EP0736026A1 - Nouvelles pyridazino 4',5':3,4]pyrrolo- 2,1-a]isoquinoleines et leur utilisation pour la preparation de compositions pharmaceutiques - Google Patents

Nouvelles pyridazino 4',5':3,4]pyrrolo- 2,1-a]isoquinoleines et leur utilisation pour la preparation de compositions pharmaceutiques

Info

Publication number
EP0736026A1
EP0736026A1 EP95904471A EP95904471A EP0736026A1 EP 0736026 A1 EP0736026 A1 EP 0736026A1 EP 95904471 A EP95904471 A EP 95904471A EP 95904471 A EP95904471 A EP 95904471A EP 0736026 A1 EP0736026 A1 EP 0736026A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
alkoxy
alkyl
compound according
hydroxy
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Withdrawn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
EP95904471A
Other languages
German (de)
English (en)
Inventor
Walter Loesel
Otto Roos
Dietrich Arndts
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP0736026A1 publication Critical patent/EP0736026A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to new pyridazino [4 ', 5': 3,4] pyrrolo
  • cardioprotective agents as brain protective agents
  • Suffer from a stroke can be used as a means for the treatment of chronic inflammatory processes (eg bronchial asthma, arthritis). Furthermore, these compounds can be used as agents with antiproliferative activity and as agents for Treatment of ulcerative colitis and Crohn's disease can be used.
  • chronic inflammatory processes eg bronchial asthma, arthritis
  • these compounds can be used as agents with antiproliferative activity and as agents for Treatment of ulcerative colitis and Crohn's disease can be used.
  • R 1 has one of the following meanings:
  • Carbon atoms, phenoxy, 1 or 2 phenyl groups (whereby the phenyl ring (s) or phenoxy can be (in turn) mono- or disubstituted by halogen, CF 3 , alkyl with 1 - 4 carbon atoms, alkoxy with 1 - 2 carbon atoms, NH-alkyl with 1 - 2
  • R 3 , R 4 and R 5 which may be the same or different, are hydrogen or an alkyl radical with 1-4
  • R 6 and R 9 which can be the same or different
  • R 8 and R 9 together form the group -O- (CH 2 ) 1 or 2 -O- and the other 2 substituents are each as defined above. Connections to those defined above are excluded
  • R 1 has one of the following meanings:
  • R 3 , R 4 and R 5 which may be the same or different, are hydrogen or an alkyl radical with 1-4
  • R 7 and R 8 which can be the same or different
  • R 6 and R 9 which can be the same or different
  • R 1 is a straight-chain or branched alkyl radical having 1 to 4
  • R 1 is one of the following groups: Also to be emphasized are compounds (I) in which R 3 , R 4 , R 5 , R 6 and R 9 are hydrogen and R 7 and R 8 are alkoxy with 1-4 carbon atoms or R 7 and Rg together -OCH 2 O- or - OCH 2 CH 2 O-, in particular wherein R 7 and R 8 are methoxy.
  • R 1 is the
  • R 13 and y are as defined above and / or in which R 7 and R 8 are methoxy and / or
  • R 1 has one of the following meanings:
  • R 1 has one of the following meanings:
  • R 1 has one of the following meanings:
  • R 1 is a straight-chain or branched alkyl group having 1-5 carbon atoms; Methoxy-C 1 -C 4 alkyl; Cyclopropyl; Cyclopentyl; cyclohexyl; Cyclopropylmethyl;
  • R 7 and R 8 are independently hydrogen, methyl
  • R 3 , R 4 , R 5 , R 6 and R 9 represent hydrogen.
  • the compounds of the formula I are bases and can be prepared in a conventional manner using inorganic or organic acids and salt and complexing agents in any physiologically acceptable manner
  • Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid,
  • Nitric acid acetic acid, propionic acid, butyric acid,
  • Succinic acid maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid,
  • Methanesulfonic acid and the like Preferred compounds of the general formula I are those in which R 3 , R 4 , R 5 , R 6 and R 9 are hydrogen and R 7 and Rg are methoxy, and / or
  • R 1 is a group- (CH 2 ) 0-3 -A, wherein A
  • the new compounds can be prepared by processes known per se.
  • Amine component of general formula III heated under reflux until the reaction is complete.
  • the reaction time is between approx. 1 and 15 hours and depends on the starting components used.
  • the reaction can also be carried out in an excess of the amine without additional solvent (e.g. in the case of, o-benzylhydroxylamine), if appropriate with
  • a reactant can also be used, which also serves as a solvent in the reaction.
  • Sulfur means with an alkylating reagent of formula V.
  • R 1 -YV where R ⁇ has the meaning given above and Y one
  • anionic leaving group e.g. Cl, Br, J, the
  • Methanesulfonic acid group the trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, or p-bromobenzenesulfonic acid residue.
  • other reagents which are suitable for transferring carbocations e.g. "Onium" compounds such as sea wine salts e.g. the
  • a starting compound of the general formula IV is reacted with the alkylating agent of the general formula V in an inert solvent, for example dimethylacetamide, hexamethylphosphoric acid trisamide, chlorobenzene or acetone.
  • an inert solvent for example dimethylacetamide, hexamethylphosphoric acid trisamide, chlorobenzene or acetone.
  • the reaction is usually carried out at room temperature and occasionally at the reflux temperature depending on the reactivity of the
  • Alkylating agent Alkylating agent.
  • the reaction time is between about 1 and 20 hours and depends on the ones used
  • the pyridazino-pyrrolo-isoquinolines (I) are bases and can be converted in a conventional manner with inorganic or organic acids into any physiologically acceptable acid addition salts.
  • Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid,
  • Nitric acid acetic acid, propionic acid, butyric acid,
  • Caproic acid valeric acid, oxalic acid, malonic acid, Succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid,
  • the present invention relates to new 9-substituted pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinolines and pharmaceutical preparations containing these compounds.
  • the present invention furthermore relates to the use of these new compounds.
  • the compounds are advantageous for the treatment of degenerative and necrotizing diseases of the brain. Preventive treatment of patients at risk from such diseases is also possible. This effect of the compounds is not based on an improvement in tissue blood flow. The compounds are therefore for a novel treatment of
  • Another object of the present invention is the use of the compounds mentioned for the preparation of agents for the treatment of chronic inflammatory processes, ulcerative colitis and Crohn's disease and agents with an antiproliferative effect.
  • the effect of the compounds can be explained by their inhibition of the unselective cation channels (UKK).
  • the receptor-regulated activation of inflammatory cells is independent of the type of stimulating agonists (eg endothelin, PAF, Leukotrienes, chemotactic peptide fMLP or antigen against sensitized mast cells) by blockers unselective
  • Phenylalkylamine type does not inhibit UKKs or inflammatory processes (WELLS et al., 1986).
  • THAPSIGARGIN is one of THASTRUP et al. (Proc. Natl. Acad. Sci. (USA), 87, 2466-2470, 1990) described tumor promoter that is selective and
  • Thapsigargin is suitable as an indirect stimulator for agonist and IP3 ⁇ independent opening
  • HL 60 cells human leukemia cells
  • RBL cells rat basophilic lymphoma cells
  • the cytoplasmic Ca 2+ concentration plays an important role in cell proliferation and tumor growth (for an overview, see LR ZACHARSKI, Journal of Medicine 19:
  • This mechanism also plays a role in the
  • Endothelin is primarily an IP3 ⁇ mediated intracellular
  • Stimulation was carried out by adding 0.1 mH endothelin;
  • the functional endothelin antagonism of the substances according to the invention is mediated by blocking unselective cations of channels. Therefore, the proof of a
  • Fura-2-loaded adhesive RBL-hm 1 cells with 0.1 mM are incubated in Ca 2+ -free incubation medium
  • the fluorometric calcium measurement in the cytoplasm of individual adherent RBL-hml cells is carried out in analogy to the method described for neuronal cells by KUDO and OGURA (1986).
  • An AXIOVERT 35 fluorescence microscope from ZEISS is used in combination with an imaging system from HAMAMATSU,
  • the kinetics of the cytoplasmic Ca +2 concentration is continuously recorded as a concentration-time curve after the cell activation stimulated by thapsigargin (0.1 ⁇ M).
  • the curves of two activated cell cultures are compared in the presence and absence of 10 ⁇ M test substance.
  • the area under the curve (AUC) is
  • % H the percentage inhibition of calcium influx by
  • AUC inh area under the curve recorded in the presence of the stimulant plus 10 ⁇ M inhibitory test substance.
  • AUC contr. Area under the curve that is only registered after the stimulant has been added.
  • the Superoxide forming NADPH oxidase of phagocytes An enzyme
  • the concentration of the test substances is 10 ⁇ 5 mol or 10 -6 mol).
  • RBL-2H3 cells (a tumor cell line related to the mast cells)
  • the RBL-2H3 cells are cultivated and adhered to in the method described by HIDE and BEAVEN (1991).
  • the cells are incubated for 2 hours at room temperature with a 1: 2000 diluted commercial gamma globulin E solution against a dinitrophenol bovine serum albumin complex (DNP-BSA antigen).
  • DNP-BSA antigen dinitrophenol bovine serum albumin complex
  • adherent RBL-2H3 cells are analogous to the method described by KUDO and OGURA (1986) for neuronal cells, which is also explained further above in this description.
  • Substances according to the invention surprisingly showed that the tested compound is 5 to 100 times more potent than the comparison substance verapamil.
  • test substances The antiproliferative effectiveness of the test substances was determined using the method described by MOSMANN (J. IMMUNOL. METH. 65: 55-63, 1983), DENIZOT et al. (J. IMMUNOL. METH. 89: 271-277, 1986) and by J. ELIASON et al. (INT. J. CANCER 46: 113-117, 1990).
  • MMTT [3- (4,5-dimethylthiazol-2yl) 2,5-diphenyl-tetrazolium bromide] from CHEMICON Inc. El Segundo, Ca, USA). This indicator is only used by living cells
  • K 562 chronic myeloid leukemia cell
  • test was carried out on microtiter plates. Each well contained 100 ⁇ l of a cell suspension (0.2 ⁇ 10 6 cells / ml). RPMI 1640 with 10% heat-inactivated fetal calf serum and 50 ⁇ g / ml gentamycin served as the incubation medium.
  • RPMI 1640 with 10% heat-inactivated fetal calf serum and 50 ⁇ g / ml gentamycin served as the incubation medium.
  • test substances were in DMSO
  • Blockage of unselective cations is subject to channels.
  • the compounds can be administered both enterally and parenterally.
  • the dose for oral use is 0.1 to 500 mg of active ingredient per dose, for the i.v. - Suggested use of 0.05 to 150 mg per dose.
  • the desired dose for oral use is 0.1 to 500 mg of active ingredient per dose, for the i.v. - Suggested use of 0.05 to 150 mg per dose.
  • Suitable forms of use are, for example, tablets,
  • Appropriate tablets can be
  • Diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate are obtained .
  • the tablets can also consist of several layers.
  • coated tablets can be prepared by coating cores which are produced analogously to the tablets with usually
  • Coated tablets used agents for example Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar, are produced.
  • the core can also consist of several layers. The same can also
  • Drage sleeve to achieve a depot effect consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Active ingredient combinations can also be a
  • Sweeteners such as saccharin, cyclamate, glycerin or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. You can also use suspending aids or thickeners, such as
  • Injection solutions are made in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates, or
  • Stabilizers such as the alkali salts of
  • Bottled injection bottles or ampoules are bottles injection bottles or ampoules.
  • the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.
  • inert carriers such as milk sugar or sorbitol
  • Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.
  • 1 coated tablet contains:
  • the mixture of the active substance with milk sugar and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with a 1 mm mesh size, dried at 40 ° C. and rubbed again through a sieve.
  • the granules obtained in this way are mixed with magnesium stearate and pressed.
  • the cores obtained in this way are coated in a conventional manner with a shell, which with the aid of an aqueous suspension of
  • the active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and mixed intimately with milk sugar and corn starch. The mixture is then compressed into tablets weighing 210 mg.
  • Active ingredient, milk sugar and corn starch are first mixed in a mixer and then in a shredder. The mixture is added to the mixer again, thoroughly mixed with the talc and filled into hard gelatin capsules by machine.
  • colloidal silica 2.0 mg
  • the active ingredient is mixed with some of the excipients and granulated with a solution of the soluble starch in water.
  • colloidal silica 2.0 mg
  • Megstium stearate 3.0 mg total 195.0 mg
  • Example a the active ingredient and the excipients are pressed into tablet cores which are coated with sugar, talc and gum arabic in the usual way. f) suppositories
  • the active ingredient and the milk sugar are mixed together and the mixture is evenly suspended in the melted suppository mass.
  • the suspensions are poured into chilled molds into suppositories weighing 1.7 g.
  • the active ingredient and the sodium chloride are in bi-distilled
  • Active ingredient according to the invention 0.70 g methyl p-hydroxybenzoate 0.07 g propyl p-hydroxybenzoate 0.03 g
  • the active ingredient and the preservative are in

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des nouvelles pyridazino[4',5':3,4]pyrrolo-[2,1-a]isoquinoléines nouvelles ayant la formule (I), dans laquelle X désigne O, S ou NHO. Ces nouveaux composés ont de précieuses propriétés thérapeutiques. Ils sont utiles comme agents protecteurs du c÷ur et du cerveau, comme agents thérapeutiques de processus inflammatoires chroniques, comme agents à action anti-proliférative et comme agents thérapeutiques de la colite ulcéreuse et de la maladie de Crohn.
EP95904471A 1993-12-21 1994-12-14 Nouvelles pyridazino 4',5':3,4]pyrrolo- 2,1-a]isoquinoleines et leur utilisation pour la preparation de compositions pharmaceutiques Withdrawn EP0736026A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4343649 1993-12-21
DE4343649A DE4343649A1 (de) 1993-12-21 1993-12-21 Neue Pyridazino[4',5':3,4]pyrrolo-[2,1-a]isochinoline und deren Verwendung für die Herstellung von pharmazeutischen Zubereitungen
PCT/EP1994/004149 WO1995017402A1 (fr) 1993-12-21 1994-12-14 Nouvelles pyridazino[4',5':3,4]pyrrolo-[2,1-a]isoquinoleines et leur utilisation pour la preparation de compositions pharmaceutiques

Publications (1)

Publication Number Publication Date
EP0736026A1 true EP0736026A1 (fr) 1996-10-09

Family

ID=6505645

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95904471A Withdrawn EP0736026A1 (fr) 1993-12-21 1994-12-14 Nouvelles pyridazino 4',5':3,4]pyrrolo- 2,1-a]isoquinoleines et leur utilisation pour la preparation de compositions pharmaceutiques

Country Status (12)

Country Link
US (1) US5688793A (fr)
EP (1) EP0736026A1 (fr)
JP (1) JPH09506881A (fr)
CN (1) CN1138333A (fr)
CA (1) CA2178094A1 (fr)
CO (1) CO4340627A1 (fr)
DE (1) DE4343649A1 (fr)
PL (1) PL315053A1 (fr)
RU (1) RU2138499C1 (fr)
TW (1) TW358095B (fr)
WO (1) WO1995017402A1 (fr)
ZA (1) ZA9410114B (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200944523A (en) * 2008-02-08 2009-11-01 Organon Nv (Dihydro)pyrrolo[2,1-a]isoquinolines

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3401018A1 (de) * 1984-01-13 1985-07-18 Boehringer Ingelheim KG, 6507 Ingelheim Verfahren zur herstellung von 5,6-dihydro-pyrrolo(2,1-a)isochinolinen
DE3525048A1 (de) * 1985-07-13 1987-01-15 Boehringer Ingelheim Kg Neue 12-amino-pyridazino(4',5':3,4)pyrrolo(2,1-a)isochinoline, verfahren zu ihrer herstellung und verwendung
DE3500941A1 (de) * 1985-01-14 1986-07-17 Boehringer Ingelheim KG, 6507 Ingelheim Neue 12-amino-pyridazino(4',5':3,4)pyrrolo(2,1-a)isochinoline, verfahren zu ihrer herstellung und verwendung
EP0190563B1 (fr) * 1985-01-14 1989-08-02 Boehringer Ingelheim Kg 12-Amino-pyridazino[4',5':3,4]pyrrolo[2,1-a]isoquinolines, leur procédé de préparation et utilisation
WO1994000451A1 (fr) * 1992-06-22 1994-01-06 Boehringer Ingelheim Kg 9-AMINO-PYRIDAZINO[4',5' : 3,4]PYRROLO[2,1-a]ISOQUINOLEINES ET LEUR UTILISATION DANS LA FABRICATION DE PREPARATIONS PHARMACEUTIQUES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9517402A1 *

Also Published As

Publication number Publication date
ZA9410114B (en) 1995-06-21
US5688793A (en) 1997-11-18
AU1314395A (en) 1995-07-10
TW358095B (en) 1999-05-11
CN1138333A (zh) 1996-12-18
CA2178094A1 (fr) 1995-06-29
PL315053A1 (en) 1996-09-30
AU688438B2 (en) 1998-03-12
DE4343649A1 (de) 1995-06-22
WO1995017402A1 (fr) 1995-06-29
JPH09506881A (ja) 1997-07-08
CO4340627A1 (es) 1996-07-30
RU2138499C1 (ru) 1999-09-27

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