NO300771B1 - Nye hetaryloxy-<beta>-carboliner og deres anvendelse til fremstilling av legemidler - Google Patents
Nye hetaryloxy-<beta>-carboliner og deres anvendelse til fremstilling av legemidler Download PDFInfo
- Publication number
- NO300771B1 NO300771B1 NO930390A NO930390A NO300771B1 NO 300771 B1 NO300771 B1 NO 300771B1 NO 930390 A NO930390 A NO 930390A NO 930390 A NO930390 A NO 930390A NO 300771 B1 NO300771 B1 NO 300771B1
- Authority
- NO
- Norway
- Prior art keywords
- carboline
- methoxymethyl
- carboxylic acid
- isopropyl ester
- acid isopropyl
- Prior art date
Links
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- 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BHNVVAZQKHLJAN-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=CC=1OC1=CC=C(C(F)(F)F)C=N1 BHNVVAZQKHLJAN-UHFFFAOYSA-N 0.000 description 1
- LAIBMPKOHCBASN-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-(1,3,5-triazin-2-yloxy)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=NC=NC=N1 LAIBMPKOHCBASN-UHFFFAOYSA-N 0.000 description 1
- IJKCSWHRNLJTDX-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-(2-methylsulfonylpyrimidin-4-yl)oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=NC(S(C)(=O)=O)=N1 IJKCSWHRNLJTDX-UHFFFAOYSA-N 0.000 description 1
- NPAVBCMELFYAIL-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-(5-methylpyrazin-2-yl)oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CN=C(C)C=N1 NPAVBCMELFYAIL-UHFFFAOYSA-N 0.000 description 1
- GUOMAVLQUIXASK-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-(6-methoxypyridin-2-yl)oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=CC(OC)=N1 GUOMAVLQUIXASK-UHFFFAOYSA-N 0.000 description 1
- IHGTYIMFKOKCSE-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-[5-(trifluoromethyl)pyridin-2-yl]oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=C(C(F)(F)F)C=N1 IHGTYIMFKOKCSE-UHFFFAOYSA-N 0.000 description 1
- MYYPMKVDZCJAJU-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-[6-(4-methylphenyl)sulfonylpyridin-3-yl]oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC(C=N1)=CC=C1S(=O)(=O)C1=CC=C(C)C=C1 MYYPMKVDZCJAJU-UHFFFAOYSA-N 0.000 description 1
- UHEAVVAFLJCZSF-UHFFFAOYSA-N propan-2-yl 6-(2,6-dimethoxypyrimidin-4-yl)oxy-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC(OC)=NC(OC)=N1 UHEAVVAFLJCZSF-UHFFFAOYSA-N 0.000 description 1
- COIMZCBCECDYBH-UHFFFAOYSA-N propan-2-yl 6-(4,6-dimethylpyrimidin-2-yl)oxy-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=NC(C)=CC(C)=N1 COIMZCBCECDYBH-UHFFFAOYSA-N 0.000 description 1
- MXNQGKKDMKHWOL-UHFFFAOYSA-N propan-2-yl 6-(5-bromopyrazin-2-yl)oxy-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CN=C(Br)C=N1 MXNQGKKDMKHWOL-UHFFFAOYSA-N 0.000 description 1
- CLEBADWJPJRIDU-UHFFFAOYSA-N propan-2-yl 6-(5-bromopyrazin-2-yl)oxy-4-ethyl-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(CC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CN=C(Br)C=N1 CLEBADWJPJRIDU-UHFFFAOYSA-N 0.000 description 1
- TYLJJOIDTVRDAK-UHFFFAOYSA-N propan-2-yl 6-(5-bromopyrazin-2-yl)oxy-4-methyl-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C3=C(C)C(C(=O)OC(C)C)=NC=C3NC2=CC=C1OC1=CN=C(Br)C=N1 TYLJJOIDTVRDAK-UHFFFAOYSA-N 0.000 description 1
- QNCJWFMQHBMPCX-UHFFFAOYSA-N propan-2-yl 6-(5-bromopyrimidin-2-yl)oxy-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=NC=C(Br)C=N1 QNCJWFMQHBMPCX-UHFFFAOYSA-N 0.000 description 1
- XOMFLFXVPSBVJZ-UHFFFAOYSA-N propan-2-yl 6-hydroxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C2=CC=C(O)C=C2C2=C1C=NC(C(=O)OC(C)C)=C2 XOMFLFXVPSBVJZ-UHFFFAOYSA-N 0.000 description 1
