WO2017017509A1 - Nouvel oligomère de neisseria meningitidis de sérogroupe y et procédé de synthèse de celui-ci - Google Patents

Nouvel oligomère de neisseria meningitidis de sérogroupe y et procédé de synthèse de celui-ci Download PDF

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Publication number
WO2017017509A1
WO2017017509A1 PCT/IB2015/057685 IB2015057685W WO2017017509A1 WO 2017017509 A1 WO2017017509 A1 WO 2017017509A1 IB 2015057685 W IB2015057685 W IB 2015057685W WO 2017017509 A1 WO2017017509 A1 WO 2017017509A1
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WO
WIPO (PCT)
Prior art keywords
compound
oligomers
neisseria meningitidis
capsular polysaccharide
meningitidis serogroup
Prior art date
Application number
PCT/IB2015/057685
Other languages
English (en)
Inventor
Davinder Gill
Manoj Kumar CHHIKARA
Kishore HARALE
Original Assignee
Msd Wellcome Trust Hilleman Laboratories Pvt. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Msd Wellcome Trust Hilleman Laboratories Pvt. Ltd. filed Critical Msd Wellcome Trust Hilleman Laboratories Pvt. Ltd.
Priority to CN201580081282.5A priority Critical patent/CN107709341A/zh
Priority to BR112018001425A priority patent/BR112018001425A2/pt
Priority to KR1020187000926A priority patent/KR20180040567A/ko
Publication of WO2017017509A1 publication Critical patent/WO2017017509A1/fr

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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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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]

Definitions

  • the present invention relates to novel oligomers of Neisseria meningitidis serogroup Y capsular polysaccharide repeating unit ('hereinafter Men-Y oligomer).
  • the present invention also relates to a process for synthesizing novel N. meningitidis serogroup Y oligomers. More specifically, the present invention relates to the chemical synthesis of the tetramer of N. meningitidis serogroup Y ('hereinafter Men-Y tetramer) capable of being used as a candidate in the development of semisynthetic and synthetic conjugate vaccines against meningococcal serogroup Y bacterial infection. BACKGROUND OF THE INVENTION
  • Bacterial meningitis causes approximately 1, 70, 000 annual deaths, with at least 5-10% of case fatality in industrialized countries and a 20% case fatality in the developing world.
  • Streptococcus pneumoniae, Haemophilus influenzae type b (Hib) and N. meningitidis are responsible for most of the cases of bacterial meningitis worldwide.
  • Hib Haemophilus influenzae type b
  • N. meningitidis still remains a major cause of bacterial meningitis and other invasive bacterial infections despite the availability of modern antibiotics.
  • Meningococcal disease is a medical emergency requiring immediate diagnosis and treatment.
  • Meningococcal polysaccharide vaccines which are available for over 30 years to prevent the disease. Meningococcal polysaccharide vaccines are available in various combinations e.g. either bivalent (groups A and C), trivalent (groups A, C and W), or tetravalent (groups A, C, Y and W) forms to control the disease.
  • Meningococcal conjugate vaccines against group C have been available since 1999. Tetravalent A, C, Y and W conjugate vaccines are widely used and have been licensed since 2005 for use in children and adults in different parts of world including Canada, the United States of America, Europe and India. Other combinations of the serogroups are also available in licensed conjugate vaccines. The currently available meningococcal conjugate vaccines except monovalent group A conjugate vaccine are out of reach for needy people in low resource countries due to their high cost.
  • vaccines available for Men-Y utilize the polysaccharide isolated from bacterial source which are associated with various risks like danger in handling the live bacterial culture. Also, many a times the isolated bacterial polysaccharide is so heterogeneous that it fails to pass the desired homogeneity criteria. The heterogeneous nature of the bacterial polysaccharide provides the heterogeneity in the conjugates prepared using it leading to large variations and hence, disqualification of the conjugate batches.
  • the meningococcal conjugate vaccines containing synthetic Men-Y oligosaccharide are advantageous over conventional vaccines.
  • the synthetic antigens are uniform in size and well characterised which reduce the heterogeneity of the conjugates produced with less batch to batch variation in the final conjugates.
  • One of the main advantages with synthetic antigens is that these can be engineered with desired linker for simplifying conjugation as well as resulting into better yields.
  • the International patent application no. PCT/US2013/ 042428 "Multivalent meningococcal conjugates and methods for preparing conjugates" relates to immunogenic conjugates including at least one polysaccharide or protein conjugated to a Neisseria surface protein, which can elicit immune responses against meningococcal polysaccharides (PS) from groups A, C, W-135, and Y.
  • PS meningococcal polysaccharides
  • the said International patent application discloses only general statement on preparation of Men Y oligomers but there is no enabling disclosure on the preparation of Men-Y oligomer.
  • the existing art available for other serogroups of N. meningitidis are either time consuming or give rise to a mixture of different sizes of oligomers.
  • the main object of present invention is to provide novel oligomers of Neisseria meningitidis serogroup Y capsular polysaccharide repeating unit.
  • Another object of present invention is to provide novel oligomers of Neisseria meningitidis serogroup Y capsular polysaccharide repeating unit capable of being used as candidates in the development of synthetic and semisynthetic conjugate vaccines against meningococcal bacterial infection.
  • Yet another object of the present invention is to provide novel Men-Y tetramer capable of being used as a candidate in the development of semisynthetic or fully synthetic vaccine against meningococcal serogroup Y bacterial infection.
  • Yet another object of the present invention is to provide a chemical process of synthesizing Men-Y oligomers using purified saccharides with specific chain length.
  • Yet another object of the present invention is to provide a chemical process of synthesizing Men-Y oligomers with improved antigenicity capable of producing immunogenic conjugate vaccine.
  • Yet another object of the present invention is to provide a process for the preparation of synthetic Men-Y capsular oligomers which meet the physico-chemical quality standards for the purity.
  • Yet another object of the invention is to provide cost effective Men-Y oligomers with increased efficacy and improved shelf-life when conjugated to a carrier protein.
  • the present invention discloses N. meningitidis serogroup Y oligomers and synthetic process to obtain thereof.
  • Said Men-Y oligomers are capable of being used as candidates in the development of semisynthetic and synthetic conjugate vaccine against meningococcal serogroup Y bacterial infection after conjugation to a suitable carrier protein.
  • Said vaccine can be administered by parental routes.
  • Men-Y oligomers of the present invention possess improved antigenicity and improved shelf-life. Said Men-Y oligomers also meet the physico-chemical quality standards for the purity and are cost effective.
  • the process of present invention discloses synthesis of Men-Y oligomers comprising of the two main building blocks; an initiation unit and a propagation unit.
  • the initiation unit is prepared by the glycosidation of suitably protected monosaccharide more particularly but not limited to neuraminic acid with another suitably protected monosaccharide.
  • Said another suitably protected monosaccharide is selected from hexose, more particularly but not limited to glucose.
  • the propagation unit is prepared by glycosidation of suitably protected monosaccharide more particularly but not limited to neuraminic acid with another suitably protected monosaccharide more particularly hexose, more particularly but not limited to glucose.
  • the initiation unit and the propagation unit are coupled at predetermined temperature together using catalyst to provide the tetrasaccharide or dimeric unit.
  • the catalyst used in the said coupling is glycosilation reagent/ Lewis acid catalyst selected from but not limited to Kilo do succinimide ( ⁇ 3), Trifluoromethanesulfonic acid (TfOH), Trimethylsilyltrifluoromethanesulfonate (TMSOTf), Silver trifluoromethanesulfonate (CFsSOsAg).
  • the dimeric unit is reacted with a basic reagent such as but not limited to sodium methoxide to facilitate ring opening.
  • the dimeric unit so obtained is again reacted with propagation unit resulting in the formation of trimer.
  • the trimer undergoes iterative reactions under similar conditions to get protected higher oligomers (Y) including tetramer, pentamer, hexamer, heptamer etc.
  • the protected higher oligomers so obtained are subjected to sequential deprotection of protecting groups resulting in Men-Y higher oligomers.
  • the higher oligomers of N. meningitidis serogroup Y so obtained have improved yields, high efficacy and are capable of being used as a candidate for development of conjugate vaccine which confers protection against disease due to Men-Y infections.
  • Figure 1 depicts ⁇ -NMR of Men-Y tetramer (compound 26)
  • Figure 2 depicts 13 C-NMR of Men-Y tetramer
  • Figure 3 depicts COSY NMR spectrum of Men-Y tetramer
  • Figure 4 depicts HMBC NMR spectrum of Men-Y tetramer
  • Figure 5 depicts HSQC NMR spectrum of Men-Y tetramer
  • Figure 6 depicts TOCSY NMR spectrum of Men-Y tetramer
  • Figure 7 depicts DEPT NMR spectrum of Men-Y tetramer
  • Figure 8 depicts HPSEC analysis for purity of Men-Y tetramer
  • Figure 9 depicts antigenicity analysis of Men-Y tetramer and Men-Y
  • TT tetramer-tetanus toxoid
  • the present invention relates to novel Men-Y oligomers.
  • the present invention further relates to a process for synthesizing novel Men-Y oligomers. More specifically, the present invention relates to the chemical synthesis of Men-Y tetramer capable of being used as a candidate in the development of semisynthetic and synthetic vaccine against meningococcal bacterial infection. Said vaccine can be administered with suitable mode of administration more particularly via parental route. Said synthesis being accomplished in the following steps:
  • Step 1 Synthesis of Propagation Unit (Compound 18 as shown in Scheme I)
  • Step 2 Synthesis of Initiation Unit (Compound 20 as shown in Scheme II)
  • N-acetyl neuraminic acid which is compound 1 undergoes methylation in presence of catalyst, such as Dowex 50W X8 (H + ) resin to obtain compound 2.
  • catalyst such as Dowex 50W X8 (H + ) resin to obtain compound 2.
  • the compound 2 so obtained undergoes acylation in presence of acylating agents such as acetic anhydride in presence of pyridine to give compound 3.
  • acylating agents such as acetic anhydride in presence of pyridine
  • This process helps in shielding of hydroxyl groups.
  • the compound 3 so obtained undergoes selective halogenation more particularly chlorination in presence of halogenating agents such as acetylcholride and HC1 to obtain compound 4.
  • Compound 4 reacts with thiolating reagent Such as p-methylphenylthiol (TolSH) in presence of DIPEA also known as Hunig's base (poor nucleophile) resulting in compound 5 with -Stol group attached to 2 nd position.
  • thiolating reagent such as p-methylphenylthiol (TolSH) in presence of DIPEA also known as Hunig's base (poor nucleophile)
  • the compound 5 so obtained undergoes deacylation in presence of MeOH, methanesulfonic acid (MsOH) to give compound 6.
  • MsOH methanesulfonic acid
  • the compound 6 so obtained reacts with carbonylation reagent such as Triphosgene, NaHC03 in presence of MeCN/H 2 O and undergoes oxazolidinones ring formation to yield compound 7.
  • the compound 7 so obtained is subjected to protection of hydroxyl groups present at terminal position in presence of protecting reagents such as ferf-butyldiphenylsilyl chloride TBDPSC1/DMF, and then for acetonide protection using 2,2-DMP, followed by acylation using AcCl to yield compound 8.
  • protecting reagents such as ferf-butyldiphenylsilyl chloride TBDPSC1/DMF
  • 2,2-DMP 2,2-DMP
  • acylation using AcCl to yield compound 8.
  • the compound 8 so obtained is reacted with reacting agents such as dibutyl phosphate (Bu 2 P0 4 H) in presence of NIS, TfOH, DCM to obtain a phosphate leaving group at terminal position which increases alpha selectivity as compound 9.
  • Compound 15 is then obtained with yield in the range of 85% to 95% by recovering one of the protected hydroxyl group of Compound 14 by reacting compound 14 with deprotecting reagents such as Tetra-n- butylammoniumfluoride (TBAF) in Tetrahydrofuran (THF).
  • TBAF Tetra-n- butylammoniumfluoride
  • THF Tetrahydrofuran
  • Remaining amount of compound 14 so obtained undergoes glycosidation with 5-azido-hexanol to yield compound 16.
  • the yield of compound 16 so obtained is in the range of 65% to 75%, more particularly 70% .
  • the compound 16 is subjected to silyl group deprotection reagent such as TBAF in THF solvent resulting in the removal of sterically hindering - OTBDPS group to yield compound 17.
  • silyl group deprotection reagent such as TBAF in THF solvent resulting in the removal of sterically hindering - OTBDPS group to yield compound 17.
  • the compound 17 so obtained acts as an intermediate in the synthesis of Initiation Unit 20.
  • Compound 9 One part of Compound 9 is then reacted with compound 15 at low temperatures, more particularly in the range of -80°C to -60°C in presence of catalyst such as TMSOTf to yield Propagation unit (compound 18).
  • Compound 9 is then reacted with compound 17 at low temperatures, more particularly in the range of -80°C to -60°C in presence of catalyst such as TMSOTf to yield compound 19.
  • Compound 19 so obtained is reacted with a basic reagent such as NaOMe in presence of Methanol (MeOH)/ Dichloromethane (DCM) to yield Initiation Unit (compound 20).
  • the Initiation Unit (20) and the Propagation Unit (18) are coupled together using catalyst at low temperatures, more particularly in the range of -50°C to— 30°C to provide the tetrasaccharide or dimeric unit (21).
  • the catalyst used in said coupling is but not limited to NB/TfOH /Trimethylsilyltrifluoromethanesulfonate (TMSOTf)/ Silver trifluoromethanesulfonate (CFsSOsAg) in presence of solvent.
  • the catalyst activates thiotolyl (Stol) group of compound 18. After activation it is prone to removal and then the Stol group is replaced by free hydroxy group of Initiation Unit (20).
  • the dimeric unit (21) is reacted with a basic reagent, such as but not limited to Sodium methoxide, which facilitate ring opening resulting into protected dimeric unit (22).
  • dimer so obtained is subjected to iterative reactions under similar conditions in presence of said catalyst and said basic reagent to yield a higher synthetic oligomers including trimer, tetramer, pentamer, hexamer, heptamer, 24, 26, 28....n) etc.
  • the dimeric unit (22) so obtained is again reacted with propagation unit under similar conditions of temperature and atmospheric pressure resulting in the formation of trimer (23, 24).
  • the trimer so obtained is again reacted with propagation unit under similar conditions to obtain tetramer unit (25).
  • the tetramer undergoes iterative reactions under similar conditions to get higher oligomers (Y) including tetramer, pentamer, hexamer, heptamer, etc.
  • the higher oligomers so obtained are subjected to final deprotection of protecting groups in presence of deprotecting reagents such as BF3:OEt 2 ACN, NaOH, MeOH, H 2 /Pd(OH) 2 .
  • deprotecting reagents such as BF3:OEt 2 ACN, NaOH, MeOH, H 2 /Pd(OH) 2 .
  • the sequential deprotection of protecting groups in presence of a deprotecting reagent resulting in deprotected Men
  • the total time taken for said process is in the range of 330 hours to 400 hours and more particularly is 370 hours, resulting in significantly low cost of production.
  • the higher oligomers so obtained are linked to carrier proteins by conjugation through in-built linker to obtain a semisynthetic conjugate vaccine against meningococcal serogroup Y bacterial infection.
  • This chemical process of synthesis can also be employed for the preparation of synthetic protein/ peptide to prepare fully synthetic conjugate vaccine as well. It is noted that such conjugation with carrier proteins result in vaccines with good yield and enhanced antigenicity.
  • Men-Y tetramer is tested for antigenicity by conducting inhibition enzyme-linked immunosorbent assay (Inhibition ELISA) and the tetramer and its conjugate with tetanus toxoid is found to give neutralization of specific antibodies against Men-Y capsular polysaccharide.
  • Inhibition ELISA enzyme-linked immunosorbent assay

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Abstract

La présente invention concerne de nouveaux oligomères de l'unité répétée du polysaccharide capsulaire de Neisseria meningitidis de sérogroupe Y (oligomères Men-Y) et un procédé de synthèse de nouveaux oligomères Men-Y. En particulier, la présente invention concerne la synthèse chimique du tétramère d'unités répétées du polysaccharide capsulaire de Men-Y qu'il est possible d'utiliser en tant que candidat dans le développement d'un vaccin conjugué semi-synthétique ou entièrement synthétique contre l'infection bactérienne à méningocoque de sérogroupe Y.
PCT/IB2015/057685 2015-07-28 2015-10-08 Nouvel oligomère de neisseria meningitidis de sérogroupe y et procédé de synthèse de celui-ci WO2017017509A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201580081282.5A CN107709341A (zh) 2015-07-28 2015-10-08 新的脑膜炎奈瑟氏菌血清组y寡聚体及其合成方法
BR112018001425A BR112018001425A2 (pt) 2015-07-28 2015-10-08 novos oligômeros de sorogrupo y de neisseria meningitidis e processos de sintetização dos mesmos
KR1020187000926A KR20180040567A (ko) 2015-07-28 2015-10-08 신규한 나이세리아 메닌지티디스 혈청군 y 올리고머 및 이의 합성방법

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IN2281/DL/2015 2015-07-28
IN2281DE2015 2015-07-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022197990A1 (fr) * 2021-03-19 2022-09-22 Brandeis University Sucre substitué par du soufre pour stabiliser un oligosaccharide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005032583A2 (fr) * 2003-10-02 2005-04-14 Chiron Srl Vaccins liquides contre de multiples serogroupes meningococciques
WO2011149778A1 (fr) * 2010-05-26 2011-12-01 Ancora Pharmaceuticals Inc. Oligosaccharides synthétiques pour un vaccin contre neisseria meningitidis
WO2014210564A1 (fr) * 2013-06-27 2014-12-31 Academia Sinica Conjugués de glycane et leur utilisation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA201700177A1 (ru) * 2014-10-09 2017-07-31 Мсд Уэлком Траст Хиллеман Лабораторис Пвт. Лтд. Улучшенный способ конъюгирования и полученные с помощью него новые синтетические конъюгаты олигосахарида с белком

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005032583A2 (fr) * 2003-10-02 2005-04-14 Chiron Srl Vaccins liquides contre de multiples serogroupes meningococciques
WO2011149778A1 (fr) * 2010-05-26 2011-12-01 Ancora Pharmaceuticals Inc. Oligosaccharides synthétiques pour un vaccin contre neisseria meningitidis
WO2014210564A1 (fr) * 2013-06-27 2014-12-31 Academia Sinica Conjugués de glycane et leur utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022197990A1 (fr) * 2021-03-19 2022-09-22 Brandeis University Sucre substitué par du soufre pour stabiliser un oligosaccharide

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BR112018001425A2 (pt) 2018-09-11
CN107709341A (zh) 2018-02-16

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