WO2004076400A1 - Agents antimicrobiens contre des bacteries, des levures, et des moisissures - Google Patents

Agents antimicrobiens contre des bacteries, des levures, et des moisissures Download PDF

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WO2004076400A1
WO2004076400A1 PCT/EP2004/001930 EP2004001930W WO2004076400A1 WO 2004076400 A1 WO2004076400 A1 WO 2004076400A1 EP 2004001930 W EP2004001930 W EP 2004001930W WO 2004076400 A1 WO2004076400 A1 WO 2004076400A1
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acid
radical
compound according
alkyl
branched
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PCT/EP2004/001930
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André RIEKS
Markus KÄHLER
Ulrike Kirchner
Kerstin Wiggenhorn
Mona Kinzer
Sabine Risch
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Dr. Rieks Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to new derivatives of perillic acid and perilla alcohol and the use of perillic acid, perilla alcohol and derivatives thereof as antimicrobial agents against bacteria, yeasts and / or molds, in particular for the production of cosmetic, dermatological, pharmaceutical or veterinary preparations, of food and animal feed -Compositions, pesticides, paper raw materials and technical preparations.
  • the antimicrobial agents are natural oxidation products of the monoterpene ⁇ 1, a (9) mentadiene (limonene) and derivatives of these oxidation products.
  • microorganisms are organic materials, especially in the case of moisture . or air access, 'desirable in immediate • ceutical NEN, pastes, tinctures, aerosols, toothpastes,
  • Gram-negative bacteria include, for example, Esche ⁇ chxa coli, Salmonella. typhimuri ⁇ m or Pseudomonas aeruginosa.
  • Gram-positive bacteria include Bacillus subtilis, Staphylococcus aureus or Micrococcus varians.
  • Molds are, for example, watering can, brush or bread mold types from the class of the askomycetes or head mold types from the class of the zygomycetes.
  • Known yeasts are, for example, Candida albica s or Saccharomyces cerevisiae.
  • antimicrobial meaning both the inhibition of the growth and the multiplication of microorganisms and the killing of existing microorganisms.
  • Halogen-organic preservative compounds with chlorine, bromine, fluorine or iodine are often irritating to the skin and can trigger allergies. Some of these compounds accumulate in the environment and in adipose tissue in humans and are suspected of being carcinogenic.
  • Natural ingredients of numerous medicinal and spice plants have antimicrobial properties. These ingredients include phenolic compounds such as flavonoids, catechols or coumarins as well as the terpenes found in various essential oils.
  • the terpenes also include the monoterpene limonene and perilla alcohol and perillic acid, which are oxidation products of limonene. All three monoterpenes are chiral compounds and exist as R and S enantiomers.
  • Perilla alcohol is an oily, slightly yellowish and slightly aromatic liquid. Perillic forms colorless, soluble in ethanol or DMSO, 'in Water-insoluble crystals. The chemical formulas of limonene, perilla alcohol and perilla acid are shown below:
  • Alcohols and aldehydes have long been known to have antimicrobial activity. As ethanol or propanol as well as form aldehyde used since 'a long time as a preservative.
  • the aromatic monoterpene carvacrol has a hydroxyl group which is essential for the antimicrobial effect of the bond has highlighted.
  • neither the methyl ester of carvacrol nor cymen, which differs from carvacrol in that it lacks the hydroxyl group has no antimicrobial activity (Ultee et al. Applied and Emrironmental Microbiology 5 68 (2002) 1561-1568).
  • Antimicrobial agents that act simultaneously against gram-negative bacteria, gram-positive bacteria, yeasts and mold are therefore of great interest. Of particular interest are those against mold such as Asper-
  • 25 gillus effective antimicrobial substances preferably those of natural origin.
  • the object is achieved by using perilla alcohol, perillic acid and compounds derived therefrom, such as esters, amides and hydroxycarboxylic acid amide esters.
  • the invention relates in particular to compounds of the general formula I.
