Antibacterial composition comprising an isomeric mixture of mono-ethers or mono-alkyl acetals of mon

专利摘要:
The present invention relates to a bactericidal or bacteriostatic composition comprising a mixture of isomers of monoethers or of mono-alkyl acetals of monosaccharides, its use in the treatment or prevention of infections with gram-positive bacteria, use as a hygiene or dermatological product for external use. as well as a method for surface disinfection.
公开号:BE1023234B1
申请号:E2015/5828
申请日:2015-12-17
公开日:2017-01-05
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；Université Claude Bernard De Lyon 1；Centre National De La Recherche Scientifique；
IPC主号:

专利说明:

Antibacterial composition comprising an isomeric mixture of mono-ethers or mono-alkyl acetals of monosaccharides
Technical area
The present invention relates to a bactericidal or bacteriostatic composition comprising a mixture of positional isomers of mono-ethers or mono-alkyl acetals of monosaccharides, its use in the treatment or prevention of infections with Gram-positive bacteria, its use as a hygiene or dermatological product in external use and a method for disinfecting 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 agri-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 (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 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 a mixture of positional isomers of monoethers or monoalkyl acetals of monosaccharide obtained in less severe conditions and being respecting the environment and not representing danger for topical application or recording.
Detailed description of the invention
Bacterial or bacteriostatic composition
The invention relates to a bactericidal or bacteriostatic composition comprising a mixture of positional isomers of mono-ethers or mono-alkyl acetals of monosaccharide or of monosaccharide derivative, said monosaccharide derivative being a glycosylated and / or hydrogenated and / or dehydrated monosaccharide, said mixture of positional isomers of mono-ethers or mono-alkyl acetals of monosaccharides or of monosaccharide derivatives are obtained by a process comprising the following steps: a) an acetalization or transacetalization of a monosaccharide or a monosaccharide derivative with an aliphatic aldehyde containing 11 to 18 carbon atoms or the acetal thereof b) optionally, catalytic hydrogenolysis of the alkyl acetal of monosaccharide or monosaccharide derivative obtained under a) preferably, without acid catalyst, and c) recovering a mixture of positional isomers of mono-alkyl ethers of monosaccharide or of monosaccharid e derivative obtained in b) wherein the alkyl group (R) comprises between 11 to 18 carbon atoms or recovering a mixture of positional isomers of mono-alkyl acetals of monosaccharide or of monosaccharide derivative obtained in a) wherein the alkyl group (R) is between 11 to 18 carbon atoms.
The invention preferably relates to a bactericidal or bacteriostatic composition comprising a mixture of positional isomers of mono-ethers or of mono-alkyl acetals of monosaccharide or of monosaccharide derivative, said monosaccharide derivative being a glycosylated and / or hydrogenated and / or dehydrated monosaccharide, said mixture of positional isomers of mono-ethers or mono-alkyl acetals of monosaccharide or of monosaccharide derivative is obtained by a method comprising the following steps: a) optionally, a dehydration of a monosaccharide or a monosaccharide derivative to obtain a monoanhydrosaccharide; b) an acetalization or transacetalization of the monosaccharide or monoanhydrosaccharide or monosaccharide derivative obtained in step a) with, i. an aliphatic aldehyde containing 11 to 18 carbon atoms, by acetalization, or ii. an acetal of an aliphatic aldehyde containing 11 to 18 carbon atoms, by transacetalization; c) optionally, a catalytic hydrogenolysis of the alkyl acetal of monosaccharide or monosaccharide derivative obtained in b) preferably, without acid catalyst, and d) recovering a mixture of monosaccharide or monosaccharide derivative monosaccharide derivative isomeric monomers wherein the alkyl group (R) comprises between 11 to 18 carbon atoms or recovering a mixture of positional isomers of mono-alkyl acetals of monosaccharide or of monosaccharide derivative obtained in b) wherein the alkyl group (R) comprises between 11 to 18 carbon atoms.
As used herein, the term "monosaccharide" refers to polyhydroxy aldehyde (aldose) or polyhydroxy ketone (ketose)
Preferably, said monosaccharide moiety comprises 6 carbon atoms, also known as "hexose". The term "hexose" refers to aldohexoses, ketohexoses, their derivatives and analogues.
Preferably said hexose is selected from the group consisting of glucose, mannose, galactose, allose, altrose, gulose, idose and talose.
In one embodiment, the monosaccharide derivative is an anhydrosaccharide or a sugar alcohol.
An "anhydrosaccharide" is to be understood as a monosaccharide obtained by dehydration, by removal of one or more water molecules from a mono-, di-, tri- or oligosaccharide corresponding or derived from a mono-, di-, tri- or oligosaccharide such as a hydrogenated mono-, di-, tri- or oligosaccharide. A suitable example of an anhydrosaccharide may be a monoanhydrosaccharide such as a hexane selected from the group consisting of 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.
The preferred hexane is obtained by dehydrating sorbitol to form, for example, 1,4-sorbitane, 3,6-sorbitane or 2,5-sorbitane.
In one embodiment, said monosaccharide derivative is a sugar alcohol. 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. Said sugar alcohol may, for example, be selected from the group consisting of erythritol, threitol, arabitol, ribitol, mannitol, sorbitol, galactitol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol and polyglycitol. Preferably, the sugar alcohol is a hexitol selected from, for example, mannitol, sorbitol, galactitol and volemitol, more preferably sorbitol, xylitol or mannitol.
According to an embodiment, the method according to the invention may comprise a step of dehydrating said monosaccharide so as to obtain, for example, a monoanhydrosaccharide, if the monosaccharide derivative is a sugar alcohol. Typically, the monosaccharide is melted before 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 monosaccharide derivative is purified after the dehydration step, for example by crystallization, recrystallization or chromatography.
According to an embodiment, the said monosaccharide derivative is a glycosylated monosaccharide, in other words an alkyl glycoside.
As used herein, the. term "alkyl glycoside" to a monosaccharide wherein the reducing moiety is linked by a bond to an alkyl group by glycosylation, as described in the prior art. Typically, the monosaccharide can be linked to the 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 varying chain length, preferably, the alkyl group is a C 1 -C 4 alkyl group. An even more preferred alkyl group is a methyl or an ethyl. Typically the alkyl glycoside is a hexoside. Alkyl glycosides may, for example, be selected from a group consisting of methyl glucoside, ethyl glucoside, propyl glucoside, butyl glucoside, methylxyloside, ethylxyloside, propylxyloside; butylxyloside, methylmannoside, ethylmannoside, propylmannoside, butylmannoside, methylgalactoside, ethylgalactoside, propylgalactoside and butylgalactoside.
According to the invention, the acetalization step or the transacetalization step comprises: i) optionally a pre-heating step of the monosaccharide or of the mixture of monosaccharides, preferably at a temperature between 70 and 130 ° C, typically between 90 and 110 ° C, ii) a step of adding the aliphatic aldehyde or aliphatic aldehyde derivative thus monosaccharide and iii) a step of adding a catalyst, preferably an acid catalyst.
Typically, the acetal of an aliphatic aldehyde can be a dialkyl acetal of the corresponding aldehyde. Dimethylacetals and diethyl acetals are preferred.
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 the acetal thereof, typically a linear or branched aliphatic aldehyde or the acetal thereof. The acetalization or transacetalization step can typically be carried out with an aliphatic aldehyde or its acetal of 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, for example selected from undecanal, dodecanal, tridecanal, tetradecanal, pentadecanal, hexadecanal, heptadecanal, octodecanal. 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 mole 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.
