WO1983004412A1 - Composes amphipathiques - Google Patents

Composes amphipathiques Download PDF

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Publication number
WO1983004412A1
WO1983004412A1 PCT/GB1983/000155 GB8300155W WO8304412A1 WO 1983004412 A1 WO1983004412 A1 WO 1983004412A1 GB 8300155 W GB8300155 W GB 8300155W WO 8304412 A1 WO8304412 A1 WO 8304412A1
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compound according
carbon atoms
amphipathic compound
group
aliphatic hydrocarbon
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PCT/GB1983/000155
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English (en)
Inventor
James Earl King Hildreth
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National Research Development Corporation
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    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03C—PHOTOSENSITIVE MATERIALS FOR PHOTOGRAPHIC PURPOSES; PHOTOGRAPHIC PROCESSES, e.g. CINE, X-RAY, COLOUR, STEREO-PHOTOGRAPHIC PROCESSES; AUXILIARY PROCESSES IN PHOTOGRAPHY
    • G03C5/00—Photographic processes or agents therefor; Regeneration of such processing agents
    • G03C5/26—Processes using silver-salt-containing photosensitive materials or agents therefor
    • G03C5/29—Development processes or agents therefor
    • G03C5/305—Additives other than developers
    • G03C5/3053—Tensio-active agents or sequestering agents, e.g. water-softening or wetting agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/38—Cationic compounds
    • C11D1/52—Carboxylic amides, alkylolamides or imides or their condensation products with alkylene oxides
    • C11D1/525—Carboxylic amides (R1-CO-NR2R3), where R1, R2 or R3 contain two or more hydroxy groups per alkyl group, e.g. R3 being a reducing sugar rest
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03C—PHOTOSENSITIVE MATERIALS FOR PHOTOGRAPHIC PURPOSES; PHOTOGRAPHIC PROCESSES, e.g. CINE, X-RAY, COLOUR, STEREO-PHOTOGRAPHIC PROCESSES; AUXILIARY PROCESSES IN PHOTOGRAPHY
    • G03C5/00—Photographic processes or agents therefor; Regeneration of such processing agents
    • G03C5/26—Processes using silver-salt-containing photosensitive materials or agents therefor
    • G03C5/29—Development processes or agents therefor
    • G03C5/30—Developers
    • G03C5/3021—Developers with oxydisable hydroxyl or amine groups linked to an aromatic ring

Definitions

  • This invention relates to amphipathic compounds which are of value as detergents or in other contexts.
  • Amphipathic compounds which contain a polar group joined to a non-polar group, find various applications including particularly the use of amphipathic compounds with surface active properties (surfactants) as detergents.
  • surfactants surface active properties
  • Detergents find very many uses and one area in which there has recently been increasing interest in the use of detergents is that of biochemistry, cell biology, immunology, etc.
  • An example of this type of use is the dissoci ation of cell membranes by means of detergents.
  • the satisfactory dissocation of cell membranes does, however, require detergents which are both non-denaturing and readily removable by dialysis, and these two properties are not usually compatible.
  • most of the detergents in current usage which are non-denaturing are non-ionic and have a very low critical micellar concentration
  • CMC CMC
  • detergents having a high CMC are mostly of the ionic type and are therefore likely to denature proteins.
  • detergents which are currently available, those most suited to the dissociation of cell membranes and like uses are cyclic pyranose sugars which are substituted through an oxygen atom by an alkyl group, for example ⁇ -D-octylglucoside.
  • alkyl group for example ⁇ -D-octylglucoside.
  • Such compounds are, however, extremely costly to prepare and I have now developed a novel group of compounds which may not only be prepared at considerably less cost but which may be used instead of detergents such as ⁇ -D-octylglucoside with results which may often be superior.
  • an amphipathic compound comprises an aliphatic hydrocarbon chain with a length of at least three carbon atoms linked to a polyhydroxy substituted acyclic aliphatic group through an amide grouping.
  • the compounds according to the present invention may, where desired, contain more than one aliphatic hydrocarbon chain and/or more than one polyhydroxy substituted acyclic aliphatic group, and these groups may be linked through one or more amide groupings which may be unsubstituted, i.e. being -CO.NH-, or N-substituted.
  • amide groupings which may be unsubstituted, i.e. being -CO.NH-, or N-substituted.
  • the valuable properties of amphipathic compounds according to the present invention derive in large measure from the use of an amide linkage to join the non-polar or hydrophobic part, i.e. the aliphatic hydrocarbon group or groups, and the polar or hydrophilic part, i.e. the polyhydroxy substituted acyclic aliphatic group or groups, of the molecule.
  • the use of the amide linkage results in a non-ionic, chemically inert compound containing a highly polar polyhydroxy head group.
  • This head group is most effective at breaking interactions of a highly polar nature between proteins and its presence leads to an elevation of the CMC of the compound which not only assists in removal of the compound by dialysis but also increases the solubilizing action of the compound on membranes.
  • the chemical inertness of the compounds of the present invention makes them compatible with all commonly used buffers and heavy metal salts and the compounds can be prepared very readily in a high state of purity through construction of the amide linkage.
  • polyhydroxy substituted acyclic aliphatic group or groups in compounds according to the present invention will usually contain at least three hydroxy groups, rather than the minimum of two required by the term "poly”, and more often will contain four or five hydroxy groups.
