USE OF A COMPOUND OF 4-(3-ETHOXY-4-HYDROXYPHENYL) ALKYL KETONE TYPE AGAINST BACTERIA OF THE BURKHOLDERIA CEPACIA COMPLEX

Abstract

The present invention relates to the use of compounds of formula (I) in the treatment of products, in particular of aqueous or nonaqueous compositions, preferably water and aqueous compositions, against bacteria of the Burkholderia cepacia complex (Bcc), and also the use thereof in a process for treating an aqueous composition or water with respect to strains of the Bcc complex.

##STR00001##

formula (I) wherein: R2 represents a hydrogen atom or a methyl or ethyl radical; R3 represents a linear C.sub.1-C.sub.12 alkyl radical (saturated), optionally substituted with a hydroxyl group; or a linear C.sub.2-C.sub.12 alkenyl radical (C═C unsaturated), optionally substituted with a hydroxyl group.

Claims

1. A process for treating a product that may be contaminated by bacteria of the Burkholderia cepacia complex (Bcc) which comprises contacting the product with an amount effective for protecting the product against bacteria of the Burkholderia cepacia complex of at least one compound of formula (I), an organic or mineral acid or base salt thereof, a solvate thereof or a mixture thereof: ##STR00006## formula (I) wherein: R2 represents a hydrogen atom or a methyl or ethyl radical; R3 represents a linear C.sub.1-C.sub.12 alkyl radical (saturated), optionally substituted with a hydroxyl group; or a linear C.sub.2-C.sub.12 alkenyl radical (C═C unsaturated), optionally substituted with a hydroxyl group, thereby protecting the product against bacteria of the Burkholderia cepacia complex (Bcc).

2. The process as claimed in claim 1, for preventing the contamination of a product that may be contaminated by bacteria of the Bcc complex selected from the group of i) of water or an aqueous composition, ii) of equipment for food, cosmetic or pharmaceutical purposes, iii) of solvents used in industrial or domestic preparations, and iv) of industrial or domestic anhydrous compositions.

3. The process as claimed in claim 1, for treating a product that may be contaminated by bacteria of the Bcc complex, the product being selected from the group of i) of water or an aqueous composition, ii) of equipment for food, cosmetic or pharmaceutical purposes, iii) of solvents used in industrial or domestic preparations, and iv) of industrial or domestic anhydrous compositions.

4. The use process as claimed in claim 1, wherein formula (I) is such that: R2 is chosen from hydrogen and methyl; R3 represents (i) a C.sub.1-C.sub.10 alkyl radical; (ii) a C.sub.2-C.sub.10 alkenyl radical; or (iii) a hydroxyalkyl radical having the structure —CH.sub.2—CH(OH)—R5 with R5 representing a linear C.sub.1-C.sub.10 alkyl radical.

5. The process as claimed in claim 1, wherein the compound of formula (I) is chosen from the following compounds: ##STR00007##

6. The process as claimed in claim 1, wherein the compound of formula (I) is 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one having the following formula: ##STR00008##

7. The process as claimed in claim 1, wherein the product is water or and aqueous composition and wherein the compound of formula (I), alone or as a mixture, is used in a proportion of at least 0.06% by weight relative to the total weight of water or of aqueous composition to be treated.

8. A process for treating a product selected from the group of water or an aqueous composition i) to prevent the contamination of said product by one or more microorganisms including bacteria of the Burkholderia cepacia complex, ii) or to treat said product that is contaminated by one or more microorganisms including bacteria of the Bcc complex, comprising at least one step of bringing a sample of the product to be treated or of a stream of water to be treated into contact with an amount effective for treating the product against bacteria of the Burkholderia cepacia complex of at least one compound of formula (I), an organic or mineral acid or base salt thereof, a solvate thereof or a mixture thereof: ##STR00009## formula (I) wherein: R2 represents a hydrogen atom or a methyl or ethyl radical; R3 represents a linear C.sub.1-C.sub.12 alkyl radical (saturated), optionally substituted with a hydroxyl group; or a linear C.sub.2-C.sub.12 alkenyl radical (C═C unsaturated), optionally substituted with a hydroxyl group.

