CN116535354A - 作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 - Google Patents
作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 Download PDFInfo
- Publication number
- CN116535354A CN116535354A CN202210089806.7A CN202210089806A CN116535354A CN 116535354 A CN116535354 A CN 116535354A CN 202210089806 A CN202210089806 A CN 202210089806A CN 116535354 A CN116535354 A CN 116535354A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- cycloalkyl
- halogen
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Aromatic ring heterocyclic compound Chemical class 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 102100034364 Potassium channel regulatory protein Human genes 0.000 title abstract description 6
- 101710120306 Potassium channel regulatory protein Proteins 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 125000001424 substituent group Chemical group 0.000 claims abstract description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- 229910052736 halogen Inorganic materials 0.000 claims description 82
- 150000002367 halogens Chemical class 0.000 claims description 82
- 150000002431 hydrogen Chemical class 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 58
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 56
- 125000003545 alkoxy group Chemical group 0.000 claims description 51
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 22
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052805 deuterium Inorganic materials 0.000 claims description 21
- 102000004257 Potassium Channel Human genes 0.000 claims description 18
- 108020001213 potassium channel Proteins 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 238000002601 radiography Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 4
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- 239000004973 liquid crystal related substance Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 208000015114 central nervous system disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229960003312 retigabine Drugs 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 206010010904 Convulsion Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108091006146 Channels Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 108010006746 KCNQ2 Potassium Channel Proteins 0.000 description 3
- 102000005453 KCNQ2 Potassium Channel Human genes 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 239000003995 emulsifying agent Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000012160 loading buffer Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 208000008882 Benign Neonatal Epilepsy Diseases 0.000 description 2
- 206010067866 Benign familial neonatal convulsions Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 206010011878 Deafness Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 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
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 201000003452 benign familial neonatal epilepsy Diseases 0.000 description 2
- 201000010295 benign neonatal seizures Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 208000016354 hearing loss disease Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 2
- 229960003081 probenecid Drugs 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- MLFIYYDKLNZLAO-UHFFFAOYSA-N 2-aminoethane-1,1-diol Chemical compound NCC(O)O MLFIYYDKLNZLAO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 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 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 208000012639 Balance disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010053398 Clonic convulsion 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101000745167 Homo sapiens Neuronal acetylcholine receptor subunit alpha-4 Proteins 0.000 description 1
- 101000994667 Homo sapiens Potassium voltage-gated channel subfamily KQT member 2 Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108010011185 KCNQ1 Potassium Channel Proteins 0.000 description 1
- 102000014021 KCNQ1 Potassium Channel Human genes 0.000 description 1
- 108010038888 KCNQ3 Potassium Channel Proteins 0.000 description 1
