EP0557375A1 - New heterocyclic compounds as antagonists of excitatory amino acid receptors, processes for their preparation and their use - Google Patents

New heterocyclic compounds as antagonists of excitatory amino acid receptors, processes for their preparation and their use

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Publication number
EP0557375A1
EP0557375A1 EP91920264A EP91920264A EP0557375A1 EP 0557375 A1 EP0557375 A1 EP 0557375A1 EP 91920264 A EP91920264 A EP 91920264A EP 91920264 A EP91920264 A EP 91920264A EP 0557375 A1 EP0557375 A1 EP 0557375A1
Authority
EP
European Patent Office
Prior art keywords
group
methylene
compounds
compound according
alkyl
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Withdrawn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
EP91920264A
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German (de)
English (en)
French (fr)
Inventor
Alf Claesson
Britt-Marie Swahn
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
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Filing date
Publication date
Application filed by Astra AB filed Critical Astra AB
Publication of EP0557375A1 publication Critical patent/EP0557375A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Definitions

  • the present invention relates to new piperazine, piperidine, and pyrrolidine compounds, to methods for their preparation, their use, and their pharmaceutical preparation.
  • the compounds are antagonists of N-methyl- D-aspartate (NMDA) receptors and are useful in the treatment of disorders known to be responsive to blockade of the NMDA excitatory amino acid receptor, especially in the treatment of disorders such as pain, anxiety and cerebral ischemia.
  • NMDA N-methyl- D-aspartate
  • NMDA antagonists have anticonvulsant activity cf. e.g. Lehmann et al. J. Pharmacol. Exp. Therap. 1988, 246, 65-75. This implicates the usefulness of NMDA antagonists as new antiepileptic agents. NMDA antagonists also give protection against neuronal cell death caused by excessive stimulation (Boast et al. Brain Res.
  • NMDA antagonists have analgetic activity (Cahusac et al. Neuropharmacology 1984, 22, 719-724) These antagonists may also be beneficial in the treatment of migraine, anxiety, and illness linked to luteinizing hormone secretion.
  • Compounds that are NMDA antagonists and are phosphonoalkyl-substituted 2-piperidine carboxylic acids have been described in e.g. U.S. Patent 4,746,653.
  • cis-4-Phosphonomethyl-2-piperidinecarboxylic acid is mentioned as an example of this class of compounds. They are also mentioned in J. Med. Chem. 1989, 32, 827-833.
  • the present invention is a new class of NMDA antagonists defined by formula I
  • X is an imino, a methylene group, a benzylidene, an 1,1-allylidene, an 1,1-alkylidene group containing from two to seven carbons, or is a group D-E in which D, being part of the ring, is nitrogen and E is a straight or branched, lower alkyl or acyl each containing one to seven carbons, an aroyl, a substituted or non-substituted allyl, benzyl or propargyl group;
  • Y is a hydroxyl- or amino-bearing carbon or is a carbonyl group
  • Z is a group consisting of one to four methylene groups or is a 1,3-all ⁇ lidene or 1,3- propargylidene group
  • W is a group P(0)(OR ) (OR ) wherein R and R is each independently hydrogen, c ⁇ " c ⁇ g alkyl, phenyl- substituted C--C 2 alkyl, acyloxymethyl or -ethyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; and in each of which compounds the carboxy group may be functionalized in form of a pharmaceutically acceptable ester or amide.
  • heterocyclic amino acids of the invention the pharmaceutically acceptable salts and base addition salts such as metal salts are included.
  • the hydrates are also included. Further included are isomeric forms including stereoisomers.
  • X is imino, C--Cg alkylimino, methylene, 1,1-ethylidene or 1,1-propylidene;
  • Y is a hydroxyl-bearing carbon or is a carbonyl group
  • Z is a group consisting of one to three methylene groups or is a 1,3-allylidene or 1,3-propargylidene group
  • W is a group P(0)(OR 1)(OR2) wherein R1 and R2 is each independently hydrogen, C.-C-g alkyl, phenyl- substituted C--C 2 alkyl, acyloxymethyl or -ethyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; and in each of which compounds the carboxy group may be functionalized in form of a pharmaceutically acceptable ester or amide.
