ES2340640T3 - Inhibidores de canales de iones. - Google Patents

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Publication number

ES2340640T3

ES2340640T3 ES08153165T ES08153165T ES2340640T3 ES 2340640 T3 ES2340640 T3 ES 2340640T3 ES 08153165 T ES08153165 T ES 08153165T ES 08153165 T ES08153165 T ES 08153165T ES 2340640 T3 ES2340640 T3 ES 2340640T3

Authority

ES

Spain

Prior art keywords

fluoro

alkyl

trifluoromethylbenzyl

thiazol

trifluoromethoxybenzyl

Prior art date

2007-03-23

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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• -1 cyano, hydroxy Chemical group 0.000 claims abstract description 1380
• 150000001875 compounds Chemical class 0.000 claims abstract description 364
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 114
• 150000003839 salts Chemical class 0.000 claims abstract description 101
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 87
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 86
• 150000002367 halogens Chemical group 0.000 claims abstract description 84
• 239000012453 solvate Substances 0.000 claims abstract description 80
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 72
• 125000001424 substituent group Chemical group 0.000 claims abstract description 72
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 65
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 56
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 53
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 45
• 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 44
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 44
• 125000003118 aryl group Chemical group 0.000 claims abstract description 42
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 40
• 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 35
• 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 35
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract 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 abstract description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 27
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 25
• 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims abstract description 24
• 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 20
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 20
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 20
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 19
• 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims abstract description 19
• 125000005554 pyridyloxy group Chemical group 0.000 claims abstract description 19
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 18
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 16
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 15
• 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 14
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims abstract description 12
• 125000005128 aryl amino alkyl group Chemical group 0.000 claims abstract description 10
• 125000005160 aryl oxy alkyl group Chemical group 0.000 claims abstract description 10
• 125000004122 cyclic group Chemical group 0.000 claims abstract description 10
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims abstract description 9
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
• 239000001257 hydrogen Substances 0.000 claims abstract description 8
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims abstract description 7
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 6
• 125000002015 acyclic group Chemical group 0.000 claims abstract description 4
• 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
• 229930195733 hydrocarbon Natural products 0.000 claims abstract description 4
• 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 3
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 258
• 208000002193 Pain Diseases 0.000 claims description 117
• 230000036407 pain Effects 0.000 claims description 102
• 238000002360 preparation method Methods 0.000 claims description 87
• 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 claims description 64
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 62
• ILWFNKLXPUKLEP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)-2-fluorobenzene Chemical group FC1=CC(CCl)=CC=C1Cl ILWFNKLXPUKLEP-UHFFFAOYSA-N 0.000 claims description 51
• 108010052164 Sodium Channels Proteins 0.000 claims description 51
• 102000018674 Sodium Channels Human genes 0.000 claims description 51
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
• 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 46
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
• 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
• 239000000460 chlorine Substances 0.000 claims description 41
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
• 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
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
• 229910052801 chlorine Inorganic materials 0.000 claims description 37
• 238000011282 treatment Methods 0.000 claims description 36
• 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
• 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 34
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 34
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 33
• 125000004429 atom Chemical group 0.000 claims description 33
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 33
• 229910052731 fluorine Inorganic materials 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 31
• 239000011737 fluorine Substances 0.000 claims description 31
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 24
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 24
• 229910052717 sulfur Inorganic materials 0.000 claims description 24
• 206010049447 Tachyarrhythmia Diseases 0.000 claims description 23
• 208000001871 Tachycardia Diseases 0.000 claims description 23
• 201000010099 disease Diseases 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 125000001475 halogen functional group Chemical group 0.000 claims description 21
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
• 239000003814 drug Substances 0.000 claims description 20
• 239000011593 sulfur Substances 0.000 claims description 20
• 208000011231 Crohn disease Diseases 0.000 claims description 19
• 229940124530 sulfonamide Drugs 0.000 claims description 18
• 150000003456 sulfonamides Chemical class 0.000 claims description 18
• 208000011580 syndromic disease Diseases 0.000 claims description 16
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 13