- 102000015686 KCNQ3 Potassium Channel Human genes 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 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
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000735234 Ligustrum Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OEHCXDNEGABFEZ-UHFFFAOYSA-N O1CCCC1.[Li].[AlH3] Chemical compound O1CCCC1.[Li].[AlH3] OEHCXDNEGABFEZ-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 231100000895 deafness Toxicity 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 210000004905 finger nail Anatomy 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002780 ion channel assay Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 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
- 239000007788 liquid Substances 0.000 description 1
- 208000004731 long QT syndrome Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003094 microcapsule Substances 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
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000010004 neural pathway Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 208000027765 speech disease Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000014221 sudden cardiac arrest Diseases 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Abstract
本发明涉及作为钾通道调节剂的芳环并杂环类化合物及其制备和应用。具体地,本发明化合物具有式I所示结构,其中各基团和取代基的定义如说明书中所述。本发明还公开了所述化合物的制备方法及其作为钾通道调节剂的用途。
Description
技术领域
本发明涉及生物医药领域,具体地涉及作为钾通道调节剂的芳环并杂环类 化合物及其制备和应用。
背景技术
Kv7钾通道是一类电压依赖性钾离子通道,具有低阈值激活、慢激活和非 失活的特点。Kv7钾通道具有五个家族成员(Kv7.1-Kv7.5),所有的Kv7钾通道成 员具有相似的拓扑学结构,即由四个亚基组成一个功能性通道,每个亚基包含 六个跨膜片段(S1-S6)。其中S4是电压感受区,在感受膜电位变化和控制构象改 变等方面具有重要作用;SS-S6是通道孔区的主要组成部分,是钾通道开放剂 的主要组合和作用区域。KV7.1钾通道是一种非神经元通路,分布于外周组织, 在心脏中表达,以介导心肌Iks,其突变可导致Long Q-T综合征。Kv7.2-Kv7.5 钾通道是神经元M电流的基础,广泛分布于神经系统中,具有多种生理活性。 Kv7.2和Kv7.3钾通道基因突变可导致多种不同的癫痫表型,如良性家族性新生 儿惊厥(Benign familial neonatal convulsions,BFNC),这些充分说明了M电流在 调节神经元兴奋性中的作用。Kv7.4钾通道高度表达于耳蜗和脑干听觉核的外毛 细胞,其突变可能导致遗传性耳聋。Kv7.5钾通道在骨骼肌和脑中高度表达,其 突变可能导致视网膜病变。许多疾病如癫痫、焦虑、耳聋等,它们的共同特征 是膜高度兴奋性,而Kv7钾通道作为M电流的分子基础,可通过感受膜电位的 变化而开放,使抑制性钾电流上调,从而控制膜兴奋性,使得Kv7钾通道在以 神经高度兴奋性为代表的疼痛和精神疾病中具有重要意义。
瑞替加滨(Retigabine)是治疗癫痫的药物,目前已经在英国、德国、丹麦 获准上市。研究证实,瑞替加滨的作用与电压门控型钾离子通道(KCNQs)有 关,其中作用于KCNQ2/3通道调节M型钾电流是其主要的作用机制。
瑞替加滨(RTG)是在2011年上市的首个用于辅助治疗成人部分发作性癫 痫的Kv7钾通道开放剂。除具有抗癫痫作用外,RTG还可用于治疗焦虑症、神 经痛、神经退行性疾病等。RTG在多种癫痫模型中均能有效地减少或阻止癫痫 发作。RTG对最大电休克(MES)模型导致的强直性发作和PTZ诱发的阵挛性发作 均表现出有效的抗癫痫作用。此外,RTG还可阻止N-甲基-D-天冬氨酸 (N-methyl-D-aspartate,NMDA)、青霉素、印防己毒素、海人酸(Kainic acid,KA) 等所致的癫痫发作。点燃模型适用于多种抗癫痫药物的筛选,RTG对该模型的 效果要强于其它模型。由于RTG对所有的Kv7钾通道成员和其它通道的广泛作 用,选择性较差,使得它具有潜在的不良作用。大量文献报道了RTG与中枢神 经系统相关的不良事件发生率较高,可导致头晕、疲劳、失语、言语障碍、平 衡障碍等其它不良反应包括肾结石、尿潴留等肾脏和泌尿系统疾病,心脏骤停、 短暂的非持续性室性心动过速等心脏相关疾病,还可导致视网膜变色、皮肤、 指甲等蓝/紫色色素沉着等。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和其作为钾通道 调节剂的用途。
本发明的第一方面,提供了一种式I所示的化合物或其药学上可接受的盐,
其中,
A环选自下组:C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱 和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基;
各R1、R2独立地选自取代或未取代的下组基团:氢、氘、卤素、氰基、-OH、 -COOH、硝基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6烯基、C2-6炔基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、 C6-10芳基、含1-3个选自N、O或S的杂原子的5-14元杂芳基、C6-12芳烷基、-N(R1’)(R2’)、 -C(O)-R1’、-C(O)-N(R1’)(R2’)、-C(O)-OR1’、-N(R1’)-C(O)-R2’、-S(O)m-R1’、 -S(O)m-N(R1’)(R2’)、-S(O)m-OR1’、-N(R1’)-S(O)m-R2’,所述取代指被选自下组的一 个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、 卤代C1-6烷基、卤代C3-6环烷基、卤代C1-6烷氧基、卤代C3-6环烷基氧基;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基、C3-6环烷基,或R1’、R2’与其共同 连接的N原子形成饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基; 上述烷基、环烷基、杂环基任选地被选自下组的一个或多个取代基取代:=O、卤 素、C1-6烷基、C3-6环烷基;
m选自下组:1、2;
X选自下组:C、CR8、N;
各R8独立地选自下组:H、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基;上述 烷基、环烷基任选地被选自下组的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基;
V选自下组:-C(R9)(R10)-、-N(R8)-;
n”选自下组:0、1;
R9、R10独立地选自下组:氢、卤素、C1-6烷基,或R9、R10与其共同连接的C 原子形成C3-6环烷基;
B环选自下组:饱和或不饱和的C3-10环烃基、饱和或不饱和的含1-3个选自N、 O或S的杂原子的3-10元杂环基;
R6、R7独立地选自下组:氢、氘、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C3-6卤代环烷基;
Y选自下组:CR8、N;
W选自下组:CR11、N;
R11选自下组:氢、氘、卤素、氰基、氨基、C1-6烷基、C3-6环烷基、C1-6烷氧 基、C3-6环烷基氧基、-N(R1’)(R2’);上述烷基、环烷基、烷氧基任选地被选自下组 的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基;
