WO1998040390A2 - Oligosaccharides et leurs derives et procede chimio-enzymatique permettant de les preparer - Google Patents

Oligosaccharides et leurs derives et procede chimio-enzymatique permettant de les preparer Download PDF

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WO1998040390A2
WO1998040390A2 PCT/EP1998/001096 EP9801096W WO9840390A2 WO 1998040390 A2 WO1998040390 A2 WO 1998040390A2 EP 9801096 W EP9801096 W EP 9801096W WO 9840390 A2 WO9840390 A2 WO 9840390A2
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aav
acetyl
formula
glucopyranosyl
nmr
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PCT/EP1998/001096
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WO1998040390A3 (fr
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Wolf-Dieter Fessner
Michael Petersen
Michael Arthur Papadopoulos
Gerd Osswald
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Bayer Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals

Definitions

  • Oli2osaccharides and their derivatives as well as a chemo-enzymatic process for their production
  • the invention relates to new oligosaccharides and their derivatives and a general
  • oligosaccharides which carry an additional ketose unit at the reducing end when DHAP-dependent aldolases are used, and their corresponding phosphate esters and suitable derivatives are of interest as components or precursors of active pharmaceutical ingredients.
  • Oligosaccharides play an eminently important role as information carriers of high information density in many biological recognition processes such as Cell growth, differentiation, aggregation and migration. With innumerable human diseases, oligosaccharide-receptor interactions are of fundamental importance, e.g. in the case of immunological defense reactions, tumor diseases or infections by parasites, bacteria or viruses. Structures derived from oligosaccharides are therefore becoming increasingly interesting as potential pharmaceuticals to moderate or block biological communication channels - especially in clinical pictures such as acute or chronic inflammation, asthma, immunological diseases, tumor metastasis, transplant rejection, infectious diseases and cardiovascular diseases.
  • the variation of Linking sites between building blocks requires the targeted provision of a free OH group on the acceptor and the protection of all other OH groups for chemical processes, g) the protective groups in the acceptor exerting a controlling influence on the reactivity of the acceptor OH group, h) the variation of the linkage on the anomeric C atom (diastereoselectivity with regard to the a / b configuration) must be controlled stereochemically by the decisive influence of the protective groups in the donor, i) additional kinetic and thermodynamic influences on the diastereoselectivity (anom rer effect) to be considered by the conduct of the reaction, what k) can be influenced by the type of activation of the anomeric center in the glycosyl donor by introducing a suitable escape group and choosing a catalytic promoter,
  • Oligosaccharides made up of the naturally occurring monosaccharides are also unsuitable for therapeutic purposes because of their high biological metabolism rate
  • the invention describes a broadly applicable process for the rapid, stereoselective generation of a large number of complex oligosaccharides and of metabolically stable non-natural derivatives from cheap or easily accessible starting materials. It has surprisingly been found that glycosylated aldehydes which, owing to their simple structure, can be compared with conventional ones Synthesis methodology are accessible conveniently and efficiently, by means of certain chemical and / or enzymatic methods for chain extension by means of CC linkage stereoselectively in one
  • Saccharide unit to convert enlarged oligosaccharides, whereby elaborate protective group techniques can be largely avoided. If chirality centers are newly created, this procedure allows the controlled stereodivergent synthesis of a large number of diastereoisomers (2 n for n new centers) from the same aldehyde starting material.
  • the invention relates to compounds of the general formula (I)
  • A represents CH 2 or a radical of the formula
  • B represents CH 2 , a bond or a radical of the formula
  • R represents hydrogen or phosphate
  • R 1 represents an optionally substituted glycosyl radical
  • R 2 and R 3 may be the same or different and represent hydrogen, hydroxy, hydroxyalkyl, glycosyloxy, glycosyloxyalkyl, alkoxyalkyl, dialkoxyalkyl or
  • 5- or 6-membered saturated ring which can contain up to 2 oxygen atoms, wherein the ring can be substituted up to twice by lower alkyl, and
  • R 4 represents hydrogen, alkyl, alkyloxycarbonyl, carboxy or glycosyloxyalkyl,
  • X represents -O-, -OCH 2 -, -N (alkanoyl) -, -S-, -SCH 2 - or a bond
  • R 1 ' independently of R 1 , can have the meanings given for R 1 ,
  • R 3 'independently of R 3 can have the meanings given for R 3 and
  • X 'can have the meanings given for X independently of X.
  • the compounds of formula (I) contain several stereocenters. They can therefore exist in stereoisomeric forms that either behave like images and mirror images (enantiomers) or that do not behave like images and mirror images (diastereomers).
  • the invention relates to both the enantiomers and the diastereomers or their respective mixtures. Mixtures of the enantiomers or also of the diastereomers can be separated into the stereoisomerically uniform constituents in a known manner, for example by crystallization or chromatography processes.
  • R 2 and R 3 can be the same or different and represent hydrogen, hydroxy
  • R 4 represents hydrogen, methyl, methoxycarbonyl, carboxy or glycosyloxymethyl
  • X represents -O-, -OCH 2 -, -N (acetyl) -, -S-, -SCH 2 - or a bond
  • R 3 'independently of R 3 can have the meanings given for R 3 and
  • X 'can have the meanings given for X independently of X.
  • glycosyl residues and for the glycosyl residues in the "glycosyloxy" and “glycosyloxyalkyl” residues are erythro mattersanosyl, threo Divisionanosyl, ribo Solutionsanosyl, arabino Solutionsanosyl, xylo Solutionsanosyl, allofuranosyl, glucofuranosyl, manno Relationanosyl,
  • Fructopyranosyl Altro-heptulo-pyranosyl, Glycero-manno-octulo-pyranosyl or Erythro-gluco-nonulo-pyranosyl, (Methyl-6-deoxy-glucopyranoside) -6-yl, (Methyl-3-deoxy-glucopyranoside) -3- yl or methyl-4-deoxy-glucopyranoside) -4-yl.
  • hydroxyl groups in the glycosyl radicals can be replaced by other substituents, for example by hydrogen, lower alkyl, halogen, lower alkoxy, oxa-lower alkyloxy, lower alkenyloxy, cycloalkoxy, tetrahydropyranyloxy, arylalkyloxy, heteroarylalkyloxy, lower alkyloxy-arylalkyloxy, alkylidendioxl, lower alkoxydoyloxy, lower alkydoyloxy which is substituted by halogen, arylcarbonyloxy or
  • Arylcarbonyloxy which is substituted by halogen or lower alkoxy, lower alkylsulfonyloxy, arylsulfonyloxy, lower alkylarylsulfonyloxy, oxo, amino, mono- or di-lower alkylamino, formylamino, lower alkanoylamino or lower alkanoylamino, which is substituted by halogen, lower alkynylamino, arylalkylthaloxy, azido Lower alkylthio
  • Phosphonooxy dialkyloxy-phosphoryloxy, dibenzyloxyphosphoryloxy, sulfooxy, alkyloxysulfonyloxy, benzyloxysulfonyloxy or sulfamoyloxy, optionally substituted glycosyloxy or optionally substituted di- or
  • glycosyl radicals in which one or more or all of the hydroxyl groups have been replaced or substituted are 2-amino-2-deoxy-glucopyranosyl, 2-amino-2-deoxy-galactopyranosyl, 2-acetylamino-2-deoxy- glucopyranosyl, 2-acetylamino-2-deoxy-galactopyranosyl, 2-azido-2-deoxy-glucopyranosyl, 2-deoxy-glucopyranosyl, 4-deoxy-glucopyranosyl, 6-chloro-6-deoxy-gluco- for anosyl, 6-deoxy-6-fluoro-glucopyranosyl, 4-chloro-4-deoxy-glucopyranosyl, gluco mattersanos-3-ulosyl, 6-thio-glucopyranosyl, 3-thio-galactoognianosyl, 5-acetylamino-3,5- dideoxy-g
  • 6-O-phosphoryl-galactopyranosyl 2,3,4,6-tetra-O-methyl-glucopyranosyl, 2,3,4,6-tetra-O-acetyl-glucopyranosyl, 2,3,4,6-tetra- O-benzyl-glucopyranosyl, 2,3,4,6-tetra-O-benzyl-galactopyranosyl, 2,3,4,6-tetra-O-benzyl-mannopyranosyl, 2,3,4-tri-O-benzyl- rhamnopyranosyl, 2,3,4-tri-O-benzyl-fucyranosyl, 2,3-di-O-allyl-4,6-di-O-benzyl-mannopyranosyl, 2,3-di-O-acetyl-4, 6-O-benzylidene-glucopyranosyl,
  • Alkyl as a separate substituent or as part of other radicals such as hydroxyalkyl, glycosyloxyalkyl, alkoxyalkyl, dialkoxyalkyl, alkoxy, alkanoyl means a straight-chain or branched alkyl radical having up to 8, preferably up to 6 and particularly preferably up to 4, carbon atoms.
  • Lower alkyloxy means a straight-chain or branched alkyl radical having up to 7, preferably up to 5 and particularly preferably up to 3 carbon atoms.
  • Lower alkenyl as a separate substituent or as part of other radicals such as, for example, lower alkenyloxy represents a straight-chain or branched alkene radical with up to
  • Alkylidene as its own radical or as part of other radicals such as, for example, alkylidendioxy means a straight-chain or branched alkylidene chain having up to 8, preferably up to 6, particularly preferably up to 4, carbon atoms.
  • Aryl as a separate substituent or as part of other radicals such as arylalkyloxy represents an aryl radical having up to 10, preferably up to 6, carbon atoms, for example phenyl.
  • Alkynyl as a separate substituent or as part of other radicals such as
  • Lower alkynylamino stands for a straight-chain or branched alkynyl radical having up to 8, preferably up to 6, particularly preferably up to 4 carbon atoms.
  • the present invention relates to a process for the preparation of enantiomerically pure and diastereomerically pure oligosaccharides and their derivatives
  • carbon nucleophiles for the second addition are dihydroxyacetone phosphate and a fructose-1,6-bisphosphataldolase ([EC 4.1.2.13]), tagatose-1,6-bisphosphataldolase ([EC 4.1.2]), fuculose-1-phosphataldolase ( [EC 4.1.2.17]) or rhamnulose-1-phosphataldolase ([EC 4.1.2.19]).
  • the compounds of the formula (I) can generally be prepared from three key steps to be carried out consecutively.
  • a schematic overview in Scheme 1 may clarify this without being restrictive
  • a glycoside that contains a polar addition-capable double bond in the aglycon part typically an aldehyde, ketone or ester-carbonyl grouping or a synthesis equivalent familiar to the person skilled in the art, from which this function is used before the next reaction step can be easily generated.
  • Such a suitable glycoside can e.g. are obtained by preparing compounds of the formula (IV) by known processes,
  • R 1 , R 2 , R 3 , R 4 and X have the meanings given above and
  • R 5 and R 6 can be the same or different and represent hydrogen, alkyl or aryl
  • R 1 , R 2 , R 3 , R 4 and X have the meanings given above.
  • a C-nucleophilic reagent with C-C linkage is added to this double bond, a heteronucleophile, which is typically an alcohol, being produced from the original double bond.
  • the reagent must itself contain an aldehyde function in a masked form, e.g.
  • R 1 , R 2 , R 3 , R 4 and X have the meanings given above and in the
  • R 1 , R 2 , R 3 , R 4 and X have the meanings given above,
  • a heteronucleophile can optionally also be contained directly in the aglycon part, whereupon the second step can then be omitted.
  • step (2) can also be repeated several times in the sense of the invention
  • the well-developed glycosidation processes according to Fischer or the numerous variants of the Konigs - &? Orr synthesis can be used (see the overviews above on the state of the art). nik)
  • the glycosidic fraction can be selected according to its constitution and the glycosidic linkage.
  • aldoses and ketoses typically with four to 8 carbon atoms in the chain
  • those with a non-natural configuration or constitution for example Aza-, thia-, phospha- or carbazucker
  • differently substituted for example O- or C-alkylated, O-acyherte, deoxy- or amino sugar
  • oxidized (glyconic and glycuronic acids, ketoaldoses, dial cans, etc.) descendants can be used
  • the part can be in its constitution (linear, branched, substituted), large (typically C2-C4), glycosidic linking position (typically alpha or beta to the aldehyde) and possibly its absolute
  • the simplest and typical case here is the allyl glycosides, of which some are also commercially available.
