BG63969B1 - Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р - Google Patents
Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р Download PDFInfo
- Publication number
- BG63969B1 BG63969B1 BG104437A BG10443700A BG63969B1 BG 63969 B1 BG63969 B1 BG 63969B1 BG 104437 A BG104437 A BG 104437A BG 10443700 A BG10443700 A BG 10443700A BG 63969 B1 BG63969 B1 BG 63969B1
- Authority
- BG
- Bulgaria
- Prior art keywords
- methoxy
- disorders
- trifluoromethyl
- methyl
- dihydroisobenzofuran
- Prior art date
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- -1 Piperidinylaminomethyl trifluoromethyl cyclic ether compounds Chemical class 0.000 title claims description 34
- 239000003890 substance P antagonist Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
- 208000035475 disorder Diseases 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 206010047700 Vomiting Diseases 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 8
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 7
- 230000000172 allergic effect Effects 0.000 claims abstract description 7
- 230000033115 angiogenesis Effects 0.000 claims abstract description 7
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 7
- 241000590002 Helicobacter pylori Species 0.000 claims abstract description 6
- 230000002411 adverse Effects 0.000 claims abstract description 6
- 229940037467 helicobacter pylori Drugs 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 5
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 8
- 239000000203 mixture Substances 0.000 claims description 55
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 19
- 102100024304 Protachykinin-1 Human genes 0.000 claims description 19
- 101800003906 Substance P Proteins 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
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- AZXGYKQBRXSPHY-UHFFFAOYSA-N 6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene Chemical compound C1COC(C(F)(F)F)(C)C=2C1=CC(OC)=CC=2 AZXGYKQBRXSPHY-UHFFFAOYSA-N 0.000 claims description 6
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- NBUDNQJPOCYIIN-UHFFFAOYSA-N 5-methoxy-1-(trifluoromethyl)-1,3-dihydro-2-benzofuran Chemical compound COC1=CC=C2C(C(F)(F)F)OCC2=C1 NBUDNQJPOCYIIN-UHFFFAOYSA-N 0.000 claims description 5
- FGGKIMGMRFUCLN-UHFFFAOYSA-N 6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran Chemical compound COC1=CC=C2C(C(F)(F)F)(C)OCC2=C1 FGGKIMGMRFUCLN-UHFFFAOYSA-N 0.000 claims description 5
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- AZXGYKQBRXSPHY-LLVKDONJSA-N (1r)-6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene Chemical compound C=1([C@](OCC2)(C)C(F)(F)F)C2=CC(OC)=CC=1 AZXGYKQBRXSPHY-LLVKDONJSA-N 0.000 claims description 4
- NASATCITWOQHEY-OGUPFJCYSA-N (2s,3s)-n-[[6-methoxy-3-phenyl-3-(trifluoromethyl)-1h-2-benzofuran-5-yl]methyl]-2-phenylpiperidin-3-amine Chemical compound C1([C@@H]2NCCC[C@@H]2NCC2=CC=3C(OCC=3C=C2OC)(C=2C=CC=CC=2)C(F)(F)F)=CC=CC=C1 NASATCITWOQHEY-OGUPFJCYSA-N 0.000 claims description 4
- DOLRECVJKHHFSD-UHFFFAOYSA-N 1-[6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran-5-yl]ethanone Chemical compound C1=C(C(C)=O)C(OC)=CC2=C1C(C)(C(F)(F)F)OC2 DOLRECVJKHHFSD-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052731 fluorine Inorganic materials 0.000 claims description 4
