EP0907656A1 - Novel anticoagulant glycosides and pharmaceutical compositions thereof - Google Patents

Novel anticoagulant glycosides and pharmaceutical compositions thereof

Info

Publication number
EP0907656A1
EP0907656A1 EP97929440A EP97929440A EP0907656A1 EP 0907656 A1 EP0907656 A1 EP 0907656A1 EP 97929440 A EP97929440 A EP 97929440A EP 97929440 A EP97929440 A EP 97929440A EP 0907656 A1 EP0907656 A1 EP 0907656A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
dithio
azido
deoxy
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97929440A
Other languages
German (de)
English (en)
French (fr)
Inventor
Eva Kovacsne Bozo
János KUSZMANN
Gabriella Szabo
Sándor BOROS
Imre Moravcsik
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar 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 Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Publication of EP0907656A1 publication Critical patent/EP0907656A1/en
Withdrawn legal-status Critical Current

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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
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • This invention relates to novel 1 ,5-dithio-pyranosides of the formula (I),
  • R- represents hydrogen, hydroxy or an azido group
  • R 2 represents hydroxy, azido, amino or an acetamido group
  • R 3 represents hydroxy or an azido group
  • R 4 represents hydrogen, methyl or a hydroxymethyl group
  • R 5 represents hydrogen
  • the compounds of the invention possess valuable pharmaceutical properties, especially anticoagulant activity, even when administered by the oral route.
  • Particularly valuable representatives of formula (I) according to the invention are the following ones:
  • R1-R3 each represent hydroxy groups
  • R 4 and R 5 are hydrogen (i.e 1 ,5-dithio-xylopyranosides)
  • R 5 represents a chloro, nitro, cyano, methyl or methoxy group
  • 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 antithrombotic activity of carbohydrate derivatives can be substantially increased, by exchanging the hydroxy groups of the carbohydrate moiety (R1-R3) with hydrogen or with azido groups.
  • a similarly increased activity was found for thioglycosides, in which the carbohydrate part was a thiohexose (R 4 represents a hydroxymethyl group) instead of a thiopentose, as well as in further derivatives, in which the cyano substituent at C-4 of the aglycon was transformed into a carboxylic acid derivative.
  • the compounds of the invention can be synthesized by different known methods.
  • the above reaction can preferably be carried out at room temperature, using a 1 :1 mixture of triethylamine-pyridine 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 can preferably be carried out, using 98% hydrazin hydrate as reagent and ethanol as solvent.
  • the compound of formula (I), in which R 1 and R 2 each represent hydroxy groups, R 3 represents an azido group, R 4 and R 5 are hydrogens and R 6 represents a cyano group, can be prepared e.g. by separating the ⁇ -anomer of an anomenc mixture of formula (II),
  • R represents a cyano group
  • removing subsequently the acetyl groups in a lower aliphatic alcohol by treatment with base can preferably be carried out by separating the anomenc mixture of formula (II) in which R represents a cyano group, by column chromatography and removing the acetyl groups from the separated ⁇ -anomer by using sodium methoxide in methanolic solution.
  • glycosides of formula (II), wherein R represents a cyano group are new compounds and can be prepared e.g. from compounds of formula (VII),
  • the same mixture of glycosides can be obtained by converting the triacetate of formula (IV), in which R represents an acetoxy group, into the diacetate of formula (IV), in which R represents a hydroxy group, and subsequently into a trichloroacetimidate of formula (IV), in which R represents an -0-C(NH)-CCI 3 group. Condensation of the latter with (III) affords the anomeric mixture of the glycosides of formula (II), in which R represents a cyano group.
  • the above reaction sequence can preferably be carried out by treating the mercaptal of formula (VII), wherein R ⁇ and R 2 represent hydrogen, in the presence of an organic base, preferably in pyridine first with
  • the latter gives on treatment with a salt of a thiocarbo ⁇ ic acid, preferably with potassium thiobenzoate in an aprotic solvent, preferably irr N ( N-dimethylformamide the ester of formula (VI), wherein R represents a benzoylthio group.
  • a salt of a thiocarbo ⁇ ic acid preferably with potassium thiobenzoate in an aprotic solvent, preferably irr N ( N-dimethylformamide the ester of formula (VI), wherein R represents a benzoylthio group.
