NO327817B1 - ``Benzodiazepin-derivater, deres fremstilling, medikament inneholdende slike samt anvendelse av disse for fremstilling av medikament for behandling av sykdom`` - Google Patents
``Benzodiazepin-derivater, deres fremstilling, medikament inneholdende slike samt anvendelse av disse for fremstilling av medikament for behandling av sykdom`` Download PDFInfo
- Publication number
- NO327817B1 NO327817B1 NO20021690A NO20021690A NO327817B1 NO 327817 B1 NO327817 B1 NO 327817B1 NO 20021690 A NO20021690 A NO 20021690A NO 20021690 A NO20021690 A NO 20021690A NO 327817 B1 NO327817 B1 NO 327817B1
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- mmol
- oxo
- butyl ester
- carbamic acid
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 42
- 239000003814 drug Substances 0.000 title claims description 13
- 229940079593 drug Drugs 0.000 title claims description 8
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title 1
- 238000000034 method Methods 0.000 claims description 545
- 150000001875 compounds Chemical class 0.000 claims description 114
- -1 hydroxyethoxy Chemical group 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 49
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- AZIZBYRGIGKTLW-UHFFFAOYSA-N 1,4-diazepin-2-one Chemical compound O=C1C=NC=CC=N1 AZIZBYRGIGKTLW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- FBPIGKDLQMIHLG-UHFFFAOYSA-N 4-(3-iodophenyl)-7-(2-methoxyethoxy)-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound COCCOC1=CC=2N=C(C=3C=C(I)C=CC=3)CC(=O)NC=2C=C1C#CC1=CC=CC=C1 FBPIGKDLQMIHLG-UHFFFAOYSA-N 0.000 claims description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical class C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- QDKZHQGXPVFLHU-UHFFFAOYSA-N 1,5-benzodiazepin-2-one Chemical compound O=C1C=CN=C2C=CC=CC2=N1 QDKZHQGXPVFLHU-UHFFFAOYSA-N 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- 208000025966 Neurological disease Diseases 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- OPTKWCKGENRFQA-UHFFFAOYSA-N methyl 2-[[4-(3-cyanophenyl)-2-oxo-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-7-yl]sulfanyl]acetate Chemical compound COC(=O)CSC1=CC=2N=C(C=3C=C(C=CC=3)C#N)CC(=O)NC=2C=C1C#CC1=CC=CC=C1 OPTKWCKGENRFQA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical class C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims description 3
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical class C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 3
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical class C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 claims description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical class C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 3
- RKIDXLGMZYYSAA-UHFFFAOYSA-N 2-[8-(2-fluorophenyl)-7-hydroxy-2-oxo-1,5-dihydro-1,5-benzodiazepin-4-yl]thiophene-3-carbonitrile Chemical compound OC1=CC=2NC(C3=C(C=CS3)C#N)=CC(=O)NC=2C=C1C1=CC=CC=C1F RKIDXLGMZYYSAA-UHFFFAOYSA-N 0.000 claims description 3
