CH619953A5 - Process for the preparation of diazepine derivatives - Google Patents
Process for the preparation of diazepine derivatives Download PDFInfo
- Publication number
- CH619953A5 CH619953A5 CH1141075A CH1141075A CH619953A5 CH 619953 A5 CH619953 A5 CH 619953A5 CH 1141075 A CH1141075 A CH 1141075A CH 1141075 A CH1141075 A CH 1141075A CH 619953 A5 CH619953 A5 CH 619953A5
- Authority
- CH
- Switzerland
- Prior art keywords
- phenyl
- hydrogen
- pyridyl
- lower alkyl
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 29
- 238000002360 preparation method Methods 0.000 title claims description 15
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 102
- -1 amino, amino Chemical group 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 39
- 239000002253 acid Substances 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- IMXWNWBXKWASOM-UHFFFAOYSA-N 3h-imidazo[1,5-a][1,4]diazepine Chemical class N1=CC=CN2CN=CC2=C1 IMXWNWBXKWASOM-UHFFFAOYSA-N 0.000 claims description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 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 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 14
- 229910052744 lithium Inorganic materials 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 411
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 169
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 155
- 239000000243 solution Substances 0.000 description 143
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- 238000002844 melting Methods 0.000 description 98
- 230000008018 melting Effects 0.000 description 98
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 70
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
- 239000000047 product Substances 0.000 description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 40
- 239000000706 filtrate Substances 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- 238000010992 reflux Methods 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 229940049706 benzodiazepine Drugs 0.000 description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 29
- 239000013078 crystal Substances 0.000 description 28
- 238000001914 filtration Methods 0.000 description 28
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 28
- 238000002425 crystallisation Methods 0.000 description 27
- 230000008025 crystallization Effects 0.000 description 27
- 239000000284 extract Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000012071 phase Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 229960000583 acetic acid Drugs 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- 229960004592 isopropanol Drugs 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- 239000007868 Raney catalyst Substances 0.000 description 18
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 18
- 229910000564 Raney nickel Inorganic materials 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 239000000538 analytical sample Substances 0.000 description 15
- 239000012362 glacial acetic acid Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
- 239000000908 ammonium hydroxide Substances 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- 230000008020 evaporation Effects 0.000 description 11
- 239000011976 maleic acid Substances 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 9
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229920000137 polyphosphoric acid Polymers 0.000 description 8
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 8
