JPH08507499A - 複素環式化合物及びその調製と使用 - Google Patents
複素環式化合物及びその調製と使用Info
- Publication number
- JPH08507499A JPH08507499A JP6519480A JP51948094A JPH08507499A JP H08507499 A JPH08507499 A JP H08507499A JP 6519480 A JP6519480 A JP 6519480A JP 51948094 A JP51948094 A JP 51948094A JP H08507499 A JPH08507499 A JP H08507499A
- Authority
- JP
- Japan
- Prior art keywords
- azabicyclo
- octane
- thiadiazol
- exo
- thiadiazole
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 230000003920 cognitive function Effects 0.000 claims abstract description 11
- 210000004129 prosencephalon Anatomy 0.000 claims abstract description 10
- 210000001320 hippocampus Anatomy 0.000 claims abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims abstract description 6
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229910052717 sulfur Chemical group 0.000 claims abstract description 5
- 239000011593 sulfur Chemical group 0.000 claims abstract description 5
- -1 -CHO Chemical group 0.000 claims description 97
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052757 nitrogen Chemical group 0.000 claims description 6
- 239000012038 nucleophile Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000004277 1,3-dioxalan-2-yl group Chemical group [H]C1([H])OC([H])(*)OC1([H])[H] 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- YCBSHDKATAPNIA-UHFFFAOYSA-N non-3-ene Chemical compound CCCCCC=CCC YCBSHDKATAPNIA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 230000004936 stimulating effect Effects 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004518 1,2,5-thiadiazol-3-yl group Chemical group S1N=C(C=N1)* 0.000 claims description 2
- ZLAUVFSNIFHZKD-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-(4-chlorobutylsulfanyl)-1,2,5-thiadiazole Chemical compound ClCCCCSC1=NSN=C1C1C(CC2)CCN2C1 ZLAUVFSNIFHZKD-UHFFFAOYSA-N 0.000 claims description 2
- PNUHPRXOKICIPB-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-(cyclopropylmethylsulfanyl)-1,2,5-thiadiazole Chemical compound N=1SN=C(C2C3CCN(CC3)C2)C=1SCC1CC1 PNUHPRXOKICIPB-UHFFFAOYSA-N 0.000 claims description 2
- 241001421185 Anomis Species 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 238000010561 standard procedure Methods 0.000 claims description 2
- 230000000638 stimulation Effects 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 230000000202 analgesic effect Effects 0.000 claims 3
- ORSNGBROJOASLE-UHFFFAOYSA-N 2-[[4-(1-azabicyclo[2.2.2]octan-3-yl)-1,2,5-thiadiazol-3-yl]sulfanyl]acetonitrile Chemical compound N#CCSC1=NSN=C1C1C(CC2)CCN2C1 ORSNGBROJOASLE-UHFFFAOYSA-N 0.000 claims 1
- WOTMEGYCCPNSSQ-UHFFFAOYSA-N 2-ethylsulfanylisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(SCC)C(=O)C2=C1 WOTMEGYCCPNSSQ-UHFFFAOYSA-N 0.000 claims 1
- ADDANRIXDNPMJE-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-(2-phenoxyethylsulfanyl)-1,2,5-thiadiazole Chemical compound N=1SN=C(C2C3CCN(CC3)C2)C=1SCCOC1=CC=CC=C1 ADDANRIXDNPMJE-UHFFFAOYSA-N 0.000 claims 1
- CSQZGLBQPMPLJG-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-(3-methylbutoxy)-1,2,5-thiadiazole Chemical compound CC(C)CCOC1=NSN=C1C1C(CC2)CCN2C1 CSQZGLBQPMPLJG-UHFFFAOYSA-N 0.000 claims 1
- XXLAHLWLBSZYCG-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-(3-thiophen-2-ylpropylsulfanyl)-1,2,5-thiadiazole Chemical compound N=1SN=C(C2C3CCN(CC3)C2)C=1SCCCC1=CC=CS1 XXLAHLWLBSZYCG-UHFFFAOYSA-N 0.000 claims 1
- QPYQPZBDWBQMGL-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-[(4-ethylphenyl)methoxy]-1,2,5-thiadiazole Chemical compound C1=CC(CC)=CC=C1COC1=NSN=C1C1C(CC2)CCN2C1 QPYQPZBDWBQMGL-UHFFFAOYSA-N 0.000 claims 1