R4、R5独立地选自下组:氢、氘、卤素、氰基、氨基、C1-6烷基、C3-6环烷基、 C1-6烷氧基、C3-6环烷基氧基、-N(R1’)(R2’);上述烷基、环烷基、烷氧基任选地被 选自下组的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基;
U选自下组:O、S、N(R1’);
Z选自下组:O、-(CH2)q-、-N(R1’)-;
q选自下组:0、1、2;
R3选自下组:C1-6烷基、C3-6环烷基、C5-8桥环基、金刚烷基、C6-10芳基、含1-3 个选自N、O或S的杂原子的3-10元杂芳基、含1-3个选自N、O或S的杂原子的4-8元 杂环烷基、C3-6环烯基、C2-6烯基、C2-6炔基,上述烷基、环烷基、桥环基、金刚烷 基、芳基、杂芳基、杂环烷基、环烯基、烯基、炔基任选地被选自下组的一个或多 个取代基取代:氢、卤素、氰基、硝基、氨基、羟基、C1-6烷基-CO-、C1-6烷基、 C3-6环烷基、C6-10芳基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基氨基、C1-6卤代烷氧基。
在另一优选例中,
A环选自下组:C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基;
各R1、R2独立地选自取代或未取代的下组基团:氢、氘、卤素、氰基、C1-6烷 基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6烯基、C2-6炔基、-N(R1’)(R2’), 所述取代指被选自下组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基、C3-6环烷基;上述烷基、环烷基任 选地被选自下组的一个或多个取代基取代:卤素;
X为C;
V为CH2;
n”选自下组:0、1;
B环为饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基;
R6、R7独立地选自下组:氢、氘;
Y为N;
W选自下组:CR11、N;
R11选自下组:氢、卤素、C1-6烷基;上述烷基任选地被选自下组的一个或多个 取代基取代:卤素;
R4、R5独立地选自下组:氢、卤素、氰基、氨基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基;上述烷基、环烷基、烷氧基任选地被选自下组的一个或 多个取代基取代:卤素;
U为O;
Z选自下组:O、CH2;
R3选自下组:C1-6烷基、C3-6环烷基、C5-8桥环基、C2-6炔基;上述烷基、环烷 基、桥环基、炔基任选地被选自下组的一个或多个取代基取代:氢、卤素、C1-6烷 基、C3-6环烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基。
在另一优选例中,
A环为C6-10芳基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C3-6环 烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下 组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
V为CH2;
n”选自下组:0、1;
B环为饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基;
R6、R7独立地选自下组:氢、氘;
Y为N;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任 选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为CH2;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下 组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,B环选自下组:
在另一优选例中,R3选自下组:C3-6环烷基、C5-8桥环基。
在另一优选例中,R3选自下组:C3-6环烷基、C5-8桥环基,上述环烷基、桥环 基被选自下组的一个或多个取代基取代:卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,所述化合物不包含以下化合物:
在另一优选例中,
A环为苯基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C1-6烷 氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代: 卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
n”为0;
B环选自下组:
R6、R7独立地选自下组:氢、氘;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任 选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为-CH2-;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下 组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,
A环为苯基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C1-6烷 氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代: 卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
n”为0;
B环选自下组:
R6、R7独立地选自下组:氢、氘;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任 选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为-CH2-;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下 组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,
A环为苯基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C1-6烷 氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代: 卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
V为-CH2-;
n”为1;
B环选自下组:
R6、R7独立地选自下组:氢、氘;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任 选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为-CH2-;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下 组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,所述化合物选自下组:
本发明的第二方面,提供了一种药物组合物,包含一种或多种药学上可接受 的载体和安全有效量的一种或多种本发明第一方面所述的化合物或其药学上可接 受的盐。
本发明的第三方面,提供了一种本发明第一方面所述的化合物或其药学上可 接受的盐的用途,用于制备用于预防和/或治疗对钾离子通道敏感的疾病的药物。
在另一优选例中,所述对钾离子通道敏感的疾病为中枢神经系统疾病。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例) 中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方 案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,通过结构优化,意外地制备了一种具有 优异的钾通道开放活性、药代动力学(如脑血比性能等)、体内药效和安全性 且结构新颖的式I所示化合物。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含 义。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,“C1-6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如 甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基 团。
在本发明中,术语“C2-6烯基”是指具有2-6个碳原子的含有一个双键的直链 或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和 己烯基等。
在本发明中,术语“C2-6炔基”是指具有2-6个碳原子的含有一个三键的直链 或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和 己炔基等。
