IE61825B1 - D-cycloserine and its prodrugs as cognitive enhancers - Google Patents
D-cycloserine and its prodrugs as cognitive enhancersInfo
- Publication number
- IE61825B1 IE61825B1 IE356788A IE356788A IE61825B1 IE 61825 B1 IE61825 B1 IE 61825B1 IE 356788 A IE356788 A IE 356788A IE 356788 A IE356788 A IE 356788A IE 61825 B1 IE61825 B1 IE 61825B1
- Authority
- IE
- Ireland
- Prior art keywords
- dosage form
- range
- therapeutically
- effective amount
- amount
- Prior art date
Links
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 title claims abstract description 24
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229940002612 prodrug Drugs 0.000 title abstract description 4
- 239000000651 prodrug Substances 0.000 title abstract description 4
- 239000002475 cognitive enhancer Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000002552 dosage form Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 13
- 230000037396 body weight Effects 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 10
- 230000006872 improvement Effects 0.000 claims description 9
- 208000012902 Nervous system disease Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 230000007278 cognition impairment Effects 0.000 claims description 4
- 230000027928 long-term synaptic potentiation Effects 0.000 claims description 4
- 230000006883 memory enhancing effect Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 2
- FERCDDZJYIRSMF-UHFFFAOYSA-N 2-amino-1,2-oxazolidin-3-one Chemical compound NN1OCCC1=O FERCDDZJYIRSMF-UHFFFAOYSA-N 0.000 claims 1
- 230000002708 enhancing effect Effects 0.000 claims 1
- 230000037411 cognitive enhancing Effects 0.000 abstract 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 12
- 125000001145 hydrido group Chemical group *[H] 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 239000004471 Glycine Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- -1 phenalkyl Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 230000035939 shock Effects 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 5
- GJNNXIYZWIZFRH-UHFFFAOYSA-N 2-(pentylamino)acetamide Chemical compound CCCCCNCC(N)=O GJNNXIYZWIZFRH-UHFFFAOYSA-N 0.000 description 4
- 239000002262 Schiff base Substances 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 description 4
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- 229950000928 milacemide Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 150000004753 Schiff bases Chemical class 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004982 dihaloalkyl group Chemical group 0.000 description 3
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- MYDMWESTDPJANS-UHFFFAOYSA-N 2-amino-7-phosphonoheptanoic acid Chemical compound OC(=O)C(N)CCCCCP(O)(O)=O MYDMWESTDPJANS-UHFFFAOYSA-N 0.000 description 2
- 102000011714 Glycine Receptors Human genes 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920005372 Plexiglas® Polymers 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
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- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 229940127427 Glycine Agonists Drugs 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- DYDCUQKUCUHJBH-REOHCLBHSA-N L-Cycloserine Chemical compound N[C@H]1CONC1=O DYDCUQKUCUHJBH-REOHCLBHSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical class CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
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- 150000008366 benzophenones Chemical class 0.000 description 1
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- 230000019771 cognition Effects 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 230000000946 synaptic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/127,121 US4904681A (en) | 1987-12-01 | 1987-12-01 | D-cycloserine and its prodrugs as cognitive enhancers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE883567L IE883567L (en) | 1989-06-01 |
| IE61825B1 true IE61825B1 (en) | 1994-11-30 |
Family
ID=22428413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE356788A IE61825B1 (en) | 1987-12-01 | 1988-11-29 | D-cycloserine and its prodrugs as cognitive enhancers |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4904681A (cg-RX-API-DMAC10.html) |
| EP (2) | EP0319824B1 (cg-RX-API-DMAC10.html) |
| JP (2) | JPH0621065B2 (cg-RX-API-DMAC10.html) |
| KR (1) | KR0134198B1 (cg-RX-API-DMAC10.html) |
| AT (1) | ATE68698T1 (cg-RX-API-DMAC10.html) |
| AU (4) | AU622630B2 (cg-RX-API-DMAC10.html) |
| CA (1) | CA1328617C (cg-RX-API-DMAC10.html) |
| DE (1) | DE3865817D1 (cg-RX-API-DMAC10.html) |
| DK (1) | DK173589B1 (cg-RX-API-DMAC10.html) |
| ES (1) | ES2040314T3 (cg-RX-API-DMAC10.html) |
| FI (1) | FI885559A0 (cg-RX-API-DMAC10.html) |
| GR (1) | GR3003571T3 (cg-RX-API-DMAC10.html) |
| IE (1) | IE61825B1 (cg-RX-API-DMAC10.html) |
| IL (1) | IL88531A (cg-RX-API-DMAC10.html) |
| NO (1) | NO885337D0 (cg-RX-API-DMAC10.html) |
| NZ (1) | NZ227131A (cg-RX-API-DMAC10.html) |
| PH (1) | PH26467A (cg-RX-API-DMAC10.html) |
| PT (1) | PT89109B (cg-RX-API-DMAC10.html) |
| WO (1) | WO1989005144A1 (cg-RX-API-DMAC10.html) |
| ZA (1) | ZA888981B (cg-RX-API-DMAC10.html) |
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5187171A (en) * | 1989-01-09 | 1993-02-16 | G. D. Searle & Co. | Use of a glycine b partial agonist as an antipsychotic |
| US5061721A (en) * | 1989-03-15 | 1991-10-29 | G. D. Searle & Co. | Composition containing d-cycloserine and d-alanine for memory and learning enhancement or treatment of a cognitive or psychotic disorder |
| US5260324A (en) * | 1990-02-06 | 1993-11-09 | G. D. Searle & Company | Composition containing D-cycloserine and D-alanine for memory and learning enhancement or treatment of a cognitive or psychotic disorder |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3050800C2 (cg-RX-API-DMAC10.html) * | 1979-03-22 | 1989-06-22 | Continental Pharma Inc., Bruessel/Bruxelles, Be |
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1987
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1988
- 1988-11-28 PH PH37866A patent/PH26467A/en unknown
- 1988-11-29 EP EP88119863A patent/EP0319824B1/en not_active Expired - Lifetime
- 1988-11-29 IL IL88531A patent/IL88531A/xx not_active IP Right Cessation
- 1988-11-29 AU AU26319/88A patent/AU622630B2/en not_active Ceased
- 1988-11-29 IE IE356788A patent/IE61825B1/en not_active IP Right Cessation
- 1988-11-29 DE DE88119863T patent/DE3865817D1/de not_active Expired - Fee Related
- 1988-11-29 PT PT89109A patent/PT89109B/pt not_active IP Right Cessation
- 1988-11-29 ES ES88119863T patent/ES2040314T3/es not_active Expired - Lifetime
- 1988-11-29 AT AT88119863T patent/ATE68698T1/de not_active IP Right Cessation
- 1988-11-29 NZ NZ227131A patent/NZ227131A/xx unknown
- 1988-11-30 KR KR1019880015895A patent/KR0134198B1/ko not_active Expired - Fee Related
- 1988-11-30 JP JP63303873A patent/JPH0621065B2/ja not_active Expired - Lifetime
- 1988-11-30 ZA ZA888981A patent/ZA888981B/xx unknown
- 1988-11-30 DK DK198806690A patent/DK173589B1/da not_active IP Right Cessation
- 1988-11-30 FI FI885559A patent/FI885559A0/fi not_active Application Discontinuation
- 1988-11-30 NO NO885337A patent/NO885337D0/no unknown
- 1988-11-30 CA CA000584621A patent/CA1328617C/en not_active Expired - Fee Related
- 1988-12-01 EP EP89900543A patent/EP0421997A1/en not_active Withdrawn
- 1988-12-01 AU AU28130/89A patent/AU2813089A/en not_active Abandoned
- 1988-12-01 WO PCT/US1988/004244 patent/WO1989005144A1/en not_active Ceased
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1992
- 1992-01-15 GR GR910401170T patent/GR3003571T3/el unknown
- 1992-02-10 AU AU10839/92A patent/AU1083992A/en not_active Abandoned
- 1992-07-03 JP JP4177094A patent/JPH05201859A/ja active Pending
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1994
- 1994-10-26 AU AU77467/94A patent/AU7746794A/en not_active Abandoned
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|---|---|
| EP0319824A1 (en) | 1989-06-14 |
| NO885337D0 (no) | 1988-11-30 |
| AU2631988A (en) | 1989-06-01 |
| PT89109A (pt) | 1989-12-29 |
| JPH0621065B2 (ja) | 1994-03-23 |
| PH26467A (en) | 1992-07-27 |
| GR3003571T3 (cg-RX-API-DMAC10.html) | 1993-03-16 |
| AU2813089A (en) | 1989-07-05 |
| IL88531A (en) | 1993-02-21 |
| EP0319824B1 (en) | 1991-10-23 |
| AU7746794A (en) | 1995-01-05 |
| AU622630B2 (en) | 1992-04-16 |
| DE3865817D1 (cg-RX-API-DMAC10.html) | 1991-11-28 |
| WO1989005144A1 (en) | 1989-06-15 |
| IE883567L (en) | 1989-06-01 |
| CA1328617C (en) | 1994-04-19 |
| ES2040314T3 (es) | 1995-04-01 |
| DK669088D0 (da) | 1988-11-30 |
| AU1083992A (en) | 1992-05-07 |
| ATE68698T1 (de) | 1991-11-15 |
| FI885559A0 (fi) | 1988-11-30 |
| KR890009392A (ko) | 1989-08-01 |
| ZA888981B (en) | 1990-01-31 |
| DK669088A (da) | 1989-06-02 |
| KR0134198B1 (ko) | 1998-04-21 |
| JPH01193220A (ja) | 1989-08-03 |
| IL88531A0 (en) | 1989-06-30 |
| JPH05201859A (ja) | 1993-08-10 |
| DK173589B1 (da) | 2001-04-02 |
| PT89109B (pt) | 1993-07-30 |
| US4904681A (en) | 1990-02-27 |
| EP0421997A1 (en) | 1991-04-17 |
| NZ227131A (en) | 1991-09-25 |
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