CS246063B2 - Method of imidazobenzodiazepines production - Google Patents

Method of imidazobenzodiazepines production Download PDF

Info

Publication number: CS246063B2
Authority: CS; Czechoslovakia
Prior art keywords: benzodiazepine; carboxylate; oxo; imidazo; group
Prior art date: 1982-07-21

Application number

CS835419A

Other languages

Czech (cs)

English (en)

Other versions

CS541983A2 (en

Inventor

Walter Hunkeler

Emilio Kyburz

Original Assignee

Hoffmann La Roche

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1982-07-21

Filing date

1983-07-19

Publication date

1986-10-16

1983-07-19 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1985-05-22 Priority to CS853682A priority Critical patent/CS246100B2/cs

1985-12-16 Publication of CS541983A2 publication Critical patent/CS541983A2/cs

1986-10-16 Publication of CS246063B2 publication Critical patent/CS246063B2/cs

Links

238000000034 method Methods 0.000 title claims description 30
KLNFAMGHSZQYHR-UHFFFAOYSA-N imidazo[4,5-i][1,2]benzodiazepine Chemical class C1=CC=NN=C2C3=NC=NC3=CC=C21 KLNFAMGHSZQYHR-UHFFFAOYSA-N 0.000 title claims description 5
238000004519 manufacturing process Methods 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims description 76
CEHKKWWXELBNPS-UHFFFAOYSA-N 1,4-benzodiazepine-1-carboxylic acid Chemical compound OC(=O)N1C=CN=CC2=CC=CC=C12 CEHKKWWXELBNPS-UHFFFAOYSA-N 0.000 claims description 52
-1 tetrahydro-2H-pyran-4-yl group Chemical group 0.000 claims description 40
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
125000004432 carbon atom Chemical group C* 0.000 claims description 24
CFMIOXCGQIHWJP-UHFFFAOYSA-N 1,2-benzodiazepine-1-carboxylic acid Chemical compound OC(=O)N1N=CC=CC2=CC=CC=C12 CFMIOXCGQIHWJP-UHFFFAOYSA-N 0.000 claims description 22
239000007858 starting material Substances 0.000 claims description 22
WXBBGXSCFXZZSI-UHFFFAOYSA-N 1h-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid Chemical compound N1=CC2=CC=CC=C2N2C(C(=O)O)N=CC2=C1 WXBBGXSCFXZZSI-UHFFFAOYSA-N 0.000 claims description 18
125000000217 alkyl group Chemical group 0.000 claims description 17
OFWFBJVJXBLXOP-UHFFFAOYSA-N 9h-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylic acid Chemical compound C1=C2C=CC=CC2=NC=C2C(C(=O)O)=CCN21 OFWFBJVJXBLXOP-UHFFFAOYSA-N 0.000 claims description 16
150000003839 salts Chemical class 0.000 claims description 14
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
229910052739 hydrogen Inorganic materials 0.000 claims description 11
239000001257 hydrogen Substances 0.000 claims description 11
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
239000002253 acid Substances 0.000 claims description 9
229910052736 halogen Inorganic materials 0.000 claims description 9
150000002367 halogens Chemical group 0.000 claims description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 7
238000002360 preparation method Methods 0.000 claims description 7
125000003342 alkenyl group Chemical group 0.000 claims description 5
125000003545 alkoxy group Chemical group 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
125000005843 halogen group Chemical group 0.000 claims description 5
238000011282 treatment Methods 0.000 claims description 5
125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
125000002947 alkylene group Chemical group 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 4
125000003277 amino group Chemical group 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
150000001721 carbon Chemical group 0.000 claims description 4
125000006410 propenylene group Chemical group 0.000 claims description 4
125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 3
150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
WQDACHQRZIFCIW-HNNXBMFYSA-N cyclohexyl (s)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9h-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate Chemical compound C1([C@@H]2CCCN2C(=O)C=2C(N1C=N1)=CC=C(C=2Cl)F)=C1C(=O)OC1CCCCC1 WQDACHQRZIFCIW-HNNXBMFYSA-N 0.000 claims description 2
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
125000000392 cycloalkenyl group Chemical group 0.000 claims 1
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 345
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 202
239000000243 solution Substances 0.000 description 144
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 134
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
239000000203 mixture Substances 0.000 description 114
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 74
229910052943 magnesium sulfate Inorganic materials 0.000 description 67
235000019341 magnesium sulphate Nutrition 0.000 description 67
239000011541 reaction mixture Substances 0.000 description 60
239000000741 silica gel Substances 0.000 description 56
229910002027 silica gel Inorganic materials 0.000 description 56
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 39
238000001953 recrystallisation Methods 0.000 description 37
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 30
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
239000002904 solvent Substances 0.000 description 28
XGZNHFPFJRZBBT-UHFFFAOYSA-N ethanol;titanium Chemical compound [Ti].CCO.CCO.CCO.CCO XGZNHFPFJRZBBT-UHFFFAOYSA-N 0.000 description 27
JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium(IV) ethoxide Substances [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 27
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 26
239000012043 crude product Substances 0.000 description 25
239000012074 organic phase Substances 0.000 description 25
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
238000002425 crystallisation Methods 0.000 description 23
230000008025 crystallization Effects 0.000 description 23
239000005909 Kieselgur Substances 0.000 description 21
238000003756 stirring Methods 0.000 description 18
238000004587 chromatography analysis Methods 0.000 description 17
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 17
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
239000001569 carbon dioxide Substances 0.000 description 15
229910002092 carbon dioxide Inorganic materials 0.000 description 15
238000006243 chemical reaction Methods 0.000 description 15
HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 15
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical class [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 14
229910000104 sodium hydride Inorganic materials 0.000 description 14
239000012312 sodium hydride Substances 0.000 description 14
239000007787 solid Substances 0.000 description 14
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
229960000583 acetic acid Drugs 0.000 description 13
GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 13
LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 13
229960001760 dimethyl sulfoxide Drugs 0.000 description 13
239000003480 eluent Substances 0.000 description 13
239000000839 emulsion Substances 0.000 description 12
239000004533 oil dispersion Substances 0.000 description 12
239000012071 phase Substances 0.000 description 12
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
241001465754 Metazoa Species 0.000 description 11
239000012362 glacial acetic acid Substances 0.000 description 11
239000000126 substance Substances 0.000 description 11
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
150000008064 anhydrides Chemical class 0.000 description 9
230000000694 effects Effects 0.000 description 9
239000000725 suspension Substances 0.000 description 9
IADUEWIQBXOCDZ-VKHMYHEASA-N (S)-azetidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
239000000047 product Substances 0.000 description 8
239000000829 suppository Substances 0.000 description 8
102000004300 GABA-A Receptors Human genes 0.000 description 7
108090000839 GABA-A Receptors Proteins 0.000 description 7
239000000284 extract Substances 0.000 description 7
239000003921 oil Substances 0.000 description 7
235000019198 oils Nutrition 0.000 description 7
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 6
229930182821 L-proline Natural products 0.000 description 6
239000002775 capsule Substances 0.000 description 6
AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 6
229960003529 diazepam Drugs 0.000 description 6
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
238000002844 melting Methods 0.000 description 6
230000008018 melting Effects 0.000 description 6
229960002429 proline Drugs 0.000 description 6
239000002585 base Substances 0.000 description 5
239000000969 carrier Substances 0.000 description 5
239000000825 pharmaceutical preparation Substances 0.000 description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
IADUEWIQBXOCDZ-UHFFFAOYSA-N (2S)-azetidine-2-carboxylic acid Natural products OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 4
MGOLNIXAPIAKFM-UHFFFAOYSA-N 2-isocyanato-2-methylpropane Chemical compound CC(C)(C)N=C=O MGOLNIXAPIAKFM-UHFFFAOYSA-N 0.000 description 4
HTSABYAWKQAHBT-UHFFFAOYSA-N 3-methylcyclohexanol Chemical compound CC1CCCC(O)C1 HTSABYAWKQAHBT-UHFFFAOYSA-N 0.000 description 4
229920002261 Corn starch Polymers 0.000 description 4
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 4
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
239000008346 aqueous phase Substances 0.000 description 4
238000009835 boiling Methods 0.000 description 4
150000007942 carboxylates Chemical class 0.000 description 4
239000008120 corn starch Substances 0.000 description 4
229940099112 cornstarch Drugs 0.000 description 4
XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 4
201000010099 disease Diseases 0.000 description 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
150000002430 hydrocarbons Chemical group 0.000 description 4
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 4
239000008101 lactose Substances 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
229920005862 polyol Polymers 0.000 description 4
150000003077 polyols Chemical class 0.000 description 4
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
MZHUTGQZAZLFKW-UHFFFAOYSA-N 1H-1,2-benzodiazepine-3-carboxylic acid Chemical compound C1=CC(C(=O)O)=NNC2=CC=CC=C21 MZHUTGQZAZLFKW-UHFFFAOYSA-N 0.000 description 3
IIGNZLVHOZEOPV-UHFFFAOYSA-N 3-Methoxybenzyl alcohol Chemical compound COC1=CC=CC(CO)=C1 IIGNZLVHOZEOPV-UHFFFAOYSA-N 0.000 description 3
WWSWHYAXEFLETD-UHFFFAOYSA-N 4,5-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C2NC(=O)C(=O)C2=C1Cl WWSWHYAXEFLETD-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
239000001828 Gelatine Substances 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000008065 acid anhydrides Chemical class 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
229940049706 benzodiazepine Drugs 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 0.000 description 3
238000000354 decomposition reaction Methods 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
238000001914 filtration Methods 0.000 description 3
229920000159 gelatin Polymers 0.000 description 3
235000019322 gelatine Nutrition 0.000 description 3
239000007788 liquid Substances 0.000 description 3
239000003158 myorelaxant agent Substances 0.000 description 3
TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 3
238000010992 reflux Methods 0.000 description 3
239000000454 talc Substances 0.000 description 3
229910052623 talc Inorganic materials 0.000 description 3
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 2
HZABUXCSZMLBHU-UHFFFAOYSA-N 1H-1,4-benzodiazepine-3-carboxylic acid Chemical compound C1=NC(C(=O)O)=CNC2=CC=CC=C21 HZABUXCSZMLBHU-UHFFFAOYSA-N 0.000 description 2
PHNMUQYFHNMYGN-UHFFFAOYSA-N 1h-1,4-benzodiazepine-2-carboxylic acid Chemical compound N1C(C(=O)O)=CN=CC2=CC=CC=C21 PHNMUQYFHNMYGN-UHFFFAOYSA-N 0.000 description 2
LUNMJRJMSXZSLC-UHFFFAOYSA-N 2-cyclopropylethanol Chemical compound OCCC1CC1 LUNMJRJMSXZSLC-UHFFFAOYSA-N 0.000 description 2
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 2
SWUGYKGLXFMLEN-UHFFFAOYSA-N 4-chloro-5-fluoro-1h-indole-2,3-dione Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1Cl SWUGYKGLXFMLEN-UHFFFAOYSA-N 0.000 description 2
MQWCXKGKQLNYQG-UHFFFAOYSA-N 4-methylcyclohexan-1-ol Chemical compound CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 2
206010010904 Convulsion Diseases 0.000 description 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
241000700159 Rattus Species 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
229910052783 alkali metal Inorganic materials 0.000 description 2
XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 2
239000002249 anxiolytic agent Substances 0.000 description 2
230000000949 anxiolytic effect Effects 0.000 description 2
235000019445 benzyl alcohol Nutrition 0.000 description 2
239000002026 chloroform extract Substances 0.000 description 2
125000004122 cyclic group Chemical group 0.000 description 2
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
239000012954 diazonium Substances 0.000 description 2
150000001989 diazonium salts Chemical class 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
239000008298 dragée Substances 0.000 description 2
239000003814 drug Substances 0.000 description 2
238000005886 esterification reaction Methods 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
HQGUQOHSCRHEFJ-LBPRGKRZSA-N ethyl (s)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9h-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-1-carboxylate Chemical compound O=C1C2=C(Cl)C=CC=C2N2C=NC(C(=O)OCC)=C2[C@@H]2CCCN21 HQGUQOHSCRHEFJ-LBPRGKRZSA-N 0.000 description 2
WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
230000008020 evaporation Effects 0.000 description 2
239000003925 fat Substances 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 2
229910052740 iodine Inorganic materials 0.000 description 2
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
239000000463 material Substances 0.000 description 2
239000012452 mother liquor Substances 0.000 description 2
230000004973 motor coordination Effects 0.000 description 2
230000003285 pharmacodynamic effect Effects 0.000 description 2
239000000843 powder Substances 0.000 description 2
238000011321 prophylaxis Methods 0.000 description 2
239000000932 sedative agent Substances 0.000 description 2
230000001624 sedative effect Effects 0.000 description 2
230000001629 suppression Effects 0.000 description 2
125000003396 thiol group Chemical class [H]S* 0.000 description 2
229910052722 tritium Inorganic materials 0.000 description 2
235000015112 vegetable and seed oil Nutrition 0.000 description 2
239000008158 vegetable oil Substances 0.000 description 2
239000001993 wax Substances 0.000 description 2
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239000008117 stearic acid Substances 0.000 description 1
239000010959 steel Substances 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
229910021653 sulphate ion Inorganic materials 0.000 description 1
239000002511 suppository base Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
IQSYKHVFMYGJER-UHFFFAOYSA-N tert-butyl 2-isocyanoacetate Chemical compound CC(C)(C)OC(=O)C[N+]#[C-] IQSYKHVFMYGJER-UHFFFAOYSA-N 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
150000003571 thiolactams Chemical class 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
230000001256 tonic effect Effects 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
238000012345 traction test Methods 0.000 description 1
238000005809 transesterification reaction Methods 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
- C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
- 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

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
Neurology (AREA)
Public Health (AREA)
Bioinformatics & Cheminformatics (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
Pharmacology & Pharmacy (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Pain & Pain Management (AREA)
Anesthesiology (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Pyrrole Compounds (AREA)
Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

CS835419A 1982-07-21 1983-07-19 Method of imidazobenzodiazepines production CS246063B2 (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
CS853682A CS246100B2 (cs)	1982-07-21	1985-05-22	Způsob výroby imidazobenzodiazepinů

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
CH446082		1982-07-21

Publications (2)

Publication Number	Publication Date
CS541983A2 CS541983A2 (en)	1985-12-16
CS246063B2 true CS246063B2 (en)	1986-10-16

Family

ID=4276529

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CS835419A CS246063B2 (en)	1982-07-21	1983-07-19	Method of imidazobenzodiazepines production

Country Status (25)

Country	Link
US (1)	US4489003A (es)
EP (1)	EP0100906B1 (es)
JP (1)	JPS5933286A (es)
KR (1)	KR840005836A (es)
AT (1)	ATE27160T1 (es)
AU (1)	AU560286B2 (es)
BR (1)	BR8303898A (es)
CA (1)	CA1202969A (es)
CS (1)	CS246063B2 (es)
CU (1)	CU21554A3 (es)
DE (1)	DE3371516D1 (es)
DK (1)	DK335083A (es)
ES (4)	ES524280A0 (es)
FI (1)	FI832654A7 (es)
GR (1)	GR79322B (es)
HU (1)	HU189719B (es)
IE (1)	IE56121B1 (es)
IL (1)	IL69242A (es)
MC (1)	MC1528A1 (es)
NO (1)	NO832633L (es)
NZ (1)	NZ204912A (es)
PH (1)	PH18980A (es)
PT (1)	PT77063B (es)
ZA (1)	ZA835147B (es)
ZW (1)	ZW14383A1 (es)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE3587913D1 (de) *	1984-01-19	1994-10-06	Hoffmann La Roche	Imidazodiazepin-Derivate.
CA1259612A (en) *	1985-02-28	1989-09-19	Emilio Kyburz	Imidazodiazepine derivatives
DK174086D0 (da) *	1986-04-16	1986-04-16	Ferrosan As	Nye benzodiazepinderivater samt fremgangsmaade til fremstilling af samme
GB8720414D0 (en) *	1987-08-28	1987-10-07	Roussel Lab Ltd	Chemical compounds
CA2015336A1 (en) *	1989-05-19	1990-11-19	F. Hoffmann-La Roche Ag	Imidazodiazepines for the treatment of neurological symptoms
IE910939A1 (en) *	1990-04-13	1991-10-23	Neurosearch As	Use of benzodiazepine compounds
US7160880B1 (en)	1999-05-14	2007-01-09	Cenes Limited	Short-acting benzodiazepines
GB9911152D0 (en) *	1999-05-14	1999-07-14	Glaxo Group Ltd	Short-acting benzodiazepines
EP1888594A2 (en) *	2005-05-16	2008-02-20	Wisys Technology Foundation, Inc.	Gabaergic agents to treat memory deficits
DE602007009128D1 (de)	2006-07-10	2010-10-21	Paion Uk Ltd	Benzodiazepinsalze mit kurzzeitwirkung und polymorphe formen davon
CA2696703C (en)	2007-08-20	2016-07-26	Evotec Neurosciences Gmbh	Treatment of sleep disorders
US20090054412A1 (en) *	2007-08-20	2009-02-26	John Alan Kemp	Treatment of Sleep Disorders
EP2450039A1 (en)	2010-11-08	2012-05-09	PAION UK Ltd.	Dosing regimen for sedation with CNS 7056 (Remimazolam)
AR094963A1 (es)	2013-03-04	2015-09-09	Ono Pharmaceutical Co	Reacción de oxidación excelente en el índice de conversión
WO2021113492A1 (en) *	2019-12-06	2021-06-10	Schrödinger, Inc.	Cyclic compounds and methods of using same

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA1143728A (en) *	1979-10-04	1983-03-29	Max Gerecke	Imidazodiazepine derivatives
CA1185602A (en) *	1981-02-27	1985-04-16	Emilio Kyburz	Imidazodiazepines
CA1173441A (en) *	1981-02-27	1984-08-28	Hoffmann-La Roche Limited	Imidazodiazepines
US4352817A (en) *	1981-02-27	1982-10-05	Hoffmann-La Roche Inc.	Imidazo-diazepines and their use
CA1184175A (en) *	1981-02-27	1985-03-19	Walter Hunkeler	Imidazodiazepines

1983
- 1983-06-19 MC MC@@@@1648A patent/MC1528A1/fr unknown
- 1983-06-24 ZW ZW143/83A patent/ZW14383A1/xx unknown
- 1983-06-24 CA CA000431129A patent/CA1202969A/en not_active Expired
- 1983-07-14 DE DE8383106920T patent/DE3371516D1/de not_active Expired
- 1983-07-14 ZA ZA835147A patent/ZA835147B/xx unknown
- 1983-07-14 US US06/513,571 patent/US4489003A/en not_active Expired - Fee Related
- 1983-07-14 AT AT83106920T patent/ATE27160T1/de not_active IP Right Cessation
- 1983-07-14 EP EP83106920A patent/EP0100906B1/de not_active Expired
- 1983-07-15 IL IL69242A patent/IL69242A/xx unknown
- 1983-07-15 NZ NZ204912A patent/NZ204912A/en unknown
- 1983-07-15 AU AU16888/83A patent/AU560286B2/en not_active Ceased
- 1983-07-18 HU HU832533A patent/HU189719B/hu unknown
- 1983-07-19 GR GR71965A patent/GR79322B/el unknown
- 1983-07-19 KR KR1019830003325A patent/KR840005836A/ko not_active Withdrawn
- 1983-07-19 NO NO832633A patent/NO832633L/no unknown
- 1983-07-19 CS CS835419A patent/CS246063B2/cs unknown
- 1983-07-20 PH PH29251A patent/PH18980A/en unknown
- 1983-07-20 IE IE1696/83A patent/IE56121B1/xx unknown
- 1983-07-20 JP JP58131150A patent/JPS5933286A/ja active Pending
- 1983-07-20 BR BR8303898A patent/BR8303898A/pt unknown
- 1983-07-20 DK DK335083A patent/DK335083A/da not_active Application Discontinuation
- 1983-07-20 PT PT77063A patent/PT77063B/pt unknown
- 1983-07-20 ES ES524280A patent/ES524280A0/es active Granted
- 1983-07-21 CU CU8335935A patent/CU21554A3/es unknown
- 1983-07-21 FI FI832654A patent/FI832654A7/fi not_active Application Discontinuation
1984
- 1984-03-16 ES ES530671A patent/ES530671A0/es active Granted
- 1984-03-16 ES ES530673A patent/ES8504805A1/es not_active Expired
- 1984-03-16 ES ES530672A patent/ES8505180A1/es not_active Expired