  • a convenient source for the polyhydroxy substituted acylic aliphatic group and the nitrogen atom of the amide grouping is provided by amino sugars, which may be readily synthesised by the "reductive alkylation" of ammonia or primary amines with reducing sugars, for example as described by Holley et al, Journal of the American Chemical Society 1950, 72, 5416 and by Karrer and Herkenrath, Helvetica Chemica Acta, 1937, 20, 83.
  • An example of such a reaction is that of D-glucose with methylamine to provide the 1-deoxy-amino sugar, N-methyl-D-glucamine.
  • Such monosaccharide amino sugars are necessarily acylic since they have lost the carbonyl functional group and the primary or secondary amino group which they contain may be utilised in the attachment of the sugar to an aliphatic hydrocarbon chain through an amide grouping.
  • aldoses and ketoses may be employed in the formation of amino sugars and thus in the preparation of compounds according to the present invention, including aldoses and ketoses, and trioses, tetroses, pentoses, hexoses and heptuloses.
  • aldoses and ketoses especially the aldopentoses and more particularly the aldohexoses, are perhaps of most interest, the naturally occuring sugars and sugars derivable therefrom of course being the most readily available, for example the D-form of various aldoses.
  • specific examples include mannose, galactose, and particularly glucose.
  • the preparation of compounds according to the present invention is not limited to the use of amino sugars and that any polyhydroxy acyclic aliphatic compound containing a reactive amino group (primary or secondary) may also be used as a ready source of the compounds.
  • any polyhydroxy acyclic aliphatic compound containing a reactive amino group may also be used as a ready source of the compounds.
  • the compound tris tris-(hydroxymethyl)-methylamine or 2-amino-2-hydroxymethyl-1,3-dihydroxypropane] may be used.
  • monosaccharide amino sugars may conveniently be used in the preparation of compounds according to the present invention, other alternative saccharide sources do exist.
  • amino sugars derived from disaccharide sugars in which one of the saccharide units is in cyclic non-reducing form through the involvement of its aldehyde (or ketone) group in the linkage formed with the second unit, which is itself in acyclic non-reducing form through involvement of its aldehyde (or ketone) group in the formation of the amine grouping.
  • a disaccharide which may be utilised in this way is maltose.
  • Such compounds will still contain a polyhydroxy substituted acyclic aliphatic group but this will be additionally substituted by a polyhydroxy substituted cyclic aliphatic group, and the principle may be extended to even larger compounds such as trisaccharide sugars and higher polysaccharides.
  • amphipathic compound will contain an acyclic aliphatic group which is either a hydrocarbon group or a group containing carbon, hydrogen and oxygen (the latter often in ether form) , which group is polyhydroxy substituted.
  • a polyhydroxy substituted acylic aliphatic group which is a polyhydroxy substituted hydrocarbon group for example one derived from a monosaccharide aldose, will be quite suitable.
  • aldoses particular reference is made to aldoses. This is partly because the use of aldose sugars is preferred and partly because the reactions involved and the formulae of the compounds obtained are more readily represented in general terms in the case of aldoses.
  • a compound containing a single aliphatic hydrocarbon group and polyhydroxy acyclic aliphatic group linked through an amide group of the form -CH 2 NR.CO- described above may very readily be prepared through acylation of the selected amino sugar containing the group -CH 2 NHR with an acylating agent containing the desired aliphatic hydrocarbon group.
  • Such an acylation reaction is conveniently effected using a suitable derivative, especially an activated derivative, of the carboxylic acid containing the desired aliphatic hydrocarbon group, for example an anhydride or particularly a mixed anhydride such as that formed by reaction with ethyl chloroformate or other activated derivatives of this type which are described in the art, particularly in the context of peptide synthesis.
  • a suitable derivative especially an activated derivative, of the carboxylic acid containing the desired aliphatic hydrocarbon group
  • an anhydride or particularly a mixed anhydride such as that formed by reaction with ethyl chloroformate or other activated derivatives of this type which are described in the art, particularly in the context of peptide synthesis.
  • R 1 -K 2 The simplest compounds according to the present invention produced by the procedures just described may be represented by the formula R 1 -K 2 wherein R 1 is an acyl group consisting of an aliphatic hydrocarbon group of at least 3 carbon atoms linked to a carbonyl group and R 2 is a polyhydroxy substituted acyclic aliphatic group linked to R 1 through an amine function -NR-, wherein R is hydrogen or an organic grouping, for example R 2 being a monosaccharide amino sugar residue such as a D-glucamine residue or an N-substituted D-glucamine residue.
  • R 2 will be derived from an amino sugar which comprises an aldose modified at the 1-posltion thereof and which may optionally have one or more of Its hydroxy groups modified through the formation of an ether linkage, and the compound will then be of formula R'CON(R)CH 2 R" or R"CON(R)R' wherein R is hydrogen or an organic grouping, R' is an aliphatic hydrocarbon group of at least 3 carbon atoms, for example a grouping R"'CH 2 in which R"' is an aliphatic hydrocarbon group of at least 2 carbon atoms, and R" is the residue of the aldose, I.e. that part thereof excluding the formyl group at the l-positlon.
  • the amino sugars may conveniently be prepared from the corresponding sugar by heating this under pressure with ammonia when the amine function has the form -NH 2 and by reductive alkylation with the approprate base when it is -NHR, for example methylamine being used to prepare amino sugars containing an amine function -NH(CH 3 ) .
  • a modification of this procedure may be used to prepare one of the various forms of compound according to the present invention which contain more than one aliphatic hydrocarbon chain and/or polyhydroxy substituted acyclic aliphatic group.
  • reaction of 3 equivalents of the aldose amino sugar with an activated derivative of the corresponding ⁇ , ⁇ , ⁇ -tricarboxylic acid results in the formation of a compound of formula R"'C(CON(R)CH 2 R" )3 wherein R,R" and R"' are as defined above.
  • the dioic and trioic acids required in this procedure may conveniently be obtained by preparing sodiomalonic ester and reacting this with a compound containing the desired group R"' attached to a suitable leaving group such as bromo, tosylate etc.
  • the dioic or trioic acid ester is first hydrolyzed and the free acid reacted with ethyl chloroformate to provide a mixed di- or tri-anhydride, the mixed anhydride then being reacted with the amino sugar.
  • the compounds of formula R"CON(R)R' described above may contain a group R which is also of the form R', the two groups R' containing either the same or different aliphatic hydrocarbon groups with a chain of at least 3 carbon atoms.
  • compounds of formula R , CON(R)CH 2 R" may contain a group R which is a polyhydroxy substituted acyclic aliphatic group, this group more usually differing from the group CH 2 R".
  • reaction of D-glucose with tris instead of methylamlne in the reaction illustrated hereinbefore will give N-(tris-hydroxy methyl)methyl-D-glucamine which can be acylated at the nitrogen atom by the several procedures described herein.
  • compounds may be prepared which contain more than one aliphatic hydrocarbon group.
  • the first group of compounds of this type is obtained by reacting an activated derivative of an acid containing two aliphatic hydrocarbon groups, for example an ⁇ , ⁇ -dialkylacetic acid such as ⁇ , ⁇ -dioctadecylacetic acid, with an equivalent of an aldose amino sugar to give compounds of formula wherein R, R"and R"' are as defined above and R"" is also an aliphatic hydrocarbon group of at least 2 carbon atoms which may be the same as or different from the group represented by R"' .
  • the ⁇ , ⁇ -dialkylacetic acids may conveniently be obtained by preparing a dialkymalonic acid ester as described hereinafter, and saponifying and decarboxylating this to give the corresponding acetic acid. This acid may then be reacted in activated form, for example as a p-nltrophenyl or other activated ester, with one equivalent of the amino sugar.
  • An alternative group of compounds according to the present Invention containing more than one aliphatic hydrocarbon group is obtainable by reacting one equivalent of an activated derivative of a dioic acid containing two such groups, for example an ⁇ ,c-dialkylmalonic acid such as ⁇ , ⁇ -dioctylmalonic acid, with two equivalents of an aldose amino sugar in order thereby to obtain compounds of formula wherein R, R", R"' and R"" are as defined above.
  • the dioic acids may conveniently be obtained by preparing sodiomalonic ester (the sodium derivative of diethylmalonate) and reacting this with a compound containing the desired group R"' attached to a suitable leaving group such as bromo, tosylate etc.
  • a dioic acid in the form of the diethyl ester, containing an aliphatic hydrocarbon group R"'.
  • the sodio derivative of this diester is then reacted in a similar manner with a similar type of compound containing a group R"", this often being the identical compound to that used before although it can contain a group R"" different from the aliphatic hydrocarbon group R"' if desired, to produce a dioic acid containing two groups, R'" and R"", again in ethyl diester form.
  • this dioic acid ester is first hydrolyzed and the free acid reacted with ethyl chloroformate to provide a mixed di-anhydride, the mixed anhydride then being reacted with two equivalents of the amino sugar.
  • the present invention comprises a compound which contains one or more acyclic amino sugar residues attached through an amide function or functions incorporating the nitrogen atom of the amino sugar residue or residues to one or more aliphatic hydrocarbon chains of at least three carbon atoms.
  • the present invention comprises a compound of the general formula (I)
  • R 1 is an aliphatic hydrocarbon group of at least 2 carbon atoms
  • R 2 is an acyclic amino sugar residue linked to a carbonyl group through which it is attached to the central carbon atom
  • R 3 and R 4 are each separately hydrogen, an aliphatic hydrocarbon group of at least 2 carbon atoms or an acyclic amino sugar residue linked to a carbonyl group.
  • Compounds of the type R'CON(CH 2 R") 2 described above may be regards as containing an acyclic amino sugar residue R 2 of the form -N(CH 2 R") 2 which itself contains two aldose residues R" .
  • the group R 1 may have as few as two carbon atoms in compounds according to the present invention employed for certain purposes, it is usual for the more routine uses as surface active agents for the compounds to contain a group R 1 of at least four and preferably five or six carbon atoms.
  • R 1 the upper limit for R 1 , in some circumstances as discussed hereinafter this may be as high as fourteen, sixteen, eighteen or nineteen carbon atoms, or even as high as twenty-two, twenty-four or twenty-six carbon atoms, but for the more routine uses as surface active agents groups of up to (and including) twelve carbon atoms, preferably of up to ten carbon atoms and especially of up to eight or nine carbon atoms, are of most interest.
  • aliphatic hydrocarbon groups contained in compounds according to the present invention will most usually be saturated and also will often be unbranched, particularly in the case of the lipid compounds discussed hereinafter, although branched alkyl groups rather than straight chain alkyl groups may be of interest in some particular applications.
  • branching within the whole aliphatic hydrocarbon chain present in the amphipathic compound may arise from the presence of groupings such as (R"') 2 C- and that such a grouping may constitute an aliphatic hydrocarbon chain containing a total of more than twenty or twenty- seven carbon atoms even though the length of the chain, i.e.
  • group R 2 present in compounds of formula (I) have already been discussed, for example groups derived from aldoses in which the original formyl group has been replaced by a group -CONH(R)- in which R is hydrogen or an organic grouping, or more particularly by a group -CH 2 NH(R)CO-, examples of specific groups R 2 being those derived from amino sugars obtained from
  • R may be hydrogen it Is often an organic grouping, and this may be an aliphatic hydrocarbon group, for example, of 1 to 19, conveniently of 1 to 12 or 1 to 8, and preferably of 1 to 3 carbon atoms.
  • the organic grouping may, for example, be a phenyl group, or a substituted C 1 - C 3 alkyl or phenyl group, the substitutent(s) being, for example one or more hydroxy, sulphydryl or carboxy groups or other polar organic residues.
  • Hydrophilic groups R such as hydroxymethyl can be of interest for the properties they confer on the compounds and certain substituted phenyl groups such as p-hydroxyphenyl are of particular interest in the context of specific uses of the compounds as described hereinafter.
  • preferred organic groups R are unsubstituted C 1 - C 3 alkyl groups, for example n-propyl, ethyl or especially methyl.
  • R 3 and R 4 are both hydrogen but compounds in which one is hydrogen and the other an acyclic sugar residue, or in which both are such a residue, more usually the same residue, can be of value in maintaining the hydrophile-lipophile balance where one or more longer aliphatic hydrocarbon groups are present, for example in an amphipathic compound having a group R 1 of C 12 , C 14 or C 16 . Similar comments apply in the case of compounds of the specific type R'CON(CH 2 R") 2 .
  • R 4 is an aliphatic hydrocarbon group, often the same one, with R 3 being an acyclic amino sugar residue or hydrogen, are of particular interest for use as synthetic lipids as discussed hereinafter.
  • Non-ionic surface active agents are currently used in a wide variety of industrial and other contexts including cosmetic and drug products, for example shampoos, lotions, acne creams, eye ointments and contraceptive formulations.
  • Another very Important use of non-Ionic surface active agents is as emulsifiers and dispensing agents for medicinal products designed for internal use and the compounds of the present invention are particularly suited to such uses which require surface active agents of high purity, low toxicity and good biodegradability.
  • amphipathic compounds according to the present invention in the preparation of liposomes may involve the solubilisation of conventional lip ⁇ some-forming lipids such as bovine brain lipids, as described hereinafter in Example 8.
  • conventional lip ⁇ some-forming lipids such as bovine brain lipids, as described hereinafter in Example 8.
  • compounds of formula (I) in which R 1 and R 4 are each aliphatic hydrocarbon groups, and R 3 is hydrogen may be used with advantage, particularly when R 1 and R 4 each contain 14 to 18 carbon atoms, in place of the lipids more conventionally employed in liposome formation.
  • Such compounds are those of formula (I) in which R 4 as well as R 1 is an aliphatic hydrocarbon group, and R 3 is either hydrogen or an acyclic amino sugar residue attached through a carbonyl group to the central carbon atom.
  • Compounds of this type may, if desired, contain a group R 4 or groups R 2 and R 3 which comprise an acyclic amino sugar residue linked to a cyclic sugar residue, for example one or both groups being a residue derived from maltose, but preferred groups comprise monosaccharide amino sugar residues.
  • the aliphatic hydrocarbon groups R 1 and R 4 are conveniently somewhat larger than usual.
  • a preferred upper limit is twenty-six carbon atoms, or especially twenty-four or twenty-two carbon atoms.
  • a more convenient upper limit is eighteen or nineteen carbon atoms so that a preferred range of size is 14 to 18 or 19 carbon atoms, for example 14, 16 or 18 carbon atoms.
  • such lipid compounds contain unbranched groups or groups which are only slightly branched so that these overall sizes for the groups R 1 and R 4 correspond closely to their chain lengths (the length of an aliphatic hydrocarbon chain being the number of carbon atoms in the longest sequence of carbon atoms in the chain so that a branched chain will contain a larger total number of carbon atoms than its length) .
  • developer molecules which are amphiphilic in nature are most strongly absorbed to film and paper surfaces and are thus most efficient for electron transfer.
  • Compounds according to the present invention can combine both surface active and developing properties and be of particular value in the photographic area.
  • Such compounds contain an amide grouping in which the nitrogen atom is substituted by a p-hydroxyphenyl group and preferably contain an aliphatic hydrocarbon group of 5 to 8 carbon atoms.
  • a specific example is a compound of formula (I) in which R 1 is a hexyl group, R 2 comprises the residue of the amino sugar obtained from D-glucose by reaction with p-hydroxyaniline and linked through a carbonyl group to the central carbon atom, and R 3 and R 4 are hydrogen, the compound thus containing the grouping -N-(p-hydroxyphenyl)-CO-.
  • amphipathic compounds for use in the formation of thin or molecular films and the compounds of the present invention are also of interest in this context, the invention being of value for the ready preparation of amphipathic compounds containing various types of head group suited to a variety of purposes.
  • Example 1 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl octanoic acid amide Crude capryllc acid anhydride (3.5ml) is stirred with N-methyl-D-glucamine (2g) in methanol (50ml) at 50oC for one hour. The solvent is then removed by rotary evaporation under reduced pressure and the residue, which consists of the title amide and octanoic acid, is taken up in ether (50ml).
  • Example 2 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-K-methyl nonanoic acid amide A solution of nonanoic acid (20ml, 16g) and pyridine (10ml) in ether (100ml) is cooled in ice for 10 minutes and is then treated very rapidly with ethyl chloroformate (11ml).
  • the resulting ethereal solution containing precipitated pyridinium hydrochloride is filtered directly Into a warm solution of N-methyl-D-glucamine (19.5g) in methanol (150ml), the residual hydrochloride being washed with cold ether (50ml) which also passes directly into the methanolic solution. After stirring for 30 minutes at 25oC, the methanol/ether solution is allowed to stand overnight at 0oC and is then filtered to remove crystals of unreacted N-methyl-D-glucamine. The solvents are removed by rotary evaporation under reduced pressure and the residue is poured with stirring into ether (300ml) cooled on ice.
  • Example 3 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl decanoic acid amide
  • a solution of capric acid (23g) and pyridine (10ml) in ether (100ml) is cooled in ice for 10 minutes and is then treated very rapidly with ethyl chloroformate (13.08g) when the precipitation of pyridinium hydrochloride is immediately initiated.
  • the ethereal solution is filtered directly into a warm solution of N-methyl-D-glucamine (20g) in methanol (150ml).
  • the residual hydrochloride is washed with cold ether (50ml) which also passes directly into the methanolic solution.
  • the amide is recrystallised by dissolving in warm methanol (lml/g) , adding diethyl ether (10ml/g), and allowing the solution to stand overnight at room temperature (68 - 90% recovery) .
  • Example 4 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl -tetradecyl eicosanoic acid amide
  • Diethyl ⁇ -tetradecyl- ⁇ -octylmalonate is added to a solution of KOH (5g) in ethanol (50ml) and the resulting solution is warmed to 45°C for 3 hours with continuous stirring.
  • the solution is then diluted with water (100ml) followed by the addition of concentrated HCl until the pH of the solution reaches 3.0.
  • the acid solution is extracted with methylene chloride (3 x 100ml) and dried with Na 2 SO 4 .
  • Rotary evaporation yields ⁇ -tetradecyl eicosanoic acid as (7.5g, 86%), ⁇ max 1705cm -1 .
  • Trituration of this paste with ethyl acetate yields a yellow solution, which on evaporation yields a pale yellow oil.
  • Trituration of this oil with methanol gives p-nitrophenyl ⁇ -tetradecyl eicosanoate as a pale yellow solid (0.85g, 71%), m.p. 31-34°C; ⁇ 1720cm -1 .
  • N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl- ⁇ -tetradecyl eicosanoic acid amide p-Nitrophenyl ⁇ -tetradecyl eicosanoate (0.4g) is dissolved in chloroform (8ml) and added to a solution of N-methyl-D-glucamine (0.6g) in dimethyl formamlde (12ml). The solution is stirred at room temperature for 24 hours and then subjected to rotary evaporation.
  • Example 5 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl- ⁇ - tetradecyl hexadecanoic acid amide This compound is obtained as a solid of m.p. 32-34oC in a yield of approximately 10% by the reaction of N-methyl-D-glucamine with p-nitrophenyl ⁇ -tetradecyl hexadecanoate in a similar procedure to that described under section 5 of Example 4.
  • the p-nitrophenyl ⁇ -tetradecyl hexadecanoate is obtained from diethyl ⁇ , ⁇ -di-(tetra decyl)-malonate (obtained from diethyl ⁇ -tetradecylmalonate using tetradecyl bromide in an analogous manner to that described in section 2 of Example 4), the formation of this p-nitrophenyl ester being effected by similar procedures to those described in sections 3 and 4 of Example 4.
  • Example 6 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl- ⁇ - octadecyl eicosanoic acid amide This compound is obtained as a solid of m.p. 38-40oC in a yield of approximately 10% by the reaction of N-methyl-D-glucamine with p-nitrophenyl ⁇ -octadecyl eicosanoate in a similar procedure to that described under section 5 of Example 4.
  • the p-nitrophenyl ⁇ -octadecyl eicosanoate is obtained from diethyl ⁇ , ⁇ -di-(octadecyl)-malonate (obtained from diethyl ⁇ -octadecylmalonate using octadecyl bromide in an analogous manner to that described in sections 1 and 2 of Example 4) , the formation of this p-nitrophenyl ester being effected by similar procedures to those described in sections 3 and 4 of Example 4.
  • Example 7 Tests on the solubilization of purified plasma membranes with surface active agents
  • Plasma membranes purified by standard techniques were solubilized by incubation for 60 minutes at 0oC in phosphate buffered saline (PBS) containing 1% w/v of one of the detergents N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl octanoic acid amide (OMEGA), N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl nonanoic acid amide (MEGA-9) or N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)-N-methyl-decanoic acid amide (MEGA-10) at a detergent to protein ratio of 1:5 w/w.
  • PBS phosphate buffered saline
  • the amount of the integral membrane HLA-A,B,C glycoproteins released through the detergent treatment with retention of its native conformation was determined through an assay based upon the inhibition by the protein of the binding of a radio labelled antibody to the surface of glutaraldehyde-fixed lymphoblastoid cells.