According to an embodiment, the method according to the invention additionally comprises 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.
The invention also relates to a bactericidal or bacteriostatic composition comprising a mixture of positional isomers of mono-ethers or of mono-alkyl acetals of monosaccharide or of monosaccharide derivative with an alkyl ether or alkylacetal radical at 2 different positions of the monosaccharide or monosaccharide derivative and pharmaceutically acceptable salts thereof, wherein the alkyl group comprises between 11 and 18 carbon atoms, preferably from 11 to 13 carbon atoms.
The term "pharmaceutically acceptable salts" refers to any salt that is 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.
Preferably, the monosaccharide is a C6 monosaccharide or their derivative, said monosaccharide derivative being a glycosylated and / or hydrogenated and / or a dehydrated monosaccharide such as an alkyl glycoside, preferably, the monosaccharide or monosaccharide derivative is: - a hexose selected from the group consisting of glucose, mannose, galactose, allose, altrose, gulose, idose and talose, - a hexitol selected from mannitol, sorbitol, galactitol and volemitol, - a hexane 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 or
Usually the alkyl glycoside is a hexoside selected from glucoside, mannoside, galactoside, alloside, altroside, iodoside and taloside
By "positional isomer" is meant isomer isomers, more particularly is isomers of mono-ethers or of mono-alkyl acetals of monosaccharide or of monosaccharide derivative in which the mono-ether or mono-alkylacetal is radically positioned on different acids of the monosaccharide or of the monosaccharide derivative.
Typically, if the monosaccharide is a hexoside, said monoalkylacetal is radical at position 1.2-0; 2,3-0-; 3,4-0- or 4,6-0- of the hexoside or if the monosaccharide derivative is a hexitol, said monoalkylacetal is radical at position 1,2-0-; 2,3-0-; 3,4-0-; 4,5-0- or 5,6-0- of the hexitol or also if the monosaccharide derivative is a hexane, said monoalkylacetal is radical at position 2,3-0-; 3.5-0 or 5.6-0 of the hexane.
Preferably, if the monosaccharide is a hexoside, said monoalkyl ether is radical at position 2-0, 3-0, 4-0, or 6-0 of the hexoside or if the monosaccharide derivative is a hexitol, said mono alkyl ether radical at positions 1-0, 0-2, 3-0, 4-0, 5-0 or 6-0 of the hexitol, or even if the monosaccharide derivative is a hexane, said mono alkyl ether radical at position 2-0, 3-0, 5-O- or 6-0 of the hexane.
According to an alternative, the monosaccharide derivative is a sorbitan and said monoalkylacetal is radical at position 3.5-0 or 5.6-0 or said monoalkyl ether is radical at position 3-0, 5- 0 or 6-0.
In an alternative, the monosaccharide derivative is a glycoside and said monoalkylacetal is radical at position 4.6-0- or said mono-alkyl ether is radical at position 4-0- or 6-0-.
Preferably, the mixture of positional isomers of mono-alkyl ethers of monosaccharide or of monosaccharide derivative comprises at least one compound selected from 4,6-O-pentylidene-D-glucopyranoside of methyl; 4,6-O-hexylidene α-D-glucopyranoside from methyl; 4,6-O-octylidene α-D-glucopyranoside from methyl, 4,6-O-decylidene α-D-glucopyranoside from methyl; 4,6-O-dodecylidene a-D-glucopyranoside from methyl; 4,6-O-dodecylidene β-D-glucopyranoside of methyl; 4,6-O-dodecylidene α-D-mannopyranoside of methyl; 4,6-O-dodecylidene a-D-galactopyranoside of methyl and their mixture.
According to one embodiment, the mixture of mono-alkyl acetal positional monomers of monosaccharide or monosaccharide derivative comprises at least 6-O-pentyl-α-D-glucopyranoside of methyl and 4-O-pentyl-α-D-glucopyranoside of methyl; 6-O-hexyl-D-glucopyranoside of methyl and 4-O-hexyl-D-glucopyranoside of methyl; 6-O-octyl α-D-glucopyranoside from methyl and 4-O-octyl α-D-glucopyranoside from methyl; 6-0-decyl α-D-glucopyranoside from methyl and 4-0-decyl α-D-glucopyranoside from methyl, 6-0-dodecyl α-D-glucopyranoside from methyl and 4-0-dodecyl α-D-glucopyranoside from methyl; 6-O-dodecyl α-D-mannopyranoside of methyl and 4-O-dodecyl α-D-mannopyranoside of methyl; 6-O-dodecyl α-o-galactopyranoside of methyl and 4-O-dodecyl α-D-galactopyranoside of methyl or their mixtures.
Typically, the composition is bactericidal or bacteriostatic to Gram-positive bacteria.
Advantageously, the bactericidal or bacteriostatic composition is included in a food, cosmetics, drug, 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 according to the invention for use in the treatment or 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 coloring 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, Thermoactinomycetaœa and Turicibacteraceae
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.
The bacteria of the genus of Staphylococcus selected for example from S. arlettae, S. agnetis, S. aureus, S. auricularis, S. capitis, S. caprae, S. camosus, 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. pulveren, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleifen, S. sciuri, S. simiae, S. simulans, 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, 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 bijbal.
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 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 alkylacetals of sugar (sorbitan and methyl glycopyranoside) were prepared by acetalizing or transacetalizing sugars according to the previously described procedure in patent 13/01375 "Process for preparing cyclic long-chain alkylacetals, based on sugars." sugar alkyl acetals are then reduced using reduction conditions without an acid catalyst as previously described in patent 14/01346. The method used is identical in the case of alkyl acetals of sorbitan and alkyl acetals of methyl glycopyranoside. The synthesis of acetals and ethers is described below for information purposes. EXAMPLE 1: General procedure for the preparation of alkyl acetals of methyl glycopyranoside (A)
In a 100 ml flask under argon atmosphere, the methyl glycopyranoside (2 equivalent) was dissolved in dry THF (10 ml) in the presence of sodium sulfate (1.5 equivalent). The aldehyde (1 equivalent) was added dropwise over a period of one minute, followed by Amberlyst 15 (20% by weight relative to the aldehyde). The reaction mixture was magnetically stirred at reflux (65 ° C) for 3 hours. 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 was purified by silica gel column chromatography (EtOAc / cyclohexane) to give the alkyl acetals of methyl glycopyranoside.