- UJXWWHIVPSILDS-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-[(4-fluorophenyl)methylsulfanyl]-1,2,5-thiadiazole Chemical compound C1=CC(F)=CC=C1CSC1=NSN=C1C1C(CC2)CCN2C1 UJXWWHIVPSILDS-UHFFFAOYSA-N 0.000 claims 1
- JSHMHTPKMSXMIK-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-[3-(1-methyltetrazol-5-yl)sulfanylbutylsulfanyl]-1,2,5-thiadiazole Chemical compound N=1SN=C(C2C3CCN(CC3)C2)C=1SCCC(C)SC1=NN=NN1C JSHMHTPKMSXMIK-UHFFFAOYSA-N 0.000 claims 1
- DLWNGVLOTUXMLM-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]octan-3-yl)-4-methylsulfanyl-1,2,5-thiadiazole Chemical compound CSC1=NSN=C1C1C(CC2)CCN2C1 DLWNGVLOTUXMLM-UHFFFAOYSA-N 0.000 claims 1
- CIBOJGMIGPKLMI-UHFFFAOYSA-N 3-(1-azabicyclo[3.3.1]non-3-en-3-yl)-4-propoxy-1,2,5-thiadiazole Chemical compound CCCOC1=NSN=C1C(C1)=CC2CN1CCC2 CIBOJGMIGPKLMI-UHFFFAOYSA-N 0.000 claims 1
- ZUBBXJQRWCNGSG-UHFFFAOYSA-N 3-butoxy-4-(4-chloro-1-azabicyclo[3.3.1]non-3-en-3-yl)-1,2,5-thiadiazole Chemical compound CCCCOC1=NSN=C1C(C1)=C(Cl)C2CN1CCC2 ZUBBXJQRWCNGSG-UHFFFAOYSA-N 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- WWXBHTZSYYGCSG-UHFFFAOYSA-N [4-(carbamoylamino)phenyl]arsonic acid Chemical compound NC(=O)NC1=CC=C([As](O)(O)=O)C=C1 WWXBHTZSYYGCSG-UHFFFAOYSA-N 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 4
- 150000004030 azacyclic compounds Chemical class 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- WJHZOWPRNOSKTK-UHFFFAOYSA-N octane;oxalic acid Chemical compound OC(=O)C(O)=O.CCCCCCCC WJHZOWPRNOSKTK-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000284 extract Substances 0.000 description 11
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- STHHLVCQSLRQNI-UHFFFAOYSA-N 1-azabicyclo[3.2.1]octane Chemical compound C1C2CCN1CCC2 STHHLVCQSLRQNI-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 7
- SDWBIJFENFPAAU-UHFFFAOYSA-N 2-(3-chloropropyl)thiophene Chemical compound ClCCCC1=CC=CS1 SDWBIJFENFPAAU-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229940125797 compound 12 Drugs 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000003551 muscarinic effect Effects 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 150000001350 alkyl halides Chemical class 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 230000009870 specific binding Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- YXZFFTJAHVMMLF-UHFFFAOYSA-N 1-bromo-3-methylbutane Chemical compound CC(C)CCBr YXZFFTJAHVMMLF-UHFFFAOYSA-N 0.000 description 4
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- MRAHIVCBBZNVHV-UHFFFAOYSA-N benzonitrile;hydrobromide Chemical compound Br.N#CC1=CC=CC=C1 MRAHIVCBBZNVHV-UHFFFAOYSA-N 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 4
- 150000003891 oxalate salts Chemical class 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- WRVHPSSSTBDGRK-UHFFFAOYSA-N sodium;sulfane;hydrate Chemical compound O.[Na].S WRVHPSSSTBDGRK-UHFFFAOYSA-N 0.000 description 4
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 3
- XZKFBZOAIGFZSU-UHFFFAOYSA-N 1-bromo-4-methylpentane Chemical compound CC(C)CCCBr XZKFBZOAIGFZSU-UHFFFAOYSA-N 0.000 description 3
- SAUGMJLWYLQPEM-UHFFFAOYSA-N 3-bromo-1,1,1-trifluoropropane Chemical compound FC(F)(F)CCBr SAUGMJLWYLQPEM-UHFFFAOYSA-N 0.000 description 3
- LOQLDQJTSMKBJU-UHFFFAOYSA-N 4-(chloromethyl)benzonitrile Chemical compound ClCC1=CC=C(C#N)C=C1 LOQLDQJTSMKBJU-UHFFFAOYSA-N 0.000 description 3
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 2
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- VRLJVDPFUDVHMJ-UHFFFAOYSA-N sodium;1,1,2,2,3,3,4-heptafluorobutan-1-olate Chemical compound [Na+].[O-]C(F)(F)C(F)(F)C(F)(F)CF VRLJVDPFUDVHMJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
