BG103807A - Антиконвулсантни изохинолил-бензамидни производни - Google Patents

Антиконвулсантни изохинолил-бензамидни производни Download PDF

Info

Publication number: BG103807A
Authority: BG; Bulgaria
Prior art keywords: alkyl; hydrogen; cycloalkyl; disorders; phenyl
Prior art date: 1997-03-18

Application number

BG103807A

Other languages

Bulgarian (bg)

English (en)

Inventor

Dr. John HARLING

Dr. Barry ORLEK

Dr. Mervyn THOMPSON

Original Assignee

Smithkline Beecham P.L.C.

Priority date (The priority date 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 date listed.)

1997-03-18

Filing date

1999-10-13

Publication date

2001-05-31

1997-03-18 Priority claimed from GBGB9705620.4A external-priority patent/GB9705620D0/en

1997-12-17 Priority claimed from GBGB9726660.5A external-priority patent/GB9726660D0/en

1999-10-13 Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.

2001-05-31 Publication of BG103807A publication Critical patent/BG103807A/bg

Links

239000001961 anticonvulsive agent Substances 0.000 title claims description 12
230000001773 anti-convulsant effect Effects 0.000 title description 5
229960003965 antiepileptics Drugs 0.000 title description 4
MWXSOBRDESEPGR-UHFFFAOYSA-N 2-isoquinolin-1-ylbenzamide Chemical class NC(=O)C1=CC=CC=C1C1=NC=CC2=CC=CC=C12 MWXSOBRDESEPGR-UHFFFAOYSA-N 0.000 title 1
125000000217 alkyl group Chemical group 0.000 claims abstract description 123
150000001875 compounds Chemical class 0.000 claims abstract description 103
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 54
239000001257 hydrogen Substances 0.000 claims abstract description 53
-1 phenoxy, benzyloxy, benzoyl Chemical group 0.000 claims abstract description 53
150000002431 hydrogen Chemical group 0.000 claims abstract description 28
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 19
150000003839 salts Chemical class 0.000 claims abstract description 19
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
229910052736 halogen Inorganic materials 0.000 claims abstract description 15
150000002367 halogens Chemical class 0.000 claims abstract description 15
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
125000002837 carbocyclic group Chemical group 0.000 claims abstract description 10
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 9
229920006395 saturated elastomer Polymers 0.000 claims abstract description 9
125000001424 substituent group Chemical group 0.000 claims abstract description 8
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 4
238000000034 method Methods 0.000 claims description 41
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
208000035475 disorder Diseases 0.000 claims description 24
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
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125000003342 alkenyl group Chemical group 0.000 claims description 15
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SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 8
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125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 8
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125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
125000004122 cyclic group Chemical group 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 3
CKVJOFALHNRRTG-UHFFFAOYSA-N 3-cyano-4-propan-2-yl-n-(2,4,4-trimethyl-1,3-dihydroisoquinolin-7-yl)benzamide Chemical compound C1=C(C#N)C(C(C)C)=CC=C1C(=O)NC1=CC=C2C(C)(C)CN(C)CC2=C1 CKVJOFALHNRRTG-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
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
210000002161 motor neuron Anatomy 0.000 claims description 2
239000008194 pharmaceutical composition Substances 0.000 claims description 2
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230000036973 muscularity Effects 0.000 claims 2
235000020824 obesity Nutrition 0.000 claims 2
VLYHYDMUTKXEGI-UHFFFAOYSA-N 5-bromo-n-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-5-yl)-2,4-dimethoxybenzamide Chemical compound C1=C(Br)C(OC)=CC(OC)=C1C(=O)NC1=CC=CC2=C1CCN(C)C2C VLYHYDMUTKXEGI-UHFFFAOYSA-N 0.000 claims 1
PYPQVUDHJIZQQU-UHFFFAOYSA-N 5-chloro-4-ethoxy-2-methoxy-n-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide Chemical compound C1=C(Cl)C(OCC)=CC(OC)=C1C(=O)NC1=CC=CC2=C1CCNC2C PYPQVUDHJIZQQU-UHFFFAOYSA-N 0.000 claims 1
208000015943 Coeliac disease Diseases 0.000 claims 1
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210000005069 ears Anatomy 0.000 claims 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 claims 1
230000000069 prophylactic effect Effects 0.000 claims 1
238000000926 separation method Methods 0.000 claims 1
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 5
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
239000000203 mixture Substances 0.000 description 39
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
239000000243 solution Substances 0.000 description 31
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
239000008186 active pharmaceutical agent Substances 0.000 description 20
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 17
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
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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
239000007787 solid Substances 0.000 description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
239000002904 solvent Substances 0.000 description 13
229940126062 Compound A Drugs 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
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HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
230000004064 dysfunction Effects 0.000 description 8
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NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
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QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
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125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
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GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 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 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
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239000002253 acid Substances 0.000 description 4
229910052786 argon Inorganic materials 0.000 description 4
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239000006260 foam Substances 0.000 description 4
150000004795 grignard reagents Chemical class 0.000 description 4
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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
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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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 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
241000699670 Mus sp. Species 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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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
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ICDBZRYXNCPKRM-UHFFFAOYSA-N 3,4-dihydroisoquinolin-7-amine Chemical compound C1CN=CC2=CC(N)=CC=C21 ICDBZRYXNCPKRM-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
ZQVKTHRQIXSMGY-UHFFFAOYSA-N 4-Ethylbenzoic acid Chemical compound CCC1=CC=C(C(O)=O)C=C1 ZQVKTHRQIXSMGY-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
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239000003240 coconut oil Substances 0.000 description 1
235000019864 coconut oil Nutrition 0.000 description 1
230000009137 competitive binding Effects 0.000 description 1
238000009833 condensation Methods 0.000 description 1
230000005494 condensation Effects 0.000 description 1
235000009508 confectionery Nutrition 0.000 description 1
238000013270 controlled release Methods 0.000 description 1
LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
125000000753 cycloalkyl group Chemical group 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
230000006378 damage Effects 0.000 description 1
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000009826 distribution Methods 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
239000002662 enteric coated tablet Substances 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
ZJNFUIGOOWEZFL-UHFFFAOYSA-N ethyl 5-bromo-2-ethoxy-4-propan-2-ylbenzoate Chemical compound CCOC(=O)C1=CC(Br)=C(C(C)C)C=C1OCC ZJNFUIGOOWEZFL-UHFFFAOYSA-N 0.000 description 1
JQDAICQKFYESSH-UHFFFAOYSA-N ethyl 5-cyano-2-ethoxy-4-propan-2-ylbenzoate Chemical compound CCOC(=O)C1=CC(C#N)=C(C(C)C)C=C1OCC JQDAICQKFYESSH-UHFFFAOYSA-N 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
150000002194 fatty esters Chemical class 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000012467 final product Substances 0.000 description 1
235000019634 flavors Nutrition 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
239000000499 gel Substances 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
239000003365 glass fiber Substances 0.000 description 1
150000002314 glycerols Chemical class 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
150000003840 hydrochlorides Chemical class 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
239000003978 infusion fluid Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
239000010410 layer Substances 0.000 description 1
238000012417 linear regression Methods 0.000 description 1
239000003589 local anesthetic agent Substances 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
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
WAWAHRXONKLDPR-UHFFFAOYSA-N methyl 5-bromo-2-methoxy-4-propan-2-ylbenzoate Chemical compound COC(=O)C1=CC(Br)=C(C(C)C)C=C1OC WAWAHRXONKLDPR-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
229940095102 methyl benzoate Drugs 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
235000019426 modified starch Nutrition 0.000 description 1
230000036651 mood Effects 0.000 description 1
238000010172 mouse model Methods 0.000 description 1
238000007040 multi-step synthesis reaction Methods 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
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
RMHJJUOPOWPRBP-UHFFFAOYSA-N naphthalene-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CC=CC2=C1 RMHJJUOPOWPRBP-UHFFFAOYSA-N 0.000 description 1
238000006396 nitration reaction Methods 0.000 description 1
230000009871 nonspecific binding Effects 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
125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
239000000546 pharmaceutical excipient Substances 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
238000012545 processing Methods 0.000 description 1
230000000216 proconvulsive effect Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
229960003415 propylparaben Drugs 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
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
229940023144 sodium glycolate Drugs 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
239000012265 solid product Substances 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
239000000600 sorbitol Substances 0.000 description 1
235000010356 sorbitol Nutrition 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
235000011150 stannous chloride Nutrition 0.000 description 1
231100000736 substance abuse Toxicity 0.000 description 1
208000011117 substance-related disease Diseases 0.000 description 1
229910021653 sulphate ion Inorganic materials 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
210000001738 temporomandibular joint Anatomy 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
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 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
208000028500 tonic seizure Diseases 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
238000005303 weighing Methods 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)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pain & Pain Management (AREA)
Psychiatry (AREA)
Psychology (AREA)
Hospice & Palliative Care (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Addiction (AREA)
Anesthesiology (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)
Other In-Based Heterocyclic Compounds (AREA)

BG103807A 1997-03-18 1999-10-13 Антиконвулсантни изохинолил-бензамидни производни BG103807A (bg)

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 (1)

Publication Number	Publication Date
BG103807A true BG103807A (bg)	2001-05-31

Family

ID=26311216

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG103807A BG103807A (bg)	1997-03-18	1999-10-13	Антиконвулсантни изохинолил-бензамидни производни

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)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP1023269A4 (en) *	1997-09-30	2001-06-27	Molecular Design Int	BETA3-ADRENORECEPTOR AGONISTS, AGONIST COMPOSITIONS AND METHODS OF USE
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)

* Cited by examiner, † Cited by third party
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
HUP9902166A3 (en) *	1996-06-17	2001-01-29	Smithkline Beecham Plc	Substituted benzamide derivatives having anticonvulsant activity, preparation and use thereof, pharmaceutical compositions containing these compounds

1998
- 1998-03-07 DZ DZ980056A patent/DZ2446A1/xx active
- 1998-03-16 ID IDW991041D patent/ID22730A/id unknown
- 1998-03-16 US US09/381,369 patent/US6277861B1/en not_active Expired - Fee Related
- 1998-03-16 SK SK1267-99A patent/SK126799A3/sk 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 KR KR1019997008444A patent/KR20000076343A/ko not_active Ceased
- 1998-03-16 IL IL13195898A patent/IL131958A0/xx unknown
- 1998-03-16 CN CN98805128A patent/CN1255917A/zh active Pending
- 1998-03-16 CO CO98014463A patent/CO4950554A1/es unknown
- 1998-03-16 PL PL98335675A patent/PL335675A1/xx unknown
- 1998-03-16 BR BR9809048-8A patent/BR9809048A/pt not_active IP Right Cessation
- 1998-03-16 CA CA002283682A patent/CA2283682A1/en not_active Abandoned
- 1998-03-16 JP JP54024798A patent/JP2001516357A/ja not_active Withdrawn
- 1998-03-16 EA EA199900836A patent/EA199900836A1/ru unknown
- 1998-03-16 NZ NZ337579A patent/NZ337579A/en unknown
- 1998-03-16 AP APAP/P/1999/001635A patent/AP9901635A0/en unknown
- 1998-03-16 AU AU64127/98A patent/AU732162B2/en not_active Ceased
- 1998-03-16 TR TR1999/02282T patent/TR199902282T2/xx unknown
- 1998-03-16 MA MA25000A patent/MA24499A1/fr unknown
- 1998-03-16 WO PCT/GB1998/000781 patent/WO1998041507A1/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 OA OA9900210A patent/OA11390A/en unknown
- 1999-09-17 NO NO19994504A patent/NO313753B1/no not_active IP Right Cessation
- 1999-10-13 BG BG103807A patent/BG103807A/bg unknown

Also Published As

Publication number	Publication date
AR012078A1 (es)	2000-09-27
MA24499A1 (fr)	1998-10-01
IL131958A0 (en)	2001-03-19
AU6412798A (en)	1998-10-12
TR199902282T2 (en)	2000-07-21
US6277861B1 (en)	2001-08-21
EP0971897A1 (en)	2000-01-19
CO4950554A1 (es)	2000-09-01
JP2001516357A (ja)	2001-09-25
PL335675A1 (en)	2000-05-08
AU732162B2 (en)	2001-04-12
TW509679B (en)	2002-11-11
NO994504D0 (no)	1999-09-17
BR9809048A (pt)	2000-08-01
CN1255917A (zh)	2000-06-07
WO1998041507A1 (en)	1998-09-24
NO313753B1 (no)	2002-11-25
EA199900836A1 (ru)	2000-04-24
PE62199A1 (es)	1999-09-10
DZ2446A1 (fr)	2003-01-11
NO994504L (no)	1999-09-17
AP9901635A0 (en)	1999-09-30
ID22730A (id)	1999-12-09
OA11390A (en)	2004-04-14
NZ337579A (en)	2001-04-27
KR20000076343A (ko)	2000-12-26
SK126799A3 (en)	2000-05-16
CA2283682A1 (en)	1998-09-24

Publication	Publication Date	Title
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US6492378B1 (en)	2002-12-10	Substituted isoquinoline derivatives and their use as anticonvulsivants
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JP2001508402A (ja)	2001-06-26	置換ベンズアミド誘導体およびそれらの抗痙攣薬としての使用
KR20000016715A (ko)	2000-03-25	치환된 벤즈아미드 유도체 및 항경련제로서의그의 용도ㅔ
HUP0000964A2 (hu)	2000-09-28	Antikonvulzáns hatású izokinolil-benzamid-származékok, eljárás előállításukra és ezeket a vegyületeket tartalmazó gyógyszerkészítmények