  • the detergent extract obtained after centrifugation was diluted serially twofold using a 1% w/v solution of the detergent in PBS and 50 microlitre samples of the extract diluted at various levels were incubated for 2 hours at 4oC with 30 microlitres of a solution of 125 I-labelled antibody against the, HLA-A,B,C glycoproteins in PBS at a concentration of lyg/ml.
  • Plasma membranes purified by standard techniques (Crumpton and Snacy, ibid) (lmg) were solubilized by treatment during 30 minutes with a 0.5%w/v solution of MEGA-9 in PBS (1ml) cooled on ice.
  • a control experiment was carried out in which the membranes were incubated for 30 minutes with PBS (1ml) containing no detergent. In both cases, the resulting mixture was dialysed overnight at 4oC against PBS (2 litres) to remove detergent and thereby reconstitute the membranes. The dialysed material was then centrifuged at 10 5 x g for 45 minutes at 4oC, the supernatant with contained non-reconstituted protein was removed and the resulting membrane pellet was resuspended in PBS (0.5ml).
  • the PBS suspension was subjected to threefold serial dilutions for use in an assay based on the inhibition by the membranes of the binding of monoclonal antibody to glutaraldehyde-fixed lymphoblastoid cells.
  • 0.1ml samples of the diluted PBS suspensions were incubated for one hour at 4oC with 0.05ml of a PBS solution (l ⁇ g/ml) of a monoclonal antibody raised against the membrane proteins HLA-A,B,C.
  • the incubation mixtures were then centrifuged at 500 x g for 10 minutes and 50 microlitres of the supernatants were added to 10 fixed cells in 50 microlitres of PBS (duplicate experiments being carried out at each dilution level) and the whole incubated for a further period of one hour at 4oC.
  • the cells were then separated by centrifugation at 500 x g, washed with PBS and incubated for another one hour at 4°C with 0.1ml of a solution in PBS (lyg/ml) of 125 I-labelled antibody specific for the monoclonal antibody described above.
  • the cells were finally washed once more with PBS and were then assayed for bound I-labelled antibody using a gamma counter.
  • Example 8 Use of surface active agents in the preparation of microvesicles Influenza virus haemmagglutinin (75 mlcrograms) purified by standard techniques (Skehel and Schild, Virology, 1971, 44 396) in 0.5% w/v aqueous sodium cholate (0.3ml) and bovine brain lipids (Sigma) (300 micrograms) in PBS containing 5% w/v MEGA-10 (0.3ml) were mixed in 0.5% w/v MEGA-9 in PBS (1.0ml) to "solubilise" the lipids which cannot be effected with the sodium cholate.
  • Influenza virus haemmagglutinin 75 mlcrograms purified by standard techniques (Skehel and Schild, Virology, 1971, 44 396) in 0.5% w/v aqueous sodium cholate (0.3ml) and bovine brain lipids (Sigma) (300 micrograms) in PBS containing 5% w/v MEGA-10
  • the mixture was dialysed for 12 hours at 4°C against PBS (2 litres) and was then centrifuged at 10 5 x g for 45 minutes (the removal of the MEGA-9 and 10 in such a short time is evidence of their high CMC) .
  • the resulting microvesicle pellet was resuspended in PBS (1.0ml) and the suspension tested for haemagglutination activity against one day old chicken red blood cells. These microvesicles showed a titre of greater than 2048 -1 whilst microvesicles prepared in a control experiment in which the haemagglutinin was omitted showed no measurable titre.
  • Examination of the active microvesicles by electron microscopy showed a population of spherical unilamellar vesicles of uniform size (600 - 1100nm).

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Abstract

Des composés amphipathiques contiennent une chaîne d'hydrocarbures aliphatiques d'une longueur d'au moins 3 atomes de carbone reliée par un groupement amide à un groupe aliphatique acyclique polyhydroxy substitué. Ce groupe comprend des composés d'intérêt général pour une utilisation en tant qu'agents tensioactifs non ioniques et d'autres composés présentent un intérêt pour une utilisation en tant que lipides.
PCT/GB1983/000155 1982-06-11 1983-06-13 Composes amphipathiques WO1983004412A1 (fr)

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155625A2 (fr) * 1984-03-21 1985-09-25 Bayer Ag Substances du type glycolipide sous forme de liposomes
EP0158291A2 (fr) * 1984-04-10 1985-10-16 Takeda Chemical Industries, Ltd. Méthode de purification d'antigène carcino-embryonaire et méthode de production d'un anticorps monoclonal reagissant avec l'antigène carcino-embryonaire
EP0180980A2 (fr) * 1984-11-06 1986-05-14 Daiichi Seiyaku Co., Ltd. Structures de membranes lipidiques
EP0220676A1 (fr) * 1985-10-29 1987-05-06 Süddeutsche Zucker-Aktiengesellschaft Amides d'acides gras d'aminopolyols comme tensio-actifs non ionogènes
EP0422508A2 (fr) * 1989-10-09 1991-04-17 Kao Corporation Composition de détergent liquide
EP0450527A2 (fr) * 1990-03-30 1991-10-09 Kao Corporation Amides N-tris (hydroxyméthyl)méthyl d'acides gras et compositions cosmétiques les contenant
WO1992006070A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Procede a forte concentration de catalyseurs utilise pour des detergents a base de glucamide
WO1992005764A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Compositions de shampooing ameliorees
WO1992006072A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Procede catalyse ameliore pour des detergents a base de glucamide
WO1992006071A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Procede assiste par transfert de phase destine a des detergents a base de glucamide
WO1992006073A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Preparation d'amides de l'acide gras de polyhydroxy en presence de solvants
US5174927A (en) * 1990-09-28 1992-12-29 The Procter & Gamble Company Process for preparing brightener-containing liquid detergent compositions with polyhydroxy fatty acid amines
WO1993001267A1 (fr) * 1991-07-08 1993-01-21 The Procter & Gamble Company Compositions detersives contenant des agents tensioactifs a base d'amides d'acide gras polyhydroxyles et un systeme d'assouplissement a base d'argile
TR25506A (tr) * 1990-09-28 1993-05-01 Procter & Gamble POLIHIDROKSI YAGLI ASIT AMID SüRFAKTANTLAR ICEREN SAMPUAN BILESIMLERI.
US5234618A (en) * 1989-10-09 1993-08-10 Kao Corporation Liquid detergent composition
US5254281A (en) * 1991-01-29 1993-10-19 The Procter & Gamble Company Soap bars with polyhydroxy fatty acid amides
US5318728A (en) * 1992-11-30 1994-06-07 The Procter & Gamble Company Low sudsing polyhydroxy fatty acid amide detergents
WO1994012598A1 (fr) * 1992-11-30 1994-06-09 The Procter & Gamble Company Compositions nettoyantes comprenant des tensioactifs non ioniques/anioniques d'amides d'acide gras polyhydroxy melanges, a faible pouvoir moussant
FR2700267A1 (fr) * 1993-01-13 1994-07-13 Oreal N-acyl amino déoxy alditols, et leur utilisation dans des compositions cosmétiques ou dermopharmaceutiques.
US5332528A (en) * 1990-09-28 1994-07-26 The Procter & Gamble Company Polyhydroxy fatty acid amides in soil release agent-containing detergent compositions
US5354425A (en) * 1993-12-13 1994-10-11 The Procter & Gamble Company Tissue paper treated with polyhydroxy fatty acid amide softener systems that are biodegradable
WO1995005152A1 (fr) * 1993-08-12 1995-02-23 Henkel Kommanditgesellschaft Auf Aktien Produits pour les soins de la peau
WO1995005151A1 (fr) * 1993-08-12 1995-02-23 Henkel Kommanditgesellschaft Auf Aktien Produits pour les soins de la peau
WO1995023839A1 (fr) * 1994-03-04 1995-09-08 Akzo Nobel N.V. Utilisation d'une composition detergente destinee au nettoyage des etoffes ou des surfaces dures
US5454982A (en) * 1990-09-28 1995-10-03 The Procter & Gamble Company Detergent composition containing polyhydroxy fatty acid amide and alkyl ester sulfonate surfactants
US5700771A (en) * 1990-09-28 1997-12-23 The Procter & Gamble Company Polyhydroxy fatty acid amide surfactants in percarbonate bleach-containing compositions
KR101338237B1 (ko) * 2013-08-23 2013-12-06 주식회사 더마랩 세라마이드 유사 화합물, 이의 제조방법 및 이를 포함하는 화장료 조성물
EP3157571B1 (fr) 2014-06-23 2021-11-24 Novartis AG Acides gras et leur utilisation dans la conjugaison de biomolécules

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GB2250998A (en) * 1990-12-21 1992-06-24 Unilever Plc Cosmetic cleansing composition

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GB771423A (en) * 1954-08-19 1957-04-03 Rohm & Haas Improvements in alkyl-n-sorbitylalkanamides
FR1165745A (fr) * 1956-01-31 1958-10-28 Unilever Nv Perfectionnements aux compositions détergentes
FR1360018A (fr) * 1963-04-26 1964-04-30 Commercial Solvents Corp Solutions de formaldéhyde stabilisées, et leur procédé de stabilisation

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CHEMICAL ABSTRACTS, Vol. 98, No. 19, 9 May 1983 (Columbus, Ohio, US) J.E.K. HILDRETH: "N-D-Gluco-N-Methylalkanamide Compounds, a new Class of Nonionic Detergents for Membrane Biochemistry", see age 216, Abstract No. 157235b, Bioche, J. 1982, 207(2), 363-6 *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155625A3 (fr) * 1984-03-21 1987-04-15 Bayer Ag Substances du type glycolipide sous forme de liposomes
EP0155625A2 (fr) * 1984-03-21 1985-09-25 Bayer Ag Substances du type glycolipide sous forme de liposomes
EP0158291A3 (fr) * 1984-04-10 1988-07-27 Takeda Chemical Industries, Ltd. Méthode de purification d'antigène carcino-embryonaire et méthode de production d'un anticorps monoclonal reagissant avec l'antigène carcino-embryonaire
EP0158291A2 (fr) * 1984-04-10 1985-10-16 Takeda Chemical Industries, Ltd. Méthode de purification d'antigène carcino-embryonaire et méthode de production d'un anticorps monoclonal reagissant avec l'antigène carcino-embryonaire
EP0180980A2 (fr) * 1984-11-06 1986-05-14 Daiichi Seiyaku Co., Ltd. Structures de membranes lipidiques
EP0180980A3 (en) * 1984-11-06 1987-06-03 Daiichi Seiyaku Co. Ltd. Lipid membrane structures
US4960595A (en) * 1984-11-06 1990-10-02 Daiichi Seiyaku Co., Ltd. Lipid membrane structures
EP0220676A1 (fr) * 1985-10-29 1987-05-06 Süddeutsche Zucker-Aktiengesellschaft Amides d'acides gras d'aminopolyols comme tensio-actifs non ionogènes
EP0422508A3 (en) * 1989-10-09 1992-08-26 Kao Corporation Liquid detergent composition
EP0422508A2 (fr) * 1989-10-09 1991-04-17 Kao Corporation Composition de détergent liquide
US5234618A (en) * 1989-10-09 1993-08-10 Kao Corporation Liquid detergent composition