  • R is CR 1 R 2 0 (CO) R 3 , COOR 4 , CONR s R 6 , C00 (CH 2 ) n CONR 7 R 8 , COR 9 or COO (CH 2 ) n COR 10 , where R 1 and R 2 are each independently hydrogen or a linear or branched alkyl radical,
  • R 3 is hydrogen or a linear or branched alkyl radical (with the exception of a methyl or propyl radical), alkenyl radical, alkynyl radical, a cycloaliphatic radical, a mono-, di-, tri- or polycyclic aryl radical, is an alkyl radical of a branched or unbranched, saturated or unsaturated mono-, di-, tri-, or polycarboxylic acid (except acetic acid and butyric acid) or fatty acid which is optionally hydroxylated, sulfonated or aminated one to more times,
  • R 4 is a linear or branched alkyl radical (except a methyl radical), alkenyl radical, alkynyl radical, a cycloaliphatic radical, a mono-, di-, tri- or polycyclic aryl radical, an alkyl radical of a branched or unbranched , saturated or unsaturated mono-, di-, tri-, or polycarboxylic acid (except acetic acid), which is optionally hydroxylated once to several times,
  • R 5 and R 6 each independently of one another hydrogen, an alkyl (except a methyl, ethyl or propyl radical), a hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfoalkyl, alkoxyalkyl, alkoxycarbonyl -, alkoxycarbonylalkyl or carboxyalkyl radical, the alkyl radical being a linear or branched alkanyl, alkenyl, alkynyl radical, an aromatic or cycloaliphatic radical,
  • n is an integer from 1 to 22 and R 7 and R 8 are independently hydrogen, an alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfoalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy radical
  • the Alkyl radical is a linear or branched alkanyl, alkenyl, alkynyl radical, an aromatic or cycloaliphatic radical or R 7 and R 8 together form a cyclic system which optionally also contains the heteroatoms o, S, N and, if appropriate, is repeatedly substituted by linear or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxy, carboxy, alkoxycarboxy, aminocarbonyl groups,
  • R 9 and R 10 are each the residue of an amino acid which is bonded to the carbonyl carbon atom via its NH 2 group
  • R and S configurations of the compounds and mixtures thereof, including racemic mixtures are included.
  • R / S thus denotes both the R and the S configuration of compounds and mixtures of these, including racemic mixtures.
  • 'salts 1 ' are essentially understood to mean acid addition salts or salts with inorganic acids, but also salts with bases.
  • Particularly preferred are water-soluble salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, carbonic acid, sulfuric acid, toluenesulfonic acid.
  • Examples of preferred basic salts are lithi um, sodium, potassium, calcium, aluminum, magnesium and ammonium salts.
  • the invention relates in particular to compounds of the formula I derived from R and S perilla alcohol, in which R CR is X (R 2 ) 0 (CO) R 3 , where R 1 , R 2 and R 3 have the meaning given above.
  • the invention thus relates to esters of the formula II
  • R 1 and R 2 have the above meaning and
  • R 3 is hydrogen or a linear or branched alkyl radical (excluding a methyl or propyl radical), alkenyl radical, alkynyl radical, a cycloaliphatic radical, a mono-, di-, tri- or polycyclic aryl radical Is an alkyl radical of a branched or unbranched, saturated or unsaturated mono-, di-, tri-, or polycarboxylic acid (except acetic acid and butyric acid) or fatty acid, which is optionally mono- to polysethylated, sulfonated or aminated,
  • linear or branched alkyl radical is understood to mean a hydrocarbon radical of the general formula C n H 2n + 1 ". Explicitly included are the radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, neopentyl, hexyl, decyl, dodecyl, eicosanyl and octacosanyl.
  • Non-limiting examples of a linear or branched alkenyl according to the invention are propenyl, 2-butenyl, 3-butenyl, 3-pentenyl, 1,3-hexadienyl and the like, i. for a hydrocarbon residue which contains one or more C-C double bonds.
  • 'Alkynyl' stands for e.g. Propynyl, 2-butynyl, 3-butynyl, 4-hexynyl, 1-decynyl, etc., i.e. for a hydrocarbon radical containing one or more C-C triple bonds.
  • Cycloaliphatic radicals are generally to be understood as cyclic aliphatic hydrocarbon ring systems which are optionally mono- or polysubstituted, e.g. by alkyl, halogen, hydroxyl and / or A ino groups.
  • branched or unbranched, saturated or unsaturated mono-, di-, tri- or polycarboxylic acids or fatty acids mentioned above and below are:
  • the abovementioned acids can also be hydroxylated one to five times.
  • examples of such acids include Glycolic acid, lactic acid, malic acid, hydroxybutyric acid, tartaric acid, citric acid, isocitric acid and glyceric acid.
  • the aforementioned acids can also be sulfonated or aminated, i.e. carry a sulfo or amino group.
