ES2897998T3 - Inhibidores de la acilsulfonamida del NaV1.7 - Google Patents
Inhibidores de la acilsulfonamida del NaV1.7 Download PDFInfo
- Publication number
- ES2897998T3 ES2897998T3 ES17794203T ES17794203T ES2897998T3 ES 2897998 T3 ES2897998 T3 ES 2897998T3 ES 17794203 T ES17794203 T ES 17794203T ES 17794203 T ES17794203 T ES 17794203T ES 2897998 T3 ES2897998 T3 ES 2897998T3
- Authority
- ES
- Spain
- Prior art keywords
- mmol
- benzenesulfonamide
- chloro
- alkyl
- fluoro
- 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.)
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- 239000003112 inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- -1 piperidinonyl Chemical group 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims abstract description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 6
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 5
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 17
- 208000002193 Pain Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000036407 pain Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- MEYXLKXNILUIND-UHFFFAOYSA-N 4-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-ylamino)-5-chloro-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)NC1CCC2CNCC21 MEYXLKXNILUIND-UHFFFAOYSA-N 0.000 claims description 2
- CABIGZVVAQTBNB-UHFFFAOYSA-N 4-(3,4,4a,5,6,7,8,8a-octahydro-1H-2,7-naphthyridin-2-yl)-5-chloro-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)N1CC2CNCCC2CC1 CABIGZVVAQTBNB-UHFFFAOYSA-N 0.000 claims description 2
- OEBNFHFNZNQLEZ-UHFFFAOYSA-N 5-chloro-2-fluoro-4-(3-piperidin-4-ylpiperidin-1-yl)-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound N1(CC(CCC1)C1CCNCC1)C1=CC(=C(C=C1Cl)S(=O)(=O)NC=1SC=CN=1)F OEBNFHFNZNQLEZ-UHFFFAOYSA-N 0.000 claims description 2
- URYVYLGECIQBHJ-UHFFFAOYSA-N 5-chloro-2-fluoro-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)N1CC(CC1)CO URYVYLGECIQBHJ-UHFFFAOYSA-N 0.000 claims description 2
- WDYWEFSNEAIOIH-UHFFFAOYSA-N 5-chloro-2-fluoro-4-[3-(methoxymethyl)pyrrolidin-1-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)N1CC(CC1)COC WDYWEFSNEAIOIH-UHFFFAOYSA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 152
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 126
- 238000005160 1H NMR spectroscopy Methods 0.000 description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 85
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 239000011541 reaction mixture Substances 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 55
- 239000000203 mixture Substances 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000000034 method Methods 0.000 description 44
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 38
- 239000005695 Ammonium acetate Substances 0.000 description 38
- 229940043376 ammonium acetate Drugs 0.000 description 38
- 235000019257 ammonium acetate Nutrition 0.000 description 38
- 239000012043 crude product Substances 0.000 description 35
- 239000000706 filtrate Substances 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 20
- 108091006146 Channels Proteins 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 239000002245 particle Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 238000001023 centrifugal evaporation Methods 0.000 description 14
- 239000013058 crude material Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- LFLSATHZMYYIAQ-UHFFFAOYSA-N 4-flourobenzenesulfonamide Chemical class NS(=O)(=O)C1=CC=C(F)C=C1 LFLSATHZMYYIAQ-UHFFFAOYSA-N 0.000 description 9
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000009739 binding Methods 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- PYCCGTAQLSDQEQ-UHFFFAOYSA-N 2,5-difluoro-4-[2-(4-oxo-1-phenylcyclohexyl)ethoxy]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound FC1=C(C=C(C(=C1)OCCC1(CCC(CC1)=O)C1=CC=CC=C1)F)S(=O)(=O)NC1=NC=NS1 PYCCGTAQLSDQEQ-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- FMVJFVQDUQSVMG-UHFFFAOYSA-N 2-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)ethanol Chemical compound OCCC1(CCC2(CC1)OCCO2)C1=CC=CC=C1 FMVJFVQDUQSVMG-UHFFFAOYSA-N 0.000 description 4
- 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 4
- GBRMQEBAZWXMBN-UHFFFAOYSA-N 4-[[1-[(4-chloro-3-fluorophenyl)methyl]-4-oxocyclohexyl]methoxy]-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound ClC1=C(C=C(CC2(CCC(CC2)=O)COC2=CC(=C(C=C2F)S(=O)(=O)NC2=NC=NS2)F)C=C1)F GBRMQEBAZWXMBN-UHFFFAOYSA-N 0.000 description 4
- HJKGDCXPISYNCT-UHFFFAOYSA-N 5-chloro-n-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-n-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN(S(=O)(=O)C=1C(=CC(F)=C(Cl)C=1)F)C1=NC=CS1 HJKGDCXPISYNCT-UHFFFAOYSA-N 0.000 description 4
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- ZKNDPAXBOVDHRC-UHFFFAOYSA-N 2-(aminomethyl)-4-phenylmethoxy-2-(2-phenylmethoxyethyl)butan-1-ol Chemical compound NCC(CO)(CCOCC1=CC=CC=C1)CCOCC1=CC=CC=C1 ZKNDPAXBOVDHRC-UHFFFAOYSA-N 0.000 description 3
- LUSTZVBYWCPJTM-UHFFFAOYSA-N 2-[1-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexyl]acetic acid Chemical compound C(C)(C)(C)OC(=O)NC1CCC(CC1)(C)CC(=O)O LUSTZVBYWCPJTM-UHFFFAOYSA-N 0.000 description 3
- ZWVWLZJDWPALFQ-UHFFFAOYSA-N 2-[2-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)ethyl]isoindole-1,3-dione Chemical compound O=C1N(CCC2(CCC3(CC2)OCCO3)C2=CC=CC=C2)C(=O)C2=C1C=CC=C2 ZWVWLZJDWPALFQ-UHFFFAOYSA-N 0.000 description 3
- NMVFLNSHUNZLMQ-UHFFFAOYSA-N 2-[4-(4-chloro-3-fluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]-2-cyanoacetic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(C(C#N)C(O)=O)C1=CC=C(Cl)C(F)=C1 NMVFLNSHUNZLMQ-UHFFFAOYSA-N 0.000 description 3
- PEQPQXGQSPWGJY-UHFFFAOYSA-N 3,4,5,6a-tetrahydro-2H-furo[2,3-b]furan-3a-ylmethanamine Chemical compound O1CCC2(C1OCC2)CN PEQPQXGQSPWGJY-UHFFFAOYSA-N 0.000 description 3
- DQKUHWQVKPXMEY-UHFFFAOYSA-N 4-[2-[4-(4-chlorophenyl)piperidin-4-yl]ethoxy]-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound ClC1=CC=C(C=C1)C1(CCNCC1)CCOC1=CC(=C(C=C1F)S(=O)(=O)NC1=NC=NS1)F DQKUHWQVKPXMEY-UHFFFAOYSA-N 0.000 description 3
- IQAWBVYQMHAKFH-UHFFFAOYSA-N 4-[[8-[(4-chloro-3-fluorophenyl)methyl]-1,4-dioxaspiro[4.5]decan-8-yl]methoxy]-N-[(2,4-dimethoxyphenyl)methyl]-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=C(CN(C2=NC=NS2)S(=O)(=O)C2=C(F)C=C(OCC3(CC4=CC(F)=C(Cl)C=C4)CCC4(CC3)OCCO4)C(F)=C2)C=C1 IQAWBVYQMHAKFH-UHFFFAOYSA-N 0.000 description 3
- OCJNALOVLBONTF-UHFFFAOYSA-N 5-chloro-2-fluoro-4-[(4-oxocyclohexyl)methylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)NCC1CCC(CC1)=O OCJNALOVLBONTF-UHFFFAOYSA-N 0.000 description 3
- HFHZBLKUSWLJPD-UHFFFAOYSA-N 5-chloro-2-fluoro-4-[2-(4-oxo-1-phenylcyclohexyl)ethylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)NCCC1(CCC(CC1)=O)C1=CC=CC=C1 HFHZBLKUSWLJPD-UHFFFAOYSA-N 0.000 description 3
- VQIDKRSFQRYBRI-UHFFFAOYSA-N 5-chloro-4-[[4-(cyclopropylamino)cyclohexyl]methylamino]-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C=1)S(=O)(=O)NC=1SC=CN=1)F)NCC1CCC(CC1)NC1CC1 VQIDKRSFQRYBRI-UHFFFAOYSA-N 0.000 description 3
- XQFQFLRZPAMIOX-UHFFFAOYSA-N 8-ethenyl-8-phenyl-1,4-dioxaspiro[4.5]decane Chemical compound C=CC1(CCC2(CC1)OCCO2)C1=CC=CC=C1 XQFQFLRZPAMIOX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000006509 Congenital Pain Insensitivity Diseases 0.000 description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- WUZFXKHGPKHOOW-UHFFFAOYSA-N N-[(2,4-dimethoxyphenyl)methyl]-2,5-difluoro-4-[2-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)ethoxy]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=C(CN(C2=NC=NS2)S(=O)(=O)C2=C(F)C=C(OCCC3(CCC4(CC3)OCCO4)C3=CC=CC=C3)C(F)=C2)C=C1 WUZFXKHGPKHOOW-UHFFFAOYSA-N 0.000 description 3
- CRGOYACQKNYVME-UHFFFAOYSA-N N-[(2,4-dimethoxyphenyl)methyl]-2,5-difluoro-4-hydroxy-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN(S(=O)(=O)C=1C(=CC(O)=C(F)C=1)F)C1=NC=NS1 CRGOYACQKNYVME-UHFFFAOYSA-N 0.000 description 3
- 241001223864 Sphyraena barracuda Species 0.000 description 3
- 101000844259 Thrixopelma pruriens Beta/omega-theraphotoxin-Tp2a Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- UUZHIOQKVWPPCZ-UHFFFAOYSA-N [8-[(4-chloro-3-fluorophenyl)methyl]-1,4-dioxaspiro[4.5]decan-8-yl]methanol Chemical compound OCC1(CC2=CC(F)=C(Cl)C=C2)CCC2(CC1)OCCO2 UUZHIOQKVWPPCZ-UHFFFAOYSA-N 0.000 description 3
- 208000037738 autosomal recessive channelopathy-associated congenital insensitivity to pain Diseases 0.000 description 3
- 150000008331 benzenesulfonamides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- UXXWGBLTOSRBAY-UHFFFAOYSA-N ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound C1CC(C(=O)OCC)CCC21OCCO2 UXXWGBLTOSRBAY-UHFFFAOYSA-N 0.000 description 3
- GKBUJPUBSPCDGF-UHFFFAOYSA-N ethyl 2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexyl]acetate Chemical compound CCOC(=O)CC1CCC(NC(=O)OC(C)(C)C)CC1 GKBUJPUBSPCDGF-UHFFFAOYSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
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- RPQXVSUAYFXFJA-HGRQIUPRSA-N saxitoxin Chemical compound NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@@H]12 RPQXVSUAYFXFJA-HGRQIUPRSA-N 0.000 description 1
- RPQXVSUAYFXFJA-UHFFFAOYSA-N saxitoxin hydrate Natural products NC(=O)OCC1N=C(N)N2CCC(O)(O)C22NC(N)=NC12 RPQXVSUAYFXFJA-UHFFFAOYSA-N 0.000 description 1
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- ZXQCHHAKXZQXMO-UHFFFAOYSA-N tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(2-hydroxyethyl)piperidine-1-carboxylate Chemical compound ClC1=C(C=C(C=C1)C1(CCN(CC1)C(=O)OC(C)(C)C)CCO)F ZXQCHHAKXZQXMO-UHFFFAOYSA-N 0.000 description 1
- MJPWKBQWBDXVQY-UHFFFAOYSA-N tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(cyanomethyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(CC#N)C1=CC=C(Cl)C(F)=C1 MJPWKBQWBDXVQY-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- MIJSDWSXCOXXJA-UHFFFAOYSA-N tert-butyl N-[2-formyl-4-phenylmethoxy-2-(2-phenylmethoxyethyl)butyl]carbamate Chemical compound C(C1=CC=CC=C1)OCCC(CNC(OC(C)(C)C)=O)(C=O)CCOCC1=CC=CC=C1 MIJSDWSXCOXXJA-UHFFFAOYSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 229960000281 trometamol Drugs 0.000 description 1
- ISNYUQWBWALXEY-OMIQOYQYSA-N tsg6xhx09r Chemical compound O([C@@H](C)C=1[C@@]23CN(C)CCO[C@]3(C3=CC[C@H]4[C@]5(C)CC[C@@](C4)(O)O[C@@]53[C@H](O)C2)CC=1)C(=O)C=1C(C)=CNC=1C ISNYUQWBWALXEY-OMIQOYQYSA-N 0.000 description 1
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- FVECELJHCSPHKY-JLSHOZRYSA-N veratridine Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@@]2(O)O[C@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-JLSHOZRYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
