EP0804415A1 - Neue farnesyltransferase-hemmer, ihre herstellung und sie enthaltende pharmazeutische zusammensetzungen - Google Patents

Neue farnesyltransferase-hemmer, ihre herstellung und sie enthaltende pharmazeutische zusammensetzungen

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Publication number
EP0804415A1
EP0804415A1 EP96901397A EP96901397A EP0804415A1 EP 0804415 A1 EP0804415 A1 EP 0804415A1 EP 96901397 A EP96901397 A EP 96901397A EP 96901397 A EP96901397 A EP 96901397A EP 0804415 A1 EP0804415 A1 EP 0804415A1
Authority
EP
European Patent Office
Prior art keywords
radical
hydrogen atom
carbon atoms
alkyl
optionally substituted
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.)
Ceased
Application number
EP96901397A
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English (en)
French (fr)
Inventor
Bernard Baudoin
Christopher Burns
Alain Commercon
Alain Lebrun
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.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
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 Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0804415A1 publication Critical patent/EP0804415A1/de
Ceased legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/12Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton

Definitions

  • the present invention relates to new farnesyl transferase inhibitors of general formula:
  • the C-terminal sequence of the Ras gene contains the motif "CAAX” or "Cys-Aaa ⁇ -Aaa2-Xaa M in which Aaa represents an aliphatic amino acid and Xaa represents any amino acid. It is known that tetrapeptides with a CAAX sequence can inhibit famesylation of the Ras protein.
  • X represents an oxygen or sulfur atom
  • R2 represents an alkyl, alkenyl or straight or branched alkynyl radical containing 1 to 6 carbon atoms optionally substituted by a hydroxy radical, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio containing 1 to 4 carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms or alkylsulfonyl containing 1 to 4 carbon atoms, it being understood that, when R2 represents an alkyl radical substituted by a hydroxy radical, R2 can form with the carboxy radical in ⁇ a lactone, R'2 represents an atom of hydrogen or a straight or branched alkyl radical containing 1 to 6 carbon atoms, and
  • R represents a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms optionally substituted by an alkoxy radical containing 1 to 4 carbon atoms, alkylthio containing 1 to 4 carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms, alkylsulfonyl containing 1 to 4 carbon atoms, phenyl, phenoxy, phenylthio, phenylsulf nyl, phenylsulfonyl, alkylamino containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, or a phenyl radical optionally substituted by a or several atoms or radicals chosen from halogen atoms and alkyl, alkyloxy, alkylthio or alkanoyl radicals.
  • Rj represents a radical of formula YS-Aj- in which Y represents a hydrogen atom or a lysine residue or a fatty acid residue containing up to 20 carbon atoms and A represents an ethylene or propylene radical optionally substituted by an amino radical,
  • R'i represents a hydrogen atom or a methyl radical
  • X represents an oxygen atom
  • R2 represents an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a hydroxy, methoxy, mercapto, methylthio, memylsulfinyl or methylsulfonyl radical
  • R'2 represents a hydrogen atom or a methyl radical
  • R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by an alkoxy radical, or a phenyl radical. More particularly still,
  • Rj represents a radical of formula Y-S-Aj- in which Y represents a hydrogen atom and Aj represents an ethylene or propylene radical optionally substituted by an amino radical,
  • R'i represents a hydrogen atom
  • X represents an oxygen atom
  • R2 represents a methyl, ethyl, propyl or butyl radical optionally substituted by a hydroxy, methoxy, mercapto or methylthio radical
  • R'2 represents a hydrogen atom
  • R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms.
  • Rj represents a 2-mercapto-ethyl or 1-amino-2-mercapto-ethyl radical
  • R'j represents a hydrogen atom
  • X represents an oxygen atom
  • R2 represents an n.butyl or 2-methylthio-ethyl radical and R'2 represents a hydrogen
  • R represents a hydrogen atom or a methyl radical.
  • the present invention also relates to the stereoisomeric forms of the products of general formula (I).
  • R ⁇ C (X ⁇ ) (Y ⁇ ) (NR' ⁇ ) and R'2CH (NR'2) CO-OH preferably have the configuration of natural amino acids.
  • the present invention also relates to the mineral or organic salts of the products of general formula (I).
  • the new products according to the invention can be prepared by applying known methods derived from the methods used more particularly in peptide chemistry for the assembly of chains.
  • R2 and R'2 are defined as above and R 'represents an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by a phenyl radical, preferably a tert-butyl radical, operating in the presence of an agent condensation, such as hydroxybenzotriazole and dicyclohexylcarbod ⁇ mide, and of a base, such as triethylamine, in an organic solvent, such as dimethylformamide, to give a product of general formula:
  • Ri-CHO (VII) in which Rj is defined as above, it being understood that the amino and mercapto functions carried by Rj are optionally protected by appropriate protective groups such as a trityl radical for the mercapto function or a tert-butoxycarbonyl radical for the amino function, on a product of general formula (V) in the presence of a reducing agent such as sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or hydrogen in the presence of a catalyst.
  • a reducing agent such as sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or hydrogen in the presence of a catalyst.
  • the reaction is carried out in an organic solvent such as an alcohol such as methanol optionally in combination with a other organic solvent such as an ether such as tetrahydrofuran. It is particularly advantageous to operate in an anhydrous medium.
  • the protective groups are replaced by hydrogen atoms by application of the usual techniques.
  • the Boc or trityl or tert-butyl protecting groups can be replaced by hydrogen atoms by means of trifluoroacetic acid in the presence of ethanedithiol.
  • the products of general formula (I) in which X represents a sulfur atom can be obtained from a product of general formula (III) in which X represents an oxygen atom by thionation then by performing the steps of reduction, condensation or reductive amination as appropriate and deprotection described above for the preparation of a product of general formula (I) in which X represents an oxygen atom.
  • the products of general formula (I) in which R represents a hydrogen atom can also be obtained by saponification of a product of general formula (VI) followed by the replacement of the protective groups carried by R ⁇ under the conditions described above.
  • 5-nitro-1,2,3,4-tetrahydro-naphthyl-l-carboxylic acid which can be obtained as a mixture with 7-nitro-1,2,3,4-tetrahydro-naphthyl-l acid -carboxylic, can be prepared according to the process described by T. NAKAYAMA et al., Chem. Pharm. Bull., 32, 3968 (1984).
  • the products of general formula (I) can be purified according to the usual methods such as chromatography.
