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EP0712401A1 - Novel dialkoxy-pyridinyl-benzimidazole derivatives - Google Patents

Novel dialkoxy-pyridinyl-benzimidazole derivatives

Info

Publication number
EP0712401A1
EP0712401A1 EP95921187A EP95921187A EP0712401A1 EP 0712401 A1 EP0712401 A1 EP 0712401A1 EP 95921187 A EP95921187 A EP 95921187A EP 95921187 A EP95921187 A EP 95921187A EP 0712401 A1 EP0712401 A1 EP 0712401A1
Authority
EP
European Patent Office
Prior art keywords
methyl
benzimidazole
carbomethoxy
sulfinyl
pyridinyl
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Withdrawn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
EP95921187A
Other languages
German (de)
English (en)
French (fr)
Inventor
Per Lennart Lindberg
Gunnel Elisabeth Sunden
Per Oskar Sverker Von Unge
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.)
AstraZeneca AB
Original Assignee
Astra AB
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 Astra AB filed Critical Astra AB
Publication of EP0712401A1 publication Critical patent/EP0712401A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation.
  • the invention also relates to novel intermediates in the preparation of the compounds of the invention.
  • the compound 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-lH benzimidazole, and therapeutically acceptable salts thereof are described in application number EP 91911618.6.
  • This compound and its therapeutically acceptable salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents.
  • the compounds, being sulfoxides, have an asymmetric center in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile.
  • the present invention provides such compounds, which are novel salts of single enantiomers of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy- 2-pyridinyl)methyl]sulfinyl]-lH benzimidazole as well as the novel single enantiomers of the neutral form of said compound.
  • omeprazole (5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyrid_nyl)methyl]sulftnyl]-lH-berLzimidazole) in analytical scale is described in e.g. J. Chromatography, 532 (1990), 305-19.
  • the isolation of single enantiomers of the sulfoxide agent Ro 18-5364 is described in Euro. J. Biochem. 166 (1987) 453-459.
  • separation of the enantiomers of omeprazole in a preparative scale is described in DE 4035455.
  • the present invention in a further aspect provides a novel method for preparing the novel compounds of the invention in large scale.
  • this novel method can be used in large scale to obtain single enantiomers of the compound of the invention in neutral form, as well as in the form of the therapeutically acceptable salts.
  • novel compounds of the invention could be expected to undergo racemization in neutral pH as well as in basic pH. See for example Brandstrom et al, Acta Chemica Scandinavia 43 (1989) p.536-547.
  • the inventors now found that the novel single enantiomers of 5-carbomethoxy-6- me yl-2-[[(3,4-dimemoxy-2-pyridinyl)memyl]sulfinyl]-lH benzimidazole as well as its therapeutically acceptable salts are stable towards racemization.
  • the present invention refers to the new single enantiomers of 5-carbomethoxy-6- memyl-2-[[(3,4-dimemoxy-2-pyridinyl)methyl]sulfinyl]-lH benzimidazole according to compounds la and lb
  • Such salts are for example the Na + , Mg2+, Ca2+, Li + , K + and N + (R)4 salts of the single enantiomers of said compound, where R is an alkyl group with 1-4 carbon atoms, i.e.
  • Particularly preferred salts of the compound of the invention are the Na + , Mg2+ and Ca ⁇ + salts of the single enantiomers of 5-carbomethoxy-6-methyl-2-[[(3,4- dirnethoxy-2-pyridmyl)me yl]sulfinyl]-lH berLzimidazole.
  • the most preferred compounds of the invention are the optically pure 5- carbomethoxy-6-methy 1-2- [ [ (3,4-dimethoxy-2-py ridinyl)methy 1] sulfinyl]-l H benzimidazole according to the above formulas la and lb. Further preferred compounds are the optically pure Na + salts of 5-carbomethoxy-6-methyl-2-[[(3,4- di ethoxy-2-pyridinyl)me yl]sulfmyl]-lH benzimidazole according to compounds Ila and Ub
  • optically pure compound of the invention is meant the (+)- enantiomer of said compound essentially free from the corresponding (-)- enantiomer and the (-)-enantiomer essentially free from the corresponding (+)- enantiomer, respectively.
  • every single compound of the invention is obtained in high optical purity.
  • the compounds of the invention are easy to obtain.
  • the novel optically pure compounds are stable towards racemization in neutral pH as well as basic pH.
  • novel optically pure compounds are stable towards racemization in basic pH, which was surprising since the known deprotonation at the carbon atom between the pyridine ring and the chiral sulphur atom was expected to cause racemization under alkaline conditions.