- C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- 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
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662413555P | 2016-10-27 | 2016-10-27 | |
| PCT/US2017/058472 WO2018081384A1 (en) | 2016-10-27 | 2017-10-26 | Acyl sulfonamide nav1.7 inhibitors |
Publications (1)
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| ES2897998T3 true ES2897998T3 (es) | 2022-03-03 |
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| ES17794203T Active ES2897998T3 (es) | 2016-10-27 | 2017-10-26 | Inhibidores de la acilsulfonamida del NaV1.7 |
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| WO2018106284A1 (en) | 2016-12-09 | 2018-06-14 | Xenon Pharmaceuticals Inc. | Benzenesulfonamide compounds and their use as therapeutic agents |
| CA3103600A1 (en) | 2018-06-13 | 2019-12-19 | Xenon Pharmaceuticals Inc. | Benzenesulfonamide compounds and their use as therapeutic agents |
| WO2020117626A1 (en) | 2018-12-05 | 2020-06-11 | Merck Sharp & Dohme Corp. | 4-amino or 4-alkoxy-substituted aryl sulfonamide compounds with selective activity in voltage-gated sodium channels |
| CN111285825B (zh) * | 2018-12-10 | 2023-02-17 | 中国科学院上海药物研究所 | 一类苯磺酰胺取代的衍生物,其制法及其用途 |
| WO2020199683A1 (zh) * | 2019-04-04 | 2020-10-08 | 上海海雁医药科技有限公司 | 氮杂环取代的磺酰基苯甲酰胺衍生物、其制法与医药上的用途 |
| WO2020248123A1 (en) | 2019-06-11 | 2020-12-17 | Merck Sharp & Dohme Corp. | Hydroxypyrrolidine-substituted arylsulfonamide compounds with selective activity in voltage-gated sodium channels |
| JP2024534364A (ja) | 2021-09-15 | 2024-09-20 | リヒター ゲデオン ニュイルヴァーノシャン ミューコェデー レースヴェーニュタールシャシャーグ | (1r,4r)-4-置換シクロヘキサン-1-アミンを生成する方法 |
| TW202530205A (zh) * | 2023-10-31 | 2025-08-01 | 加拿大商再諾製藥公司 | 經取代之芳基磺醯胺及其組合物及用途 |
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| EP2598481B1 (en) * | 2010-07-26 | 2016-08-31 | Bristol-Myers Squibb Company | Sulfonamide compounds useful as cyp17 inhibitors |
| MX2014005297A (es) * | 2011-10-31 | 2014-09-11 | Xenon Pharmaceuticals Inc | Compuestos de bencenosulfonamida y su uso como agentes terapeuticos. |
| US8889741B2 (en) * | 2012-02-09 | 2014-11-18 | Daiichi Sankyo Company, Limited | Cycloalkane derivatives |
| WO2015077905A1 (en) * | 2013-11-29 | 2015-06-04 | Merck Sharp & Dohme Corp. | Bicycloamine-substituted-n-benzenesulfonamide compounds with selective activity in voltage-gated sodium channels |
| CA2944115A1 (en) * | 2014-03-29 | 2015-10-08 | Lupin Limited | Sulfonamide compounds as voltage gated sodium channel modulators |
| TW201718629A (zh) * | 2015-09-25 | 2017-06-01 | 韓美藥品股份有限公司 | 包含多個生理多肽及免疫球蛋白Fc區之蛋白質接合物 |
| GB201518888D0 (en) * | 2015-10-24 | 2015-12-09 | Smiths Medical Int Ltd | Medico-surgical tubes and their manufacture |
| KR20180096683A (ko) * | 2015-12-18 | 2018-08-29 | 머크 샤프 앤드 돔 코포레이션 | 전압-게이팅 나트륨 채널에서 선택적 활성을 갖는 디아미노-알킬아미노-연결 아릴술폰아미드 화합물 |
| TW201726637A (zh) * | 2015-12-18 | 2017-08-01 | 默沙東藥廠 | 對電位閘控鈉通道具選擇活性之羥基烷基胺-及羥基環烷基胺-取代之二胺-芳基磺胺化合物 |
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Also Published As
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| JP7072569B2 (ja) | 2022-05-20 |
| CN110088093A (zh) | 2019-08-02 |
| JP2019536764A (ja) | 2019-12-19 |
| KR102561076B1 (ko) | 2023-07-28 |
| MA46615A (fr) | 2019-09-04 |
| CN110088093B (zh) | 2023-06-13 |
| US10836758B2 (en) | 2020-11-17 |
| US20200048240A1 (en) | 2020-02-13 |
| KR20190067895A (ko) | 2019-06-17 |
| EP3532462B1 (en) | 2021-10-13 |
| EP3532462A1 (en) | 2019-09-04 |
| WO2018081384A1 (en) | 2018-05-03 |
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