CN107709341A - New Neisseria meningitidis serum group Y oligomer and its synthetic method - Google Patents
New Neisseria meningitidis serum group Y oligomer and its synthetic method Download PDFInfo
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- CN107709341A CN107709341A CN201580081282.5A CN201580081282A CN107709341A CN 107709341 A CN107709341 A CN 107709341A CN 201580081282 A CN201580081282 A CN 201580081282A CN 107709341 A CN107709341 A CN 107709341A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
Abstract
Method the present invention relates to the new oligomer (Men Y oligomer) of Neisseria meningitidis serum group Y CPS repeat unit and for synthesizing new Men Y oligomer.Particularly, the present invention relates to the chemical synthesis of the tetramer of Men Y CPS repeat units, it can act as exploitation for the semi-synthetic of meningococcus serum group Y bacterium infections and the candidate of the conjugate vaccines of synthesis.
Description
Technical field
The present invention relates to the new oligomer of Neisseria meningitidis serum group Y CPS repeat unit (hereinafter referred to as
Men-Y oligomer).The invention further relates to the method for synthesizing new Neisseria meningitidis serum group Y oligomer.Particularly
For, the present invention relates to can act as exploitation for the semi-synthetic of meningococcus serum group Y bacterium infections and synthesize conjugated
The chemical synthesis of the Neisseria meningitidis serum group Y of the candidate of the vaccine tetramer (the hereinafter referred to as Men-Y tetramers).
Background technology
Meningitis causes the death of about 170,000 people every year, and developed country's at least 5-10% case is died of illness
There are 20% case case fatality rate in rate, developing country.Streptococcus pneumonia, b types haemophilus influenzae (Hib) and Neisseria meningitdis
The reason for bacterium is most of meningitis case in world wide.However, in spite of modern antibiotics, Neisseria meningitdis
The main reason for bacterium is still meningitis and other invasive bacterium infections.
Meningococcal disease is the medical acute disease for needing to diagnose and treat immediately.
Identified 13 kinds of different serum groups altogether of Neisseria meningitidis at present, i.e. A, B, C, D, 29E, H, I,
K, L, W135, X, Y and Z, but about 90% infection is caused by serum group A, B, C, Y and W135.
Following kind of vaccine can be used for meningococcal infection：
For preventing polysaccharide vaccine of the disease more than 30 years.Meningococcal polysaccharide vaccine can be to control the disease
Various combinations, (group A and C), trivalent (group A, C and W) or tetravalence (group A, C, Y and W) form obtain for example, divalence.
Since 1999, there is the meningococcal conjugate vaccine for group C.A, C, Y and W of tetravalence are conjugated
Vaccine is widely used, and the world being approved for since two thousand five including Canada, the U.S., Europe and India is each
The children and adult on ground.Other combinations of serum group can also be obtained with the conjugate vaccines of approval.Except the group A conjugate vaccines of unit price
Outside, available meningococcal conjugate vaccine because its is with high costs, is for the poor crowd of natural resources shortage country at present
It can not contact.
At present, the vaccine available for Men-Y utilizes the polysaccharide from bacterial origin separation, and these polysaccharide are with such as handling bacterium living
The various risks such as the danger of culture are related.In addition, the bacterial polysaccharides being generally separated is heterogeneous, so that it cannot pass through the phase
The homogeney standard of prestige.The heterogeneity of bacterial polysaccharides result in the heterogeneity of the conjugate prepared using it, and then cause difference
Property is big, therefore causes the unqualified of conjugate batch.
In the past ten years, people increasingly pay close attention to organic conjunction of the bacterial antigens of the analog including capsular oligosaccharide
Into.In view of prior art, the meningococcal conjugate vaccine containing synthesis Men-Y oligosaccharides is than conventional vaccine advantageously.Synthesis
Antigen is uniform in size and characterizes fully, it reduce the heterogeneity of caused conjugate, and in final conjugate between batch
Change is smaller.One of major advantage of synthetic antigen is can be engineered with required joint, for simplify it is conjugated and
Obtain more preferable yield.
There is presently no the production of open Men-Y organic syntheses and the prior art of purifying procedure.International patent application
No. PCT/US2013/042428 " Multivalent meningococcal conjugates and methods for
Prepari ng conjugates " are related to immunogenic conjugate, and it includes at least one be conjugated with Neisseria surface protein
Kind polysaccharide or protein, it can trigger should for the immune of the meningococcal polysacharide (PS) from group A, C, W-135 and Y
Answer.The international patent application only discloses the general description of Men Y oligomer preparation, but few without that can disclose Men-Y
The preparation of aggressiveness.In addition, either the prior art available for other serum groups of Neisseria meningitidis is time-consuming, or produce not
With the mixture of the oligomer of size.
Goal of the invention
It is a primary object of the present invention to provide the new widow of Neisseria meningitidis serum group Y CPS repeat unit
Aggressiveness.
It is another object of the present invention to provide in the synthesis for meningococcus bacterium infection and semi-synthetic conjugated
The new oligomer of the Neisseria meningitidis serum group Y CPS repeat unit of candidate is can act as in vaccine development.
It is another object of the present invention to provide for the semi-synthetic or complete of meningococcus serum group Y bacterium infections
The new Men-Y tetramers of candidate are can act as in the exploitation of fully synthetic vaccine.
It is another object of the present invention to provide the change using the purifying sugar synthesis Men-Y oligomer with certain chain lengths
Method.
It is another object of the present invention to provide can produce the antigenic with improving of immunogenicity conjugate vaccines
The chemical synthesis process of Men-Y oligomer.
It is another object of the present invention to provide a kind of synthesis for the physical chemistry quality standard for preparing and meeting purity
The method of Men-Y pod membrane oligomer.
It is another object of the present invention to provide the preservation for having increased effect when being conjugated with carrier protein and improving
Time limit has cost-benefit Men-Y oligomer.
The content of the invention
Therefore, the invention discloses Neisseria meningitidis serum group Y oligomer and its synthetic method is obtained.It is described
Men-Y oligomer can be used as half for meningococcus serum group Y bacterium infections after suitable carrier protein is conjugated to
Synthesis and the candidate of synthesis conjugate vaccines exploitation.The vaccine can be applied by parental routes.
The Men-Y oligomer of the present invention has improved antigenicity and improved shelf-life.The Men-Y oligomer also accords with
Close the physical chemistry quality standard of purity and there is cost benefit.
The method of the present invention discloses the synthesis of Men-Y oligomer, and Men-Y oligomer includes two kinds of main composition units：
Start element and Growth Units.Start element by the monose of another suitably protecting to the monose of suitably protecting (more particularly
But be not limited to neuraminic acid) glycosylation prepare.The monose of another suitably protecting is selected from hexose, more particularly but not
It is limited to glucose.Growth Units (more particularly hexose, are particularly but not limited to grape by the monose of another suitably protecting
Sugar) it is prepared by the glycosylation of the monose (being particularly but not limited to neuraminic acid) of suitably protecting.
Start element and Growth Units are linked together to provide tetrose or dimerization in predetermined temperature using catalyst
Body unit.The catalyst used in the connection is glycating agent/lewis acid catalyst, and it is selected from, but not limited to, N- iodo fourths
Imidodicarbonic diamide (NIS), trifluoromethanesulfonic acid (TfOH), trifluoromethanesulfonic acid trimethyl silyl ester (TMSOTf), trifluoromethanesulfonic acid
Silver (CF3SO3Ag).Dimerization body unit is reacted with such as, but not limited to alkaline reagent such as sodium methoxide to promote open loop.So obtain
Dimerization body unit reacts with Growth Units again, to form tripolymer.Tripolymer is iterated reaction under condition of similarity, with
To protected higher oligomers (Y), it includes the tetramer, pentamer, six aggressiveness, heptamer etc..
The protected higher oligomers for making so to obtain carry out the deprotection of blocking group successively, and it is advanced to obtain Men-Y
Oligomer.
The Neisseria meningitidis serum group Y so obtained higher oligomers have improve yield, high effect and
It can act as candidate of the exploitation for the conjugate vaccines of the disease as caused by infecting Men-Y.
All more preferable yields for being used to obtain the tetramer using the illustrative steps of new method synthesis Men-Y oligomer, Fig. 8
Middle display purity>95%, and antigenicity enhancing is shown in Fig. 9.
Brief description of the drawings
Fig. 1 depicts the Men-Y tetramers (compound 26)1H-NMR；
Fig. 2 depicts the Men-Y tetramers13C-NMR；
Fig. 3 depicts the COSY H NMR spectroscopies of the Men-Y tetramers；
Fig. 4 depicts the HMBC H NMR spectroscopies of the Men-Y tetramers；
Fig. 5 depicts the HSQC H NMR spectroscopies of the Men-Y tetramers；
Fig. 6 depicts the TOCSY H NMR spectroscopies of the Men-Y tetramers；
Fig. 7 depicts the DEPT H NMR spectroscopies of the Men-Y tetramers；
Fig. 8 depicts the HPSEC analyses for Men-Y tetramer purity；
Fig. 9 depicts poly- to the Men-Y tetramers and Men-Y tetra- by the suppression ELISA for anti-Men-Y polyclonal serums
The antigenicity analysis of body-tetanus toxoid (TT) conjugate.
Special embodiment
Therefore, the present invention relates to new Men-Y oligomer.The invention further relates to the method for synthesizing new Men-Y oligomer.
More especially, the present invention relates to the time that the semi-synthetic and synthetic vaccine that can act as meningococcus bacterium infection is developed
Select the chemical synthesis of the Men-Y tetramers of thing.The vaccine can be applied with suitable mode of administration, more especially, pass through
Parental routes are applied.The synthesis is completed in following steps：
Step 1：The synthesis of Growth Units (compound 18 shown in scheme I)；
Step 2：The synthesis of start element (compound 20 shown in scheme II)；
Step 3：The synthesis of higher oligomers (compound 21 shown in scheme III, 22,23,24,25, d26).
Before a preferred embodiment of the present invention is described, it should be appreciated that the invention is not restricted to described special
Material, because they can change.It is to be further understood that terms used herein is only to describe particular implementation as mesh
, it is not intended to the scope limiting the invention in any way.
Must be noted that unless the context clearly indicates otherwise, otherwise singulative "one", " one kind " and "the"
Including plural form.
In a non-limiting examples of methods described, the N-acetylneuraminic acid as compound 1 is such as
Dowex 50W X8(H+) methylate in the presence of the catalyst such as resin, obtain compound 2.The compound 2 so obtained
It is acylated in the presence of pyridine in the presence of the acylating agents such as acetic anhydride, obtains compound 3.This method helps to shield
Cover hydroxyl.
It is (more special that the compound 3 so obtained carries out selective halogenation in the presence of the halogenating agent such as chloroacetic chloride and HCl
It is not chlorination), obtain compound 4.Compound 4 in the presence of the DIPEA (weak nucleophilic reagent) of also referred to as Hunig alkali with it is all
Such as p-methylphenyl mercaptan (TolSH) thiolating reagent reacts and obtains the compound 5 that second is connected with-Stol groups.Such as
This compound 5 obtained carries out deacylation in the presence of MeOH, methanesulfonic acid (MsOH), obtains compound 6.The chemical combination so obtained
Thing 6 is in MeCN/H2In the presence of O with such as triphosgene, NaHCO3Reacted Deng carbonylation agent and carry out the shape of oxazolidone ring
Into obtaining compound 7.The compound 7 so obtained is in t-butyldiphenylsilyl chloride TBDPSCl/DMF etc.
Hydroxyl existing for end is protected in the presence of protection reagent, then protected using 2,2-DMP for acetonide, so
It is acylated afterwards using AcCl, obtains compound 8.The compound 8 so obtained is in the presence of NIS, TfOH, DCM and such as
Dibutylphosphoric acid ester (Bu2PO4The reaction reagent reaction such as H), to obtain the phosphate radical leaving group in terminal position, this improves work
For the alpha selective of compound 9.
In commercially available 10 β of compound-D-Glucose pentaacetate and thiocresol and (catalyst) DCM (solvent)
BF3:OEt2Reaction obtains compound 11 to protect α positions.Deacetylation is carried out in compound 11MeOH in the presence of MeONa
Reaction, obtains compound 12.The compound 12 so obtained and t-butyldiphenylsilyl chlorine (TBDPS-Cl) etc.
Silyl-protecting groups react, and so as to protect-OH the bases of the 6th of compound 12 the, obtain the compound 13 that yield is 80%.Such as
This obtained compound 13 is alkylated and with Benzylation protection ad-hoc location, reacts and obtains yield at 0 DEG C to room temperature and be
76% compound 14.
The above method is known method.
Then by making the deprotection such as tetra-n-butyl ammonium fluoride (TBAF) in compound 14 and tetrahydrofuran (THF)
Reagent reacting, recover a protected hydroxyl of compound 14, so as to obtain the compound that yield scope is 85% to 95%
15.Compound 14 is as the intermediate in the synthesis of Growth Units 18.
The compound 14 and 5- azidos hexanol progress of the surplus so obtained is glycosylation, obtains compound 16.So
The yield of the compound 16 of acquisition is in the range of 65% to 75%, and more particularly 70%.Make compound 16 by such as THF solvents
In the processing of the silicyl deprotecting regent such as TBAF, cause to remove-OTBDPS the groups spatially hindered, obtain compound
17.Above-mentioned reaction obtains compound 17, generally α:β ratios increase (95:, and scope of the reaction yield 55% to 65% 5)
It is interior, more particularly 60%.The compound 17 so obtained is used as the intermediate during start element 20 synthesizes.
Then a part for compound 9 in the presence of the catalyst such as TMSOTf at low temperature, more especially-
In the range of 80 DEG C to -60 DEG C, reacted with compound 15 to produce Growth Units (compound 18).
Then the remainder of compound 9 in the presence of the catalyst such as TMSOTf at low temperature, more especially
Reacted in the range of -80 DEG C to -60 DEG C with compound 17, obtain compound 19.
The compound 19 so obtained in the presence of methanol (MeOH)/dichloromethane (DCM) with the alkalescence such as NaOMe
Reagent reacting, obtain start element (compound 20).
Using catalyst, start element (20) and Growth Units (18) at low temperature, more particularly at -50 DEG C to -30 DEG C
In the range of link together, to provide tetrose or dimerization body unit (21).Catalyst for the connection is but not limited to,
NIS/TfOH/ trifluoromethayl sulfonic acid trimethyl silyl esters (TMSOTf)/silver trifluoromethanesulfonate in the presence of solvent
(CF3SO3Ag).Tolyl sulphur (thiotolyl, Stol) group of activation of catalyst compound 18.It is easily removed after activation, so
Stol groups are substituted by the free hydroxyl group of start element (20) afterwards.
Dimerization body unit (21) reacts with such as, but not limited to alkaline reagent such as sodium methoxide, is formed and is protected in order to open loop
The dimerization body unit (22) of shield.Hereafter, the dimer so obtained in the presence of the catalyst and the alkaline reagent
Be iterated reaction under conditions of similar, obtain including tripolymer, the tetramer, pentamer, six aggressiveness, heptamer, 24,26,
The advanced synthesis oligomer such as 28...n).
The dimerization body unit (22) so obtained reacts with Growth Units at similar temperature and atmospheric pressure again,
Result in tripolymer (23,24).The tripolymer so obtained is reacted to obtain four under condition of similarity with Growth Units again
Polymer unit (25).The tetramer undergo at similar conditions iteration reaction with obtain including the tetramer, pentamer, six aggressiveness,
The higher oligomers (Y) of heptamer etc..
The higher oligomers so obtained are in such as BF3:OEt2ACN、NaOH、MeOH、H2/Pd(OH)2Deng deprotecting regent
In the presence of carry out blocking group final deprotection.In the presence of deprotecting regent, the order deprotection of blocking group produces
The advanced oligomers of Men-Y (d22, d24, d26, d28...dn) of deprotection.
Total time needed for methods described in the range of 330 hours to 400 hours, more particularly 370 hours, causes to show
Relatively low production cost.
The higher oligomers so obtained are conjugated by built-in attachment to be connected with carrier protein, and acquisition is directed to meningitis
The semi-synthetic conjugate vaccine of pneumoniae serotype group Y bacterium infections.This chemical synthesis process can be used for preparing synthetic proteins
Matter/peptide is to prepare completely synthetic conjugate vaccine.It should be noted that there is good yield with this conjugated generation of carrier protein
With antigenic vaccine of enhancing.
In one embodiment, it is poly- by carrying out suppression enzyme linked immunosorbent assay (ELISA) (suppressing ELISA) test Men-Y tetra-
The antigenicity of body, find the tetramer and its can be neutralized for the special of Men-Y capsular polysaccharides with the conjugate of tetanus toxoid
Property antibody.
The complete scheme of MenY tetramers synthesis：
Scheme I：The synthesis of Growth Units 18
The synthesis of phosphoric acid sialic acid donor：
Glucoreceptor 15＆17 synthesis
Scheme II：The synthesis of start element 20
Scheme III：The synthesis of dimer, tripolymer and the tetramer
The synthesis of dimer, tripolymer and tetramer unit
The detailed description of above method is explained by non-limiting example as follows：
Embodiment：
Embodiment 1：The preparation of step 1- compounds 2
Process：Added to agitating solution of the N-acetylneuraminic acid (2.0kg, 6.472mol) in methanol (32L)
Dowex 50W X8 resins.Reaction is stirred at room temperature 24 hours.Pass through TLC (20% methanol；DCM) monitoring reaction.After the completion of,
Reactant mixture is filtered, resin is washed with methanol (2 liters).Filtrate is concentrated, obtains the required product (2.0kg as white solid；
95%).
Embodiment 2：The preparation of step 2- compounds 3
Process：DMAP is added in 0 DEG C of mechanical agitation solution to compound 2 (1kg, 3.095mol) in pyridine (10 liters)
(38g, 0.0309mol), then add acetic anhydride (11.7 liters).Reaction is stirred at room temperature 24 hours.After the completion of, reaction is mixed
Compound is concentrated in vacuo (10 millibars).By the flash column chromatography crude compound on silica gel (230 mesh to 400 mesh), with 30%
Ethylacetate-hexane to 100% ethyl acetate elutes.Obtain (the 1.4kg of compound -3 as white foam solid；
87%).
Embodiment 3：The preparation of step 3- compounds 4
Process：Agitating solution of the compound -3 (1.4kg, 2.626mol) in chloroacetic chloride (7.5 liters) is cooled to 0 DEG C；
And add solution (4.5 liter) of the freshly prepared HCl in chloroacetic chloride.Gained reactant mixture is warmed to room temperature and stirs 16
Hour.After the completion of, reactant mixture is concentrated under reduced pressure.The compound of acquisition and toluene (2 × 2.5 liters) condistillation, and will slightly produce
Thing is sent into next step (1.4kg, 99%).
Embodiment 4：Step 4：The preparation of compound 5
Process：The addition pair into mechanical agitation solution of the compound -4 (1.35kg, 2.652mol) in DCM (13.5 liters)
Thiocresol (324g, 2.652mol).The solution is cooled to 0 DEG C, it is in a nitrogen atmosphere, slow with 30 minutes with dropping funel
Add diisopropylethylamine (548ml, 3.135mol).Gained reactant mixture is warmed to room temperature and stirred 18 hours.Complete
Afterwards, monitored and reacted by TLC；Reactant mixture is cooled to 0 DEG C and with (5.0 liters) of DCM dilution, washed with water (2 × 5 liters).
Organic layer is separated, with aqueous salt solu-tion, is dried and concentrated with sodium sulphate.The compound of acquisition 25% ethyl acetate/oil
Ether processing.The white solid being filtrated to get and drying (900g, 60%).
Embodiment 5：The preparation of step 5- compounds 6
Process：At 0 DEG C into agitating solution of the compound -5 (500g, 0.8375mol) in methanol (5.0L) slowly
Add methanesulfonic acid (322g, 3.35mol).Obtained reactant mixture is heated to reflux 36 hours.Reactant mixture is cooled to 0
DEG C, it is quenched with triethylamine (790.0ml).Mixture is concentrated and is used for residue without any further purification in next step
Suddenly.LC MS purity 96%.It is (big and heavy：650g).
Embodiment 6：The preparation of step 6- compounds 7
Process：At room temperature, compound -6 is dissolved in churned mechanically acetonitrile (4.0 liters), water (5.0 liters) and NaHCO3
In the mixture (1.8kg, 4.651mol) of (2.352kg, 46.51mol).Reactant mixture is cooled with an ice bath to 0 DEG C, and
Solution of the triphosgene (0.895kg, 4.651mol) in acetonitrile (1.0 liters) is added dropwise in 60 minutes.Reactant is stirred at 0 DEG C
3 hours.After the completion of, with 10%HCl (3 liters) neutralization reaction mixture.With (2 × 4.0 liters) extraction products of ethyl acetate.Organic layer
With water, salt water washing, through Na2SO4It is dried and concentrated.Crude compound is by flash column chromatography, with 2-5% methanol；DCM is washed
It is de-.Totally 56%) (700g, 2 steps for the compound -6 for obtaining as pale solid.
Embodiment 7：Step 7- compounds 7A preparation
Process：To agitating solution of the compound -7 (700g, 1.694mol) in DMF (6.0 liters) add imidazoles (288g,
4.237mol).T-butyldiphenylsilyl chlorine (557g, 2.033mol) is slowly added at 0 DEG C 10 minutes.By reaction temperature
It is warmed to room temperature and stirs 16 hours.Pass through the process of TLC monitoring reactions.After the completion of, (10 liters) RM is diluted with water.Use ethyl acetate
(2 × 4 liters) extraction products.Organic layer is separated, with salt water washing, uses Na2SO4It is dried and concentrated.It is pure by silica gel flash column chromatography
Change product, using 60% ethylacetate-hexane as eluant, eluent, obtain pale solid (1000g, 90%).
Embodiment 8：Step 8- compounds 7B preparation
Process：Add to agitating solutions of the compound 7A (1050g, 1.697mol) in 2,2-dimethoxypropane (7 liters)
Enter camphorsulfonic acid (470g, 2.036mol).Mixture is stirred at room temperature 3 hours.Reaction process is monitored by TLC.Pass through TLC
After the completion of；By reactant mixture triethylamine (350mL；2.515mol) be quenched.Reactant mixture is concentrated.Crude compound passes through
Silica gel flash column chromatography.Obtain the compound -7B (1000g, 92%) as canescence foaming solid.
Embodiment 9：The preparation of step 9- compounds 8
Process：Diisopropyl second is added to agitating solutions of the compound 7B (590g, 0.8538mol) in DCM (5.0 liters)
Base amine (1500ml, 8.538mol).Solution is cooled to 0 DEG C, is slowly added to chloroacetic chloride with dropping funel in a nitrogen atmosphere
(490ml, 6.83mol) 10 minutes.Gained reactant mixture is warmed to room temperature and stirred 18 hours.After the completion of supervised by TLC
Survey reaction；Reactant mixture is cooled to 0 DEG C, and with (3 liters) dilutions of DCM, washed with water (3 liters).Organic layer is separated, uses salt solution
Solution washs, and is dried and concentrated with sodium sulphate.Product purifies on silica gel column chromatography；10-20% ethyl acetate；Hexane is used as and washed
De- agent (yield：500g, 80%).
Embodiment 10：The preparation of step 10- compounds 9
Process：In a nitrogen atmosphere, to compound -8 (100g, 0.1364mol) and dibutylphosphoric acid ester (54mL；
0.2728mol) 4A ° of MS is added in the stirring mixture in DCM (1 liter) (to activate 2 hours under 140 DEG C of high vacuum；
100g, wt/wt).Mixture is stirred at room temperature 2 hours, is subsequently cooled to 0 DEG C, add NIS (61.11g,
0.2728mol), it is subsequently added into trifluoromethanesulfonic acid (3.62mL, 0.0409mol).Reaction temperature is kept for 5 hours at 0 DEG C.Pass through
TLC monitors reaction process.After the completion of, reactant mixture is quenched with the hypo solution (250ml) of saturation.Filtered through diatomite,
Extraction.Organic layer is separated, is then washed with water, uses Na2SO4It is dried and concentrated.It is roughened by silica gel flash column chromatography and is closed
Thing.Obtain the compound -9 (80.0g, 70%) as cohesive material.
Embodiment 11：The preparation of step 11- compounds 11
Process：In flame-dried flask, under an argon atmosphere, β-D-Glucose is added in dichloromethane (5 liters)
Pentaacetate 10 (500g, 1.2816mol), toluene-ω-thiol (255g, 2.050mol) and 4A ° of molecular sieve powder (500g).Will
The solution is cooled to 0 DEG C, adds BF3·Et2O (49%；1000ml, 3.5886mol).The mixture is stirred 16 hours.Will be anti-
(2 liters) dilutions of mixture dichloromethane are answered, is washed with sodium acid carbonate (2 × 2.5L saturated aqueous solutions), is then washed with water (3 liters)
Wash.Organic layer Na2SO4Dry, filter and be concentrated in vacuo.By flash column chromatography residue, obtain as white solid
Compound -11 (417g, 72%).
Embodiment 12：The preparation of step 12- compounds 12
Process：In flame-dried RB flasks, under an argon atmosphere, compound 11 (417g, 0.9182mol) is dissolved in
In methanol (4.0 liters).The solution (39.6ml 25% solution) of sodium methoxide in methyl alcohol is added, and gained mixture is stirred 2
Hour.After the completion of, amberlite IR-120 is added portionwise+Ion exchange resin, until solution becomes neutral.By reactant mixture
Filter vacuum is concentrated to remove resin, obtains the compound 12 (254g, 95%) as white crystalline solid by filtering.
Embodiment 13：The preparation of step 13- compounds 13
Process：To agitating solution of the compound -12 (200g, 0.402mol) in DMF (2.0 liters) add imidazoles (114g,
1.678mol).10 points of t-butyldiphenylsilyl chlorine (269g, 0.979mol) is slowly added into above-mentioned solution at 0 DEG C
Clock.Reaction temperature is warmed to room temperature and stirred 16 hours.Pass through the process of TLC monitoring reactions.After the completion of, reactant mixture is used
(4 liters) dilutions of water.Product (2 × 1 liters) extractions of ethyl acetate.Organic layer is separated, with salt water washing, uses Na2SO4It is dry and dense
Contracting.By silica gel flash column chromatography product, using 60% ethylacetate-hexane as eluent, pale solid is obtained
(260g, 72%).
Embodiment 14：The preparation of step 14- compounds 14
Process：By compound 13 (260g, 0.4962mol) and benzyl bromide a-bromotoluene (273ml, 2.2328mol) at DMF (2.5 liters)
In stirring mixture be cooled to 0 DEG C, sodium hydride (99g, 2.480mol) is added portionwise at 0 DEG C.RM is stirred at room temperature 16
Hour.TLC shows SM consumption, is then quenched RM with icy water (4 liters), and with ethyl acetate (2 × 1 liters) extract.Separation has
Machine layer is simultaneously concentrated under reduced pressure.By crude compound by flash column chromatography, 5% ethyl acetate-hexane elution of product, made
For the compound 14 (300g, 76% yield) of colourless liquid.
Embodiment 15：The preparation of step 15- compounds 15
Process：Compound 14 (145g, 0.1826mol) is dissolved in THF (1.4 liters), is cooled to 0 DEG C, adds 1M THF
In TBAF (219mL, 0.2191mol).Remove cooling bath and reactant mixture is stirred at room temperature 16 hours.Pass through TLC
Monitoring reaction, after the completion of, reaction is diluted with water, is extracted with ethyl acetate (2 × 500ml).Organic layer Na2SO4Dry, filtering
And concentrate.Crude product is purified by FCC, with 20%EtOAc/ Hex.Obtain as thick liquid compound (90g,
89%).
Embodiment 16：The preparation of step 16- compounds 16
Process：In a nitrogen atmosphere, to compound -14 (50g, 0.0629mol) and 6- azido hexanols (18g；
4A ° of MS 0.1259mol) is added in the stirring mixture in diethyl ether (500ml) (2 hours under 140 DEG C of high vacuum；50g,
wt/wt).Mixture is stirred at room temperature 2 hours, is subsequently cooled to -40 DEG C.NIS (28.2g, 0.1259mol) is added, so
Trifluoromethanesulfonic acid (2.8ml, 0.0314mol) is added afterwards and continues stirring 2 hours.After the completion of TLC, by adding saturation sea
Reactant mixture is quenched in ripple solution (100ml).Reactant mixture is filtered by diatomite, and filtrate is transferred in separatory funnel.Point
From organic layer, it is washed with water, uses Na2SO4It is dried and concentrated.Crude compound is by flash column chromatography, with 10% ethyl acetate
And Hex.Obtain the compound -16 (35g, 70%) of the Anomeric Mixture as cohesive material.
Embodiment 17：The preparation of step 17- compounds 17
Process：Compound 16 (100g, 0.123mol) is dissolved in THF (1 liter), 0 DEG C is cooled to, adds in 1M THF
TBAF (148mL, 0.1476mol).Cooling bath is removed and is stirred at room temperature 16 hours.Monitored and reacted by TLC.Complete
Afterwards, reaction is diluted with water, is extracted with ethyl acetate (2 × 500ml).Organic layer Na2SO4It is dried, filtered and concentrated.Crude product
By flash column chromatography, with 20%EtOAc/ Hex.Obtain the compound (55g, 78%) as thick liquid.
Embodiment 18：The preparation of step 18- compounds 18
Process：By compound -15 (43.3g, 0.0778mol) and (84g of compound -9；Mixture 0.1307mol) is molten
Solution adds MS 4A ° (45g) in DCM (430ml).Reactant mixture is stirred at room temperature 2 hours.It is subsequently cooled to -78
DEG C, add TMSOTf (15.58mL, 0.0855mol).Reaction is maintained at -78 DEG C and stirred 1 hour.After the completion of, supervised by TLC
Survey reaction process；Reactant mixture is quenched with triethylamine (1.2 equivalent), filtered by diatomite.It is molten with saturated sodium bicarbonate
Liquid (300mL) washs organic layer, separates organic layer and with water and aqueous salt solu-tion, uses Na2SO4It is dried, filtered and concentrated.Slightly
Compound passes through flash column chromatography；With 30% ethyl acetate and Hex, the compound 18 as white solid is obtained
(85g, 93%).
Embodiment 19：The preparation of step 19- compounds 19
Process：To compound -17 (45g, 0.0778mol) and (85g of compound -9；0.1037mol) at DCM (450mL)
In mixture in add MS 4A ° (45g), reactant mixture is stirred at room temperature 2 hours.- 78 DEG C are subsequently cooled to, is added
Enter TMSOTf (15.66mL, 0.0855mol).Continue stirring 2 hours at that same temperature.Reaction process is monitored by TLC；
After the completion of, reactant mixture will be quenched using triethylamine (1.2 equivalent), be filtered by diatomite.Use saturated sodium bicarbonate solution
(500mL) washs organic layer, then with water and aqueous salt solu-tion, uses Na2SO4It is dried, filtered and concentrated.Crude compound passes through
Flash column chromatography；With 30% ethyl acetate and Hex, the compound -19 of white foam solid is used as using offer
(80g, 86%).
Embodiment 20：The preparation of step 20- compounds 20
Process：Under an argon atmosphere, compound -19 (80g, 0.0676mol) is dissolved in methanol (533mL) and DCM
In (267mL).The solution (14.6mL, the NaOMe in 25% methanol) of sodium methoxide in methyl alcohol is added, by mixture at room temperature
Stirring 1 hour.After the completion of reaction, ion exchange resin (IR 120+) is added portionwise until solution is neutralized.Filtering reaction mixing
Thing, filtrate is concentrated, passes through flash column chromatography crude product (ethyl acetate:Petroleum ether=2:1 is used as eluant, eluent), to provide work
For the compound -20 (55g, 70%) of white foam solid.
Embodiment 21：The preparation of step 21- compounds 21
Process：To compound -18 (53g, 0.0453mol) and (35g of compound -20；0.0302mol) in ether
4A ° of molecular sieve (35g) is added in agitating solution in (350mL) and is stirred at room temperature 2 hours.The mixture is cooled to 0
℃.Into the mixture disposably add NIS (13.54g, 9.030mmol), then add trifluoromethanesulfonic acid (1.34mL,
0.0151mol).Reaction temperature is warmed to room temperature and kept for 16 hours.Reaction process is monitored by TLC.After the completion of, use saturation
Reactant mixture is quenched in hypo solution (250ml), is diluted with ethyl acetate (300ml).Filtered through diatomite, separation has
Machine layer.Organic layer is washed with water, uses anhydrous Na2SO4It is dried, filtered and concentrated.Crude compound by flash column chromatography,
With 30% ethyl acetate and Hex, the compound -21 (32g, 48%) as white solid is obtained.
Embodiment 22：The preparation of step 22- compounds 22
Process：In flame-dried flask, under an argon atmosphere, compound -21 (10g, 4.5454mmol) is dissolved in
In methanol (65mL) and DCM (35mL).It is (molten in 0.982mL 25% methanol to add the solution of sodium methoxide in methyl alcohol
Liquid), and mixture is stirred at room temperature 1 hour.After the completion of reaction, it is quenched using the amberlite IR 120 being added portionwise
Reactant mixture, until solution is neutralized.Reactant mixture is filtered, filtrate is concentrated and passes through flash column chromatography (acetic acid second
Ester:Petroleum ether=2:1-3:1 is used as eluant, eluent), to provide the compound -22 (6.1g, 62%) as white foam solid.
Embodiment 23：The preparation of step 23- compounds 23
Process：To compound -22 (15g, 6.899mmol) and (12g of compound -18；10.349mmol) in absolute ether
4A ° of molecular sieve (15g) is added in agitating solution in (150mL), mixture is stirred at room temperature 2 hours.The mixture is cold
But to 0 DEG C.Into the mixture add NIS (3.1g, 13.790mmol), then add trifluoromethanesulfonic acid (0.306ml,
3.450mmol).The reactant mixture of gained is stirred at room temperature 16 hours.After the completion of TLC, the thio sulphur of saturation is added
Reactant mixture is quenched in acid sodium solution (150ml).Reactant mixture is filtered by diatomite, by filtrate organic layer water and salt
Water washing, use anhydrous Na2SO4It is dried, filtered and concentrated.Crude compound by flash column chromatography, with 50% ethyl acetate and
Hex.Obtain the compound -23 (12g, 41%) as white foam solid.
Embodiment 24：The preparation of step 24- compounds 24
Process：In flame-dried flask, under an argon atmosphere, compound 23 (12g, 3.732mmol) is dissolved in first
In alcohol (80mL) and DCM (40mL).The solution (0.806mL, 25%) of sodium methoxide in methyl alcohol is added, and by mixture at 0 DEG C
Lower stirring 1 hour.After the completion of TLC, reactant mixture is quenched by the way that ion exchange resin (IR 120+) is added portionwise, directly
It is neutralized to solution.Reactant mixture is filtered, concentrates, passes through flash column chromatography (ethyl acetate:Petroleum ether=2:1 conduct is washed
De- liquid) purification of crude product, to provide the compound 24 (7g, 60%) as white foam solid.
Embodiment 25：The preparation of step 25- compounds 25
Process：To compound -24 (4.1g, 1.4733mmol) and (3.1g of compound -18；2.6505mmol) in ether
4A ° of molecular sieve (4.1g) is added in agitating solution in (40mL) and is stirred at room temperature 2 hours.Immediately add NIS (0.34g,
1.5175mmol), trifluoromethanesulfonic acid (0.13mL, 1.4733mmol) is then added at room temperature.Continue stirring 60 at room temperature
Hour.Pass through TLC (35% ethyl acetate；Hexane) monitoring reaction process.After the completion of, use saturated sodium thiosulfate solution
Reactant mixture is quenched in (40mL).Filtered through diatomite, separate organic layer.Organic layer is washed with water, uses anhydrous Na2SO4It is dry
It is dry, filter and concentrate.By crude compound by flash column chromatography, with 20-30% ethyl acetate and Hex.Made
For the compound -25 (2.06g, 38%) of white solid.
Embodiment 26：Step 26- compounds 25A preparation
Process：Under an argon atmosphere, compound -25 (3g, 0.7088mmol) is dissolved in methanol (624mL) and DCM
In (12mL).The solution (0.184mL, 25%) of sodium methoxide in methyl alcohol is added, and mixture is stirred at room temperature 1 hour.
After the completion of TLC, reactant mixture is quenched using ion exchange resin amberlite IR 120, until solution is neutralized.Will
Mixture is filtered and concentrated.Pass through flash column chromatography (ethyl acetate:Petroleum ether=2:1) purification of crude product, to provide as white
Compound-the 25A (1.7g, 58%) of color solid.
Embodiment 27：Step 27- compounds 25B preparation
Process：Compound 25A (1.7g, 0.4040mmol) is dissolved in acetonitrile (45mL) and is cooled to 0 DEG C, addition 45%
BF3:OEt2(7.65mL, 24.2453mmol) and continue stirring 3 hours.Reactant mixture is diluted with ethyl acetate (100mL),
Use NaHCO3Saturated aqueous solution (80mL) washs, and then uses aqueous salt solu-tion.Then by organic layer Na2SO4Dry, filtering
And concentrate.
With hexane debris, gained solid product is placed in second alcohol and water.Addition lithium hydroxide (0.17g,
4.0408mmol) and by reaction it is stirred overnight at 80 DEG C.Removal of solvent under reduced pressure；Roughage is dissolved in water (20mL), uses second
Ether (20mL) washing and separate aqueous layer.The pH of water layer is adjusted to 5 using 1N HCl (0.4mL) solution.10% methanol of product:
DCM (2 × 60mL) is extracted.Organic layer Na2SO4It is dried, filtered and concentrated, obtains compound 25B (0.8g；Totally 80%) two steps.
Embodiment 28：Step 28- compounds d26 preparation
Process：Compound -25B (0.8g, 0.2638mmol) is dissolved in methanol (50mL) and water in 250mL hydrogenates flask
In the mixture of (12mL).20%Pd (OH) is added in a nitrogen atmosphere2/C(0.8g).With hydrogen purge flask three times, then
Content is stirred 24 hours under nitrogen atmosphere (100psi).After the completion of, reactant mixture is filtered by diatomite and 25
DEG C it is concentrated under reduced pressure.Product by gel-filtration purified, is eluted with water by Sephadex-G-10 posts.Collect compound fraction simultaneously
The lyophilized Men-Y tetramers (d26) (350mg to obtain as white solid；70%).
Embodiment 29：The antigenicity analysis of the Men-Y tetramers and the Men-Y tetramers-tetanus toxoid (TT) conjugate
Process：Elisa plate is coated with bacterial polysaccharides, the bacterial polysaccharides for anti-Men-Y bacterial eapsular polysaccharides with producing
Raw polyclonal serum reaction, the Men-Y tetramers using various concentrations or the Men-Y tetramers using thioether chemistry preparation-
TT conjugates are suppressed or without suppressing.As shown in figure 9, when the secondary antibody marked using HRP is developed the color, with not having
The control for having antigen is compared, and after different antigen concentration stripped serum dilutions, the Men-Y tetramers and its conjugate neutralize
Men-Y specific IgGs, this is apparent by the reduction (% suppression) of optical density.
Claims (14)
1. a kind of novel method for synthesizing of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit, the side
Method comprises the following steps：
(a) Growth Units (18) are synthesized,
(b) start element (20) is synthesized,
(c) in the presence of at least one catalyst and at least one alkaline reagent, by the start element (20) and the increasing
Long unit (18) is connected to synthesize higher oligomers,
(d) iteration that step (c) is carried out in the presence of the catalyst and the alkaline reagent is reacted to obtain advanced synthesis
Oligomer (22,24,26,28 ... .n),
(e) the advanced synthesis oligomer of step (d) is made to be protected successively in the presence of at least one deprotecting regent
The deprotection of group, the Men-Y higher oligomers (d22, d24, d26, d28....dn) of deprotection are obtained,
So that methods described produces the new advanced synthesis oligomer with higher yield and high-purity.
2. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 1
Into method, wherein, the advanced synthesis oligomer (Y) is the new tetramer (d26).
3. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 2
Into method, wherein, the time needed for the tetramer is synthesized in the range of 330 hours to 400 hours, more preferably 370 hours.
4. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 1
Into method, wherein, the start element (20) is synthesized by following steps：
(a) by known method, monosaccharide compounds 1 are made to carry out the acquisition compound 2 that methylates in the presence of a catalyst, in acyl group
It is acylated compound 2 in the presence of agent and obtains compound 3, the halogenation of compound 3 is obtained chemical combination in the presence of halogenating agent
Thing 4, compound 4 is reacted with thiolating reagent and obtain compound 5, compound 5 is obtained chemical combination with deacylation reagent reacting
Thing 6, compound 6 is reacted with carbonylation agent and obtain compound 7, compound 7 is obtained compound 8 with protection reagent effect,
Make compound 8 that phosphorylation reaction occur and obtain compound 9,
(b) by known method, the commercial compound 10 bought is made to obtain compound 11, making with acceptor and catalyst reaction
Compound 11 obtains compound 12 with deacetylating agent effect, compound 12 is acted on blocking group and obtains compound 13, makes
Compound 13, which is alkylated, obtains compound 14,
Wherein, carry out the compound 14：
(c) in the presence of at least one catalyst, with alcohol glycosylation acquisition compound 16 occurs for compound 14,
(d) compound 16 is acted on at least one deprotecting regent and obtain compound 17,
(e) in the presence of at least one catalyst, compound 17 and compound 9 is made to react and obtain compound 19,
(f) compound 19 is acted on at least one alkaline reagent and obtain the start element compound 20.
5. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 1
Into method, wherein, the Growth Units (18) are synthesized by following steps：
(a) compound 14 is acted on at least one deprotecting regent and obtain compound 15,
(b) in the presence of at least one catalyst, the compound 15 is reacted with the compound 9 and obtain growth list
Member 18.
6. the oligomer of the Neisseria meningitidis serum group Y CPS repeat unit as described in claim 1,4 and 5 is new
Type synthetic method, wherein, the catalyst is selected from NIS, TfOH, TMSOTf.
7. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 4
Into method, wherein, the alcohol is 6- nitrine hexanols.
8. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 1
Into method, wherein, the deprotecting regent is selected from BF3:OEt2、ACN、NaOH、MeOH、H2/Pd(OH)2。
9. the new conjunction of the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claim 4
Into method, wherein, the monose is neuraminic acid, more particularly N-acetyl-neuraminate.
10. the oligomer of Neisseria meningitidis serum group Y CPS repeat unit as claimed in claims 4 and 5 is new
Type synthetic method, wherein, the deprotecting regent is selected from TABF, THF, CSA, HCl, PTSA.
11. the oligomer of the Neisseria meningitidis serum group Y CPS repeat unit as described in claim 1 and 4 is new
Type synthetic method, wherein, the alkaline reagent is selected from NaOMe, NaOEt, KOtBu.
A kind of 12. Neisseria meningitidis serum group Y CPS repeat unit prepared by method by described in claim 1
New advanced synthesis oligomer, wherein, the new advanced synthesis oligomer (Y) is the synthesis that high-purity and antigenicity improve
Oligomer.
13. the Neisseria meningitidis serum group Y CPS repeat unit prepared by the method described in claim 1 is new
Advanced synthesis oligomer, wherein, the new advanced synthesis oligomer (Y) is that purity is more than 95% and having of improving of effect
The tetramer (d26) of following structural formula：
14. the Neisseria meningitidis serum group Y CPS repeat unit prepared by the method described in claim 1 is new
Advanced synthesis oligomer, it is semi-synthetic or fully synthetic for meningococcus serum group Y bacterium infections that it can act as exploitation
The candidate of conjugate vaccines.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2281/DL/2015 | 2015-07-28 | ||
| IN2281DE2015 | 2015-07-28 | ||
| PCT/IB2015/057685 WO2017017509A1 (en) | 2015-07-28 | 2015-10-08 | Novel neisseria meningitidis serogroup y oligomer and process for synthesizing thereof |
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| KR (1) | KR20180040567A (en) |
| CN (1) | CN107709341A (en) |
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| WO (1) | WO2017017509A1 (en) |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005032583A2 (en) * | 2003-10-02 | 2005-04-14 | Chiron Srl | Liquid vaccines for multiple meningococcal serogroups |
| WO2011149778A1 (en) * | 2010-05-26 | 2011-12-01 | Ancora Pharmaceuticals Inc. | Synthetic oligosaccharides for neisseria meningitis vaccine |
| WO2014210564A1 (en) * | 2013-06-27 | 2014-12-31 | Academia Sinica | Glycan conjugates and use thereof |
| CN106795194A (en) * | 2014-10-09 | 2017-05-31 | 默沙东和惠康基金会合资的希勒曼实验室私人有限公司 | Improved conjugation methods and the new Oligosaccharide Protein matter conjugate for synthesizing obtained by it |
-
2015
- 2015-10-08 CN CN201580081282.5A patent/CN107709341A/en active Pending
- 2015-10-08 KR KR1020187000926A patent/KR20180040567A/en unknown
- 2015-10-08 WO PCT/IB2015/057685 patent/WO2017017509A1/en active Application Filing
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005032583A2 (en) * | 2003-10-02 | 2005-04-14 | Chiron Srl | Liquid vaccines for multiple meningococcal serogroups |
| WO2011149778A1 (en) * | 2010-05-26 | 2011-12-01 | Ancora Pharmaceuticals Inc. | Synthetic oligosaccharides for neisseria meningitis vaccine |
| WO2014210564A1 (en) * | 2013-06-27 | 2014-12-31 | Academia Sinica | Glycan conjugates and use thereof |
| CN106795194A (en) * | 2014-10-09 | 2017-05-31 | 默沙东和惠康基金会合资的希勒曼实验室私人有限公司 | Improved conjugation methods and the new Oligosaccharide Protein matter conjugate for synthesizing obtained by it |
Non-Patent Citations (2)
| Title |
|---|
| IRINA CARLESCU，等: "Synthesis of poly(aspartimide)-based bio-glycoconjugates", 《CARBOHYDRATE RESEARCH》 * |
| PUI HANG TAM，等: "Epimeric and amino disaccharide analogs as probes of an a-(1→6)-mannosyltransferase involved in mycobacterial lipoarabinomannan biosynthesis", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
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| BR112018001425A2 (en) | 2018-09-11 |
| KR20180040567A (en) | 2018-04-20 |
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