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 229910010272 inorganic material Inorganic materials 0.000 description 6
- 239000011147 inorganic material Substances 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 5
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- LSQOUBKWMBDIPL-UHFFFAOYSA-N [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-yl]methanamine Chemical compound C12=CC(Cl)=CC=C2NC(CN)CN=C1C1=CC=CC=C1F LSQOUBKWMBDIPL-UHFFFAOYSA-N 0.000 description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 4
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 125000004971 nitroalkyl group Chemical group 0.000 description 4
- 238000010899 nucleation Methods 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- XYGVIBXOJOOCFR-BTJKTKAUSA-N (z)-but-2-enedioic acid;8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F XYGVIBXOJOOCFR-BTJKTKAUSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- XTOQMDCHFVDCCL-UHFFFAOYSA-N 4-[chloro(morpholin-4-yl)phosphoryl]morpholine Chemical compound C1COCCN1P(=O)(Cl)N1CCOCC1 XTOQMDCHFVDCCL-UHFFFAOYSA-N 0.000 description 3
- GIDGIKTWONUSTH-UHFFFAOYSA-N 6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound C12=CC=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F GIDGIKTWONUSTH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 239000004157 Nitrosyl chloride Substances 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- KLNFAMGHSZQYHR-UHFFFAOYSA-N imidazo[4,5-i][1,2]benzodiazepine Chemical group C1=CC=NN=C2C3=NC=NC3=CC=C21 KLNFAMGHSZQYHR-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 3
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- VPCDQGACGWYTMC-UHFFFAOYSA-N nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 description 3
- 235000019392 nitrosyl chloride Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- WZESWJLHROPFLG-BTJKTKAUSA-N (z)-but-2-enedioic acid;8-chloro-6-(2-fluorophenyl)-1,4-dimethyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC(Cl)=CC=C2N2C(C)=NC=C2C(C)N=C1C1=CC=CC=C1F WZESWJLHROPFLG-BTJKTKAUSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- HBLKCUXIDJJFKB-UHFFFAOYSA-N 7-chloro-2-(nitromethylidene)-5-phenyl-1,3-dihydrothieno[2,3-e][1,4]diazepine Chemical compound C1=2C=C(Cl)SC=2NC(=C[N+](=O)[O-])CN=C1C1=CC=CC=C1 HBLKCUXIDJJFKB-UHFFFAOYSA-N 0.000 description 2
- SRJIQZQLBFVWGG-UHFFFAOYSA-N 8-chloro-1-methyl-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1 SRJIQZQLBFVWGG-UHFFFAOYSA-N 0.000 description 2
- OJENZBZGZBRYIL-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1,4-dimethyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2C(C)N=C1C1=CC=CC=C1F OJENZBZGZBRYIL-UHFFFAOYSA-N 0.000 description 2
- HSKSYECIYICPMM-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1,4-dimethyl-4h-imidazo[1,5-a][1,4]benzodiazepine;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2N2C(C)=NC=C2C(C)N=C1C1=CC=CC=C1F HSKSYECIYICPMM-UHFFFAOYSA-N 0.000 description 2
- FIDBLKWFRFIVLJ-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-5-oxido-4h-imidazo[1,5-a][1,4]benzodiazepin-5-ium Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2C[N+]([O-])=C1C1=CC=CC=C1F FIDBLKWFRFIVLJ-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PYRMWWVAHMGMNZ-SPIKMXEPSA-N OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.C1=2C=C(Cl)SC=2NC(CN)CN=C1C1=CC=CC=C1 Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.C1=2C=C(Cl)SC=2NC(CN)CN=C1C1=CC=CC=C1 PYRMWWVAHMGMNZ-SPIKMXEPSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000005059 halophenyl group Chemical group 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WAQXEXNGCAPWBE-UHFFFAOYSA-N n-(nitrosomethyl)-5-phenyl-3h-thieno[3,2-e][1,4]diazepin-2-amine Chemical compound N=1CC(NCN=O)=NC=2C=CSC=2C=1C1=CC=CC=C1 WAQXEXNGCAPWBE-UHFFFAOYSA-N 0.000 description 2
