CN1128030A - 具有中枢神经系统活性的杂环胺 - Google Patents
具有中枢神经系统活性的杂环胺 Download PDFInfo
- Publication number
- CN1128030A CN1128030A CN94192910A CN94192910A CN1128030A CN 1128030 A CN1128030 A CN 1128030A CN 94192910 A CN94192910 A CN 94192910A CN 94192910 A CN94192910 A CN 94192910A CN 1128030 A CN1128030 A CN 1128030A
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- Prior art keywords
- compound
- mixture
- solution
- methoxyl group
- quinoline
- Prior art date
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- -1 Heterocyclic amines Chemical class 0.000 title abstract description 41
- 230000000694 effects Effects 0.000 title abstract description 9
- 210000003169 central nervous system Anatomy 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 8
- 230000036506 anxiety Effects 0.000 claims abstract description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000003203 everyday effect Effects 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 238000000151 deposition Methods 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 6
- 208000018737 Parkinson disease Diseases 0.000 abstract description 4
- 201000000980 schizophrenia Diseases 0.000 abstract description 4
- 208000019695 Migraine disease Diseases 0.000 abstract description 3
- 230000001430 anti-depressive effect Effects 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- 239000002249 anxiolytic agent Substances 0.000 abstract 2
- 230000000949 anxiolytic effect Effects 0.000 abstract 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 2
- 206010027603 Migraine headaches Diseases 0.000 abstract 1
- 230000036772 blood pressure Effects 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- 239000000203 mixture Substances 0.000 description 60
- 239000000243 solution Substances 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000007788 liquid Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 238000004587 chromatography analysis Methods 0.000 description 22
- 238000002425 crystallisation Methods 0.000 description 22
- 230000008025 crystallization Effects 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- DMYQOTDBVCENSW-UHFFFAOYSA-N n-(trifluoromethyl)acetamide Chemical compound CC(=O)NC(F)(F)F DMYQOTDBVCENSW-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000019587 texture Nutrition 0.000 description 5
- 206010001488 Aggression Diseases 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical class IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- IQDMUSPYIULEGD-SECBINFHSA-N (3r)-n-methyl-1,2,3,4-tetrahydroquinolin-3-amine Chemical compound C1=CC=C2C[C@@H](NC)CNC2=C1 IQDMUSPYIULEGD-SECBINFHSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YGRFXPCHZBRUKP-UHFFFAOYSA-N Methoxamine hydrochloride Chemical compound Cl.COC1=CC=C(OC)C(C(O)C(C)N)=C1 YGRFXPCHZBRUKP-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 229960004269 methoxamine hydrochloride Drugs 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000001525 receptor binding assay Methods 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- QGICDLYPUUZBIV-SECBINFHSA-N (2r)-2-(methoxycarbonylamino)-3-phenylpropanoic acid Chemical compound COC(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 QGICDLYPUUZBIV-SECBINFHSA-N 0.000 description 2
- QNHSPNWGYBHELH-SNVBAGLBSA-N 1,1,1-trifluoro-3-[(3R)-3-(methylamino)-3,4-dihydro-2H-quinolin-1-yl]propan-2-one Chemical compound CN[C@H]1CN(C2=CC=CC=C2C1)CC(=O)C(F)(F)F QNHSPNWGYBHELH-SNVBAGLBSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- 239000005909 Kieselgur Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 239000003814 drug Substances 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
