CN1443166A - 4-苄基-1-[2-(4-羟基-苯氧基)乙基]-哌啶-3,4-二醇 - Google Patents
4-苄基-1-[2-(4-羟基-苯氧基)乙基]-哌啶-3,4-二醇 Download PDFInfo
- Publication number
- CN1443166A CN1443166A CN01808591A CN01808591A CN1443166A CN 1443166 A CN1443166 A CN 1443166A CN 01808591 A CN01808591 A CN 01808591A CN 01808591 A CN01808591 A CN 01808591A CN 1443166 A CN1443166 A CN 1443166A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzyl
- formula
- disease
- piperidines
- 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.)
- Granted
Links
- QDLSQZUNQXEAFR-UHFFFAOYSA-N 4-benzyl-1-[2-(4-hydroxyphenoxy)ethyl]piperidine-3,4-diol Chemical compound C1CC(CC=2C=CC=CC=2)(O)C(O)CN1CCOC1=CC=C(O)C=C1 QDLSQZUNQXEAFR-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 8
- 208000002193 Pain Diseases 0.000 claims abstract description 7
- 230000001154 acute effect Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 6
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 6
- 230000009385 viral infection Effects 0.000 claims abstract description 6
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 5
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 5
- 230000036506 anxiety Effects 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 230000000626 neurodegenerative effect Effects 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- 230000002490 cerebral effect Effects 0.000 claims description 5
- 230000006726 chronic neurodegeneration Effects 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 230000008733 trauma Effects 0.000 claims description 5
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 208000024732 dysthymic disease Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000030886 Traumatic Brain injury Diseases 0.000 abstract 1
- 208000036142 Viral infection Diseases 0.000 abstract 1
- 208000005298 acute pain Diseases 0.000 abstract 1
- 230000001580 bacterial effect Effects 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- 201000000980 schizophrenia Diseases 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 13
- 238000013016 damping Methods 0.000 description 11
- 239000012530 fluid Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 8
- 102000014649 NMDA glutamate receptor activity proteins Human genes 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000007787 solid 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
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 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 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- IOXXSUNFSUCRNX-NWDGAFQWSA-N (3s,4s)-4-benzylpiperidine-3,4-diol Chemical class O[C@H]1CNCC[C@@]1(O)CC1=CC=CC=C1 IOXXSUNFSUCRNX-NWDGAFQWSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 description 4
- 108010038912 Retinoid X Receptors Proteins 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- IOXXSUNFSUCRNX-NEPJUHHUSA-N (3r,4r)-4-benzylpiperidine-3,4-diol Chemical class O[C@@H]1CNCC[C@]1(O)CC1=CC=CC=C1 IOXXSUNFSUCRNX-NEPJUHHUSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000036982 action potential Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 229960001289 prazosin Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 102000009427 Ether-A-Go-Go Potassium Channels Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101001010792 Homo sapiens Transcriptional regulator ERG Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 2
