IL125480A - History 2, 3 - Benzodiazepine tricyclics with multiple transducers, pharmaceutical preparations containing them and processes for their preparation - Google Patents
History 2, 3 - Benzodiazepine tricyclics with multiple transducers, pharmaceutical preparations containing them and processes for their preparationInfo
- Publication number
- IL125480A IL125480A IL12548097A IL12548097A IL125480A IL 125480 A IL125480 A IL 125480A IL 12548097 A IL12548097 A IL 12548097A IL 12548097 A IL12548097 A IL 12548097A IL 125480 A IL125480 A IL 125480A
- Authority
- IL
- Israel
- Prior art keywords
- benzodiazepine
- llh
- imidazo
- dioxolo
- methoxy
- Prior art date
Links
- RPBDCDQMCRHNLM-UHFFFAOYSA-N C1=NNC=C2C=CC=CC2=C1 Chemical class C1=NNC=C2C=CC=CC2=C1 RPBDCDQMCRHNLM-UHFFFAOYSA-N 0.000 title claims description 74
- 238000000034 method Methods 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 title claims 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- -1 hydroxy, thiocyanato Chemical group 0.000 claims abstract description 59
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 30
- 150000002367 halogens Chemical class 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 15
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 239000011593 sulfur Substances 0.000 claims abstract description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 3
- 125000002252 acyl group Chemical group 0.000 claims abstract 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract 2
- 229940049706 benzodiazepine Drugs 0.000 claims description 54
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 46
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 230000002829 reductive effect Effects 0.000 claims description 22
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 18
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 15
- JENALEDAZIFLGS-UHFFFAOYSA-N 3h-imidazo[1,2-c][2,3]benzodiazepine Chemical compound C1=NN2CC=NC2=CC2=CC=CC=C21 JENALEDAZIFLGS-UHFFFAOYSA-N 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- UWAHBPUHTZEWOC-UHFFFAOYSA-N 3H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine Chemical compound N1=NCN2N=CC3=C(C=C21)C=CC=C3 UWAHBPUHTZEWOC-UHFFFAOYSA-N 0.000 claims description 11
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 102000003678 AMPA Receptors Human genes 0.000 claims description 7
- 108090000078 AMPA Receptors Proteins 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 239000008177 pharmaceutical agent Substances 0.000 claims description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- LRJRPHROCLHMHK-UHFFFAOYSA-N boron;n,n-dimethylmethanamine Chemical compound [B].CN(C)C LRJRPHROCLHMHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003257 excitatory amino acid Substances 0.000 claims description 4
- 230000002461 excitatory amino acid Effects 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims description 3
- 208000013403 hyperactivity Diseases 0.000 claims description 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 230000004770 neurodegeneration Effects 0.000 claims 1
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 1
- 125000004001 thioalkyl group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 abstract description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 1
- 208000015114 central nervous system disease Diseases 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 160
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
- 238000002844 melting Methods 0.000 description 87
- 230000008018 melting Effects 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- 239000000243 solution Substances 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- 238000001704 evaporation Methods 0.000 description 41
- 230000008020 evaporation Effects 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- 238000000354 decomposition reaction Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- 150000002828 nitro derivatives Chemical class 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000009835 boiling Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
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- 239000002244 precipitate Substances 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000000706 filtrate Substances 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
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- WZUODJNEIXSNEU-UHFFFAOYSA-N 2-Hydroxy-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(O)=C1 WZUODJNEIXSNEU-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- 239000012362 glacial acetic acid Substances 0.000 description 6
- 239000013067 intermediate product Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- SUMMWKHSCFGUEV-UHFFFAOYSA-N 2,3-benzodiazepine-8-thione Chemical compound C1=NN=CC=C2C1=CC(C=C2)=S SUMMWKHSCFGUEV-UHFFFAOYSA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- FMSJHWUIRRQXMH-UHFFFAOYSA-N 3H-imidazo[1,5-c][2,3]benzodiazepine Chemical compound C1=NCN2N=CC3=C(C=C21)C=CC=C3 FMSJHWUIRRQXMH-UHFFFAOYSA-N 0.000 description 4
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 4
- ZCPGZXDGDWHJCS-UHFFFAOYSA-N 8-methoxy-1-(4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepine-4-thione Chemical compound C12=CC(OC)=CC=C2CC(=S)NN=C1C1=CC=C([N+]([O-])=O)C=C1 ZCPGZXDGDWHJCS-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
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- 239000008346 aqueous phase Substances 0.000 description 4
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- 238000002347 injection Methods 0.000 description 4
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- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
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- QSDBXXXZPYVJOT-UHFFFAOYSA-N 1,2-benzodiazepin-8-one Chemical compound N1=NC=CC=C2C1=CC(C=C2)=O QSDBXXXZPYVJOT-UHFFFAOYSA-N 0.000 description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- ZJEHXSSAXVIPJF-UHFFFAOYSA-N [5-(4-nitrophenyl)-9h-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-yl]methanol Chemical compound C12=CC=3OCOC=3C=C2CC(CO)=NN=C1C1=CC=C([N+]([O-])=O)C=C1 ZJEHXSSAXVIPJF-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 239000003638 chemical reducing agent 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
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
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- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- NVIFVTYDZMXWGX-UHFFFAOYSA-N sodium metaborate Chemical compound [Na+].[O-]B=O NVIFVTYDZMXWGX-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid 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
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- MRXQMNWIADOAJY-UHFFFAOYSA-M tetrabutylazanium;fluoride;dihydrofluoride Chemical compound F.F.[F-].CCCC[N+](CCCC)(CCCC)CCCC MRXQMNWIADOAJY-UHFFFAOYSA-M 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19604919A DE19604919A1 (de) | 1996-02-01 | 1996-02-01 | Neue 2,3-Benzodiazepinderivate, deren Herstellung und Verwendung als Arzneimittel |
| PCT/DE1997/000234 WO1997028163A1 (de) | 1996-02-01 | 1997-01-29 | Kondensierte 2,3-benzodiazepin derivate und deren verwendung als ampa-rezeptoren-hemmer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL125480A0 IL125480A0 (en) | 1999-03-12 |
| IL125480A true IL125480A (en) | 2002-07-25 |
Family
ID=7785064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL12548097A IL125480A (en) | 1996-02-01 | 1997-01-29 | History 2, 3 - Benzodiazepine tricyclics with multiple transducers, pharmaceutical preparations containing them and processes for their preparation |
Country Status (31)
| Country | Link |
|---|---|
| US (2) | US6323197B1 (xx) |
| EP (1) | EP0888356B1 (xx) |
| JP (1) | JP4141499B2 (xx) |
| KR (1) | KR100465269B1 (xx) |
| CN (1) | CN1096464C (xx) |
| AT (1) | ATE214703T1 (xx) |
| AU (1) | AU724956B2 (xx) |
| BG (1) | BG63394B1 (xx) |
| BR (1) | BR9707335A (xx) |
| CA (1) | CA2245539C (xx) |
| CZ (1) | CZ289658B6 (xx) |
| DE (2) | DE19604919A1 (xx) |
| DK (1) | DK0888356T3 (xx) |
| EE (1) | EE04017B1 (xx) |
| ES (1) | ES2173435T3 (xx) |
| HK (1) | HK1018782A1 (xx) |
| HU (1) | HU224636B1 (xx) |
| IL (1) | IL125480A (xx) |
| IS (1) | IS2103B (xx) |
| MY (1) | MY119140A (xx) |
| NO (1) | NO983510L (xx) |
| NZ (1) | NZ331187A (xx) |
| PL (1) | PL187128B1 (xx) |
| PT (1) | PT888356E (xx) |
| RU (1) | RU2179557C2 (xx) |
| SK (1) | SK283563B6 (xx) |
| TR (1) | TR199801485T2 (xx) |
| TW (1) | TW438801B (xx) |
| UA (1) | UA56157C2 (xx) |
| WO (1) | WO1997028163A1 (xx) |
| ZA (1) | ZA97848B (xx) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP9701325A1 (hu) * | 1997-07-31 | 2000-08-28 | Gyógyszerkutató Intézet Kft. | Új 2,3-benzodiazepin-származékok |
| UA67749C2 (uk) * | 1997-08-12 | 2004-07-15 | Егіш Дьйодьсердьяр Рт. | Похідна 8-заміщеного-9н-1,3-діоксол/4,5-h//2,3/бензодіазепіну з властивостями амра/каїнатного антагоніста, спосіб одержання похідних, фармацевтична композиція (варіанти), спосіб її одержання та спосіб лікування |
| JP2002519373A (ja) * | 1998-07-02 | 2002-07-02 | エーザイ株式会社 | 製薬組成物及びそれらの使用 |
| WO2001098280A2 (en) * | 2000-06-16 | 2001-12-27 | Annovis, Inc. | 5h-2,3-benzodiazepine antagonists of excitatory amino acid receptors |
| DE10041671C1 (de) | 2000-08-10 | 2002-06-13 | Schering Ag | Verfahren zur Herstellung von Imidazo[1,2-c][2,3]benzodiazepinen sowie Phenylessigsäureester und Oxazol-Derivate als Zwischenprodukte bei deren Herstellung |
| WO2005113434A1 (en) * | 2004-03-25 | 2005-12-01 | William Marsh Rice University | Functionalization of carbon nanotubes in acidic media |
| US20060166969A1 (en) * | 2005-01-14 | 2006-07-27 | Turski Lechoslaw A | AMPA antagonists for the treatment of dizziness, including vertigo and Meniere's disorder |
| EP2338492A1 (en) | 2009-12-24 | 2011-06-29 | Universidad del Pais Vasco | Methods and compositions for the treatment of alzheimer |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5891871A (en) | 1996-03-21 | 1999-04-06 | Cocensys, Inc. | Substituted 2,3-benzodiazepin-4-ones and the use thereof |
| HU9600871D0 (en) * | 1996-04-04 | 1996-05-28 | Gyogyszerkutato Intezet | New 2,3-benzodiazepine derivatives |
-
1996
- 1996-02-01 DE DE19604919A patent/DE19604919A1/de not_active Withdrawn
-
1997
- 1997-01-29 SK SK1033-98A patent/SK283563B6/sk unknown
- 1997-01-29 US US09/117,508 patent/US6323197B1/en not_active Expired - Fee Related
- 1997-01-29 PL PL97328224A patent/PL187128B1/pl not_active IP Right Cessation
- 1997-01-29 PT PT97916315T patent/PT888356E/pt unknown
- 1997-01-29 KR KR10-1998-0705917A patent/KR100465269B1/ko not_active IP Right Cessation
- 1997-01-29 EE EE9800225A patent/EE04017B1/xx not_active IP Right Cessation
- 1997-01-29 EP EP97916315A patent/EP0888356B1/de not_active Expired - Lifetime
- 1997-01-29 DE DE59706686T patent/DE59706686D1/de not_active Expired - Lifetime
- 1997-01-29 UA UA98084653A patent/UA56157C2/uk unknown
- 1997-01-29 WO PCT/DE1997/000234 patent/WO1997028163A1/de active IP Right Grant
- 1997-01-29 IL IL12548097A patent/IL125480A/en not_active IP Right Cessation
- 1997-01-29 ES ES97916315T patent/ES2173435T3/es not_active Expired - Lifetime
- 1997-01-29 HU HU9901417A patent/HU224636B1/hu not_active IP Right Cessation
- 1997-01-29 AU AU25029/97A patent/AU724956B2/en not_active Ceased
- 1997-01-29 JP JP52724897A patent/JP4141499B2/ja not_active Expired - Fee Related
- 1997-01-29 CZ CZ19982427A patent/CZ289658B6/cs not_active IP Right Cessation
- 1997-01-29 NZ NZ331187A patent/NZ331187A/xx unknown
- 1997-01-29 BR BR9707335A patent/BR9707335A/pt not_active IP Right Cessation
- 1997-01-29 CA CA002245539A patent/CA2245539C/en not_active Expired - Fee Related
- 1997-01-29 TR TR1998/01485T patent/TR199801485T2/xx unknown
- 1997-01-29 RU RU98116292/04A patent/RU2179557C2/ru not_active IP Right Cessation
- 1997-01-29 DK DK97916315T patent/DK0888356T3/da active
- 1997-01-29 AT AT97916315T patent/ATE214703T1/de not_active IP Right Cessation
- 1997-01-29 CN CN97192012A patent/CN1096464C/zh not_active Expired - Fee Related
- 1997-01-31 MY MYPI97000379A patent/MY119140A/en unknown
- 1997-01-31 ZA ZA9700848A patent/ZA97848B/xx unknown
- 1997-02-01 TW TW086101218A patent/TW438801B/zh not_active IP Right Cessation
-
1998
- 1998-07-06 IS IS4794A patent/IS2103B/is unknown
- 1998-07-29 BG BG102658A patent/BG63394B1/bg unknown
- 1998-07-30 NO NO983510A patent/NO983510L/no unknown
-
1999
- 1999-09-02 HK HK99103802A patent/HK1018782A1/xx not_active IP Right Cessation
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2001
- 2001-11-27 US US09/993,646 patent/US6600036B2/en not_active Expired - Fee Related
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| MM9K | Patent not in force due to non-payment of renewal fees |