TW200914452A - Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators - Google Patents
Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators Download PDFInfo
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- TW200914452A TW200914452A TW097122339A TW97122339A TW200914452A TW 200914452 A TW200914452 A TW 200914452A TW 097122339 A TW097122339 A TW 097122339A TW 97122339 A TW97122339 A TW 97122339A TW 200914452 A TW200914452 A TW 200914452A
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- Prior art keywords
- compound
- alkyl
- formula
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- chr6
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- 102000004257 Potassium Channel Human genes 0.000 title abstract description 8
- 108020001213 potassium channel Proteins 0.000 title abstract description 8
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 title 1
- 150000003931 anilides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 249
- 239000000203 mixture Substances 0.000 claims abstract description 64
- 125000001424 substituent group Chemical group 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 112
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 111
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 73
- 229910052736 halogen Inorganic materials 0.000 claims description 52
- 150000002367 halogens Chemical class 0.000 claims description 43
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
- 125000003342 alkenyl group Chemical group 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- -1 imi Azyl Chemical group 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 150000002923 oximes Chemical class 0.000 claims description 12
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 11
- 229910052805 deuterium Inorganic materials 0.000 claims description 11
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 11
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 229910052707 ruthenium Inorganic materials 0.000 claims description 5
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 4
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 3
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 125000006612 decyloxy group Chemical group 0.000 claims 4
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims 1
- 238000010899 nucleation Methods 0.000 claims 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 229940002612 prodrug Drugs 0.000 abstract description 4
- 239000000651 prodrug Substances 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000035475 disorder Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 101150041968 CDC13 gene Proteins 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 241000208340 Araliaceae Species 0.000 description 5
- 108091006146 Channels Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 5
- 235000003140 Panax quinquefolius Nutrition 0.000 description 5
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 5
- 235000008434 ginseng Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- 125000004970 halomethyl group Chemical group 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108010006746 KCNQ2 Potassium Channel Proteins 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 230000002999 depolarising effect Effects 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- VUAXHMVRKOTJKP-UHFFFAOYSA-N 2,2-dimethylbutyric acid Chemical compound CCC(C)(C)C(O)=O VUAXHMVRKOTJKP-UHFFFAOYSA-N 0.000 description 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 150000001924 cycloalkanes Chemical class 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- JCMVPOVHKWWBAU-UHFFFAOYSA-N 1,2-dichlorohydrazine Chemical compound ClNNCl JCMVPOVHKWWBAU-UHFFFAOYSA-N 0.000 description 1
- NBZLULAOPCARMB-UHFFFAOYSA-N 1,3-dichloro-4-phenylbut-3-en-2-one Chemical compound ClCC(=O)C(Cl)=CC1=CC=CC=C1 NBZLULAOPCARMB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical group O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- JIQXRLOYKOJECL-UHFFFAOYSA-N 1-(2-chloroethoxy)-2-methoxyethane Chemical compound COCCOCCCl JIQXRLOYKOJECL-UHFFFAOYSA-N 0.000 description 1
- DSPHFASHOJAOKN-UHFFFAOYSA-N 1-[(7-oxobenzo[a]phenalen-2-yl)amino]anthracene-9,10-dione Chemical compound C1=CC2=CC(NC3=C4C(=O)C5=CC=CC=C5C(C4=CC=C3)=O)=CC(C=3C(=CC=CC=3)C3=O)=C2C3=C1 DSPHFASHOJAOKN-UHFFFAOYSA-N 0.000 description 1
- WCUDWYLAQUZKTO-UHFFFAOYSA-N 1-azido-10,10-dimethylundecane Chemical compound CC(C)(C)CCCCCCCCCN=[N+]=[N-] WCUDWYLAQUZKTO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- XSZKVKMGSAAAJZ-UHFFFAOYSA-N 2,4-dimethylpyridine-3-carboxylic acid Chemical compound CC1=CC=NC(C)=C1C(O)=O XSZKVKMGSAAAJZ-UHFFFAOYSA-N 0.000 description 1
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 1
- DGHSLOHHVSPBIK-UHFFFAOYSA-N 2-(3,4-dihydro-1h-isoquinolin-2-yl)-4,6-dimethoxypyrimidin-5-amine Chemical compound COC1=C(N)C(OC)=NC(N2CC3=CC=CC=C3CC2)=N1 DGHSLOHHVSPBIK-UHFFFAOYSA-N 0.000 description 1
- CKMCVIMYBWEVKX-UHFFFAOYSA-N 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine Chemical compound C1NCCC2=NC(C(F)(F)F)=NC=C21 CKMCVIMYBWEVKX-UHFFFAOYSA-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
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- KUCWUAFNGCMZDB-UHFFFAOYSA-N 2-amino-3-nitrophenol Chemical compound NC1=C(O)C=CC=C1[N+]([O-])=O KUCWUAFNGCMZDB-UHFFFAOYSA-N 0.000 description 1