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- IOXXSUNFSUCRNX-PIJUOVFKSA-N (4s)-4-benzylpiperidine-3,4-diol Chemical class OC1CNCC[C@@]1(O)CC1=CC=CC=C1 IOXXSUNFSUCRNX-PIJUOVFKSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BPCKWVMOXOYTQI-UHFFFAOYSA-N 4-(piperidin-1-ylmethyl)phenol Chemical class C1=CC(O)=CC=C1CN1CCCCC1 BPCKWVMOXOYTQI-UHFFFAOYSA-N 0.000 description 1
- IOXXSUNFSUCRNX-UHFFFAOYSA-N 4-benzylpiperidine-3,4-diol Chemical class OC1CNCCC1(O)CC1=CC=CC=C1 IOXXSUNFSUCRNX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- FTEDXVNDVHYDQW-UHFFFAOYSA-N BAPTA Chemical compound OC(=O)CN(CC(O)=O)C1=CC=CC=C1OCCOC1=CC=CC=C1N(CC(O)=O)CC(O)=O FTEDXVNDVHYDQW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GKRYOTUQPZKDFB-UHFFFAOYSA-N C1=CC=CC=C1C(=O)OO.[Cl] Chemical compound C1=CC=CC=C1C(=O)OO.[Cl] GKRYOTUQPZKDFB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 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
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100029458 Glutamate receptor ionotropic, NMDA 2A Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- -1 benzyl ester Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 108091008634 hepatocyte nuclear factors 4 Proteins 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LLYKPZOWCPVRPD-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=CC=N1 LLYKPZOWCPVRPD-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229950007002 phosphocreatine Drugs 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical class OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 229940125422 potassium channel blocker Drugs 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic 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
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- C07D211/50—Aroyl radical
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
本发明涉及式(I)的化合物、其R,R-和S,S-对映体及其可药用酸加成盐。式(I)的化合物及其R,R-和S,S-对映体可以用作治疗疾病的药物,其中治疗适应症包括由中风或脑外伤引起的急性神经变性;慢性神经变性,例如阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病或ALS(肌萎缩性侧索硬化症);与细菌或病毒感染有关的神经变性及诸如神经分裂症、焦虑、抑郁症及急/慢性疼痛的疾病。
Description
本发明涉及下式的化合物其R,R-和S,S-对映体及其可药用酸加成盐。
本发明的化合物是NMDA(N-甲基-D-天冬氨酸)受体亚型选择性阻断剂,在调节神经元活性和粘性方面起着关键的作用,使其成为介导CNS发育过程(包括学习和记忆形成和功能)的关键角色。
在急性或慢性神经变性的病理状态下,NMDA受体过度兴奋(overactivation)是引发神经元细胞死亡的关键因素。NMDA受体由两个亚单元族的成员组成,即源自不同基因的NR-1(8个不同的剪接变体)和NR-2(A-D)。来自两个不同的亚单元族的成员在不同的脑区域具有不同的分布。NR-1成员与不同的NR-2亚单元异数组合得到表现不同药理学特性的NMDA受体。对于NMDA受体亚型特异性阻断剂可能的治疗适应症包括例如由中风或脑外伤引起的急性神经变性;慢性神经变性,例如阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病或ALS(肌萎缩性侧索硬化症);与细菌或病毒感染有关的神经变性,诸如神经分裂症、焦虑和抑郁症及急/慢性疼痛的疾病。
本发明的目的是式I的新化合物,其R,R-和S,S-对映体及其可药用盐,在治疗或预防由各NMDA受体亚型过度兴奋引起的疾病(包括由中风或脑外伤引起的急性神经变性;慢性神经变性,例如阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病或ALS(肌萎缩性侧索硬化症);与细菌或病毒感染有关的神经变性和诸如神经分裂症、焦虑、抑郁症及急/慢性疼痛的疾病)中的应用,这些化合物在制备相应药物中的应用,制备这些新化合物和含有这些新化合物的药物的方法。
术语“可药用酸加成盐”包括无机和有机酸(例如盐酸、硝酸、硫酸、乳酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸,对甲苯磺酸等)的盐。
4-羟基-哌啶衍生物例如在EP824 098中描述,其中哌啶环的4位被一个羟基取代。据描述这些化合物对NMDA受体具有活性并可用于治疗由中风或脑外伤引起的急性神经变性和慢性神经变性如阿尔茨海默氏病、帕金森氏病、ALS(肌萎缩性侧索硬化症);与细菌或病毒感染有关的神经变性及急/慢性疼痛。
从EP824 098中已知这些化合物是良好的NMDA受体亚型特异性阻断剂,对含有NR2B亚单元的受体亲和力高并对含有NR2A亚单元的受体亲和力低。
对α1-肾上腺素能受体的活性也低并且这些化合物在低mg/kg范围内对小鼠的听源性惊厥具有体内活性。重要的是,这些化合物在动物中风模型,即大脑中动脉永久梗塞中具有神经保护作用。然而,体外和体内的心脏毒性研究表明这些化合物有体外延长心脏动作电位持续时间并因此延长体内‘QT’-间隔的倾向,因此具有导致心脏心律失常的潜在倾向。这些化合物延长心脏动作电位的作用被确定为由对hERG型钾通道的作用引起,该通道对人类和其他物种的动作电位复极化是重要的,并且已知能延长人QT-间隔的大多数化合物都有阻断这种通道的活性。因此,现有技术中的化合物阻断异种重组人ERG钾通道。
现在,我们惊奇地发现式I的以下化合物
(3R,4R)和(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇,
(3R,4R)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇和
(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇是NMDA NR2B亚型选择性拮抗剂并同时具有现有技术化合物(例如1-[2-(4-羟基-苯氧基)乙基]-4-(4-甲基-苄基)-哌啶-4-醇(EP 824 098))的高度特异性亚型选择性阻断特性并且是体内神经保护剂,其作为hERG钾通道阻断剂的活性小并因此不大可能具有致人心律失常的作用。
下表可以证实本发明的化合物具有高选择性。
NMDA NR2B亚型选择性拮抗剂的选择性列表
化合物 | 抑制[3H]-Ro25-6981结合IC50(μM)a | 抑制[3H]-哌唑嗪结合IC50(μM)b | 抑制hERG K+流IC50(μM)(在10μM下的作用(%)c) |
EP8240981-[2-(4-羟基-苯氧基)乙基]-4-(4-甲基-苄基)-哌啶-4-醇 | 0.010 | 3.5 | 0.69μM |
I(外消旋体) | 0.045 | 27 | >10μM(45%) |
I-1(R,R) | 0.038 | 25 | >10μM(44%) |
I-2(S,S) | 0.039 | 30 | >10μM(40%) |
a抑制[3H]-Ro 25-6981结合表示对含有NMDA NR2B亚单元的受体的亲和力。
b抑制[3H]-哌唑嗪结合表示对α1-肾上腺素能受体的亲和力。
c表示阻断在哺乳动物细胞系(中国仓鼠卵巢细胞,CHO)中表达的重组人ERG钾通道的能力。
式I的新化合物及其可药用盐可以通过本领域已知的技术制备,例如通过下述的方法,该方法包括使下式的化合物与下式的化合物反应或或并将羟基解保护,得到下式的化合物 并且如果需要,将所得化合物转化为可药用酸加成盐。
根据所述方法的变体,将4-苄基-3,4-二羟基-哌啶、(3R,4R)-4-苄基-3,4-二羟基-哌啶或(3S,4S)-4-苄基-3,4-二羟基-哌啶用1-苄氧基-4-(2-氯-乙氧基)-苯在K2CO3存在下处理。反应在约80-100℃下进行。然后将O-保护基用常用的方法(例如通过在Pb/C存在下氢化)脱掉。
式I化合物的酸加成盐特别适合药用。
以下方案1和2描述了式I化合物及其所需对映异构形式的制备。式III原料和1-苄氧基-4-(2-氯-乙氧基)-苯为已知的化合物或可以通过本领域已知的方法制备。
在方案1和2中采用了以下缩写:
Z-Cl 氯甲酸苄酯
MCPBA 间-氯过苯甲酸
DMAP 二甲氨基吡啶
Pd/C 碳载钯催化剂
DMF 二甲基甲酰胺
Bn 苄基
方案1 其中“hal”可以是氯或溴。
上述方法在实施例1-17中进行详述描述。
如前所述,式I化合物及其可药用加成盐具有重要的药效学特性。它们是NMDA-受体亚型选择性阻断剂,在调节神经元活性和粘性方面起着关键的作用,使其成为介导CNS发育过程及学习和记忆形成的关键角色。
该化合物按照下文的试验进行了研究。
方法1
3H-Ro 25-6981结合(Ro 25-6981是[R-(R*,S*)]-α-(4-羟基-苯基)-β-甲基-4-(苯基-甲基)-1-哌啶丙醇)
使用重量在150-200g之间的雄性Füllinsdorf albino大鼠。通过将整个脑除去小脑和延髓使用Polytron在25倍体积的冷Tris-HCl 50mM,EDTA10mM,pH7.1缓冲液中均化(10,000rpm,30秒)制备膜。组织匀浆在48,000g、4℃下离心10分钟。沉淀用Polytron重新悬浮在相同体积的缓冲液中并将组织匀浆在37℃培养10分钟。离心以后将沉淀在相同的缓冲液中均化并在-80℃下冷冻至少16小时但是不要多于10天。在结合实验中将组织匀浆在37℃解冻,离心并将沉淀在Tris-HCl 5mM,pH7.4冷缓冲液中如上所述洗涤三次。最终沉淀重新悬浮于相同的缓冲液中并在200μg蛋白质/ml的最终浓度下使用。
3H-Ro 25-6981结合实验使用Tris-HCl 5mM,pH7.4缓冲液来进行。在置换实验中使用5nM的3H-Ro 25-6981,使用10μM四氢异喹啉测量非特异性结合并且通常其占总量的10%。在4℃下培养2小时并通过使用Whatmann GF/B玻璃纤维滤器(Unifilter-96,Packard,Zürich,瑞士)过滤结束实验。滤器用冷缓冲液洗涤5次。加入40ml闪烁剂(microscint)40(Canberra Packard S.A.,Zürich,瑞士)后使用Packard Top-count微量培养板闪烁计数器计数滤器上的放射性。
化合物的效果最少使用8个浓度来测量并至少重复一次。使用非线性回归计算程序分析收集的标准化值来提供IC50及其相对的上下95%置信界限(RS1,BBN,USA)。
方法2
3H-哌唑嗪结合
使用重量在150-200g之间的雄性Fiillinsdorf albino大鼠。通过将整个脑除去小脑和延髓使用Polytron在25倍体积的冷Tris-HCl 50mM,EDTA10mM,pH7.1缓冲液中均化(10,000rpm,30秒)制备膜。组织匀浆在48,000g、4℃下离心10分钟。沉淀用Polytron重新悬浮在相同体积的缓冲液中并将组织匀浆在37℃培养10分钟。离心以后将沉淀在相同的缓冲液中均化并在-80℃下冷冻至少16小时但是不要多于10天。在结合实验中将组织匀浆在37℃解冻,离心并将沉淀在Tris-HCl 5mM,pH7.4冷缓冲液中如上所述洗涤三次。最终沉淀重新悬浮于相同的缓冲液中并在200mg蛋白质/ml的最终浓度下使用。
3H-哌唑嗪结合实验使用Tris-HCl 5mM,pH7.4缓冲液来进行。在置换实验中使用0.2nM的3H-哌唑嗪并且使用100mM氯丙嗪测量非特异性结合。室温培养30分钟并通过使用Whatmann GF/B玻璃纤维滤器(Unifilter-96,Canberra Packard S.A.,Zürich,瑞士)过滤结束实验。滤器用冷缓冲液洗涤5次。加入40ml闪烁剂(microscint)40(CanberraPackard S.A.,Zürich,瑞士)后使用Packard Top-count微量培养板闪烁计数器计数滤器上的放射性。
化合物的效果最少使用8个浓度来测量并至少重复一次。使用非线性回归计算程序分析收集的标准化值来提供IC50及其相对的上下95%置信界限(RS1,BBN,USA)。
对本发明化合物测得的活性在0.039-0.045(μM)的范围内,如上表所示。
方法3
研究抑制hERG K
+
通道的方法
使用含有用于筛选的SV40-neo盒的pcDNA3-hERG表达载体稳定转染CHO细胞。将细胞稀薄地铺于35mm的盘上并在-3天后用于电生理学实验。
在实验过程中连续使用胞外盐水(包含(mM):NaCl 150,KCl 10,MgCl21,CaCl2 3,HEPES 10(通过加入NaOH使pH=7.3)将细胞超融合(superfused)。10mM供试化合物的储备溶液由纯DMSO制得。将储备溶液至少稀释1000倍成胞外盐水制得供试溶液。使用以下物质(mM)将用于全细胞膜片嵌记录的玻璃微量移液管充满:KCl 110,BAPTA 10,HEPES10,MgCl2 4.5,Na2ATP 4,Na2-磷酸肌酸20,肌酸激酶200μg/ml(通过加入KOH使pH=7.3)。