在本发明中,术语“C3-6环烃基”包括选自下组的基团:C3-6环烷基、C3-6环烯 基、C3-6环炔基。
在本发明中,术语“C3-6环烷基”是指在环上具有3-6个碳原子的环状烷基, 非限制性地包括环丙基、环丁基、环戊基、环己基等。
在本发明中,术语“C5-8桥环基”是指具有桥且具有5-8个碳原子的环状烷基, 非限制性地包括等。
在本发明中,术语“C1-6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基, 非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-4烷氧基。
在本发明中,术语“杂环基”为含1、2或3个选自N、O、S的杂原子的4-8 元杂环基,包括(但并不限于)如下基团:
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选为“C6-10芳基”。 术语“C6-10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基,如 苯基、萘基等。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到 多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1~4个选自氧、硫 和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括:呋喃基、 噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、 四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体 结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“卤代”是指被卤素取代。
在本发明中,术语“氘代”是指被氘取代。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取 代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出 现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位 点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或 不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的 或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基 (-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环 基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷 氧基、C1-C10磺酰基等。
在本发明中,术语1-6指1、2、3、4、5或6。其他类似术语各自独立地具有 类似含义。术语“多个”指2-6个,如2、3、4、5或6个。
应理解,当某一基团同时存在于化合物的多个不同位置时,其在各位置的 定义是相互独立的,可以相同也可以不同。亦即,术语“选自下组:”与术 语“各独立地选自下组:”具有相同含义。
化合物
本发明提供了一种式I所示的化合物或其药学上可接受的盐,
其中,各基团如上文定义。
在另一优选例中,所述的化合物中,R1、R2、R3、R4、R5、R6、R7、A环、 n、n’、X、V、n”、Y、B环、W、U、Z中任一个分别独立地为所述具体化合 物中所对应的基团。
在另一优选例中,所述化合物优选为各实施例所制备化合物。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的 适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是 本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、 氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、 丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、 苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨 酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐 或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药 学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺 盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺 盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
应理解,本发明化合物可采用如下实施例所示方法制备,还可以任选将在 本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样 的组合可由本发明所属领域的技术人员容易地进行。
药物组合物和施用方法
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上 可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化 合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物 含有1-2000mg本发明化合物/剂,更佳地,含有5-1000mg本发明化合物/剂。较 佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝 胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性” 在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不 明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物 (如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润 滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄 油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿 剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式 包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局 部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这 些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬 酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、 蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、 明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩 解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、 和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润 湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑 剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或 其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备, 如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中 活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可 采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上 述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆 或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂, 如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙 酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉 米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮 剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、 聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混 合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分 散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉 末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及 其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和 吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂, 或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物联合 给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺 乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重 的人而言,日给药剂量通常为1~2000mg,优选5~1000mg。