- UVPDZJUTLGSHOW-UHFFFAOYSA-N 3-(7-chloro-2-oxo-8-phenyl-1,3-dihydro-1,5-benzodiazepin-4-yl)benzonitrile Chemical compound ClC1=CC=2N=C(C=3C=C(C=CC=3)C#N)CC(=O)NC=2C=C1C1=CC=CC=C1 UVPDZJUTLGSHOW-UHFFFAOYSA-N 0.000 claims description 3
- QRRFEMJQTYRNMN-UHFFFAOYSA-N 3-[7-(4-methylpiperazin-1-yl)-2-oxo-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-4-yl]benzonitrile Chemical compound C1CN(C)CCN1C(C(=C1)C#CC=2C=CC=CC=2)=CC2=C1NC(=O)CC(C=1C=C(C=CC=1)C#N)=N2 QRRFEMJQTYRNMN-UHFFFAOYSA-N 0.000 claims description 3
- FGIWPVCRHZHHAO-UHFFFAOYSA-N 3-[7-(cyanomethyl)-2-oxo-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-4-yl]benzonitrile Chemical compound C1=C2NC(=O)CC(C=3C=C(C=CC=3)C#N)=NC2=CC(CC#N)=C1C#CC1=CC=CC=C1 FGIWPVCRHZHHAO-UHFFFAOYSA-N 0.000 claims description 3
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- JSFNPUJTYTWCLA-UHFFFAOYSA-N 3-[8-(2,5-difluorophenyl)-7-hydroxy-2-oxo-1,3-dihydro-1,5-benzodiazepin-4-yl]benzonitrile Chemical compound OC1=CC=2N=C(C=3C=C(C=CC=3)C#N)CC(=O)NC=2C=C1C1=CC(F)=CC=C1F JSFNPUJTYTWCLA-UHFFFAOYSA-N 0.000 claims description 3
- MTOSFHOAULLKRN-UHFFFAOYSA-N 4-[8-(2-fluorophenyl)-7-hydroxy-2-oxo-1,3-dihydro-1,5-benzodiazepin-4-yl]pyridine-2-carbonitrile Chemical compound OC1=CC=2N=C(C=3C=C(N=CC=3)C#N)CC(=O)NC=2C=C1C1=CC=CC=C1F MTOSFHOAULLKRN-UHFFFAOYSA-N 0.000 claims description 3
- DXDDOWBFRGJDFS-UHFFFAOYSA-N 4-[8-(2-fluorophenyl)-7-methoxy-2-oxo-1,3-dihydro-1,5-benzodiazepin-4-yl]pyridine-2-carbonitrile Chemical compound COC1=CC=2N=C(C=3C=C(N=CC=3)C#N)CC(=O)NC=2C=C1C1=CC=CC=C1F DXDDOWBFRGJDFS-UHFFFAOYSA-N 0.000 claims description 3
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- DFPPYGYDEAPNML-UHFFFAOYSA-N 5-[8-(2-fluorophenyl)-7-methoxy-2-oxo-1,3-dihydro-1,5-benzodiazepin-4-yl]thiophene-2-carbonitrile Chemical compound COC1=CC=2N=C(C=3SC(=CC=3)C#N)CC(=O)NC=2C=C1C1=CC=CC=C1F DFPPYGYDEAPNML-UHFFFAOYSA-N 0.000 claims description 3
- BAOSWBZMDZMRIY-UHFFFAOYSA-N 8-(2-fluorophenyl)-7-methoxy-4-[3-(2-methylimidazol-1-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound COC1=CC=2N=C(C=3C=C(C=CC=3)N3C(=NC=C3)C)CC(=O)NC=2C=C1C1=CC=CC=C1F BAOSWBZMDZMRIY-UHFFFAOYSA-N 0.000 claims description 3
- FFZSVPXVCARFFX-UHFFFAOYSA-N 8-(4-fluorophenyl)-7-[4-(2-hydroxyethoxy)piperidin-1-yl]-4-(3-imidazol-1-ylphenyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1CC(OCCO)CCN1C(C(=C1)C=2C=CC(F)=CC=2)=CC2=C1NC(=O)CC(C=1C=C(C=CC=1)N1C=NC=C1)=N2 FFZSVPXVCARFFX-UHFFFAOYSA-N 0.000 claims description 3
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- RFKFAFMEFPSHAN-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethynyl]-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound OC1=CC=2N=C(C=3C=C(C=CC=3)N3C=NC=C3)CC(=O)NC=2C=C1C#CC1=CC=C(F)C=C1 RFKFAFMEFPSHAN-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
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- HHKGHOHNMXZGJC-UHFFFAOYSA-N chembl404886 Chemical compound OC1=CC=2N=C(C=3C=C(C=CC=3)N3N=NC=C3)CC(=O)NC=2C=C1C#CC1=CC=C(F)C=C1 HHKGHOHNMXZGJC-UHFFFAOYSA-N 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical class C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
