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    • 专利摘要:
    The present invention relates to a bactericidal or bacteriostatic composition comprising an acetal or a hexane ether, preferably of sorbitan, arlitane or mannitan with long-chain alkyls, its use in the treatment or prevention of infections with Gram-positive bacteria, its use as a hygiene or dermatological product for external use as well as a method for disinfecting surfaces.
    公开号:BE1023165B1
    申请号:E2015/5831
    申请日:2015-12-17
    公开日:2016-12-07
    发明作者:Charlotte Gozlan；Dorine Belmessieri；Marie-Christine Duclos；Nicolas Duguet；Marc Lemaire；Gérard Lina；Oana Dumitrescu；Andreas Redl
    申请人:Syral Belgiumnv；Université Claude Bernard Lyon 1 Domaine Scientifique de la Doua；Centre National De La Recherche Scientifique；
    IPC主号:
    专利说明:

    Antibacterial composition comprising an acetal or a long chain alkyl hexane ether
    Technical area
    The present invention relates to the use of a bactericidal or bacteriostatic composition comprising an acetal or a long-chain alkyl hexane ether, its use in the treatment or prevention of infections with Gram-positive bacteria, its use as a hygiene or dermatological product for external use and a method for the disinfection of surfaces.
    State of the art
    The antimicrobial compounds are defined as molecules that are capable of inhibiting or stopping the growth of microorganisms or killing them. In this context, they are commonly used to prevent or treat human and animal infections, and in the food industry to prevent the propagation of pathogenic bacteria in food. The wide range of use of antimicrobial compounds has led to the emergence of resistant infectious agents. The proliferation of bacteria that have acquired resistance mechanisms to the most commonly used antimicrobial compounds are a public health problem that is becoming more worrying (J.S. Bradley et al. Lancet Infect Dis 2007; 7: 68-78).
    For example, many antibiotic-resistant strains of the pathogenic species of the genus Staphylococcus, namely Staphylococcus aureus, have been isolated. However, staph infections are a significant percentage of serious infections. In addition, nearly half of nosocomial infections are linked to a staph. One can also mention the many strains of Enterococcus faecalis or Enterococcus faecium resistant to commonly used antibiotics. Although they are less virulent compared to staphylococci, more and more multi-resistant enterococci strains and more recently epidemics of enterococci resistant to glycopeptides, the antibiotics used against this bacterial family, are counted.
    Another phenomenon of antibiotic resistance has been described that is not only linked to the excessive use of antibiotics, but to food preservation techniques. For example, Listeria monocytogenes has been shown to be more resistant to antibiotics after surviving an osmotic stress, at a low temperature or in an acidic medium (Ana A. et al. (2015) Microbiology, Volume 46, April, pages 154-160). Or the human infection is food transferred. In addition, although it is relatively rare, human listeriosis is a serious infection with an estimated mortality rate of 50%. For example, the emergence of antibiotic resistance in L. monocytogenes, which can be caused by modern methods of conservation or food processing, is a major threat to public health.
    Although different mechanisms are often involved in antibiotic resistance at the same time, it is common to classify them into three categories: (a) lack of antibiotic penetration into the bacterium (b) inactivation or secretion of the antibiotic by bacterial enzyme systems and (c) the lack of affinity between bacterial target and antibiotics. These three categories of resistance mechanism have a structural component, the mechanisms depend on the structure of the molecule in question.
    Thus, in order to obtain an antibiotic composition with a reduced chance of developing a resistance, the inventors have considered using a composition comprising a mixture of compounds with an antibiotic action but with small structural differences that are capable of reducing the chance of developing a resistance. reduce the development of bacterial resistance. They have therefore considered a composition comprising an isomeric mixture of compounds with antibiotic action.
    The inventors also wished to develop an antibiotic composition having a low toxicity and a low environmental impact. A biodegradable antibiotic composition that is available in large quantities from renewable sources at low cost to be fully accessible for industrial use, but also as effective as non-bio-based antimicrobials.
    However, no prior art method allows obtaining an isomeric mixture of bio-based compounds with low toxicity and at low cost.
    However, bio-based compounds are described in the prior art. Thus, the prior art describes various compounds used as antimicrobials such as the fatty acids and their corresponding active polyhydroxized esters active against Gram-positive bacteria and including long aliphatic chains. For information, one of the most active antimicrobials is monolaurin, a glycerol monoester with a C12 aliphatic chain. His trademark is the Lauricidin®. This compound is used as a food additive for the purpose of inhibiting the growth of bacteria (Freese, CW Sheu, E. Gauls. Nature 1973, 241, 321-325; EGA Verhaegh, DL Marshall, D.-H. Oh, Int. J. Food Microbiol (1996, 29, 403-410). However, the ester function of monolaurin is sensitive to esterases, this compound is rapidly degraded and has a low half-life.
    The prior art also describes antimicrobials obtained from sugar as particularly attractive due to their biodegradability, their low toxicity and environmental impact.
    Examples of antimicrobial substances obtained from sugar are esters obtained from sugar that are also used industrially in antimicrobial applications because their raw materials and their production costs remain relatively low. Mention may also be made, for example, of sorbitan caprylate described in international patent application WO2014 / 025413 mixed with hinokitiol in an antimicrobial formula. According to this application, this formula would allow to inhibit or kill Gram-positive and Gram-negative bacteria, fungi and / or mycoses.
    The prior art also describes the use of disaccharide esters as an antimicrobial agent in the food industry. Sucrose dodecanoyl is one of the most used. The latter would be particularly active against L. monocytogenes (M. Ferrer, J. Soliveri, FJ Plou, N. López-Cortés, D. Reyes-Duarte, M. Christensen, JL Copa-Patino, A. Ballesteros, Etc. Microb Tech., 2005, 36, 391-398). Yet it is also described as a weak inhibitor of S. aureus growth, for use in hospitals (J.D. Monk, L.R. Beuchat, A.K. Hathcox, J. Appl. Microbiol., 1996, 81, 7-18). So the sucrose ester has bacteriostatic properties (stops bacterial growth), but no bactericidal properties (kills bacteria).
    Moreover, the synthesis of sugar esters has many disadvantages. First, despite the low production costs, the synthesis of esters, in particular di- and trisaccharides, is problematic because of the high functionality of sugars that lead to the formation of a mixture of mono-, di- and polyesters and the presence of polar solvents , such as dimethylformamide (DMF) and pyridine, is generally required to make the highly polar reagents more soluble. However, these solvents are classified as carcinogenic, mutagenic and reprotoxic (KMR) and their use must be avoided. Enzymatic synthesis has been used to solve this problem, but the need to turn into highly diluted conditions makes production limited.
    In addition, the ester functional groups of these compounds are easily hydrolyzable by esterases present in the cells. But the molecules released after this hydrolysis, namely sugar and fatty acid, have little or no antimicrobial properties (the fatty acid is slightly active). This causes an instability responsible for a reduction in the time of the activity of these compounds.
    Thus, in order to obtain an antibiotic composition that is less conducive to the development of a resistance comprising effective and stable antimicrobials, the invention provides an alkyl acetal or a long chain alkyl sorbitan alkyl ether with very good antimicrobial activity either in pure form or as a mixture of isomers, such a product can in particular be obtained in less expensive circumstances and being respectful of the environment and not representing a danger for topical application or uptake.
    Detailed description of the invention
    Bacterial or bacteriostatic composition
    The invention relates to the use of a bactericidal or bacteriostatic composition comprising an alkyl acetal or a hexitane alkyl ether preferably of sorbitan, arlitane or mannitan wherein the alkyl group comprises 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or mixture of isomers thereof. Preferably, said alkyl is acetal radical or alkyl ether radical at position 2-0, 3-0, 5-0 and / or 6-0. Advantageously, said alkyl acetal radical is at position 2,3-O; 3.5-O or 5.6-0. Advantageously, said alkyl ether is radical at position 2-0, 3-0, 5-0 or 6-0.
    The term "pharmaceutically acceptable salts" refers to any salt capable of forming (directly or indirectly) a compound as described herein after administration to the patient. The preparation of salts can be carried out according to methods known in the art.
    According to the invention, a "hexane" is obtained by dehydration of a hydrogenated hexose (or hexitol) such as a sorbitol or a mannitol. Typically the hexane is selected from sorbitane, arlitane or mannitane. Advantageously, the hexane is selected from 1,4-anhydro-D-sorbitol (1,4-arlitane or sorbitane); 1,5-anhydro-D-sorbitol (polygalitol); 3,6-anhydro-D-sorbitol (3,6-sorbitane); 1,4 (3,6) -anhydro-D-mannitol (mannitan); 1,5-anhydro-D-mannitol (styracitol); 3,6-anhydro-D-galactitol; 1,5-anhydro-D-galactitol; 1,5-anhydro-D-talitol and 2,5-anhydro-L-iditol.
    Such a sorbitan acetal can be obtained by methods known to those skilled in the art such as direct acetalization, e.g. transacetalization. Furthermore, a sorbitan alkyl ether can be obtained by methods known to those skilled in the art, such as the Williamson ether synthesis, epoxide gap, condensation of alcohols, telomerization of alcohols, reduction of acetals, direct or indirect reductive alkylation.
    The inventors have developed a particularly advantageous process for obtaining this compound in pure form or in the form of a mixture of isomers of mono-ethers or alkyl mono-acetals of hexane, preferably the isomers are positional isomers and / or diastereomers.
    The invention also relates to a bactericidal or bacteriostatic composition comprising a monoether or alkyl monoacetal of hexane or a mixture of isomers, the latter preferably positional, obtained by a method comprising the following steps: a) a dehydration of a hexitol to a mono-anhydrohexitol; b) an acetalization or transacetalization of hexitol or mono-anhydrohexitol obtained in a) with an aliphatic aldehyde with 11 to 18 carbon atoms or the acetal thereof, typically by i. an aliphatic aldehyde with 11 to 18 carbon atoms, by acetalization, or ii. a derivative of an aliphatic aldehyde with 11 to 18 carbon atoms, by transacetalization; c) optionally, catalytic hydrogenolysis of the hexane alkyl acetal obtained in step b) preferably, without acid catalyst, recovery of a mixture of isomers of alkyl monoethers of hexane obtained in c) wherein the alkyl group (R) is 11 to 18 carbon atoms includes or recovering a mixture of isomers of alkyl monoacetals of hexane obtained in b) wherein the alkyl group (R) comprises between 11 to 18 carbon atoms, and e) optionally, purification of one or the other of mixtures obtained in d) , in particular by chromatography.
