• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a bactericidal or bacteriostatic composition comprising an alkyl ether or an alkyl acetal of deoxyhexose or a mixture of isomers thereof, their use in treating or preventing infections by gram-positive bacteria, their use as a care product or dermatologically product for external use as well as a method for disinfecting surfaces.
    公开号:BE1023858B1
    申请号:E2016/5946
    申请日:2016-12-19
    公开日:2017-08-22
    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 Belgium Nv；Universite Claude Bernard - Lyon 1；Centre National De La Recherche Scientifique；
    IPC主号:
    专利说明:

    ANTIBACTERIAL COMPOSITION CONTAINING A MONO-ETHER OR MONO-ACETAL OF ALKYLESOXYHEXOSE
    FIELD OF THE INVENTION
    The present invention relates to a bactericidal or bacteriostatic composition comprising an alkyl acetal or an alkyl ether of deoxyhexose or a derivative of deoxyhexose, wherein the alkyl group is from 11 to 18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof includes, its use in treating or preventing infections of gram-positive bacteria, its use as a care product or as a dermatological product for external use, as well as a method for disinfecting surfaces.
    State of the art
    The antimicrobial compounds are defined as molecules that can inhibit or stop the growth of microorganisms or kill them. In this regard, they are commonly used to prevent or treat infections in humans and animals and in the food industry to prevent the multiplication of pathogenic bacteria in the food. The wide range of applications of the antimicrobial compounds has favored the appearance of resistant infectious agents. The spread of bacteria with acquired resistance mechanisms to the most commonly used antimicrobial compounds is a major and increasingly alarming public health problem (J. S. Bradley et al. Lancet Infect. Dis. 2007; 7: 68 - 78).
    Illustratively, numerous strains resistant to the antibiotic of the most pathogenic species of the genus Staphylococcus, i.e. Staphylococcus aureus, have been isolated. However, Staphylococcus infections represent a large percentage of the serious infections. In addition, nearly half of the hospital infections are associated with a Staphylococcus. The numerous strains of Enterococcus faecalis or Enterococcus faecium, which are resistant to commonly used antibiotics, can also be mentioned. Although they are less virulent compared to Staphylococcus in particular, a growing number of multi-resistant strains of Enterococcus have been identified and more recently Enterococcus epidemics, which are resistant to glycopeptides, the antibiotics used for this family of bacteria.
    Another phenomenon of antibiotic resistance, which may be associated not only with the excessive use of antibiotics, but with food preservation methods, has been described. For example, it has been shown that Listeria monocytogenes appears to be more resistant to antibiotics after having survived an osmotic strain, a low temperature or an acidic environment (Anas A. et al. (2015) Food Microbiology, Volume 46, April, p. 154 - 160). In other words, the contamination of people is transmitted through food. In addition, although it is relatively rare, listeriosis is a serious infection in humans with an estimated mortality rate of 50%. Thus, the appearance of antibiotic resistance in L. monocytogenes, which may be caused by modern preservation methods or food treatment, poses a serious threat to public health.
    Although several mechanisms are often involved in resistance to antibiotics at the same time, it is common to classify them into three classes; (a) inadequate penetration of the antibiotic into the bacterium; (b) inactivation or secretion of the antibiotic by the enzyme systems of the bacteria; and (c) inadequate affinity between the target bacterium and the antibiotic. These three classes of resistance mechanisms have a structural component, i.e. the mechanisms used depend on the structure of the molecule in question.
    Therefore, in order to obtain an antibiotic composition with less chance of developing a resistance, the inventors envisaged the use of a composition comprising a mixture of compounds with an antibiotic action, but with slight structural differences, which chances of developing a bacterial resistance are likely to decrease. They have therefore intended a composition comprising a mixture of isomers of compounds with an antibiotic action.
    The inventors wish to develop an antibiotic composition with also a low toxicity and a small effect on the environment. A biodegradable antibiotic composition that can be obtained in large quantities from sustainable resources at low cost, so that it is certainly available for industrial use, but also as effective as antimicrobial agents from non-biological sources.
    However, with any prior art method, a mixture of isomers of compounds derived from biological sources with low toxicity and at low cost cannot be obtained.
    Nevertheless, compounds from biological sources have been described in the prior art. The prior art also discloses various compounds which are used as antimicrobial agents, including fatty acids and their corresponding esters with polyhydroxy compounds, which are active against gram-positive bacteria and which have long aliphatic chains. As an illustration, one of the most active antimicrobials is the monolaurin, a monoester of glycerol with an aliphatic chain of 12 carbon atoms. Its commercial name is LAURICIDIN®. This compound is used as a food additive for inhibiting bacterial growth (E. 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 the monolaurin is sensitive to esterases, this compound is rapidly degraded and has a short half-life.
    The prior art also describes antimicrobials derived from sugar, which are considered to be particularly attractive in view of their biodegradability, their low toxicity and their effect on the environment.
    Examples of sugar-derived antimicrobial agents are sugar-derived esters, which are also used on an industrial scale for antimicrobial applications, because their starting materials and their production costs remain relatively low. For example, the sorbitan caprylate can be mentioned, which is described in International Patent Application WO2014 / 025413 mixed with Hinokitiol in an antimicrobial formulation. According to this application, this formulation would inhibit or kill gram-positive and 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 dodecanoate is one of the most used. The latter is said to be particularly effective against L. monocytogenes (M. Ferrer, J. Soliveri, FJ Plou, N. López-Cortés, D. Reyes-Duarte, M. Christensen, JL Copa-Patiho, A. Ballesteros, Enz Microb. Tech., 2005, 36, 391 - 398). Nevertheless, it has also been described as a weak inhibitor of S. aureus growth for field hospital applications (J. D. Monk, L. R. Beuchat, A. K. Hathcox, J. Appl. Microbiol., 1996, 81, 7-18). For example, the sucrose ester would have baetriostatic properties (stops the growth of bacteria) but no bactericidal properties (kills the bacteria).
    Moreover, the preparation of sugar esters has numerous drawbacks. First of all, despite the low production costs, the preparation of esters, more particularly the di- and trisaccharides, is difficult because of the high number of functional groups of sugars which entail the formation of a mixture of mono-, di- and polyesters and the presence of a polar solvent, such as dimethylformamide (DMF) and pyridine, is generally necessary to better dissolve the highly polar reagents. However, these solvents are classified as carcinogenic, mutagenic and reprotoxic (CMR) and their use must be avoided. The enzymatic preparation has been used to solve this problem, but the need to place it in a highly diluted environment under these conditions limits production.
    Furthermore, the ester functions of these compounds are easily hydrolysed by the esterases present in the cells. Now the molecules released as a result of this hydrolysis, i.e. the sugar and the fatty acid, have little or no antimicrobial properties (the fatty acid being poorly active). This induces an instability that is responsible for shortening the duration of action of these compounds.
    Therefore, in order to obtain an antibiotic composition unfavorable for developing a resistance comprising effective and stable antimicrobial agents, the invention proposes a monoether or monoacetal of alkyl deoxyhexose, the alkyl group 11-18 carbon atoms, preferably in the form of a mixture of regioisomers and / or diastereoisomers, which are obtained under low cost conditions while respecting the environment, and which have no danger of topical applications or ingestion.
    Detailed description of the invention
    Bacterial or bacteriostatic composition
    The invention relates to a characteristic bactericidal or bacteriostatic composition, characterized in that it comprises an alkyl acetal or an alkyl ether of deoxyhexose and / or an alkyl acetal or an alkyl ether of glycosylated and / or hydrogenated and / or dehydrated deoxyhexose, wherein the alkyl group comprises 11-18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, wherein said alkyl acetal or alkyl ether group is preferably in position 2-0, 3-0, 4-0, wherein the isomers are preferably selected from the regioisomers and / or the diastereoisomers. Typically, the deoxyhexose is selected from the rhamnose or fucose. Advantageously, the alkyl acetal or alkyl ether of deoxyhexose is a monoalkyl ether or monoalkylacetal of deoxyhexose. Typically, said deoxyhexose is a glycosylated and / or hydrogenated and / or dehydrated deoxyhexose.
    The invention also relates to a composition comprising a monoalkyl ether or monoalkylacetal of deoxyhexose or a derivative of deoxyhexose or a mixture of isomers thereof, wherein said derivative of deoxyhexose is a glycosylated and / or hydrogenated and / or dehydrated deoxyhexose, wherein the isomers are preferably selected from the regioisomers and / or the diastereoisomers, wherein said monoalkyl ether or said monoalkylacetal of deoxyhexose or a derivative of deoxyhexose or the mixture of isomers thereof is obtained by a process which comprises the following steps: a) acetalizing or trans-acetalizing a deoxyhexose or a derivative of deoxyhexose with an aliphatic aldehyde containing 11-18 carbon atoms, or the acetal thereof b) optionally catalytically hydrogenating the alkyl acetal of deoxyhexose or of the derivative of deoxyhexose obtained in a), preferably without an acid cat alysator and c) recovering a mixture of isomers of monoalkylethers of deoxyhexose or of the derivative of deoxyhexose obtained in b), wherein the alkyl group (R) comprises 11 to 18 carbon atoms or recovering a mixture of isomers of mono - alkyl acetals of deoxyhexose or the derivative of deoxyhexose obtained in a), wherein the alkyl group (R) comprises 11 to 18 carbon atoms.
    A "deoxyhexose" is to be understood as a hexose of which one of the hydroxyl groups (OH) has been replaced by a hydrogen. The deoxyhexoses can be isolated from plants, for example the rhamnose comes from buckthorn (Rhamnus) or sumac, the fucose from membrane polysaccharides of cells of mammals or insects. An example of a suitable deoxyhexose can be fucose or rhamnose.
    As used herein, the term "rhamnose" refers to D - (-) - rhamnose or to L - (+) - rhamnose. The rhamnose is a hexose with the gross formula C6 H12 O5 which is also called isoducitol or 6-deoxy-L-mannose.
    As used herein, the term "fucose" refers to D - (-) - fucose or to L - (+) - fucose. The fucose is a hexose with the gross formula C6 H12 O5 which is also called 6-deoxy-L-galactose.
    In one embodiment, the deoxyhexose is a glycosylated and / or hydrogenated and / or dehydrated deoxyhexose. Such glycosylated and / or hydrogenated and / or dehydrated deoxyhexoses are referred to herein as "deoxyhexose derivatives". For example, the rhamnose derivative is an anhydrorhamnose or rhamnitol.
    An "anhydrorhamnose" is to be understood as a compound obtained by dehydration, by removing one or more water molecules from the rhamnose. An example of an anhydrorhamnose may be 1,2-anhydrorhamnose, 1,2-anhydrorhamnose, 1,3-anhydrorhamnose, 2,3-anhydrorhamnose.
    The anhydrorhamnose can be obtained by dehydrating rhamnitol to form, for example, the 1,5-anhydrorhamnitol.
    In one embodiment, said rhamnose derivative is a sugar alcohol, the rhamnitol. As used herein, the term "sugar alcohol", also known as "polyol", refers to a hydrogenated form of monosaccharide whose carbonyl group (aldehyde or ketone) is reduced to a primary or secondary hydroxyl group.
    Similarly, when the deoxyhexose is a fucose, the said hydrogenated derivative of fucose is a sugar alcohol, the fucositol.
    The derivative of fucose is advantageously an anhydrofucose. An "anhydroflucosis" is to be understood as a fucose obtained by dehydration, by removing one or more water molecules from the fucose. An example of an anhydrofucose can be the 1,2-anhydrofucose, the 1,3-anhydrofucose.
    According to an embodiment, the method according to the invention may comprise a dehydration of said deoxyhexose or its derivative to obtain, for example, a monoanhydrorhamnose or a monoanhydrofucose. Typically, the deoxyhexose is melted prior to dehydration. The dehydration can be carried out with a catalyst, for example with 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 is advantageously carried out at a temperature of 120 - 170 ° C, preferably 130 - 140 ° C.
    Typically, the deoxyhexose derivative is purified after dehydration, e.g., by crystallization, recrystallization, or chromatography.
    In one embodiment, said deoxyhexose derivative is a glycosylated deoxyhexose, i.e., an alkyl glycoside.
    As used herein, the term "glyeosylated" or "glyeosylation" refers to a reaction between an alkyl group and a saccharide at the anomeric position (hemiacetal function) of the saccharide leading to a mixed acetal function (IUPAC Compendium of Chemical Terminology Gold book Version 2.3 .3 2014-02-24 p. 633 - 636 et PAC, 1995, 67, 1307 ("Glossary of common names and organic compounds and reactivity intermediates based on structure" IUPAC Recommendations 1995) p. 1338 White Book, p. 136) . This glycosylation reaction is the opposite of the alkylation in that the latter can take place between an alkyl group and a saccharide but at any oxygen atom of the saccharide to form an ether function.
    As used herein, the term "alkyl glycoside" refers to a deoxyhexose in which the reductive moiety is bonded to an alkyl group by glycosylation as described in the prior art. Typically, the deoxyhexose or its derivative may be bonded to an alkyl group by an oxygen atom (an O-glycoside), a nitrogen atom (a glycosylamine), a sulfur atom (a thioglycoside) or a carbon atom (a C-glycoside). The alkyl group can have a preferably varying chain length, the alkyl group is a C1 -C4 alkyl group. An even more preferred alkyl group is a methyl or an ethyl. Typically, the glycosylated deoxyhexose is a glycosylated rhamnose, a glycosylated rhamnitol, a glyeosylated fucose or a glycosylated fucositol. For example, alkyl glycosides may be selected from a group consisting of methyl rhamnoside, ethyl rhamnoside, propyl rhamnoside, butyl rhamnoside, methyl fucoside, ethyl fucoside, propyl fucoside and butyl fucoside.
    According to the invention, the acetalysing or trans-acetalysing comprises: i) optionally preheating said deoxyhexose or its derivative, preferably at a temperature of 70 - 130 ° C, typically 90 - 110 ° C, ii) adding the aliphatic aldehyde or an aliphatic aldehyde derivative to the deoxyhexose or derivative thereof and iii) adding a catalyst, preferably an acid catalyst.
    Typically, the acetal of an aliphatic aldehyde may be a dialkyl acetal of the corresponding aldehyde. The dimethyl acetals and the diethyl acetals are preferred.
    Step i) is particularly advantageous since it can be carried out in the absence of solvent.
    Preferably, the acid catalyst used during acetalysing or trans-acetalysing and optionally during dehydration may be a homogeneous or heterogeneous acid catalyst. The term "homogeneous" as used in the term "homogeneous acid catalyst" refers to a catalyst which is in the same phase (solid, liquid or gas) or in the same aggregation state as the reagent. In contrast, 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) than the reagents.
    Said acid catalyst, which is used in acetalysing or trans-acetalysing and optionally during dehydration, can be independently selected from the solid or liquid, organic or inorganic acids, with the solid acids being preferred. In particular, the preferred acid catalyst is selected from para-toluenesulfonic acid, methanesulfonic acid, camphorosulfonic acid (CSA) and the sulfone resins.
    Typically, the acetalysing or trans-acetalysing is carried out at temperatures of 70 - 130 ° C, typically 70 - 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 acetalysing or trans-acetalysing can be carried out with an aliphatic aldehyde or acetal thereof, typically a linear or branched aliphatic aldehyde or acetal thereof. The acetalizing or trans-acetalizing can typically be carried out with an aliphatic aldehyde or acetal thereof having 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, for example selected from the un-decanal, dodecanal, tridecanal, tetradecanal, pentadecanal, hexadecanal, heptadecalene, octadecanal and the acetal. Preferably, the C 1 -C 13 aldehyde or acetal thereof is an aliphatic C 12 aldehyde or acetal thereof, for example a dodecanal or the acetal thereof.
    The term "acetal thereof" or "their acetal (acetals)", as used herein, includes the dialkyl acetal of the corresponding aliphatic C 1 -C 18 aldehyde. More in particular, the dimethyl or diethyl acetals of the aliphatic C 1-8 aldehyde are preferred.
    According to an embodiment, the acetalysing or trans-acetalysing 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 (CH3CN), tetrahydrofuran (THF), 2-methyhetrahydrofuran (2Me-THF), cyclo-pentenemethylethyl ether (CPME), methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (iPrOH), butanol (BuOH), dibutyl ether (DBE), methyl tert-butyl ether (MTBE) and trimethoxypropane (TMP).
    Extensive experimental research has been carried out under a selection of conditions, whereby conversion levels and optimum yields could be observed during acetalization or trans-acetalization. The best results are obtained when the molar ratio [(aliphatic C 11 -C 18 aldehyde or acetal thereof): deoxyhexose or its derivative] is 5: 1 - 1: 5, preferably 4: 1 -1: 4 and advantageously 3: 1 - 1: 3.