  • sulfonated acids include Sulfoacetic acid, 3-sulfopropanoic acid, 3-sulfobutanoic acid, homocysteic acid and others
  • aminated acids are amino acids such as glycine, alanine, glutamine and others.
  • the invention further relates in particular to compounds of the formula I derived from R- or S-perillic acid, in which R is COOR 4 , where R 4 has the meaning given above.
  • esters of formula III a This particularly includes esters of formula III a where
  • R 4 is a linear or branched alkyl radical (except methyl radical), alkenyl radical, alkynyl radical, a cycloaliphatic radical, a mono-, di-, tri- or polycyclic aryl radical, an alkyl radical of a branched or unbranched, saturated or is unsaturated mono-, di-, tri-, or polycarboxylic acid (except acetic acid), the carboxylic acid optionally being hydroxylated one to more times,
  • linear or branched alkyl radicals are: methyl, ethyl, propylene, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, neopentyl, hexyl, decyl, do-decyl, eicosanyl and octacosanyl.
  • Non-limiting examples of a linear or branched alkenyl according to the invention are propenyl, 2-butenyl, 3-butenyl, 3-pentenyl, 1,3-hexadienyl and others, i.e. for a hydrocarbon residue that contains one or more C-C double bonds.
  • 'Alkynyl stands for, for example, propynyl, 2-butynyl, 3-butynyl, 4-hexynyl, 1-decynyl, etc., ie for a hydrocarbon radical which contains one or more CC triple bonds. . It is understood that hydrocarbon residues are also included which contain both double and triple bonds.
  • 'Cycloaliphatic radicals' are generally understood to mean cyclic aliphatic hydrocarbon ring systems which are optionally mono- or polysubstituted, e.g. by alkyl, halogen, hydroxyl and / or amino groups.
  • 'Aryl' can be mono-, di-, tri- or polycyclic aryl such as, for example, phenyl, naphthyl, indenyl, fluorenyl, biphenylyl, indacenyl and others, and the term generally denotes individual aromatic carbon rings or fused aromatic ring systems which may be mono- or are multiply substituted, such as by alkyl, halogen, OH and / or NH 2 groups.
  • the abovementioned mono-, di-, tri- or polycarboxylic acids can be hydroxylated once or several times. Particularly suitable are e.g. one to five times hydroxylated carboxylic acids, especially glycolic acid, lactic acid, malic acid, hydroxybutyric acid, tartaric acid, citric acid, isocitric acid and glyceric acid.
  • the invention relates to amides of the formula IV
  • R s and R s have the meaning given above.
  • R 5 and R s independently of one another are hydrogen, an alkyl (with the exception of a methyl, ethyl or propyl radical), a hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfoalkyl, alkoxyalkyl are particularly preferred -, Alkoxycarbonyl, alkoxycarbonylalkyl or carboxyalkyl radicals, the alkyl radical, as already explained in detail under formula III above, being a linear or branched alkanyl, alkenyl, alkynyl radical, an aromatic or cycloaliphatic radical can.
  • Hydroxyalkyl stands for an alkyl radical mentioned above which is hydroxylated. For example, hydroxyethyl may be mentioned here.
  • Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl each represent an alkyl radical mentioned above which bears an amino group which can be mono- or dialkylated. Examples are the aminoethyl and the dimethylaminoethyl radical.
  • Sulfoalkyl is understood to mean an alkyl radical mentioned above which bears a sulfo group. One example is the sulfoethyl residue.
  • Alkoxyalkyl stands for an alkyl radical mentioned above, to which an alkoxy group is bonded. Examples of this are the ethoxyethyl and the ethoxypropyl radical.
  • Alkoxycarbonyl stands for a carbonyl radical to which an alkoxy group is attached. Examples are the methoxycarbonyl and the ethoxycarbonyl radical.
  • Alkoxycarbonylalkyl stands for an alkyl radical mentioned above to which an alkoxycarbonyl group is bonded. Examples of this are the ethoxycarbonylmethyl and the methoxycarbonylmethyl radical.
  • a further embodiment of the invention relates to hydroxycarboxylic acid amide esters of R-perillic acid and S-perillic acid of the formula V.
  • n is an integer from 1 to 22 and
  • R 7 and R 8 have the meaning given above
  • hydroxycarboxylic acid amide esters of R- or S-perillic acid in which R 7 and R 8 independently of one another are hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfoalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, Carboxyalkyl or carboxy radicals, the alkyl radical, as already explained in detail under formula III above, being a linear or branched alkanyl, alkenyl, alkynyl radical, an aromatic or cycloaliphatic radical or R 7 and R 8 together form a cyclic system which optionally also contains the heteroatoms 0, S, N and optionally one to more times by linear or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxy, carboxy, alkoxycarboxy, aminocarbonyl Groups is substituted.
