NO313753B1 - Anti-konvulsive isokinolyl-benzamid-derivater, farmasöytiske preparater inneholdende dem, anvendelse av dem og fremgangsmåtefor fremstilling av dem - Google Patents
Anti-konvulsive isokinolyl-benzamid-derivater, farmasöytiske preparater inneholdende dem, anvendelse av dem og fremgangsmåtefor fremstilling av dem Download PDFInfo
- Publication number
- NO313753B1 NO313753B1 NO19994504A NO994504A NO313753B1 NO 313753 B1 NO313753 B1 NO 313753B1 NO 19994504 A NO19994504 A NO 19994504A NO 994504 A NO994504 A NO 994504A NO 313753 B1 NO313753 B1 NO 313753B1
- Authority
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- Norway
- Prior art keywords
- alkyl
- hydrogen
- disorders
- formula
- dimethyl
- Prior art date
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- 238000000034 method Methods 0.000 title description 36
- 230000002082 anti-convulsion Effects 0.000 title 1
- OMLUWEHKCFFWOP-UHFFFAOYSA-N n-isoquinolin-1-ylbenzamide Chemical class N=1C=CC2=CC=CC=C2C=1NC(=O)C1=CC=CC=C1 OMLUWEHKCFFWOP-UHFFFAOYSA-N 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- -1 (±) N-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy -2-methoxy-benzamide N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxy-benzamide Chemical compound 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 12
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 12
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 12
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- 230000000694 effects Effects 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
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- 230000002265 prevention Effects 0.000 claims description 7
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 6
- 208000030507 AIDS Diseases 0.000 claims description 6
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- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 6
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- 229940079593 drug Drugs 0.000 claims description 3
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- DOLKPFPCQQAQRD-UHFFFAOYSA-N 3-bromo-4-ethoxy-n-(2,4,4-trimethyl-1,3-dihydroisoquinolin-7-yl)benzamide Chemical compound C1=C(Br)C(OCC)=CC=C1C(=O)NC1=CC=C2C(C)(C)CN(C)CC2=C1 DOLKPFPCQQAQRD-UHFFFAOYSA-N 0.000 claims description 2
- UZOGCWQTUIIRKJ-UHFFFAOYSA-N 3-bromo-n-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-7-yl)-4-ethoxybenzamide Chemical compound C1=C(Br)C(OCC)=CC=C1C(=O)NC1=CC=C(CCN(C)C2C)C2=C1 UZOGCWQTUIIRKJ-UHFFFAOYSA-N 0.000 claims description 2
- AMTIQANOOBNZPV-UHFFFAOYSA-N 5-chloro-n-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-5-yl)-4-ethoxy-2-methoxybenzamide Chemical compound C1=C(Cl)C(OCC)=CC(OC)=C1C(=O)NC1=CC=CC2=C1CCN(C)C2C AMTIQANOOBNZPV-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- KLSVMERGLCFVBL-UHFFFAOYSA-N n-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-6-yl)benzamide Chemical compound C=1C=C2C(C)N(C)CCC2=CC=1NC(=O)C1=CC=CC=C1 KLSVMERGLCFVBL-UHFFFAOYSA-N 0.000 claims description 2
- XLJVEZLNTFVGIH-UHFFFAOYSA-N n-(1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide Chemical compound C=1C=C2C(C)NCCC2=CC=1NC(=O)C1=CC=CC=C1 XLJVEZLNTFVGIH-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 150000001557 benzodiazepines Chemical class 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 239000008186 active pharmaceutical agent Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 229940126062 Compound A Drugs 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
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- 229910002027 silica gel Inorganic materials 0.000 description 9
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 206010010904 Convulsion Diseases 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