当然,具体剂量 还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明具有以下主要优点:
(1)所述化合物具有更优的药代动力学性能,如更优的脑血比、半衰期、 暴露量、代谢稳定性等性能;
(2)所述化合物具有更好的钾离子通道开放活性、更好的钾离子通道激 动率、更优的离子通道选择性、更优的体内药效以及更好的安全性;
(3)所述化合物有望用于治疗和/或预防受钾离子通道的活性影响的疾病 和病症。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明 本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通 常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非 另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉 的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明 方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1化合物3001的制备
步骤一、化合物2
将化合物1(5.0g,37.3mmol,1.0eq)溶于硝基甲烷(45mL),25℃下向上述反 应液中加入醋酸铵(3.4g,44.7mmol,1.2eq),加热回流4小时。反应结束后温度降至 25℃并将反应液浓缩,加入乙酸乙酯(80mL)。有机相依次用水(50mL)、饱和氯 化钠溶液(50mL)洗涤、无水硫酸钠干燥。浓缩后的残留物用硅胶柱层析(石油醚/ 乙酸乙酯=100/1)纯化得到化合物2(3.0g,46%)为黄色固体。
LCMS:[M+H]+=178.1
步骤二、化合物3
将化合物2(2.0g,11.3mmol,1.0eq)溶于四氢呋喃(30mL),将上述溶液缓慢滴 加到四氢铝锂的四氢呋喃溶液(1M,45mL,45mmol,4.0eq)中,完毕后将反应液 加热回流16小时。反应液降温至25℃并用十水合硫酸钠淬灭,过滤后用乙酸乙酯洗 涤,将得到的滤液浓缩后得到化合物3(1.6g,95%)为黄色固体。
LCMS:[M+H]+=150.1
步骤三、化合物4
将三光气(1.3g,4.3mmol,0.4eq)溶于二氯甲烷(10mL)并将上述溶液缓慢 滴加至化合物3(1.6g,10.7mmol,1.0eq)的二氯甲烷(10mL)溶液中,冷却至0℃, 缓慢滴加三乙胺(2.2g,21.5mmol,2.0eq)。反应液在25℃搅拌2小时后过滤,用少量 二氯甲烷洗涤固体,将得到的滤液缓慢滴加至三氯化铝(5.7g,42.9mmol,4.0eq)的二 氯甲烷(25mL)悬浊液中。继续搅拌16小时后加水淬灭,分层后有机相用无水硫酸钠 干燥,浓缩后得到的残留物用快速硅胶柱层析(石油醚/乙酸乙酯=2/1)纯化,得到化 合物4(0.6g,32%)为黄色固体。
LCMS:[M+H]+=176.1
步骤四、化合物5
将化合物4(200mg,1.14mmol,1.0eq)溶于氯仿(2mL)并冷却至0℃,滴加硝 酸钾(127mg,1.26mmol,1.1eq)的浓硫酸(98%,3mL)溶液。反应在0℃下搅拌0.5小 时后用碎冰淬灭,过滤得到的固体用水打浆纯化得到化合物5(213mg,85%)为黄色 固体。
LCMS:[M+H]+=221.1
步骤五、化合物7
将化合物5(280mg,1.27mmol,1.0eq)溶于N,N-二甲基甲酰胺(5mL),依次加 入化合物6(339mg,1.53mmol,1.2eq)、碘化亚铜(48mg,0.25mmol,0.2eq)和碳酸钾 (352mg,2.54mmol,2.0eq)。反应液在氮气氛围下升温至140℃搅拌6小时,冷却至25 ℃后用乙酸乙酯(10mL)稀释。将反应液过滤,固体用乙酸乙酯淋洗,所得的滤液用 水洗涤(10mL),有机相用无水硫酸钠干燥后浓缩,残留物用快速硅胶柱层析(石油 醚/乙酸乙酯=10/1)纯化得到化合物7(145mg,36%)为黄色固体。
LCMS:[M+H]+=315.1
步骤六、化合物8
将化合物7(530mg,1.69mmol,1.0eq)溶于四氢呋喃(70mL),将上述溶液缓慢 滴加到四氢铝锂的四氢呋喃溶液(1M,17mL,17mmol,10.0eq)中,滴加完毕后升温 回流6小时。冷却至25℃后用十水合硫酸钠淬灭反应,过滤后固体用乙酸乙酯洗涤, 将得到的滤液浓缩,得到化合物8(423mg,93%)为黄色固体。
LCMS:[M+H]+=271.1
步骤七、化合物3001
将化合物8(200mg,0.74mmol,1.0eq)溶于N,N-二甲基甲酰胺(6mL),依次加入 化合物9(102mg,0.89mmol,1.2eq)、吡啶(1170mg,14.8mmol,20.0eq)和1-丙基磷 酸酐(50%乙酸乙酯溶液,4.8g,7.4mmol,10.0eq),升温至50℃并搅拌16小时。冷却 至25℃后反应液用乙酸乙酯稀释,有机相依次用水、饱和氯化钠溶液洗涤并用无水 硫酸钠干燥,浓缩后得到的残留物用硅胶柱层析(石油醚/乙酸乙酯=2/1)纯化,得到 化合物3001(139.1mg,52%)为淡黄色固体。
LCMS:[M+H]+=367.1
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.08-7.06(m,4H),6.88(s,1H),4.16 (s,2H),3.42(t,J=5.6Hz,2H),2.86(t,J=5.6Hz,2H),2.22(s,2H),2.11(s,3H),2.07 (s,3H),1.16(s,3H),0.56-0.54(m,2H),0.34-0.31(m,2H).
实施例2化合物3002的制备
步骤一、化合物3
将化合物1(500mg,2.27mmol,1.0eq)溶于N,N-二甲基甲酰胺(5mL),依次加入 化合物2(926mg,3.40mmol,1.5eq)、碳酸钾(784mg,5.68mmol,2.5eq)和碘化亚铜(86 mg,0.45mmol,0.2eq),反应液升温至140℃并搅拌4小时。将反应液冷却至25℃后加 入水(50mL)并用乙酸乙酯(3x50mL)萃取,合并后的有机相用饱和氯化钠溶液洗 涤、无水硫酸钠干燥后浓缩,残留物用硅胶柱层析(石油醚/乙酸乙酯=10/1)纯化后 得到化合物3(400mg,48%)为白色固体。
LCMS:[M+H]+=365.1
步骤二、化合物4
将化合物3(200mg,0.548mmol,1.0eq)溶于四氢呋喃(2mL),冷却至0℃并滴 加四氢铝锂的四氢呋喃溶液(1M,5.48mL,5.48mmol,10.0eq),滴加完毕后将反应液 升温至60℃并搅拌1小时。将反应液冷却至0℃,然后用十水合硫酸钠淬灭。将过滤 后的滤液浓缩后得到化合物4(150mg,85%)为白色固体。
LCMS:[M+H]+=321.1
步骤三、化合物3002
将化合物4(150mg,0.468mmol,1.0eq)溶于N,N-二甲基甲酰胺(5mL),依次加 入化合物5(64mg,0.561mmol,1.2eq)、1-丙基磷酸酐(50%,3.5g,5.500mmol,11.7 eq)和吡啶(740mg,9.36mmol,20.0eq)。反应液升温至50℃并搅拌2小时,冷却至25 ℃后加入水(50mL)并用乙酸乙酯(3x50mL)萃取。合并后的有机相用饱和氯化钠溶 液洗涤、无水硫酸钠干燥后浓缩,残留物用pre-HPLC(0.1%甲酸/乙腈/水)纯化后得 到化合物3002(40mg,20%)为白色固体。
LCMS:[M+H]+=417.3
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.52(d,J=8.8Hz,2H),7.16(d,J=8.8Hz,2H),6.91(s,1H),4.35(s,2H),3.60(t,J=5.5Hz,2H),2.87(t,J=5.6Hz,2H), 2.23(s,2H),2.11(d,J=4.6Hz,6H),1.16(s,3H),0.56-0.54(m,2H),0.34-0.31(m,2H).
