Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/005—Antimicrobial preparations
• • 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
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
• • 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
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
  • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
• • 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—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor 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—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using chemical substances
  • A61L2/18—Liquid substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
  • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
  • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
  • C11D3/16—Organic compounds
  • C11D3/26—Organic compounds containing nitrogen
  • C11D3/28—Heterocyclic compounds containing nitrogen in the ring
• • C—CHEMISTRY; METALLURGY
  • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
  • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
  • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
  • C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
• • D—TEXTILES; PAPER
  • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
  • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
  • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
  • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
  • D06M13/35—Heterocyclic compounds
  • D06M13/355—Heterocyclic compounds having six-membered heterocyclic rings
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T442/00—Fabric [woven, knitted, or nonwoven textile or cloth, etc.]
  • Y10T442/20—Coated or impregnated woven, knit, or nonwoven fabric which is not [a] associated with another preformed layer or fiber layer or, [b] with respect to woven and knit, characterized, respectively, by a particular or differential weave or knit, wherein the coating or impregnation is neither a foamed material nor a free metal or alloy layer
  • Y10T442/2525—Coating or impregnation functions biologically [e.g., insect repellent, antiseptic, insecticide, bactericide, etc.]

Definitions

• the present invention relates to the use of substituted 2 J 4-bis(alkylamino)pyrimidines in the antimicrobial treatment of surfaces and to the preparation of such compounds.
• the present invention relates to the use of 2 ] 4-bis(alkylamino)pyrimidines of formula
• Ri is CrC 12 alkyl or C 6 -C ⁇ 0 aryl
• R 2 is hydrogen or CrC 12 alkyl; or R. and R 2 together form a radical of formula
• R' and R" are each independently of the other hydrogen, CrC ⁇ alkyl or CrC 6 alkoxy;
• R 3 and R 5 are each independently of the other hydrogen or C ,-C 8 alkyl
• F ⁇ is C C 20 alkyl, unsubstituted phenyl, C 6 -C 10 aryl, preferred C 7 -C 10 aryl; C 6 -C 10 aryl-C ⁇ - C 6 alkyl, hydroxy-CrC 6 alkyI, di-C ⁇ -C 6 alkylamino-C.-C 6 alkyl, mono-CrC ⁇ alkylamino-Cr C 6 alkyl, -(CH 2 ) 2 -(0-(CH 2 ) 2 ) 1-4 -OH or -(CH 2 ) 2 -(O-(CH 2 ) 2 ) 1-4 -NH 2 ;
• R 6 is C 1 -C 2 oalkyI, Ce-Ci . aryl, Ce-Cioaryl-C Cealkyl, hydroxy-CrC 6 alkyl, di-CrC ⁇ alkylamino-CrCealkyl, mono-Ci-Cealkylamino-CrCealkyl,
• R 3 and R and/or R 5 and R 6 together form a pyrrolidine, piperidine, hexamethyleneimine or morpholine ring; in the antimicrobial treatment of surfaces.
• C ⁇ -C 20 Alkyl is straight-chain or branched alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, hexyl, isohexyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl or eicosyl.
• alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or
• Alkyl is straight-chain or branched alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, hexyl, isohexyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl or dodecyl.
• alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, hexyl, isohexyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl or
• CrC 8 Alkyl is straight-chain or branched alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, isohexyl, hexyl, heptyl, octyl or isooctyl.
• d-OAIkyl is straight-chain or branched alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
• C 3 -C 8 lkyl is straight-chain or branched alkyl, e.g. n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, amyl, isoamyl or tert-amyl, isohexyl, hexyl, heptyl, octyl or isooctyl, especially hexyl.
• d-C ⁇ Alkyl is straight-chain or branched alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, hexyl or isohexyl.
• CrC ⁇ Alkoxy is a straight-chain or branched radical, e.g. methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.
• C 6 -C 10 Aryl denotes naphthyl and especially phenyl.
• C ⁇ -CioAryl radicals may be unsubstituted or may carry one or more, for example one, two, three or four, identical or different substituents, which may be in any desired position(s). Examples of such substituents are
• C-i-C ⁇ alkyl halogen, hydroxy, C C 4 alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, d-C 4 - alkoxycarbonyl, aminocarbonyl, amino, C C4alkylamino, di-C- ⁇ -C 4 alkylamino and C 1 -C4- alkylcarbonylamino.
• R 1 is C ⁇ -C 8 alkyl or phenyl; or to compounds of formula (1) wherein
• R 2 is hydrogen or C 3 -C 8 alkyl; or to compounds of formula (1) wherein
• R 3 and R 5 are each independently of the other hydrogen or CrC 8 alkyl; or to compounds of formula (1) wherein
• R . is C ⁇ -C 12 alkyl, unsubstituted phenyl, C 6 -C ⁇ oaryl-C ⁇ -C 6 alkyl, hydroxy-C 2 -C 6 alkyl, di-d-C 4 - alkylamino-C ⁇ -C 4 alkyl, mono-CrC 4 alkylamino-C ⁇ -C 4 alkyl, -(CH 2 ) 2 -(O-(CH 2 ) 2 ) ⁇ , 2 -OH or -(CH 2 ) 2 -(O-(CH 2 ) 2 ) ⁇ , z -NH 2 ; and R 6 is CrC ⁇ alkyl, C 6 -C ⁇ oaryl, C6-C ⁇ oaryl-d-C 6 alkyl, hydroxy-C 2 -C 6 alkyl, di-C ⁇ -C alkylamino-C ⁇ -C 4 alkyl, mono-C ⁇ -C alkylamino-C ⁇ -C alkyl, -(
• R' is hydrogen, C C 3 alkyl or C C 3 alkoxy;
• R" is d-C 3 alkyl or C C 3 alkoxy;
• R 3 and R 5 are each independently of the other hydrogen or C ⁇ -C 8 alkyl; and R 4 and R 6 are each independently of the other d-C ⁇ alkyl, phenyl-d-C 3 alkyl, hydroxy-C ⁇ -C 6 - alkyl or di-C ⁇ -C 6 alkylamino-C ⁇ -C 6 alkyl, mono-d-C 6 alkylamino-C ⁇ -C 6 alkyl, -(CH 2 ) 2 -(O-(CH 2 ) 2 ) 1-4 -OH or -(CH 2 ) 2 -(O-(CH 2 ) 2 ) 1-4 -NH 2 ; or R 3 and R 4 and/or R 5 and R 6 together form a pyrrolidine, piperidine, hexamethyleneimine or morpholine ring.
• R 2 is hydrogen or hexyl; or R-, and R 2 together form a radical of formula (1a) wherein R' is hydrogen, C ⁇ -C 3 alkyl or C.-C 3 alkoxy, and R" is C C 3 alkyl or C C 3 alkoxy;
• R 3 and R 5 are each independently of the other hydrogen or C r C 8 alkyl;
• R 4 is d-d 2 alkyl, unsubstituted phenyl, C 6 -C 10 aryl-CrC 6 alkyl, hydroxy-C 2 -C 6 alkyl, di-d-d- alkylamino-C C 4 alkyl, mono-C ⁇ -C 4 alkylamino-d-C 4 aIkyl, -(CH 2 ) 2 -(O-(CH 2 ) 2 ) ⁇ , 2 -OH or -(CH 2 )2-(O-(CH 2 ) 2 ) 1 ,2-NH 2 ; and R 6 is CrC ⁇ 2 alkyl, C 6 -C ⁇ oaryl, C 6 -C ⁇ oaryl-C ⁇ -C 6 alkyl, hydroxy-C 2 -C 6 alkyl, di-d-C 4 alkyl- amino-CrC alkyl, mono-d-C 4
• the compounds used according to the invention are prepared according to methods known perse.
• the substituted 2,4-bis(alkylamino)pyrimidines are obtained by reacting the corresponding dichloropyrimidine compound (formula (1b)) with a primary or secondary amine - depending upon the meanings of the radicals R 3 and R 5 - in a suitable solvent, e.g. DMF, di- oxa ⁇ e, toluene, xylene, ethanol or butanol, and an auxiliary base, e.g. triethylamine, DIEA, sodium carbonate, potassium carbonate, etc., or using an excess of the amine compound, for a period of from 1 to 24 hours at 40-150°C.
• a suitable solvent e.g. DMF, di- oxa ⁇ e, toluene, xylene, ethanol or butanol
• an auxiliary base e.g. triethylamine, DIEA, sodium carbonate
• guanidine compound with a suitable ⁇ -keto ester using an auxiliary base, e.g. sodium carbonate, potassium carbonate, sodium ethanolate, sodium methanolate or potassium tert-butanolate, in a suitable solvent, e.g. methanol, ethanol, butanol, tert-butanol, tetrahydrofuran, dimethyl- formamide, acetonitrile, toluene or xylene, for a period of from 1 hour to 24 hours at a temperature of from 40 to 150°C.
• the resulting 2-alkylamino-4-hydroxy-pyrimidine is then converted into the corresponding 2-alkylamino-4-chloro-pyrimidine compound according to customary methods by means of phosphorus oxychloride.
• the substituted 2,4-alkylamino-pyrimidines are obtained by reacting the 2-alkylamino-4- chloro-pyrimidine compound with a primary or secondary amine (R R 5 NH) in a suitable solvent, e.g. methanol, ethanol, butanol, tetrahydrofuran, dimethylformamide, dioxane, toluene or xylene, and an auxiliary base, e.g. triethylamine, DIEA, sodium carbonate, potassium carbonate or an excess of amine, for a period of from 1 to 24 hours at a temperature of from 40 to 150°C.
• a suitable solvent e.g. methanol, ethanol, butanol, tetrahydrofuran, dimethylformamide, dioxane, toluene or xylene
• an auxiliary base e.g. triethylamine, DIEA, sodium carbonate, potassium carbonate or an excess of amine, for
• the 2,4-bis(alkylamino)pyrimidines used according to the invention exhibit a pronounced antimicrobial action, especially against pathogenic gram-positive and gram-negative bacteria and against bacteria of skin flora, and also against yeasts and moulds. They are therefore suitable especially in the disinfection, deodorisation and the general and antimicrobial treatment of the skin and mucosa and also of integumentary appendages (hair), more especially in the disinfection of the hands and of wounds.
• the invention therefore relates also to a personal care preparation comprising at least one compound of formula (1) as well as cosmetically tolerable carriers or adjuvants.
• the personal care preparation according to the invention contains from 0.01 to 15 % by weight, preferably from 0.1 to 10 % by weight, based on the total weight of the composition, of a compound of formula (1) and cosmetically tolerable adjuvants.
• the personal care preparation will comprise, in addition to the 2,4-bis(alkyIamino)pyrimidine of formula (1 ), further constituents, for example sequestering agents, colourings, perfume oils, thickening or solidifying agents (consistency regulators), emollients, UV absorbers, skin-protective agents, antioxidants, additives that improve mechanical properties, such as dicarboxylic acids and/or Al, Zn, Ca and Mg salts of C ⁇ -C 22 atty acids, and optionally preservatives.
• further constituents for example sequestering agents, colourings, perfume oils, thickening or solidifying agents (consistency regulators), emollients, UV absorbers, skin-protective agents, antioxidants, additives that improve mechanical properties, such as dicarboxylic acids and/or Al, Zn, Ca and Mg salts of C ⁇ -C 22 atty acids, and optionally preservatives.
• the personal care preparation according to the invention may be formulated as a water-in-oil or oil-in-water emulsion, as an alcoholic or alcohol-containing formulation, as a vesicular dispersion of an ionic or non-ionic amphiphilic lipid, as a gel, a solid stick or as an aerosol formulation.
• the cosmetically tolerable adjuvant contains preferably from 5 to 50 % of an oily phase, from 5 to 20 % of an emulsifier and from 30 to 90 % water.
• the oily phase may contain any oil suitable for cosmetic formulations, e.g. one or more hydrocarbon oils, a wax, a natural oil, a silicone oil, a fatty acid ester or a fatty alcohol.
• Pre- ferred mono- or poly-ols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.
• Cosmetic formulations according to the invention may be used in a variety of fields. Especially the following preparations, for example, come into consideration: skin-care preparations, e.g. skin-washing and cleansing preparations in the form of tablet-form or liquid soaps, synthetic detergents or washing pastes; bath preparations, e.g. liquid (foam baths, milks, shower preparations) or solid bath preparations, e.g. bath cubes and bath salts; - skin-care preparations, e.g. skin emulsions, multi-emulsions or skin oils; cosmetic personal care preparations, e.g.
• skin-care preparations e.g. skin-washing and cleansing preparations in the form of tablet-form or liquid soaps, synthetic detergents or washing pastes
• bath preparations e.g. liquid (foam baths, milks, shower preparations) or solid bath preparations, e.g. bath cubes and bath salts
• - skin-care preparations e.g. skin
• eye-care preparations e.g. eyeshadow preparations, mascara, eyeliner, eye creams or eye-fix creams
• lip-care preparations e.g. lipsticks, lip gloss, lip contour pencils
• nail-care preparations such as nail varnish, nail varnish removers, nail hardeners or cuticle removers
• intimate hygiene preparations e.g. intimate washing lotions or intimate sprays
• foot-care preparations e.g.
• foot baths foot powders, foot creams or foot balsams, special deodorants and antiperspirants or callus-removing preparations
• - light-protective preparations such as sun milks, lotions, creams and oils, sun blocks or tropicals, pre-tanning preparations or after-sun preparations
• skin-tanning preparations e.g. self-tanning creams
• depigmenting preparations e.g. preparations for bleaching the skin or skin-lightening preparations
• - insect-repellents e.g.
• insect-repellent oils lotions, sprays or sticks
• deodorants such as deodorant sprays, pump-action sprays, deodorant gels, sticks or roll-ons
• antiperspirants e.g. antiperspirant sticks, creams or roll-ons
• preparations for cleansing and caring for blemished skin e.g. synthetic detergents (solid or liquid), peeling or scrub preparations or peeling masks
• shaving preparations e.g.
• fragrance preparations e.g. fragrances (eau de Cologne, eau de toilette, eau de perfume, perfume de toilette, perfume), perfume oils or cream perfumes
• dental-care, denture-care and mouth-care preparations e.g. toothpastes, gel toothpastes, tooth powders, mouthwash concentrates, anti-plaque mouthwashes, denture cleaners or denture fixatives
• cosmetic hair-treatment preparations e.g. hair-washing preparations in the form of shampoos and conditioners, hair-care preparations, e.g.
• pretreatment preparations hair tonics, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments, hair-structuring preparations, e.g. hair-waving preparations for permanent waves (hot wave, mild wave, cold wave), hair-straightening preparations, liquid hair- setting preparations, hair foams, hairsprays, bleaching preparations, e.g. hydrogen peroxide solutions, lightening shampoos, bleaching creams, bleaching powders, bleaching pastes or oils, temporary, semi-permanent or permanent hair colourants, preparations containing self-oxidising dyes, or natural hair colourants, such as henna or camomile.
• hair-structuring preparations e.g. hair-waving preparations for permanent waves (hot wave, mild wave, cold wave), hair-straightening preparations, liquid hair- setting preparations, hair foams, hairsprays, bleaching preparations, e.g. hydrogen peroxide solutions, lightening shampoos, bleaching cream
• An antimicrobial soap has, for example, the following composition:
• stearic acid ad 100 % soap base, e.g. the sodium salts of tallow fatty acid and coconut fatty acid or glycerol.
• a shampoo has, for example, the following composition: 0.01 to 5 % by weight of a compound of formula (1) 12.0 % by weight sodium laureth-2-sulfate 4.0 % by weight cocamidopropyl betaine 3.0 % by weight NaCI and water ad 100 %.
• a deodorant has, for example, the following composition: 0.01 to 5 % by weight of a compound of formula (1 ) 60 % by weight ethanol 0.3 % by weight perfume oil and water ad 100 %.
• the invention relates also to an oral composition containing from 0.01 to 15 % by weight, based on the total weight of the composition, of a compound of formula (1) and orally tolerable adjuvants.
• the oral composition according to the invention may be, for example, in the form of a gel, a paste, a cream or an aqueous preparation (mouthwash).
• the oral composition according to the invention may also comprise compounds that release fluoride ions which are effective against the formation of caries, for example inorganic fluoride salts, e.g. sodium, potassium, ammonium or calcium fluoride, or organic fluoride salts, e.g. amine fluorides, which are known under the trade name Olafluor.
• fluoride ions which are effective against the formation of caries
• inorganic fluoride salts e.g. sodium, potassium, ammonium or calcium fluoride
• organic fluoride salts e.g. amine fluorides, which are known under the trade name Olafluor.
• the 2,4-bis(alky!amino)pyrimidines of formula (1) used according to the invention are also suitable for the treatment, especially preservation, of textile fibre materials.
• Such materials are undyed and dyed or printed fibre materials, e.g. of silk, wool, polyamide or poly- urethanes, and especially cellulosic fibre materials of all kinds.
• Such fibre materials are, for example, natural cellulose fibres, such as cotton, linen, jute and hemp, as well as cellulose and regenerated cellulose.
• Preferred suitable textile fibre materials are made of cotton.
• the 2,4-bis(alkylamino)pyrimidines according to the invention are also suitable for the treatment of plastics, especially for imparting antimicrobial properties to or preserving plastics, e.g. polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc..
• Plastics e.g. polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc.
• Fields of use therefor are, for example, floor coverings, plastics coatings, plastics container and packaging materials; kitchen and bathroom utensils (e.g. brushes, shower curtains; sponges, bathmats), latex, filter materials (air and water Filters), plastics articles used in the field of medicine, e.g. dressing materials, syringes, catheters etc., so-called “medical devices", gloves and mattresses.
• Paper for example papers used for hygiene purposes, may also be provided with antimicrobial properties using the 2,4-bis(alkyIamino)pyrimidines of formula (1) according to the invention.
• nonwovens e.g. nappies/diapers, sanitary towels, panty liners, and cloths for hygiene and household uses
• nonwovens e.g. nappies/diapers, sanitary towels, panty liners, and cloths for hygiene and household uses
• the 2,4-bis(alkylamino)pyrimidines of formula (1) are also used in washing and cleaning formulations, e.g. in liquid and powder washing agents or softeners.
• the 2,4-bis(alkylamino)pyrimidines of formula (1) may especially also be used in household and all-purpose cleaners for cleaning and disinfecting hard surfaces.
• a cleaning preparation has, for example, the following composition: 0.01 to 5 % by weight of a compound of formula (1) 3.0 % by weight octyl alcohol 4EO 1.3 % by weight fatty alcohol C 8 -C ⁇ 0 polyglucoside 3.0 % by weight isopropanol ad 100 % by weight water.
• the preservation of technical products In addition to preserving cosmetic and household products, the preservation of technical products, the provision of technical products with antimicrobial properties and use as a biocide in technical processes are also possible, for example in paper treatment, especially in paper treatment liquors, in printing ink thickeners consisting of starch or of cellulose derivatives, in surface-coating compositions and in paints.
• the 2,4-bis(alkylamino)pyrimidines of formula (1) are also suitable for the antimicrobial treatment of wood and for the antimicrobial treatment of leather, the antimicrobial preservation of leather and the provision of leather with antimicrobial properties.
• the compounds according to the invention are also suitable for the protection of cosmetic products and household products from microbial spoilage.
• the 2,4-bis(alkyIamino)pyrimidines of formula (1) according to the invention are moreover capable of penetrating biofilms on living and non-living surfaces, of preventing the adhesion of bacteria to surfaces and any further build-up of the biofilm, of detaching such biofilm and/or inhibiting the further growth of the biofilm-forming micro-ogranisms in the biological matrix, or of killing such micro-organisms.
• Biofilms are understood, very generally, to be aggregations of living and dead micro- organisms, especially bacteria, that adhere to living and non-living surfaces, together with their metabolites in the form of extracellular polymeric substances (EPS matrix), e.g. poly- saccharides.
• EPS matrix extracellular polymeric substances
• the activity of antimicrobial substances that normally exhibit a pronounced growth-inhibiting or lethal action with respect to planktonic cells may be greatly reduced with respect to microorganisms that are organised in biofilms, for example because of inadequate penetration of the active substance into the biological matrix.
• this relates, very especially, to biofilms on human tooth surfaces and oral mucosa, which play a crucial role in the onset of degenerative diseases in the oral cavity, e.g. caries or periodontitis, as a result of the biofilm-forming micro-organisms or their metabolites.
• Example 3 Preparation of N,N'-bis(2,4-diphenylethylamino)-6-methylpyrimidine (PY9) 8.15 g of 2,4-dichloro-6-methyl-pyrimidine (50 mmol) are heated with 18.17 g of phenyl- ethylamine (150 mmol) and 20.73 g of potassium carbonate (150 mmol) in 20 ml of dioxane for 16 hours at 100°C. After cooling, the product is taken up in 300 ml of ethyl acetate and washed with 0.5 mol/litre of sodium hydroxide solution and saturated sodium chloride solution.
• PY9 Preparation of N,N'-bis(2,4-diphenylethylamino)-6-methylpyrimidine (PY9) 8.15 g of 2,4-dichloro-6-methyl-pyrimidine (50 mmol) are heated with 18.17 g of phenyl- ethylamine (150 m
• Example 6 Reaction of 4-chloro-2-phenylamino-6-phenylpyrimidine with amines The reactions are carried out in parallel robotically.
• the compounds (PY10) - (PY29) (see Table 1) are prepared according to this method. They were analysed by LC-MS.
• Example 11 Preparation of the compound of formula G 13.16 g (0.041 mol) of a compound of formula F are reacted in 40 ml of toluene with 18.89 g of phosphorus oxychloride. The reaction mass is heated to 80°C. After a reaction time of 2 hours at 80°C, the mass is cooled in an ice bath and 4M sodium hydroxide solution is added dropwise thereto. The aqueous phase is extracted three times with toluene. After concentration of the organic phase by evaporation, 13.65 g (98% of theory) of the compound of formula G are obtained. Purity in GC: 100%
• Example 13 Determination of the minimum inhibiting concentration (MIC value) in microtitre plates
• Casein/soybean flour peptone bouillon for the preparation of the precultures of the test bacteria and yeast.
• test organisms Bacteria: Staphylococcus aureus ATCC 6583 Corynebacterium xerosis ATCC 373 (**) Actinomyces viscosus ATTC 43146 Escherichia Coli ATTC 10536
• test substances are predissolved in dimethyl sulfoxide (DMSO) and tested in a serial dilution of 1:2.
• DMSO dimethyl sulfoxide
• test substances are prepipetted into microtitre plates in an amount of 8 ⁇ l per well.
• the previously adjusted organism suspensions are diluted 1 :100 in CASO bouillon and added to the test substances in an amount of 192 ⁇ l per well.
• test batches are incubated for 48 hours at 37°C.
• the growth is determined by reference to the turbidity of the test batches (optical density) at 620 nm in a microplate reader.
• the minimum inhibiting concentration is the concentration of substance at which (compared with the growth control) an appreciable inhibition of the growth ( ⁇ 20 % growth) of the test organisms is ascertained.
• Example 14 Determination of the minimum inhibiting concentration MIC [ppm. of a broadened organism spectrum
• Test organisms Staphylococcus aureus ATCC 6853 and 9144 Staphylococcus epidermidis ATCC 12228 C. xerosis ATCC 373 ** C. minutissimum ATCC 23348 Propionibacterium acnes ATCC 6919 *** Escherichia coli ATCC 10536 and NCTC 8196 Proteus vulgaris ATCC 6896 Klebsiella pneumoniae ATCC 4352 Salmonella choleraesuis ATCC 9184 Pseudomonas aeruginosa ATCC 15442 *Candida albicans ATCC 10231 *Aspergillus niger ATCC 6275
• Test solution 1% stock solutions of all the test substances in a suitable solvent are prepared and diluted in serial dilutions (1 :10, 1 :100 and 1 :1000 dilution), where possible diluted to such an extent that the end concentrations in agar are from 500 ppm to 10 ppm.
• 0.3 ml of the dilution stage in question is mixed with 15 ml of still-liquid nutrient medium.
• 10 ⁇ l portions of a suitable organism dilution of the test strains in 0.85% NaCI solution are spotted onto the agar medium:
• Example 15 Determination of the minimum inhibiting concentration MIC Ippml of a broad- ened organism spectrum: oral organisms
• Dilution medium the appropriate amount of the substances was pipetted directly into the medium.
• Test organisms Actinobacillus actinomycetemcomitans ATCC 43718 Streptococcus gordonii ATCC 10558 Streptococcus mutans ATCC 33402 Actinomyces viscosus ATCC 43146 Fusobacterium nucleatum subsp. polymorphum ATCC 10953 Porphyromonas gingivalis ATCC 33277 Prevotella nigrescens ATCC 33563
• Bacteria are removed from blood agar plates using cotton wool buds and a suitable optical density (McFarland 0.5) is adjusted in an appropriate medium; that solution is used undiluted for F. nucleatum and P. nigrescens, and in a dilution of 1 :20 for the other strains. 0.1 ml of bacterial culture is added per 2 ml of active ingredient solution and incubation is carried out as described above.
• a suitable optical density McFarland 0.5

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