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- 208000021822 hypotensive Diseases 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
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- 150000003016 phosphoric acids Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 238000001556 precipitation Methods 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229940086735 succinate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- YKDGRGQHSOGQJV-UHFFFAOYSA-N 4,5-dihydro-3H-benzo[cd]indol-1-amine Chemical class NN1C=C2C=3C(=CC=CC1=3)CCC2 YKDGRGQHSOGQJV-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
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- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
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Classifications
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Abstract
具有抗焦虑和抗抑郁活性和中枢神经系统活性的下列结构式含氮三环化合物及其可药用盐:
其中R1和R2独立地为氢,C16烷基或R1和R2连接起来形成吡咯烷,哌啶,吗啉或咪唑。X为OCH3,SO2R3,SO2CF3或CN,其中R3为C16烷基或芳香;并且Z为氢,Cl,Br,F,CN,CONR1R2,CF3,OCH3,SO2NR1R2。这些化合物适用于治疗抗焦虑紊乱,精神分裂症,帕金森氏病,焦虑,抑郁或在需要这种治疗的病人中作为降血压或治疗偏头疼的化合物。
Description
本发明涉及含氮三环的化合物(杂环胺),它具有抗焦虑和抗抑郁活性。这些新的化合物适于治疗中枢神经系统疾病,包括精神分裂症,帕金森氏病,焦虑,或作为降血压或治疗偏头疼的化合物。
在PCT Int.Pub.No.WO87/04153和PCT Int.Pub.No.WO88/04292中描述了一系列二氢菲那啉(dihydrophenalenes)(取代的三环胺)和具有中枢神经系统活性的相关化合物。这些化合物和本发明之间的主要区别是在三环的环状结构中,本主题化合物至少具有一个氮原子,它由两个环状结构共同占有。通常,本主题化合物显示抗焦虑活性和较好的口服生物利用度。
PCT Int.Pub.No.WO87/04153和PCT Int.Pub.No.WO88/04292各叙述了具有中枢神经系统活性的三环结构。
美国专利4,110,339公开了用作催乳激素抑制剂和治疗帕金森氏病的化合物4—(二—正丙基)氨基—1,3,4,5—四氢苯并(cd)吲哚。欧洲专利申请书153,083和德国专利3,346,573公开了甲氧基取代的4—(二—正丙基)氨基—1,3,4,5—四氢苯并(cd)吲哚化合物。这些出版物公开了含氮三环环状结构,但任何环都有共用氮。
Evans,D.D.Peter,D.J.,J.Chem Soc.,Perkin Trans.1,PP258—88(1974)公开了含氮三环环状结构,其中由两个环状结构共用氮原子,但另外包含其它不同于本主题化合物的取代基。
PCT Int.Pub.No.WO90/15058公开了除环氮上″X″取代基外,具有本发明含氮三环结构特征的化合物。
及其可药用盐。R1和R2独立地为氢,C1—C6烷基或R1和R2连接起来形成吡咯烷,哌啶,吗啉或咪唑。X为OCH3,SO2R3,SO2CF3或CN,其中R3为C1—C6烷基或—芳基;并且Y为氢,Cl,Br,F,CN,CONR1R2,CF3,OCH3,SO2NR1R2。
已发现,在由孤立引起的攻击行为和血浆皮质酮模型中,这些新的化合物显示抗焦虑活性。它们也适于治疗受5—HT1A受体影响的各种中枢神经系统疾病,如精神分裂症,帕金森氏病,焦虑,抑郁,或在需要这种治疗的病人中作为降血压或治疗偏头疼的化合物。
另一方面,本发明还提供一种方法,通过给予动物或人药学上有效量的式I化合物(包括其可药用的盐)来治疗受5—HT1A受体影响的中枢神经系统(CNS)疾病,如焦虑,抑郁,高血压及其相关的病,帕金森氏病和精神分裂症。这些化合物的其它应用包括恐惧症发作,饮食失调,在癫痫病中所见到的强迫观念与形为的失调。另外,认为在性行为传递中涉及中枢5—HT受体的激活,因此,这些化合物可用来刺激性活动和减轻阳蒌。
本发明叙述具有中枢神经系活性的上述式I化合物。该化合物的特征是三环结构,它在两环之间有共用氮原子,并具有胺取代基(NR1R2)和取代的环上氮(X),其结构如式I所述。通过查阅Chemical Abstracts Service出版的1988年版Ring SystemHandbook可以发现这些化合物环系的系统名称。通过将苯或单环杂环的名称与稠合的双环朵环的名称结合起来产生这些化合物的名称。指定与稠合的环共用的原子和键来区分具有类似名称的异构系。
在各种中枢神经系统检查如低温和缺氧应激反应试验中,发现特定化合物是活性的并发现是多巴胺和5—羟色胺(如5HT1A)受体结合分析的拮抗刻。
下列定义用于上述式I代表的结构式中。
“C1—C6烷基”指甲基,乙基,丙基,丁基,戊基和己基及其异构形式。
“芳基”指含有5—10个碳原子的芳香环结构,并可有可无地由卤原子,C16烷基(可有可无地由卤素或羟基取代的)和羟基取代,如苯基,α—萘基,áβ—萘基,间—甲基苯基,对—三氟甲基苯基等。芳基也包括各种杂芳香基,它含有杂原子氮,硫或氧来形成吡啶,噻吩,呋喃,嘧啶,2—吡啶基,3—吡啶基,4—吡啶基,2—嘧啶基,4—嘧啶基,5—嘧啶基,3—哒嗪基,4—哒嗪基,3—吡嗪基,2—喹啉基,3—喹啉基,1—异喹啉基,3—异喹啉基,4—异喹啉基,2—喹唑啉基,4—喹唑啉基,2—喹喔啉基,1—2,3—二氮杂萘基,2—咪唑基,4—咪唑基,3—异噁唑基,4—异噁唑基,5—异噁唑基,3—吡唑基,4—吡唑基,5—吡唑基,2—噁唑基,4—噁唑基,5—噁唑基,2—噻唑基,4—噻唑基,5—噻唑基,2—吲哚基,3—吲哚基,3—吲唑基,2—苯并恶唑基,2—苯并噻唑基,2—苯并咪唑基,2—苯并呋喃基,3—苯并呋喃基,2—呋喃基,3—呋喃基,2—噻吩基,3—噻吩基,2—吡咯基,3—吡咯基,1,2,4,—恶二唑—3—基,1,2,4—恶二唑—5—基,1,2,4—噻二唑—3—基,1,2,4—噻二唑—5—基,1,2,4—三唑—3—基,1,2,4—三唑—5—基,1,2,3,4—四唑—5—基,5—恶唑基,1—吡咯基,1—吡唑基,1,2,3—三唑—1—基,1,2,4—三唑—1—基,1—四唑基,1—吲哚基,1—吲唑基,2—异吲哚基,1—嘌吟基,3—异噻唑基,4—异噻唑基和5—异噻唑基。
“可药用盐”为盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,磷酸盐,醋酸盐,丙酸盐,乳酸盐,马来酸盐,苹果酸盐,琥珀酸盐,酒石酸盐,环己环氨基磺酸盐,甲磺酸盐,乙烷磺酸盐,苯磺酸盐,甲苯磺酸盐和其它可药用胺的相反离子。另外,可以以适宜的水合形式给予本发明化合物。
本发明化合物包括外消旋的和旋光纯的产品,按常规方法可将它们分成R—和S—异构体。通过使用拆分试剂,如旋光的二苯甲酰酒石酸,樟脑磺酸,双—邻—甲苯酰酒石酸,酒石酸和二乙酰基酒石酸可以拆开外消旋混合物。
用于拆分式I伯和仲胺化合物的第二种方法包含用旋光酸将其转化为非对映异构的酰胺。分离非对映异构体酰胺并将酰胺键裂开,得到旋光纯的式I化合物。在PCT国际专利No.W090/15058(实施例49和50)用叔丁氧基羰基—L—苯基丙氨酸作拆分试剂来制备光学异构体中说明了该方法。为了拆开外消旋混合物,将外消旋的化合物与叔丁氧基羰基—L—苯基氨酸结合并用色谱法将非对映异构的酰胺产生分成(+)和(-)形式。将(-)异构体与三氟乙酸反应得到(-)N—(5,6—二氢—2—氧代—4H—咪唑并(4,5,1—ij)喹啉—5—基)—L—苯基丙氨酸酰胺,通过与异硫氰酸苯酯反应再与三氟乙酸反应对该化合物进行Edman降解来除去苯基丙氨酸残基并得到(-)型化合物。该产品进一步与丙醛和氰基硼氢钠反应,得到(-)型活性异构体。
在下文路线1和2中显示了制备式I化合物的一般方法,并作为相互参照也在实施例中进行了叙述。在PCT国际专利No.WO90/15058中叙述了制备主题化合物的各种中间体的方法,将该文献引入本文供参考。
按大量因素来选择用本发明化合物治疗病人的剂量制度,这些因素包括病人的种类,年令,体重,性别和用药情况,精神病的严重性,给药途径和所使用的特定化合物。一名普通的专业医生或精神病学家可以很容易地确定并开出有效量的化合物来阻止疾病的进展。在该过程中开始时,医生或精神病学家可使用相对低的剂量。随后增大剂量直至获得最大的反应。
通常,本发明化合物的初始剂量为每天口服10mg—约1200mg的化合物,可以单剂量或多剂量给予。当采用其它形式时,给予相当的剂量。当使用600mg以上的剂量时,每次再给剂量时都要小心地监测可能的毒性作用。
用单位剂量形式如片剂,胶囊剂,丸剂,粉剂或颗粒剂来给予本发明化合物。也可以用药学领域已知的形式非肠道(例如,皮下,静脉内或肌肉内)给药。也可以以柱剂或杆剂经直肠或阴道给药。通常,优选的给药途径为口服。
也可以以可药用或可治疗用的盐来给予本发明化合物,所述盐如,盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,磷酸盐,醋酸盐,丙酸盐,乳酸盐,马来酸盐,苹果酸盐,琥珀酸盐,酒石酸盐,环己烷氨基磺酸盐,甲磺酸盐,乙磺酸盐,苯磺酸盐,甲苯磺酸盐等。另外,也可以以适宜的水合形式给予本发明化合物。
在孤独诱导的攻击行为分析中,通过以盐水为“对照”,测定化合物控制或阻止攻击行为的能力来评价本发明化合物。将雄性CF—1鼠(Charles River Labs)单独关在金属丝笼中放在抽屉里,经七周孤独和攻击行为训练。之后,当将入侵的老鼠放入笼子中时,孤独的老鼠(体得30—50g)开始“攻击”。入侵的老鼠为雄性CF—1 Charles River鼠,与孤独的老鼠大小大约相同并关在每只笼子里有12只鼠的笼中。为了试验药物的作用,给孤独的老鼠口服(P.O)药物或0.25%甲基纤维素赋形剂。30分钟后,放入入侵的老鼠并记录攻击的潜伏期。通过一名对治疗未知的观察者试验包括阳性对照的治疗组(n=6),并另外有一组非盲赋形剂组。结果如下:
化合物 秒
对照 66
实施例1 600
对照 152
实施例22 565
对照 66
实施例23 600
1:式I,其中R1为氢,R2为甲基,Y为氢并且X为—OCH3(R—对映体)
2:式I,其中R1为甲基,R2为甲基,Y为氢并且X为—OCH3(外消旋物);
3:式I,其中R1为甲基,R2为甲基,Y为氢并且X为—OCH3(R—对映体)
用受体结合分析(5HT配位体)计算IC50值和Ki(nm)值来评价实施例4化合物(式I,其中R1和R2为丙基,Y为氢并且X为—OCH3)。受体结合分析是“Cloning and PharmacologicalCharacterization of a Novel Human 5—hydroxy—1—tryptamine1D Receptor Sub—Type”Mol.pharm.,42 439—44(1992)中所述的评价化合物活性的公知的试验方法,本文引入该文献供参考。结果如下:
实施例4化合物 | 受体 | 配位体 | Ki(nm) |
外消旋物外消旋物R—对映体R—对映体R—对映体S—对映体 | 5—HTIDA一克隆5—HTIDA—克隆5—HTIDA—克隆5—HTIDA—克隆5—HTIDA—克隆5—HTIDA—克隆 | 5HT5HT5HT5HTDPATDPAT | 15.207.1738.0058.0097904 |
上述数据表明外消旋化合物对5HTIDB受体具有选择性并且其活性存在于R—对映体化合物。实施例1:(R)—5—甲氨基—1—甲氧基—5,6—二氢—4H—咪
唑并〔4,5,1—ij〕—喹啉—2(1H)—酮(8a):
制备(R)—N—(1,2,3,4—四氢—1—甲氧基—2—氧代—3—喹啉基)氨基甲酸甲酯(2a):
在0℃下,用10分钟的时间,将氯甲酸甲酯(42.8g,0.453mol)的氯仿(50ml)溶液加到(R)—1,2,3,4—四氢—1—甲氧基—2—氧代—喹啉胺1(M.Kawase T.Kitamura,Y.Kikugawa,J.Org.chem 54,19893394—3403)(0.15mol)和碳酸氢钠(54.0g,0.600mol)的氯仿(250ml)和水(100ml)的混合物中。在室温下,将混合物搅拌过夜,用戊烷稀释并分层。用乙醚萃取水层,并用盐水洗涤合并的有机萃取液,然后干燥(MgSO4)。真空除去溶剂得到琥珀色油。用闪式层析法纯化(230—400目的硅胶,35—40%乙酸乙酯的己烷液,得到淡黄色油状的标题化合物(37.0g,99%)。NMR(CDCl3,TMS)δ2.865(t,j=14.7Hz,1H),3.437(dd,j=6.0 & 15.3Hz,1H),3.723(s,3H,NOCH3),3.932(s,3H,COOCH3),4.426(dt,J=5.& & 14.2Hz,1H,N-CH),5.856(br.s,1H,NH),7.098(t of d,j=1.2 & 7.4Hz,1H),7.228(m,2H),7.331(t,j=7.7Hz,1H).[α]D=-47°(25℃,CHCl3,c=0.9977).
制备(R)—3—甲氨基—1,2,3,4—四氢喹啉(3a):
将(R)—N—(1,2,3,4—四氢—1—甲氧基—2—氧代—3—喹啉基)氨基甲酸酯(2a,36.25g,0.145mol)的四氢呋喃(400ml)溶液在冰中冷却,并加入甲硼烷二硫醚的复合物(10M,73ml,0.73mol)。除去冰浴,用冰浴冷却的混合物逐渐达到剧烈回流。反应结束后,在蒸汽浴上加热回流过夜。将混合物用冰冷却,并滴加水(80ml),10%盐酸水溶液(70ml)。在蒸汽浴上回流下,将混合物(PH试纸检查为酸性)搅拌1.25小时。将混合物在冰中冷却并用固体氢氧化钠逐渐碱化。将混合物用水和戊烷稀释并分层。用乙醚萃取水层,干燥(MgSO4)合并的有机萃取液。真空除去溶剂得到油(23.96g,100%)。用重力色谱法(70—230目的硅胶;6%甲醇,0.6%氢氧化铵,氯仿)纯化样品(1.3g)得到淡黄包油状标题化合物(0.84g)。NMR(CDCl3,TMS)δ1.529(br.s,1H,methylamine NH),2.503(s,3H,N-CH3),2.62-2.71(m,1H),2.93-3.14(m,3H),3.394(d of t,j=2.2 & 10.9Hz,1H),3.814(br.s,1H,NH),6.483(d,j=7.7Hz,1H),6.624(d oft,j=1.0 & 7.4Hz,1H),6.95-6.98(m,2H).
将化合物(0.83g,5.12mmol)溶解在甲醇中并与氯化三甲基硅(0.54g,5.0mmol)的甲醇溶液合并,真空除去溶剂。残余物从甲醇/乙醚中结晶,得到标题化合物盐酸盐的淡黄绿色结晶(0.56g,m.p.193—195℃)。
〔α)D=+26°(25℃,CH3OH;C=1.0232)。
制备(R)—N—甲基—N—〔3—((1—三氟甲基乙酰基)—1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(4a):
将(R)—3—甲氨基—1,2,3,4—四氢喹啉(3a,21.32g,0.131mol)的四氢呋喃(200ml)溶液在冰浴中冷却,并滴加三氟乙酸酐((69.2g,0.329mol)。将混合物在0℃下搅拌1小时并在室温下搅拌2小时。再次在冰浴中冷却混合物并加入水(150ml)。分批加入固体碳酸氢钠直至停止放出气体。将混合物用乙醚萃取三次,并用饱和碳酸氢钠和盐水洗涤合并的有机萃取液。将溶液干燥(MgSO4)并真空除去溶剂得到黄色油(42.2g)。用闪式层析法纯化(230—400目的硅胶;15%乙酸乙酯的己烷溶液)得到黄色油状标题化合物(31.12g,67%产率)。
〔α〕D=+59°(25℃,CHCl3,C=0.5495)。NMR(CDCl3,TMS)δ2.75-3.40(m,5H),3.65-3.95(m,1H),3.95-4.30(m,1H),4.572(quintet,j=7.6Hz,0.3H),4.921(m,0.7H),7.15-7.45(m,3.7H),7.697(m,0.3H).
制备(R)—3—甲氨基—1—三氟甲基乙酰基—1,2,3,4—四氢喹啉(5a):
将(R)—N—甲基—N—〔3—((1—三氟甲基乙酰基)—1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(4a 29.78g,84.1mmol)的四氢呋喃(140ml)溶液在冰浴中冷却并加入氢氧化钾(45.6%溶液,7.5ml,89.3mmol)的水(40ml)溶液。将混合物在0℃下搅拌30分钟并在室温下搅拌1小时。将混合物用乙醚萃取两次。用盐水洗涤合并的有机萃取液并干燥(MgSO4)。真空除去溶剂,得到黄色油(21.7g,100%)。用闪式层析法(230—400目的硅胶,15%乙酸乙酯的己烷液)纯化样品(1.05g),得到黄色油(0.90g)。从乙酸乙酯/己烷中结晶,得到标题化合物的无色固体(0.45g,m.p.68—69℃)。NMR(CDCl3,TMS)δ2.871-3.182(m,5H,N-CH3 & Ar-CH2),3.33-3.449(m,2H,N-CH2),3.890(br.s,1H,NH),4.35-4.48(m,0.4H,N-CH),4.800-4.888(m,0.6H,N-CH),6.553(t,j=7.6Hz,1H),6.660-6.735(m,1H),6.996-7.068(m,2H).[α]D=-29°(25C,CHCl3,c=0.9917).
制备(R)—N—甲基—N—〔3—(1—(N—甲氧基氨基羰基)—1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(6a):
将碳酰氯(1.93M的甲苯液,1.56ml,30.1mmol)的无水四氢呋喃(75ml)溶液在冰浴中冷却并滴加(R)—3—甲氨基—1—三氟甲基乙酰基—1,2,3,4—四氢喹啉(5a)7.75g,30.0mmol)和三乙胺(4.20ml,30.1mmol)的无水四氢呋喃(75ml)溶液。将混合物在冰浴中搅拌50分钟并加入盐酸甲氧胺(5.01g,60.0mmol)和三乙胺(8.40ml,60mmol)。在室温下将混合物搅拌24小时,用乙醚稀释并用水,10%盐酸,饱和碳酸氢钠溶液和盐水洗涤。将溶液干燥(MgSO4)并真空除去溶剂,得到油(8.85g)。用闪式层析法(230—400目的硅胶,50%乙酸乙酯的己烷液)来纯化得到标题化合物的无色油(7.42g,75%产率)。NMR(CDCl3,TMS)δ2.817-3.097(m,5H,N-CH3 & Ar-CH2),3.66-4.035(m,5H,N-CH2 &O-CH3),4.38-4.863(m,1H,N-CH),7.148-7.366(m,4H),7.813 & 7.829(two s.1H,NH).[α]D=+5°(25℃,CHCl3,c=1.137).
制备(R)—5—N—(N—甲基三氟甲基乙酰胺)—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(7a):
用氩将(R)—N—甲基—N—〔3—(1—N—甲氧基氨基羰基)—1,2,3,4—四氢喹啉基)三氟甲基乙酰胺(6a,6.61g,20.0mmol)的氯仿(100ml)溶液中的气体排出并分批滴加双(三氟乙酸基)碘代苯(10.32g,24mmol)。在回流下,将溶液搅拌7分钟。将反应混合物冷却,用戊烷稀释并用饱和碳酸氢钠溶液洗涤两次,用盐水洗涤一次。将溶液干燥(MgSO4)并真空除去溶剂得到红棕色的油(11.5g)。用闪式层析法(230—400目的硅胶;35—40%乙酸乙酯的己烷液)来纯化得到琥珀色固体(4.74g,72%产率)。用乙酸乙酯/己烷来结晶得到标题化合物的灰白色结晶(4.55g,m.p.148.5—150.5℃)。NMR(CDCl3.TMS)δ2.995-3.299(m,5H,N-CH3 & Ar-CH2),3.724-3.839(m.1H),4.089 &4.099(two s,3H,O-CH3),5.059-4.227(m,1H),4.520(heptet,j=5.4Hz,0.3H),4.931(heptet,j=5.1Hz,0.7H),6.900-7.121(m,3H).[α]D=+38°(25℃,CHCl3,c=1.0215).
制备(R)—5—甲氨基—1—甲氧基—5,6—二氢—4H—咪唑并—〔4,5,1—ij〕喹啉2—(1H)—酮(8a):
将碳酸钾(2.05g,14.8mmol)加到(R)—5—N(N—甲基三氟甲基乙酰氨基)—1—甲氧基—5.6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2—(1H)—酮(7a,3.75g,114mmol)的甲醇(75ml)溶液中。在回流下,将混合物搅拌7小时。真空除去溶剂,并将残余物在乙醚和水(75ml)之间分配,用盐水来饱和水层溶液并用乙醚萃取两次以上。干燥(MgSO4)合并的有机萃取液并真空除去溶剂得到油。放置三天后,用750%四氢呋喃的乙醚液萃取水层的产生沉淀。干燥(MgSO4)合并的有机萃取液,并真空除去溶液,得到棕色半固体。用闪式层析法(230—400目的硅胶;70—80%四氢呋喃的乙酸乙酯液)来纯化合并的样品,得到标题化合物的琥珀色油(2.7g,100%)。NMR(CDCl3,TMS)δ2.545(s,3H,N-CH3),2.781(dd,j=7.4 & 16.1Hz,1H),3.071(dd,j=4.0 &16.0Hz,1H),3.233(heptet,j=3.8Hz,1H),3.645(dd,j=7.0 & 12.4Hz,1H),4.045(m,1H),4.088(s,3H,NOCH3),6.893(d,j=7.4Hz,1H),6.964(d,j=7.1Hz,1H),7.039(t,j=7.7Hz,1H).
将样品(0.70g)溶解在四氢呋喃中,用乙醚稀释并加入过量用乙醚配制的盐酸。过滤沉淀物;用乙醚洗涤并用甲醇/乙醚结晶,得到标题化合物(8a)盐酸盐的褐色结晶(0.68g.m.p.196—197℃)。
〔α〕D=-26(25℃,CH3OH,C=1.0139)。
实施例2:(R)—5—二甲氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(9a):
按实施例1的方法,在室温下,将(R)—5—甲氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(8a,1.88g,8.06mmol)的甲醇(40ml)溶液搅拌,并加入37%甲醛水溶液(2.40ml,32mmol)和乙酸(0.98g,16.2mmol)。将混合物在冰浴中冷却,并用5分钟的时间分批滴加氰基硼氢化钠(1.15g,17.0mmol)。将混合物在0℃下搅拌5分钟并在室温下搅拌6小时。真空除去溶剂,并用10%碳酸钠溶液稀释残余物和用乙醚萃取两次。用盐水洗涤合并的有机萃取液并干燥(MgSO4)。真空除去溶剂得到琥珀色油(2.06g)。用闪式层析法(230—400目的硅胶,65%四氢呋喃的乙酸乙酯液)来纯化,得到标题化合物的琥珀色油(1.77g,89%产率)。NMR(CDCl3,TMS)δ2.436(s,6H,N-CH3),2.853-3.068(m,3H),3.525-3.596(m,1H),4.081(s,3H,O-CH3),4.188-4.243(m,1H),6.890(d,j=7.4Hz,1H),6.954(d,j=7.1Hz,1H),7.033(t,j=7.6Hz.1H).
将化合物溶解在乙醚中并加入过量用乙醚配制的盐酸。过滤沉淀物,用乙醚洗涤并用甲醇/乙醚结晶,得到标题化合物(9a)盐酸盐的黄色结晶(1.76g,195℃)。
〔α〕D=-19°(25℃,CH3OH,C=1.0234)。
实施例3:(R)—5—丙氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(8b)
(R)—N—(1,2,3,4—四氢—1—甲氧基—2—氧代—3—喹啉基)丙酰胺(2b):
将胺(1,33.51g,0.135mol)溶解在丙酸酐(78.2g,0.60mol)中,同时用冰浴控制温度。在室温下,将混合物搅拌5小时,并加入水(100ml)。缓慢加入饱和NaHCO3(200ml),然后缓慢加入10%Na2CO3来中和化合物至PH7.5。将混合物用乙醚萃取,用氯化钠饱和并用乙醚和乙醚与氯仿的混合物再次萃取。用5%NaCO3和盐水洗涤合并的萃取液,将溶液干燥(MgSO4),并真空除去溶剂,得到琥珀色的油。用闪式层析法(230—400目的硅胶,60%乙酸乙酯的己烷液)来纯化得到油。用乙酸乙酯/己烷结晶样品,得到标题化合物(2b)的无色结晶(m.p.98—99℃)。[α]D=-100°(25C,CHCl3,c=0.9698).NMR(CDCl3,TMS)δ1.206(t,J=7.6Hz,3H,CO-C-CH3),2.343(q,J=7.6 Hz,2H,COCH2),2.768(t,J=14.7Hz,1H),3.527(dd,J=6.1 & 15.1Hz,1H),3.934(s,3H,O-CH3),4.614(d of t,J=5.6 &14.2Hz,1H,N-CH),6.633(br.d,J=4.5Hz,1H,NH),7.099(d of t,J=1.2 & 7.4Hz,1H),7.230(d,J=7.9Hz,2H),7.327(t,J=7.7Hz,1H).
制备(R)—1,2,3,4—四氢—N—丙基—3—喹啉胺的—盐酸盐(3b):
在室温搅拌下,将甲硼烷二甲硫(10M,42.5ml,0.425mol)加到(R)—N—(1,2,3,4—四氢—1—甲氧基—2—氧代—3—喳啉基)丙酰胺(2b,21.29g,85.7mmol)的四氢呋喃(250ml)溶液中。反应是放热的,并用冰浴控制反应。将混合物在0℃下搅拌30分钟,在室温下搅拌过夜,然后回流4小时。将混合物在冰浴中冷却,并小心滴加水(50ml)。当反应结束时,滴加10%HCl至用PH试纸检查混合物为酸性。将混合物在室温下搅拌1小时并在回流下搅拌1小时。用戊烷洗涤混合物并过滤。将滤涤用15%氢氧化钠碱化并用乙醚萃取。用氯化钠饱和水层并用乙醚萃取两次。干燥(MgSO4)合并的乙醚萃取液,并真空除去溶剂,得到油(14.8g91%)。用重力色谱法(70—230目的硅胶,90g;3%甲醇,0.3%NH4OH,CHCl3)来纯化样品(1.0g),得到标题化合物的无色油。NMR(CDCl3,TMS)δ0.924(t,J=7.4Hz,3H,CH3),1.518(sextet,J=7.4Hz,3H),2.641-2.711(m,3H),2.965(dd,J=4.0 & 14.7Hz,1H),3.048-3.131(m,2H),3.361-3.432(m,1H),3.825(br.s,1H),6.488(d,J=7.9Hz,1H),6.626(d of t,J=1.0 & 7.4Hz,1H),6.951-7.002(m,2H).
将化合物(0.85g,4.47mmol)与氯化三甲基硅(0.57ml,4.49mmol)的甲醇溶液合并。真空除去溶剂,得到固体并用甲醇/乙醚结晶两次,得到标题化合物(3b)盐酸盐的灰白色结晶(m.p.185—192℃)。[α]D=+12°(CH3OH,25℃,c=0.8073).NMR(CD3OD,TMS)δ1.038(t,J=7.4Hz,3H,CH3),1.705-1.833(m,2H,propyl N-C-CH2),2.986(dd,J=5.5 & 17.2Hz,1H),3.065-3.120(m,2H,N-CH2),3.265-3.342(m,1H),3.436-3.572(m,2H),3.734-3.800(m,1H),6.731-6.805(m,2H),7.037-7.084(m,2H).
制备(R)—N—丙基—N—〔3—((1—三氟甲基乙酰基)—1,2,3,4,—四氢喹啉基)〕三氟甲基乙酰胺(4b):
将(R)—1,2,3,4—四氢—N—丙基—3—喹啉胺(3b,14.73g,77.4mmol)的四氢呋喃(50ml)溶液在冰浴中冷却并滴加三氟乙酸酐(40.6g,0.193mol)。加完后,撤去冰浴,并在室温将混合搅拌过夜。加入水(75ml)并分批加入碳酸氢钠,将混合物碱化至石蕊变色。用乙醚萃取混合物三次,并用饮和碳酸氢钠溶液和盐水洗涤合并的萃取液。干燥(MgSO4)溶液并真空除去溶剂,得到琥珀色油(28.4g)。用闪式层析法(230—400目的硅胶,5—6%乙酸乙酯的己烷液)来纯化样品(0.87g),将得到的无色油用己烷结晶,得到标题化合物(4b)的无色结晶(0.61g,m.p.77—79℃)。NMR(CDCl3,TMS)δ0.897-0.985(m,3H,propyl CH3),1.706(sextet,j=7.7Hz,2H,propylN-C-CH2),2.85-3.69(m,4H),3.69-4.38(m,2.6H),4.500(quintet,0.4H),7.15-7.40(m,3.6H),7.726(br.s,0.4H).[α]D=+8°(25℃,CHCl3,c=1.0067).
制备(R)—N—丙基—N—〔3—(1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(5b):
将N—丙基—N—〔3—((1—三氟甲基乙酰基)—1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(4b,27.64g,72.3mmol)的四氢呋喃(200ml)溶液在冰浴中冷却,并加入氢氧化钾(45.6%的水溶液,6.07ml,72.3mmol)溶液,将混合物在0℃下搅拌15分钟并在室温下搅拌30分钟。用乙醚稀释混合物,并分层。用乙醚萃取水层,并用盐水洗涤合并的有机萃取液并干燥(MgSO4)。真空除去溶液得到油(21.4g)。用闪式层析法(230—400目硅胶;10%乙酸乙酯的己烷液)来纯化,得到黄色油(16.68g,81%产率)。用相同的条件将样品(0.75g)再层析,得到结晶的油(0.66g)。用乙烷结晶,得到标题化合物(5b)的无色结晶(0.54g;m.p.68—69℃)。NMR(CDCl3,TMS)δ0.883-0.946(m,3H,propyl CH3),1.58-1.77(m,2H,propyl N-C-CH2).2.83-2.95(m,1H),3.104-3.483(m,4.5H),3.708(t,j=10.4Hz,0.5H),3.893(br.s,NH),4.16-4.28 &4.32-4.46(m,1H,N-CH),6.546(t,j=6.9Hz,1H),6.647-6.725(m,1H),6.965-7.063(m,2H).[α]D=-62°(25℃,CH3OH,c=0.9991).
制备(R)—N—丙基—N—〔3—(1—(N—甲氧基氨基羰基)—1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(6b):
将碳酰氯(1.93M的甲苯液,10.4ml,20.0mmol)的无水四氢呋喃(50ml)溶液在冰浴中冷却并经过5分钟的时间加入N—丙基—N—〔3—(1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(5b,5.73g,20.0mmol)和三乙胺(2.03g,20.1mmol)的无水四氢呋喃(50ml)溶液。在冰浴中,将混合物搅拌30分钟,并加入盐酸甲氧胺(3.34g,40.0mmol)和三乙胺(4.06g,40.2mmol)。在室温下,将混合物搅拌24小时,用乙醚稀释并用水洗涤,用10%盐酸溶液,饱和碳酸氢钠溶液和盐水洗涤两次。干燥(MgSO4)溶液并真空除去溶剂得到油(7.88g)。用闪式层析法(230—400目的硅胶;40%乙酸乙酯的己烷液)来纯化,得到标题化合物(6b)的油(6.25g)。NMR(CDCl3,TMS)δ0.899-0.969(m,3H,propyl CH3),1.62-1.83(m,2H,propyl N-C-CH2),2.849-3.074(m,4H),3.774(s,3,O-CH3).3.623-3.880(m,1.5H),4.089-4.154(m,0.5H),4.303-4.398(m,1H),7.121-7.382(m,4H),7.794&7.858(two s,1H,NH).[α]D=-29°(25℃,CHCl3,c =1.0139).
制备(R)—5—N—(N—丙基三氟甲基乙酰氨基)—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(7b):
用氩将(R)—N—丙基—N—〔3—(1—(N—甲氧基氨基羰基)—1,2,3,4—四氢喹啉基)〕三氟甲基乙酰胺(6b,5.92g,16.5mmol)的氯仿溶液中的气体排出并在蒸汽浴上加热到回流。分批滴加双(三氟乙酸基)碘代苯(8.50g,19.8mmol)。反应是放热的。加完后,在回流下将溶液搅拌5分钟。将反应混合物冷却,用戊烷稀释,并用饱和碳酸氢钠溶深洗涤两次,用盐水洗涤一次。将溶液干燥(MgSO4)并真空除去溶剂,得到油(9.2g)。用闪式层析法(230—400目的硅胶;30%乙酸乙酯的己烷液)来纯化,得到标题化合物(7b)的琥珀色油(3.75g,61%产率)。NMR(CDCl3,TMS)δ0.918-0.967(m,3H,propyl CH3),1.60-1.87(m,2H,propyl N-C-CH2),2.91-3.08(m,1H),3.16-3.42(m,2H),3.63-3.79(m.1H).4.089 & 4.101(two s,3H.O-CH3),3.97-4.26(m,2.6H),4.42-4.56(m.0.4H),6.884-7.097(m,4H).
制备(R)—5—丙氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(8b):
将(R)—5—N—(N—丙基三氟甲基乙酰氨基)—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—21(1H)—酮(76,3.50g,9.79mmol)的甲醇(30ml)和水(5ml)的溶液在冰浴中冷却并加入氢氧化钾(45.6%的水溶液,1.0ml,11.9mmol)。将混合物在0℃下搅拌1小时并在室温下搅拌18小时。真空下将溶剂浓缩,并将残余物在水和乙醚之间分配。用氯化钠将水层饱和并再次用乙醚萃取。干燥(MgSO4)合并的有机萃取液,并真空除去溶剂得到油(2.43g)。用闪式层析法(230—400目的硅胶;乙酸乙酯到20%四氢呋喃的乙酸乙酯液)来纯化,得到标题化合物(8b)的固体(1.79g,69%产率)。NMR(CDCl3,TMS)δ0.927(t,j=7.4Hz,3H,propyl CH3),1.112(br.s,1H,NH),1.507(sextet,j=7.3Hz,2H,propy N-C-CH2),2.629-2.804(m,3H),3.062(dd,j=4.2 & 16.0Hz,1H),3.291(heptet,j=4.0Hz,1H,N-CH),3.557(dd,j=7.7 & 12.2Hz,1H),4.066-4.156(m,1H),4.088(s,3H,O-CH3),6.887(d,j=7.4Hz,1H),6.961(d,j=7.3Hz,1H),7.036(t,j=7.5Hz,1H).
将样品溶解在乙醚中并加入过量的用乙醚配制的盐酸。过滤沉淀物并用乙醚充分洗涤,用甲醇/乙醚结晶,得到标题化合物(8b)盐酸盐的黄色固体(m.p.229℃分解)。
〔α〕D=-31°(25℃,CH3OH,C=1.1099)
实施例4:(R)—5—二丙氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(9b):
按实施例3的方法,在氮气下,将(R)—5—丙氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(8b,0.93g,3.56mmol),1—碘丙烷(3.05g,17.9mmol)和碳酸钾(1.97g,14.3mmol)在乙腈(25ml)中的混合物加热回流17小时。再加入1—碘丙烷(3.05g,17.9mmol),并将混合物再回流5小时。真空除去溶剂,并用水稀释混合物和用乙醚萃取两次。用盐水洗涤有机萃取液并干燥(MgSO4)。真空除去溶剂得到琥珀色的油。用闪式层析法(230—400目的硅胶;10—25%乙酸乙酯的己烷液,来纯化,得到标题化合物(9b)的琥珀色油(0.87g,90%产率)。NMR(CDCl3,TMS)δ0.894(t,j=7.3Hz,6H,propyl CH3),1.456(sextet,j=7.3Hz,4H,propylN-C-CH2),2.524(m,8 lines,4H,propyl N-CH2),2.823-2.975(m,2H),3.277(heptet,J=5.1Hz,1H),3.435(t,j=11.4hz,1H),4.076(s,3H,O-CH3),4.168(dd,j=4.1 & 11.5Hz,1H),6.883(d,j=7.6Hz,1H),6.942(d,j=7.5Hz,1H),7.021(t,j=7.6Hz,1H).
将化合物溶解在乙醚中,并加入过量的用乙醚配制的盐酸。过滤沉淀物,用乙醚洗涤,并用甲醇/乙醚结晶,得到标题化合物(9b)盐酸盐的灰白色固体(1.12g,m.p.175—176℃)。
〔α〕D=-13°(25℃,CH3OH,C=1.0682)。
实施例5:(R)—5—甲氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮(8a)(流程式2:实施例1的另一种方法):
制备(R)—2—(甲氧基羰基氨基)—3—苯丙酸(2):
将D—苯基丙氨酸(25.00g,0.151mol)和氢氧化钠(6.05g,0.151mol)的水(170ml)和四氢呋喃(225ml)溶液冷却至-15℃,并滴加氯甲酸甲酯(18.6g,0.197mol)的四氢呋喃(50ml)溶液。当加入一半时,也滴加氢氧化钠(9.10g,0.227mol)的水(20ml)溶液。当加完后,在室温下,将混合物再搅拌2小时并用10%盐酸酸化。将酸性溶液用乙醚萃取两次,并用盐水洗涤萃取液,然后干燥(MgSO4)。真空除去溶剂,得到纯净的油(38.38g)。HPLC 6.01分钟(78.9%),7.32分钟(5.0%),8.29分钟(10.8%),8.42分钟(0.5%),9.95分钟(1.2%),10.27分钟(2.8%),11.92分钟(0.7%)。
制备(R)—N—甲氧基—2—(甲氧基羰基氨基)—3—苯丙酰胺(3):
将碳酸钠(10.20g,96.2mmol)的水(170ml)溶液加到上述酸(~0.148mol)的二氯甲烷溶液中。加入盐酸甲氧胺(14.2g,0.170mol)和1—(3—二甲氨基丙基)—3—乙基碳化二亚胺(31.21g,0.163mol),并在室温下,将混合物搅拌22小时。用四氢呋喃(溶解沉淀物)来稀释混合物并分层。用1∶1的四氢呋喃/乙醚来萃取水层,并用10%盐酸溶液和饱和碳酸氢钠溶液来洗涤合并的有机萃取液,并干燥(MgSO4)溶液。真空除去溶剂,得到白色固体(34.2g)。用乙酸乙酯结晶,得到无色结晶(22.6g,m.p.154—155℃)。
〔α〕D=+5°(25℃,CH3OH,1.0450)。
制备(R)—N—(1,2,3,4,—四氢—1—甲氧基—2—氧代—3—喹啉基)氨基甲酸甲酯(4):
将(R)—N—甲氧基—2—(甲氧基羰基氨基)—3—苯丙酰胺(11.25g.44.6mmol)的1,2—二氯乙烷(170ml)悬浮液在冰中冷却并加入三氟乙酸(9.25ml,13.7g,0.120mol)。在0℃下,经10分钟的时间分批滴加双(三氟乙酸基)碘代苯(19.78g,0.046mol)并在同样的温度下,将混合物搅拌1小时。用10%碳酸钠溶液来洗涤混合物并干燥(MgSO4)。真空除去溶剂,得到琥珀色的油(19.58g)。用闪式层析法(230—400目的硅胶,40—50%乙酸乙酯的己烷液)来纯化,得到固化的琥珀色油(9.45g,85%产率)。用乙酸乙酯/己烷来结晶样品(1.5g)得到白色结晶(1.36g,m.p.117—119℃)。
〔α〕D=+34°(25℃,CH3OH,0.9279)。
制备(R)—3—甲氨基—1,2,3,4—四氢喹啉的马来酸盐(5):
将(R)—N—(1,2,3,4)—四氢—1—甲氧基—2—氧代—3—喹啉基)氨基甲酸盐(7.27g,29.1mmol)的无水四氢呋喃(100ml)容液在水浴中(~10℃)冷却,并加入二甲硫化硼复合物(10.0M,17.5ml,6.0eq)。将混合物在水浴中搅拌1小时,在室温下搅拌1.5小时。在蒸汽浴上,将混合物加热回流30小时,在冰中冷却,并滴加10%盐酸(40ml)。在蒸汽浴中,将混合物回流1.5小时,在冰中冷却,并用45%氢氧化钾碱化。将混合物用乙醚萃取两次,并用盐水洗涤合并的萃取液,然后干燥(MgSO4)。真空除去溶剂,得到纯净的油4.89g。将混合物(0.029mol)与马来酸(3.38g,0.029mol)合并,并用甲醇/乙醚来结晶混合物,得到标题化合物的灰白色结晶(5.77g,71%产率,VPC显示5.451分钟(100%))。用甲醇/乙醚将样品(1.0g)重结晶,得到无色固体(m.p.173.5—175℃)。制备(R)—甲基—(1,2,3,4—四氢—3—喹啉基)氨基甲酸,苯甲基酯(6):
将(R)—1,2,3,4—四氢—N—甲基—3—喹啉胺(6.00g,31.5mmol)和三乙胺(4.8g,47.4mmol)的氯仿(200ml)溶液冷却至—30℃,并滴加氨基甲酸苄酯(5.68g,95%纯,31.6mmol)的氯仿(50ml)溶液。在—30℃—0℃下,将混合物搅拌2小时,并加入10%碳酸钠溶液(100ml)。在室温下将混合物搅拌1小时,用戊烷和乙醚稀释,并分层。用乙醚萃取水层,用盐水洗涤合并的有机萃取液并干燥(MgSO4)。真空除去溶剂得到油(10.91g)。用闪式层析法(0—400目的硅胶;4∶1己烷/乙酸乙酯)来纯化得到油(7.53g,81%产率)。用乙酸乙酯/己烷来结晶样品(0.75g),得到白色结晶(0.42g,m.p.78.5℃—80℃)。
〔α〕D=—47°(25℃,CH3OH,0.8166)。
制备(R)—甲基—〔1,2,3,4—四氢—1—〔甲氧基氨基羰基〕—3—喹啉基〕氨基甲酸,苯基甲酯(7):
在0℃搅拌下,迅速将(R)—甲基—(1,2,3,4,—四氢—3—喹啉基)氨基甲酸,苯甲基酯(3.81g,12.86mmol)和三乙胺(3.9g,39mmol)的无水四氢呋喃(50ml)溶液加到碳酰氯(1.93M的甲苯液)的四氢呋喃(100ml)溶液中。除去冷浴,并将混合物搅拌1.25小时。加入甲氧胺(2.15g,25.7mmol)和三乙胺(7.9g,78mmol),在室温下将混合物搅拌3天,用乙醚稀释混合物并用水和盐水洗涤。将溶液干燥(MgSO4),并真空除去溶剂,得到油(5.13g,7100%),其纯度足够在下一步中使用。用闪式层析法(230—400目的硅胶;50%乙酸乙酯/己烷)来纯化样品(0.91g)得到油。〔α〕D=+38°(25℃,CH3OH,0.9805)。ass spec.m+369m/g。最强的峰在43,65,91,118,130,158,173,204m/z。C20H23N3O4分子量精密计算值为369.1688。实测值为369.16882。
制备甲基—(1,2,5,6—四氢—1—甲氧基—2—氧代—4H—咪唑并〔4,5,1—ij〕喹啉基—5—基〕氨基甲酸,苯甲基酯(8):
用氩将(R)—甲基—〔1,2,3,4—四氢—1—〔(甲氧基氨基)羰基〕—3—喹啉基〕氨基甲酸,苯甲基酯(7.26g,19.7mmmol)的氯仿(150ml)溶液中的气体排出,并在冰—盐浴中将混合物冷却至—5℃。加入双(三氟乙酸基)碘代苯(10.14g,23.6mmol),并将混合物在—5℃—0℃下搅拌4小时,在室温下搅拌2小时,然后在—15℃下贮存过夜。用10%碳酸钠溶液洗涤混合物,用乙醚重新萃取水性洗涤液。干燥(MgSO4)合并的有机萃取液,并真空除去溶剂,得到棕色油(10.7g)。用闪式层析法(230—400目的硅胶,50%乙酸乙酯的己烷液)来纯化,得到缓慢固化的琥珀色油(5.67g,78%)。用乙乙酯/己烷来结晶样品(0.54g)得到灰白色结晶(0.41g.m.p.105—106.5℃)。〔α〕D=+44°(25℃,CH3OH,0.7311)。
制备(R)—5,6—二氢—1—甲氧基—5—(甲氨基)—4H—咪唑并〔4,5,1—ij〕喹啉—2—酮(8a)
选择性氢化:
在一大气压氢下,将甲基—(1,2,5,6—四氢—1—甲氧基—2—氧代—4H—咪唑并〔4,5,1—ij〕喹啉基—5—基)氨基甲酸苯甲基酯(1.48g,4.03mmol)和10%披钯碳(0.25g)在无水乙醇(100ml)中的混合物搅拌。吸收1当量氢气后,将混合物经硅藻土滤器过滤,并真空除去溶剂,得到油。
制备(R)—5,6—二氢—5—(甲氨基)—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮的—盐酸盐(不是本发明化合物,在美国专利5,273,975中公开:
彻底氢化:
在初始氢气压为50Psi的Parr装置中,将甲基—(1,2,5,6—四氢—1—甲氧基—2—氧代—4H—咪唑并〔4,5,1—ij〕喹啉基—5—基)氨基甲酸苯甲酯(1.48g,4.03mmol)和20%含氢氧化钯碳0.50g(在无水乙醇(100ml)中的混合物振摇17小时。将混合物经硅藻土滤器过滤并真空除去溶剂,得到油(0.86g)。将化合物溶解在甲醇中,并加入过量用乙醚配制的盐酸。用乙醚来稀释混合物并过滤沉淀物,用甲醇/乙醚来结晶,得到灰白色固体(0.61g,63%产率,m.p.310—311℃)。〔α〕D=-30°(25℃,CH3OH,1.0182)。
路线1
Claims (9)
2.权利要求1的化合物,其中R1和R2各为丙基。
3.权利要求1的化合物,其中R1和R2各为甲基。
4.权利要求1的化合物,其中X为—OCH3。
5.权利要求1的化合物,其中Y为氢。
6.权利要求1的化合物为:
a)(R)—5—甲氨基1—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕—喹啉—2(1H)—酮;
b)(R)—5—二甲氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮;
c)(R)—5—丙氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)酮,或
d)(R)—5—二丙氨基—1—甲氧基—5,6—二氢—4H—咪唑并〔4,5,1—ij〕喹啉—2(1H)—酮。
7.将权利要求1的式I化合物制备的存物用于治疗动物或人中枢神经系统疾病,包含给予药学上有效量的式工化合物。
8.权利要求7的应用,其中每天以约10mg—约1200mg的量的口服给予所述化合物。
9.权利要求7的应用,其中给予所述化合物来治疗抗焦虑紊乱。
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IL74222A (en) | 1984-02-06 | 1988-07-31 | Lilly Co Eli | 6-substituted-4-dialkylamino tetrahydrobenz(c,d)indoles,their preparation and pharmaceutical compositions comprising them |
EP0234113A1 (en) | 1985-12-31 | 1987-09-02 | The Upjohn Company | 2,3-Dihydro-1H-phenalene-2-amino compounds as anti-psychotic drugs |
AU8325987A (en) | 1986-12-11 | 1988-06-30 | Upjohn Company, The | Antipsychotic amino-polyhydro-benz-(iso)quinolines and intermediates |
HU210264B (en) * | 1989-06-09 | 1995-03-28 | Upjohn Co | Process for producing amines of condensed ring-systems containing nitrogen and pharmaceutical compositions containing them |
JP2899757B2 (ja) * | 1989-06-26 | 1999-06-02 | 持田製薬株式会社 | ジヒドロイミダゾキノリノンオキシムスルホン酸誘導体 |
GB9012062D0 (en) * | 1990-05-30 | 1990-07-18 | Phillips Cables Ltd | Moisture-impermeable stranded electric conductor |
-
1994
- 1994-06-17 WO PCT/US1994/006648 patent/WO1995004056A1/en active IP Right Grant
- 1994-06-17 JP JP50580895A patent/JP3433804B2/ja not_active Expired - Fee Related
- 1994-06-17 AU AU72461/94A patent/AU684808B2/en not_active Ceased
- 1994-06-17 CA CA002166700A patent/CA2166700C/en not_active Expired - Fee Related
- 1994-06-17 US US10/117,634 patent/USRE40278E1/en not_active Expired - Fee Related
- 1994-06-17 AT AT94921952T patent/ATE159943T1/de not_active IP Right Cessation
- 1994-06-17 ES ES94921952T patent/ES2108474T3/es not_active Expired - Lifetime
- 1994-06-17 CN CN94192910A patent/CN1043574C/zh not_active Expired - Fee Related
- 1994-06-17 KR KR1019960700407A patent/KR100335548B1/ko not_active IP Right Cessation
- 1994-06-17 DE DE69406678T patent/DE69406678T2/de not_active Expired - Fee Related
- 1994-06-17 DK DK94921952.1T patent/DK0724584T3/da active
- 1994-06-17 NZ NZ269018A patent/NZ269018A/en unknown
- 1994-06-17 EP EP94921952A patent/EP0724584B1/en not_active Expired - Lifetime
- 1994-06-17 US US08/592,328 patent/US5652245A/en not_active Ceased
- 1994-07-26 MX MX9405676A patent/MX9405676A/es not_active IP Right Cessation
-
1997
- 1997-11-26 GR GR970403131T patent/GR3025482T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
DK0724584T3 (da) | 1998-05-25 |
ES2108474T3 (es) | 1997-12-16 |
CN1043574C (zh) | 1999-06-09 |
CA2166700C (en) | 2000-04-18 |
NZ269018A (en) | 1996-12-20 |
DE69406678D1 (de) | 1997-12-11 |
JPH09500898A (ja) | 1997-01-28 |
US5652245A (en) | 1997-07-29 |
KR960703912A (ko) | 1996-08-31 |
USRE40278E1 (en) | 2008-04-29 |
CA2166700A1 (en) | 1995-02-09 |
AU7246194A (en) | 1995-02-28 |
EP0724584A1 (en) | 1996-08-07 |
ATE159943T1 (de) | 1997-11-15 |
US20020187981A1 (en) | 2002-12-12 |
JP3433804B2 (ja) | 2003-08-04 |
GR3025482T3 (en) | 1998-02-27 |
KR100335548B1 (ko) | 2002-10-04 |
MX9405676A (es) | 1995-01-31 |
DE69406678T2 (de) | 1998-03-26 |
AU684808B2 (en) | 1998-01-08 |
WO1995004056A1 (en) | 1995-02-09 |
EP0724584B1 (en) | 1997-11-05 |
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