    More particularly, the inventors have shown that during an acetalization reaction the molar ratio of aliphatic C 1 -C 18 aldehyde: deoxyhexose or its derivative of 1: 1 - 1: 5, preferably 1: 1 - 1: 4 and advantageously 1: 3 -1: 2 improves yields and delivers optimum conversion levels.
    The inventors have furthermore shown that during the trans-acetalization reactions a molar ratio of aliphatic C1 -C18 acetal: (deoxyhexose or derivative of deoxyhexose) of 1: 1 - 5: 1, preferably 5: 4 - 4: 1, at preferably 3: 1 - 4: 3, even more preferably 3: 2 - 2: 5 improves yield and yields optimum conversion levels. The catalysts used are the same as during the acetalization reaction.
    According to an embodiment, the method according to the invention furthermore comprises at least one neutralization and / or filtration and / or purification after each of the deshydration, if applicable, acetalysation or trans-acetalysation.
    When a purification is provided, said purification can be, for example, a crystallization, a recrystallization or a chromatography. The chromatography is preferably carried out by using a non-aqueous polar solvent. In general, when a filtration and / or purification is provided for the hydrogenation, the non-aqueous polar solvent may be identical to that used during the hydrogenation.
    The hydrogenation is advantageously carried out at a temperature of 80 ° C - 140 ° C and / or at a hydrogen pressure of 15 - 50 bar, preferably 20 - 40 bar.
    The hydrogenation is advantageously carried out in an aprotic polar solvent, preferably a non-aqueous solvent. After all, the aprotic solvents offer a better conversion. Examples of aprotic solvents include, without limitation, alkanes, 1,2,3-trimethoxypropane (TMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dibutyl ether (DBE) and cyclopentyl methyl ether (CPME). Preferably the aprotic solvent is CPME. The alkanes are beneficial because they dissolve hydrogen better in the environment. However, the conversion is less high than with other aprotic solvents, such as CPME. Of the alkanes, dodecane and heptane are preferred.
    The hydrogenolysis is preferably carried out in a polar aprotic solvent at a temperature of 80 ° C - 140 ° C and / or under a hydrogen pressure of 15 - 50 bar, in the presence of a catalyst suitable for hydrogenolysis reactions.
    The hydrogenolysis is preferably carried out in a non-aqueous polar solvent at a temperature of 100 ° C - 130 ° C and / or at a pressure of 25 - 35 bar.
    In general, the hydrogenolysis is carried out in the presence of a suitable catalyst, such as a catalyst based on noble metals or non-noble metals. More particularly, the non-noble metals may be ferrous or non-ferrous metals. Typically, the hydrogenolysis is carried out in the presence of an iron-based metal catalyst.
    As an illustration, a catalyst of a metal belonging to the iron-containing metal group can be nickel, cobalt or iron.
    The hydrogenolysis is preferably effected by using a catalyst based on noble metals, such as palladium, rhodium, ruthenium, platinum or iridium.
    As a rule, the catalyst used during the hydrogenolysis may be fixed on a support such as carbon, alumina, zirconia or silica or a mixture of any of these. Such a carrier is, for example, a pearl. Thus, a palladium catalyst fixed on carbon beads (Pd / C) can be used advantageously. These catalysts can be doped by adding noble metals or non-noble metals. This is referred to as a dopant. Typically, the dopant represents 1-10% by weight of the catalyst.
    The invention also relates to a bactericidal or bacteriostatic composition which comprises a mixture of positional isomers of mono-ethers or mono-acetals of alkyldesoxyhexose with an alkyl ether or alkylacetal group at two distinct positions of the deoxyhexose or a derivative of deoxyhexose as well as the pharmaceutically acceptable salts thereof, wherein the alkyl group comprises 11 to 18 carbon atoms, preferably 11 to 13 carbon atoms.
    The term "pharmaceutically acceptable salts" means any salt which, by administration to a patient, is capable of delivering (directly or indirectly) a compound as described herein. The preparation of salts can be carried out by methods known in the art.
    By "isomers" is meant molecular units that have the same atomic composition (molecular formula), but different linear formulas or different stereochemical formulas (PAC, 1994, 66, 1077 (Glossary of terms used in physical organic chemistry (IUPAC Recommendations 1994)) 1129
    Typically, the isomers are regioisomers and / or diastereoisomers.
    According to the present invention, the term "diastereoisomer" refers to stereoisomers (isomers that have an identical composition but differ in the arrangement of their atoms in space) that are not enantiomers (molecular units with stereochemical formulas which are mirror images that cannot be stacked on top of each other).
    According to the present invention, the term "regioisomer" or the term "position isomer" refers to isomers of which a functional group is placed on different carbon atoms of the carbon chain. More in particular is meant isomers of monoethers or monoacetals of alkyldesoxyhexose or a derivative of deoxyhexose in which the monoether or monoacetal group is present on various oxygen substances present on the skeleton of deoxyhexose or the derivative of deoxyhexose.
    Typically, for example, 2,3-O-dodecylidene-methyl-α-L-rhamnopyranoside and / or 2-O-dodecyl-methyl-α-L-rhamnopyranoside and / or 3-O-dodecyl-methyl-α-L-rhamnopyranoside can be mentioned.
    Characteristic is the bactericidal or baeteriostatic composition against gram-positive bacteria. The invention also relates to the use of such a composition as a bactericidal or bacteriostatic agent against gram-positive bacteria.
    Advantageously, the bactericidal or bacteriostatic composition or the bactericidal or bacteriostatic agent is included in a food composition, cosmetic composition, pharmaceutical composition, phytosanitary composition, veterinary composition or surface treatment composition. Such as, for example, a cosmetic and / or dermatological composition for cleansing and / or caring for the skin, in particular in the form of a cream, gel, powder, lotion, butter, in particular a shower gel, soap, shampoo, bath foam, deodorant, antiperspirant, wet wipes, sunscreen formulation or decorative cosmetic formulation.
    The invention also relates to a composition characterized in that it comprises an alkyl acetal or an alkyl ether of deoxyhexose or of a derivative of deoxyhexose, wherein the alkyl group comprises 11-18 carbon atoms, a pharmaceutically acceptable salt or an isomer or a mixture of isomers thereof, wherein said deoxyhexose derivative is a glycosylated and / or hydrogenated and / or dehydrated deoxyhexose, for use as a bactericidal or bacteriostatic agent, said alkyl acetal or alkyl ether group preferably being located at position 2-0-, 3-0, 4-0, wherein the isomers are preferably selected from the regioisomers and / or the diastereoisomers.
    The invention furthermore relates to a composition characterized in that it comprises an alkyl acetal or an alkyl ether of deoxyhexose or a derivative of deoxyhexose, wherein the alkyl group comprises 11-18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers of these, wherein said derivative of deoxyhexose is a glycosylated and / or hydrogenated and / or dehydrated deoxyhexose, for its use as a care product or dermatological product for external use.
    Typically, a "care product" refers to any product used for cleaning, disinfecting, or care, including, for example, a lotion, foam, spray, and liquid, but also wipes or any carrier that can be impregnated with the composition of the invention. The term "dermatological product" refers to any product intended for application to the skin or mucous membranes.
    Use in the treatment or prevention of infection with gram-positive bacteria
    The invention furthermore relates to a composition according to the invention for use in the treatment or prevention of bacterial infections by gram-positive bacteria.
    With "treatment" is a healing treatment (with a view to at least reducing, eradicating or stopping the development of the infection) in a patient. By "prevention" is meant prophylactic treatment (with a view to reducing the risk of an outbreak of injection) 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) who has been affected by or is prone to be affected by bacterial infections and especially of gram-positive bacteria. Preferably the individual is a human.
    The term "gram-positive" refers to bacteria that are dark blue or violet stained by the Gram stain, as opposed to gram-negative bacteria, which cannot retain the violet color. The coloring technique is generally known to those skilled in the art and is based on the properties of the membrane and the wall of the bacterium.
    Typically, gram-positive bacteria are bacteria of the genus of Fir-micutes, typically of the Bacilli class particularly selected from the bacteria of the order of the Lactobacillales or the Bacillales.
    In accordance with an embodiment of the invention, the bacteria of the order of the Bacillales are selected from the family of Alicyclobacillaceae, Bacillaceae, Caryophanaceae, Listeriaceae, Paenibacillaceae, Pasteuriaceae, Planococcaceae, Sporolactobacillaceae, Staphylococcaceae, Theraceaaceaeeaeaceaeaceaeaceaeea, Thermoeaaceaceaeea
    Typically, the bacteria of the Listeriaceae family are of the genus of the Brochothrix or Listeria and can typically be selected from L. fleischmannii, L. grayi, L. innocua, L. ivanovii, L. marthii, L. monocytogenes , L. rocourtiae, L. seeligeri, L. weihenstephanensis and L. M'elshimeri.
    When the gram-positive bacteria are bacteria from the family of the Staphylococcaceae, they are typically selected from the bacteria of the genus of the Staphylococcus, Gemella, Jeotgalicoccus, Macrococcus, Salinicoccus and No-socomiicoccus.
    For example, the bacteria of the genus Staphylococcus are selected from S. arlettae, S. agnetis, S. aureus, S. auricularis, S. capitis, S. caprae, S. carosus, 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. petten-koferi , S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulons, S. stepanovicii, S succinus, S. vitulinus, S. warneri and S. xylosus.
    According to another embodiment of the invention, the bacteria of the order of Lactobacillales are selected from a family of Aerococcaceae, Carno-bacteriaceae, Enterococcaceae, Lactobacillaceae, Leuconostocaceae and Streptococ-caceae.
    Typically, the bacteria of the Enterococcaceae family are selected from the bacteria of the genus of Bavariicoccus, Catellicoccus, Enterococcus, Melissococcus, Pilibacter, Tetragenococcus, Vagococcus.
    The bacteria of the genus of Enterococcus are, for example, selected from E. malodoratus, E. avium, E. dur ans, E. faecalis, E. faecium, E. gallininum, 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 numerous infections of the skin or mucous membranes such as the mucosa of the vagina or nose. For example, infections such as folliculitis, abscesses, fetus, boils, beard scab, interdigitalis, anthrax (Staphylococcus anthrax), cellulite, superinfections of wounds, otitis sinusitis, hydride sites, infectious mastitis, post-traumatic skin infections or skin burn infections.
    The bacteria of the genus of Enterococcus and in particular E. faecalis are particularly responsible for endocardites, infections of the bladder, the prostate, or bijbal.
    The invention also relates to a method for treating or preventing a bacterial infection by gram-positive bacteria, preferably an infection of the skin or mucous membranes, by administering, preferably topically, to an individual in need thereof an therapeutically effective amount of the composition of the invention.
    In a person infected with a gram-positive bacterium, a "therapeutically effective amount" means an amount sufficient to prevent the infection from becoming more serious, even sufficient for the regression of the infection. In an uninfected person, the "therapeutically effective amount" is the amount sufficient to protect a person who might come into contact with a gram-positive bacterium and the unexpected occurrence of the infection caused by this gram-positive bacterium, to avoid.
    Typically, topical administration is by applying to the skin or mucous membranes of the composition of the invention.
    Method for disinfecting or preventing the colonization of bacteria on a substrate
    The invention furthermore relates to a method for disinfecting or preventing colonization of bacteria by gram-positive bacteria of a substrate, which comprises contacting the substrate with a composition according to the invention.
    Typically, the substrate is any carrier that can be colonized by gram-positive bacteria and can transmit 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 foods, or an extract of these foods and in particular of grains, fruits, vegetables, meat, fish, entrails.
    The substrate can also consist of one or more elements selected from metals, plastics, glass, concrete, stone.
    The substrate is preferably a tool, a tool or a device that is used in the food industry (kitchen utensils, packaging, cold preservation system, refrigerator, cold rooms ...) in hospitals, such as surgical instruments or prostheses or in public places. transport (holding-rod in public transport, seats ...) is used.
    The invention also relates to a composition for disinfecting, purifying, sterilizing or cleaning surfaces.
    Although they have different meanings, the terms "include", "contain", "contents" and "consist of" in the description of the invention are used interchangeably and may be replaced by each other.
    The invention will be better understood after reading the following figures and examples which are given as examples only.
    Examples
    The acetals of methylglyeopyranoside have been prepared by ate analysis or trans-acetalization of sugars according to the method previously described in patent no. 13/01375 "Process for preparation of acetals cyclics alkyl-to-the-long-term chaos". The alkyl lactals of methyl glycopyranoside are then reduced by using reduction conditions without an acid catalyst previously described in Patent No. 14/01346. For information, the preparation of acetals and lethers of methyl glycopyranoside is described in detail below. EXAMPLE 1: General process for the preparation of alkyl acetals of methyl glycopyranoside (A)
    In an 100 ml flask, methylglycopyranoside (two equivalents) is dissolved in dry THF (10 ml) in the presence of sodium sulfate (1.5 equivalent) under argon atmosphere. The aldehyde (1 equivalent) is added dropwise over a 1 minute period, followed by Amberlyst 15 (20% by weight based on the aldehyde). The reaction mixture is stirred for 3 hours at reflux temperature (65 ° C) with a magnetic stirrer. After returning to ambient temperature, the reaction mixture is filtered, washed with ethyl acetate (2 x 25 ml) and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (AeOEt / cyelohexane) to give the alkyl glycopyranoside alkyl languages.
    Example la:
    4,6-O-dodecylidene-methyl-α-D-glucopyranoside (la): Compound la is prepared from the methyl-α-D-glueopyranoside (3.22 g, 16.6 mmol) and dodeeanol (1.52 g, 8.3 mmol) according to method (A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOHAc / cyclohexane 60:40), whereby la (0.77 g, 26%) was obtained in the form of a white solid. Melting point = 69 ° C; NMR TT (300 MHz, CDCl 3) δΗ: 0.86 (3H, t, J = 7, CH 3), 1.17 - 1.32 (16 H, m, 8 CH 2), 1.33 - 1.47 (2 H, m, CH 2), 1.53 - 1.74 (2 H, m, CH 2), 2.64 (2 H, br s, OH 3 + OH 2), 3.24 (1 H, t, J = 9.0, CH 3) , 3.41 (3H, s, OCH 3), 3.49-3.68 (3H, m, CH 5 + CH 6 + CH 2), 3.84 (1 H, t, J = 9.0, CH 4), 4, 10 (1H, dd, J = 10.0 and 5.0, CH6), 4.52 (1H, t, J = 5.0, CH7), 4.74 (1H, d, J = 4.0, CH1); NMR 13 C (75 MHz, CDCl 3) 5 C: 14.24 (CH3), 22.80 (CH2), 24.20 (CH2), 29.46 (CH2), 29.58 (CH2), 29.62 (CH2) ), 29.67 (CH2), 29.74 (CH2), 29.76 (CH2), 32.03 (CH2), 34.36 (CH2), 55.57 (OCH3), 62.63 (CH5) , 68.57 (CH26), 71.81 (CH4), 73.02 (CH2), 80.46 (CH3), 99.85 (CH1), 102.84 (CH7); IRvax: 3388 (OH), 2921, 2852, 1466, 1378, 1089, 1063, 1037, 991; HRMS (ESI +) calculated for C 19 H 36 Na 6 O: 383.2404 [M + Na] +; measured: 383.2398 (+1.6 ppm); Rf = 0.30 (EtOAc / cyclohexane 60:40).
    Example lb:
    4.6-O-Dodecylidene-methyl-β-D-glucopyranoside (lb): The compound 1b is prepared from methyl-β-D-glucopyranoside (5.00 g, 25.7 mmol) and dodecanal (2.37 g, 12 , 8 mmol) according to the method (A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane, from 30:70 to 50:50), whereby lb (1.30 g, 28%) was obtained in the form of a white solid. Melting point = 84 ° C; NMR II (300 MHz, CDCl 3) δΗ: 0.87 (3H, t, 6.7, CH3), 1.25 (16H, apparent br s, 8 CH2), 1.34 - 1.45 (2H, m, CH2) , 1.53 - 1.73 (2H, m, CH2), 3.25 - 3.34 (2H, m, CH2 + CH5), 3.44 (1H, dd, J = 9.0, 7.0 (CH3), 3.56 (4H, s, CH26 + OCH3), 3.73 (1H, m, CH4), 4.18 (1H, dd, J = 10.4, 4.4, CH26), 4 28 (1H, d, J = 7.7, CH 1), 4.54 (1 H, t, J = 5.1, CH 7); NMR 13 C (75 MHz, CDCl 3) 8 C: 14.13 (CH3), 22.70 (CH2), 24.14 (CH2), 29.35 (CH2), 29.45 (CH2), 29.50 (CH2) ), 29.56 (CH2), 29.63 (CH2), 29.65 (CH2), 31.92 (CH2), 34.23 (CH2), 55.51 (OCH3), 66.21 (CH5) , 68.21 (CH26), 73.19 (CH4), 74.61 (CH2), 80.00 (CH3), 102.83 (CH7), 104.07 (CH1); IR ν max: 3650 (OH), 2950, 2824, 2867, 2159, 2028, 1112; HRMS (ESf) calcd for C 11 H 17 N 6 O 4: 383.2404 [M + Na] +; measured: 383.2395 (+2.3 ppm). Rf = 0.30 (EtOAc / cyclohexane 40:60).
    Example 1c
    4.6-O-dodecylidene-methyl-α-D-mannopyranoside (1c): The compound 1c is prepared from the methyl-α-D-mannopyranoside (4.00 g, 20.5 mmol) and dodecanol (3.45 g, 18.7 mmol) ) according to the method (A). After the reaction, the reaction mixture is concentrated under reduced pressure and dissolved in CH 2 Cl 2. The organic phase is washed with water (3 x 100 ml), with a saturated NaCl solution (2 x 100 ml), dried (Na 2 SO 4) and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane, from 20:80 to 50:50) to give 1c (0.73 g, 11%) as a white solid. Melting point = 104 ° C; NMR 1 H (300 MHz, CDCl 3) δΗ: 0.88 (3H, t, J = 6.9, CH 3), 1.17 - 1.32 (16 H, m, 8 CH 2), 1.37 - 1.42 (2 H, m, CH 2), 1.58 - 1.68 (2 H, m, CH 2), 3.37 (3 H, s, OCH 3), 3.53 - 3.72 (3 H, m, CH 3 + CH 5 + CH 6), 3.98 (1H, dd, J = 9.0, 3.7, CH2), 4.13 (1H, dd, J = 3.6, 1.4, CH4), 4.58 (1H, dd, J = 8.8, 2.9, CH6), 4.10 (1H, t, ./ = 5.1, CH7), 4.73 (1H, d, ./ = 1.3, CH1); RMN 13 C (75 MHz, CDCl 3) 5 C: 14.13 (CH3), 22.69 (CH2), 24.10 (CH2), 29.35 (CH2), 29.46 (CH2), 29.51 (CH2) ), 29.56 (CH2), 29.63 (CH2), 29.65 (CH2), 31.92 (CH2), 34.40 (CH2), 55.05 (OCH3), 63.00 (CH5) , 68.38 (CH26), 68.81 (CH2), 70.82 (CH4), 78.23 (CH3), 101.15 (CH1), 103.06 (CH7); IR ν max: 3380 (OH), 2924, 2852, 1466, 1156, 1029, 682; HRMS (ESI1) calculated for C 10 H 14 NaO 6: 383.2404 [M + Na] +; measured: 383.2396 (+2.2 ppm). Rf = 0.2 (cyelohexane / EtOAe, 70:30).
    Example ld:
    4,6-O-Dodecylidene-methyl-α-D-galactopyranoside (Id): The compound Id is prepared from the methyl-α-D-galactopyranoside (5.00 g, 25.7 mmol) and dodecanol (2.37 g, 12, 9 mmol) according to the method (A). After the reaction, the reaction mixture was concentrated under reduced yielding 1d (2.30 g, 45%) in the form of a white solid without purification by chromatography. Melting point = 115 ° C; NMR 1 U (300 MHz, CDCl 3) δΗ: 0.89 (3H, t, J = 6.7, CH 3), 1.15-1.50 (18 H, m, 9 CH 2), 1.61 - 1.71 (2H, m, CH 2), 3.45 (3 H, s, OCH 3), 3.61 (1 H, apparent, s, CH 5), 3.77-3.94 (3 H, m, CH 4 + CH 2 CH 6), 4 , 04 (1H, d, J = 2.5, H3), 4.14 (1H, dd, J = 12.5, 1.4, CH6), 4.59 (1H, t, J = 5.2 , CH7), 4.91 (1H, d, J = 3.2, CH1); NMR 13 C (75 MHz, CDCl 3) δ: 14.06 (CH3), 22.50 (CH2), 23.49 (CH2), 29.27 (CH2), 29.34 (CH2), 29.41 (CH2) ), 29.48 (CH2), 29.55 (CH2), 29.61 (CH2), 31.97 (CH2), 34.47 (CH2), 55.66 (0CH3), 62.45 (CH5) , 68.92 (CH26), 69.82 (CH2), 69.92 (CH4), 75.42 (CH3), 100.1 (CH7), 102.1 (CH1); IR max: 3414, 3328 (OH), 2916, 2850, 2160, 1121, 1032; HRMS (ESI +) calculated for C 18 H 17 NaO 6 383.2404 [M + Na] +; measured: 383.2389 (+4.0 ppm). Rf = 0.6 (EtOAc / cyclohexane, 60:40).
    Example le:
    2,3-O-dodecylidene-methyl-al-rhamnopyranoside (le): The compound le is prepared from the methyl-al-rhamnopyranoside (1.00 g, 5.60 mmol) and dodecanal (0.94 g, 5, 10 mmol) according to the method (A). After the reaction, the reaction mixture is concentrated under reduced pressure and dissolved in CH 2 Cl 2. The organic phase is washed with water (3 x 100 ml), with a saturated NaCl solution (2 x 100 ml), dried (Na 2 SO 4) and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / cyclohexane, from 0: 100 followed by 10:90 to 100: 0). An inseparable 53:47 mixture of two diastereomers of Ie (0.85 g, 49%) has been obtained in the form of a beige solid. Melting point = 46 ° C; NMR: H (300 MHz, CDCl3) δπ for the mixture of diastereoisomers: 0.88 (6H, t, J = 6.7, 2xCH3), 1.25 - 1.32 (42H, m, 18 (CH2) ) + 2 x CH 3), 1.57 - 1.63 (2 H, m, CH 2), 1.67-1.74 (2 H, m, CH 2), 3.34 - 3.42 (2 H, m, 2 x CH 4) ), 3.38 (3H, s, OCH3), 3.39 (3H, s, OCH3), 3.65 - 3.67 (2H, m, 2 x CH5), 3.93 - 4.00 (2H , m, CH 2 + CH 3), 4.00 - 4.08 (1 H, m, CH 2), 4.18 (1 H, dd, J = 7.4, 5.4, CH 3), 4.85 (1 H, s (CH1), 4.88 (1H, s, CH1), 4.98 (1H, t, J = 5.0, CH6), 5.24 (1H, t, J = 4.8, CH6); NMR 13 C (75 MHz, CDCl 3) Sc for the mixture of diastereoisomers: 14.13 (2 x CH 3), 17.41 (CH 3), 17.56 (CH 3), 22.70 (2 CH 2), 23, 77 (CH2), 24.23 (CH2), 29.35 (2 CH2), 29.49 (CH2), 29.50 (CH2), 29.53 (2 CH2), 29.56 (2 CH2), 29.62 (2 CH2), 29.65 (2 CH2), 31.92 (2 CH2), 34.90 (CH2), 35.41 (CH2), 54.96 (2 OCH3), 65.24 ( CH5), 65.87 (CH5), 71.57 (CH4), 74.94 (CH4), 75.17 (CH3), 77.37 (CH2), 77.40 (CH2), 78.99 (CH3) ), 97.96 (CH1), 98.28 (CH1), 104.2 (CH6), 104.3 (CH6); IRvax: 3650, 3238 (OH), 2921, 2852, 2159, 2029, 1136, 1029; HRMS (ESI +) calculated for C 19 H 36 Na 5 O 367.2455 [M + Na] +; measured: 367.2452 (+ 0.9 ppm). Rf = 0.5 (EtOAc / cyclohexane, 50:50). EXAMPLE 2: General method for preparing the mixture of regioisomers of alkyl ethers of methyl glycopyranoside (B).
    In a 100 ml stainless steel autoclave, the alkyl acetal of methyl glycopyranoside (3 mmol) is dissolved in eyelopentyl methyl ether (CPME, 30 ml) and 5% Pd / C (0.45 g, 5 mol% palladium) is then added. The reactor is hermetically sealed, hydrogen sprayed three times, and hydrogen is added at a pressure of 30 bar. The reaction mixture is stirred mechanically and heated at 120 ° C for 15 hours. After cooling to ambient temperature, the hydrogen pressure is released and the reaction mixture is diluted with absolute ethanol (100 ml) and filtered (Millipore Durapore 0.01 µm filter). The alkylate is concentrated under reduced pressure to give the mixture of regioisomers of alkyl ethers of methyl glycopyranoside.
