WO1998024792A1 - Glycosides anticoagulants et leurs compositions pharmaceutiques - Google Patents

Glycosides anticoagulants et leurs compositions pharmaceutiques Download PDF

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Publication number
WO1998024792A1
WO1998024792A1 PCT/HU1997/000078 HU9700078W WO9824792A1 WO 1998024792 A1 WO1998024792 A1 WO 1998024792A1 HU 9700078 W HU9700078 W HU 9700078W WO 9824792 A1 WO9824792 A1 WO 9824792A1
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WO
WIPO (PCT)
Prior art keywords
formula
anhydro
dithio
mannopyranoside
mixture
Prior art date
Application number
PCT/HU1997/000078
Other languages
English (en)
Inventor
Éva KOVÁCSNÉ BOZÓ
János KUSZMANN
Gabriella Szabó
Sándor BOROS
Tivadar Rettegi
Éva KASZÁS
Lászlóné KENYERES
Éva MATUCZ
Imre Moravcsik
Ottóné ORBÁN
Mónika TURUCZNÉ FERWAGNER
Original Assignee
Richter Gedeon Vegyészeti Gyár Rt.
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 Richter Gedeon Vegyészeti Gyár Rt. filed Critical Richter Gedeon Vegyészeti Gyár Rt.
Priority to AU50646/98A priority Critical patent/AU5064698A/en
Publication of WO1998024792A1 publication Critical patent/WO1998024792A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical

Definitions

  • This invention relates to novel 2,6-anhydro-1 ,2-dithio-pyranosides of the formula (I), more particularly to D-manno- and D-altropyranosides of formula (la-Id)
  • R ⁇ represents a hydroxy or an azido group
  • the compounds of the invention possess valuable pharmaceutical properties, especially anticoagulant activity, even when administered by the oral route.
  • the aim of the invention was to synthesize such new carbohydrate derivatives which are stronger inhibitors of the coagulation process than the known ones and are orally active too.
  • the compounds of the invention can be synthesized by different known methods.
  • represents a hydroxy group and R2 represents a cyano group, can be prepared e.g. by treatment of an anomeric mixture of glycosides of formula (III),
  • the above reaction can preferably be carried out by hydrolyzing the anomeric mixture of glycosides of formula (III) by using sodium methoxide in methanolic solution, and separating the obtained a, b-anomers (la and lb) by crystallization and/or column chromatography.
  • glycosides of formula (III), which are new compounds, can be prepared e.g. by acetylating the known [I.I. Cubero et al.: Carbohydr. Res., 242,
  • glycosides of formula (III) can preferably be carried out by using sulfuric acid in acetic anhydride for the methoxy acetoxy exchange reaction, and trimethylsilyl triflate as promoter for the condensation with 4- cyanothiophenol.
  • represents a hydroxy group and R2 represents an aminothiocarbonyl group, can be prepared e.g. by treatment of a compound of formula (lb), wherein the meaning of R-j is as defined above and R2 is a cyano group, with hydrogen sulfide using an organic base as solvent.
  • the above reaction can preferably be carried out, using acetone as solvent and methyl iodide as reagent at reflux temperature.
  • the above reaction can preferably be carried out, using methanol or ethanol as solvent at reflux temperature.
  • the above reaction sequence can preferably be carried out by using ethanol as solvent and sodium borohydride - nickel(ll) chloride as reagent for the reduction, pyridine as a base for the acetylation and sodium methoxide in methanol for removing the ester groups.
  • the above reaction sequence can preferably be carried out by using sodium methoxide in methanolic solution for the hydrolysis of the anomeric mixture of glycosides of formula (VI), and separating the so obtained a, b-anomers (lc and Id) by crystallization and/or column chromatography.
  • glycosides of formula (VI), which are new compounds, can be prepared e.g. by reacting the known [K. Toshima et al.: Tetrahedr. Lett., 33, 1491 (1992)] triacetate of formula (VII)
  • glycosides of formula (VI) can preferably be carried out at low temperature, preferably at 0 °C, using trimethylsilyl triflate as promoter.
  • the compounds of formula (la and lb), in which R-j represents an azido group and R2 represents a nitro group, can be prepared e.g. by reacting the diacetate of formula (VIII) with 4-nitrothiophenol in the presence of a promoter, removing the acetyl groups of the obtained anomeric glycosides in a lower aliphatic alcohol by treatment with base, and optionally separating the anomers.
  • the above reaction sequence can preferably be carried out by reacting the diacetate of formula (VIII) with 4-nitrothiophenol in dichloromethane at low temperature, preferably at 0 °C, using trimethylsilyl triflate as promoter, or in 1 ,2-dichloroethane at 20 °C, using boron trifluorid etherate as promoter, hydrolyzing the obtained anomeric glycosides by sodium methoxide in methanol, and optionally separating the obtained a, b-anomers by crystallization and/or column chromatography.
  • the compounds of formula (I) of the invention possess valuable anticoagulant activity.
  • the compounds of the present invention as well as their pharmaceutically acceptable salts can be used as such or suitably in the form of pharmaceutical compositions. These compositions also fall within the scope of the present invention.
  • compositions contain an amount required to excert the therapeutical effect of a compound of formula (I) or its pharmaceutically acceptable salt, in admixture with known carriers, excipients, diluents and/or other additives commonly used in the pharmaceutical practice.
  • the antithrombotic compound is formulated in capsules or tablets which may contain excipients such as binders, lubricants, disintegration agents and the like.
  • the antithrombotic compound is formulated in a pharmaceutically acceptable diluent, e.g. physiological saline (0.9 %), 5% dextrose, Ringer's solution and the like.
  • the doses required to excert the therapeutical effect of the compounds according to the invention may be varied depending on the individual condition and age of the patient to be treated and finally these doses are determined by the attending physician. However, for the prevention and/or treatment of diseases, where the application of an anticoagulant is desirable, daily doses of these compounds falling between about 0.01 mg/kg of body weight and about 100 mg/kg of body weight and preferably between about 0.1 mg/kg of body weight and about 10 mg/kg of body weight are used by the oral or parenteral, e.g. intravenous, route.
  • the compounds according to the invention and the process for the preparation thereof are illustrated in detail by the following not limiting Examples.
  • Multiplicities of the 1 3 C NMR spectra were obtained from DEPT experiments. The assignment of the protons were based on homonuclear decoupling and DNOE experiments. Connectivities between identified protons and protonated carbons were determined by HETCOR experiments. MS spectra were recorded with a Finnigan MAT 8430 mass spectrometer. In the case of FAB spectra samples were dissolved in 3-nitrobenzaldehyde or in glycerin.
  • the starting anomeric mixture of formula (III) can be prepared the following way:
  • the starting compound of formula (VIII) can be prepared the following way:

Abstract

Cette invention concerne de nouveaux 2,6-anhydro-1,2-dithio-D-manno- et D-altropyrannosides de la formule (I) dans laquelle R1 représente un groupe hydroxy ou un groupe azido, R2 représente un groupe nitro, cyano, amidino, aminothiocarbonyle, -C(=NH)-OCH3, -C(=NH)-NH-NH2, -C(=NH)-SCH3 ou un groupe acétamido, ainsi que leurs sels d'addition d'acide formés avec des acides organiques ou inorganiques, si possible, ainsi que des compositions pharmaceutiques les contenant. Les composés de l'invention présentent des propriétés thérapeutiques, notamment anticoagulantes avantageuses.
PCT/HU1997/000078 1996-12-04 1997-12-01 Glycosides anticoagulants et leurs compositions pharmaceutiques WO1998024792A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50646/98A AU5064698A (en) 1996-12-04 1997-12-01 Anticoagulant glycosides and pharmaceutical compositions thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9603341A HUP9603341A3 (en) 1996-12-04 1996-12-04 Glucosides as blood-clotting-inhibitors and pharmaceutical compositions containing them
HUP9603341 1996-12-04

Publications (1)

Publication Number Publication Date
WO1998024792A1 true WO1998024792A1 (fr) 1998-06-11

Family

ID=89994513

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1997/000078 WO1998024792A1 (fr) 1996-12-04 1997-12-01 Glycosides anticoagulants et leurs compositions pharmaceutiques

Country Status (3)

Country Link
AU (1) AU5064698A (fr)
HU (1) HUP9603341A3 (fr)
WO (1) WO1998024792A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0290321A1 (fr) * 1987-05-04 1988-11-09 Fournier Industrie Et Sante Nouveaux beta-D-phényl-thioxylosides, leur procédé de préparation et leur application en thérapeutique
EP0365397A2 (fr) * 1988-10-18 1990-04-25 Fournier Industrie Et Sante Nouveaux beta-D-phényl-thioxylosides, leur procédé de préparation et leur utilisation en thérapeutique
WO1995005182A1 (fr) * 1993-08-13 1995-02-23 Glycomed Incorporated Oligosaccharides pontes et leurs derives sulfates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0290321A1 (fr) * 1987-05-04 1988-11-09 Fournier Industrie Et Sante Nouveaux beta-D-phényl-thioxylosides, leur procédé de préparation et leur application en thérapeutique
EP0365397A2 (fr) * 1988-10-18 1990-04-25 Fournier Industrie Et Sante Nouveaux beta-D-phényl-thioxylosides, leur procédé de préparation et leur utilisation en thérapeutique
WO1995005182A1 (fr) * 1993-08-13 1995-02-23 Glycomed Incorporated Oligosaccharides pontes et leurs derives sulfates

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
F BELLAMY ET AL: "Thioxyloside derivatives as orally active venous antithrombotics", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, 1995, pages 101 - 115, XP002056034 *
K TOSHIMA: "The use of 2,6-anhydro-2-thio sugar for a highly stereocontrolled glycosylation", TETRAHEDRON LETTERS, vol. 31, no. 23, 1990, pages 3339 - 3342, XP002056035 *
MASSON P J ET AL: "The effect of the.beta.-D-xyloside naroparcil on circulating plasma glycosaminoglycans. An explanation for its known antithrombotic activity in the rabbit", J. BIOL. CHEM. (JBCHA3,00219258);95; VOL.270 (6); PP.2662-8, LABORATOIRES FOURNIER S.C.A.;CENTRE DE RECHERCHE ET DEVELOPPEMENT; DAIX; 21121; FR. (FR), XP002056036 *

Also Published As

Publication number Publication date
HUP9603341A2 (hu) 1998-10-28
AU5064698A (en) 1998-06-29
HU9603341D0 (en) 1997-01-28
HUP9603341A3 (en) 1999-05-28

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