实施例A1钾离子通道开放剂活性测试(FDSS/μCELL检测)
1.实验方法:
1.1实验流程
细胞准备:CHO-KCNQ2细胞培养于175cm2培养瓶中,待细胞密度生长到 60~80%,移走培养液,用7mL PBS(Phosphate Buffered Saline,磷酸盐缓 冲液)洗一遍,然后加入3mL 0.25%Trypsin消化。待消化完全后加入7mL培 养液(90%DMEM/F12+10%FBS+500μg/mL G418)中和,800rpm离心3分 钟,吸走上清液,再加入5mL培养液重悬,细胞计数。
细胞铺板:根据细胞计数结果,调整密度至3x104个/孔,室温静置30分钟 后,放置于37℃ CO2培养箱培养过夜,培养16-18小时,细胞密度达到约80%。
荧光染料孵育:弃去细胞培养液,加入80μL/孔的上样缓冲液,室温避光 孵育60分钟。
化合物孵育:弃去上样缓冲液,加入配制好的化合物溶液80μL/孔,室温 避光孵育20分钟。
荧光数据采集:采用FDSS/μCELL仪器进行实时荧光信号记录,激发波长480 nm、发射波长540nm,每秒记录1次,记录10秒基线后开始加入20μL/孔的刺 激缓冲液,再持续记录至180秒结束。
1.2溶液配制
上样缓冲液:10mL/板,配制方式如下:
成分 | 体积 |
PowerLoadTM浓缩物,100X(成分C) | 100μL |
FluxORTM试剂,在DMSO中重建(步骤1.2) | 10μL |
去离子水 | 8.8mL |
FluxORTM测试缓冲液,10X(成分B) | 1mL |
丙磺舒,在去离子水中重建(步骤1.1) | 100μL |
总体积 | 10mL |
测试缓冲样:100mL/板,配制方式如下:
成分 | 体积 |
去离子水 | 8.9mL |
FluxORTM测试缓冲液,10X(成分B) | 1mL |
丙磺舒,在去离子水中重建(步骤1.1) | 100μL |
总体积 | 10mL |
刺激缓冲液:5mL/板,配制方式如下:
/>
上述缓冲液来源于市售的试剂盒,试剂盒名称为FluxOR potassium ion channelassay。
1.3化合物准备
配制20mM的DMSO化合物母液,取10μL 20mM的化合物母液至20μL DMSO 溶液中,3倍连续稀释成8个中间浓度;再分别取中间浓度的化合物至测试缓冲 液中,200倍稀释得到需要测试的最终浓度,取80μL加入至检测板中。
最高测试浓度为100μM,依次分别为100,33.33,11.11,3.70,1.23, 0.41,0.137,0.045μM共8个浓度。每个浓度3复孔。
最终测试浓度中的DMSO含量不超过0.5%,此浓度的DMSO对KCNQ2钾通道没 有影响。
1.4数据分析
实验数据由Excel 2007、GraphPad Prism 5.0软件进行分析,统计180秒 的比值计算激动效应。化合物激动效应由如下公式计算:
1.5质量控制
环境:温度~25℃
试剂:FluxORTM检测试剂盒(Invitrogen,Cat#F0017)
报告中的实验数据必须满足以下标准:Z’Factor>0.5
2.测定结果:详见表1,其中EC50越小,表示相应化合物的活性越高。
表1.本发明所述的部分化合物测试结果
上述测试方法的参考文献:
Zhaobing Gao等人.Journal of Biological Chemistry.2010,285(36): 28322-28332.