    Example 2a:
    6-O-Dodecyl-methyl-α-D-glucopyranoside (2a) and 4-O-dodecyl-methyl-α-D-glucopyranoside (2a '): Compounds 2a and 2a' are prepared from 4,6-O-dodecylidene-methyl- α-D-glucopyranoside la (5.00 g, 14 mmol) according to the general method (B). A 73:27 mixture of 2a and 2a '(2.52 g, 51%) in the form of a white solid was obtained. To facilitate labeling of the compounds, the regioisomers of the mixture can be chromatographically separated over a silica gel column (EtOAc / cyclohexane, from 50:50 to 100: 1 followed by EtOH / EtOAc 10: 9). 2a: Solid white matter. NMR 11 T (300 MHz, CDCl 3) δΗ: 0.87 (3H, t./ = 7, CH 3 alkyl), 1.09 - 1.44 (18 H, m, 9 (CH 2) alkyl), 1.47 - 1.70 (2H, m, CH 2 alkyl), 3.41 (3 H, s, OCH 3), 3.43 - 3.84 (7 H, m), 4.21 (3 H, br s, OH), 4, 74 (1H, d, J = 4, CH anomer); RMN 13 C (75 MHz, CDCl 3) δ0: 14.25 (CH3), 22.82 (CH2), 26.17 (CH2), 29.50 (CH2), 29.67 (CH2), 29.73 (CH2) ), 29.77 (CH2), 29.80 (2CH2), 29.83 (CH2), 32.06 (CH2), 55.35 (OCH3), 70.33 (CH), 70.51 (CH2) , 71.23 (CH), 72.10 (CH), 72.30 (CH2), 74.49 (CH), 99.57 (CH); IR max: 3402 (OH), 2918, 2851, 1467, 1370, 1057, 1015, 902; HRMS (ESI +) calculated for C 19 H 38 Na 6 O: 385.2561 [M + Na] +; measured: 385.2558 (+0.6 ppm); Rf = 0.16 (EtOAc / EtOH 10: 1), 2a ': white solid, NMR11 (300 MHz, CDCl3) δΗ: 0.87 (3H, t, J = 7, CH3 alkyl), 1, 14 - 1.42 (18 H, m, 9 (CH 2) alkyl), 1.47 - 1.71 (2 H, m, CH 2 alkyl), 2.16 (3 H, br s, OH), 3.24 (1 H , t, J = 10); 3.41 (3H, s, OCH 3), 3.49 (1H, dd, J = 10 and 4), 3.54 - 3.66 (2H, m), 3.69 - 3.91 (4H, m ), 4.74 (1H, d, J = 4, CH anomer); RMN 13 C (75 MHz, CDCl 3) δ <+ 14.26 (CH3), 22.83 (CH2), 26.20 (CH2), 29.49 (CH2), 29.64 (CH2), 29.74 ( 2CH2), 29.77 (CH2), 29.80 (CH2), 30.47 (CH2), 32.06 (CH2), 55.46 (OCH3), 62.15 (CH2), 70.99 (CH ), 72.81 (CH), 73.28 (CH2), 75.05 (CH), 77.94 (CH), 99.20 (CH); IR ν max: 3295 (OH), 2913, 2848, 1739, 1469, 1370, 1114, 1067, 1042, 993; HRMS (ESI +) calculated for C 18 H 18 NaO 6: 385.2561 [M + Na] +; measured: 385.2574 (-3.5 ppm); Rf = 0.24 (EtOAc / EtOH 10: 1).
    Example 2b:
    6-D-dodecyl-methyl-α-D-mannopyranoside (2b) and 4-O-dodecyl-methyl-α-D-mannopyranoside (2b '): Compounds 2b and 2b' are prepared from 4,6-O-dodecylidene-methyl- aD-mannopyranoside 1c (0.70 g, 1.94 mmol) according to the general method (B). After the reaction, the residue is purified by chromatography on a silica gel column (EtOAc / cyclohexane, 40:60). An inseparable 75:25 mixture of 2b and 2b '(0.24 g, 34%) has been obtained in the form of a colorless oil. NMR1H (300 MHz, CDCl3) δκ for the major regioisomer 2b: 0.88 (3H, t, J = 6.7, CH3), 1.20 - 1.35 (18H, m, 9 CH2), 1 , 55 - 1.61 (2H, m, CH 2), 3.35 (3H, s, OCH 3), 3.44 - 3.57 (2H, m, OCH 2), 3.60 - 3.98 (6H, m, CH 2 + CH 3 + CH 4 + CH 5 + CH 26), 4.73 (1 H, d, J = 1.5, CH 1); RMN 13 C (75 MHz, CDCl 3) δ (for the major regioisomer 2b: 14.06 (CH 3), 22.63 (CH 2), 25.95 (CH 2), 29.30 (CH 2), 29.42 ( CH2), 29.44 (CH2), 29.54 (CH2), 29.57 (CH2), 29.58 (CH2), 29.61 (CH2), 31.86 (CH2), 54.96 (OCH3) ), 69.50 (CH5), 69.65 (CH4), 70.37 (CH2), 71.12 (CH26), 71.67 (CH3), 72.14 (OCH2), 100.7 (CH1) IR ν max: 3650, 3238 (OH), 2921, 2852, 2159, 2029, 1976, 1156; HRMS (ESI +) calculated for 0.19388Νη06: 385.2561 [M + Na] +; measured: 385.2555 (+1, 5 ppm); Rf = 0.22 (cyclohexane / EtOAc, 60:40).
    Example 2c:
    6-O-dodecyl-methyl-α-D-galactopyranoside (2c) and 4-O-dodecyl-methyl-α-D-galactopyranoside (2c '): Compounds 2c and 2c' are prepared from 4,6-O-dodecylidene methyl α-D-galactopyranoside Id (0.69 g, 1.09 mmol) according to the general method (B). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane, 50:50). An inseparable 90:10 mixture of 2c and 2c '(0.19 g, 27%) was obtained in the form of a white solid.
    Melting point = 110 ° C. NMR 1H (300 MHz, CDCl3) δΗ for the major regioisomer 2c: 0.87 (3H, t, J = 6.6, CH3), 1.24 (18H, br s, 9 CH2), 1.55 - 1.60 (2H, m, CH 2), 3.41 (3 H, s, OCH 3), 3.48 (2 H, t, J = 6.7, OCH 2), 3.67-3.90 (5 H, m, 3 CH + CH 2), 4.04 - 4.05 (1 H, m, CH), 4.83 (1 H, d, J = 3.5, CH 1); RMN 13 C (75 MHz, CD-C 13) δ C for the major regioisomer 2c ': 14.24 (CH3), 22.81 (CH2), 26.17 (CH2), 29.47 (CH2), 29, 59 (CH2), 29.61 (CH2), 29.70 (CH2), 29.74 (CH2), 29.76 (2 CH2), 29.78 (CH2), 32.44 (CH2), 55, 59 (OCH3), 69.68 (CH), 70.47 (CH), 71.11 (CH), 71.34 (CH), 72.30 (CH2), 99.84 (CH1); IR ν max: 3651, 3250 (OH), 2917, 2849, 2493, 2430, 2159, 2029, 1976, 1042; HRMS (ESI +) calculated for C 19 H 38 NaO 6: 385.2561 [M + Na] +; measured: 385.2548 (+3.2 ppm); Rf = 0.30 (cyclohexane / EtOAc, 40:60).