- WFNJKFVJCIEZMQ-UHFFFAOYSA-N n-[6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-8-yl]acetamide Chemical compound C=1C(NC(=O)C)=CC=C(N2C(C)=NC=C2CN=2)C=1C=2C1=CC=CC=C1F WFNJKFVJCIEZMQ-UHFFFAOYSA-N 0.000 description 2
- 238000007034 nitrosation reaction Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000004967 organic peroxy acids Chemical class 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- HAYNMBQGUNAMTP-UHFFFAOYSA-N (5-phenyl-2,3-dihydro-1h-1,4-benzodiazepin-2-yl)methanamine Chemical compound C12=CC=CC=C2NC(CN)CN=C1C1=CC=CC=C1 HAYNMBQGUNAMTP-UHFFFAOYSA-N 0.000 description 1
- OARIABLWKUVDRZ-SPIKMXEPSA-N (z)-but-2-enedioic acid;(5-phenyl-2,3-dihydro-1h-thieno[3,2-e][1,4]diazepin-2-yl)methanamine Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.C1=2SC=CC=2NC(CN)CN=C1C1=CC=CC=C1 OARIABLWKUVDRZ-SPIKMXEPSA-N 0.000 description 1
- RHBVCSZRPBSIJB-UHFFFAOYSA-N 1-(1-methyl-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepin-8-yl)ethanol;2,4,6-trinitrophenol Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O.C=1C(C(O)C)=CC=C(N2C(C)=NC=C2CN=2)C=1C=2C1=CC=CC=C1 RHBVCSZRPBSIJB-UHFFFAOYSA-N 0.000 description 1
- OZZJJBGOVXEKEH-UHFFFAOYSA-N 1-(1-methyl-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepin-8-yl)ethanone;2,4,6-trinitrophenol Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O.C=1C(C(=O)C)=CC=C(N2C(C)=NC=C2CN=2)C=1C=2C1=CC=CC=C1 OZZJJBGOVXEKEH-UHFFFAOYSA-N 0.000 description 1
- KXKXRTKCELUICN-UHFFFAOYSA-N 1-methyl-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound C12=CC=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1 KXKXRTKCELUICN-UHFFFAOYSA-N 0.000 description 1
- QJZCHYQIEWWPKD-UHFFFAOYSA-N 1-oxoguanidine Chemical compound NC(=N)N=O QJZCHYQIEWWPKD-UHFFFAOYSA-N 0.000 description 1
- ABUFEAKDTQPJQZ-UHFFFAOYSA-N 2,2-diethylbutane-1,1,1-triol Chemical compound CCC(CC)(CC)C(O)(O)O ABUFEAKDTQPJQZ-UHFFFAOYSA-N 0.000 description 1
- PFRDOBKXVZBAJN-UHFFFAOYSA-N 2-(aminomethyl)-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-7-amine Chemical compound C12=CC(N)=CC=C2NC(CN)CN=C1C1=CC=CC=C1F PFRDOBKXVZBAJN-UHFFFAOYSA-N 0.000 description 1
- NQRTTZCFYZVDLL-UHFFFAOYSA-N 2-(nitromethylidene)-5-phenyl-1,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC=CC=C2NC(=C[N+](=O)[O-])CN=C1C1=CC=CC=C1 NQRTTZCFYZVDLL-UHFFFAOYSA-N 0.000 description 1
- PIYJTLNGBTZSMD-UHFFFAOYSA-N 2-(nitromethylidene)-5-phenyl-1,3-dihydrothieno[3,2-e][1,4]diazepine Chemical compound C1=2SC=CC=2NC(=C[N+](=O)[O-])CN=C1C1=CC=CC=C1 PIYJTLNGBTZSMD-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- CRZJPEIBPQWDGJ-UHFFFAOYSA-N 2-chloro-1,1-dimethoxyethane Chemical compound COC(CCl)OC CRZJPEIBPQWDGJ-UHFFFAOYSA-N 0.000 description 1
- IBQRFBMPFFEAJO-UHFFFAOYSA-N 3-(chloromethyl)-4-(2-fluorophenyl)-6-nitro-3-oxido-2H-quinazolin-3-ium Chemical compound ClC[N+]1(CN=C2C=CC(=CC2=C1C1=C(C=CC=C1)F)[N+](=O)[O-])[O-] IBQRFBMPFFEAJO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- JTXPYKQMWMPOHY-UHFFFAOYSA-N 6-(2-fluorophenyl)-n,1-dimethyl-4h-imidazo[1,5-a][1,4]benzodiazepin-8-amine Chemical compound C=1C(NC)=CC=C(N2C(C)=NC=C2CN=2)C=1C=2C1=CC=CC=C1F JTXPYKQMWMPOHY-UHFFFAOYSA-N 0.000 description 1
- ZXHNAAHHWHGSDK-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepine-2-carboxamide Chemical compound C12=CC(Cl)=CC=C2NC(C(=O)N)CN=C1C1=CC=CC=C1F ZXHNAAHHWHGSDK-UHFFFAOYSA-N 0.000 description 1