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- 238000012360 testing method Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000001773 anti-convulsant effect Effects 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
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- 150000004795 grignard reagents Chemical class 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- PBKYPTQBAQQVPT-UHFFFAOYSA-N 4-methoxy-3-(trifluoromethyl)benzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1C(F)(F)F PBKYPTQBAQQVPT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
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- 206010043994 Tonic convulsion Diseases 0.000 description 3
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- 238000001035 drying Methods 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- OGHSMOUGIDUPFX-UHFFFAOYSA-N 1,2-dimethyl-3,4-dihydro-1h-isoquinolin-5-amine Chemical compound C1=CC=C2C(C)N(C)CCC2=C1N OGHSMOUGIDUPFX-UHFFFAOYSA-N 0.000 description 2
- VGWAQMUVFWPCLM-UHFFFAOYSA-M 1,2-dimethyl-3,4-dihydroisoquinolin-2-ium-7-amine;iodide Chemical compound [I-].C1=C(N)C=C2C(C)=[N+](C)CCC2=C1 VGWAQMUVFWPCLM-UHFFFAOYSA-M 0.000 description 2
- JBXUYMPSEDWNSW-UHFFFAOYSA-N 1-methyl-3,4-dihydroisoquinolin-7-amine Chemical compound C1=C(N)C=C2C(C)=NCCC2=C1 JBXUYMPSEDWNSW-UHFFFAOYSA-N 0.000 description 2
- JVXQHSHEHLIEPE-UHFFFAOYSA-N 2,4,4-trimethyl-7-nitroisoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC=C2C(C)(C)C(=O)N(C)C(=O)C2=C1 JVXQHSHEHLIEPE-UHFFFAOYSA-N 0.000 description 2
- GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 2
- NVCUKQLXOGOZPZ-UHFFFAOYSA-N 2-benzyl-1-methyl-1h-isoquinolin-5-amine Chemical compound C1=CC2=C(N)C=CC=C2C(C)N1CC1=CC=CC=C1 NVCUKQLXOGOZPZ-UHFFFAOYSA-N 0.000 description 2
- BANZVKGLDQDFDV-UHFFFAOYSA-N 2-propan-2-ylbenzoic acid Chemical compound CC(C)C1=CC=CC=C1C(O)=O BANZVKGLDQDFDV-UHFFFAOYSA-N 0.000 description 2
- ICDBZRYXNCPKRM-UHFFFAOYSA-N 3,4-dihydroisoquinolin-7-amine Chemical compound C1CN=CC2=CC(N)=CC=C21 ICDBZRYXNCPKRM-UHFFFAOYSA-N 0.000 description 2
- LQFMXKIGVFPAGJ-UHFFFAOYSA-N 3-bromo-4-ethoxybenzoyl chloride Chemical compound CCOC1=CC=C(C(Cl)=O)C=C1Br LQFMXKIGVFPAGJ-UHFFFAOYSA-N 0.000 description 2
- HXDRDQKKWREBNN-UHFFFAOYSA-N 3-bromo-4-ethylbenzoyl chloride Chemical compound CCC1=CC=C(C(Cl)=O)C=C1Br HXDRDQKKWREBNN-UHFFFAOYSA-N 0.000 description 2
- QPDMEVCCQAQDQE-UHFFFAOYSA-N 3-bromo-n-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-7-yl)-4-ethylbenzamide Chemical compound C1=C(Br)C(CC)=CC=C1C(=O)NC1=CC=C(CCN(C)C2C)C2=C1 QPDMEVCCQAQDQE-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- QHQFQDKUACTCCJ-UHFFFAOYSA-N 4-methoxy-3-(trifluoromethyl)-n-(2,4,4-trimethyl-1,3-dihydroisoquinolin-7-yl)benzamide Chemical compound C1=C(C(F)(F)F)C(OC)=CC=C1C(=O)NC1=CC=C2C(C)(C)CN(C)CC2=C1 QHQFQDKUACTCCJ-UHFFFAOYSA-N 0.000 description 2
- VNWUPESTVBTYJM-UHFFFAOYSA-N 4-methoxy-3-(trifluoromethyl)benzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1C(F)(F)F VNWUPESTVBTYJM-UHFFFAOYSA-N 0.000 description 2
- DTVYNUOOZIKEEX-UHFFFAOYSA-N 5-aminoisoquinoline Chemical compound N1=CC=C2C(N)=CC=CC2=C1 DTVYNUOOZIKEEX-UHFFFAOYSA-N 0.000 description 2
- WOPJFSQYDOHZMK-UHFFFAOYSA-N 5-bromo-2,4-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C=C1Br WOPJFSQYDOHZMK-UHFFFAOYSA-N 0.000 description 2
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- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- YZDXFUGIDTUCDA-UHFFFAOYSA-N isoquinoline-1-carboxamide Chemical class C1=CC=C2C(C(=O)N)=NC=CC2=C1 YZDXFUGIDTUCDA-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- ZSBIMTDWIGWJPW-UHFFFAOYSA-N methyl 3-chloro-4-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(O)C(Cl)=C1 ZSBIMTDWIGWJPW-UHFFFAOYSA-N 0.000 description 1
- VJROGSBBDLIEMZ-UHFFFAOYSA-N methyl 5-bromo-2,4-dimethoxybenzoate Chemical compound COC(=O)C1=CC(Br)=C(OC)C=C1OC VJROGSBBDLIEMZ-UHFFFAOYSA-N 0.000 description 1
- JQJJGBDRZOUEAL-UHFFFAOYSA-N methyl 5-cyano-2-methoxy-4-propan-2-ylbenzoate Chemical compound COC(=O)C1=CC(C#N)=C(C(C)C)C=C1OC JQJJGBDRZOUEAL-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- ZANGENJVDPXYQH-UHFFFAOYSA-N n-(1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide Chemical class N1CCC2=CC=CC=C2C1NC(=O)C1=CC=CC=C1 ZANGENJVDPXYQH-UHFFFAOYSA-N 0.000 description 1
- SNLMALWZNRCFBB-UHFFFAOYSA-N n-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-5-yl)-2-methoxy-4-methyl-5-(trifluoromethyl)benzamide Chemical compound COC1=CC(C)=C(C(F)(F)F)C=C1C(=O)NC1=CC=CC2=C1CCN(C)C2C SNLMALWZNRCFBB-UHFFFAOYSA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 230000000216 proconvulsive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008221 sterile excipient Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- KKXRPHONDRYDRT-UHFFFAOYSA-N tert-butyl 5-amino-1-methyl-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1=CC=C2C(C)N(C(=O)OC(C)(C)C)CCC2=C1N KKXRPHONDRYDRT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Addiction (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9705620.4A GB9705620D0 (en) | 1997-03-18 | 1997-03-18 | Novel compounds |
GBGB9726660.5A GB9726660D0 (en) | 1997-12-17 | 1997-12-17 | Novel compounds |
PCT/GB1998/000781 WO1998041507A1 (en) | 1997-03-18 | 1998-03-16 | Anti-convulsant isoquinolyl-benzamide derivatives |
Publications (3)
Publication Number | Publication Date |
---|---|
NO994504D0 NO994504D0 (no) | 1999-09-17 |
NO994504L NO994504L (no) | 1999-09-17 |
NO313753B1 true NO313753B1 (no) | 2002-11-25 |
Family
ID=26311216
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19994504A NO313753B1 (no) | 1997-03-18 | 1999-09-17 | Anti-konvulsive isokinolyl-benzamid-derivater, farmasöytiske preparater inneholdende dem, anvendelse av dem og fremgangsmåtefor fremstilling av dem |
Country Status (26)
Country | Link |
---|---|
US (1) | US6277861B1 (zh) |
EP (1) | EP0971897A1 (zh) |
JP (1) | JP2001516357A (zh) |
KR (1) | KR20000076343A (zh) |
CN (1) | CN1255917A (zh) |
AP (1) | AP9901635A0 (zh) |
AR (1) | AR012078A1 (zh) |
AU (1) | AU732162B2 (zh) |
BG (1) | BG103807A (zh) |
BR (1) | BR9809048A (zh) |
CA (1) | CA2283682A1 (zh) |
CO (1) | CO4950554A1 (zh) |
DZ (1) | DZ2446A1 (zh) |
EA (1) | EA199900836A1 (zh) |
ID (1) | ID22730A (zh) |
IL (1) | IL131958A0 (zh) |
MA (1) | MA24499A1 (zh) |
NO (1) | NO313753B1 (zh) |
NZ (1) | NZ337579A (zh) |
OA (1) | OA11390A (zh) |
PE (1) | PE62199A1 (zh) |
PL (1) | PL335675A1 (zh) |
SK (1) | SK126799A3 (zh) |
TR (1) | TR199902282T2 (zh) |
TW (1) | TW509679B (zh) |
WO (1) | WO1998041507A1 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001518468A (ja) * | 1997-09-30 | 2001-10-16 | モレキュラー デザインズ インターナショナル,インコーポレイテッド | β3アドレナリン受容体拮抗薬、拮抗薬合成物およびこれらの応用方法 |
GB9817424D0 (en) * | 1998-08-11 | 1998-10-07 | Smithkline Beecham Plc | Novel compounds |
GB9915589D0 (en) * | 1999-07-02 | 1999-09-01 | Smithkline Beecham Plc | Novel compounds |
US6593341B2 (en) | 2001-03-29 | 2003-07-15 | Molecular Design International, Inc. | β3-adrenoreceptor agonists, agonist compositions and methods of making and using the same |
US6596734B1 (en) | 2002-10-11 | 2003-07-22 | Molecular Design International, Inc. | Tetrahydroisoquinoline compounds for use as β3-adrenoreceptor agonists |
CN109608325A (zh) * | 2018-12-27 | 2019-04-12 | 先尼科化工(上海)有限公司 | 一种卤代苯甲酸衍生物的工业化合成方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4022900A (en) * | 1970-09-09 | 1977-05-10 | Marion Laboratories, Inc. | Compositions containing 1,2,3,4-tetrahydroisoquinolines used as hypotensive agents |
AU600992B2 (en) * | 1986-10-28 | 1990-08-30 | Smith Kline & French Laboratories Limited | Tetrahydroisoquinolin-2-yl derivatives of carboxylic acids |
GB8807922D0 (en) * | 1988-04-05 | 1988-05-05 | Fujisawa Pharmaceutical Co | Isoquinoline compound & process for preparation thereof |
US4883593A (en) * | 1988-10-27 | 1989-11-28 | Bend Research, Inc. | Ultrathin-skinned asymmetric membranes by immiscible solvents treatment |
GB9112721D0 (en) * | 1991-06-13 | 1991-07-31 | Smithkline Beecham Plc | Novel treatment |
TR199802745T2 (xx) * | 1996-06-17 | 1999-04-21 | Smithkline Beecham Plc | �kameli benzamid t�revleri ve bunlar�n ihtiya�lar� durdurucu veya engelleyici maddeler olarak kullan�lmas�. |
-
1998
- 1998-03-07 DZ DZ980056A patent/DZ2446A1/xx active
- 1998-03-16 EA EA199900836A patent/EA199900836A1/ru unknown
- 1998-03-16 NZ NZ337579A patent/NZ337579A/en unknown
- 1998-03-16 AR ARP980101173A patent/AR012078A1/es not_active Application Discontinuation
- 1998-03-16 EP EP98909646A patent/EP0971897A1/en not_active Withdrawn
- 1998-03-16 CA CA002283682A patent/CA2283682A1/en not_active Abandoned
- 1998-03-16 BR BR9809048-8A patent/BR9809048A/pt not_active IP Right Cessation
- 1998-03-16 SK SK1267-99A patent/SK126799A3/sk unknown
- 1998-03-16 CN CN98805128A patent/CN1255917A/zh active Pending
- 1998-03-16 CO CO98014463A patent/CO4950554A1/es unknown
- 1998-03-16 WO PCT/GB1998/000781 patent/WO1998041507A1/en not_active Application Discontinuation
- 1998-03-16 US US09/381,369 patent/US6277861B1/en not_active Expired - Fee Related
- 1998-03-16 MA MA25000A patent/MA24499A1/fr unknown
- 1998-03-16 AP APAP/P/1999/001635A patent/AP9901635A0/en unknown
- 1998-03-16 JP JP54024798A patent/JP2001516357A/ja not_active Withdrawn
- 1998-03-16 ID IDW991041D patent/ID22730A/id unknown
- 1998-03-16 IL IL13195898A patent/IL131958A0/xx unknown
- 1998-03-16 KR KR1019997008444A patent/KR20000076343A/ko not_active Application Discontinuation
- 1998-03-16 TR TR1999/02282T patent/TR199902282T2/xx unknown
- 1998-03-16 PL PL98335675A patent/PL335675A1/xx unknown
- 1998-03-16 AU AU64127/98A patent/AU732162B2/en not_active Ceased
- 1998-03-17 PE PE1998000190A patent/PE62199A1/es not_active Application Discontinuation
- 1998-03-20 TW TW087104134A patent/TW509679B/zh not_active IP Right Cessation
-
1999
- 1999-09-17 NO NO19994504A patent/NO313753B1/no not_active IP Right Cessation
- 1999-09-17 OA OA9900210A patent/OA11390A/en unknown
- 1999-10-13 BG BG103807A patent/BG103807A/bg unknown
Also Published As
Publication number | Publication date |
---|---|
CO4950554A1 (es) | 2000-09-01 |
NZ337579A (en) | 2001-04-27 |
WO1998041507A1 (en) | 1998-09-24 |
CA2283682A1 (en) | 1998-09-24 |
KR20000076343A (ko) | 2000-12-26 |
AU6412798A (en) | 1998-10-12 |
EP0971897A1 (en) | 2000-01-19 |
JP2001516357A (ja) | 2001-09-25 |
TW509679B (en) | 2002-11-11 |
CN1255917A (zh) | 2000-06-07 |
BR9809048A (pt) | 2000-08-01 |
PE62199A1 (es) | 1999-09-10 |
AR012078A1 (es) | 2000-09-27 |
US6277861B1 (en) | 2001-08-21 |
MA24499A1 (fr) | 1998-10-01 |
TR199902282T2 (en) | 2000-07-21 |
AU732162B2 (en) | 2001-04-12 |
DZ2446A1 (fr) | 2003-01-11 |
PL335675A1 (en) | 2000-05-08 |
OA11390A (en) | 2004-04-14 |
IL131958A0 (en) | 2001-03-19 |
NO994504D0 (no) | 1999-09-17 |
NO994504L (no) | 1999-09-17 |
BG103807A (bg) | 2001-05-31 |
AP9901635A0 (en) | 1999-09-30 |
SK126799A3 (en) | 2000-05-16 |
EA199900836A1 (ru) | 2000-04-24 |
ID22730A (id) | 1999-12-09 |
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Legal Events
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MM1K | Lapsed by not paying the annual fees |