CA2681572C - Inhibitors of ion channels - Google Patents
Inhibitors of ion channels Download PDFInfo
- Publication number
- CA2681572C CA2681572C CA2681572A CA2681572A CA2681572C CA 2681572 C CA2681572 C CA 2681572C CA 2681572 A CA2681572 A CA 2681572A CA 2681572 A CA2681572 A CA 2681572A CA 2681572 C CA2681572 C CA 2681572C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- member selected
- fluoro
- thiazol
- trifluoromethylbenzyl
- 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.)
- Expired - Fee Related
Links
- 102000004310 Ion Channels Human genes 0.000 title description 8
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 339
- 208000002193 Pain Diseases 0.000 claims abstract description 126
- 230000036407 pain Effects 0.000 claims abstract description 108
- 102000018674 Sodium Channels Human genes 0.000 claims abstract description 49
- 108010052164 Sodium Channels Proteins 0.000 claims abstract description 49
- 238000011282 treatment Methods 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 36
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 21
- -1 cyano, hydroxy Chemical group 0.000 claims description 1213
- 125000000217 alkyl group Chemical group 0.000 claims description 229
- 150000003839 salts Chemical class 0.000 claims description 123
- 125000005843 halogen group Chemical group 0.000 claims description 121
- 239000012453 solvate Substances 0.000 claims description 99
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 98
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 93
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 87
- 229910052736 halogen Inorganic materials 0.000 claims description 86
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 86
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 80
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 77
- 125000001424 substituent group Chemical group 0.000 claims description 77
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 75
- 150000002367 halogens Chemical group 0.000 claims description 73
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 73
- 125000003118 aryl group Chemical group 0.000 claims description 70
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 65
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 claims description 61
- ILWFNKLXPUKLEP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)-2-fluorobenzene Chemical group FC1=CC(CCl)=CC=C1Cl ILWFNKLXPUKLEP-UHFFFAOYSA-N 0.000 claims description 51
- 125000001072 heteroaryl group Chemical group 0.000 claims description 49
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 46
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 45
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 44
- 125000003282 alkyl amino group Chemical group 0.000 claims description 44
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
- 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 125000000984 3-chloro-4-fluorobenzyl group Chemical group [H]C1=C(F)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims description 32
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 32
- 125000006500 3-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC(F)(F)F)=C1[H])C([H])([H])* 0.000 claims description 31
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 30
- 208000011231 Crohn disease Diseases 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 30
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 30
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000001153 fluoro group Chemical group F* 0.000 claims description 29
- 206010049447 Tachyarrhythmia Diseases 0.000 claims description 28
- 208000001871 Tachycardia Diseases 0.000 claims description 28
- 125000004429 atom Chemical group 0.000 claims description 28
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 22
- 125000004076 pyridyl group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000001475 halogen functional group Chemical group 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 20
- 150000003456 sulfonamides Chemical class 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 19
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 19
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 239000011593 sulfur Substances 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 15
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 15
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 13
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 13
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 12
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 11
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 11
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 11
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 10
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 10
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 10
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 10
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 9
- 125000001769 aryl amino group Chemical group 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 9
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004803 chlorobenzyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 6
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 3
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 claims description 3
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 13
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 3
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 125
- 239000000203 mixture Substances 0.000 abstract description 24
- 208000004296 neuralgia Diseases 0.000 abstract description 19
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 abstract description 18
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 abstract description 18
- 208000021722 neuropathic pain Diseases 0.000 abstract description 18
- 230000004907 flux Effects 0.000 abstract description 15
- 150000002500 ions Chemical class 0.000 abstract description 12
- 206010065390 Inflammatory pain Diseases 0.000 abstract description 11
- 208000000094 Chronic Pain Diseases 0.000 abstract description 9
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 230000000903 blocking effect Effects 0.000 abstract description 5
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002981 neuropathic effect Effects 0.000 abstract description 3
- 208000027232 peripheral nervous system disease Diseases 0.000 abstract description 3
- 229910001415 sodium ion Inorganic materials 0.000 abstract description 3
- 208000015114 central nervous system disease Diseases 0.000 abstract description 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 289
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 231
- 201000006417 multiple sclerosis Diseases 0.000 description 206
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 160
- 125000003545 alkoxy group Chemical group 0.000 description 70
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 60
- 150000001412 amines Chemical class 0.000 description 56
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- 238000002360 preparation method Methods 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 32
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 30
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 29
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 26
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 108091006146 Channels Proteins 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 15
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- 125000006239 protecting group Chemical group 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
- 238000002953 preparative HPLC Methods 0.000 description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 208000027418 Wounds and injury Diseases 0.000 description 11
- 230000006378 damage Effects 0.000 description 11
- 125000001207 fluorophenyl group Chemical group 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 210000000929 nociceptor Anatomy 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 210000003169 central nervous system Anatomy 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 9
- 230000001154 acute effect Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 208000009935 visceral pain Diseases 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 208000005298 acute pain Diseases 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 108091008700 nociceptors Proteins 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000003195 sodium channel blocking agent Substances 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 208000008035 Back Pain Diseases 0.000 description 7
- 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 7
- 108090000862 Ion Channels Proteins 0.000 description 7
- 102100031367 Sodium channel protein type 9 subunit alpha Human genes 0.000 description 7
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 7
- 206010015037 epilepsy Diseases 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 210000002569 neuron Anatomy 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 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 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 206010058019 Cancer Pain Diseases 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- 101000654386 Homo sapiens Sodium channel protein type 9 subunit alpha Proteins 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
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Classifications
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- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
- C07D231/38—Nitrogen atoms
- C07D231/42—Benzene-sulfonamido pyrazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
- C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/14—Nitrogen atoms
- C07D261/16—Benzene-sulfonamido isoxazoles
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- 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
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- 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
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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
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-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
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (5)
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|---|---|---|---|
| US89673507P | 2007-03-23 | 2007-03-23 | |
| US60/896,735 | 2007-03-23 | ||
| US3532408P | 2008-03-10 | 2008-03-10 | |
| US61/035,324 | 2008-03-10 | ||
| PCT/US2008/057730 WO2008118758A1 (en) | 2007-03-23 | 2008-03-20 | Inhibitors of ion channels |
Publications (2)
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| CA2681572A1 CA2681572A1 (en) | 2008-10-02 |
| CA2681572C true CA2681572C (en) | 2014-02-11 |
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| CA2681572A Expired - Fee Related CA2681572C (en) | 2007-03-23 | 2008-03-20 | Inhibitors of ion channels |
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| US (2) | US8357711B2 (show.php) |
| EP (1) | EP1995241B1 (show.php) |
| JP (1) | JP5361857B2 (show.php) |
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| AT (1) | ATE461177T1 (show.php) |
| CA (1) | CA2681572C (show.php) |
| CL (1) | CL2008000835A1 (show.php) |
| DE (1) | DE602008000809D1 (show.php) |
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| TW (1) | TW200845969A (show.php) |
| UY (1) | UY30978A1 (show.php) |
| WO (1) | WO2008118758A1 (show.php) |
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