  • heterocyclic amino acids of the invention the pharmaceutically acceptable salts and base addition salts such as metal salts are included.
  • the hydrates are also included. Further included within this class of compounds are isomeric forms including stereoisomers.
  • X is imino, C--C. alkylimino, methylene, 1,1-ethylidene or 1,1-propylidene;
  • Y is a hydroxyl-bearing carbon or is a carbonyl group
  • Z is a group consisting of one to three methylene groups or is a 1,3-allylidene or 1,3-propargylidene group;
  • W is a group P(O) (OR 1)(OR2) wherein R1 and R2 is each independently hydrogen, C-i-C-g alkyl, phenyl- substituted C.-C- alkyl, acyloxymethyl or -ethyl;
  • R1 and R2 is each independently hydrogen, C-i-C-g alkyl, phenyl- substituted C.-C- alkyl, acyloxymethyl or -ethyl
  • R1 and R2 is each independently hydrogen, C-i-C-g alkyl, phenyl- substituted C.-C- alkyl, acyloxymethyl or -ethyl
  • R1 and R2 is each independently hydrogen, C-i-C-g alkyl, phenyl- substituted C.-C- alkyl, acyloxymethyl or -ethyl
  • R1 and R2 is each independently hydrogen, C-i-C-g alkyl, phenyl- substituted C.-C
  • aroyl used above has the meaning benzoyl or substituted benzoyl such as 2,6-dimethylbenzoyl or 4- bromobenzoyl, furancarbonyl, thiophenecarbonyl or pyridinecarbonyl.
  • Method A involves addition of either alpha-metallated methanephosponic acid dialkylester, beta-metallated ethane- or ethenephosphonic acid dialkyl ester, gamma- metallated propanephosphonic acid dialkylester, alpha- or gamma-metallated allylphosphonic acid dialkyl ester or metallated 1-propynylphosphonic acid dialkyl ester, in an inert solvent such as tetrahydrofuran at temperatures ranging from -75°C to room temperature, to an unsaturated heterocyclic dicarboxylic derivative III,
  • R is alkoxy or dialkylamino containing up to ten carbon atoms
  • L is a suitable leaving group such as chloro, fluoro, alkoxy, azido or similar groups used to activate carboxylic acids towards nucleophilic attack, or is hydrido
  • A denotes that the ring is aromatic or partly unsaturated.
  • the ring of the product is then saturated by conventional means such as catalytic hydrogenation, and the compounds of the invention are obtained by removal of the protecting ester or amido groups or by first removing the protecting groups and then hydrogenate the ring.
  • An intermediate containing a ketone function may be optionally reduced to an alcohol using well known reducing agents e.g. sodium borohydride and an intermediate or product containing an alcohol function may also be oxidized to a ketone using standard techniques.
  • Method B The metallated phosphonic acids mentioned in Method A can also be added to a heterocyclic compound of formula IV
  • R, X, L and n are as defined above using the same general conditions mentioned.
  • the nitrogen in the ring can be optionally protected for example in the form of a carbamate ester.
  • Alcohol and ketone functions may be interconverted as described in Method A.
  • the compounds of the invention are obtained by removal of the protecting ester or amido groups.
  • X, n, R, and A are as defined above
  • Q represents a leaving group such as chloro, bromo, iodo or a sulphonate ester such as tosyloxy
  • m is 1-3
  • a trialkyl phosphite under conditions usually employed in the Arbuzov reaction or with a dialkyl trialkylsilyl, preferrably trimethylsilyl, phosphite or with a metallated dialkyl ester of phosphonic acid.
  • the nitrogen in the ring may be optionally protected for example in the form of a carbamate ester.
  • the ketone functionality may also require temporary protection for example in the form of a ketal.
  • the compounds of the invention are obtained by removal of the protecting groups.
  • Method D Reacting a product or partly protected inter ⁇ mediate from Methods A or B containing a ketone functionality in the side chain that contains phosphorus, with ammonia or a source of ammonia such as ammonium acetate under conditions known to lead to introduction of a primary amino group.
  • Such conditions are usually referred to as reductive amination conditions and can be exemplified by reacting in the presence of hydrogen and a catalyst such as palladium or in the presence of a hydride source such as sodium cyanoborohydride in a suitable solvent e.g. ethanol.
  • the starting compounds of formulas III, IV, V, and VI are known or can be prepared by processes known to those skilled in the art.
  • Reduction of heteroaromatic or parly unsaturated rings is carried out by methods known in the art for the reduction of pyrrole, pyridine or pyrazin rings.
  • the reduction of the pyridine ring is advantageously carried out by catalytic hydrogenation e.g. in the presence of Adams catalyst and in an acidic solvent such as acetic acid.
  • Protecting groups are used whenever necessary to hinder side-reactions and are of types well known to the art such as tert-butoxycarbonyl or carbobenzoxy for amines, C- to Cg straight or branched alkyl, allyl or benzyl esters for carboxylic acids and the phosphonate group, and silyl-based or ketal type protecting groups for alcohols.
  • Alkyl means straight or branched alkyl chains containing from one to eight carbon atoms and is advantageously ethyl, butyl or isopropyl.
  • Metallated means that an organometallic reagent is formed by methods such as reacting a carbon acid or a dialkyl ester of phosphonic acid, i.e. slightly acidic compounds, with a strong base such as butyllithium, sodium hydride or lithium diisopropylamide or by recting a halide with a metal such as e.g. zinc, a zinc-copper couple, magnesium, lithium or sodium in an inert and otherwise suitable solvent.
  • the so formed reagent may be further modified by addition of other metal compounds e.g. cuprous cyanide.
  • the starting material was prepared as follows. A mix ⁇ ture of 12.5 ml of butyllithium (1.54 M in hexane) and 2.1 ml of dimethyl methylphosphonate in 20 ml of tetra- hydrofuran (THF) was added to 4.0 g of isopropyl 3- chlorocarbonyl-2-pyridinecarboxylate in 20 ml of THF at -78°C. After stirring for 15 minutes saturated ammonium chloride was added and the mixture was allowed to warm to room temperature. After drying over sodium sulfate the solvent was removed in vacuo.
  • THF tetra- hydrofuran
  • the starting material was prepared as follows. A mix ⁇ ture of 19.6 g of tert-butyl 3-carboxy-2-pyridinecarbo- xylate and 5 g of 10 % palladium on charcoal in 250 ml of acetic acid was hydrogenated at 300 kPa for 6 hours. The mixture was filtered and the solvent was removed in vacuo to afford cis-tert-butyl 3-carboxy-2-piperidine- carboxylate as an oil.
  • the starting material was prepared by adding 2.3 g of isopropyl 3-chlorocarbonyl-2-pyridinecarboxylate in 10 ml of toluene to a mixture of 1.5 g of Zn-Cu, 10 ml of toluene, 2 ml of dimethylacetamide, 5 g of beta-iodo- ethyl diethylphosphonate, 100 mg of palladium chloride and 170 mg of tri-o-tolylphosphine under ultrasonic activation.
  • Example 3 Cis-isopropyl 3-(l-oxo-2-phosphonoeth ⁇ l)-2- piperidine-carboxylate.
  • Example 4 3-(l-Oxo-2-phosphonoethyl)-2-piperidinecar- boxylic acid.
  • a mixture of 0.20 g of 3-(l-oxo-2-phosphonoethyl)-2- pyridinecarboxylic acid and 0.20 g of 10 % platinum on charcoal in 10 ml of water was hydrogenated at 300 kPa at room temperature for 1.5 hours. The mixture was fil ⁇ tered and the solvent was removed in vacuo. The residue was eluted with water through Dowex 50Wx8H to afford a 4:1 cis/trans mixture of 3-(l-oxo-2-phosphonoethyl)-2- piperidinecarboxylic acid.
  • the product was a mixture of stereisomers in which it was possible to discern the title compound as a major component having the following characteristic H-NMR signals (HDO at 4.74 ppm as reference): 3.82 (d,J 4Hz,H-2), 3.72 (t, H-3), 1.14 (d, 3H, 4-Me).
  • the starting material was prepared as follows, tert-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Butyl 3-carboxy-4-methyl-2-pyridinecarboxylate (5.0 g), which was prepared from the corresponding anhydride and tert-butyl alcohol, was hydrogenated in acetic acid at 300 kPa in the presence of 10 % Pd-C (3 g). After fil- tration and evaporation of solvent the residue, which was almost pure tert-butyl 3-carboxy-4-methylpiperi- dine-2-carboxylate, was treated with an equivalent of triethylamine in a mixture of dichloromethane and methanol (3:1) and one equivalent of di-tert-butyl dicarbonate was added.
  • the acid can be purified by silica gel chromatography using dichloromethane/methanol (98/2) as an eluent, and then be converted to the acid fluoride by treatment with cyanuric fluoride.
  • a solution of the acid chlo- ride in THF, kept at -70 °C a solution of 3 equiva ⁇ lents of lithiated diethyl ethanephosphonate in THF was added. After stirring for 10 min saturated ammonium chloride was added, the mixture was allowed to reach room temperature and was extracted with ethyl acetate.
  • Example 6 Cis-3-(l-hydroxy-2-phosphonoethyl)-2-piperi- dinecarboxylic acid.
  • the starting material was prepared as follows. A mix ⁇ ture of 22.6 ml of butyllithium (1.37 M in hexane) and 4.7 g of diethyl methylphosphonate in 50 ml of THF was added to 5.45 g of isopropyl 3-formyl-2-pyridine- carboxylate in 50 ml of THF at -60°C. After stirring for 1 hour at -65°C 7 g of trimethylammonium chloride was added and the mixture was allowed to warm to room temperature.
  • a mixture of 1.0 g of 3-(2-diethylphosphono-l- hydroxy)-2-pyridinecarboxylic lactone and 0.2 g of pla ⁇ tinum oxide in 20 ml of acetic acid was hydrogenated at 300 kPa at room temperature for 12 hours.
  • the mixture was filtered and the solvent was removed in vacuo.
  • the residue was dissolved in 20 ml of methylene chloride and saturated sodium hydrogen carbonate was added.
  • the mixture was stirred at 0°C and 0.61 ml of benzyl chlo- roformiate was added. After stirring for 3 hours at room temperature the organic phase was separated and dried over sodium sulfate.
  • the mixture was filtered and the solvent was removed in vacuo.
  • the starting material was prepared as follows. A mix ⁇ ture of 4.7 ml of butyllithium ( 1.44 M in hexane ) and 1.0 g of diethyl methylphosphonate in 10 ml of THF was added to 2.0 g of cis-dimethyl 1,4-di-(tert-butyloxy- ⁇ arbonyl)-2,3-piperazinedicarboxylate in 20 ml of THF at -78°C. After stirring for 30 minutes saturated ammo ⁇ nium chloride was added and the mixture was allowed to warm to room temperature and extracted with chloroform. After drying over sodium sulfate the solvent was re ⁇ moved in vacuo.
  • compositions containing a compound of the formula I are made according to known methods.
  • a compound accor- ding to the invention is dissolved in a liquid diluent suitable for injection. It is especially preferred to dissolve the compounds in isotonic sodium chloride solution.
  • the compounds are used in the treatment of convulsive disorders, anxiety and cerebral ischemia it is also possible to adminster them in form of an oral or rectal preparation such as tablets, capsules or suppositories.
  • the selected com ⁇ pound may be mixed with a solid excipient, e.g. lactose or cellulose derivatives, a binder such as gelatine, and a lubricant such as magnesium stearate, and then compressed into tablets.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of supposi ⁇ tories.
  • Liquid preparations for oral application may be in the form of syrups or suspensions e.g. solutions containing from about 0.2 % to about 20 % by weight of the active substance herein described.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active sub ⁇ stance.
  • These solutions may optionally contain stabili ⁇ zing agents and/or buffering agents and may con- veniently be provided in various dosage unit ampoules.
  • Suitable unit dosages of the compounds of the invention in therapeutical treatment of human adults are 10 to 200 mg at peroral administration and 0.1 to 100 ⁇ g at intrathecal administration.
  • the compounds of the invention exhibit valuable pharma ⁇ cological properties, e.g. blocking the NMDA excitatory amino acid receptor in mammals.
  • the compounds are thus useful for treating disorders responsive to such block ⁇ ade particularly convulsive disorders, anxiety, cereb ⁇ ral ischemia, and pain. These effects are demonstrable in tests in vitro or in vivo e.g. in mice, rats, dogs or monkeys. Said compounds can be administered to them orally or parenterally.
  • the inhibitory effect on the NMDA-type excitatory amino acid receptors is determined also by an in vitro assay that measures the inhibition of binding of H-CGS 19755 to brain tissue preparations essentially according to
  • the anticonvulsive effect of the compounds of the in ⁇ vention is determined in vivo by inhibition of electro- shock- or NMDA-induced convulsions in the mouse essen ⁇ tially as described in the last mentioned reference.
  • the analgetic effect of said compounds is determined in the rat and the mouse by intrathecal injection essen- tially according to Cahusac et al. Neuropharmacology 1984, 23, 719-24.

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  • Animal Behavior & Ethology (AREA)
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  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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EP91920264A 1990-11-15 1991-11-07 New heterocyclic compounds as antagonists of excitatory amino acid receptors, processes for their preparation and their use Withdrawn EP0557375A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9003652A SE9003652D0 (sv) 1990-11-15 1990-11-15 New heterocyclic compounds
SE9003652 1990-11-15

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EP0557375A1 true EP0557375A1 (en) 1993-09-01

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EP91920264A Withdrawn EP0557375A1 (en) 1990-11-15 1991-11-07 New heterocyclic compounds as antagonists of excitatory amino acid receptors, processes for their preparation and their use

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EP (1) EP0557375A1 (sv)
JP (1) JPH06502421A (sv)
CN (1) CN1061595A (sv)
AU (1) AU652399B2 (sv)
CA (1) CA2095224A1 (sv)
CZ (1) CZ80993A3 (sv)
FI (1) FI932206A0 (sv)
HU (1) HU9301417D0 (sv)
IE (1) IE913922A1 (sv)
IS (1) IS3782A7 (sv)
LT (1) LTIP1718A (sv)
MX (1) MX9101979A (sv)
NO (1) NO931679D0 (sv)
PT (1) PT99515A (sv)
SE (1) SE9003652D0 (sv)
SK (1) SK46993A3 (sv)
WO (1) WO1992008724A1 (sv)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5194430A (en) * 1990-05-17 1993-03-16 Merrell Dow Pharmaceuticals Inc. Heterocyclic-nmda antagonists
TW281670B (sv) * 1993-09-02 1996-07-21 Hoffmann La Roche
US5491241A (en) * 1993-10-18 1996-02-13 Eli Lilly And Company Bicyclic intermediates for excitatory amino acid receptor antagonists
LT3411358T (lt) 2016-02-04 2022-04-25 Takeda Pharmaceutical Company Limited Pakeistas piperidino junginys ir jo naudojimas

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1248531A (en) * 1984-04-17 1989-01-10 Jeffrey C. Watkins 4-substituted piperazine-2-carboxylic acids
JPS612519A (ja) * 1984-04-24 1986-01-08 Aron Kasei Co Ltd 射出成形法
US4906621A (en) * 1985-05-24 1990-03-06 Ciba-Geigy Corporation Certain 2-carboxypiperidyl-alkylene phosphonic acids and esters thereof useful for the treatment of disorders responsive to N-methyl-D-aspartate receptor blockade
US4740346A (en) * 1986-02-26 1988-04-26 The Budd Company Perimeter resin feeding of composite structures
JPS63112129A (ja) * 1986-10-30 1988-05-17 Toyoda Gosei Co Ltd 多色樹脂成形用金型
IL84492A0 (en) * 1986-11-21 1988-04-29 Ciba Geigy Ag Unsaturated phosphonic acids and derivatives

Non-Patent Citations (1)

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Title
See references of WO9208724A1 *

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CZ80993A3 (en) 1994-02-16
NO931679L (no) 1993-05-07
LTIP1718A (en) 1995-07-25
HU9301417D0 (en) 1993-09-28
AU652399B2 (en) 1994-08-25
CA2095224A1 (en) 1992-05-16
JPH06502421A (ja) 1994-03-17
FI932206A (fi) 1993-05-14
SK46993A3 (en) 1993-10-06
MX9101979A (es) 1992-07-08
AU8939191A (en) 1992-06-11
SE9003652D0 (sv) 1990-11-15
IE913922A1 (en) 1992-05-20
IS3782A7 (is) 1992-05-16
FI932206A0 (fi) 1993-05-14
NO931679D0 (no) 1993-05-07
PT99515A (pt) 1992-09-30
CN1061595A (zh) 1992-06-03
WO1992008724A1 (en) 1992-05-29

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