Example 1a:
4.6-O-Pentylidene α-D-glucopyranoside from methyl (1a): The compound 1a was prepared from methyl α-D-glucopyranoside (7.49 g, 38.5 mmol) and pentanal (1.64 g, 19 mmol) according to the method ( A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane 80: 20) to give 1a (2.14 g, 43%) as a white solid. Melting point = 78 ° C; RMN 1H (300 MHz, CDCl 3) δΗ: 0.88 (3H, t, J = 7, CH 3 alkyl), 1.21-1.44 (4 H, m, 2 (CH 2) alkyl), 1.52-1, 72 (2H, m, CH 2 alkyl), 2.80 (1 H, d, J = 9, OH 3), 3.23 (1 H, t, J = 9, H 3), 3.31 (1 H, d, J = 2, OH 2), 3.40 (3 H, s, OCH 3), 3.48 (1 H, t, J = 10, H 2), 3.52-3.67 (2 H, m, Hs + H 6), 3, 83 (1H, td, J = 9 and 2, H4), 4.09 (1H, dd, J = 10 and 4, H6), 4.52 (1H, t, J = 5, H7), 4.73 (1H, d, J = 4, H1); RMN 13 C (75 MHz, CDCl 3) 5 C: 14.05 (CH3), 22.62 (CH2), 26.30 (CH2), 34.03 (CH2), 55.54 (OCH3), 62.62 (CH5) 68.57 (CH26), 71.70 (CH4), 72.98 (CH2), 80.47 (CH3), 99.87 (CH1), 102.81 (CH7). IR ν max: 3399 (OH), 2956, 2862, 1428, 1390, 1062, 1041, 989; HRMS (ESI +) calculated for C 12 H 22 NaO 6: 285.1309 [M + Na] +, measured: 285.1315 (-2.2 ppm); Rf = 0.27 (EtOAc / cyclohexane 80:20).
Example 1b:
4.6-O-Hexylidene α-D-glucopyranoside from methyl (1b): The compound 1b was prepared from methyl α-D-glucopyranoside (3.22 g, 16.6 mmol) and hexanal (0.83 g, 8.3 mmol) according to the method (A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane 80: 20) to give 1b (0.98 g, 43%) as a white solid. Melting point = 84 ° C; RMN 1H (300 MHz, CDCl 3) δΗ: 0.86 (3H, t, J = 7, CH 3 alkyl), 1.05-1.30 (4 H, m, 2 (CH 2) alkyl), 1.31-1.46 (2H, m, CH 2 alkyl), 1.52-1.74 (2 H, m, CH 2 alkyl), 3.02 (1 H, br s, OH 3), 3.23 (1 H, t, J = 9, H 3 ), 3.40 (3H, s, OCH 3), 3.47 (1H, t, J = 10, H 2), 3.52-3.66 (2H, m, H5 + H6), 3.83 (1H , t, J = 9, H4), 4.09 (1H, dd, J = 10 and 5, H4.52 (1H, t, J = 5, H7), 4.72 (1H, d, J = 4 H1) RMN 13 C (75 MHz, CDCl 3) 5 C: 14.10 (CH 6), 3), 22.62 (CH 2), 23.86 (CH 2), 31.74 (CH 2), 34.28 (CH 2) ), 55.51 (OCH3), 62.62 (CH5), 68.56 (CH26), 71.61 (CH4), 72.95 (CH2), 80.49 (CH3), 99.90 (CH1) , 102.81 (CH7); IR ν max: 3433 (OH), 2925 (-CH 3), 2860 (-CH 2 -), 1465, 1379, 1061, 983; HRMS (ESI +) calculated for C 13 H 24 Na 6 O: 299.1465 [M + Na] +; measured: 299,1464 (+0.4 ppm); Rf = 0.27 (80:20 EtOAc / cyclohexane).
Example 1c:
4.6-O-Octylidene α-D-glucopyranoside from methyl (1c): The compound 1c was prepared from methyl α-D-glucopyranoside (3.22 g, 16.6 mmol) and octanal (1.06 g, 8.3 mmol) according to the method (A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane 50:50) to give 1c (0.94 g, 37%) as a white solid. Melting point = 80 ° C; RMN 1H (300 MHz, CDCl 3) δΗ: 0.85 (3H, t, J = 7, CH 3 alkyl), 1.07-1.31 (8 H, m, 4 (CH 2) alkyl), 1.32-1 47 (2H, m, CH 2 alkyl), 1.50-1.73 (2 H, m, CH 2 alkyl), 3.02 (2 H, brs, OH 2 + OH 3), 3.23 (1 H, t, J = 9, H3), 3.40 (3H, s, OCH3), 3.48 (1H, t, J = 10, H2), 3.52-3.67 (2H, m, H5), 3.83 ( 1H, t, J = 9, H4), 4.09 (1H, dd, J = 10 and 5, H6), 4.52 (1H, t, J = 5, H7), 4.72 (1H, d , J = 4, H1); RMN 13 C (75 MHz, CDCl 3) 5c: 14.18 (CH3), 22.73 (CH2), 24.18 (CH2), 29.26 (CH2), 29.51 (CH2), 31.85 (CH2) ), 34.33 (CH2), 55.53 (OCH3), 62.62 (CH5), 68.56 (CH26), 71.68 (CH4), 72.97 (CH2), 80.48 (CH3) , 99.88 (CH1), 102.82 (CH7); IR ν max: 3368 (OH), 2924, 2857, 1465, 1378, 1128, 1090, 1064, 1037, 993; HRMS (ESI +) calculated for C 15 H 28 Na 6 O: 327.1778 [M + Na] +; measured: 327.1780 (-0.6 ppm); Rf = 0.21 (50:50 EtOAc / cyclohexane).
Example 1d:
4.6-O-Decylidene α-D-glucopyranoside from methyl (1d): The compound 1d was prepared from methyl α-D-glucopyranoside (20 g, 102 mmol) and decanal (7.97 g, 51 mmol) according to the method (A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane 80: 20) to obtain 1d (7.48 g, 44%) in the form of a white solid. Melting point = 72 ° C; RMN1H (300 MHz, CDCl3) δΗ: 0.87 (3H, t, J = 7, CH3 alkyl), 1.16-1.32 (12H, m, 6 (CH2) alkyl), 1.33-1, 45 (2H, m, CH 2 alkyl), 1.55-1.72 (2 H, m, CH 2 alkyl), 2.61 (2 H, br s, OH 3 + OH 2), 3.24 (1 H, t, J = 9, H3), 3.42 (3H, s, OCH3), 3.49 (1H, t, J = 10, H2), 3.53-3.68 (2H, m, H5), 3.84 ( 1H, t, J = 9, H4), 4.11 (1H, dd, J = 10 and 5, H6), 4.53 (1H, t, J = 5, H7), 4.74 (1H, d , J = 4, H1); RMN 13 C (75 MHz, CDCl 3) δ: 14.03 (CH3), 22.59 (CH2), 24.08 (CH2), 29.25 (CH2), 29.46 (CH2), 29.49 (2CH2) ), 31.82 (CH2), 34.19 (CH2), 55.20 (OCH3), 62.54 (CH5), 68.43 (CH26), 70.90 (CH4), 72.65 (CH2) , 80.53 (CH3), 100.02 (CH1), 102.64 (CH7); IR ν max: 3393 (OH), 2922, 2853, 1466, 1378, 1112, 1088, 1063, 1037, 990; HRMS (ESI +) calculated for C 17 H 32 Na 6: 355.2091 [M + Na] +; measured: 355.2102 (-3.2 ppm); Rf = 0.32 (80:20 EtOAc / cyclohexane).