Also Published As

Publication number	Publication date
ZW14383A1 (en)	1985-01-23
HU189719B (en)	1986-07-28
IE56121B1 (en)	1991-04-24
GR79322B (es)	1984-10-22
ES530673A0 (es)	1985-05-01
EP0100906B1 (de)	1987-05-13
NO832633L (no)	1984-01-23
ES8505179A1 (es)	1985-05-16
ES8504805A1 (es)	1985-05-01
ATE27160T1 (de)	1987-05-15
ES8500945A1 (es)	1984-11-16
BR8303898A (pt)	1984-04-10
IL69242A (en)	1986-09-30
PH18980A (en)	1985-11-29
FI832654A7 (fi)	1984-01-22
DE3371516D1 (de)	1987-06-19
CS541983A2 (en)	1985-12-16
ES530671A0 (es)	1985-05-16
ES530672A0 (es)	1985-05-16
PT77063B (en)	1986-07-15
NZ204912A (en)	1986-10-08
KR840005836A (ko)	1984-11-19
JPS5933286A (ja)	1984-02-23
DK335083A (da)	1984-01-22
US4489003A (en)	1984-12-18
IL69242A0 (en)	1983-11-30
AU560286B2 (en)	1987-04-02
DK335083D0 (da)	1983-07-20
CA1202969A (en)	1986-04-08
ES8505180A1 (es)	1985-05-16
EP0100906A2 (de)	1984-02-22
CU21554A3 (en)	1987-06-09
IE831696L (en)	1984-01-21
ZA835147B (en)	1984-03-28
MC1528A1 (fr)	1984-04-13
EP0100906A3 (en)	1984-08-22
PT77063A (en)	1983-08-01
AU1688883A (en)	1984-01-26
FI832654A0 (fi)	1983-07-21
ES524280A0 (es)	1984-11-16

Publication	Publication Date	Title
CS246063B2 (en)	1986-10-16	Method of imidazobenzodiazepines production
EP0150040B1 (de)	1994-08-31	Imidazodiazepin-Derivate
EP0804438B1 (en)	2006-03-15	Tricyclic benzazepine vasopressin antagonists
CS247064B2 (en)	1986-11-13	Production method of tetracyclic imidazodiazepins
EP0672666B1 (de)	2001-07-25	Imidazodiazepine
AU2005277283A1 (en)	2006-03-02	Fused triazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
DE60016566T2 (de)	2005-12-15	Triazolopyridazinderivate als liganden für gaba-rezeptoren
AU2007319952A1 (en)	2008-05-22	Tricyclic heteroaromatic compounds as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
CS231957B2 (en)	1985-01-16	Manufacturing process of heterocyclic compounds
CZ185092A3 (en)	1993-12-15	Imidazodiazepines
DE2540522A1 (de)	1976-04-08	Diazepin-derivate
SK283075B6 (sk)	2003-02-04	Deriváty 4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-acetamidu a farmaceutický prostriedok, ktorý ich obsahuje
EP0285837B1 (de)	1992-07-08	Imidazodiazepin-Derivate
US4587245A (en)	1986-05-06	Method of treating neuropsychic disturbances by benzodiazepine derivatives and composition therefor
EP0443312B1 (en)	1997-05-07	3H,6H-1,4,5a,8a-Tetraazaacenaphthylene-3,5-(4H)-diones
US3886174A (en)	1975-05-27	1-Substituted-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 benzodiazepines
CS246100B2 (cs)	1986-10-16	Způsob výroby imidazobenzodiazepinů
US5021411A (en)	1991-06-04	Imidazodiazepine derivatives
GB2174695A (en)	1986-11-12	Heteroanalogs of imidazobenzodiazepines
US3996230A (en)	1976-12-07	1-Piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines
CS209929B2 (en)	1981-12-31	Method of making the new substituted 4h-s-triazolo/3,4c/-thieno/2,3e/-1,4 diazepins
HK1004132B (en)	2006-06-02	Tricyclic benzazepine vasopressin antagonists