CN1859949A - 4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂䓬的新衍生物,其制备方法及其在药剂制备中的应用 - Google Patents
4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂䓬的新衍生物,其制备方法及其在药剂制备中的应用 Download PDFInfo
- Publication number
- CN1859949A CN1859949A CNA2004800283471A CN200480028347A CN1859949A CN 1859949 A CN1859949 A CN 1859949A CN A2004800283471 A CNA2004800283471 A CN A2004800283471A CN 200480028347 A CN200480028347 A CN 200480028347A CN 1859949 A CN1859949 A CN 1859949A
- Authority
- CN
- China
- Prior art keywords
- medicament
- galantamine
- compound
- preparation
- nmr
- 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.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims description 41
- 238000000034 method Methods 0.000 title claims description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 title abstract 2
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims abstract description 105
- 229960003980 galantamine Drugs 0.000 claims abstract description 84
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims abstract description 78
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 238
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 68
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- -1 hydroxypropyl Chemical group 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 claims description 11
- 230000003287 optical effect Effects 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 206010021143 Hypoxia Diseases 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 230000006907 apoptotic process Effects 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 206010002091 Anaesthesia Diseases 0.000 claims description 2
- 206010002660 Anoxia Diseases 0.000 claims description 2
- 241000976983 Anoxia Species 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- 206010008748 Chorea Diseases 0.000 claims description 2
- 206010012289 Dementia Diseases 0.000 claims description 2
- 238000003747 Grignard reaction Methods 0.000 claims description 2
- 206010019196 Head injury Diseases 0.000 claims description 2
- 208000010496 Heart Arrest Diseases 0.000 claims description 2
- 208000023105 Huntington disease Diseases 0.000 claims description 2
- 206010061050 Labour complication Diseases 0.000 claims description 2
- 208000002720 Malnutrition Diseases 0.000 claims description 2
- 206010027202 Meningitis bacterial Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- 230000037005 anaesthesia Effects 0.000 claims description 2
- 230000007953 anoxia Effects 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 201000009904 bacterial meningitis Diseases 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- 208000012601 choreatic disease Diseases 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125961 compound 24 Drugs 0.000 claims description 2
- 229940127204 compound 29 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 230000007850 degeneration Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 238000009792 diffusion process Methods 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 2
- 230000007954 hypoxia Effects 0.000 claims description 2
- 230000001771 impaired effect Effects 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 210000004153 islets of langerhan Anatomy 0.000 claims description 2
- 230000001071 malnutrition Effects 0.000 claims description 2
- 235000000824 malnutrition Nutrition 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 231100000572 poisoning Toxicity 0.000 claims description 2
- 230000000607 poisoning effect Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 238000010306 acid treatment Methods 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 abstract 2
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 abstract 2
- 206010012218 Delirium Diseases 0.000 abstract 2
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 abstract 2
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 abstract 2
- 230000002980 postoperative effect Effects 0.000 abstract 2
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 303
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 189
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 108
- 208000035126 Facies Diseases 0.000 description 89
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- 238000003756 stirring Methods 0.000 description 66
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 54
- 229910052938 sodium sulfate Inorganic materials 0.000 description 54
- 235000011152 sodium sulphate Nutrition 0.000 description 54
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 53
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 53
- 235000011114 ammonium hydroxide Nutrition 0.000 description 53
- 238000001914 filtration Methods 0.000 description 52
- 239000000047 product Substances 0.000 description 48
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 47
- 238000004440 column chromatography Methods 0.000 description 46
- 239000000376 reactant Substances 0.000 description 40
- 238000003810 ethyl acetate extraction Methods 0.000 description 38
- 239000012141 concentrate Substances 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 29
- 238000010992 reflux Methods 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000000605 extraction Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 14
- 229960004756 ethanol Drugs 0.000 description 14
- 238000009835 boiling Methods 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229960001866 silicon dioxide Drugs 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 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 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000012452 mother liquor Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 3
- QENVUHCAYXAROT-UHFFFAOYSA-N Galanthaminon Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(=O)C=C2 QENVUHCAYXAROT-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 3
- QENVUHCAYXAROT-YOEHRIQHSA-N Narwedine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1CC(=O)C=C2 QENVUHCAYXAROT-YOEHRIQHSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000010355 oscillation Effects 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLRBJYMANQKEAW-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)benzene Chemical compound BrCC1=CC=C(Br)C=C1 YLRBJYMANQKEAW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- OGUQCRDMRMUCFR-UHFFFAOYSA-N Br.C=1NC=CC=C2C1C=CC=C2 Chemical compound Br.C=1NC=CC=C2C1C=CC=C2 OGUQCRDMRMUCFR-UHFFFAOYSA-N 0.000 description 2
- REVWWKMCEJOLJL-UHFFFAOYSA-N C=CC.ClC1(C(C(C(=O)O)=CC=C1)C)C(=O)O Chemical group C=CC.ClC1(C(C(C(=O)O)=CC=C1)C)C(=O)O REVWWKMCEJOLJL-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 2
- 229910007857 Li-Al Inorganic materials 0.000 description 2
- 229910008447 Li—Al Inorganic materials 0.000 description 2
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 2
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- OVZIBEZHXZLITQ-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]propan-1-one Chemical compound CCC(=O)C1=CC=C(CN)C=C1 OVZIBEZHXZLITQ-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- ASUTZQLVASHGKV-IFIJOSMWSA-N 1668-85-5 Chemical class O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@H](O)C=C2 ASUTZQLVASHGKV-IFIJOSMWSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- IHBVNSPHKMCPST-UHFFFAOYSA-N 3-bromopropanoyl chloride Chemical compound ClC(=O)CCBr IHBVNSPHKMCPST-UHFFFAOYSA-N 0.000 description 1
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 1
- 102100033639 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- YYRORVJHIBLKMW-UHFFFAOYSA-N C=1NC=CC=C2C1C=CC=C2N Chemical compound C=1NC=CC=C2C1C=CC=C2N YYRORVJHIBLKMW-UHFFFAOYSA-N 0.000 description 1
- WHRFUXWYDMCHTO-UHFFFAOYSA-N CC(C)N=C=O.N(=C=O)C(C)C Chemical compound CC(C)N=C=O.N(=C=O)C(C)C WHRFUXWYDMCHTO-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102100032404 Cholinesterase Human genes 0.000 description 1
- 101710083761 Cholinesterase Proteins 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- ASUTZQLVASHGKV-SUYBPPKGSA-N ent-galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@@]23[C@H]1C[C@H](O)C=C2 ASUTZQLVASHGKV-SUYBPPKGSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000009991 scouring Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P25/08—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
- A61P25/28—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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- C07D491/10—Spiro-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及通式Ia、Ib和Ic的4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂䓬的新衍生物。所述化合物Ia、Ib和Ic不仅以有效方法具有所希望的光学纯度地在工业等级上制备,而且基于其药理学作用,其适合于制备治疗不同症状的药剂,特别是中枢神经系统(ZNS)疾病。
Description
本发明涉及4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂的新衍生物,其制备方法及其在药剂制备中的应用。
属于文端所述的化合物类型的,尤其还有加兰他敏衍生物。
加兰他敏是一种四环生物碱,其属于起可逆作用的胆碱脂酶抑制剂类,并且在阿尔茨海默氏病疗法-见Neurologist 9,235,2003;Clinical Geriatrics 9(11),55,2001-中作为活性物质使用。另外从文献中还得知,天然存在的加兰他敏的结构类似物具有不同的化学性质-见Proc.Chem.Soc.357,1964。因此,取代基在不对称碳原子上空间排列的改变引起药理学性质的显著变化-见Farmakol.Alkaloidov Serdech.Glikozidov 96,1971,Russ。鉴于药理学性质,特别是加兰他敏基体的碳原子6的空间排列具有决定性。
尽管已知大量的制备加兰他敏的方法,但是至今不可能制备天然的或合成的加兰他敏的前述6-表类似物(6-Epianaloga)的光学活性衍生物,因为无法获得用于合成所必需的光学活性中间产物11-去甲基-6-表加兰他敏。例如在WO-A-96/12692,WO-A-97/40049和WO-A-01/74820中公开了11-去甲基-加兰他敏和11-去甲基-溴代加兰他敏的手性分离。(-)-11-去甲基-加兰他敏可以从植物提取液中得到(见Nat.Prod.Sci.4,148,1998)或者以合成方式从(-)-加兰他敏得到(见US-A-5958903、WO-A-03/080623、WO-A-97/03987)。Phytochemistry 34,1656,1993中仅仅公开的是,在毫克范围内,从植物提取液中得到一种11-去甲基-表加兰他敏的1-溴-衍生物的外消旋混合物。
因此,本发明的要解决的任务是,对(+)和(-)-11-去甲基-6-表加兰他敏的制备提出改进,其也应该能够有效应用在工业等级上。
本发明提出一种通式Ia或Ib的4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂的新衍生物及其盐,
其中
·Ia是加兰他敏光学活性(-)衍生物而Ib是加兰他敏光学活性(+)-衍生物,他们是以相互间空间排列镜像形式存在的,并且其中
·Y1和Y2任选为H或OH,
·X=H或Br,以及
·Z1=下列结构式的基团
其中
·R1=H、Cl、Br、I、F、OH、直链或分支的(C1-C6)烷基、直链或分支的(C1-C6)烷氧基,NO2、NR2R3,
·R2=R3=H、直链或分支的(C1-C6)烷基,
·W=H、O、S
·n=0、1-6
并且,其中
·Z1仅仅在化合物1,3,13和24中为H
其中,化合物1和13是6-表-去甲基加兰他敏(-)-衍生物,化合物3和24是6-表-去甲基加兰他敏(+)-衍生物,且其中
·Z1仅仅在化合物29中为羟丙基
且
·Z1仅仅在化合物26中为乙基
且
·Z1仅仅在下列化合物中为甲基,且
其中,化合物29、31和55是加兰他敏(+)-衍生物,化合物26、28和56是加兰他敏(+)-表-衍生物。
根据本发明,通过将天然的以及合成的11-去甲基-加兰他敏转化为相应的6-表类似物而完成化合物Ia和Ib的制备。通过用稀酸处理,这种方法也适合于制备11-去甲基-6-表加兰他敏的光学活性衍生物,因为在制备过程中,仅仅在位置6中改变构象,而其他两个不对称中心的4a和8a保持不变。
源于这种光学活性起始物质,本发明提供了一种有效的和可工业应用的方法以用于制备(-)-表加兰他敏的光学活性衍生物以及(+)-表加兰他敏的光学活性衍生物。通过应用本发明,不仅天然存在的4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂的(-)-衍生物,而且其非天然存在的(+)-衍生物都可以用合成方法制备。
本发明方法的优点在于,在具有加兰他敏光学活性类似物以及不具有6-表加兰他敏类似物的天然或者非天然存在的衍生物上进行构象的转变。通过这样的方法,可以在一次性外消旋物分离之后,制备全部4种衍生物,即(-)-加兰他敏的、(+)-加兰他敏的以及(-)-6-表加兰他敏的和(+)-6-表加兰他敏的N-去甲基-类似物。
本发明还涉及其他具有通式Ic的4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂的新(-)-衍生物及其盐,
其中
·X是H或Br,
·Z2是H、直链或分支的(C1-C6)烷基、直链或分支的(C2-C7)链烯基、直链或分支的(C2-C7)炔基,以及
·Y3是直链或分支的(C1-C6)烷基、苯基、直链或分支的(C1-C6)烷苯基、硝苯基、氯苯基、溴苯基、氨苯基、羟苯基。
具有通式Ic的化合物就其重要性而言,其也显示出药理学作用,这可以从下述总表中得知,“AchE”代表乙酰胆碱酯酶、“BchE”代表丁酰胆碱酯酶以及IC50代表浓度,在出现50%抑制的情况下。
根据IC50值,证实了本发明化合物Ia、Ib和Ic的药理学作用。
据此,本发明同样涉及药剂,其含有一种或多种作为制药活性物质的本发明的化合物Ia、Ib或Ic。
另外,本发明还涉及一种或多种以纯净形式的或以制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗阿尔茨海默氏病症以及相关的痴呆症状、用于治疗帕金森氏症、亨廷顿舞蹈症(舞蹈病)、用于治疗多发性硬化症或肌萎缩性脊髓侧索硬化症、用于治疗癫痫症、中风后遗症或颅脑创伤后遗症、用于治疗和预防大脑中扩散氧缺乏和营养缺乏的效应,如在缺氧、低氧、窒息、心脏停搏、中毒之后,在麻醉之后以及在难产并发症出现之后对婴儿所观察到的效应,用于预防性治疗被局部的脑瘤放射疗法或化学疗法损坏或将受损的神经元的凋亡变性。
此外,本发明还涉及一种或多种以纯净形式的或以制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗细菌性脑膜炎、用于治疗具有凋亡成分的病症,特别是以淀粉状蛋白相关的细胞变性为后果的病症,以及用于治疗糖尿病,特别是当伴生有胰岛细胞的淀粉状蛋白变性病症时。
另外,本发明还涉及一种或多种以纯净形式的或以制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗或预防性治疗手术后谵妄症和/或亚综合征性手术后谵妄症。
下列实施例显示了可能的合成方式,用于提供本发明的化合物Ia、Ib和Ic。
实施例1
(4aS,6S,8S)-1-溴-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-6-醇,(Ia Y1=H,Y2=OH,X=Br,Z1=H)
20g(-)-溴-去甲基加兰他敏,其根据WO-A-97/40049制备,在800ml的2%HCl溶液中在回流冷却条件下,于沸腾温度下搅拌。3小时后,冷却反应混合物,用氨溶液调至碱性,并用3×300ml氯仿萃取。所合并的有机相通过硫酸钠干燥。过滤干燥剂并在真空中蒸发滤液。
产量:14.9g(75%理论值)
熔点:198-203℃
Rf:0.25(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.85(s,1H),6.10(d,1H),5.82(d,1H),4.59(m,2H),4.49(d,1H),3.83(d,1H),3.80(s,3H),3.30(dd,1H),3.22(dt,1H),2.72(d,1H),1.88(m,2H),1.71(t,1H);
ATP-NMR(CDCl3):δ146.8(s)143.9(s)134.2(s),132.4(d),131.5(s),126.3(d),115.4(d),112.5(s),88.6(d),62.7(d),56.2(q),52.4(t),49.2(s),46.9(t)40.6(t),32.1(t);
实施例2
(4aS,6S,8aS)-1-溴-6-羟基-3-甲氧基-4a,5,9,10-四氢-6H-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-11(12H)-硫代碳酸烯丙基酰胺,(Ia Y1=H,Y2=OH,X=Br,Z1=C4H5NS)
2.0g(5.6mmol)的(-)-表溴去甲基加兰他敏(Ia Y1=H,Y2=OH,X=Br,Z1=H)溶解在60ml四氢呋喃中,加入0.6ml烯丙基异硫氰酸酯,在回流冷却条件下于60℃搅拌。40小时后,在真空条件下蒸馏出溶剂,从氯仿/正己烷中结晶出残留物。
产量:2.28g(76%理论值)
熔点:199-207℃
Rf:0.75(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.88(s,1H),6.05(d,1H),5.90(m,2H),5.53(d,1H),5.19(d,1H),5.10(d,1H),4.64(b,2H),4.50(d,1H),4.31(m,1H),4.19(m,1H),3.88(s,3H),3.55(t,1H),2.77(m,1H),2.30(t,1H),2.08(b,1H),1.92(d,1H),1.78(dt,1H);
ATP-NMR(CDCl3):δ180.8(s),148.2(s)145.7(s)134.3(s),133.9(d),133.5(d),125.7(d),125.3(s),117.9(s),115.4(d),112.3(s),89.0(d),63.3(d),56.7(q),52.0(d),49.5(2t),49.3(s),36.8(t),32.3(t);
实施例3
(4aR,6R,8aR)-1-溴-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-6-醇,(Ib Y1=H,Y2=OH,X=Br,Z1=H)
20g(+)-溴-去甲基加兰他敏,其根据WO-A-97/40049制备,在800ml的2%HCl溶液中在回流冷却条件下,于沸腾温度下搅拌。3小时后,冷却反应混合物,用cc氨的溶液调至碱性,并用3×300ml氯仿萃取。所合并的有机相通过硫酸钠干燥。过滤干燥剂并在真空中蒸发滤液。
产量:15.5g(78%理论值)
熔点:103-205℃
Rf:0.25(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.88(s,1H),6.07(d,1H),5.82(d,1H),4.59(m,2H),4.51(d,1H),3.83(d,1H),3.80(s,3H),3.28(d,1H),3.22(t,1H),2.78(d,1H),1.91(m,2H),1.73(t,1H);
ATP-NMR(CDCl3):δ146.8(s)143.9(s)134.2(s),132.4(d),131.5(s),126.3(d),115.4(d),112.5(s),88.6(d),62.7(d),56.2(q),52.4(t),49.2(s),46.9(t)40.6(t),32.1(t);
实施例4
(4aR,6R,8aR)-1-溴-4a,5,9,10-四氢-6-羟基-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]-11(12H)-硫代碳酸甲基酰胺(Ib Y1=H,Y2=OH,X=Br,Z1=C2H4NS)
1.96g(+)-表溴去甲基加兰他敏(Ib Y1=H,Y2=OH,X=Br,Z1=H)和0.7g异硫氰酸甲酯在回流温度下在50ml甲苯中搅拌。16小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将200ml的2N HCl和50ml的乙酸乙酯混入残留物。分离有机相之后,用2×50ml的乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:1.4g(54%理论值)
熔点:80-88℃
Rf:0.45(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ8.35(b,1H,N-H),6.99(s,1H),6.01(b,1H),5.72(d,1H),4.98(d,1H),4.61(b,1H),4.29(m,1H),3.79(d,1H),3.74(s,3H),2.90(d,3H),2.51(d,1H),2.48(t,1H),1.98(t,1H),1.81(m,2H),1.65(t,1H);
ATP-NMR(DMSO):δ182.0(s),147.7(s)144.6(s)134.4(s),133.8(d),128.6(s),126.8(d),116.4(d),113.5(s),88.5(d),62.0(d),56.8(q),49.2(t),40.0(s),36.5(t)33.7(q),32.4(t);
实施例5
1-[(4aR,6S,8aR)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-11(12H)基]-3-(1-吡咯烷基)丙-1-酮,(Ib Y1=OH,Y2=H,X=Br,Z1=C7H12NO)
2.0g(+)-溴-去甲基加兰他敏,其根据WO-A-97/40049制备,以及1.0ml三乙胺和0.6ml的3-溴丙酸氯在100ml的四氢呋喃中于0℃下搅拌。10分钟后,将1.6g碳酸钾和0.6ml吡咯烷混入反应混合物,在90℃继续搅拌。17小时后,蒸馏出溶剂,将50ml水和50ml氯仿混入残留物。分离有机相之后,用2×50ml的氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH∶氨溶液=90∶9∶1)提纯。
产量:1.88g(69.3%理论值)
熔点:80-85℃
Rf:0.4(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.90(s,1H),6.07(dd,1H),5.18(d,1H),4.59(m,2H),4.31(d,1H),4.18(m,1H),3.80(s,3H),3.78(d,1H),3.22(t,1H),2.90(m,3H),2.68(m,3H),2.6-2.35(m,8H),2.01(dd,1H),1.89(dt,1H);
ATP-NMR(CDCl3):δ171.4(s),146.5(s),144.9(s),133.6(s),128.8(d),127.3(s),126.0(d),115.7(d),112.8(s),88.3(d),61.6(d),56.2(q),54.2(2t),51.8(t),51.4(t)49.0(s),44.5(t),35.6(t),33.0(t),29.6(t)23.4(2t);
实施例6
(4aR,6S,8aR)-11-苯甲基-1-溴-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-6-醇,(Ib Y1=OH,Y2=H,X=Br,Z1=C7H7)
2.0g(+)-溴去甲基加兰他敏,其根据WO-A-97/40049制备,以及4.0g碳酸钾和0.71ml苄基溴在回流温度下在40ml乙腈中搅拌。3小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将60ml水和50ml的乙酸乙酯混入残留物。分离有机相之后,用2×50ml的乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=99∶1)提纯。
产量:1.76g(69.8%理论值)黄色的油
Rf:0.75(氯仿∶MeOH=99∶1)
1H-NMR(DMSO):δ7.28(m,5H),6.92(s,1H),6.18(d,1H),5.85(dd,1H),4.59(b,1H),4.35(d,1H),4.12(m,2H),3.78(s,3H),3.64(d,1H),3.55(d,1H),2.98(d,1H),2.52(s,2H),2.27(d,1H),2.09(m,2H);
ATP-NMR(DMSO):δ146.9(s),144.6(s),139.7(s)135.0(s),129.5(d),129.5(2d),129.0(2d),128.7(s),127.7(d),127.4(d),116.3(d),113.3(s),87.7(d),60.5(d),56.7(q),56.4(t)51.2(t),49.3(s),39.9(t)34.2(t),31.6(t);
实施例7
1-[(4aR,6S,8aR)-1-溴-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-11(12H)基]-2-(4-甲基哌嗪基)乙-1-酮,(Ib Y1=OH,Y2=H,X=Br,Z1=C7H13N2O)
2.0g(+)-溴-去甲基加兰他敏,其根据WO-A-97/40049制备,以及3.92g碳酸钾在50ml的四氢呋喃中搅拌并且该悬浮液借助冰浴冷却至0℃。滴加0.48ml氯乙酰氯之后,在0℃继续搅拌30分钟,之后加入1.4ml的N-甲基哌嗪。48小时后,使其能够回流冷却,加入150ml水,用3×40ml乙酸乙酯振荡萃取。所合并的有机相用硫酸钠干燥并蒸发。将产物柱层析(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)提纯。
产量:0.7g(17.9%理论值)白色泡沫
Rf:0.42(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.88(s,1H),6.05(dd,1H),5.94(d,1H),5.59(d,1H),4.58(b,1H),4.31(d,1H),4.12(t,1H),3.85(s,3H),3.83(d,1H),3.30(d,1H),3.21(m,1H),3.03(d,1H),2.71(d,1H),2.42(m,8H),2.29(s,3H),2.04(dd,1H),1.95(dd,1H),1.78(d,1H);
ATP-NMR(CDCl3):δ169.9(s),146.9(s)144.9(s)133.4(s),129.1(d),128.3(s),126.6(d),116.3(d),113.4(s),88.8(d),62.0(d),61.4(t)56.6(q),55.4(2t),53.7(2t),52.0(s),49.5(t),46.6(q),45.2(t),35.9(t),30.1(t);
实施例8
(4aR,6R,8aR)-11-(3-(4-甲基哌嗪)-1-基-丙基)-3-甲氧基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]-苯并氮杂-6-醇,三氢氯(Ib Y1=OH,Y2=H,X=Br,Z1=C7H17N2)
步骤1
2g(+)-溴去甲基加兰他敏,其根据WO-A-97/40049制备,以及5.6ml的1-溴-3-氯丙烷和3.92g碳酸钾于80℃在10ml乙腈中搅拌4.5小时。过滤碳酸钾之后,添加70ml水,用2N HCl酸化,并用每次30ml乙酸乙酯萃取2次。用2N氢氧化钠溶液将水相调至碱性,并用每次50ml二氯甲烷振荡萃取2次。分离溶剂之后,剩余1.12g(46%理论值)黄色油。立即将产物再加工。
步骤2
1.1g的N-(3-氯丙基)-(+)-溴去甲基加兰他敏(步骤1),2.85mlN-甲基哌嗪和2.1g碳酸钾于90℃在8ml乙腈中搅拌3小时。过滤碳酸钾,蒸发溶液。用氯仿∶甲醇∶氨溶液=90∶9∶1作为洗提剂将所得2.27g物质在170g硅胶上柱层析。蒸发浓缩含产物级份,将残留物溶解在15ml乙醚中,并且在0℃用醚化HCl将其酸化。在过滤和每次5ml乙醚的两次洗涤之后,产物在30℃下,在50mbar的真空干燥箱中干燥16小时。
产量:440mg(32%理论值)白色晶体
熔点:220-238℃
Rf:0.37(氯仿∶甲醇∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ7.19(s,1H),6.21(d,1H),5.89(d,1H),4.89(d,1H),4.70(b,1H),4.55(d,1H),4.09(b,1H),3.81(s,3H),3.01-3.80(m,12H),2.80(m,3H),2.02(s,3H),2.31(m,2H),2.08(m,2H),1.85(b,1H);
ATP-NMR(DMSO):δ172.7(s),147.3(s)146.3(s)134.8(s),132.1(d),131.9(d),125.7(d),117.1(d),115.0(s),87.4(d),65.7(2t),65.0(2t),60.1(d),53.2(q),49.9(d),48.2(d),43.7(s),42.8(q),41.1(d),41.0(d),40.9(d),31.4(t);
实施例9
4-((4aR,6S,8aR)-1-溴-4a,5,9,10,11,12-六氢-6-羟基-3-甲氧基-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂-11-基)γ-氧-丁酸甲酯(Ib Y1=OH,Y2=H,X=Br,Z1=C5H7O3)
步骤1:
2.0g(+)-溴去甲基加兰他敏,其根据WO-A-97/40049制备,以及1.18ml三乙胺和0.6g琥珀酸酐于75℃在70ml四氢呋喃中强烈搅拌。30分钟后冷却反应混合物,真空蒸馏去溶剂,并将100ml的2N HCl和50ml乙酸乙酯混入残留物。分离有机相之后,用2×50ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。
产量:1.91g黄色泡沫
步骤2
1.91g泡沫,其根据步骤1制备,溶解在20ml甲醇中,混入0.6ml硫酸二甲酯,并在室温(RT)下搅拌。24小时后,将50ml水和40ml乙酸乙酯混入反应混合物。分离有机相之后,用2×30ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。产物用柱层析(乙酸乙酯)提纯。
产量:0.54g(24.3%理论值)无色油
Rf:0.35(乙酸乙酯)
1H-NMR(DMSO):δ7.25(s,1H),6.12(d,1H),5.81(m,1H),5.01(d,1H),4.69(d,1H),4.51(d,1H),4.42(m,1H),4.09M,1H),3.78(s,3H),3.53(s,3H),3.29(m,1H),2.77(m,1H),2.52(m,3H),2.28(d,1H),2.04(m,1H),1.85(m,1H),1.69(m,1H);
ATP-NMR(DMSO):δ173.6(s),170.7(s),147.4(s),144.7(s),134.3(s),129.6(d),128.3(s),127.2(d),116.2(d),111.9(s),87.4(d),60.2(d),56.8(q),52.0(q),51.2(t),49.3(s),46.2(t)39.9(t),37.0(t),31.2(t),28.7(t);
实施例10
(4aR,6S,8aR)-11-(4-氨基丙基)-3-甲氧基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇,甲烷磺酸盐(Ib Y1=OH,Y2=H,X=Br,Z1=C3H8N)
步骤1:
2.0g(+)-溴去甲基加兰他敏,其根据WO-A-97/40049制备,以及7.2ml的1-溴-3-氯丙烷和5.0g碳酸钾于室温在10ml乙腈中搅拌。19小时后,过滤沉淀物,并将80ml水、25ml的2N HCl和50ml乙酸乙酯混入过滤物。分离有机相之后,用2×40ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。
产量:1.5g无色泡沫
步骤2
1.5g泡沫,其根据步骤1制备,溶解在15ml甲醇中,混入15gNH4Cl、150ml的25%氨溶液,并在室温下搅拌。18小时后,将400ml水和75ml氯仿混入反应混合物。分离有机相之后,用2×75ml氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将残留物溶解在5ml四氢呋喃中,并用甲烷磺酸盐酸化至pH为1。分离所形成的沉淀,用四氢呋喃后洗涤,并在真空干燥箱中干燥。
产量:1.3g(71%理论值)
熔点:63-67℃
Rf:0.15(氯仿∶MeOH∶氨溶液=0∶18∶2)
1H-NMR(DMSO):δ7.88(b,2H,NH2),6.85(s,1H),6.19(d,1H),5.89(d,1H),4.70(d,1H),4.60(b,1H),4.48(b,1H),4.18(m,1H),3.80(s,3H),3.70(m,1H),3.59(b,2H),3.42(m,2H),2.88(b,2H),2.52(m,1H),1.91-2.34(m,4H);
ATP-NMR(DMSO):δ147.3(s)145.6(s)133.6(s),130.4(d),126.5(s),123.6(d),112.9(d),112.1(s),87.3(d),7.9(2t),60.4(d),56.5(q),49.8(t),40.9(t),40.8(s),37.3(t)31.7(t),25.9(t);
实施例11
(4aR,6S,8aR)-1-溴-4a,5,9,10-四氢-6-羟基-3-甲氧基-6H-[1]苯并呋喃-[3a,3,2-ef][2]苯并氮杂-11(12H)-硫代碳酸甲基酰胺(Ib Y1=OH,Y2=H,X=Br,Z1=C2H4NS)
2.0g(+)-溴去甲基加兰他敏,其根据WO-A-97/40049制备,以及0.7g异硫氰酸甲酯于回流温度在50ml甲苯中搅拌。16小时后将反应混合物冷却至室温,真空蒸馏去溶剂,并将200ml的2N HCl和50ml乙酸乙酯混入残留物。分离有机相之后,用2×50ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。产物用柱层析(氯仿∶MeOH=95∶5)提纯。
产量:2.2g(93%理论值)
熔点:98-102℃
Rf:0.7(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ7.38(b,1H,NH),6.97(s,1H),6.07(d,1H),5.80(dd,1H),4.51(b,1H),4.37(m,2H),4.09(d,1H),3.80(m,1H),3.72(s,3H),3.31(b,1H),2.81(s,3H),2.28(d,1H),2.02(d,1H),1.85(t,1H),1.61(d,1H);
ATP-NMR(DMSO):δ182.0(s),147.5(s)144.7(s)134.0(s),129.4(d),128.6(s),127.6(d),116.4(d),113.2(s),87.3(d),60.2(d),56.8(q),57.1(t),49.1(s),48.4(t)36.7(t),33.7(q),31.2(t);
实施例12
(4aS,6R,8aS)-1-溴-6-羟基-3-甲氧基-4a,5,9,10-四氢-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-硫代碳酸烯丙基酰胺(Ia Y1=OH,Y2=H,X=Br,Z1=C4H6NS)
2.0g(-)-溴去甲基加兰他敏,其根据WO-A-97/40049制备,以及0.6ml异硫氰酸烯丙酯于回流温度在60ml四氢呋喃中搅拌。9小时后将反应混合物冷却至室温,真空蒸馏去溶剂,残留物用柱层析(氯仿∶MeOH=98∶2)提纯。
产量:2.14g(83.5%理论值)
熔点:175-179℃
Rf:0.45(氯仿∶MeOH=9∶1)
1H-NMR(DMSO):δ7.41(b,1H,NH),6.95(s,1H),6.06(d,1H),5.76(m,2H),5.08(t,2H),4.42(m,3H),4.09(m,2H),3.83(m,1H),3.72(s,3H),2.51(d,2H),2.28(d,1H),2.05(d,1H),1.88(t,2H),1.76(t,1H);
ATP-NMR(DMSO):δ181.3(s),147.5(s)144.8(s),136.1(d),134.0(s),129.4(d),128.2(s),127.5(d),116.3(d),116.3(s),113.1(d),87.3(d),60.2(d),56.8(q),49.0(t),48.8(s),41.0(t)40.9(t),36.7(t),31.1(t);
实施例13
(4aS,6S,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=H,Y2=OH,X=H,Z1=H)
1g(-)-去甲基加兰他敏,其根据WO-A-00/174820制备,溶解在80ml的2%HCl溶液中,在回流条件下搅拌3小时。使反应混合物冷却至室温,用浓缩的氨的水溶液调至碱性,并用每次30ml氯仿萃取3次。所合并的有机相用硫酸钠干燥、过滤并蒸发浓缩。用氯仿∶甲醇∶氨溶液=90∶9∶1作为洗提剂将所得1.06g物质在80g硅胶上柱层析提纯,蒸发浓缩所得含产物的级份。
产量:690mg(69%理论值)白色粉末
熔点:151-155
Rf:0.29(氯仿∶甲醇∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.65(d,1H),6.49(d,1H),6.02(d,1H),5.65(d,1H),4.48(b,1H),4.25(m,1H),3.85(d,1H),3.74(d,1H),3.65(s,3H),3.15(dd,1H),3.03(m,1H),2.43(m,1H),1.79(m,2H),1.63(t,1H);
ATP-NMR(CDCl3):δ147.6(s),43.8(s),135.1(s),134.2(s),133.3(d),127.3(d),120.3(d),112.0(d),88.7(d),62.2(d),56.4(q),53.8(t),49.0(s),47.5(t)39.7(t),32.9(t);
实施例14
(4aS,6S,8aS)-6-羟基-3-甲氧基-4a,5,9,10-四氢-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-硫代碳酸甲基酰胺(Ia Y1=H,Y2=OH,X=H,Z1=C4H8NO)
2.32g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)和0.9ml异氰酸异丙酯在回流温度下在150ml甲苯中搅拌。16小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将200ml的2N HCl和50ml的乙酸乙酯混入残留物。分离有机相之后,用2×50ml的乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:1.49g(49.1%理论值)
熔点:182-186℃
Rf:0.5(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.69(b,2H),5.98(d,1H),5.81(d,1H),4.61(m,2H),4.48(d,1H),4.32(d,(1H),4.21(d,1H),3.89(m,1H),3.87(s,3H),3.42(t,1H),2.79(d,1H),2.01(dt,1H),1.79(dd,1H),1.61(d,1H),1.11(d,3H),0.98(d,3H);
13C-NMR(CDCl3):δ157.0(s),148.3(s)144.8(s)132.9(d),132.8(s),129.4(d),126.4(d),120.0(d),111.3(d),88.8(d),63.3(d),56.3(q),51.8(t),48.8(s),46.0(t),42.9(d),37.7(t),32.6(t),23.9(q),23.6(q);
实施例15
(4a S,6S,8aS)-4a,5,9,10,11,12-六氢-11-(2-(吗啉-4-基)-乙基)-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(IaY1=H,Y2=OH,X=H,Z1=C6H12NO)
1.55g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、2.35g碳酸钾和1.11g N-(2-氯乙基)吗啉盐酸化物在回流温度下在30ml乙腈中搅拌。48小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将200ml的2N HCl和40ml的乙酸乙酯混入残留物。分离之后去除有机相。用氨溶液将水相调至碱性,并用3×40ml的乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=9∶1)提纯。
产量:0.51g(23.3%理论值)白色泡沫
Rf:0.5(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.69(d,1H),6.57(d,1H),6.07(d,1H),5.78(d,1H),4.61(m,2H),4.18(d,1H),4.35(s,3H),3.80(d,1H),3.65(m,4H),3.31(t,1H),3.09(d,1H),2.69(d,1H),2.57(m,2H),2.50(m,5H),2.28(b,1H),2.19(t,1H),1.72(t,1H),1.59(d,1H);
13C-NMR(CDCl3):δ146.7(s)143.9(s)133.0(s),131.8(d),129.4(d),126.4(d),121.5(d),110.9(d),88.4(d),66.8(2t),63.0(d),57.7(d),57.1(q),55.8(t),54.1(2t),52.1(s),48.3(t),47.9(t),33.5(t),32.4(t);
实施例16
(4aS,6S,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-(2-嘧啶基)-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=H,Y2=OH,X=H,Z1=C3H3N2)
2.0g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、2.45g NaHCO3和0.88g 2-氯嘧啶在回流温度下在120ml乙醇中搅拌。44小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将120ml水和200ml的乙酸乙酯混入残留物。分离有机相之后,用2×100ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:1.24g(48.2%理论值)
熔点:223-226℃
Rf:0.65(氯仿∶MeOH=9∶1)
1H-NMR(DMSO):δ8.30(d,2H),6.72(d,1H),6.65(d,1H),6.54(t,1H),6.20(d,1H),5.72(d,1H),5.29(d,1H),5.08(d,1H),4.79(d,1H),4.48(m,2H),4.25(m,1H),3.68(s,3H),2.45(m,1H),1.95(t,1H),1.78(d,1H),1.65(t,1H);
13C-NMR(DMSO):δ161.1(s),158.8(s),147.9(s),144.1(s)133.6(s),133.5(2d),130.6(d),126.9(d),122.1(d),111.9(d),110.7(d),88.4(d),62.2(d),56.4(q),48.8(t),45.5(s),41.0(t),36.5(t),32.8(t);
实施例17
(4aS,6S,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-(2-甲基-丙-2-烯基)-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(IY1=H,Y2=OH,X=H,Z1=C4H7)
2.0g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、2.02g碳酸钾、1.27g碘化钾和0.85ml 3-氯-2-甲基-1-丙烯在回流温度下在80ml丙酮中搅拌。48小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将200ml的2N HCl和50ml的乙酸乙酯混入残留物。分离之后去除有机相。用30%氢氧化钠溶液将水相调至碱性,并用3×100ml的乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:1.8g(75.1%理论值)树脂状油
Rf:0.65(氯仿∶MeOH=95∶5)
1H-NMR(CDCl3):δ6.72(d,1H),6.53(d,1H),6.11(d,1H),5.82(d,1H),4.85(d,2H),4.60(m,1H),4.54(b,1H),4.09(d,1H),3.87(s,3H),3.67(d,1H),3.32(t,1H),3.05(m,2H),2.83(d,1H),2.18(dt,1H),1.93(b,1H),1.65(s,3H),1.71(d,1H),1.59(d,1H);
13C-NMR(CDCl3):δ146.7(s)143.9(s)133.0(s),131.8(d),129.4(d),126.4(d),121.5(d),110.9(d),88.4(d),66.8(2t),63.0(d),57.7(d),57.1(q),55.8(t),54.1(2t),52.1(s),48.3(t),47.9(t),33.5(t),32.4(t);
实施例18
(4aS,6S,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-炔丙基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=H,Y2=OH,X=H,Z1=C3H3)
2.6g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、6.1g碳酸钾、3.64g碘化钾和1.47ml的3-溴-1-丙炔在回流温度下在150ml乙腈中搅拌。12小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将300ml的2N HCl和100ml的乙酸乙酯混入残留物。分离之后去除有机相。用氨溶液将水相调至碱性,并用3×100ml的亚甲基氯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:0.8g(26.1%理论值)
熔点:157-160℃
Rf:0.45(氯仿∶MeOH=95∶5)
1H-NMR(CDCl3):δ6.65(d,1H),6.58(d,1H),6.08(d,1H),5.85(d,1H),4.72(m,1H),4.65(b,1H),4.12(d,1H),3.87(s,3H),3.79(d,1H),3.38(s,2H),3.31(m,1H),3.20(d,1H),2.45(b,1H),2.31(s,1H),2.10(dt,1H),1.72(m,2H);
13C-NMR(CDCl3):δ146.7(s)143.9(s)132.9(s),131.9(d),128.5(s),126.4(d),121.6(d),111.0(d),88.4(d),79.5(s),72.9(t),63.0(d),58.0(t),55.9(q),51.7(t),48.0(t),43.9(s),34.9(t),32.3(t);
实施例19
(4aS,6S,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-苯甲酰-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=H,Y2=OH,X=H,Z1=C7H5O)
2.0g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、3.0g碳酸钾和0.9ml苯甲酰氯在回流温度下在50ml乙腈中搅拌。1小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将100ml水和50ml乙酸乙酯混入残留物。分离有机相之后,用2×50ml的乙酸乙酯萃取。所合并的有机相用2×40ml的1N HCl和1×20ml饱和NaCl溶液(盐水)洗涤,并用硫酸钠干燥、过滤并在真空中浓缩。残留物从2-丁酮中结晶。
产量:1.5g(54%理论值)
熔点:198-199℃
Rf:0.4(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)
1H-NMR(DMSO):δ7.61(m,4H),7.18(d,1H),6.69(m,2H),6.12(d,1H),5.78(b,1H),4.61(b,2H),4.28(b,2H),3.71(s,3H),3.53(m,1H),3.52(m,2H),1.92(m,2H),1.63(m,2H);
13C-NMR(DMSO):δ170.2(s)147.1(s)143.5(s),136.6(s),132.9(s),132.7(d),128.7(s),128.0(d),126.2(d),126.0(d),125.8(d),125.5(d),120.8(d),119.3(d),111.3(d),87.4(d),61.1(d),55.4(q),53.1(t),48.1(s),47.3(t),43.1(t),31.8(t);
实施例20
(4aS,6S,8aS)-6-羟基-3-甲氧基-4a,5,9,10-四氢-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-硫代碳酸烯丙基酰胺(Ia Y1=H,Y2=OH,X=H,Z1=C7H5O)
1.5g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)和0.6ml异硫氰酸烯丙酯在回流温度下在50ml四氢呋喃中搅拌。3小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂。将残留物柱层析(氯仿∶MeOH=97∶3)提纯。
产量:1.9g(92%理论值)白色泡沫
Rf:0.25(氯仿∶MeOH=97∶3)
1H-NMR(CDCl3):δ6.67(m,2H),6.01(d,1H),5.88(m,2H),5.50(b,1H),5.31(d,1H),5.09(t,2H),4.02(d,1H),4.61(m,2H),4.23(m,2H),3.85(s,3H),3.60(t,1H),2.78(d,1H),2.22(t,1H),1.88(d,1H),1.75(t,1H);
ATP-NMR(DMSO):δ181.6(s),148.7(s)145.3(s)134.2(d),132.8(d),126.8(s),126.4(d),1120.3(d),117.2(s),111.5(d),88.7(d),63.4(d),56.4(q),54.0(t),51.4(s),48.9(t),48.7(t),36.7(t),32.4(t);
实施例21
(4a S,6S,8aS)-4a,5,9,10-四氢-6-羟基-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-羧酰胺(Ia Y1=H,Y2=OH,X=H,Z1=CH2NO)
2.2g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)和1.05g氰化钠在室温下在112ml水中搅拌,并逐份地混入16ml的2N HCl。24小时后,过滤析出的沉淀,用2×2ml水洗涤,并在50℃的真空干燥箱中干燥18小时。
产量:0.56g(22%理论值)
熔点:168-173℃
Rf:0.25(氯仿∶MeOH=9∶1)
1H-NMR(DMSO):δ6.62(d,1H),6.49(d,1H),6.00(d,1H),5.58(d,1H),4.47(b,1H),4.26(t,1H),3.85(d,1H),3.72(d,1H),3.70(s,3H),3.09(m,2H),2.45(m,2H),1.75(m,1H),1.59(t,(1H);
13C-NMR(DMSO):δ147.6(s)143.8(s)135.1(s),134.2(s),133.3(d),127.2(d),120.3(d),112.0(d),88.7(d),62.2(d),56.4(q),53.8(t),49.0(s),47.4(t),41.1(t),32.9(t);
实施例22
(4a S,6S,8a S)-4a,5,9,10,11,12-六氢-3-甲氧基-11-(3-甲基丁-2-烯-1-基)-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=H,Y2=OH,X=H,Z1=C5H9)
2.0g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、2.02g碳酸钾和1.0ml的3,3-二甲基烯丙基溴化物在回流温度下在80ml乙腈中搅拌。48小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将200ml的2N HCl和50ml的乙酸乙酯混入残留物。分离之后去除有机相。用氨溶液将水相调至碱性,并用3×100ml的乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=9∶1)提纯。
产量:1.93g(77%理论值)
熔点:36-48℃
Rf:0.2(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ6.63(d,1H),6.48(d,1H),6.01(d,1H),5.67(d,1H),3.25(m,1H),3.04(d,1H),4.49(s,1H),4.24(b,1H),3.99(d,1H),3.71(s,3H),3.58(d,1H),3.21(t,1H),3.10(m,2H),2.48(m,2H),2.01(dt,1H),1.68(s,3H),1.62(dt,1H),1.43(s,3H);
13C-NMR(DMSO):δ147.1(s),144.0(s)134.4(s),133.5(d),130.6(s),126.7(d),123.2(d),121.1(d),112.1(d),88.7(d),62.2(d),57.8(s),56.3(q),51.8(t),50.4(s),48.6(t),41.0(t),40.0(t),39.7(t)26.6(q),18.8(q);
实施例23
(4aS,6S,8aS)-1-溴-11-(4-溴苯甲基)-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(IaY1=H,Y2=OH,X=H,Z1=C7H4Br)
2.0g(-)-表-去甲基加兰他敏(Ia Y1=H,Y2=OH,X=H,Z1=H)、6.0g碳酸钾和1.92g的4-溴苯甲基溴化物在室温下在40ml四氢呋喃中搅拌。12小时后,将反应混合物冷却至室温,过滤沉淀并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:1.81g(56%理论值)
熔点:77-100℃
Rf:0.3(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ7.47(d,2H),7.21(d,2H),6.68(d,1H),6.39(d,1H),6.08(d,1H),5.69(d,1H),3.98(d,1H),4.56(b,1H),4.11(d,1H),3.71(s,3H),4.50(m,3H),3.32(m,1H),2.95(d,1H),2.49(m,1H),2.13(t,1H),1.62(t,1H),1.48(d,1H);
13C-NMR(DMSO):δ147.3(s),144.2(s),139.6(s)134.2(s),133.6(d),131.9(2d),131.6(2d),130.2(s),126.6(d),121.8(d),120.6(s),112.2(d),88.6(d),62.2(d),57.6(t),55.3(q),51.6(t),48.7(s),41.0(t),34.0(t),33.0(t);
实施例24
(4aR,6R,8R)-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ib Y1=H,Y2=OH,X=H,Z1=H)
10g(+)-去甲基加兰他敏,其根据WO-A-01/74820制备,在400ml的2%HCl溶液中,在回流冷却条件下于沸腾温度搅拌。3小时后,冷却反应混合物,用cc氨溶液调至碱性,并分离析出的沉淀。
产量:7.6g(76%理论值)
熔点:166-168℃
Rf:0.2(氯仿∶甲醇∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.70(d,1H),6.62(d,1H),6.00(d,1H),5.78(d,1H),4.68(b,2H),3.95(d,1H),3.85(d,1H),3.79(s,3H),3.32(d,1H),3.20(t,1H),2.75(m,1H),1.90(d,1H),1.82(dt,1H),1.59(dt,1H);
13C-NMR(CDCl3):δ147.5(s)144.2(s)133.5(s),133.4(s),132.5(d),126.9(d),120.5(d),111.2(d),88.9(d),63.0(d),56.3(q),54.1(t),49.0(s),47.6(t),41.4(t),32.7(t);
实施例25
(4aR,6R,8aR)-4a,5,9,10-四氢-6-羟基-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-羧酰胺(Ib Y1=H,Y2=OH,X=H,Z1=CH2NO)
2.2g(+)-表-去甲基加兰他敏(Ib Y1=H,Y2=OH,X=H,Z1=H)溶解在112ml重蒸馏水中,用2N HCl调至pH=3,加入1.05g的NaOCN,重新用2N HCl将pH值调至3。在室温下将反应混合物搅拌20小时,过滤形成的沉淀,在50mbar和60℃的真空干燥箱中干燥20小时。所得2.2g粗产物通过加热至回流溶解在15ml的MeOH中,在冰浴条件下搅拌1小时并且过滤。
产量:1.1g(43.2%理论值)白色结晶
熔点:208-214℃
Rf:0.45(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ6.72(d,1H),6.68(d,1H),6.08(d,1H),5.87(b,2H,NH2),5.69(d,1H),5.00(d,1H),4.59(d,1H),4.48(s,1H),4.28(m,1H),4.11(m,1H),3.71(s,3H),3.38(m,2H),2.49(m,2H),1.88(dt,1H),1.62(m,2H);
13C-NMR(DMSO):δ158.3(s),147.8(s),144.2(s)133.6(d),133.5(s),131.1(s),126.8(d),121.3(d),112.0(d),88.5(d),62.2(d),56.4(q),48.7(t),45.5(s),41.0(t),37.9(t),32.8(t);
实施例26
(4aR,6R,8aR)-4a,5,9,10,11,12-六氢-3-甲氧基-11-乙基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ib Y1=H,Y2=OH,X=H,Z1=C2H5)
1.35g(+)-表-去甲基加兰他敏(Ib Y1=H,Y2=OH,X=H,Z1=H)、2.0g碳酸钾和0.8ml乙基溴化物在回流温度下在50ml四氢呋喃中搅拌。70小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将50ml水和50ml的乙酸乙酯混入残留物。分离有机相之后,用2×50ml的乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)提纯。
产量:1.0g(67.2%理论值)
熔点:135-136℃
Rf:0.2(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)
1H-NMR(DMSO):δ6.63(d,1H),6.50(d,1H),6.05(d,1H),5.68(d,1H),4.95(b,1H),4.48(s,1H),4.27(b,1H),4.02(d,1H),3.72(s,3H),3.68(d,1H),3.29(t,1H),3.08(d,1H),2.41(m,2H),2.03(t,1H),1.62(t,1H),1.57(d,1H),0.91(t,3H);
13C-NMR(DMSO):δ147.2(s)144.0(s)134.1(s),133.5(d),130.3(s),126.7(d),121.8(d),112.1(d),88.6(d),62.2(d),56.9(d),56.3(q),51.7(t),48.7(s),45.5(t),33.7(t),33.0(t),13.5(q);
实施例27
甲基(4aR,6R,8aR)-N11-氰基-6-羟基-3-甲氧基-4a,5,9,10-四氢-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-羧亚胺硫醚(Ib Y1=H,Y2=OH,X=H,Z1=C2H5)
2.5g(+)-表-去甲基加兰他敏(Ib Y1=H,Y2=OH,X=H,Z1=H)和1.05g二甲基-N-氰基二硫亚氨基碳酸酯在回流温度下在80ml乙醇和20ml二甲基甲酰胺中搅拌。21小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂。将残留物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:0.72g(20.5%理论值)
熔点:78-79℃
Rf:0.35(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ6.72(m,2H),6.12(d,1H),5.72(d,1H),5.05(m,2H),6.19(m,2H),4.26(b,1H),3.72(s,3H),3.32(b,1H),2.62(s,3H),2.49(m,1H),1.89(m,2H),1.65(m,1H);
13C-NMR(DMSO):δ148.0(s),144.9(s)134.1(d),133.0(s),127.3(s),126.3(d),121.7(d),115.5(s),115.0(s),112.3(d),88.2(d),62.0(d),56.4(q),48.4(t),41.0(s),40.9(t),40.8(t),32.7(t),16.6(q);
实施例28
(4aR,6R,8aR)-4a,5,9,10,11,12-六氢-3-甲氧基-11-甲基-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-胺,二盐酸化物
3.0g(+)-加兰他敏,其根据Kametani,Heterocycles 4,1111,1976制备,以及3.3g三苯基膦和18ml叠氮酸(1.06mol/L粗苯)溶解在225ml四氢呋喃中,在室温下混入7.0ml偶氮二羧酸二乙酯(占甲苯的40%)并且强烈搅拌。20小时后,将反应混合物与150ml的2NHCl混合,强烈搅拌1小时,分离有机相,用2×50ml的乙酸乙酯洗涤水相。用氨溶液将水相pH值调至12,用3×80ml亚甲基氯萃取混浊的悬浮液。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)提纯。所得油溶解在异丙醇中,氯氢盐从醚化的HCl中沉淀出来。
产量:1.54g(41%理论值)
熔点:235-250℃
Rf:0.45游离碱(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)
1H-NMR(CDCl3):δ6.69(d,1H),6.60(d,1H),6.21(d,1H),5.75(d,1H),4.62(b,1H),4.37(m,1H),4.08(d,1H),3.89(s,3H),3.67(d,1H),3.29(t,1H),3.09(d,1H),2.81(m,1H),2.41(s,3H),2.22(dt,1H),1.85(dt,1H),1.67(d,1H);
13C-NMR(CDCl3):δ146.9(s)144.3(s)132.8(s),129.8(s),129.3(d),126.9(d),122.1(d),111.5(d),87.9(d),60.8(d),56.3(q),54.4(t),53.8(q),48.6(s),42.5(d),34.7(t),29.1(t);
实施例29
(4aR,6S,8aR)-11-(3-羟丙基)-3-甲氧基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ib Y1=OH,Y2=H,X=H,Z1=C3H7O)
1.3g(+)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及2.6g碳酸钾和0.65ml的3-溴-1-丙醇在回流温度下在70ml乙腈中搅拌。48小时后,将反应混合物冷却至室温,在真空条件下蒸馏出溶剂,将90ml水和40ml氯仿混入残留物。分离有机相之后,用2×30ml氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=9∶1)提纯。
产量:0.86g(54.5%理论值)树脂状油
Rf:0.45(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.66(m,2H),6.05(m,2H),4.59(b,1H),4.14(m,1H),4.09(d,1H),3.95(d,1H),3.81(s,3H),3.79(t,2H),3.31(m,2H),2.75(m,3H),2.05(m,2H),1.78(m,1H),1.59(m,2H);
13C-NMR(CDCl3):δ146.2(s)144.7(s)133.5(s),128.7(s),128.2(d),127.0(d),122.7(d),111.6(d),89.1(d),64.8(t),62.4(d),57.8(d),56.3(q),52.4(t),52.1(t),48.7(s),33.3(t),30.3(t),27.9(t);
实施例30
(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-羧硫代酰胺(Ib Y1=OH,Y2=H,X=H,Z1=CH2NO)
2.2g(+)-去甲基加兰他敏,其根据WO-A-01/74820制备,溶解在112ml重蒸馏水中,用2N HCl调至pH=3,加入1.05g的NaOCN,重新用2N HCl将pH值调至3。在室温下将反应混合物搅拌20小时,用浓缩的氨溶液调至碱性,并用每次40ml二氯甲烷振荡分离3次。所合并的有机相用硫酸钠干燥、过滤并蒸发浓缩。用氯仿∶甲醇=95∶5作为洗提剂将所得2.5g物质在170g硅胶上层析提纯。蒸发浓缩提纯了的级份。
产量:1.08g(42.4%理论值)白色结晶
熔点:101-114℃
Rf:0.29(氯仿∶MeOH=95∶5)
1H-NMR(DMSO):δ6.75(d,1H),6.69(d,1H),6.08(d,1H),5.87(b,2H,NH2),5.78(dd,1H),5.60(d,1H),4.54(b,1H),4.22(m,2H),4.05(m,1H),3.70(s,3H),3.39(m,1H),2.29(d,1H),2.05(dd,1H),1.78(t,1H),1.60(d,1H);
13C-NMR(DMSO):δ158.3(s),147.6(s),144.2(s)133.1(d),131.1(s),129.0(d),127.8(d),121.1(d),111.9(d),87.3(d),60.6(d),56.4(q),51.0(t),48.6(s),45.5(t),38.1(t),31.6(t);
实施例31
(4aS,6S,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-苯甲酰基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇
步骤1
-种在42ml冰乙酸中6.0g根据Kametani,Heterocycles 4,1111,1976制备的(+)-加兰他敏的溶液,在0-5℃下逐份地混入-种12.7ml硝酸和21ml冰乙酸的混合物。15分钟后,将反应混合物滴加入100ml水中,用氨溶液将pH值调至12,并混入100ml氯仿。分离有机相之后,用3×50ml氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:1.47g(19.4%理论值)棕色油
Rf:0.25(氯仿∶MeOH=95∶5)
步骤2
1.47g步骤1所得产物、2.94g锌粉和1.47g CaCl2在回流温度下在44ml乙醇和22ml水中搅拌。3小时后,过滤所得沉淀并蒸馏去溶剂。将产物柱层析(氯仿∶MeOH∶氨溶液=90∶9∶1)提纯。
产量:0.36g(43.4%理论值)
熔点:166-167℃
Rf:0.3(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ6.18(s,1H),6.04(d,1H),5.78(dd,1H),4.41(b,2H,NH2),4.33(b,1H),4.01(d,1H),3.82(d,1H),3.58(s,3H),3.55(d,1H),3.18(t,1H),2.87(d,1H),2.28(s,3H),2.22(d,1H),1.98(d,1H),1.89(t,1H),155(d,1H);
13C-NMR(DMSO):δ158.3(s),147.6(s),144.2(s)133.1(d),131.1(s),129.0(d),127.8(d),121.1(d),111.9(d),87.3(d),60.6(d),56.4(q),51.0(t),48.6(s),45.5(t),38.1(t),31.6(t);
实施例32
2-((4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)-1-甲基-1-(3-苯氧苯基)乙烷盐酸化物(Ia Y1=OH,Y2=H,X=H,Z1=C15H15O)
步骤1
3.63g(+/-)-2-[3-苯氧基苯基]-1-丙酸溶解在20ml四氢呋喃中,加入700mg锂铝氢化物并在室温下搅拌1小时。之后小心地滴加50ml水,搅拌1小时并过滤。用每次20ml乙酸乙酯萃取透明滤液3次,所合并的有机相用硫酸钠干燥、过滤并移除溶剂。
产量:2.4g(70%理论值)无色油
Rf:0.36(石油醚∶乙酸乙酯=4∶1)
步骤2
3.15g三苯基膦溶解在90ml四氢呋喃中,滴加0.6ml溴,将源于步骤1的2.4g(+/-)-2-[3-苯氧基苯基]-1-丙醇以固态加入到所形成的悬浮液中。30分钟后,加入100ml水,用每次30ml的乙酸乙酯萃取3次,将有机相合并,用硫酸钠干燥、过滤,并且通过短硅胶柱层析该透明滤液。溶剂蒸发去除后,得到2.7g(88%理论值)无色油。产生的(+/-)-2-[3-苯氧基苯基]-1-溴丙烷立即应用到下一步骤中。
步骤3
4.56g(-)-去甲基加兰他敏HCl,其根据WO-A-01/74820制备,以及4g的3-(1-溴-2-丙基)-二苯基醚和9.97g碳酸钾在85℃下在53ml乙腈中搅拌40小时。将悬浮液注入10ml水中,用每次30ml乙酸乙酯萃取3次。用硫酸钠干燥有机相之后,将其过滤并蒸发浓缩,用乙酸乙酯将所得4.5g物质在400g硅胶上柱层析提纯。去除含产物级分中的溶剂,吸收入50ml二乙基醚中,盐酸化物用醚化的HCl沉淀出来。
产量:1.5g(19%理论值)
熔点:109-115℃
Rf:0.67(乙酸乙酯)
1H-NMR(CDCl3):δ7.35(m,2H),7.24(m,1H),7.13(m,1H),7.00(m,2H),6.89(m,3H),6.62(m,2H),6.04(m,2H),4.60(b,1H),4.14(m,2H),3.85(s,3H),3.77(t,1H),3.38(m,1H),3.12(m,1H),2.91(m,1H),2.70(m,2H),2.48(m,1H),1.99(m,2H),1.48(m,1H),1.25(m,3H);
13C-NMR(CDCl3):δ157.3(s),157.2(s),157.0(s),148.3(s),148.2(s),145.8(s)144.0(s)133.2(s),133.1(s),129.9(s),129.6(d),129.5(d),129.4(d),127.5(d),127.4(d),127.0(d),123.0(d),122.9(d),122.2(d),122.1(d),121.9(d),121.8(d),118.7(d),118.6(d),111.0(d),88.7(d),62.1(d),58.0(t),57.0(t),55.9(q),52.3(t),51.2(t),48.5(s),48.4(s),37.9(d),37.7(d),32.8(t),32.5(t),29.9(t),20.0(q),19.5(q);
实施例33
(4aS,6R,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-苯甲酰基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=OH,Y2=H,X=H,Z1=C7H5O)
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,在稍微加热条件下溶解在50ml乙腈中并冷却至0-10℃。将3.0g碳酸钾和0.9ml苯甲酰氯混入反应混合物,在室温下继续搅拌。1小时后,在真空条件下蒸馏出溶剂,将50ml水和20ml乙酸乙酯混入残留物。分离有机相后用3×20ml的乙酸乙酯萃取水相,所合并的有机相用2×20ml的1N HCl和1×20ml水洗涤,用硫酸钠干燥、过滤并在真空中浓缩。将残留物从2-丁酮和叔丁甲醚(MTBE)中结晶出来。
产量:1.76g(63.7%理论值)
熔点:152-154℃
Rf:0.75(氯仿∶MeOH∶氨溶液=95∶4.5∶0.5)
1H-NMR(DMSO):δ7.39(m,4H),7.11(d,1H),6.72(b,1H),6.63(d,1H),6.09(m,1H),5.81(b,1H),4.62(d,1H),4.55(b,1H),4.31(m,2H),4.09(d,1H),3.71(s,3H),3.48(m,1H),2.32(t,1H),2.09(m,1H),1.89(b,1H),1.70(m,1H);
13C-NMR(DMSO):δ171.0(s)147.8(s)144.5(s),137.5(s),133.3(s),130.1(d),129.7(s),129.4(d),129.3(d),129.0(d),127.7(d).127.5(d),121.6(d),120.3(d),112.3(d),87.3(d),60.5(d),56.4(q),54.2(t),48.5(s),44.0(t),37.4(t),31.4(t);
实施例34
2-((4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)乙酰胺(Ia Y1=OH,Y2=H,X=H,Z1=C2H4NO)
3.0g(-)-去甲基加兰他敏HCl,其根据WO-A-01/74820制备,以及3.0g碳酸钾和1.4g的2-溴乙酰胺在回流条件下在50ml乙腈中搅拌。3小时后,在温热条件下过滤所得沉淀,在真空条件下去除溶剂,将残留物从乙醇中结晶出来。
产量:1.74g(54.4%理论值)
熔点:107-113℃
Rf:0.5(氯仿∶MeOH∶氨溶液=89∶10∶1)
1H-NMR(DMSO):δ7.18(d,2H,NH2),6.71(d,1H),6.52(d,1H),6.07(d,1H),5.81(dd,1H),4.48(b,1H),4.27(d,1H),4.19(d,1H),4.05(b,1H),3.71(s,3H),3.63(d,1H),3.28(t,1H),3.00(d,1H),2.88(d,1H),2.27(d,1H),2.06(m,1H),1.93(t,1H),1.46(d,1H);
13C-NMR(DMSO):δ173.2(s),147.1(s),144.3(s)133.6(s),130.2(s),129.2(d),127.7(d),121.9(d),112.1(d),87.6(d),60.8(d),58.5(t),56.4(q),56.3(t),52.6(s),48.6(t),35.1(t),31.7(t);
实施例35
3-[(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基]-2-甲基-1(-4-甲基苯基)丙-1-酮,盐酸化物(Ia Y1=OH,Y2=H,X=H,Z1=C11H13O)
6.0g(-)-去甲基加兰他敏HCl,其根据WO-A-017/4820制备,以及3.3g的4-甲基苯基·乙基甲酮、6.0ml的1,3-二氧杂环戊烷和0.2ml的2N HCl在回流条件下搅拌。3小时后,蒸馏出溶剂,将100ml水和50ml乙酸乙酯混入残留物。用氨溶液将水相的pH值调至9。分离有机相之后,用3×50ml乙酸乙酯萃取水相。用1×20ml饱和NaCl溶液(盐水)和1×20ml水洗涤所合并的有机相,用硫酸钠干燥、过滤并在真空中浓缩,将产物柱层析(乙酸乙酯∶正己烷=1∶1到8∶2)提纯。将所得物质吸收入乙酸乙酯,用酯化HCl将盐酸化物盐沉淀出来。
产量:4.4g(48%理论值)
熔点:143-151℃
Rf:0.4(氯仿∶MeOH=97∶3)
1H-NMR(CDCl3):δ7.84(m,2H),7.26(m,2H),6.68(m,2H),6.05(m,2H),4.61(b,1H),4.14(m,2H),3.86(s,3H),3.71(m,2H),3.34(m,1H),3.12(m,2H),2.69(d,1H),2.55(m,1H),2.30(m,4H),2.03(m,2H),1.49(d,1H),1.15(m,3H);
13C-NMR(CDCl3):δ203.4(s),145.9(s),144.2(s)143.8(s),134.4(s),133.3(s),129.7(s),129.3(d),129.2(d),128.4(d),128.3(d),127.6(d),126.9(d),122.0(d),111.1(d),88.7(d),62.1(d),57.8(t),55.9(q),54.1(t),52.2(t),48.5(s),39.1(d),32.9(t),29.9(t),21.6(q),16.5(q);
实施例36
1-[(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基]-2-(1-哌啶基)乙-1-酮(Ia Y1=OH,Y2=H,X=H,Z1=C7H12NO)
3.0g(-)-去甲基加兰他敏,其根据WO-A-017/4820制备,以及1.86ml三乙胺和0.6ml氯乙酰氯在0℃在150ml四氢呋喃中搅拌。10分钟后,将3.0g碳酸钾和0.93ml哌啶混入反应混合物,并在90℃继续搅拌。48小时后,蒸馏出溶剂,将50ml水和50ml氯仿混入残留物。分离有机相之后,用2×30ml氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩,将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:2.06g(47.1%理论值)树脂状油
Rf:0.3(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.69(m,2H),5.98(m,2H),5.19(d,1H),4.56(b,1H),4.37(d,1H),4.15(d,1H),3.80(s,3H),3.27(d,1H),3.18(m,1H),2.89(d,1H),2.69(d,1H),2.41(m,5H),2.06(d,1H),1.91(m,1H),1.75(d,1H),1.50(m,4H),1.39(b,1H);
13C-NMR(CDCl3):δ196.5(s),146.8(s),144.6(s),132.5(s),128.7(s),128.0(s),28.2(d),126.5(d),122.0(d),111.3(d),88.4(d),62.3(t),61.8(d),55.9(d),55.8(q),55.6(t),52.2(s),45.0(t),38.6(t),35.7(t),29.9(t),25.8(t),23.9(t);
实施例37
(4aS,6R,8aS)-3-甲氧基-11-(2-嘧啶基)-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=OH,Y2=H,X=H,Z1=C4H3N2)
2.0g(-)-去甲基加兰他敏,其根据WO-A-017/4820制备,以及2.45g的NaHCO3和0.88ml的2-氯嘧啶在沸腾温度下在120ml乙醇中搅拌。44小时后,蒸馏出溶剂,将120ml水和100ml乙酸乙酯混入残留物。分离有机相之后,用2×100ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩,将产物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:1.26g(49%理论值)
熔点:232-235℃
Rf:0.7(氯仿∶MeOH∶氨溶液=89∶10∶1)
1H-NMR(DMSO):δ8.28(m,2H),6.78(d,1H),6.69(d,1H),6.58(t,1H),6.23(d,1H),5.82(dd,1H),5.25(d,1H),4.66(d,1H),4.52(d,1H),4.30(b,1H),4.11(b,1H),3.80(s,3H),3.73(m,1H),2.28(d,1H),2.02(d,1H),1.81(t,1H),1.72(d,1H);
12C-NMR(DMSO):δ161.2(s),158.7(d),147.6(s),144.1(s)133.3(s),130.6(s),129.0(2d),128.0(d),121.9(d),112.0(d),110.7(d),87.2(d),60.6(d),56.4(q),51.3(t),48.7(s),45.5(t),36.6(t),31.5(t);
实施例38
1-[(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基]-3-(1-吡咯烷基)丙-1-酮(Ia Y1=OH,Y2=H,X=H,Z1=C7H12NO)
2.0g(-)-去甲基加兰他敏,其根据WO-A-017/4820制备,以及0.86ml三乙胺和0.76ml的3-溴丙酸氯化物在室温下在130ml丙酮中搅拌。60分钟后,蒸馏出溶剂,将100ml的2N HCl溶液和50ml乙酸乙酯混入残留物。分离有机相之后,用2×50ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥,过滤并在真空下浓缩。将油性残留物吸收入50ml乙腈中,混入5ml吡咯烷并在沸腾温度下搅拌。8小时后,冷却反应混合物,在真空中去除溶剂,用30ml的25%氨溶液和30ml乙酸乙酯混入残留物。分离有机相之后,用2×30ml乙酸乙酯萃取水性母液。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩,将产物柱层析(氯仿∶MeOH∶氨溶液=89∶10∶1)提纯。
产量:1.4g(48.0%理论值)
熔点:56-63℃
Rf:0.25(氯仿∶MeOH∶氨溶液=89∶10∶1)
1H-NMR(DMSO):δ6.81(b,2H),6.71(d,1H),6.65(d,1H),6.15(d,1H),5.79(dd,1H),4.68(d,1H),4.60(d,1H),4.45(m,2H),4.08(b,1H),3.75(s,3H),3.43(b,1H),2.25(m,1H),2.70(m,1H),2.59(m,1H),2.38(m,6H),2.06(d,1H),1.82(t,1H),1.62(m,4H);
13C-NMR(DMSO):δ171.3(s),147.9(s),144.6(s)133.0(s),129.7(s),129.2(d),127.7(d),121.5(d),112.1(d),87.4(d),60.6(d),56.4(q),52.3(2t),48.6(s),46.5(t),44.5(t),39.2(t),37.2(t),32.8(t),31.5(t),23.9(2t);
实施例39
((4aS,6R,8aS)-4a,5,9,10,11,12-六氢-6-羟基-3-甲氧基-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂-11-基)γ-氧-丁酸(Ia Y1=OH,Y2=H,X=H,Z1=C4H5O3)
2.0g(-)-去甲基加兰他敏,其根据WO-A-017/4820制备,以及1.53ml三乙胺和0.76g琥珀酸酐在沸腾温度下在70ml四氢呋喃中搅拌。1小时后,蒸馏出溶剂,将100ml的1N HCl和100ml乙酸乙酯混入残留物。分离有机相之后,用2×50ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。
产量:1.4g(51.28%理论值)
熔点:156-158℃
Rf:0.7(乙酸乙酯∶蚁酸=99∶1)
1H-NMR(DMSO):δ11.95(b,1H,OH),6.81(b,1H),6.71(dd,1H),6.12(d,1H),5.85(dd,1H),4.68(d,1H),4.60(d,1H),4.43(m,2H),4.09(b,1H),3.71(s,3H),2.25(t,1H),2.89(m,1H),2.35(m,3H),2.09(m,2H),1.80(b,1H),1.65(m,1H);
13C-NMR(DMSO):δ174.8(s),171.2(s),147.9(s),144.6(s)133.0(s),129.5(s),129.2(d),127.7(d),121.4(d),112.1(d),87.3(d),60.6(d),56.3(q),51.9(t),48.6(s),46.4(t),39.7(t),31.5(t),29.8(t),28.5(t);
实施例40
1-((4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)-2-[2-(2,6-二氯苯胺基)]-苯基乙烷(Ia Y1=OH,Y2=H,X=H,Z1=C11H13O)
步骤1
6.75g邻-(2,6)-二氯苯胺基-苯乙醇,其根据DE-A-2007700制备,在室温下逐份加入到7.12g三苯基膦和1.36ml溴在100ml四氢呋喃的悬浮液中。1个半小时之后,加入100ml水,用每次25ml乙酸乙酯萃取3次,有机相用硫酸钠干燥、过滤并浓缩到40ml。加入100ml正己烷并在冰浴中搅拌1个半小时之后,过滤析出的三苯基膦氧化物。通过短硅胶柱过滤透明滤液并蒸馏除去溶剂。剩余8.2g黄色油,不净化而直接投入下一步骤中使用。
步骤2
2.16g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及2.7g(2,6-二氯苯基)-2-(2-溴乙基)苯胺和4.72g碳酸钾在室温下在25ml乙腈中搅拌24小时。之后将悬浮液注入到100ml水中,用每次30ml乙酸乙酯萃取3次。用硫酸钠干燥有机相,过滤之后蒸馏去溶剂。所得4g物质用乙酸乙酯在200g硅胶上柱层析提纯,并且蒸发浓缩含产物的级份。在15ml二乙醚中剩余的800mg物质用醚化HCl在0℃沉淀出830mg盐酸化物盐,其从30ml乙醇中再结晶出来。
产量:700mg(16%理论值)白色结晶
熔点:163-165℃
Rf:0.5(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ7.42(b,1H,NH),7.35(d,2H),7.13(dd,1H),7.05(td,1H),7.01(t,1H),6.88(td,1H),6.64(d,1H),6.56(d,1H),6.40(d,1H),6.10(d,1H),6.03(dd,1H),4.63(m,1H),4.22(d,1H),4.16(m,1H),4.03(d,1H),3.78(s,3H),3.48(td,1H),3.29(dt,1H),2.89(m,4H),2.71(ddd,1H),2.42(b,1H,OH),2.13(td,1H),2.01(ddd,1H),1.51(ddd,1H);
13C-NMR(CDCl3):δ145.8(s),144.2(s),142.8(s),137.9(s),133.2(s),139.5(s),130.5(d),130.3(s),128.8(d),128.5(s),27.7(d),126.8(d),126.7(d),124.1(d),122.3(d),120.9(d),116.3(d);110.9(d),88.7(d),62.0(t),57.3(t),55.7(q),52.5(t),52.0(t),48.4(s),32.5(t),30.7(t),29.9(t);
实施例41
(4a S,6R,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-(4-溴-苯甲酰)-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=OH,Y2=H,X=H,Z1=C11H13O)
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及4.0g的碳酸钾和1.65g的4-溴苯甲酰氯在沸腾温度下在70ml乙腈中搅拌。3小时后,蒸馏出溶剂,将100ml水和100ml乙酸乙酯混入残留物。分离有机相之后,用2×50ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:3.3g(99%理论值)
熔点:98-112℃
Rf:0.35(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ7.51(d,2H),7.13(d,2H),6.65(d,1H),6.24(d,1H),6.08(td,1H),5.98(d,1H),4.90(b,1H),4.68(b,1H),4.42(s,1H),4.18(d,1H),3.85(s,3H),3.45(m,1H),2.73(dt,1H),2.10(m,2H),1.93(d,1H),1.71(b,1H);
13C-NMR(CDCl3):δ170.9(s),147.2(s),145.0(s),135.5(s),133.1(s),131.8(2d),128.9(2d),182.5(d),128.4(s),126.8(d),124.3(s),121.0(d),112.0(d),88.8(d),62.2(t),56.3(q),54.9(t),48.7(s),44.5(t),36.6(t),30.2(t);
实施例42
(4aS,6R,8aS)-11-(4,6-二氯-1,3,5,-三嗪-2-基)-3-甲氧基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=OH,Y2=H,X=H,Z1=C11H13O)
将1.32g氰尿酰氯(Cyanurchlorid)的32ml丙酮溶液注入70ml冰水中,并在0℃与根据WO-A-01/74820制备的2.0g(-)-去甲基加兰他敏混合。反应混合物与4.0ml的2N氢氧化钠溶液混合,并在沸腾温度下搅拌。40小时后,将反应混合物冷却至室温,并与60ml乙酸乙酯混合。分离有机相之后,用2×60ml乙酸乙酯萃取水性母液。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:1.58g(51%理论值)
熔点:245-149℃
Rf:0.75(氯仿∶MeOH=9∶1)
1H-NMR(DMSO):δ6.79(b,2H),6.19(d,1H),5.81(dd,1H),5.12(d,1H),4.79(d,1H),4.58(d,1H),4.49(b,1H),4.10(b,1H),3.79(m,1H),3.72(s,3H),2.29(d,1H),2.09(m,1H),1.80(m,2H);
13C-NMR(DMSO):δ170.0(s),169.9(s),164.3(s),147.9(s),144.7(s)132.9(s),129.4(d),127.6(d),127.5(s),121.8(d),112.2(d),87.0(d),60.4(d),56.4(q),52.1(t),48.5(s),46.6(t),40.0(t),31.4(t);
实施例43
(4aS,6R,8aS)-11-(4-溴苯甲基)-4a,5,9,10,11,12-六氢-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=OH,Y2=H,X=H,Z1=C7H6Br)
3.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及3.0g的碳酸钾和2.5g的4-溴苯甲基溴在室温下在70ml乙腈中搅拌。24小时后,在真空条件下去除溶剂,将100ml水和40ml乙酸乙酯混入残留物。分离有机相之后,用2×40ml乙酸乙酯萃取水性母液。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=99∶1)提纯。
产量:3.0g(70.2%理论值)
熔点:148-149℃
Rf:0.8(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ7.53(d,2H),7.18(d,2H),6.65(d,1H),6.40(d,1H),6.15(d,1H),6.03(d,1H),4.68(b,1H),4.12(m,1H),3.85(s,3H),3.66(d,1H),3.61(s,2H),3.41(t,1H),3.18(d,1H),2.71(dd,1H),2.44(d,1H),2.15(dd,1H),2.03(dd,1H),1.65(d,1H);
13C-NMR(CDCl3):δ146.3(s),144.5(s),138.4(s),133.7(s),131.8(2d),131.0(2d),129.8(s),128.1(d),127.2(d),122.5(d),121.2(s),111.6(d),89.2(d),62.5(t),57.7(t),56.3(q),56.0(t),52.2(t),48.9(s),33.9(t),30.4(t);
实施例44
2-((4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)乙酸乙酯(Ia Y1=OH,Y2=H,X=H,Z1=C4H7O2)
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及4.0g的碳酸钾和1.0ml溴乙酸乙酯在室温下在50ml四氢呋喃中搅拌。16小时后,过滤沉淀,将100ml水和50ml乙酸乙酯与滤液混合。分离有机相之后,用2×50ml乙酸乙酯萃取水性母液。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(纯乙酸乙酯)提纯。
产量:1.46g(55.5%理论值)
熔点:75-78℃
Rf:0.8(乙酸乙酯)
1H-NMR(DMSO):δ6.69(d,1H),6.49(d,1H),6.08(d,1H),5.80(dd,1H),4.49(b,1H),4.21(m,2H),4.08(m,2H),3.75(s,3H),3.68(m,1H),3.32(m,2H),2.23(d,1H),3.00(d,1H),2.28(d,1H),2.07(td,1H),1.93(t,1H),1.58(d,1H),1.18(t,3H);
13C-NMR(DMSO):δ171.4(s),147.1(s),144.2(s),133.6(s),130.1(s),129.2(d),127.8(d),121.7(d),112.2(d),87.7(d),60.7(d),60.6(t),58.0(t),56.3(q),54.6(t),52.5(t),48.6(s),35.1(t),31.9(t),15.0(q);
实施例45
2-((4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)乙酸(Ia Y1=OH,Y2=H,X=H,Z1=C2H3O2)
步骤1
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及4.0g的碳酸钾和1.0ml溴乙酸乙酯在室温下在50ml四氢呋喃中搅拌。16小时后,分离沉淀,在真空条件下去除溶剂,并将100ml水和50ml乙酸乙酯与残留物混合。分离有机相之后,用2×50ml乙酸乙酯萃取水性母液。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。获得了2.8g泡沫状材料。
步骤2
1.6g步骤1所得产物溶解在24ml乙醇中,与3.2ml的2N氢氧化钠溶液混合,并在室温下搅拌。30分钟后,将4.8g的IRA-120离子交换剂与透明溶液混合,并继续搅拌10分钟。过滤离子交换剂,在真空中浓缩滤液,并从甲醇和叔丁甲醚(MTBE)的混合物中结晶出残留物。
产量:0.8g白色粉末
熔点:144-161℃
Rf:0.2(氯仿∶MeOH=6∶4)
1H-NMR(DMSO):δ6.69(d,1H),6.49(d,1H),6.08(d,1H),5.80(dd,1H),4.49(b,1H),4.21(m,2H),4.08(m,2H),3.75(s,3H),3.68(m,1H),3.32(m,2H),2.23(d,1H),3.00(d,1H),2.28(d,1H),2.07(td,1H),1.93(t,1H),1.58(d,1H),1.18(t,3H);
13C-NMR(DMSO):δ171.4(s),147.1(s),144.2(s),133.6(s),130.1(s),129.2(d),127.8(d),121.7(d),112.2(d),87.7(d),60.7(d),60.6(t),58.0(t),56.3(q),54.6(t),52.5(t),48.6(s),35.1(t),31.9(t),15.0(q);
实施例46
(4aS,6R,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-(2-甲基-丙-2-烯基)-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇,盐酸化物(Ia Y1=OH,Y2=H,X=H,Z1=C2H3O2)
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及2.02g碳酸钾、1.27g碘化钾和0.85ml的3-氯-2-甲基-1-丙烯在回流温度下在80ml丙酮中搅拌。4小时后,将反应混合物冷却至室温,在真空中蒸馏去溶剂,并将200ml的2N HCl和50ml乙酸乙酯与残留物混合。分离之后去除有机相,用30%氢氧化钠溶液将水相调至碱性,并用3×100ml乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。所得油溶解在乙醇中,并用醚化 HCl沉淀盐酸化物盐。
产量:2.38g(99%理论值)
熔点:233-234℃
Rf:0.8(氯仿∶MeOH∶氨溶液=89∶10∶1)
1H-NMR(DMSO):δ6.88(d,1H),6.70(d,1H),6.17(d,1H),5.93(d,1H),5.39(d,1H),5.20(d,1H),4.62(m,2H),4.28(m,1H),4.12(b,1H),3.95(b,1H),3.81(s,3H),3.62(m,3H),2.29(d,1H),2.10(d,2H),1.93(d,3H),1.58(d,1H);
13C-NMR(DMSO):δ147.4(s),145.8(s),136.5(s),134.1(s),130.9(d),126.3(d),123.5(d),122.6(s),112.8(d),87.4(d),67.9(t),64.2(t),57.7(d),56.6(t),56.4(q),50.5(t),47.6(s),31.9(t),26.0(t),22.2(q);
实施例47
3-((4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)丙酸乙酯,盐酸化物(Ia Y1=OH,Y2=H,X=H,Z1=C5H9O2)
0.55g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及0.3ml的丙烯酸乙酯在回流温度下在20ml的无水乙醇中搅拌。72小时后,蒸馏去溶剂,将产物柱层析(氯仿∶MeOH=95∶5)提纯。所得油溶解在氯仿中,并用醚化HCl沉淀盐酸化物盐。
产量:0.5g(60.6%理论值)
Rf:0.6(氯仿∶MeOH=95∶5)
1H-NMR(DMSO):δ6.88(d,1H),6.70(d,1H),6.17(d,1H),5.93(d,1H),5.39(d,1H),5.20(d,1H),4.62(m,2H),4.28(m,1H),4.12(b,1H),3.95(b,1H),3.81(s,3H),3.62(m,3H),2.29(d,1H),2.10(d,2H),1.93(d,3H),1.58(d,1H);
13C-NMR(DMSO):δ147.4(s),145.8(s),136.5(s),134.1(s),130.9(d),126.3(d),123.5(d),122.6(s),112.8(d),87.4(d),67.9(t),64.2(t),57.7(d),56.6(t),56.4(q),50.5(t),47.6(s),31.9(t),26.0(t),22.2(q);
实施例48
1-[(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基]-2-(4-吗啉基)乙-1-酮(Ia Y1=OH,Y2=H,X=H,Z1=C8H14N3O)
3.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及1.86ml三乙胺和0.9ml氯乙酰氯在0℃在150ml四氢呋喃中搅拌。10分钟后,反应混合物与3.0g碳酸钾和1.2ml吗啉混合,并在90℃继续搅拌。60小时后,蒸馏去溶剂,并将50ml水和50ml氯仿与残留物混合。分离有机相之后,用2×30ml氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:2.5g(56.8%理论值)
熔点:92-101℃
Rf:0.45(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.67(m,2H),6.01(m,2H),4.99(d,1H),4.63(d,1H),4.55(b,1H),4.37(d,1H),4.12(b,1H),3.82(s,3H),3.67(m,4H),3.25(d,1H),3.14(m,2H),3.00(d,1H),2.48(m,4H),2.01(dd,1H),1.88(t,1H),1.75(d,1H);
13C-NMR(CDCl3):δ169.2(s),147.3(s),145.0(s),132.9(s),128.9(s),128.8(d),126.8(d),122.4(d),111.7(d),88.7(d),67.1(2t),62.1(d),56.3(q),54.1(2t),52.7(t),48.7(s),45.5(t),38.9(t),36.1(t),30.3(t);
实施例49
1-[(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基]-2-(二乙氨基)乙-1-酮(Ia Y1=OH,Y2=H,X=H,Z1=C6H12NO)
3.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及1.86ml三乙胺和0.9ml氯乙酰氯在0℃在150ml四氢呋喃中搅拌。10分钟后,反应混合物与3.0g碳酸钾和0.75ml二乙胺混合,并在90℃继续搅拌。24小时后,蒸馏去溶剂,并将50ml水和50ml氯仿与残留物混合。分离有机相之后,用2×30ml氯仿萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:2.0g(48.5%理论值)
熔点:114-126℃
Rf:0.45(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.68(m,2H),6.01(m,2H),5.19(d,1H),4.60(m,1H),4.33(d,1H),4.09(b,1H),3.78(s,3H),3.37(d,1H),3.21(m,1H),2.95(d,1H),2.64(m,3H),2.49(m,3H),2.03(dd,1H),1.92(t,lH),1.75(d,1H),1.01(m,6H);
13C-NMR(CDCl3):δ170.8(s),147.2(s),145.0(s),132.9(s),129.1(s),128.6(d),126.9(d),121.0(d),111.7(d),88.7(d),62.3(d),56.3(t),56.2(q),52.4(t),48.7(2t),47.8(s),38.9(t),36.1(t),30.3(t),12.0(2q);
实施例50
(4a S,6R,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-[3-(1-哌啶基)丁基]-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇,(+)二-O-对-甲苯酰酒石酸盐(Ia Y1=OH,Y2=H,X=H,Z1=C9H18N)
步骤1
4.1g的4-溴丁酸哌啶酰胺(17.5mmol)溶解在100ml乙腈中。向该溶液中添加3.8g根据WO-A-01/74820制备的(-)-去甲基加兰他敏和9.7g碳酸钾,并在80℃搅拌30小时。过滤碳酸钾之后,蒸馏去溶剂,并将残留物吸收入100ml甲苯和100ml的1N HCl中。用30%氢氧化钠溶液将水相调至碱性,并用每次40ml乙酸乙酯振荡萃取3次。所合并的有机相用硫酸钠干燥、过滤并蒸发浓缩。用氯仿∶甲醇=98∶2作为洗提剂将所得4.4g棕色油在200g硅胶上柱层析提纯。
产量:1.6g(30%理论值)
步骤2
3.6g步骤1的产物溶解在50ml四氢呋喃中,冷却到0℃,并在20分钟时间内逐份加入705mg锂铝氢化物。添加结束后,加热至室温并搅拌1.5小时。用水逐步淬灭反应,过滤所产生的沉淀并用10ml四氢呋喃洗涤。用硫酸钠干燥溶液之后,将其过滤并吸除溶剂。用氯仿∶甲醇∶氨溶液=90∶9∶1作为洗提剂将所得3.4g物质在200g硅胶上柱层析。所得2.4g物质溶解在80ml乙酸乙酯中,并用2.5g的(+)-二-对-甲苯酰-D-酒石酸在30ml乙酸乙酯中将其沉淀,过滤并用10ml乙酸乙酯洗涤。
产量:4.4g(78.7%理论值)无色结晶
1H-NMR(CDCl3):δ6.67(d,1H),6.61(d,1H),6.12(d,1H),6.01(dd,1H),4.63(m,1H),4.15(m,2H),3.88(s,3H),3.82(d,1H),3.35(d,1H),3.18(d,1H),2.70(dd,1H),2.49(m,4H),2.31(m,4H),2.02(m,4H),1.71(m,4H),1.49(m,5H);
13C-NMR(CDCl3):δ146.1(s),144.4(s),133.5(s),129.9(s),127.9(d),127.4(d),122.4(d),111.5(d),89.1(d),66.1(t),62.5(d),59.7(t),58.3(t),56.2(q),54.9(2t),51.9(t),48.8(s),33.4(t),30.3(t),26.3(2t),26.0(t),25.1(t),24.9(t);
实施例51
3-((4aS,6R,8aS)-1-溴-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基)丙腈(Ia Y1=OH,Y2=H,X=H,Z1=C3H4N)
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及2.0g CaCl2和0.5ml丙烯腈在沸腾温度下在200ml乙醇中搅拌。8小时后,蒸馏去溶剂,并将残留物吸收入500ml的2N HCl,用3×200ml乙酸乙酯萃取。用25%氨溶液将水性母液调至碱性,并用3×200ml亚甲基氯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=9∶1)提纯。
产量:1.7g(62%理论值)
熔点:69-72℃
Rf:0.45(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(CDCl3):δ6.67(d,1H),6.60(d,1H),6.06(d,1H),5.98(dd,1H),4.69(b,1H),4.21(d,1H),4.10(m,1H),3.82(s,3H),3.79(d,1H),3.45(t,1H),3.27(d,1H),2.80(m,2H),2.67(dd,1H),2.43(m,2H),1.99(m,2H),1.59(d,1H);
13C-NMR(CDCl3):δ146.5(s),144.8(s),133.4(s),129.0(s),128.3(d),126.9(d),122.4(d),119.3(s),111.7(d),89.0(d),62.3(d),57.4(t),56.3(q),52.1(t),48.9(s),47.0(t),33.5(t),30.4(t),17.2(t);
实施例52
(4aS,6R,8aS)-11-((3-二甲基氨基)丙基)-3-甲氧基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(Ia Y1=OH,Y2=H,X=H,Z1=C5H12N)
3.0g(-)-去甲基加兰他敏HCl,其根据WO-A-01/74820制备,以及5.0g碳酸钾和2.1g的3-二甲基氨基丙基氯HCl在沸腾温度下在70ml乙腈中搅拌。28小时后,过滤沉淀并在真空中去除溶剂。将产物柱层析(氯仿∶MeOH=9∶1)提纯。
产量:2.35g(59.8%理论值)棕色油
Rf:0.35(氯仿∶MeOH=9∶1)
1H-NMR(DMSO):δ6.67(d,1H),6.60(d,1H),6.11(d,1H),5.94(dd,1H),4.59(b,1H),4.13(m,2H),3.82(s,3H),3.78(d,1H),3.21(m,11H),2.52(m,2H),2.29(m,1H),2.05(d,1H),2.65(m,2H),1.51(d,1H);
13C-NMR(DMSO):δ146.3(s),144.2(s),133.5(s),129.8(s),128.0(d),127.5(d),122.2(d),111.6(d),88.7(d),61.9(d),58.0(t),57.8(t),56.2(q),52.0(t),50.0(t),48.7(s),45.7(2q),33.4(t),30.7(t),25.8(t);
实施例53
(4a S,6R,8aS)-N11-环己基-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-碳酸异丙酰胺(Ia Y1=OH,Y2=H,X=H,Z1=C7H12NO)
2.0g(-)-去甲基加兰他敏,其根据WO-A-01/74820制备,以及0.92g异氰酸环己酯溶解在100ml甲苯中,并在沸腾温度下搅拌。5小时后,在真空中蒸馏去溶剂,并用200ml的2N HCl和100ml二乙醚与残留物混合。分离有机相之后,用25%氨溶液将水性母液调至碱性,并用3×100ml乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空条件下蒸馏去溶剂。从乙醇中结晶出残留物。
产量:1.97g(67.5%理论值)
熔点:168-170
Rf:0.6(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.69(d,1H),6.62(d,1H),5.95(m,2H),4.57(b,1H),4.46(d,1H),4.31(d,2H),4.12(b,1H),3.80(s,3H),3.41(m,1H),3.32(t,1H),2.63(d,1H),2.03(dd,1H),1.91(d,2H),1.70(d,2H),1.55(m,2H),1.25(m,2H),1.09(m,2H),0.95(m,2H);
13C-NMR(CDCl3):δ156.9(s),147.3(s),145.0(s),132.9(s),129.6(s),128.4(d),126.9(d),120.7(d),111.5(d),88.8(d),62.2(d),56.3(q),52.0(t),49.6(d),48.9(t),46.0(s),36.9(t),34.2(t),33.9(t),30.2(t),6.0(t),25.2(t),25.1(t);
实施例54
1-[(4aS,6R,8aS)-6-羟基-3-甲氧基-5,6,9,10-四氢-4aH-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-11(12H)-基]-2-氯乙-1-酮(Ia Y1=OH,Y2=H,X=H,Z1=C2H2ClO)
一种根据WO-A-01/74820制备的3.0g(-)-去甲基加兰他敏,以及1.9ml三乙胺在150ml四氢呋喃中的溶液在0℃与0.93ml氯乙酰氯化物混合。10分钟后,在真空中去除溶剂,用100ml水、10ml的2N盐酸与残留物混合并用3×30ml二乙醚萃取。所合并的有机相用硫酸钠干燥、过滤并在真空条件下蒸馏去溶剂。
产量:1.42g(37.1%理论值)
熔点:88-90℃
Rf:0.8(氯仿∶MeOH=9∶1)
1H-NMR(CDCl3):δ6.73(m,2H),6.02(m,2H),4.69(d,1H),4.65(d,1H),4.52(d,1H),4.19(d,1H),4.09(m,2H),3.95(d,1H),3.85(s,3H),3.30(t,1H),2.73(d,1H),2.09(dd,1H),1.91(d,1H),1.71(d,1H);
13C-NMR(CDCl3):δ166.5(s),147.5(s),145.5(s),132.8(s),129.0(s),128.2(d),126.5(d),122.6(d),111.7(d),88.8(d),62.2(d),56.4(q),53.4(t),48.7(d),46.0(s),41.9(t),35.9(t),30.2(t);
实施例55
(4aR,6S,8aR)-6-羟基-3-甲氧基-11-甲基-4a,5,9,10-四氢-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂溴化物
将一种根据Kametani,Heterocycles 4,1111,1976制备的2.0g(+)-加兰他敏的20ml氯仿溶液强烈搅拌,并在室温下将与1.26g的N-溴琥珀酰亚胺的20ml氯仿溶液逐滴混合。1小时后,分离黄色沉淀,用氯仿洗涤,并在50℃的真空干燥箱中干燥。产物从乙醇中再结晶。
产量:2.28g(90.2%理论值)
熔点:223-229℃
Rf:0.2(氯仿:MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ9.15(s,1H),7.57(d,1H),7.20(d,1H),5.89(dd,1H),5.72(d,1H),4.67(b,1H),4.61(d,1H),4.13(m,3H),3.95(s,3H),3.80(s,3H),2.35(d,1H),2.15(m,2H);
13C-NMR(DMSO):δ167.3(d),151.3(s),146.2(s),136.9(s),133.0(d),129.8(d),126.4(d),115.0(s),112.9(d),86.9(d),58.9(d),56.4(q),54.0(t),51.5(t),45.9(q),40.7(t),31.1(t),29.7(t);
实施例56
(4aR,6R,8aR)-6-羟基-3-甲氧基-11-甲基-4a,5,9,10-四氢-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂溴化物
在室温下,向根据J.Chem.Soc.806,1962制备的2.0g(+)-表加兰他敏的强烈搅拌的80ml氯仿溶液中加入1.35g的N-溴琥珀酰亚胺。1小时后,分离出现的沉淀,用氯仿洗涤,并在50℃的真空干燥箱中干燥。产物从乙醇中再结晶。
产量:2.09g(82.7%理论值)
熔点:236-244℃
Rf:0.2(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ9.15(s,1H),7.58(d,1H),7.20(d,1H),5.85(dd,1H),5.74(d,1H),5.15(d,1H),4.79(b,1H),4.30(m,1H),4.13(m,2H),3.93(s,3H),3.80(s,3H),2.55(d,1H),2.20(m,1H),1.73(dt,1H);
13C-NMR(DMSO):δ168.1(d),152.1(s),147.3(s),138.1(s),135.4(d),133.9(d),126.9(d),116.0(s),113.9(d),88.9(d),61.7(d),57.3(q),55.1(t),52.3(t),47.1(q),41.0(t),32.3(t),31.7(t);
实施例57
(4aS,6R,8aS)-1-溴-4a,5,9,10,11,12-六氢-11-(2-(吗啉-4-基)-乙基)-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(IaY1=OH,Y2=H,X=Br,Z1=C6H12NO)
2.0g(-)-溴去甲基加兰他敏(Ia Y1=OH,Y2=H,X=Br,Z1=H)、2.35g碳酸钾和1.11g N-(2-氯乙基)-吗啉盐酸化物在回流温度下在30ml乙腈中搅拌。48小时后,将反应混合物冷却至室温,在真空中蒸馏去溶剂,并用200ml的2N HCl和40ml乙酸乙酯与残留物混合。分离之后去除有机相。用氨溶液将水相调至碱性,并用3×40ml乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=95∶5)提纯。
产量:1.39g(53%理论值)白色泡沫
Rf:0.2(氯仿∶MeOH∶氨溶液=90∶9∶1)
1H-NMR(DMSO):δ6.91(s,1H),6.15(d,1H),6.03(dd,1H),4.51(b,1H),4.41(d,1H),4.16(b,1H),4.05(d,1H),3.85(s,3H),3.71(t,4H),3.39(t,1H),3.15(d,1H),2.69(m,3H),2.51(m,5H),2.03(m,3H),1.55(d,1H);
13C-NMR(CDCl3):δ145.9(s),144.7(s),134.6(s),128.5(d),128.4(s),127.4(d),116.3(d),114.9(s),89.2(d),67.3(2t),62.3(d),57.3(2t),56.6(q),56.6(t),54.6(2t),52.6(t),49.4(t),33.6(t),30.2(t);
实施例58
(4aR,6R,8aRS)-1-溴-4a,5,9,10,11,12-六氢-11-(2-(吗啉-4-基)-乙基)-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇(IbY1=OH,Y2=H,X=Br,Z1=C6H12NO)
3.0g(+)-溴去甲基加兰他敏(Ib Y1=OH,Y2=H,X=Br,Z1=H)、4.8g碳酸钾和1.47g N-(2-氯乙基)-吗啉盐酸化物在回流温度下在30ml乙腈中搅拌。22小时后,将反应混合物冷却至室温,在真空中蒸馏去溶剂,并用100ml水和40ml乙酸乙酯与残留物混合。分离之后,用3×40ml乙酸乙酯萃取水相。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(洗提剂96%乙醇)提纯。
产量:1.9g(48%理论值)
熔点:58-64℃
Rf:0.2(96%乙醇)
1H-NMR(DMSO):δ6.99(s,1H),6.12(d,1H),5.82(dd,1H),4.55(b,1H),4.37(b,1H),4.20(d,1H),4.05(m,2H),3.79(s,3H),3.51(m,4H),3.32(d,1H),3.28(d,1H),2.99(d,1H),2.51(m,2H),2.35(m,4H),2.25(d,1H),2.00(m,2H),1.49(d,1H);
13C-NMR(CDCl3):δ146.9(s),144.6(s),134.9(s),129.6(d),128.7(s),127.4(d),116.3(d),113.3(s),87.8(d),67.1(2t),60.5(d),57.1(2t),56.7(q),55.9(t),54.5(2t),52.2(t),49.4(t),34.0(t),31.7(t);
实施例59
(4aS,8aS)-Δ5,6-4a,5,9,10,11,12-六氢-11-甲基-3-甲氧基-6-苯基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂(Ic Y3=苯基,X=H,Z2=CH3)
向一种1.16g镁的15ml四氢呋喃混合物中滴加3.35ml溴苯。将形成的反应混合物强烈搅拌1小时,与一种根据EP-A-0787115制备的3.0g(-)Narwedin的50ml四氢呋喃溶液混合并继续搅拌。2小时后,向反应混合物中滴加60ml水和40ml的2N HCl,在60℃搅拌形成的悬浮液。50分钟后,将反应混合物冷却至室温,用氨溶液将pH值调至9,并用3×100ml乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=99∶1)提纯。
产量:1.8g(49%理论值)无色泡沫
Rf:0.35(氯仿∶MeOH=99∶1)
1H-NMR(CDCl3):δ7.50(d,2H),7.39(m,3H),6.65(b,2H),6.42(d,1H),6.33(m,2H),5.00(d,1H),4.28(d,1H),3.89(s,3H),3.75(d,1H),3.51(t,1H),3.09(d,1H),2.41(s,3H),2.13(dt,1H),1.79(dd,1H);
13C-NMR(CDCl3):δ148.2(s),144.3(s),139.8(s),139.5(s),131.6(s),131.2(d),130.0(s),129.0(2d),128.6(d),126.6(2d),123.2(d),122.2(d),116.1(d),110.7(d),86.5(d),60.8(t),56.2(q),54.5(t),48.7(t),42.2(q),35.4(t);
实施例60
(4aS,8aS)-Δ5,6-4a,5,9,10,11,12-六氢-6,11-二甲基-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂(Ic Y3=CH3,X=H,Z2=CH3)
一种根据EP-A-0787115制备的2.04g(-)Narwedin的60ml四氢呋喃溶液与10.0ml甲基镁溴化物的二乙醚溶液逐滴混合,并在室温下搅拌。45分钟后,向反应混合物中滴加60ml水和20ml的2N HCl,在60℃搅拌所产生的悬浮液。50分钟后,将反应混合物冷却至室温,用氨溶液将pH值调至9,并用3×100ml乙酸乙酯萃取。所合并的有机相用硫酸钠干燥、过滤并在真空中浓缩。将产物柱层析(氯仿∶MeOH=98∶2)提纯。
产量:2.18g(72%理论值)无色泡沫
Rf:0.5(氯仿∶MeOH=99∶1)
1H-NMR(CDCl3):δ6.57(m,2H),6.01(d,1H),5.87(d,1H),5.69(m,1H),4.80(d,1H),4.15(d,1H),3.80(s,3H),3.68(d,1H),3.34(t,1H),3.01(d,1H),2.41(s,3H),2.09(dt,1H),1.91(s,3H),1.71(dd,1H);
13C-NMR(CDCl3):δ148.2(s),144.2(s),136.6(s),131.8(s),130.2(s),130.0(d),125.2(d),121.9(d),115.3(d),110.5(d),88.9(d),60.8(t),56.2(q),54.6(t),48.5(t),42.4(q),35.4(t),22.2(q);
实施例61
(4aS,8aS)-Δ5,6-4a,5,9,10,11,12-六氢-6-(异丙基)-11-甲基-3-甲氧基-6H-[1]苯并呋喃[3a,3,2-ef][2]苯并氮杂(Ic,Y3=异丙基,X=H,Z2=CH3)
在氮气氛围下,将0.66ml的2-溴丙烷滴加入220mg镁粉的1.5ml无水四氢呋喃溶液中。在格氏反应开始15分钟后,在冰冻条件下,滴加根据EP-A-787115制备的500mg Narwedin的12ml无水四氢呋喃溶液,在室温下搅拌。2小时后,在并冻条件下,用30ml水将反应混合物水解,用2N盐酸酸化,并在60℃搅拌30分钟。随后,用浓缩的氨的水溶液将溶液调至碱性,用每次30ml乙酸乙酯萃取三次。用饱和氯化钠水溶液将所合并的有机相洗涤一次,用硫酸钠干燥、过滤并蒸发浓缩。将产物柱层析(氯仿∶MeOH=97∶3)提纯。
产量:399mg(69%理论值)油性物质
Rf:0.55(氯仿∶MeOH=97∶3)
1H-NMR(CDCl3):δ1.76-1.81(m,6H),1.64(ddd,1H),2.13(ddd,1H),1.97(ddd,1H),2.37(ddd,1H),3.06(ddd,1H),3.31(ddd,1H),2.48(s,3H),3.80(s,3H),3.66(d,1H),4.10(d,1H),4.62(b,1H),5.76(d,1H),6.51(d,1H),6.56(d,1H),6.61(d,1H)
13C-NMR(CDCl3):δ19.8(q),20.7(q),26.3(t),34.8(t),48.1(s),53.9(t),41.9(q),55.6(q),60.6(t),128.8(s),89.0(d),122.9(d),110.6(d),121.1(d),121.4(s),124.4(d),130.8(s),133.6(s),143.7(s),146.3(s),
总而言之,具有通式Ia、Ib和Ic的4a,5,9,10,11,12-六氢-苯并呋喃[3a,3,2][2]-苯并氮杂的新衍生物,其不仅能够以有效方式具有所希望的光学纯度地在工业等级上制备,而且基于其药理学作用,其还适合于制备用于治疗不同疾病症状的药剂,特别是中枢神经系统(ZNS)疾病。
Claims (26)
1.具有通式Ia或Ib的4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂的新衍生物及其盐,
Ia Ib
其中
·Ia是加兰他敏光学活性(-)衍生物,Ib是加兰他敏光学活性(+)衍生物,他们相互间是以空间排列镜像形式存在的,并且
·Y1和Y2任选为H或OH,
·X=H或Br,以及
·Z1=下列结构式的基团
其中
·R1=H、Cl、Br、I、F、OH、直链或分支的(C1-C6)烷基、直链或分支的(C1-C6)烷氧基、NO2、NR2R3,
·R2=R3=H,直链或分支的(C1-C6)烷基,
·W=H、O、S
·n=0、1-6,
并且,其中
·Z1仅仅在化合物1、3、13和24中为H
1 3 13 24
其中,化合物1和13是6-表-去甲基加兰他敏(-)-衍生物,化合物3和24是6-表-去甲基加兰他敏(+)-衍生物,且其中
·Z1仅仅在化合物29中为羟丙基
29
以及
·Z1仅仅在化合物26中为乙基
26
以及
·Z1仅仅在下列化合物中为甲基
28 31步骤1 31步骤2 56 55
其中,化合物29、31和55是加兰他敏(+)-衍生物,化合物26、28和56是加兰他敏(+)-表-衍生物。
3.制备根据权利要求1所述的化合物的方法,其特征在于,所述光学活性11-去甲基加兰他敏衍生物用稀酸、优选用稀盐酸处理。
4.根据权利要求3所述的方法,其特征在于,通过稀酸的处理,将光学活性11-去甲基加兰他敏衍生物转变为加兰他敏的6-表-衍生物。
5.根据权利要求3或4所述的方法,其特征在于,在酸处理中,碳原子6的空间排列被改变,而不对称的碳原子4a和8a的空间排列保持不变。
6.制备根据权利要求1或2所述化合物的方法,其特征在于,在选自甲苯、乙腈、乙醇、丙酮、2-丁酮、二甲基甲酰胺或氯仿的溶剂中进行烷基化反应或酰基化反应。
7.根据权利要求6所述的方法,其特征在于,通过在多步格式反应中烷基化,由相应的(-)-Narwedin基础结构制备具有通式Ic的化合物。
9.根据权利要求7所述的方法,其特征在于,碳酸氢钠、碳酸钾、氢氧化钠、氢氧化钾、三乙胺或吡啶或它们的混合物作为碱使用。
10.根据权利要求8或9所述的方法,其特征在于,基于100重量%起始产物,碱的用量介于5和20重量%之间。
11.含有一种或多种化合物Ia、Ib或Ic作为制药活性物质的药剂。
12.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗阿尔茨海默氏病或相关的痴呆症状。
13.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗帕金森氏病。
14.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗亨廷顿舞蹈症(舞蹈病)。
15.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗多发性硬化症。
16.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗肌萎缩性脊髓侧索硬化症。
17.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗癫痫症。
18.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗中风后遗症。
19.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗颅脑创伤后遗症。
20.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于治疗和预防大脑中扩散氧和营养缺乏的效应,如在缺氧、低氧、窒息、心脏停搏、中毒之后,在麻醉之后以及在难产并发症出现之后对婴儿所观察到的效应。
21.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备药剂中的应用,该药剂用于预防性治疗被局部的脑瘤放射疗法或化学疗法损坏或将受损的神经元的凋亡变性。
22.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备一种药剂中的应用,该药剂用于治疗细菌性脑膜炎。
23.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备一种药剂中的应用,该药剂用于治疗具有凋亡成分的病症,特别是以淀粉状蛋白有关的细胞变性为后果的病症。
24.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备一种药剂中的应用中的应用,该药剂用于治疗糖尿病,特别是当该疾病伴生有胰岛细胞的淀粉状蛋白变性时。
25.一种或多种以纯净形式的或以基制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备一种药剂中的应用,该药剂用于治疗手术后谵妄症和/或亚综合征性手术后谵妄症。
26.一种或多种以纯净形式的或以其制药可接受的酸加成盐形式的化合物Ia、Ib或Ic在制备一种药剂中的应用,该药剂用于预防性治疗手术后谵妄症和/或亚综合性手术后谵妄症。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ATA1538/2003 | 2003-09-29 | ||
AT15382003 | 2003-09-29 | ||
ATA1174/2004 | 2004-07-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1859949A true CN1859949A (zh) | 2006-11-08 |
Family
ID=34382391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004800283471A Pending CN1859949A (zh) | 2003-09-29 | 2004-09-09 | 4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂䓬的新衍生物,其制备方法及其在药剂制备中的应用 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20060111341A1 (zh) |
EP (1) | EP1667769A2 (zh) |
CN (1) | CN1859949A (zh) |
CA (1) | CA2506282A1 (zh) |
MX (1) | MXPA05005570A (zh) |
NO (1) | NO20052177L (zh) |
WO (1) | WO2005030332A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104860955A (zh) * | 2015-04-22 | 2015-08-26 | 华东理工大学 | 加兰他敏类似物及其用途 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090253654A1 (en) | 2005-09-22 | 2009-10-08 | Galantos Pharma Gmbh | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment |
WO2008022365A2 (de) * | 2006-08-24 | 2008-02-28 | Sanochemia Ltd. | Mittel zum beeinflussen der wirkungen von organophosphorverbindungen und verwendung von galanthamin, dessen derivaten und analoga zum herstellen solcher mittel |
WO2013160728A1 (en) | 2012-04-26 | 2013-10-31 | Alma Mater Studiorum - Universita' Di Bologna | Dual targeting compounds for the treatment of alzheimer's disease |
WO2017189834A1 (en) * | 2016-04-29 | 2017-11-02 | New Mexico Tech Research Foundation | Methods for treatment of resistant cancer |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6150354A (en) * | 1987-01-15 | 2000-11-21 | Bonnie Davis | Compounds for the treatment of Alzheimer's disease |
US6407229B1 (en) * | 1994-10-21 | 2002-06-18 | Sanochemia Pharmazeutika Ag | Processes for the preparation of derivatives of 4a,5,9,10,11,12-hexahydro-6H-benzofuro-[3a,3,2-ef][2] benzazapine |
BR9509406A (pt) * | 1994-10-21 | 1998-11-03 | Waldheim Pharmazeutica Ges M B | Processo para a preparação de 4a,5,9,10,11,12,-hedaxidro-6h-benzofuro(3a,3,2,-ef) [2] benzazepina |
GB9514821D0 (en) * | 1995-07-19 | 1995-09-20 | Sod Conseils Rech Applic | Galanthamine derivatives |
EP1133290B1 (de) * | 1998-11-27 | 2003-03-12 | Sanochemia Pharmazeutika Aktiengesellschaft | Verwendung von acetylcholinesterase-inhibitoren zur behandlung von delirien |
-
2004
- 2004-07-12 CA CA002506282A patent/CA2506282A1/en not_active Abandoned
- 2004-07-12 US US10/537,568 patent/US20060111341A1/en not_active Abandoned
- 2004-07-12 MX MXPA05005570A patent/MXPA05005570A/es not_active Application Discontinuation
- 2004-07-12 EP EP04737381A patent/EP1667769A2/de not_active Withdrawn
- 2004-07-12 WO PCT/AT2004/000251 patent/WO2005030332A2/de not_active Application Discontinuation
- 2004-09-09 CN CNA2004800283471A patent/CN1859949A/zh active Pending
-
2005
- 2005-05-03 NO NO20052177A patent/NO20052177L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104860955A (zh) * | 2015-04-22 | 2015-08-26 | 华东理工大学 | 加兰他敏类似物及其用途 |
Also Published As
Publication number | Publication date |
---|---|
WO2005030332A3 (de) | 2005-06-02 |
EP1667769A2 (de) | 2006-06-14 |
US20060111341A1 (en) | 2006-05-25 |
NO20052177D0 (no) | 2005-05-03 |
MXPA05005570A (es) | 2005-10-18 |
WO2005030332A2 (de) | 2005-04-07 |
CA2506282A1 (en) | 2005-04-07 |
NO20052177L (no) | 2005-06-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1040874C (zh) | 三唑并哒嗪化合物及制备法和以该化合物作为活性成分的组合物 | |
CN1045206C (zh) | 一种环酰胺衍生物的制备方法 | |
CN1032203C (zh) | 制备取代2-吡啶酮和吡啶-2-硫酮的方法 | |
CN101035781A (zh) | 2-吗啉基-4-嘧啶酮化合物 | |
CN1073939A (zh) | 一种环胺化合物的制备方法 | |
CN86100090A (zh) | 萘衍生物的制备方法 | |
CN1458921A (zh) | N-芳基邻氨基苯甲酸和它们的衍生物的制备方法 | |
CN1432015A (zh) | 可用作细胞增殖抑制剂的被1,1-二氧代异噻唑烷取代的吲唑 | |
CN1246315C (zh) | 氨基烷基苯甲酰基-苯并呋喃或苯并噻吩类,它们的制备方法与含有它们的组合物 | |
CN1738806A (zh) | 氧代-氮杂双环化合物 | |
CN1610664A (zh) | 3-氮杂二环[3.1.0]己烷衍生物作为类阿片受体拮抗剂 | |
CN87100978A (zh) | 新的二氢苯并呋喃—和苯并二氢吡喃—羧酰胺衍生物及其制备方法以及作为精神抑制药的应用 | |
CN1115337C (zh) | 嘧啶酮衍生物 | |
CN1190427C (zh) | 制备嘧啶衍生物的方法 | |
CN1020104C (zh) | 3-丙烯基头孢烯衍生物的制备方法 | |
CN1571781A (zh) | 4-咪唑啉-2-酮化合物 | |
CN1100425A (zh) | 噻唑并嘧啶衍生物 | |
CN1027536C (zh) | 4,5,6,7-四氢化苯并咪唑衍生物制备方法 | |
CN1805947A (zh) | 合成2-羟基-n , n-二甲基-3-[[2-[[1 ( r )-(5-甲基-2-呋喃基)丙基]氨基]-3 , 4-二氧代-1-环丁烯-1-基]氨基] 苯甲酰胺 | |
CN1197863C (zh) | 新的八氢-2H-吡啶并[1,2-a]吡嗪化合物、它们的制备方法和含有它们的药物组合物 | |
CN1323300A (zh) | 制备新的抗糖尿病剂的改进方法 | |
CN1590379A (zh) | 新的杂环肟化合物、它们的制备方法和含有它们的药物组合物 | |
CN1859949A (zh) | 4a,5,9,10,11,12-六氢苯并呋喃[3a,3,2][2]-苯并氮杂䓬的新衍生物,其制备方法及其在药剂制备中的应用 | |
CN1289509C (zh) | 新的苯并噻嗪和苯并噻二嗪衍生物,其制备方法以及包含所述化合物的药物组合物 | |
CN1039909C (zh) | 氨基苯甲酸衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |