WO2005012210A2 - Preparations a activite antimicrobienne - Google Patents

Preparations a activite antimicrobienne Download PDF

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WO2005012210A2
WO2005012210A2 PCT/EP2004/008605 EP2004008605W WO2005012210A2 WO 2005012210 A2 WO2005012210 A2 WO 2005012210A2 EP 2004008605 W EP2004008605 W EP 2004008605W WO 2005012210 A2 WO2005012210 A2 WO 2005012210A2
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acid
group
butyl
radical
branched
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PCT/EP2004/008605
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German (de)
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WO2005012210A3 (fr
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André RIEKS
Markus KÄHLER
Ulrike Kirchner
Kerstin Wiggenhorn
Mona Kinzer
Sabine Risch
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Dr. Andre Rieks - Labor Für Enzymtechnologie Gmbh
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Publication of WO2005012210A3 publication Critical patent/WO2005012210A3/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61P33/00—Antiparasitic agents

Definitions

  • the present invention relates to the use of perillic acid, geranic acid, citronellic acid and derivatives of geranic acid, citronellic acid, geraniol and citronellol as antimicrobial agents against bacteria, yeasts and / or molds, hereinafter called microorganisms.
  • the present invention relates to the use of the aforementioned antimicrobial active ingredients for the production of cosmetic or pharmaceutical preparations, and of food and feed compositions.
  • the antimicrobial agents are natural monoterpenes and derivatives of their oxidation products. 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 monoterpenes found in various essential oils.
  • a common characteristic of many monoterpenes is a more or less distinctive smell.
  • the group of monoterpenes also includes perillic acid, geraniol and geranic acid as well as citronellol and citronellic acid.
  • Perillic acid forms white, slightly aromatic crystals.
  • Geraniol is an oily, aromatic liquid.
  • Geranic acid is a colorless, slightly aromatic liquid that is soluble in ethanol or DMSO and sparingly soluble in water.
  • Citronellol is a clear liquid with a rose-like aroma.
  • Citronellic acid is a clear, slightly aromatic liquid.
  • the chemical formulas of perillic acid, geranic acid, citronellic acid, citronellol and geraniol are shown below:
  • Monoterpenes are in part effective bactericides, yeasticides or fungicides.
  • monoterpenes with free hydroxyl groups such as, for example, Carvol, Carvacrol,
  • Perilla alcohol was disclosed in DE 692 18 933 T2, which also describes the synthesis of perilla alcohol, as a bacterial and yeast-killing agent. Perillic acid was not mentioned here.
  • DE 27 28 921 C3 proposes the use of farnesol as a bacteriostat in body deodorants because of the specific activity against Corynebacteria and staphylococci, but at an application concentration of at least 0.3% by weight. Farnesol is described herein as ineffective against yeast. Antibacterial activities against gram-negative bacteria (E.
  • Alcohols and aldehydes are already known to have antimicrobial activity.
  • ethanol or propanol as well as formaldehyde have been used as preservatives for a long time.
  • the compound phenoxyethanol which belongs to the phenylhydroxyalkyl ethers, has also long been used as a preservative in the pharmaceutical and cosmetic industry.
  • Eugenol, isoeugenol, citral or hydroxycitral are monoterpenes with free hydroxyl or Aldehyde groups that show antimicrobial activity and are used in cosmetics or pharmaceuticals.
  • aldehydic compounds in particular in cosmetics or pharmaceuticals is very unsafe for health.
  • Aldehydes are known contact allergens.
  • the monoterpene calls perilla aldehyde in contrast to perillic acid, it causes skin irritation (Okazaki et al. Skin Research 24 (1982) 250-256).
  • Motoyoschi et al. (Cosmetics & Toiletries 94 (1979) 41-48) showed that the monoterpenes used as perfume components are Linalool.
  • Geraniol, Citral and citronellol have a significantly greater skin-irritating potential than the esters linalyl acetate or geranyl acetate. Because of their significantly lower allergenic and skin-sensitizing potential, monoterpenic acids or derivatives of monoterpenic acids or alcohols would represent particularly attractive antimicrobial compounds.
  • Lemongrass essential oil consists of approximately 70% citral, coriander oil 74% linalool, cinnamon oil approximately 60% cinnamaldehyde and geranium oil 30% citronellol and 10% linalool.
  • Monoterpenic acids accumulate in plants only in small percentages. Because of the problems mentioned above when using alcohols and aldehydes, the use of most essential oils in cosmetics should be rejected and the application of defined monoterpenic acids should be preferred.
  • monoterpenic acids which include, for example, perillic acid, citronellic acid or geranic acid, derivatives of monoterpene alcohols and derivatives of monoterpenic acids are almost not associated with antimicrobial effects in the literature.
  • the aromatic monoterpene carvacrol has a hydroxyl group which has been found to be essential for the antimicrobial activity of the compound.
  • neither the methyl ester of carvacrol nor cymen, which differs from carvacrol in that it lacks the hydroxyl group has no antimicrobial activity (excellenttee et al. Applied and Environmen tal Microbiology 68 (2002) 1561-1568).
