CN1112365C - 哌啶衍生物及制备方法和用途 - Google Patents
哌啶衍生物及制备方法和用途 Download PDFInfo
- Publication number
- CN1112365C CN1112365C CN98812049A CN98812049A CN1112365C CN 1112365 C CN1112365 C CN 1112365C CN 98812049 A CN98812049 A CN 98812049A CN 98812049 A CN98812049 A CN 98812049A CN 1112365 C CN1112365 C CN 1112365C
- Authority
- CN
- China
- Prior art keywords
- compound
- piperidines
- spiral shell
- hydrogen
- dihydro
- 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.)
- Expired - Fee Related
Links
- 150000003053 piperidines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 208000002193 Pain Diseases 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 208000024891 symptom Diseases 0.000 claims abstract description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- 206010010904 Convulsion Diseases 0.000 claims abstract description 5
- 206010012289 Dementia Diseases 0.000 claims abstract description 5
- 230000036461 convulsion Effects 0.000 claims abstract description 5
- 230000006735 deficit Effects 0.000 claims abstract description 5
- 206010015037 epilepsy Diseases 0.000 claims abstract description 5
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 4
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 4
- 208000008589 Obesity Diseases 0.000 claims abstract description 4
- 230000001154 acute effect Effects 0.000 claims abstract description 4
- 208000005298 acute pain Diseases 0.000 claims abstract description 4
- 230000036506 anxiety Effects 0.000 claims abstract description 4
- 208000035475 disorder Diseases 0.000 claims abstract description 4
- 235000020824 obesity Nutrition 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 30
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 15
- 239000000654 additive Substances 0.000 claims description 14
- 230000000996 additive effect Effects 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 241001289721 Lethe Species 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 230000002503 metabolic effect Effects 0.000 claims description 4
- 210000005036 nerve Anatomy 0.000 claims description 4
- 238000005576 amination reaction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 239000008011 inorganic excipient Substances 0.000 claims description 2
- 239000008012 organic excipient Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 239000005557 antagonist Substances 0.000 abstract description 3
- 108010020615 nociceptin receptor Proteins 0.000 abstract description 2
- 208000000044 Amnesia Diseases 0.000 abstract 1
- 208000027796 Blood pressure disease Diseases 0.000 abstract 1
- 208000026139 Memory disease Diseases 0.000 abstract 1
- 208000013200 Stress disease Diseases 0.000 abstract 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 abstract 1
- 230000004872 arterial blood pressure Effects 0.000 abstract 1
- 230000029142 excretion Effects 0.000 abstract 1
- 230000006984 memory degeneration Effects 0.000 abstract 1
- 208000023060 memory loss Diseases 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 230000000926 neurological effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 102100031292 Prepronociceptin Human genes 0.000 description 11
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 10
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical compound C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 description 6
- -1 isobutyl- Chemical group 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010065952 Hyperpathia Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000020341 sensory perception of pain Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- LKRZCUQFUCYWLZ-UHFFFAOYSA-N 2-chloroacetyl bromide Chemical compound ClCC(Br)=O LKRZCUQFUCYWLZ-UHFFFAOYSA-N 0.000 description 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- OUGMRQJTULXVDC-UHFFFAOYSA-N 9h-fluoren-9-amine Chemical compound C1=CC=C2C(N)C3=CC=CC=C3C2=C1 OUGMRQJTULXVDC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 108010065372 Dynorphins Proteins 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- 102100024622 Proenkephalin-B Human genes 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 150000001721 carbon Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- YQYJSBFKSSDGFO-FWAVGLHBSA-N hygromycin A Chemical compound O[C@H]1[C@H](O)[C@H](C(=O)C)O[C@@H]1Oc1ccc(\C=C(/C)C(=O)N[C@@H]2[C@@H]([C@H]3OCO[C@H]3[C@@H](O)[C@@H]2O)O)cc1O YQYJSBFKSSDGFO-FWAVGLHBSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002400 pro-nociceptive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—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
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及式(I-1)化合物及其可药用酸加成盐,其中X为-O-或-CH2-;Y为-C(O)-,-(CH2)n-或-N(CH3)-;n为1或2;或X和Y一起为-CH=CH-;Z为-NH-,-CH2-,-O-或=CH-;A1为基团(a)或(b);B为-(CH2)m-;m为0,1或2;R1和R2各自独立地为氢或低级烷基;R3为氢或卤素;R4为氢或羟基且虚线为任选的-CH2-CH2-基团。本发明化合物是OFQ受体的拮抗剂。因此它们可用于治疗记忆和注意力缺陷,精神病,神经和生理疾病,尤其是但不限于改善焦虑和紧张疾病、抑郁、因阿尔茨海默疾病或其他痴呆引起的记忆缺失、癫痫和惊厥的症状、急性和/或慢性疼痛病症、药瘾戒断的症状、水平衡控制、Na+***、动脉血压疾病和代谢疾病如肥胖。
Description
式I-1化合物及其盐的特征在于有价值的治疗性能。已惊人地发现本发明化合物是OFQ受体的拮抗剂。因此它们可用于治疗记忆和注意力缺陷、精神病、神经和生理疾病,尤其是但不限于改善焦虑和紧张疾病、抑郁、因阿尔茨海默疾病或其他痴呆引起的记忆缺失、癫痫和惊厥的症状、急性和/或慢性疼痛病症、药瘾戒断的症态、水平衡控制、Na+***和动脉血压疾病以及代谢疾病如肥胖。
孤独素(Orphanin)FQ(OFQ)是一种十七氨基酸肽(F-G-G-F-T-G-A-R-K-S-A-R-K-L-A-N-Q),业已从大鼠脑中分离且为在脑组织中以高浓度存在的G-蛋白偶联受体(OFQ-R)的天然配体。
OFQ在体内和体外均对OFQ-R产生激动活性。
Julius(自然,377,476,[1995])讨论了OFQ的发现,提到该肽与强啡肽A-一种阿片样物质受体的已知内源性配体-具有最大的序列相似性。OFQ在脑室内给药于小鼠时在培养物中的CHO(LC 132+)细胞中抑制腺苷酸环化酶且诱发痛觉过敏。结果表明该十七肽是LC132受体的内源性激动剂且似乎具有原感受伤害(pro-nociceptive)性能。其描述到,当脑室内给药于小鼠时,OFQ减缓运动活性且诱发痛觉过敏,因此结论是OFQ可以用作脑神经递质来调节感受伤害行为和运动行为。
本发明的目的是提供式I-1的新化合物本身以及其可药用加成盐,外消旋混合物和对应的对映体,制备上述化合物的方法,包含它们的药物及其制备方法以及上述化合物在控制或预防疾患,尤其是前面提及的疾患中的用途。
本发明的另一目的是如下通式的化合物及其可药用盐在治疗或预防记忆和注意力缺陷、精神病、神经和生理疾病,尤其是但不限于改善紧张疾病、因阿尔茨海默疾病或其他痴呆引起的记忆缺失、癫痫和惊厥的症状、药瘾戒断的症状、水平衡控制、Na+***、动脉血压疾病和代谢疾病如肥胖或制备相应药物中的用途:其中A2为二苯基甲基且所有其他取代基如上所定义。
其中X为O且A2为二苯基甲基的式I-2化合物一般性地描述于US3,985,889和DE-24 58 176中,它们可用作安定药、抗抑郁药和镇痛药。
本说明书中所用通用术语使用下列定义,不论所述术语单独出现还是组合出现。
本文所用的术语“低级烷基”表示含1-6个碳原子的直链或支链烷基,如甲基、乙基、丙基、异丙基、正丁基、异丁基、2-丁基、叔丁基。
术语“卤素”表示氯、碘、氟和溴。
“离去基团”指在化学反应中由另一基团替换的不稳定基团。离去基团的实例是氯、溴、碘、三氟甲基磺酸根、甲磺酸根或甲苯磺酸根。
本发明涉及一组下式的新化合物及其可药用酸加成盐:其中X为-O-或-CH2-;Y为-C(O)-,-(CH2)n-或-N(CH3)-;n为1或2;或X和Y一起为-CH=CH-;Z为-NH-,-CH2-,-O-或=CH-;B为-(CH2)m-;m为0,1或2;R1和R2各自独立地为氢或低级烷基;R3为氢或卤素;R4在Z为-NH-,-CH2-或-O-时为氢或羟基,以及虚线为任选的-CH2-CH2-基团;以及一组下式化合物及其可药用加成盐:其中X为-O-或-CH2-;Y为-C(O)-,-(CH2)n-或-N(CH3)-;n为1或2;或X和Y一起为-CH=CH-;Z为-NH-,-CH2-,-O-或=CH-;B为-(CH2)m-;m为0,1或2;R1和R2各自独立地为氢或低级烷基;R3为氢或卤素;R4在Z为-NH-,-CH2-或-O-时为氢或羟基,以及虚线为任选的-CH2-CH2-基团。
优选的示例化合物为下式化合物:其中X为O或-CH2-;Y为-C(O)-或-CH2-;Z为NH或-CH2-;B为-(CH2)m-;m为0或2;例如下列化合物:1’-[2-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基氨基)乙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮,(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)-[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]胺,(9H-芴-9-基)-[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]胺,1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3H-螺[异苯并呋喃-1,4’-哌啶],1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-2,3-二氢螺[茚-1,4’-哌啶]。
式I-1的本发明化合物及其可药用盐可以通过本领域已知的方法制备,例如通过下述方法,所述方法包括
b)将式II化合物用式IV的醛还原胺化:其中A1和Z如上所定义,或
c)将其中Y为-C(O)-的式I-1化合物还原为其中Y为-CH2-的式I-1化合物,和
d)若需要,将得到的式I-1化合物转化为可药用酸加成盐。
按照工艺步骤a)的烷基化反应在碱如三乙胺、吗啉、碳酸锂、碳酸钠或碳酸钾存在下在惰性溶剂如乙腈、异丁基甲基酮、二甲基甲酰胺或二甲亚砜中进行。
按照工艺变体b)的还原性胺化以常规方式在溶剂如四氢呋喃、1,2-二氯乙烷、甲醇或乙醇中在还原剂如氰基硼氢化钠或三乙酰氧基硼氢化钠存在下进行。
另一方法是由II与IV反应,第一步失去水,得到烯胺,然后在第二步中还原该烯胺得到式I-1化合物。此时可能的还原剂是硼氢化物、氰基硼氢化钠和在至少一种氢化催化剂如碳载钯、铂或钌存在下的氢。
此外,带有3H-螺[异苯并呋喃-1,4’-哌啶]结构的化合物可以通过还原由相应的螺[异苯并呋喃-1,4’-哌啶]-3-酮制备。合适的还原剂例如为硼烷,氢化铝锂,三氟化硼与复合氢化物如硼氢化钠或氢化铝锂、酸性溶液中的硼氢化钠、锂、苯基硅烷或三氯硅烷的混合物,以及在至少一种催化剂如二氧化铂或Raney镍存在下的氢。
若需要,可以将式I化合物转化为可药用酸加成盐。成盐反应在室温下通过身本已知且本领域熟练技术人员所熟知的方法进行。不仅可以考虑与无机酸的盐,而且可以考虑与有机酸的盐。此类盐的实例有盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、柠檬酸盐、乙酸盐、马来酸盐、琥珀酸盐、甲磺酸盐、对甲苯磺酸盐等。
用作原料的式II胺是已知化合物或根据《有机化学杂志》,41(1976),2628通过2-溴苯甲酸的锂化并与相应的1-苄基哌啶-4-酮反应、随后脱苄基而制备,该制备过程如下所示:
如前所述,式I化合物及其可药用加成盐具有有价值的药效性能。已发现本发明化合物是OFQ受体的拮抗剂且在患有如下疾病的动物模型中有效:记忆和注意力缺陷,精神病,神经和生理疾病,如焦虑、紧张疾病、抑郁、因阿尔茨海默疾病或其他痴呆引起的记忆缺失、癫痫和惊厥、急性和/或慢性疼痛病症、药瘾戒断的症状、水平衡控制、Na+***、动脉血压疾病和代谢疾病如肥胖。
根据下述试验研究化合物:OFQ-R结合分析方法细胞培养
将适于悬浮生长的HEK-293细胞(293s)在加有2%FBS的HL培养基中培养。使用脂质转染试剂(Life Technologies,Bethesha,MD,USA)将细胞用克隆在表达载体pCEP4(Invitrogen,SanDiego,CA,USA)中的大鼠OFQ受体cDNA(LC132)转染(FEBS Lett.347,284-288,1994)。在潮霉素(1000U/ml)(Calbiochem,SanDiego,CA,USA)存在下选取转染的细胞。通过[3H]-OFQ(Amersham PLC,Buckinghamshire,英国)的结合来测试一池抗性细胞的OFQ-R表达。使这些细胞(293s-OFQ-R)膨胀以用于大规模培养和制备膜。膜制备
通过离心收集293s-OFQ-R细胞,用磷酸盐缓冲盐水(PBS)洗涤3次,然后再悬浮于缓冲液A(50mM Tris-HCl,pH7.8,5mM MgCl2,1mM EGTA)中并用组织匀浆器破坏(30秒,设定为4,Pt20,Kinematica,Kriens-Lucern,瑞士)。通过于4℃在49,000xg下离心得到总的膜级分。重复该程序两次并将所得沉淀再悬浮于缓冲液A中。将等份试样储存在-70℃下并使用BCATM蛋白分析试剂(Pierce,Rockford,IL)按照制造商的推荐测定蛋白浓度。结合分析
使用77μg膜蛋白在最终分析体积为0.5ml、含0.1%BSA和0.01%杆菌肽(Boehringer-Mannheim,Mannheim,德国)的缓冲液A中于室温下进行1小时的[3H]-OFQ竞争研究。使用50nM未标记的OFQ定义非特异性结合。通过滤过Whatman GF/C过滤器(Unifilter-96,Canberra PackardS.A.,苏黎士,瑞士)而终止分析,该过滤器用0.3%聚乙烯亚胺(Sigma,St.Louis,MO,USA)和0.1%BSA(Sigma)预处理1小时。过滤器用1ml冰冷的50nM Tris-HCl(pH7.5)洗涤6次。加入40μl Microscint 40(CanberraPackard)后在Packard Top-Count微滴板闪烁计数器上计数残留放射性。使用至少6个浓度一式三份地测量化合物的效果,测量两次。通过曲线拟合确定IC50值,通过Cheng和Prusoff的方法(Biochem.Pharmacol.,22,3099,1973)将这些值转化为Ki值。
对OFQ受体的亲和性(以pKi给出)在6.7-8.2范围内,例如下述化合物的pKi如下:A/1 1’-[2-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基氨基)乙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮甲磺酸盐(1∶2)B/5 [2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]-(5,6,7,8-四氢-4H-苯并环庚烯-4-基)胺盐酸盐(1∶2)C 1’-(2-二苯甲氧基乙基)-3H-螺[异苯并呋喃-1,4’-哌啶]盐酸盐(1∶1)
式I化合物及其可药用酸加成盐可用作药物,例如以药物制剂形式。该药物制剂可以口服给药,例如以片剂、包衣片剂、糖锭剂、硬和软明胶胶囊、溶液、乳液或悬浮液形式。但也可以直肠给药,例如以栓剂形式,或经非肠道给药,例如以注射溶液形式。
式I化合物及其可药用酸加成盐可以与用于生产片剂、包衣片剂、糖锭剂和硬明胶胶囊的药物上呈惰性的无机或有机赋型剂一起加工。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等可以用作例如用于片剂、糖锭剂和硬明胶胶囊的此类赋型剂。
软明胶胶囊的合适赋型剂例如为植物油、蜡、脂肪、半固体和液体多元醇等。
用于制备溶液和糖浆的合适赋型剂例如为水、多元醇、蔗糖、转化糖、葡萄糖等。
用于注射溶液的合适赋型剂例如为水、醇、多元醇、甘油、植物油等。
用于栓剂的合适赋型剂例如为天然或硬化油、蜡、脂肪、半固体或液体多元醇等。
此外,药物制剂可以含有防腐剂、加溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、改变渗透压的盐、缓冲剂、掩盖剂或抗氧剂。它们也可含有其他治疗上有价值的物质。
剂量可以在宽范围内变化,当然在各种特定情况下适于个体要求。通常而言,在口服给药时,每人约10-1000mg通式I化合物的日剂量是合适的,但在需要时也可超过上一上限。
下列实施例说明本发明,但并不以任何方式限制本发明。
实施例11’-[2-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基氨基)乙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮甲磺酸盐(1∶2)
将5-氨基-10,11-二氢-5H-二苯并[a,d]环庚烯(10mmol)溶于丙酮(25ml)中并加入碳酸钠(1.6g)。冷却混合物(0-5℃)并缓慢加入氯乙酰氯(15mmol)。室温搅拌1小时后,加入水(25ml)和乙酸乙酯(25ml)。分离有机相,用饱和NaHCO3溶液洗涤,干燥(MgSO4)并浓缩得到88%氯乙酰胺,其不经进一步提纯而使用。将粗氯乙酰胺(4mmol)溶于THF(10ml)中。在氩气下于0-5℃缓慢加入硼烷-THF配合物(1M THF溶液,12ml)。室温搅拌混合物2小时。加入盐酸(4M,8ml)后,将混合物搅拌15分钟,然后浓缩。将残余物分配于二氯甲烷(10ml)和饱和NaHCO3(10ml)之间,用浓NaOH溶液将水相pH调至8-9。分离有机层,水层用二氯甲烷萃取几次,干燥(MgSO4)合并的有机相。蒸发得到粗2-氯乙基胺。将该化合物溶于DMF(15ml)中,然后加入螺[异苯并呋喃-1(3H),4’-哌啶]-3-酮(4mmol)、碳酸钾(5.5mmol)和碘化钾(0.2mmol)。140℃下3小时后,减压蒸发溶剂。加入饱和NaHCO3溶液并用二氯甲烷萃取混合物。将合并的有机层干燥(MgSO4)并浓缩。残余物在硅胶上层析(乙酸乙酯)。将甲磺酸加入该产物的乙酸乙酯/乙醇溶液中得到1’-[2-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基氨基)乙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮甲磺酸盐(1.06g,42%),无色固体,m.p.196℃。
实施例21’-[2-(3-氯-10,11-二氢-5H-二苯并[a,d]环庚烯-5-基氨基)乙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮盐酸盐(1∶2)
按照实施例1的通用方法由5-氨基-3-氯-10,11-二氢-5H-二苯并[a,d]环庚烯、氯乙酰氯、螺[异苯并呋喃-1(3H),4’-哌啶]-3-酮和HCl制备标题化合物,m.p.228℃和MS:m/e=473(M+H+)。
实施例3(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)-[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]胺盐酸盐(1∶2)
按照实施例1的通用方法由5-氨基-10,11-二氢-5H-二苯并[a,d]环庚烯、氯乙酰氯、螺[异苯并呋喃-1(3H),4’-哌啶]和HCl制备标题化合物,m.p.215℃和MS:m/e=425.3(M+H+)。
实施例4(9H-芴-9-基)-[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]胺盐酸盐(1∶2)
按照实施例1的通用方法由9-氨基芴、氯乙酰氯、螺[异苯并呋喃-1(3H),4’-哌啶]和HCl制备标题化合物,m.p.244℃和MS:m/e=397.3(M+H+)。
实施例5[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]-(5,6,7,8-四氢-4H-苯并环庚烯-4-基)胺盐酸盐(1∶2)
按照实施例1的通用方法由(5,6,7,8-四氢-4H-苯并环庚烯-4-基)胺、氯乙酰氯、螺[异苯并呋喃-1(3H),4’-哌啶]和HCl制备标题化合物,m.p.220℃和MS:m/e=377.3(M+H+)。
实施例6(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)-[2-(2,3-二氢-螺[茚-1,4’-哌啶]-1’-基)乙基)胺盐酸盐(1∶2)
按照实施例1的用通方法由5-氨基-10,11-二氢-5H-二苯并[a,d]环庚烯、氯乙酰氯、2,3-二氢-螺[1H-茚-1,4’-哌啶]和HCl制备标题化合物,m.p.170℃和MS:m/e=423.4(M+H+)。
实施例7(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)-[2-(螺[茚-1,4’-哌啶]-1’-基)乙基]胺盐酸盐(1∶2)
按照实施例1的通用方法由5-氨基-10,11-二氢-5H-二苯并[a,d]环庚烯、氯乙酰氯、螺[1H-茚-1,4’-哌啶]和HCl制备标题化合物,m.p.186℃和MS:m/e=421.3(M+H+)。
实施例81’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮盐酸盐(1∶1)
将3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇(1mmol)和三乙胺(1.5mmol)在二氯甲烷中的溶液冷却至0-5℃。滴加甲磺酰氯(1.5mmol)在二氯甲烷(1.5ml)中的溶液。于0-5℃下搅拌1小时后,减压浓缩混合物,得到油状粗甲磺酸盐。将其与螺[异苯并呋喃-1(3H),4’-哌啶]-3-酮(1mmol)和碳酸钾(2.5mmol)一起溶于乙腈中,然后回流20小时。蒸发溶剂之后,加入饱和NaHCO3溶液并用二氯甲烷萃取混合物。合并的有机层用MgSO4干燥并浓缩。残余物在硅胶上层析(乙酸乙酯)。将乙醇中的HCl加入产物的乙酸乙酯/乙醇溶液中得到无色固体状1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮盐酸盐(0.25g,53%),m.p.210℃和MS:m/e=438.4(M+H+)。
实施例91’-(3-(5-羟基-10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-螺[异苯并呋喃-1,4’-哌啶]-3-酮盐酸盐(1∶1)
按照实施例8的通用方法由3-(5-羟基-10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和螺[异苯并呋喃-1(3H),4’-哌啶]-3-酮制备标题化合物,m.p.178℃和MS:m/e=454.5(M+H+)。
实施例101’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3H-螺[异苯并呋喃-1,4’-哌啶]盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和螺[异苯并呋喃-1(3H),4’-哌啶]制备标题化合物,m.p.235℃和MS:m/e=424.3(M+H+)。
实施例115-[3-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’基)丙基]-10,11-二氢-5H-二苯并[a,d]环庚烯-5-醇盐酸盐(1∶1)
按照实施例8的通用方法由5-[3-羟丙基]-10,11-二氢-5H-二苯并[a,d]环庚烯-5-醇和螺[异苯并呋喃-1(3H),4’-哌啶]制备标题化合物,m.p.201℃和MS:m/e=440.3(M+H+)。
实施例121’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-亚基)丙基]-3H-螺[异苯并呋喃-1,4’-哌啶]盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-亚基)丙-3-醇和螺[异苯并呋喃-1(3H),4’-哌啶]制备标题化合物,m.p.231℃和MS:m/e=422.3(M+H+)。
实施例131’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-2,3-二氢-螺[茚-1,4’-哌啶]盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和2,3-二氢-螺[茚-1,4’-哌啶]制备标题化合物,m.p.220℃和MS:m/e=422.3(M+H+)。
实施例141’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-螺[茚-1,4’-哌啶]盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和螺[茚-1,4’-哌啶]制备标题化合物,m.p.227℃和MS:m/e=420.3(M+H+)。
实施例15(1RS,3’SR)-1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和(1RS,3’SR)-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮制备标题化合物,m.p.214℃和MS:m/e=452.4(M+H+)。
实施例16(1RS,3’SR)-1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基)-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]盐酸盐(1∶1)
将(1RS,3’SR)-1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮(0.5mmol)溶于四氢呋喃中并在氩气下加入硼烷-THF配合物(1M THF溶液,3mmol)。回流加热所得混合物18小时。将其冷却至0℃并滴加1M HCl直至不再观察到气体放出。真空浓缩反应混合物并将HCl(1N,5ml)加入所得白色泡沫中,所得混合物于100℃搅拌1小时。然后冷却溶液并用浓氨水溶液碱化。将产物萃取到二氯甲烷中并在硅胶上柱层析而纯化(乙酸乙酯)。将乙醇中的HCl加入该产物的乙酸乙酯/乙醇溶液中得到无色固体状(1RS,3’SR)-1’-[-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]盐酸盐(0.18g,82%),m.p.225℃和MS:m/e=438.4(M+H+)。
实施例17(1R,3’R,5’S)-1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3’,5’-二甲基-3H-螺[异苯并呋喃-1,4’-哌啶]盐酸盐(1∶1)
按照实施例8的通用方法,然后根据实施例16进行硼烷还原,由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基]丙-3-醇和(1R,3’R,5’S)-3’,5’-二甲基-3H-螺[异苯并呋喃-1,4’-哌啶]制备标题化合物,m.p.237℃和MS:m/e=452.5(M+H+)。
实施例181’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-1-甲基-1,2-二氢-螺[吲哚-3,4’-哌啶]盐酸盐(1∶1)
为了合成标题化合物,m.p.222℃和MS:m/e=437.4(M+H+),根据实施例16用硼烷还原1-甲基-螺[3H-吲哚-3,4’-哌啶]-2(1H)-酮,得到1-甲基-1,2-二氢-螺[吲哚-3,4’-哌啶],按照实施例8的通用方法将其进一步与3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-酮反应。
实施例19(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)-[2-(螺[异苯并二氢吡喃-1,4’-哌啶]-1’-基)乙基]胺盐酸盐(1∶2)
按照实施例1的通用方法由5-氨基-10,11-二氢-5H-二苯并[a,d]环庚烯、氯乙酰氯、螺[异苯并二氢吡喃-1,4’-哌啶]和HCl制备标题化合物,m.p.190℃和MS:m/e=439.4(M+H+)。
实施例201’-[3-(9,10-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-螺[异苯并二氢吡喃-1,4’-哌啶]盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和螺[异苯并二氢吡喃-1,4’-哌啶]制备标题化合物,m.p.243℃和MS:m/e=438.4(M+H+)。
实施例21(1RS,5SR)-8-[3-(9,10-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-螺[8-氮杂双环[3.2.1]辛烷-3,1’-异苯并呋喃]-3’-酮盐酸盐(1∶1)
按照实施例8的通用方法由3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙-3-醇和(1RS,5SR)-螺[8-氮杂双环[3.2.1]辛烷-3,1’-异苯并呋喃]-3’-酮-1RS,3’SR)-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮制备标题化合物,m.p.284℃和MS:m/e=464.3(M+H+)。
新中间体的合成
实施例22(1RS,3’SR)-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮
将2-溴苯甲酸(70mmol)加入装有加料漏斗、低温温度计、惰性气体入口和机械搅拌器的干燥三颈烧瓶中。加入无水四氢呋喃(250ml)并将溶液冷却至-78℃。缓慢加入正丁基锂(2小时),同时保持混合物低于-70℃并将所得溶液另外搅拌1小时。在30分钟内加入在己烷和四氢呋喃混合物(25ml/25ml)中的1-苄基-3-甲基哌啶-4-酮(98mmol),同时维持混合物低于-70℃(1小时内)且将混合物温热至室温。搅拌一夜后,将混合物倾入水(300ml)中,用***萃取并用浓HCl酸化(至pH2-3),用***萃取。使酸性溶液沸腾1小时,然后冷却(0-5℃)并用NaOH水溶液调为碱性(至pH9-10)。用二氯甲烷萃取该***液。干燥(MgSO4)合并的有机萃取液并浓缩得到黄色油状物(7.0g)。将其在硅胶上层析(乙酸乙酯),得到6.35g(1RS,3’SR)-1’-苄基-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮,为无色油状物(20.6mmol,30%)。为了脱去苄基,将该化合物溶于乙醇(250ml)中并加入碳载钯(10%,0.64g)。将该悬浮液搅拌并氢化(1巴)一夜。滤出催化剂后浓缩溶液。剩余的固体从乙酸乙酯中重结晶,得到(1RS,3’SR)-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮,为无色固体(2.7g,60%),m.p.131 ℃和MS:m/e=218.3(M+H+)。
实施例23(1R,3’R,5’S)-3’,5’-二甲基-3H-螺[异苯并呋喃-1,4’-哌啶]-3-酮
按照合成(1RS,3’SR)-3’-甲基-螺[异苯并呋喃-1,4’-哌啶]-3-酮的方法,使用1-苄基-3,5-二甲基哌啶-4-酮制备标题化合物,m.p.125℃和MS:m/e=231(M+)。
实施例A
具有下列组成的片剂以常见方式制造:
mg/片剂
活性物质 5
乳糖 45
玉米淀粉 15
微晶纤维素 34
硬脂酸镁 1
片剂重量 100
实施例B
制造具有下列组成的胶囊:
mg/胶囊
活性物质 10
乳糖 155
玉米淀粉 30
滑石 5
胶囊填充重量 200
首先将活性物质、乳糖和玉米淀粉在混合器中混合,然后在粉碎机中混合。将混合物送回混合器中,往其中加入滑石并彻底混合。通过机器将混合物填充至硬明胶胶囊中。
实施例C
制造具有如下组成的栓剂:
mg/栓剂
活性物质 15
栓剂基质 1285
总计 1300
在玻璃或钢制容器中熔化栓剂基质,彻底混合并冷却至45℃。然后往其中加入细粉状活性物质并搅拌直至完全分散。将混合物倾入合适尺寸的栓剂模具中,冷却,然后从模具中取出栓剂并单独包装在蜡纸或金属箔中。
Claims (10)
1.下式的化合物及其可药用酸加成盐:其中X为-O-或-CH2-;Y为-C(O)-,-(CH2)n-或-N(CH3)-;n为1或2;或X和Y一起为-CH=CH-;Z为-NH-,-CH2-,-O-或=CH-;A1为基团或
B为-(CH2)m-;m为0,1或2;R1和R2各自独立地为氢或C1-C6烷基;R3为氢或卤素;R4在Z为-NH-,-CH2-或-O-时为氢或羟基,以及虚线为任选的-CH2-CH2-基团。
4.根据权利要求1~3中任一项的化合物,其中化合物为:1’-[2-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基氨基)乙基]-螺-[异苯并呋喃-1,4’-哌啶]-3-酮,(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)-[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]胺,(9H-芴-9-基)-[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]胺,1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-3H-螺-[异苯并呋喃-1,4’-哌啶],1’-[3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)丙基]-2,3-二氢螺[茚-1,4’-哌啶]。
5.根据权利要求1的下式化合物及其可药用酸加成盐:其中X为-O-或-CH2-;Y为-C(O)-,-(CH2)n-或-N(CH3)-;n为1或2;或X和Y一起为-CH=CH-;Z为-NH-,-CH2-,-O-或=CH-;B为-(CH2)m-;m为0,1或2;R1和R2各自独立地为氢或C1-C6烷基;R3为氢或卤素;R4在Z为-NH-,-CH2-或-O-时为氢或羟基,以及虚线为任选的-CH2-CH2-基团。
6.根据权利要求1或5的化合物,其中该化合物为[2-(3H-螺[异苯并呋喃-1,4’-哌啶]-1’-基)乙基]-(5,6,7,8-四氢-4H-苯并环庚烯-4-基)胺。
7.一种用于治疗疾病的药物制剂,其含有一种或多种权利要求1-6中任一项的化合物或其可药用盐和药物上呈惰性的无机或有机赋型剂。
8.根据权利要求7的药物制剂,用于治疗孤独素FQ受体相关疾病。
9.根据权利要求7的药物制剂,用于治疗记忆和注意力缺陷,精神病,神经和生理疾病,焦虑和紧张疾病,抑郁,因阿尔茨海默疾病或其他痴呆引起的记忆缺失,癫痫和惊厥,急性和/或慢性疼痛病症,药瘾戒断的症状,水平衡控制,Na+***,动脉血压疾病和包括肥胖在内的代谢疾病。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97121844 | 1997-12-11 | ||
EP97121844.1 | 1997-12-11 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1281459A CN1281459A (zh) | 2001-01-24 |
CN1112365C true CN1112365C (zh) | 2003-06-25 |
Family
ID=8227781
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98812049A Expired - Fee Related CN1112365C (zh) | 1997-12-11 | 1998-12-03 | 哌啶衍生物及制备方法和用途 |
Country Status (16)
Country | Link |
---|---|
US (1) | US6166209A (zh) |
EP (1) | EP1037892B1 (zh) |
JP (1) | JP3453121B2 (zh) |
KR (1) | KR100369689B1 (zh) |
CN (1) | CN1112365C (zh) |
AR (1) | AR016431A1 (zh) |
AT (1) | ATE278695T1 (zh) |
AU (1) | AU744192B2 (zh) |
BR (1) | BR9813543A (zh) |
CA (1) | CA2310458C (zh) |
DE (1) | DE69826891T2 (zh) |
ES (1) | ES2229557T3 (zh) |
PT (1) | PT1037892E (zh) |
TR (1) | TR200001669T2 (zh) |
WO (1) | WO1999029696A1 (zh) |
ZA (1) | ZA9811345B (zh) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6462053B1 (en) | 1999-08-20 | 2002-10-08 | Banyu Pharmaceutical Co., Ltd. | Spiro compounds |
TWI279402B (en) | 1999-08-20 | 2007-04-21 | Banyu Pharma Co Ltd | Spiro compounds having NPY antagonistic activities and agents containing the same |
US6803372B2 (en) | 1999-08-20 | 2004-10-12 | Banyu Pharmaceutical Co., Ltd. | Spiro compounds |
JP3989247B2 (ja) | 1999-12-06 | 2007-10-10 | ユーロ−セルティーク エス.エイ. | ノシセプチン受容体親和性を有するトリアゾスピロ化合物 |
AU2063201A (en) | 1999-12-06 | 2001-06-12 | Euro-Celtique S.A. | Tertiary amino compounds having opioid receptor affinity |
JP2003524634A (ja) | 1999-12-06 | 2003-08-19 | ユーロ−セルティーク,エス.エイ. | ノシセプチン受容体親和性を有するベンズイミダゾール化合物 |
DE60112725T2 (de) * | 2000-02-18 | 2006-06-01 | Meiji Seika Kaisha Ltd. | Phenoxyalkylaminderivate als agonisten des opioid-delta rezeptors |
HUP0402510A3 (en) | 2001-04-18 | 2012-08-28 | Euro Celtique Sa | Nociceptin analogs and pharmaceutical compositions containing them |
SI1975164T1 (sl) | 2001-04-18 | 2010-05-31 | Euro Celtique Sa | Oktahidrobenzimidazolonske spojine kot analgetiki |
ATE403429T1 (de) | 2001-04-18 | 2008-08-15 | Euro Celtique Sa | Spiropyrazol-verbindungen |
SI1598340T1 (sl) | 2001-04-18 | 2009-08-31 | Euro Celtique Sa | Derivati 1-(4-piperidinil)-1,3-dihidro-2H-benzoksazol-2-ona in sorodne spojine kot analogi nociceptina in ligandi ORL1 za zdravljenje bolečine |
SI1385514T1 (sl) | 2001-04-18 | 2009-04-30 | Euro Celtique Sa | Spiroindenske in spiroindanske spojine |
WO2002088089A1 (fr) * | 2001-04-19 | 2002-11-07 | Banyu Pharmaceutical Co., Ltd. | Derives de spiropiperidine, antagonistes du recepteur de nociceptine les contenant en tant qu'ingredient actif et compositions medicinales |
WO2002094825A1 (fr) * | 2001-05-22 | 2002-11-28 | Banyu Pharmaceutical Co., Ltd. | Nouveau derive de spiropiperidine |
US20030078278A1 (en) * | 2001-06-26 | 2003-04-24 | Pfizer Inc. | Spiropiperidine compounds as ligands for ORL-1 receptor |
AU2003220886A1 (en) * | 2002-03-29 | 2003-10-13 | Mitsubishi Pharma Corporation | Remedy for sleep disturbance |
US20050228023A1 (en) * | 2003-12-19 | 2005-10-13 | Sri International | Agonist and antagonist ligands of the nociceptin receptor |
EP1726590A4 (en) * | 2004-03-05 | 2009-07-15 | Banyu Pharma Co Ltd | D RIV CYCLOALKANOPYRIDINE |
EP1824853A4 (en) * | 2004-12-09 | 2010-06-09 | Virochem Pharma Inc | NEW SPIROTROPAN COMPOUNDS AND METHOD FOR MODULATING THE ACTIVITY OF THE CHEMOKIN RECEPTOR |
CA2587508A1 (en) * | 2004-12-09 | 2006-06-15 | Virochem Pharma Inc. | Novel spirotropane compounds and methods for the modulation of chemokine receptor activity |
CN101233139A (zh) * | 2005-06-17 | 2008-07-30 | 辉瑞有限公司 | 作为ORL1-受体拮抗剂的α-(芳基-或杂芳基-甲基-)-β-哌啶基丙酸化合物 |
US8193208B2 (en) | 2005-09-09 | 2012-06-05 | Purdue Pharma L.P. | Fused and spirocycle compounds and the use thereof |
JP2009525269A (ja) * | 2006-01-30 | 2009-07-09 | ユーロ−セルティーク エス.エイ. | カルシウムチャネルブロッカーとしての環状尿素化合物 |
WO2008068185A1 (en) | 2006-12-07 | 2008-06-12 | F. Hoffmann-La Roche Ag | Spiro-piperidine derivatives as via receptor antagonists |
US7501432B2 (en) | 2006-12-22 | 2009-03-10 | Hoffman-La Roche Inc. | Spiro-piperidine derivatives |
AU2007338115A1 (en) | 2006-12-22 | 2008-07-03 | F. Hoffmann-La Roche Ag | Spiro-piperidine derivatives |
US8728275B2 (en) | 2012-07-27 | 2014-05-20 | Ecolab Usa Inc. | Glycerol-based polymers for reducing deposition of organic contaminants in papermaking processes |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5665725A (en) * | 1991-06-13 | 1997-09-09 | H. Lundbeck | Piperidine derivatives having anxiolytic effect |
CN1191862A (zh) * | 1997-01-30 | 1998-09-02 | 弗·哈夫曼-拉罗切有限公司 | 8-取代的1,3,8-三氮杂螺[4.5]癸烷-4-酮衍生物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3962259A (en) * | 1973-12-12 | 1976-06-08 | American Hoechst Corporation | 1,3-Dihydrospiro[isobenzofuran]s and derivatives thereof |
-
1998
- 1998-11-20 US US09/196,992 patent/US6166209A/en not_active Expired - Fee Related
- 1998-12-03 AT AT98965753T patent/ATE278695T1/de not_active IP Right Cessation
- 1998-12-03 BR BR9813543-0A patent/BR9813543A/pt not_active Application Discontinuation
- 1998-12-03 CA CA002310458A patent/CA2310458C/en not_active Expired - Fee Related
- 1998-12-03 WO PCT/EP1998/007864 patent/WO1999029696A1/en active IP Right Grant
- 1998-12-03 ES ES98965753T patent/ES2229557T3/es not_active Expired - Lifetime
- 1998-12-03 JP JP2000524289A patent/JP3453121B2/ja not_active Expired - Lifetime
- 1998-12-03 AU AU21578/99A patent/AU744192B2/en not_active Ceased
- 1998-12-03 KR KR10-2000-7006304A patent/KR100369689B1/ko not_active IP Right Cessation
- 1998-12-03 EP EP98965753A patent/EP1037892B1/en not_active Expired - Lifetime
- 1998-12-03 PT PT98965753T patent/PT1037892E/pt unknown
- 1998-12-03 TR TR2000/01669T patent/TR200001669T2/xx unknown
- 1998-12-03 CN CN98812049A patent/CN1112365C/zh not_active Expired - Fee Related
- 1998-12-03 DE DE69826891T patent/DE69826891T2/de not_active Expired - Lifetime
- 1998-12-09 AR ARP980106249A patent/AR016431A1/es unknown
- 1998-12-10 ZA ZA9811345A patent/ZA9811345B/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5665725A (en) * | 1991-06-13 | 1997-09-09 | H. Lundbeck | Piperidine derivatives having anxiolytic effect |
CN1191862A (zh) * | 1997-01-30 | 1998-09-02 | 弗·哈夫曼-拉罗切有限公司 | 8-取代的1,3,8-三氮杂螺[4.5]癸烷-4-酮衍生物 |
Also Published As
Publication number | Publication date |
---|---|
CN1281459A (zh) | 2001-01-24 |
AU744192B2 (en) | 2002-02-21 |
ZA9811345B (en) | 1999-06-11 |
DE69826891T2 (de) | 2005-11-24 |
TR200001669T2 (tr) | 2001-01-22 |
DE69826891D1 (de) | 2004-11-11 |
AR016431A1 (es) | 2001-07-04 |
EP1037892A1 (en) | 2000-09-27 |
EP1037892B1 (en) | 2004-10-06 |
KR20010032958A (ko) | 2001-04-25 |
CA2310458A1 (en) | 1999-06-17 |
CA2310458C (en) | 2008-11-04 |
JP3453121B2 (ja) | 2003-10-06 |
US6166209A (en) | 2000-12-26 |
WO1999029696A1 (en) | 1999-06-17 |
PT1037892E (pt) | 2005-01-31 |
ATE278695T1 (de) | 2004-10-15 |
ES2229557T3 (es) | 2005-04-16 |
JP2001525414A (ja) | 2001-12-11 |
KR100369689B1 (ko) | 2003-01-30 |
AU2157899A (en) | 1999-06-28 |
BR9813543A (pt) | 2000-10-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1112365C (zh) | 哌啶衍生物及制备方法和用途 | |
DE60009663T2 (de) | Piperidin-, tetrahydropyridin- und piperazin-derivate, ihre herstellung und anwendung | |
CN1117568C (zh) | 3-或4-取代的4-(氨基甲基)-哌啶衍生物胃动力双环苯甲酰胺 | |
EP0856514B1 (en) | 8-substituted-1,3,8-triazaspiro[4.5]decan-4-on derivatives | |
PT885220E (pt) | Derivados de tropano a sua preparacao e utilizacao | |
JP2013539470A (ja) | ロルカセリンと光学活性な酸との塩 | |
CN1044910C (zh) | 吲哚衍生物 | |
WO1997017343A1 (en) | Indolealkyl derivatives of benzodioxanmethylamine as 5-ht1a receptor ligands | |
CN1110496C (zh) | 四氢γ-咔啉类化合物 | |
JP3286268B2 (ja) | ジアザ−スピロ〔3,5〕−ノナン誘導体 | |
CN1097053C (zh) | 1,2,3,4-四氢-苯并呋喃并[3,2,-c]吡啶衍生物,其制备方法和用途 | |
TW589316B (en) | Antidepressant azaheterocyclylmethyl derivatives of 1,4,5-trioxa-phenanthrene | |
CN1131868C (zh) | 作为药物的三环△3-哌啶 | |
CN1042228C (zh) | 抗过敏咪唑并吖庚因 | |
JP2002513015A (ja) | セロトニン作動薬としてのインドリル誘導体 | |
CN1278816A (zh) | 5,11-二氢二苯并[b,e][1,4]氧氮杂䓬衍生物和含有相同物质的药用组合物 | |
AU704216C (en) | Indolealkyl derivatives of benzodioxanmethylamine as 5-HT1A receptor ligands | |
JP2010536919A (ja) | ノルエピネフリン、セロトニンまたはドーパミン再取り込み阻害剤として有用な3−アザビシクロ(4.1.0)ヘプタン誘導体 | |
MXPA00005605A (en) | Piperidine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20030625 Termination date: 20101203 |