JP2000503997A - 縮合した2,3―ベンゾジアゼピン誘導体及びampa―レセプター抑制剤としての使用 - Google Patents
縮合した2,3―ベンゾジアゼピン誘導体及びampa―レセプター抑制剤としての使用Info
- Publication number
- JP2000503997A JP2000503997A JP9527248A JP52724897A JP2000503997A JP 2000503997 A JP2000503997 A JP 2000503997A JP 9527248 A JP9527248 A JP 9527248A JP 52724897 A JP52724897 A JP 52724897A JP 2000503997 A JP2000503997 A JP 2000503997A
- Authority
- JP
- Japan
- Prior art keywords
- benzodiazepine
- compound
- imidazo
- aminophenyl
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- RPBDCDQMCRHNLM-UHFFFAOYSA-N C1=NNC=C2C=CC=CC2=C1 Chemical class C1=NNC=C2C=CC=CC2=C1 RPBDCDQMCRHNLM-UHFFFAOYSA-N 0.000 title description 28
- 102000003678 AMPA Receptors Human genes 0.000 title description 6
- 108090000078 AMPA Receptors Proteins 0.000 title description 6
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 229910052736 halogen Chemical group 0.000 claims abstract description 29
- 150000002367 halogens Chemical group 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- -1 hydroxy, thiocyanato Chemical group 0.000 claims description 75
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 18
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 17
- 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 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 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 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- LRJRPHROCLHMHK-UHFFFAOYSA-N boron;n,n-dimethylmethanamine Chemical compound [B].CN(C)C LRJRPHROCLHMHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 2
- LXBMPCINEXLXPD-UHFFFAOYSA-N 4-(5-methyl-13,15-dioxa-4,7,8-triazatetracyclo[8.7.0.03,7.012,16]heptadeca-1(17),3,5,8,10,12(16)-hexaen-9-yl)aniline Chemical compound C12=CC=3OCOC=3C=C2CC2=NC(C)=CN2N=C1C1=CC=C(N)C=C1 LXBMPCINEXLXPD-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- KLUBZWBRWCUHTF-UHFFFAOYSA-N 8-methoxy-2,3-dimethyl-6-phenyl-11h-imidazo[1,2-c][2,3]benzodiazepine Chemical compound C12=CC(OC)=CC=C2CC2=NC(C)=C(C)N2N=C1C1=CC=CC=C1 KLUBZWBRWCUHTF-UHFFFAOYSA-N 0.000 claims 1
- QWKPBPPJPZEELH-UHFFFAOYSA-N 8-methyl-5-phenyl-11h-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine Chemical compound N=1N2C(C)=CN=C2CC2=CC=3OCOC=3C=C2C=1C1=CC=CC=C1 QWKPBPPJPZEELH-UHFFFAOYSA-N 0.000 claims 1
- NITKRBAZSBDGJA-UHFFFAOYSA-N NC1=CC=C(C=C1)C1=NN2C(CC3=C1C=C(C=C3)OC)=NN=C2CCC.N2=NCN3N=CC1=C(C=C32)C=CC=C1 Chemical compound NC1=CC=C(C=C1)C1=NN2C(CC3=C1C=C(C=C3)OC)=NN=C2CCC.N2=NCN3N=CC1=C(C=C32)C=CC=C1 NITKRBAZSBDGJA-UHFFFAOYSA-N 0.000 claims 1
- 238000005695 dehalogenation reaction Methods 0.000 claims 1
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 claims 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003042 antagnostic effect Effects 0.000 abstract description 3
- 210000003169 central nervous system Anatomy 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 156