- ALPOVKYFXHSNRA-UHFFFAOYSA-N propan-2-yl 6-isoquinolin-1-yloxy-4-(methoxymethyl)-9-(4-methylphenyl)sulfonylpyrido[3,4-b]indole-3-carboxylate Chemical compound C12=CC=C(OC=3C4=CC=CC=C4C=CN=3)C=C2C=2C(COC)=C(C(=O)OC(C)C)N=CC=2N1S(=O)(=O)C1=CC=C(C)C=C1 ALPOVKYFXHSNRA-UHFFFAOYSA-N 0.000 description 1
- BXKAAZLCJXWSQR-UHFFFAOYSA-N propan-2-yl 6-isoquinolin-1-yloxy-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=CC=C2C(OC3=CC=C4NC=5C=NC(=C(C=5C4=C3)COC)C(=O)OC(C)C)=NC=CC2=C1 BXKAAZLCJXWSQR-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IPMPHGOTHAOAHA-UHFFFAOYSA-N tert-butyl 4-(methoxymethyl)-6-(5-methylpyrazin-2-yl)oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)(C)C)N=CC=3NC2=CC=C1OC1=CN=C(C)C=N1 IPMPHGOTHAOAHA-UHFFFAOYSA-N 0.000 description 1
- LQINRSMNQLFGKS-UHFFFAOYSA-N tert-butyl 4-(methoxymethyl)-6-(6-methoxypyridin-2-yl)oxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)(C)C)N=CC=3NC2=CC=C1OC1=CC=CC(OC)=N1 LQINRSMNQLFGKS-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse angår nye hetaryloxy-p-carbolinderivater og deres anvendelse i legemidler.
I EP-A-237 467 og EP-A-305 322 er det beskrevet 6-carboliner substituert med en hetaryloxy-rest, som innvirker på sentralnervesystemet og som anvendes som psykofarmaka. Ifølge disse patentsøknader var det ikke å forvente at det ved innføring av hetaryloxy-substituenten ifølge oppfinnelsen inntraff en forskyvning av virkningsprofilen av forbindelsene, og at forbindelsene på grunn av den manglende muskelrelaksasjon utviser en forbedret bivirkningsprofil.
Oppfinnelsen angår således forbindelser, hvilke forbindelser er kjennetegnet ved at de har formel I
H
hvori
RA betegner isokinolinyl-, kinolinyl- eller kinoxalinyl som kan være substituert med C^-alkyl eller halogen;
1,3,5-triazin-2-yl som kan være substituert med C^g-alkoxy eller C^-alkyltio; pyridinyl som er substituert med -CF3, tosyl eller C-^-alkoxy; pyrazinyl som er substituert med halogen eller C^-alkyl; pyrimi-dinyl som er substituert med C^-alkyl, C^-alkyl-thio, SOjR<1>, halogen eller C^-alkoxy; pyridazin som er substituert med halogen, hvorved RA kan være substituert én eller flere ganger,
R<1>betegner C1.4-alkyl eller fenyl eventuelt substituert
1-2 ganger med C^-alkyl,
R<4>betegner C^-alkoxy-C^-alkyl, Cx.6-alkyl,
R<3>betegner -C02-C1.6-alkyl, eller
R<b>er -CHj-O-C^-alkyl,
så vel som deres isomerer og syreaddisjonssalter.
Substituenten RA kan i A-ringen stå i stilling 5-8, fortrinnsvis i 5-, 6- eller 7-stilling.
Alkyl omfatter såvel rettkjedede som også forgrenede rester slik som for eksempel methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sek.butyl, tert.butyl, pentyl, isopentyl og hexyl.
Blant halogen skal det forstås fluor, klor, brom og jod.
De fysiologisk akseptable syreaddisjonssalter er avledet fra kjente uorganiske og organiske syrer, slik som for eksempel saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, maursyre, eddiksyre, benzosyre, maleinsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, oxalsyre, glyoxylsyre så vel som alkan-sulfonsyrer som for eksempel methansulfonsyre, ethansulfonsyre, benzensulfonsyre, p-toluensulfonsyre.
Forbindelsene av formel I så vel som deres syreaddisjonssalter er på grunn av deres affinitet til benzodiazepin-reseptorer anvendbare som legemidler, og utøver en partiell-agonistisk virkning på de kjente egenskaper for benzodiazepin, som er kjennetegnet ved at forbindelsene eksempelvis virker antikonvulsivt og anxiolytisk og ikke er ataksiske/muskel-relakserende. For undersøkelse av den anxiolytiské virkning ble forbindelsene testet i 4-platetesten ifølge metoden ifølge Boissier et al Extr. J. Pharmacol. 4, 145-150 (1968). I tabellen er det angitt den minimale laveste dose (MED) som høyner den lokomotoriske aktivitet av de straffede mus etter i.p. behandling.
På grunn av den gode virksomhet i PTZ-krampetesten
og i 4-platetesten er forbindelsene ifølge oppfinnelsen i særdeleshet egnet til behandling av epilepsi og angsttilstander.
For anvendelse av forbindelsene ifølge oppfinnelsen som legemidler bringes disse i form av et farmasøytisk preparat, som ved siden av virkestoffet inneholder farmasøytiske, organiske eller uorganiske inerte bærermaterialer egnet for enteral eller parenteral administrering, slik som for eksempel vann, gelatin, gummiarabikum, melkesukker, stivelse, magnesiumstearat, talkum, planteoljer, polyalkylenglykoler osv. De farmasøytiske preparater kan foreligge i fast form, for eksempel som tabletter, dragéer, stikkpiller, kapsler, eller i flytende form, for eksempel som løsninger, suspensjoner eller emulsjoner. Eventuelt inneholder de enn videre hjelpestoffer slik som konserverings-, stabiliserings-, fuktemidler eller emulgatorer, salter for forandring av det osmotiske trykk eller buffere.
For parenteral anvendelse er i særdeleshet injek-sjonsløsninger eller suspensjoner, i særdeleshet vandige løs-ninger av den aktive forbindelse i polyhydroxyethoxylert ricinusolje, egnet.
Som bærersysterner kan også grenseflateaktive hjelpestoffer slik som salter av gallesyrer eller animalske eller planteaktige fosfolipider, og også blandinger derav, så vel som liposomer eller deres bestanddeler, anvendes.
For oral anvendelse er i særdeleshet tabletter, dragéer eller kapsler med talkum og/eller hydrocarbonbærere eller -bindemidler, slik som for eksempel lactose, mais- eller potets tivelse, egnet. Anvendelsen kan også skje i flytende form, for eksempel som saft, som eventuelt er tilsatt et søtnings-stoff.
Forbindelsene ifølge oppfinnelsen bringes i en dose-enhet på 0,05 til 100 mg aktiv substans i en fysiologisk aksep-tabel bærer.
Forbindelsene ifølge oppfinnelsen anvendes generelt i en dose på 0,1 til 300 mg/dag, fortrinnsvis 0,1 til 30 mg/dag,
i særdeleshet 1-20 mg/dag, eksempelvis som anxiolytika analogt med diazepam.
Fremstillingen av forbindelsene ifølge oppfinnelsen skjer etter i og for seg kjente metoder. Eksempelvis erholdes forbindelsene av formel I ved at
a) forbindelser av formel II
hvori R 4 og R 3 har den ovenfor angitte betydning, forethres med
R A Y, hvori R A har den ovenfor angitte betydning og Y betegner halogen eller en reaktiv gruppe, eller
b) forbindelser av formel III
4 A'
hvori R har den ovenfor angitte betydning, R betegner hydrogen eller R , og Z betegner hydrogen, C1_4~alkoxy eller et reaktivt syrederivat, omsettes med en lithium-organisk forbindelse, eventuelt etter innføring av en beskyttelsesgruppe i 9-stilling, til forbindelser av formel I hvori R 3 = -CO-R 2,
eller
c) forbindelser av formel IV
A' A 4
hvori R betegner hydrogen eller R , og R har den ovenfor angitte.betydning, cykliseres med en forbindelse av formel V
hvori Ra, R<b>, R<c>og Rd har de ovenfor angitte betydninger, til forbindelser av formel I hvori R 3 betegner
eller
d) forbindelser av formel VI
A' A 4 a c d hvori R betegner hydrogen eller R , og R , R , R og R har de ovenfor angitte betydninger, cykliseres med et nitriloxyd av formel VII hvori R fø har den ovenfor angitte betydning, til forbindelser av formel I hvori R 3 betegner
eller
e) forbindelser av formel VIII
A' A 4
hvori R betegner hydrogen eller R , og R har den ovenfor angitte betydning, cykliseres med en forbindelse av formel (R^CO) -0 hvori R"' 3har den ovenfor angitte betydning, til for-bmdelser hvori R betegner
eller
f) forbindelser av formel IX
L
A' A 4
hvori R betegner hydrogen eller R T R har den ovenfor angitte betydning og R^ betegner OH eller et reaktivt syrederivat, omsettes med en forbindelse av formel
til forbindelser hvori R betegner
og deretter at eventuelt beskyttelsesgrupper avspaltes eller omestres, eller at estergruppen hydrolyseres eller at syreaddisjonssalter dannes eller at isomerer separeres.
Innføringen av substituenten R ifølge fremgangsmåtevariant a) skjer etter vanlige metoder for forethring, som eksempelvis er beskrevet i EP-A-237 467.
Den reaktive forbindelse R -Y hvori Y eksempelvis betegner halogen, tosylat, mesylat eller triflat, omsettes i nærvær av en base slik som jordalkali- eller alkali-alkoholat eller -hydroxyd, alkali- eller jordalkali-carbonat i polare løsningsmidler slik som dimethylsulfoxyd, dimethylformamid, acetonitril eller alkoholer ved romtemperatur eller forhøyet temperatur, eventuelt i nærvær av faseoverføringskatalysatorer. 3 . 2 Innføring av substituenten R i betydningen -CO-R etter fremgangsmåtevariant b) skjer etter den i WO 91/09858 beskrevne metode. Eksempelvis omsettes et 8-carbolin-3-carboxyl-syrealkylesterderivat eller dets reaktive syrederivat slik som carboxylsyreimidazolid med en lithium-organisk forbindelse R 2Li i aprotiske polare løsningsmidler slik som cykliske eller acykliske ethere eller hydrocarboner ved temperaturer på -70°C til romtemperatur. Hensiktsmessig kan en beskyttelsesgruppe foreligge i 9-stilling av 8-carbolin, slik som tosyl, mesyl eller en trialkylsilylgruppe, som ved opparbeidelsen av reaksjonsblandingen eller deretter avspaltes på vanlig måte alt etter arten av beskyttelsesgruppen.
Cykloaddisjonen av forbindelsene av formel IV og VI ifølge fremgangsmåte c) og d) skjer etter de i EP-A-305 322 beskrevne metoder. Addisjonen utføres ved temperaturer på 0°C til 40° C i et aprotisk løsningsmiddel slik som alifatiske eller cykliske ethere, halogenerte hydrocarboner, dimethylformamid og lignende. Eventuelt kan det anvendes beskyttede 8-carbolinderivater i 9-stilling i reaksjonen. Beskyttelsesgruppen avspaltes på vanlig måte ved opparbeidelsen av reaksjonsblandingen,eller deretter ved behandling med baser eller syrer alt etter arten av beskyttelsesgruppen.
Fremstillingen av nitriloxydet skjer eksempelvis ved omsetning av B-carbolin-3-carbaldehyder til de tilsvarende oximer, som eksempelvis kan overføres med N-halogen-succinimid, tertiært butoxykloritt eller Na-hypokloritt i de ovenfor angitte aprotiske løsningsmidler i hydroxamsyrehalogenider. Med baser slik som Na- eller K-alkoholater, trialkylaminer, Hiinig-base, DBU eller diazabicyklooktan avspaltes halogenhydrogen fra hydroxamsyrehalogenidene og nitriloxydet erholdes, som uten isolering underkastes cykloaddisjonen (R. Annunziata et al.,
J. Chem. Soc. 1987, 529).
Innføringen av oxadiazolresten etter fremgangsmåte-variantene e) og f) kan skje etter de i EP-161 574 beskrevne metoder. Fremstillingen av 1,2,4-oxadiazol-3-yl-carboliner skjer eksempelvis ved omsetning av B-carbolin-3-carboxamid-oximer med syreanhydrider (R^CO)20 ved romtemperatur til blandingens koketemperatur.
For innføring av 1,2,4-oxadiazol-5-yl-resten omsettes B-carbolin-3-carboxylsyre eller dens reaktive syrederivat slik som halogenid, imidazolid eller blandet anhydrid eller carboxyl-syrealkylester i nærvær av alkoholat med et amidoxim
i aprotiske løsningsmidler slik som hydrocarboner slik som toluen, ethere eller dimethylformamid ved romtemperatur eller forhøyet temperatur.
Hvis det ønskes en omestring, kan det anvendes de i EP-A-237 467 beskrevne metoder, idet man omestrer med alkali-alkoholater eller den tilsvarende alkohol, eventuelt under tilsetning av titantetra-isopropylat som katalysator ved forhøyet temperatur. Innføringen av den tertiære butylestergruppe skjer eksempelvis ved omsetning av carboxylsyren med tertiært butoxy-bis-dimethyl-aminomethan. Hydrolyse av estergruppen kan skje surt eller alkalisk på vanlig måte, eksempelvis med Na- eller K-hydroxyd i protiske løsningsmidler, eller etter de i EP-A-161 574 beskrevne metoder.
Isomerblandingen kan separeres etter vanlige metoder slik som for eksempelrkrystallisasjon, kromatografi eller salt-dannelse i diasteromerene hhv. enantiomerene.
For dannelse av de fysiologisk akseptable syreaddisjonssalter oppløses en forbindelse av formel I eksempelvis i litt alkohol og tilsettes en konsentrert løsning av den ønskede syre.
Såfremt fremstillingen av utgangsforbindelsene ikke er beskrevet, er disse kjente eller kan fremstilles analogt med kjente forbindelser eller de her beskrevne metoder.
Eksempelvis er fremstillingen av 3-carboxylesteren av formel II beskrevet i EP-A-130 140.
De etterfølgende eksempler illustrerer fremgangsmåten ifølge oppfinnelsen.
Eksempel 1
6- ( l- isoKinoly- l- oxy;)- 4- methoxymethyl- B- carbolin- 3- carboxylsyre-isopropylester
1,3 g kaliumhydroxydpulver ble tilsatt til 25 ml dimethylsulfoxyd ved romtemperatur. Deretter ble først 3,14 g 6-hydroxy-B-carbolin-3-carboxylsyreisopropylester porsjonsvis tilsatt til blandingen, og deretter ble en løsning av 2 g 1-klorisokiholyl. i 2 ml dimethylsulfoxyd dråpevis tilsatt. Etter 3 timers oppvarming til 90 - 95° C badtemperatur ble ytterligere 375 mg 1-klorisokinolin tilsatt, og blandingen ble oppvarmet i 2 timer til 100° C. Blandingen ble helt over på -is, ble innstilt til pH 5 med iseddik, bunnfallet ble fraskilt og vasket med eddikester. Residuet ble kromatografert
over kiselgel med methylenklori.d:ethanol = 13:1 som eluerings-middel. Etter inndampning av de tilsvarende kombinerte fraksjoner og omkrystallisering ble det erholdt 2,5 g (55 % av teoretisk) 6- (1-isO'kinolinoxy) -4-methoxymethyl-B~carbolin-3-carboxylsyreisopropylester med smeltepunkt 10° C.
På analog måte ble det fremstilt: 6- (4-kiho lylpxy ) -4-methoxymethyl-B-carbolin-3-carboxylsyreiso-propylester. Smeltepunkt 165 - 167° C
6- (4-methyl-2- kino'ly 1 oxy) -4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 174 - 176° C. 6-(2-k i noi yloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreiso-propylester. Smeltepunkt 108° C,
6-(3-klor-2 - kih o x_a ly 1 oxy) >- 4 -me thoxyme thy 1- B~c arbo1in-3-carboxylsyreisopropylester. Smeltepunkt 223 - 228° C
5- (l-iso-kinol-y-laæsy.) -4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 235 - 237° C 6- (5-tosyl)-2-pyridyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 206 - 207° C 6-(2-tosyl-5-pyridyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 206 - 207° C 6- (5-brom-2-pyrazinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 180 - 181°.-C 6- (5-brom-2-pyrazinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-tert^but<y>lester^Smeltepunkt 195 - 196° C 6-(2-methylmercapto-4-pyrimidinyloxy)-4-methoxy-B~carbolin-3-carboxylsyreisopropylester. Smeltepunkt 209 - 210° C 6-(2-methylsulfonyl-4-pyrimidinyloxy)-4-methoxymethy1~B~carbolin-3-carboxylsyreisopropylester. Smeltepunkt 178 - 179°C 6- (5-trifluormethyl-2-pyridyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 215 - 216° C 6- (4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 130 - 132° C 6- (5-brom-2-pyrimidinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 211 - 212° C 6- (4,6-dimethyl-2-pyrimidinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 84- 85° C. 6- [4,6-bis (methylthio) -1,3,5-triazin-2-yloxyT|-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 167 - 170° C
6-(2,6-dimethoxy-4-pyrimidinyloxy)-4-methoxymethyl-B-carbolin-3- carboxylsyreisopropylester. Smeltepunkt 159 - 161° C 6-( 4/ 6-dimethoxy-l,3,5-triazin-2-yloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 159 - 162° C 6-(1,3,5-triazin-2-yloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 168 - 170° C 6-(5-methyl-2-pyrazinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 180° C 6-(5-methyl-2-pyrazinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-tert.-butylester. Smeltepunkt 196° C 6-(5-methyl-2-pyrazinyloxy)-3-(5-methoxymethyl-3-isoxazolyl)-4- methoxymethyl-B-carbolin. Smeltepunkt 194 - 196° C 6-(5-methylpyrazin-2-yl)-oxy-4-ethyl-8-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 175 - 177° C 6-(5-brompyrazin-2-yl)-oxy-4-ethyl-B-carbolin-3-carboxylsyre-isopropylester. Smeltepunkt 227 - 228° C
6- (5-brompyrazin-2-yl)-oxy-4-methyl-B-carbolin-3-carboxylsyre-isopropy lester. Smeltepunkt 245 - 246° C
6-(6-methoxypyridin-2-yl)-oxy-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 92 - 99° C 6t(5-klorpyridazin-2-yl)-oxy-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 223° C 6-(5-klorpyridazin-2-yl)-oxy-4-methoxymethyl-B-carbolin-3-carboxylsyre-tert,-;butylester. Smeltepunkt 197° C 6-(6-methoxypyridin-2-yl)-oxy-4-methoxymethyl-B-carbolin-3-carboxylsyre-tert.-butylester. Smeltepunkt 166° C 5- (5-trifluormethylpyridin-2-yl)-oxy-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester. Smeltepunkt 206° C 5-(5-trifluormethylpyridin-2-yl)-oxy-4-methoxymethyl-B-carbolin-5- carboxylsyre^tert.-butylester. Smeltepunkt 178 - 180° C
Eksempel 2
6- ( l- isoikinolyloxy- 4- methoxymethyl- 3-( 5- methoxymethylisoxazol-3- yl)- B- carbolin
330 mg 6-(1-isokinolyloxy ) -4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester ble i 10 ml toluen tilsatt 0,62 ml triethylamin og 0,2 ml klortrimethylsilan, og ble oppvarmet i 45 minutter til 50 - 60° C badtemperatur. Etter inndamping til
til ca. 6 ml ble blandingen avkjølt til -78° C under argon,
og ble dråpevis tilsatt 1,25 ml av et 1,2 molar diisobutyl-aluminiumhydrid i hexan. Etter 30 minutter ved -78° C ble blandingen tilsatt 3 ml ethanol og 0,75 ml lN-NaOH. Blandingen ble tilsatt eddikester og meget lite vann. Den organiske fase ble fraskilt og ble inndampet uten tørking. Residuet ble omrørt med hexan og ga 440 mg 6-(1-isokinolyloxy)-4-methoxymethyl-B-:carbolin-3-carbaldehyd, 254 mg derav ble i 2,5 ml dimethylfuran tilsatt 67,5 mg hydroxylaminhydroklorid og 69 mg kaliumhydroxydpulver, og fikk stå i 16 timer ved romtemperatur. Blandingen ble helt over på is og bunnfallet ble fraskilt og vasket med vann. Det ble erholdt 133 mg 6-(1-isokinolyloxy)-4-methoxymethyl-B-carbolin-3-carbaldehydoxim med smeltepunkt 215 - 218° C.
450 mg av dette oxim ble oppløst i 7 ml dimethylformamid og ble omrørt med 218 mg N-bromsuccinimid i 30 minutter ved romtemperatur. Etter tilsetning av 0,8 ml triethylamin og 0,16 ml methylpropargylether ble blandingen omrørt i 3 timer ved romtemperatur. Etter inndampning ble blandingen fordelt i eddikester/vann og den organiske fase ble tørket, filtrert og inndampet. Residuet ble kromatografert to ganger over kiselgel først med methylenklorid-cethanol = 10:1 og deretter med methylenklorid:ethanol = 12:1. Etter omkrystallisering av de tilsvarende kombinerte og inndampede fraksjoner ble det erholdt 200 mg 6-(1-isokinolyooxy)-4-methoxymethyl-3-(5-methoxymethylisox;azol-3-yl)-3-carbolin med smeltepunkt 107 - 112° C (eddikester/hexan).
Eksempel 3
6-( 1- iso. kinolyloxy)- 4- methoxymethyl- 3- benzoyl- B- carbolin
476 mg 6-(1-isokinolyloxy)-4-methoxymethy1-9-tosyl-B-carbolin-3-carboxylsyreisopropylester ble i 10 ml tetrahydro-furan under argon ved -60° C tilsatt 0,79 ml av en 0,9m løsning av fenyllithium i benzen. Etter 1 time ved -6 0° C ble blandingen omrørt i 16 timer ved romtemperatur.Blandingen ble sur-gjort med iseddik og ble inndampet.Residuet ble fordelt i eddikester/vann og den organiske fase ble suksessivt vasket med mettet natriumbicarbonat- og koksaltløsning, ble tørket,
filtrert og inndampet. Residuet ble kromatografert over kiselgel med methylenklorid:ethanol =10:1. De tilsvarende fraksjoner ble kombinert, inndampet og omkrystallisert. Det ble erholdt 30 mg 6-(1-isokinolyloxy)-4-methoxymethyl-3-benzoyl-g-carbolin med smeltepunkt 159 - 160° C (eddikester/vann).
Claims (3)
1. Forbindelser,
karakterisert vedat de har formel I
hvori
RA betegner isokinolinyl-, kinolinyl- eller kinoxalinyl
som kan være substituert med C^-alkyl eller halogen; 1,3,5-triazin-2-yl som kan være substituert med Cx_6-alkoxy eller C^-alkyltio; pyridinyl som er substituert med -CF3, tosyl eller C^-alkoxy; pyrazinyl som er substituert med halogen eller Cj_6-alkyl; pyrimi-dinyl som er substituert med Cj_6-alkyl, C^g-alkyl-thio, SC^R<1>, halogen eller C^-alkoxy; pyridazin som er substituert med halogen, hvorved RA kan være substituert én eller flere ganger,
R<1>betegner C^-alkyl eller fenyl eventuelt substituert 1-2 ganger med C^-alkyl,
R<4>betegner C1.6-alkoxy-C1.2-alkyl, C^-alkyl,
R<3>betegner -CO,-C, 6-alkyl, eller
R<b>er -CHj-O-C^-alkyl,
så vel som deres isomerer og syreaddisjonssalter.
2. Forbindelser ifølge krav 1,karakterisert vedat disse er: 6-(1-isokinolyloxy) —4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester
6-(4-methyl-2-kinolyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester
6- (2-kinolyloxy) -4-methoxymethyl-8-carbolih-3-carboxylsyre-isopropylester
6- (3-klor-2- kinoxa.lyloxy) -4-methoxymethyl-B-carbolin-3-carboxylsyreisoproppylester
5- (2-isokinolyloxy) -4-meth'oxymeth"yl-g-carbolin-3-carboxyl-syrepropylester
6- (1-isokinolyloxy)-4-methoxymethyl-3-benzoyl-8-carbolin-3-carboxylsyrepropylester 6-(5-tosyl-2-pyridyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester 6-(2-tosyl-5-pyridyloxy)-4-methoxymethyl-0-carbolin-3-carboxylsyreisopropylester 6-(5~brom-2-pyrazinyloxy)-4-methoxymethyl-6-carbolin-3-carboxylsyreisopropylester 6-(5-brom-2-pyrazihyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyre-rtert. -rbutylester 6-(2-methylmercapto-4-pyrimidinyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester 6-(2-methylsulfonyl-4-pyrimidinyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester 6-(5-trifluormethyl-2-pyridyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester
6- (4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxymethylrø-carbolin-3-carboxylsyreisopropylester 6-(5-brom-2-pyrimidinyloxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester 6-(4,6-dimethyl-2-pyrimidinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester 6-[4,6-bis(methylthio)-1,3,5-triazin-2-yloxy]-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester
6-(2,6Tdimethoxy-4-pyrimidinyloxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester 6-(4,6-dimethoxy-l,3,5-triazin-2-yloxy)-4-methoxymethyl-6-carbolin-3-carboxylsyreisopropylester 6-(1,3,5-triazin-2-yloxy>4-methoxymethyl-B-carbolin-3-carboxyl-syreisopropylester 6-(5-methyl-2-pyrazinyloxy)-4-methoxymethyl-S-carbolin-3-carboxylsyreisopropylester
6- (5-methyl-2-pyrazinyloxy)-4-methoxymethyl-6-carbolin-3-carboxylsyre-tert.-butylester
6- (5-methyl-2-pyrazinyloxy) -3- (5-methoxymethyl-3-isoxazolyl.) -4-metoxymethyl-B-carbolin.
3. Anvendelse av forbindelsene ifølge kravene 1 og 2 for fremstilling av legemidler.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4118741A DE4118741A1 (de) | 1991-06-05 | 1991-06-05 | Neue hetaryloxy-(beta)-carboline, deren herstellung und verwendung in arzneimitteln |
| PCT/DE1992/000465 WO1992021679A1 (de) | 1991-06-05 | 1992-06-04 | NEUE HETARYLOXY-β-CARBOLINE, DEREN HERSTELLUNG UND VERWENDUNG IN ARZNEIMITTELN |
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| NO930390L NO930390L (no) | 1993-02-04 |
| NO930390D0 NO930390D0 (no) | 1993-02-04 |
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| AU (1) | AU658631B2 (no) |
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| CZ (1) | CZ281810B6 (no) |
| DE (1) | DE4118741A1 (no) |
| FI (1) | FI930293A (no) |
| HU (1) | HUT63166A (no) |
| IE (1) | IE921825A1 (no) |
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| PT (1) | PT100565A (no) |
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| DE4118741A1 (de) * | 1991-06-05 | 1992-12-10 | Schering Ag | Neue hetaryloxy-(beta)-carboline, deren herstellung und verwendung in arzneimitteln |
| DE4308788A1 (de) * | 1993-03-18 | 1994-09-22 | Bayer Ag | Hetero-tricyclisch-substituierte Phenyl-cyclohexan-carbonsäurederivate |
| DE4330175A1 (de) * | 1993-08-31 | 1995-03-02 | Schering Ag | Alkoxy-substituierte beta-Carboline |
| GB0108337D0 (en) * | 2001-04-03 | 2001-05-23 | Novartis Ag | Organic compounds |
| US8927551B2 (en) * | 2009-05-18 | 2015-01-06 | Infinity Pharmaceuticals, Inc. | Isoxazolines as inhibitors of fatty acid amide hydrolase |
| US8765735B2 (en) * | 2009-05-18 | 2014-07-01 | Infinity Pharmaceuticals, Inc. | Isoxazolines as inhibitors of fatty acid amide hydrolase |
| US9149465B2 (en) * | 2009-05-18 | 2015-10-06 | Infinity Pharmaceuticals, Inc. | Isoxazolines as inhibitors of fatty acid amide hydrolase |
| WO2021104618A1 (de) * | 2019-11-27 | 2021-06-03 | Wacker Chemie Ag | Verfahren zur entfernung einer verunreinigung aus einem chlorsilangemisch |
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| AU619203B2 (en) * | 1987-08-28 | 1992-01-23 | Schering Aktiengesellschaft | Isoxazole-beta-carboline derivatives |
| DE4118741A1 (de) * | 1991-06-05 | 1992-12-10 | Schering Ag | Neue hetaryloxy-(beta)-carboline, deren herstellung und verwendung in arzneimitteln |
-
1991
- 1991-06-05 DE DE4118741A patent/DE4118741A1/de not_active Withdrawn
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1992
- 1992-06-02 MX MX9202616A patent/MX9202616A/es not_active IP Right Cessation
- 1992-06-04 CN CN92105684A patent/CN1039906C/zh not_active Expired - Fee Related
- 1992-06-04 CZ CS923968A patent/CZ281810B6/cs unknown
- 1992-06-04 PL PL92297839A patent/PL172481B1/pl unknown
- 1992-06-04 NZ NZ243014A patent/NZ243014A/en unknown
- 1992-06-04 WO PCT/DE1992/000465 patent/WO1992021679A1/de not_active Application Discontinuation
- 1992-06-04 PT PT100565A patent/PT100565A/pt not_active Application Discontinuation
- 1992-06-04 RU RU93005125A patent/RU2105766C1/ru active
- 1992-06-04 CA CA002087098A patent/CA2087098A1/en not_active Abandoned
- 1992-06-04 HU HU9300595A patent/HUT63166A/hu unknown
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- 1992-06-04 EP EP92911058A patent/EP0541757A1/de not_active Withdrawn
- 1992-06-05 ZA ZA924127A patent/ZA924127B/xx unknown
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- 1992-06-05 AU AU18074/92A patent/AU658631B2/en not_active Ceased
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- 1992-07-01 IE IE182592A patent/IE921825A1/en not_active Application Discontinuation
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1993
- 1993-01-25 FI FI930293A patent/FI930293A/fi not_active Application Discontinuation
- 1993-02-04 NO NO930390A patent/NO300771B1/no unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| US5348958A (en) | 1994-09-20 |
| KR930701440A (ko) | 1993-06-11 |
| NZ243014A (en) | 1995-04-27 |
| AU1807492A (en) | 1992-12-10 |
| FI930293A0 (fi) | 1993-01-25 |
| RU2105766C1 (ru) | 1998-02-27 |
| CA2087098A1 (en) | 1992-12-06 |
| HUT63166A (en) | 1993-07-28 |
| PT100565A (pt) | 1993-08-31 |
| US5698555A (en) | 1997-12-16 |
| CZ281810B6 (cs) | 1997-02-12 |
| CZ396892A3 (en) | 1993-10-13 |
| WO1992021679A1 (de) | 1992-12-10 |
| MX9202616A (es) | 1993-09-01 |
| PL172481B1 (pl) | 1997-09-30 |
| FI930293A (fi) | 1993-01-25 |
| ZA924127B (en) | 1993-02-24 |
| CN1039906C (zh) | 1998-09-23 |
| DE4118741A1 (de) | 1992-12-10 |
| NO930390L (no) | 1993-02-04 |
| JPH06500341A (ja) | 1994-01-13 |
| CN1069270A (zh) | 1993-02-24 |
| AU658631B2 (en) | 1995-04-27 |
| IE921825A1 (en) | 1992-12-16 |
| EP0541757A1 (de) | 1993-05-19 |
| IL102116A (en) | 1997-02-18 |
| PL297839A1 (en) | 1993-11-02 |
| IL102116A0 (en) | 1993-01-14 |
| NO930390D0 (no) | 1993-02-04 |
| HU9300595D0 (en) | 1993-05-28 |
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