EP0450527A2 (fr) * 1990-03-30 1991-10-09 Kao Corporation Amides N-tris (hydroxyméthyl)méthyl d'acides gras et compositions cosmétiques les contenant
EP0450527A3 (fr) * 1990-03-30 1991-10-30 Kao Corporation Amides N-tris (hydroxyméthyl)méthyl d'acides gras et compositions cosmétiques les contenant
US5194639A (en) * 1990-09-28 1993-03-16 The Procter & Gamble Company Preparation of polyhydroxy fatty acid amides in the presence of solvents
WO1992006071A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Procede assiste par transfert de phase destine a des detergents a base de glucamide
WO1992006073A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Preparation d'amides de l'acide gras de polyhydroxy en presence de solvants
WO1992006072A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Procede catalyse ameliore pour des detergents a base de glucamide
US5174927A (en) * 1990-09-28 1992-12-29 The Procter & Gamble Company Process for preparing brightener-containing liquid detergent compositions with polyhydroxy fatty acid amines
US5454982A (en) * 1990-09-28 1995-10-03 The Procter & Gamble Company Detergent composition containing polyhydroxy fatty acid amide and alkyl ester sulfonate surfactants
TR25398A (tr) * 1990-09-28 1993-03-01 Procter & Gamble CÖZüCüLERIN YANINDA POLIHIDROKSI YAG ASIT AMIDLERIN HAZIRLANISI
WO1992005764A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Compositions de shampooing ameliorees
TR25506A (tr) * 1990-09-28 1993-05-01 Procter & Gamble POLIHIDROKSI YAGLI ASIT AMID SüRFAKTANTLAR ICEREN SAMPUAN BILESIMLERI.
WO1992006070A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Procede a forte concentration de catalyseurs utilise pour des detergents a base de glucamide
US5700771A (en) * 1990-09-28 1997-12-23 The Procter & Gamble Company Polyhydroxy fatty acid amide surfactants in percarbonate bleach-containing compositions
CN1039281C (zh) * 1990-09-28 1998-07-29 普罗格特-甘布尔公司 改进的洗发剂组合物
US5338487A (en) * 1990-09-28 1994-08-16 The Procter & Gamble Company Catalyzed process for glucamide detergents
AU660948B2 (en) * 1990-09-28 1995-07-13 Procter & Gamble Company, The Phase transfer assisted process for glucamide detergents
US5332528A (en) * 1990-09-28 1994-07-26 The Procter & Gamble Company Polyhydroxy fatty acid amides in soil release agent-containing detergent compositions
US5338486A (en) * 1990-09-28 1994-08-16 The Procter & Gamble Company High catalyst process for glucamide detergents
US5254281A (en) * 1991-01-29 1993-10-19 The Procter & Gamble Company Soap bars with polyhydroxy fatty acid amides
WO1993001267A1 (fr) * 1991-07-08 1993-01-21 The Procter & Gamble Company Compositions detersives contenant des agents tensioactifs a base d'amides d'acide gras polyhydroxyles et un systeme d'assouplissement a base d'argile
WO1994012598A1 (fr) * 1992-11-30 1994-06-09 The Procter & Gamble Company Compositions nettoyantes comprenant des tensioactifs non ioniques/anioniques d'amides d'acide gras polyhydroxy melanges, a faible pouvoir moussant
US5318728A (en) * 1992-11-30 1994-06-07 The Procter & Gamble Company Low sudsing polyhydroxy fatty acid amide detergents
FR2700267A1 (fr) * 1993-01-13 1994-07-13 Oreal N-acyl amino déoxy alditols, et leur utilisation dans des compositions cosmétiques ou dermopharmaceutiques.
WO1995005151A1 (fr) * 1993-08-12 1995-02-23 Henkel Kommanditgesellschaft Auf Aktien Produits pour les soins de la peau
WO1995005152A1 (fr) * 1993-08-12 1995-02-23 Henkel Kommanditgesellschaft Auf Aktien Produits pour les soins de la peau
US5354425A (en) * 1993-12-13 1994-10-11 The Procter & Gamble Company Tissue paper treated with polyhydroxy fatty acid amide softener systems that are biodegradable
WO1995023839A1 (fr) * 1994-03-04 1995-09-08 Akzo Nobel N.V. Utilisation d'une composition detergente destinee au nettoyage des etoffes ou des surfaces dures
KR101338237B1 (ko) * 2013-08-23 2013-12-06 주식회사 더마랩 세라마이드 유사 화합물, 이의 제조방법 및 이를 포함하는 화장료 조성물
EP3157571B1 (fr) 2014-06-23 2021-11-24 Novartis AG Acides gras et leur utilisation dans la conjugaison de biomolécules
US11752211B2 (en) 2014-06-23 2023-09-12 Novartis Ag Fatty acids and their use in conjugation to biomolecules

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