  • R / S-glycolamide perillate R / SN-hydroxyethylglycolamide perillate, R / SN-aminoethyl-glycolamide perillate, R / SN-methylglycolamide perillate, R / SN-ethylglycolamide perillate, R / SN, N-dimethylglycolamide perillate and R / SN, N- Diethylglycolamide perillate.
  • R 9 is the residue of an amino acid which is bonded to the carbonyl carbon atom via its NH 2 group
  • Another embodiment of the invention relates to hydroxycarboxylic acid amide esters of R-perillic acid and S-perillic acid of the formula VII
  • R 10 is the residue of an amino acid which is bonded to the carbonyl carbon atom via its NH 2 group
  • amino acids are preferably glycine, alanine, cysteine, serine, threonine, asparagine, glutamine, aspartate and glutamate.
  • the invention accordingly also relates to all derivatives of R / S-perillic acid and R / S-perilla alcohol according to formulas II to VII which are active against bacteria and / or yeasts and / or molds.
  • the invention relates in particular to all those compounds which work better against bacteria and / or yeasts and / or molds than R / S limonene and / or R / S perilla alcohol.
  • Preferred compounds according to formula II are, for example: esters of R / S perilla alcohol and a branched or unbranched, saturated or unsaturated mono-, di-, tri- or
  • Polycarboxylic acid or fatty acid which can be hydroxylated, sulfonated or amidated.
  • Preferred compounds according to formula III are:
  • R / S-perillic acid esters with a linear or branched or cyclic alkyl radical or carboxyalkyl radical of a carboxylic acid or aromatic radical.
  • Preferred compounds according to formulas IV and VI are, for example:
  • Examples of such preferred compounds are: N-HydroxyethylperiHamid, N, N-Di (Hydroxyethyl) perillamide, N-EthoxycarbonylperiHamid, N, N-Diethoxycarbonylperillamid and N-Methoxycarbonyl-Methylperillamid.
  • Preferred compounds according to formulas V and VII are, for example:
  • Hydroxycarboxylic acid amide esters of R / S-perillic acid resulted from the esterification of R / S-perillic acid with a hydroxycarboxylic acid amide.
  • R / S-glycolamide perillate examples include: R / S-glycolamide perillate, R / SN-hydroxyethylglycolamide perillate, R / SN-aminoethylglycolamide perillate, R / SN-methylglycolamide perillate, R / SN-ethylglycolamide perillate, R / SN, N-dimethylglycolamide perillate or R / SN, N-diethylglycolamide perillate.
  • An essential aspect of the present invention is the use of the abovementioned compounds and perillic acid, methyl perillate, perillamide, N-methylperillamide, N, N-dimethylperillamide, N-ethylperillamide, N, N-diethylperillamide, N-propylperillamide, N, N- Dipropyl perillamide, perillyl acetate, peryl butyrate to fight bacteria, yeast and / or mold.
  • the invention also relates to the use of perilla alcohol for combating molds, in particular for combating bacteria, yeasts and molds at the same time.
  • an essential aspect of the invention is the use of one or more compounds of the formula II, III, IV, V, VI and / or VII ' and methyl perillate, perillamide, N- MethylperiHamid, N, N- Dimethylperillamid, N-
  • EthylperiHamid, N, N-Diethylperillamid, N-PropylperiHamid, N, N-Dipropylperillamid, Perillylacetat, Perillylbutyrat taking into account the specific effect against gram-negative or gram-positive bacteria and / or yeasts and / or molds optimized by derivatization.
  • perilla alcohol or perillic acid new compounds with new, specific effects against gram-positive and / or gram-negative bacteria and / or yeasts and / or molds can be produced.
  • Compounds of the formula V according to the invention for example R- or S-glycolamide perillate, have particularly good activity against gram-positive and gram-negative bacteria, against yeasts and against molds, in particular against gram-negative bacteria, against yeasts and in particular against molds ,
  • Compounds of the formula II for example S-perillyl succinate, have better antibacterial activity against gram-positive bacteria than S-perilla alcohol.
  • Compounds of the formula III according to the invention for example R- or S-ethyl perillate, specifically show better activity against Gram-positive bacteria than R- or S-perillic acid.