Example 1st:
4.6-O-Dodecylidene α-D-glucopyranoside from methyl (1e): The compound 1e was prepared from methyl α-D-glucopyranoside (3.22 g, 16.6 mmol) and dodecanal (1.52 g, 8.3 mmol) according to the method (A). After the reaction, the residue was purified by chromatography on a silica gel column (EtOAc / cyclohexane 60:40) to obtain 1d (0.77 g, 26%) as a white solid. Melting point = 69 ° C; RMN 1H (300 MHz, CDCl3) δΗ: 0.86 (3H, t, J = 7, CH3), 1.17-1.32 (16H, m, 8CH2), 1.33-1.47 (2H, 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); RMN 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); IR ν max: 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 1f:
4.6-O-Dodecylidene β-D-glucopyranoside from methyl (1f): The compound 1f was 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 silica gel column chromatography (EtOAc / cyclohexane, 30:70 to 50:50) to give 1f (1.30 g, 28%) as a white solid. Melting point = 84 ° C; RMN 1H (300 MHz, CDCl3) δΗ: 0.87 (3H, t, J = 6.7, CH3), 1.25 (16H, app brs, 8 CH2), 1.34-1.45 (2H, m, CH a), 1.53-1.73 (2 H, m, CH 2), 3.25-3.34 (2 H, m, CH 2 + CH 5), 3.44 (1 H, 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, CH1), 4.54 (1H, t, ^ = 5.1, CH7); RMN 13 C (75 MHz, CDCl 3) δ: 14.13 (CH 3), 22.70 (CH 3), 24.14 (CH 2), 29.35 (CH 2), 29.45 (CH 2), 29.50 (CH 2) ), 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 (ESI +) calculated for C 19 H 36 Na 6 O: 383.2404 [M + Na] +; measured: 383.2395 (+2.3 ppm). Rf = 0.30 (EtOAc / cyclohexane 40:60)
Example 1Q:
4,6-O-Dodecylidene α-mannopyranoside of methyl (1 g): The compound 1 g was prepared from methyl α-D-mannopyranoside (4.00 g, 20.5 mmol) and dodecanal (3.45 g, 18.7 mmol) according to the method (A). After 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 was purified by silica gel column chromatography (EtOAc / cyclohexane, 20:80 to 50:50) to give 1 g (0.73 g, 11%) as a white solid. Melting point = 104 ° C; RMN 1 H (300 MHz, CDCl 3) δ H: 0.88 (3 H, t, J = 6.9, CH 3), 1.17-1.32 (16 H, m, 8 CH 3), 1.37-1.42 (2H, m, CH2), 1.58-1.68 (2H, m, CH2), 3.37 (3H, s, OCH3), 3.53-3.72 (3H, m, CH3 + CH5 + CH6), 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, J = 5.1, CH7), 4.73 (1H, d, J = 1.3, CH1); RMN 13 C (75 MHz, CDCl 3) 5c: 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 (ESI *) calculated for C 19 H 36 Na 6 O: 383.2404 [M + Na] +; measured: 383.2396 (+2.2 ppm). Rf = 0.2 (cyclohexane / EtOAc, 70:30).
Example 1h:
4,6-O-dodecylidene α-D-galactopyranoside of methyl <1 h): The compound 1 h was prepared from methyl α-D-galactopyranoside (5.00 g, 25.7 mmol) and dodecanal (2.37 g, 12, 9 mmol) according to the method (A). After reaction, the reaction mixture is concentrated under reduced pressure to give 1 h (2.30 g, 45%) as a white solid without chromatographic purification. Melting point = 115 ° C; RMN 1H (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, app. 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); RMN 13 C (75 MHz, CDCl 3) 5 C: 14.06 (CH 3), 22.50 (CH 2), 23.49 (CH 2), 29.27 (CH 2), 29.34 (CH 2), 29.41 (CH 2) ), 29.48 (CH2), 29.55 (CH2), 29.61 (CH2), 31.97 (CH2), 34.47 (CH2), 55.66 (OCH3), 62.45 (CH5) , 68.92 (CH26), 69.82 (CH2), 69.92 (CH4), 75.42 (CH3), 100.1 (CH7), 102.1 (CH1); IR ν max: 3414, 3328 (OH), 2916, 2850, 2160, 1121, 1032; HRMS (ESI +) calculated for C 19 H 36 Na 6 O 383.2404 [M + Na] +; measured: 383.2389 (+4.0 ppm). Rf = 0.6 (EtOAc / cyclohexane, 60:40). EXAMPLE 2: Procedure General procedure for the preparation of 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 cyclopentyl methyl ether (CPME, 30 ml) and 5% -Pd / C (0.45 g, 5 mol% palladium) is added. The reactor was hermetically sealed, flushed three times with hydrogen and the hydrogen was introduced at a pressure of 30 bar. The reaction mixture was stirred mechanically and heated to 120 ° C for 15 hours. After cooling to room temperature, the hydrogen pressure is released and the reaction mixture is diluted with absolute ethanol (100 ml) and filtered (Millipore Durapore filter 0.01 µm). The filtrate was concentrated under reduced pressure to give the mixture of alkyl isylethers of methyl glycopyranoside.
Example 2a:
6-O-Pentyl α-D-glucopyranoside from methyl (2a) and 4-O-pentyl ao-glucopyranoside from methyl (2a '): Compounds 2a and 2a' were prepared from 4,6-O-pentylidene methyl α- D-glucopyranoside 1a (4.00 g, 15 mmol) according to the general procedure (B). A 70:30 mixture of 2a and 2a "(1.51 g, 38%) is obtained in the form of a white paste. To facilitate the characterization of the compounds, the regioisomers can be separated from the mixture by chromatography on a silica gel column (EtOA / cyclohexane, from 50:50 to 100: 0 then EtOH / EtOAc 10:90). 2a: Colorless oil. RMN 1H (300 MHz, CDCl 3) δΗ: 0.84 (3H, t, J = 7, CH 3 alkyl), 1.14-1.36 (4 H, m, 2 (CH 2) alkyl), 1.41-1 68 (2H, m, CH 2 alkyl), 3.34 (3 H, s, OCH 3), 3.40-3.82 (7 H, m), 4.53-4.81 (4 H, m, CH anomeric + 30H); RMN 13 C (75 MHz, CDCl 3) 5c: 14.06 (CH 3), 22.53 (CH 2), 28.20 (CH 2), 29.29 (CH 2), 55.12 (OCH 3), 70.20 (CH 2) ), 70.57 (CH), 70.74 (CH), 71.91 (CH), 72.05 (CH2), 74.26 (CH), 99.56 (CH); IR ν max: 3382 (OH), 2929, 2861, 1455, 1363, 1192, 1144, 1108, 1040, 900; HRMS (ESI +) calculated for C 12 H 24 Na 6 O: 287.1465 [M + Na] +; measured: 287,1467 (-0.8 ppm); Rf = 0.35 (EtOAc / EtOH 10: 1). 2a ’: Colorless oil. RMN 1H (300 MHz, CDCl 3) δΗ: 0.86 (3H, t, J = 7, CH 3 alkyl), 1.16-1.38 (4 H, m, 2 (CH 2) alkyl), 1.42-1 66 (2H, m, CH 2 alkyl), 3.16 (3 H, br s, OH), 3.21 (1 H, t, J = 10), 3.37 (3 H, s, OCH 3), 3.42 -3.87 (7H, m), 4.71 (1H, d, J = 3, CH anomeric); RMN 13 C (75 MHz, CDCl 3) δ: 14.11 (CH3), 22.61 (CH2), 28.26 (CH2), 30.05 (CH2), 55.32 (OCH3), 61.92 (CH2) ), 71.00 (CH), 72.61 (CH), 73.14 (CH2), 74.52 (CH), 77.86 (CH), 99.35 (CH); IR ν max: 3388 (OH), 2928, 2852, 1452, 1371, 1092, 1083, 1037, 931; HRMS (ESI +) calculated for C 12 H 24 Na 6 O: 287.1465 [M + Na] +; measured: 287.1465 (+0.2 ppm); Rf = 0.40 (EtOAc / EtOH 10: 1).
Example 2b:
6-O-Hexyl α-D-glucopyranoside from methyl (2b) and 4-O-hexyl od-glucopyranoside from methyl (2b '): Compounds 2b and 2b' are prepared from 4,6-O-hexylidene methyl α- D-glucopyranoside 1b (5.50 g, 20 mmol) according to the general procedure (B). A 72:28 mixture of 2b and 2b "(2.18 g, 37%) was obtained in the form of a colorless oil. To facilitate the characterization of the compounds, the regioisomers can be separated from the mixture by chromatography on a silica gel column (EtOAc / cyclohexane, from 50:50 to 100: 0 then EtOH / EtOAc 10:90). 2b: Colorless oil. RMN 1H (300 MHz, CDCl 3) δΗ: 0.84 (3H, t, J = 7, CH 3 alkyl), 1.13-1.38 (6 H, m, 3 (CH 2) alkyl), 1.44-1 , 64 (2H, m, CH 2 alkyl), 3.38 (3 H, s, OCH 3), 3.39-3.78 (8 H, m), 4.53 (3 H, br s, OH), 4.71 (1H, d, J = 4, CH anomeric); RMN 13 C (75 MHz, CDCl 3) 5 C: 14.10 (CH 3), 22.66 (CH 2), 25.75 (CH 2), 29.60 (CH 2), 31.75 (CH 2), 55.18 (OCH 3) ), 70.24 (CH2), 70.55 (CH), 70.79 (CH), 71.94 (CH), 72.13 (CH2), 74.28 (CH), 99.56 (CH) ; IR ν max: 3376 (OH), 2928, 2859, 1455, 1364, 1192, 1144, 1006, 1043, 900; HRMS (ESI +) calculated for C 13 H 26 Na 6 O: 301.1622 [M + Na] +; measured: 301.1612 (+3.3 ppm); Rf = 0.32 (EtOAc / EtOH 10: 1). 2b "; Colorless oil. RMN 1 H (300 MHz, CDCl 3) δΗ: 0.87 (3H, t, J = 7, CH 3 alkyl), 1.17-1.40 (6 H, m, 3 (CH 2) alkyl), 1.46-1, 66 (2H, m, CH 2 alkyl), 2.43-2.78 (3 H, br s, OH), 3.23 (1 H, t, J = 10), 3.39 (3 H, s, OCH 3) , 3.48 (1H, dd, J = 10 and 4), 3.53-3.64 (2H, m), 3.64-3.91 (4H, m), 4.73 (1H, d, J = 4, CH anomeric); RMN 13 C (75 MHz, CDCl 3) 5 C: 14.16 (CH3), 22.72 (CH2), 25.83 (CH2), 30.38 (CH2), 31.80 (CH2), 55.41 (OCH3) ), 62.05 (CH2), 71.00 (CH), 72.72 (CH), 73.24 (CH2), 74.80 (CH), 77.91 (CH), 99.27 (CH) ; IR ν max: 3395 (OH), 2927, 2852, 1456, 1365, 1192, 1114, 1027, 896; HRMS (ESI +) calculated for C 13 H 26 Na 6 O: 301.1622 [M + Na] +; measured: 301.1610 (+4.0 ppm); Rf = 0.38 (EtOAc / EtOH 10: 1).
Example 2c:
6-O-Octyl α-D-glucopyranoside from methyl (2c) and 4-O-octyl α-D-glucopyranoside from methyl (2c '):
Compounds 2c and 2c 'were prepared from 4,6-O-octylidene methyl α-D-glucopyranoside 1c (5.00 g, 16.4 mmol) according to the general procedure (B). A 75:25 mixture of 2c and 2c "(2.30 g, 40%) was obtained in the form of a colorless oil. To facilitate the characterization of the compounds, the regioisomers can be separated from the mixture by chromatography on a silica gel column (EtOAc / cyclohexane, from 50:50 to 100: 0 then EtOH / EtOAc 10:90). 2c: Colorless oil. RMN 1H (300 MHz, CDCl 3) δΗ: 0.86 (3H, t, J = 7, CH 3 alkyl), 1.15-1.38 (10 H, m, 5 (CH 2) alkyl), 1.48-1 68 (2H, m, CH 2 alkyl), 3.40 (3 H, s, OCH 3), 3.42-3.92 (8 H, m), 4.22 (3 H, br s, OH), 4.73 (1H, d, J = 4, CH anomeric); RMN 13 C (75 MHz, CDCl 3) δ0: 14.22 (CH3), 22.78 (CH2), 26.15 (CH2), 29.39 (CH2), 29.59 (CH2), 29.72 (CH2) ), 31.96 (CH2), 55.30 (OCH3), 70.44 (CH2), 71.12 (CH), 72.08 (CH), 72.24 (CH), 74.44 (CH2) , 77.36 (CH), 99.60 (CH); IR ν max: 3371 (OH), 2923, 2854, 1456, 1365, 1192, 1144, 1108, 1044, 900; HRMS (EST) calculated for C 15 H 30 Na 6 O ·. 329.1935 [M + Na] +; measured: 329.1943 (-2.5 ppm); Rf = 0.26 (EtOAc / EtOH 10: 1). 2c ’: White solid. RMN 1H (300 MHz, CDCl 3) δΗ: 0.86 (3H, t, J = 7, CH 3 alkyl), 1.09-1.39 (10 H, m, 5 (CH 2) alkyl), 1.43-1 66 (2H, m, CH 2 alkyl), 2.58 (3H, brs, OH), 3.23 (1H, t, J = 10); 3.39 (3H, s, OCH 3), 3.48 (1H, dd, J = 10 and 4), 3.53-3.64 (2H, m), 3.66-3.89 (4H, m ), 4.73 (1H, d, J = 4, CH anomeric); RMN 13 C (75 MHz, CDCl 3) 5 C: 14.20 (CH 3), 22.76 (CH 2), 26.18 (CH 2), 29.37 (CH 2), 29.58 (CH 2), 30.44 (CH 2) ), 31.93 (CH2), 55.41 (OCH3), 62.08 (CH2), 71.01 (CH), 72.75 (CH), 73.25 (CH2), 74.84 (CH) , 77.94 (CH), 99.28 (CH); IR ν max: 3388 (OH), 2922, 2853, 1456, 1365, 1192, 1144, 1110, 1045, 899; HRMS (ESI +) calculated for C 15 H 30 NaO 6: 329.1935 [M + Na] +; measured: 329.1935 (-0.2 ppm); Rf = 0.38 (EtOAc / EtOH 10: 1).