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献 被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后, 本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申 请所附权利要求书所限定的范围。
Claims (10)
1.一种式I所示的化合物或其药学上可接受的盐,
其中,
A环选自下组:C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基;
各R1、R2独立地选自取代或未取代的下组基团:氢、氘、卤素、氰基、-OH、-COOH、硝基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6烯基、C2-6炔基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-14元杂芳基、C6-12芳烷基、-N(R1’)(R2’)、-C(O)-R1’、-C(O)-N(R1’)(R2’)、-C(O)-OR1’、-N(R1’)-C(O)-R2’、-S(O)m-R1’、-S(O)m-N(R1’)(R2’)、-S(O)m-OR1’、-N(R1’)-S(O)m-R2’,所述取代指被选自下组的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、卤代C1-6烷基、卤代C3-6环烷基、卤代C1-6烷氧基、卤代C3-6环烷基氧基;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基、C3-6环烷基,或R1’、R2’与其共同连接的N原子形成饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基;上述烷基、环烷基、杂环基任选地被选自下组的一个或多个取代基取代:=O、卤素、C1-6烷基、C3-6环烷基;
m选自下组:1、2;
X选自下组:C、CR8、N;
各R8独立地选自下组:H、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基;上述烷基、环烷基任选地被选自下组的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基;
V选自下组:-C(R9)(R10)-、-N(R8)-;
n”选自下组:0、1;
R9、R10独立地选自下组:氢、卤素、C1-6烷基,或R9、R10与其共同连接的C原子形成C3-6环烷基;
B环选自下组:饱和或不饱和的C3-10环烃基、饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基;
R6、R7独立地选自下组:氢、氘、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C3-6卤代环烷基;
Y选自下组:CR8、N;
W选自下组:CR11、N;
R11选自下组:氢、氘、卤素、氰基、氨基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、-N(R1’)(R2’);上述烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基;
R4、R5独立地选自下组:氢、氘、卤素、氰基、氨基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、-N(R1’)(R2’);上述烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素、C1-6烷基、C3-6环烷基;
U选自下组:O、S、N(R1’);
Z选自下组:O、-(CH2)q-、-N(R1’)-;
q选自下组:0、1、2;
R3选自下组:C1-6烷基、C3-6环烷基、C5-8桥环基、金刚烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的3-10元杂芳基、含1-3个选自N、O或S的杂原子的4-8元杂环烷基、C3-6环烯基、C2-6烯基、C2-6炔基,上述烷基、环烷基、桥环基、金刚烷基、芳基、杂芳基、杂环烷基、环烯基、烯基、炔基任选地被选自下组的一个或多个取代基取代:氢、卤素、氰基、硝基、氨基、羟基、C1-6烷基-CO-、C1-6烷基、C3-6环烷基、C6-10芳基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基氨基、C1-6卤代烷氧基。
2.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
A环选自下组:C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基;
各R1、R2独立地选自取代或未取代的下组基团:氢、氘、卤素、氰基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6烯基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基、C3-6环烷基;上述烷基、环烷基任选地被选自下组的一个或多个取代基取代:卤素;
X为C;
V为CH2;
n”选自下组:0、1;
B环为饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基;
R6、R7独立地选自下组:氢、氘;
Y为N;
W选自下组:CR11、N;
R11选自下组:氢、卤素、C1-6烷基;上述烷基任选地被选自下组的一个或多个取代基取代:卤素;
R4、R5独立地选自下组:氢、卤素、氰基、氨基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基;上述烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z选自下组:O、CH2;
R3选自下组:C1-6烷基、C3-6环烷基、C5-8桥环基、C2-6炔基;上述烷基、环烷基、桥环基、炔基任选地被选自下组的一个或多个取代基取代:氢、卤素、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基。
3.如权利要求2所述的化合物或其药学上可接受的盐,其特征在于,
A环为C6-10芳基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
V为CH2;
n”选自下组:0、1;
B环为饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基;
R6、R7独立地选自下组:氢、氘;
Y为N;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为CH2;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
4.如权利要求3所述的化合物或其药学上可接受的盐,其特征在于,
A环为苯基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C1-6烷氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
n”为0;
B环选自下组:
R6、R7独立地选自下组:氢、氘;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为-CH2-;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
5.如权利要求4所述的化合物或其药学上可接受的盐,其特征在于,
A环为苯基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C1-6烷氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
n”为0;
B环选自下组:
R6、R7独立地选自下组:氢、氘;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为-CH2-;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