    Example 2d:
    2-O-dodecyl-methyl-al-rhamnopyranoside (2d) and 3-O-dodecyl-methyl-al-rhamnopyranoside (2d '): Compounds 2d and 2d' are prepared from 2,3-O-dodecylidene-methyl- aL-rhamnopyranoside 1e (0.70 g, 2.03 mmol) according to the general method (B). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane, 40:60). An inseparable 93: 7 mixture of 2d and 2d "(0.19 g, 27%) was obtained in the form of a colorless oil. NMR 1 H (300 MHz, CDCl 3) δΗ for the major regioisomer 2d: 0.87 (3H, t, J = 6.7, CH 3), 1.18 - 1.35 (21 H, m, 9 (CH 2) + CH3), 1.53 - 1.59 (2H, m, CH2), 2.35 (2H, br s, OH), 3.31 - 3.47 (5H, m, CH3 + CH6 + OCH3), 3.52 (1H, dd, J = 3.9, 1.3, CH2), 3.54-3.62 (1H, m, CH5), 3.62-3.71 (2H, m, CH6 + CH4), 4.71 (1H, apparent s, CH1); RMN 13 C (75 MHz, CDCl 3) δC for the major regioisomer 2d ': 14.11 (CH3), 17.54 (CH3), 22.68 (CH2), 25.99 (CH2), 29.34 ( CH2), 29.41 (CH2), 29.56 (CH2), 29.59 (CH2), 29.62 (CH2), 29.65 (CH2), 29.80 (CH2), 31.91 (CH2) ), 54.75 (OCH3), 67.38 (CH5), 71.24 (CH2), 71.51 (CH4), 74.07 (CH3), 78.53 (CH2), 97.83 (CH1) ; IR ν max: 3650, 3238 (OH), 2921, 2852, 2519, 2029, 2029, 1976, 1070; HRMS (ESI +) calculated for C 10 H 5 NaO 3: 369.2611 [M + Na] +; measured: 369.2605 (+1.8 ppm); Rf = 0.51 (cyclohexane / EtOAc, 60:40). EXAMPLE 3: Measuring the bacteriostatic properties of acetal and ether derivatives of monosaccharides with C12 on the gram-positive bacteria
    The best results have been observed with compounds having an alkyl group with 12 carbon atoms, tests have been carried out on a very large panel of gram-positive strains with the compounds obtained according to examples 1 and 2. 3.1 Materials and methods 3.1.1 The investigated compounds of interest:
    Acetals of methyl glucopyranoside • 4,6-O-Dodecylidene-methyl-α-D-glucopyranoside (1 a) • 4,6-O-Dodecylidene-methyl-β-D-glucopyranoside (lb)
    Mixture of ethers of methyl glycopyranoside • 6-O-dodecyl-methyl-a-D-glueopyranoside (2a) and 4-O-dodecyl-methyl-aD-glueopyranoside (2a ') • 6-O-dodecyl-methyl-aD-mannopyranoside (2b) ) and 4-O-dodecylmethyl-α-D-mannopyranoside (2b ') • 6-O-dodecyl-methyl-αD-galaetopyranoside (2e) and 4-O-dodecylmethyl-α-D-galactopyranoside (2c') • 2 -O-dodecyl-methyl-al-rhamnopyranoside (2d) and 3-O-dodecyl-methyl-al-rhamnopyranoside (2d ')
    Mixture of ethers of sorbitan • 3-O-dodecyl-1, 4-D-sorbitan, 5-O-dodecyl-1, 4-D-sorbitan and 6-O-dodecyl-1,4-D-sorbitan 3.1.2 The gram-positive bacteria studied
    The strains examined are reference strains and antibiotic multi-resistant cultures, clinical strains isolated at the Lyon hospital and are the following: • - Staphylococd S. aureus: ATCC® 29213 ™, ATCC 25923, • Strains of Staphylococcus S. aureus, which are resistant to methicillin (Lac-Deleo USA 300), (MU 3), (HT 2004-0012), LY 199-0053, (HT 2002-0417), (HT 2006-1004) , • Strains of Staphylococcus S. aureus, which are resistant to dap-tomycin (ST 2015-0188) (ST 2014 1288), (ST 2015-0989). • - Enterococci: E. faecalis (ATCC® 29212 ™), clinical strains of Enterococci E. faecalis, isolated from urine: strain 015206179901 (hereinafter referred to as 9901), strain 015205261801 (hereinafter referred to as 1801) • - Enterococci: E. faecium (CIP 103510), clinical strains of terococcus E. faecium: Van A 0151850763 (hereinafter referred to as Van A); the strain 015 205731401 (hereinafter referred to as 1401), - Listeria: L. monocytogenes (CIP 103575), clinical strain isolated from a blood culture (015189074801, LM1), strain isolated from cerobrospinal fluid (015170199001, LM2), clinical strain isolated from a blood culture (015181840701, LM3). 3.1.3 Preparation of inoculum:
    The cultures studied, which are freshly isolated (after 18 μm incubation on a blood agar at 30 ° C), were taken up in sterile water (10 ml) until a suspension of 0.5 Mac Farlang (Mc) was obtained, i.e. 1 -2 x 10 UFC (bacteria) / cm. The bacterial suspension was then diluted to give a final concentration of 1 x 10 6 CFU / cm 3. 3.1.4 Preparation of multi-storey plates for reading the MIC:
    Each floor contains an identical amount of the Mueller-Fiinton medium (rich medium that ensures the cultivation of bacteria) and bacteria in a final concentration of 0.5x10 CFU / cm.
    The compounds of interest to be investigated are dissolved in ethanol or DM-SO in an amount of 25 mg / ml by diluting two out of two to different concentrations. A first series is provided on the multi-storey plate, which comprises the culture medium without the compound of interest to be examined. It corresponds to the growth check (control floors). These controls serve as a reference for comparing the bacterial growth with those of the following floors, which include different concentrations of the compound of interest to be tested. The second series of floors comprises the parent solution of the test compound of interest for a concentration in the floor of 256 mg / l (7 mM). Each series of floors is diluted two to two to the last series to a final concentration of 0.25 mg / l (0.0007 mM). Each concentration is duplicated in the same plate. The plate is incubated for 18 hours at 37 ° C. Reading after incubation shows a cloudiness in the control levels (indication of bacterial growth). With antibacterial activity, bacterial growth is inhibited, which translates into the absence of the appearance of cloudiness or a saliva sediment.
    The minimum growth inhibitory concentration (MIC) has been achieved with the gram-positive bacterial strains according to the recommendations of "Clinical Laboratory Standards Institute (Clinical-Laboratory-Standards-Institute, 6th edition Approved standard M100-S17. CLSI, Wayne, PA, 2007). 3.1 .5 Preparation of the inoculum:
    The cultures studied that are freshly isolated (after 18 hours of culturing on a blood agar at 37 ° C) are taken up in sterile water (10 ml) to a suspension of 0.5 Mac Farland (Mc), ie 10 CFU (bacterium) ) / cm is obtained. The bacterial suspension is then diluted to obtain a final concentration of 10 6 CFU / cm. 3.2 Results 3.2.1 Results for the strains of the genus Staphylococcus
    According to the observation of the 96-storey microtiter plates, all acetal or ether derivatives of monosaccharides are active against the strains of Staphylococci (8 <MIC <64 mg / l) examined except the ether of galactose (C12-Eth-u-MeGalac) and the α acetal of glucose (C12-Ac-u-MeGlu) (MIC> 256 mg / l).
    During the analysis of the results (Table 6), it is noted that all of these derivatives most certainly comprise a carbon chain of 12 carbon atoms. Or only a portion of the two are effective against the Staphylococci strains investigated (8 <MIC <64 mg / l). Moreover, when the molecules 1a and 1b are compared, it is noted that while these molecules only distinguish themselves by their anomer, only one of them has an effective antibacterial effect.
    Table 6. Antimicrobial results of ether and acetal derivatives of methylglycopyranoside as well as the sorbitan on different strains of Staphylo coccus S. Aureus: Minimum Inhibitory Concentration (MIC) in mg / l.
    Similarly, when the molecules 1a and 2a + 2a 'are compared, which are distinguished by the ether or acetal bond, only one of these molecules has an effective antibacterial effect. In short, the nature of the sugar is also capable of altering the antibacterial effect of the molecule. Thus, it is noted that the C12-Eth-a-MeGlu, C12-Eth-a-MeRham and C12-Eth-a-MeMan have an antibacterial action similar to C12-Eth-a-MeGalac. These information clearly indicate that the bacterial action of a molecule depends on both the nature of the sugar, the configuration of the anomeric carbon atom and the nature of the bond with the carbon chain.
    Results for the strains of the genus of Enterococcus
    Table 7. Antimicrobial results of ether ether and sugars and the actals of sugars and sorbitan on different Enterococci strains. Minimum Inhibitory Concentration (MIC) in mg / l.
    A good antibacterial effect is observed for all Enterococci strains 32 <MIC <8 mg / l for all the molecules investigated except C12-Ac-a-MeGlu and C12-Eth-a-MeGalac.
    Results for the strains of the genus of Listeria
    Table 8. The antimicrobial results of the ether derivatives of sugar and the actals of sugars and sorbitan on different strains of Listeria. Minimum Inhibitory Concentration (MIC) in mg / l.
    In addition to the compounds C12-Ac-a-MeGlu and C12-Eth-a-MeGalac, it is noted that good antibacterial activity is observed on all strains of Listeria 64 <MIC <8 mg / l for all the molecules investigated.
    权利要求:
    Claims (16)
    [1]
    CONCLUSIONS
    A composition, characterized in that it comprises an alkyl acetal or an alkyl ether of deoxyhexose, wherein the alkyl group comprises 11-18 carbon atoms, a pharmaceutically acceptable salt, an isomer or a mixture of isomers thereof, the isomers being selected from the region isomers and / or the diastereoisomers, wherein said alkyl acetal or alkyl ether group is preferably in positions 2-0, 3-0 and / or 4-0.
    [2]
    Composition according to claim 1, characterized in that the deoxyhexose is glycosylated and / or hydrogenated and / or dehydrated, preferably the deoxyhexose is rhamnose or fiacose.
    [3]
    Composition according to one of claims 1 and 2, characterized in that the alkyl group comprises 11-13 carbon atoms.
    [4]
    Composition according to any one of claims 2-3, characterized in that it is glycosylated and / or hydrogenated and / or dehydrated deoxyhexose, a rhamnopyranoside, preferably a methyl rhamnopyranoside.
    [5]
    Composition according to any one of claims 1-4, characterized in that the alkylacetal or the alkyl ether of deoxyhexose is a mono-alkyl ether or mono-alkylacetal of deoxyhexose, wherein said mono-alkylacetal group is preferably in position 2.3 -0- or 3,4-O- or wherein said mono-alkyl ether group is in position 2-0, 3-0 or 4-0-.
    [6]
    A composition according to any one of claims 1-5 for use as a bactericidal or bacteriostatic agent against gram-positive bacteria.
    [7]
    Composition according to claim 6, characterized in that the gram-positive bacteria are bacteria of the Firmicutes, typically of the Bacilli class, in particular selected from the bacteria of the order of the Lactobacillales or Ba-cillales.
    [8]
    Composition according to one of claims 6 and 7, characterized in that the gram-positive bacteria are bacteria of the order of the Bacillales selected from the family of Alicyclobacillaceae, Bacillaceae, Caryophana-ceae, Listeriaceae, Paenibacillaceae, Pasteuriaceae, Planococcaceaeae , Sporo-lactobacillaceae, Staphylococcaceae, Thermoactinomycetacea and Turicibac-teraceae and / or the gram-positive bacteria are bacteria of the order of Lac-iobacillales, selected from the family of Aerococcaceae, Carno-bacteriaceae, Enterococcaceaea, Lacobacaceaea, Lacobacaceaea, Lacobacaceae, Lacobacaceae
    [9]
    A composition according to claim 8, characterized in that the gram-positive bacteria are bacteria from the Listeriaceae family, such as a bacterium of the genus Brochothrix or Listeria, which is typically selected from L. fleischmannii, L. grayi, L. innocua, L. ivanovii, L. marthii, L. monocytogenes, L. rocourtiae, L. seeligeri, L. weihenstephanensis and L. welshimeri and / or the gram-positive bacteria are bacteria of the Staphylococcaeae family selected from the bacteria of the genus of Staphylococcus, Gerneia, Jeotgalicoccus, Macrococcus, Salinicoccus and Nosocomiicoccus.
    [10]
    Composition according to claim 9, 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. gal-linarum, 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. pseudinter-medius, 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.
    [11]
    A composition according to claim 8, characterized in that the gram-positive bacteria are bacteria from the Enterococcaceae family selected from the bacteria of the genus of Bavariicoccus, Catellicoccus, Terterococcus, Melissococcus, Pilibacter, Tetragenococcus, Vagococcus.
    [12]
    A composition 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. durons, E. faecalis, E. faecium, E. gal- linarum, E. hirae, E. solitarius, preferably E. avium, E. durons, E. faecalis and E. faecium.
    [13]
    Composition according to any one of claims 1-5, characterized in that it is included in a food composition, cosmetic composition, pharmaceutical composition, phytosanitary composition, veterinary composition or a composition for treating a surface.
    [14]
    Composition according to any one of claims 1-5 for its use as a care product or dermatological product for external use and / or for its use in the treatment or prevention of bacterial infections by gram-positive bacteria.
    [15]
    The composition according to claim 14, wherein the infection by gram-positive bacteria is an infection of the skin or mucous membranes, preferably an infection selected from folliculitis, an abscess, fever, boil, currant beard, interdigitalis, anthrax, cellulitis, superinfection of wounds, otitis sinusitis, hydradenitis, infectious mastitis, post-traumatic skin infection and burn skin infection.
    [16]
    A method for disinfecting or preventing bacterial colonization by gram-positive bacteria on a substrate, which comprises contacting the substrate with a composition according to any of claims 1-5.
    类似技术:
    公开号 | 公开日 | 专利标题
    KR101140194B1|2012-05-02|Antibacterial agent and external preparation for skin containing the same
    BE1023858B1|2017-08-22|ANTIBACTERIAL COMPOSITION CONTAINING A MONO-ETHER OR MONO-ACETAL OF ALKYLESOXYHEXOSE
    JP5363697B2|2013-12-11|Biofilm inhibitor / removal agent
    CA2526538C|2011-04-05|Aqueous compositions for disinfection and/or sterilization
    EP1854354B1|2012-10-24|Agent for enhancing antiseptic power
    BE1023165A1|2016-12-07|Antibacterial composition comprising an acetal or a long chain alkyl hexane ether
    BE1023165B1|2016-12-07|Antibacterial composition comprising an acetal or a long chain alkyl hexane ether
    BE1023234B1|2017-01-05|Antibacterial composition comprising an isomeric mixture of mono-ethers or mono-alkyl acetals of monosaccharides
    JP2009183210A|2009-08-20|Ricinoleic acid monoester of glycerol and method for producing ricinoleic acid monoester of glycerol
    US10653664B2|2020-05-19|Antibacterial compositions of mono-alkyl ethers of monoanhydro-hexitols and antibacterial methods using of the same
    KR20170038214A|2017-04-07|Antimicrobial composition comprising sugar aicds and flavonoid
    同族专利:
    公开号 | 公开日
    BE1023858A1|2017-08-21|
    CN108495656A|2018-09-04|
    JP6755314B2|2020-09-16|
    EP3389731B1|2020-07-29|
    KR20180091914A|2018-08-16|
    FR3045382B1|2020-02-07|
    US20200281956A1|2020-09-10|
    FR3045382A1|2017-06-23|
    CA3008791A1|2017-06-22|
    WO2017103904A1|2017-06-22|
    BR112018012076A2|2018-11-27|
    EP3389731A1|2018-10-24|
    CN108495656B|2021-02-02|
    JP2019501158A|2019-01-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA2242411A1|1996-01-12|1997-07-17|The Procter & Gamble Company|Disinfecting compositions and processes for disinfecting surfaces|
    US20050271711A1|2004-04-26|2005-12-08|The Procter & Gamble Company|Therapeutic antimicrobial compositions and methods|
    EP2879492B1|2012-08-06|2018-10-03|Isp Investments Inc.|Eco-friendly non-aqueous antimicrobial composition comprising hinokitiol with 1,3-propanediol or sorbitan caprylate|
    FR3007031B1|2013-06-14|2015-07-24|Syral Belgium Nv|PROCESS FOR THE PREPARATION OF ALKYL LONG CHAINS CYCLIC ACETALS BASED ON SUGAR|
    FR3022246B1|2014-06-13|2018-03-02|Centre National De La Recherche Scientifique|MONOANHYDRO-HEXITOL MONO-ALKYL ETHERS COMPOSITIONS, METHODS OF PREPARATION AND USE THEREOF|WO2021095741A1|2019-11-11|2021-05-20|国立大学法人九州大学|Novel sugar derivative useful in freezing of cells|
    法律状态:
    2017-11-30| FG| Patent granted|Effective date: 20170822 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1502629|2015-12-17|
    FR1502629A|FR3045382B1|2015-12-17|2015-12-17|ANTIBACTERIAL COMPOSITION CONTAINING A MONOETHER OR A MONOACETAL OF DEOXYHEXOSE ALKYL|
    [返回顶部]