Example 2d:
6-O-Decyl α-D-glucopyranoside from methyl (2d) and 4-O-decyl α-D-glucopyranoside from methyl (2d '):
Compounds 2d and 2d 'were prepared from 4,6-O-decylidene methyl α-D-glucopyranoside 1d (6.00 g, 18 mmol) according to the general procedure (B). A 77:23 mixture of 2d and 2d "(1.52 g, 25%) was obtained in the form of a white paste. To facilitate the characterization of the compounds, the regioisomers can be separated from the mixture by chromatography on a silica gel column (EtOAc / cyclohexane, from 50:50 to 100: 0 then EtOH / EtOAc 10:90). 2d: Colorless oil. RMN 1H (300 MHz, CDCl 3) δΗ: 0.86 (3H, t, J = 7, CH 3 alkyl), 1.11-1.38 (14 H, m, 7 (CH 2) alkyl), 1.47-1 66 (2H, m, CH 2 alkyl), 3.40 (3 H, s, OCH 3), 3.42-3.89 (8 H, m), 4.32 (3 H, br s, OH), 4.73 (1H, d, J = 4, CH anomeric); RMN 13 C (75 MHz, CDCl 3) δ: 14.22 (CH3), 22.79 (CH2), 26.15 (CH2), 29.45 (CH2), 29.65 (CH2), 29.72 (2CH2) ), 29.74 (CH2), 32.02 (CH2), 55.27 (OCH3), 70.41 (CH2), 70.48 (CH), 71.02 (CH), 72.04 (CH) , 72.23 (CH 2), 74.40 (CH), 99.60 (CH); IR ν max: 3400 (OH), 2919, 2852, 1467, 1369, 1123, 1043, 1014, 901; HRMS (ESI +) calculated for C 17 H 34 Na 6 O 6: 357.2248 [M + Na] +; measured: 357.2247 (+0.1 ppm); Rf = 0.30 (EtOAc / EtOH 10: 1). 4d: White solid. RMN 1H (300 MHz, CDCl 3) δΗ: 0.88 (3H, t, J = 7, CH 3 alkyl), 1.10-1.39 (14 H, m, 7 (CH 2) alkyl), 1.47-1, 68 (2H, m, CH 2 alkyl), 2.13 (4 H, brs, OH + H), 3.25 (1 H, t, J = 10), 3.41 (3 H, s, OCH 3), 3.48 (1H, dd, J = 10 and 4), 3.54-3.68 (2H, m), 3.69-3.94 (3H, m), 4.75 (1H, d, J = 4, CH anomeric); RMN 13 C (75 MHz, CDCl 3) δ0: 14.25 (CH3), 22.82 (CH2), 26.21 (CH2), 29.45 (CH2), 29.63 (CH2), 29.70 (CH2) ), 29.73 (CH2), 30.47 (CH2), 32.02 (CH2), 55.47 (OCH3), 62.18 (CH2), 70.99 (CH), 72.82 (CH) , 73.28 (CH 2), 75.08 (CH), 77.95 (CH), 99.19 (CH); IR ν max: 3370 (OH), 2923, 2853, 1466, 1370, 1317, 1192, 1112, 1070, 1050, 899; HRMS (ESI +) calculated for C 17 H 34 Na 6 O 6: 357.2248 [M + Na] +; measured: 357.2252 (-1.2 ppm); Rf = 0.38 (EtOAc / EtOH 10: 1).
Example 2e:
6-O-Dodecyl α-D-glucopyranoside from methyl (2e) and 4-O-dodecyl α-D-glucopyranoside from methyl (2e '): The compounds 2e and 2e' were prepared from 4,6-O-dodecylidene methyl aD-glucopyranoside 1e (5.00 g, 14 mmol) according to the general procedure (B). A 73:27 mixture of 2nd and 2nd "(2.52 g, 51%) was obtained in the form of a white solid. To facilitate characterization of the compounds, regioisomers can be separated from the mixture by chromatography on a silica gel column (EtOAc / cyclohexane, from 50:50 to 100: 0 then EtOH / EtOAc 10:90). 2nd: White solid. RMN 1H (300 MHz, CDCl 3) δΗ: 0.87 (3H, t, J = 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 anomeric); RMN 13 C (75 MHz, CDCl 3) 5 C: 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 ν 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). 2e ": white solid. RMN 1H (300 MHz, CDCl 3) δΗ: 0.87 (3H, t, J = 7, CH 3 alkyl), 1.14-1.42 (18 H, m, 9 (CH 2) alkyl), 1.47-1 71 (2H, m, CH 2 alkyl), 2.16 (3 H, brs, OH), 3.24 (1 H, t, J = 10), 3.41 (3 H, 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 anomeric); RMN 13 C (75 MHz, CDCl 3) 5 C: 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 19 H 38 Na 6 O: 385.2561 [M + Na] +; measured: 385.2574 (-3.5 ppm); Rf = 0.24 (EtOAc / EtOH 10: 1).
Example 2f:
6-O-Dodecyl α-D-mannopyranoside of methyl (2f) and 4-O-dodecyl α-D-mannopyranoside of methyl (2f): Compounds 2f and 2f 'were prepared from 4,6-O-dodecylidene methyl α-D -mannopyranoside 1 g (0.70 g, 1.94 mmol) according to the general procedure (B). After the reaction, the residue was purified by chromatography on a silica gel column (EtOA / cyclohexane, 40:60). An inseparable 75:25 mixture of 2f and 2f (0.24 g, 34%) was obtained in the form of a colorless oil. RMN 1H (300 MHz, CDCl3) δh for the majority of region isomer 2f: 0.88 (3H, t, J = 6.7, CH3), 1.20-1.35 (18H, m, 9 CH2), 1.55-1.61 (2H, m, CH2), 3.35 (3H, s, OCH3), 3.44-3.57 (2H, m, OCH2), 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) - for the majority of region isomer 2f: 14.06 (CH 3), 22.63 (CH 2), 25.95 (CH 2), 29.30 (CH 2), 29.42 (CH 2) ), 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 C 19 H 38 Na 6 O: 385.2561 [M + Na] +; measured: 385.2555 (+1.5 ppm); Rf = 0.22 (cyclohexane / EtOAc, 60:40).
Example 2q:
6-O-Dodecyl α-α-galactopyranoside from methyl (2g) and 4-O-dodecyl α-galactopyranoside from methyl (2g '): Compounds 2g and 2g' were prepared from 4,6-O-dodecylidene methyl aD- galactopyranoside 1h (0.69 g, 1.90 mmol) according to the general procedure (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 2 g and 2 g "(0.19 g, 27%) was obtained in the form of a white solid. Melting point = 110 ° C; RMN 1H (300 MHz, CDCl3) δΗ for the majority of region isomer 2g: 0.87 (3H, t, J = 6.6, CH3), 1.24 (18H, brs, 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 (1H, m, CH), 4.83 (1H, d, J = 3.5, CH1); RMN 13 C (75 MHz, CDCl 3) - for the majority of region isomer 2g ': 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 Na 6 O: 385.2561 [M + Na] +; measured: 385.2548 (+3.2 ppm); Rf = 0.30 (cyclohexane / EtOAc, 40:60). EXAMPLE 3: Synthesis of a sorbane acetal
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) in the form of 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. .
Acetalization of sorbitan in DMF:
In a sealed tube, 1,4-sorbitane (0.5 g, 3 mmol) was dissolved in DMF (1.4 ml). Valeraldehyde (107 µL, 1 mmol) was added dropwise under argon, followed by addition of camphorsulfonic acid (10 mg, 10% w) to close the tube. The mixture is heated to 95 ° C with magnetic stirring. After 15 hours, the reaction mixture was cooled and the solvent evaporated under reduced pressure. A conversion of 95% was achieved. The residue was diluted in ethyl acetate and the excess of 1,4-sorbitane was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc: cyclohexane 80:20 to 100: 0) to give the sorbitan acetal (0.22 g, 89% isolated yield) in the form of a colorless oil. The HPLC showed a mixture of 4 isomers.
Transacetaliser of sorbitan in ethanol:
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 4: 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 5: Measurement of bacteriostatic properties of derivatives of acetals and ethers of methyl glucopyranoside 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).