    Preferably, the invention also relates to a bactericidal or bacteriostatic composition comprising a monoether or alkyl monoacetal of sorbitan or a mixture of isomers, the latter preferably positional, obtained by a process comprising the following steps: a) a dehydration of a sorbitol to obtain a mono-anhydrosorbitol; b) an acetalization or transacetalization of sorbitol or mono-anhydrosorbitol obtained in a) with an aliphatic aldehyde with 11 to 18 carbon atoms or the acetal thereof, typically by i. an aliphatic aldehyde with 11 to 18 carbon atoms, by acetalization, or ii. a derivative of an aliphatic aldehyde with 11 to 18 carbon atoms, by transacetalization; c) optionally, catalytic hydrogenolysis of the sorbitan alkyl acetal obtained in step b) preferably, without acid catalyst, d) recovering a mixture of isomers of alkyl monoethers of sorbitan obtained in c) wherein the alkyl group (R) is 11 to 18 comprises carbon atoms or recovering a mixture of isomers of alkyl monoacetals of sorbitan obtained in step b) wherein the alkyl group (R) comprises 11 to 18 carbon atoms, and e) optionally, purification of one or the other of mixtures obtained in d ), in particular by chromatography.
    Typically, the derivative of an aliphatic aldehyde may be a dialkyl acetal of the corresponding aldehyde. The dimethyl acetals and the diethyl acetals are preferred.
    A "mono-anhydrohexitol" or a "mono-anhydrosorbitol" is to be understood as having been obtained by dehydration, by the removal of one or more molecules of water from a hexitol or sorbitol. A suitable example mono-anhydrosorbitol can be 1,4-anhydro-D-sorbitol (1,4-arlitane or sorbitane); 1,5-anhydro-D-sorbitol (polygalitol) or 3,6-anhydro-D-sorbitol (3,6-sorbitane).
    The preferred mono-anhydrosorbitol is derived from the dehydration of sorbitol to form, for example, 1,4-sorbitane, 3,6-sorbitane or 2,5-sorbitane.
    By "positional isomer" is meant regioisomers, more particularly isomers of mono-ethers or alkyl mono-acetals of hexane and in particular sorbitane, wherein the mono-ether radical or alkyl mono-acetal radical is on different carbon atoms of hexane positioned. Usually the positional isomers of alkyl monoacetal of sorbitan are 2.3-0-; 3,5-O or 5,6-O-alkyl monoether of sorbitane. The isomers of alkyl mono-ether sorbitane are the 2-O, 3-O, 5-O or 6-O-alkyl mono-ether of sorbitan.
    The term "diastereomers" means optical isomers that are not superimposable or mirror image. Examples of diastereomers of alkyl monoacetal of sorbitane are:
    According to an embodiment, the method of the invention may comprise a step of dehydrating hexitol to obtain a mono-anhydrohexitol. Typically, sorbitol is melted prior to the dehydration step. The dehydration step can be carried out with a catalyst, for example an acid catalyst.
    According to the invention, the dehydration is carried out under a hydrogen atmosphere at a pressure of preferably about 20 to 50 bar.
    The dehydration step is advantageously carried out at a temperature between 120 and 170 ° C, preferably between 130 and 140 ° C.
    Typically, the sorbitol is purified after the dehydration step, for example by crystallization, recrystallization or chromatography.
    According to the invention, the acetalization step or the transacetalization step i) optionally comprises a pre-heating step of sorbitol, preferably at a temperature between 70 and 130 ° C, usually between 90 and 110 ° C, ii) a step of adding the aliphatic aldehyde or aliphatic aldehyde derivative such as sorbitol and iii) an addition step of a catalyst, preferably an acid catalyst.
    Step i) is particularly advantageous in that it can be carried out in the absence of solvent.
    Preferably, the acid catalyst used during the acetalization or transacetalization step and optionally during the dehydration step may be a homogeneous or heterogeneous acid catalyst. The term "homogeneous" as used in the expression "homogeneous acid catalyst" refers to a catalyst that is in the same phase (solid, liquid or gas) or in the same aggregation state as the reagent. Conversely, the term "heterogeneous" as used in the term "heterogeneous acid catalyst" refers to a catalyst that is in a different phase (solid, liquid or gas) as the reagents.
    Said acid catalyst used during the acetalization or transacetalization step and optionally during the dehydration step can be independently selected from solid or liquid acids, organic or inorganic, solid acids are preferred. In particular, the preferred acid catalyst is selected from para-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid (CSA) and the sulfone resins.
    Typically, the acetalization or transacetalization step is carried out at temperatures between 70 and 130 ° C, usually between 70 and 90 ° C. The temperature of the reaction mixtures can vary depending on the reagents and solvents used. The reaction time is determined by the degree of conversion achieved.
    According to an embodiment, the acetalization or transacetalization step can be carried out with an aliphatic aldehyde or acetal thereof, typically a linear or branched aliphatic aldehyde or the acetal thereof. The acetalization or transacetalization step can typically be performed with an aliphatic aldehyde or acetal thereof having 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, for example selected between the undecanal, dodecanal, tridecanal, tetradecanal, pentadecanal, hexadecanal, heptadecanal, octodecanal acetal. Preferably, the C 11 -C 13 aliphatic aldehyde or the acetal thereof is a C 12 aliphatic aldehyde or acetal thereof, for example a dodecanal or the acetal thereof.
    The term "acetal thereof" or "their acetals" as used herein includes the dialkyl acetal of the corresponding C11-C18 aliphatic aldehyde, more particularly the dimethyl or diethyl acetals of the C11-C18 aliphatic aldehyde are preferred.
    According to an embodiment, the acetalization or transacetalization step can be carried out with or without solvent. When the reaction is carried out in the presence of a solvent, the solvent is preferably a polar solvent.
    Typically, the solvent may be selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile (CH3 CN), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2 Me-THF), methyl ether of cyclopentyl (CPME), methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (iPrOH), butanol (BuOH), dibutyl ether (DBE), methyl tert-butyl ether (MTBE) and trimethoxypropane (TMP).
    Extensive experimental works have led to a selection of conditions permitting the observation of conversion rates and optimal yields during the acetalization or transacetalization steps. The best results were obtained when the molar ratio [(C 11 -C 18 aliphatic aldehyde or their acetal): monosaccharide] is between 5: 1 and 1: 5, preferably between 4: 1 and 1: 4, and more preferably between 3 : 1 and 1: 3.
    The inventors have additionally demonstrated that during an acetalization reaction, the mole ratio of C11-C18 aliphatic aldehyde: monosaccharide is between 1: 1 and 1: 5, preferably between 1: 1 and 1: 4, and preferably between 1: 3 and 1: 2 improved yields and ensures optimum conversion.
    The inventors have also shown that further in transacetalization reactions a molar ratio of C11-C18 aliphatic acetal: monosaccharide is between 1: 1 and 5: 1, preferably between 5: 4 and 4: 1, preferably between 3: 1 and 4: 3, preferably between 3: 2 and 2: 5 improves the returns and ensures optimum conversion. The catalysts used are the same as in the acetalization reaction.
    Such a method according to the invention may additionally comprise at least one step of neutralization and / or filtration and / or purification after one of the steps of dehydration optionally, acetalization or transacetalization.
    When a purification step is provided, said purification step may be, for example, a crystallization, a recrystallization or a chromatography. The chromatography is preferably carried out using a non-aqueous polar solvent. Generally, when a filtration step and / or purification step is provided for the hydrogenolysis step, the non-aqueous polar solvent may be identical to that used during the hydrogenolysis step.
    The hydrogenolysis step is advantageously carried out at a temperature between 80 ° C and 140 ° C, and / or at a hydrogen pressure between 15 and 50 bar, preferably between 20 and 40 bar.
    The hydrogenolysis step is preferably carried out in an aprotic polar solvent, preferably a non-aqueous solvent. Indeed, aprotic solvents offer better conversions. Examples of aprotic solvents include, but are not limited to, alkanes, 1,2,3-trimethoxypropane (TMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), 2-methyl tetrahydrofurane (2 Me-THF) , dibutyl ether (DBE) and cyclopentyl methyl ether (CPME). Preferably the aprotic solvent is CPME. The alkanes are advantageous because they allow better dissolution of hydrogen in the medium. However, the conversion is lower than with other aprotic solvents such as CPME. In general, with alkanes, dodecane and heptane are preferred.
    The hydrogenolysis is preferably carried out in a polar aprotic solvent at a temperature between 80 ° C and 140 ° C and / or under a hydrogen pressure between 15 and 50 bar, in the presence of a catalyst suitable for hydrogenolysis reactions.
    The hydrogenolysis step is preferably carried out in a non-aqueous polar solvent at a temperature between 100 ° C and 130 ° C and / or at a pressure between 25 and 35 bar.
    In general, hydrogenolysis is carried out in the presence of a suitable catalyst such as a catalyst based on noble metals or base metals. Specifically, the base metals may be ferrous or non-ferrous. Typically, the hydrogenolysis is carried out in the presence of a ferrous metal-based catalyst.
    As an indication, a metal catalyst may belong to the group of ferrous metals such as, for example, nickel, cobalt or iron.
    Preferably, the hydrogenolysis is carried out using a catalyst based on noble metal, such as palladium, rhodium, ruthenium, platinum or iridium.