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
• 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
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 12
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 12
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 10
• 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
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 10
• 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 9
• 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
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 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
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 7
• 150000003254 radicals Chemical class 0.000 claims description 7
• 125000003831 tetrazolyl group Chemical group 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
• 125000001425 triazolyl group Chemical group 0.000 claims description 7
• 125000004803 chlorobenzyl group Chemical group 0.000 claims description 6
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 6
• 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 5
• 125000000068 chlorophenyl group Chemical group 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000004385 trihaloalkyl group Chemical group 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
• 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000006682 monohaloalkyl group Chemical group 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
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 3
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 3
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 3
• 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 2
• 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 description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 2
• 125000004952 trihaloalkoxy group Chemical group 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract description 12
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 6
• 150000002148 esters Chemical class 0.000 abstract description 6
• 125000003282 alkyl amino group Chemical group 0.000 abstract description 3
• 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 145
• 238000000034 method Methods 0.000 description 131
• 238000006243 chemical reaction Methods 0.000 description 78
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
• 239000000203 mixture Substances 0.000 description 49
• 239000011541 reaction mixture Substances 0.000 description 45
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
• 239000002253 acid Substances 0.000 description 42
• 239000000243 solution Substances 0.000 description 42
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 41
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
• 239000002904 solvent Substances 0.000 description 34
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 28
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
• 201000006417 multiple sclerosis Diseases 0.000 description 26
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 24
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
• 239000000047 product Substances 0.000 description 23
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
• 235000019439 ethyl acetate Nutrition 0.000 description 22
• 230000008569 process Effects 0.000 description 22
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• 108091006146 Channels Proteins 0.000 description 20
• 150000001412 amines Chemical class 0.000 description 20
• 238000002953 preparative HPLC Methods 0.000 description 20
• 230000000694 effects Effects 0.000 description 19
• 238000001914 filtration Methods 0.000 description 19
• 208000035475 disorder Diseases 0.000 description 18
• 208000004296 neuralgia Diseases 0.000 description 17
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
• 239000011734 sodium Substances 0.000 description 16
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
• 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 15
• 208000014674 injury Diseases 0.000 description 15
• 208000021722 neuropathic pain Diseases 0.000 description 15
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 15
• 229910052708 sodium Inorganic materials 0.000 description 15
• 239000012074 organic phase Substances 0.000 description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 13
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
• 239000002585 base Substances 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 13
• 150000002500 ions Chemical class 0.000 description 13
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• 230000001419 dependent effect Effects 0.000 description 12
• 125000005843 halogen group Chemical group 0.000 description 12
• 239000000651 prodrug Substances 0.000 description 12
• 229940002612 prodrug Drugs 0.000 description 12
• 235000011152 sodium sulphate Nutrition 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 11
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
• 208000027418 Wounds and injury Diseases 0.000 description 11
• 150000001408 amides Chemical class 0.000 description 11
• 239000003795 chemical substances by application Substances 0.000 description 11
• 230000006378 damage Effects 0.000 description 11
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
• 210000000929 nociceptor Anatomy 0.000 description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
• 229910052938 sodium sulfate Inorganic materials 0.000 description 11
• 239000000126 substance Substances 0.000 description 11
• 206010065390 Inflammatory pain Diseases 0.000 description 10
• 239000012317 TBTU Substances 0.000 description 10
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 10
• 239000000463 material Substances 0.000 description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 description 10
• 239000000843 powder Substances 0.000 description 10
• 239000002244 precipitate Substances 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
• 238000005481 NMR spectroscopy Methods 0.000 description 9
• 239000012267 brine Substances 0.000 description 9
• 210000003169 central nervous system Anatomy 0.000 description 9
• 239000000706 filtrate Substances 0.000 description 9
• 125000005842 heteroatom Chemical group 0.000 description 9
• 238000004128 high performance liquid chromatography Methods 0.000 description 9
• 238000001727 in vivo Methods 0.000 description 9
• 230000002401 inhibitory effect Effects 0.000 description 9
• 239000000377 silicon dioxide Substances 0.000 description 9
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