- URZUOAKBDKORRD-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)-2-(nitromethylidene)-1,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2NC(=C[N+](=O)[O-])CN=C1C1=CC=CC=C1F URZUOAKBDKORRD-UHFFFAOYSA-N 0.000 description 1
- LSIVUTJGFANTKT-UHFFFAOYSA-N 7-chloro-5-phenyl-1,3-dihydrothieno[2,3-e][1,4]diazepin-2-one Chemical compound S1C(Cl)=CC2=C1NC(=O)CN=C2C1=CC=CC=C1 LSIVUTJGFANTKT-UHFFFAOYSA-N 0.000 description 1
- JORFEHUIBCMLTP-UHFFFAOYSA-N 7-chloro-6-(2-fluorophenyl)-3-methyl-2-(nitromethylidene)-1,3-dihydro-1,4-benzodiazepine Chemical compound ClC=1C=CC2=C(C=NC(C(N2)=C[N+](=O)[O-])C)C=1C1=C(C=CC=C1)F JORFEHUIBCMLTP-UHFFFAOYSA-N 0.000 description 1
- XVGCWVGAGPKKJK-UHFFFAOYSA-N 7-chloro-n-(nitrosomethyl)-5-phenyl-3h-thieno[2,3-e][1,4]diazepin-2-amine Chemical compound S1C(Cl)=CC2=C1N=C(NCN=O)CN=C2C1=CC=CC=C1 XVGCWVGAGPKKJK-UHFFFAOYSA-N 0.000 description 1
- PIJQREVPCOJDHG-UHFFFAOYSA-N 7-chloro-n-methyl-5-phenyl-3h-thieno[2,3-e][1,4]diazepin-2-amine Chemical compound N=1CC(NC)=NC=2SC(Cl)=CC=2C=1C1=CC=CC=C1 PIJQREVPCOJDHG-UHFFFAOYSA-N 0.000 description 1
- VYMRAMGKFRHSMP-UHFFFAOYSA-N 7-ethyl-5-(2-fluorophenyl)-2-(nitromethylidene)-1,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(CC)=CC=C2NC(=C[N+]([O-])=O)CN=C1C1=CC=CC=C1F VYMRAMGKFRHSMP-UHFFFAOYSA-N 0.000 description 1
- OMXRYYPDXHPHQN-UHFFFAOYSA-N 7h-thieno[2,3-e][1,4]diazepine Chemical compound C1=CN=CC2=CCSC2=N1 OMXRYYPDXHPHQN-UHFFFAOYSA-N 0.000 description 1
- LIUMNBVCHBTLKH-UHFFFAOYSA-N 7h-thieno[3,2-e][1,4]diazepine Chemical compound N1=CC=NC2=CCSC2=C1 LIUMNBVCHBTLKH-UHFFFAOYSA-N 0.000 description 1
- TVPGOECPODWLTA-UHFFFAOYSA-N 8-chloro-1-methyl-5-oxido-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepin-5-ium Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2C[N+]([O-])=C1C1=CC=CC=C1 TVPGOECPODWLTA-UHFFFAOYSA-N 0.000 description 1
- YBNYBXQPESOEJU-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1,3-dimethyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound CC=1N=C(C)N(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1F YBNYBXQPESOEJU-UHFFFAOYSA-N 0.000 description 1
- UUGUSEWJNOCDEF-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-3a,4-dihydro-3h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NCC2CN=C1C1=CC=CC=C1F UUGUSEWJNOCDEF-UHFFFAOYSA-N 0.000 description 1
- XRBCTHMVRDCXIT-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F XRBCTHMVRDCXIT-UHFFFAOYSA-N 0.000 description 1
- HMQYFIKOHHSETE-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-5,6-dihydro-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CNC1C1=CC=CC=C1F HMQYFIKOHHSETE-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- QDBJVRUXALFPFV-UHFFFAOYSA-N C12=CC(Cl)=CC=C2NC(=C[N+](=O)[O-])C[N+]([O-])=C1C1=CC=CC=C1 Chemical compound C12=CC(Cl)=CC=C2NC(=C[N+](=O)[O-])C[N+]([O-])=C1C1=CC=CC=C1 QDBJVRUXALFPFV-UHFFFAOYSA-N 0.000 description 1
- UDNPXOMHIWOQQE-UHFFFAOYSA-N C12=CC(Cl)=CC=C2NC(C(Cl)Cl)[N+]([O-])=C1C1=CC=CC=C1 Chemical compound C12=CC(Cl)=CC=C2NC(C(Cl)Cl)[N+]([O-])=C1C1=CC=CC=C1 UDNPXOMHIWOQQE-UHFFFAOYSA-N 0.000 description 1
- VTAPEAUNLIWZOA-UHFFFAOYSA-N C=C(C(NC1=C2SC=C1)[N+]([O-])=O)N=C2C1=CC=CC=C1 Chemical compound C=C(C(NC1=C2SC=C1)[N+]([O-])=O)N=C2C1=CC=CC=C1 VTAPEAUNLIWZOA-UHFFFAOYSA-N 0.000 description 1
