JPH0127074B2 - - Google Patents
Info
- Publication number
- JPH0127074B2 JPH0127074B2 JP8788386A JP8788386A JPH0127074B2 JP H0127074 B2 JPH0127074 B2 JP H0127074B2 JP 8788386 A JP8788386 A JP 8788386A JP 8788386 A JP8788386 A JP 8788386A JP H0127074 B2 JPH0127074 B2 JP H0127074B2
- Authority
- JP
- Japan
- Prior art keywords
- compounds
- benzodiazepine
- compound
- methyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 208000015114 central nervous system disease Diseases 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000001961 anticonvulsive agent Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000002249 anxiolytic agent Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 230000001773 anti-convulsant effect Effects 0.000 claims description 4
- 229960003965 antiepileptics Drugs 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- AXDNGJPEZJTYAN-UHFFFAOYSA-N 1h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound N1=CC2=CC=CC=C2N2CN=CC2=C1 AXDNGJPEZJTYAN-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 78
- 238000000034 method Methods 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 19
- -1 benzodiazepine compound Chemical class 0.000 description 18
- 238000012360 testing method Methods 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 102000004300 GABA-A Receptors Human genes 0.000 description 10
- 108090000839 GABA-A Receptors Proteins 0.000 description 10
- 230000027455 binding Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229960005152 pentetrazol Drugs 0.000 description 7
- 208000019901 Anxiety disease Diseases 0.000 description 6
- 206010053398 Clonic convulsion Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000036506 anxiety Effects 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 206010043994 Tonic convulsion Diseases 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000000949 anxiolytic effect Effects 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 230000036461 convulsion Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000009870 specific binding Effects 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000004590 computer program Methods 0.000 description 3
- 230000002920 convulsive effect Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 2
- XHBHKHBUALFEOU-UHFFFAOYSA-N 4,5-dihydroimidazo[1,5-a][1,4]benzodiazepin-6-one Chemical class O=C1NCC2=CN=CN2C2=CC=CC=C12 XHBHKHBUALFEOU-UHFFFAOYSA-N 0.000 description 2
- FXAXGHCUXZNILI-UHFFFAOYSA-N 6-bromo-4-methyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound O=C1N(C)CC(=O)NC2=CC=CC(Br)=C21 FXAXGHCUXZNILI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- 102000005915 GABA Receptors Human genes 0.000 description 2
- 108010005551 GABA Receptors Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 238000011785 NMRI mouse Methods 0.000 description 2
- 206010034759 Petit mal epilepsy Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 229940005530 anxiolytics Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 125000003310 benzodiazepinyl group Chemical group N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 2
- 229960003120 clonazepam Drugs 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960002200 flunitrazepam Drugs 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000002555 ionophore Substances 0.000 description 2
- 230000000236 ionophoric effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 229940107390 pentasol Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000004129 prosencephalon Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- WZOHLCSHEMAGGA-UHFFFAOYSA-N 1-fluoro-3,1-benzoxazine-2,4-dione Chemical compound FN1C(OC(C2=C1C=CC=C2)=O)=O WZOHLCSHEMAGGA-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 1
- VWNMNXWYGRHGET-UHFFFAOYSA-N 2-[(2-amino-6-fluorobenzoyl)-methylamino]acetic acid Chemical compound OC(=O)CN(C)C(=O)C1=C(N)C=CC=C1F VWNMNXWYGRHGET-UHFFFAOYSA-N 0.000 description 1
- ZSJUKDUHDOMINL-UHFFFAOYSA-N 3-(1H-1,2-benzodiazepin-3-yl)-1,2,4-oxadiazole Chemical class C1=CC2=CC=CC=C2NN=C1C=1N=CON=1 ZSJUKDUHDOMINL-UHFFFAOYSA-N 0.000 description 1
- RDCYQWTZMRFSTQ-UHFFFAOYSA-N 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-methyl-6-oxo-2,4-dihydro-1H-imidazo[1,5-a][1,4]benzodiazepine-7-carbonitrile Chemical compound C(#N)C1=CC=CC2=C1C(N(CC=1N2CNC=1C1=NOC(=N1)C1CC1)C)=O RDCYQWTZMRFSTQ-UHFFFAOYSA-N 0.000 description 1
- QCARCLMQEYKUQZ-UHFFFAOYSA-N 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound N1=CN2C3=CC=CC(F)=C3C(=O)N(C)CC2=C1C(N=1)=NOC=1C1CC1 QCARCLMQEYKUQZ-UHFFFAOYSA-N 0.000 description 1
- SADOJDRAQISFAK-UHFFFAOYSA-N 4-(1H-1,2-benzodiazepin-3-yl)oxadiazole Chemical class C1=CC2=CC=CC=C2NN=C1C1=CON=N1 SADOJDRAQISFAK-UHFFFAOYSA-N 0.000 description 1
- OUVUFAZUKYKNCJ-UHFFFAOYSA-N 4-imidazo[4,5-i][1,2]benzodiazepin-3-yloxadiazole Chemical class N=1N=C2C3=NC=NC3=CC=C2C=CC=1C1=CON=N1 OUVUFAZUKYKNCJ-UHFFFAOYSA-N 0.000 description 1
- BAQNPAZPDWIUHZ-UHFFFAOYSA-N 4-methyl-2,5-dioxo-1,3-dihydro-1,4-benzodiazepine-6-carbonitrile Chemical compound O=C1N(C)CC(=O)NC2=CC=CC(C#N)=C21 BAQNPAZPDWIUHZ-UHFFFAOYSA-N 0.000 description 1
- ORTCZMNIUUYVHG-UHFFFAOYSA-N 7-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound N1=CN2C3=CC=CC(Cl)=C3C(=O)N(C)CC2=C1C(N=1)=NOC=1C1CC1 ORTCZMNIUUYVHG-UHFFFAOYSA-N 0.000 description 1
- ZAMMFLQIVBVQMQ-UHFFFAOYSA-N 7-chloro-5-methyl-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile Chemical compound O=C1N(C)CC2=C(C#N)N=CN2C2=CC=CC(Cl)=C21 ZAMMFLQIVBVQMQ-UHFFFAOYSA-N 0.000 description 1
- OMYWEBATCXKXLI-UHFFFAOYSA-N 7-chloro-n'-hydroxy-5-methyl-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboximidamide Chemical compound O=C1N(C)CC2=C(C(N)=NO)N=CN2C2=CC=CC(Cl)=C21 OMYWEBATCXKXLI-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- QRMYUTKQKNVCJP-UHFFFAOYSA-N C1=NC(=C2N1C1=C(C=NC2)C=CC=C1)C(N)=NO Chemical compound C1=NC(=C2N1C1=C(C=NC2)C=CC=C1)C(N)=NO QRMYUTKQKNVCJP-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- BEGOWLXWPNPRSK-UHFFFAOYSA-N O1N=NC(=C1)C1=NC=CC=2C3=CC=CC=C3NC12 Chemical class O1N=NC(=C1)C1=NC=CC=2C3=CC=CC=C3NC12 BEGOWLXWPNPRSK-UHFFFAOYSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical class ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- LDDOSDVZPSGLFZ-UHFFFAOYSA-N ethyl cyclopropanecarboxylate Chemical compound CCOC(=O)C1CC1 LDDOSDVZPSGLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 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
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- OYPIXUZKTODLAC-UHFFFAOYSA-N n-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]formamide Chemical compound O=CNCC1=NOC(C2CC2)=N1 OYPIXUZKTODLAC-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 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
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000012859 sterile filling Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- MLGCXEBRWGEOQX-UHFFFAOYSA-N tetradifon Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)C1=CC(Cl)=C(Cl)C=C1Cl MLGCXEBRWGEOQX-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK2204/85 | 1985-05-17 | ||
| DK220485A DK220485D0 (da) | 1985-05-17 | 1985-05-17 | Nye oxadiazolylimidazobenzodiazepinderivater samt fremgangsmaade tilfremstilling heraf |
| DK3659/85 | 1985-08-12 | ||
| DK4769/85 | 1985-10-17 | ||
| DK5994/85 | 1985-12-20 | ||
| US816732 | 1992-01-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61263979A JPS61263979A (ja) | 1986-11-21 |
| JPH0127074B2 true JPH0127074B2 (enrdf_load_stackoverflow) | 1989-05-26 |
Family
ID=8110769
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61076422A Granted JPS6293289A (ja) | 1985-05-17 | 1986-04-02 | オキサジアゾリルイミダゾベンゾジアゼピン及びその合成法，並びに抗けいれん及び抗不安剤 |
| JP8788386A Granted JPS61263979A (ja) | 1985-05-17 | 1986-04-16 | オキサジアゾリルイミダゾベンゾジアゼピン、並びに抗けいれん及び抗不安剤 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61076422A Granted JPS6293289A (ja) | 1985-05-17 | 1986-04-02 | オキサジアゾリルイミダゾベンゾジアゼピン及びその合成法，並びに抗けいれん及び抗不安剤 |
Country Status (3)
| Country | Link |
|---|---|
| JP (2) | JPS6293289A (enrdf_load_stackoverflow) |
| DK (1) | DK220485D0 (enrdf_load_stackoverflow) |
| ZA (2) | ZA863574B (enrdf_load_stackoverflow) |
-
1985
- 1985-05-17 DK DK220485A patent/DK220485D0/da unknown
-
1986
- 1986-04-02 JP JP61076422A patent/JPS6293289A/ja active Granted
- 1986-04-16 JP JP8788386A patent/JPS61263979A/ja active Granted
- 1986-05-14 ZA ZA863574A patent/ZA863574B/xx unknown
- 1986-05-14 ZA ZA863573A patent/ZA863573B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK220485D0 (da) | 1985-05-17 |
| JPS6293289A (ja) | 1987-04-28 |
| JPH0329795B2 (enrdf_load_stackoverflow) | 1991-04-25 |
| JPS61263979A (ja) | 1986-11-21 |
| ZA863574B (en) | 1987-01-28 |
| ZA863573B (en) | 1987-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0225013B1 (en) | Heterocyclic compounds and their preparation and use | |
| DK155524B (da) | Kondenserede imidazolderivater og farmaceutiske praeparater indeholdende disse | |
| US4772599A (en) | Benzodiazepine derivatives and their preparation and use | |
| US4771051A (en) | 3-substituted-4,5-dihydro-5-oxo imidazoquinazolines, their preparation, and their use in treating benzodiazepin receptor-related ailments | |
| JPH01190684A (ja) | イミダゾキノキサリン化合物、その製造方法および用途 | |
| EP0226282B1 (en) | Heterocyclic compounds and their preparation and use | |
| CA1256864A (en) | Oxadiazolylimidazobenzodiazepine, compositions, and method ii | |
| JPH0225486A (ja) | 新規イミダゾキノキサリン化合物、その製造方法並びにその使用 | |
| EP0202441B1 (en) | Oxadiazolylimidazobenzodiazepines, process for their preparation and pharmaceutical compositions | |
| JPH0127074B2 (enrdf_load_stackoverflow) | ||
| CA1256865A (en) | Oxadiazolylimidazobenzodiazepine, compositions, and method iii | |
| JP2662426B2 (ja) | ヘテロ環式化合物ならびにその製造方法および使用方法 |