  • Another aspect of the present invention is the use of one or more compounds of the formulas I, II, III, IV, V, VI and / or VII, of perillic acid or perilla alcohol for the preparation of compositions for combating bacteria, yeasts and / or molds.
  • perillic acid and / or perilla alcohol for the production of a compound setting for controlling bacteria, yeasts and molds and a use of perilla alcohol and / or perillic acid for producing a composition for combating molds is particularly preferred.
  • composition is an agent for preserving cosmetic, dermatological, pharmaceutical or veterinary preparations.
  • composition is an agent for preserving water-containing preparations.
  • composition is an ointment, cream, hydrogel, emulsion, lotion, paste, tincture, shampoo, aerosol, toothpaste, cleansing milk, soap, mouthwash or juice.
  • composition is a food preservative.
  • composition is an agent for preserving fruit, vegetables and live animals.
  • live animals are lobsters, mussels or oysters.
  • composition is an agent for treating casings, skins, or skins of cheese or sausages to prevent bacterial growth. to prevent yeasts and / or molds that impair edibility, shelf life and harmlessness to health.
  • composition is an agent for preserving animal feed.
  • the composition is a means of preserving paper raw materials.
  • Paper raw materials include all water-containing intermediates, such as pulps, that occur in the production of newsprint, letter, stationery and paper, as well as paper for use in books and magazines and as a basic material for textiles, packaging, drinking cups or wallpaper. Mixtures • of pulps and rags, ground wood or pulp, understood.
  • composition is a crop protection agent.
  • composition is a pharmaceutical preparation.
  • composition is a veterinary preparation.
  • the composition is a means of preserving technical preparations such as colors, lacquers, ke, wood preservative, glue or a component of wall mold removal preparations effective against wall mold.
  • Perillyl acetate, perillyl butyrate or perilla alcohol means that the use of conventional, but in particular several different preservatives can be dispensed with, since both antibacterial activity and activity against yeasts and molds have been demonstrated for the aforementioned active substances in the context of the present invention.
  • Another advantage of cosmetics is that perilic acid and perilla alcohol are naturally occurring compounds.
  • Cosmetic, dermatological, pharmaceutical or veterinary preparations foodstuffs, animal feed or plant protection products, paper raw materials and technical preparations such as paints, varnishes, wood preservatives or wall mold removers which contain one or more compounds of the formulas my I to VII, perilla acid, methyl perillate, and / or perillyl butyrate, form a further aspect of the invention.
  • Cosmetic, dermatological, pharmaceutical or veterinary preparations, foods, animal feed, pesticides, paper raw materials or technical preparations are preferred, which contain one or more of the above-mentioned active ingredients in a total concentration of 0.001 to 10% by weight, preferably 0.1 to 2% by weight.
  • Pillar 40 ° C; 1 ml / min; Eluent: 20% water, 32% ammonium acetate
  • This assay was used to test the growth inhibition of gram-negative and gram-positive bacteria, yeasts and molds.
  • the diffusion of an antimicrobial agent from a filter sheet into a solid, inoculated medium results in growth-free zones of inhibition.
  • the size of the zone of inhibition depends on the antimicrobial effect.
  • the test was carried out on a reference medium standardized according to DIN 58940, the Müller-Hinton agar. Petri dishes with a diameter of 9 cm were used, into which 20 +/- 1 ml of medium were filled.
  • test strains were used (at the specified incubation temperature): Bacillus subtilis DSM 347 (gram-positive; 30 ° C), Staphylococcus aureus DSM 346 (gram-positive; 37 ° C), Micrococcus luteus DSM 1790 (gram-positive; 30 ° C) ), Escherichia coli DSM 498 (gram-negative; 37 ° C), Pseudomonas aeruginosa.
  • DSM 1117 (gram-negative; 37 ° C), Candida kefyr DSM 70073 (yeast; 30 ° C), Candida albicans DSM 1665 (yeast; 30 ° C), Aspergillus niger DSM 1988 (mold; 30 ° C).
  • Methyl perillate, S-methyl perillate, R-ethyl perillate, S-perilla alcohol, S-perillyl succinate, The following substances used as preservatives in the cosmetics industry were used as reference substances:
  • the bacteria and the yeast were applied to the Müller-Hinton agar as a preculture with a defined number of cells and plated out. About 5 x 10 s CFUs (colony forming units) were applied to each plate. A sufficient amount of a stock culture plate was taken from Aspergillus niger and plated onto Müller-Hinton agar. After the inoculated plates had dried, filter sheets (cellulose, grade 740e, Schleicher &Schull; diameter 6 mm) were applied with slight pressure.