  • the ethylmercapto groups of this intermediate are split off, preferably in aqueous acetone with mercury(ll) chloride in the presence of cadmium carbonate when aldehyde of formula (V) is obtained.
  • the ester group of the aldehyde of formula (V) is removed with sodium methoxide in methanol and subsequently the isopropylidene group is split off
  • a mixture of the ⁇ - and ⁇ -triacetates of formula (IV), wherein R represents an acetoxy group is obtained, when the above solution is neutralized and the residue obtained after evaporation is treated with acetic anhydride in pyridine.
  • the acidified methanolic solution is kept for a longer time, or when it is heated before neutralization and acetylation, a mixture of the acetylated ⁇ - and ⁇ -methylglycosides of formula (IV), wherein R represents a methoxy group, is obtained.
  • This latter compound can be converted with sulfuric acid in acetic anhydride into the former triacetates of formula (IV), wherein R represents an acetoxy group.
  • R represents a cyano group
  • the xylopyranose derivative of formula (VIII) wherein R represents an acetoxy group is also a new compound and can be prepared e.g. by converting the known [H. Ohrui et al.: Agric. Biol. Chem. 34 (1970) 375] 3-azido-3-deoxy-
  • reaction sequence can preferably be carried out by treating 3-azido- 3-deoxy-1 ,2-0-isopropylidene-5-0-tosyl-D-xylofuranose with potassium thiobenzoate in N,N-dimethylformamide at 100 °C.
  • the formed ester of formula (IX) is debenzoylated with sodium methoxide in methanol, the solution is then acidified with aqueous hydrochloric acid, boiled and the obtained trihydroxy derivative is converted with acetic anhydride in pyridine into its peracetate of formula (VIII), in which R represents an acetoxy group, h)
  • the compound of formula (I), in which R 1 t R 4 and R 5 are hydrogens, R 2 and R 3 represent hydroxy groups, and RQ represents a cyano group, can be prepared e.g. by the addition of hydrogen bromide in an aprotic solvent to the pentose derivative of formula (XI),
  • the same mixture of glycosides of formula (XII), wherein R represents a 4-cyanophenylthio group can be obtained by exchanging first the bromo atom of the bromide of structure (XII), wherein R represents a bromo atom with an acetoxy group, and reacting the resulting acetate of structure (XII), wherein R represents an acetoxy group, with 4-cyanothiophenol of structure (III) in the presence of a promoter.
  • the above reaction sequence can preferably be carried out by saturating the double bond of the pentose derivative of formula (XI), wherein R represents a benzoyl group, with hydrogen bromide in benzene solution and treating the obtained reactive intermediate of formula (XII), wherein R represents a bromo atom, without isolation with the sodium salt of 4-cyanothiophenol, prepared in situ from compound (III) and sodium hydride.
  • the formed mixture of anomers of structure (XII), wherein R represents a 4-cyanophenylthio group is separated from the formed elimination product of formula (XI), wherein R represents a benzoyl group, by column chromatography.
  • the benzoyl groups of the obtained mixture of glycosides of structure (XII), wherein R represents a 4-cyanophenylthio group, can be removed with sodium methoxide in methanol affording a mixture of the anomeric glycosides from which the needed ⁇ -anomer of formula (I), in which R-, , R 4 and R5 are hydrogens, R 2 and R 3 represent hydroxy groups, and R Q represents a cyano group, is separated by crystallization.
  • the compound of formula (I), in which R-j represents an azido group, R 2 and R 3 represent hydroxy groups, R 4 and R 5 are hydrogens and R 6 represents a cyano group can be prepared e.g. by the azidonitration of the pentose derivative of formula (XI), wherein R represents a benzoyl group, in an aprotic solvent, exchange of the O-nitro group of the obtained intermediate of formula
  • R represents a O-nitro group, by an acetoxy group, and coupling of the formed triester of formula (XIII), wherein R represents an acetoxy group, with 4- cyanothiophenol of structure (III) in the presence of a promoter.
  • the two anomers of the obtained mixture of glycosides of structure (XIII), wherein R represents a 4-cyanophenylth ⁇ o group, are separated, and the ester groups of the ⁇ -anomer are removed by treatment with base in a lower aliphatic alcohol.
  • the above reaction sequence can preferably be carried out by using acetonitrile as solvent and sodium azide and ce ⁇ c ammonium nitrate as reagents for the azidonitration of the pentose derivative of formula (XI), wherein R represents a benzoyl group.
  • the formed intermediate of formula (XIII), wherein R represents a O-nitro group is treated with potassium acetate in acetic acid at elevated temperature, preferable at 100 °C to yield the tnester of formula (XIII), wherein R represents an acetoxy group, and this is treated with 4-cyanoth ⁇ ophenol of formula (III) using trimethylsilyl triflate as promoter.
