IL97100A - 3-piperidino-4-hydroxychroman analogs intermediates for their preparation and neuroprotective pharmaceutical compositions - Google Patents

3-piperidino-4-hydroxychroman analogs intermediates for their preparation and neuroprotective pharmaceutical compositions

Info

Publication number: IL97100A
Authority: IL; Israel
Prior art keywords: compound; hydroxy; mmol; preparation; cis
Prior art date: 1990-02-06

Application number

IL9710091A

Other languages

English (en)

Other versions

IL97100A0 (en

Original Assignee

Pfizer

Priority date (The priority date 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 date listed.)

1990-02-06

Filing date

1991-01-30

Publication date

1996-06-18

1991-01-30 Application filed by Pfizer filed Critical Pfizer

1992-03-29 Publication of IL97100A0 publication Critical patent/IL97100A0/xx

1996-06-18 Publication of IL97100A publication Critical patent/IL97100A/en

Links

238000002360 preparation method Methods 0.000 title claims abstract description 30
239000000543 intermediate Substances 0.000 title abstract description 12
239000008194 pharmaceutical composition Substances 0.000 title abstract description 5
230000000324 neuroprotective effect Effects 0.000 title description 8
KUBLZEAOYLPCTH-UHFFFAOYSA-N 3-piperidin-1-yl-3,4-dihydro-2h-chromen-4-ol Chemical class C1OC2=CC=CC=C2C(O)C1N1CCCCC1 KUBLZEAOYLPCTH-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 56
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 3
150000003839 salts Chemical class 0.000 claims description 14
125000006239 protecting group Chemical group 0.000 claims description 8
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
239000003814 drug Substances 0.000 claims description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
125000000217 alkyl group Chemical group 0.000 claims description 2
VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 2
239000013543 active substance Substances 0.000 claims 1
239000000825 pharmaceutical preparation Substances 0.000 claims 1
CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims 1
238000000034 method Methods 0.000 abstract description 35
229910052794 bromium Inorganic materials 0.000 abstract description 5
208000015114 central nervous system disease Diseases 0.000 abstract 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
239000000047 product Substances 0.000 description 57
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
238000006243 chemical reaction Methods 0.000 description 24
239000000203 mixture Substances 0.000 description 20
239000007787 solid Substances 0.000 description 19
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
239000003921 oil Substances 0.000 description 15
235000019198 oils Nutrition 0.000 description 15
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
239000012267 brine Substances 0.000 description 10
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
238000005481 NMR spectroscopy Methods 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
238000010828 elution Methods 0.000 description 9
239000000741 silica gel Substances 0.000 description 9
229910002027 silica gel Inorganic materials 0.000 description 9
239000000243 solution Substances 0.000 description 9
-1 4-hydroxy-4-tolylpiperazino Chemical group 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
239000002253 acid Substances 0.000 description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 5
230000002253 anti-ischaemic effect Effects 0.000 description 5
ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
150000004678 hydrides Chemical class 0.000 description 5
239000002904 solvent Substances 0.000 description 5
238000003756 stirring Methods 0.000 description 5
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-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
HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 4
210000003169 central nervous system Anatomy 0.000 description 4
210000001638 cerebellum Anatomy 0.000 description 4
238000007796 conventional method Methods 0.000 description 4
239000012442 inert solvent Substances 0.000 description 4
239000011541 reaction mixture Substances 0.000 description 4
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
KQKFQBTWXOGINC-UHFFFAOYSA-N 4-phenylpiperidin-4-ol Chemical compound C=1C=CC=CC=1C1(O)CCNCC1 KQKFQBTWXOGINC-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
208000006011 Stroke Diseases 0.000 description 3
230000000903 blocking effect Effects 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
239000007853 buffer solution Substances 0.000 description 3
239000003153 chemical reaction reagent Substances 0.000 description 3
239000003085 diluting agent Substances 0.000 description 3
238000001914 filtration Methods 0.000 description 3
125000004356 hydroxy functional group Chemical group O* 0.000 description 3
230000001077 hypotensive effect Effects 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
208000015122 neurodegenerative disease Diseases 0.000 description 3
230000000269 nucleophilic effect Effects 0.000 description 3
230000009467 reduction Effects 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
238000000926 separation method Methods 0.000 description 3
239000011734 sodium Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
238000005160 1H NMR spectroscopy Methods 0.000 description 2
AYNCWMIFKFADCZ-UHFFFAOYSA-N 2-bromo-3,4-dihydro-2h-naphthalen-1-one Chemical class C1=CC=C2C(=O)C(Br)CCC2=C1 AYNCWMIFKFADCZ-UHFFFAOYSA-N 0.000 description 2
SIJMTZYXQQNOJB-UHFFFAOYSA-N 2-bromo-5-tri(propan-2-yl)silyloxy-2,3-dihydroinden-1-one Chemical compound CC(C)[Si](C(C)C)(C(C)C)OC1=CC=C2C(=O)C(Br)CC2=C1 SIJMTZYXQQNOJB-UHFFFAOYSA-N 0.000 description 2
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
UIGVPKWORHBCNV-UHFFFAOYSA-N 3,3-dibromo-2h-chromen-4-one Chemical class C1=CC=C2C(=O)C(Br)(Br)COC2=C1 UIGVPKWORHBCNV-UHFFFAOYSA-N 0.000 description 2
YITDKQCEZARMJL-UHFFFAOYSA-N 3,3-dibromo-7-tri(propan-2-yl)silyloxy-2h-chromen-4-one Chemical compound O=C1C(Br)(Br)COC2=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C21 YITDKQCEZARMJL-UHFFFAOYSA-N 0.000 description 2
UYNVMODNBIQBMV-UHFFFAOYSA-N 4-[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]propyl]phenol Chemical compound C1CC(CC=2C=CC=CC=2)CCN1C(C)C(O)C1=CC=C(O)C=C1 UYNVMODNBIQBMV-UHFFFAOYSA-N 0.000 description 2
208000024827 Alzheimer disease Diseases 0.000 description 2
102000015404 Amino Acid Receptors Human genes 0.000 description 2
108010025177 Amino Acid Receptors Proteins 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
102000018899 Glutamate Receptors Human genes 0.000 description 2
108010027915 Glutamate Receptors Proteins 0.000 description 2
208000023105 Huntington disease Diseases 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
238000000023 Kugelrohr distillation Methods 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
208000018737 Parkinson disease Diseases 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
230000004071 biological effect Effects 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
239000000872 buffer Substances 0.000 description 2
XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
239000006071 cream Substances 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
238000006073 displacement reaction Methods 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
229960003998 ifenprodil Drugs 0.000 description 2
150000002576 ketones Chemical class 0.000 description 2
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
229910052943 magnesium sulfate Inorganic materials 0.000 description 2
235000019341 magnesium sulphate Nutrition 0.000 description 2
239000000463 material Substances 0.000 description 2
239000012452 mother liquor Substances 0.000 description 2
239000002674 ointment Substances 0.000 description 2
239000003208 petroleum Substances 0.000 description 2
239000012071 phase Substances 0.000 description 2
150000003053 piperidines Chemical class 0.000 description 2
235000018102 proteins Nutrition 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
238000000746 purification Methods 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
239000000725 suspension Substances 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
ICZHJFWIOPYQCA-OAHLLOKOSA-N (1r)-1-anthracen-9-yl-2,2,2-trifluoroethanol Chemical compound C1=CC=C2C([C@@H](O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 ICZHJFWIOPYQCA-OAHLLOKOSA-N 0.000 description 1
HXPYIWCZWWHAHA-RTBURBONSA-N (1r,2r)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2,3-dihydro-1h-indene-1,5-diol Chemical compound C1CN([C@H]2[C@@H](C3=CC=C(O)C=C3C2)O)CCC1(O)C1=CC=CC=C1 HXPYIWCZWWHAHA-RTBURBONSA-N 0.000 description 1
CUYIBIIXRWZLMQ-MJGOQNOKSA-N (3r,4s)-3-(4-hydroxy-4-phenylpiperidin-1-yl)-3,4-dihydro-2h-chromene-4,7-diol Chemical compound C1CN([C@H]2[C@H](C3=CC=C(O)C=C3OC2)O)CCC1(O)C1=CC=CC=C1 CUYIBIIXRWZLMQ-MJGOQNOKSA-N 0.000 description 1
BTPSOIMWUANJOG-WOJBJXKFSA-N 1-[(1r,2r)-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]-4-phenylpiperidin-4-ol Chemical compound C1CN([C@H]2[C@@H](C3=CC=CC=C3CC2)O)CCC1(O)C1=CC=CC=C1 BTPSOIMWUANJOG-WOJBJXKFSA-N 0.000 description 1
HUIKRQLZKUKPMQ-VSGBNLITSA-N 1-[(1r,2r)-1-hydroxy-5-tri(propan-2-yl)silyloxy-2,3-dihydro-1h-inden-2-yl]-4-phenylpiperidin-4-ol Chemical compound C1CN([C@H]2[C@H](O)C3=CC=C(C=C3C2)O[Si](C(C)C)(C(C)C)C(C)C)CCC1(O)C1=CC=CC=C1 HUIKRQLZKUKPMQ-VSGBNLITSA-N 0.000 description 1
YYIYWNQJRLJDGC-FQLXRVMXSA-N 1-[(1r,2r)-1-hydroxy-6-tri(propan-2-yl)silyloxy-1,2,3,4-tetrahydronaphthalen-2-yl]-4-phenylpiperidin-4-ol Chemical compound C1CN([C@H]2[C@H](O)C3=CC=C(C=C3CC2)O[Si](C(C)C)(C(C)C)C(C)C)CCC1(O)C1=CC=CC=C1 YYIYWNQJRLJDGC-FQLXRVMXSA-N 0.000 description 1
HIDHBHIDQMQQAG-IXCJQBJRSA-N 1-[(3r,4r)-4-hydroxy-7-tri(propan-2-yl)silyloxy-3,4-dihydro-2h-chromen-3-yl]-4-phenylpiperidin-4-ol Chemical compound C1CN([C@H]2[C@H](O)C3=CC=C(C=C3OC2)O[Si](C(C)C)(C(C)C)C(C)C)CCC1(O)C1=CC=CC=C1 HIDHBHIDQMQQAG-IXCJQBJRSA-N 0.000 description 1
XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 1
NDCYVYDLBWHCMF-UHFFFAOYSA-N 2-(4-hydroxy-4-phenylpiperidin-1-yl)-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CN(C2C(C3=CC=CC=C3CC2)=O)CCC1(O)C1=CC=CC=C1 NDCYVYDLBWHCMF-UHFFFAOYSA-N 0.000 description 1
WQKPXPLPAOAGMX-UHFFFAOYSA-N 2-(4-hydroxy-4-phenylpiperidin-1-yl)-5-tri(propan-2-yl)silyloxy-2,3-dihydroinden-1-one Chemical compound C1C2=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C2C(=O)C1N(CC1)CCC1(O)C1=CC=CC=C1 WQKPXPLPAOAGMX-UHFFFAOYSA-N 0.000 description 1
VDTSLQPJVFOXTM-UHFFFAOYSA-N 2-(4-hydroxy-4-phenylpiperidin-1-yl)-6-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CC2=CC(OC)=CC=C2C(=O)C1N(CC1)CCC1(O)C1=CC=CC=C1 VDTSLQPJVFOXTM-UHFFFAOYSA-N 0.000 description 1
BPBFIAIFXJDDMS-UHFFFAOYSA-N 2-(4-hydroxy-4-phenylpiperidin-1-yl)-6-tri(propan-2-yl)silyloxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CC2=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C2C(=O)C1N(CC1)CCC1(O)C1=CC=CC=C1 BPBFIAIFXJDDMS-UHFFFAOYSA-N 0.000 description 1
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
NAXVBXDTOCUKNH-UHFFFAOYSA-N 2-bromo-6-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1C(Br)CCC2=CC(OC)=CC=C21 NAXVBXDTOCUKNH-UHFFFAOYSA-N 0.000 description 1
LYUGOEZQIYQABF-UHFFFAOYSA-N 2-bromo-7-tri(propan-2-yl)silyloxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CC(Br)C(=O)C2=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C21 LYUGOEZQIYQABF-UHFFFAOYSA-N 0.000 description 1
WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
MGSHXMOLUWTMGP-UHFFFAOYSA-N 3'-carboxy-alpha-chromanol Chemical compound C1=CC=C2C(O)CCOC2=C1 MGSHXMOLUWTMGP-UHFFFAOYSA-N 0.000 description 1
XLFGWPOHFKKTNB-UHFFFAOYSA-N 3,3-dibromo-6-chloro-2h-chromen-4-one Chemical compound O1CC(Br)(Br)C(=O)C2=CC(Cl)=CC=C21 XLFGWPOHFKKTNB-UHFFFAOYSA-N 0.000 description 1
PEXNBXHBSNSWJM-UHFFFAOYSA-N 3,3-dibromo-6-fluoro-2h-chromen-4-one Chemical compound O1CC(Br)(Br)C(=O)C2=CC(F)=CC=C21 PEXNBXHBSNSWJM-UHFFFAOYSA-N 0.000 description 1
IXZMKISWJZVFDN-UHFFFAOYSA-N 3,3-dibromo-7-tri(propan-2-yl)silyloxy-2h-chromen-4-one;3-(4-hydroxy-4-phenylpiperidin-1-yl)-7-tri(propan-2-yl)silyloxychromen-4-one Chemical compound O=C1C(Br)(Br)COC2=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C21.C=1C(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C(C2=O)C=1OC=C2N(CC1)CCC1(O)C1=CC=CC=C1 IXZMKISWJZVFDN-UHFFFAOYSA-N 0.000 description 1
HKFHRWZPGMYGIJ-UHFFFAOYSA-N 3-(4-benzyl-4-hydroxypiperidin-1-yl)-7-tri(propan-2-yl)silyloxychromen-4-one Chemical compound C=1C(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C(C2=O)C=1OC=C2N(CC1)CCC1(O)CC1=CC=CC=C1 HKFHRWZPGMYGIJ-UHFFFAOYSA-N 0.000 description 1
NGNUQWHJZLEUFD-UHFFFAOYSA-N 3-(4-benzylpiperidin-1-yl)-7-tri(propan-2-yl)silyloxychromen-4-one Chemical compound C=1C(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C(C2=O)C=1OC=C2N(CC1)CCC1CC1=CC=CC=C1 NGNUQWHJZLEUFD-UHFFFAOYSA-N 0.000 description 1
DWLGEXCUINTICY-UHFFFAOYSA-N 3-(4-hydroxy-4-phenylpiperidin-1-yl)chromen-4-one Chemical compound C1CN(C=2C(C3=CC=CC=C3OC=2)=O)CCC1(O)C1=CC=CC=C1 DWLGEXCUINTICY-UHFFFAOYSA-N 0.000 description 1
UCSCEJQLXPZOPX-UHFFFAOYSA-N 3-[4-hydroxy-4-(2-phenylethyl)piperidin-1-yl]-7-tri(propan-2-yl)silyloxychromen-4-one Chemical compound C=1C(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C(C2=O)C=1OC=C2N(CC1)CCC1(O)CCC1=CC=CC=C1 UCSCEJQLXPZOPX-UHFFFAOYSA-N 0.000 description 1
MLNVYYWVCITBMV-UHFFFAOYSA-N 3-bromo-7-tri(propan-2-yl)silyloxy-2,3-dihydrochromen-4-one Chemical compound O=C1C(Br)COC2=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=C21 MLNVYYWVCITBMV-UHFFFAOYSA-N 0.000 description 1
MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical class C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 1
ZRKQOVXGDIZYDS-UHFFFAOYSA-N 5-hydroxy-2,3-dihydroinden-1-one Chemical compound OC1=CC=C2C(=O)CCC2=C1 ZRKQOVXGDIZYDS-UHFFFAOYSA-N 0.000 description 1
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XSESNNZUNIRKFT-UHFFFAOYSA-N 6-chloro-3-(4-hydroxy-4-phenylpiperidin-1-yl)chromen-4-one Chemical compound C1CN(C=2C(C3=CC(Cl)=CC=C3OC=2)=O)CCC1(O)C1=CC=CC=C1 XSESNNZUNIRKFT-UHFFFAOYSA-N 0.000 description 1
AUYSEVBAYLJIBH-UHFFFAOYSA-N 6-fluoro-3-(4-hydroxy-4-phenylpiperidin-1-yl)chromen-4-one Chemical compound C1CN(C=2C(C3=CC(F)=CC=C3OC=2)=O)CCC1(O)C1=CC=CC=C1 AUYSEVBAYLJIBH-UHFFFAOYSA-N 0.000 description 1
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HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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125000002768 hydroxyalkyl group Chemical group 0.000 description 1
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125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
239000012948 isocyanate Substances 0.000 description 1
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239000010410 layer Substances 0.000 description 1
239000007788 liquid Substances 0.000 description 1
239000006210 lotion Substances 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
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238000001819 mass spectrum Methods 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
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ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
150000002989 phenols Chemical class 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
239000000843 powder Substances 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
239000002243 precursor Substances 0.000 description 1
239000003586 protic polar solvent Substances 0.000 description 1
230000000506 psychotropic effect Effects 0.000 description 1
239000000376 reactant Substances 0.000 description 1
238000010992 reflux Methods 0.000 description 1
239000000523 sample Substances 0.000 description 1
239000003579 shift reagent Substances 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
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229910052708 sodium Inorganic materials 0.000 description 1
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238000010561 standard procedure Methods 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
239000001384 succinic acid Substances 0.000 description 1
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ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
230000000699 topical 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
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
238000007514 turning Methods 0.000 description 1
150000003673 urethanes Chemical class 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- 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
- A61P25/28—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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

IL9710091A 1990-02-06 1991-01-30 3-piperidino-4-hydroxychroman analogs intermediates for their preparation and neuroprotective pharmaceutical compositions IL97100A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
PCT/US1990/000674 WO1991012005A1 (en)	1990-02-06	1990-02-06	Neuroprotective 3-piperidino-4-hydroxychroman derivatives and analogs

Publications (2)

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IL97100A0 IL97100A0 (en)	1992-03-29
IL97100A true IL97100A (en)	1996-06-18

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IL9710091A IL97100A (en)	1990-02-06	1991-01-30	3-piperidino-4-hydroxychroman analogs intermediates for their preparation and neuroprotective pharmaceutical compositions

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US (1)	US5356905A (da)
EP (1)	EP0441506B1 (da)
JP (1)	JPH0768214B2 (da)
KR (1)	KR930011041B1 (da)
CN (1)	CN1029960C (da)
AT (1)	ATE108787T1 (da)
AU (1)	AU626490B2 (da)
BR (1)	BR9100490A (da)
CA (1)	CA2035653C (da)
CZ (1)	CZ286218B6 (da)
DE (2)	DE69102893T4 (da)
DK (1)	DK0441506T3 (da)
EG (1)	EG19643A (da)
ES (1)	ES2056571T3 (da)
FI (1)	FI94957C (da)
HU (1)	HU222726B1 (da)
IE (1)	IE63836B1 (da)
IL (1)	IL97100A (da)
MX (1)	MX24433A (da)
MY (1)	MY105293A (da)
NO (1)	NO178399C (da)
NZ (1)	NZ237025A (da)
PH (1)	PH31061A (da)
PL (1)	PL164866B1 (da)
PT (1)	PT96664B (da)
RU (1)	RU2099339C1 (da)
SK (1)	SK281729B6 (da)
WO (1)	WO1991012005A1 (da)
ZA (1)	ZA91830B (da)

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Publication number	Priority date	Publication date	Assignee	Title
US5594007A (en) *	1991-04-18	1997-01-14	Pfizer Inc.	Method for treating spinal cord trauma with phenolic 2-piperidino-1-alkanols
BR9205893A (pt) *	1991-04-18	1994-11-08	Pfizer	Ésteres pró droga de 2-piperidino-1-alcanóis fenólicos
US5436255A (en) *	1992-07-23	1995-07-25	Pfizer Inc.	Method of treating diseases susceptable to treatment by blocking NMDA-receptors
US5498610A (en) *	1992-11-06	1996-03-12	Pfizer Inc.	Neuroprotective indolone and related derivatives
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1990
- 1990-02-06 MX MX2443391A patent/MX24433A/es unknown
- 1990-02-06 RU SU5053040/04A patent/RU2099339C1/ru not_active IP Right Cessation
- 1990-02-06 US US07/916,130 patent/US5356905A/en not_active Expired - Lifetime
- 1990-02-06 HU HU9202568A patent/HU222726B1/hu active IP Right Grant
- 1990-02-06 WO PCT/US1990/000674 patent/WO1991012005A1/en not_active Ceased
1991
- 1991-01-21 PH PH41875A patent/PH31061A/en unknown
- 1991-01-24 EP EP91300549A patent/EP0441506B1/en not_active Expired - Lifetime
- 1991-01-24 DK DK91300549.2T patent/DK0441506T3/da active
- 1991-01-24 AT AT91300549T patent/ATE108787T1/de not_active IP Right Cessation
- 1991-01-24 DE DE69102893A patent/DE69102893T4/de not_active Expired - Fee Related
- 1991-01-24 ES ES91300549T patent/ES2056571T3/es not_active Expired - Lifetime
- 1991-01-30 IL IL9710091A patent/IL97100A/en not_active IP Right Cessation
- 1991-02-01 SK SK250-91A patent/SK281729B6/sk unknown
- 1991-02-01 CZ CS1991250A patent/CZ286218B6/cs not_active IP Right Cessation
- 1991-02-04 PT PT96664A patent/PT96664B/pt not_active IP Right Cessation
- 1991-02-04 CA CA002035653A patent/CA2035653C/en not_active Expired - Fee Related
- 1991-02-04 PL PL91288949A patent/PL164866B1/pl not_active IP Right Cessation
- 1991-02-05 CN CN91100705A patent/CN1029960C/zh not_active Expired - Fee Related
- 1991-02-05 ZA ZA91830A patent/ZA91830B/xx unknown
- 1991-02-05 MY MYPI91000171A patent/MY105293A/en unknown
- 1991-02-05 NZ NZ237025A patent/NZ237025A/en unknown
- 1991-02-05 JP JP3014569A patent/JPH0768214B2/ja not_active Expired - Fee Related
- 1991-02-05 IE IE37291A patent/IE63836B1/en not_active IP Right Cessation
- 1991-02-05 AU AU70293/91A patent/AU626490B2/en not_active Ceased
- 1991-02-06 DE DE9101346U patent/DE9101346U1/de not_active Expired - Lifetime
- 1991-02-06 EG EG7291A patent/EG19643A/xx active
- 1991-02-06 KR KR1019910002022A patent/KR930011041B1/ko not_active Expired - Fee Related
- 1991-02-06 BR BR919100490A patent/BR9100490A/pt not_active Application Discontinuation
1992
- 1992-08-05 FI FI923527A patent/FI94957C/fi active
- 1992-08-05 NO NO923081A patent/NO178399C/no not_active IP Right Cessation

Also Published As

Publication number	Publication date
IE63836B1 (en)	1995-06-14
BR9100490A (pt)	1991-10-29
FI94957C (fi)	1995-11-27
IL97100A0 (en)	1992-03-29
FI923527L (fi)	1992-08-05
JPH04211058A (ja)	1992-08-03
KR910015568A (ko)	1991-09-30
ZA91830B (en)	1992-09-30
PT96664A (pt)	1991-10-31
US5356905A (en)	1994-10-18
IE910372A1 (en)	1991-08-14
RU2099339C1 (ru)	1997-12-20
EP0441506A3 (en)	1991-11-21
MY105293A (en)	1994-09-30
HU222726B1 (hu)	2003-09-29
JPH0768214B2 (ja)	1995-07-26
FI923527A0 (fi)	1992-08-05
EP0441506A2 (en)	1991-08-14
AU7029391A (en)	1991-09-05
CS25091A3 (en)	1991-09-15
PL288949A1 (en)	1991-07-29
ATE108787T1 (de)	1994-08-15
NO923081D0 (no)	1992-08-05
EP0441506B1 (en)	1994-07-20
CA2035653C (en)	1999-12-21
DK0441506T3 (da)	1994-09-05
NZ237025A (en)	1992-11-25
CN1029960C (zh)	1995-10-11
NO178399C (no)	1996-03-20
KR930011041B1 (ko)	1993-11-20
DE69102893T4 (de)	1995-08-10
DE69102893T2 (de)	1994-11-03
ES2056571T3 (es)	1994-10-01
CN1053923A (zh)	1991-08-21
WO1991012005A1 (en)	1991-08-22
EG19643A (en)	1995-09-30
DE69102893D1 (de)	1994-08-25
PT96664B (pt)	1998-07-31
NO178399B (no)	1995-12-11
FI94957B (fi)	1995-08-15
NO923081L (no)	1992-08-05
CA2035653A1 (en)	1991-08-07
PH31061A (en)	1998-02-05
DE9101346U1 (de)	1991-06-06
CZ286218B6 (cs)	2000-02-16
MX24433A (es)	1993-05-01
SK281729B6 (sk)	2001-07-10
AU626490B2 (en)	1992-07-30
PL164866B1 (pl)	1994-10-31

Legal Events

Date	Code	Title
1996-11-14	FF	Patent granted
1997-02-18	KB	Patent renewed
1997-04-15	KB	Patent renewed
2001-06-14	KB	Patent renewed
2005-11-20	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
IL97100A (en)	1996-06-18	3-piperidino-4-hydroxychroman analogs intermediates for their preparation and neuroprotective pharmaceutical compositions
EP0554247B1 (en)	2000-04-26	Neuroprotective indolone and related derivatives
US5436255A (en)	1995-07-25	Method of treating diseases susceptable to treatment by blocking NMDA-receptors
JPH0680634A (ja)	1994-03-22	ピペラジニル−およびピペリジニル−シクロヘキサノール化合物
AU684874B2 (en)	1998-01-08	Heterocyclic compounds for the treatment of cns and cardiovascular disorders
HU218668B (hu)	2000-10-28	Eljárás gyűrűben helyettesített 2-amino-1,2,3,4-tetrahidronaftalinek, 3-amino-krománok és a vegyületeket tartalmazó gyógyszerkészítmények előállítására
DE69102889T2 (de)	1994-11-03	Chirurgische Nähnadel, Verfahren und Gerät zum Schleifen von chirurgischen Nähnadeln.
US4870084A (en)	1989-09-26	Bicyclic benzo fused pyran compounds used for nausea treatment and prevention
US5118693A (en)	1992-06-02	4,4-disubstituted piperidine derivatives, pharmaceutical compositions containing them and process for preparing same
JPH06287190A (ja)	1994-10-11	新規な３−アミノクロマンスピロ化合物、それらの製造法およびそれらを含む薬学組成物
US4680404A (en)	1987-07-14	Benzopyrans
AU705431B2 (en)	1999-05-20	Indanylpiperidines as melatonergic agents
JPH0533696B2 (da)	1993-05-20
EP0502031B1 (en)	1997-08-20	N-substituted azaheterocyclic carboxylic acids and a pharmaceutical composition
US4788201A (en)	1988-11-29	3-methylenespiro (benzofuranpiperidines)