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- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- 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
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.次式I: (式中、Xは酸素又は硫黄であり; Rは水素、アミノ、ハロゲン,−CHO,−NO2,−OR4,−SOR4,−SO2R4,C3- 7 −シクロアルキル,C4-8−(シクロアルキルアルキル),−Z−C3-7−シク ロアルキルおよび−Z−C4-8−(シクロアルキルアルキル)であり、ここにお いてR4は直鎖又は分枝C1-15−アルキル、直鎮又は分枝C2-15アルケニル、直 鎖又は分技C2-15アルキニルであり、これらの各々は所望により1種又はそれ以 上のハロゲン、−CF3,−CN,−OH、フェニル又はフェノキシ(ここにおいてフ ェニル又はフェノキシは所望によりハロゲン、−CF3,−CN,C1-4−アルキル、 C1-4−アルコキシ、−OCF3,−CONH2又は−CSNH2で置換される)で置換される か;又はRはフェニル又はベンジルオキシカルボニルであり、これらの各々は所 望によりハロゲン、−CN,C1-4−アルキル、C1-4−アルコキシ、−OCF3,−CO NH2又は−CSNH2で置換されるか;又はRは−OR5Y,−SR5Y,−OR5ZY,−O−R4 −Z−R5又は−S−R4−Z−R5(ここにおいてZは酸素又は硫黄であり、R5 は直鎖又は分枝C1-15アルキル、直鎖又は分枝C2-15アルケニル、直鎖又は分枝 C2-15アルキニルであり、そしてYは1〜4個のN,O又はS原子又はそれらの 組合せを含有する5員又は6員の複素環式基であり、この 複素環式基は炭素又は窒素原子において直鎖又は分技C1-6アルキル、フェニル 又はベンジルで所望により置換されるか、又は該複素環式基は所望によりフェニ ル基と縮合する;そして Gは次のアザ二環式環: (ここにおいてチアジアゾール又はオキサジアゾール環は、アザ二環式環のどの ような炭素原子においても結合され得る;R1およびR2はチアジアゾール又はオ キサジアゾールの結合点を含めて、どのような位置においても存在してもよく、 そして独立に水素、直鎖又は分技C1-15−アルキル、直鎖又は分枝C2-5−アル ケニル、直鎖又は分技C2-5−アルキニル、直鎮又は分枝C1-10−アルコキシ、 −OHで置換された直鎮又は分枝C1-5−アルキル、−OH,ハロゲン、−NH2又はカ ルボキシであり;R3はH、直鎖又は分枝C1-5−アルキル、直鎮又は分技C2-5 −アルケニル又は直鎮又は分技C2-5−アルキニルであり;nは0,1又は2で あり;mは0,1又 重結合である) の1つから選ばれる) で表わされる化合物又はその医薬として許容し得る塩。 2.次の群: (−)−エキソ−6−(3−ブチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−プロピルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−プロピルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−ブチルスルホニル−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(2,2,3,3,4,4,4−ヘプタフルオロブチルオキ シ)−1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2. 1〕オクタン; エキソ−6−(3−メトキシ−1,2,5−チアジアゾール−4−イル)−1− アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−エトキシ−1,2,5−チアジアゾール−4−イル)−1− アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−プロポキシ−1,2,5−チアジアゾール−4−イル)−1 −アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−ブトキシ−1,2,5−チアジアゾール−4−イル)−1− アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−ペンチルオキシ−1,2,5−チアジアゾール−4−イル) −1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−ヘキシルオキシ−1,2,5−チアジアゾール−4−イル) −1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−イソヘキシルオキシ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(2−ブチニルオキシ)−1,2,5−チアジアゾール−4 −イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(3−(2−チエニル)−1−プロピルチオ) −1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕 オクタン; エンド−6−(3−(3−(2−チエニル)−1−プロピルチオ)−1,2,5 −チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4,4,4−トリフルオロブチルチオ)−1,2,5−チ アジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(6,6,6−トリフルオロ−1−ヘキシルチオ)−1,2 ,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン ; (+)−エキソ−6−(3−ブチルスルホニル−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−(4,4,4−トリフルオロ−1−ブチルチオ)− 1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オ クタン; 3−(1,2,5−チアジアゾール−3−イル)−1−アザビシクロ〔2.2. 2〕オクタン; エキソ−3−(3−メチルチオ−1,2,5−チアジアゾール−4−イル)−1 −アザビシクロ〔2.2.1〕ヘプタン; エキソ−3−(3−エチルチオ−1,2,5−チアジアゾール−4−イル)−1 −アザビシクロ〔2.2.1〕ヘプタン; エンド−3−(3−(2−フェノキシエチルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔2.2.1〕ヘプタン; エンド−3−(3−(2−チエニル)プロピルチオ−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔2.2.1〕ヘプタン; エンド−3−(3−(2−フェニルチオ)エチルチオ−1,2,5−チアジアゾ ール−4−イル)−1−アザビシクロ〔2.2.1〕ヘプタン; エキソ−6−(3−メチルチオ−1,2,5−チアジアゾール−4−イル)−1 −アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−ヘプチルチオ−1,2,5−チアジアゾール−4−イル)− 1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−イソヘキシルチオ−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−イソペンチルチオ−1,2,5−チアジアゾール−4−イル )−1−アザビジクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−シアノブチルチオ)−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−シアノメチルチオ−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(2−シアノメチルチオ)−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(3−シアノプロピルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−シアノベンジルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(3−フェニルプロピルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(2−フェノキシエチルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−ベンジルチオ−1,2,5−チアジアゾール−4−イル)− 1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(2−フェノキシエチルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−メチルチオ−1,2,5−チアジアゾール−4−イル)−1 −アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−イソペンチルチオ−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−イソヘキシルチオ−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−ベンジルチオ−1,2,5−チアジアゾール−4−イル)− 1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−シアノメチルチオ−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(2−シアノエチルチオ)−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(3−シアノプロピルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4−シアノブチルチオ)−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; 4−クロロ−3−(3−ブトキシ−1,2,5−チアジアゾール−4−イル)− 1−アザビシクロ〔3.3.1〕ノン−3−エン; 4−クロロ−3−(3−ヘキシルオキシ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.3.1〕ノン−3−エン; 3−(3−ブトキシ−1,2,5−チアジアゾール−4−イル)−1−アザビシ クロ〔3.3.1〕ノン−3−エン; 3−(3−メトキシ−1,2,5−チアジアゾール−4−イル)−1−アザビシ クロ〔3.3.1〕ノン−3−エン; 3−(3−プロポキシ−1,2,5−チアジアゾール−4−イル)−1−アザビ シクロ〔3.3.1〕ノン−3−エン; 3−(3−ヘキシルオキシ−1,2,5−チアジアゾール−4−イル)−1−ア ザビシクロ〔3.3.1〕ノン−3−エン; 3−(3−イソペンチルオキシ−1,2,5−チアジアゾール−4−イル)−1 −アザビシクロ〔2.2.2〕オクタン; 3−(3−(1−メチルプロピルオキシ)−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−イソブチルチオ−1,2,5−チアジアゾール−4−イル)−1−ア ザビシクロ〔2.2.2〕オクタン; 3−(3−(2−フェノキシエチルチオ)−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−シアノメチルチオ−1,2,5−チアジアゾール−4−イル)−1− アザビシクロ〔2.2.2〕オクタン; 3−(3−(3−(2−チエニル)プロピルチオ)−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(4−クロロブチルチオ)−1,2,5−チアジアゾール−4−イル )−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−メチルチオ−1,2,5−チアジアゾール−4−イル)−1−アザビ シクロ〔2.2.2〕オクタン; 3−(3−(1−メチルテトラゾール−5−イルチオ)ブチルチオ−1,2,5 −チアジアゾール−4−イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(2−メチル−1,3,4−チアジアゾール−5−イルチオ)ブチル チオ)−1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔2.2 .2〕オクタン; 3−(3−(4−(2−ベンゾチアゾリル)チオ)ブチルチオ−1,2,5−チ アジアゾール−4−イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(4−エチルベンジルオキシ)−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(3−(2−チエニル)プロピル)−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔2.2.2〕オクタン; (+)−エキソ−6−(3−ブチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; 3−(3−(N−(2−エチルチオ)フタルイミド)−1,2,5−チアジアゾ ール−4−イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(2−メトキシエチルチオ)−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(2−(1,3−ジオキサラン−2−イル)エチルチオ)−1,2, 5−チアジアゾール−4−イル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−(4−ピリジルメチルチオ)−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔2.2.2〕オクタン; 3−(3−シクロプロピルメチルチオ1,2,5−チアジアゾール−4−イル) −1−アザビシクロ〔2.2.2〕オクタン; 3−(4−フルオロベンジルチオ−1,2,5−チアジアゾール−4−イル)− 1−アザビシクロ〔2.2.2〕オクタン; エキソ−6−(3−(4−フルオロベンジルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−クロロベンジルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−メチルベンジルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−トリフルオロメトキシベンジルチオ)−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−チオカルバミルベンジルチオ)−1,2,5−チアジ アゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4−メチルスルホニルベンジルチオ)−1,2,5−チア ジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(5,5,5−トリフルオロペンチルチオ)−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(3,3,3−トリフルオロプロピルチオ)−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4−トリフルオロメトキシベンジルチオ)−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4−メチルベンジルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4−フルオロベンジルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−(5R,6R)−6−(3−プロピルスルホニル−1,2,5 −チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−(5S,6S)−6−(3−プロピルスルホニル−1,2,5 −チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−(5R,6R)−6−(3−(4−シアノベンジルチオ)−1 ,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オク タン; (−)−エキソ−(5S,6S)−6−(3−(4−シアノベンジルチオ)−1 ,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オク タン; (−)−エンド−6−(3−プロピルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−(5R,6R)−6−(3−イソヘキシルチオ−1,2,5− チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−イソヘキシルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エンド−6−(3−イソヘキシルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エンド−(5S,6R)−6−(3−(4,4,4−トリフルオロブチ ルチオ)−1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3. 2.1〕オクタン; (+)−エンド−(5R,6S)−6−(3−(4,4,4−トリフルオロブチ ルチオ)−1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3. 2.1〕オクタン; (−)−エンド−(5S,6R)−6−(3−(4−シアノベンジルチオ)−1 ,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オク タン; (+)−エンド−(5R,6S)−6−(3−(4−シアノベンジルチオ)−1 ,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オク タン; (+)−エンド−6−(3−プロピルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−(3,3,3−トリフルオロプロピルチオ)−1, 2,5−チアジアゾール−4−イル)−1−アザビシ クロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−(3−(2−チエニル)プロピルチオ)−1,2, 5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−(4,4,4−トリフルオロブチルチオ)−1,2 ,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン ; (+)−エンド−6−(3−(3,3,3−トリフルオロプロピルチオ)−1, 2,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタ ン; エキソ−2−メチル−6−(3−クロロ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−2−メチル−6−(3−クロロ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−8−メチル−6−(3−クロロ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−8−メチル−6−(3−クロロ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−2−メチル−6−(3−プロピルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−8−メチル−6−(3−プロピルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−2−メチル−6−(3−プロピルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン: エキソ−8−メチル−6−(3−プロピルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−2−メチル−6−(3−ブチルチオ−1,2,5−チアジアゾール−4 −イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−8−メチル−6−(3−ブチルチオ−1,2,5−チアジアゾール−4 −イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−2−メチル−6−(3−ヘキシルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−8−メチル−6−(3−ヘキシルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; 5−(3−(4−シアノベンジルチオ)−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−3−(3−(4−シアノベンジルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔2.2.1〕ヘプタン; エンド−3−(3−(4−シアノベンジルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔2.2.1〕ヘプタン; エキソ−6−(3−シクロプロピルメチルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(2−(1,3−ジオキサラン−2−イル)− エチルチオ)−1,2,5−チアジアゾール−4−イル)−1−アザビシクロ〔 3.2.1〕オクタン; エキソ−6−(3−(4−メトキシベンジルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(2−メトキシエチルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(3−ヒドロキシプロピルチオ)−1,2,5−チアジアゾ ール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−(4,4,4−トリフルオロブチルチオ)−1,2,5−チ アジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−シクロプロピルメチルチオ−1,2,5−チアジアゾール− 4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4−メトキシベンジルチオ)−1,2,5−チアジアゾー ル−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(2−メトキシエチルチオ)−1,2,5−チアジアゾール −4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エンド−6−(3−(4−トリフルオロメチルベンジルチオ)−1,2,5−チ アジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; エキソ−6−(3−プロピルスルホニル−1,2,5−チアジアゾ ール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−メチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−エチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−ペンチルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−ヘキシルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−メチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−エチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−ペンチルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エキソ−6−(3−ヘキシルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エンド−6−(3−メチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エンド−6−(3−エチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エンド−6−(3−ペンチルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エンド−6−(3−ヘキシルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エンド−6−(3−メチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エンド−6−(3−エチルチオ−1,2,5−チアジアゾール−4−イ ル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エンド−6−(3−ペンチルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (−)−エンド−6−(3−ヘキシルチオ−1,2,5−チアジアゾール−4− イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−(4−トリフルオロメチルベンジルチオ)−1,2 ,5−チアジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン ; (+)−エキソ−6−(3−(4−ニトロベンジルチオ)−1,2,5−チアジ アゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン; (+)−エキソ−6−(3−(2−ヒドロキシメチルチオ)−1,2,5−チア ジアゾール−4−イル)−1−アザビシクロ〔3.2.1〕オクタン から選ばれる請求の範囲第1項記載の化合物又はその医薬として許容し得る塩。 3.請求の範囲第1項記載の化合物の製造方法であって、 a)次式II: (式中、Gは先に定義した意味を有し、 又はO−アルキルである) で表わされる化合物をS2Cl3と反応させ次式III: (式中、Gは先に定義した意味を有する) で表わされる化合物を得、引き続きClを適当な求核剤で置換して式I(式中、 XはSである)の化合物を得るか、 b)次式IV: (式中、Gは先に定義した意味でありそしてR7はアルキル、アミノ、ハロゲ ン、アルコキシ又はアルキルチオである) で表わされる化合物を脱水し、次式V: (式中、GおよびR7は先に定義した意味を有する) で表わされる化合物を形成するか、又は c)式V中のR7はアミノであるとき、アノミ基は公知方法によりクロロにより 置換でき、次いで引き続きClを適当な求核剤で置換して式I(式中、Xは0であ る)の化合物を得るか、又は d)次式VI: (式中、G,R4およびXは先に定義した意味を有する) で表わされる化合物を標準的手順により酸化し、次式VII: で表わされる化合物を形成し、次いで引き続き−SO2R4を適当な求核剤で置換 して式Iの化合物を形成することを含んでなる、前記方法。 4.請求の範囲第1項記載の化合物並びに医薬として許容し得る担体又は希釈 剤を含んでなる、医薬組成物。 5.経口用量単位又は非経口用量単位の形態にある、請求の範囲第4項記載の 医薬組成物。 6.前記用量単位が、約1mg〜約100mgの請求の範囲第1項記載の化合物を含 んでなる、請求の範囲第5項記載の医薬組成物。 7.前脳および海馬の認識機能を剌激する方法であって、それを必要とする被 験者に請求の範囲第1項記載の化合物の有効量を投与することを含んでなる、前 記方法。 8.アルツハイマー疾患の治療方法であって、それを必要とする被験者に請求 の範囲第1項記載の化合物の有効量を投与することを含んでなる、前記方法。 9.緑内障の治療方法であって、それを必要とする被験者に請求 の範囲第1項記載の化合物の有効量を投与することを含んでなる、前記方法。 10.鎮痛作用を付与する方法であって、それを必要とする被験者に請求の範囲 第1項記載の化合物の有効量を投与することを含んでなる、前記方法。 11.前脳および海馬の認識機能を刺激する方法であって、それを必要とする被 験者に請求の範囲第4項記載の医薬組成物の有効量を投与することを含んでなる 、前記方法。 12.アルツハイマー疾患の治療方法であって、それを必要とする被験者に請求 の範囲第4項記載の医薬組成物の有効量を投与することを含んでなる、前記方法 。 13.緑内障の治療方法であって、それを必要とする被験者に請求の範囲第4項 記載の医薬組成物の有効量を投与することを含んでなる、前記方法。 14.鎮痛作用を付与する方法であって、それを必要とする被験者に請求の範囲 第4項記載の医薬組成物の有効量を投与することを含んでなる、前記方法。 15.前脳および海馬の刺激のための医薬の製造のための請求の範囲第1項記載 の化合物の使用。 16.アルツハイマー疾患の治療のための医薬の製造のための請求の範囲第1項 記載の化合物の使用。 17.緑内障の治療のための医薬の製造のための請求の範囲第1項記載の化合物 の使用。 18.鎮痛作用を付与するための医薬の製造のための請求の範囲第1項記載の化 合物の使用。
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US08/026,943 US5418240A (en) | 1990-08-21 | 1993-03-05 | Heterocyclic compounds and their preparation and use |
PCT/DK1994/000092 WO1994020496A1 (en) | 1993-03-05 | 1994-03-04 | Heterocyclic compounds and their preparation and use |
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US (1) | US5418240A (ja) |
EP (1) | EP0687266B1 (ja) |
JP (1) | JP3411923B2 (ja) |
KR (1) | KR100344329B1 (ja) |
CN (1) | CN1046722C (ja) |
AT (1) | ATE173257T1 (ja) |
AU (1) | AU694415B2 (ja) |
CZ (1) | CZ290639B6 (ja) |
DE (1) | DE69414554T2 (ja) |
DK (1) | DK0687266T3 (ja) |
ES (1) | ES2126099T3 (ja) |
FI (1) | FI954130A (ja) |
HU (1) | HUT72443A (ja) |
IL (1) | IL108865A (ja) |
NO (1) | NO312676B1 (ja) |
NZ (1) | NZ262372A (ja) |
PH (1) | PH31394A (ja) |
SK (1) | SK281005B6 (ja) |
TW (1) | TW350846B (ja) |
WO (1) | WO1994020496A1 (ja) |
ZA (1) | ZA941542B (ja) |