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
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- RDOKLDFJIBLNAR-UHFFFAOYSA-N 6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene-7-carbaldehyde Chemical compound C1COC(C)(C(F)(F)F)C2=C1C=C(OC)C(C=O)=C2 RDOKLDFJIBLNAR-UHFFFAOYSA-N 0.000 claims description 3
- UTEFTKTYELSUJY-UHFFFAOYSA-N 6-methoxy-3-phenyl-3-(trifluoromethyl)-1h-2-benzofuran-5-carbaldehyde Chemical compound C1=2C=C(C=O)C(OC)=CC=2COC1(C(F)(F)F)C1=CC=CC=C1 UTEFTKTYELSUJY-UHFFFAOYSA-N 0.000 claims description 3
- CZRCXUGPHJTJCZ-UHFFFAOYSA-N n-methyl-2-phenylpiperidin-1-amine Chemical compound CNN1CCCCC1C1=CC=CC=C1 CZRCXUGPHJTJCZ-UHFFFAOYSA-N 0.000 claims description 3
- RDOKLDFJIBLNAR-GFCCVEGCSA-N (1r)-6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene-7-carbaldehyde Chemical compound C1CO[C@@](C)(C(F)(F)F)C2=C1C=C(OC)C(C=O)=C2 RDOKLDFJIBLNAR-GFCCVEGCSA-N 0.000 claims description 2
- NITVFOGGUFSYNJ-MTNREXPMSA-N (2S,3S)-3-[(3R)-6-methoxy-3-methyl-3-(trifluoromethyl)-1H-2-benzofuran-5-yl]-N-methyl-2-phenylpiperidin-1-amine Chemical compound COC1=C(C=C2[C@@](OCC2=C1)(C(F)(F)F)C)[C@H]1[C@H](N(CCC1)NC)C1=CC=CC=C1 NITVFOGGUFSYNJ-MTNREXPMSA-N 0.000 claims description 2
- ARZVJUKNXGNLEF-UHFFFAOYSA-N 6-methoxy-3,3-bis(trifluoromethyl)-1h-2-benzofuran Chemical compound COC1=CC=C2C(C(F)(F)F)(C(F)(F)F)OCC2=C1 ARZVJUKNXGNLEF-UHFFFAOYSA-N 0.000 claims description 2
- ZMSIXMWTEKXFEN-UHFFFAOYSA-N 6-methoxy-3,3-bis(trifluoromethyl)-1h-2-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C(F)(F)F)(C(F)(F)F)OC2 ZMSIXMWTEKXFEN-UHFFFAOYSA-N 0.000 claims description 2
- GPWGSWJZRDEAJI-UHFFFAOYSA-N 6-methoxy-3-(trifluoromethyl)-2,3-dihydro-1-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C(F)(F)F)CO2 GPWGSWJZRDEAJI-UHFFFAOYSA-N 0.000 claims description 2
- WKAUHBLYGCROEW-UHFFFAOYSA-N 6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C)(C(F)(F)F)OC2 WKAUHBLYGCROEW-UHFFFAOYSA-N 0.000 claims description 2
- XIRBHTNKLIOEGN-UHFFFAOYSA-N 6-methoxy-3-phenyl-3-(trifluoromethyl)-1h-2-benzofuran Chemical compound C=1C(OC)=CC=C2C=1COC2(C(F)(F)F)C1=CC=CC=C1 XIRBHTNKLIOEGN-UHFFFAOYSA-N 0.000 claims description 2
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- NAWOVAZMDQTKQU-ICTUGDKOSA-N (2S,3S)-3-[6-methoxy-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]-N-methyl-2-phenylpiperidin-1-amine Chemical compound COC1=C(C=C2C(OCC2=C1)C(F)(F)F)[C@H]1[C@H](N(CCC1)NC)C1=CC=CC=C1 NAWOVAZMDQTKQU-ICTUGDKOSA-N 0.000 claims 1
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- GQOAORJRRSLOQA-KBPBESRZSA-N tert-butyl (2s,3s)-3-amino-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1C1=CC=CC=C1 GQOAORJRRSLOQA-KBPBESRZSA-N 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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- C07D311/76—Benzo[c]pyrans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Landscapes
- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Reproductive Health (AREA)
- Endocrinology (AREA)
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- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Oncology (AREA)
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- Communicable Diseases (AREA)
- Vascular Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IB9701466 | 1997-11-19 | ||
| PCT/IB1998/001704 WO1999025714A1 (en) | 1997-11-19 | 1998-10-26 | Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| BG104437A BG104437A (en) | 2001-02-28 |
| BG63969B1 true BG63969B1 (bg) | 2003-08-29 |
Family
ID=11004634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG104437A BG63969B1 (bg) | 1997-11-19 | 2000-05-15 | Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р |
Country Status (39)
| Country | Link |
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| US (2) | US20030208079A1 (cs) |
| EP (1) | EP1032571B1 (cs) |
| JP (2) | JP3394239B2 (cs) |
| KR (1) | KR100366902B1 (cs) |
| CN (1) | CN1173974C (cs) |
| AP (1) | AP909A (cs) |
| AR (1) | AR016422A1 (cs) |
| AT (1) | ATE219078T1 (cs) |
| AU (1) | AU734218B2 (cs) |
| BG (1) | BG63969B1 (cs) |
| CA (1) | CA2310627C (cs) |
| CO (1) | CO4771153A1 (cs) |
| CZ (1) | CZ297315B6 (cs) |
| DE (1) | DE69806045T2 (cs) |
| DK (1) | DK1032571T3 (cs) |
| DZ (1) | DZ2655A1 (cs) |
| EA (1) | EA002621B1 (cs) |
| ES (1) | ES2177058T3 (cs) |
| HR (1) | HRP20000313B1 (cs) |
| HU (1) | HUP0101112A3 (cs) |
| ID (1) | ID24240A (cs) |
| IL (1) | IL135631A0 (cs) |
| IS (1) | IS2202B (cs) |
| MA (1) | MA26567A1 (cs) |
| MY (1) | MY120558A (cs) |
| NO (2) | NO20002544L (cs) |
| NZ (1) | NZ503912A (cs) |
| OA (1) | OA11380A (cs) |
| PA (1) | PA8463001A1 (cs) |
| PE (1) | PE20000021A1 (cs) |
| PL (1) | PL193484B1 (cs) |
| PT (1) | PT1032571E (cs) |
| RS (1) | RS49792B (cs) |
| SK (1) | SK283460B6 (cs) |
| TN (1) | TNSN98210A1 (cs) |
| TR (1) | TR200001463T2 (cs) |
| TW (1) | TW426667B (cs) |
| UA (1) | UA59417C2 (cs) |
| WO (1) | WO1999025714A1 (cs) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9812662D0 (en) * | 1998-06-11 | 1998-08-12 | Merck Sharp & Dohme | Therapeutic use |
| GB9812617D0 (en) * | 1998-06-11 | 1998-08-12 | Merck Sharp & Dohme | Therapeutic use |
| CA2373079A1 (en) * | 1999-05-06 | 2000-11-16 | Susan Beth Sobolov-Jaynes | Substituted benzolactam compounds |
| RS49964B (sr) | 1999-05-17 | 2008-09-29 | Pfizer Products Inc., | Postupak za dobijanje 2-fenil-3-aminopiridina,njegovih supstituisanih fenil derivata, i njegovih soli |
| HUP0201443A3 (en) * | 1999-05-21 | 2005-09-28 | Pfizer Prod Inc | 1-trifluoromethyl-4-hydroxy-7-piperidinyl-aminomethylchroman derivatives and pharmaceutical compositions containing them |
| DE60012953T2 (de) * | 1999-10-07 | 2005-08-18 | Hisamitsu Pharmaceutical Co., Inc., Tosu | 3-amino-2-phenylpiperidinderivate als substanz p antagonisten |
| DK1095939T3 (da) * | 1999-10-18 | 2004-04-13 | Pfizer Prod Inc | Fremgangsmåde til fremstilling af cykliske piperidinylaminomethyltrifluormethyletherforbindelser |
| CA2324116A1 (en) * | 1999-10-25 | 2001-04-25 | Susan Beth Sobolov-Jaynes | Nk-1 receptor antagonists and eletriptan for the treatment of migraine |
| IL142810A0 (en) * | 2000-05-03 | 2002-03-10 | Pfizer Prod Inc | Pharmaceutical uses for fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles |
| US20020049211A1 (en) * | 2000-09-06 | 2002-04-25 | Sobolov-Jaynes Susan Beth | Combination treatment for depression and anxiety |
| EP1192952A3 (en) * | 2000-09-28 | 2003-03-26 | Pfizer Products Inc. | Combination, for treating depression and anxiety, containing an NK-3 receptor antagonist and a CNS penetrant NK-1 receptor antagonist |
| US6555581B1 (en) | 2001-02-15 | 2003-04-29 | Jones Pharma, Inc. | Levothyroxine compositions and methods |
| US7067148B2 (en) | 2001-02-15 | 2006-06-27 | King Pharmaceutical Research & Development, Inc. | Stabilized pharmaceutical and thyroid hormone compositions and method of preparation |
| US7101569B2 (en) | 2001-08-14 | 2006-09-05 | Franz G Andrew | Methods of administering levothyroxine pharmaceutical compositions |
| DE60213043T2 (de) | 2001-08-30 | 2007-01-04 | Pfizer Products Inc., Groton | Verfahren zur Herstellung von 2-(4-Alkyl-1-Piperazinyl)-Benzaldehyd und -Benzylidenyl-Derivaten durch Nucleophile Substitution von 2-Fluorobenzaldehyd mit 4-Alkyl-1-Piperazinen in Wasser als Lösungsmittel |
| US20040001895A1 (en) * | 2002-06-17 | 2004-01-01 | Pfizer Inc. | Combination treatment for depression and anxiety |
| WO2004019865A2 (en) * | 2002-08-27 | 2004-03-11 | Witten Mark L | Amelioration of effects of cigarette smoke |
| US6911544B2 (en) * | 2002-10-23 | 2005-06-28 | Pfizer Inc. | Process for the preparation of (S,S)-cis-2-phenyl-3-aminopiperidine |
| US7122700B2 (en) | 2004-07-30 | 2006-10-17 | Xerox Corporation | Arylamine processes |
| DE102008000891A1 (de) | 2008-03-31 | 2009-10-01 | Robert Bosch Gmbh | Schutzsystem für Werkzeugmaschinen |
| ES2672099T3 (es) | 2011-07-04 | 2018-06-12 | Irbm - Science Park S.P.A. | Antagonistas del receptor NK-1 para el tratamiento de la neovascularización corneal |
| EP4371613A3 (en) | 2018-02-26 | 2024-07-24 | Ospedale San Raffaele S.r.l. | Compounds for use in the treatment of ocular pain |
| US20230134843A1 (en) | 2020-03-11 | 2023-05-04 | Ospedale San Raffaele S.R.L. | Treatment of stem cell deficiency |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9317987D0 (en) * | 1993-08-26 | 1993-10-13 | Glaxo Group Ltd | Chemical compounds |
| EP0826684B1 (en) * | 1995-03-27 | 2001-11-21 | Hisamitsu Pharmaceutical Co., Inc. | Piperidine derivatives |
| TW475930B (en) * | 1995-04-24 | 2002-02-11 | Novartis Ag | Novel compound, its use and pharmaceutical composition comprising it |
| ATE199552T1 (de) * | 1995-07-07 | 2001-03-15 | Pfizer | Substituierte benzolaktamverbindungen als substanz-p-antagonisten |
| TW340842B (en) * | 1995-08-24 | 1998-09-21 | Pfizer | Substituted benzylaminopiperidine compounds |
| US6329396B1 (en) * | 1996-06-10 | 2001-12-11 | Pfizer Inc. | Substituted benzylaminopiperidine compounds |
| HUP0201443A3 (en) * | 1999-05-21 | 2005-09-28 | Pfizer Prod Inc | 1-trifluoromethyl-4-hydroxy-7-piperidinyl-aminomethylchroman derivatives and pharmaceutical compositions containing them |
| DK1095939T3 (da) * | 1999-10-18 | 2004-04-13 | Pfizer Prod Inc | Fremgangsmåde til fremstilling af cykliske piperidinylaminomethyltrifluormethyletherforbindelser |
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1998
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- 1998-10-26 DK DK98947726T patent/DK1032571T3/da active
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- 1998-10-26 WO PCT/IB1998/001704 patent/WO1999025714A1/en not_active Ceased
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- 1998-11-18 DZ DZ980265A patent/DZ2655A1/xx active
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2003
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