6.如权利要求3所述的化合物或其药学上可接受的盐,其特征在于,
A环为苯基;
各R1、R2独立地选自取代或未取代的下组基团:氢、卤素、C1-6烷基、C1-6烷氧基、C2-6炔基、-N(R1’)(R2’),所述取代指被选自下组的一个或多个取代基取代:卤素;
n选自下组:0、1、2;
n’选自下组:0、1、2;
各R1’、R2’独立地选自下组:氢、C1-6烷基;
X为C;
V为-CH2-;
n”为1;
B环选自下组:
R6、R7独立地选自下组:氢、氘;
W为CH;
R4、R5独立地选自下组:卤素、C1-6烷基、C1-6烷氧基;上述烷基、烷氧基任选地被选自下组的一个或多个取代基取代:卤素;
U为O;
Z为-CH2-;
R3选自下组:C3-6环烷基、C5-8桥环基;上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代:氢、卤素、C1-6烷基、C1-6卤代烷基。
7.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述化合物选自下组:
8.一种药物组合物,其特征在于,包含一种或多种药学上可接受的载体和安全有效量的一种或多种权利要求1所述的化合物或其药学上可接受的盐。
9.一种权利要求1所述的化合物或其药学上可接受的盐的用途,其特征在于,用于制备用于预防和/或治疗对钾离子通道敏感的疾病的药物。
10.如权利要求9所述的用途,其特征在于,所述对钾离子通道敏感的疾病为中枢神经系统疾病。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210089806.7A CN116535354A (zh) | 2022-01-25 | 2022-01-25 | 作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 |
PCT/CN2023/073185 WO2023143386A1 (zh) | 2022-01-25 | 2023-01-19 | 作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210089806.7A CN116535354A (zh) | 2022-01-25 | 2022-01-25 | 作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116535354A true CN116535354A (zh) | 2023-08-04 |
Family
ID=87452968
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210089806.7A Pending CN116535354A (zh) | 2022-01-25 | 2022-01-25 | 作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116535354A (zh) |
WO (1) | WO2023143386A1 (zh) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7960436B2 (en) * | 2006-06-05 | 2011-06-14 | Valeant Pharmaceuticals International | Substituted arylamino-1,2,3,4-tetrahydro naphthalenes and-2,3-dihydro-1H-indenes as potassium channel modulators |
US9321750B2 (en) * | 2012-04-20 | 2016-04-26 | Innov17 Llc | ROR modulators and their uses |
CN103508960B (zh) * | 2012-06-29 | 2017-12-12 | 江苏先声药业有限公司 | 苯并杂环衍生物 |
CN112010808B (zh) * | 2019-05-31 | 2021-11-30 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的四氢-1h-苯氮杂卓类化合物及其制备和应用 |
CN114057641A (zh) * | 2020-08-07 | 2022-02-18 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的四氢异喹啉类化合物及其制备和应用 |
-
2022
- 2022-01-25 CN CN202210089806.7A patent/CN116535354A/zh active Pending
-
2023
- 2023-01-19 WO PCT/CN2023/073185 patent/WO2023143386A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
WO2023143386A1 (zh) | 2023-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2005247864A (ja) | 8−アザ、6−アザ、および6,8−ジアザ−1,4−ジヒドロキノキサリン−2,3−ジオン類 | |
RU2595894C2 (ru) | Замещенные 2-окси-хинолин-3-карбоксамиды в качестве модуляторов kcnq2/3 | |
KR100694752B1 (ko) | 말초형 벤조디아제핀 수용체의 기능 장애와 연관된 질병치료용 의약을 제조하기 위한피리다지노[4,5-b]인돌-1-아세트아미드 유도체의 용도 | |
CN113698345B (zh) | 作为钾通道调节剂的化合物及其制备和应用 | |
JP7327839B2 (ja) | カリウムチャネル調節剤としてのテトラヒドロ―1h―ベンザゼピン化合物ならびにその調製および応用 | |
CN116535353A (zh) | 作为钾通道调节剂的酰胺类化合物及其制备和应用 | |
CN106749271A (zh) | 一类[1,2,4]‑三氮唑并[1,5‑a]嘧啶酮类杂环化合物、其制备方法及其用途 | |
CN114845995B (zh) | 作为钾通道调节剂的四氢异喹啉类化合物及其制备和应用 | |
CN116535354A (zh) | 作为钾通道调节剂的芳环并杂环类化合物及其制备和应用 | |
RU2800873C1 (ru) | Соединение тетрагидроизохинолина в качестве модулятора калиевых каналов, его получение и применение | |
DE60007168T2 (de) | Benzopyranyl-guanidin-derivate, verfahren zu deren herstellung sowie diese enthaltenden pharmazeutische zusammensetzungen | |
CN111108083B (zh) | 氨基亚甲基环己烷1,3-二酮化合物的用途 | |
WO2020001298A1 (zh) | 一种4-(对三氟甲基苄基)-3-氟-1,2,4三苯胺衍生物及其药物组合物与用途 | |
CA3151863C (en) | Compound as potassium channel regulator and preparation and use thereof | |
TWI466670B (zh) | 治療β-地中海型貧血及鐮刀型貧血症之方法及組合物 | |
RU2798327C1 (ru) | Соединение в качестве регулятора калиевых каналов, его получение и применение | |
WO2022022678A1 (zh) | 一种吡嗪类化合物及其制备方法和应用 | |
CN117088837A (zh) | 乙烯基吡喃酮类化合物及其在治疗阿尔茨海默病中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |