having formula I has an antimicrobial effect against a microorganism selected from Listeria, Salmonella, Bacillus, Saccharomyces, Pseudomonas, Clostridium, Lactobac ⁇ lus, Brochothrix, Micrococcus, Yersinia, Enterobacter and Zygosaccharomyces, Staphylococcus, Escherichia.
  • a microorganism selected from Listeria, Salmonella, Bacillus, Saccharomyces, Pseudomonas, Clostridium, Lactobac ⁇ lus, Brochothrix, Micrococcus, Yersinia, Enterobacter and Zygosaccharomyces, Staphylococcus, Escherichia.
  • the cyclic compound having formula I has an antimicrobial effect against a microorganism selected from Listeria monocytogenes, E. coli, Staphylococcus aureus, Listeria innocua, Salmonella Typhimurium, Salmonella sp., Bacillus cereus, Bacillus subtilis, Saccharomyces cerevisiae, Saccharomyces cerevisiae var.
  • a microorganism selected from Listeria monocytogenes, E. coli, Staphylococcus aureus, Listeria innocua, Salmonella Typhimurium, Salmonella sp., Bacillus cereus, Bacillus subtilis, Saccharomyces cerevisiae, Saccharomyces cerevisiae var.
  • the cyclic compound having formula I has an antimicrobial effect against a micro-organism selected from Listeria monocytogenes, E. coli, Bacillus cereus, Saccharomyces cerevisiae, Saccharomyces carlsbergensis, Pseudomonas fluorescens, Clostridium sporogenes, Lactobacillus sake, Brochothrix thermosphacta and Micrococcus luteus.
  • a micro-organism selected from Listeria monocytogenes, E. coli, Bacillus cereus, Saccharomyces cerevisiae, Saccharomyces carlsbergensis, Pseudomonas fluorescens, Clostridium sporogenes, Lactobacillus sake, Brochothrix thermosphacta and Micrococcus luteus.
  • a derivative of the compound of formula I is a compound of the formula
  • This compound (3,6-di-O-acetyl-l ,5-anhydro-4-deoxy-D-g/ycero-hex-3-enopyranose-2- ulose) may be prepared in accordance with the teaching of Andersen et al. (1998), Structure of 1,5-anhydro-D-fructose: X-ray analysis of crystalline acetylated dimeric forms, J. Carbohydr. Chem. 17: 1027-1035.
  • the derivative of the compound of formula I is an ester is particularly preferred because the compound may be lipophilic and/or may have both hydrophobic and hydrophilic properties.
  • the compound When the compound has both hydrophobic and hydrophilic properties the compound readily resides at a water/oil interface of an emulsion.
  • the residence of the compound at a water/oil interface of an emulsion may allow it to act as an emulsifier.
  • the present invention may further provide compounds having a dual functional effect.
  • the compounds may act both as an antimicrobial and as an emulsifier.
  • 1,5-anhydrofructose is monoketo sugar found in bacteria, red algae, fungi and mammals.
  • red algae and fungi 1,5-anhydrofructose is produced by the action of ⁇ -l,4-glucan lyase [EC 4.2.2.13] from floridean starch and glycogen, respectively.
  • the 1,5-anhydro-D-fructose is prepared in accordance with GB-A-2296717.
  • the 1,5-anhydro-D-fructose is prepared by a method comprising treating an -l,4-glucan with the enzyme ⁇ -l,4-glucan lyase characterised in that enzyme is used in substantially pure form.
  • the cyclic compound of the invention comprises a five or a six membered ring.
  • the compounds of the present invention comprise at least one ester group.
  • ester includes mono-, di-, tri- and poly-esters.
  • the compound of formula I is a diester wherein the R 1 substituent is an -OH group and wherein the ester linkages are formed from the -OH group of the R 4 substituent and from the -OH group of the R 3 substituent.
  • the compound is 6-O-acyl-l ,5-anhydro-D-fructose, as represented below.
  • 6-O-acyl- 1,5-anhydro-D-fructose may be addressed by a chemical approach or by an enzymatic approach, in accordance with the methods detailed in WO 00/56745.
  • the chemical approach may comprise the following reaction to synthesise C 12 esters of anhydrofructose:
  • the reaction is carried out with lauroyl chloride and pyridine.
  • the acylation sites were assigned through derivatisation of NH 2 OR followed by separation and NMR of the products.
  • the products were found to be 50% 6-O-acyl-l, 5-anhydro-D-fructose 11% 3-O-acyl- 1,5-anhydro-D-fructose
  • the enzymatic approach to prepare 6-O-acyl-l, 5-anhydro-D-fructose may comprise the use of Upases and proteases.
  • Upases and proteases cleave ester linkages. Lipases are sugar specific and proteases fatty acid specific.
  • Synthesis 1990, 112-115 discloses that Upases and proteases in non-aqueous solution offer a reversal of activity, and form ester bonds.
  • lipases and proteases in non-aqueous solution may be used in the preparation of a compound in accordance with the present invention.
  • lipases were screened to identify suitable lipases for the preparation of compounds in accordance with the present invention. Screening with pyridine identified Candida antarctica, Pseudomonas cepacia, Pseudomonas fluorescens, and hog pancreas. Screening with tBu ⁇ H:pyridine 2:1 identified Candida antarctica, Candida cylindracea, Pseudomonas cepacia, Pseudomonas fluorescens, hog pancreas.
  • the compound in accordance with the present invention is prepared with a lipase obtained from Candida antarctica, Pseudomonas cepacia, Pseudomonas fluorescens, hog pancreas, or Candida cylindracea.
  • the compound in accordance with the present invention is prepared with lipase from Candida antarctica.
  • Candida antarctica may be obtained from Novo Nodisk A/S, Denmark under the name Novozym 435.
  • the chemical approach may comprise the quantitative conversion with lauric, palmitic and stearic acid of 1,5-anhydro-D-fructose to 6-O-acyl-l, 5-anhydro-D-fructose as follows:
  • the reaction forms a composition comprising monomer ketone/dimer type 1/dimer type 2 - 1:3:1.
  • the mixture may be purified by chromatography on silica to give approximately 70% yield.
  • the cyclic compound of the invention may be used alone, or in combination with other components, for example, one or more preservatives, one or more chelators (such as EDTA sodium salt, polyphosphate or citrate) and/or one or more antioxidants (such as ascorbate, isoascorbate, ascorbate palmitate, BHA or BHT).
  • chelators such as EDTA sodium salt, polyphosphate or citrate
  • antioxidants such as ascorbate, isoascorbate, ascorbate palmitate, BHA or BHT.
  • preservative is intended to encompass all substances which inhibit the development of, or kill, micro-oganisms. In a narrower sense, it is generally understood that preservatives are used in concentrations of 0.5 % or less. Food additives which are allowed to be used as preservatives are listed in the Regulation No. 95/2/EG of the European Parliament and Council of 20 February 1995, relating to food additives other than colouring agents and sweeteners.
  • Typical food preservatives permitted in the EU which are suitable for use in combination with the compounds of the invention include sorbic acid, benzoic acid, PHB ester (p- hydroxybenzoate), and sulphur dioxide.
  • sorbic acid benzoic acid
  • PHB ester p- hydroxybenzoate
  • sulphur dioxide sulphur dioxide
  • Mode of action inhibits different enzymes in the cells of the microorganisms.
  • Range of effects mainly against yeasts and moulds as well as catalase-positive bacteria.
  • Catalase-negative bacteria as well as lactic acid bacteria and clostridia are not inhibited.
  • Effective concentration 500 - 3000 ppm.
  • Permitted maximum quantities in food up to 2000 ppm in potato dough, processed cheese, packed bread, fine bakery products, emulsified sauces etc.
  • Mode of action inhibits exchange of oxygen through the cellular membrane and affects the enzymatic structure.
  • Range of effects for acid products only, up to approx. pH 4.5; inhibits yeasts and moulds, restricted inhibition of bacteria (no, or only very little, inhibition of lactic acid bacteria and clostridia).
  • Permitted maximum quantities in food 500 ppm in aspic, fruit preparations, marmalades etc.
  • Mode of action damages the bacterial membrane because of the surface activity, poisonous to protoplasm because of protein denaturation.
  • Range of effects mainly inhibits yeasts and fungi, but also Gram-positive bacteria in a pH range between 3.0 and 8.0.
  • Effective concentration sensorical influence at concentrations beyond approx. 0.08 %.
  • Mode of action depends on pH to a great extent, in practice it is only effective at acidic pH values ( ⁇ 4,0). Very complex mechanisms. Range of effects: mainly antibacterial, above all against Gram-negative, aerobic bacteria.
  • Effective concentrations 250 - 500 ppm for inhibition of aerobic, Gram-negative bacteria
  • Permitted maximum quantity in food products max. 2000 ppm in dry fruits, grape juice concentrate for home production of wine, in some cases only max. quantities of 20 - 30 ppm are permitted.
  • the compounds of the present invention may also be used in combination with the following preservatives: biphenyl, diphenyl, orthophenylphenol, thiabendazol, nisin, natamycin, hexamethylentetramine, dimethyldicarbonate, boric acid, sodiumtetraborate, nitrite, propionic acid and propionate, and lysozyme.
  • preservatives biphenyl, diphenyl, orthophenylphenol, thiabendazol, nisin, natamycin, hexamethylentetramine, dimethyldicarbonate, boric acid, sodiumtetraborate, nitrite, propionic acid and propionate, and lysozyme.
  • Substance for treatment of fruits surface treatment of citrus fruits. Permitted maximum quantity: 70 ppm Orthophenylphenol (E 231 / E 232)
  • Mode of action Disturbance of membrane functions.
  • Range of effects Gram-positive bacteria, no influence on Gram-negative bacteria.
  • Permitted maximum quantity in food products (EU): 3ppm in semolina pudding and similar products, 12.5 ppm ( 12.5 IU/g) in ripened cheese and processed cheese, 10 ppm in clotted cream, 10 ppm in mascarpone.
  • Natamvcin (Pimaricin) (E235) Mode of action: specifically attacks cell membrane, where - in general - an interaction with sterines occurs which increases the permeability of the membrane.
  • Range of effects Moulds and yeasts, not effective against bacteria. Usual dosage rates are below approx. 50 mg / 1. Maximum level is 1 mg/dm 2 on the surface, with a maximum penetration of 5 mm.
  • Applications surface treatment of hard, semi-hard and semi-soft cheese and of dried, cured sausages.
  • Hexamethylentetramine is formed by adding ammonia to formaldehyde in an aqueous solution.
  • the microbicidal effect is due to the formaldehyde. Permitted only for Provolone cheese (25 ppm residual quantity).
  • moulds are inhibited at an pH of 5.5 by concentrations of 125 to
  • the antimicrobial effectiveness of chemical substances in food and feed products is thus determined by a range of different factors.
  • the composition of the population of micro-organisms, the composition of the food product (ingredients, pH, water activity, content of salt, etc.), the packaging, time-temperature-conditions, etc. are key factors that influence the inhibitory activities of the antimicrobial agent.
  • Figure 1 shows a photograph of well diffusion tests on M. luteus (top plate), B. cereus
  • Middle right segment 0.3 % C 8 anhydrofructose ester
  • Middle left segment equivalent methanol control at 25 % methanol
  • Figure 2 shows a photograph of a well diffusion test on M. luteus treated with the following:
  • Segment 1 3 % C 8 anhydrofructose ester; Segment 2: 0.3 % C 8 anhydrofructose ester; Segment 3: 3 % C 12 anhydrofructose ester; Segment 4: 0.3 % C 12 anhydrofructose ester; Segment 5: equivalent methanol control at 25 % methanol; Segment 6: equivalent methanol control at 2.5 % methanol.
  • the compounds of the invention were prepared, characterised and purified in accordance with the general methods disclosed in WO 00/56745.
  • Bioscreen C An automated Microbiology Reader Bioscreen C was used to measure growth curves of the strains in the presence and absence of test samples.
  • the Bioscreen C measures the development of turbidity (i.e. growth) kinetically by vertical photometry in 200 wells of a honeycomb microtitre plate, simultaneously.
  • the system consists of a Bioscreen C analyser, which is an incubator and measurement unit, integrated with a PC, software (BioLink v 5.30), printer and a 'Honeycomb 2' cuvette multiwell plate. Growth curve data can be analysed within the BioLink software or exported to programs such as Excel.
  • this solution was then diluted 1 in 4 in sterile distilled water. This was necessary because the level of alcohol in the sample would otherwise be inhibitory to the test micro-organism. This made a final solution of 3% (w/v).
  • test sample could not be filter sterilised because too much would have been lost, and only ca. 470 ⁇ l was available.
  • the sample had been handled aseptically and it was hoped that it was sterile. For the same reason the pH of the sample was not measured.
  • AF ester 1 C 8 ester of anhydrofructose (structure shown in claim 32 - LHS).
  • Anhydrofructose ester C8 Cg ester of anhydrofructose (structure shown in claim 32 - LHS)
  • Anhydrofructose ester C12 C 12 ester of anhydrofructose (structure shown in claim 32 - RHS)
  • AF esters were dissolved in water by either heating at 70 °C for 10 - 15 min, or 100 °C for 5-10 minutes. Both methods were unsuccessful, and the esters were eventually tested as 0.5 % (w/v) solutions in 50:50 methanol/water that had been heated. AFC 8 did not dissolve, but the others were better.
  • Controls for this run were based on the final - OD for 18 or 24 h growth at 30 °C for growth in equivalent methanol levels. Inhibition by the AF esters was judged by whether the number was lower than the number derived for the methanol control.
  • Bioscreen confirmed the order of activity was as follows: AFC12 > AFC8. Bioscreen also confirmed activity against Bacillus, but activity was also observed against E. monocytogenes, and Lb sake, as well as some activity against gram negatives (GN).
  • AF ester 0.3% was made up in 2.5% methanol. Serial dilutions were made. The following concentrations were tested: 0.3, 0.15, 0.075, 0.038 and 0%. APP was made up in water. The samples were analysed after 24 h at 30 °C (Table 4).

Abstract

La présente invention concerne une composition anti-microbienne comprenant un composé cyclique de formule I dans laquelle R1 et R2 sont indépendamment -OH, =O, ou -OC(O)R', où R' est un groupe hydrocarbyle; R3 est OH, =O, un substituant comprenant une groupe OH, ou -OC(O)R', où R' est H ou une groupe hydrocarbyle; R4 et R5 sont chacun indépendamment un groupe hydrocarbyle, H, OH, =O, ou -OC(O)R', où R' est H ou un groupe hydrocarbyle; ou R4 et R5 représentent une liaison avec un atome adjacent sur la partie cyclique du composé cyclique; ledit composé comprenant au moins un groupe ester. Cette invention concerne également un procédé permettant de supprimer et/ou d'inhiber la croissance de microorganismes présents dans une matière et/ou de les détruire, ainsi que l'utilisation d'un composé cyclique de formule I.