  • This high stability towards racemization, both in neutral pH and basic pH makes it possible to use a single enantiomeric compound of the invention in the neutral form as well as salts thereof in therapy.
  • the specific method of preparation of the single enantiomers of the compound of the invention is a further aspect of the invention as mentioned above and it can be used to obtain the single enantiomeric compounds in the neutral form as well as the salts thereof.
  • the single enantiomeric compounds of the invention as well as the racemate have a high level of bioavailability, and does not block the uptake of iodine into the thyroid gland, and still said compounds are very effective as inhibitors of gastric acid secretion and exhibit high stability properties at neutral pH.
  • the compounds according to the invention may be used for inhibiting gastric acid secretion in mammals and man.
  • the single enantiomeric compounds of the invention may be used for the treatment of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.
  • the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable e.g. in patients on NSAID therapy, in patients with gastrinomas, and in patients with accute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration.
  • the compound of the invention may also be used for treatment or prophylaxis of inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be sepcifically mentioned are rheumatoid arthritis and gout.
  • the compound of the invention may also be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections.
  • a further aspect of the invention is the diasteromeric mixture of a regioisomeric mixture having the formula IV, which is an intermediate used in the specific method of preparation, wherein the carbomethoxy and methyl substituents in the benzimidazole moiety are in the 5 or 6 position, respectively.
  • optically pure compounds of the invention i.e. the single enantiomers
  • the Acyl moiety in the diastereomeric ester may be a chiral acyl group such as mandeloyl, and the asymmetric center in the chiral acyl group can have either R or S configuration.
  • the diastereomeric esters can be separated either by chromatography or fractional crystallization.
  • the solvolysis usually takes place together with a base in a protic solvent such as alcohols or water; or with a base in a mixture of acetonitrile and water, but the acyl group may also be hydrolysed off by a base in an aprotic solvent such as dimethylsulfoxide or dimethylformamide.
  • the reacting base may be OH" or RlO" where Rl can be any alkyl or aryl group.
  • the resulting compound in neutral form is treated with a base, such as NaOH, in an aqueous or nonaqueous medium, or with NaOR ⁇ wherein R ⁇ is an alkyl group containing 1-4 carbon atoms, or with Na H2-
  • alkaline salts wherein the cation is Li + or K + may be prepared using lithium or potassium salts of the above mentioned bases.
  • the crystalline form of the single enantiomers of the Na + salts In order to obtain the crystalline form of the single enantiomers of the Na + salts, to the optically pure Na + salts as a syrup are added a mixture of 2-butanone and toluene, but the crystalline form of the single enantiomers of the Na+ salt may also be prepared by adding NaOH to a mixture of the single enantiomeric compound of invention and a non-aqueous medium, such as a mixture of 2-butanone and toluene.
  • optically pure Na + salts are treated with an aqueous solution of an inorganic magnesium salt such as
  • MgCl2 whereupon the Mg2+ salts are precipitated.
  • the optically pure Mg2+ salts may also be prepared by treating single enantiomeric compound of the invention with a base, such as Mg(OR 3 )2, wherein R 3 is an alkyl group containing 1-4 carbon atoms, in a non-aqueous solvent such as alcohol (only for alcoholates), e.g. ROH, or in an ether such as tetrahydrofuran.
  • a base such as Mg(OR 3 )2, wherein R 3 is an alkyl group containing 1-4 carbon atoms
  • a non-aqueous solvent such as alcohol (only for alcoholates), e.g. ROH, or in an ether such as tetrahydrofuran.
  • alkaline salts wherein the cation is Ca ⁇ + can be prepared, using an aqueous solution of an inorganic calcium salt such as CaC-2- Alkaline salts of the single enantiomers of the invention are, as mentioned above, beside the sodium salts (compounds Ha and Ub) and the magnesium salts (compound Ula and HTb), exemplified by their salts with Li + , K + , Ca 2+ and N + (R)4, where R is an alkyl group with 1-4 C-atoms.
  • the single enantiomers, i.e. the optically pure compounds, of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other modes of administrations.