- FFOAODKSWRZPES-UHFFFAOYSA-N CN=C1CN=CC2=C(N1)SC=C2 Chemical compound CN=C1CN=CC2=C(N1)SC=C2 FFOAODKSWRZPES-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- PLRDJNAMXQBJTF-UHFFFAOYSA-N FC1=C(C=CC=C1)C1=[N+](CC(NC2=C1C=C(C=C2)[N+](=O)[O-])=C[N+](=O)[O-])[O-] Chemical compound FC1=C(C=CC=C1)C1=[N+](CC(NC2=C1C=C(C=C2)[N+](=O)[O-])=C[N+](=O)[O-])[O-] PLRDJNAMXQBJTF-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- PIMIDQIMQDHAPB-BTJKTKAUSA-N OC(=O)\C=C/C(O)=O.N1C=CN=CC2=CC=CC=C12 Chemical compound OC(=O)\C=C/C(O)=O.N1C=CN=CC2=CC=CC=C12 PIMIDQIMQDHAPB-BTJKTKAUSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- IBDWEQVFNZSVFU-UHFFFAOYSA-N [1,3]oxazolo[3,2-d][1,4]benzodiazepine Chemical compound C1=CN=C2C=CC=CC2=C2OC=CN21 IBDWEQVFNZSVFU-UHFFFAOYSA-N 0.000 description 1
- IPBDWBAENLPMLD-UHFFFAOYSA-N [5-chloro-2-[5-(hydroxymethyl)-2-methylimidazol-1-yl]phenyl]-(2-fluorophenyl)methanone Chemical compound CC1=NC=C(CO)N1C1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1F IPBDWBAENLPMLD-UHFFFAOYSA-N 0.000 description 1
- ARDJDVFBZNLIAW-UHFFFAOYSA-N [7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-yl]methanamine Chemical compound C12=CC(Cl)=CC=C2NC(CN)CN=C1C1=CC=CC=C1Cl ARDJDVFBZNLIAW-UHFFFAOYSA-N 0.000 description 1
- DMSKNXCILMZZMN-UHFFFAOYSA-N [7-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-yl]methanamine Chemical compound C12=CC(CC)=CC=C2NC(CN)CN=C1C1=CC=CC=C1F DMSKNXCILMZZMN-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- CHCISLOJADQUNQ-UHFFFAOYSA-N climazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1Cl CHCISLOJADQUNQ-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical class N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 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
- 150000004820 halides Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- PLYSCVSCYOQVRP-UHFFFAOYSA-N midazolam hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F PLYSCVSCYOQVRP-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- KEFDQTADIHWZMS-UHFFFAOYSA-N n-[6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-8-yl]-n-methylacetamide Chemical compound C=1C(N(C(C)=O)C)=CC=C(N2C(C)=NC=C2CN=2)C=1C=2C1=CC=CC=C1F KEFDQTADIHWZMS-UHFFFAOYSA-N 0.000 description 1
- VXCCGNWORHEEDF-UHFFFAOYSA-N n-[7-chloro-5-(2-fluorophenyl)-3h-1,4-benzodiazepin-2-yl]-n-methylnitrous amide Chemical compound N=1CC(N(N=O)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F VXCCGNWORHEEDF-UHFFFAOYSA-N 0.000 description 1
- DONGQQPBNMVVLD-UHFFFAOYSA-N n-[[1-acetyl-7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1,4-benzodiazepin-2-yl]methyl]acetamide Chemical compound C12=CC(Cl)=CC=C2N(C(C)=O)C(CNC(=O)C)CN=C1C1=CC=CC=C1F DONGQQPBNMVVLD-UHFFFAOYSA-N 0.000 description 1
- XOHKQMLLOMJLJP-UHFFFAOYSA-N n-[[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-yl]methyl]acetamide Chemical compound C12=CC(Cl)=CC=C2NC(CNC(=O)C)CN=C1C1=CC=CC=C1F XOHKQMLLOMJLJP-UHFFFAOYSA-N 0.000 description 1
- KZIDPUBSPKGKDA-UHFFFAOYSA-N n-[[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-yl]methyl]propanamide Chemical compound C12=CC(Cl)=CC=C2NC(CNC(=O)CC)CN=C1C1=CC=CC=C1F KZIDPUBSPKGKDA-UHFFFAOYSA-N 0.000 description 1
- FCQMSIWSMKWRQL-UHFFFAOYSA-N n-methyl-5-phenyl-3h-1,4-benzodiazepin-2-amine Chemical compound N=1CC(NC)=NC2=CC=CC=C2C=1C1=CC=CC=C1 FCQMSIWSMKWRQL-UHFFFAOYSA-N 0.000 description 1
- HKPRLCIDOANWOI-UHFFFAOYSA-N n-methyl-5-phenyl-3h-thieno[3,2-e][1,4]diazepin-2-amine Chemical compound N=1CC(NC)=NC=2C=CSC=2C=1C1=CC=CC=C1 HKPRLCIDOANWOI-UHFFFAOYSA-N 0.000 description 1
- FAQUSGFYTCTEMJ-UHFFFAOYSA-N n-methyl-n-(5-phenyl-3h-1,4-benzodiazepin-2-yl)nitrous amide Chemical compound N=1CC(N(N=O)C)=NC2=CC=CC=C2C=1C1=CC=CC=C1 FAQUSGFYTCTEMJ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical group [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- CZPZWMPYEINMCF-UHFFFAOYSA-N propaneperoxoic acid Chemical compound CCC(=O)OO CZPZWMPYEINMCF-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurosurgery (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH9580A CH623325A5 (en) | 1974-09-11 | 1980-01-08 | Process for the preparation of diazepine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50492474A | 1974-09-11 | 1974-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH619953A5 true CH619953A5 (en) | 1980-10-31 |
Family
ID=24008278
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1141075A CH619953A5 (en) | 1974-09-11 | 1975-09-03 | Process for the preparation of diazepine derivatives |
| CH133781A CH628053A5 (en) | 1974-09-11 | 1981-02-27 | Process for the preparation of diazepine derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH133781A CH628053A5 (en) | 1974-09-11 | 1981-02-27 | Process for the preparation of diazepine derivatives |
Country Status (32)
| Country | Link |
|---|---|
| JP (1) | JPS51125099A (xx) |
| AT (1) | AT360023B (xx) |
| AU (1) | AU505998B2 (xx) |
| BE (1) | BE833248A (xx) |
| BR (1) | BR7505864A (xx) |
| CA (1) | CA1067491A (xx) |
| CH (2) | CH619953A5 (xx) |
| CU (1) | CU34346A (xx) |
| DD (1) | DD121640A5 (xx) |
| DE (1) | DE2540522A1 (xx) |
| DK (1) | DK157615C (xx) |
| ES (1) | ES440850A1 (xx) |
| FI (1) | FI63234C (xx) |
| FR (2) | FR2285890A1 (xx) |
| GB (1) | GB1527131A (xx) |
| HK (1) | HK63381A (xx) |
| HU (1) | HU174752B (xx) |
| IE (1) | IE41844B1 (xx) |
| IL (1) | IL48069A (xx) |
| KE (1) | KE3173A (xx) |
| LU (1) | LU73356A1 (xx) |
| MX (1) | MX160600A (xx) |
| MY (1) | MY8200214A (xx) |
| NL (1) | NL171060C (xx) |
| NO (4) | NO147109C (xx) |
| NZ (1) | NZ178635A (xx) |
| PH (2) | PH16152A (xx) |
| PL (1) | PL106563B1 (xx) |
| SE (4) | SE425785B (xx) |
| SU (1) | SU814278A3 (xx) |
| YU (1) | YU40267B (xx) |
| ZA (1) | ZA755418B (xx) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4125726A (en) * | 1977-03-11 | 1978-11-14 | Hoffmann-La Roche Inc. | Imidazo[1,5-a][1,4]benzodiazepines |
| US4118386A (en) * | 1977-04-04 | 1978-10-03 | Hoffmann-La Roche Inc. | Synthesis of imidazo[1,5-a]diazepine-3-carboxylates |
| US4226768A (en) * | 1979-05-29 | 1980-10-07 | Hoffmann-La Roche Inc. | Process for the preparation of imidazobenzodiazepines |
| US4226771A (en) * | 1979-07-25 | 1980-10-07 | Hoffmann-La Roche Inc. | 1,2,5-Oxadiazino[5,4-a][1,4]benzodiazepine derivatives |
| US4256637A (en) * | 1979-12-20 | 1981-03-17 | Hoffmann-La Roche Inc. | Intermediates for the production of imidazobenzodiazepines |
| FR2479818A1 (en) * | 1980-04-03 | 1981-10-09 | Roussel Uclaf | 2-Substd. phenyl 7-nitro 3H 1,4-benzodiazepinyl aminoacid derivs. - are anxiolytics, tranquillisers, sedatives and anticonvulsants, prepd. by reacting aminoacid or peptide with benzodiazepin-2-thione |
| US4335042A (en) * | 1980-04-21 | 1982-06-15 | Hoffmann-La Roche Inc. | Process to produce imidazobenzodiazepine intermediates |
| DE3329515C2 (de) * | 1983-08-16 | 1985-11-14 | Krohne Meßtechnik GmbH & Co KG, 4100 Duisburg | Elektrische Schaltanordnung für einen magnetisch-induktiven Meßwertgeber |
| ZA845757B (en) * | 1983-08-25 | 1985-04-24 | Hoffmann La Roche | Benzodiazepine derivatives |
| PH30676A (en) * | 1986-07-22 | 1997-09-16 | Boehringer Ingelhein Kg | Hetrazepine compounds which have useful pharmaceutical utility |
| FI880814A (fi) * | 1987-03-10 | 1988-09-11 | Hoffmann La Roche | Imidazodiazepin-derivat. |