  • Citronellic acid also described other monoterpenic acids or their antimicrobial effects. No antimicrobial effects against microorganisms that cause dandruff, dermatomycoses, body odor or acne are described.
  • the 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 albicans or Saccharomyces cerevisiae.
  • preservatives are therefore added to the products; these are antimicrobial, the term antimicrobial both for the inhibition of the growth and the multiplication of microorganisms and for 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.
  • the allergenic and skin-sensitizing potential, in particular of compounds, including monoterpenes, with a free aldehyde group has already been discussed above.
  • antibacterial compounds normally have no activity against yeasts or fungi, while compounds which act against yeasts and fungi are not or have little antibacterial activity. This phenomenon is found in many antibiotics. Antibacterial antibiotics such as ampicillin or streptomycin are ineffective against fungi, while yeast or mold-killing substances such as nystatin or clotrimazole are ineffective against bacteria.
  • the common preservative phenoxyethanol works especially against gram-negative bacteria and only inadequately against many gram-positive bacteria.
  • 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 antimicrobial substances which are also effective against molds such as Aspergillus, preferably those of natural origin. It is therefore a preferred object of the present invention to provide compounds and compositions which are active against bacteria, yeasts and / or molds, preferably compounds which are simultaneously active against bacteria, yeasts and molds.
  • Lipophilic yeast species especially Malassezia for (formerly Pi tyrosporum ovale) in the mycelium form are responsible for skin changes associated with the formation of dandruff. This organism settles in particular in skin areas with high concentrations of free, long-chain fatty acids. If the sebum glands on the hairy head or face, for example, increasingly excrete sebum (sebum), undesirable and sometimes pathological skin changes can occur as a result of Malassezia furfur being colonized in these regions.
  • Such skin changes are, for example, Pi tyrlasis versi color (bran fungus), Seborrhoea oleosa and Seborrhoea si cca, in particular in the form of dandruff (Seborrhoea capi tis) or Pityrosporum folliculitis.
  • People with such skin scales are usually treated with keratolytic or anti-inflammatory, proliferation-inhibiting (cell division-inhibiting) preparations.
  • Proliferation-inhibiting preparations often contain malodorous active substances, for example tar preparations, or controversial metal compounds such as cadmium, zinc or selenium salts from a health and / or environmentally relevant point of view.
  • the sole use of a keratolytic, for example salicylic acid has only the detachment of the currently existing dandruff Do not follow and eliminate the real cause of dandruff.
  • antimicrobial agents for the cosmetic or pharmaceutical treatment of yeast causing dandruff is particularly attractive, since these agents combat the actual cause of dandruff formation.
  • antifungal agents currently used also include the metal compounds, such as cadmium, zinc or selenium salts, which are controversial from a health and / or environmental point of view, or unpleasant-smelling essential oils such as thyme or rosemary oil.
  • Another problem to be solved is the cosmetic or pharmaceutical treatment of certain dermatomycosis causing microorganisms.
  • the specialist speaks of dermatomycoses when certain types of fungus penetrate the skin, hair, hair follicles as well as fingernails and toenails and consequently symptoms such as blisters, redness, peeling, cracks or erosions, often associated with itching or allergic eczema.
  • yeast mycoses can be caused by facultatively pathogenic Candida species. Mold mycoses occur as a result of infection with, for example, Aspergillus species.
  • dermatomycoses can be combated with antifungal antibiotics.
  • the cosmetic or pharmaceutical prevention and / or treatment of microorganisms causing body odor also plays a special role.
  • Deodorants are used to prevent or treat unpleasant body odors, which are caused by the action of certain skin bacteria on the initially almost odorless sweat due to the formation of strong-smelling decomposition products.
  • molecules are used which only absorb or mask odors, but do not prevent the actual microbial decomposition of sweat.
  • antiperspirants are also used, which prevent or strongly inhibit perspiration, such as the aluminum or zirconium salts, which act as astringents.
  • antiperspirants The effectiveness of the above-mentioned antiperspirants is based on the formation of poorly soluble precipitates, which block the outlets of eccrine sweat glands and consequently suppress the sweat flow. While zirconium salts can form toxic aerosols when used as a pump spray, skin irritation, redness and itching are frequently observed when using aluminum salts, especially acidic aluminum salts.
  • cosmetic or pharmaceutical agents with a deodorant effect are a class of agents which do not affect the volume of sweat, but, because of their antimicrobial action, kill the bacteria involved in the decomposition of sweat. Coryneform bacteria, especially the bacterial species Corynebacteri um xerosis, play a major role in the development of unpleasant body odors.
  • Phenol derivatives with or without halogen substituents, quaternary ammonium compounds or organic mercury compounds are increasingly being critically questioned in the cosmetics industry as antimicrobial agents against Corynebacteri um xerosis.
  • the widely used halogenated phenol derivatives are considered to be harmful to health and often have an unpleasant phenolic smell.
  • the terpene farnesol is used, especially in combination with phexoxyethanol, as an antimicrobial additive to deodorant formulations.
  • Farnesol is not particularly effective against gram-positive bacteria, which also include body odor-causing corynebacteria, in concentrations below 0.5%. Another problem is that farnesol has skin-irritating and allergenic potential.
  • the skin disease acne is characterized by inflammatory or non-inflammatory nodules, starting from blocked hair follicles, which can lead to the formation of blackheads (comedones), pustules, abscesses or scars.
  • blackheads comedones
  • pustules pustules
  • abscesses abscesses or scars.
  • acne vulgaris occurs mainly during puberty.
  • the causes of acne vulgaris include the cornification and constipation of the hair follicle mouths, an increased production of taig and the production of " tissue-damaging enzymes and free fatty acids by the anaerobic, gram-positive, coryneform bacterium Propionibacteri um acnes.
  • Consequences of the metabolic activities of Propionibacteri um acnes are the activation of Complement cascade and the triggering of inflammatory reactions.
  • topical acne treatment in addition to strong skin-irritating comedolytic retinoids, for example tretinoin, in particular antibacterial active substances against Propionibacteri um acnes are used. It is not advisable to administer antibiotics at present, since resistance to the usual antibiotics is advisable , such as erythromycin or clindamycin, are frequently observed in Propionibacterium acnes
  • Antibacterial compounds are benzoyl peroxide or azelaic acid. A topical application of benzoyl peroxide leads to skin irritation such as burning, reddening or scaling in many sufferers.
  • the strong oxidizing agent benzoyl peroxide bleaches hair and clothing.
  • Azelaic acid is less irritating to the skin, but also shows significantly lower antibacterial activities against Propionibacterium acnes.
  • the use of terpenes to treat acne vulgaris has hardly been described. Only the use of a formulation of indole and a natural substance, for example farnesol, citronellol or limonene, is mentioned in US Pat. No. 5,453,276 for the treatment of Propionibacterium acnes. Monoterpenic acids, geraniol or derivatives of geranic acid, citronellic acid, geraniol or citronellol are not described. US Pat. No.
  • 5,175,190 describes the treatment of skin injuries using various acids, including geranic acid.
  • the underlying effect is not antimicrobial but based on cell lysis, triggered by the application of formulations with over 7% acid. In the given concentration, topical application of acids is not recommended due to the tissue-damaging potential.
  • geraniol is suggested as an additive to acne treatment agents. Geraniol is only used as a perfume or penetration enhancer and not as an antimicrobial agent.
  • the tasks are solved by using perillic acid, geranic acid, citronellic acid and compounds derived from geranic acid, citronellic acid, geraniol and citronellol, such as esters, amides and hydroxycarboxylic acid amide esters.
  • the invention relates in particular to compounds of the general formula I.
  • R is CRVo (CO) R 3 , COOR 4 , CONR 5 R 6 , COO (CH 2 ) n CONR 7 R 8 , COR s or COO (CH 2 ) n COR 1 l 0 u , 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, 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 or fatty acid, which is optionally hydroxylated, sulfonated or aminated one to more times,
  • R 4 is a linear or branched alkyl 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, which is optionally hydroxylated once to several times,
  • R 5 and R 6 each independently of one another are hydrogen, an alkyl, a hydroxyalkyl, aminoalkyl, alkylaminoalkyl, Are dialkylaminoalkyl, sulfoalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl or carboxyalkyl radicals, 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 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,
  • 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 3 is hydrogen or a linear or branched alkanyl radical with a chain length of 1 or 3 to 8 carbon atoms from the group consisting of methyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • R 4 is a linear or branched alkanyl radical with one
  • R 5 and R 6 are each independently hydrogen, a linear or branched alkanyl, alkenyl, or alkynyl radical with a chain length of 1 to 8 carbon atoms, where the alkanyl radical from the group consisting of methyl, ethyl, hydroxyethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • R 7 and R 8 independently of one another are hydrogen, a linear or branched alkanyl, alkenyl or alkynyl radical with a chain length of 1 to 5 carbon atoms, the alkanyl radical being selected from the group consisting of methyl, ethyl, hydroxyethyl, Propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • salts essentially means acid addition salts or salts with inorganic acids, but also salts with bases.
  • acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, carbonic acid, sulfur ⁇ acid, toluenesulfonic acid are preferred.
  • preferred basic Salts are lithium, sodium, potassium, calcium, aluminum, magnesium and ammonium salts.
  • the invention relates in particular to compounds of the formula I derived from geraniol or citronellol, in which R is CR 1 (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 is hydrogen or a linear or branched alkyl 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 ⁇ saturated Mono-, di-, tri- or polycarboxylic acid or fatty acid, which is optionally hydroxylated, sulfonated or aminated one to more times,
  • linear or branched alkyl radical is understood to mean a hydrocarbon radical of the general formula C n H 2n + .
  • the residues methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Are explicitly included.
  • 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 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 understood to mean cyclic aliphatic hydrocarbon ring systems which are optionally mono- or polysubstituted, e.g. by alkyl, halogen, hydroxyl and / or amino groups.