  • the following examples illustrate the preparation of the products according to the invention.
  • the organic solution is washed twice with 50 cm3 of an aqueous solution of sodium hydrogencarbonate at 10% (w / v) then once with 50 cm3 of an aqueous solution of citric acid at 10%, once distilled water, and finally with a saturated aqueous solution of sodium chloride.
  • the organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 3.68 g of the methyl ester of N- (5-nitro-1,2,3,4,4-tetrahydro-naphthyl-1 (R, S) -carbonyl) - (L) - methionine are obtained.
  • the filtrate is concentrated to dryness under reduced pressure.
  • the residue is dissolved in 150 cm3 of ethyl acetate and washed with 100 cm3 of an aqueous solution of sodium hydrogencarbonate at 10% (w / v), 100 cm3 of an aqueous solution of citric acid at 10 % (w / v), 100 cm3 of distilled water, another 100 cm3 of an aqueous solution of sodium hydrogenocrbonate at 10% (w / v), and finally per 100 cm3 of a saturated aqueous solution of sodium chloride sodium.
  • the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • the farnesyltransferase activity is determined by the amount of ( ⁇ H) farnesyl transferred from ( ⁇ H) farnesylpyrophosphate [( ⁇ H) FPP) to the p21 H-Ras protein.
  • the standard reaction mixture is composed, for a final volume of 60 ⁇ l, of 50 mM Tris-HCl, 5 mM MgCl2, 5 mM dithiotreitol, octyl- ⁇ -D-glucopyranoside 0.2, p21 H-ras 200 picomoles, ( 3 H) FPP (at 61,000 dpm / picomole) 4.5 picomoles.
  • the reaction is initiated by the addition of approximately 5 ng of human farnesyltransferase purified from cultures of THP1 cells. After incubation for 20 minutes at 37 ° C. in a microtiter plate containing 96 holes of 1 cm 3 per plate (Titer Plate®, Beckman), the reaction is stopped by adding 0.4 cm 3 of 0.1% SDS in methanol. at 0 ° C. 0.4 cm 3 of trichloroacetic acid (TCA) 30% in methanol is then added to the mixture. The plates are left for 1 hour in ice.
  • TCA trichloroacetic acid
  • the precipitated content is then retained on a fiberglass membrane Filtermat®, Pharmacia) with the filtration unit (Combi Cell Harvester®, Skatron) and rinsed with 6% trichloroacetic acid in distilled water.
  • the membranes are dried in the microwave oven then impregnated with scintillant by melting under hot air of Meltilex® OPharmacia) and finally counted in cpm in a ⁇ -Plate® counter (LKB). Each test is repeated 3 times.
  • the activity unit is defined by 1 picomole of (-1H) FPP transferred to p21 H-Ras in 20 minutes.
  • the inhibition percentages are obtained by comparison of the tests with and without inhibitor after deduction of the blanks, the IC50 being measured from the inhibitions obtained with 9 different concentrations using the Enzfitter® or Grafit® software.
  • Cell activity can be determined as follows:
  • the cell line is the THAC line (CCL 39 cells transfected with activated Ha-Ras) according to K. Seu en et al., EMBO J., 2 (1) 161-168 (1988).
  • the cells are seeded in 6 cm diameter petri dishes containing DMEM medium, 5% fetal calf serum, 1% G418. After 24 hours of culture, the culture medium is changed (with or without serum) and the product to be studied is added in solution in dimethylformamide (DMF), in the presence or in the absence of DTT (final concentrations of 0.5% in DMF and O.lmM in DTT).
  • DMF dimethylformamide
  • the lysates are clarified by centrifugation at 4,000 rpm for 10 minutes. Extraction with Triton XI 14 makes it possible to separate the farnesylated Ras protein from the non-famesylated Ras protein [C. BORDIER, J. Biol. Chem., 25â (4), 1604-1607 (1981)].
  • the famesylated Ras protein which is more hydrophobic, is found in the detergent phase while the non-famesylated Ras protein is found in the aqueous phase.
  • the samples are denatured by heating to 95 ° C. in denaturation buffer for electrophoresis and deposited on a 14% polyacrylamide gel. When the dye reaches the bottom of the gel, the proteins in the gel are transferred to a PVDF membrane.
  • the Ras protein is revealed by the Western blot technique: the membrane is incubated with a specific anti-Ras monoclonal antibody (pan-Ras Ab3, Oncogene Science) then with protein A labeled at 125 d. After autoradiography, the bands are identified, cut and counted in a ⁇ counter. The radioactivity of the bands corresponding to famesylated Ras and to non-famesylated Ras makes it possible to determine the percentage inhibition of famesylation of the Ras protein. The results obtained are collated in Table I. TABLE I
  • the new products of general formula (I) can be in the form of non-toxic and pharmaceutically acceptable salts.
  • These non-toxic salts include the salts with mineral acids (hydrochloric, sulfuric, hydrobromic, phosphoric, nitric) or with organic acids (acetic, propionic, succinic, maleic, hydroxymaleic, benzoic, fumaric, methanesulfonic, trifluoroacetic or oxalic acids) or with mineral bases (soda, potash, lithine, lime) or organic bases (tertiary amines such as triethylamine, piperidine, benzylamine) depending on the nature of the Rjet R symbols of the product of general formula (I).
  • the present invention also relates to pharmaceutical compositions which contain at least one product of general formula (I) in combination with one or more diluents or pharmaceutically acceptable adjuvants whether inert or physiologically active.
  • compositions can be administered orally, parenterally or rectally.
  • compositions for oral administration include tablets, pills, powders or granules.
  • the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch.
  • these compositions can include substances other than diluents, for example a lubricant such as magnesium stearate.
  • compositions for oral administration can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
  • the compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate, can be used.
  • compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, incorporating sterilizing agents into the composition or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter.
  • compositions according to the invention are particularly useful in human therapy in the treatment of cancers of various origins.
  • the doses depend on the desired effect, on the duration of the treatment and on the factors specific to the subject to be treated.
  • the doses are, in humans, between 0.1 and 20 mg / kg per day intraperitoneally.
  • the following example illustrates a composition according to the invention.
  • Example 2 200 mg of the product obtained in Example 1 are dissolved in 100 cm 3 of physiological saline. The solution obtained is aseptically distributed in 10 cm 3 ampoules. The ampoules are administered as a single injection or as an infusion.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP96901397A 1995-01-18 1996-01-16 Neue farnesyltransferase-hemmer, ihre herstellung und sie enthaltende pharmazeutische zusammensetzungen Ceased EP0804415A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9500494 1995-01-18
FR9500494A FR2729390A1 (fr) 1995-01-18 1995-01-18 Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
PCT/FR1996/000067 WO1996022278A1 (fr) 1995-01-18 1996-01-16 Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent

Publications (1)

Publication Number Publication Date
EP0804415A1 true EP0804415A1 (de) 1997-11-05

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EP96901397A Ceased EP0804415A1 (de) 1995-01-18 1996-01-16 Neue farnesyltransferase-hemmer, ihre herstellung und sie enthaltende pharmazeutische zusammensetzungen

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Country Link
US (1) US5750567A (de)
EP (1) EP0804415A1 (de)
JP (1) JPH10512560A (de)
KR (1) KR19980701469A (de)
CN (1) CN1169145A (de)
AU (1) AU4543696A (de)
BR (1) BR9606970A (de)
CA (1) CA2211786A1 (de)
CZ (1) CZ228297A3 (de)
FI (1) FI973039A0 (de)
FR (1) FR2729390A1 (de)
NO (1) NO973222L (de)
PL (1) PL321380A1 (de)
SK (1) SK95997A3 (de)
TR (1) TR199700660T1 (de)
WO (1) WO1996022278A1 (de)
ZA (1) ZA96258B (de)

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FI973039A (fi) 1997-07-17
FR2729390B1 (de) 1997-02-21
WO1996022278A1 (fr) 1996-07-25
ZA96258B (en) 1996-08-01
KR19980701469A (ko) 1998-05-15
TR199700660T1 (xx) 1998-01-21
US5750567A (en) 1998-05-12
CA2211786A1 (fr) 1996-07-25
SK95997A3 (en) 1997-12-10
NO973222D0 (no) 1997-07-10
PL321380A1 (en) 1997-12-08
CZ228297A3 (en) 1997-10-15
MX9705270A (es) 1997-10-31
BR9606970A (pt) 1997-11-04
FI973039A0 (fi) 1997-07-17
AU4543696A (en) 1996-08-07
CN1169145A (zh) 1997-12-31
NO973222L (no) 1997-07-10
JPH10512560A (ja) 1998-12-02
FR2729390A1 (fr) 1996-07-19

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