  • CFUs colony forming units
  • test substances are dissolved as a 5% solution in dimethyl sulfoxide (with 0.1% Tween 20) and 10 ⁇ l are dropped onto a filter sheet. After a subsequent incubation (24 h), the diameters of the growth-free, clear zones of inhibition (minus the 6 mm filter plate diameter) were measured. The results are shown in Table 1:
  • the macrodilution method with a total volume of 2 ml Müller-Hinton broth was used.
  • a series of test tubes with defined organism inoculum (1 X 10 5 CFU / ml) the same volume of Müller-Hinton broth (1.98 ml) and the same volume of differently concentrated drug solutions (20 ⁇ l) were used. filled.
  • the minimum inhibitory concentration (MIC) represents the lowest concentration (in%) of an active ingredient that prevents the in vitro multiplication of bacteria or yeasts within the specified period of 48 hours.
  • the multiplication of the microorganisms was determined photometrically by measuring the optical density at 600 nm (OD 600 ).
  • the MIC corresponds to the concentration of the active ingredient at which no increase in the OD 600 was found after 48 h of incubation.
  • test strains (and incubation temperatures) were used:
  • Bacillus subtilis DSM 347 (gram-positive; 30 ° C), Micrococcus luteus DSM 1790 (gram-positive; 30 ° C), Esch.erich.ia coli DSM 498 (gram-negative; 37 ° C), Candida kefyr DSM 70073 (Yeast; 30 ° C).
  • Table 2 Results of the macrodilution tests to determine the minimum inhibitory concentration (MIC).
  • the active substance concentration is shown (in% v / v, based on 2 ml total volume) at which no increase in the OD 600 was found after 48 h of incubation.
  • 20 ⁇ l of an active ingredient solution in dimethyl sulfoxide (with 0.1% Tween 20) were used.
  • the incubation was 48 h.
  • the test was carried out in 1.98 ml Müller-Hinton broth.
  • Example 18 Preparation of formulations which contain the compounds according to the invention as antimicrobial substances
  • the compounds can serve, for example, as preservatives or as active substances against certain bacteria, yeasts or molds.
  • the substances bacteria, yeasts or molds can kill or prevent their growth.

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Abstract

L'invention concerne de nouveaux dérivés d'acide de pérille et d'alcool de pérille ainsi que l'utilisation d'acide et d'alcool de pérille et de leurs dérivés en tant qu'agents antimicrobiens agissant contre des bactéries, des levures, des moisissures, et utilisés en particulier dans la fabrication de préparations cosmétiques, dermatologiques, pharmaceutiques ou vétérinaires, des compositions pour la nourriture des animaux et des compositions pour des aliments pour animaux, des produits phytosanitaires, des matières premières de papier ainsi que des préparations techniques. Les agents antimicrobiens sont constitués de produits d'oxydation naturels du monoterpène Δ1,8 (9)- menthadiène (limonène) et des dérivés desdits produits d'oxydation.
PCT/EP2004/001930 2003-02-26 2004-02-26 Agents antimicrobiens contre des bacteries, des levures, et des moisissures WO2004076400A1 (fr)

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CN110464718A (zh) * 2010-08-27 2019-11-19 尼昂克技术公司 包含poh衍生物的药物组合物
US11297835B2 (en) * 2016-01-29 2022-04-12 BRAIN Biotech AG Aqueous compositions of perillic acid compounds
CN115843790A (zh) * 2022-12-04 2023-03-28 吉林大学 一种负载紫苏酸的抗菌水凝胶的制备及应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110464718A (zh) * 2010-08-27 2019-11-19 尼昂克技术公司 包含poh衍生物的药物组合物
US20200078355A1 (en) * 2010-08-27 2020-03-12 Neonc Technologies, Inc. Pharmaceutical compositions comprising poh derivatives
US20220133712A1 (en) * 2010-08-27 2022-05-05 Neonc Technologies, Inc. Pharmaceutical compositions comprising poh derivatives
US11297835B2 (en) * 2016-01-29 2022-04-12 BRAIN Biotech AG Aqueous compositions of perillic acid compounds
CN115843790A (zh) * 2022-12-04 2023-03-28 吉林大学 一种负载紫苏酸的抗菌水凝胶的制备及应用

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