WO2003077656A1 - 4-aminopyrimidines and their use for the antimicrobial treatment of surfaces - Google Patents

4-aminopyrimidines and their use for the antimicrobial treatment of surfaces Download PDF

Info

Publication number
WO2003077656A1
WO2003077656A1 PCT/EP2003/002438 EP0302438W WO03077656A1 WO 2003077656 A1 WO2003077656 A1 WO 2003077656A1 EP 0302438 W EP0302438 W EP 0302438W WO 03077656 A1 WO03077656 A1 WO 03077656A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
formula
use according
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2003/002438
Other languages
French (fr)
Inventor
Sophie Marquais-Bienewald
Werner Hölzl
Wolfgang Haap
Andrea Preuss
Andreas Mehlin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Schweiz AG
Original Assignee
Ciba Spezialitaetenchemie Holding AG
Ciba SC Holding AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Spezialitaetenchemie Holding AG, Ciba SC Holding AG filed Critical Ciba Spezialitaetenchemie Holding AG
Priority to JP2003575716A priority Critical patent/JP2005520821A/en
Priority to EP03709767A priority patent/EP1484971B1/en
Priority to DE60314730T priority patent/DE60314730T2/en
Priority to US10/507,800 priority patent/US7731985B2/en
Priority to AU2003214110A priority patent/AU2003214110A1/en
Publication of WO2003077656A1 publication Critical patent/WO2003077656A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—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
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to substituted 4-aminopyrimidines, to the preparation of such compounds, and to the use of such compounds in the antimicrobial treatment of surfaces, as antimicrobial active substances against gram-positive and gram-negative bacteria, yeasts and fungi and also in the preservation of cosmetics, household products, textiles and plastics and for use in disinfectants.
  • the present invention relates to the use of 4-aminopyrimidines of formula
  • R, and R 2 are each independently of the other hydrogen; C.-C 5 alkyl which is unsubstituted or substituted by one or more halogen atoms; biphenyl or C 6 -C 10 aryl which is unsubstituted or substituted by halogen, C.-C 5 alkyl, C.-C 5 alkoxy or by amino; a 5- to 7-membered heteroaryl radical; or cyclo-C 3 -C 7 alkyl;
  • R- is hydrogen; phenyl or C.-C 5 alkyl which is unsubstituted or substituted by one or more halogen atoms;
  • R 4 is hydrogen; C.-C. 0 alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;
  • R 5 is C.-C-.alkyl which is unsubstituted or substituted by one or more halogen atoms or by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
  • R' bivalent heterocyclic radical NR"R'"-C.-C 20 alkyl which is unsubstituted or substituted by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
  • R' is hydrogen; or C.-C 3 alkyl
  • R" and R"' are each independently of the other hydrogen; C.-C.alkyl; or hydroxy-C.-C.alkyl; X is ⁇ O; ⁇ CH-R 1 '" ; or ⁇ N-R"" ;
  • R" is hydrogen; C.- alkyl; or heteroaryl-C.-C 4 aIkyl; and n. and n 2 are each independently of the other from 1 to 8; in the antimicrobial treatment of surfaces.
  • Ci-C 2 oAlkyl radicals are straight-chain or branched alkyl radicals, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl or eicosyl.
  • Cycloalkyl denotes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.
  • Those radicals may be substituted, for example by one or more identical or different C.-C 4 alkyl radicals, especially by methyl, and/or by hydroxy.
  • cycloalkyl radicals are substituted by one or more substituents, they are substituted preferably by one, two or four, especially by one or two, identical or different substituents.
  • C C 5 Alkoxy radicals are straight-chain or branched radicals such as, for example, methoxy, ethoxy, propoxy, butoxy or pentyloxy.
  • C 6 -C 10 Aryl and heteroaryl radicals may be unsubstituted or may carry one or more, for example one, two, three or four, identical or different substituents, which may be located in any positions.
  • substituents are, for example, C.-C 4 alkyl, halogen, hydroxy, C.-C 4 alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, C.-C 4 alkoxycarbonyl, aminocarbonyl, amino, C.-C 4 alkylamino, di-C.-C 4 aIkylamino and C.- alkylcarbonylamino.
  • Heteroaryl radicals are derived from heterocydes containing one, two, three or four identical or different ring hetero atoms, especially from heterocydes containing one, two or three, more especially one or two, identical or different hetero atoms.
  • the heterocydes may be mono- or poly-cyclic, for example mono-, bi- or tri-cydic. They are preferably mono- or bi- cyclic, especially monocyclic.
  • the rings preferably contain 5, 6 or 7 ring members.
  • Examples of monocyclic and bicyclic heterocyclic systems from which radicals occurring in the compounds of formula (1) can be derived are, for example, pyrrole, furan, thiophene, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1 ,4-dioxane, 1 ,2-oxazine, 1,3-oxazine, 1 ,4-oxazine, indole, benzo- thiophene, benzofuran, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
  • Unsaturated heterocydes may contain, for example, one, two or three unsaturated double bonds in the ring system.
  • 5-membered rings and 6-membered rings in monocyclic and polycyclic heterocydes may also be, especially, aromatic.
  • Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 5 is R"R"'N-C,-C 20 alkyl which is uninterrupted or interrupted by one or more -O- or
  • R' is hydrogen; or C.-C.alkyl
  • R" and R"' are each independently of the other hydrogen; or methyl
  • R., R 2 , R 3 and R 4 are as defined for formula (1 ).
  • R 5 is R"R'"N-C.-C 20 alkyl which is uninterrupted or interrupted by — N N — .
  • R 5 is R"R"'N-C 5 -C 20 alkyl which is uninterrupted or interrupted by one or more -O- or — N — groups;
  • R' R' is hydrogen; or C.-C.alkyl; and
  • R" and R'" are each independently of the other hydrogen; or methyl.
  • preference is given to those wherein
  • R. is R"R'"N-C 5 -C 20 alkyl
  • R" and R" 1 are each independently of the other hydrogen; or methyl.
  • R 4 is hydrogen; or C.-C.alkyl
  • R. is C 3 -C 20 alkyl which is unsubstituted or interrupted by -NH-;
  • R 1 and R 3 are as defined for formula (1); especially compounds of formula (1) wherein
  • R is hydrogen; C.-C.alkyl; unsubstituted or C.-C 4 alkyl-substituted phenyl or phenyl-
  • R 2 is hydrogen; or C.-C.alkyl; especially methyl;
  • R 3 is hydrogen; or C.-C.alkyl
  • R 4 is hydrogen; or C.-C.alkyl
  • R 5 is C 5 -C 20 alkyl; and very especially compounds of formula (1) wherein
  • R is hydrogen; C.-C.alkyl, especially isopropyl or methyl; unsubstituted or C.-C 4 alkyl- substituted phenyl; or pyridino;
  • R 2 is methyl
  • R 3 and R 4 are hydrogen
  • R 5 is C 8 -C 1B alkyl.
  • R 5 is linear C 8 -C 18 alkyl.
  • R" is hydrogen; or pyridyl-C.-C 3 alkyl; and n, and n 2 are each 2.
  • R. and R 2 are each independently of the other hydrogen; C.-C 5 alkyl; phenyl which is unsubstituted or substituted by halogen, C.-C.alkyl, C.-C 3 alkoxy or by amino; biphenyl; cyclo-C 3 -C 7 alkyl; 3-pyridyl; 4-pyridyl; 2-thiophenyl; 3-thiophenyl; or thiazolyl; or compounds of formula (1 ) wherein
  • R 3 is hydrogen; or phenyl; or compounds of formula (1 ) wherein
  • R 4 is hydrogen
  • X is -O-; or — N— ; R'
  • R' is hydrogen; or C,-C 3 alkyl; n is 1 -3; and m is 1 -3; and
  • R., R 2 and R 3 are as defined for formula 1 ,
  • the 4-aminopyrimidines used in accordance with the invention are prepared by methods known per se (J. Org. Chem.; 1967, 32, 1591 ).
  • auxiliary base such as, for example, sodium carbonate, potassium hydroxide, sodium ethanolate, sodium methanolate, potassium tert-butanolate etc.
  • a suitable solvent such as, for example, methanol, ethanol, butanol, tert-butanol, THF, DMF, acetonitrile, toluene, xylene etc., over a period of from 1 to 24 hours at a temperature of from 40 to 120°C.
  • pyrimidine compound with a primary or secondary amine R 4 R 5 NH
  • a suitable solvent such as, for example, DMF, dioxane, toluene, xylene, ethanol, butanol, and an auxiliary base such as, for example, triethylamine, DIEA, sodium carbonate, potassium hydroxide etc., or using an excess of amine at from 40 to 130°C over a period of from 1 to 24 hours.
  • Preparation of the compounds of formula (2) is carried out by reacting an excess of from 2 to 10 equivalents of the diamine compound H 2 N(CH 2 ) n X(CH 2 ) m NH 2 in, for example, DMF, dichloromethane, THF or dioxane with trityl chloride polystyrene resin at a temperature of from 10 to 50°C over a period of from 0.5 to 24 hours. From 2 to 10 equivalents of the diamine compound H 2 N(CH 2 ) n X(CH 2 ) m NH 2 in, for example, DMF, dichloromethane, THF or dioxane with trityl chloride polystyrene resin at a temperature of from 10 to 50°C over a period of from 0.5 to 24 hours. From 2 to 10 equivalents of the diamine compound H 2 N(CH 2 ) n X(CH 2 ) m NH 2 in, for example, DMF, dichloromethane, THF or
  • suitable solvent such as, for example, dichloromethane, DMF, THF or toluene
  • suitable solvent such as, for example, dichloromethane, DMF, THF or toluene
  • the 4- chloropyrimidines are reacted with from 2 to 10 equivalents of various boronic acids, from 1 to 10 % of palladium catalyst and from 2 to 10 equivalents of auxiliary base such as, for example, CaCO. and NaCO 3 , in, for example, THF, DMF or dioxane.
  • the target compounds are split off using from 1 to 30 % trifluoroacetic acid (TFA) in dichloromethane (DCM) at 25°C over a period of from 1 to 5 hours.
  • THF trifluoroacetic acid
  • DCM dichloromethane
  • the substances are freeze-dried from -BuOH/water 4:1 with from 1 to 10 % HOAc and once from -BuOH/water 4:1.
  • R Nitrogen R 2 , R 3 , X, m and n being as defined for formula (2).
  • R, and R 2 are each independently of the other hydrogen; C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms; biphenyl or C 6 -C 10 aryl which is unsubstituted or substituted by halogen, C.-C.alkyl, C.-C.alkoxy or by amino; a 5- to 7-membered heteroaryl radical; or cyclo-C--C 7 alkyl;
  • R 3 is hydrogen; phenyl or C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms;
  • R 4 is hydrogen; C.-C 10 alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;
  • R. is C.-C-.alkyl which is unsubstituted or substituted by one or more halogen atoms or by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
  • bivalent heterocyclic radical NR"R'"-C 1 -C 20 alkyl which is unsubstituted or substituted by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
  • R 1 bivalent heterocyclic radical; cydo-C.-C 8 alkyI; hydroxy-C C 20 alkyl; phenyl-C.-C 3 alkyl; a heterocyclic radical; or R 4 and R 5 , together with the nitrogen atom linking them, form a radical of
  • R' is hydrogen; or C,-C 3 alkyl
  • R" and R'" are each independently of the other hydrogen; C,-C.alkyl; or hydroxy-C.-C.alkyl;
  • R" is hydrogen; C.-C ⁇ alkyl; or heteroaryl-C,-C 4 alkyl; and n. and n 2 are each independently of the other from 1 to 8; not including compounds of formula (V) wherein simultaneously
  • R is C 6 -C 10 aryl; or C.-C 4 alkyl
  • R 5 is C C 7 alkyl.
  • the 4-aminopyrimidines used in accordance with the invention exhibit pronounced antimicrobial action, especially against pathogenic gram-positive and gram-negative bacteria and against bacteria of the skin flora, and also against yeasts and moulds. They are accordingly suitable especially for disinfection, deodorisation, and for general and antimicrobial treatment of the skin and mucosa and of integumentary appendages (hair), more especially for the disinfection of hands and wounds.
  • Suitable as antimicrobial active substances and preservatives in personal care preparations such as, for example, shampoos, bath additives, haircare preparations, liquid and solid soaps (based on synthetic surfactants and salts of saturated and/or unsaturated fatty acids), lotions and creams, deodorants, other aqueous or alcoholic solutions, e.g. cleansing solutions for the skin, moist cleaning cloths, oils or powders.
  • personal care preparations such as, for example, shampoos, bath additives, haircare preparations, liquid and solid soaps (based on synthetic surfactants and salts of saturated and/or unsaturated fatty acids), lotions and creams, deodorants, other aqueous or alcoholic solutions, e.g. cleansing solutions for the skin, moist cleaning cloths, oils or powders.
  • the invention accordingly relates also to a personal care preparation comprising at least one compound of formula (1) and 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 comprises, in addition to the 4-aminopyrimidine of formula (1), further constituents such as, for example, sequestering agents, colorants, perfume oils, thickeners or solidifiers (consistency regulators), emollients, UV-absorbers, skin protective agents, antioxidants, additives that improve the mechanical properties, such as dicarboxylic acids and/or aluminium, zinc, calcium or magnesium salts of C 14 -C 22 fatty acids, and, optionally, preservatives.
  • further constituents such as, for example, sequestering agents, colorants, perfume oils, thickeners or solidifiers (consistency regulators), emollients, UV-absorbers, skin protective agents, antioxidants, additives that improve the mechanical properties, such as dicarboxylic acids and/or aluminium, zinc, calcium or magnesium salts of C 14 -C 22 fatty acids, and, optionally, preservatives.
  • the personal care preparation according to the invention may be in the form of a water-in-oil or oil-in-water emulsion, an alcoholic or alcohol-containing formulation, a vesicular dispersion of an ionic or non-ionic amphiphilic lipid, a gel, a solid stick or an aerosol formulation.
  • the cosmetically tolerable adjuvant contains preferably from 5 to 50 % of an oil phase, from 5 to 20 % of an emulsifier and from 30 to 90 % water.
  • the oil phase may comprise any oil suitable for cosmetic formulations such as, for example, one or more hydrocarbon oils, a wax, a natural oil, a silicone oil, a fatty acid ester or a fatty alcohol.
  • Preferred mono- or poly-ols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.
  • Cosmetic formulations according to the invention are used in various fields. There come into consideration, for example, especially the following preparations: 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. facial make-up in the form of day creams or powder creams, face powder (loose or pressed), rouge or cream make-up, eye-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 preparation
  • eyeshadow preparations mascaras, eyeliners, 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 or 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 perfume creams
  • 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 colorants, preparations containing self-oxidising dyes, or natural hair colorants, 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 1 to 10 % by weight stearic acid, soap base ad 100 %, e.g. a sodium salt of tallow fatty acid or 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:
  • perfume oil 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 4-aminopyrimidines of formula (1) used in accordance with the invention are also suitable for treating, especially preserving, textile fibre materials.
  • Such materials are undyed and dyed or printed fibre materials, for example of silk, wool, polyamide or polyurethanes, 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 4-aminopyrimidines according to the invention are suitable also for treating, especially imparting antimicrobial properties to or preserving, plastics such as, for example, polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc..
  • plastics such as, for example, polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc.
  • Fields of use therefor are, for example, floor coverings, plastics coatings, plastics containers 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 such as, for example, 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 4-aminopyrimidines according to the invention. It is also possible for nonwovens such as, for example, nappies/diapers, sanitary towels, panty liners, and cloths for hygiene and household uses, to be provided with antimicrobial properties in accordance with the invention.
  • the 4-aminopyrimidines of formula (1) are also used in washing and cleaning formulations such as, for example, liquid or powder washing agents or softeners.
  • the 4-aminopyrimidines of formula (1) can also be used especially in household and general-purpose cleaners for cleaning and disinfecting hard surfaces.
  • a cleaning preparation has, for example, the following composition:
  • the 4-aminopyrimidines of formula (1) are also suitable for the antimicrobial treatment of wood and for the antimicrobial treatment of leather, the preserving 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 damage.
  • the crude product is concentrated by evaporation and taken up in 30 ml of toluene.
  • the product solution is dried over sodium sulfate and concentrated by evaporation.
  • Example 2 Reaction of 4-chloro-6-methyl-2-phenylpyrimidine with monoamines 20.5 mg of 4-chloro-6-methyl-2-phenylpyrimidine (0.1 mmol) are heated with 3 equivalents of monoamines (0.3 mmol) in 0.5 ml of absolute dioxane at 100°C for 20 hours. After cooling, the products are concentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze- dried. The end products are analysed by LC-MS.
  • Example 3 Loading of trityl chloride polystyrene resin with N,N-bis.3-aminopropyl)methyl- amines and reaction with 4,6-dichloro-2,5-diphenylpyrimidine
  • the resin is filtered off and washed with DCM, MeOH, THF, MeOH, DCM and MeOH and dried in vacuo.
  • Example 4 Parallel reaction of 4-amino-6-chloro-1 5-diphenylpyrimidine-TCP resins with various boronic acids and splitting off
  • the resin is heated with 126.1 g of caesium carbonate (6 eq., 0.387 mmol) and 300 ⁇ l of a toluene solution of 0.1 eq. of a palladium catalyst (WO 01 /16057) at 95°C for 15 minutes.
  • the products are split off using 1 .5 ml of a 5 % TFA/DCM solution at room temperature for
  • Example 6 Reaction of 4-chloro-6-methyi-2-(4-methyl)-phenylpyrimidine with monoamines 21 .9 mg of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (0.1 mmol) are heated with 3 eq. of monoamines (0.3 mmol) in 0.5 ml of absolute dioxane at 100°C for 20 hours. After cooling, the products are concentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze- dried. The end products are analysed by LC-MS.
  • the end product is analysed by NMR, GC-MS and GC.
  • Example 8 Preparation of 4-chloro-2-isopropyl-6-methylpyrimidine 76.1 g of 2-isopropyl-6-methyl-4-pyrimidinol [2814-20-2] (500 mmol) are dissolved in 300 ml of toluene at 90°C. 80.5 g of phosphorus oxychloride (525 mmol) are added dropwise thereto at from 90 to 103°C, and the reaction mixture is heated at 1 10°C for 2 hours. After cooling to 20°C, the reaction mixture is adjusted to pH 8 using 4M sodium hydroxide solution, with cooling. The aqueous phase is separated off and extracted with 100 ml of toluene. The combined organic phases are washed three times with 100 ml of water each time and dried at RT under 2 mbar. 89.7 g (105 %; contains toluene) are obtained.
  • Example 10 Determination of the minimum inhibitory concentration (MIC value) in microtitre plates
  • test organisms examples include test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms:
  • test substances are pre-dissolved in dimethyl sulfoxide (DMSO) and tested in a dilution series of 1 :2.
  • DMSO dimethyl sulfoxide
  • Bacteria and yeast are cultured overnight in CASO broth.
  • test organism suspensions are adjusted to an organism count of 1 - 5 x 10 6 CFU/ml using 0.85 % sodium chloride solution.
  • test substances are pre-pipetted into microtitre plates in amounts of 8 ⁇ l per well.
  • the pre-adjusted organism suspensions are diluted 1 :100 in CASO broth and are added in amounts of 192 ⁇ l per well to the test substances.
  • test batches are incubated for 48 hours at 37°C.
  • the growth is determined on the basis of the turbidity of the test batches (optical density) at 620 nm in a microplate reader.
  • the minimum inhibitory concentration is the concentration of substance at which (compared to the growth of the control) an appreciable inhibition of growth ( ⁇ 20 % growth) of the test organisms is observed.
  • Example 1 Agar incorporation test CG1 8e
  • Test solution 1 % stock solutions of all the test substances are prepared in a suitable solvent and diluted in serial dilutions to end concentrations of from 1000 ppm to 10 ppm.
  • each dilution step is mixed with 15 ml of nutrient medium while the latter is still liquid. After the nutrient medium has solidified, 10 ⁇ l of each of the following organism dilutions of the test strains in 0.85 % NaCl solution are spotted onto the agar medium:
  • the plates are incubated at 37°C for 24 hours (A. niger at 28°C for 3 days) and then the highest dilution (lowest concentration) of the test substance at which growth is just no longer discernible (corresponds to the MIC) is determined.
  • the results are shown in Table 3.
  • Example 12 "Microbicidal activity" suspension test CG 161 /EN! 040
  • test organisms examples include test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms, test organisms:
  • test substances are dissolved in dimethyl sulfoxide (DMSO) and tested in a concentration of 120 ⁇ g/ml.
  • DMSO dimethyl sulfoxide
  • Bacteria are incubated overnight in CASO broth and adjusted to an organism count of
  • test substances are pre-pipetted into microtitre plates in amounts of 8 ⁇ l per well.
  • test organism suspensions are added in amounts of 192 ⁇ l per well to the test substances and mixed. After defined contact times, the test batches are mixed, an aliquot is withdrawn and diluted in several steps in a dilution series of 1 :10 in a suitable inactivation medium.
  • test plates are incubated for 24 hours at 37°C. After incubation, the growth is determined on the basis of the turbidity of the test batches (optical density) at 620 nm in a microplate reader.
  • the reduction in the test organism concentration is determined in powers of ten (log value).
  • One microtitre plate is used for each test organism.
  • Example 13 Determination of the minimum inhibitory concentration (MIC value) in microtitre plates
  • test organisms there are used:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Agronomy & Crop Science (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Plant Pathology (AREA)
  • Zoology (AREA)
  • Pest Control & Pesticides (AREA)
  • Environmental Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Cosmetics (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Detergent Compositions (AREA)
  • Paints Or Removers (AREA)
  • Inks, Pencil-Leads, Or Crayons (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Use of 4-aminopyrimidines of formula (1), wherein R1, R2, R3, R4 and R5 are as described in the description in the antimicrobial treatment of surfaces.

Description

4-AMINOPYRIMIDINES AND THEIR USE FOR THE ANTIMICROBIAL TREATMENT OF SURFACES
The present invention relates to substituted 4-aminopyrimidines, to the preparation of such compounds, and to the use of such compounds in the antimicrobial treatment of surfaces, as antimicrobial active substances against gram-positive and gram-negative bacteria, yeasts and fungi and also in the preservation of cosmetics, household products, textiles and plastics and for use in disinfectants.
The present invention relates to the use of 4-aminopyrimidines of formula
(1) . wherein
Figure imgf000002_0001
R, and R2 are each independently of the other hydrogen; C.-C5alkyl which is unsubstituted or substituted by one or more halogen atoms; biphenyl or C6-C10aryl which is unsubstituted or substituted by halogen, C.-C5alkyl, C.-C5alkoxy or by amino; a 5- to 7-membered heteroaryl radical; or cyclo-C3-C7alkyl;
R- is hydrogen; phenyl or C.-C5alkyl which is unsubstituted or substituted by one or more halogen atoms;
R4 is hydrogen; C.-C.0alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;
R5 is C.-C-.alkyl which is unsubstituted or substituted by one or more halogen atoms or by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
R' bivalent heterocyclic radical; NR"R'"-C.-C20alkyl which is unsubstituted or substituted by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
R' bivalent heterocyclic radical; cyclo-Cj-C.alkyl; hydroxy-C.-C20aIkyl; phenyl-C.-C.alkyl; a heterocyclic radical; or R4 and R5, together with the nitrogen atom linking them, form a radical of
formula (l a)
Figure imgf000002_0002
R' is hydrogen; or C.-C3alkyl;
R" and R"' are each independently of the other hydrogen; C.-C.alkyl; or hydroxy-C.-C.alkyl; X is ^O; ^CH-R1'" ; or ^N-R"" ;
R"" is hydrogen; C.- alkyl; or heteroaryl-C.-C4aIkyl; and n. and n2 are each independently of the other from 1 to 8; in the antimicrobial treatment of surfaces.
Ci-C2oAlkyl radicals are straight-chain or branched alkyl radicals, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl or eicosyl.
C3-C10Cycloalkyl denotes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. Those radicals may be substituted, for example by one or more identical or different C.-C4alkyl radicals, especially by methyl, and/or by hydroxy. When cycloalkyl radicals are substituted by one or more substituents, they are substituted preferably by one, two or four, especially by one or two, identical or different substituents.
C C5Alkoxy radicals are straight-chain or branched radicals such as, for example, methoxy, ethoxy, propoxy, butoxy or pentyloxy.
C6-C10Aryl and heteroaryl radicals may be unsubstituted or may carry one or more, for example one, two, three or four, identical or different substituents, which may be located in any positions. Examples of such substituents are, for example, C.-C4alkyl, halogen, hydroxy, C.-C4alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, C.-C4alkoxycarbonyl, aminocarbonyl, amino, C.-C4alkylamino, di-C.-C4aIkylamino and C.- alkylcarbonylamino.
Heteroaryl radicals are derived from heterocydes containing one, two, three or four identical or different ring hetero atoms, especially from heterocydes containing one, two or three, more especially one or two, identical or different hetero atoms. The heterocydes may be mono- or poly-cyclic, for example mono-, bi- or tri-cydic. They are preferably mono- or bi- cyclic, especially monocyclic. The rings preferably contain 5, 6 or 7 ring members. Examples of monocyclic and bicyclic heterocyclic systems from which radicals occurring in the compounds of formula (1) can be derived are, for example, pyrrole, furan, thiophene, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1 ,4-dioxane, 1 ,2-oxazine, 1,3-oxazine, 1 ,4-oxazine, indole, benzo- thiophene, benzofuran, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
Unsaturated heterocydes may contain, for example, one, two or three unsaturated double bonds in the ring system. 5-membered rings and 6-membered rings in monocyclic and polycyclic heterocydes may also be, especially, aromatic.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In accordance with the invention, preference is given to the use of compounds of formula (1 ) wherein
R5 is R"R"'N-C,-C20alkyl which is uninterrupted or interrupted by one or more -O- or
— N— groups or by a bivalent heterocyclic radical; R'
R' is hydrogen; or C.-C.alkyl;
R" and R"' are each independently of the other hydrogen; or methyl; and
R., R2, R3 and R4 are as defined for formula (1 ).
Very special preference is given to the use of compounds of formula (1) wherein
R5 is R"R'"N-C.-C20alkyl which is uninterrupted or interrupted by — N N — .
In accordance with the invention, there are furthermore used compounds of formula (1) wherein
R5 is R"R"'N-C5-C20alkyl which is uninterrupted or interrupted by one or more -O- or — N — groups; R' R' is hydrogen; or C.-C.alkyl; and R" and R'" are each independently of the other hydrogen; or methyl. Among those compounds, preference is given to those wherein
R. is R"R'"N-C5-C20alkyl; and
R" and R"1 are each independently of the other hydrogen; or methyl.
Very special preference is also given to the use of compounds of formula (1) wherein
R4 is hydrogen; or C.-C.alkyl;
R. is C3-C20alkyl which is unsubstituted or interrupted by -NH-; and
R„ R2 and R3 are as defined for formula (1); especially compounds of formula (1) wherein
R, is hydrogen; C.-C.alkyl; unsubstituted or C.-C4alkyl-substituted phenyl or phenyl-
C,-C4alkyl; or pyridino;
R2 is hydrogen; or C.-C.alkyl; especially methyl;
R3 is hydrogen; or C.-C.alkyl;
R4 is hydrogen; or C.-C.alkyl; and
R5 is C5-C20alkyl; and very especially compounds of formula (1) wherein
R, is hydrogen; C.-C.alkyl, especially isopropyl or methyl; unsubstituted or C.-C4alkyl- substituted phenyl; or pyridino;
R2 is methyl;
R3 and R4 are hydrogen; and
R5 is C8-C1Balkyl.
Among the last-mentioned compounds very special preference is given to the use of those wherein
R5 is linear C8-C18alkyl.
Also preferably used are compounds of formula (1) wherein, in formula (la), R"" is hydrogen; or pyridyl-C.-C3alkyl; and n, and n2 are each 2.
Preference is also given to the use of compounds of formula (1) wherein R. and R2 are each independently of the other hydrogen; C.-C5alkyl; phenyl which is unsubstituted or substituted by halogen, C.-C.alkyl, C.-C3alkoxy or by amino; biphenyl; cyclo-C3-C7alkyl; 3-pyridyl; 4-pyridyl; 2-thiophenyl; 3-thiophenyl; or thiazolyl; or compounds of formula (1 ) wherein
R3 is hydrogen; or phenyl; or compounds of formula (1 ) wherein
R4 is hydrogen.
Special preference is given to the use of compounds of formula
Figure imgf000006_0001
wherein
X is -O-; or — N— ; R'
R' is hydrogen; or C,-C3alkyl; n is 1 -3; and m is 1 -3; and
R., R2 and R3 are as defined for formula 1 ,
The Table that follows lists, by way of example, further 4-aminopyrimidines according to the invention:
Figure imgf000006_0002
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
The 4-aminopyrimidines used in accordance with the invention are prepared by methods known per se (J. Org. Chem.; 1967, 32, 1591 ). For that purpose, a cyano compound (R.-C=N) is reacted, in a suitable solvent such as, for example, methanol, ethanol, isopropanol, DMF, tetrahydrofuran etc., with ammonium acetate or ammonium chloride at a temperature of from -10°C to 100°C over a period of from 1 hour to 24 hours to form the corresponding amidine compound ( ' ^ ).
NH- The amidine compound is then condensed with an appropriate β-keto ester
) using an auxiliary base such as, for example, sodium carbonate,
Figure imgf000037_0001
potassium hydroxide, sodium ethanolate, sodium methanolate, potassium tert-butanolate etc., in a suitable solvent such as, for example, methanol, ethanol, butanol, tert-butanol, THF, DMF, acetonitrile, toluene, xylene etc., over a period of from 1 to 24 hours at a temperature of from 40 to 120°C.
The thereby obtained is then converted
Figure imgf000037_0002
into the corresponding 4-chloro-2-pyrimidine compound by conventional
Figure imgf000037_0003
methods using phosphorus oxychloride.
The substituted 4-aminopyrimidines ) are obtained by reacting the 4-chloro-2-
Figure imgf000037_0004
pyrimidine compound with a primary or secondary amine (R4R5NH) in a suitable solvent such as, for example, DMF, dioxane, toluene, xylene, ethanol, butanol, and an auxiliary base such as, for example, triethylamine, DIEA, sodium carbonate, potassium hydroxide etc., or using an excess of amine at from 40 to 130°C over a period of from 1 to 24 hours.
The entire reaction proceeds according to the following scheme:
a
Figure imgf000038_0001
POCI
R2
Figure imgf000038_0002
R„ R2, R3, R4 and R5 being as defined for formula (1 ).
Preparation of the compounds of formula (2) is carried out by reacting an excess of from 2 to 10 equivalents of the diamine compound H2N(CH2)nX(CH2)mNH2 in, for example, DMF, dichloromethane, THF or dioxane with trityl chloride polystyrene resin at a temperature of from 10 to 50°C over a period of from 0.5 to 24 hours. From 2 to 10 equivalents of the
appropriately substituted 4,6-dichloropyrimidines
Figure imgf000038_0003
suitable solvent such as, for example, dichloromethane, DMF, THF or toluene, with the polymer-bound diamines at from 10 to 120°C over a period of from 2 to 48 hours. The 4- chloropyrimidines are reacted with from 2 to 10 equivalents of various boronic acids, from 1 to 10 % of palladium catalyst and from 2 to 10 equivalents of auxiliary base such as, for example, CaCO. and NaCO3, in, for example, THF, DMF or dioxane. After washing the resin to remove the excess, the target compounds are split off using from 1 to 30 % trifluoroacetic acid (TFA) in dichloromethane (DCM) at 25°C over a period of from 1 to 5 hours. For the purpose of further purification, the substances are freeze-dried from -BuOH/water 4:1 with from 1 to 10 % HOAc and once from -BuOH/water 4:1.
The entire reaction proceeds according to the following scheme: H2N(CH2)nX(CH2)mNH2
(TCPV-CI (TCP )-NH(CH2)nX(CH2)mNH2
Figure imgf000039_0001
R„ R2, R3, X, m and n being as defined for formula (2).
Some of the 4-aminopyrimidines used in accordance with the invention are known from the literature and some are novel compounds. The invention relates also to those novel compounds.
The novel compounds correspond to formula
(T) wherein
Figure imgf000039_0002
R, and R2 are each independently of the other hydrogen; C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms; biphenyl or C6-C10aryl which is unsubstituted or substituted by halogen, C.-C.alkyl, C.-C.alkoxy or by amino; a 5- to 7-membered heteroaryl radical; or cyclo-C--C7alkyl;
R3 is hydrogen; phenyl or C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms;
R4 is hydrogen; C.-C10alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;
R. is C.-C-.alkyl which is unsubstituted or substituted by one or more halogen atoms or by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
bivalent heterocyclic radical; NR"R'"-C1-C20alkyl which is unsubstituted or substituted by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
R1 bivalent heterocyclic radical; cydo-C.-C8alkyI; hydroxy-C C20alkyl; phenyl-C.-C3alkyl; a heterocyclic radical; or R4 and R5, together with the nitrogen atom linking them, form a radical of
formula (1 a)
Figure imgf000040_0001
R' is hydrogen; or C,-C3alkyl;
R" and R'" are each independently of the other hydrogen; C,-C.alkyl; or hydroxy-C.-C.alkyl;
Figure imgf000040_0002
R"" is hydrogen; C.-C^alkyl; or heteroaryl-C,-C4alkyl; and n. and n2 are each independently of the other from 1 to 8; not including compounds of formula (V) wherein simultaneously
R, is C6-C10aryl; or C.-C4alkyl; and
R5 is C C7alkyl.
The 4-aminopyrimidines used in accordance with the invention exhibit pronounced antimicrobial action, especially against pathogenic gram-positive and gram-negative bacteria and against bacteria of the skin flora, and also against yeasts and moulds. They are accordingly suitable especially for disinfection, deodorisation, and for general and antimicrobial treatment of the skin and mucosa and of integumentary appendages (hair), more especially for the disinfection of hands and wounds.
They are accordingly suitable as antimicrobial active substances and preservatives in personal care preparations such as, for example, shampoos, bath additives, haircare preparations, liquid and solid soaps (based on synthetic surfactants and salts of saturated and/or unsaturated fatty acids), lotions and creams, deodorants, other aqueous or alcoholic solutions, e.g. cleansing solutions for the skin, moist cleaning cloths, oils or powders.
The invention accordingly relates also to a personal care preparation comprising at least one compound of formula (1) and 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.
Depending upon the form of the personal care preparation, it comprises, in addition to the 4-aminopyrimidine of formula (1), further constituents such as, for example, sequestering agents, colorants, perfume oils, thickeners or solidifiers (consistency regulators), emollients, UV-absorbers, skin protective agents, antioxidants, additives that improve the mechanical properties, such as dicarboxylic acids and/or aluminium, zinc, calcium or magnesium salts of C14-C22fatty acids, and, optionally, preservatives.
The personal care preparation according to the invention may be in the form of a water-in-oil or oil-in-water emulsion, an alcoholic or alcohol-containing formulation, a vesicular dispersion of an ionic or non-ionic amphiphilic lipid, a gel, a solid stick or an aerosol formulation.
As a water-in-oil or oil-in-water emulsion, the cosmetically tolerable adjuvant contains preferably from 5 to 50 % of an oil phase, from 5 to 20 % of an emulsifier and from 30 to 90 % water. The oil phase may comprise any oil suitable for cosmetic formulations such as, for example, one or more hydrocarbon oils, a wax, a natural oil, a silicone oil, a fatty acid ester or a fatty alcohol. Preferred mono- or poly-ols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.
Cosmetic formulations according to the invention are used in various fields. There come into consideration, for example, especially the following preparations: 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. facial make-up in the form of day creams or powder creams, face powder (loose or pressed), rouge or cream make-up, eye-care preparations, e.g. eyeshadow preparations, mascaras, eyeliners, 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 or 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; hair-removal preparations in chemical form (depilation), e.g. hair-removing powders, liquid hair-removing preparations, cream- or paste-form hair-removing preparations, hair- removing preparations in gel form or aerosol foams; shaving preparations, e.g. shaving soap, foaming shaving creams, non-foaming shaving creams, foams and gels, preshave preparations for dry shaving, aftershaves or aftershave lotions; fragrance preparations, e.g. fragrances (eau de Cologne, eau de toilette, eau de parfum, parfum de toilette, perfume), perfume oils or perfume creams; 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 colorants, preparations containing self-oxidising dyes, or natural hair colorants, such as henna or camomile.
An antimicrobial soap has, for example, the following composition:
0.01 to 5 % by weight of a compound of formula (1)
0.3 to 1 % by weight titanium dioxide,
1 to 10 % by weight stearic acid, soap base ad 100 %, e.g. a sodium salt of tallow fatty acid or 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.
Example of an oral composition:
10 % by weight sorbitol,
10 % by weight glycerol,
15 % by weight ethanol,
15 % by weight propylene glycol,
0.5 % by weight sodium lauryl sulfate,
0.25 % by weight sodium methylcocyl taurate, 0.25 % by weight polyoxypropylene/polyoxyethylene block copolymer,
0.10 % by weight peppermint flavouring,
0.1 to 0.5 % by weight of a compound of formula (1), and
48.6 % by weight water.
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.
The 4-aminopyrimidines of formula (1) used in accordance with the invention are also suitable for treating, especially preserving, textile fibre materials. Such materials are undyed and dyed or printed fibre materials, for example of silk, wool, polyamide or polyurethanes, 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 4-aminopyrimidines according to the invention are suitable also for treating, especially imparting antimicrobial properties to or preserving, plastics such as, for example, polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc.. Fields of use therefor are, for example, floor coverings, plastics coatings, plastics containers 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 such as, for example, 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 4-aminopyrimidines according to the invention. It is also possible for nonwovens such as, for example, nappies/diapers, sanitary towels, panty liners, and cloths for hygiene and household uses, to be provided with antimicrobial properties in accordance with the invention.
The 4-aminopyrimidines of formula (1) are also used in washing and cleaning formulations such as, for example, liquid or powder washing agents or softeners.
The 4-aminopyrimidines of formula (1) can also be used especially in household and general-purpose cleaners for cleaning and disinfecting hard surfaces.
A cleaning preparation has, for example, the following composition:
0.01 to 5 % of a compound of formula (1)
3.0 % octyl alcohol 4EO
1.3 % fatty alcohol C8-C10polyglucoside
3.0 % isopropanol water ad 100 %.
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, printing thickeners of starch or cellulose derivatives, surface- coatings and paints.
The 4-aminopyrimidines of formula (1) are also suitable for the antimicrobial treatment of wood and for the antimicrobial treatment of leather, the preserving 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 damage.
The following Examples illustrate, but do not limit, the present invention. Implementation Examples
General work procedure for parallel svnthesis of 4-aminopvrimidines:
Example 1 :
Reaction Scheme
Figure imgf000046_0001
POCI,
Figure imgf000046_0002
Preparation of 4-chloro-6-methyl-2-phenylpyrimidine
2.2 g of benzamidine hydrochloride (14.05 mmol) are reacted, in 10 ml of absolute EtOH, with 5.43 ml (14.05 mmol) of 20 % sodium ethanolate solution and then condensed with
1 .66 g of methyl acetoacetate (14.29 mmol) for 4 hours at 90°C.
The crude product is concentrated by evaporation and taken up in 30 ml of toluene.
4.31 g of phosphorus oxychloride (28.1 mmol) are added and the reaction mixture is heated at 120°C for 3 hours. After cooling to 20°C, the excess is neutralised with sodium hydroxide solution, and the mixture is diluted with ethyl acetate and then washed with water and saturated sodium chloride solution.
The product solution is dried over sodium sulfate and concentrated by evaporation.
2.2 g of 4-chloro-6-methyl-2-phenylpyrimidine (77.7 % of theory) are obtained. Example 2: Reaction of 4-chloro-6-methyl-2-phenylpyrimidine with monoamines 20.5 mg of 4-chloro-6-methyl-2-phenylpyrimidine (0.1 mmol) are heated with 3 equivalents of monoamines (0.3 mmol) in 0.5 ml of absolute dioxane at 100°C for 20 hours. After cooling, the products are concentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze- dried. The end products are analysed by LC-MS.
Example 3: Loading of trityl chloride polystyrene resin with N,N-bis.3-aminopropyl)methyl- amines and reaction with 4,6-dichloro-2,5-diphenylpyrimidine
In each case, 50 mg of resin (1.29 mmol/g) are shaken in 1 ml of DMF with 94 mg of N,N- bis(3-aminopropyl)methylamine (0.645 mmol) at 25°C for 3 hours. The resin is filtered off and washed with DCM, MeOH, THF, MeOH and DCM and dried in vacuo.
The resin is shaken in 1 ml of DMF with 0.194 g of 4,6-dichloro-2,5-diphenylpyrimidine
(0.645 mmol) and 90 μl of triethylamine (0.645 mmol) at 25°C for 3 hours.
The resin is filtered off and washed with DCM, MeOH, THF, MeOH, DCM and MeOH and dried in vacuo.
Example 4: Parallel reaction of 4-amino-6-chloro-1 5-diphenylpyrimidine-TCP resins with various boronic acids and splitting off
The resin is heated with 126.1 g of caesium carbonate (6 eq., 0.387 mmol) and 300 μl of a toluene solution of 0.1 eq. of a palladium catalyst (WO 01 /16057) at 95°C for 15 minutes.
After adding 3 eq. of a boronic acid, dissolved in 700 μl of toluene solution, the mixture is heated at 90°C for 1 hour.
After cooling, the resin is filtered off and washed with DMF, MeOH, THF, MeOH and DCM and dried in vacuo.
The products are split off using 1 .5 ml of a 5 % TFA/DCM solution at room temperature for
3 hours. The resin is then washed with 1 ml of DCM and 1 ml of MeOH, and the combined solutions are concentrated to dryness by evaporation. The end products are analysed by
LC-MS.
Example 5: Preparation of 4-chloro-6-methyl-2-tolylpyrimidine
2.5 g of 4-methyl-benzamidine hydrochloride (14.65 mmol) are reacted in 10 ml of absolute EtOH with 5.66 ml of a 20 % solution of sodium ethanolate (14.65 mmol) and then condensed with 1.73 g of methyl acetoacetate (14.88 mmol) at 90°C for 4 hours. The crude product is concentrated by evaporation and taken up in 30 ml of toluene. 6.74 g of phosphorus oxychloride (44.0 mmol) are added and the reaction mixture is heated at 120°C for 3 hours. After cooling to 20°C, the excess is neutralised with sodium hydroxide solution, and the mixture is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and then with water. The product solution is concentrated by evaporation and separated by column chromatography (hexane/EE: 5/1 ). 2.1 g of 4-chloro- 6-methyl-2-tolylpyrimidine (66.5 % of theory) are obtained. NMR: 1 H (ppm in DMSO): 2.4,s,3H; 2.55,s,3H; 7.3,d,2H; 7.5,s,1 H; 8.25,d,2H
Example 6: Reaction of 4-chloro-6-methyi-2-(4-methyl)-phenylpyrimidine with monoamines 21 .9 mg of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (0.1 mmol) are heated with 3 eq. of monoamines (0.3 mmol) in 0.5 ml of absolute dioxane at 100°C for 20 hours. After cooling, the products are concentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze- dried. The end products are analysed by LC-MS.
Example 7: Reaction of 4-chloro-6-methyl-2-(4-methylVphenylpyrimidine with octylamine
1 .36 g of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (6.23 mmol) are heated with
886 mg of octylamine (6.85 mmol) and 2.58 g of potassium carbonate (18.68 mmol) in
10 g of dioxane at 100°C for 48 hours. After cooling, the product is taken up in 100 ml of ethyl acetate and washed with sodium hydroxide solution 0.5 mol/ . saturated sodium hydrogen carbonate solution and water. The product is concentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze-dried.
1.92 g of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (6.15 mmol, 98.7 % of theory) are obtained.
The end product is analysed by NMR, GC-MS and GC.
NMR 1 H (ppm in DMSO): 0.9,t,3H; 1.25,m,12H; 1.55,m,2H; 2.25,s,3H; 2.3,s,3H; 6.4,s,1 H;
7.1 ,171,114; 7.2,d,2H; 8.2,d,2H; (m/z = 311); GC: 95 % purity
Example 8: Preparation of 4-chloro-2-isopropyl-6-methylpyrimidine 76.1 g of 2-isopropyl-6-methyl-4-pyrimidinol [2814-20-2] (500 mmol) are dissolved in 300 ml of toluene at 90°C. 80.5 g of phosphorus oxychloride (525 mmol) are added dropwise thereto at from 90 to 103°C, and the reaction mixture is heated at 1 10°C for 2 hours. After cooling to 20°C, the reaction mixture is adjusted to pH 8 using 4M sodium hydroxide solution, with cooling. The aqueous phase is separated off and extracted with 100 ml of toluene. The combined organic phases are washed three times with 100 ml of water each time and dried at RT under 2 mbar. 89.7 g (105 %; contains toluene) are obtained.
Example 9: Preparation of 4-dodecylamino-2-isopropyl-6-methylpyrimidine (compound of formula (93))
79.2 g of 4-chloro-2-isopropyl-6-methylpyrimidine (464.1 mmol) are heated in 100 ml of dioxane at 100°C. A heated solution of 189.3 g of dodecylamine (1021 mmol, 2.2 eq) in 30 ml of dioxane is added dropwise thereto over the course of 2 hours, and the reaction mixture is further heated for 2 hours at 100°C and for 9 hours at 109°C. After cooling, 400 ml of ethyl acetate and 150 ml of 4M sodium hydroxide solution (600 mmol) are added thereto and the mixture is stirred at 50°C for 10 minutes. The lower, aqueous phase is discarded, the organic phase is washed with 300 ml of water, and 10 ml of saturated NaCl solution are added thereto. The organic phase is separated off and concentrated, and the excess dodecylamine is distilled in vacuo up to a bath temperature of 160°C. 1 36.1 g (91.8 %); GC purity: 98 %
NMR 1 H (ppm in CDC)3): 0.7,t,3H; 1.1 , m, 24H; 1 .4, m, 2H; 2.15, s, 3H; 2.75,Q, 1 H; 3.05, m, 2H; 4.9, s, 1 H; 5.8, s, 1 H
Example 10: Determination of the minimum inhibitory concentration (MIC value) in microtitre plates
Nutrient medium:
Casein/soymeal peptone broth for preparation of pre-cultures of test bacteria and yeast.
Examples of test organisms:
Bacteria: Pseudomonas aeruginosa CIP A-22 (=PA)
Escherichia coli NCTC 8196 (= EC)
Staphylococcus aureus ATCC 9144 (= SA)
Candida albicans ATCC 10231 (= CA) Procedure:
The test substances are pre-dissolved in dimethyl sulfoxide (DMSO) and tested in a dilution series of 1 :2.
Bacteria and yeast are cultured overnight in CASO broth.
All the test organism suspensions are adjusted to an organism count of 1 - 5 x 106 CFU/ml using 0.85 % sodium chloride solution.
The test substances are pre-pipetted into microtitre plates in amounts of 8 μl per well.
The pre-adjusted organism suspensions are diluted 1 :100 in CASO broth and are added in amounts of 192 μl per well to the test substances.
The test batches are incubated for 48 hours at 37°C.
After incubation, the growth is determined on the basis of the turbidity of the test batches (optical density) at 620 nm in a microplate reader.
The minimum inhibitory concentration (MIC value) is the concentration of substance at which (compared to the growth of the control) an appreciable inhibition of growth (< 20 % growth) of the test organisms is observed.
Three microtitre plates are used for each test organism and substance concentration. All the substances are tested in duplicate.
The microbiological test results are compiled in Table 2:
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Example 1 1 : Agar incorporation test CG1 8e
Medium: Casein/soymeal peptone agar (Merck)
*Sabouraud 4 % glucose agar (Merck)
Diluent: Sterile 0.85 % NaCl solution
Incubation: 24 hours at 37°C *3 days at 28°C
Test solution: 1 % stock solutions of all the test substances are prepared in a suitable solvent and diluted in serial dilutions to end concentrations of from 1000 ppm to 10 ppm.
Test principle:
0.3 ml of each dilution step is mixed with 15 ml of nutrient medium while the latter is still liquid. After the nutrient medium has solidified, 10 μl of each of the following organism dilutions of the test strains in 0.85 % NaCl solution are spotted onto the agar medium:
Microorganisms used:
Figure imgf000056_0001
The plates are incubated at 37°C for 24 hours (A. niger at 28°C for 3 days) and then the highest dilution (lowest concentration) of the test substance at which growth is just no longer discernible (corresponds to the MIC) is determined. The results are shown in Table 3.
Figure imgf000057_0001
Example 12: "Microbicidal activity" suspension test CG 161 /EN! 040
Test method:
Nutrient medium:
Casein/soymeal peptone broth for preparation of pre-cultures of test bacteria
Examples of test organisms:
Staphylococcus aureus ATCC 6538 Escherichia coli ATCC 10536 Actynomyces viscosus ATCC 43146 Procedure:
The test substances are dissolved in dimethyl sulfoxide (DMSO) and tested in a concentration of 120 μg/ml.
Bacteria are incubated overnight in CASO broth and adjusted to an organism count of
1 - 5 x 105 CFU/ml using 0.85 % sodium chloride solution.
The test substances are pre-pipetted into microtitre plates in amounts of 8 μl per well.
The adjusted test organism suspensions are added in amounts of 192 μl per well to the test substances and mixed. After defined contact times, the test batches are mixed, an aliquot is withdrawn and diluted in several steps in a dilution series of 1 :10 in a suitable inactivation medium.
The test plates are incubated for 24 hours at 37°C. After incubation, the growth is determined on the basis of the turbidity of the test batches (optical density) at 620 nm in a microplate reader.
On the basis of the number of steps in the dilution series that exhibit growth, the reduction in the test organism concentration is determined in powers of ten (log value).
One microtitre plate is used for each test organism.
All the substances are tested in duplicate.
The results (log reduction) are shown in Table 4:
Figure imgf000058_0001
Figure imgf000059_0001
Example 13: Determination of the minimum inhibitory concentration (MIC value) in microtitre plates
Nutrient medium and test procedure correspond to Example 10.
As test organisms there are used:
Staphylococcus aureus ATCC 6538 Escherichia coli ATCC 10536 Actynomyces viscosus ATCC 43146
The microbiological test results are compiled in Table 5:
Figure imgf000059_0002
Figure imgf000060_0001

Claims

What is claimed is:
1 . Use of a 4-aminopyrimidine of formula
0 ) / Wherein
Figure imgf000061_0001
R1 and R2 are each independently of the other hydrogen; C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms; biphenyl or C6-C10aryl which is unsubstituted or substituted by halogen, C.-C.alkyl, C,-C5alkoxy or by amino; a 5- to 7-membered heteroaryl radical; or cyclo-C3-C7alkyl;
R3 is hydrogen; phenyl or C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms;
R4 is hydrogen; C C10aIkyl; phenyl; or a 5- to 7-membered heteroaryl radical;
R5 is C C20alkyl which is unsubstituted or substituted by one or more halogen atoms or by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
R' bivalent heterocyclic radical; NR"R'"-C.-C20alkyl which is unsubstituted or substituted by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
R' bivalent heterocyclic radical; cydo-C-C-alkyl; hydroxy-C C20alkyl; phenyl-C.-C3alkyl; a heterocyclic radical; or
R4 and R,, together with the nitrogen atom linking them, form a radical of
formula (1 a) ;
Figure imgf000061_0002
R' is hydrogen; or C.-C3alkyl;
R" and R"' are each independently of the other hydrogen; C.-C.alkyl; or hydroxy-C.-C3alkyl;
Figure imgf000061_0003
R"" is hydrogen; C.-C4alkyl; or heteroaryl-C.-C4alkyl; and n, and n2 are each independently of the other from 1 to 8; in the antimicrobial treatment of surfaces.
2. Use according to claim 1 , wherein
R. is R"R"'N-C.-C20alkyl which is uninterrupted or interrupted by one or more -O- or
— N— groups or by a bivalent heterocyclic radical; R'
R' is hydrogen; or C.-C.alkyl;
R" and R'" are each independently of the other hydrogen; or methyl; and
R R2, R3 and R4 are as defined in claim 1.
3. Use according to either claim 1 or claim 2, wherein
is R"R'"N-C.-C20alkyl which is uninterrupted or interrupted by — N N-
4. Use according to either claim 1 or claim 2, wherein
R. is R"R"'N-C.-C20alkyl which is uninterrupted or interrupted by one or more -O- or
— N— groups; R'
R' is hydrogen; or C.-C5alkyl; and
R" and R"1 are each independently of the other hydrogen; or methyl.
5. Use according to claim 4, wherein R. is R"R'"N-C,-C20alkyl; and
R" and R'" are each independently of the other hydrogen; or methyl.
6. Use according to claim 1 , wherein R4 is hydrogen; or C.-C.alkyl;
R5 is C.-C20alkyl which is unsubstituted or interrupted by -NH-; and R., R2 and R3 are as defined in claim 1.
7. Use according to claim 6, wherein
R, is hydrogen; C.-C.alkyl; unsubstituted or C.-C4alkyl-substituted phenyl or phenyl-
C.-C4alkyl; or pyridino;
R2 is hydrogen; or C.-C.alkyl; especially methyl; R3 is hydrogen; or C.-C.alkyl; R4 is hydrogen; or C.-C.alkyl; and R, is C.-C20alkyl.
8. Use according to either claim 6 or claim 7, wherein
R, is hydrogen; C.-C.alkyl, especially isopropyl or methyl; unsubstituted or C C4alkyl- substituted phenyl; or pyridino;
R2 is methyl;
R3 and R4 are hydrogen; and
R5 is C8-C18alkyl.
9. Use according to any one of claims 6 to 8, wherein R. is linear C8-C18alkyl.
10. Use according to claim 1 , wherein, in formula (l a), R"" is hydrogen; or pyridyl-C.-C-alkyl; and n, and n2 are in each case 2.
1 1. Use according to any one of claims 1 to 8, wherein
R, and R2 are each independently of the other hydrogen; C.-C.alkyl; phenyl which is unsubstituted or substituted by halogen, C,-C5alkyl, C.-C,alkoxy or by amino; biphenyl; cyclo-C3-C7alkyl; 3-pyridyl; 4-pyridyl; 2-thiophenyl; 3-thiophenyl; or thiazolyl.
12. Use according to any one of claims 1 to 6, wherein R3 is hydrogen; or phenyl.
1 3. Use according to any one of claims 1 to 10, wherein R4 is hydrogen.
14. Use according to claim 1, relating to compounds of formula
Figure imgf000063_0001
wherein
X is -O-; or — N— ; R'
R' is hydrogen; or C.-C.alkyl; n is 1 -3; and m is 1 -3; and
R., R2 and R3 are as defined in claim 1.
15. A process for the preparation of a compound of formula (1), which comprises reacting 2- amidinopyridine with a keto ester using an auxiliary base in a suitable solvent in accordance with the following scheme:
,
Figure imgf000064_0001
POCI,
Figure imgf000064_0002
wherein
R,, R2, R3, R4 and R, are as defined in claim 1.
16. A process for the preparation of a compound of formula (2), which comprises preparing the compound in a solid-phase synthesis using a trityl (TCP) resin in accordance with the following scheme : H2N(CH2)nX(CH2)mNH2
(TCP V-CI fτcpV-1 NH(CH2)nX(CH2)mNH2
Figure imgf000065_0001
wherein
R., R2, R3, X, m and n are as defined in claim 14.
17. Use according to claim 1 , wherein the compound of formula (1) is used in the antimicrobial treatment, deodorisation and disinfection of the skin, mucosa and hair.
18. Use according to claim 1 , wherein the compound of formula (1) is used in the treatment of textile fibre materials.
19. Use according to claim 1 , wherein the compound of formula (1 ) is used in preservation.
20. Use according to claim 1 , wherein the compound of formula (1 ) is used in washing and cleaning formulations.
21. Use according to claim 1 , wherein the compound of formula (1 ) is used in imparting antimicrobial properties to, and preserving, plastics, paper, nonwovens, wood or leather.
22. Use of a compound of formula (1) in imparting antimicrobial properties to, and preserving, technical products, especially printing thickeners of starch or of cellulose derivatives, surface-coatings and paints.
23. Use of a compound of formula (1) as a biocide in technical processes.
24. A personal care preparation comprising from 0.01 to 15 % by weight, based on the total weight of the composition, of a compound of formula (1), and cosmetically tolerable adjuvants.
25. An oral composition comprising 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.
26. A compound of formula
(V) wherein
Figure imgf000066_0001
R, and R2 are each independently of the other hydrogen; C.-C5alkyl which is unsubstituted or substituted by one or more halogen atoms; biphenyl or C.-C10aryl which is unsubstituted or substituted by halogen, C.- alkyl, C.-C.alkoxy or by amino; a 5- to 7-membered heteroaryl radical; or cyclo-C3-C7alkyl;
R3 is hydrogen; phenyl or C.-C.alkyl which is unsubstituted or substituted by one or more halogen atoms;
R4 is hydrogen; C.-C-.alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;
Rs is C.-C-0alkyl which is unsubstituted or substituted by one or more halogen atoms or by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
R1 bivalent heterocyclic radical; NR"R"'-C.-C20alkyl which is unsubstituted or substituted by a heterocyclic radical or interrupted by one or more -O- or — N— groups or by a
FV bivalent heterocyclic radical; cyclo-C.-C8alkyl; hydroxy-C C20alkyl; phenyl-C C3alkyl; a heterocyclic radical; or
R4 and R5, together with the nitrogen atom linking them, form a radical of
formula (1 a) ;
Figure imgf000066_0002
R' is hydrogen; or C.-C3alkyl; R" and R'" are each independently of the other hydrogen; C.-C.alkyl; or hydroxy-C.-C.alkyl;
X is O; ^CH-R'^ j or ^N-R"";
R"" is hydrogen; C C4alkyl; or heteroaryl-C.-C4alkyl; and n1 and n2 are each independently of the other from 1 to 8; not including compounds of formula (1 ') wherein simultaneously
R, is C6-C10aryl; or C.-C4alkyl; and
R5 is C.-C7alkyl.
PCT/EP2003/002438 2002-03-15 2003-03-10 4-aminopyrimidines and their use for the antimicrobial treatment of surfaces Ceased WO2003077656A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2003575716A JP2005520821A (en) 2002-03-15 2003-03-10 4-Aminopyrimidine and its use for antimicrobial treatment of surfaces
EP03709767A EP1484971B1 (en) 2002-03-15 2003-03-10 Use of 4-aminopyrimidines for the antimicrobial treatment of surfaces
DE60314730T DE60314730T2 (en) 2002-03-15 2003-03-10 USE OF 4-AMINOPYRIMIDINES FOR ANTIMICROBIAL TREATMENT OF SURFACES
US10/507,800 US7731985B2 (en) 2002-03-15 2003-03-10 4-aminopyrimidines and their use for the antimicrobial treatment of surfaces
AU2003214110A AU2003214110A1 (en) 2002-03-15 2003-03-10 4-aminopyrimidines and their use for the antimicrobial treatment of surfaces

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02405201.1 2002-03-15
EP02405201 2002-03-15

Publications (1)

Publication Number Publication Date
WO2003077656A1 true WO2003077656A1 (en) 2003-09-25

Family

ID=27838195

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/002438 Ceased WO2003077656A1 (en) 2002-03-15 2003-03-10 4-aminopyrimidines and their use for the antimicrobial treatment of surfaces

Country Status (9)

Country Link
US (1) US7731985B2 (en)
EP (1) EP1484971B1 (en)
JP (1) JP2005520821A (en)
CN (1) CN1642422A (en)
AT (1) ATE366045T1 (en)
AU (1) AU2003214110A1 (en)
DE (1) DE60314730T2 (en)
ES (1) ES2290436T3 (en)
WO (1) WO2003077656A1 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004065380A1 (en) * 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2004062609A3 (en) * 2003-01-10 2004-11-25 Pharmacopeia Inc Pyrimidine derivatives as il-8 receptor antagonists
WO2005099711A1 (en) * 2004-04-13 2005-10-27 Icagen, Inc. Polycyclic pyrimidines as potassium ion channel modulators
EP1927594A1 (en) 2003-01-14 2008-06-04 Arena Pharmaceuticals, Inc. 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US7449470B2 (en) 2003-10-03 2008-11-11 Universiteit Leiden Substituted pyrimidines as ligands of adenosine receptors
US7470699B2 (en) 2003-07-11 2008-12-30 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7524849B2 (en) 2003-09-24 2009-04-28 Wyeth Holdings Corporation 5-arylpyrimidines as anticancer agents
WO2013004332A1 (en) * 2011-07-07 2013-01-10 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
WO2014105952A3 (en) * 2012-12-28 2014-10-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibitors of the usp1/uaf1 deubiquitinase complex and uses thereof
US9725432B2 (en) 2012-04-30 2017-08-08 Janssen Sciences Ireland Us Pyrimidine derivatives for the treatment of bacterial diseases
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11993580B1 (en) 2022-12-02 2024-05-28 Neumora Therapeutics, Inc. Methods of treating neurological disorders
US12156866B2 (en) 2018-06-06 2024-12-03 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018249550B2 (en) 2017-04-05 2023-11-30 Curza, Inc. Compositions and methods comprising a triaryl polyamine
CN108162528B (en) * 2017-12-22 2020-07-10 宿迁市金田塑业有限公司 Novel high-performance antibacterial antifogging film

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435402A (en) * 1981-01-29 1984-03-06 Sankyo Company, Limited Aminopyrimidine derivatives, processes for their preparation, and fungicidal, insecticidal and acaricidal compositions containing them
EP0323757A2 (en) * 1988-01-07 1989-07-12 Ube Industries, Ltd. Alkylaminopyrimidine derivative, process for producing the same, and insecticide, acaricide and fungicide containing the same as active ingredient
EP0407899A2 (en) * 1989-07-11 1991-01-16 Hoechst Schering AgrEvo GmbH Aminopyrimidine derivatives, process for their preparation, agent containing them and their use as fungicides
EP0424125A2 (en) * 1989-10-18 1991-04-24 Ube Industries, Ltd. Aralkylamine derivatives, preparation method thereof and fungicides containing the same
EP0519211A1 (en) * 1991-05-17 1992-12-23 Hoechst Schering AgrEvo GmbH Substituted 4-aminopyrimidine, process for their preparation and their use as parasiticide
WO1995007278A1 (en) * 1993-09-09 1995-03-16 E.I. Du Pont De Nemours And Company Fungicidal, miticidal and arthropodicidal aminopyrimidines
US6207668B1 (en) * 1996-04-03 2001-03-27 Hoechst Schering Substituted pyridines/pyrimidines, their preparation, and their use as pesticides

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1143167A (en) * 1967-01-25 1969-02-19 Ucb Sa Derivatives of pyrimidine
US3755583A (en) * 1970-06-05 1973-08-28 Chas0!nhx
US3707560A (en) * 1970-10-05 1972-12-26 Pfizer Certain 4-amino-6-aryl-pyrimidines
DE2202385A1 (en) * 1972-01-19 1973-07-26 Boehringer Mannheim Gmbh Nitrofuryl-pyrimidines and -1,2,4-thiadiazoles - - with antimicrobial activity
US4144338A (en) * 1977-02-17 1979-03-13 Merck & Co., Inc. N-pyrimidinyl-N-dialkylaminoalkyl ureas
JPS6059883B2 (en) * 1978-05-08 1985-12-27 北興化学工業株式会社 Fungicide for agriculture and horticulture
MA18829A1 (en) * 1979-05-18 1980-12-31 Ciba Geigy Ag PYRIMIDINE DERIVATIVES, METHODS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS AND THEIR THERAPEUTIC USE
JPS57126481A (en) * 1981-01-29 1982-08-06 Sankyo Co Ltd Aminopyrimidine derivative, fungicide, insecticide, and acaricide
JPS57176967A (en) * 1981-04-21 1982-10-30 Sankyo Co Ltd Aminopyrimidine derivative and antibacterial, insecticidal and miticidal agent
JPS5936666A (en) * 1982-07-23 1984-02-28 Sankyo Co Ltd Aminopyrimidine derivative
EP0136976A3 (en) * 1983-08-23 1985-05-15 Ciba-Geigy Ag Use of phenyl pyrimidines as plant regulators
GB8417852D0 (en) * 1984-07-13 1984-08-15 Fujisawa Pharmaceutical Co Pyrimidine derivatives
DE3642452A1 (en) * 1986-12-12 1988-06-23 Bayer Ag SUBSTITUTED 4-AMINO-PYRIMIDINE
JPH01250363A (en) * 1987-12-28 1989-10-05 Kumiai Chem Ind Co Ltd 4-benzylaminopyrimidine derivative and herbicide
JPH0745481B2 (en) * 1988-01-07 1995-05-17 宇部興産株式会社 Alkylaminopyrimidine derivative, method for producing the same, and insecticide, acaricide and fungicide containing the derivative as an active ingredient
JPH0368563A (en) * 1989-08-09 1991-03-25 Kumiai Chem Ind Co Ltd (r)s)-alpha-methylbenzylaminopyrimidine derivative and herbicide
EP0555478A4 (en) * 1990-08-31 1993-11-18 Nippon Shinyaku Company, Limited Pyrimidine derivative and medicine
DE4031798A1 (en) * 1990-10-08 1992-04-09 Hoechst Ag Pyridyl-pyrimidine derivs. - fungicides useful as plant protectants and as preservatives in paints or oils
DE4034762A1 (en) * 1990-11-02 1992-05-07 Hoechst Ag Pyridyl pyrimidine derivs. - are fungicides for plant protection and for protecting and preserving industrial materials
ATE176226T1 (en) * 1990-11-19 1999-02-15 Du Pont INSECTICIDES, ACARICIDES AND FUNGICIDES AMINOPYRIMIDINES
JPH05194418A (en) * 1992-01-23 1993-08-03 Kirin Brewery Co Ltd 2-aminopyrimidine derivative and its use
JP3086316B2 (en) * 1992-01-31 2000-09-11 アグロカネショウ株式会社 Phenylcarbamate derivative, method for producing the same, and agricultural / horticultural fungicide containing the derivative as an active ingredient
JP2649119B2 (en) * 1992-04-21 1997-09-03 宇部興産株式会社 Alkylaminopyrimidine compounds, their preparation and pest control agents
US5354738A (en) * 1992-09-04 1994-10-11 G. D. Searle & Co. Platelet aggregation inhibitors
AU7938994A (en) * 1993-10-25 1995-05-22 Shell Internationale Research Maatschappij B.V. Pyrimidine derivatives
JPH08283246A (en) * 1994-06-01 1996-10-29 Nippon Soda Co Ltd Pyrimidine derivative, its production and controlling agent for pest
DE19511562A1 (en) * 1995-03-29 1996-10-02 Hoechst Schering Agrevo Gmbh Cyclohexylamino and alkoxy nitrogen heterocycles, process for their preparation and their use as pesticides and fungicides
DE19600934A1 (en) * 1996-01-12 1997-07-17 Basf Ag Substituted aza and diazacycloheptane and cyclooctane compounds and their use
US6011029A (en) * 1996-02-26 2000-01-04 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
JPH10130149A (en) * 1996-07-12 1998-05-19 Sankyo Co Ltd TNF production inhibitor
JPH11246528A (en) * 1997-12-05 1999-09-14 Tomono Agrica Co Ltd Nitrogen-containing aromatic compounds and salts thereof
DK1091957T3 (en) 1998-05-23 2005-04-11 Altana Pharma Ag Pyrimidine-aminomethyl-pyridine derivatives, their preparation and their use in the control of Helicobacter bacteria
GB9816729D0 (en) * 1998-08-01 1998-09-30 Hoechst Schering Agrevo Gmbh Substituted cyclohexylaminopyrimidines
DE19836697A1 (en) 1998-08-13 2000-02-17 Hoechst Marion Roussel De Gmbh New substituted 4-amino-2-aryl-pyrimidines, are soluble guanylate cyclase activators useful e.g. for treating atherosclerosis, hypertension, angina pectoris, thrombosis, asthma or diabetes
JP2001139561A (en) * 1999-11-17 2001-05-22 Dainippon Pharmaceut Co Ltd 5-halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative
JP2001247411A (en) * 2000-03-09 2001-09-11 Tomono Agrica Co Ltd Pest control agent
GB0018951D0 (en) * 2000-08-03 2000-09-20 Smithkline Beecham Plc Novel compounds
AU2002227905B2 (en) * 2000-11-10 2006-10-05 F. Hoffmann-La Roche Ag Pyrimidine derivatives and their use as neuropeptide Y receptor ligands
US20020137755A1 (en) * 2000-12-04 2002-09-26 Bilodeau Mark T. Tyrosine kinase inhibitors
WO2002068409A1 (en) * 2001-02-23 2002-09-06 Merck & Co., Inc. N-substituted nonaryl-heterocyclic nmda/nr2b antagonists
ES2242839T3 (en) * 2001-04-20 2005-11-16 Ciba Specialty Chemicals Holding Inc. 4-AMINO-2- (PIRIDIN-2-IL) PYRIMIDINE AS ACTIVE SUBSTANCES MICROBICIDES.
EP1254903B1 (en) * 2001-04-20 2005-06-08 Ciba SC Holding AG 4-Amino-2-(pyridin-2-yl)pyrimidine as microbicidal active substances
DE10131543A1 (en) * 2001-06-29 2003-01-16 Abbott Lab Pyrimidinoxyalkylpiperazines and their therapeutic use
JPWO2003026661A1 (en) * 2001-09-14 2005-01-06 山之内製薬株式会社 Insulin secretion promoter and novel pyrimidine derivatives
GB0226724D0 (en) * 2002-11-15 2002-12-24 Merck Sharp & Dohme Therapeutic agents
ATE527250T1 (en) * 2002-11-21 2011-10-15 Novartis Ag 2,4,6-TRISUBSTITUTED PYRIMIDINES AS PHOSPHOTIDYLINOSITOL (PI) 3-KINASE INHIBITORS AND THEIR USE IN THE TREATMENT OF CANCER

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435402A (en) * 1981-01-29 1984-03-06 Sankyo Company, Limited Aminopyrimidine derivatives, processes for their preparation, and fungicidal, insecticidal and acaricidal compositions containing them
EP0323757A2 (en) * 1988-01-07 1989-07-12 Ube Industries, Ltd. Alkylaminopyrimidine derivative, process for producing the same, and insecticide, acaricide and fungicide containing the same as active ingredient
EP0407899A2 (en) * 1989-07-11 1991-01-16 Hoechst Schering AgrEvo GmbH Aminopyrimidine derivatives, process for their preparation, agent containing them and their use as fungicides
EP0424125A2 (en) * 1989-10-18 1991-04-24 Ube Industries, Ltd. Aralkylamine derivatives, preparation method thereof and fungicides containing the same
EP0519211A1 (en) * 1991-05-17 1992-12-23 Hoechst Schering AgrEvo GmbH Substituted 4-aminopyrimidine, process for their preparation and their use as parasiticide
WO1995007278A1 (en) * 1993-09-09 1995-03-16 E.I. Du Pont De Nemours And Company Fungicidal, miticidal and arthropodicidal aminopyrimidines
US6207668B1 (en) * 1996-04-03 2001-03-27 Hoechst Schering Substituted pyridines/pyrimidines, their preparation, and their use as pesticides

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037916B2 (en) 1999-07-15 2006-05-02 Pharmacopeia Drug Discovery, Inc. Pyrimidine derivatives as IL-8 receptor antagonists
WO2004062609A3 (en) * 2003-01-10 2004-11-25 Pharmacopeia Inc Pyrimidine derivatives as il-8 receptor antagonists
AU2004205642B2 (en) * 2003-01-14 2011-01-27 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2004065380A1 (en) * 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EP1927594A1 (en) 2003-01-14 2008-06-04 Arena Pharmaceuticals, Inc. 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
HRP20050696B1 (en) * 2003-01-14 2008-10-31 Arena Pharmaceuticals Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
AU2004205642C1 (en) * 2003-01-14 2012-01-12 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EA011009B1 (en) * 2003-01-14 2008-12-30 Арена Фармасьютикалз Инк. 1,2,3-substituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US7470699B2 (en) 2003-07-11 2008-12-30 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7524849B2 (en) 2003-09-24 2009-04-28 Wyeth Holdings Corporation 5-arylpyrimidines as anticancer agents
US7449470B2 (en) 2003-10-03 2008-11-11 Universiteit Leiden Substituted pyrimidines as ligands of adenosine receptors
US7560464B2 (en) 2004-04-13 2009-07-14 Icagen, Inc. Polycyclic pyrimidines as potassium ion channel modulators
WO2005099711A1 (en) * 2004-04-13 2005-10-27 Icagen, Inc. Polycyclic pyrimidines as potassium ion channel modulators
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2013004332A1 (en) * 2011-07-07 2013-01-10 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
US9199962B2 (en) 2011-07-07 2015-12-01 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
AU2012280725B2 (en) * 2011-07-07 2017-02-02 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
US9725432B2 (en) 2012-04-30 2017-08-08 Janssen Sciences Ireland Us Pyrimidine derivatives for the treatment of bacterial diseases
US10221157B2 (en) 2012-04-30 2019-03-05 Janssen Pharmaceutica Nv Pyrimidine derivatives for the treatment of bacterial diseases
US9802904B2 (en) 2012-12-28 2017-10-31 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibitors of the USP1/UAF1 deubiquitinase complex and uses thereof
WO2014105952A3 (en) * 2012-12-28 2014-10-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibitors of the usp1/uaf1 deubiquitinase complex and uses thereof
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US12156866B2 (en) 2018-06-06 2024-12-03 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11993580B1 (en) 2022-12-02 2024-05-28 Neumora Therapeutics, Inc. Methods of treating neurological disorders
US12371414B2 (en) 2022-12-02 2025-07-29 Neumora Therapeutics, Inc. Methods of treating neurological disorders

Also Published As

Publication number Publication date
US20050143387A1 (en) 2005-06-30
DE60314730T2 (en) 2008-06-05
EP1484971B1 (en) 2007-07-04
EP1484971A1 (en) 2004-12-15
DE60314730D1 (en) 2007-08-16
CN1642422A (en) 2005-07-20
ATE366045T1 (en) 2007-07-15
AU2003214110A1 (en) 2003-09-29
JP2005520821A (en) 2005-07-14
ES2290436T3 (en) 2008-02-16
US7731985B2 (en) 2010-06-08

Similar Documents

Publication Publication Date Title
EP1484971B1 (en) Use of 4-aminopyrimidines for the antimicrobial treatment of surfaces
US7015228B2 (en) 4-amino-2-(2-pyridyl)pyrimidines as microbicidal active substances
US7722893B2 (en) Use of substitute 2,4-bis (alkylamino) pyrimidines or quinzolines as antimicrobials
EP1254903B1 (en) 4-Amino-2-(pyridin-2-yl)pyrimidine as microbicidal active substances
US6689372B1 (en) Microbicidal active substances
US20040006061A1 (en) Alkoxybenzylamine
US6346260B1 (en) Microbicidal active ingredients
AU2003254560B2 (en) Pyridyl-triazine derivatives as microbicidal active substances
US6624182B1 (en) Hydroxyphenylvinylthiazoles
US20060052375A1 (en) Bis-alkylbenzylamines
US6967215B2 (en) Tetrahydrocarbazoles, a process for the preparation of those compounds, and the use thereof
US7078550B2 (en) Silanyl phenols and naphthols
US6743940B2 (en) 4-aminobut-2-ynecarboxylic acid derivatives
EP1074179B1 (en) Microbicidal active ingredients
EP1651177A1 (en) 3-aryl-2-cyano-3-hydroxy-acrylic acid derivatives
EP1215198A1 (en) 4-Aminobut-2-yne carboxylic acid derivatives and their use as antimicrobial agents

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003709767

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10507800

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 20038059894

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2003575716

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2294/CHENP/2004

Country of ref document: IN

WWP Wipo information: published in national office

Ref document number: 2003709767

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2003709767

Country of ref document: EP