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- 206010027175 memory impairment Diseases 0.000 claims description 3
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- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
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- OBKSPYGKOAVWPB-UHFFFAOYSA-N 2-[4-(3-cyanophenyl)-2-oxo-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-7-yl]acetamide Chemical compound NC(=O)CC1=CC=2N=C(C=3C=C(C=CC=3)C#N)CC(=O)NC=2C=C1C#CC1=CC=CC=C1 OBKSPYGKOAVWPB-UHFFFAOYSA-N 0.000 claims description 2
- MIKJDYQBHVZYBY-UHFFFAOYSA-N 2-[[4-(3-imidazol-1-ylphenyl)-2-oxo-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-7-yl]oxy]acetonitrile Chemical compound C1=C2NC(=O)CC(C=3C=C(C=CC=3)N3C=NC=C3)=NC2=CC(OCC#N)=C1C#CC1=CC=CC=C1 MIKJDYQBHVZYBY-UHFFFAOYSA-N 0.000 claims description 2
- RMNNCRGKNMWAII-UHFFFAOYSA-N 4-(3-imidazol-1-ylphenyl)-7-(2-methoxyethoxy)-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound COCCOC1=CC=2N=C(C=3C=C(C=CC=3)N3C=NC=C3)CC(=O)NC=2C=C1C#CC1=CC=CC=C1 RMNNCRGKNMWAII-UHFFFAOYSA-N 0.000 claims description 2
- CHFZTXQHQRTDEM-UHFFFAOYSA-N 8-(2-fluorophenyl)-7-hydroxy-4-[3-(triazol-1-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound OC1=CC=2N=C(C=3C=C(C=CC=3)N3N=NC=C3)CC(=O)NC=2C=C1C1=CC=CC=C1F CHFZTXQHQRTDEM-UHFFFAOYSA-N 0.000 claims description 2
- JGIATRRZRPYCNH-UHFFFAOYSA-N 8-(4-fluorophenyl)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound OC1=CC=2N=C(C=3C=C(C=CC=3)N3C=NC=C3)CC(=O)NC=2C=C1C1=CC=C(F)C=C1 JGIATRRZRPYCNH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
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- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
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- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 229910004373 HOAc Inorganic materials 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 208000027089 Parkinsonian disease Diseases 0.000 description 4
- 206010034010 Parkinsonism Diseases 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 4
- OEQIEDAWGSZELP-UHFFFAOYSA-N [1-[4-[[3-(3-cyanophenyl)-3-oxopropanoyl]amino]-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-3-phenylprop-2-ynyl] 2,2-dimethylpropanoate Chemical compound CC(C)(C)OC(=O)NC1=CC(C(OC(=O)C(C)(C)C)C#CC=2C=CC=CC=2)=CC=C1NC(=O)CC(=O)C1=CC=CC(C#N)=C1 OEQIEDAWGSZELP-UHFFFAOYSA-N 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
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- 125000004432 carbon atom Chemical group C* 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
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- XBGDPLROEPFJDG-UHFFFAOYSA-N methyl 2-[2-iodo-5-[(2-methylpropan-2-yl)oxycarbonylamino]-4-nitrophenyl]sulfanylacetate Chemical compound COC(=O)CSC1=CC(NC(=O)OC(C)(C)C)=C([N+]([O-])=O)C=C1I XBGDPLROEPFJDG-UHFFFAOYSA-N 0.000 description 4
- VAZWRTOCBOACHN-UHFFFAOYSA-N methyl 2-[4-(3-cyanophenyl)-2-oxo-8-(2-phenylethynyl)-1,3-dihydro-1,5-benzodiazepin-7-yl]acetate Chemical compound COC(=O)CC1=CC=2N=C(C=3C=C(C=CC=3)C#N)CC(=O)NC=2C=C1C#CC1=CC=CC=C1 VAZWRTOCBOACHN-UHFFFAOYSA-N 0.000 description 4
- RAPFRRQKZXDDEJ-UHFFFAOYSA-N methyl 2-[4-[[3-(3-cyanophenyl)-3-oxopropanoyl]amino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]-2-(2-phenylethynyl)phenyl]acetate Chemical compound C1=C(C#CC=2C=CC=CC=2)C(CC(=O)OC)=CC(NC(=O)OC(C)(C)C)=C1NC(=O)CC(=O)C1=CC=CC(C#N)=C1 RAPFRRQKZXDDEJ-UHFFFAOYSA-N 0.000 description 4
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- XOHRGNCNWBXUHT-UHFFFAOYSA-N methyl 5-[(2-methylpropan-2-yl)oxycarbonylamino]-4-nitro-2-(2-phenylethynyl)benzoate Chemical compound COC(=O)C1=CC(NC(=O)OC(C)(C)C)=C([N+]([O-])=O)C=C1C#CC1=CC=CC=C1 XOHRGNCNWBXUHT-UHFFFAOYSA-N 0.000 description 4
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- 150000002828 nitro derivatives Chemical class 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- QVBPZZKELHNMDZ-UHFFFAOYSA-M potassium;3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoate Chemical compound [K+].CC(C)(C)OC(=O)CC([O-])=O QVBPZZKELHNMDZ-UHFFFAOYSA-M 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
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- IIBLRUHSCJFXSR-UHFFFAOYSA-N tert-butyl n-[2-[[3-(3-cyanothiophen-2-yl)-3-oxopropanoyl]amino]-4-(2-fluorophenyl)-5-[(2-methylpropan-2-yl)oxy]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(OC(C)(C)C)=C(C=2C(=CC=CC=2)F)C=C1NC(=O)CC(=O)C=1SC=CC=1C#N IIBLRUHSCJFXSR-UHFFFAOYSA-N 0.000 description 1
- SUEHEZJDLWZWSR-UHFFFAOYSA-N tert-butyl n-[2-[[3-(5-cyanothiophen-2-yl)-3-oxopropanoyl]amino]-4-(2-fluorophenyl)-5-[(2-methylpropan-2-yl)oxy]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(OC(C)(C)C)=C(C=2C(=CC=CC=2)F)C=C1NC(=O)CC(=O)C1=CC=C(C#N)S1 SUEHEZJDLWZWSR-UHFFFAOYSA-N 0.000 description 1
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- LHNJEKCZBAKCSX-UHFFFAOYSA-N tert-butyl n-[2-amino-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4-(2-fluorophenyl)phenyl]carbamate Chemical compound C=1C=CC=C(F)C=1C=1C=C(N)C(NC(=O)OC(C)(C)C)=CC=1N(CC1)CCC21OCCO2 LHNJEKCZBAKCSX-UHFFFAOYSA-N 0.000 description 1
- CHXZKWLMKXHUCI-UHFFFAOYSA-N tert-butyl n-[2-amino-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4-(4-fluorophenyl)phenyl]carbamate Chemical compound C=1C=C(F)C=CC=1C=1C=C(N)C(NC(=O)OC(C)(C)C)=CC=1N(CC1)CCC21OCCO2 CHXZKWLMKXHUCI-UHFFFAOYSA-N 0.000 description 1
- XGPYBZCXADCJBD-UHFFFAOYSA-N tert-butyl n-[2-nitro-4-(2-phenylethynyl)-5-thiomorpholin-4-ylphenyl]carbamate Chemical compound C=1C=CC=CC=1C#CC=1C=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC=1N1CCSCC1 XGPYBZCXADCJBD-UHFFFAOYSA-N 0.000 description 1
- IXQQTXASXPOKKL-UHFFFAOYSA-N tert-butyl n-[2-nitro-5-(oxan-2-yloxymethyl)-4-(2-phenylethynyl)phenyl]carbamate Chemical compound C=1C=CC=CC=1C#CC=1C=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC=1COC1CCCCO1 IXQQTXASXPOKKL-UHFFFAOYSA-N 0.000 description 1