| AU6909194A (en) * | 1993-05-14 | 1994-12-12 | Board Of Regents, The University Of Texas System | Preparation of n-cyanodithioimino-carbonates and 3-mercapto-5-amino-1h-1,2,4-triazole |
| IN184976B (xx) * | 1996-06-13 | 2000-10-14 | Ranbaxy Lab Ltd | |
| IT1399764B1 (it) * | 2010-05-04 | 2013-05-03 | F S I Fabbrica Italiana Sint | Procedimento per la sintesi di 4h-imidazo [1,5-a][1,4]benzodiazepine, in particolare di midazolam. |
| CN103086986B (zh) * | 2011-11-01 | 2015-11-04 | 上海医药工业研究院 | 1,4-苯二氮卓-n-亚硝胺类中间体的制备方法及其应用 |
| CN103804384B (zh) * | 2014-01-27 | 2016-01-20 | 李宏 | 苯并二氮杂卓类化合物的制备方法 |
| DK3439665T3 (da) * | 2016-03-18 | 2022-09-26 | Uwm Res Foundation Inc | Behandling af kognitive og sindsstemningssymptomer ved neurodegenerative og neuropsykiatriske lidelser med alpha5-holdige gabaa-receptoragonister |
| CN109790170B (zh) | 2016-08-16 | 2022-08-02 | Uwm研究基金会有限公司 | Gaba(a)受体调节剂和控制哮喘中气道高反应性和炎症的方法 |
| CN111410658B (zh) * | 2020-03-30 | 2021-03-26 | 江苏恩华药业股份有限公司 | 咪达唑仑或其药物组合物的杂质a和杂质b及其用途 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA721060B (en) * | 1970-10-30 | 1972-11-29 | Takeda Chemical Industries Ltd | Benzodiazepine derivatives |
| DE2056265A1 (en) * | 1970-11-16 | 1972-05-31 | Sumitomo Chemical Co. Ltd., Osaka (Japan) | Benzodiazepine derivs - from glycylamidobenzophenone derivs in dmso |
| JPS4932874B1 (xx) * | 1970-12-11 | 1974-09-03 | ||
| BE787251A (fr) * | 1971-08-04 | 1973-02-05 | Upjohn Co | Nouvelles benzodiazepines et leur preparation |
| BE790839A (fr) * | 1971-11-02 | 1973-04-30 | Upjohn Co | Nouvelles benzodiazepines, leur procede de preparation et medicament les contenant |
| BE792972A (fr) * | 1971-12-20 | 1973-06-19 | Hoffmann La Roche | Derives de benzodiazepine |
| FR2183716A1 (en) * | 1972-05-05 | 1973-12-21 | Centre Etd Ind Pharma | Substd-6-phenyl-4h-imidazo (1,2-a)-1,4-benzo diazepines - - tranquillisers anxiolytics,sedatives and muscle-relaxants |
| CA1005443A (en) * | 1972-06-22 | 1977-02-15 | Michio Nakanishi | Thienodiazepine compounds |
-
1975
- 1975-08-25 ZA ZA755418A patent/ZA755418B/xx unknown
- 1975-09-03 CH CH1141075A patent/CH619953A5/de not_active IP Right Cessation
- 1975-09-08 FI FI752517A patent/FI63234C/fi not_active IP Right Cessation
- 1975-09-08 SE SE7509991A patent/SE425785B/xx active Protection Beyond IP Right Term
- 1975-09-08 NO NO753069A patent/NO147109C/no unknown
- 1975-09-09 FR FR7527599A patent/FR2285890A1/fr active Granted
- 1975-09-09 LU LU73356A patent/LU73356A1/xx unknown
- 1975-09-09 NZ NZ178635A patent/NZ178635A/xx unknown
- 1975-09-09 MX MX201652A patent/MX160600A/es unknown
- 1975-09-09 IL IL48069A patent/IL48069A/xx unknown
- 1975-09-09 NL NLAANVRAGE7510620,A patent/NL171060C/xx not_active IP Right Cessation
- 1975-09-10 JP JP50109060A patent/JPS51125099A/ja active Granted
- 1975-09-10 BE BE159891A patent/BE833248A/xx not_active IP Right Cessation
- 1975-09-10 GB GB37252/75A patent/GB1527131A/en not_active Expired
- 1975-09-10 DD DD188275A patent/DD121640A5/xx unknown
- 1975-09-10 SU SU752170852A patent/SU814278A3/ru active
- 1975-09-10 AU AU84704/75A patent/AU505998B2/en not_active Expired
- 1975-09-10 YU YU2285/75A patent/YU40267B/xx unknown
- 1975-09-10 AT AT697775A patent/AT360023B/de not_active IP Right Cessation
- 1975-09-10 ES ES440850A patent/ES440850A1/es not_active Expired
- 1975-09-10 CA CA235,138A patent/CA1067491A/en not_active Expired
- 1975-09-10 PL PL1975204027A patent/PL106563B1/pl unknown
- 1975-09-10 DK DK404175A patent/DK157615C/da not_active IP Right Cessation
- 1975-09-10 PH PH17566A patent/PH16152A/en unknown
- 1975-09-10 HU HU75HO1835A patent/HU174752B/hu unknown
- 1975-09-11 CU CU34346A patent/CU34346A/es unknown
- 1975-09-11 IE IE1973/75A patent/IE41844B1/en unknown
- 1975-09-11 DE DE19752540522 patent/DE2540522A1/de active Granted
- 1975-09-11 BR BR7505864*A patent/BR7505864A/pt unknown
-
1976
- 1976-06-10 FR FR7617552A patent/FR2303016A1/fr active Granted
-
1979
- 1979-03-23 SE SE7902667A patent/SE433080B/sv not_active IP Right Cessation
- 1979-03-23 SE SE7902666A patent/SE440504B/sv not_active IP Right Cessation
- 1979-03-23 SE SE7902668A patent/SE449098B/sv not_active IP Right Cessation
- 1979-05-24 PH PH22557A patent/PH15091A/en unknown
-
1980
- 1980-09-12 NO NO802718A patent/NO146573C/no unknown
- 1980-09-12 NO NO802719A patent/NO147914C/no unknown
- 1980-09-12 NO NO802720A patent/NO148188C/no unknown
-
1981
- 1981-02-27 CH CH133781A patent/CH628053A5/de not_active IP Right Cessation
- 1981-11-24 KE KE3173A patent/KE3173A/xx unknown
- 1981-12-17 HK HK633/81A patent/HK63381A/xx unknown
-
1982
- 1982-12-30 MY MY214/82A patent/MY8200214A/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0150040B1 (de) | Imidazodiazepin-Derivate | |
| EP0801651B1 (de) | Hydroxymethyl-imidazodiazepine und deren ester | |
| CH619953A5 (en) | Process for the preparation of diazepine derivatives | |
| EP0672666B1 (de) | Imidazodiazepine | |
| DE2609486C2 (xx) | ||
| US3910946A (en) | 4H-Imidazo{8 1,2-a{9 {8 1,4{9 benzodiazepines | |
| EP0285837B1 (de) | Imidazodiazepin-Derivate | |
| US4587245A (en) | Method of treating neuropsychic disturbances by benzodiazepine derivatives and composition therefor | |
| DE3020267C2 (xx) | ||
| EP0072029B1 (de) | Triazolobenzazepine, Verfahren und Zwischenprodukte zu deren Herstellung und diese enthaltende Arzneimittel | |
| DE2220694A1 (de) | 1-substituierte 6-Phenyl-4 H-s-triazolo [4,3-a][1,4]-benzodiazepine und Verfahren zur Herstellung desselben | |
| US4377523A (en) | Imidazodiazepines and processes therefor | |
| CH623325A5 (en) | Process for the preparation of diazepine derivatives | |
| AT395152B (de) | Verfahren zur herstellung von neuen imidazo (1,5-a)(1,4)diazepinverbindungen | |
| AT378960B (de) | Verfahren zur herstelllung von neuen imidazo (1,5-a) (1,4)diazepinverbindungen, ihren salzen und optisch aktiven formen | |
| FI66384C (fi) | Vid framstaellning av terapeutiskt anvaendbara 6-fenyl-4h-imidazo(1,5-a)(1,4)-diazepinfoereningar saosom mellanprodukter anvaendbara 3a 4-dihydroimidazo(1,5-a)(1,4)diazepinderivat | |
| AT395154B (de) | Verfahren zur herstellung von neuen imidazo(1,5-a)(1,4)diazepinverbindungen | |
| PL106837B1 (pl) | Sposob wytwarzania imidazo 1,5-a1,4 diazepin | |
| AT395155B (de) | Verfahren zur herstellung von neuen imidazo(1,5-a)(1,4)diazepinverbindungen | |
| US4349477A (en) | Process for producing imidazodiazepines | |
| CH645897A5 (de) | Verfahren zur herstellung von benzodiazepinderivaten. | |
| DE2700539A1 (de) | Benzodiazepine, verfahren zu ihrer herstellung und diese enthaltende arzneimittel | |
| AT395153B (de) | Verfahren zur herstellung von neuen imidazo(1,5-a)(1,4)diazepinverbindungen | |
| CH617937A5 (en) | Process for the preparation of 8-chloro-1-hydroxymethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine and 8-chloro-1-hydroxymethyl-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benz odiazepine | |
| US4073785A (en) | Certain as-triazino 4,3-a! 1,4!benzodiazepine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUE | Assignment |
Owner name: F. HOFFMANN-LA ROCHE AG |
|
| PL | Patent ceased |