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 239000000203 mixture Substances 0.000 description 69
- 238000002844 melting Methods 0.000 description 68
- 230000008018 melting Effects 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 67
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 57
- 239000000243 solution Substances 0.000 description 45
- 238000003756 stirring Methods 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000000047 product Substances 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 239000003480 eluent Substances 0.000 description 22
- 238000000354 decomposition reaction Methods 0.000 description 20
- 150000002828 nitro derivatives Chemical class 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 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 description 17
- 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 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- WZUODJNEIXSNEU-UHFFFAOYSA-N 2-Hydroxy-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(O)=C1 WZUODJNEIXSNEU-UHFFFAOYSA-N 0.000 description 10
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 9
- 229910000564 Raney nickel Inorganic materials 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000007868 Raney catalyst Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 6
- RQKDTQACQPHOQL-UHFFFAOYSA-N 3h-2,3-benzodiazepine Chemical compound C1=NNC=CC2=CC=CC=C21 RQKDTQACQPHOQL-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 229940049706 benzodiazepine Drugs 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 241001061127 Thione Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 3
- 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 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000005605 benzo 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
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000000460 chlorine 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
- 239000013078 crystal Substances 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
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- 229910052698 phosphorus Inorganic materials 0.000 description 1
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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- 239000003755 preservative agent Substances 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 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
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
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- 102220240796 rs553605556 Human genes 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 208000019116 sleep disease Diseases 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
- 239000011780 sodium chloride Substances 0.000 description 1
- JGFYQVQAXANWJU-UHFFFAOYSA-M sodium fluoroacetate Chemical class [Na+].[O-]C(=O)CF JGFYQVQAXANWJU-UHFFFAOYSA-M 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- DXMISFVOLRPPNP-UHFFFAOYSA-M sodium;nitrite;hydrate Chemical compound O.[Na+].[O-]N=O DXMISFVOLRPPNP-UHFFFAOYSA-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
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000003826 tablet Substances 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- ZWYDDDAMNQQZHD-UHFFFAOYSA-L titanium(ii) chloride Chemical compound [Cl-].[Cl-].[Ti+2] ZWYDDDAMNQQZHD-UHFFFAOYSA-L 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar 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
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- 238000005303 weighing Methods 0.000 description 1
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Classifications
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- 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
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
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- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 式I: [式中、 R1及びR2は同一又は異なるものを表わし、水素、C1-6−アルキル、ニトロ、 ハロゲン、シアノ、基−NR8R9、−O−C1-4−アルキル、−CF3、OH又は C1-6−アルカノイルオキシを表わし、 R3及びR4は同一又は異なるものを表わし、水素、ハロゲン、C1-6−アルコ キシ、ヒドロキシ、チオシアナト、C1-6−アルキルチオ、シアノ、COOR12 、PO3R13R14、C1-6−アルカノイル、C16−アルカノイルオキシ、非置換又 はC1-4−アルコキシ又はフェニル置換C2-6−アルキニル、非置換又はC1-4− アルコキシ又はフェニル置換C2-6−アルケニル、非置換又はハロゲン、ヒドロ キシ、C1-6−アルコキシ、C1-6−チオアルキル、NR10R11置換C1-6−アル キル、C3-7-シクロアルキル、又は非置換又は置換アリール又はヘテロアリール 基を表わし、 R8及びR9は同一又は異なるものを表わし、水素、C1-6−アルキル又は基− CO−C1-6−アルキルを表わし、 R10及びR11は同一又は異なるものを表わし、水素、C1- 6−アルキル又はC1-6 −アルカノイルを表わすか、又は窒素原子と一緒になって5〜7員の飽和複 素環を形成し、この環は更に酸素、硫黄又は窒素原子を有していてもよいし、か つ置換されていてもよい、 R12、R13、R14は同一又は異なるものを表わし、 H又はC1-6−アルキルを表わし、 Xは水素又はハロゲンを表わし、 YはC1-6−アルコキシを表わすか、又はX及びYが一緒になって−O−(C H2)n−O−を表わし、 nは1、2又は3を表わし、かつ Aは窒素と一緒になって、飽和又は不飽和の5員の複素環を形成し、この環は 窒素原子1〜3個及び/又は酸素原子1個及び/又はカルボニル基1又は2個を 含有していてよい]の化合物又はその異性体又は生理学的に認容性の塩。 2. 請求項1記載の、 5−(4−アミノフェニル)−8−メチル−11H−1,3−ジオキソロ[4 ,5−h][1,2,4]トリアゾロ[4,3−c][2,3]ベンゾジア ゼピン 5−(4−アミノフェニル)−8−シクロプロピル−11H−1,3−ジオキ ソロ[4,5−h][1,2,4]トリアゾロ[4,3−c][2,3]ベンゾ ジアゼピン 6−(4−アミノフェニル)−8−メトキシ−3−プロピル−11H−[1, 2,4]トリアゾロ[4,3−c][2,3]ベンゾジアゼピン 6−(4−アミノフェニル)−8−メトキシ−3−エチル−11H−[1,2 ,4]トリアゾロ[4,3−c][2,3]ベンゾジアゼピン 6−(4−アミノフェニル)−8−メトキシ−3−シクロプロピル−11H− [1,2,4]トリアゾロ[4,3−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−9−メチル−11H−1,3−ジオキソロ[4 ,5−h]イミダゾ[1,2−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−8−シクロプロピル−11H−1,3−ジオキ ソロ[4,5−h]イミダゾ[1,2−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−8−メチル−11H−1,3−ジオキソロ[4 ,5−h]イミダゾ[1,2−c][2,3]ベンゾジアゼピン 8−シクロプロピル−5−(4−アミノフェニル)−11H−1,3−ジオキ ソロ[4,5−h]イミ ダゾ[3,4−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−9−エチル−11H−1,3−ジオキソロ[4 ,5−h]イミダゾ[1,2−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−8,9−ジメチル−11H−1,3−ジオキソ ロ[4,5−h]イミダゾ[1,2−c][2,3]ベンゾジアゼピン 8−メトキシ−3−メチル−6−フェニル−11H−イミダゾ[1,2−c] [2,3]ベンゾジアゼピン 8−メトキシ−2−メチル−6−フェニル−11H−イミダゾ[1,2−c] [2,3]ベンゾジアゼピン 8−メトキシ−3−メチル−6−フェニル−11H−イミダゾ[1,2−c] [2,3]ベンゾジアゼピン 8−メトキシ−6−フェニル−3−(4−ピリジル)−11H−イミダゾ[1 ,2−c][2,3]ベンゾジアゼピン 8−メトキシ−6−フェニル−3−(2−ピリジル)−11H−イミダゾ[1 ,2−c][2,3]ベンゾジアゼピン 8−メトキシ−6−フェニル−3−(3−ピリジル)−11H−イミダゾ[1 ,2−c][2,3]ベンゾジアゼピン 2,3−ジメチル−8−メトキシ−6−フェニル−11H−イミダゾ[1,2 −c][2,3]ベンゾジアゼピン 6−(4−アミノフェニル)−2,3−ジメチル−8−メトキシ−11H−イ ミダゾ[1,2−c][2,3]ベンゾジアゼピン 6−(4−アミノフェニル)−8−メトキシ−3−(2−ピリジル)−11H −イミダゾ[1,2−c][2,3]ベンゾジアゼピン 6−(4−アミノフェニル)−8−メトキシ−3−(4−ピリジル)−11H −イミダゾ[1,2−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−8−(4−ピリジル)−11H−1,3−ジオ キソロ[4,5−h]イ ミダゾ[1,2−c][2,3]ベンゾジアゼピン 5−(4−アミノフェニル)−9−エチル−8−メチル−11H−1,3−ジ オキソロ[4,5−h]イミダゾ[1,2−c][2,3]ベンゾジアゼピン 8−メチル−5−フェニル−11H−1,3−ジオキソロ[4,5−h]イミ ダゾ[1,2−c][2,3]ベンゾジアゼピン。 3. 請求項1記載の式Iの化合物を含有する薬剤。 4. 請求項1記載の式Iの化合物を製造する方法において、 a)一般式II [式中、R1、R2、X及びYは前記のものを表わす]の化合物であって、 α)Z=COOC1-6−アルキルである一般式IIの化合物を、R3−N=C= Oと反応させて、Aの意味が−CO−NR3−CO−である化合物に環化するか 、 β)Z=−CH2OH又は−CH2−NHR3である一般式IIの化合物をホス ゲンと反応させて、Aの意味が−CH2−O−CO−又は−CH2−NR3−CO −である化合物に環化するか、 γ)Z=−CH2OHである一般式IIの化合物を、R3−CO−R4と反応さ せて、Aの意味が−CH2−O−CR3R4(式中のR3及びR4は前記のものを表 わす)である化合物に環化するか、 b)一般式III又はIV [式中、R1、R2、X及びYは前記のものを表わす]の化合物であって、 α)Z’=−CH=CH−COOC1-6−アルキルである一般式III又はI Vの化合物を、ボラントリメチルアミン−錯体及び三フッ化硼素エーテル錯体と 反応させて、Aが意味−(CH2)3−及び−(CH2)2−CO−を有する化合物 に環化するか、 β)Z’=−CH=N−NH2である一般式III又はIVの化合物を硫酸銅 の存在下に、Aの意味が=CH−N=N−である化合物に環化するか、 γ)Z’=−S−C1-4−アルキルである一般式III又はIVの化合物を、 ヒドラジン水和物及び酸無水物と、又は酸ヒドラジドと反応させて、Aの意味が =N−N=CR3−である化合物に環化するか、 δ)Z’=−S−C1-4−アルキルである一般式III又はIVの化合物を、 α−アミノアセタールと反応させて、Aの意味が=N−CR3=CR4−である化 合物に環化するか、 ε)Z’=CH2OHである一般式III又はIVの化合物において、Z’を CH2NH2に変換し、これをアシル化し、Aの意味が=CH−N=CR3−であ る化合物に環化するか、 c)一般式V [式中、R1、R2、X及びYは前記のものを表わす]の化合物をα−アミノア セタール、α−アミノケタール、H2N−CH2−C≡C−R3と、又はアンモニ ア及びα−ハロゲンケトンと反応させ、かつ引き続き所望の場合、ニトロ基R1 及び/又はR2を還元し、アミノ基をアシル化又はアルキル化するか、又はハロ ゲン又はヒドロキシ又はシアノに変換するか、又は脱アミノ化するか、又はXを ニトロ基の還元と同時に又は順次脱ハロゲン化し又は水素をハロゲンにより置換 するか、又はハロゲンを他のハロゲン、−PO3R13R14、シアノ、C1-6−アル カノイル、C1-6−アルカノイルオキシ、ヒドロキシ、非置換又は置換C2-6−ア ルキニル、非置換又は置換C2-6−アルケニル、非置換又は置換C1-6−アルキ ル、C1-6-アルコキシ、CF3、C1-6−チオアルキル、COOR12と交換するか 、又はYをエーテル交換するか、又は異性体に分離するか、又はその塩を形成す ることを特徴とする、式Iの化合物又はその異性体又は生理学的に認容性の塩の 製法。 5. 式IIa及びIIIa: [式中、R1、R2、X及びYは前記のものを表わし、かつZ”は、を表わし、かつR3は前記のものを表わす]の化合物、その異性体及び塩。
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DE19604919.9 | 1996-02-01 | ||
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 |
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JP2000503997A true JP2000503997A (ja) | 2000-04-04 |
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DE (2) | DE19604919A1 (ja) |
DK (1) | DK0888356T3 (ja) |
EE (1) | EE04017B1 (ja) |
ES (1) | ES2173435T3 (ja) |
HK (1) | HK1018782A1 (ja) |
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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 |
EP1100504A2 (en) * | 1998-07-02 | 2001-05-23 | Eisai Co., Ltd. | Pharmaceutical compositions and their uses for treatment of demyelinating disorders |
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 |
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HU9600871D0 (en) * | 1996-04-04 | 1996-05-28 | Gyogyszerkutato Intezet | New 2,3-benzodiazepine derivatives |
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