Classifications

• • C—CHEMISTRY; METALLURGY
  • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
  • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
  • C25B3/00—Electrolytic production of organic compounds
  • C25B3/20—Processes
  • C25B3/25—Reduction
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
  • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
  • C25B11/00—Electrodes; Manufacture thereof not otherwise provided for
  • C25B11/04—Electrodes; Manufacture thereof not otherwise provided for characterised by the material
  • C25B11/042—Electrodes formed of a single material
  • C25B11/046—Alloys
• • C—CHEMISTRY; METALLURGY
  • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
  • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
  • C25B9/00—Cells or assemblies of cells; Constructional parts of cells; Assemblies of constructional parts, e.g. electrode-diaphragm assemblies; Process-related cell features
  • C25B9/17—Cells comprising dimensionally-stable non-movable electrodes; Assemblies of constructional parts thereof
  • C25B9/19—Cells comprising dimensionally-stable non-movable electrodes; Assemblies of constructional parts thereof with diaphragms
  • C25B9/23—Cells comprising dimensionally-stable non-movable electrodes; Assemblies of constructional parts thereof with diaphragms comprising ion-exchange membranes in or on which electrode material is embedded

Definitions

• the present invention relates to a new process for the preparation of 5 taxane derivatives of general formula:
• Ar represents an aryl radical
• R4 represents a benzoyl radical or an R5-O-CO radical in which R5 represents an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.
• the present invention relates to a process for the preparation of products of general formula (I) in which R and R2 being defined as above, R3 represents a hydrogen atom or a radical of general formula (H) in which:
• Ar represents a phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted by one or more atoms or radicals chosen from fluorine or chlorine atoms and alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl radicals , mercapto, acylamino, aroylamino,
• alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and the aryl radicals are the phenyl or ⁇ - or ⁇ -naphthyl radicals, or a heterocyclic radical aromatic having 5 links and containing one or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms ( fluorine, chlorine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino
• R4 represents a benzoyl radical or an R5-O-CO- radical in which R5 represents: - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 atoms of carbon, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from fluorine or chlorine atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of which
• a phenyl radical optionally substituted by one or more radicals chosen from alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, acylamino, aroylamino, alkoxycarbonylamino radicals, amino, alkyllamino, dialkoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkoylcarbamoyl, cyano and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms - or a heterocyclyl nitrogen saturated radical containing 4 to 6 members optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionally substituted by one or
• the products of general formula (I) can be obtained by electrolytic reduction of a product of general formula:
• the electrolytic reduction from a product of general formula (III) is carried out in an electrolyzer containing a catholyte consisting of a support electrolyte containing magnesium, calcium, cerium, strontium or lithium ions or optionally, when R represents an acetyl radical or alkoxyacetyl, ammonium ions (NH4 + ) and a solvent or a mixture of solvents or a hydro-organic mixture in which the product of general formula (III) is dissolved at a concentration between 0.1 g 1 and the saturation of the solution.
• a catholyte consisting of a support electrolyte containing magnesium, calcium, cerium, strontium or lithium ions or optionally, when R represents an acetyl radical or alkoxyacetyl, ammonium ions (NH4 + ) and a solvent or a mixture of solvents or a hydro-organic mixture in which the product of general formula (III) is dissolved at a concentration between 0.1 g 1 and the saturation
• the reduction . takes place in a diaphragm electrolyser.
• the electrolytic reduction is carried out in an electrolyser comprising a cathode, a cathode compartment, a separating diaphragm, an anode compartment and an anode the characteristics of which are as follows: a) the cathode consists of an electrically conductive material on which the reduction takes place at a potential greater than that of the reduction of the solvent or of one of the constituents of the support electrolyte, or at a potential such as reduction of solvent or one of the constituents of the support electrolyte is not large enough to hinder the reduction of the product, b) the cathode compartment contains the catholyte which consists of a solution of the product of general formula (III) in an organic or hydroorganic medium and an electrolyte containing magnesium, calcium, ffl cerium, strontium or lithium or possibly ammonium (NH4 + ).
• the pH can be kept slightly alkaline, that is to say preferably between 7 and 9, by addition of ammonia
• the separating diaphragm consists of a porous material such as a plate, a sleeve or a candle of sintered glass or porcelain or by an ion exchange membrane, preferably a cation exchange membrane
• the anode compartment contains either the anolyte consisting of preferably by the same solvent or mixture of solvents and the same support electrolyte as that used in the cathode compartment, or else an acid diluted in the same solvent or mixture of solvents as that contained in the catholyte
• the anode is made of an electrically conductive material, the nature of which is not essential for the implementation of the process.
• the anode consists of a material that conducts electricity that cannot be attacked under the conditions of electrolysis, such as, for example, polished, solid or supported platinum, graphite or vitreous carbon.
• the cathode consists of a sheet of mercury.
• the support electrolyte consists of a magnesium or calcium salt or optionally of ammonium, such as magnesium chloride, calcium chloride, cerium chloride m , strontium chloride, lithium chloride or ammonium chloride, soluble in solvent or mixture of solvents.
• the solvents will be chosen from aliphatic alcohols containing 1 to 4 carbon atoms such as methanol, ethanol, isopropanol or tbutanol and the hydro-organic mixture is an alcohol-water mixture.
• the pH must be compatible with the stability of the substrate and it can be kept slightly alkaline during the electrolysis, that is to say preferably between 7 and 9, by addition of ammonia in aqueous solution or by bubbling ammonia gas when using ammonium chloride.
• the nature of the diaphragm separating the anolyte from the catholyte is not an essential characteristic of the invention. This is how any diaphragm of known type can be used, constituted by a porous material such as sintered glass, porcelain with or without conductive gel limiting the diffusion of reagents or by ion exchange membranes, preferably cation exchange membranes. .
• the anolyte contains a dilute acid
• a cation exchange membrane in order to maintain the pH in the catholyte by migration of H + ions through the membrane during electrolysis.
• the membranes can be of homogeneous or heterogeneous type and they can optionally be reinforced by a weft.
• the anode, the cathode and the separating diaphragm are arranged in horizontal parallel planes in the case of a cathode formed by a sheet of mercury.
• the temperature of the electrolysis bath is generally between 0 and 30 ° C.
• the electrolysis is carried out at controlled potential, this can be fixed approximately between -1.65 and -2.1 volts relative to a reference electrode to the calomel, depending on the nature of the cation of the electrolyte.
• the theoretical amount of electricity used is 2 Faradays (or 193,000 coulombs) per mole of a product of general formula (III). Practically the amount of electricity used can be 2 to 5 times the theoretical amount, but can also be very much higher.
• the reaction is followed by the disappearance of the starting product which is determined by thin layer chromatography.
• the catholyte can be circulated for example under the action of a pump.
• the circuit can also include ancillary devices such as temperature exchangers or expansion vessels; such an expansion vessel makes it possible in particular to supply the catholyte with a product of general formula (III) and also makes it possible to draw up for the extraction of the products of general formula (I).
• the anolyte can also be subjected to circulation.
• the catholyte circuit is similar to that of the anolyte, which makes it possible to balance the pressures on either side of the separating diaphragm.
• spacers in the anode and cathode compartments. These spacers serve to avoid, on the one hand, the deformations of the ion exchange membrane and, on the other hand, the contacts of this membrane with the electrodes. They also serve to improve the homogeneity of concentration of the catholyte.
• the speed of circulation of the catholyte in the cathode compartment is usually greater than 10 cm / s, preferably greater than 50 cm / s.
• the apparent speed of the catholyte (speed in the cathode compartment assumed to be without interlayer) is usually greater than 1 cm / s, preferably greater than 10 cm / s.
• the cell can consist simply of a container, parallelepiped or cylindrical, made of a material inert with respect to the constituents of the electrolytes.
• any electrolytic cell comprising an anode and a cathode separated by one or more diaphragms ensuring ionic conductivity can be used, the arrangement of the elements not being essential for the implementation of the process.
• the products of general formula (I) obtained by implementing the process according to the invention are separated by application of the usual methods.
• R3 represents a radical of general formula (II) in which Ar represents an aryl radical and R4 represents a benzoyl radical respectively correspond to 10-deacetyl taxol and to taxol which can be obtained according to the methods described in European patents EP 0 253 739, EP 0 336 840, EP 0400 971 and EP 0428 376 or in the international PCT application WO 9209589.
• X represents a halogen atom (fluorine, chlorine) or a residue -O-R5 or -O-CO- R5 on a derivative of baccatin read or of deacetyl-10 baccatin read of general formula:
• Gi represents a group protecting the hydroxy function such as a trialkylsilyl, dialkoylarylsilyl, alkyldiarylsilyl or triarylsilyl group in which each alkyl part contains 1 to 4 carbon atoms and each aryl part preferably represents a phenyl radical and G2 represents a hydrogen atom or an acetyl or alkoxyacetyl (methoxyacetyl) radical, to give a product of general formula:
• G2 of the product of general formula (VI) with a hydrogen atom is carried out by treatment in an acid medium such as for example hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, isopropanol) or aqueous hydrofluoric acid at a temperature between 0 and 40 ° C when G represents a silylated radical and G2 represents an alkoxyacetyl radical.
• an acid medium such as for example hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, isopropanol) or aqueous hydrofluoric acid at a temperature between 0 and 40 ° C when G represents a silylated radical and G2 represents an alkoxyacetyl radical.
• Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, the lymphatic or renal systems, the mammary or blood cells, the liver, the digestive system, the pancreas and the thyroid glands or adrenal.
• pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas.
• the new products according to the invention are particularly useful for the treatment of ovarian cancer.
• the products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.
• the products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route.
• Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.
• the present invention also comprises the pharmaceutical compositions which contain at least one product of general formula (I) in a sufficient amount suitable for use in human or veterinary therapy.
• the compositions can be prepared according to the usual methods using one or more adjuvants, carriers or pharmaceutically acceptable excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
• Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
• the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers.
• the choice of adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.
• aqueous or non-aqueous sterile solutions or suspensions are used.
• non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate .
• the sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water.
• Aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.
• compositions can contain at least 0.01% of therapeutically active product.
• the amount of active ingredient in a composition is such that a suitable dosage can be prescribed.
• the compositions are prepared in such a way that a unit dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.
• the therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses.
• Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (a, b or d) and TNF.
• chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin, bleomycin,
• the doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response.
• the doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation.
• the products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient concerned. It is also possible that for some patients it is necessary to use only one or two daily administrations.
• the doses are generally between 0.01 and 200 mg / kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg / kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg / kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account. The following examples illustrate the present invention.
• the cell is a 100 cm3 glass vase divided into two compartments by a cation exchange membrane
• the cathode is a sheet of mercury whose useful surface is approximately 10 cm2,
• the anode is a platinum grid
• the reference electrode is a saturated calomel electrode
• the potential of the cathode is fixed at -1.95 volts relative to the electrode of reference.
• the solution is electrolyzed for the time necessary for the passage of 14.2 coulombs.
• the cell is a 10 cm3 glass vase divided into 2 compartments by a cation exchange membrane
• the cathode is a sheet of mercury whose useful surface is 4 cm2,
• the anode is a platinum grid
• the reference electrode is a saturated calomel electrode
• the cell is a 100 cm3 glass vase divided into 2 compartments by a cation exchange membrane
• the cathode is a sheet of mercury whose useful surface is 4 cm2,
• the anode is a platinum grid
• the reference electrode is a saturated calomel electrode.
• the solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -1.95 volts relative to the reference electrode. After 3 hours 49 minutes of electrolysis, that is to say the time necessary for the passage of 197 coulombs, the electrolysis is stopped. 0.1 cm3 of pure acetic acid are added and 0.5 cm3 of a saturated aqueous solution of sodium hydrogencarbonate. After removing the solvent by concentration under reduced pressure, the residue is taken up in 20 cm3 of ethyl acetate and 20 cm3 of deionized water. After decantation, the aqueous phase is extracted with 2 times 10 cm3 of ethyl acetate.
• the organic phase is washed with 20 cm3 of a 0.2 M aqueous phosphate buffer solution at a pH close to 7. After drying and dry concentration of the organic phase, 381.2 mg of a crude product are obtained, the constituents are separated by preparative chromatography on a thin layer of silica gel.
• the crude product is taken up in the minimum of a dichloromethane-methanol mixture (50-50 by volume) then injected onto 8 plates of silica gel (Kieselgel 60 F 254, Merck) 2 mm thick, eluting with a mixture dichloromethane-acetonitrile-methanol (55-40-5 by volume).
• the cell is a 120 cm3 glass vase divided into 2 compartments by a cation exchange membrane
• the cathode is a sheet of mercury whose useful surface is 12 cm2
• the anode is a platinum grid
• the reference electrode is a saturated calomel electrode.
• the solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -2.0 volts relative to the reference electrode. After 2 hours 30 minutes of electrolysis, that is to say the time necessary for the passage of 224 coulombs, the electrolysis is stopped. 10 cm 3 of a 0.1 M solution of sodium acetate in methanol are added. After removing the solvent by concentration under reduced pressure at a temperature below 35 ° C, the residue is taken up in 50 cm3 of ethyl acetate and 50 cm3 of deionized water. After decantation, the aqueous phase is extracted with 2 times 25 cm3 of ethyl acetate.
• the organic phase is washed with 25 cm3 of a 0.2 M aqueous phosphate buffer solution at a pH close to 7. After drying and dry concentration of the organic phase at a temperature below 35 ° C, 594.8 is obtained mg of a crude product, the constituents of which are separated by preparative chromatography on a thin layer of silica gel.
• the crude product is taken up with the minimum of a dichloromethane-methanol mixture (50-50 by volume) then injected onto 12 plates of silica gel (Kieselgel 60 F 254, Merck) 2 mm thick, eluting with a mixture dichloromethane-acetonitrile-methanol (80-16-4 by volume).
• the cell is a 100 cm3 glass vase divided into 2 compartments by a cation exchange membrane
• the cathode is a sheet of mercury whose useful surface is 4 cm2
• the anode is a platinum grid
• the reference electrode is a saturated calomel electrode.
• the solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -1.95 volts relative to the reference electrode at the start of the electrolysis then at -2.0 volts after the passage of 10.5 coulombs. After 79 minutes of electrolysis, that is to say the time necessary for the passage of 25.6 coulombs, the electrolysis is stopped.
• a second electrolytic reduction of t.butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of acetoxy-4 is carried out.
• the solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -2.0 volts relative to the reference electrode. After 2 hours 4 minutes of electrolysis, that is to say the time necessary for the passage of 66.5 coulombs, the electrolysis is stopped.
• the electrolysis solutions are combined, then the medium is buffered by adding a few cm 3 of a methanolic solution of acetic buffer. After removing the solvent by concentration under reduced pressure at a temperature below 35 ° C, the residue is taken up in 20 cm3 of ethyl acetate and 20 cm3 of deionized water. After decantation, the aqueous phase is extracted with 2 times 10 cm3 of ethyl acetate. The organic phase is washed with 20 cm3 of a 0.2 M aqueous phosphate buffer solution at a pH close to 7.
• composition is administered by introduction into an infusion of a physiological solution for 1 hour.

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Citations (1)

• 1992
  • 1992-11-12 FR FR9213586A patent/FR2697841B1/fr not_active Expired - Fee Related
• 1993
  • 1993-11-04 MX MX9306883A patent/MX9306883A/es unknown
  • 1993-11-09 ZA ZA938366A patent/ZA938366B/xx unknown
  • 1993-11-10 PL PL93308957A patent/PL308957A1/xx unknown
  • 1993-11-10 WO PCT/FR1993/001102 patent/WO1994011547A1/fr not_active Application Discontinuation
  • 1993-11-10 CA CA002149240A patent/CA2149240A1/fr not_active Abandoned
  • 1993-11-10 SK SK608-95A patent/SK60895A3/sk unknown
  • 1993-11-10 KR KR1019950701883A patent/KR950704540A/ko not_active Application Discontinuation
  • 1993-11-10 RU RU95112464/04A patent/RU95112464A/ru unknown
  • 1993-11-10 AU AU54257/94A patent/AU5425794A/en not_active Abandoned
  • 1993-11-10 EP EP93924688A patent/EP0667922A1/fr not_active Withdrawn
  • 1993-11-10 JP JP6511786A patent/JPH08503261A/ja active Pending
  • 1993-11-10 CZ CZ951224A patent/CZ122495A3/cs unknown
• 1995
  • 1995-05-05 NO NO951772A patent/NO951772D0/no unknown
  • 1995-05-11 FI FI952294A patent/FI952294A/fi not_active Application Discontinuation

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