    In general, the catalyst used during a hydrogenolysis can be fixed on a support such as carbon, aluminum, zirconium or silicon or any mixture thereof. Such a support is, for example, a ball. Thus, a palladium catalyst on carbon balls (Pd / C) can preferably be used. These catalysts can be doped by adding noble metals or base metals. One speaks of a doping agent. Typically, the doping agent represents 1 to 10% by weight of the catalyst.
    Typically the use of the composition is bactericidal or bacteriostatic against Gram-positive bacteria.
    Advantageously, the bactericidal or bacteriostatic composition comprising an alkyl acetal or a hexitane alkyl ether is preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, is preferably the alkyl acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers included in a foodstuff, cosmetics , medicines, phytosanitary composition, veterinary composition or surface treatment composition. Such as, for example, a cosmetic and / or dermatological cleansing composition and / or skin care composition, in particular in the form of a cream, a gel, a powder, a lotion, a butter, a shower gel, soap, shampoo, shower foam, deodorant , antiperspirant, moist cloth, sunscreen formulation or decorative cosmetic formulation.
    The invention also relates to a use of a bactericidal or bacteriostatic composition according to the invention as a hygiene or dermatological product for external use.
    Typically a "hygiene product" refers to a product used for cleaning, disinfection or hygiene, including, for example, a lotion, mousse, spray and liquid, but also wipes or any medium that can be impregnated with the composition of the invention. The term "dermatological product" refers to a product intended for application to the skin or mucous membranes.
    Use in the treatment or prevention of a Gram-positive bacterial infection.
    The invention further relates to a composition comprising an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, preferably the alkyl acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers for use in the treatment or the prevention of bacterial infections by Gram-positive bacteria.
    By "treatment" is meant a curative treatment (including at least reducing, eliminating or stopping the development of infection) in a patient. By "prevention" is meant prophylactic treatments (to reduce the risk of developing an infection) in a patient.
    The "patient" may be, for example, a human or non-human mammal (e.g., a rodent (mouse, rat), a cat, a dog, or a primate) affected by or prone to being affected by bacterial infections, in particular Gram positive . Preferably the subject is a human.
    The term "Gram-positive" refers to bacteria that are dark blue or violet stained by Gram staining, in contrast to Gram-negative bacteria that cannot retain the violet dye. The Gram staining technique is based on the membrane properties and wall properties of the bacteria.
    Typically, the Gram-positive bacteria are bacteria of the Firmicutes strain, typically of the Bacilli class particularly selected from the bacteria of the order Lactobacillales or Bacillales.
    According to an embodiment of the invention, the bacteria of the order of Bacillales are selected from the family of Alicyclobacillaceae, Bacillaceae, Caryophanaceae, Listeriaceae, Paenibacillaceae, Pasteuriaceae, Planococcaceae, Sporolactobacillaceae, Staphylococcaceae, Theraceaaceabiceabacteric
    Typically, the bacteria of the Listeriaceae family are, for example, of the genus Brochothrix or Listeria and are typically selected from L. fleischmannii, L. grayi, L. innocua, L. ivanovii, L. marthii, L. monocytogenes, L. rocourtiae, L seeligeri, L. weihenstephanensis and L. welshimeri.
    Since the Gram-positive bacteria are bacteria from the family of Staphylococcaceae, they are specifically selected from bacteria of the genus Staphylococcus, Gemella, Jeotgalicoccus, Macrococcus, Salinicoccus and Nosocomiicoccus.
    For example, the bacteria of the genus of Staphylococcus selected from S. arlettae, S. agnetis, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnosus, S. caseolyticus, S. chromogenes, S. cohnii, S. condimenti, S. Delphini, S. devriesei, S. epidermidis, S. equorum, S. felis, S. fleurettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lentus, S. Lugdunensis, S. lutrae, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. pettenkoferi, S. piscifermentans, S. pseudintermedius. S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophvticus. S. schleifen, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S. succinus, S. vitulinus, S. wameri and S. xylosus.
    According to another embodiment of the invention, the bacteria of the order of Lactobacillales are selected from a family of / Aerococcaceae, Carnobacteriaceae, Enterococcaceae, Lactobacillaceae, leuconostocaceae and Streptococcaceae.
    Typically, the bacteria of the Enterococcaceae family are selected from bacteria of the genus Bavariicoccus, Catellicoccus, Enterococcus, Melissococcus, Pilibacter, Tetragenococcus, Vagococcus.
    Bacteria of the genus of Enterococcus are selected from, for example, E. malodoratus, E. avium, E. Durans, E. faecalis, E. faecium, E. gallinarum, E. hirae, E. solitarius, preferably E. avium, E. Durans, E. faecalis and E. faecium.
    The bacteria of the genus Staphylococcus and more particularly S. aureus are responsible for many infections of the skin or mucous membranes such as vaginal and nasal mucosa. For example, infections such as folliculitis, abscesses, paronychia, boils, scabies, interdigital infections, anthrax (anthrax staphylococcique), cellulite, secondary wounds infections, otitis sinusitis, hydradenitis, infectious mastitis, post-traumatic skin infections or skin infections.
    The bacteria of the genus of Enterococcus, in particular E. faecalis, are particularly responsible for endocarditis, infections of the bladder, prostate or ulcer.
    The invention also relates to a method for treating or preventing a bacterial infection with Gram-positive bacteria, preferably an infection of the skin or mucous membranes, by topical administration to an individual in need of a therapeutically effective amount of the composition according to the invention. invention.
    In a person infected with a Gram-positive bacterium, the term "therapeutically effective amount" means a sufficient amount to prevent the infection from progressing to deterioration or sufficient to reverse the infection. In an uninfected person, the "therapeutically effective amount" is the amount sufficient to protect a person who comes into contact with a Gram-positive bacterium and would prevent the occurrence of infection by the Gram-positive bacterium.
    Typically, topical administration is by application to the skin or mucous membranes of the composition of the invention.
    Method for disinfecting or preventing bacterial colonization of a substrate
    The invention further relates to a method for disinfecting or preventing bacterial colonization by Gram-positive bacteria of a substrate comprising contacting the substrate with a composition according to the invention.
    Typically, the carrier is a medium prone to be colonized by Gram positive bacteria and prone to transfer the infection to an animal through contact or ingestion.
    For example, the substrate may be a food of vegetable or animal origin or a food composition comprising such food or an extract of these food, in particular grains, fruit, vegetables, meat, fish, organ meats.
    However, the substrate can also be one or more elements selected from metals, plastics, glass, concrete and stone.
    The substrate is preferably a tool, tool or device used in the food industry (kitchen utensils, container, cold storage system, refrigerator, cold rooms ...) in a hospital environment, such as, for example, surgical instruments or prostheses or in public transport (tenable). in public transport, seats, ...).
    The invention also relates to a composition comprising an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, preferably the alkyl is acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers for disinfecting, cleaning, sterilizing or cleaning surfaces.
    Although they have different meanings, the terms "comprising", "containing", "having" and "consisting of" are used interchangeably in the description of the invention and may be interchanged.
    The invention will be better understood after reading the following figures and examples by way of example.
    Examples
    The sorbitan acetals were prepared by acetalizing or transacetalizing sugars according to the previously described procedure in patent 13/01375 "Process for preparing cyclic long chain alkyl acetals, based on sugars." sugar acetals are then reduced using reduction conditions without acid catalyst as previously described in patent 14/01346. For information, the synthesis of acetals and sorbitan ethers is described below. EXAMPLE 1: General procedure for the synthesis of sorbitan acetals (A)
    The dehydration of sorbitol: D-sorbitol (20 g, 110 mmol) and 0.1 mol% of camphorsulfonic acid were added to a 150 ml autoclave of stainless steel. The reactor is hermetically sealed, flushed three times with hydrogen, and then hydrogen is introduced to a pressure of 50 bar. The system is then heated to 140 ° C and stirred with a mechanical stirrer for 15 hours. After cooling to room temperature, the hydrogen pressure was released and the crude reaction mixture was diluted in ethanol (200 mL) to obtain a yellow homogeneous mixture. The solvent was evaporated under reduced pressure and the residue was then crystallized from cold methanol and filtered vacuum. The crystalline material was washed with cold methanol to give the 1,4-sorbitane (5.88 g, 35% theoretical) as a white solid. The purity is> 98% as determined by HPLC, while the crystals had a melting point of 113-114 ° C. The degree of conversion of the reaction was determined to be 73%, whereby a mixture of sorbitol, 1,4-sorbitane, isosorbide and some by-products was obtained in a very limited amount, so that the ratio of 1,4-sorbitan: isosorbide was determined at 80: 20 .
    General procedure for the acetalization of sorbitan
    In a round bottom flask equipped with a cooler and a shielding of CaCl 2, under an argon atmosphere, the 1,4-D sorbitane (5.00 g, 30.5 mmol, 3 equiv) was dissolved in dry ethanol (15 ml). The aldehyde (10.2 mmol, 1 equiv) is then added dropwise, followed by camphorsulfonic acid (CSA, 10 mass% relative to the aldehyde). The reaction mixture is heated at 80 ° C for 15 hours with magnetic stirring. The reaction mixture is cooled and the solvent is evaporated under reduced pressure. The residue is titrated in ethyl acetate and the excess of sorbitane is eliminated by filtration and washing with cold ethyl acetate. This operation can be repeated to eliminate all traces of sorbitan. The filtrate was concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column to give the sorbitan alkyl acetals. The composition of the mixture of regioisomers 5,6-O-alkylidene and 3,5-O-alkylidene-1,4-D-sorbitane was determined by HPLC. In addition, each regioisomer was obtained in the form of a mixture of two diastereomers.
    Procedure for transacetaliserina of sorbitan:
    In a round bottom flask, 1,4-sorbitane (0.5 g, 3 mmol) was dissolved in ethanol (7.5 ml) and 1,1-diethoxypentane (1.15 ml, 6 mmol) was added under an argon stream, followed by camphorsulfonic acid (50 mg; 10% p / p). The mixture is heated to 80 ° C and with magnetic stirring. After 3 hours, the mixture was neutralized and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate / cyclohexane 80:20 to 100: 0) to give the sorbitan acetal (0.43 g, 66% isolated yield) as a colorless oil. The HPLC showed a mixture of 4 isomers.
    Example 1a:
    5,6-O-pentylidene-1,4-D-sorbitan 1a and 1a 'and 3,5-O-pentylidene-1,4-D-sorbitan 1a "and 1a": The compounds were obtained from the 1, 4-D-sorbitane (0.49 g, 3 mmol) and valeraldehyde (0.107 ml, 1 mmol) according to the general procedure (A). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 80:20 -> 100: 0) to obtain a mixture of 43:57 of regioisomers of sorbitan acetals with positions 5.6-0- and 3, 5-0- (0.189 g, 81%) in the form of a colorless oil. The product obtained is a mixture of regioisomers 5,6-0 and 3,5-0 sorbitan acetals, each regioisomer is a mixture of diastereomers (26: 17: 47: 10) as determined by HPLC. RMN 1H (300 MHz, cfe-DMSO) δΗ for all isomers: 0.85 (3H, t, J = 7.2), 1.16-1.35 (4H, m), 1.35-1.60 (2H, m), 3.30-4.30 (8H, sorbitan protons), 4.67-5.33 (3H, 3m, 1H acetal and 2 OH); RMN 13 C (75 MHz, d 6 -DMSO) 5 C for the regioisomers 5,6-0-1a and 1a ': 13.90 (CH3), 22.06 (CH2), 25.68 and 25.81 (CH2), 33.16 (CH2), 66.59 and 66.93 (CH2), 72.79 and 73.19 (CH), 73.43 (CH2), 75.46 and 75.68 (CH), 76.55 and 76.61 (CH), 80.74 and 81.01 (CH), 103.29 and 103.37 (CH); 5C for the regional isomers 3,5-0-1a "and 1a": 13.92 and 13.93 (CH3), 21.95 and 22.00 (CH2), 25.53 and 25.75 (CH2), 33.73 and 34.13 (CH2), 60.78 and 61.92 (CH2), 72.37 and 73.55 (CH2), 72.58 and 72.99 (CH), 73.19 and 73.96 (CH), 74.87 and 76.45 (CH), 78.38 and 79.08 (CH), 93.83 and 96.06 (CH); IR ν max: 3386 (OH), 2954, 2873, 1716, 1412, 1145, 1461, 1061, 1029, 967; HRMS (ESI +) calculated C 11 H 20 Na 5 O 5: 255.1208 [M + Na] +; measured: 255.1203 (+1.8 ppm); HPLC (isocratic 80:20 H 2 O / CH 3 CN + 0.1% H 3 PO 4): Rt for the regioisomers 3.5-0- = 9.70 min (1a ', 47%) and 11.25 min (1a' ', 10%); Rt for the regional isomers 5.6-0- = 12.50 min (1a, 26%) and 14.49 (1a ', 17%).
    Example 1b:
    5,6-O-hexylidene-1,4-D-sorbitan 1b and 1b and 3,5-O-hexylidene-1,4-D-sorbitan 1b "and 1b": The compounds were obtained from 1, 4-D-sorbitane (0.49 g, 3 mmol) and the hexanal (0.124 ml, 1 mmol) according to the general procedure (A). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 80:20 -> 100: 0) to a mixture 57:43 of regioisomers of sorbitan acetals with positions 5.6-0- and 3.5 -0- (0.144 g, 58%) in the form of yellow oil. The product obtained is a mixture of regioisomers 5,6-0 and 3,5-0 of sorbitan acetals, each regioisomer is a mixture of diastiomers (32: 25: 31: 12) as determined by HPLC. RMN 1H (300 MHz, cfe-DMSO) δΗ for all isomers: 0.85 (3H, t, J = 6.5), 1.12-1.40 (6H, m), 1.45-1.58 (2H, m), 3.30 ^ 1.30 (8H, m, sorbitan protons), 4.72-4.90 (1H, m, acetal proton), 5.07-5.28 (2H, 2m, OH); RMN 13 C (75 MHz, cfe-DMSO) δ for the regioisomers 5,6-0-1b and 1b ': 13.91 (CH3), 22.12 (CH2), 23.24 and 23.38 (CH2), 31.24 (CH2), 33.50 (CH2), 66.64 and 66.98 (CH2), 72.86 and 73.24 (CH), 73.48 (CH2), 75.50 and 75.73 (CH), 76.60 and 76.66 (CH), 80.78 and 81.06 (CH), 103.34 and 103.42 (CH) ; 5C for the region isomers 3,5-0-1b "and 1b": 13.93 (CH3), 22.12 (CH2), 23.09 and 23.31 (CH2), 31.17 (CH2), 34.06 and 34.48 (CH2), 60.85 and 61.97 (CH2), 72.42 and 73.61 (CH2), 72.64 and 72.86 (CH), 73.08 and 74.01 (CH), 74.94 and 76.48 (CH), 78.40 and 79.13 (CH), 93.90 and 96.13 (CH); IR ν max: 3386 (OH), 2929 (CH 3), 2871 (CH 2), 2360, 2341, 1465, 1407, 1143, 1034; HRMS (ESI +): [M + Na] + C 12 H 22 Na 5 O calculated 269.1359, measured 269.1360 (-0.4 ppm); HPLC (isocratic 80:20 H 2 O / CH 3 CN + 0.1% H 3 PO 4): Rt for the regioisomers 3.5-0- = 20.77 min (1b ", 31%) and 24.65 min (1b", 12%); Rt for the region isomers 5.6-0- = 28.28 min (1b, 32%) and 33.90 (1b ", 25%).
    Example 1c:
    5,6-O-octylidene-1,4-D-sorbitan 1c and 1c 'and 3,5-O-octylidene-1,4-D-sorbitan 1c "and 1c": The compounds were obtained from 1, 4-D-sorbitane (1.00 g, 6 mmol) and the octanal (0.317 ml, 2 mmol) according to the general procedure (A). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 60:40 -> 100: 0) to a mixture 61:39 of regioisomers of sorbitan acetals with positions 5.6-0- and 3.5 -0- (0.102 g, 37%) in the form of a white paste. The product obtained is a mixture of regioisomers 5,6-0 and 3,5-0 of sorbitan acetals, each regioisomer is a mixture of diastereomers (32: 29: 28: 11) as determined by HPLC. RMN 1H (300 MHz, cfe-DMSO) δΗ for all isomers: 0.86 (3H, t, J = 8.7), 1.10-1.42 (10H, m), 1.43-1.62 (2H, m), 3.38-4.31 (8H, m, sorbitan protons), 4.70-4.90 (1H, m, acetal proton), 5.02-5.28 (2H, 2m, OH); RMN 13 C (75 MHz, cfe-DMSO) 5 C for the regioisomers 5,6-0-1c and 1c ': 13.96 (CH3), 22.13 (CH2), 23.40 and 23.58 (CH2), 28.72 (2 CH2), 31.26 (CH2), 33.54 (CH2), 66.22 and 66.96 (CH2), 72.85 and 73.24 (CH), 73.47 (CH2), 75.49 and 75.72 (CH), 76.59 and 76.64 (CH), 80.77 and 81.05 (CH), 103.31 and 103.40 (CH); 5C for the regional isomers 3,5-0-1c "and 1c": 13.96 (CH3), 22.13 (CH2), 23.62 and 23.70 (CH2), 28.92 and 28.99 (2 CH2), 31.26 (CH2), 34.09 and 34.51 (CH2), 60.85 and 61.95 (CH2), 72.42 and 73.60 (CH2), 72.62 and 72.90 (CH), 73.10 and 73.99 (CH), 74.93 and 76.46 (CH), 78.36 and 79.10 (CH), 93.88 and 96.09 (CH); IR ν max: 3425 (OH), 2953 (CH 3), 2920 (CH 2), 2855, 1467, 1414, 1257, 1047; HRMS (ESI +): [M + Na] + C 14 H 26 Na 5 O calculated 297.1672, measured 297.1670 (+1.0 ppm); HPLC (isocratic 60:40 H 2 O / CH 3 CN + 0.1% H 3 PO 4): R t for the regioisomers 3.5-0 = 11.50 min (1c ", 28%) and 12.93 min (1c", 11%); Rt for the region isomers 5.6-0- = 14.83 min (1c, 32%) and 16.56 (1c ’, 29%).
    Example 1d:
    5,6-O-decylidene-1,4-D-sorbitan 1d and 1d 'and 3,5-O-decylidene-1,4-D-sorbitan 1d "and 1 d'": The compounds were obtained from 1 4-D-sorbitane (1.00 g, 6 mmol) and the decanal (0.382 ml, 2 mmol) according to the general procedure (A). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 50:50 80:20) to a mixture 64:36 of regioisomers of sorbitan acetals with positions 5.6-0- and 3.5-0 - (0.098 g, 32%) in the form of a white solid (m.p. = 72 ° C). The resulting product is a mixture of regioisomers 5,6-0 and 3,5-0 sorbitan acetals, each regioisomer is a mixture of diastereomers (35: 29: 25: 11) as determined by HPLC. RMN 1H (300 MHz, CDCl 3) δΗ especially isomers: 0.85 (3H, t, J = 6.9), 1.10-1.45 (14H, m), 1.47-1.70 (2H, m), 3.45 (2H, br s, OH protons ), 3.60-4.39 (8H, m, sorbitan protons), 4.75 (t, 29% H acetal, J = 5.1), 4.83 (t, 11% H acetal, J = 4.8), 4.85 (t, 35% H acetal , J = 5.3), 4.97 (t, 26% H acetal, J = 4.8); RMN 13 C (75 MHz, CDCl 3) 5 C for the regioisomers 5,6-0-1d and 1d ': 14.19 (CH3), 22.76 (CH2), 24.12 and 24.17 (CH2), 29.40 (CH2), 29.63 (3 CH2), 31.97 (CH2), 33.98 and 34.12 (CH2), 68.17 and 68.57 (CH2), 73.57 and 73.66 (CH), 73.77 and 74.13 (CH2), 75.51 and 75.91 (CH), 77.30 and 77.56 (CH), 79.64 and 81.15 (CH), 104.99 and 105.14 (CH); 5C for the regioisomers 3.5-0-1d "and 1d": 14.19 (CH3), 22.76 (CH2), 23.84 and 24.12 (CH2), 29.40 (CH2), 29.63 (3 CH2), 31.97 (CH2) ), 34.19 and 34.83 (CH2), 61.76 and 63.41 (CH2), 72.80 and 73.14 (CH), 73.81 (CH2), 75.15 and 75.34 (CH), 77.25 and 77.90 (CH), 81.37 (CH), 95.73 and 97.92 (CH); IR ν max: 3433 (OH), 2918 (CH3), 2851 (CH2), 1739, 1123, 1080, 1048; HRMS (ESI +): [M + Na] + C 16 H 30 NaO 5 calculated 325.1985, measured 325.1991 (-1.7 ppm); HPLC (isocratic 50:50 H 2 O / CH 3 CN + 0.1% H 3 PO 4): Rt for the isomers 3.5-0- = 11.97 min (1d ", 25%) and 13.27 min (1d", 11%); Rt for the regional isomers 5.6-0- = 15.21 min (1d, 35%) and 16.60 (1d ", 29%).
    Example 1st:
    5,6-O-dodecylidene-1,4-D-sorbitan 1st and 1st 'and 3,5-O-dodecylidene-1,4-D-sorbitan 1st "and 1st": The compounds were obtained from the 1, 4-D-sorbitane (1.00 g, 6 mmol) and the dodecanal (0.450 ml, 2 mmol) according to the general procedure (A). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 50:50 -> 70:30) to a mixture 48:52 of regioisomers of sorbitan acetals with positions 5.6-0- and 3.5 -0- (0.095 g, 29%) in the form of a white solid (m.p. = 82 ° C). The product obtained is a mixture of regioisomers 5,6-0 and 3,5-0 sorbitan acetals, each regioisomer is a mixture of diastereomers (25: 23: 40: 12) as determined by HPLC. RMN 1H (300 MHz, cfe-DMSO) δΗ for all isomers: 0.85 (3H, t, J = 6.9), 1.12-1.42 (18H, m), 1.43-1.59 (2H, m), 3.41-4.30 (8H, m, sorbitan protons), 4.72-4.89 (1H, m, acetal proton), 5.00-5.12 and 5.17-5.33 (2H, 2m, OH protons); RMN 13 C (75 MHz, cfe-DMSO) 5 C for the regioisomers 5,6-0- 1st and 1st ': 13.95 (CH3), 22.15 (CH2), 23.60 and 23.69 (CH2), 28.79 (CH2), 28.93 (CH2), 29.05 (CH2), 29.07 (CH2), 29.08 (CH2), 29.10 (CH2), 31.37 (CH2), 33.54 (CH2), 66.59 and 66.93 (CH2), 72.87 and 73.26 (CH), 73.46 (CH2) CH2), 75.49 and 75.72 (CH), 76.58 and 76.63 (CH), 80.75 and 81.04 (CH), 103.29 and 103.38 (CH); 5C for the regional isomers 3,5-O- 1st "and 1st": 13.95 (CH3), 22.15 (CH2), 23.38 and 23.60 (CH2), 28.79 (CH2), 28.93 (CH2), 29.05 (CH2) , 29.07 (CH2), 29.08 (CH2), 29.10 (CH2), 31.37 (CH2), 34.10 and 34.51 (CH2), 60.84 and 61.94 (CH2), 72.60 and 72.95 (CH), 72.43 and 73.59 (CH2), 73.17 and 73.98 (CH), 74.92 and 76.43 (CH), 78.31 and 79.07 (CH), 93.87 and 96.06 (CH); IR ν max: 3412 (OH), 2917 (CH 3), 2849 (CH 2), 1468, 1418, 1256, 1082, 1050; HRMS (ESI +): [M + Na] + C18 H34 Na5 O5 calcd 353.2298, measured 353.2300 (-0.3 ppm); HPLC (isocratic 50:50 H 2 O / CH 3 CN + 0.1% H 3 PO 4): Rt for the regional isomers 3.5-0- = 31.89 min (1st ", 40%) and 35.77 min (1st", 12%); Rt for the region isomers 5.6-0- = 41.72 min (1st, 25%) and 46.18 (1st, 23%).
    Example 2: General procedure for the synthesis of a sorbitan ether (B)
    In a 300 ml autoclave in stainless steel, the mixture of regioisomers and diastereomers of acetals of 1,4-D-sorbitane (20 mmol) is diluted in cyclopentyl methyl ether (CPME, 200 ml) and 5% -Pd / C ( 1.00 g, 5 mol% palladium) is added. The reactor is hermetically sealed, flushed three times with hydrogen and the hydrogen is introduced at a pressure of 30 bar. The reaction mixture was stirred mechanically and heated to 120 ° C for 15 hours. After returning to room temperature, the hydrogen pressure is released and the reaction mixture is diluted in absolute ethanol (EtOH, 100 ml) and filtered (Millipore Durapore 0.01 µm filter). The filtrate was concentrated under reduced pressure to give the mixture of regioisomers of sorbitan ethers.
    Example 2a:
    Pentyl-1,4-D-sorbitane 2a, 2a 'and 2a': The compounds were obtained from the 43:57 mixture of 5,6-O-pentylidene-1,4-D-sorbitane 1a and 1a 'and 3, 5-O-pentylidene-1,4-D-sorbitane 1a "and 1a (0.98 g, 4.22 mmol) according to the general procedure (B). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 90:10 -> 100: 0 then EtOH / EtOAc 10:90) to give a mixture of sorbitan ethers regioisomers 2a, 2a 'and 2a "(0.686 g, 69%) in the form of a white paste . The product is a mixture 26:33:41 of 5-O-pentyl-2a, 3-O-pentyl-2a "and 6-O-pentyl-1,4-D-sorbitane 2a" as determined by HPLC. RMN 1 H (300 MHz, d 6 -DMSO) δ H for all isomers: 0.86 (3 H, t, J = 6.9), 1.19-1.35 (4 H, m), 1.39-1.56 (2 H, m), 3.22-3.99 and 4.05-4.11 (10H, m, sorbitan protons + OCH2 ethers), δΗ for the isomer 2a: 4.31 (1H, t, J = 5.8, OH6), 4.84 (1H, d, J = 4.3, OH3), 5.00 (1H, d, J = 2.9, OH2), δΗ for the isomer 2a, 14b: 4.31 (1H, t, J = 5.2, OH6), 4.37 (1H, d, J = 5.4, OH5), 5.06 (1H, d, J = 3.3, OH2), δΗ for the isomer 2a ”: 4.55 (1H, d, J = 5.8, OH5), 4.82 (1H, d, J = 4.3, OH3), 4.99 (1H, d, J = 2.8, OH 2); RMN 13 C (75 MHz, d 6 -DMSO) δ0 for the minority isomer (26%) 2a: 14.03 (CH 3), 22.06 (CH 2), 27.88 (CH 2), 29.55 (CH 2), 62.02 (CH 2), 69.79 (CH 2) , 73.15 (CH2), 75.53 (CH), 76.46 (CH), 77.38 (CH), 79.29 (CH); cc for the intermediate isomer (33%) 2a ': 13.99 (CH3), 22.03 (CH2), 27.91 (CH2), 29.22 (CH2), 64.20 (CH2), 68.72 (CH), 69.52 (CH2), 73.23 (CH ), 73.61 (CH 2), 80.10 (CH), 83.96 (CH); 5c for the majority isomer (41%) 2a ': 13.99 (CH3), 22.02 (CH2), 27.87 (CH2), 28.99 (CH2), 67.50 (CH), 70.60 (CH2), 73.36 (CH2), 73.49 (CH2) 75.66 (CH), 76.38 (CH), 80.34 (CH); HRMS (ESI +): [M + Na] + C 11 H 22 Na 5 O calculated 257.1359, measured 257.1363 (-1.4 ppm); H PLC (C18 column, isocratic 80:20 H2 O / CH3 CN + 0.1% H3 PO4): Rt 7.20 min (2a, 26%), 9.25 min (2a ', 33%) and 10.79 min (2a', 41%).
    Example 2b:
    Hexyl-1,4-D-sorbitane 2b, 2b 'and 2b': The compounds were obtained from the mixture 57:43 of 5,6-O-hexylidene-1,4-D-sorbitane 1b and 1b 'and 3, 5-O-hexylidene-1,4-D-sorbitane 1b "and 1b '" (4.92 g, 20.0 mmol) according to the general procedure (B). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 80:20 -> 100: 0 then EtOH / EtOAc 10:90) to give a mixture of sorbitan ethers regioisomers 2b, 2b 'and 2b' (3.25 g, 65%) in the form of a white paste. The product is a mixture 33:16:51 of 5-O-hexyl-2b, 3-O-hexyl-2b "and 6-O-hexyl-1,4-D-sorbitane 2b" as determined by HPLC. RMN 1H (300 MHz, de-DMSO) δΗ for all isomers: 0.86 (3H, t, J = 6.9), 1.16-1.36 (6H, m), 1.38-1.56 (2H, m), 3.25-4.00 and 4.05- 4.11 (10H, m, sorbitan protons + OCH2 ethers), δΗ for the isomer 2b: 4.31 (1H, t, J = 5.5, OH6), 4.83 (1H, d, J = 4.4, OH3), 4.99 (1H, d , J = 2.9, OH2), δΗ for the isomer 2b ': 4.31 (1H, t, J = 5.5, OH6), 4.36 (1H, d, J = 5.4, OH5), 5.06 (1H, d, J = 3.3, OH2), δΗ for the isomer 2b ”: 4.54 (1H, d, J = 5.8, OH5), 4.81 (1H, d, J = 4.3, OH3), 4.99 (1 H, d, J = 2.9 OH2); RMN 13 C (75 MHz, cfe-DMSO) δ c for the isomer 2b (33%): 14.00 (CH 3), 22.14 (CH 2), 25.36 (CH 2), 29.87 (CH 2), 31.27 (CH 2), 62.03 (CH 2), 69.84 (CH2), 73.17 (CH2), 75.57 (CH), 76.49 (CH), 77.40 (CH), 79.31 (CH); 5C for the isomer 2b '(16%): 13.97 (CH3), 22.17 (CH2), 25.34 (CH2), 29.52 (CH2), 31.19 (CH2), 64.21 (CH2), 68.74 (CH), 69.56 (CH2) , 73.27 (CH), 73.62 (CH2), 80.11 (CH), 83.98 (CH); 5C for the isomer 2b '(51%): 13.97 (CH3), 22.17 (CH2), 25.40 (CH2), 29.31 (CH2), 31.23 (CH2), 67.54 (CH), 70.65 (CH2), 73.38 (CH2) 73.50 (CH 2), 75.70 (CH), 76.40 (CH), 80.35 (CH); HRMS (ESI +): [M + Na] + C 12 H 24 Na 5 O calculated 271.1516, measured 271.1521 (-1.7 ppm); HPLC (C18 column, 80:20 H 2 O / CH 3 CN + 0.1% H 3 PO 4): Rt 17.49 min (2b, 33%), 24.45 min (2b ", 16%) and 29.58 min (2b", 51%).
    Example 2c:
    Octyl-1,4-D-sorbitane 2c, 2c 'and 2c': The compounds were obtained from the mixture 61:39 of 5,6-O-octylidene-1,4-D-sorbitane 1c and 1c 'and 3, 5-O-octylidene-1,4-D-sorbitane 1c "and 1c" (5.61 g, 20.4 mmol) according to the general procedure (B). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 80:20 -> 100: 0 then EtOH / EtOAc 10:90) to a mixture of sorbitan ethers regioisomers 2c, 2c 'and 2c' (4.79 g, 85%) in the form of a white solid. The product is a mixture 33:22:45 of 5-O-octyl-2c, 3-O-octyl-2c "and 6-O-octyl-1,4-D-sorbitane 2c" as determined by HPLC. RMN 1H (300 MHz, de-DMSO) δΗ especially isomers: 0.86 (3H, t, J = 6.8), 1.13-1.35 (10H, m), 1.36-1.55 (2H, m), 3.27-3.99 and 4.05- ^ 4.11 (10H, m, sorbitan protons + OCH2 ethers), δΗ for the isomer 2c: 4.31 (1H, t, J = 5.8, OH6), 4.84 (1H, d, J = 4.5, OH3), 5.00 (1H, d , J = 2.8, OH2), δΗ for the isomer 2c ': 4.31 (1 H, t, J = 5.2, OH6), 4.37 (1 H, d, J = 5.4, OH5), 5.06 (1 H, d, J = 3.3, OH2), δΗ for the isomer 2c ": 4.54 (1H, d, J = 5.8, OH5), 4.81 (1H, d, J = 4.3, OH3), 4.99 (1 H, d, J = 2.8 OH2); RMN 13 C (75 MHz, d 6 -DMSO): δ for the isomer 2c (33%): 13.98 (CH 3), 22.13 (CH 2), 25.66 (CH 2), 28.78 (CH 2), 28.99 (CH 2), 29.89 (CH 2) 31.32 (CH2), 62.01 (CH2), 69.83 (CH2), 73.15 (CH2), 75.53 (CH), 76.45 (CH), 77.38 (CH), 79.29 (CH); δ0 for the isomer 2c '(22%): 13.98 (CH3), 22.13 (CH2), 25.70 (CH2), 28.75 (CH2), 28.90 (CH2), 29.53 (CH2), 31.30 (CH2), 64.18 (CH2) , 68.71 (CH), 69.52 (CH2), 73.23 (CH), 73.60 (CH2), 80.08 (CH), 83.95 (CH); voorc for the isomer 2c '(45%): 13.98 (CH3), 22.13 (CH2), 25.70 (CH2), 28.75 (CH2), 28.93 (CH2), 29.32 (CH2), 31.30 (CH2), 67.49 (CH) 70.61 (CH 2), 73.36 (CH 2), 73.49 (CH 2), 75.66 (CH), 76.37 (CH), 80.34 (CH); HRMS (ESI +): [M + Na] + C 14 H 28 Na 5 O calculated 299.1829, measured 299.1832 (-1.2 ppm); HPLC (C18 column, isocratic 60:40 H2 O / CH3 CN + 0.1% H3 PO4): Rt 8.79 min (2c, 33%), 9.80 min (2c ", 22%) and 11.77 min (2c", 45%).
    Example 2d:
    Decyl-1,4-d-sorbitane 2d, 2d 'and 2d': The compounds were obtained from the mixture 64:36 of 5,6-O-decylidene-1,4-D-sorbitane 1d and 1d 'and 3, 5-O-decylidene-1,4-D-sorbitane 1d "and 1d" (6.12 g, 20.2 mmol) according to the general procedure (B). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 70:30 -> 100: 0 then EtOH / EtOAc 10:90) to a mixture of sorbitan ethers regioisomers 2d, 2d and 2d "(3.66 g, 59%) in the form of a white solid. The product is a mixture 32:16:52 of 5-O-decyl-2d, 3-O-decyl-2d "and 6-O-decyl-1,4-D-sorbitane 2d" as determined by HPLC. RMN 1H (300 MHz, cf6-DMSO) δΗ for all isomers: 0.85 (3H, t, J = 6.9), 1.14-1.35 (14H, m), 1.37-1.55 (2H, m), 3.25-3.98 and 4.05- 4.11 (10H, m, sorbitan protons + OCH2 ethers), δΗ for the isomer 2d: 4.31 (1H, t, J = 5.4, OH6), 4.82 (1H, d, J = 4.3, OH3), 4.99 (1H, d , J = 2.9, OH2), δΗ for the isomer 2d ': 4.31 (1H, t, J = 5.4, OH6), 4.35 (1H, d, J = 5.5, OH5), 5.06 (1H, d, J = 3.3 , OH2), δΗ for the isomer 2d ': 4.53 (1H, d, J = 5.8, OH5), 4.80 (1H, d, J = 4.3, OH3), 4.98 (1H, d, J = 1.9, OH2); RMN 13 C (75 MHz, cf 6 -DMSO) δ0 for the isomer 2d (32%): 13.98 (CH 3), 22.16 (CH 2), 25.69 (CH 2), 28.79 (CH 2), 29.07 (CH 2), 29.10 (CH 2), 29.17 (CH2), 29.92 (CH2), 31.37 (CH2), 62.01 (CH2), 69.84 (CH2), 73.16 (CH2), 75.56 (CH), 76.48 (CH), 77.41 (CH), 79.30 (CH); 5C for the isomer 2d '(16%): 13.98 (CH3), 22.16 (CH2), 25.72 (CH2), 28.79 (CH2), 28.98 (CH2), 29.07 (CH2), 29.12 (CH2), 29.57 (CH2) 31.37 (CH2), 64.18 (CH2), 68.72 (CH), 69.55 (CH2), 73.27 (CH), 73.60 (CH2), 80.08 (CH), 83.96 (CH); 5C for the isomer 2d '(52%): 13.98 (CH3), 22.16 (CH2), 25.72 (CH2), 28.79 (CH2), 29.01 (CH2), 29.07 (CH2), 29.14 (CH2), 29.35 (CH2) 31.37 (CH2), 67.53 (CH), 70.64 (CH2), 73.37 (CH2), 73.50 (CH2), 75.69 (CH), 76.40 (CH), 80.35 (CH); HRMS (ESI +): [M + Na] + C16 H32 Na5 O5 calculated 327.2142, measured 327.2135 (+2.1 ppm); HPLC (C18 column, isocratic 50:50 H2 O / CH3 CN + 0.1% H3 PO4): Rt 9.03 min (2d, 32%), 9.67 min (2d ", 16%) and 11.61 min (2d", 52%).
    Example 2e:
    Dodecyl-1,4-d-sorbitane 2e, 2e 'and 2e': The compounds were obtained from the mixture 48:52 of 5,6-O-dodecylidene-1,4-D-sorbitane 1e and 1e 'and 3, 5-O-dodecylidene-1,4-D-sorbitane 1st "and 1st" (1.29 g, 3.92 mmol) according to the general procedure (B). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane 70:30 -> 100: 0 then EtOH / EtOAc 10:90) to a mixture of sorbitan ethers regioisomers 2e, 2e 'and 2e' (0.72 g, 55%) in the form of a colorless oil. The product is a mixture 27:33:40 of 5-O-dodecyl-2e, 3-O-dodecyl-2nd "and 6-O-dodecyl-1,4-D-sorbitane 2nd" as determined by HPLC. RMN 1H (300 MHz, cfe-DMSO) δΗ for all isomers: 0.85 (3H, t, J = 6.9), 1.16-1.34 (18H, m), 1.38-1.54 (2H, m), 3.26-3.98 and 4.05- 4.11 (10H, m, sorbitan protons + OCH2 ethers), δΗ for the isomer 2e: 4.32 (1H, t, J = 5.5, OH6), 4.84 (1H, d, J = 3.7, OH3), 5.00 (1H, d, J = 2.8, OH2), δΗ for the isomer 2e ': 4.32 (1H, t, J = 5.5, OH6), 4.37 (1H, d, J = 5.4, OH5), 5.06 (1H, d, J = 3.3, OH 2), "for the isomer 2e": 4.55 (1 H, d, J = 5.8, OH 5), 4.82 (1 H, d, J = 4.1, OH 3), 4.99 (1 H, d, J = 2.1, OH 2) ); RMN 13 C (75 MHz, d 6 -DMSO) δ0 for the isomer 2e (27%): 13.97 (CH 3), 22.11 (CH 2), 25.64 (CH 2), 28.74 (CH 2), 29.05 (3 CH 2), 29.08 (2 CH 2) ), 29.88 (CH2), 31.32 (CH2), 62.00 (CH2), 69.81 (CH2), 73.14 (CH2), 75.52 (CH), 76.44 (CH), 77.38 (CH), 79.27 (CH); voorc for the isomer 2e '(33%): 13.97 (CH3), 22.11 (CH2), 25.68 (CH2), 28.74 (CH2), 29.05 (3 CH2), 29.08 (2 CH2), 29.52 (CH2), 31.32 ( CH2), 64.16 (CH2), 68.69 (CH), 69.51 (CH2), 73.22 (CH), 73.58 (CH2), 80.06 (CH), 83.93 (CH); óc for the isomer 2e '(40%): 13.97 (CH3), 22.11 (CH2), 25.68 (CH2), 28.74 (CH2), 28.92 (CH2), 28.96 (CH2), 29.05 (2 CH2), 29.08 (CH2) ), 29.31 (CH2), 31.32 (CH2), 67.47 (CH), 70.59 (CH2), 73.35 (CH2), 73.48 (CH2), 75.63 (CH), 76.35 (CH), 80.34 (CH); HRMS (ESI +): [M + Na] + C 18 H 36 Na 5 O calculated 355.2455, found 355.2458 (-0.9 ppm); HPLC (C18 column, 50:50 H 2 O / CH 3 CN + 0.1% H 3 PO 4): Rt22.65 min (2nd, 27%), 25.04 min (2nd, 33%) and 30.81 min (2nd, 40%). EXAMPLE 3: "One-pot" procedure for the synthesis of a sorbitan ether
    «One-pot» synthesis of sorbitan ethers starting from 1,4-sorbitane:
    In a 100 ml round bottom flask, 1,4-sorbitane (10 g, 62 mmol) was dissolved in dry CPME (30 ml) in the presence of Na 2 SO 4 (6.5 g, 50 mmol), under an argon atmosphere. Valeraldehyde (3.3 ml, 31 mmol) was added dropwise, followed by Amberlyst 15 (530 mg, 20 wt% in valeraldehyde). The mixture was heated to 80 ° C with magnetic stirring. After 3 hours the warm mixture was filtered, washed with CPME (2 x 25 ml) and the filtrate was concentrated under reduced pressure. Without further purification, the mixture is diluted in CPME (300 ml), dried over MgSO 4 and filtered. The filtrate is introduced into a 500 ml stainless steel autoclave, and 5% Pd / C (3.3 mg) was added. The reactor is properly closed, flushed three times with hydrogen before the hydrogen is introduced under pressure (30 bar). The system is heated to 120 ° C and stirred for 15 hours. After being cooled to room temperature, the hydrogen is released under pressure, the reaction mixture is dissolved in absolute ethanol (250 ml) and filtered (Millipore Durapore 0.01 micron filter). The filtrate is evaporated under reduced pressure and the residue (5.8 g) is purified by flash chromatography (EtOAc / cyclohexane 90:10 to 100: 0, then EtOH / EtOAc 10:90). A mixture of ethers of pentyl (1.4) sorbitane (3.97 g, 56%) is thus obtained in the form of a colorless oil (> 98% purity with 1 H NMR). EXAMPLE 4: Measurement of bacteriostatic properties of derivatives of sorbitan acetals and ethers on Gram-positive bacteria
    The bacteriostatic properties of the derivatives are evaluated by measuring the minimum inhibitory concentration (MRC) relative to the bacteria tested. Such a measurement is performed by the method of microdilution performed in 96-well microplate under the conditions below.
    The tested bacteria:
    The minimal inhibitory growth (MRG) is performed on bacterial Gram-positive strains, as recommended by the Clinical Laboratory Standards Institute, 6th ed. Approved standard M100-S17. CLSI, Wayne, PA, 2007).
    The Gram-positive bacteria studied are the following: L. monocytogenes (CIP 103.575), E. faecalis (ATCC® 29212 ™) and S. aureus (ATCC® 292.213 TM).
    Preparation of the inoculum:
    The cultures studied, freshly isolated (after incubation on a blood agar at 37 ° C for 18 hours) were taken up in sterile water (10 ml) to obtain a suspension of 0.5 Mac Farland (Mc) according to 1 to 2 x 108 CFU (bacteria) / cm3. The bacterial suspension was then diluted to obtain a final concentration of 5 x 10 5 CFU / cm 3.
    Preparation of the multiwell plates for reading the MRC:
    Each well contains an identical amount of Mueller-Hinton medium (rich medium for growing bacteria) bacteria and bacterium of 5 x 105 CFU / cm3 final.
    The compounds of interest to be tested were dissolved in 2.5% ethanol before being diluted to different concentrations two to two.
    On the multiwell plate, a first series is provided comprising the culture medium without the connection of interest to be tested. It corresponds to the growth control (control wells). These controls serve as a reference for comparing bacterial growth with those of the following wells comprising different concentrations of the compound to be tested. The second set of wells comprises the stock solution of the compound of interest to be tested for a concentration in the wells of 4 mM. Each series of wells is diluted two by two to the final series to a final concentration of 0.003 mM. Each concentration is replicated within the same plate. The plate is incubated for 18 hours at 37 ° C. Reading after the incubation shows a deviation in the control wells (indication of bacterial growth). In the case of antibacterial activity, bacterial growth is inhibited, which is translated into the absence of occurrence of abnormality or bacterial pellet. The inhibition of this bacterial growth by the test compound may correspond to a bacteriostatic activity of the molecule (inhibits bacterial growth) or bactericidal activity of the molecule (causes the death of the bacteria).
    Germinal:
    To determine whether the agents tested are bactericidal, the minimum bactericidal concentration (MBC) is determined. The MCB is the concentration that leaves the number of surviving bacteria <4 log. To do this, a bacterial count is made from the clear or without bacterial pellet (C <MRC) wells. For this a 1/100 dilution was performed with the two wells of the same concentration for inoculation on a blood agar using the spiral technique. After incubation for 24 hours at 37 ° C, the visual count was used to determine the minimum concentration at which there is no bacterial growth.
    The tests are performed on Gram-positive bacteria with the sorbitan derivatives. The solutions of the test compounds are diluted in ethanol at a concentration of solvent that has no influence on bacterial growth (2.5% m). The solutions after sterilization are diluted in water. The results of the antimicrobial tests obtained on the 3 bacterial strains L. monocytogenes (CIP 103575), E. faecalis (ATCC® 29212 ™) and S. aureus (ATCC® 292.213 TM) are summarized in Table 1.
    Table 1. Antimierobial results for the sorbitan derivatives on Gram positive: Minimum inhibitory concentration (MRC) in mmol / L
    After the observation of the 96-well microplates, the ethers and acetals of sorbitan with aliphatic chains lower or equal to 10 carbon atoms, have no antimicrobial properties because all wells contain a defect or a bacterial pellet. The single bacterial inhibition is observed for the compounds derived from dodecyl (input 5).
    Indeed, with concentrations of less than 12 mM, the acetal and the ether with C12 sorbitan, the bacterial strains investigated inhibit. EXAMPLE 5: Bacterial property of the derivatives of sorbitan acetals or esters on Gram-positive bacteria
    To determine the bactericidal effect of the compounds with bacteriostatic properties, the wells that do not exhibit aberration are again plotted on agar. The results obtained after overnight incubation are shown in Table 2.
    Table 2. Antimicrobial results for derivatives of sorbitan on Gram positive: Minimum inhibitory concentration (MRC) in mmol / L, Minimum bactericidal concentration (MBC) in mmol / L (in italics)
    Regarding the sorbitan derivatives, only the compounds with chains of 12 carbons and showing a bacterial inhibition are analyzed. The sorbitan dodecylidene acetal was found to be a bactericidal compound for strains L. monocytogenes and E. faecalis at 0.03 mM and bacteriostatic compound for S. aureus at 0.12 mM. To confirm that the measured properties of the acetals are those of the amphiphilic compound and not of the hydrolysis products, the dodecanal properties were tested on the different bacterial strains and no antimicrobial activity was observed at concentrations lower than or equal to 4 mM. Thus, the C12 sorbitan is acetally active as such and the activity does not come from the corresponding aldehyde. The dodecyl sorbitan ethers mixture has an MBC of 0.12 mM for all Gram-positive strains tested.
    We can therefore conclude that the C12 sorbitan acetals and ethers, also in the form of a mixture of regioisomers and diastereomers, exhibit very interesting antimicrobial and bactericidal properties.
    These results show that sorbitan derivatives can introduce a new line of highly active bio-based bacteriostatic and bactericidal products. EXAMPLE 6: Evaluation of surfactant and antimicrobial properties
    The physico-chemical and antimicrobial properties of the best synthesized products are tested. These analyzes demonstrate different profiles of surfactants, as well as the values of the minimum inhibitory concentrations (MRC) of each compound on Gram-positive bacteria. The best surfactant and antimicrobial results are compared in Table 3.
    Table 3. Comparative results between the critical micelle concentrations (CMC) and the minimum inhibitory concentrations (MRC) in (mmol / L) on products of interest: Minimum inhibitory concentration (MRC) in mmol / L
    For the dodecylamine sorbitane (input 1), the value of the CMC is in the range of MRC. The dodecyl sorbitan ether, meanwhile, has a slightly lower CMC (0.09 mmol) as MRC (0.12 mmol), but these concentrations are still relatively dense (input 2). EXAMPLE 7: Comparative tests with compounds of the prior art
    The activity of sorbitan derivatives was compared with that of compounds with structures close by or commercial compounds such as monolaurin (ML) in the table below.
    Table 4. Comparative results between the reference products (ML) and the acetals and ethers of sorbitan: Minimum inhibitory concentration (MRC) in mmol / L
    The results obtained show that the derivatives of the invention are as effective as monolaurin (ML), since the difference between the MRC obtained between the mixtures of acetals (C12AcSorb) or C12 sugar ethers (C12EthSorb) and monolaurin is low.
    In addition, the stability of the ether functions in biological media is higher than the esters (sensitive to esterases), so the compounds comprising an ether function have an extended effect, making these compounds particularly advantageous compounds. EXAMPLE 8: Measurement of the bacteriostatic properties of a C12 sorbitan ether on Gram-positive bacteria
    The best results have been observed with compounds having a C12 alkyl group, the tests were carried out on a larger number of Gram-positive strains carried out with a mixture of sorbitan ethers as obtained according to the preceding examples. - Preparation of the seeding material:
    The cultures studied, freshly isolated (after incubation on a blood agar at 37 ° C for 18 hours), were taken up in sterile water (10 ml) until a suspension of 0.5 Mac Farland (Mc) was obtained according to 1 to 2 x 108 CFU (bacteria) / cm3. The bacterial suspension was then diluted to obtain a final concentration of 1 x 10 6 CFU / cm 3. - Preparation of the multiwell plates for reading the MRC:
    Each well contains an identical amount of Mueller-Hinton medium (rich medium for growing bacteria) and bacteria of 0.5 x 10 6 CFU / cm3 final.
    The compounds of interest to be tested were dissolved in ethanol or DMSO at 25 mg / ml before being diluted to different concentrations two to two. On the multiwell plate, a first series was provided comprising the culture medium without the compound of interest to be tested. It corresponds to the growth control (control wells). These indicators serve as a reference for comparing bacterial growth with those of the following wells comprising different concentrations of the compound of interest to be tested. The second set of wells comprises the stock solution of the compound of interest to be tested for a concentration in the well of 256 mg / L (7 mM). Each series of wells was diluted two by two to the final series to a final concentration of 0.25 mg / L (0.0007 mM). Each concentration is replicated within the same plate. The plate is incubated for 18 hours at 37 ° C. Reading after incubation shows a deviation from the control wells (indication of bacterial growth). In the case of antibacterial activity, bacterial growth is inhibited which translates into the lack of occurrence of abnormality or bacterial pellet.
    The minimal inhibitory growth (MRG) was performed on bacterial Gram-positive strains, according to the recommendations of the "Clinical Laboratory Standards Institute" (Clinical-Laboratory-Standards-Institute, 6th ed. Approved standard M100-S17. CLSI, Wayne, PA , 2007) The clinical strains were isolated at the Lyon hospital.
    The Gram-positive bacteria studied are the following: - Staphylocoques S. aureus. ATCC®29213 ™, ATCC 25923,
    Strains of Staphylocoques S. aureus resistant to methicillin (Lac-Deleo USA 300), (MU 3), (HT 2004-0012), LY 199-0053, (HT 2002-0417), (HT 2006-1004),
    Strains of Staphylocoques S. aureus resistant to daptomycin (ST 2015-0188), (ST 2014 1288). - Enterococci: E. faecalis (ATCC® 29212 ™), clinical enterococci strains £. faecalis isolated from urine: The strain 015206179901 (hereinafter 9901), The strain 015205261801 (hereinafter 1801) - Enterococci: E. faecium (CIP 103510), clinical enterococci strains E. faecium: Van A 0151850763 (hereinafter Van A); the strain 015 205731401 (hereafter 1401), - Listeria: L. monocytogenes (CIP 103575), clinical strains isolated from blood culture (015189074801, LM1), strain isolated from the cerobrospinal fluid (015170199001, LM2), clinical strain isolated from blood culture (015181840701 , LM3).
    Preparation of the inoculum:
    The cultures studied, freshly isolated (after incubation on blood agar at 37 ° C for 18 hours) were seeded in sterile water (10 ml) until a suspension of 0.5 Mac Farland (Mc) was obtained with 108 CFU (bacteria) / cm3 . The bacterial suspension was then diluted to obtain a final concentration of 10 6 CFU / cm 3. - Results of the strains of the Staphylokoccus genus
    Table 5. Antimicrobial results for a sorbitan ether on different strains of Staphylococcus Aureus: minimum inhibitory concentration (MRC) in mg / L.
    According to the observation of 96-well microplates, the C12 sorbitan ether (C12-Eth-Sorb) is active against the strains tested for staphylococci (32 <MIC <64 mg / l). - Results for the strains of the genus of des Enterococci
    Table 6. Antimicrobial results for sorbitan ether on different strains of enterococci. Minimum inhibitory concentration (MRC) in mg / l
    We observe good antibacterial activity of C12 sorbitan ether for all strains of enterococci 8 <MIC <16 mg / L tested. - Results for the strains of the genus Listeria
    Table 7. Antimicrobial results for a sorbitan ether from different strains of Listeria minimal inhibitory concentration (MRC) in mg / L.
    Good antibacterial activity of C12 sorbitan ether was observed on all Listeria strains 16 <MIC <32 mg / L tested.
    权利要求:
    Claims (18)
    [1]
    Conclusions
    The use of a bactericidal or bacteriostatic composition, characterized in that it comprises an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or an mixture of isomers thereof, preferably the alkyl is acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O- and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers.
    [2]
    Use according to claim 1, characterized in that the alkyl group comprises between 11 to 13 carbon atoms.
    [3]
    Use according to one of claims 1 and 2, characterized in that the alkyl acetal radical in position 2,3-O-; Is 3,5-O- or 5,6-O- or the alkyl ether is radical in position 2-O, 3-O, 5-O- or 6-O-.
    [4]
    Use according to any of claims 1 to 3, characterized in that it is bactericidal or bacteriostatic relative to Gram-positive bacteria.
    [5]
    Use according to claim 4, characterized in that the Gram-positive bacteria are bacteria of the Firmicutes strain, typically of the Bacilli class, in particular selected from bacteria of the order of Lactobacillales or Bacillales.
    [6]
    The use according to claim 5, characterized in that the Gram-positive bacteria are bacteria of the order of Bacillales selected from the family of Alicyclobacillaceae, Bacillaceae, Caryophanaceae, listeriaceae, Paenibacillaceae, Pasteuriaceae, Planococcaceae, Sporolactobacillaceae, Staphylococacaceaceacicacaceaceacicacaceaceacicacaceaceacaceaceacaceacea
    [7]
    Use according to any of claims 5 and 6, characterized in that the Gram-positive bacteria are bacteria of the family of listeriaceae such as a bacterium of the genus of Brochothrix or Listeria typically selected from L. fleischmannii, L. grayi, L innocua, L. ivanovii marthii, L. monocytogenes, L. rocourtiae, L. seeligeri, L. weihenstephanensis and L. welshimeri.
    [8]
    Use according to any of claims 5 and 6, characterized in that the Gram-positive bacteria are bacteria from the family of Staphylococcaceae selected from bacteria of the genus of Staphylococcus, Gemella, Jeotgalicoccus, Macrococcus, Salinicoccus and Nosocomiicoccus.
    [9]
    Use according to claim 8, characterized in that the Gram-positive bacteria are bacteria of the genus of Staphylococcus selected from S. arlettae, S. agnetis, S. aureus, S. auricularis, S. capitis, S. caprae, S carnosus, S. caseolyticus, S. chromogenes, S. cohnii, S. condimenti, S. delphini, S. devriesei, S. epidermidis, S. equorum, S. felis, S. fleurettii, S. gallinarum, S. haemolyticus , S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lentus, S. lugdunensis, S. lutrae, S. massiliensis, S. microti, S. muscae, S. nepalensis, S pasteuri, S. pettenkoferi, S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans , S. stepanovicii, S. succinus, S. vitulinus, S. warneri and S. xylosus.
    [10]
    Use according to claim 5, characterized in that the Gram-positive bacteria Lactobacillales are selected from a family of Aerococcaceae, Carnobacteriaceae, Enterococcaceae, Lactobacillaceae, Leuconostocaceae and Streptococcaceae.
    [11]
    Use according to claim 10, characterized in that the Gram-positive bacteria are bacteria from the family of Enterococcaceae selected from bacteria of the genus of Bavariicoccus, Catellicoccus, Enterococcus, Melissococcus, Pilibacter, Tetragenococcus, Vagococcus.
    [12]
    Use according to claim 11, characterized in that the Gram-positive bacteria are bacteria of the genus of Enterococcus selected from E. malodoratus, E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum, E hirae, E. solitarius, preferably, E. avium, E. durans, E. faecalis and E. faecium.
    [13]
    Use according to any of claims 1 to 12, characterized in that said composition is included in a food, cosmetic, drug, phytosanitary, veterinary or surface treatment agent.
    [14]
    A composition characterized in that it comprises an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, preferably the alkyl acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers, for its use as hygiene or dermatological product for external use.
    [15]
    A composition characterized in that it comprises an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, is preferably the alkyl acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers, for use in disinfection , cleaning, sterilization or purification of surfaces.
    [16]
    A composition characterized in that it comprises an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group comprises between 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, preferably the alkyl acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O and / or 6-O-, the isomers are preferably selected from the regioisomers and / or diastereomers, for use in the treatment or prevention of bacterial infections by Gram-positive bacteria.
    [17]
    The composition of claim 16, wherein the infection with Gram-positive bacteria is an infection of the skin or mucous membranes, preferably an infection selected from a folliculitis, an abscess, paronychia, a boil, beard scabies, an interdigital infection, an anthrax (anthrax staphylococcique), cellulite, a secondary infection of wounds, a sinusitis otitis, a hydradenitis, a contagious mastitis, a post-traumatic skin infection and a burned skin infection.
    [18]
    A method for disinfecting or preventing bacterial colonization by Gram-positive bacteria of a substrate comprising contacting the substrate with a composition comprising an alkyl acetal or a hexitane alkyl ether, preferably arlitane sorbitan or mannitan sorbitane wherein the alkyl group is between 11 up to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, preferably the alkyl is acetyl radical or alkyl ether radical in position 2-O, 3-O, 5-O- and / or 6-O- the isomers are preferably selected from the regioisomers and / or diastereomers.
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    FR1402894|2014-12-17|
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