PCT/GB2001/004330 2000-09-27 2001-09-27 Agent anti-microbien WO2002026061A1 (fr)

Priority Applications (6)

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CA002423139A CA2423139A1 (fr) 2000-09-27 2001-09-27 Agent anti-microbien
EP01970015A EP1322189A1 (fr) 2000-09-27 2001-09-27 Agent anti-microbien
AU2001290135A AU2001290135A1 (en) 2000-09-27 2001-09-27 Antimicrobial agent
GB0302415A GB2381456B (en) 2000-09-27 2001-09-27 An anhydrofructose derived antimicrobial agent
NZ523687A NZ523687A (en) 2000-09-27 2001-09-27 Antimicrobial agent
JP2002529896A JP2004509908A (ja) 2000-09-27 2001-09-27 抗菌剤

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GB0023686A GB0023686D0 (en) 2000-09-27 2000-09-27 Antimicrobial
GB0023687A GB0023687D0 (en) 2000-09-27 2000-09-27 Antimicrobial
GB0023687.7 2000-09-27
GB0023686.9 2000-09-27

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EP1690859A1 (fr) * 2003-11-20 2006-08-16 Nihon Starch Co., Ltd. Procede de production a haut rendement d'ascopyrone p
JP2006306810A (ja) * 2005-04-28 2006-11-09 Nihon Starch Co Ltd 抗炎症剤
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
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US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form

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WO2003038085A1 (fr) * 2001-10-31 2003-05-08 Danisco A/S 1,5-anhydro-d-fructose dehydratase
WO2003037906A1 (fr) * 2001-10-31 2003-05-08 Danisco A/S Utilisation antimicrobienne de derives d'anhydrofructose
WO2004039820A1 (fr) * 2002-10-30 2004-05-13 Danisco A/S Materiau
JP4825413B2 (ja) * 2003-10-28 2011-11-30 日本澱粉工業株式会社 抗腫瘍剤
WO2005121114A2 (fr) * 2004-06-07 2005-12-22 Glycom Aps 1,5- et 1,4-anhydrocetoses, procedes de preparation de 1,5- et 1,4-anhydrocetoses, intermediaires, et utilisations de 1,5- et 1,4-anhydrocetoses
JP4825957B2 (ja) * 2005-03-29 2011-11-30 国立大学法人 鹿児島大学 抗腫瘍剤
CN105851484A (zh) * 2016-03-24 2016-08-17 宋介珍 一种微生物饲料添加剂及其制备工艺和应用

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US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
WO2004083226A1 (fr) * 2003-03-19 2004-09-30 Danisco A/S Preparation antimicrobienne comprenant de la microthecine ou des derives de cette substance et ses utilisations a des fins prophylactiques et therapeutiques
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
WO2005040147A1 (fr) 2003-10-28 2005-05-06 Nihon Starch Co., Ltd. Antitumoral
US7649016B2 (en) 2003-10-28 2010-01-19 Nihon Starch Co., Ltd. Antitumor medicine
US7517981B2 (en) 2003-11-20 2009-04-14 Nihon Starch Co., Ltd. Efficient production method of ascopyrone P
JP4813903B2 (ja) * 2003-11-20 2011-11-09 日本澱粉工業株式会社 アスコピロンｐの効率的な製造方法
EP1690859A4 (fr) * 2003-11-20 2009-08-19 Nihon Starch Co Ltd Procede de production a haut rendement d'ascopyrone p
EP1690859A1 (fr) * 2003-11-20 2006-08-16 Nihon Starch Co., Ltd. Procede de production a haut rendement d'ascopyrone p
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
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US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
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US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
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US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
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GB0302473D0 (en) 2003-03-05
EP1322188A1 (fr) 2003-07-02
GB2381456B (en) 2004-08-04
GB2381456A (en) 2003-05-07
CN1466422A (zh) 2004-01-07
WO2002026060A1 (fr) 2002-04-04
GB2381196A (en) 2003-04-30
CA2423134A1 (fr) 2002-04-04
NZ523687A (en) 2005-03-24
GB0302415D0 (en) 2003-03-05
JP2004509908A (ja) 2004-04-02
AU2001290133A1 (en) 2002-04-08
CN1466423A (zh) 2004-01-07
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