The bacteria tested are important:
The acetals and ethers of methyl glucopyranoside with C5, C6, C8, C10 and C12 (number of carbon atoms in the alkyl chain).
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).
Germaetal:
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.
Testing for the derivatives of acetates and ethers of methyl glucopvranoside
The tests were performed on the Gram-positive bacteria with the methyl glucopyranoside derivatives. The solutions of the compounds to be tested 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. However, the acetals of C10 and C12 methyl glucopyranoside have low solubility in water. Due to the formation of precipitate in the solutions, the effect of these acetals of C10 and C12 methyl glucopyranoside could not be evaluated. The results of the antimicrobial tests obtained on the 3 bacterial strains L. monocytogenes (CIP 103575), E. faecalis (ATCC® 29212 TM) and S. aureus (ATCC® 292.213 TM) are summarized in Table 1.
The results below (Table 1) show that the derivatives of methyl glucopyranoside comprising a hydrophobic chain of less than 8 carbon atoms (inputs 1 and 2) have a minimal inhibitory concentration above 4 mM. In other words, these compounds have no inhibitory effect on the growth of Gram-positive bacteria. Inhibition of bacterial growth is observed from the compounds with aliphatic chains greater than or equal to 8 carbon atoms. Indeed, this is indicated by the absence of turbidity corresponding to the octylidene methyl glucopyranoside and mixtures of ethers (4-O-alkyl and 6-O-alkyl) with C8 and C10 (inputs 3 and 4). These compounds have an MRC of between 0.12 and 4 mM and more particularly between 2 and 4 mM. The dodecyl methyl glucopyranoside (input 5) shows the best results. Indeed, an MRC of less than 0.12 mM and more specifically between 0.12 and 0.03 mM based on the bacterial strains investigated was measured.
Table 1. Antimicrobial results for the derivatives of methyl glucopyranoside on the Gram-positive: Minimum inhibitory concentration (MRC) in mmol / L EXAMPLE 6: Measurement of the bacteriostatic properties of the derivatives of acetals and sorbitan ethers on the Gram-positive bacteria
The C5, C6, C8, C10 and C12 acetals and sorbitan ethers were then tested under the same conditions as above and the same bacterial strains (see Example 5). The results obtained are summarized in Table 2.
Table 2. Antimicrobial 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 bacteria strains investigated inhibit. We note that the inventors were able to obtain more soluble C12 compounds that allowed an analysis of their bacteriostatic properties compared to previous methyl glucopyranoside compounds, more particularly the 4,6-O-methyl dodecylidene methyl glucopyranoside. EXAMPLE 7: Bacterial property of derivatives of acetals or sorbitan ethers or methyl glucopyranoside on Gram-positive bacteria
In order to determine the bactericidal effect of the compounds with bacteriostatic properties, the wells that do not exhibit a deviation in Examples 5 and 6 are again plotted on agar. The results obtained after overnight incubation are shown in Table 3.
Table 3. Antimicrobial results for the derivatives of methyl glucopyranoside and the derivatives of sorbitan against Gram positive: Minimum inhibitory concentration (MRC) in mmol / L, Minimum bactericidal concentration (MBC) in mmol / L (in italics)
These results show that the compounds comprising a C8 group have no bactericidal effect because then 2 to 4 mM, the clones were observed on agar after seeding. The decyl methyl glucopyranoside (EthCIOMeGlu,) has an MBC of 0.5 mM relative to L. monocytogenes and E. faecalis (Inputs 1 and 3). However, for S. aureus, which is a virulent strain, the MCB increases to 2 mM (input 2). The strongest bactericidal effect is observed for the C12 ethers of methyl glycopyranoside (EthC12 MeGlu). Indeed, an MBC of 0.12 mM (input 2) was measured for S. aureus and 0.03 mM (Inputs 1 and 3) relative to L. monocytogenes and E. faecalis.
Regarding the sorbitan derivatives, only the compounds with chains of 12 carbons and showing a bacterial inhibition are analyzed and compared with products with the same chain length but on the methyl glucopyranoside. 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 amphilic 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 acetal is active as such and the activity does not come from the corresponding aldehyde.
While the dodecyl sorbitan ethers mixture has an MBC of 0.12 mM for all Gram-positive strains tested. With MRC of 0.03 mM, the sorbitan acetals are as effective as the methyl glucopyranoside ethers of the same chain length relative to L. monocytogenes and E. faecalis. (Inputs 1 and 3).
However, the mixture of C12 sorbitan ethers is on the same scale as the EthCl2 of methyl glucopyranoside for S. aureus (entry 2). In addition, the C12 sorbitan acetals show identical results to those of EthCl2 of methyl glucopyranoside for all strains tested. We can therefore conclude that the acetals and ethers of C12 sorbitane, even in the form of a mixture of regioisomers and diastereomers, display very valuable antimicrobial and antibacterial properties.
These results show that sorbitan derivatives can yield a new line of highly active bio-based bacteriostatic and bactericidal products. EXAMPLE 8: Evaluation of surfactant and antimicrobial properties
In the study of the physicochemical and antimicrobial properties, all synthesized products were tested. These analyzes show different profiles of the amphibious compounds: the hydrotrophic as the 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 4.
Table 9. 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
From the above results, we find that the C12 derivatives of methyl glucopyranoside and of sorbitan are those that include the best results for both surface active and antimicrobial properties (on Gram positive) because they exhibit the lowest CMC and MRC. For dodecyl methyl glucopyranoside and dodecylidene sorbitan (inputs 1 and 2), 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 3). EXAMPLE 9 Comparative tests with compounds of the prior art
The activity of the derivatives of sorbitan or methyl glucopyranoside were compared with that of compounds with structures close by or a commercial compound such as monolaurin (ML) in the table below.
Table 5. Comparative results between the reference products and methyl glucopyranoside ethers and 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 C12 ethers of sugar (EthCl2 MeGlu and EthCl2 Sorb) and the monolaurin is low. In addition, the presence in the form of the mixture of regioisomers of ethers does not affect the antimicrobial properties of the results between pure 6-0-EthC12MeGlu (MRC of 0.04 mM on L. monocytogenes) and the mixture (4+ 6) -0-EthCl 2 MeGlu (MRC of 0.03 mmol on L. monocytogenes). This clearly shows that each of the isomers of the mixture can be active to varying degrees on different bacterial strains. While the 4-O-EthCl 2 MeGlu was completely inactive, the observed MRC of the mixture (4 + 6) -0-EthCl 2 MeGlu is necessarily greater than 0.04 mM.
The linking function between the lipophilic and hydrophilic part also influences the values of the MRC. Thus in the case of dodecyl methyl glucopyranoside derivatives, the MRC are somewhat lower for the ethers compared to the corresponding ester (0.03-0.12 mM for EthCl2 MeGlu and 0.08-0.31 mM for EstCl2 MeGlu). However, the stability of the ether functions in the biological environment is higher than with the esters (sensitive to esterases), so the compounds comprising an ether function have an extended effect, which makes these derivatives of compounds particularly advantageous. EXAMPLE 10: Measurement of bacteriostatic properties of derivatives of acetals and ethers of C12 monosaccharide on Gram-positive bacteria
The best results were observed with the compounds comprising a C12 alkyl group, the tests were performed on a larger number of Gram-positive strains with the obtained compounds according to Examples 1 and 2.