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US5641791A (en) * | 1991-08-13 | 1997-06-24 | Novo Nordisk A.S | Heterocyclic compounds and their preparation and use |
MX9300875A (es) | 1992-02-20 | 1993-08-31 | Smithkline Beecham Plc | Procedimiento para la preparacion de compuestos azabiciclicos. |
US5663182A (en) * | 1993-08-19 | 1997-09-02 | Bymaster; Franklin Porter | Antipsychotic method |
US6281232B1 (en) | 1993-08-19 | 2001-08-28 | Novo Nordisk A/S | Method of treating gastrointestinal motility disorders |
US6265419B1 (en) * | 1993-12-21 | 2001-07-24 | Novo Nordisk A/S | Method of treating gastrointestinal motility disorders |
NZ336596A (en) * | 1993-08-19 | 2001-02-23 | Novo Nordisk As | Oxa or thia-diazole substituted azabicyclic ring compounds for treating schizophreniform diseases |
GB9409705D0 (en) * | 1994-05-14 | 1994-07-06 | Smithkline Beecham Plc | Novel compounds |
US5821370A (en) * | 1994-10-24 | 1998-10-13 | Eli Lilly And Company | Heterocyclic compounds and their preparation and use |
US5605908A (en) * | 1994-10-24 | 1997-02-25 | Eli Lilly And Company | Heterocyclic compounds and their use |
US5998404A (en) | 1994-10-24 | 1999-12-07 | Eli Lilly And Company | Heterocyclic compounds and their use |
US5726193A (en) * | 1994-10-31 | 1998-03-10 | Eli Lilly And Company | Method for treating anxiety |
US5488056A (en) * | 1994-10-31 | 1996-01-30 | Eli Lilly And Company | Method for treating anxiety |
US5612351A (en) * | 1994-11-08 | 1997-03-18 | Novo Nordisk A/S | Method of treating urinary bladder dysfunctions |
AU7125096A (en) * | 1995-09-22 | 1997-04-09 | Novo Nordisk A/S | Novel substituted azacyclic or azabicyclic compounds |
TR199800628T2 (xx) * | 1995-10-13 | 1998-07-21 | Neurosearch A/S | 8-Azabisiklo$3.2.1]okt-2-en t�revleri, bunlar�n haz�rlanmas� ve kullan�m�. |
AU1128297A (en) * | 1995-12-06 | 1997-06-27 | Eli Lilly And Company | Composition for treating pain |
WO1997020561A1 (en) * | 1995-12-07 | 1997-06-12 | Eli Lilly And Company | Composition for treating pain |
AU1093797A (en) * | 1996-01-04 | 1997-08-01 | Novo Nordisk A/S | A method of treating hypercholesterolemia and related disorders |
US5914338A (en) * | 1996-04-02 | 1999-06-22 | Novo Nordisk | Heterocyclic compounds and their preparation and use |
AU2991397A (en) * | 1996-04-23 | 1997-11-12 | Eli Lilly And Company | Heterocyclic compounds |
JP2000513712A (ja) * | 1996-04-24 | 2000-10-17 | ノボ ノルディスク アクティーゼルスカブ | 複素環化合物およびその調製およびその使用 |
US5733912A (en) * | 1997-02-19 | 1998-03-31 | Abbott Laboratories | 7A-heterocycle substituted hexahydro-1H-pyrrolizine compounds useful in controlling chemical synaptic transmission |
EP1009403A4 (en) * | 1997-04-11 | 2002-08-28 | Lilly Co Eli | METHOD FOR TREATING SCHIZOPHRENIA |
JP2002503224A (ja) * | 1997-04-11 | 2002-01-29 | エリ リリー アンド カンパニー | 疼痛を処置するための組成物 |
US6015813A (en) * | 1997-04-22 | 2000-01-18 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
AU6919398A (en) * | 1997-04-22 | 1998-11-13 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
CA2291157A1 (en) * | 1997-05-29 | 1998-12-03 | Eli Lilly And Company | Process for preparing heterocyclic compounds |
EP1098883A4 (en) * | 1997-05-29 | 2001-11-14 | Lilly Co Eli | USEFUL PROCESS FOR THE PREPARATION OF HETEROCYCLIC COMPOUNDS |
US6465467B1 (en) * | 1999-05-21 | 2002-10-15 | Biovitrum Ab | Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases |
AU8656101A (en) * | 2000-08-21 | 2002-03-04 | Univ Georgetown | 2-3-disubstituted quinuclidines as modulators of monoamine transporters and therapeutic and diagnostic methods based thereon |
EP2296471A4 (en) | 2008-05-15 | 2012-03-14 | Univ Toledo | MUSCARIC ACID AGONISTS AS COGNITIVE ENHANCERS |
WO2012149524A1 (en) | 2011-04-29 | 2012-11-01 | The University Of Toledo | Muscarinic agonists as enhancers of working memory and cognitive flexibility |
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NZ219646A (en) * | 1986-03-27 | 1990-10-26 | Merck Sharp & Dohme | Oxadiazole derivatives of azacyclics for treating cns disorders |
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GB8714789D0 (en) * | 1987-06-24 | 1987-07-29 | Lundbeck & Co As H | Heterocyclic compounds |
GB8717446D0 (en) * | 1987-07-23 | 1987-08-26 | Merck Sharp & Dohme | Chemical compounds |
NZ225999A (en) * | 1987-09-10 | 1992-04-28 | Merck Sharp & Dohme | Azacyclic- or azabicyclic-substituted thiadiazole derivatives and pharmaceutical compositions |
IE63906B1 (en) * | 1987-11-13 | 1995-06-14 | Novo Nordisk As | Azabicyclic compounds and their preparation and use |
EP0322182A3 (en) * | 1987-12-22 | 1992-01-02 | Beecham Group Plc | Azabicyclic compounds, process for their preparation and pharmaceutical compositions containing them |
NZ227841A (en) * | 1988-02-12 | 1991-08-27 | Merck Sharp & Dohme | Heterocyclic compounds with at least two non-condensed five membered rings and pharmaceutical compositions |
DK162892C (da) * | 1988-07-04 | 1992-05-11 | Novo Nordisk As | 1,2,5,6-tetrahydropyridinforbindelser, deres fremstilling og farmaceutiske praeparater indeholdende disse |
US5043345A (en) * | 1989-02-22 | 1991-08-27 | Novo Nordisk A/S | Piperidine compounds and their preparation and use |
EP0459568A3 (en) * | 1990-05-31 | 1992-09-30 | Merck Sharp & Dohme Ltd. | Substituted oxadiazoles and thiadiazoles for use in the treatment of glaucoma and novel compounds having such use |
DK198590D0 (da) * | 1990-08-21 | 1990-08-21 | Novo Nordisk As | Heterocykliske forbindelser, deres fremstilling og anvendelse |
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1993
- 1993-03-05 US US08/026,943 patent/US5418240A/en not_active Expired - Lifetime
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- 1994-03-04 AU AU62027/94A patent/AU694415B2/en not_active Ceased
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- 1994-03-04 DK DK94908990T patent/DK0687266T3/da active
- 1994-03-04 ZA ZA941542A patent/ZA941542B/xx unknown
- 1994-03-04 PH PH47880A patent/PH31394A/en unknown
- 1994-03-04 NZ NZ262372A patent/NZ262372A/en unknown
-
1995
- 1995-09-04 FI FI954130A patent/FI954130A/fi not_active Application Discontinuation
- 1995-09-05 NO NO19953491A patent/NO312676B1/no not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
SK110195A3 (en) | 1996-10-02 |
NO312676B1 (no) | 2002-06-17 |
NZ262372A (en) | 1997-07-27 |
EP0687266B1 (en) | 1998-11-11 |
JP3411923B2 (ja) | 2003-06-03 |
EP0687266A1 (en) | 1995-12-20 |
HUT72443A (en) | 1996-04-29 |
KR960701049A (ko) | 1996-02-24 |
AU6202794A (en) | 1994-09-26 |
HU9502588D0 (en) | 1995-11-28 |
FI954130A0 (fi) | 1995-09-04 |
CN1046722C (zh) | 1999-11-24 |
NO953491D0 (no) | 1995-09-05 |
IL108865A0 (en) | 1994-06-24 |
CZ225195A3 (en) | 1996-04-17 |
ATE173257T1 (de) | 1998-11-15 |
TW350846B (en) | 1999-01-21 |
DE69414554T2 (de) | 1999-06-17 |
IL108865A (en) | 2000-07-16 |
KR100344329B1 (ko) | 2002-11-30 |
SK281005B6 (sk) | 2000-10-09 |
US5418240A (en) | 1995-05-23 |
ES2126099T3 (es) | 1999-03-16 |
FI954130A (fi) | 1995-10-27 |
ZA941542B (en) | 1995-09-04 |
AU694415B2 (en) | 1998-07-23 |
WO1994020496A1 (en) | 1994-09-15 |
DK0687266T3 (da) | 1999-07-26 |
CZ290639B6 (cs) | 2002-09-11 |
PH31394A (en) | 1998-10-29 |
CN1121349A (zh) | 1996-04-24 |
NO953491L (no) | 1995-09-05 |
DE69414554D1 (de) | 1998-12-17 |
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