  • other aldehyde precursors can also be used, such as glycosylated acetals, alcohols, esters, carboxylic acids and other synthetic equivalents known to the person skilled in the art
  • linkages can also be used for the process according to the invention, such as N-, S- or C-glycosides, the production of which is known to the person skilled in the art and which have a significantly higher metabolic stability compared to the O-glycosides exhibit
  • the 1-O- and 2-O-glycosides of 3-butene-1,2-diol and compounds to be derived therefrom are also advantageous, since here the point of attachment in the glycosyl acceptor can be optionally determined and secondly the heteronucleophile for later ring formation.
  • Butenediol is commercially available in both racemic and enantiomerically pure form.
  • the allenyl adducts are formed in addition to the corresponding propargyl compounds in good selectivity ( 3 50%).
  • the former react in the sense of vinyl derivatives to form aldehydes glycosylated in the a-position.
  • the same compounds can also be obtained, for example, by adding allyl or vinyl Grignard reagents to protected glycosyl aldehydes (chemoselectively even with O-acetyl protective groups)
  • the reaction of the second stage of the process creates a new chiral center at the addition site.
  • the above-mentioned processes each give both diastereomers at comparable proportions. However, separation of the diastereomers at this or the subsequent stage can be avoided if asymmetric allyl silicon, allyl tin or allyl boron reagents are used However, these processes can only be used in aprotic organic solvents and therefore require the introduction of suitable protective groups in the glycoside
  • the third step of the method according to the invention uses an enzymatic aldol addition to complete the transformation of the aglycone into a sugar residue.
  • the aldehyde function is first generated from the synthesis equivalent introduced in the previous step and an aldol donor enzyme-catalyzed is added as a nucleophile.
  • the structure of the aldol Donors should be chosen so that they match the substrate selectivity of the aldolase.
  • the additions are highly diastereoselective and allow the synthesis of all diastereoisomeric oligosaccharides to be derived from this step as glycosyl ketoses and their derivatives in high chemical and optical purity
  • This finding is highly surprising since the used here
  • the glycosylated aldehydes are sterically extraordinarily demanding due to the large glycoside residues.
  • DHAP aldolases have a wide substrate tolerance for simple and substituted aliphatic aldehydes and themselves thus also well suited for the synthesis of monosaccharides and their derivatives (cf.
  • the additions are highly diastereoselective and that the oligosaccharides and their derivatives can be prepared in high chemical and optical purity. Since all four known types of DHAP aldolases can be used optionally, starting from a common one Precursors can generate all corresponding possible diastereomers in a predictable manner.
  • the enzymatic aldol additions in an aqueous environment are free of protective groups under particularly mild reaction conditions at room temperature and practically neutral pH (preferably 6 8-7 0), which increases the stability of both the glycosidic bond (s) and the reaction component DHAP remain guaranteed at a sufficiently high reaction rate
  • the high tolerance of the enzyme reaction can advantageously also be used in the process according to the invention for the synthesis of higher oligosaccharides (tri-, tetra-, etc.) and for the synthesis of chemically modified (typically substituted, alkylated, acylated) , acetalized) oligosaccharides with a modified activity profile
  • each of the aldolases listed above preferably uses DHAP as the nucleophilic aldol donor, but a number of structurally related donors can also be used.
  • the third key step according to the process of the invention can alternatively also be catalyzed by other aldolases with differing substrate specificity, which Instead of DHAP, for example, use pyruvate or phosphoenol pyruvate as the preferred donor substrate and thereby generate 2-keto acids derived from sugars with an interesting biological activity profile.
  • Further aldolases use acetaldehyde or glycine for the synthesis of aldoses or a-amino-b-hydroxy acids.
  • the method according to the invention can also be used to generate combinatorial oligosaccharide libraries
  • the DHAP used for the synthesis is commercially available or can be produced economically, for example, by glycerol phosphate oxidase-mediated oxidation of commercial glycerol phosphate (cf. DE-4 304 097 7).
  • the phosphorylated products can be easily isolated by standard processes, for example by ion exchange processes, while after phosphate ester hydrolysis ( eg catalyzed by
  • DHAP aldolases with different diastereospecificity and from different organisms are commercially available (e.g. Boeh ⁇ nger Mannheim GmbH, Sandhofer Str 1 16, 68298 Mannheim, DE, Sigma Chemie GmbH, Grunwalder Weg 30,
  • the compounds of the formula (I) according to the invention are useful for the inhibition and prevention of cell adhesion and cell adhesion-mediated diseases. They can be used for the treatment of inflammatory diseases, asthma, dermatitis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, malignant diseases, autoimmune diseases and infections of bacterial, fungal and viral pathogens can be used
  • the compounds according to the invention are valuable precursors or constituents for active pharmaceutical ingredients, in particular for the treatment of the diseases mentioned above
  • a 0 5M solution of the monosaccharide in alcohol is heated under reflux for 1 5 h with an acidic ion exchanger (100 g per mol monosaccharide).
  • the ion exchanger is filtered off and excess alcohol is removed in vacuo.
  • the glycosid is purified by recrystallization or chromatography on silica gel
  • a 0 4 M solution of the unprotected saccharide in acetic anhydride is mixed with 1% o (w / v) sodium acetate and heated to reflux for 2 h.
  • the solution is poured onto 2 volumes of ice water and neutralized with solid sodium hydrogen carbonate. It is extracted three times with 2 volumes of chloroform combined organic phases are washed thoroughly with sodium bicarbonate and sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo.
  • the peracetate obtained is further purified, if necessary, by recrystallization or chromatography
  • the product is a mixture of free aldehyde and two diastereomeric methyl hemiacetals in a ratio of 1: 2: 2.
  • AAV 7 from 12b-Ac ⁇ (18.9g).
  • the product is present as a mixture of two diastereomeric methyl hemiacetals in approximately equal proportions and about 10% free aldehyde.
  • AAV 7 from 13b-Ac ⁇ (9.68g).
  • the product is present as a mixture of two diastereomeric methyl hemiacetals in approximately equal proportions and about 25% free aldehyde.
  • a 1 M solution of the peracetylated saccharide is mixed with 1 volume of THF and 4 volumes of saturated aqueous NH ⁇ Cl solution (for solubility problems up to four times the amount of ethyl acetate and THF can be used).
  • 2 to 4 equivalents of zinc dust are added and with vigorous stirring 2 to 4 equivalents of allyl bromide added dropwise over 2 h with incomplete conversion (DC
  • AAV 9 (5 equivalents of 3,3-dimethylallyl bromide instead of allyl bromide) and AAV 10, from 2a-Ac 4 , 950 mg (81%).
  • AAV 6 AAV 7, AAV 9 and AAV 10, from 2a, 10.0g (82% for 4 steps).
  • the product corresponds to that produced according to AAV 8 from 2a-O.
  • AAV 6 AAV 7, AAV 9 and AAV 10, from 3a, 7.5g (83% for 4 steps).
  • the product corresponds to that produced according to AAV 8 from 3a.
  • AAV 7 AAV 9 and AAV 10, from 3b-Ac 3 , 130g (68% for 3 steps).
  • the product corresponds to that produced according to AAV 8 from 3b.
  • 109 (2RS) -10- (methyl- ⁇ -D-glucopyranuronosyl) -4-pentene-1,2-diol (55b).
  • AAV 6 AAV 7, AAV 9 and AAV 10, from 11b, 7 34g (60%)
  • AAV 1 from 51a (2.64g); according to NMR mixture of free aldehyde, hydrate and diastereomeric methyl hemiacetals.
  • AAV 1 from 67b (2 50g), according to the NMR mixture of free aldehyde (approx. 20%), aldehyde hydrate and diastereomeric methyl hemiacetals
  • the aldehyde dissolved in some water is taken up with an aqueous solution of DHAP (80-100mM), adjusted to pH 6 8-7 3 and aldolase (FruA, RhuA or FucA, 50-150 U per 1 mmol aldehyde) is added if the conversion is incomplete DHAP and, if necessary, enzyme are added after 1 or 2 days, and the pH is checked.
  • the ketose phosphate is bound to anion exchangers (HCO3 form) and with 150-200 mM Methyl ammonium bicarbonate buffer eluted The buffer is removed by concentrating in vacuo, taking up several times in water and then concentrating.
  • the ketose phosphate is obtained as the sodium salt by cation exchange (sodium-loaded cation exchanger or acidic ion exchanger and neutralization with sodium hydroxide solution)
  • a 20-100 mM solution of the isolated or crude ketose phosphate is adjusted to pH 75 (60) and mixed with 80-200 (20) U / mmol alkaline (acidic) phosphatase. After complete conversion (1-4 d), the mixture is activated carbon filtered and the solution (optional) desalted by filtration through an ion exchanger (HCO3 " and H form). The solution is concentrated in vacuo and the remaining syrup on silica gel, chromatographed on Ca2 + -loaded cation exchanger, on Biogel P2 or on an activated carbon / keselguhr (1/1) mixture
  • AAV 12 FluA
  • AAV 13 acid phosphatase
  • AAV 1 1 AAV 12 (FruA) and AAV 13 (alkal phosphatase), from 59b, 130mg
  • AAV 12 (FruA) and AAV 13 (alkal phosphatase), from 53b, 330mg (11%) lOld and 690mg (23%) 102d
  • AAV 1 1 AAV 12 (FucA) and AAV 13 (alkal phosphatase), from 52a, 66mg
  • AAV 11 AAV 12 (FucA) and AAV 13 (alkaline phosphatase); from 59b; 20mg (3%) mixture of 103b and 104b in the ratio 1: 2.
  • 13 C-NMR (75.4 MHz; D 2 O): d 106.0 (C-l '), 105.49 (C-l'), 101.2 (C -2), 100.92
  • AAV 12 FlucA
  • AAV 13 alkaline phosphatase
  • AAV 12 (FucA) and AAV 13 (alkaline phosphatase); from 53b; 372mg (12%) 103d and 62mg (2%) 104d.
  • AAV 1 1 AAV 12 (RhuA) and AAV 13 (alkaline phosphatase); from 52a; 550mg (19%) 105a and 120mg (4%) 106a.
  • AAV 12 (RhuA) and AAV 13 (alkaline phosphatase); from 53a; 150mg (6%) 105c and 201mg (7%) 106c
  • AAV 1 1 AAV 12 (RhuA) and AAV 13 (alkal phosphatase), from 53b, 247mg (8%) 105d and 440mg (14%) 106d
  • AAV 12 (FruA) and AAV 13 (alkaline phosphatase), from 26b, 154mg (45%) 108 and 109 in the ratio 6 5
  • AAV 12 FluA
  • AAV 13 alkal phosphatase
  • AAV 1 1 AAV 12 (RhuA) and AAV 13 (alkaline phosphatase), from 68b, 130mg (18%) mixture of 113 and 114 in a ratio of 1 1

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Abstract

L'invention concerne de nouvelles oligosaccharides et leurs dérivés, ainsi qu'un procédé général de préparation stéréodivergente d'oligosaccharides à partir de glycosides simples aisément accessibles, à partir de la part aglycone desquels une autre unité saccharide est créée de manière stéréosélective par réactions de prolongement de chaîne. A cet effet, il est prévu une addition chimique (optionnelle) d'un équivalent aldéhyde à une liaison double C=X dans l'aglycone, suivie d'une addition enzymatique diastéréosélective d'un donneur aldol nucléophile à l'aldéhyde glycosylé en présence de différentes aldolases stéréospécifiques. Les oligosaccharides obtenues qui portent une unité cétose supplémentaire à l'extrémité réductrice, en cas d'utilisation d'aldolases DHAP-dépendantes, ainsi que leurs esters de phosphate correspondants et leurs dérivés appropriés, s'utilisent comme constituants ou précurseurs de principes actifs pharmaceutiques.
PCT/EP1998/001096 1997-03-11 1998-02-26 Oligosaccharides et leurs derives et procede chimio-enzymatique permettant de les preparer WO1998040390A2 (fr)

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DE1997109787 DE19709787A1 (de) 1997-03-11 1997-03-11 Oligosaccaride und deren Derivate sowie ein chemo-enzymatisches Verfahren zu deren Herstellung
DE19709787.1 1997-03-11

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FR2999076A1 (fr) * 2012-12-07 2014-06-13 Oreal Nouveaux composes c-xylosides carboxyles et utilisation en cosmetique.
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JP2020522514A (ja) * 2017-06-05 2020-07-30 フラッグシップ パイオニアリング イノベーションズ ブイ， インコーポレイテッド マルチバイオティック剤及びその使用方法

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