  • the pharmaceutical formulations contain the single enantiomers of the invention normally in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in form of a solid, semi- solid or liquid diluent, or capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compound is between 0.1- 95% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1-50% by weight in preparations for oral administration.
  • An active compound in a form with high solubility in water is requested for parenteral preparations, for some oral preparations an active compound in a form with low solubility is suitable.
  • the single enantiomeric compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatin or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes.
  • a solid, powdered carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatin or another suitable carrier
  • stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium
  • Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalysed degradation as long as the dosage form remains in the stomach.
  • the enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different amounts of the active compound present.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules may also be enteric-coated as described above.
  • Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivates or gelatin. The capsules may be enteric-coated as described above.
  • Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and /or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations for oral administration may also be prepared in the form of dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administrations may be prepared as solutions of the single enantiomeric compounds of the invention in pharmaceutically acceptable solvents, preferably in a concentration from 0.1 to 10% by weight. These soultions may also contain stabilizing agents and /or buffering agents and may be manufactured in different unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as dry preparations to be reconsituted with a suitable solvent extemporaneously before use.
  • the typical daily dose of the active compound will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.
  • Example 7 Preparation of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridmy methyl]-(R/SVsulfinyl1-l-ffR)-mandeloyloxymethyl]-lH-benzimidazole and 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyll-( ' R/SV sulfinyl]-l-[(R)-mandeloyloxymethyll-lH-benzimidazole
  • Chloroform 50 ml
  • the reaction mixture was chilled and then partitioned between ethyl acetate and water.
  • compositions containing the compounds of the invention as active ingredient are illustrated in the following formulations.
  • a syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
  • An enteric coated tablet containing 50 mg of active compound was prepared from the following ingredients:
  • a parenteral formulation for intravenous use containing 4 mg of active compound per ml, was prepared from the following ingredients:
  • the active compound was dissolved in water to a final volume of 1000 ml.
  • the solution was filtered through a 0.22 um filter and immediately dispensed into 10 ml sterile ampoules. The ampoules were sealed.
  • Capsules containing 30 mg of active compound were prepared from the following ingredients:
  • the active compound was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate.
  • the wet mass was forced through an extruder and spheronized and dried in a fluidized bed dryer.
  • the final coated pellets were filled into capsules.
  • Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
  • the active compound was homogenously mixed with Witepsol H-15 at a temperature of 41° C.
  • the molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed.
  • Each suppository contained 40 mg of active compound.
  • the stability of the optically pure compounds of the invention towards racemization has been measured at low concentrations (10 ⁇ 5 M) at 37°C in aqueous buffer solutions at pH 7 and pH 11.
  • the stereo chemical stability was measured by comparing the optical purity for the (-)-enantiomer of 5-carbomethoxy-6-methyl-2- [[(3,4-dimemoxy-2-pyridinyl)memyl]sulfinyl]-l-H-benzimidazole in buffer solution immediately after dissolving and after several hours.
  • the surprising high stereo chemical stability in neutral conditions as well as in alkaline conditions for the compounds of invention is exemplified by the fact that no racemization for the test compound was obtained neither at pH 7 nor at pH 11, even after 24 hours. At pH 7, however, the chemical degradation of the compound is much apparent after 28 hours.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP95921187A 1994-05-27 1995-05-11 Novel dialkoxy-pyridinyl-benzimidazole derivatives Withdrawn EP0712401A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9400511 1994-05-27
WOPCT/SE94/00511 1994-05-27
PCT/SE1995/000519 WO1995032959A1 (en) 1994-05-27 1995-05-11 Novel dialkoxy-pyridinyl-benzimidazole derivatives

Publications (1)

Publication Number Publication Date
EP0712401A1 true EP0712401A1 (en) 1996-05-22

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ID=20392945

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Application Number Title Priority Date Filing Date
EP95921187A Withdrawn EP0712401A1 (en) 1994-05-27 1995-05-11 Novel dialkoxy-pyridinyl-benzimidazole derivatives

Country Status (18)

Country Link
EP (1) EP0712401A1 (cs)
JP (1) JPH09504557A (cs)
CN (1) CN1128997A (cs)
AU (1) AU2633095A (cs)
BR (1) BR9506235A (cs)
CA (1) CA2166988A1 (cs)
CZ (1) CZ24396A3 (cs)
EE (1) EE9600011A (cs)
FI (1) FI960367A0 (cs)
HU (1) HU9600005D0 (cs)
IL (1) IL113604A0 (cs)
IS (1) IS4321A (cs)
MA (1) MA23563A1 (cs)
NO (1) NO960268L (cs)
PL (1) PL312692A1 (cs)
TN (1) TNSN95062A1 (cs)
WO (1) WO1995032959A1 (cs)
ZA (1) ZA954125B (cs)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9423968D0 (en) * 1994-11-28 1995-01-11 Astra Ab Resolution
GB9423970D0 (en) * 1994-11-28 1995-01-11 Astra Ab Oxidation
US5840737A (en) 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
JP4610086B2 (ja) 1998-11-18 2011-01-12 アストラゼネカ・アクチエボラーグ 改善された化学的方法および医薬処方物
US8206741B2 (en) 2001-06-01 2012-06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
WO2008057802A2 (en) 2006-10-27 2008-05-15 The Curators Of The University Of Missouri Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same
CN101980700A (zh) 2008-02-20 2011-02-23 密苏里大学董事会 包含奥美拉唑和兰索拉唑以及缓冲剂的组合的组合物及其使用方法
CN102209529A (zh) 2008-09-09 2011-10-05 阿斯利康(瑞典)有限公司 将药物组合物递送至有需要的患者的方法
SG176724A1 (en) 2009-06-25 2012-01-30 Astrazeneca Ab Method for treating a patient at risk for developing an nsaid-associated ulcer
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
EP0593463B1 (en) * 1990-06-20 1999-09-15 Astra Aktiebolag Dialkoxy-pyridinyl-benzimidazole derivatives, process for their preparation and their pharmaceutical use
DE4035455A1 (de) * 1990-11-08 1992-05-14 Byk Gulden Lomberg Chem Fab Enantiomerentrennung

Non-Patent Citations (1)

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Title
See references of WO9532959A1 *

Also Published As

Publication number Publication date
IL113604A0 (en) 1995-08-31
CZ24396A3 (en) 1996-06-12
MA23563A1 (fr) 1995-12-31
NO960268D0 (no) 1996-01-23
BR9506235A (pt) 1997-08-12
WO1995032959A1 (en) 1995-12-07
IS4321A (is) 1996-01-17
ZA954125B (en) 1995-11-27
AU2633095A (en) 1995-12-21
PL312692A1 (en) 1996-05-13
JPH09504557A (ja) 1997-05-06
CA2166988A1 (en) 1995-12-07
FI960367L (fi) 1996-01-26
NO960268L (no) 1996-01-23
HU9600005D0 (en) 1996-03-28
TNSN95062A1 (fr) 1996-02-06
FI960367A0 (fi) 1996-01-26
EE9600011A (et) 1996-04-15
CN1128997A (zh) 1996-08-14

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