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- IFEUVABEKCGLJC-UHFFFAOYSA-N tert-butyl n-[4-(4-fluorophenyl)-2-nitro-5-[4-(oxan-2-yloxy)piperidin-1-yl]phenyl]carbamate Chemical compound C=1C=C(F)C=CC=1C=1C=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC=1N(CC1)CCC1OC1CCCCO1 IFEUVABEKCGLJC-UHFFFAOYSA-N 0.000 description 1
- DPHHKVJOAWWWPW-UHFFFAOYSA-N tert-butyl n-[4-[2-(4-fluorophenyl)ethynyl]-2-nitro-5-(oxan-2-yloxymethyl)phenyl]carbamate Chemical compound C=1C=C(F)C=CC=1C#CC=1C=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC=1COC1CCCCO1 DPHHKVJOAWWWPW-UHFFFAOYSA-N 0.000 description 1
- IYDWJAYDJTVPIQ-UHFFFAOYSA-N tert-butyl n-[4-iodo-2-nitro-5-(2-oxo-1,3-oxazolidin-3-yl)phenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2C(OCC2)=O)=C1I IYDWJAYDJTVPIQ-UHFFFAOYSA-N 0.000 description 1
- WELAETIILLBYBH-YJJYDOSJSA-N tert-butyl n-[4-iodo-2-nitro-5-[(3r)-3-(oxan-2-yloxy)pyrrolidin-1-yl]phenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2C[C@@H](CC2)OC2OCCCC2)=C1I WELAETIILLBYBH-YJJYDOSJSA-N 0.000 description 1
- YPUHYOHHVAKLFI-UHFFFAOYSA-N tert-butyl n-[4-iodo-2-nitro-5-[4-(oxan-2-yloxy)piperidin-1-yl]phenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2CCC(CC2)OC2OCCCC2)=C1I YPUHYOHHVAKLFI-UHFFFAOYSA-N 0.000 description 1
- XESPICUIDDDAFA-UHFFFAOYSA-N tert-butyl n-[4-iodo-5-[methyl-[2-(oxan-2-yloxy)ethyl]amino]-2-nitrophenyl]carbamate Chemical compound C=1C(NC(=O)OC(C)(C)C)=C([N+]([O-])=O)C=C(I)C=1N(C)CCOC1CCCCO1 XESPICUIDDDAFA-UHFFFAOYSA-N 0.000 description 1
- XFZVNMMEAMYQAE-UHFFFAOYSA-N tert-butyl n-[5-(1,1-dioxo-1,4-thiazinan-4-yl)-4-iodo-2-nitrophenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2CCS(=O)(=O)CC2)=C1I XFZVNMMEAMYQAE-UHFFFAOYSA-N 0.000 description 1
- NAQNGEDYQDGLEN-UHFFFAOYSA-N tert-butyl n-[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4-(2-fluorophenyl)-2-nitrophenyl]carbamate Chemical compound C=1C=CC=C(F)C=1C=1C=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC=1N(CC1)CCC21OCCO2 NAQNGEDYQDGLEN-UHFFFAOYSA-N 0.000 description 1
- BVQPNXUZFDWHSU-UHFFFAOYSA-N tert-butyl n-[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4-(4-fluorophenyl)-2-nitrophenyl]carbamate Chemical compound C=1C=C(F)C=CC=1C=1C=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC=1N(CC1)CCC21OCCO2 BVQPNXUZFDWHSU-UHFFFAOYSA-N 0.000 description 1
- YASZPGYUCZHJSZ-UHFFFAOYSA-N tert-butyl n-[5-(2,3-dihydroxypropoxy)-4-iodo-2-nitrophenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(OCC(O)CO)=C(I)C=C1[N+]([O-])=O YASZPGYUCZHJSZ-UHFFFAOYSA-N 0.000 description 1
- JVBAPDRJZQDPBR-UHFFFAOYSA-N tert-butyl n-[5-(2,5-dihydropyrrol-1-yl)-4-iodo-2-nitrophenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2CC=CC2)=C1I JVBAPDRJZQDPBR-UHFFFAOYSA-N 0.000 description 1
- CGUYKIYUZWXELL-UHFFFAOYSA-N tert-butyl n-[5-(2-hydroxyethylamino)-4-iodo-2-nitrophenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(NCCO)=C(I)C=C1[N+]([O-])=O CGUYKIYUZWXELL-UHFFFAOYSA-N 0.000 description 1
- WHJOLISQLQBDTO-UHFFFAOYSA-N tert-butyl n-[5-(cyanomethoxy)-4-(4-fluorophenyl)-2-[[3-(3-imidazol-1-ylphenyl)-3-oxopropanoyl]amino]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(OCC#N)=C(C=2C=CC(F)=CC=2)C=C1NC(=O)CC(=O)C(C=1)=CC=CC=1N1C=CN=C1 WHJOLISQLQBDTO-UHFFFAOYSA-N 0.000 description 1
- UMMOLDKPRFIQKL-GASCZTMLSA-N tert-butyl n-[5-[(3ar,6as)-2,2-dimethyl-3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl]-4-iodo-2-nitrophenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2C[C@@H]3OC(C)(C)O[C@@H]3C2)=C1I UMMOLDKPRFIQKL-GASCZTMLSA-N 0.000 description 1
- AUOJEGKKAWFGNW-UHFFFAOYSA-N tert-butyl n-[5-[(dimethylamino)methyl]-4-(4-fluorophenyl)-2-[[3-(3-imidazol-1-ylphenyl)-3-oxopropanoyl]amino]phenyl]carbamate Chemical compound C1=C(C=2C=CC(F)=CC=2)C(CN(C)C)=CC(NC(=O)OC(C)(C)C)=C1NC(=O)CC(=O)C(C=1)=CC=CC=1N1C=CN=C1 AUOJEGKKAWFGNW-UHFFFAOYSA-N 0.000 description 1
- YRPQXMLUULQKPB-UHFFFAOYSA-N tert-butyl n-[5-[4-(2-hydroxyethoxy)piperidin-1-yl]-4-iodo-2-nitrophenyl]carbamate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=CC(N2CCC(CC2)OCCO)=C1I YRPQXMLUULQKPB-UHFFFAOYSA-N 0.000 description 1
- AARXCEBPINROGX-UHFFFAOYSA-N tert-butyl n-[5-chloro-4-(4-fluorophenyl)-2-[[3-(3-imidazol-1-ylphenyl)-3-oxopropanoyl]amino]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(Cl)=C(C=2C=CC(F)=CC=2)C=C1NC(=O)CC(=O)C(C=1)=CC=CC=1N1C=CN=C1 AARXCEBPINROGX-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
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Applications Claiming Priority (2)
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EP99120520 | 1999-10-15 | ||
PCT/EP2000/009553 WO2001029011A2 (en) | 1999-10-15 | 2000-09-29 | Benzodiazepine derivatives as metabotropic glutamate receptor antagonists |
Publications (3)
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NO20021690L NO20021690L (no) | 2002-04-10 |
NO20021690D0 NO20021690D0 (no) | 2002-04-10 |
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NO20021690A NO327817B1 (no) | 1999-10-15 | 2002-04-10 | ``Benzodiazepin-derivater, deres fremstilling, medikament inneholdende slike samt anvendelse av disse for fremstilling av medikament for behandling av sykdom`` |
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EP (1) | EP1224174B1 (xx) |
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CN (1) | CN1195522C (xx) |
AR (1) | AR026029A1 (xx) |
AT (1) | ATE250039T1 (xx) |
AU (1) | AU774451B2 (xx) |
BR (1) | BR0014859A (xx) |
CA (1) | CA2386974C (xx) |
CO (1) | CO5261604A1 (xx) |
CZ (1) | CZ20021653A3 (xx) |
DE (1) | DE60005386T2 (xx) |
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EG (1) | EG24079A (xx) |
ES (1) | ES2204704T3 (xx) |
GC (1) | GC0000263A (xx) |
HK (1) | HK1051038A1 (xx) |
HR (1) | HRP20020259A2 (xx) |
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IL (2) | IL148816A0 (xx) |
JO (1) | JO2262B1 (xx) |
MA (1) | MA26831A1 (xx) |
MY (1) | MY125540A (xx) |
NO (1) | NO327817B1 (xx) |
NZ (1) | NZ517999A (xx) |
PE (1) | PE20010681A1 (xx) |
PL (1) | PL357418A1 (xx) |
PT (1) | PT1224174E (xx) |
RU (1) | RU2259360C2 (xx) |
SI (1) | SI1224174T1 (xx) |
TR (1) | TR200201023T2 (xx) |
WO (1) | WO2001029011A2 (xx) |
YU (1) | YU26202A (xx) |
ZA (1) | ZA200202544B (xx) |
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CZ20033003A3 (cs) | 2001-04-12 | 2004-05-12 | F@Áhoffmann@Laárocheáag | Dihydrobenzo [b][�Ź@]diazepin@onové deriváty jako MGLUR@ antagonisty II |
US20030051728A1 (en) | 2001-06-05 | 2003-03-20 | Lloyd Peter M. | Method and device for delivering a physiologically active compound |
US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
US6949542B2 (en) | 2002-02-06 | 2005-09-27 | Hoffman-La Roche Inc. | Dihydro-benzo[b][1,4]diazepin-2-one derivatives |
US8354447B2 (en) * | 2002-09-10 | 2013-01-15 | The Scripps Research Institute | mGLU receptors antagonists for treating disorders associated with mGLU receptors including addiction and depression |
ATE510174T1 (de) | 2003-05-21 | 2011-06-15 | Alexza Pharmaceuticals Inc | Schlag gezündete unabhängige heizeinheit |
BRPI0412919A (pt) * | 2003-07-25 | 2006-09-26 | Hoffmann La Roche | combinação de antagonista de mglur2 e inibidor de ache para o tratamento de distúrbios neurológicos crÈnicos e/ou agudos |
FR2862969A1 (fr) | 2003-11-28 | 2005-06-03 | Oreal | Procede de preparation de derives paraphenylenediamine a groupement pyrrolidinyle, substitue par un radical azote, et composes intermediaires |
DE102004010893A1 (de) * | 2004-03-06 | 2005-09-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue ß-Ketoamid-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel |
US7459563B2 (en) | 2004-11-05 | 2008-12-02 | Hoffmann-La Roche Inc. | Process for the preparation of isonicotinic acid derivatives |
AP2007004047A0 (en) | 2005-01-20 | 2007-06-30 | Pfizer Ltd | Substituted triazole derivatives as oxtocin antagonists |
TWI417095B (zh) * | 2006-03-15 | 2013-12-01 | Janssen Pharmaceuticals Inc | 1,4-二取代之3-氰基-吡啶酮衍生物及其作為mGluR2-受體之正向異位性調節劑之用途 |
TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
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ES2594867T3 (es) | 2007-03-09 | 2016-12-23 | Alexza Pharmaceuticals, Inc. | Unidad de calentamiento para usar en un dispositivo de administración de fármaco |
EP2137167B1 (en) * | 2007-04-19 | 2011-08-10 | F. Hoffmann-La Roche AG | Dihydro-benzo[b][1,4]diazepin-2-one sulfonamide derivatives |
TW200927731A (en) * | 2007-09-14 | 2009-07-01 | Ortho Mcneil Janssen Pharm | 1,3-disubstituted-4-phenyl-1H-pyridin-2-ones |
EA019085B1 (ru) | 2007-09-14 | 2014-01-30 | Янссен Фармасьютикалз, Инк. | 1',3-двузамещенные 4-(арил-х-фенил)-1н-пиридин-2-оны |
US9114138B2 (en) | 2007-09-14 | 2015-08-25 | Janssen Pharmaceuticals, Inc. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones |
RU2488591C2 (ru) * | 2007-09-26 | 2013-07-27 | Маунт Синай Скул Оф Медсин | Аналоги азацитидина и их применение |
JP5433582B2 (ja) * | 2007-11-14 | 2014-03-05 | ジャンセン ファーマシューティカルズ, インコーポレイテッド. | イミダゾ[1,2−a]ピリジン誘導体およびmGluR2受容体の正のアロステリック調節因子としてのその使用 |
WO2010025890A1 (en) | 2008-09-02 | 2010-03-11 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
AU2009304293B2 (en) | 2008-10-16 | 2012-04-26 | Addex Pharma S.A. | Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors |
AU2009319387B2 (en) | 2008-11-28 | 2012-05-10 | Addex Pharma S.A. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
JP5634506B2 (ja) | 2009-05-12 | 2014-12-03 | ジャンセン ファーマシューティカルズ, インコーポレイテッド | 1,2,3−トリアゾロ[4,3−a]ピリジン誘導体ならびに神経障害および精神障害の治療または予防のためのその使用 |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
CA2760259C (en) | 2009-05-12 | 2018-05-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
CN101891706B (zh) * | 2010-04-09 | 2013-05-29 | 复旦大学 | 3,4-二氢苯并[f][1,4]噻氮杂*类化合物或其盐及其药物用途 |
EP2599775A4 (en) | 2010-07-29 | 2014-04-30 | Taisho Pharmaceutical Co Ltd | ETHINYLPYRAZOLDERIVAT |
JP5852665B2 (ja) | 2010-11-08 | 2016-02-03 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | 1,2,4−トリアゾロ[4,3−a]ピリジン誘導体およびmGluR2受容体のポジティブアロステリックモジュレーターとしてのそれらの使用 |
ES2552455T3 (es) | 2010-11-08 | 2015-11-30 | Janssen Pharmaceuticals, Inc. | Derivados de 1,2,4-triazolo[4,3-a]piridina y su uso como moduladores alostéricos positivos de receptores mGluR2 |
JP5852666B2 (ja) | 2010-11-08 | 2016-02-03 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | 1,2,4−トリアゾロ[4,3−a]ピリジン誘導体およびmGluR2受容体のポジティブアロステリックモジュレーターとしてのそれらの使用 |
JP2012153674A (ja) * | 2011-01-28 | 2012-08-16 | Astellas Pharma Inc | ジ(アリールアミノ)アリール化合物の製造方法及びその合成中間体 |
CN104736140A (zh) | 2012-10-23 | 2015-06-24 | 霍夫曼-拉罗奇有限公司 | 用于治疗自闭症的mGlu2/3拮抗剂 |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
LT3096790T (lt) | 2014-01-21 | 2019-10-10 | Janssen Pharmaceutica, N.V. | Deriniai, apimantys 2 potipio metabotropinio glutamaterginio receptoriaus teigiamus alosterinius moduliatorius arba ortosterinius agonistus, ir jų panaudojimas |
WO2015110435A1 (en) | 2014-01-21 | 2015-07-30 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
US9895324B2 (en) | 2014-03-26 | 2018-02-20 | University Of Kentucky Research Foundation | Halogenated diarylacetylenes and methods of treating cancer |
EP3134089A2 (en) | 2014-04-23 | 2017-03-01 | F. Hoffmann-La Roche AG | Mglu2/3 antagonists for the treatment of intellectual disabilities |
CA2950952C (en) | 2014-06-10 | 2023-01-10 | Sanford-Burnham Medical Research Institute | Metabotropic glutamate receptor negative allosteric modulators (nams) and uses thereof |
CN106243050B (zh) * | 2016-08-10 | 2019-09-06 | 安徽恒星制药有限公司 | 一种适合工业化生产氯巴占的方法 |
CN109836356B (zh) * | 2017-11-24 | 2022-03-08 | 沈阳化工研究院有限公司 | 一种芳甲醚衍生物及其应用 |
RU2702358C1 (ru) * | 2019-06-04 | 2019-10-08 | Федеральное государственное бюджетное научное учреждение Уфимский федеральный исследовательский центр Российской академии наук | Способ получения 2,2,4-триалкил-2,3-дигидро-1Н-1,5-бензодиазепинов |
CN114349779B (zh) * | 2021-12-29 | 2023-09-26 | 智仑超纯环氧树脂(西安)有限公司 | 一种改性二氧化硅颗粒除氯剂及其制备方法及应用 |
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JPH11509847A (ja) * | 1995-07-31 | 1999-08-31 | ノボ ノルディスク アクティーゼルスカブ | ヘテロ環式化合物、それらの調製及び使用 |
CN1158264C (zh) * | 1997-11-21 | 2004-07-21 | Nps药物有限公司 | 用于治疗中枢神经系统疾病的代谢性谷氨酸受体拮抗剂 |
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2003
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