The compounds to be tested are methyl glucopyranoside acetals • 4,6-O-dodecylidene a-D-glycopyranoside from methyl (1e) • 4,6-O-Dodecylidene ß-D-glycopyranoside from methyl (1f)
Mixture of methyl glycopyranoside ethers • 6-O-Dodecyl aD-glucopyranoside from methyl (2e) and 4-O-dodecyl aD-glucopyranoside from methyl (2e ') • 6-O-Dodecyl aD-mannopyranoside from methyl (2f) and 4 -O-dodecyl aD-mannopyranoside from methyl (2f) • 6-O-Dodecyl aD-galactopyranoside from methyl (2g) and 4-O-dodecyl od-galactopyranoside from methyl (2g ')
Mixture of sorbitan ethers • 3-O-dodecyl-1,4-D-sorbitane, 5-O-dodecyl-1,4-D-sorbitane and 6-O-dodecyl-1,4-D-sorbitane - Preparation of the seed 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) to a suspension of 0.5
Mac Farland (Mc) was obtained with 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) (ST 2015-0989). - - Enterococci: E. faecalis (ATCC® 29212 ™), clinical enterococci strains E. 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 cerebrospinal 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 Stafvlokokken genus
Table 6. Antimicrobial results for the derivatives of ethers and acetates of methyl glycopyranoside as well as of sorbitan on different strains of Staphylococcus S. Aureus: Minimum inhibitory Concentration (MRC) in mg / L
According to the observation of the 96-well microplates, all acetal or ether derivatives of monosaccharides are active against tested strains of staphylococci (8 <MRC <64 mg / l), with the exception of galactose ether (C12 -eth-a-Megalac) and the α-acetal of glucose (C12-Ac-a-MeGlu) (MRC> 256 mg / l). - Results for the strains of the genus of Enterococci
Table 7. Antimicrobial results of the derivatives of sugar ethers and sugar acetals and sorbitan on different strains of enterococci. Minimum Inhibitory Concentration (MRC) in mg / l
Good antibacterial activity observed for all strains of enterococci 32 <MRC <8 mg / l for all molecules tested except α acetal of glucose (C12-Ac-a-MeGlu). - Results for the strains of the genus Listeria
Table 8. Antimicrobial results of the derivatives of sugar ethers and sugar acetals and sorbitan on different strains of Listeria Minimum Inhibitory Concentration (MRC) in mg / L.
Good antibacterial activity was observed in all strains of Listeria 64 <MRC <8 mg / l for all molecules tested.

权利要求:
Claims (19)
[1]
CONCLUSIONS
A bactericidal or bacteriostatic composition comprising a mixture of positional isomers of mono-ethers or of mono-alkyl acetals of monosaccharide or of monosaccharide derivative, said monosaccharide derivative being a glycosylated and / or hydrogenated and / or dehydrated monosaccharide, said mixture of positional isomers of mono-ethers or of mono-alkyl acetals of monosaccharide or of monosaccharide derivative are obtained by a process comprising the following steps: a) an acetalization or transacetalization of a monosaccharide or of a monosaccharide derivative with an aliphatic aldehyde containing 11 to 18 carbon atoms or the acetal thereof, b) optionally, catalytic hydrogenolysis of the alkyl acetal of monosaccharide or of monosaccharide derivative obtained in a) preferably, without acid catalyst, and c) recovering a mixture of positional isomers of mono-alkyl ethers of monosaccharide or of monosaccharide deriv aat obtained in b) wherein the alkyl group (R) comprises between 11 to 18 carbon atoms or the recovery of a mixture of positional isomers of mono-alkyl acetals of monosaccharide or of a monosaccharide derivative obtained in a) wherein the alkyl group (R) is between 11 to 18 carbon atoms.
[2]
Bacterial or bacteriostatic composition comprising a mixture of positional mono-ethers or mono-alkyl acetals of monosaccharide or of monosaccharide derivative, comprising an alkyl ether or alkylacetal radical at 2 different positions of the monosaccharide or of the monosaccharide derivative as well as the pharmaceutically acceptable salts thereof wherein the alkyl group comprises between 11 and 18 carbon atoms, said monosaccharide derivative is a glycosylated and / or hydrogenated and / or dehydrated monosaccharide, preferably the alkyl group comprises 11 to 13 carbon atoms.
[3]
Composition according to one of claims 1 and 2, characterized in that the monosaccharide is a C 6 monosaccharide or their alkyl glycoside, preferably the monosaccharide is: - A hexose selected from the group consisting of glucose, mannose, galactose, allose, altrose, gulose, idose and talose - A hexane 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 or - A hexitol selected from mannitol, sorbitol, galactitol and volemitol.
[4]
Composition according to any one of claims 1 to 3, characterized in that the monosaccharide is a sorbitan and said monoalkylacetal is radical at a position 3.5-0 or 5.6-0 or said mono- alkyl ether is radical at a position 3-0, 5-0 or 6-0.
[5]
A composition according to any one of claims 1 to 3, characterized in that the monosaccharide is a glucoside and said mono-alkyl acetal is radical at a position 4.6-0 - or said mono-alkyl ether is radical at a position 4 -0- or 6-0-.
[6]
Composition according to any of claims 1 to 5, characterized in that it is bactericidal or bacteriostatic relative to Gram-positive bacteria.
[7]
Composition according to claim 6, 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.
[8]
Composition according to any of claims 6 and 7, 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, Stapeayloce, Stapeayloce Thermoactinomycetacea and Turicibacteraceae.
[9]
Composition according to claim 8, characterized in that the Gram-positive bacteria are bacteria from 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.
[10]
Composition according to claim 8, 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.
[11]
Composition according to claim 10, 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. camosus, 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. pulveren, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleifen, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S. succinus, S. vitulinus, S. warnen and S. xylosus.
[12]
Composition according to any of claims 6 and 7, characterized in that the Gram-positive bacteria Lactobacillales are selected from a family of Aerococcaceae, Camobacteriaceae, Enterococcaceae, Lactobacillaceae, Leuconostocaceae and Streptococcaceae.
[13]
Composition according to claim 12, characterized in that the Gram-positive bacteria are bacteria from the family of Enterococcaceae selected from bacteria of the genus of Bavanicoccus, Catellicoccus, Enterococcus, Melissococcus, Pilibacter, Tetragenococcus, Vagococcus.
[14]
Composition according to any of claims 12 and 13, 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.
[15]
Composition according to any of claims 1 to 14, characterized in that it is included in a food, cosmetic, medicine, phytosanitary, veterinary or surface treatment agent.
[16]
A composition according to any one of claims 1 to 14, for its use as a hygiene or dermatological product for external use.
[17]
A composition as defined in any one of claims 1 to 14 for use in the treatment or prevention of bacterial infections by Gram-positive bacteria.
[18]
A composition according to claim 17 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.
[19]
A method for disinfecting or preventing bacterial colonization by Gram-positive bacteria of a substrate comprising contacting the substrate with a composition according to any of claims 1 to 14.

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EP3233874A1|2017-10-25|

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WO2016098046A1|2016-06-23|

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CN107835636A|2018-03-23|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR1402895A|FR3030279B1|2014-12-17|2014-12-17|ANTIBACTERIAL COMPOSITION CONTAINING AN ISOMERIC MIXTURE OF MONOETHERS OR ALKYL MONOACETALS OF MONOSACCHARIDES|

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FR14/02895|2014-12-17|

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