Patent Grant
6967215
The present invention relates to novel tetrahydrocarbazoles, to a process for the preparation of those compounds and to the use thereof as antimicrobial active ingredients.
The tetrahydrocarbazoles according to the invention correspond to formula
wherein
C1-C20Alkyl denotes straight-chain or branched alkyl radicals, such as 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-C12Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclodocecyl and especially cyclohexyl.
Within the scope of the meanings given, alkenyl includes inter alia allyl, isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, n-penta-2,4-dienyl, 3-methylbut-2-enyl, n-oct-2-enyl, n-dodec-2-enyl, isododecenyl, n-dodec-2-enyl or n-octadec-4-enyl.
C1-C20Alkoxy denotes straight-chain or branched radicals, such as methoxy, ethoxy, propoxy, butoxy or pentyloxy, hexyloxy, heptyloxy, octyloxy, isooctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy or eicosyloxy.
Halogen is fluorine, chlorine, bromine or iodine.
Preference is given to the use of compounds of formula (1) or (2) wherein
In formula (1)
Preference is given also to compounds of formula (1) wherein
Very special preference is given to compounds of formula
wherein
Preference is given to compounds of formula (3) or (4) wherein
More especially preferred compounds according to the invention correspond to formula
wherein
In formulae (5) and (6) preferably
Special preference is given to compounds of formula (5) and (6) wherein R6′ and R6″ and R6 are each independently of the others hydrogen; C1-C5alkyl; C1-C7-alkoxycarbonyl; phenyl or benzyl.
Further preferred compounds according to the invention correspond to formula
wherein
Compounds according to the invention are listed in Tables 1 a and b below by way of example:
The preparation of the tetrahydrocarbazoles according to the invention is carried out according to widely known methods in a 3-component reaction, as described in the publication by W. Noland et al., J. Heterocycl. Chem., 1993, 30, 81-91.
For that purpose, mixtures of a (substituted) indole, ketone or aldehyde and a dienophile are reacted in a suitable solvent, e.g. 1-butanol, toluene, DMF, DMSO or Tetralin, using acid catalysts, e.g. hydrochloric acid, trifluoroacetic acid, toluenesulfonic acid, etc. The ketone or aldehyde component can also serve as solvent. The mixture is heated for several hours at a temperature of from 50° C. to 140° C. The resulting tetrahydrocarbazoles are filtered off and washed, or precipitated from the solvent with cold n-hexane and filtered off. Some of the substances are also obtained by concentrating the reaction mixture by evaporation.
The course of the reaction can be represented schematically as follows:
The tetrahydrocarbazoles obtained in that manner are generally obtained in the form of racemates and are mainly in the cis stereochemical form. Some compounds also form trans stereochemical isomers.
The invention relates also to the process for the preparation of those compounds.
The tetrahydrocarbazoles according to the invention exhibit pronounced antimicrobial activity, 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 especially suitable for disinfection, deodorisation, and for the general and antimicrobial treatment of the skin and mucosa, and integumentary appendages (hair), especially for the disinfection of hands and wounds.
The compounds are accordingly suitable as antimicrobial active ingredients and as preservatives in personal care preparations, such as 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 wipes, oils or powders.
The invention accordingly relates also to a personal care preparation comprising at least one compound of formula (1) or (2) 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) or (2) and cosmetically tolerable adjuvants.
Depending upon the form of the personal care preparation, it comprises, in addition to the compound of formula (1) or (2), further constituents, such as sequestering agents, colourings, perfume oils, thickening or solidifying agents (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-C22 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.
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, 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:
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
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 tetrahydrocarbazoles of formula (1) or (2) used according to the invention are also suitable for treating, especially preserving, 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 tetrahydrocarbazoles according to the invention are suitable also for treating, especially imparting antimicrobial properties to or preserving, plastics, e.g. polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex, etc. Fields of use therefore are, for example, floor coverings, plastics coatings, plastics container and packaging materials; kitchen and bathroom utensils (e.g. brushes, shower curtains, sponges, bathmats), latex, filter materials (air and water filters), plastics articles used in the field of medicine, e.g. dressing materials, syringes, catheters, etc., so-called “medical devices”, gloves and mattresses.
Paper, for example papers used for hygiene purposes, may also be provided with antimicrobial properties using the tetrahydrocarbazoles 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 in accordance with the invention.
The tetrahydrocarbazoles of formula (1) or (2) are also used in washing and cleaning formulations, e.g. in liquid or powder washing agents or softeners.
The tetrahydrocarbazoles of formula (1) or (2) can be used especially in household and general-purpose cleaners for cleaning and disinfecting hard surfaces.
A cleaning preparation has, for example, the following composition:
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, print thickeners of starch or of cellulose derivatives, surface coatings and paints.
The tetrahydrocarbazoles of formula (1) or (2) according to the invention are suitable also for the antimicrobial treatment of wood and for the antimicrobial treatment of leather, the 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 damage.
The tetrahydrocarbazoles according to the invention are suitable also as medicaments for the treatment of bacterial infections for oral, intravenous, subcutaneous or parenteral administration of the active ingredient.
The invention accordingly relates also to a medicament comprising a compound of formula (1) or (2) and therapeutically tolerable adjuvants, for the treatment of bacterial infections.
The following Examples illustrate the invention.
General Procedure for the Preparation of the Tetrahydrocarbazoles According to the Invention:
The appropriate (substituted) indole (compound (I)) (1 mmol) is dissolved with (substituted) maleimide (compound (IV) (1.2 mmol) and an aldehyde/ketone (compound (II) (2 mmol) in 1-butanol (1 ml).
There is then added to the mixture aqueous hydrochloric acid (2N; 50 μl; 0.1 mmol) or, in the case of piperidones, concentrated hydrochloric acid (32%; 220 μl; 1.1 mmol). The mixture is then heated at 95° C. for 3 hours.
After cooling to 25° C., the resulting tetrahydrocarbazole (compound (1)) is precipitated with n-hexane (3 ml).
After filtration, the filtrate is cooled to 5° C. in order to obtain further crystals. The combined crystals are washed with n-hexane/ethyl acetate and dried in vacuo.
All the compounds, that is to say the compounds of formulae (9) to (181), are characterised by LC-MS (for yields, see Table 1). Some of the compounds are analysed by NMR spectroscopy. The compounds are obtained in the form of mixtures of isomers (racemates or exo/endo isomers).
Yield: 72%
LC-MS: [M+H]+=386 (79Br)
NMR Data:
For reasons of clarity, the numbering used is not in accordance with IUPAC.
3JH-21,H-4 = 7.9 Hz;
3JH-4,H-5 = 5.1 Hz
Yield: 79%
LC-MS: [M+H]+=322
NMR Data:
For reasons of clarity, the numbering used is not in accordance with IUPAC.
Yield: 71%
LC-MS: [M+H]+=386 (79Br)
7.02d
7.00d
Yield: 71%
LC-MS: [M+H]+386 (79Br)
NMR Data:
For reasons of clarity, the numbering used is not in accordance with IUPAC.
3JH-21,H-4 = 7.9 Hz
3JH-4,H-5 = 4.1 Hz
The remaining compounds listed in Table 1 can be prepared in analogous manner.
4. Microbiological Test Results
Nutrient:
Casein/soybean flour peptone bouillon for the preparation of pre-cultures of the test bacteria and yeast.
Mycological slant agar for the pre-culture of moulds
Examples of Test Organisms:
Staphylococcus hominis DMS 20328
Staphylococcus epidermidis
Escherichia coli NCTC 8196
Corynebacterium xerosis ATCC 373
P. ovale ATCC 14521
Enterococcus hirae ATCC 10541
Actinomyces viscosus DSM 43329
Micrococcus luteus ATCC 9341
Porphyromonas gingivalis DSM 20709
Candida albicans ATCC 10259
Selenomonas artemidis ATCC 43528
Staphylococcus aureus (methicillin-resistant) NCTC
Streptococcus mutans ATCC 25175
Streptococcus sobrinus DSM 20742
Staphylococcus aureus (methicillin-resistant)
Epidermophyton floccosum DSM 10709
Staphylococcus aureus (penicillin-resistant)
Trichophyton rubrum DSM 4167
Staphylococcus aureus (rifampicin-resistant)
Trichoderma longibrachiatum
Propionibacterium acnes ATCC 25746
Aspergillus niger ATCC 6175
Procedure:
The test substances are predissolved in dimethyl sulfoxide (DMSO) and tested in a dilution series of 1:2.
Bacteria and yeast are cultured overnight in CASO bouillon, the mould is cultured overnight on mycological slant agar, and washed off with 10 ml of 0.85% sodium chloride solution (+0.1% TritonX-100).
All the test organisms are adjusted to an organism count of 1-5×106 CFU/ml using 0.85% sodium chloride solution.
The test substances are pre-pipetted into microtitre plates in an amount of 8 μl per well.
Pre-diluted organism suspensions are diluted 1:100 in CASO bouillon (bacteria and yeast) or Sabouraud 2% glucose bouillon (mould) and are added in an amount of 192 μl per well to the test substances.
The test batches are incubated for 48 hours at 37° C. (bacteria and yeast) or for 5 days at 28° C. (mould).
After incubation, the growth is evaluated by reference to 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 with the growth of the control) an appreciable inhibition of growth (≦20% growth) of the test organisms is ascertained.
One microtitre plate is used for each test organism and substance concentration. All the substances are tested in duplicate.
The results are compiled in Table 2:
S. hominis
E. coli
Staphylococcus hominis DSM
Staphylococcus epidermidis
Corynebacterium xerosis
Enterococcus hirae
Micrococcus luteus ATCC 9341
Candida albicans ATCC 10259
Staphylococus aureus ATCC 9144
P. ovale ATCC 14521
Staphylococcus hominis DSM 20328
Actinomyces viscosus
Staphylococcus aureus (methicillin-
Porphyromonas gingivalis
Staphylococcus aureus (methicillin-
Selenomonas artemidis
Staphylococcus aureus (penicillin-
Streptococcus mutans
Staphylococcus aureus (rifampicin-
Streptococcus sobrinus
S. epidermidis ATCC 12228
Candida albicans ATCC
Corynebacterium xerosis ATCC 373
Epidermophyton floccosum
Micrococcus luteus ATCC 9341
Enterococcus hirae ATCC 10541
Trichophyton rubrum DSM
Propionibacterium acnes ATCC
Trichoderma longibrachiatum
Aspergillus niger ATCC
S. hominis
E. coil
P. aeruginosa
A. niger
| Number | Date | Country | Kind |
|---|---|---|---|
| 008108441 | Sep 2000 | EP | regional |
| 84301 | May 2001 | CH | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP01/10479 | 9/11/2001 | WO | 00 | 3/13/2003 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO02/24699 | 3/28/2002 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 5645988 | Vande Woude et al. | Jul 1997 | A |
| Number | Date | Country |
|---|---|---|
| 653675 | Jan 1986 | CH |
| Number | Date | Country | |
|---|---|---|---|
| 20040097535 A1 | May 2004 | US |
