WO2005075490A2 - Synthese de glycosides polysulfates d'acide uronique - Google Patents

Synthese de glycosides polysulfates d'acide uronique Download PDF

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Publication number
WO2005075490A2
WO2005075490A2 PCT/US2005/003297 US2005003297W WO2005075490A2 WO 2005075490 A2 WO2005075490 A2 WO 2005075490A2 US 2005003297 W US2005003297 W US 2005003297W WO 2005075490 A2 WO2005075490 A2 WO 2005075490A2
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Prior art keywords
alkali
general formula
earth metal
atom
hydrogen atom
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PCT/US2005/003297
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English (en)
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WO2005075490A3 (fr
Inventor
Tahir Ahmed
Nicholas Bodor
Sandor Boros
Janos Kuszmann
Gabor Medgyes
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Ivax Corporation
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Publication of WO2005075490A2 publication Critical patent/WO2005075490A2/fr
Publication of WO2005075490A3 publication Critical patent/WO2005075490A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof

Definitions

  • the invention relates to the synthesis of polysulfated uronic acid glycosides of general formula (I), more specifically compounds of general formulas (IA) and (IB),
  • (l) can be prepared by nitrous acid treatment of such natural products as for example heparin or heparan sulfate, followed by reduction with borohydride and subsequent sulfation of the partially purified samples.
  • natural products as for example heparin or heparan sulfate
  • reduction with borohydride followed by reduction with borohydride and subsequent sulfation of the partially purified samples.
  • the synthesis of the single isomers of general formulas (IA) and (IB) has not been described in the literature.
  • the invention provides a new, synthetic method for the synthesis of pure polysulfated glycosides of general formulas (IA) and (IB), having well-defined chemical structures.
  • glucose amine and glucuronic acid and glucose amine respectively, can be transformed into compounds of general formulas (IA) and (IB), having well-defined chemical structures.
  • the invention provides a process for the synthesis of polysulfated glycosides of general formulas (IA) and (IB), wherein M' means a hydrogen atom, alkali metal or alkali-earth metal atom and M represents an alkali metal or alkali-earth metal atom, which comprises sulfating either a) a glycoside of the general formula (IX), wherein M' means a hydrogen atom, alkali metal or alkali-earth metal atom, to obtain a compound of general formula (IA) , or b) a glycoside of the general formula (XII), wherein R x represents a hydrogen atom, a C* ⁇ alkyl group or alkali metal or alkali-earth metal atom , to obtain a compound of general formula (IB), then transforming the sulfated product into a salt, and if desired, hydrolizing the ester group of the carboxylic acid of the so obtained product with base, and
  • M' represents a hydrogen atom, alkali metal or alkali-earth metal atom and the use of the compound for the synthesis of an uronic acid glycoside of the general formula (IA), wherein M' represents hydrogen atom, alkali metal or alkali-earth metal and M means an alkali metal or alkali-earth metal atom.
  • uronic acid glycosides of the general formula (XII) are also disclosed.
  • R x represents a C alkyl group, hydrogen atom, alkali metal or alkali-earth metal atom, and the use of the compound for the synthesis of an uronic acid glycoside of the general formula (IB), wherein M' represents hydrogen atom, alkali metal or alkali-earth metal and M means an alkali metal or alkali-earth metal atom.
  • Fig. 1 is a graphical representation of a possible synthesis of a compound of general formula (IX) described in detail in the Examples.
  • Fig. 2 is a graphical representation of a possible synthesis of a compound of general formula (XII) described in detail in the Examples.
  • the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
  • variable can be equal to any integer value of the numerical range, including the end-points of the range.
  • variable can be equal to any real value of the numerical range, including the end-points of the range.
  • a variable which is described as having values between 0 and 2 can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.
  • Ph phenyl
  • NIS N-iodosuccinimide
  • TfOH trifluoromethanesulfonic acid
  • An aspect of the invention provides a process for the synthesis of polysulfated glycosides of the general formulas (IA) and (IB),
  • M' stands for a hydrogen atom, alkali metal or alkali-earth metal atom, to obtain a compound of the general formula (IA), or b) a glycoside of general formula (XII),
  • R x represents a hydrogen atom, a C alkyl group or alkali metal or alkali-earth metal atom, to obtain a compound of the general formula (IB), and subsequently transforming the sulfated product into a salt, and if desired, hydrolizing the ester group of the carboxylic acid of the obtained product with base, and, if desired, liberating the compounds of the general formula (IA) or (IB), wherein M' means a hydrogen atom, from the compounds of the general formula (IA) or (IB) formed, wherein M' represents an alkali metal or alkali-earth metal atom.
  • compounds of general formula (IA) are synthesized by sulfating a glycoside of general formula (IX) (wherein M' is as described above) in a polar, aprotic solvent with sulfur trioxide or an adduct thereof formed with an organic base (for example, triethylamine or pyridine) or with a non-basic compound (for example, dimethylformamide), using the adduct in excess, at a temperature below 0 °C.
  • a polar, aprotic solvent with sulfur trioxide or an adduct thereof formed with an organic base (for example, triethylamine or pyridine) or with a non-basic compound (for example, dimethylformamide)
  • compounds of the general formula (IB) are synthesized by sulfating a glycoside of the general formula (XII) (wherein R x is as described above) according to the method described above, and when R x represents a C M alkyl group, the ester group is hydrolyzed by base at a pH of about pH 8.0 to about pH 9.0.
  • R means an acetyl group and (X) represents an acetoxy group, either in three steps, or directly from the known compound of formula (III)
  • R x represents a C M alkyl group, hydrogen atom, alkali metal or alkali-earth metal atom, can be synthesized, for example, by glycosylating the known donor molecule of formula (X)
  • (XI) is transformed by benzoylation into a compound of the general formula (XI) where R represents a benzoyl group, and the latter is deacylated to give the compound of formula (XII).
  • the methyl ester of formula (XII) is hydrolyzed by base, and if desired the carboxylic acid is liberated from the obtained carboxylic acid salt with acid.
  • the spots were detected either in UV light or by spraying the plates with a 1 : 1 mixture of 0.1 M KMnO 4 - 1 M H 2 SO followed by heating to 200 °C
  • Column chromatography was performed on Kieselgel 60.
  • Optical rotations were measured at 20 °C NMR spectra were recorded with Bruker Avans 500 MHz spectrometer using Me Si as the internal standard.
  • the assignments of the protons were based on homonuclear decoupling and DNOE experiments. Multiplicities of the C spectra were obtained from DEPT experiments. Connectivities between identified protons and protonated carbons were observed by means of HETCOR experiments.
  • the starting material - 2,5-anhydro-3-O-( ⁇ -L-idopyranosyl uronic acid)-D- mannitol sodium salt can be synthesized, for example, by the following method (the reaction pathway shown in Scheme 1, Fig. 1):
  • the title compound can also be obtained by the following method: 13.5 g (30.5 mmol) of the known [Ch. Tabeur, F. Machetto, J.-M. Mallet, P. Duchaussoy, M. Petitou, P. Sinay, Carbohydr.
  • reaction mixture was poured into a stirred solution of 2 g sodium acetate in 20 ml methanol at -5 °C.
  • the precipitated crystals were filtered off and washed with methanol.
  • the so obtained solid product was dissolved in 5 ml of water, the pH of the solution was adjusted to 8-9 with M sodium hydroxide solution and further 1 ml of M sodium hydroxide solution was added to hydrolyze the methyl ester of the formula (XIII).
  • the solution was kept at room temperature for 15 h, then diluted with 25 ml of water and 1 M aqueous stroncium acetate solution was added until no more precipitate (SrSO 4 ) was formed.
  • Ci 2 Hi 3 O 29 S 6 Na 7 Calculated: C 14.79 ; H 1.34 ; Na 16.51 ; S 19.74. Found: C 14.58 ; H 1.72 ; Na 16.44 ; S 19.55.
  • the starting material of the formula (XII) can be synthesized for example by the following method:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de synthèse destiné à la synthèse de glycosides polysulfatés pures possédant des structures chimiques bien définies. Ces composés peuvent être synthétisés par synthèse stéréospécifique à partir de glucose et de glucose amine, et d'acide glucuronique et de glucose amine. L'invention concerne également un procédé destiné à la synthèse de glycosides polysulfatés transformés en sels.
PCT/US2005/003297 2004-02-03 2005-02-03 Synthese de glycosides polysulfates d'acide uronique WO2005075490A2 (fr)

Applications Claiming Priority (2)

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US54157504P 2004-02-03 2004-02-03
US60/541,575 2004-02-03

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WO2005075490A2 true WO2005075490A2 (fr) 2005-08-18
WO2005075490A3 WO2005075490A3 (fr) 2005-10-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102711463A (zh) * 2009-12-03 2012-10-03 Opko健康公司 超硫酸化双糖制剂
JP2013028541A (ja) * 2011-06-20 2013-02-07 Foundation For Biomedical Research & Innovation α−Ｋｌｏｔｈｏ／ＦＧＦ２３複合体形成阻害化合物
CN103269585A (zh) * 2010-10-29 2013-08-28 Opko健康公司 治疗弹性蛋白酶相关病症的超硫酸化双糖
US10829509B2 (en) 2016-08-16 2020-11-10 Opko Pharmaceuticals, Llc Pure heptasulfated disaccharides having improved oral bioavailability

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083700A2 (fr) * 2001-04-16 2002-10-24 Ivax Research, Inc. Disaccharides hypersulfates et leur utilisation en traitement contre les inflammations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083700A2 (fr) * 2001-04-16 2002-10-24 Ivax Research, Inc. Disaccharides hypersulfates et leur utilisation en traitement contre les inflammations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KUSZMANN, JANOS ET AL: "Synthesis of 2,5-anhydro-(.beta.-D-glucopyranosyluronat e)- and (.alpha.-L-idopyranosyluronate)-D-mannitol hexa-O-sulfonate hepta sodium salt" CARBOHYDRATE RESEARCH , 339(8), 1569-1579 CODEN: CRBRAT; ISSN: 0008-6215, 2004, XP004512910 *
LEDER, IRWIN G.: "Radioactive substrates for iduronate sulfatase and .alpha.-L-iduronidase" METHODS IN ENZYMOLOGY , 50(COMPLEX CARBOHYDR., PART C), 150-4 CODEN: MENZAU; ISSN: 0076-6879, 1978, XP009050306 *
WEISSMANN, BERNARD ET AL: "Characterization of reference disaccharides from nitrous acid deamination of beef lung heparin" GLYCOCONJUGATES , MEETING DATE 1977, VOLUME 2, 959-62. EDITOR(S): GREGORY, JOHN D.; JEANLOZ, ROGER W. PUBLISHER: ACADEMIC, NEW YORK, N. Y. CODEN: 38KRAU, 1979, XP009050305 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102711463A (zh) * 2009-12-03 2012-10-03 Opko健康公司 超硫酸化双糖制剂
US8546351B2 (en) 2009-12-03 2013-10-01 Opko Health, Inc. Hypersulfated disaccharide formulations
CN102711463B (zh) * 2009-12-03 2015-05-13 Opko健康公司 超硫酸化双糖制剂
CN103269585A (zh) * 2010-10-29 2013-08-28 Opko健康公司 治疗弹性蛋白酶相关病症的超硫酸化双糖
CN103269585B (zh) * 2010-10-29 2016-12-21 Opko健康公司 治疗弹性蛋白酶相关病症的超硫酸化双糖
JP2013028541A (ja) * 2011-06-20 2013-02-07 Foundation For Biomedical Research & Innovation α−Ｋｌｏｔｈｏ／ＦＧＦ２３複合体形成阻害化合物
US10829509B2 (en) 2016-08-16 2020-11-10 Opko Pharmaceuticals, Llc Pure heptasulfated disaccharides having improved oral bioavailability

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