  • the above reaction can preferably be carried out by using pyridine as a base and sodium methoxide in methanol for removing the ester groups.
  • the compound of formula (I), in which R-pR 3 each represent hydroxy groups, R 4 represents a hydroxymethyl group, R 5 represents hydrogen and R 6 represents a cyano group can be prepared e.g. by separating the two anomers of formula (XIV),
  • R represents an acetoxy group and X represents a cyano group
  • removing the acetyl groups from the ⁇ -anomer by treatment with base in a lower aliphatic alcohol preferably column chromatography is applied and deacetylation of the separated ⁇ -anomer is carried out with sodium methoxide in methanol.
  • glycosides of formula (XIV), wherein R represents an acetoxy group and X represents a cyano group are new compounds and can be prepared e.g. by reacting the known [W. Korytnyk et al.: Carbohydrate res., 108 (1982) 293] acetobromo 5-thio-D-glucose with 4-cyanothiophenol of formula (III) in the presence of a base in an aprotic solvent.
  • the above reaction can preferably be carried out under reflux, using acetone as solvent and potassium carbonate as base.
  • -R 3 each represent hydroxy groups, R 4 represents a methyl group, R 5 represents hydrogen and R 6 represents a cyano group, can be prepared e.g. by removing the acetyl groups of the ⁇ - anomer of formula (XIV), in which R represents hydrogen and X represents a cyano group in a lower aliphatic alcohol by treatment with base.
  • the ⁇ -glycoside of formula (XIV), in which R represents hydrogen and X represents a cyano group is a new compound and can be prepared e.g.
  • the obtained mesylate of formula (XIV), in which R represents a mesyloxy group and X represents a cyano group, is treated with sodium iodide in diethylketone at reflux temperature and from the iodo derivative of the resulting compound of formula (XIV), in which R represents an iodo atom and X represents a cyano group, the iodo substituent is reductivefy removed by using sodium borohydride - nickel(ll) chloride as reagents.
  • the reaction sequence mentioned in method B) can preferably be carried out the following way.
  • Acetobromo-6-deoxy-5-thio-D-glucose is converted with 4- cyanothiophenol of formula (III) in boiling acetone in the presence of potassium carbonate into a mixture of the anomeric glycosides of formula (XIV), wherein R represents hydrogen and X represents a cyano group, and the ⁇ -anomer of structure (I), in which R1-R3 each represent hydroxy groups, R 4 represents a methyl group, R5 represents hydrogen and R 6 represents a cyano group, is separated from this mixture by crystallization.
  • the above reaction can preferably be carried out with sodium methoxide in methanol.
  • the ⁇ -glycoside of formula (XV) is a new compound and can be prepared e.g. by elimination of hydrogen iodide from the iodide of formula (XIV), wherein R represents an iodo atom and X represents a cyano group.
  • the above mentioned elimination reaction can preferably be carried out in pyridine, using silver fluoride as reagent.
  • the above reaction sequence can preferably be carried out by treating the xylopyranose derivative of formula (VIII), wherein R represents an acetoxy group, with 4-nitrothiophenol in dichloromethane at low temperature, preferably at -10 °C using trimethylsilyl triflate as promoter, or in 1 ,2-dichloroethane at 20 °C using boron trifluoride etherate as promoter.
  • VIII xylopyranose derivative of formula (VIII), wherein R represents an acetoxy group
  • the above reaction can preferably be carried out at room temperature, using a 1:1 mixture of triethylamine-pyridine as solvent.
  • the compound of formula (I), in which R., , R 4 and R 5 are hydrogens, R 2 and R 3 represent hydroxy groups, and R 6 represents an aminothiocarbonyl group can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R1-R5 is as defined above and R 6 is a cyano group, with hydrogen sulfide using an organic base as solvent.
  • R 3 represent hydroxy groups
  • R 6 represents an amidino group
  • the above reactions can preferably be carried out, by using methyl iodide as reagent and acetone as solvent for the methylation, and exchanging the formed methylthio group with ammonium acetate in methanol or ethanol as solvent at reflux temperature.
  • the compound of formula (I), in which R1-R3 each represent hydroxy groups, R 4 represents a hydroxymethyl group, R 5 represents hydrogen and R 6 represents an aminothiocarbonyl group can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R-1-R5 is as defined above and R 6 is a cyano group, with hydrogen sulfide using an organic base as solvent.
  • the above reaction can preferably be carried out at room temperature, using a 1 :1 mixture of triethylamine-pyridine as solvent, v)
  • the above reaction can preferably be carried out at reflux temperature, using acetone as solvent and methyl iodide as reagent.
  • -R 3 each represent hydroxy groups, R 4 represents a methyl group, R 5 represents hydrogen and R 6 represents a nitro group, can be prepared e.g. by removing the acetyl groups from the ⁇ -anomer of formula (XIV), wherein R represents hydrogen and X represents a nitro group, with base using a lower aliphatic alcohol as solvent.
  • the ⁇ -anomer of formula (XIV), wherein R represents hydrogen and X represents a nitro group, is also a new compound and can be prepared e.g. by converting the known 1 ,2,3,4-tetra-O-acetyl-6-deoxy-5-thio-D-glucopyranose into its acetobromo derivative the reaction of which with 4-nitrothiophenol yields a mixture of the ⁇ , ⁇ -anomers of formula (XIV), wherein R represents hydrogen and X represents a nitro group, from which the ⁇ -anomer is separated.
  • the above reaction sequence can preferably be carried out by using for the reaction of acetobromo-6-deoxy-5-thio-D-glucopyranose with 4-nitrothiophenol acetone as solvent, and carrying out the reaction in the presence of potassium carbonate at reflux temperature.
  • the ⁇ -anomer is preferably separated from the mixture of the ⁇ , ⁇ -anomers by crystallization.
  • , R 4 and R 5 are hydrogens, R 2 and R 3 represent hydroxy groups, and R 6 represents a nitro group, can be prepared e.g.
  • the above reaction sequence can preferably be carried out by using benzene as solvent for the saturation of the double bond of the pentenose derivative of formula (XI), wherein R represents a benzoyl group, with hydrogen bromide.
  • the reactive 1 -bromo compound of formula (XII), wherein R represents a bromo atom is treated without isolation with silver acetate in acetonitrile and the formed ester of formula (XII), wherein R represents an acetoxy group, is reacted with 4-nitrothiophenol in dichloromethane, using trimethylsilyl triflate as promoter.
  • glycosides of formula (II), wherein R represents a nitro group are new compounds and can be prepared e.g. by reacting triacetate (IV), wherein R represents an acetoxy group, with 4-nitrothiophenol.
  • the above reaction can preferably be carried out in an aprotic solvent, preferably in dichloromethane or 1 ,2-dichloroethane in the presence of a promoter, preferably boron trifluoride etherate.
  • a promoter preferably boron trifluoride etherate.
  • the condensation reaction mentioned above can preferably be carried out in the presence of boron trifluoride etherate as a promoter, and the benzoyl groups are removed from the separated ⁇ -anomer with sodium methoxide in methanol.
  • the compounds of formula (I) of the invention possess valuable anticoagulant activity.
  • This anticoagulant activity of the compounds of formula (I) of the invention was determined on male SPRD rats, using the Pescador's venous thrombosis model [D. Bagdy et al.: Thromb. Haemost. 68 (1992) 125]. Accordingly 12.5 mg of the individual compounds was dissolved in 300 ⁇ l DMSO and this solution was diluted to 1 ml with physiological saline. From this solution a dose of 12.5 mg/kg was administered orally to the animals 3h prior to provoking the thrombus.
  • Table 1 the antithrombotic activity of several representatives of the compounds of the invention is given in percentage of the inhibition caused at the same dose level by Beciparcil (4-cyanophenyl 1 ,5-dithio- ⁇ -D- xylopyranoside, EP 365.397) which was used as reference compound. Table 1.
  • 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.
  • a compound of formula (I) or its pharmaceutically acceptable salt for oral administration the antithrombotic compound is formulated in capsules or tablets which may contain excipients such as binders, lubricants, disintegration agents and the like.
  • parenteral administration 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 an 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.
  • Steps d)-h) of method B) are identical to steps c)-g) of method A).
  • Steps a) and b) of method B) are identical to steps a) and b) of method A).
  • a stirred solution of 1.7 g of 1 ,5-anhydro-3,4-di-0-benzoyi-5-thio-2- deoxy-D-threo-pent-2-enitol (XI, R Bz) in 20 ml of dry benzene was saturated with anhydrous hydrogen bromide during 20 min at 10 °C, then nitrogen was bubbled through the solution to remove the excess hydrogen bromide.
  • ⁇ , ⁇ -anomer 1 3 C 72.9 and 73.2 (C-1), 65.3 and 66.9 (C-2), 72.6, 72.5, 72.3 and 71.1 (C- 3,4), 26.4 and 27.9 (C-5), 128.4, 128.8, 129.7, 133.5, 165.2 and 165.5 (aromatic C), 20.6 and 21.0 (OCOCH 3 ), 168.5 and 168.8 ppm (OCOCH 3 ).

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP97929440A 1996-06-25 1997-06-23 Novel anticoagulant glycosides and pharmaceutical compositions thereof Withdrawn EP0907656A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU9601756A HUP9601756A3 (en) 1996-06-25 1996-06-25 New anticoagulant glycosides and pharmaceutical compositions containing them
HU9601756P 1996-06-25
PCT/HU1997/000031 WO1997049716A1 (en) 1996-06-25 1997-06-23 Novel anticoagulant glycosides and pharmaceutical compositions thereof

Publications (1)

Publication Number Publication Date
EP0907656A1 true EP0907656A1 (en) 1999-04-14

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EP97929440A Withdrawn EP0907656A1 (en) 1996-06-25 1997-06-23 Novel anticoagulant glycosides and pharmaceutical compositions thereof

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EP (1) EP0907656A1 (cs)
JP (1) JP2000512989A (cs)
AU (1) AU3354797A (cs)
CA (1) CA2256504A1 (cs)
CZ (1) CZ414998A3 (cs)
HU (1) HUP9601756A3 (cs)
PL (1) PL330727A1 (cs)
SK (1) SK175798A3 (cs)
WO (1) WO1997049716A1 (cs)

Families Citing this family (8)

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EP1043321A1 (en) 1999-03-29 2000-10-11 Nisshin Flour Milling Co., Ltd. Process for the preparation of tetrahydropyran derivatives
AU2013241341B2 (en) 2012-03-28 2016-09-08 Fujifilm Corporation Salt of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine
HUE044412T2 (hu) 2012-08-13 2019-10-28 Fujifilm Corp Intermedier l-(2-deoxi-2-fluor-4-tio-beta-D-arabinofuranozil)-citozin szintézisére, intermedier tionukleozid szintézisére és eljárások ezen intermedierek elõállítására
EP3109245B1 (en) 2014-02-18 2018-01-03 FUJIFILM Corporation Method for producting thiolane skeleton-type glycoconjugate, and thiolane skeleton-type glycoconjugate
JP6204223B2 (ja) * 2014-02-19 2017-09-27 富士フイルム株式会社 チオピラノース化合物等の製造方法
TWI678373B (zh) 2014-10-31 2019-12-01 日商富士軟片股份有限公司 硫代核苷衍生物或其鹽及醫藥組合物
BR112019003946A2 (pt) 2016-08-31 2019-05-21 Fujifilm Corporation agente antitumoral, reforçador do efeito antitumoral e kit antitumoral
AU2018404329B2 (en) 2018-01-29 2021-09-09 Fujifilm Corporation Antitumor agent for biliary tract cancer and method for treating biliary tract cancer

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Publication number Priority date Publication date Assignee Title
FR2614893B1 (fr) * 1987-05-04 1989-12-22 Fournier Innovation Synergie Nouveaux b-d-phenyl-thioxylosides, leur procede de preparation et leur application en therapeutique
IE63544B1 (en) * 1988-10-18 1995-05-17 Fournier Ind & Sante Novel Beta-d-phenylthioxylosides their method of preparation and their use in therapy
FR2660313B1 (fr) * 1990-04-02 1992-07-03 Fournier Ind & Sante Nouveau sulfonyl-phenyl-betha-d-thioxylosides, leur procede de preparation et leur utilisation en therapeutique.

Non-Patent Citations (1)

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Title
See references of WO9749716A1 *

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SK175798A3 (en) 1999-05-07
HUP9601756A2 (en) 1997-12-29
AU3354797A (en) 1998-01-14
WO1997049716A1 (en) 1997-12-31
PL330727A1 (en) 1999-05-24
HUP9601756A3 (en) 1999-05-28
JP2000512989A (ja) 2000-10-03
CZ414998A3 (cs) 1999-03-17
HU9601756D0 (en) 1996-08-28
CA2256504A1 (en) 1997-12-31

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