- FETZNGVNMWWJPO-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-5-nitropyrimidine Chemical compound COC1=NC(Cl)=NC(OC)=C1[N+]([O-])=O FETZNGVNMWWJPO-UHFFFAOYSA-N 0.000 description 1
- PBEKEFWBLFBSGQ-UHFFFAOYSA-N 2-chloro-4,6-dimethoxypyrimidine Chemical compound COC1=CC(OC)=NC(Cl)=N1 PBEKEFWBLFBSGQ-UHFFFAOYSA-N 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- KCHQXPGUJBVNTN-UHFFFAOYSA-N 4,4-diphenylbut-3-en-2-one Chemical compound C=1C=CC=CC=1C(=CC(=O)C)C1=CC=CC=C1 KCHQXPGUJBVNTN-UHFFFAOYSA-N 0.000 description 1
- STXKJIIHKFGUCY-UHFFFAOYSA-N 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine Chemical compound C1=NC=C2CNCCC2=N1 STXKJIIHKFGUCY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000001613 Gambling Diseases 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
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 208000002193 Pain Diseases 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
- 102100034364 Potassium channel regulatory protein Human genes 0.000 description 1
- 101710120306 Potassium channel regulatory protein Proteins 0.000 description 1
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- 229960002442 glucosamine Drugs 0.000 description 1
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- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
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- 150000002431 hydrogen Chemical class 0.000 description 1
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- 238000011534 incubation Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052762 osmium Chemical group 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical group [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 235000010987 pectin Nutrition 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- 238000007363 ring formation reaction Methods 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| TW (1) | TW200914452A (enExample) |
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| US8563566B2 (en) * | 2007-08-01 | 2013-10-22 | Valeant Pharmaceuticals International | Naphthyridine derivatives as potassium channel modulators |
| US7786146B2 (en) * | 2007-08-13 | 2010-08-31 | Valeant Pharmaceuticals International | Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators |
| WO2010122064A1 (en) | 2009-04-21 | 2010-10-28 | Neurosearch A/S | Substituted naphthyridine derivatives and their medical use |
| EP2590961A1 (en) | 2010-07-08 | 2013-05-15 | Pfizer Inc | Piperidinyl pyrimidine amides as kv7 potassium channel openers |
| RU2014144951A (ru) | 2012-04-10 | 2016-06-10 | Сумитомо Дайниппон Фарма Ко., Лтд. | Новое 1-замещенное производное индазола |
| CN108250128A (zh) * | 2012-09-27 | 2018-07-06 | 江苏先声药业有限公司 | 作为钾通道调节剂的化合物 |
| WO2017004791A1 (en) | 2015-07-07 | 2017-01-12 | Colgate-Palmolive Company | Oral care implement and monofilament bristle for use with the same |
| CN110511220B (zh) | 2018-05-22 | 2022-04-01 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的对二氨基苯衍生物、其制备方法及其在医药上的应用 |
| WO2023125935A1 (zh) * | 2021-12-31 | 2023-07-06 | 上海翰森生物医药科技有限公司 | 苯并哌啶衍生物调节剂、其制备方法和应用 |
| CN116535353A (zh) * | 2022-01-25 | 2023-08-04 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的酰胺类化合物及其制备和应用 |
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-
2008
- 2008-06-12 US US12/138,251 patent/US8367684B2/en active Active
- 2008-06-13 KR KR1020107000706A patent/KR20100018618A/ko not_active Withdrawn
- 2008-06-13 PT PT08771077T patent/PT2170861E/pt unknown
- 2008-06-13 CN CN200880102338A patent/CN101868451A/zh active Pending
- 2008-06-13 SI SI200830745T patent/SI2170861T1/sl unknown
- 2008-06-13 CA CA002689208A patent/CA2689208A1/en not_active Abandoned
- 2008-06-13 BR BRPI0812564-3A2A patent/BRPI0812564A2/pt not_active Application Discontinuation
- 2008-06-13 HR HRP20120857AT patent/HRP20120857T1/hr unknown
- 2008-06-13 DK DK08771077.8T patent/DK2170861T3/da active
- 2008-06-13 ES ES08771077T patent/ES2392774T3/es active Active
- 2008-06-13 EP EP08771077A patent/EP2170861B1/en not_active Not-in-force
- 2008-06-13 JP JP2010512399A patent/JP2010530002A/ja active Pending
- 2008-06-13 MX MX2009013581A patent/MX2009013581A/es active IP Right Grant
- 2008-06-13 AU AU2008266009A patent/AU2008266009B2/en not_active Ceased
- 2008-06-13 RU RU2010100893/04A patent/RU2010100893A/ru not_active Application Discontinuation
- 2008-06-13 WO PCT/US2008/066984 patent/WO2008157404A2/en not_active Ceased
- 2008-06-13 PL PL08771077T patent/PL2170861T3/pl unknown
- 2008-06-13 TW TW097122339A patent/TW200914452A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SI2170861T1 (sl) | 2012-12-31 |
| PL2170861T3 (pl) | 2013-01-31 |
| US20080318979A1 (en) | 2008-12-25 |
| KR20100018618A (ko) | 2010-02-17 |
| JP2010530002A (ja) | 2010-09-02 |
| CA2689208A1 (en) | 2008-12-24 |
| PT2170861E (pt) | 2012-09-06 |
| AU2008266009A1 (en) | 2008-12-24 |
| RU2010100893A (ru) | 2011-07-20 |
| WO2008157404A3 (en) | 2009-02-19 |
| ES2392774T3 (es) | 2012-12-13 |
| DK2170861T3 (da) | 2012-11-26 |
| BRPI0812564A2 (pt) | 2015-02-10 |
| EP2170861A2 (en) | 2010-04-07 |
| US8367684B2 (en) | 2013-02-05 |
| AU2008266009B2 (en) | 2013-06-06 |
| WO2008157404A2 (en) | 2008-12-24 |
| CN101868451A (zh) | 2010-10-20 |
| HRP20120857T1 (hr) | 2012-11-30 |
| MX2009013581A (es) | 2010-01-26 |
| EP2170861B1 (en) | 2012-08-29 |
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