CN102206214B - 苯并吡喃酮类衍生物及其应用 - Google Patents
苯并吡喃酮类衍生物及其应用 Download PDFInfo
- Publication number
- CN102206214B CN102206214B CN201110086701.8A CN201110086701A CN102206214B CN 102206214 B CN102206214 B CN 102206214B CN 201110086701 A CN201110086701 A CN 201110086701A CN 102206214 B CN102206214 B CN 102206214B
- Authority
- CN
- China
- Prior art keywords
- hydrogen
- chromen
- fluoro
- piperidino
- butoxy
- 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.)
- Active
Links
- 150000008375 benzopyrones Chemical class 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 14
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 63
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 16
- 201000000980 schizophrenia Diseases 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 68
- 238000002474 experimental method Methods 0.000 abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 description 50
- 238000000034 method Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- 239000012530 fluid Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 238000013016 damping Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 239000000370 acceptor Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- -1 anion salt Chemical class 0.000 description 14
- 230000027455 binding Effects 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 13
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 12
- 238000003304 gavage Methods 0.000 description 12
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 229960001534 risperidone Drugs 0.000 description 11
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 10
- 229960004372 aripiprazole Drugs 0.000 description 10
- 239000002775 capsule Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 230000009870 specific binding Effects 0.000 description 9
- 239000006228 supernatant Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- UQSJMGQSZNHTHX-UHFFFAOYSA-N 6-piperidin-4-yl-1,2-benzoxazole Chemical compound C1CNCCC1C1=CC=C(C=NO2)C2=C1 UQSJMGQSZNHTHX-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000000164 antipsychotic agent Substances 0.000 description 8
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 8
- 229960004046 apomorphine Drugs 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 210000001577 neostriatum Anatomy 0.000 description 8
- 210000002442 prefrontal cortex Anatomy 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 229960000607 ziprasidone Drugs 0.000 description 8
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 8
- 102100036321 5-hydroxytryptamine receptor 2A Human genes 0.000 description 7
- 101710138091 5-hydroxytryptamine receptor 2A Proteins 0.000 description 7
- 238000012449 Kunming mouse Methods 0.000 description 7
- 229940005529 antipsychotics Drugs 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 229960004756 ethanol Drugs 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 208000020016 psychiatric disease Diseases 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 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 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000009194 climbing Effects 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000003365 glass fiber Substances 0.000 description 6
- 229960003878 haloperidol Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229960005017 olanzapine Drugs 0.000 description 6
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 6
- 235000007715 potassium iodide Nutrition 0.000 description 6
- 229960004839 potassium iodide Drugs 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- DGBNUTJYQXQLSV-UHFFFAOYSA-N 1h-triazol-1-ium;chloride Chemical compound Cl.C1=CNN=N1 DGBNUTJYQXQLSV-UHFFFAOYSA-N 0.000 description 5
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 5
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 208000010877 cognitive disease Diseases 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- SWZVJOLLQTWFCW-UHFFFAOYSA-N 2-chlorobenzene-1,3-diol Chemical compound OC1=CC=CC(O)=C1Cl SWZVJOLLQTWFCW-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- MASVCBBIUQRUKL-UHFFFAOYSA-N POPOP Chemical compound C=1N=C(C=2C=CC(=CC=2)C=2OC(=CN=2)C=2C=CC=CC=2)OC=1C1=CC=CC=C1 MASVCBBIUQRUKL-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000000561 anti-psychotic effect Effects 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 230000001149 cognitive effect Effects 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 230000008676 import Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 230000009871 nonspecific binding Effects 0.000 description 4
- 239000002287 radioligand Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 0 CC1=C(C=CC=C*)C(*2CCN(*c3c(*)cc(C(*)=C(C)C(O4)=*)c4c3*)CC2)=N*1 Chemical compound CC1=C(C=CC=C*)C(*2CCN(*c3c(*)cc(C(*)=C(C)C(O4)=*)c4c3*)CC2)=N*1 0.000 description 3
- 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 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003693 atypical antipsychotic agent Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000008451 emotion Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000012447 hatching Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 235000019154 vitamin C Nutrition 0.000 description 3
- 239000011718 vitamin C Substances 0.000 description 3
- ZZJYIKPMDIWRSN-TZBSWOFLSA-N (+)-butaclamol Chemical compound C12=CC=CC=C2CCC2=CC=CC3=C2[C@@H]1CN1CC[C@@](C(C)(C)C)(O)C[C@@H]13 ZZJYIKPMDIWRSN-TZBSWOFLSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- WYCMFCPHWDZHMR-UHFFFAOYSA-N 1-(4,7-dimethyl-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-9-yl)-n,n-dimethylmethanesulfonamide Chemical compound C1=CC(C2CC(CN(C)C2C2)CS(=O)(=O)N(C)C)=C3C2=CN(C)C3=C1 WYCMFCPHWDZHMR-UHFFFAOYSA-N 0.000 description 2
- ZTMADXFOCUXMJE-UHFFFAOYSA-N 2-methylbenzene-1,3-diol Chemical compound CC1=C(O)C=CC=C1O ZTMADXFOCUXMJE-UHFFFAOYSA-N 0.000 description 2
- FPCCSQOGAWCVBH-PSQIVULCSA-N 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]-1,1,2,2-tetratritioethyl]-1h-quinazoline-2,4-dione Chemical compound O=C1NC2=CC=CC=C2C(=O)N1C([3H])([3H])C([3H])([3H])N(CC1)CCC1C(=O)C1=CC=C(F)C=C1 FPCCSQOGAWCVBH-PSQIVULCSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical group C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229940127236 atypical antipsychotics Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 208000024732 dysthymic disease Diseases 0.000 description 2
- KQWWVLVLVYYYDT-UHFFFAOYSA-N ethyl 3-oxohexanoate Chemical compound CCCC(=O)CC(=O)OCC KQWWVLVLVYYYDT-UHFFFAOYSA-N 0.000 description 2
- UDRCONFHWYGWFI-UHFFFAOYSA-N ethyl 3-oxopentanoate Chemical compound CCOC(=O)CC(=O)CC UDRCONFHWYGWFI-UHFFFAOYSA-N 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 229960003955 mianserin Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 230000007433 nerve pathway Effects 0.000 description 2
- 229960001779 pargyline Drugs 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229950001675 spiperone Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000020985 whole grains Nutrition 0.000 description 2
- 230000003936 working memory Effects 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- KPJZHOPZRAFDTN-ZRGWGRIASA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CN(C)C3=C1 KPJZHOPZRAFDTN-ZRGWGRIASA-N 0.000 description 1
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 1
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- UWCDQWWCQCZTAN-UHFFFAOYSA-N C=C(CC1c2ccccc2)Nc2c1ccc(NCCCCBr)c2 Chemical compound C=C(CC1c2ccccc2)Nc2c1ccc(NCCCCBr)c2 UWCDQWWCQCZTAN-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000009132 Catalepsy Diseases 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
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- OLYCMBRBWGJPRL-UHFFFAOYSA-N N=C(CC1c2ccccc2)Nc2c1ccc(NCCCCN(CC1)CCC1c1n[o]c3cc(F)ccc13)c2 Chemical compound N=C(CC1c2ccccc2)Nc2c1ccc(NCCCCN(CC1)CCC1c1n[o]c3cc(F)ccc13)c2 OLYCMBRBWGJPRL-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-N OC(/C=C/c1ccccc1)=O Chemical compound OC(/C=C/c1ccccc1)=O WBYWAXJHAXSJNI-VOTSOKGWSA-N 0.000 description 1
- FPHAXRIFTRBSSY-UHFFFAOYSA-N Oc1cc(OC(CC2c3ccccc3)=O)c2cc1 Chemical compound Oc1cc(OC(CC2c3ccccc3)=O)c2cc1 FPHAXRIFTRBSSY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000594182 Sarcophaga sigma Species 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000001720 action spectrum Methods 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940124604 anti-psychotic medication Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002152 aqueous-organic solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 229950006479 butaclamol Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical group [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000003715 limbic system Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 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
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 229960001186 methysergide Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical class N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000003723 serotonin 1A agonist Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域,具体涉及一种苯并吡喃酮类衍生物及其应用。苯并吡喃酮类衍生物具有式(I)结构。经实验发现,该类化合物可应用于制备治疗神经精神类疾病药物方面。
Description
技术领域
本发明属于药物化学领域,具体涉及一种苯并吡喃酮类衍生物及其在治疗精神神经疾病中的应用。
背景技术
精神***症是以认知力和情感深度***为特征的一种疾病,表现为最基本的人类行为受到影响,例如语言、思想、知觉和自我感知等。该疾病的症状所包含的范围较广,最常见的为精神方面的障碍,比如产生幻觉、妄想症和错觉等。
精神***症是最严重的心理疾病,全球范围内约有1%的人患精神***症,而在所有接受治疗的患者中只有5%最终能够得以完全康复。此外,由于精神***症通常会引发合并症,例如焦虑障碍、抑郁或精神性药物滥用等,据Datamonitor的一项调查研究显示,超过1/3的精神***症患者要遭受至少一项或多项并发的精神病或认知障碍等疾病的困扰。
传统上习惯把通过阻断多巴胺D2受体发挥药理作用的抗精神病药物称为第一代抗精神病药物,即“典型”抗精神病药物(如氟哌啶醇),它们治疗精神***症阳性症状有突破性,但未能治疗阴性症状和认知障碍。典型抗精神病药物一般有严重的EPS副作用,并且对三分之一的精神***症病人无效。
20世纪60年代以后,又陆续开发了一系列新一代抗精神病药,包括齐拉西酮(Ziprasidone,)、利培酮(Risperidone)等,被称为第二代抗精神病药物,即新型抗精神病药,虽然它们各自的药理作用不完全一致,但却具有共同的药理特征,即对5-羟色胺(5-HT)受体(5-HT1A、2A、2c)和去甲肾上腺素(NA)受体(α1、α2)的亲和力远比对D2受体的要高,导致D2/5-HT2A的比值较低。其临床效果与第一代抗精神病药物相比有更多优势,不但对阳性症状与传统抗精神病药同样有效,而且对阴性症状、认知缺陷症状有效,作用谱更广,但是这些药物有QT间隙延长,高泌乳素血症和体重增加等不良反应。因此寻找能对精神***症阳性、阴性症状和认知障碍有效,而且副作用小的药物是现在研究的热点。
阿立哌唑是一种苯丁哌唑嗪类化合物,2002年11月已获FDA批准上市。该药具有独特的作用机制,与多巴胺D2、D3、5-HT1A和5-HT2A受体有很高的亲和力,与D4、5-HT2c、5-HT7、α1、H1受体及5-HT重吸收位点具有中度亲和力。阿立哌唑是通过对D2和5-HT1A受体的部分激动作用及对5-HT2A受体的拈抗作用来产生抗精神***症,具有稳定多巴胺***活性的作用。临床试验研究表明,阿立哌唑对精神***症阳性和阴性症状都有效,长期应用还能降低精神***症的复发率,改善情绪和认知功能障碍。其EPS不良反应及升高血清催乳素水平的作用比传统的抗精神病药物或前述的非典型抗精神病药都小。
5-羟色胺***在调节的前额叶皮层(PFC)的功能中起着重要作用,包括情绪控制,认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度羟色胺受体亚型5-HT1A和5-HT2A。最近得到证明PFC和NMDA受体通道是5-HT1AR的目标,这两个受体调节大脑皮层兴奋性神经元,从而影响认知功能。实际上,各种临床前数据表明5-HT1AR可能是抗精神病药发展药物的新目标。非典型抗精神药物(如olanzapine,aripiprazole等)对5-HT1AR的高亲和力及其低的EPS副作用均说明5-羟色胺***在调节的前额叶皮层(PFC)的功能中起着重要作用,包括情绪控制、认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度5-羟色胺受体亚型5-HT1A和5-HT2A。最近研究表明5-HT1A激动剂与非典型抗精神病药物治疗相关,能改善阴性症状和认知障碍。在应用非典型抗精神病药物氯氮平治疗精神***症中,人们发现5-HT2A在其中起着很重要的作用,涉及到感知、情绪调节以及运动控制的各个方面。阻断5-HT2A受体可使多巴胺的释放正常化,而起到抗精神病作用。另外,5-HT2C受体与体重增加密切相关。
D3受体在脑内的分布情况主要选择性分布于边缘***,脑内有两条主要DA神经通路,一条是黑质纹状体通路调控运动功能,另一条是中脑腹侧被盖区伏隔核前额叶皮层DA通路与学习认知和情感活动密切相关,其功能异常将导致精神***症,该DA通路也是脑内奖赏效应(reward efects)的主要通路,D3R在两条DA神经通路中都有分布,并和其他DA受体亚型间存在着复杂相互作用,可能作为抗精神病药物治疗的一个目标,选择性D3受体的拈抗作用能减少精神***症的消极和认知症状,此外能阻止锥体外系副作用,包括迟发性运动障碍,帕金森病。因此,寻找一个多受体结合副作用小的抗精神***症药物对临床治疗具有重要意义。
发明内容
本发明的目的是在现有技术的基础上,提供一种新的具有活性的苯并吡喃酮类衍生物。
本发明的另一目的是提供一种上述苯并吡喃酮类衍生物在制备治疗神经精神类疾病药物方面的应用。
本发明的目的可以通过以下措施达到:
一种具有式(I)结构的苯并吡喃酮类衍生物,
其中,
Z为取代或未取代的-(CH2)nO-,n为2~6的整数,所述取代基为羟基或甲基,或者Z中的碳链上含有双键;Z基团中的O端与苯基相连;
Y为O或S;
Q为N或CH;
X为O、S或NH;
虚线处为单键或双键;
R1、R3、R4或R5分别独立地为氢、卤素、氰基、取代或未取代的芳基、羟基、取代或未取代的C1-5烷基或取代或未取代的C1-5烷氧基,所述取代基为卤素、氨基或羟基,其中卤素优选为氯或氟;
R2为氢或取代或未取代的C1-5烷基,所述取代基为卤素、氨基或羟基。
在式(I)中,Z优选为取代或未取代的-(CH2)nO-,n为2~5的整数,所述取代基为羟基,或者Z中的碳链上含有双键;n最优选为3、4或5。
在式(I)中,Y优选为O;X优选为O或S。
在式(I)中,R1优选为氢、苯基、卤代苯基、C1-5烷基、C1-5卤代烷基或C1-5羟烷基,其中卤素优选为氯或氟。R1最优选为氢、苯基、甲基、乙基、丙基、三氟甲基或羟甲基。
在式(I)中,R3、R4或R5优选分别独立地为氢、卤素或C1-5烷基,其中卤素优选为氯或氟。R3最优选为氢、氯或甲基;R4最优选为氢、氯或甲基;R5最优选为氢、氟或甲基。
在式(I)中,R2优选为氢或甲基。
在式(I)中,所述Q为CH时,X为O,R5为氟;所述的Q为N时,X为S,R5为氢。
上述苯并吡喃酮类衍生物选自如下化合物:
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(5-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正戊氧基))-4-甲基-2氢-苯并吡喃-2-酮;
(E)-7-(4-(4-(3-(6-氟-苯并异恶唑)-3-哌啶基)-2-烯丁氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4,8-二甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-8-二甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-正丙基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-正丙基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-乙基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-乙基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-3,4-二甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-3,4-二甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-羟甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-羟甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-2-羟基丙氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-2-羟基丙氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-苯基--苯并吡喃-2-酮。
本发明还包括式(I)结构化合物及上述各具体化合物的盐,所述的盐为含有药物上可接受的阴离子盐:如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐或硫酸氢盐、磷酸盐或酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐等。
本类化合物的通用合成方法是先合成苯并吡喃酮的母体,然后通过一个碳链与哌嗪基或哌啶基取代的1,2-苯并异噁唑或1,2-苯并异噻唑连接而成。
本发明提供一种药物组合物,其包含式I化合物,和药学上可接受的辅料(如载体和/或赋形剂等),该药物组合物是含有足以产生抗精神病作用的本发明化合物的抗精神病组合物。
本发明化合物的有效剂量可与如惰性稀释剂或某种载体一起口服。可将其包于明胶胶囊中或压制成片。为口服治疗的目的,本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。这些制剂应含有至少0.5wt%的本发明的活性化合物,但可根据特定的剂型变化,占单位重量的4%至约70%是便利的。在这样的组合物中活性化合物的量应达到适当的剂量。本发明优先的组合物和制剂的口服单位剂量含有1.0-300毫克的本发明活性化合物。
本发明提供的化合物及其药学上可接受的盐,溶剂化物和水合物可以与药学上可以接受的载体或稀释剂联合应用组成药物制剂。药学上可接受的适当的载体包括惰性固体填充剂或稀释剂和无菌水溶液或有机溶液。
本发明化合物的用量取决于疾病或病症的类型和严重性,还取决于对象的特征,例如一般健康、年龄、性别、体重和药物耐受性。技术人员能够根据这些或其它因素来确定适当的剂量。通常所用的中枢神经***药物的有效剂量是技术人员熟知的。每日总剂量通常在约0.05mg到2000mg之间。
本发明涉及药物组合物,其每单位剂量能提供约0.01到1000mg的活性成分。组合物可通过任何适当的途径施用,例如胶囊形式口服,以注射液的形式胃肠外施用,以膏剂或洗剂的形式局部施用,以栓剂的形式直肠施用,以贴片的传递***的形式经皮施用。
本发明提供的化合物可与适当的固体或液体载体或稀释剂组合形成胶囊、片剂、丸剂、散剂、糖浆剂、溶液剂等。片剂、丸剂、胶囊等包含约0.01到约99重量百分比的活性成分和粘合剂例如明胶、玉米淀粉、***树胶;赋形剂例如磷酸氢钙;崩解剂例如玉米淀粉、马铃薯淀粉或藻酸;润滑剂例如硬脂酸镁;和甜味剂例如蔗糖、乳糖。当制剂形式为胶囊时,除上述类型的原料外,还可包含液体载体,例如油脂。
对于胃肠外施用,本发明提供的化合物可与无菌水或有机介质组合形成可注射的溶液或悬液。
通式I的化合物可以含有手性中心,且由此可以以不同对映体和非对映体形式存在。本发明涉及通式I化合物的所有旋光异构体和所有立体异构体,作为这类化合物的外消旋混合物和各对映体和非对映体的形式,且本发明分别涉及如上述所定义的含有或使用它们的所有药物组合物和治疗方法。
此外,本发明提供的衍生物以及由衍生物组成的药物组合物可应用于制备治疗或预防神经精神类疾病药物方面,所述神经精神类疾病选自精神障碍、焦虑症、人格障碍、抑郁症、狂躁症、偏头痛、癫痫或痉挛性障碍、儿童期障碍、帕金森病、认知障碍、神经变性、神经毒性和局部缺血;优选精神***症。本发明涉及所述的衍生物还可能用于制备其他中枢神经***疾病药物,例如用于治抑郁症、记忆障碍以及与智力、学习相关的功能障碍性疾病的药物。
体外受体结合试验表明,本发明所涉及的衍生物对多巴胺D2,D3,5HT1A和5HT2A受体具有较高的亲和力,而与5HT2C的亲和力低。
动物试验结果显示,这类化合物既能明显改善MK-801诱导的高活动性,又能有效改善阿扑***诱导的攀爬症状,并且在有效剂量下不引起EPS。由于这些体外作用靶点和体内药理模型与多巴胺功能紊乱导致的神经***疾病,特别是精神***症密切相关,因此本发明涉及的化合物具有治疗神经精神类疾病的作用,尤其对精神***症有治疗作用。
具体实施方式
下面的实施例只是以说明为目的而不作为本发明的限制。
A、合成方面的实施例
实施例1、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-2氢-苯并吡喃-2-酮(1)
反应式1
1)取间苯二酚5.5g,d,l-苹果酸6.7g,加入70%HCl04 50ml,加热到90℃反应,溶液慢慢变澄清,4小时后反应完毕,冷至室温,将反应液倒入冰水混合物中,有大量固体析出,过滤,滤饼水洗,用95%的乙醇重结晶得白色晶体4.5g,熔点226-228℃,收率60.8%。
2)取第一步产物5g,无水碳酸钾6g,丙酮50ml,1,4-二溴丁烷8.2g,加热回流反应6小时,冷至室温,过滤,蒸干溶剂,得浅黄色油状物,过柱得白色固体5.4g,熔点55-57℃,收率60.7%。
3)取第二步产物0.52g,加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐0.65g,无水碳酸钾2g,碘化钾0.2g和乙腈25ml,加热回流反应12小时,冷至室温,蒸干溶剂,加入适量二氯甲烷,水洗,分去水层,有机层加无水硫酸镁干燥,蒸干溶剂,得浅黄色油状物,柱层析得白色固体0.55g,熔点:116-118℃,收率72.3%。
1H NMR(CDCl3)δ1.73-1.88(m,4H),2.06-2.16(m,6H),2.48(t,2H,J=14.4Hz),3.07-3.10(m,4H),4.07(t,2H,J=12Hz),6.24(d,1H,J=9.6Hz),6.80-6.86(m,2H),7.05(t,1H,J=1.6Hz),7.22-7.24(m,1H),7.37(d,1H,J=8.4Hz),7.63-7.69(m,2H)MS(ESI)m/z437.2([M+H]+)
实施例2、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-2氢-苯并吡喃-2-酮(2)
将6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐换成3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐,按实施例1的方法制备目标化合物。
熔点:103-105℃。
1H NMR(CDCl3)δ1.75-1.76(m,2H),1.87-1.91(m,2H),2.51(t,2H,J=14.8Hz),2.68-2.71(m,4H),3.56-3.59(m,4H),4.06(t,2H,J=12.4Hz),6.23(d,1H,J=9.6Hz),6.80-6.85(m,2H),7.33-7.37(m,2H),7.44-7.48(m,1H),7.62(d,1H,J=9.6Hz),7.80(d,1H,J=8Hz),7.91(d,1H,J=8Hz)MS(ESI)m/z436.2([M+H]+)
实施例3、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-2氢-苯并吡喃-2-酮(3)
用1,3-二溴丙烷代替1,4-二溴丁烷,按实施例1的方法制备目标化合物。
熔点:128-130℃。
1H NMR(CDCl3)δ2.03-2.19(m,8H),2.60(t,2H,J=14.4Hz),3.07-3.10(m,3H),4.12(t,2H,J=12.8Hz),6.25(d,1H,J=9.2Hz),6.84-6.87(m,2H),7.05-7.06(m,1H),7.23-7.27(m,1H),7.37(d,1H,J=8.4Hz),7.63-7.70(m,2H)MS(ESI)m/z423.2([M+H]+)
实施例4、7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-2氢-苯并吡喃-2-酮(4)用1,3-二溴丙烷代替1,4-二溴丁烷,按实施例1的方法制备目标化合物。
熔点:91-93℃。
1H NMR(CDCl3)δ2.04-2.08(m,2H),2.64(t,2H,J=14.4Hz),2.70-2.73(m,4H),3.57-3.59(m,4H),4.12(t,2H,J=12.8Hz),6.23(d,1H,J=9.6Hz),6.82-6.86(m,2H),7.33-7.37(m,2H),7.44-7.48(m,1H),7.62(d,1H,J=9.6Hz),7.80(d,1H,J=8Hz),7.91(d,1H,J=8Hz)MS(ESI)m/z422.2([M+H]+)
实施例5、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-甲基-2氢-苯并吡喃-2-酮(5)
反应式2
1)取30ml浓硫酸,冰浴下搅拌,加入间苯二酚(5.5g),滴加乙酰乙酸乙酯(9.2g),溶液由浅黄变为黄色,18小时后反应完毕,将反应液倒入冰水混合物中,析出白色固体,过滤,滤饼水洗至中性,用75%的乙醇重结晶得白色晶体8.5g,熔点186-188℃,收率73.9%。
2)取第一步产物5g,无水碳酸钾6g,丙酮50ml和1,4-二溴丁烷8.7g,加热回流反应4小时,冷至室温,过滤,蒸干溶剂,得浅黄色油状物,过柱得白色固体6.5g,熔点58-60℃,收率77.8%。
3)取第二步产物0.5g,加入3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐0.6g,无水碳酸钾2g,碘化钾0.2g和乙腈25ml,加热回流20小时,冷至室温,过滤,蒸干溶剂,得浅黄色油状物,用过柱得白色固体0.52g,熔点110-112℃,收率72.2%。
1H NMR(CDCl3)δ1.75-1.90(m,4H),2.38(s,3H),2.51(t,2H,J=14.4Hz),2.68-2.71(m,4H),3.56-3.58(m,4H),4.06(t,2H,J=12Hz),6.11(s,1H),6.80-6.86(m,2H),7.29-7.36(m,1H),7.43-7.48(m,2H),7.79(d,1H,J=8Hz),7.90(d,1H,J=8.4Hz)MS(ESI)m/z450.2([M+H]+)
实施例6、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-甲基-2氢-苯并吡喃-2-酮(6)
用6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐代替3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐,按实施例5的方法制备目标化合物。
熔点:126-128℃。
1H NMR(CDCl3)δ1.71-1.92(m,4H),2.09-2.19(m,6H),2.09(s,3H),2.50(t,2H,J=14.4Hz),3.09-3.12(m,3H),4.07(t,2H,J=12.8Hz),6.13(s,1H),6.81-6.88(m,2H),7.03-7.08(m,1H),7.23-7.25(m,1H),7.49(d,1H,J=8.8Hz),7.69-7.72(m,1H)MS(ESI)m/z451.3([M+H]+)
实施例7、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-甲基-2氢-苯并吡喃-2-酮(7)
用1,3-二溴丙烷代替1,4-二溴丁烷,按实施例6的方法制备目标化合物。
熔点:138-140℃。
1H NMR(CDCl3)δ2.02-2.23(m,8H),2.40(s,3H),2.60(t,2H,J=14.4Hz),3.07-3.10(m,3H),4.12(t,2H,J=12.8Hz),6.13(s,1H),6.84-6.89(m,2H),7.06(t,1H,J=2Hz),7.23-7.27(m,1H),7.50(d,1H,J=8.8Hz),7.71(t,1H,J=8.8Hz)MS(ESI)m/z437.2([M+H]+)
实施例8、7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-甲基-2氢-苯并吡喃-2-酮(8)
用1,3-二溴丙烷代替1,4-二溴丁烷,按实施例5的方法制备目标化合物。
熔点:113-115℃。
1H NMR(CDCl3)δ2.06-2.08(m,2H),2.38(s,3H),2.64(t,2H,J=14.4Hz),2.70-2.73(m,4H),3.57-3.59(m,4H),4.12(t,2H,J=12.4Hz),6.12(s,1H),6.82-6.88(m,2H),7.35-7.49(m,3H),7.80(d,1H,J=8Hz),7.91(d,1H,J=8.4Hz)MS(ESI)m/z436.2([M+H]+)
实施例9、7-(5-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正戊氧基))-4-甲基-2氢-苯并吡喃-2-酮(9)
用1,5-二溴戊烷代替1,4-二溴丁烷,按实施例6方法制备目标化合物。
熔点:119-121℃。
1HNMR(CDCl3)δ1.53-1.63(m,4H),1.85-1.89(m,2H),2.05-2.14(m,6H),2.40(s,3H),2.43(t,2H,J=14.8Hz),3.06-3.08(m,3H),4.04(t,2H,J=12.8Hz),6.12(s,1H),6.80-6.87(m,2H),7.02-7.07(m,1H),7.22-7.24(m,1H),7.49(d,1H,J=4.8Hz),7.67-7.71(m,1H)MS(ESI)m/z465.3([M+H]+)
实施例10、(E)-7-(4-(4-(3-(6-氟-苯并异恶唑)-3-哌啶基)-2-烯丁氧基))-4-甲基-2氢-苯并吡喃-2-酮(10)
用1,4-二溴-2-丁烯代替1,4-二溴丁烷,按实施例6的方法制备目标化合物。
熔点:129-130℃。
1H NMR(CDCl3)δ2.05-2.17(m,6H),2.39(s,3H),3.05-3.13(m,5H),4.06(t,2H,J=12.8Hz),5.91-5.96(m,2H),6.13(s,1H),6.83-6.90(m,1H),7.05-7.06(m,1H),7.22-7.27(m,1H),7.49(d,1H,J=8.8Hz),7.68-7.70(m,1H)MS(ESI)m/z449.2([M+H]+)
实施例11、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-苯基-2氢-苯并吡喃-2-酮(11)
1)取间苯二酚5.5g,苯甲酰乙酸乙酯9.6g,再加入30ml磷酸,室温搅拌,溶液由浅黄变为黄色,12小时后反应完毕,将反应液倒入冰水混合物中,有大量固体析出,过滤,滤饼水洗,用95%的乙醇重结晶得白色晶体9.3g,熔点237-239℃,收率80.9%。
2)取第一步产物4.8g,无水碳酸钾6g,丙酮50ml和1,3-二溴丙烷8.4g,加热回流反应4小时,冷至室温,过滤,旋干溶剂,过柱得白色固体5.6g,熔点67-69℃,收率78.0%。
3)取第二步产物0.5g,加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐0.6g,无水碳酸钾2g,碘化钾0.2g和乙腈25ml,加热回流反应24小时,冷至室温,过滤,蒸干溶剂,得浅黄色油状物,过柱得白色固体0.5lg,熔点:185-187℃,收率73.9%。。
1H NMR(CDCl3)δ2.04-2.19(m,8H),2.67-2.77(m,6H),3.07-3.10(m,3H),4.13(t,2H,J=12.4Hz),6.22(s,1H),6.79-6.82(m,1H),6.91-6.92(m,1H),7.05-7.06(m,1H),7.23-7.27(m,1H),7.37-7.51(m,6H),7.68-7.71(m,1H)MS(ESI)m/z499.3([M+H]+)
实施例12、7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-苯基-2氢-苯并吡喃-2-酮(12)
用3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐代替6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐,按实施例11的方法制备目标化合物。
熔点:96-98℃。
1H NMR(CDCl3)δ2.05-2.08(m,2H),2.62-2.72(m,6H),3.57-3.59(m,4H),4.13(t,2H,J=14Hz),6.20(s,1H),6.79-6.82(m,2H),6.90(d,1H,J=2Hz),7.36-7.51(m,8H),7.81(d,1H,J=8Hz),7.92(d,1H,J=8Hz)MS(ESI)m/z498.3([M+H]+)
实施例13、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-苯基-2氢-苯并吡喃-2-酮(13)
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例11的方法制备目标化合物。
熔点:97-99℃。
1HNMR(CDCl3)δ1.72-1.76(m,2H),1.87-1.91(m,2H),2.07-2.18(m,6H),2.48(t,2H,J=14.8Hz),3.07-3.10(m,3H),4.08(t,2H,J=12.4Hz),6.21(s,1H),6.80-6.81(m,1H),6.88-6.89(m,1H),7.03-7.07(m,1H),7.21-7.24(m,1H),7.37-7.52(m,6H),7.68-7.71(m,1H)MS(ESI)m/z4514.3([M+H]+)
实施例14、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-苯基-2氢-苯并吡喃-2-酮(14)
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例12的方法制备目标化合物。
熔点:116-118℃。
1H NMR(CDCl3)δ1.76-1.90(m,4H),2.53(t,2H,J=14.8Hz),2.70-2.72(m,4H),3.57-3.59(m,4H),4.09(t,2H,J=12.4Hz),6.21(s,1H),6.78-6.80(m,1H),6.89(d,1H,J=2.4Hz),7.35-7.52(m,8H),7.81(d,1H,J=8Hz),7.91(d,1H,J=8.4Hz)MS(ESI)m/z512.3([M+H]+)
实施例15、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮(15)
1)取30ml浓硫酸,冰浴下搅拌,加入间苯二酚5.5g,滴加三氟乙酰乙酸乙酯9.2g,溶液由浅黄变,反应18小时,将反应液倒入冰水混合物中,有大量白色固体析出,过滤,滤饼水洗至中性,用75%的乙醇重结晶得白色晶体8.5g,熔点218-220℃,收率73.9%。
2)取第一步产物4.6g,无水碳酸钾6g,丙酮50ml和1,3-二溴丙烷8.4g,加热回流反应4小时,冷至室温,过滤,旋干溶剂,得浅黄色油状物,过柱得白色固体5.6g,熔点72-74℃,收率80.1%。
3)取第二步产物0.5g,加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐0.6g,无水碳酸钾2g,碘化钾0.2g和乙腈25ml,加热回流反应12小时,冷至室温,过滤,旋干溶剂,得浅黄色油状物,过柱得白色固体0.50g,熔点146-148℃,收率71.4%。
1H NMR(CDCl3)δ2.04-2.23(m,8H),2,60(t,2H,J=6.8Hz),3.07-3.13(m,3H),4.15(t,2H,J=12.8Hz),6.12(s,1H),6.90-6.95(m,2H),7.03-7.08(m,1H),7.23-7.26(m,1H),7.61-7.71(m,2H)MS(ESI)m/z491.3([M+H]+)
实施例16、7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮(16)
用3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐代替6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐,按实施例15的方法合成制备目标化合物。
熔点:103-105℃。
1H NMR(CDCl3)δ2.10-2.13(m,2H),2.67-2.77(m,6H),3.62(br,4H),4.16(t,2H,J=12.4Hz),6.62(s,1H),6.90-6.95(m,2H),7.36-7.38(m,1H),7.46-7.47(m,1H),7.61-7.62(m,1H),7.63-7.64(m,1H),7.81-7.90(m,1H)MS(ESI)m/z490.2([M+H]+)
实施例17、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮(17)
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例15的方法制备目标化合物。
熔点:125-127℃。
1H NMR(CDCl3)δ1.77-1.92(m,4H),2.11-2.23(m,6H),2.52(t,2H,J=14.8Hz),3.10-3.13(m,3H),4.10(t,2H,J=12.4Hz),6.61(s,1H),6.87-6.93(m,2H),7.03-7.08(m,1H),7.22-7.25(m,1H),7.60-7.63(m,1H),7.70-7.73(m,1H)MS(ESI)m/z505.3([M+H]+)
实施例18、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮(18)
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例16的方法制备目标化合物。
熔点:93-95℃。
1H NMR(CDCl3)δ1.76-1.77(m,2H),1.89-1.91(m,2H),2.52(t,2H,J=14.8Hz),2.70(t,4H,J=9.6Hz),3.58(t,4H,J=9.6Hz),4.10(t,2H,J=12.4Hz),6.61(s,1H),6.87(d,1H,J=2.4Hz),6.90-6.93(m,1H),7.35(t,1H,J=15.2Hz),7.46(t,1H,J=14.8Hz),7.61(d,1H,J=1.2Hz),7.63(d,1H,J=1.2Hz)MS(ESI)m/z504.3([M+H]+)
实施例19、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮(19)
用2-氯间苯二酚为原料,按实施例6的方法制备目标化合物。
熔点:128-130℃。
1HNMR(CDCl3)δ1.78-1.80(m,2H),1.93-2.15(m,8H),2.41(s,3H),2.50(t,2H,J=14.4Hz),3.07-3.10(m,3H),4.19(t,2H,J=12.4Hz),6.15(s,1H),6.92(d,1H,J=8.8Hz),7.02-7.07(m,1H),7.22-7.28(m,1H),7.46(d,1H,J=8.8Hz),7.68-7.71(m,1H)MS(ESI)m/z485.2([M+H]+)
实施例20、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮(20)
用2-氯间苯二酚为原料,按实施例5的方法制备目标化合物。
熔点:133-135℃。
1H NMR(CDCl3)δ1.79-1.85(m,2H),1.93-1.98(m,2H),2.39(s,3H),2.55(t,2H,J=7.2Hz),2.72(t,2H,J=9.6Hz),3.58(t,4H,J=9.6Hz),4.18(t,2H,J=12.4Hz),6.14(s,1H),6.88-6.91(m,1H),7.33-7.37(m,1H),7.43-7.48(m,2H),7.80(d,1H,J=8.4Hz),7.90(d,1H,J=8Hz)MS(ESI)m/z 484.2([M+H]+)
实施例21、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮(21)
用2-氯间苯二酚为原料,按实施例7的方法制备目标化合物。
熔点:185-187℃。
1H NMR(CDCl3)δ2.07-2.20(m,8H),2.41(s,3H),2.64(t,2H,J=7.2Hz),3.08-3.10(m,3H),4.24(t,2H,J=12Hz),6.17(s,1H),6.94(d,1H,J=8.8Hz),7.05(t,1H,J=2Hz),7.25(t,1H,J=16Hz),7.46(d,1H,J=8.8Hz),7.66-7.70(m,1H)MS(ESI)m/z 471.2([M+H]+)
实施例22、7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮(22)
用2-氯间苯二酚为原料,按实施例8的方法制备目标化合物。
熔点:162-164℃。
1H NMR(CDCl3)δ1.79-1.98(m,4H),2.39(s,3H),2.55(t,2H,J=7.2Hz),2.72(t,4H,J=9.6Hz),3.58(t,4H,J=9.6Hz),4.18(t,2H,J=12.4Hz),6.14(s,1H),6.90(d,1H,J=8.8Hz),7.35(t,1H,J=14.8Hz),7.43-7.48(m,2H),7.80(d,1H,J=8.4Hz),7.90(d,1H,J=8Hz)MS(ESI)m/z 470.2([M+H]+)
实施例23、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4,8-二甲基-2氢-苯并吡喃-2-酮(23)
用2-甲基间苯二酚为原料,按实施例6的方法制备目标化合物。
熔点:117-119℃。
1HNMR(CDCl3)δ1.72-1.80(m,2H),1.88-1.94(m,2H),2.05-2.19(m,6H),2.31(s,3H),2.39(s,3H),2.49(t,2H,J=14.8Hz),3.09(d,3H,J=10Hz),4.11(t,2H,J=12.4Hz),6.11(s,1H),6.84(d,1H,J=8.8Hz),7.05(t,1H,J=2Hz),7.22-7.24(m,1H),7.40(d,1H,J=8.8Hz),7.68-7.71(m,1H)MS(ESI)m/z 465.3([M+H]+)
实施例24、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-8-二甲基-2氢-苯并吡喃-2-酮(24)
用2-甲基间苯二酚为原料,按实施例5的方法制备目标化合物。
熔点:106-108℃。
1H NMR(CDCl3)δ1.73-1.86(m,4H),2.05-2.17(m,9H),2.36(s,3H),2.48(t,2H,J=14.8Hz),3.07-3.10(m,3H),4.05(t,2H,J=12.4Hz),6.78-6.86(m,2H),7.02-7.07(m,1H),7.21-7.24(m,1H),7.48(d,1H,J=8.8Hz),7.68-7.71(m,1H)MS(ESI)m/z464.3([M+H]+)
实施例25、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-正丙基-2氢-苯并吡喃-2-酮(25)
用丁酰乙酸乙酯为原料,按实施例6的方法制备目标化合物。
熔点:139-141℃。
1H NMR(CDCl3)δ1.00(t,3H,J=14.4Hz),1.64-1.69(m,2H),1.93-2.22(m,6H),2.64(t,2H,J=14.4Hz),3.00-3.74(m,9H),4.04(t,2H,J=12.8Hz),6.05(s,1H),6.71-6.78(m,2H),7.05-7.23(m,2H),7.80(d,1H,J=8Hz),7.91(d,1H,J=8Hz)MS(ESI)m/z 479.3([M+H]+)
实施例26、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-正丙基-2氢-苯并吡喃-2-酮(26)
用丁酰乙酸乙酯为原料,按实施例5的方法制备目标化合物。
熔点:114-116℃。
1H NMR(CDCl3)δ1.04(t,3H,J=14.4Hz),1.69-1.90(m,6H),2.51(t,2H,J=14.8Hz),2.67-2.71(m,6H),3.56-3.58(m,4H),4.06(t,2H,J=12.8Hz),6.11(s,1H),6.81-6.86(m,2H),7.28-7.52(m,3H),7.80(d,1H,J=8Hz),7.91(d,1H,J=8Hz)MS(ESI)m/z478.3([M+H]+)
实施例27、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-乙基-2氢-苯并吡喃-2-酮(27)
用丙酰乙酸乙酯为原料,按实施例6的方法制备目标化合物。
熔点:96-98℃。
1H NMR(CDCl3)δ1.32(t,3H,J=14.8Hz),1.74-1.90(m,4H),2.06-2.16(m,6H),2.48(t,2H,J=14.8Hz),2.75-2,81(m,2H),3.05-3.10(m,3H),4.07(t,2H,J=12.8Hz),6.14(s,1H),6.82-6.87(m,2H),7.03-7.07(m,1H),7.23-7.25(m,1H),7.52(d,1H,J=8.8Hz),7.68-7.71(m,1H)MS(ESI)m/z465.3([M+H]+)
实施例28、7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-乙基-2氢-苯并吡喃-2-酮(28)
用丙酰乙酸乙酯为原料,按实施例5的方法制备目标化合物。
熔点:110-112℃。
1H NMR(CDCl3)δ1.32(t,3H,J=14.8Hz),1.76-1.91(m,4H),2.53(t,2H,J=14.4Hz),2.71-2.79(m,6H),3.58(br,4H),.07(t,2H,J=12.4Hz),6.15(s,1H),6.82-6.87(m,2H),7.36(t,1H,J=14.8Hz),7.47(t,1H,J=14.8Hz),7.52(d,1H,J=8.8Hz),7.81(d,1H,J=8.4Hz),7.91(d,1H,J=8Hz)MS(ESI)m/z464.3([M+H]+)
实施例29、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-3,4-二甲基-2氢-苯并吡喃-2-酮(29)
用2-甲基乙酰乙酸乙酯为原料,按实施例6的方法制备目标化合物。
熔点:106-108℃。
1H NMR(CDCl3)δ1.73-1.86(m,4H),2.05-2.17(m,9H),2.36(s,3H),2.48(t,2H,J=14.8Hz),3.07-3.10(m,3H),4.05(t,2H,J=12.4Hz),6.78-6.86(m,2H),7.02-7.07(m,1H),7.21-7.24(m,1H),7.48(d,1H,J=8.8Hz),7.68-7.71(m,1H)MS(ESI)m/z464.3([M+H]+)
实施例30、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-羟甲基-2氢-苯并吡喃-2-酮(30)
反应式3
1)取50ml浓硫酸,冰浴下搅拌,加入间苯二酚5.5g,滴加4-氯乙酰乙酸乙酯8g,溶液变浅黄色,慢慢变浑浊,在室温下反应过夜。将反应液倒入冰水混合物中,有大量白色固体析出,过滤,滤饼水洗,滤饼用40%的乙醇重结晶得白色晶体7.5g,熔点183-185℃,收率84%。
2)取第一步的产物5g,加入300ml水,加热回流反应30h。反应完毕,趁热过滤,将滤液用冰冷却,有针状固体析出,放置1小时,有大量固体析出,过滤,滤饼水洗,干燥,用30%的乙醇重结晶,得白色固体4.1g,熔点212-214℃,收率91%。
3)取第二步的产物6g,无水碳酸钾8g,丙酮100ml和1,3-二溴丙烷8g,加热回流反应12小时,冷至室温,过滤,蒸干溶剂,得浅黄色油状物,过柱得白色固体4.5g,收率72.68%。
4)取第三步的产物0.62g,加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐0.6g,无水碳酸钾2g,碘化钾0.2g和乙腈25ml,加热回流反应12小时,冷至室温,蒸干溶剂,用二氯甲烷溶解,水洗,无水硫酸镁干燥,过滤,蒸干溶剂得浅黄色油状物,过柱得白色固体0.3g,熔点144-146℃,收率33.7%。
1H NMR(CDCl3)δ2.05-2.09(m,8H),2.60(t,2H,J=14.4Hz),3.08-3.11(m,3H),4.11(t,2H,J=12.8Hz),4.88(s,2H),6.47(s,1H),6.84-6.86(m,2H),7.06-7.07(m,1H),7.23-7.25(m,1H),7.41-7.43(m,1H),7.71-7.72(m,1H)MS(ESI)m/z453.3([M+H]+)
实施例31、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-羟甲基-2氢-苯并吡喃-2-酮(31)
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例30的方法制备目标化合物。
熔点:160-162℃。
1H NMR(CDCl3)δ1.73-1.89(m,4H),2.08-2.17(m,6H),2.49(t,2H,J=14.4Hz),3.08-3.11(m,3H),3.62(br,1H),4.05(t,2H,J=12.4Hz),4.88(s,2H),6.46(s,1H),6.83-6.85(m,2H),7.03-7.08(m,1H),7.23-7.25(m,1H),7.42(d,1H,J=8.8Hz),7.68-7.72(m,1H)MS(ESI)m/z467.3([M+H]+)
实施例32、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-2-羟基丙氧基))-4-甲基-2氢-苯并吡喃-2-酮(32)
反应式4
4-甲基-7-羟基香豆素3.2g,环氧氯丙烷20ml,10%氢氧化钾溶液5ml,加入25ml乙醇,回流反应4小时,反应完毕,冷至室温,蒸干溶剂,在剩余物中加入二氯甲烷,水洗,无水硫酸镁干燥,蒸干溶剂,得固体,用无水乙醇重结晶得白色固体3g,收率71.8%。
取第一步产物0.84g,以及6-氟-3-(4-哌啶基)-1,2-苯并异噁唑0.83g,加入无水甲醇50ml,回流反应4小时,析出白色固体,冷至室温,过滤,用冷的甲醇洗涤滤饼,得白色固体1.2g,熔点183-185℃,收率66.8%。
1H NMR(CDCl3)δ2.08-2.14(m,4H),2.26-2.27(m,1H),2.40(s,3H),2.59-2.65(m,3H),3.02-3.20(m,3H),3.63(br,1H),4.08-4.18(m,3H),6.15(s,1H),6.85(d,1H,J=2.8Hz),6.91-6.93(m,1H),7.06-7.09(m,1H),7.24-7.27(m,1H),7.51(d,1H,J=8.8Hz),7.66-7.69(m,1H)MS(ESI)m/z453.2([M+H]+)
实施例33、7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-2-羟基丙氧基))-4-苯基-2氢-苯并吡喃-2-酮(33)
用4-苯基-7-羟基香豆素代替4-甲基-7-羟基香豆素,按实施例32的方法制备目标化合物。
熔点:193-195℃。
1H NMR(CDCl3)δ2.08-2.14(m,4H),2.24-2.27(m,1H),2.52-2.68(m,3H),3.02-3.21(m,3H),3.63(br,s,1H),4.09(t,2H,J=9.6Hz),4.17-4.18(m,1H),6.23(s,1H),6.84-6.87(m,1H),6.93-6.94(m,1H),7.05-7.10(m,1H),7.24-7.27(m,1H),7.39-7.51(m,6H),7.66-7.69(m,1H)MS(ESI)m/z515.3([M+H]+)
实施例34、7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-苯基--苯并吡喃-2-酮(34)
反应式5
1)取间苯二酚5.5g,肉桂酸7.4g,加入浓盐酸200ml,通入氯化氢气体,加热回流反应6小时,然后冷至室温,析出固体,过滤,水洗滤饼,真空干燥,用甲苯重结晶,得白色固体8.1g,熔点104-106℃,收率67.5%。
2)取第一步产物3.1g,无水碳酸钾6g,丙酮50ml,1,4-二溴丁烷6g,加热回流反应,TLC监测,约6h反应完毕,然后冷至室温,过滤,旋干溶剂,得浅黄色油状物,过柱得无色油状物2.9g,收率60.4%。
3)取第二步产物1.8g,加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐1.26g,无水碳酸钾2.6g,碘化钾0.3g和乙腈30ml,加热回流反应12小时,反应完毕,冷至室温,旋干溶剂,加入适量二氯甲烷,水洗,无水硫酸镁干燥,蒸干溶剂,得浅黄色油状物,过柱得无色油状物1.6g,收率65.0%。
1H NMR(CDCl3)δ1.61-1.76(m,5H),2.07-2.16(m,6H),2.47(t,2H,J=14.8Hz),3.08-3.10(m,5H),3.89(t,2H,J=12.4Hz),6.38-6.40(m,2H),7.01-7.05(m,2H),7.22-7.27(m,6H),7.65-7.70(m,1H)MS(ESI)m/z515.3([M+H]+)
表1实施例制备的优选化合物编号及其结构式
B、药理方面的实施例
实施例35
5HT1A膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含0.1%的抗坏血酸、10um优降宁和4mM CaCl2)于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液(0.05M的Tris-HCl缓冲液,含0.1%的抗坏血酸、10um优降宁和4mM CaCl2),于37℃孵化10min,孵化完后试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3ml B液,用旋涡混合器混匀,再加入5ml C液,离心,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃储存备用。
受体结合实验材料:
同位素配基3H-8-OH-DPAT(67.0Ci/mmol),购自PerkinElmer公司;5-HT,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,匀浆液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入5-HT 100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体3H-8-OH-DPAT 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵10min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2
实施例36
5HT2A膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液:取6.05gTris溶于1000ml双蒸水中,用浓HCl调PH为7.5)于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液,于37℃孵化10min,孵化完后试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3mlA液,用旋涡混合器混匀,再加入5ml缓冲液,离心,(重复三次离心),离心完毕,弃上清液,将沉淀于-80℃储存备用。
受体结合实验材料:
同位素配基[3H]-Ketanserin(67.0Ci/mmol),购自PerkinElmer公司;Methysergide,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,缓冲液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入Methysergide100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体3H-Ketanserin 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵15min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2
实施例37
D2膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含NaCl 120mM、KCl 5mM、MgCl2 1mM、CaCl2 1mM),于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液,将匀浆完的试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3mlB液,用旋涡混合器混匀,再加入5mlB液,离心,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃储存备用。受体结合实验材料:
同位素配基3H-Spiperone(67.0Ci/mmol),购自PerkinElmer公司;Butaclamol,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,缓冲液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入100μLButaclamol(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体3H-Spiperone 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵20min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2。
实施例38、D3受体实验
细胞
HEK-293细胞,经48-72小时后受体蛋白在膜上大量表达,将细胞1000rpm离心5min后弃上清,收胞体,存放于-200C冰箱保存。实验时用Tris-Cl(pH 7.4)重悬。
实验材料:
D3受体同位素配基[3H]-Spiperone,购自Amersham公司;(+)Butaclamol,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;脂溶性闪烁液。Tris由吉泰科技有限公司分装。
实验方法:
受体竞争结合实验:将待测化合物与放射性配基各20ul及160ul受体蛋白加入反应试管中,使受试化合物及阳性药物终浓度均为10μmol/L,30℃水浴孵育50min后,即刻移至冰浴终止其反应;在Millipore细胞样品收集器上,经过GF/C玻璃纤维滤纸快速抽滤,并用洗脱液(50mM Tris-HCl,PH 7.4)3mlX3次,用微波炉4~5min烘干,将滤纸移入0.5ml离心管中,加入500ul脂溶性闪烁液。避光静置30min以上,计数测定放射性强度。按以下公式计算各化合物对同位素配基结合的抑制率百分率:
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
实验结果见表2
实施例39、5HT2C膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液:取6.05gTris溶于1000ml双蒸水中,用浓HCl调PH为7.5)于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液,于37℃孵化10min,孵化完后试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3mlA液,用旋涡混合器混匀,再加入5ml缓冲液,离心,(重复三次离心),离心完毕,弃上清液,将沉淀于-80℃储存备用。
受体结合实验材料:
同位素配基[3H]-mesulergine(67.0Ci/mmol),购自PerkinElmer公司;mianserin,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,缓冲液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入mianserin 100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体[3H]-mesulergine 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵15min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2
体外实验结果表明化合物1,6,7,12,18和22对四种受体(D2,D3,5HT1A,5HT2A)较强的亲和力,而对5HT2C的亲和力低。
实施例40、MK-801诱导的高活动性化合物体内抗精神***活性
实验动物及试剂
健康昆明种小鼠,雌雄各半,体重(20±2)g,由南京青龙山动物养殖中心提供。
抗坏血酸,国药集团化学试剂有限公司;
MK-801,由美国Sigma公司生产,配制方法:用0.1%的维生素C配成1mg/ml的溶液;
受试阳性药物:氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平;
吐温80,浓度10%。
实验方法
选择体重合格的小鼠,随机分为空白组、模型组、阳性对照组(利培酮组)、药物组。空白组、模型组灌胃10%吐温0.1ml/10g,阳性对照组灌胃给利培酮0.1mg/kg,药物组分别灌胃给与相应剂量药物。给药后1h空白组腹腔注射0.1%抗坏血酸0.1ml/10g,模型组、阳性对照组(30min)、药物组腹腔注射MK-801溶液0.1mg/kg。其后测定各组小鼠90分钟内自发活动。结果见表3。
本实验结果表明:与模型组相比,利培酮,化合物19和23既能明显改善MK-801诱导的高活动性,又能有效的改善阿扑***诱导的攀爬症状,并且在有效剂量下不引起EPS,表明其有明显的抗精神***作用。
实施例41、阿扑***诱导小鼠攀爬实验
实验动物
健康KM小鼠,雄性,体重18~22g,由南京青龙山动物养殖中心提供。
主要试剂
受试阳性药物:氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平;
阿扑***,Sigma公司提供,临用前0.9%NaCl(含0.1%维生素C)溶解,现配现用;
维生素C,F20061113,国药集团化学试剂有限公司;
氯化钠注射液,H32026305,徐州市第五制药厂有限公司。
仪器:自制攀爬笼,秒表。
实验方法:阿扑***诱导小鼠攀爬实验
KM小鼠,雄性,体重18~22g,随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组(具体给药剂量见下表),每组10只。阴性对照组和模型组灌胃给予相应溶剂双蒸水,阳性药物组灌胃给予相应阳性药物(溶解时先加微量乙酸,再加双蒸水),化合物各剂量组灌胃给予相应剂量化合物,灌胃体积为0.1ml/10g。灌胃给药1小时后皮下注射阿扑***(1mg/kg),体积为0.1ml/10g。注射阿扑***后,立即放入攀爬笼中,适应5分钟,观察注射阿扑***后第10-11,20-21,30-31分钟的行为并进行评分,评分标准:四足在地板上得分为0;两前足在网笼上得分为1;四只足在网笼上得分为2。
实施例42、僵住症实验方法
实验动物
健康昆明种小鼠,雌雄各半,(22±2)g,由南京青龙山动物养殖中心提供。
主要试剂:
受试药、氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮
仪器:
自制抓棒器材:小鼠盒内放置直径0.3cm,高于工作台5cm的不锈钢棒。
实验方法:
KM小鼠,雌雄各半,体重20~24g,随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组,每组10只。阴性对照组和模型组灌胃给予相应溶剂双蒸水,阳性药物组灌胃给予相应阳性药物(溶解时先加微量乙酸,再加双蒸水),化合物各剂量组灌胃给予相应剂量化合物,灌胃体积为0.1ml/10g。灌胃给药30min、60min、90min时,将小鼠两只前爪轻柔地放在长20cm,直径0.3cm,高于工作台5.5cm的小棒上,再将动物后肢轻放于盒底面,记录小鼠两只前爪在棒上保持姿势的持续时间,以30s僵直不动为阳性反应。如果小鼠前爪一直没有放下,60s时终止观察。统计每个化合物剂量组阳性反应动物数。
实施例43、急性毒性研究
序贯法之限度实验取KM小鼠,雌雄各半,随机分为若干组,每组2-5只,分别为各化合物2000mg/kg组和溶剂组,按0.2ml/10g灌胃给药。观察动物3日内的死亡情况。(如果动物在三日内有3只或3只以上存活,生命状态无明显异常时,继续观察,直至7日后实验结束。如果动物在三日内死亡3只或3只以上时,采用半数致死量法测定其LD50。)
半数致死量法预试验取KM小鼠,雌雄各半,随机分若干组,每组4只,分别为各化合物1500mg/kg、1000mg/kg、500mg/kg组和溶剂组,按0.2m1/10g灌胃给药,观察动物1-3日内的死亡情况。
结果:小鼠单次灌服的LD50大于2000mg/kg,与阿立哌唑(93mg/kg)和齐拉西酮(>2000mg/kg)相当,远远高于利培酮(82.1mg/kg),具有较小的急性毒性。
表2化合物对各受体的抑制率或IC50
(注:a表示单元格中数据为IC50值)
表3.优选化合物体内动物模型试验结果
C、组合物实施例
实施例44、片剂
原辅料过80目筛备用,称取处方量活性成分、微晶纤维素、乳糖、聚维酮K30,加入到高速混合制剂机中,低速搅拌混合均匀,加入适量纯化水,低速搅拌,高速切割制粒,湿颗粒60℃干燥3h,24目筛整粒,加入处方量羧甲淀粉钠、二氧化硅和硬脂酸镁,总混,旋转压片机压片。
实施例45、胶囊剂(230mg)
原辅料过80目筛备用,称取处方量活性成分、乳糖、淀粉、聚维酮K30,加入到高速混合制剂机中,低速搅拌混合均匀,加入适量纯化水,低速搅拌,高速切割制粒,湿颗粒60℃干燥3h,24目筛整粒,加入处方量二氧化硅和硬脂酸镁,总混,胶囊灌装机填充胶囊。
Claims (12)
2.根据权利要求1所述的苯并吡喃酮类衍生物,其特征在于:所述Z为取代或未取代的-O(CH2)n-,n为2~5的整数,所述取代基为羟基,或者Z中的碳链上含有双键。
3.根据权利要求1所述的苯并吡喃酮类衍生物,其特征在于:所述Y为O;X为O或S。
4.根据权利要求1所述的苯并吡喃酮类衍生物,其特征在于:所述R1为氢、苯基、卤代苯基、C1-5烷基、C1-5卤代烷基或C1-5羟烷基。
5.根据权利要求4所述的苯并吡喃酮类衍生物,其特征在于:所述R1为氢、苯基、甲基、乙基、丙基、三氟甲基或羟甲基。
6.根据权利要求1所述的苯并吡喃酮类衍生物,其特征在于:所述R3、R4或R5分别独立地为氢、卤素或C1-5烷基。
7.根据权利要求6所述的苯并吡喃酮类衍生物,其特征在于:所述R3为氢、氯或甲基;所述R4为氢、氯或甲基;所述R5为氢、氟或甲基。
8.根据权利要求1所述的苯并吡喃酮类衍生物,其特征在于:所述R2为氢或甲基。
9.根据权利要求1所述的苯并吡喃酮类衍生物,其特征在于:所述Q为CH时,X为O,R5为氟;所述的Q为N时,X为S,R5为氢。
10.根据权利要求1~9任一所述的苯并吡喃酮类衍生物,其特征在于:选自
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(5-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正戊氧基))-4-甲基-2氢-苯并吡喃-2-酮;
(E)-7-(4-(4-(3-(6-氟-苯并异恶唑)-3-哌啶基)-2-烯丁氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-(三氟甲基)-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丙氧基))-4-甲基-8-氯-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4,8-二甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4,8-二甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-正丙基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-正丙基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-乙基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基))-4-乙基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-3,4-二甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-3,4-二甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-羟甲基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丁氧基))-4-羟甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-2-羟基丙氧基))-4-甲基-2氢-苯并吡喃-2-酮;
7-(3-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-2-羟基丙氧基))-4-苯基-2氢-苯并吡喃-2-酮;
7-(4-(4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基))-4-苯基--苯并吡喃-2-酮。
11.一种药物组合物,其特征在于:该药物组合物包含权利要求1~9任一所述的苯并吡喃酮类衍生物和药学上可接受的辅料。
12.根据权利要求1所述的苯并吡喃酮类衍生物在制备治疗精神***症药物中的应用。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110086701.8A CN102206214B (zh) | 2011-04-07 | 2011-04-07 | 苯并吡喃酮类衍生物及其应用 |
EP12768109.6A EP2698369B1 (en) | 2011-04-07 | 2012-04-06 | Benzopyrone derivative and use thereof |
PCT/CN2012/073588 WO2012136147A1 (zh) | 2011-04-07 | 2012-04-06 | 苯并吡喃酮类衍生物及其应用 |
US14/009,581 US9315496B2 (en) | 2011-04-07 | 2012-04-06 | Benzopyrone derivative and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110086701.8A CN102206214B (zh) | 2011-04-07 | 2011-04-07 | 苯并吡喃酮类衍生物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102206214A CN102206214A (zh) | 2011-10-05 |
CN102206214B true CN102206214B (zh) | 2014-03-12 |
Family
ID=44695308
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110086701.8A Active CN102206214B (zh) | 2011-04-07 | 2011-04-07 | 苯并吡喃酮类衍生物及其应用 |
Country Status (4)
Country | Link |
---|---|
US (1) | US9315496B2 (zh) |
EP (1) | EP2698369B1 (zh) |
CN (1) | CN102206214B (zh) |
WO (1) | WO2012136147A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108290880A (zh) * | 2015-11-20 | 2018-07-17 | 江苏恩华药业股份有限公司 | 内酰胺类化合物衍生物及其应用 |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102206214B (zh) * | 2011-04-07 | 2014-03-12 | 华中科技大学 | 苯并吡喃酮类衍生物及其应用 |
CN102267971B (zh) | 2011-08-03 | 2013-03-27 | 华中科技大学 | 脂环并[c]苯并吡喃酮衍生物及其应用 |
CN102924417A (zh) * | 2012-10-25 | 2013-02-13 | 天津希恩思生化科技有限公司 | 化合物4-(氯甲基)-7-羟基香豆素及其制备方法 |
CN102964326B (zh) * | 2012-11-06 | 2015-11-18 | 北京大学 | 具有mek抑制功能的化合物及其制备方法与应用 |
CN104059046B (zh) * | 2013-03-18 | 2017-02-08 | 江苏恩华药业股份有限公司 | 黄酮类衍生物及其应用 |
KR20170102896A (ko) * | 2015-01-13 | 2017-09-12 | 크로모셀 코포레이션 | 단맛을 조정하기 위한 화합물, 조성물 및 방법 |
EP3133066A1 (en) * | 2015-08-21 | 2017-02-22 | Merck Patent GmbH | Hydrophilic compounds for optically active devices |
EP3133065A1 (en) | 2015-08-21 | 2017-02-22 | Merck Patent GmbH | Compounds for optically active devices |
EP3484310A4 (en) * | 2016-07-12 | 2020-04-01 | Chromocell Corporation | COMPOUNDS, COMPOSITIONS AND METHODS FOR MODULATING SWEET FLAVOR |
EP3363793A1 (en) | 2017-02-15 | 2018-08-22 | Merck Patent GmbH | Hydrophobic compounds for optically active devices |
EP3363786A1 (en) | 2017-02-15 | 2018-08-22 | Merck Patent GmbH | Compounds for optically active devices |
CN107936172B (zh) * | 2018-01-08 | 2023-04-28 | 无锡佶达德光电子技术有限公司 | 一种香豆素类聚合物半导体激光材料的制备方法 |
CN107987209B (zh) * | 2018-01-08 | 2023-05-02 | 无锡佶达德光电子技术有限公司 | 一种香豆素类聚合物半导体激光材料及其应用 |
CN113024533B (zh) * | 2019-12-24 | 2022-03-15 | 江苏谛奇医药科技有限公司 | 一种抗精神***症药物甲磺酸盐的固体形式 |
CN113024532B (zh) * | 2019-12-24 | 2022-08-12 | 江苏谛奇医药科技有限公司 | 一种抗精神***症药物甲磺酸盐的晶型 |
CN113816944B (zh) * | 2020-06-20 | 2023-06-27 | 中山大学 | 抗丝状病毒化合物及其应用 |
CN114409625B (zh) * | 2022-01-19 | 2022-08-16 | 中南民族大学 | 一种具有神经保护活性的炭角酮及其制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN85106970A (zh) * | 1985-06-18 | 1987-04-01 | 沃纳兰伯特公司 | 用作抗精神病剂及镇定剂的氨基烷氧基苯并吡喃酮的制备方法 |
WO1999035144A1 (en) * | 1997-12-30 | 1999-07-15 | Ferrer Internacional, S.A. | 7-[(piperidin-1-yl)-propoxy]-chromen-4-one derivatives, their preparation and their pharmaceutical use |
CN1264379A (zh) * | 1997-07-18 | 2000-08-23 | 默克专利股份公司 | 哌嗪衍生物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4701456A (en) * | 1984-09-19 | 1987-10-20 | Warner-Lambert Company | Aminoalkoxybenzopyranones as antipsychotic and anxiolytic agents |
US4678787A (en) * | 1985-01-30 | 1987-07-07 | Warner-Lambert Company | 4H-1-benzopyran-4-ones and their sulfur containing analogs |
AR055203A1 (es) * | 2005-08-31 | 2007-08-08 | Otsuka Pharma Co Ltd | Derivados de benzotiofeno con propiedades antipsicoticas |
CN102206214B (zh) * | 2011-04-07 | 2014-03-12 | 华中科技大学 | 苯并吡喃酮类衍生物及其应用 |
CN102267971B (zh) * | 2011-08-03 | 2013-03-27 | 华中科技大学 | 脂环并[c]苯并吡喃酮衍生物及其应用 |
-
2011
- 2011-04-07 CN CN201110086701.8A patent/CN102206214B/zh active Active
-
2012
- 2012-04-06 US US14/009,581 patent/US9315496B2/en active Active
- 2012-04-06 EP EP12768109.6A patent/EP2698369B1/en active Active
- 2012-04-06 WO PCT/CN2012/073588 patent/WO2012136147A1/zh active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN85106970A (zh) * | 1985-06-18 | 1987-04-01 | 沃纳兰伯特公司 | 用作抗精神病剂及镇定剂的氨基烷氧基苯并吡喃酮的制备方法 |
CN1264379A (zh) * | 1997-07-18 | 2000-08-23 | 默克专利股份公司 | 哌嗪衍生物 |
WO1999035144A1 (en) * | 1997-12-30 | 1999-07-15 | Ferrer Internacional, S.A. | 7-[(piperidin-1-yl)-propoxy]-chromen-4-one derivatives, their preparation and their pharmaceutical use |
Non-Patent Citations (1)
Title |
---|
王冠,等.N-吲哚烷基哌啶类化合物及其类似物的合成和活性研究.《中国药物化学杂志》.2009,第19卷(第3期),第161-169页. * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108290880A (zh) * | 2015-11-20 | 2018-07-17 | 江苏恩华药业股份有限公司 | 内酰胺类化合物衍生物及其应用 |
CN108290880B (zh) * | 2015-11-20 | 2021-03-09 | 江苏恩华药业股份有限公司 | 内酰胺类化合物衍生物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
EP2698369A4 (en) | 2014-09-10 |
EP2698369B1 (en) | 2017-02-01 |
US9315496B2 (en) | 2016-04-19 |
WO2012136147A1 (zh) | 2012-10-11 |
EP2698369A1 (en) | 2014-02-19 |
US20140113911A1 (en) | 2014-04-24 |
CN102206214A (zh) | 2011-10-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102206214B (zh) | 苯并吡喃酮类衍生物及其应用 | |
CN110483501A (zh) | 作为bcl-2抑制剂的n-(苯基磺酰基)苯甲酰胺及相关化合物 | |
CN104854103B (zh) | 适用于治疗对多巴胺d3受体的调节有反应的病症的酰基氨基环烷基化合物 | |
CN102267971B (zh) | 脂环并[c]苯并吡喃酮衍生物及其应用 | |
CA2939570A1 (fr) | Nouveaux composes de type phenylazetidine carboxylate ou carboxamide | |
EP3027597A1 (en) | 1,7-naphthyridine derivatives | |
WO2014177596A1 (en) | Neurogenesis-stimulating isoquinoline derivatives | |
CN102180872B (zh) | [1,3,4]噁二唑类衍生物及其应用 | |
CN102267966B (zh) | 取代的苯并吡喃酮类衍生物及其应用 | |
AU2014350371B2 (en) | Pyrido[4,3-b]pyrazine-2-carboxamides as neurogenic agents for the treatment of neurodegenerative disorders | |
CN104583210A (zh) | 杂芳基化合物及其使用方法 | |
AU2014350371A1 (en) | Pyrido[4,3-b]pyrazine-2-carboxamides as neurogenic agents for the treatment of neurodegenerative disorders | |
CN104059046B (zh) | 黄酮类衍生物及其应用 | |
Del Bello et al. | The versatile 2‐substituted imidazoline nucleus as a structural motif of ligands directed to the serotonin 5‐HT1A receptor | |
CN108368106B (zh) | 稠和杂环类化合物衍生物及其应用 | |
CN103242219B (zh) | 2,6-二酮-哌嗪(哌啶)类衍生物及其应用 | |
CN107793362B (zh) | 一种苯基哒嗪酮类衍生物的合成及其应用 | |
Oliveira et al. | Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells | |
Kaminski et al. | Conformational considerations in the design of dual antagonists of platelet-activating factor (PAF) and histamine | |
TW200413392A (en) | C6- and C9-substituted isoxazoline derivatives and their use as anti-depressants | |
CN103420989A (zh) | 苯并二噁烷类衍生物及其应用 | |
CN109232549A (zh) | 一种治疗精神***症的化合物及其应用 | |
TW202321222A (zh) | 蕈毒鹼受體4拮抗劑及使用方法 | |
PL243066B1 (pl) | Pochodne chinazoliny o aktywności psychotropowej i prokognitywnej | |
TW202204334A (zh) | Menin抑制劑及治療癌症之使用方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |