Patent Application
20060052375
The present invention relates to bis-alkylbenzylamines, to the preparation of those compounds, and to their use in the antimicrobial treatment of surfaces, as antimicrobial active ingredients against gram-positive and gram-negative bacteria, yeasts and fungi, and in the preservation of cosmetics, household products, textiles, plastics, and for use in disinfectants.
The bis-alkylbenzylamines according to the invention correspond to formula
wherein
C1-C20Alkyl 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-C8Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Those radicals can be substituted, e.g. by one or more identical or different C1-C4alkyl radicals, especially by methyl, and/or by hydroxy. When cycloalkyl radicals are substituted by one or more substituents, they are preferably substituted by one, two or four, especially by one or two, identical or different substituents.
C1-C5Alkoxy are straight-chain or branched radicals, for example methoxy, ethoxy, propoxy, butoxy or pentyloxy.
Heteroaryl radicals can be unsubstituted or carry one or more, e.g. one, two, three or four, identical or different substituents, which may be located in any positions. Examples of such substituents are e.g. C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, C1-C4alkoxycarbonyl, aminocarbonyl, amino, C1-C4alkylamino, di-C1-C4-alkylamino and C1-C4alkylcarbonylamino.
Heteroaryl radicals are derived from heterocycles having one, two, three or four identical or different ring hetero atoms, especially from heterocycles having one, two or three, especially one or two, identical or different hetero atoms. The heterocycles can be mono- or poly-cyclic, e.g. mono-, bi- or tri-cyclic. They are preferably mono- or bi-cyclic, especially mono-cyclic. The rings preferably contain 5, 6 or 7 ring members. Examples of monocyclic and bicyclic heterocyclic systems from which radicals appearing in the compounds of formula (1) may 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, benzothiophene, benzofuran, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
Unsaturated heterocycles can 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 heterocycles may especially also be aromatic.
Preference is given to alkylbenzylamines of formula (1) wherein
Special preference is given to compounds of formula (1) wherein
Special preference is given to compounds of formula (1) wherein
Special preference is given to compounds of formula (1) wherein R1 and R2 have the same meanings.
Of those compounds, preference is given to those wherein
Special preference is given to compounds of formula (1) wherein
Very special preference is given to compounds of formula (1) wherein
The preparation of the compounds according to the invention is carried out by processes known per se in accordance with the following scheme:
wherein R1 and R2 are as defined for formula (1).
The 4,4′-biphenyl carboxaldehyde is reacted with from 1 to 3 equivalents of amine and a reducing agent, e.g. hydrogen and a metal catalyst, formic acid, metal hydrides, e.g. borane complexes, borohydrides, aluminium hydrides, etc., in a suitable solvent, e.g. THF, DMF, dioxane, toluene, xylene, methanol or ethanol, with or without acid catalysis (acetic acid, TMOF) at a temperature of from −10° C. to 150° C. in the course of from 1 to 24 h, to form the corresponding amine compound.
In a further preparation variant, the bis-alkylbenzylamines according to the invention can be prepared in only one reaction step by direct alkylamination of BCMD. The process, which is a further subject of the invention, can be carried out as follows:
The alkylamination of BCMD is generally carried out in an excess of R1—NH2. The solvent (toluene) and the excess of R, —NH2 can be recycled by distillation. The reaction time is from 0.5 to 12, preferably from 1 to 3 hours. The reaction temperature is from 50 to 120, preferably from 70 to 90° C.
Preferred solvents are toluene, xylene or fractions from petrol.
Examples of compounds according to the invention are listed in Table 1:
The bis-alkylbenzylamines used according to the invention exhibit a pronounced antimicrobial action, especially against pathogenic gram-positive and gram-negative bacteria and also against bacteria of skin flora. They are therefore especially suitable for the disinfection, deodorisation and the general and antimicrobial treatment of the skin and mucosa and also of integumentary appendages (hair), more especially for the disinfection of the hands and of wounds. They are therefore suitable as antimicrobial active ingredients and preservatives in personal care preparations, for example shampoos, bath additives, hair-care products, 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 cleansing cloths, oils or powders.
The invention therefore relates also to a personal care preparation comprising at least one compound of formula (1) as well as cosmetically tolerable carriers or adjuvants.
The personal care preparation according to the invention comprises from 0.01 to 15% by weight, preferably from 0.1 to 10% by weight, based on the total weight of the composition, of bis-alkylbenzylamines of formula (1), and cosmetically tolerable adjuvants.
Depending upon the form of the personal care preparation, it comprises, in addition to the bis-alkylbenzylamine compound of formula (1), further constituents, for example sequestering agents, colourings, perfume oils, thickening or solidifying agents (consistency regulators), emollients, UV absorbers, skin-protective agents, antioxidants, additives that improve mechanical properties, such as dicarboxylic acids and/or Al, Zn, Ca and Mg salts of C14-C22-fatty acids, and optionally preservatives.
The personal care preparation according to the invention may be formulated as a water-in-oil or oil-in-water emulsion, as an alcoholic or alcohol-containing formulation, as a vesicular dispersion of an ionic or non-ionic amphiphilic lipid, as a gel, a solid stick or as an aerosol formulation.
As a water-in-oil or oil-in-water emulsion, the cosmetically tolerable adjuvant contains preferably from 5 to 50% of an oily phase, from 5 to 20% of an emulsifier and from 30 to 90% water. The oily phase may contain any oil suitable for cosmetic formulations, e.g. one or more hydrocarbon oils, a wax, a natural oil, a silicone oil, a fatty acid ester or a fatty alcohol. Preferred mono- or poly-ols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.
Cosmetic formulations according to the invention are used in a variety of fields. Especially the following preparations, for example, come into consideration:
An antimicrobial soap has, for example, the following composition:
A shampoo has, for example, the following composition:
A deodorant has, for example, the following composition:
The invention relates also to 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.
Example of an oral composition:
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 bis-alkylbenzylamines of formula (1) according to the invention are also suitable for the treatment, especially the preservation, of textile fibre materials. Such materials are undyed and dyed or printed fibre materials, e.g. 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 bis-alkylbenzylamines according to the invention are also suitable for the treatment of plastics, especially for imparting antimicrobial properties to or preserving plastics, e.g. polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc. Fields of use therefor are, for example, floor coverings, plastics coatings, plastics container and packaging materials; kitchen and bathroom utensils (e.g. brushes, shower curtains; sponges, bathmats), latex, filter materials (air and water filters), plastics articles used in the field of medicine, e.g. dressing materials, syringes, catheters etc., so-called “medical devices”, gloves and mattresses.
Paper, for example papers used for hygiene purposes, may also be provided with anti-microbial properties using the bis-alkylbenzylamines according to the invention.
It is also possible for nonwovens, e.g. nappies/diapers, sanitary towels, panty liners, and cloths for hygiene and household uses, to be provided with antimicrobial properties according to the invention.
The bis-alkylbenzylamines of formula (1) are also used in washing and cleaning formulations, e.g. in liquid and powder washing agents or in softeners.
The bis-alkylbenzylamines can be used especially also in household and all-purpose cleaners for cleaning and disinfecting hard surfaces. A cleaning preparation has, for example, the following composition:
Also possible, in addition to the preservation of cosmetic and household products, is the preservation of technical products and the provision of such products with antimicrobial properties as well as use as a biocide in technical processes, such as in paper treatment, especially in paper treatment liquors, printing thickeners of starch or of cellulose derivatives, surface-coatings and paints.
The bis-alkylbenzylamines of formula (1) are also suitable for the antimicrobial treatment of wood and for the antimicrobial treatment of leather, the antimicrobial preservation of leather and the provision of leather with antimicrobial properties.
The compounds according to the invention are also suitable for the protection of cosmetic products and household products from microbial spoilage.
The following Examples serve to illustrate the invention but do not limit the invention.
4.20 g (20 mmol) of 4,4′-biphenyl dicarboxaldehyde are dissolved in 50 ml of absolute THF under nitrogen. 4.80 g (80 mmol) of acetic acid and 5.69 g (44 mmol) of octylamine are added dropwise thereto and the mixture is heated for 1 hour at 60° C. After cooling with an ice-bath, 10.17 g (48 mmol) of sodium triacetoxyborohydride are added in portions. The reaction mixture is stirred overnight at room temperature. 100 ml of water are placed in a container and the reaction mixture is added using a pipette. The pH is adjusted to 1 with 6N hydrochloric acid. The THF is distilled off, and the product is filtered off and washed with 900 ml of water.
The product is then suspended in ethyl acetate, adjusted to pH 13 with sodium hydroxide solution and then filtered off again.
The product is washed with 300 ml of water. Excess octylamine is distilled off under a high vacuum.
Yield: 84% (GC purity: 88%)
NMR (methanol): 0.8 ppm (6H); 1.2 ppm (20H); 1.45 ppm (4H); 2.5 ppm (4H); 3.7 ppm (4H); 7.3 ppm (4H); 7.5 ppm (4H)
A suspension of BCMD (1.00 mol) in toluene (2600 ml) is treated while cold with an excess of n-octylamine (5.00 mol). After reaction for one hour at 80° C., the conversion is complete. The reaction suspension is washed out with water (1000 ml) and 50% NaOH (200 g). The solvents (toluene/n-octylamine) are distilled off in vacuo (60-120° C./20 mbar).
The oily residue is taken up in warm ethyl acetate (1200 ml), clarified on a suction-filter (BCMD polymer), cooled to 35° C. and seeded.
After further cooling to 0° C., the crystalline product is filtered off, washed with solvent and dried.
Nutrient Medium:
Casein/soybean flour peptone bouillon for the preparation of the precultures of the test bacteria and yeast.
Examples of Test Organisms:
Bacteria: Escherichia coli ATCC 10536 (=EC) Staphylococcus aureus ATCC 6538(=SA)
Procedure:
The test substances are predissolved in dimethyl sulfoxide (DMSO) and tested in a serial dilution of 1:2.
Bacteria and yeast are cultured overnight in CASO bouillon.
All test organism suspensions are adjusted to an organism count of 1-5×106 CFU/ml with 0.85% sodium chloride solution.
The test substances are prepipetted into microtitre plates in an amount of 8 μl per well. The previously adjusted organism suspensions are diluted 1:100 in CASO bouillon and added to the test substances in an amount of 192 μl per well.
The test batches are incubated for 48 hours at 37° C.
After incubation, the growth is determined by reference to the turbidity of the test batches (optical density) at 620 nm in a microplate reader.
The minimum inhibiting concentration (MIC value) is the concentration of substance at which an appreciable inhibition of the growth (<20% growth compared with the growth control) of the test organisms is ascertained.
Three microtitre plates are used for each test organism and substance concentration.
The microbiological test results are compiled in Table 2:
The compound of formula (3) (see Table 1; GC purity 88%; prepared in accordance with Example 1) is tested on the microorganisms indicated in Table 3.
The test for determining the minimum inhibiting concentration is effected in an agar incorporation test.
| Number | Date | Country | Kind |
|---|---|---|---|
| 02405898.4 | Oct 2002 | EP | regional |
| 0091/03 | Jan 2003 | CH | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP03/11384 | 10/14/2003 | WO | 4/13/2005 |