9. The process as claimed in claim 8, wherein the product, is chosen from domestic or industrial waters from industrial tanks, waters from aquatic media, swimming pool/spa waters, and air-conditioning system waters, and cosmetic products.

10. The process as claimed in claim 8, wherein the compound of formula (I), alone or as a mixture, is used in a proportion of at least 0.06% by weight, relative to the total weight of water or of aqueous composition to be treated.

11. A process for preserving a product that may be contaminated by bacteria of the Burkholderia cepacia complex, comprising a step of incorporating into said product, during the production thereof, or after the production thereof, and before storage, one or more compounds of formula (I), an organic or mineral acid or base salt thereof, a solvate thereof or a mixture thereof: ##STR00010## formula (I) wherein: R2 represents a hydrogen atom or a methyl or ethyl radical; R3 represents a linear C.sub.1-C.sub.12 alkyl radical (saturated), optionally substituted with a hydroxyl group; or a linear C.sub.2-C.sub.12 alkenyl radical (C═C unsaturated), optionally substituted with a hydroxyl group.

12. The process as claimed in claim 11, which comprises the step of incorporating one or more compounds of formula (I), during the phase of producing said product.

13. The process as claimed in claim 11, which comprises introducing into a preparation tank, beforehand, one or more compounds of formula (I) and then introducing, into said tank, the product to be treated and to be preserved, or the ingredients required to produce said product.

14. The process as claimed in claim 11, wherein each ingredient required for the production of the product has been treated beforehand with one or more compounds of formula (I), or each ingredient is introduced as a mixture with one or more compounds of formula (I); and then the product is preserved and made available to the a user in the presence of one or more compounds of formula (I).

15. The process as claimed in claim 11, wherein the process comprises the step of incorporating one or more compounds of formula (I) after the phase of producing said product, the product, once produced, is brought into contact with one or more compounds of formula (I), then the product is preserved and made available to a user in the presence of one or more compounds of formula (I).

16. An “anhydrous” composition comprising one or more compounds of formula (I) as defined in claim 1 an organic or mineral acid or base salt thereof, a solvate thereof or a mixture thereof: ##STR00011## formula (I) wherein: R2 represents a hydrogen atom or a methyl or ethyl radical; R3 represents a linear C.sub.1-C.sub.12 alkyl radical (saturated), optionally substituted with a hydroxyl group; or a linear C.sub.2-C.sub.12 alkenyl radical (C═C unsaturated), optionally substituted with a hydroxyl group.

17. A composition as claimed in claim 16, comprises one or more ingredients chosen from i) anionic, nonionic, cationic or zwitterionic surfactants, ii) fatty substances, which are natural or synthetic, or derived from hydrocarbons, iii) anionic, nonionic, cationic or zwitterionic, associative or non-associative thickening or non-thickening polymers, iv) dyes, v) pigments, vi) fillers and vii) their mixture.

18. The process as claimed in claim 8, wherein formula (I) is such that: R2 is chosen from hydrogen and methyl; R3 represents (i) a C.sub.1-C.sub.10 alkyl radical; (ii) a C.sub.2-C.sub.10 alkenyl radical; or (iii) a hydroxyalkyl radical having the structure —CH.sub.2—CH(OH)—R5 with R5 representing a linear C.sub.1-C.sub.10 alkyl radical.

19. The process as claimed in claim 8, wherein the compound of formula (I) is chosen from the following compounds: ##STR00012##

20. The process as claimed in claim 8, wherein the compound of formula (I) is 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one having the following formula: ##STR00013##

Description

DETAILED DESCRIPTION OF THE INVENTION

[0040] Use

[0041] The compound of the following formula (I) and also the organic or mineral acid or base salts thereof, or solvates thereof such as hydrates:

##STR00003##

formula (I) wherein: [0042] R2 represents a hydrogen atom or a methyl or ethyl radical; [0043] R3 represents a linear C.sub.1-C.sub.12 alkyl radical (saturated), optionally substituted with a hydroxyl group; or a linear C.sub.2-C.sub.12 alkenyl radical (C═C unsaturated), optionally substituted with a hydroxyl group.

[0044] Preferably, the compounds correspond to formula (I), wherein: [0045] R2 is chosen from a hydrogen atom and a CH.sub.3 group; even better still, R2 represents a hydrogen atom; and/or [0046] R3 represents (i) a C.sub.1-C.sub.10alkyl radical; (ii) a C.sub.2-C.sub.10 alkenyl radical, in particular a —CH═CH—R4 radical with R4 representing a linear C.sub.1-C.sub.6 alkyl radical; or else (iii) a hydroxyalkyl radical having the structure —CH.sub.2—CH(OH)—R5 with R5 representing a linear C.sub.1-C.sub.10, preferably C.sub.4-C.sub.10, alkyl radical.

[0047] A mixture of compounds of formula (I) can be used.

[0048] Mention may particularly be made of the following compounds of formula (I):

##STR00004##

[0049] The compounds of formula (I) can be readily prepared by those skilled in the art on the basis of their general knowledge. Mention may be made especially of the following bibliographic references: J. Asian Natural Products Research, 2006, 8(8), 683-688; Helv. Chimica Acta, 2006, 89(3), 483-495; Chem. Pharm. Bull., 2006, 54(3), 377-379; and Bioorg. Med. Chem. Lett., 2004, 14(5), 1287-1289.

[0050] They may thus be prepared from ethylvanillin, in the manner described in the published patent application WO 2011/039445.

[0051] In one preferred embodiment of the present invention, use is made of 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one having the following formula:

##STR00005##

[0052] The compounds of formula (I) can be used in combination with at least one active agent chosen from anionic, cationic, nonionic or zwitterionic surfactants, descaling agents, coagulants, and mixtures thereof.

[0053] In one preferred embodiment, the compounds of formula (I) are used in combination with an effective amount of at least one organic solvent having solubility parameters according to the Hansen solubility space such that: 14.5<δ a<30 and 15<δ d<22.

[0054] Advantageously, the organic solvents used in the context of the present invention can be chosen from those described in the published patent application WO 2012/130953.

[0055] The total solubility parameter 6 according to the Hansen solubility space is defined in the article “Solubility parameter values” by Eric A. Grulke in the book “Polymer Handbook”, 3rd Edition, Chapter VII, pages 519-559, by the relationship:

δ=(δ.sup.2=δ.sub.d.sup.2+δ.sub.p.sup.2+δ.sub.h.sup.2).sup.1/2  [Math. 1]

[0056] wherein [0057] δ d characterizes the London dispersion forces derived from the formation of dipoles induced during molecular impacts, [0058] δ p characterizes the Debye interaction forces between permanent dipoles, [0059] δ h characterizes the specific interaction forces (such as hydrogen bonding, acid/base, donor/acceptor, etc.). The definition of solvents in the Hansen three-dimensional solubility space is described in the article by C. M. Hansen: “The three dimensional solubility parameters” J. Paint Technol. 39, 105 (1967).

[0060] The parameter δ a is defined by the following relationship:

δ.sub.a.sup.2=δ.sub.p.sup.2+δ.sub.h.sup.2=δ.sup.2−δ.sub.d.sup.2  [Math. 2]

[0061] The parameters δ d, δ p, δ h s and δ a are expressed in (J/cm3)½.

[0062] Preferably, the organic solvent has solubility parameters such that 14.5<δ a<28 and 15<δ d<20.

[0063] The organic solvent used according to the invention can be chosen from ethanol (δ a=20.20; δ d=15.10), 1,2-propylene glycol (δ a=25.00; δ d=16.00), 1,3-propanediol (δ a=26.32; δ d=18.00), PEG-8 (polyethylene glycol containing 8 ethylene glycol units) (δ a=14.80; δ d=17.90), propylene carbonate (δ a=18.46; δ d=20.00), dipropylene glycol (δ a=19.48; δ d=16.20), 1,2-hexylene glycol (δ a=19.20; δ d=16.40), PEG-4 (δ a=18.60; δ d=18.00).

[0064] Preferably, the organic solvent is chosen from ethanol, 1,2-propylene glycol, 1,3-propanediol, PEG-8 and propylene carbonate.

[0065] The solvent may be used in a content ranging from 0.05% to 10% by weight relative to the total weight of the water to be treated comprising bacteria of the Burkholderia cepacia complex Bcc, preferably ranging from 0.1% to 5% by weight and preferentially ranging from 0.1% to 2.5% by weight relative to the total weight of the water to be treated comprising bacteria of the Burkholderia cepacia complex Bcc.

[0066] The compounds of formula (I), alone or as a mixture, can be used in a proportion of at least 0.06% by weight, preferably at least 0.1% by weight, even better still at least 0.5% by weight relative to the total weight of water to be treated comprising bacteria of the Burkholderia cepacia complex Bcc.

[0067] In one preferred embodiment, the compounds of formula (I), alone or as a mixture, can be used in a proportion of at least 1% by weight relative to the total weight of water to be treated comprising bacteria of the Burkholderia cepacia complex. The compounds of formula (I), alone or as a mixture, can be used in a concentration ranging from 0.06% to 10% by weight, preferably from 0.06% to 10% by weight, even better still from 0.06% to 5% by weight relative to the total weight of water to be treated comprising bacteria of the Burkholderia cepacia complex. In one preferred embodiment, the compounds of formula (I), alone or as a mixture, can be used in a concentration ranging from 0.05% to 2%, preferably ranging from 0.1% to 1% by weight relative to the total weight of water to be treated comprising bacteria of the Burkholderia cepacia complex.

[0068] Process for Treating Water Against the of the Burkholderia cepacia Complex

[0069] Preferably, said step of bringing the water to be treated and the aqueous composition into contact with the compound of formula (I) can in particular be carried out by injection in liquid form of said compound, by passage through a filter or a filtering cartridge comprising said compound, or by administration in solid form of said compound notably in the form of granules, lozenges or pellets.

[0070] Process for Treating a Product that May be Contaminated by Bacteria of the Burkholderia cepacia Complex

[0071] According to one particular embodiment of the invention, the process for treating—in particular for preserving—a product that may be soiled by bacteria of the Burkholderia cepacia complex comprises the step of incorporating one or more compounds of formula (I) as defined above, preferably EZ, during the phase of producing said product.

[0072] The incorporation can be carried out by introducing into the preparation tank, beforehand, one or more compounds of formula (I), preferably EZ, preferably at a temperature of less than or equal to 80° C., better still at ambient temperature (25° C.), and particularly at atmospheric pressure, then introducing into said tank the product to be preserved, or the ingredients required to produce said product. According to one variant, each ingredient required for the production of the product was treated beforehand with one or more compounds of formula (I), in particular EZ, or else each ingredient is introduced as a mixture with one or more compounds of formula (I), in particular EZ. The product is then preserved and made available to the user in the presence of one or more compounds of formula (I), in particular EZ.

[0073] According to another particular embodiment of the invention, the process for preserving a product that may be soiled by bacteria of the Burkholderia cepacia complex comprises the step of incorporating one or more compounds of formula (I) as defined above, preferably EZ, after the phase of producing said product. The product, once produced, is brought into contact with one or more compounds of formula (I), in particular EZ, preferably at a temperature of less than or equal to 80° C., better still at ambient temperature (25° C.), and particularly at atmospheric pressure, then the product is preserved and made available to the user in the presence of one or more compounds of formula (I), in particular EZ.

[0074] According to yet another particular embodiment of the invention, the process for preserving a product that may be soiled by bacteria of the Burkholderia cepacia complex comprises the step of incorporating one or more compounds of formula (I) as defined above, preferably EZ, after the phase of producing said product. The product, once produced, is stored under an inert atmosphere, then once opened by the user it is brought into contact with one or more compounds of formula (I), in particular EZ, preferably at ambient (25° C.), and at atmospheric pressure, then the product is preserved in the presence of one or more compounds of formula (I), in particular EZ.

[0075] Preferably, the product is a composition, particularly comprising a physiologically acceptable medium, more particularly a cosmetic or pharmaceutical composition.

[0076] According to another embodiment of the invention, the product of the preserving process is not cosmetic.

[0077] The expressions “between . . . and . . . ” and “ranging from . . . to . . . ”, “at least . . . ” or “at most” should be understood as being limits inclusive, unless otherwise specified.

[0078] The examples and figures that follow are provided as illustrations which do not limit the field of the invention.

EXAMPLES

[0079] Sensitivity Test

[0080] The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of compounds of formula (I) of the invention, in particular EZ, were determined by standardized agar dilution and broth dilution tests, described by Rushton et al. Key role for efflux in the preservative susceptibility and adaptive resistance of Burkholderia cepacia complex bacteria. Antimicrobial Agents and Chemotherapy, 2013. 57(7): p. 2972-2980 using TSA/TSB. The culture was carried out at 30° C. in order to be representative of the production and storage of industrial products. Preserving stock solutions (50% w/v) were prepared in DMSO (Sigma-Aldrich, United Kingdom) and volumes were added to the medium so as to achieve the test concentration. The final concentration of DMSO in the presence of the bacterium was verified to be non-toxic (not exceeding 4% v/v) and was included as control condition in the tests in order to eliminate the effect on growth. The MIC is defined as the lowest concentration of preservative at which there is an 80% reduction in the liquid OD in culture (at 630 nm), or no visible growth of the organisms tested on an agar medium. The MBC was determined as being the lowest concentration for causing a 99% destruction rate, and for which the growth on the recovery medium (TSA) stopped. The preservatives were inactivated before the recovery and counting of the surviving organisms tested, by dilution in a neutralizing solution containing 1.5% v/v of Tween 80 containing 3% of lecithin, as described in the scientific publication by Rushton et al. (Rushton et al, ibid). The efficacy and toxicity of the neutralizing solution were evaluated before the experiment, as described in the scientific publication by Lear, J. C., et al. (J. C., et al., Chloroxylenol- and triclosan-tolerant bacteria from industrial sources—Susceptibility to antibiotics and other biocides. International Biodeterioration and Biodegradation, 2006. 57(1): p. 51-56).

Example 1—Evaluation of the Inhibitory Activity of a Compound of Formula (I) with Respect to the Burkholderia cepacia Complex

[0081] Bacterial Strains and Culture Conditions.

[0082] A panel of 59 Burkholderia used to profile the sensitivity to the compounds of formula (I), in particular EZ, was established. The collection comprised 20 of the current groups of species of the Burkholderia cepacia complex (Bcc), reference strains for the panel of Bcc experimental strains (Mahenthiralingam, E., et al., Diagnostically and experimentally useful panel of strains from the Burkholderia cepacia complex. Journal of Clinical Microbiology, 2000. 38(2): p. 910-913) and 39 strains previously profiled for sensitivity to the preservative by Rushton et al. (Rushton, L., et al., Key role for efflux in the preservative susceptibility and adaptive resistance of Burkholderia cepacia complex bacteria. Antimicrobial Agents and Chemotherapy, 2013. 57(7): p. 2972-2980). The strains of the Burkholderia panel were isolated from strains of clinical (n=28), environmental (n=23) and industrial (n=8) origin. The strains were cultured once at 30° C. on tryptone soy (TSB/TSA) (Oxoid Ltd, United Kingdom). The strains were stored in TSB containing 8% v/v of dimethyl sulfoxide (DMSO) (Sigma-Aldrich, UK) at −80° C.

TABLE-US-00001 TABLE 1 S1. Burkholderia strains tested BCCM/LMG culture collection Name of species accession number Isolation source and strain (Other strain designations) code B. ambifaria AMMD .sup.ESP a LMG 19182 .sup.T ENV BCC0267 .sup.ESP a LMG 19467 CLIN BCC0338 .sup.a LMG 17828 ENV B. anthina BCC0635 .sup.ESP a LMG 16670 ENV BCC0639 .sup.ESP a LMG 20980 .sup.T ENV BCC0485 .sup.ESP LMG 21821 CLIN B. arboris BCC0049 .sup.a — CLIN BCC1306 .sup.a — ENVI BCC1310 .sup.a — ENVI B. cenocepacia III-A BCC0018 .sup.ESP a LMG 16659 CLIN J2315 .sup.ESP LMG 16856 .sup.T CLIN B. cenocepacia III-B HI2424 .sup.a — ENV B. cepacia BCC0001 .sup.ESP a LMG 1222 .sup.T ENV BCC0002 .sup.ESP a LMG 2161 ENV BCC0003 .sup.ESP a LMG 18821 CLIN B. contaminans SAR-1 .sup.a LMG 23255 CLIN BCC1315 .sup.a — ENVI BCC0339 — CLIN B. diffusa BCC0106 .sup.a LMG 24286 CLIN BCC0169 .sup.a (ATCC 29352) ENV AU1075 .sup.a LMG 24085 CLIN B. dolosa BCC0161 FC0380 CLIN AU0645 .sup.ESP a LMG 18943 .sup.T CLIN AU3556 .sup.a — CLIN B. lata Strain 383 .sup.a LMG 22485 .sup.T EW BCC1296 .sup.a — ENVI BCC1406 .sup.a — ENVI B. latens BCC1625 LMG 24064 .sup.T CLIN BCC1626 LMG 24264 CLIN BCC1892 LMG 24265 CLIN B. metallica BCC0095 .sup.a — CLIN AU0553 .sup.a LMG 24068 .sup.T CLIN B. multivorans BCC0149 CLIN ATCC17616 .sup.ESP a LMG 17588 ENV BCC1560 .sup.a — ENVI B. pseudomultivorans BCC1884 LMG 26883 CLIN BCC1191 .sup.a D1443 CLIN B. pyrrocinia BCC0171 .sup.ESP a LMG 21822 ENV BCC0180 .sup.T ESP a LMG 14191 .sup.T ENV BCC0476 .sup.ESP a LMG 21823 ENV B. seminalis BCC1627 .sup.T LMG 24067 CLIN BCC1628 LMG 19587 ENV BCC1893 LMG 24272 CLIN B. stabilis BCC0023.sup.ESF a LMG 14294 .sup.T CLN BCC0286 .sup.a (ATCC 35254) ENV AU6735.sup.a — CLIN B. stagnalis BCC1350 HI3541 ENV BCC1887 .sup.T LMG 28156 ENV BCC1896 LMG 28157 ENV B. territorii BC1888 .sup.T LMG 28158 ENV BCC1897 LMG 28159 ENV B. ubonensis BCC1603 .sup.a LMG 20358 ENV B. vietnamiensis BCC0028 .sup.ESP A LMG 16232 CLIN BCC0195 LMG 22486, G4 ENV BCC1309 .sup.a — ENVI B. gladioli BCC1317 .sup.a ENVI BCC0238 MA4 CLIN BCC0507 PF(#428) CLIN B. plantarii BCC0777 LMG 9035 ENV BCCM/LMG, Belgian co-ordinated collections of micro-organisms, Ghent. ATCC, American type culture collection BCC. CLIN, clinical; ENV, environmental; ENVI, environmental industrial. T Type strain. ESP experimental panel of experimental Burkholderia cepacia complex strains

[0083] The compounds of formula (I), in particular EZ, are very efficacious against bacteria of the Burkholderia cepacia complex Bcc. The compounds of the invention, in particular EZ, demonstrated excellent efficacy against a diversified panel of 57 Burkholderia strains representing species commonly encountered as contaminants.

[0084] In FIG. 1, [0085] the center lines indicate the medians; the limits of the “box” indicate the 25th and 75th % determined by the free statistical software R; the Whiskers (i.e. method of representation of data in the box plot format—rectangle ranging from the first quartile to the third quartile cut by the median in purple on the graph above) extend over 1.5 times the interquartile range of the 25th and 75th %; [0086] the data points are represented in the form of open circles; [0087] the aberrant values are represented by dots; [0088] the crosses represent examples of means; and [0089] the width of the boxes is proportional to the square root of the size of the sample.

[0090] It appears that the compounds of formula (I) of the invention and in particular EZ act as a preservative with a high activity against bacteria of the Burkholderia cepacia complex leading in particular to a reduction in viability of several log after several hours (6 log in 4 hours).

[0091] All these experimental results show that the compounds of formula (I), in particular EZ, have a very significant inhibitory activity with respect to bacteria of the Burkholderia cepacia complex.