  • Non-limiting examples of the branched or unbranched, saturated or unsaturated mono-, di-, tri- or polycarboxylic acids or fatty acids mentioned above and below are:
  • Formic acid acetic acid, propanoic acid, butyric acid, valeric acid, hexanoic acid, sorbic acid, ascorbic acid, lauric acid, palmitic acid, stearic acid, heptanoic acid, octane acid, pelagonic acid, stearic acid, oleic acid, palmitic acid, amic acid, lamic acid, lmoleic acid, lmoleic acid - Steric acid, malonic acid, malic acid, fumaric acid, phthalic acid, adipic acid, pimelic acid, azelaic acid or sebacic acid.
  • the abovementioned acids can also be hydroxylated once 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. wear a sulfo or ammo group.
  • sulfonated acids include Sulfoacetic acid, 3-sulfopropanoic acid, 3-sulfobutanoic acid, homocystic acid, etc.
  • aminated acids are amino acids such as Glycm, Alanin, Glutamm and others.
  • R 3 is hydrogen or a linear or branched alkanyl radical with a chain length of 1 or 3 to 8 carbon atoms from the group consisting of methyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • the invention further relates in particular to compounds of the formula I derived from geranic acid or citronellic acid, in which R is COOR 4 , where R 4 has the meaning given above.
  • esters of formula III This particularly includes esters of formula III
  • R 4 is a linear or branched alkyl radical, alkenyl radical, alkynyl radical, a cycloaliphatic radical, a mono-, di-, tri- or polycyclic aryl radical, an alkyl radical is branched or unbranched, saturated or unsaturated mono-, di-, tri-, or polycarboxylic acid, the carboxylic acid being optionally hydroxylated to multiple, and salts thereof.
  • linear or branched alkyl radicals are: 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 others, i.e. for a hydrocarbon residue that contains one or more C-C double bonds.
  • ⁇ lkmyl stands for e.g. Propyl, 2-butyl, 3-butyl, 4-hexyl, 1-decyl, etc., i. for a hydrocarbon residue containing one or more C-C 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 ammo groups.
  • 'Aryl' can be mono-, di-, tri- or polycyclic aryl such as, for example, phenyl, naphthyl, indenyl, fluorenyl, biphenylyl, indacenyl and the like generally single aromatic carbon rings or condensed aromatic ring systems which are optionally mono- or polysubstituted, such as by alkyl, halogen, OH and / or NH 2 groups.
  • the mono-, di-, tri- or polycarboxylic acids mentioned above can be hydroxylated once or several times.
  • Particularly suitable examples em to five times hydroxylated carboxylic acids, especially glycolic acid, lactic acid, malic acid, hydroxybutyric acid, tartaric acid, lemon ⁇ acid, Isozitronensaure and Glycermsaure.
  • R em is a linear or branched alkanyl radical with a chain length of 1 to 8 carbon atoms from the group consisting of methyl, ethyl, hydroxyethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • the invention relates to amides of the formula IV
  • R 5 and R 6 have the meaning given above
  • R 5 and R 6 independently of one another are hydrogen, an alkyl, a hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfoalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl or carboxyalkyl radical are particularly preferred are, where the alkyl radical, as already explained in detail above under formula III, can be a linear or branched alkanyl, alkenyl, alkynyl radical, an aromatic or cycloaliphatic radical.
  • 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 carries 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 radical.
  • 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.
  • Citronellic acid amide N-methylcitronellic acid amide, N, N-dimethylcitronellic acid amide, N-ethylcitronellic acid amide, N, N-diethylcitronellic acid amide, N-hydroxyethylcitronellic acid amide, N, N-di (hydroxyethyl) citronellic acid amide, N-ethoxycarbonyl-diethylamide, nitronic acid amide, methoxycarbonyl-methylcitronellklamid.
  • R and R ⁇ are each independently hydrogen, a linear or branched alkanyl, alkenyl or alkynyl radical with a chain length of 1 to 8 carbon atoms, the alkanyl radical from the group consisting of methyl, ethyl, hydroxyethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • a further embodiment of the invention relates to hydroxycarboxylic acid amide esters of geranic acid and citronellic 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 geranic acid and citronellic 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 radical where the alkyl radical, as already explained in detail above for formula III, 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 0, S, N and optionally one to more times by linear or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyl, carboxy, alkoxycarboxy, aminocarbonyl Groups is substituted.
  • Examples of such a cyclic (substituted) system include Pyrrolidine, piperidine, morpholine, 4-piperidine and piperazine.
  • Glycolamide geranylate N-hydroxyethylglycolamide geranylate, N-aminoethylglycolamide geranylate, N-methylglycolamide geranylate, N-ethylglycolamide geranylate, N, N-dimethylglycolamide geranylate and N, N-diethylglycolamide geranylate as well
  • Glycolamide citronellate N-hydroxyethylglycolamide citronellate, N-aminoethylglycolamide citronellate, N-methylglycolamide citronellate, N-ethylglycolamide citronellate, N, N-dimethylglycolamide citronellate and N, N-diethylglycolamide citronellate.
  • R and R 8 are independently hydrogen, is a linear or branched alkanyl, alkenyl or alkynyl radical with a chain length of 1 to 5 carbon atoms, the alkanyl radical from the group consisting of methyl, ethyl, hydroxyethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • R 9 is the residue of an amino acid which is bonded to the carbonyl carbon atom via its NH 2 group
  • the amino acids are preferably glycine, alanine, cysteine, serine, threonine, lysine, aspartic acid and glutamic acid.
  • a further embodiment of the invention relates to hydroxycarboxylic acid amide esters of geranic acid and citronellic acid of the formula VII VI I,
  • n is an integer from 1 to 22 and
  • R, 10 is the residue of an amino acid which is bonded to the carbonyl carbon atom via its NH 2 group
  • the amino acids are preferably glycine, alanine, cysteine, serine, threonine, lysine, aspartic acid and glutamic acid.
  • the invention accordingly also relates to all derivatives of geranic acid, citronellic acid, geraniol and citronellol 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 geraniol and / or citronellol.
  • Preferred compounds according to formula II are, for example: Esters of geraniol and a branched or unbranched, saturated or unsaturated mono-, di-, tri- or polycarboxylic acid or polyfatty acid, which is optionally hydroxylated, sulfonated or amidated, and esters of citronellol and a branched or unbranched, saturated or unsaturated mono-, Di-, tri- or polycarboxylic acid or fatty acid, which is optionally hydroxylated, sulfonated or amidated.
  • Examples of such preferred esters of geraniol are: geranyl malate, geranyl succat, geranyl butyrate, geranyl tartrate, geranyl citrate, geranyl glycolate or geranyl glycerate.
  • Citronellylmalate Citronellylsuccmat, Citronellylbutyrat, Citronellyltartrat, Citronellylcitrat, Citronellylglycolat or Citronellylglycerat.
  • Preferred compounds according to formula III are: esters of geranic acid with a linear or branched or cyclic alkyl radical or carboxyalkyl radical of a carboxylic or aromatic radical and esters of citric acid with a linear or branched or cyclic alkyl radical or carboxyalkyl radical of a carboxylic acid or aromatic radical.
  • esters examples include: methyl geranylate, ethyl geranylate, propyl geranylate, butyl geranylate, hexadienylgeranylate, phenylgeranylate, glycylgeranylate, hydroxybutylgeranylate, citrylgeranylate or glycerylgeranylate, and methylcitronellate, ethylcitronitellate, ethyl citronellellate, Phenyl citronellate, glycyl citronellate, hydroxybutyl citronellate, citryl citronellate or glyceryl citronellate.
  • Preferred compounds according to formulas IV and VI are, for example:
  • Geranic acid amides which are derived from geranic acid and various amines, for example also amino acids, according to formulas IV and VI
  • citronellic acid amides which are derived from citronellic acid and various amines, for example also amino acids, according to formulas IV and VI.
  • Examples of such preferred compounds are: geranic acid amide, N-methylgeranic acid amide, N, N-dimethylgeranic acid amide, N-ethylgeranic acid amide, N, N-diethylgeranic acid amide, N-hydroxyethylgeranic acid amide, N, N-di (hydroxyethyl) geranic acid amide, N-
  • Preferred compounds according to formulas V and VII are, for example: hydroxycarboxylic acid amide esters of geranic acid, obtainable by esterifying geranic acid with a hydroxycarboxylic acid amide, and hydroxycarboxylic acid amide esters of citronellic acid, obtainable by esterifying citronellic acid with a hydroxycarboxylic acid amide.
  • glycolamide geranylate N-hydroxyethylglycolamide geranylate, N-aminoethylglycolamide geranylate, N-methylglycolamide geranylate, N-ethylglycolamide geranylate, N, N-dimethylglycolamide geranylate or N, N-diethylglycolamide geranylate, nitrous glycolate, Methyl glycol amide citronellate, N-ethyl glycol amide citronellate, N, N-dimethyl glycol amide citronellate or N, N-diethyl glycol amide citronellate.
  • the compounds according to the invention and mixtures thereof are suitable as antimicrobial active ingredients or active ingredient mixtures • for the preservation of microbially perishable preparations and compositions • and / or for the treatment of undesirable microorganisms on or in food or inanimate matter • and / or for the cosmetic or pharmaceutical treatment of dandruff Microorganisms • and / or for cosmetic or pharmaceutical treatment of certain dermatomycosis-causing microorganisms • and / or for cosmetic or pharmaceutical prevention and / or treatment of body odor-causing microorganisms • and / or for cosmetic or pharmaceutical treatment of acne-causing microorganisms.
  • An essential aspect of the present invention is thus the use of the abovementioned compounds, in particular for combating bacteria, yeasts and / or molds for the simultaneous control of bacteria, yeast and mold.
  • the invention also relates to the use of derivatives of geranic acid, citronellic acid or geraniol and citronellol (with the exception of geranyl acetate and citronellyl acetate) for combating bacteria, yeasts and / or molds, in particular geranic acid, citronellic acid, perillic acid, geranyl acetate and citronellyl acetate for the simultaneous control of bacteria, yeast and mold.
  • 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, taking into account the specific activity against gram-negative or gram-positive bacteria and / or yeasts optimized by the derivatization and / or mold.
  • the derivatization of geranic acid, citronellic acid, geraniol or citronellol can provide new compounds with new, specific effects against gram-positive and / or gram-negative bacteria and / or yeasts and / or molds.
  • perillic acid, geranic acid and / or citric acid to control dandruff-causing microorganisms, especially to combat the dandruff-causing yeast Malassezia furfur, has unexpectedly turned out to be particularly advantageous.
  • the use of perillic acid and / or citronellic acid to combat body odor-causing microorganisms, especially to combat the body odor-causing bacterium Corynebacteri um xerosis has also unexpectedly proven to be particularly advantageous.
  • carboxylic acid amide esters of geranic acid and citronellic acid in particular glycolamide pellet and glycolamide citronellate, have a significantly stronger action against molds such as Aspergillus niger and against yeasts such as Candida kefyr.
  • the invention further relates to the use of one or more compounds from the group consisting of compounds of the formulas I to VII, derivatives of geranic acid, citronellic acid or geraniol and citronellol (except geranyl acetate and citronellyl acetate) for the preparation of compositions for combating bacteria, yeasts and / or molds, in particular geranic acid, citric acid, perillic acid, geranyl acetate and citric acid acetate, for the production of compositions for the simultaneous control of bacteria, yeasts and molds.
  • perillic acid, geranic acid or citronellic acid is used to produce a composition for combating Molds particularly preferred.
  • compositions may optionally also contain phenoxyethanol in addition to the aforementioned compounds.
  • phenoxyethanol in addition to the aforementioned compounds. The antimicrobial effect of phenoxyethanol can thereby be supplemented or enhanced.
  • em aspect of the invention relates to the use of the compounds of the formulas I to VII, which are also active against molds and yeasts, and perilla acid, geranic acid, citronellic acid, geranyl acetate and / or citronellyl acetate in combination with phenoxyethanol, which has only a slight antimicrobial activity against molds and yeasts Manufacture of compositions for the simultaneous control of bacteria, yeasts and molds. Due to the limited spectrum of activity, phenoxyethanol is usually used in combination with such antimicrobial agents - for example chlorhexide - which have the above-mentioned disadvantages with regard to skin irritation, allergies, cancer or environmental pollution. These disadvantages are avoided by the combinations according to the invention.
  • a preferred aspect of the present invention is the use of one or more compounds from the group consisting of compounds of the formulas I to VII, perillic acid, geranic acid, citronellic acid, citronellol, geranyl acetate and / or citronellyl acetate for the preparation of compositions for treating dandruff-causing microorganisms and of Perillic acid, geranic acid, citric acid, geraniol, geranyl acetate and / or citric acid acetate for the preparation of compositions for Treatment of acne-causing microorganisms or the use of one or more compounds from the group consisting of compounds of the formulas I to VII, perillic acid, citric acid, geranyl acetate and / or citric acid acetate for the preparation of compositions for the treatment of body odor-causing microorganisms or the use of one or several compounds from the group consisting of compounds of the formulas I to VII, perillic acid, citronellic acid,
  • the composition can be an agent for the preservation of cosmetic, dermatological or pharmaceutical preparations.
  • the composition can generally be a means of preserving water-containing preparations.
  • the composition is preferably an ointment, a cream, a hydrogel, an emulsion, a lotion, a paste, a tincture, a shampoo, a pump spray, a toothpaste, a cleansing milk, a soap, a mouthwash or a juice.
  • the composition is a food preservative.
  • composition that is a means of preserving fruits, vegetables, and live animals.
  • a use in which the living animals are lobsters, mussels or oysters is particularly preferred.
  • Another preferred aspect is a use in which the composition is an agent for treating casings,
  • the invention relates to the use for the production of a crop protection agent.
  • composition is particularly preferably a pharmaceutical preparation.
  • the composition is a means of preserving technical preparations such as paints, varnishes, wood preservatives, glues or a component of wall mold removal preparations which is effective against wall mold.
  • a particular advantage of the use according to the invention of compounds of the formula I to VII, of perillic acid, geranic acid, citronellic acid, geraniol, citronellol, citronellyl acetate and / or geranyl acetate is that the use of conventional, but in particular several different preservatives can be dispensed with, since for the above-mentioned active substances in the context of the present invention, both antibacterial activity and activity against yeasts and molds have been demonstrated.
  • perillic acid, geranic acid, citronellic acid, geraniol and citronellol are naturally occurring compounds.
  • Cosmetic, dermatological or pharmaceutical preparations, food or pesticides as well as technical preparations such as paints, varnishes, wood preservatives or wall mold removers which contain one or more compounds of the formulas I to VII and, if appropriate, additionally perillic acid, geranic acid, citronellic acid, geraniol, citronellol, citronelly acetate and / or contain Gernay acetate form a further aspect of the invention.
  • Preferred cosmetic, dermatological or pharmaceutical preparations, foods, crop protection agents or technical preparations are those which contain the compound or compounds from the group consisting of compounds of the formulas I to VII, perillic acid, geranic acid, citronellic acid, geraniol, citronellol, citronelly acetate and / or Gernay acetate in a total concentration of 0.001 to 10% by weight, preferably 0.1 to 2% by weight.
  • the present invention likewise relates to processes for the preparation of compounds of the formulas III, IV, V, VI and VII, in which geranic acid or citronellic acid is esterified chemically or enzymatically with alcohols or hydroxylated carboxylic acids or geranic acid or citronellic acid is amidated with amines or amino acids or geranic acid or Citronellic acid esterified with a chlorocarboxamide.
  • N-substituted chlorocarboxamides the process is modified in such a way that the amide function of a compound of the formula III in which R 4 is an alkenyl radical such as propenyl, 2-butenyl, 3-butenyl, 3-pentenyl or 1,3-hexadienyl, or an alkynyl radical, such as propynyl, 2-butynyl, 3-butynyl, 4-hexynyl or 1-decynyl, is converted into the corresponding carboxylic acid by base-catalyzed hydrolysis and subsequently converted into the corresponding carboxylic acid chloride by halogenating agents, which is then substituted with an appropriate N-substituted one Amine is implemented.
  • R 4 is an alkenyl radical such as propenyl, 2-butenyl, 3-butenyl, 3-pentenyl or 1,3-hexadienyl
  • an alkynyl radical such as propynyl,
  • This assay was used to test the growth inhibition of gram-negative and gram-positive bacteria, yeasts and molds.
  • agar diffusion test In the agar diffusion test, growth-free zones of inhibition result from the diffusion of an antimicrobial agent from a filter sheet into a solid, inoculated medium. The size of the zone of inhibition depends on the antimicrobial effect.
  • the testing was carried out on a reference medium standardized according to DIN 58940, the Müller-Hinton agar.
  • the Testing against Propionibacteri um acnes was carried out on anaerobic cooking meat medium (medium 78, DSMZ). Malassezia furfur was tested on Pityrosporum medium (Medium 472, DSMZ). Petri dishes with a diameter of 9 cm were used, into which 20 +/- 1 ml of medium were filled.
  • test strains (at the indicated incubation temperature) were used: Bacill us subtilis DSM 347 (gram ⁇ positive; 30 ° C), Micrococcus l uteus 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), Aspergill us niger DSM 1988 (mold; 30 ° C).
  • the yeast Malassezia furfur DSM 6171 (30 ° C.) was used to test the antimicrobial activity against dandruff-causing microorganisms.
  • the yeast Candida albicans was used to test the antimicrobial activity against microorganisms causing dermatomycoses
  • the gram-positive, anaerobic, coryneform bacterium Propionibacteri by acnes DSM was used to test the antimicrobial activity against acne-causing microorganisms
  • Geranium acid citric acid, perilla acid, glycolamide geranylate, N, N-diethylglycolamide geranylate,
  • Phenylethanol, R-limonene, linalool Phenylethanol, R-limonene, linalool.
  • the bacteria and yeasts were applied to the agar plates as a preculture with a defined number of cells and plated out. Per plate approximately 5 x 10 5 CFUs (colony forming units ⁇ ) were abandoned. A sufficient amount of a stock culture plate was removed from the Aspergillus niger and plated out. After the inoculated plates had dried, filter sheets (cellulose, grade 740e, Schleicher &Schull; diameter 6 mm) were applied with slight pressure.
  • test substances are dissolved as a 5% solution in dimethyl sulfoxide (with 0.1% Tween 20) and 10 .mu.l in each case are dropped on a filter pad. After a subsequent incubation (24 h), the diameters of the growth-free, clear zones of inhibition were measured. The results are shown in Tables 1 and 2: Table 1: Results of the agar diffusion test (diameter of the inhibition zones in mm) 10 ⁇ l of a 5% active ingredient solution of dimethyl sulfoxide (with 0.1% Tween 20) were used in each case. The incubation was carried out for 24 hours.
  • Table 2 Results of the agar diffusion test (diameter of the inhibition zones in mm) 10 ⁇ l of a 5% active ingredient solution in dimethyl sulfoxide (with 0, Tween 20) were used in each case. The incubation was carried out for 24 hours.
  • the macrodilution method with a total volume of 2 ml of medium was used. Malassezia furfur was tested in Pityrosporum medium, Propionibacteri um acnes in cooking meat broth and all other microorganisms in Müller-Hinton broth. To determine the MIC, 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
  • the multiplication of the microorganisms was determined photometrically by measuring the optical density at 600 nm (OD 60 o).
  • the MIC corresponds to the concentration of the active ingredient, in which no increase in OD 6 oo after 48 h of incubation was determined.
  • test strains (and incubation temperatures) were used:
  • Bacillus subtilis DSM 347 (gram-positive; 30 ° C), Micrococcus luteus DSM 1790 (gram-positive; 30 ° C), Escheri chia coli DSM 498 (gram-negative; 37 ° C), Candida kefyr DSM 70073 (yeast; 30 ° C);
  • Candida albicans DSM 1665 (dermatomycosis-causing yeast, 30 ° C); Propionibacteri um acnes DSM 1897 (acne causing, gram positive, 37 ° C);
  • Corynebacteri um xerosis DSM 20743 body odor, gream positive, 37 ° C. Molds cannot be cultivated under the conditions of this method.
  • Geranium acid citric acid, perilla acid,
  • Table 3 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 OD 6 oo 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 of medium.
  • Citric acid 0.05% 0.08% 0.08% 0.015%
  • Table 4 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 OD ⁇ oo 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 medium.
  • Geranic acid amides of geranic acid, esters of
  • Geranic acid, geraniol or esters of geraniol are Geranic acids, geraniol or esters of geraniol
  • Citronellic acid Citronellic acid, amides of citronellic acid, esters of citronellic acid, citronellolol or esters of citronellol are prepared.
  • the term "geranium compound” is used for all of the substances mentioned.
  • the term “formulations” is used here as a synonym for the term “preparations”.
  • the compounds can serve, for example, as preservatives or as active substances against certain bacteria, yeasts or molds. If the formulations are mixed with the compounds according to the invention, the substances can kill bacteria, yeasts or mold or prevent their growth.

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Abstract

L'invention concerne l'utilisation d'acide périllique, d'acide géranique, d'acide citronellique, et de dérivés d'acide géranique, d'acide citronellique, du géraniol et du citronellol, en tant que principes actifs antimicrobiens contre des bactéries, des levures et/ou des hyphomycètes, ci-après désignés par « micro-organismes ». L'invention concerne en particulier l'utilisation des principes actifs antimicrobiens précités pour la production de préparations cosmétiques ou pharmaceutiques, ainsi que de compositions de produits alimentaires et de produits pour l'alimentation des animaux. On mentionne comme principes actifs antimicrobiens, des monoterpènes naturels et des dérivés de leurs produits d'oxydation.
PCT/EP2004/008605 2003-08-01 2004-07-30 Preparations a activite antimicrobienne WO2005012210A2 (fr)

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DE10335634A DE10335634B4 (de) 2003-08-01 2003-08-01 Verwendung von Perilla-, Geranium- und Citronellsäure sowie ausgewählten Derivaten zur Konservierung, zur Behandlung von Akne, Schuppen oder Dematomykosen sowie zur Bekämpfung Körpergeruch verursachender Mikroorganismen

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Cited By (7)

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WO2012107252A2 (fr) 2011-02-07 2012-08-16 Firmenich Sa Ingrédients aromatisants et compositions aromatisantes antifongiques
DE102011077070A1 (de) * 2011-06-07 2012-12-13 Beiersdorf Ag Wirkstoffkombinationen aus Epsilon-Polylysin und einem oder mehreren Estern mit Terpenstruktur
CZ303724B6 (cs) * 2012-03-09 2013-04-03 Univerzita Tomáse Bati ve Zlíne Antimikrobiální komponenta a její pouzití
WO2013087401A1 (fr) 2011-12-13 2013-06-20 Firmenich Sa Compositions aromatisantes antifongiques
FR2990857A1 (fr) * 2012-05-25 2013-11-29 Oreal Utilisation cosmetique d'une huile essentielle obtenue a partir d'une monarde hybride enrichie en geraniol comme actif deodorant
CN104892446A (zh) * 2015-05-25 2015-09-09 江苏耐雀生物工程技术有限公司 芳樟醇的酰胺类衍生物及其制法与其在抗菌中的应用
CN104918614A (zh) * 2012-09-28 2015-09-16 株式会社资生堂 Vegfc产生促进剂

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ES2715509T3 (es) 2016-01-29 2019-06-04 Brain Biotechnology Res & Information Network Ag Composiciones acuosas de compuestos de ácido perílico
WO2017129338A1 (fr) * 2016-01-29 2017-08-03 B.R.A.I.N. Biotechnology Research And Information Network Ag Associations actives d'acide périllique et de substances renforçant l'activité

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JPH05271073A (ja) * 1992-02-10 1993-10-19 Takasago Internatl Corp 抗緑膿菌剤
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012107252A2 (fr) 2011-02-07 2012-08-16 Firmenich Sa Ingrédients aromatisants et compositions aromatisantes antifongiques
DE102011077070A1 (de) * 2011-06-07 2012-12-13 Beiersdorf Ag Wirkstoffkombinationen aus Epsilon-Polylysin und einem oder mehreren Estern mit Terpenstruktur
WO2013087401A1 (fr) 2011-12-13 2013-06-20 Firmenich Sa Compositions aromatisantes antifongiques
CZ303724B6 (cs) * 2012-03-09 2013-04-03 Univerzita Tomáse Bati ve Zlíne Antimikrobiální komponenta a její pouzití
WO2013131498A2 (fr) 2012-03-09 2013-09-12 Tomas Bata University In Zlin Constituant antimicrobien et son utilisation
FR2990857A1 (fr) * 2012-05-25 2013-11-29 Oreal Utilisation cosmetique d'une huile essentielle obtenue a partir d'une monarde hybride enrichie en geraniol comme actif deodorant
CN104918614A (zh) * 2012-09-28 2015-09-16 株式会社资生堂 Vegfc产生促进剂
CN104892446A (zh) * 2015-05-25 2015-09-09 江苏耐雀生物工程技术有限公司 芳樟醇的酰胺类衍生物及其制法与其在抗菌中的应用

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