将膜片嵌技术的全细胞构造用于实验中。将细胞夹到-80mV的维持电位并使用由1-s调节去极化至20mV紧接着持续50ms超极化至-120mV组成的电压脉冲方式(0.1Hz)反复刺激。在施用化合物之前(对照),膜电流至少记录3分钟(18次刺激),然后在存在两种不同浓度的化合物下再间隔另外两个3分钟。将各化合物施用间隔末期的电流幅度(I实验)除以初始对照阶段的平均电流幅度(I对照)来计算化合物的效果百分数:
效果(%)=(1-I实验/I对照)·100
化合物的浓度围绕期望50%抑制浓度(IC50)按照十进制(通常为1和10μM)选择。如果第一次实验后IC50结果位于两种选择浓度之间的范围之外,则在以后的实验中改变浓度使其包含IC50。化合物至少在三种细胞上试验。然后使用以下函数通过非线性回归从所有效果百分数值的统计数据中估计其IC50。
效果=100/(1-IC50/浓度)Hill)
对高于10μM的浓度没有试验。如果10μM的化合物产生小于50%的效果,则IC50标记为“>10μM”且化合物用在10μM下观察到的平均效果来表征。
本文描述的式I化合物及其盐可与药物惰性赋形剂一起组成标准的药物剂型,例如与常用的药物辅料(例如有机或无机惰性载体材料如水、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、树胶、聚亚烷基二醇等)一起用于口服或肠胃外施用。固体形式的药物制剂的例子是片剂、栓剂、胶囊或液体形式的是溶液、悬浮液或乳液。
药用辅料包括防腐剂、稳定剂、湿润剂或乳化剂、改变渗透压或作为缓冲液的盐。药物制剂也可以含有其它治疗活性物质。
式I化合物的每日给药剂量随着所用具体化合物、选定的给药途径和接受者而变化。式I化合物的代表性给药方法是口服和肠胃外给药途径。式I化合物的口服配方优选对成年人的给药剂量在1mg-1000mg/日的范围内。式I化合物的肠胃外配方优选对成年人的给药剂量在5-500mg/目的范围内。
本发明在以下的实施例中进一步说明。
实施例1
4-苄基-4-羟基-哌啶-1-羧酸苄酯
向5g(26.2mmol)4-羟基苄基哌啶于50mlCH2Cl2中的溶液中在氩气下于0℃加入5.5ml(39.3mmol)Et3N和3.7ml(26.2mmol)氯甲酸苄酯。室温搅拌反应混合物3小时以后加入100ml 1N HCl并将水相用CH2Cl2萃取两次,然后将合并的有机层用50ml水洗涤,用MgSO4干燥并减压除去溶剂,得到粗产物。用层析法在硅胶上纯化(己烷/乙酸乙酯4∶1-2∶1),得到3.9g黄色油状4-苄基-4-羟基-哌啶-1-羧酸苄酯(11.9mmol,48%)。
MS:m/e=326(M+1)
实施例2
4-苄基-3,6-二氢-2H-吡啶-1-羧酸苄酯
向40.0g(123mmol)4-苄基-4-羟基-哌啶-1-羧酸苄酯于250ml CH2Cl2中的溶液中加入39.6ml(492mmol)吡啶并在0℃加入17.8ml(246mmol)SOCl2。将反应混合物在0℃搅拌30分钟,然后加入250ml 2N盐酸。将水相用CH2Cl2萃取两次并水洗合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到36.3g(118mmol,96%)橙色油状4-苄基-3,6-二氢-2H-吡啶-1-羧酸苄酯。
MS:m/e=308(M+1)
实施例3
(1R,6S)和(1S,6R)-6-苄基-7-氧杂-3-氮杂-二环[4.1.0l庚烷-3-羧酸苄酯
向36.0g(117mmol)4-苄基-3,6-二氢-2H-吡啶-1-羧酸苄酯于250mlCH2Cl2中的溶液中加入40.9g(166mmol,~70%)MCPBA。将反应混合物搅拌2小时并加入1N NaOH溶液。将水相用CH2Cl2萃取两次并用1NNaOH洗涤合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到36.7g(116mmol,99%)油状(1R,6S)和(1S,6R)-6-苄基-7-氧杂-3-氮杂-二环[4.1.0]庚烷-3-羧酸苄酯。
MS:m/e=324(M+1)
实施例4
(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯
向37.6g(116mmol)(1R,6S)和(1S,6R)-6-苄基-7-氧杂-3-氮杂-二环[4.1.0]庚烷-3-羧酸苄酯于170mlTHF中的溶液中加入37mlH2SO4(10%)。将反应混合物搅拌16小时,然后减压浓缩。将残余物溶于乙酸乙酯并用饱和NaHCO3萃取。将水相用乙酸乙酯萃取两次并用饱和NaHCO3洗涤合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到40.8g(100%,纯度~95%)的粗(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯。
MS:m/e=342(M+1)
实施例5
(4R,4R),4-苄基-4-羟基-3-((2S)-三氟乙酰基-环戊烷羰氧基)哌啶-1-
羧酸苄酯
向43.0g(126mmol)(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯和23.1g(189mmol)DMAP于600mlCH2Cl2中的溶液中在氩气下滴加入500ml(340mmol,0.70N)(S)-N-三氟乙酰基-脯氨酰氯。将反应混合物室温搅拌16小时,然后加入饱和NaHCO3溶液。将水相用CH2Cl2萃取三次并用饱和NaHCO3和1N HCl洗涤合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到粗产物。用层析法在硅胶上纯化(己烷∶乙酸乙酯4∶1-1∶1)并从二乙醚中结晶,得到17.9g(33mmol,27%)的(3R,4R),4-苄基-4-羟基-3-((2S)-三氟乙酰基-环戊烷羰氧基)哌啶-1-羧酸苄酯。
MS:m/e=535(M+1),(c=1.11,CH2Cl2)。
实施例6
(3S,4S),4-苄基-4-羟基-3-((2S)-三氟乙酰基-环戊烷羰氧基)哌啶-1-羧
酸苄酯
向43.0g(126mmol)(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯和23.1g(189mmol)DMAP于600ml CH2Cl2中的溶液中在氩气下滴加入500ml(340mmol,0.70N)(S)-N-三氟乙酰基-脯氨酰氯。将反应混合物室温搅拌16小时,然后加入饱和NaHCO3溶液。将水相用CH2Cl2萃取三次并用饱和NaHCO3和1N HCl洗合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到粗产物。用层析法在硅胶上纯化(己烷∶乙酸乙酯4∶1-1∶1)并从二乙醚中结晶,得到14.3g(27mmol,21%)的(3S,4S)-4-苄基-4-羟基-3-((2S)-三氟乙酰基-环戊烷羰氧基)哌啶-1-羧酸苄酯。
MS:m/e=535(M+1),(c=1.11,CH2Cl2)。
实施例7
(3R,4R)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯
向17.9g(33.5mmol)(3R),(4R),4-苄基4羟基-3-((2S)-三氟乙酰基-环戊烷羰氧基)哌啶-1-羧酸苄酯于500ml EtOH中的溶液中加入250ml(250mmol)1N NaOH。将反应混合物搅拌16小时,然后加入水。将水相用CH2Cl2萃取三次并水洗合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到11.2g(32.8mmol,98%)的油状(3R,4R)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯。
MS:m/e=342.3(M+1),[α]D 20=-36.75(c=1.02,CH2Cl2)。
实施例8
(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯
向14.3g(27mmol)(3S,4S)-4-苄基-4-羟基-3-((2S)-三氟乙酰基-环戊烷羰氧基)哌啶-1-羟酸苄酯于500ml EtOH中的溶液中加入250ml(250mmol)1NNaOH。将反应混合物搅拌16小时后加入水。将水相用CH2Cl2萃取三次并水洗合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到8.4g(25mmol,92%)的油状(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯。
MS:m/e=342.3(M+1),[α]D 20=35.30(c=1.02,CH2Cl2)。
实施例9
(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶
将(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯1.46g(4.3mmol)溶于30ml EtOH中并在400mg Pd/C(10%)存在下在大气压力的H2下室温氢化。16小时以后结束反应并滤出催化剂,然后减压除去溶剂,得到796mg(3.8mmol,89%)的油状(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶。
MS:m/e=207.1(M)
实施例10
(3R,4R)-4-苄基-3,4-二羟基-哌啶
将(3R,4R)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯11.0g(32mmol)溶于250ml EtOH中并在1.1gPd/C(10%)存在下在大气压力的H2下室温氢化。16小时以后结束反应并滤出催化剂,然后减压除去溶剂,得到6.6g(32mmol,100%)的油状(3R,4R)-4-苄基-3,4-二羟基-哌啶。
MS:m/e=207.1(M),[α]D 20=-42.3(c=1.00,乙醇)。
实施例11
(3S),(4S)-4-苄基-3,4-二羟基-哌啶
将(3S,4S)-4-苄基-3,4-二羟基-哌啶-1-羧酸苄酯8.2g(24mmol)溶于250ml EtOH中并在1.1g Pd/C(10%)存在下在大气压力下室温氢化。16小时以后结束反应并滤出催化剂,然后减压除去溶剂,得到5.5g(定量,~95%纯度)的油状(3S,4S)-4-苄基-3,4-二羟基-哌啶。
MS:m/e=207.1(M),[α]D 20=+42.57(c=1.05,乙醇)。
实施例12
(3R,4R)和(3S,4S)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-
二醇
向0.2g(1.0mmol)(3R,4R)和(3S,4S)-4-苄基-3,4-二羟基-哌啶于10mlDMF中的溶液中加入297mg(1.0mmol)1-苄氧基-4-(2-氯-乙氧基)-苯和0.2g(1.5mmol)K2CO3,将反应混合物加热到90℃并保持16小时。加入水后,将水相用乙酸乙酯萃取三次并水洗合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到551mg(100%,~80%纯度)的固体(3R,4R)和(3S,4S)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇。
MS:m/e=434.5(M+1)
实施例13
(3R,4R)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇向5.0g(24mmol)(3R,4R)-4-苄基-3,4-二羟基-哌啶于150ml DMF中的溶液中加入7.4g(24mmol)1-苄氧基-4-(2-氯-乙氧基)-苯和5.0g(36mmol)K2CO3,将反应混合物加热到90℃并保持72小时。加入水后,将水相用乙酸乙酯萃取三次并水洗合并的有机层,用MgSO4干燥有机层并减压除去溶剂,得到10.5g(24mmol,100%)的固体(3R,4R)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇。
MS:m/e=434.5(M+1),[α]D 20=-27.5(c=0.95,CH2Cl2)。
实施例14
(3S,4S)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇
向5.0g(24mmol)(3S,4S)-4-苄基-3,4-二羟基-哌啶于150ml DMF中的溶液中加入7.4g(24mmol)1-苄氧基-4-(2-氯-乙氧基)-苯和5.0g(36mmol)K2CO3,将反应混合物加热到90℃并保持72小时。加入水后,将水相用乙酸乙酯萃取三次并水洗合并的有机层,MgSO4干燥有机层并减压除去溶剂,得到10.9g(定量,~95%纯度)的固体(3S,4S)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇。
MS:m/e=434.5(M+1),[α]D 20=+26.2(c=1.04,CH2Cl2)。
实施例15
(3R,4R)和(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二
醇
将(3R,4R)和(3S,4S)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇550mg(1.3mmol)溶于10ml EtOH中并在100mgPd/C(10%)存在下在大气压力和50℃下氢化。4小时以后结束反应并滤出催化剂,然后减压除去溶剂,得到粗产物。使用层析法(CH2Cl2/MeOH 9∶1)纯化,得到249mg(0.73mmol,56%)固体(3R,4R)和(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇。
MS:m/e=344.4(M+1)
实施例16
(3R,4R)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇
将(3R,4R)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇10.3g(24mmol)溶于300ml EtOH中并在1.1gPd/C(10%)存在下在大气压力和50℃下氢化。4小时以后结束反应并滤出催化剂,然后减压除去溶剂,得到粗产物。使用层析法(CH2Cl2/MeOH 10∶1)纯化并从乙酸乙酯和己烷中结晶,得到4.6g(10.6mmol,45%)固体(3R,4R)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇。
MS:m/e=344.4(M+1),[α]D 20=-36.2(c=1.03,CH2Cl2)。
实施例17
(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇
将(3S,4S)-4-苄基-1-[2-(4-苄氧基-苯氧基)-乙基]-哌啶-3,4-二醇10.3g(24mmol)溶于300mlEtOH中并在1.1gPd/C(10%)存在下在大气压力和50℃下氢化。4小时以后结束反应并滤出催化剂,然后减压除去溶剂,得到粗产物。使用层析法(CH2Cl2/MeOH 10∶1)纯化并从乙酸乙酯和己烷中结晶,得到5.7g(16.6mmol,69%)固体(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇。
MS:m/e=344.3(M+1),[α]D 20=+37.1(c=1.04,CH2Cl2)。
实施例A
片剂配方(湿法造粒)成分 mg/片1.活性化合物 5 25 100 5002.无水乳糖DTG 125 105 30 1503.Sta-Rx 1500 6 6 6 304.微晶纤维素 30 30 30 1505.硬脂酸镁 1 1 1 1
总共 167 167 167 831
制备过程1.将第1、2、3和4项混合并用纯化水造粒。2.在50℃下干燥颗粒。3.将颗粒通过合适的研磨装置。4.加入第5项并混合3分钟;在合适的压片机上压片。
胶囊配方
成分 mg/胶囊1.活性化合物 5 25 100 5002.含水乳糖 159 123 148 ---3.玉米淀粉 25 35 40 704.滑石 10 15 10 255.硬脂酸镁 1 2 2 5
总共 200 200 300 600
制备过程1.将第1、2和3项在合适的混合器中混合30分钟。2.加入第4和5项并混合3分钟。3.填充到合适的胶囊中。
Claims (11)
1.一种下式的化合物其R,R-和S,S-对映体及其可药用酸加成盐。
2.根据权利要求1的式I化合物,为(4R,3R)和(4S,3S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇。
3.根据权利要求1的式I化合物,为(3R,4R)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇。
4.根据权利要求1的式I化合物,为(3S,4S)-4-苄基-1-[2-(4-羟基-苯氧基)-乙基]-哌啶-3,4-二醇。
5.一种药物,含有一种或多种根据权利要求1-4中任意一项的化合物和药物惰性赋形剂。
6.根据权利要求5的药物,用于治疗包括以下的疾病:由中风或脑外伤引起的急性神经变性;慢性神经变性,例如阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病或ALS(肌萎缩性侧索硬化症);与细菌或病毒感染有关的神经变性及诸如神经分裂症、焦虑、抑郁症及急/慢性疼痛的疾病。
8.根据权利要求1-4中任意一项的化合物,由权利要求7所要求的方法或由等同方法制备。
9.根据权利要求1-4中任意一项的式I化合物在治疗疾病中的用途。
10.根据权利要求1-4中任意一项的式I化合物在制备用于治疗疾病的药物中的用途,其中治疗适应症包括由中风或脑外伤引起的急性神经变性;慢性神经变性,例如阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病或ALS(肌萎缩性侧索硬化症);与细菌或病毒感染有关的神经变性及诸如神经分裂症、焦虑、抑郁症及急/慢性疼痛的疾病。
11.本文前面所述的发明。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00108769 | 2000-04-25 | ||
EP00108769.1 | 2000-04-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1443166A true CN1443166A (zh) | 2003-09-17 |
CN1178914C CN1178914C (zh) | 2004-12-08 |
Family
ID=8168543
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018085911A Expired - Fee Related CN1178914C (zh) | 2000-04-25 | 2001-04-17 | 4-苄基-1-[2-(4-羟基-苯氧基)乙基]-哌啶-3,4-二醇 |
Country Status (18)
Country | Link |
---|---|
US (1) | US6432985B2 (zh) |
EP (1) | EP1278730B1 (zh) |
JP (1) | JP3831255B2 (zh) |
KR (1) | KR100527527B1 (zh) |
CN (1) | CN1178914C (zh) |
AR (1) | AR028357A1 (zh) |
AT (1) | ATE313527T1 (zh) |
AU (1) | AU785153B2 (zh) |
BR (1) | BR0110233A (zh) |
CA (1) | CA2407345C (zh) |
DE (1) | DE60116080T2 (zh) |
DK (1) | DK1278730T3 (zh) |
ES (1) | ES2254422T3 (zh) |
MX (1) | MXPA02010573A (zh) |
PE (1) | PE20011229A1 (zh) |
UY (1) | UY26681A1 (zh) |
WO (1) | WO2001081309A2 (zh) |
ZA (1) | ZA200208134B (zh) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7684859B2 (en) | 2002-04-25 | 2010-03-23 | Brainsgate Ltd. | Stimulation of the OTIC ganglion for treating medical conditions |
US7005432B2 (en) * | 2002-05-16 | 2006-02-28 | Hoffman-La Roche Inc. | Substituted imidazol-pyridazine derivatives |
JP2006515999A (ja) | 2002-11-14 | 2006-06-15 | ブレインズゲート リミティド | 刺激のための外科用ツール及び技法 |
US8010189B2 (en) * | 2004-02-20 | 2011-08-30 | Brainsgate Ltd. | SPG stimulation for treating complications of subarachnoid hemorrhage |
US8055347B2 (en) | 2005-08-19 | 2011-11-08 | Brainsgate Ltd. | Stimulation for treating brain events and other conditions |
US9233245B2 (en) | 2004-02-20 | 2016-01-12 | Brainsgate Ltd. | SPG stimulation |
WO2007076875A2 (en) * | 2006-01-06 | 2007-07-12 | Aarhus Universitet | Compounds acting on the serotonin transporter |
JP5466147B2 (ja) * | 2007-05-21 | 2014-04-09 | レビバ ファーマシューティカルズ,インコーポレーテッド | キノリノン系非定型抗精神病薬剤の組成物、合成、及び使用方法 |
US8008253B2 (en) * | 2007-07-03 | 2011-08-30 | Andrew Tasker | Treatment for anxiety |
US7860569B2 (en) | 2007-10-18 | 2010-12-28 | Brainsgate, Ltd. | Long-term SPG stimulation therapy for prevention of vascular dementia |
JP2011516417A (ja) * | 2008-03-27 | 2011-05-26 | エヴォテック・ノイロサイエンシーズ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Nmdanr2b−サブタイプ選択的アンタゴニストを使用する障害の処置方法 |
US8846315B2 (en) | 2008-08-12 | 2014-09-30 | Zinfandel Pharmaceuticals, Inc. | Disease risk factors and methods of use |
BRPI0917948A2 (pt) | 2008-08-12 | 2017-06-20 | Zinfandel Pharrmaceuticals Inc | métodos de identificar uma variante genética que está associada com o desenvolvimento de uma condição de interesse e um paciente em um ensaio clínico de um tratamento para doença de alzheimer, de determinar riscos incrementando de desenvolvimento de uma condição de interesse, doença de alzheimer em um paciente, de um prognóstico ou o risco de desenvolver doença de alzheimer em um paciente, de tratar um paciente para doença de alzheimer, uma condição de interesse e doença de alzheimer em um paciente, de estratificar um paciente em um subgrupo de um ensaio clínico de uma terapia para o tratamento de doença de alzheimer, uso de um agente ativo anti-doença de alzheimer e kits para determinar se um paciente encontra-se em risco incrementado de desenvolver doença de alzheimer e se um paciente é responsivo a tratamento para uma condição de interesse |
CN107362165A (zh) | 2011-01-10 | 2017-11-21 | 金帆德尔制药股份有限公司 | 用于治疗阿尔茨海默病的方法和药物产品 |
US8703763B2 (en) * | 2011-03-02 | 2014-04-22 | Hoffmann-La Roche Inc. | Bridged piperidine derivatives |
EP2878335B1 (en) | 2013-11-10 | 2018-01-03 | Brainsgate Ltd. | Implant and delivery system for neural stimulator |
WO2016100940A1 (en) | 2014-12-19 | 2016-06-23 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
US10752588B2 (en) | 2014-12-19 | 2020-08-25 | The Broad Institute, Inc. | Dopamine D2 receptor ligands |
US10271907B2 (en) | 2015-05-13 | 2019-04-30 | Brainsgate Ltd. | Implant and delivery system for neural stimulator |
CN109790149B (zh) * | 2016-11-08 | 2022-05-17 | 豪夫迈·罗氏有限公司 | 苯氧基三唑类化合物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA9610745B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
TW498067B (en) | 1996-07-19 | 2002-08-11 | Hoffmann La Roche | 4-hydroxy-piperidine derivatives |
-
2001
- 2001-03-19 US US09/811,888 patent/US6432985B2/en not_active Expired - Fee Related
- 2001-04-17 MX MXPA02010573A patent/MXPA02010573A/es active IP Right Grant
- 2001-04-17 CN CNB018085911A patent/CN1178914C/zh not_active Expired - Fee Related
- 2001-04-17 JP JP2001578404A patent/JP3831255B2/ja not_active Expired - Fee Related
- 2001-04-17 DE DE60116080T patent/DE60116080T2/de not_active Expired - Lifetime
- 2001-04-17 BR BR0110233-8A patent/BR0110233A/pt not_active Application Discontinuation
- 2001-04-17 EP EP01933833A patent/EP1278730B1/en not_active Expired - Lifetime
- 2001-04-17 CA CA002407345A patent/CA2407345C/en not_active Expired - Fee Related
- 2001-04-17 ES ES01933833T patent/ES2254422T3/es not_active Expired - Lifetime
- 2001-04-17 WO PCT/EP2001/004305 patent/WO2001081309A2/en active IP Right Grant
- 2001-04-17 AT AT01933833T patent/ATE313527T1/de not_active IP Right Cessation
- 2001-04-17 KR KR10-2002-7014261A patent/KR100527527B1/ko not_active IP Right Cessation
- 2001-04-17 AU AU60213/01A patent/AU785153B2/en not_active Ceased
- 2001-04-17 DK DK01933833T patent/DK1278730T3/da active
- 2001-04-19 PE PE2001000359A patent/PE20011229A1/es not_active Application Discontinuation
- 2001-04-23 AR ARP010101869A patent/AR028357A1/es active IP Right Grant
- 2001-04-24 UY UY26681A patent/UY26681A1/es not_active Application Discontinuation
-
2002
- 2002-10-09 ZA ZA200208134A patent/ZA200208134B/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN1178914C (zh) | 2004-12-08 |
PE20011229A1 (es) | 2001-12-08 |
UY26681A1 (es) | 2001-10-25 |
BR0110233A (pt) | 2003-01-21 |
CA2407345C (en) | 2009-04-07 |
WO2001081309A2 (en) | 2001-11-01 |
ATE313527T1 (de) | 2006-01-15 |
EP1278730A2 (en) | 2003-01-29 |
AR028357A1 (es) | 2003-05-07 |
KR100527527B1 (ko) | 2005-11-09 |
ES2254422T3 (es) | 2006-06-16 |
JP2004509837A (ja) | 2004-04-02 |
DE60116080D1 (de) | 2006-01-26 |
US6432985B2 (en) | 2002-08-13 |
DK1278730T3 (da) | 2006-05-01 |
ZA200208134B (en) | 2004-01-22 |
EP1278730B1 (en) | 2005-12-21 |
DE60116080T2 (de) | 2006-08-24 |
AU785153B2 (en) | 2006-10-05 |
WO2001081309A3 (en) | 2002-01-17 |
AU6021301A (en) | 2001-11-07 |
JP3831255B2 (ja) | 2006-10-11 |
MXPA02010573A (es) | 2003-03-10 |
KR20040007216A (ko) | 2004-01-24 |
CA2407345A1 (en) | 2001-11-01 |
US20010047014A1 (en) | 2001-11-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1178914C (zh) | 4-苄基-1-[2-(4-羟基-苯氧基)乙基]-哌啶-3,4-二醇 | |
US11708326B2 (en) | Immunomodulator compounds | |
US6020346A (en) | Piperidine derivatives having tachykinin antagonist activity | |
DE60106287T2 (de) | Chemische verbindungen | |
DE69925730T2 (de) | 4-benzyl-piperidin-alkylsulfoxid-heterozyklen und ihre verwendung als subtyp-selektive nmda rezeptor antagonisten | |
RU2351588C2 (ru) | Производные n-фенил(пиперидин-2-ил)метил-бензамида и их применение в терапии | |
US5716961A (en) | Treatment of tinnitus using neuroprotective agents | |
EP1870405A1 (en) | Carbonylated (Aza)cyclohexanes as dopamine D3 receptor ligands | |
JP2002541104A (ja) | ピロリジン系ケモカイン受容体活性調節剤 | |
JP2005537293A (ja) | N−[フェニル(ピペリジン−2−イル)メチル]ベンズアミド誘導体、その製造法、およびその治療用途 | |
EP1277737A1 (en) | Diphenylalkylamine derivatives useful as opioid delta receptor agonists | |
CN1142141C (zh) | 乙磺酰基哌啶衍生物 | |
JP2006527236A (ja) | オピオイド鎮痛薬と組合せた置換1,4−ジ−ピペリジン−4−イル−ピペラジン誘導体ならびに疼痛およびオピオイドに基づく処置に伴う副作用の処置のためのそれらの使用 | |
US20060252797A1 (en) | Receptor regulator | |
DE60204015T2 (de) | Piperidincarboxamid-derivate, ein verfahren zu ihrer herstellung und sie enthaltende zusammensetzungen | |
CN1131862C (zh) | 经吡咯烷基、哌啶基或高哌啶基取代的(苯并二噁烷,苯并呋喃或苯并吡喃)衍生物 | |
CN102648179A (zh) | 作为趋化因子受体活性调节剂的哌啶基衍生物的前药 | |
CN102317280A (zh) | 具有胃动素受体激动活性的羟基吲哚衍生物 | |
RU2272027C2 (ru) | Производные 3-гидроксипиперидина и фармацевтическая композиция на их основе | |
EP1785415B1 (en) | Piperidine derivative or pharmaceutically acceptable salt thereof | |
CA2290392C (en) | Salts of optically active sulfoxide derivative | |
JP2993124B2 (ja) | 1,4−ジ置換ピペリジン誘導体 | |
ES2426915T3 (es) | Diastereoisómeros de 4-ariloxi-3-hidroxipiperidinas | |
JP2007091732A (ja) | チオモルホリン化合物及びその製法 | |
JP2010031063A (ja) | 医薬組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20041208 Termination date: 20110417 |