JP7163482B2 - 新規なハロ-(3-(フェニルスルホニル)プロプ-1-エニル)ピリジン誘導体及びこの用途 - Google Patents
新規なハロ-(3-(フェニルスルホニル)プロプ-1-エニル)ピリジン誘導体及びこの用途 Download PDFInfo
- Publication number
- JP7163482B2 JP7163482B2 JP2021508298A JP2021508298A JP7163482B2 JP 7163482 B2 JP7163482 B2 JP 7163482B2 JP 2021508298 A JP2021508298 A JP 2021508298A JP 2021508298 A JP2021508298 A JP 2021508298A JP 7163482 B2 JP7163482 B2 JP 7163482B2
- Authority
- JP
- Japan
- Prior art keywords
- vinyl
- methylphosphonate
- diethyl
- compound
- pyridine
- 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.)
- Active
Links
- 150000003222 pyridines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 135
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 77
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 claims description 71
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 claims description 71
- -1 1 -substituted phenyl Chemical group 0.000 claims description 67
- 230000000694 effects Effects 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 22
- 239000000126 substance Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 208000018737 Parkinson disease Diseases 0.000 claims description 14
- 230000003247 decreasing effect Effects 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 239000012190 activator Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 9
- LGGQRIBNNAJLAR-UHFFFAOYSA-N OC1=C(C=CC=C1)S(=O)(=O)CP(OCC)(OCC)=O Chemical compound OC1=C(C=CC=C1)S(=O)(=O)CP(OCC)(OCC)=O LGGQRIBNNAJLAR-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- LFPWIMWBXKJPJS-VQHVLOKHSA-N 2-[(E)-2-(2-chlorophenyl)sulfonylethenyl]-3-fluoropyridine Chemical compound ClC1=C(C=CC=C1)S(=O)(=O)/C=C/C1=NC=CC=C1F LFPWIMWBXKJPJS-VQHVLOKHSA-N 0.000 claims description 6
- BWSWMXFXNOFCPC-VQHVLOKHSA-N 3-chloro-2-[(E)-2-(2-fluorophenyl)sulfonylethenyl]pyridine Chemical compound ClC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=C(C=CC=C1)F BWSWMXFXNOFCPC-VQHVLOKHSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- LDMAVNGXDLRPDS-SOFGYWHQSA-N 2-[(E)-2-(3-chlorophenyl)sulfonylethenyl]-3-fluoropyridine Chemical compound ClC=1C=C(C=CC=1)S(=O)(=O)/C=C/C1=NC=CC=C1F LDMAVNGXDLRPDS-SOFGYWHQSA-N 0.000 claims description 5
- OQOCRFIHFOOAJN-VQHVLOKHSA-N 2-[(E)-2-(4-chlorophenyl)sulfonylethenyl]-3-fluoropyridine Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)/C=C/C1=NC=CC=C1F OQOCRFIHFOOAJN-VQHVLOKHSA-N 0.000 claims description 5
- MYERRJWEEFOODT-VQHVLOKHSA-N 3-chloro-2-[(E)-2-(4-fluorophenyl)sulfonylethenyl]pyridine Chemical compound ClC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=CC=C(C=C1)F MYERRJWEEFOODT-VQHVLOKHSA-N 0.000 claims description 5
- CASFVQRYJDMSOG-UHFFFAOYSA-N C1=CC=C(C(=C1)O)SCP(=O)(O)O Chemical compound C1=CC=C(C(=C1)O)SCP(=O)(O)O CASFVQRYJDMSOG-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- RWIGWWBLTJLKMK-UHFFFAOYSA-N diethoxyphosphorylmethanol Chemical compound CCOP(=O)(CO)OCC RWIGWWBLTJLKMK-UHFFFAOYSA-N 0.000 claims description 5
- 210000001147 pulmonary artery Anatomy 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010069351 acute lung injury Diseases 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- KWUXCQZSEYOICQ-RIYZIHGNSA-N 2-[4-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]-1-(4-methylpiperazin-1-yl)ethanone Chemical compound FC=1C(=NC=CC=1)/C=C/S(=O)(=O)C1=CC=C(OCC(=O)N2CCN(CC2)C)C=C1 KWUXCQZSEYOICQ-RIYZIHGNSA-N 0.000 claims description 3
- IQHALPOQOOPKOK-VQHVLOKHSA-N 3-chloro-2-[(E)-2-(2-chlorophenyl)sulfonylethenyl]pyridine Chemical compound ClC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=C(C=CC=C1)Cl IQHALPOQOOPKOK-VQHVLOKHSA-N 0.000 claims description 3
- PVCXTYQNIWTPIN-SOFGYWHQSA-N 3-chloro-2-[(E)-2-(3-chlorophenyl)sulfonylethenyl]pyridine Chemical compound ClC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=CC(=CC=C1)Cl PVCXTYQNIWTPIN-SOFGYWHQSA-N 0.000 claims description 3
- MKVTZVWJCGSAHV-SOFGYWHQSA-N 3-chloro-2-[(E)-2-(3-fluorophenyl)sulfonylethenyl]pyridine Chemical compound ClC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=CC(=CC=C1)F MKVTZVWJCGSAHV-SOFGYWHQSA-N 0.000 claims description 3
- GPWCCPNKJFDCPI-VQHVLOKHSA-N 3-chloro-2-[(E)-2-(4-chlorophenyl)sulfonylethenyl]pyridine Chemical compound ClC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=CC=C(C=C1)Cl GPWCCPNKJFDCPI-VQHVLOKHSA-N 0.000 claims description 3
- OYOITEAFSJLOLM-VQHVLOKHSA-N 3-fluoro-2-[(E)-2-(2-fluorophenyl)sulfonylethenyl]pyridine Chemical compound FC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=C(C=CC=C1)F OYOITEAFSJLOLM-VQHVLOKHSA-N 0.000 claims description 3
- YXPPUPITMIKNSR-SOFGYWHQSA-N 3-fluoro-2-[(E)-2-(3-fluorophenyl)sulfonylethenyl]pyridine Chemical compound FC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=CC(=CC=C1)F YXPPUPITMIKNSR-SOFGYWHQSA-N 0.000 claims description 3
- HXIMBPXZVXKUBD-VQHVLOKHSA-N 3-fluoro-2-[(E)-2-(4-fluorophenyl)sulfonylethenyl]pyridine Chemical compound FC=1C(=NC=CC=1)\C=C\S(=O)(=O)C1=CC=C(C=C1)F HXIMBPXZVXKUBD-VQHVLOKHSA-N 0.000 claims description 3
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 206010039163 Right ventricular failure Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000000925 erythroid effect Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000001631 hypertensive effect Effects 0.000 claims description 3
- 208000019423 liver disease Diseases 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- TVXLKFHMOPVCRG-RIYZIHGNSA-N 2-[4-[(E)-2-(3-chloropyridin-2-yl)ethenyl]sulfonylphenoxy]-1-(4-methylpiperazin-1-yl)ethanone Chemical compound CN1CCN(CC1)C(=O)COC2=CC=C(C=C2)S(=O)(=O)/C=C/C3=C(C=CC=N3)Cl TVXLKFHMOPVCRG-RIYZIHGNSA-N 0.000 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 208000004683 Corneal Endothelial Cell Loss Diseases 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 206010014561 Emphysema Diseases 0.000 claims description 2
- 208000024412 Friedreich ataxia Diseases 0.000 claims description 2
- 206010019799 Hepatitis viral Diseases 0.000 claims description 2
- 208000023105 Huntington disease Diseases 0.000 claims description 2
- 206010067125 Liver injury Diseases 0.000 claims description 2
- 208000004852 Lung Injury Diseases 0.000 claims description 2
- 201000002169 Mitochondrial myopathy Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 2
- 206010069363 Traumatic lung injury Diseases 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 230000001363 autoimmune Effects 0.000 claims description 2
- 239000003637 basic solution Substances 0.000 claims description 2
- 231100000012 chronic liver injury Toxicity 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- UQTWJQDADQIBSH-UHFFFAOYSA-N ethyl 2-[2-(diethoxyphosphorylmethylsulfonyl)phenoxy]acetate Chemical compound C(C)OP(=O)(OCC)CS(=O)(=O)C1=C(OCC(=O)OCC)C=CC=C1 UQTWJQDADQIBSH-UHFFFAOYSA-N 0.000 claims description 2
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 claims description 2
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 claims description 2
- 206010022437 insomnia Diseases 0.000 claims description 2
- 231100000515 lung injury Toxicity 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 238000009423 ventilation Methods 0.000 claims description 2
- 201000001862 viral hepatitis Diseases 0.000 claims description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-L methylphosphonate(2-) Chemical compound CP([O-])([O-])=O YACKEPLHDIMKIO-UHFFFAOYSA-L 0.000 claims 6
- 125000005843 halogen group Chemical group 0.000 claims 3
- IIHCVOAZCSLENS-VQHVLOKHSA-N 2-chloro-3-[(E)-2-(2-chlorophenyl)sulfonylethenyl]pyridine Chemical compound ClC1=NC=CC=C1\C=C\S(=O)(=O)C1=C(C=CC=C1)Cl IIHCVOAZCSLENS-VQHVLOKHSA-N 0.000 claims 1
- KFXKDCZRUNWJSN-CMDGGOBGSA-N 2-chloro-6-[(E)-2-(2-chlorophenyl)sulfonylethenyl]pyridine Chemical compound ClC1=NC(=CC=C1)\C=C\S(=O)(=O)C1=C(C=CC=C1)Cl KFXKDCZRUNWJSN-CMDGGOBGSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 165
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 92
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 235000019439 ethyl acetate Nutrition 0.000 description 39
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 25
- 102000004190 Enzymes Human genes 0.000 description 25
- 108090000790 Enzymes Proteins 0.000 description 25
- 229940125758 compound 15 Drugs 0.000 description 24
- 239000003814 drug Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 19
- 230000003078 antioxidant effect Effects 0.000 description 19
- 239000003963 antioxidant agent Substances 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- 230000004913 activation Effects 0.000 description 17
- SUVMJBTUFCVSAD-UHFFFAOYSA-N sulforaphane Chemical compound CS(=O)CCCCN=C=S SUVMJBTUFCVSAD-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 210000005064 dopaminergic neuron Anatomy 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 101150051438 CYP gene Proteins 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- SUVMJBTUFCVSAD-JTQLQIEISA-N 4-Methylsulfinylbutyl isothiocyanate Natural products C[S@](=O)CCCCN=C=S SUVMJBTUFCVSAD-JTQLQIEISA-N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 239000013642 negative control Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 229960005559 sulforaphane Drugs 0.000 description 8
- 235000015487 sulforaphane Nutrition 0.000 description 8
- UMWZRDQGPYEKQM-UHFFFAOYSA-N 1-(diethoxyphosphorylmethylsulfonyl)-2-fluorobenzene Chemical compound FC1=C(C=CC=C1)S(=O)(=O)CP(OCC)(OCC)=O UMWZRDQGPYEKQM-UHFFFAOYSA-N 0.000 description 7
- 206010048610 Cardiotoxicity Diseases 0.000 description 7
- 231100000259 cardiotoxicity Toxicity 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 230000036542 oxidative stress Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 101150116862 KEAP1 gene Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000001853 liver microsome Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 125000002757 morpholinyl group Chemical group 0.000 description 5
- QJMGVOCLOVTAKZ-UHFFFAOYSA-N 2-[4-(diethoxyphosphorylmethylsulfonyl)phenoxy]-1-(4-methylpiperazin-1-yl)ethanone Chemical compound CN1CCN(CC1)C(COC1=CC=C(C=C1)S(=O)(=O)CP(OCC)(OCC)=O)=O QJMGVOCLOVTAKZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 108700032225 Antioxidant Response Elements Proteins 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 108091023040 Transcription factor Proteins 0.000 description 4
- 102000040945 Transcription factor Human genes 0.000 description 4
- 239000003125 aqueous solvent Substances 0.000 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 230000036267 drug metabolism Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- KVDYSDOWSIXKPB-ZHACJKMWSA-N 1-chloro-2-[(e)-2-(2-methoxyphenyl)sulfonylethenyl]benzene Chemical compound COC1=CC=CC=C1S(=O)(=O)\C=C\C1=CC=CC=C1Cl KVDYSDOWSIXKPB-ZHACJKMWSA-N 0.000 description 3
- AOIFQPBLOBKSEE-UHFFFAOYSA-N 2-[4-(diethoxyphosphorylmethylsulfonyl)phenoxy]acetic acid Chemical compound C(C)OP(=O)(OCC)CS(=O)(=O)C1=CC=C(OCC(=O)O)C=C1 AOIFQPBLOBKSEE-UHFFFAOYSA-N 0.000 description 3
- OZIMPUNGBUYCSP-UHFFFAOYSA-N 3-fluoropyridine-2-carbaldehyde Chemical compound FC1=CC=CN=C1C=O OZIMPUNGBUYCSP-UHFFFAOYSA-N 0.000 description 3
- YXIIXGYUTXRAIY-UHFFFAOYSA-N 3-morpholin-4-ylpropyl methanesulfonate Chemical compound CS(=O)(=O)OCCCN1CCOCC1 YXIIXGYUTXRAIY-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 102100039696 Glutamate-cysteine ligase catalytic subunit Human genes 0.000 description 3
- 102100033398 Glutamate-cysteine ligase regulatory subunit Human genes 0.000 description 3
- 108010018924 Heme Oxygenase-1 Proteins 0.000 description 3
- 102100028006 Heme oxygenase 1 Human genes 0.000 description 3
- 101001034527 Homo sapiens Glutamate-cysteine ligase catalytic subunit Proteins 0.000 description 3
- 101000870644 Homo sapiens Glutamate-cysteine ligase regulatory subunit Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 3
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 150000001788 chalcone derivatives Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000001120 cytoprotective effect Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- FWCJXBARZMESDT-UHFFFAOYSA-N ethyl 2-[4-(diethoxyphosphorylmethylsulfonyl)phenoxy]acetate Chemical compound C(C)OP(=O)(OCC)CS(=O)(=O)C1=CC=C(OCC(=O)OCC)C=C1 FWCJXBARZMESDT-UHFFFAOYSA-N 0.000 description 3
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 210000001589 microsome Anatomy 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 210000003523 substantia nigra Anatomy 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DBNNTJYVUHIRFS-XHIXCECLSA-N 2-[4-[(E)-2-(3-chloropyridin-2-yl)ethenyl]sulfonylphenoxy]-1-(4-methylpiperazin-1-yl)ethanone hydrochloride Chemical compound CN1CCN(CC1)C(=O)COC2=CC=C(C=C2)S(=O)(=O)/C=C/C3=C(C=CC=N3)Cl.Cl DBNNTJYVUHIRFS-XHIXCECLSA-N 0.000 description 2
- BHYJKXNORBQCRW-XHIXCECLSA-N 2-[4-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]-1-(4-methylpiperazin-1-yl)ethanone hydrochloride Chemical compound CN1CCN(CC1)C(=O)COC2=CC=C(C=C2)S(=O)(=O)/C=C/C3=C(C=CC=N3)F.Cl BHYJKXNORBQCRW-XHIXCECLSA-N 0.000 description 2
- XGSSJQNBAGXPMT-CMDGGOBGSA-N 2-chloro-1-[(E)-2-(2-chlorophenyl)sulfonylethenyl]-2H-pyrimidine Chemical compound ClC1N=CC=CN1\C=C\S(=O)(=O)C1=C(C=CC=C1)Cl XGSSJQNBAGXPMT-CMDGGOBGSA-N 0.000 description 2
- UCVHKMUOUDAFMV-CSKARUKUSA-N 2-chloro-3-[(e)-2-(2-methoxyphenyl)sulfonylethenyl]pyridine Chemical compound COC1=CC=CC=C1S(=O)(=O)\C=C\C1=CC=CN=C1Cl UCVHKMUOUDAFMV-CSKARUKUSA-N 0.000 description 2
- ZCMLQTUUEUEJMP-SOFGYWHQSA-N 2-chloro-4-[(E)-2-(2-chlorophenyl)sulfonylethenyl]pyrimidine Chemical compound ClC1=NC(=CC=N1)\C=C\S(=O)(=O)C1=C(C=CC=C1)Cl ZCMLQTUUEUEJMP-SOFGYWHQSA-N 0.000 description 2
- QQOHNCKCIOOUJE-UHFFFAOYSA-N 4-[3-[2-(diethoxyphosphorylmethylsulfonyl)phenoxy]propyl]morpholine Chemical compound O1CCN(CC1)CCCOC1=C(C=CC=C1)S(=O)(=O)CP(OCC)(OCC)=O QQOHNCKCIOOUJE-UHFFFAOYSA-N 0.000 description 2
- XDAORHICEOALHZ-UHFFFAOYSA-N 4-[3-[3-(diethoxyphosphorylmethylsulfonyl)phenoxy]propyl]morpholine Chemical compound O1CCN(CC1)CCCOC=1C=C(C=CC=1)S(=O)(=O)CP(OCC)(OCC)=O XDAORHICEOALHZ-UHFFFAOYSA-N 0.000 description 2
- MPVJANNAQFTBNN-HAZZGOGXSA-N 4-[3-[3-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]propyl]morpholine hydrochloride Chemical compound C1COCCN1CCCOC2=CC(=CC=C2)S(=O)(=O)/C=C/C3=C(C=CC=N3)F.Cl MPVJANNAQFTBNN-HAZZGOGXSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- NIEMPHLOLLQRFV-UHFFFAOYSA-N O1CCN(CC1)CCCOC1=CC=C(C=C1)S(=O)(=O)CP(OCC)(OCC)=O Chemical group O1CCN(CC1)CCCOC1=CC=C(C=C1)S(=O)(=O)CP(OCC)(OCC)=O NIEMPHLOLLQRFV-UHFFFAOYSA-N 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 241000286209 Phasianidae Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000006851 antioxidant defense Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000006739 dopaminergic cell death Effects 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- GMHKMTDVRCWUDX-LBPRGKRZSA-N (S)-Mephenytoin Chemical compound C=1C=CC=CC=1[C@]1(CC)NC(=O)N(C)C1=O GMHKMTDVRCWUDX-LBPRGKRZSA-N 0.000 description 1
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 description 1
- YSDBJKNOEWSFGA-UHFFFAOYSA-N 1-(4-methylpiperazin-1-yl)ethanone Chemical compound CN1CCN(C(C)=O)CC1 YSDBJKNOEWSFGA-UHFFFAOYSA-N 0.000 description 1
- OYIGTYNZQITMMG-UHFFFAOYSA-N 1-(diethoxyphosphorylmethylsulfonyl)-3-fluorobenzene Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)CP(OCC)(OCC)=O OYIGTYNZQITMMG-UHFFFAOYSA-N 0.000 description 1
- UBQWMBMEKGFKOK-UHFFFAOYSA-N 1-(diethoxyphosphorylmethylsulfonyl)-4-fluorobenzene Chemical compound CCOP(=O)(OCC)CS(=O)(=O)C1=CC=C(F)C=C1 UBQWMBMEKGFKOK-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- UPTFMYMQESNJIA-UHFFFAOYSA-N 1-chloro-2-(diethoxyphosphorylmethylsulfonyl)benzene Chemical compound ClC1=C(C=CC=C1)S(=O)(=O)CP(OCC)(OCC)=O UPTFMYMQESNJIA-UHFFFAOYSA-N 0.000 description 1
- PHMNMIUKTYDDKK-UHFFFAOYSA-N 1-chloro-3-(diethoxyphosphorylmethylsulfonyl)benzene Chemical compound ClC=1C=C(C=CC=1)S(=O)(=O)CP(OCC)(OCC)=O PHMNMIUKTYDDKK-UHFFFAOYSA-N 0.000 description 1
- LCEUVFGKRKDMHU-UHFFFAOYSA-N 1-chloro-4-(diethoxyphosphorylmethylsulfonyl)benzene Chemical compound CCOP(=O)(OCC)CS(=O)(=O)C1=CC=C(Cl)C=C1 LCEUVFGKRKDMHU-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- NMUAWEUZGFYRKF-UHFFFAOYSA-N 2-(diethoxyphosphorylmethylsulfanyl)phenol Chemical compound OC1=C(C=CC=C1)SCP(OCC)(OCC)=O NMUAWEUZGFYRKF-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- QXNVCYJXFQPEKQ-UHFFFAOYSA-N 3-chloropyridine-2-carbaldehyde Chemical compound ClC1=CC=CN=C1C=O QXNVCYJXFQPEKQ-UHFFFAOYSA-N 0.000 description 1
- VZKSLWJLGAGPIU-UHFFFAOYSA-N 3-morpholin-4-ylpropan-1-ol Chemical compound OCCCN1CCOCC1 VZKSLWJLGAGPIU-UHFFFAOYSA-N 0.000 description 1
- HKXGTJAVLQOQMS-VIZOYTHASA-N 4-[3-[3-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]propyl]morpholine Chemical compound FC=1C(=NC=CC=1)/C=C/S(=O)(=O)C=1C=C(OCCCN2CCOCC2)C=CC=1 HKXGTJAVLQOQMS-VIZOYTHASA-N 0.000 description 1
- LSEHVCGMSFHAEG-LZYBPNLTSA-N 4-[3-[4-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]propyl]morpholine Chemical compound FC=1C(=NC=CC=1)/C=C/S(=O)(=O)C1=CC=C(OCCCN2CCOCC2)C=C1 LSEHVCGMSFHAEG-LZYBPNLTSA-N 0.000 description 1
- AGAQGTBXHZGAGE-OHGISNTKSA-N 4-[3-[4-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]propyl]morpholine hydrochloride Chemical compound C1COCCN1CCCOC2=CC=C(C=C2)S(=O)(=O)/C=C/C3=C(C=CC=N3)F.Cl AGAQGTBXHZGAGE-OHGISNTKSA-N 0.000 description 1
- BNNMDMGPZUOOOE-UHFFFAOYSA-N 4-methylbenzenesulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1 BNNMDMGPZUOOOE-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 1
- 235000017647 Brassica oleracea var italica Nutrition 0.000 description 1
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 1
- 235000010149 Brassica rapa subsp chinensis Nutrition 0.000 description 1
- 235000000536 Brassica rapa subsp pekinensis Nutrition 0.000 description 1
- 241000499436 Brassica rapa subsp. pekinensis Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 102100026398 Cyclic AMP-responsive element-binding protein 3 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000855520 Homo sapiens Cyclic AMP-responsive element-binding protein 3 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 1
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102100026517 Lamin-B1 Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101150041793 Nfe2l2 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 125000003277 amino group Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000001767 chemoprotection Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- UJTPZISIAWDGFF-UHFFFAOYSA-N ethenylsulfonylbenzene Chemical group C=CS(=O)(=O)C1=CC=CC=C1 UJTPZISIAWDGFF-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 108010052263 lamin B1 Proteins 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- GXHMMDRXHUIUMN-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O GXHMMDRXHUIUMN-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000013577 regulation of ventricular cardiomyocyte membrane repolarization Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LELAOEBVZLPXAZ-UHFFFAOYSA-N sulfpraphane Natural products CS(=O)CCCN=C=S LELAOEBVZLPXAZ-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/52—Sulfur atoms
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Hospice & Palliative Care (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
2.(E)-3-フルオロ-2-(2-(3-フルオロフェニルスルホニル)ビニル)ピリジン、
3.(E)-3-フルオロ-2-(2-(4-フルオロフェニルスルホニル)ビニル)ピリジン、
4.(E)-3-クロロ-2-(2-(2-フルオロフェニルスルホニル)ビニル)ピリジン、
5.(E)-3-クロロ-2-(2-(3-フルオロフェニルスルホニル)ビニル)ピリジン、
6.(E)-3-クロロ-2-(2-(4-フルオロフェニルスルホニル)ビニル)ピリジン、
7.(E)-2-(2-(2-クロロフェニルスルホニル)ビニル)-3-フルオロピリジン、
8.(E)-2-(2-(3-クロロフェニルスルホニル)ビニル)-3-フルオロピリジン、
9.(E)-2-(2-(4-クロロフェニルスルホニル)ビニル)-3-フルオロピリジン、
10.(E)-3-クロロ-2-(2-(2-クロロフェニルスルホニル)ビニル)ピリジン、
11.(E)-3-クロロ-2-(2-(3-クロロフェニルスルホニル)ビニル)ピリジン、
12.(E)-3-クロロ-2-(2-(4-クロロフェニルスルホニル)ビニル)ピリジン、
13.(E)-2-クロロ-6-(2-(2-クロロフェニルスルホニル)ビニル)ピリミジン、
14.(E)-2-クロロ-3-(2-(2-クロロフェニルスルホニル)ビニル)ピリミジン、
15.(E)-4-(3-(4-(2-(3-フルオロピリジン-2-イル)ビニルスルホニル)フェノキシ)プロピル)モルホリン、
16.(E)-4-(3-(3-(2-(3-フルオロピリジン-2-イル)ビニルスルホニル)フェノキシ)プロピル)モルホリン、
17.(E)-2-(4-(2-(3-フルオロピリジン-2-イル)ビニルスルホニル)フェノキシ)-1-(4-メチルピペラジン-1イル)エタノンまたは
18.(E)-2-(4-(2-(3-クロロピリジン-2-イル)ビニルスルホニル)フェノキシ)-1-(4-メチルピペラジン-1-イル)エタノン
であってもよい。
である場合、反応物として用いられるジエチル((R1置換されたフェニル)スルホニル)メチルホスホネートは(ヒドロキシ-C1-5アルキル)モルホリンをメタンスルホニルハライドと反応させてモルホリノ(C1-5アルキル)メタンスルホネートを製造する第a-1段階;及びモルホリノ(C1-5アルキル)メタンスルホネートをジエチル(ヒドロキシフェニルスルホニル)メチルホスホネートと反応させる第a-2段階;を通じて準備することができるが、これに制限されない。例えば、市販される製品を購入して用いたり、当業界において公知となった方法を制限なく利用及び/又は修正して合成したものを用いることができる。
である場合、反応物として用いられるジエチル((R1置換されたフェニル)スルホニル)メチルホスホネートはジエチル(ヒドロキシフェニルスルホニル)メチルホスホネートをC1-4アルキルハロアセテートと反応させてC1-4アルキル(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)アセテートを製造する第b-1段階;エチル(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)アセテートを塩基性溶液と酸性溶液に順に処理して(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)酢酸に転換する第b-2段階;及び(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)酢酸を2~4倍当量のカルボニルジイミダゾールの存在下にピパレジンまたは1-(C1-4アルキル)ピペラジンと反応させてジエチル((2-(4-ピペラジン-1-イル)-2-オキソエトキシ)フェニルスルホニル)メチルホスホネートまたはジエチル((2-(4-(C1-4アルキル)ピペラジン-1-イル)-2-オキソエトキシ)フェニルスルホニル)メチルホスホネートを製造する第b-3段階;を通じて準備することができるが、これに制限されない。例えば、市販される製品を購入して用いたり、当業界において公知となった方法を制限なく利用及び/又は修正して合成したものを用いることができる。
Rf=0.3(hexanes:Et0Ac=1:2);
透明なオイル状(colorless oil);
収率:83%;
Rf=0.30(hexane:EtOAc=1:3);
透明なオイル状;
収率:86%;
Rf=0.35(hexane:Et0Ac=1:1);
収率:62%;
Rf=0.45(hexane:EtOAc=1:2);
収率:80%;
Rf=0.37(hexane:Et0Ac=1:2);
収率:90%;
Rf=0.30(hexane:EtOAc=1:2);
収率:94%;
Rf=0.33(hexane:EtOAc=1:3);
収率:58%;
Rf=0.45(hexane:EtOAc=31:3);
収率:87%;
Rf=0.33(hexane:EtOAc=1:3);
収率:58%;
Rf=0.22(hexane:EtOAc=1:3);
透明なオイル状;
収率:60%;
Rf=0.53(hexane:EtOAc=1:3);
透明なオイル状;
収率:98%;
Rf=0.53(hexane:Et0Ac=1:3);
透明なオイル状;
収率:100%;
Rf=0.28(hexane:EtOAc=1:7);
透明なオイル状;
収率:99%;
Rf=0.34(hexane:EtOAc=1:3);
透明なオイル状;
収率:90%;
Rf=0.34(hexane:EtOAc=1:3);
透明なオイル状;
収率:90%;
Rf=0.34(hexane:EtOAc=1:5);
透明なオイル状;
収率:69%;
Rf=0.22(hexane:EtOAc=1:7);
透明なオイル状;
収率:84%;
Rf=0.22(hexane:EtOAc=1:7);
透明なオイル状;
収率:95%;
Rf=0.21(hexane:EtOAc=1:7);
Rf=0.33(2%MeOH/MC);
13C NMR (100 MHz, CDCl3): δ 117.2 (d, JC-F = 20.7 Hz), 124.2 (d, JC-F = 18.9 HzF), 124.8 (d, JC-F = 3.7 Hz), 126.9 (d, JC-F = 4.4Hz), 128.2 (d, JC-F = 13.9Hz), 129.9, 132.2 (d, JC-F = 3.3 Hz), 135.0, 136.2 (d, JC-F = 8.5Hz), 139.5 (d, JC-F = 11.0 Hz), 146.0 (d, JC-F = 5.0 Hz), 158.5 (d, JC-F= 264.3 Hz), 159.7 (d, JC-F = 255.6Hz).
Rf=0.41(hexanes:Et0Ac=1:1);
13C NMR (75 MHz, DMSO): δ 114.7 (d, JC-F = 24.4 Hz), 121.2 (d, JC-F= 21.1 Hz), 123.8 (d, JC-F = 3.0 Hz), 124.8 (d, JC-F = 18.8 Hz), 128.0 (d, JC-F = 4.7 Hz), 132.1 (d, JC-F = 13.5 Hz), 132.1, 133.7, 138.4 (d, JC-F = 10.9 Hz), 141.7 (d, JC-F= 6.7 Hz), 146.3 (d, JC-F = 4.8 Hz),158.3 (d, JC-F = 288.2 Hz), 161.7 (d, JC-F = 273.9Hz).
Rf=0.42(hexanes:EtOAc=1:1);
13C NMR (75 MHz, DMSO): δ 114.7 (d, JC-F = 24.4 Hz), 121.2 (d, JC-F= 21.1 Hz), 123.8 (d, JC-F =3.0 Hz), 124.8 (d, JC-F = 18.9 Hz), 128.0 (d, JC-F = 4.8 Hz), 132.1 (d, JC-F = 13.7 Hz), 132.1, 133.7, 138.4 (d, JC-F = 10.9 Hz), 141.7 (d, JC-F= 6.7 Hz), 146.3 (d, JC-F = 4.8 Hz), 158.3 (d, JC-F = 288.1 Hz), 161.7 (d, JC-F = 273.9 Hz).
Rf=0.37(hexanes:EtOAc=2:1);
13C NMR (100 MHz, DMSO): δ 118.0 (d, JC-F = 20.6 Hz), 126.1 (d, JC-F= 3.5 Hz), 127.6 (d, JC-F = 13.8Hz), 127.8, 130.1, 132.8, 133.4, 137.4, 137.8 (d, JC-F = 8.6 Hz), 138.9, 147.1, 149.1, 159.2 (d, JC-F= 253.1Hz).
Rf=0.27(hexanes:EtOAc=2:1);
13C NMR (75 MHz, DMSO): δ 114.7 (d, JC-F = 24.4 Hz), 121.3 (d, JC-F= 21.2 Hz), 123.8 (d, JC-F = 3.1 Hz), 127.1, 132.1 (d, JC-F= 7.9 Hz), 132.3, 133.3, 135.9, 138.4, 141.6 (d, JC-F = 6.7 Hz), 146.8, 148.5, 161.9 (d, JC-F = 248.0 Hz).
Rf=0.36(hexanes:EtOAc=2:1);
13C NMR (75 MHz, DMSO): δ 116.8, 117.1, 127.0, 130.9, 131.0, 132.2 , 133.9, 135.1, 135.8 (d, JC-F = 2.8 Hz), 138.36, 146.91, 148.54, 165.17 (d, JC-F= 251.8 Hz).
Rf=0.34(hexanes:EtOAc=2:1);
13C NMR (100 MHz, DMSO): δ 125.4 (d, JC-F = 18.9 Hz), 128.7 (d, JC-F= 4.7Hz), 128.9, 131.2, 131.3 (d, JC-F = 4.3Hz), 131.9, 132.6, 135.8, 136.3, 137.2, 138.7 (d, JC-F = 10.9 Hz), 147.0 (d, JC-F= 4.7 Hz), 158.7 (d, JC-F = 262.0 Hz).
Rf=0.38(hexanes:EtOAc=2:1);
13C NMR (100 MHz, DMSO): δ 124.8 (d, JC-F = 18.8 Hz), 126.3, 127.3, 128.0 (d, JC-F = 4.6 Hz), 131.6, 132.2 (d, JC-F = 4.1 Hz), 133.9 (d, JC-F = 12.2 Hz), 134.2, 138.4 (d, JC-F = 10.9 Hz), 141.6, 146.3 (d, JC-F = 4.7 Hz), 158.1 (d, JC-F= 262.1 Hz).
Rf=0.32(hexanes:EtOAc=3:1);
13C NMR (100 MHz, DMSO): δ 124.8 (d, JC-F =1 8.8 Hz), 128.0 (d, JC-F= 4.7 Hz), 129.6, 129.8, 132.5 (d, JC-F = 4.2 Hz), 133.3, 138.4, 138.5, 139.1, 146.4 (d, JC-F = 4.8 Hz), 158.1 (d, JC-F = 262.0 Hz).
Rf=0.37(hexanes:Et0Ac=2:1);
13C NMR (100 MHz, DMSO): δ 127.8, 128.9, 131.3, 131.9, 132.5, 132.6, 132.8, 136.4, 137.1, 138.3, 138.9, 147.2, 149.2.
Rf=0.50(hexanes:Et0Ac=2:1);
13C NMR (100 MHz, DMSO): δ 126.8, 127.6,127.8, 132.2, 132.8, 133.9, 134.5, 134.8, 136.6, 138.9, 141.9, 147.4, 149.0.
Rf=0.40(hexanes:Et0Ac=3:1);
13C NMR (100 MHz, DMSO): δ 127.6, 130.1, 130.3, 132.8, 134.2, 136.1, 138.8, 138.9, 139.7, 147.4, 149.0.
Rf=0.30(hexanes:EtOAc=1:1);
13C NMR (100 MHz, DMSO): δ 124.3, 127.4, 128.9, 131.2, 131.5, 132.0, 132.6, 136.3, 137.2, 138.6, 139.1, 150.8, 152.4.
Rf=0.30(hexanes:EtOAc=2:1);
13C NMR (100 MHz, DMSO): δ 125.5, 126.8, 128.3, 131.1, 131.2, 132.1, 132.6, 136.3, 137.3, 141.6, 142.4, 151.1, 151.6.
段階2-1:3-モルホリノプロピルメタンスルホネートの合成
Rf=0.35(MeOH:EtOAc=1:4);
13C NMR (100 MHz, DMSO): δ 23.2, 51.5, 53.7, 63.6, 66.1, 115.9, 125.3 (d, JC-F= 9.6 Hz), 128.2, 130.5, 131.7, 132.1, 134.06 (d, JC-F = 4.2 Hz), 139.10 (d, JC-F = 10.9 Hz), 146.87 (d, JC-F = 4.6 Hz), 158.5 (d, JC-F = 261.3 Hz), 163.0.
Rf=0.35(MeOH:EtOAc=1:4);
13C NMR (100 MHz, CDCl3): δ 26.2, 53.7, 55.3, 66.6, 66.9, 112.8, 120.1, 120.6, 124.1 (d, JC-F = 19.0 Hz), 126.67 (d, JC-F = 4.4 Hz), 130.5, 132.9, 133.2 (d, JC-F = 4.4 Hz), 141.1, 145.94 (d, JC-F= 5.1 Hz), 158.4 (d, JC-F = 264.1 Hz), 159.6.
Rf=0.30(EtOAC:Acetone=6:1);
Rf=0.34(20% MeOH/MC);
Rf=0.33(10%のMeOH/MC);
Rf=0.50(10% MeOH/MC);
13C NMR (100 MHz, DMSO): δ 42.4, 52.3 (d, JC-F = 15.6 Hz), 66.1, 66.8, 116.1, 125.2 (d, JC-F = 18.8 Hz), 128.2 (d, JC-F = 4.4 Hz), 130.3, 131.7, 132.1, 134.0 (d, JC-F = 4.0 Hz), 139.1 (d, JC-F= 11.0 Hz), 146.8 (d, JC-F = 4.8 Hz), 158.5 (d, JC-F = 261.4 Hz), 159.8, 162.8.
Rf=0.50(10% MeOH/MC);
13C NMR (100 MHz, DMSO): δ 42.5, 52.5, 66.0, 99.1, 116.2, 127.4, 130.3, 131.6, 132.5, 134.4, 135.2, 138.8, 147.5, 149.0, 162.8, 165.9.
上記本発明の実施例1~18により合成された化合物の薬理活性を確認するために、Nrf2機能化細胞基盤分析方法(Nrf2 functional cell based assay, DiscoveRx)を構築して合成された誘導体の、酸化ストレス防御の主な調節因子である、Nrf2活性誘導効果を評価した。具体的には、U2OS細胞を用い、CP O試薬で細胞ペレットを解いた後、96-ウェルプレートに1.5×104細胞/ウェルの密度で80μLずつ分注して24時間の間培養した。上記実施例1~18により合成した化合物をDMSOに7つの濃度で3倍希釈して原液(stock solution)を準備し、各化合物溶液10μLを90μLのCPOと混合して上記96-ウェルプレートの各ウェル当たり20μLずつ添加し、各実験は3回反復した。陽性対照群としては、5μMのスルフォラファン(sulforaphane)を処理し、プレートをホイルで包んで6時間の間培養した。細胞アッセイ緩衝液(cell assay buffer)に基質試薬(substrate reagent)1と2を入れていずれも混ぜた後、96-ウェルプレートに基質試薬をウェル当たり50μLずつ入れてホイルで包んで1時間の間培養した後、発光分光光度計(1uminescence spectrophotometer, Molecular Devices)を用いて全波長(all wavelength)及び累積時間(integaration time)1000msで発光値を測定した。各化合物の効果を高濃度の最大効果比50%を活性化する濃度で示した。結果は下記表5に示し、スルフォラファン処理群に対する百分率で化合物の効能を比較した。他の対照群としては、本発明と類似の母核構造を有し、Keap1の構造的変化を通じてNrf2の活性化を誘導することが確認されたカルコン(Chalcone)誘導体、VSC2((E)-1-(2-((2-Methoxyphenyl)sulfonyl)vinyl)-2-chlorobenzene, Woo et al., J. Med. Chem., 2014, 57: 1473-1487)を用いた。
本発明の実施例による化合物の実際に体内に投与する薬物としての活用の可能性を確認するために、薬物代謝に75%程度に関与するCYP活性阻害能を確認した。具体的には、代表的に選択した化合物1、4、13及び15~18に対し、全体CYPによる代謝の90%以上を占めることが報告された、5種の同種酵素である1A2、2C9、2C19、2D6及び3A4を対象に活性抑制を評価した。ヒト肝ミクロゾーム(human liver microsomes、0.25mg/mL)と0.1Mのリン酸緩衝溶液(pH7.4)、上記5種の薬物代謝酵素の基質薬物カクテル(フェナセチン(Phenacetin)50μM、ジクロフェナク(Diclofenac)10μM、S-メフェニトイン(Smephenytoin)100μM、デキストロメトルファン(Dextromethorphan)5μM及びミダゾラム(Midasolam)2.5μM)及び化合物1、4、13及び15~18をそれぞれ0または10μMの濃度で添加して37℃で5分間予め培養した後、NADPH生成システム(NADPH generation system)溶液を添加し、37℃で15分間培養した。その後、内部標準物質(Terfenadine)を含むアセトニトリル溶液を添加して反応を終了し、5分間遠心分離(14,000rpm、4℃)した後、上清をLC-MS/MSシステムに注入して基質薬物の代謝物を同時に分析し、これら化合物の薬物代謝酵素阻害能を評価した。上記反応を通じて生成されたそれぞれのCYP同種酵素指標薬物の代謝物はShimadzu Nexera XRシステム及びTSQ vantage(Thermo)を用いて分析した。HPLCカラムとしては、Kinetex C18カラムを用い、移動相としては、0.1%のギ酸含有蒸溜水及び0.1%のギ酸含有アセトニトリルを用いた。生成された代謝物は多重反応モニタリング(multiple reaction monitoring;MRM)定量モードを用いて定量し、データはXcalibur(バージョン1.6.1)で分析した。実施例17及び18とVSC2によるそれぞれのCYP同種酵素に対する活性抑制能は上記化合物を添加していない陰性対照群に対する%活性に換算し、その結果を下記表6に示した。
代謝安定性は薬物の清掃率(clearance)、半減期(half-life)、経口的生体利用率(oral bioavailability)のような薬動学的変数(pharmacokinetic parameter PK parameter)に影響を及ぼし得る要因であるため、薬物候補群が備えるべき特性の1つである。これについて、薬物代謝の主要器官である肝臓による薬物の代謝程度を試験管内(in vitro)実験を通じて予測するために、肝ミクロゾームを用いて薬物の代謝安定性を評価した。具体的には、候補薬物、本発明の化合物中、化合物1、4、13、15及び17とVSC2をミクロゾームに処理して一定時間インキュベーションして残留する薬物の量を確認する、ミクロゾームを用いた安定性テストを行った。具体的には、ヒト肝ミクロゾーム(0.5mg/mL)と0.1Mのリン酸緩衝溶液(pH6.4)に化合物を1μMの濃度で添加して37℃で5分間予め培養した後、NADPH再生システム(NADPH regeneration system)溶液を添加して37℃で30分間培養した。その後、内部標準物質(chloropropamide)を含むアセトニトリル溶液を添加して反応を終了し、5分間遠心分離(14,000rpm、4℃)した後、上清をLC-MS/MSシステムに注入して基質薬物を分析することにより、これら化合物に関する代謝安定性を評価した。上記反応を通じて残留する基質の量はShimadzu Nexera XRシステム及びTSQ vantageを用いて分析した。HPLCカラムとしては、Kinetex C18カラムを用い、移動相としては、0.1%のギ酸含有蒸溜水及び0.1%のギ酸含有アセトニトリルを用いた。データはXcalibur(バージョン1.6.1)で分析し、その結果を下記表7に示した。
新薬の開発において薬物の溶解度は、生体吸収率と連関する非常に重要な要因の1つである。例えば、水溶液に対する溶解度が低い化合物は全般的に低い生体吸収率を示すことがある。また、低い溶解度の薬物は組織内で結晶化したり深刻な毒性を誘発することがあるため、FDAは低い溶解度を有する経口薬物に対して付加的な研究結果を要求している。さらに、低い溶解度は候補物質の開発において失敗する最大の原因になることもある。これに対し、本発明の化合物1~18に対し、水に対する溶解度を測定し、その結果、置換基としてモルホリニル基を含む化合物である化合物15及び16が高い溶解度を示すことを確認した。具体的には、化合物15は10mg/mL以上の高い溶解度を示した。これは、モルホリニル基を導入した化合物15が対照群、即ち、既存のNrf2の活性化を誘導することが知られている合成化合物であるVSC2の溶解度(≦0.01mg/mL)より卓越した溶解度を有することを示した。また、これは、薬物の考案の時にモルホリニル基の導入により溶解度を向上させられることを示すものである。
hERG(human ether-a-go-go related gene)イオンチャネルは、心室再分極の重要な要素であり、このチャネルの阻害剤は不整脈と突然死を誘発することがある。従って、新薬開発の過程で候補物質がhERGイオンチャネルの潜在的な阻害剤であると確認される場合、心臓毒性による副作用を誘発することがあるため、これを最小化する努力が必要である。蛍光性hERGチャネル追跡者(tracer)をhERGチャネルタンパク質が含まれた膜に結合させれば、追跡者の回転(rotation)が制限され、高い分極化(polarization)状態を維持するようになるが、hERGチャネルに競争的阻害剤が結合する場合、追跡者が膜から競争的に押し出され、方向性を喪失して脱分極化する原理を用いて、本発明の化合物のhERG結合阻害能を確認した。本発明の化合物としては、優れた薬理活性を示しながら水溶液に対する高い溶解度を示して高い生体吸収率が期待される化合物15を代表として選択した。陽性対照群としては、E-4031化合物を3倍に段階的に希釈させた後、予め準備されたhERGチャネルが含まれた膜と蛍光性追跡者と共に混合して4時間の間反応させた後、濃度による分極化値を測定してIC50値を算出した。上記化合物15に対しても多様な濃度で蛍光強度を測定した後、対照群と比較してIC50値を算出し、その結果として化合物15は20μMのIC50値を有することを確認した。これは、本発明の化合物は、高い20μM以上の高濃度で心臓毒性を示すため、安全性が確保された化合物であることを示すものである。
上記実験例1を通じて、本発明の化合物によるNrf2活性化を間接的に確認した。これについて、Nrf2活性化に対する本発明の化合物の効果を直接的に確認するために、ウェスタンブロットを行った。本発明により合成した代表的な化合物として化合物15を選択し、これを濃度別に処理し、Nrf2の核内累積有無及び/又は程度を確認した。具体的には、BV2細胞を25Tフラスコで2×106細胞/フラスコの密度で4mLずつ分注してRPM1640培地に24時間の間培養した。翌日化合物15をDMSO 0.1%の条件で最終濃度0~10μMになるようにそれぞれの培地に混合して準備した後、細胞を入れて6時間の間培養した。培養した細胞は回収して核と細胞質抽出物を分離した。分離した核抽出物は10%のSDS-PAGEで電気泳動し、PVDF膜に移転した後、ウシ血清アルブミン(bovine serum albumin;BSA)で遮断(blocking)した。その後、抗-Nrf2抗体を用いて核内のNrf2タンパク質量を測定し、その結果を図1に示した。核抽出物の同一量を意味するラミン(Lamin)B1比でNrf2量を測定した。
Nrf2は転写因子であり、核内で抗酸化酵素を増加させて細胞を保護する役割をする。先の実験例1及び実験例6を通じて本発明の化合物によるNrf2活性化を直接・間接的に確認した。これについて、ウェスタンブロットを用いて抗酸化酵素の量を測定することにより、これら活性化されたNrf2が抗酸化酵素を増加させるかを確認した。検出しようとする抗酸化酵素としては、Nrf2により発現が増加することが知られているGCLC、GCLM及びHO-1を選択した。具体的には、BV2細胞を6-ウェルプレートで5×105細胞/ウェルの密度で1.5mLずつ分注してRPM1640培地に24時間の間培養した。翌日、化合物15をDMS0 0.1%の条件で最終濃度0~10μMになるようにそれぞれの培地に混合して準備した後、細胞を入れて24時間の間培養した。培養した細胞は回収して溶解させて全体タンパク質を抽出し、10%のSDS-PAGEで電気泳動した。電気泳動した全体抽出物をPVDF膜に移転した後、ウシ血清アルブミンで遮断した。その後、各抗酸化酵素に対応する抗体を用いて細胞内に発現された抗酸化酵素の量を測定し、その結果を図2に示した。
上記実験例6及び7では、試験管内実験を通じて本発明の化合物15が細胞内Nrf2を活性化し、抗酸化酵素の発現を増加させることを直接的に立証した。これについて、上記本発明の化合物が動物モデルでも細胞保護効果を奏するかを確認するために、神経毒性物質であるMPTP(1-methyl-4-phenyl-1, 2, 3, 6tetrahydropyridine)を投与してドーパミン性神経細胞のみを死滅させてパーキンソン病を誘導したマウス動物モデルを用いた。具体的に考案された動物実験の日程を図3の上段に示した。動物モデルとしては、10週齢のC57/BL6マウスを用い、生理食塩水を腹腔注入し、化合物15を含まない溶液を口腔投与した陰性対照群;MPTPを腹腔注入し、化合物15を含まない溶液を口腔投与した陽性対照群;及びMPTPを腹腔注入し、化合物15を含む溶液を口腔投与した実験群の3つ群に分けて動物実験モデルを準備した。MPTP誘導パーキンソン病モデルは20mg/kgのMPTPを1日に2時間の間隔で計4回腹腔注入して製造した。陰性対照群には同一時点にMPTPを含まない生理食塩水を注入した。パーキンソン病の誘導如何を確認するために、パーキンソン病の主要症状として知られているドーパミン性神経細胞死滅による運動障害を垂直グリッド(vertical grid)テスト及びコートハンガー(coat-hanger)テストで確認した。化合物15はMPTP注入の前日から3日間1日1回20mg/mLの用量で経口投与し、MPTP注入日から6日が経過した後、行動実験を実施してその結果をそれぞれ図3の中央と下段に示した。
上記実験例8の結果から、本発明の化合物による運動能力回復効果を確認した。このような運動能力の回復が本発明の化合物による神経保護効果によるものであるかを確認するために、マウスから脳を摘出してドーパミン性神経細胞の標識として用いられるチロシン水酸化酵素を用いた免疫組織化学染色法で分析した。分析のための部位としては、ドーパミン性神経細胞が密集した線条体及び黒質を選択した。
薬物候補群として、本発明の化合物の効果を立証するために、Nrf2活性化を誘導することが知られている公知のカルコン誘導体中、優れた活性を有する2種の化合物、(E)-1-クロロ-2-(2-(2-メトキシフェニルスルホニル)ビニル)ベンゼン((E)-1-chloro-2-(2-(2-methoxyphenylsulfonyl)vinyl)benzene、VSC2、比較例1)及び(E)-2-クロロ-3-(2-(2-メトキシフェニルスルホニル)ビニル)ピリジン((E)-2-chloro-3-(2-(2methoxyphenylsulfonyl)vinyl)pyridine、比較例2)を合成して比較例として用いた。これら化合物は、韓国登録特許第10-1438655号(特許文献1)及びJ. Med. Chem.、2014、57:1473-1487(非特許文献3)に開示された。実際の薬物としての有用性を確認するために、Nrf2活性誘導効果の以外に、生体利用率と関連する溶解度、代謝安定性及び心臓毒性と関連するhERGチャネル結合阻害能を共に確認し、その結果を下記表8に示した。
Claims (23)
- 上記化合物は
1.(E)-3-フルオロ-2-(2-(2-フルオロフェニルスルホニル)ビニル)ピリジン、
2.(E)-3-フルオロ-2-(2-(3-フルオロフェニルスルホニル)ビニル)ピリジン、
3.(E)-3-フルオロ-2-(2-(4-フルオロフェニルスルホニル)ビニル)ピリジン、
4.(E)-3-クロロ-2-(2-(2-フルオロフェニルスルホニル)ビニル)ピリジン、
5.(E)-3-クロロ-2-(2-(3-フルオロフェニルスルホニル)ビニル)ピリジン、
6.(E)-3-クロロ-2-(2-(4フルオロフェニルスルホニル)ビニル)ピリジン、
7.(E)-2-(2-(2-クロロフェニルスルホニル)ビニル)-3-フルオロピリジン、
8.(E)-2-(2-(3-クロロフェニルスルホニル)ビニル)-3-フルオロピリジン、
9.(E)-2-(2(4-クロロフェニルスルホニル)ビニル)-3-フルオロピリジン、
10.(E)-3-クロロ-2-(2-(2-クロロフェニルスルホニル)ビニル)ピリジン、
11.(E)-3-クロロ-2-(2-(3-クロロフェニルスルホニル)ビニル)ピリジン、
12.(E)-3-クロロ-2-(2-(4-クロロフェニルスルホニル)ビニル)ピリジン、
13.(E)-2-クロロ-6-(2-(2-クロロフェニルスルホニル)ビニル)ピリジン、または
14.(E)-2-クロロ-3-(2-(2-クロロフェニルスルホニル)ビニル)ピリジンである、請求項1に記載の化合物またはこの薬学的に許容可能な塩。 - 上記化合物は
16.(E)-4-(3-(3-(2-(3-フルオロピリジン-2-イル)ビニルスルホニル)フェノキシ)プロピル)モルホリンである、請求項2に記載の化合物またはこの薬学的に許容可能な塩。 - 上記化合物は
17.(E)-2-(4-(2-(3-フルオロピリジン-2-イル)ビニルスルホニル)フェノキシ)-1-(4-メチルピペラジン-1-イル)エタノンまたは
18.(E)-2-(4-(2-(3-クロロピリジン-2-イル)ビニルスルホニル)フェノキシ)-1-(4-メチルピペラジン-1-イル)エタノンである、請求項3に記載の化合物またはこの薬学的に許容可能な塩。 - ジエチル((R1置換されたフェニル)スルホニル)メチルホスホネートをハロピコリンアルデヒドと反応させる段階を含む、請求項1~3のいずれか一項に記載の化合物またはこの薬学的に許容可能な塩の製造方法。
- 上記反応は無水有機溶媒の条件下に、ジエチル((R1置換されたフェニル)スルホニル)メチルホスホネートとハロピコリンアルデヒドとの混合物を-100~-60℃に冷却させた後、ブチルリチウムを添加して反応させて行う、請求項7に記載の製造方法。
- 上記反応の後、過量の酸性溶液と反応させる段階をさらに含む、請求項7に記載の製造方法。
- 第a-1段階は、有機溶媒に(ヒドロキシ-C1-5アルキル)モルホリンを溶解させた溶液にメタンスルホニルハライド及び塩基を-10~10℃で添加した後、10~35℃で反応させて行う、請求項10に記載の製造方法。
- 第a-2段階は、反応物を10~35℃で混合し、ジエチル(ヒドロキシフェニルスルホニル)メチルホスホネート使用量を基準に1~2当量のK2CO3の存在下に70~90℃に加熱して行う、請求項10に記載の製造方法。
- 上記R1が
ジエチル(ヒドロキシフェニルスルホニル)メチルホスホネートをC1-4アルキルハロアセテートと反応させてC1-4アルキル(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)アセテートを製造する第b-1段階;
エチル(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)アセテートを塩基性溶液と酸性溶液で順に処理して(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)酢酸に転換する第b-2段階;及び
(((ジエトキシホスホリル)メチルスルホニル)フェノキシ)酢酸を2~4倍当量のカルボニルジイミダゾールの存在下にピパレジンまたは1-(C1-4アルキル)ピペラジンと反応させてジエチル((2-(4-ピペラジン-1-イル)-2オキソエトキシ)フェニルスルホニル)メチルホスホネートまたはジエチル((2-(4-(C1-4アルキル)ピペラジン-1-イル)-2-オキソエトキシ)フェニルスルホニル)メチルホスホネートを製造する第b-3段階;を通じて準備される、請求項7に記載の製造方法。 - 第b-1段階は、ジエチル(ヒドロキシフェニルスルホニル)メチルホスホネートの使用量を基準に1~2当量のK2CO3の存在下に80~100℃に加熱して行う、請求項13に記載の製造方法。
- 第b-2段階は、10~40℃で行う、請求項13に記載の製造方法。
- 第b-3段階は、10~40℃でカルボニルジイミダゾールと反応させた後、ピペラジンまたは1-(C1-4アルキル)ピペラジンを添加して10~40℃で反応させて行う、請求項13に記載の製造方法。
- 上記ジエチル(ヒドロキシフェニルスルホニル)メチルホスホネートは
ジエチルヒドロキシメチルホスホネートをトルエンスルホニルハライドと反応させて(ジエトキシホスホリル)メチルメチルベンゼンスルホネートを製造する第c-1段階;
(ジエトキシホスホリル)メチルメチルベンゼンスルホネートをメルカプトフェノールと反応させて(ヒドロキシフェニルチオ)メチルホスホネートを製造する第c-2段階;及び
(ヒドロキシフェニルチオ)メチルホスホネートにメタークロロ過安息香酸(meta-chloroperoxybenzoic acid;mCPBA)を0℃で加えた後、室温で攪拌しながら反応させる第c-2段階を通じて準備される、請求項10に記載の製造方法。 - 上記ジエチル(ヒドロキシフェニルスルホニル)メチルホスホネートは
ジエチルヒドロキシメチルホスホネートをトルエンスルホニルハライドと反応させて(ジエトキシホスホリル)メチルメチルベンゼンスルホネートを製造する第c-1段階;
(ジエトキシホスホリル)メチルメチルベンゼンスルホネートをメルカプトフェノールと反応させて(ヒドロキシフェニルチオ)メチルホスホネートを製造する第c-2段階;及び
(ヒドロキシフェニルチオ)メチルホスホネートにメタークロロ過安息香酸(meta-chloroperoxybenzoic acid;mCPBA)を0℃で加えた後、室温で攪拌しながら反応させる第c-2段階を通じて準備される、請求項13に記載の製造方法。 - 各段階の後、次の段階に進行する以前に、選択的に生成された化合物を分離する段階、精製する段階または両方をいずれも順に行う段階をさらに含む、請求項7に記載の製造方法。
- 各段階は、メチレンクロリド(methylene chloride;MCまたはdichloromethane;DCM)、ジメチルホルムアミド(dimethylformamide;DMF)、アセトニトリル(acetonitrile;ACNまたはMeCN)、エタノール及びテトラヒドロフラン(tetrahydrofuran;THF)で構成された群から選択される有機溶媒に溶解させた溶液で行う、請求項7に記載の製造方法。
- 請求項1~3のいずれか一項に記載の化合物またはこの薬学的に許容可能な塩を有効成分として含むNrf2(nuclear factor erythroid-derived 2-related factor 2)活性化剤。
- 請求項1~3のいずれか一項に記載の化合物またはこの薬学的に許容可能な塩を有効成分として含むNrf2活性の低下により誘導される疾患の予防または治療用薬学的組成物であって、
上記Nrf2活性の低下により誘導される疾患はアルコール性肝臓疾患(alcoholic liver disease)、非アルコール性肝臓疾患(non-alcoholic liver disease)、非アルコール性脂肪肝(non-alcoholic fatty liver disease;NAFLD)、慢性肝臓損傷(chronic liver injury)、ウイルス性肝炎(viral hepatitis)及び肝細胞癌種(hepatocellular carcinoma)で構成された群から選択される肝臓疾患(liver diseases);糖尿病性腎症(diabetic nephropathy)、巣状糸球体硬化症(focal segmental glomerulosclerosis)、腎線維症(renal fibrosis)、ループス-様自己免疫性腎炎(lupus-like autoimmune nephritis)、慢性腎臓疾患(chronic kidney disease;CKD)、及び高血圧性腎臓疾患(hypertensive kidney disease)で構成された群から選択される腎臓疾患(kidney diseases);慢性閉塞性肺疾患(chronic obstructive pulmonary disease;COPD)、肺気腫(pulmonary emphysema)、人工呼吸器関連肺傷害(ventilation-associated lung injury)、急性肺損傷(acute lung injury; ALI)、急性呼吸困難症候群(acute respiratory distress syndrome;ARDS)、肺動脈高血圧(Pulmonary artery hypertension;PAH)及び上記肺動脈高血圧により誘導される右心不全(right heart failure)で構成された群から選択される肺疾患(pulmonary diseases);パーキンソン病(Parkinson's disease;PD)、アルツハイマー認知症(Alzheimer's disease;AD)、ハンチントン病(huntington's disease)、ルー・ゲーリッグ病(Lou Gehrig's disease)、癲癇(epilepsy)、うつ病(depression)、不眠症(insomnia)、不安症(anxiety)及び多発性硬化症(Multiple sclerosis;MS)で構成された群から選択される神経退行性疾患(neurodegenerative diseases);ミトコンドリア筋症(Mitochondrial myopathy);フリードライヒ運動失調症(Friedreich's ataxia);角膜内皮細胞減少(Corneal endothelial cell loss);または乾癬(Psoriasis)である、薬学的組成物。 - 薬学的に許容可能な担体、希釈剤または賦形剤をさらに含む、請求項22に記載の薬学的組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2018-0096167 | 2018-08-17 | ||
KR1020180096167A KR102127407B1 (ko) | 2018-08-17 | 2018-08-17 | 신규한 할로-(3-(페닐설포닐)프로프-1-에닐)피리딘 유도체 및 이의 용도 |
PCT/KR2019/010513 WO2020036474A1 (ko) | 2018-08-17 | 2019-08-19 | 신규한 할로-(3-(페닐설포닐)프로프-1-에닐)피리딘 유도체 및 이의 용도 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021534191A JP2021534191A (ja) | 2021-12-09 |
JP7163482B2 true JP7163482B2 (ja) | 2022-10-31 |
Family
ID=69525720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021508298A Active JP7163482B2 (ja) | 2018-08-17 | 2019-08-19 | 新規なハロ-(3-(フェニルスルホニル)プロプ-1-エニル)ピリジン誘導体及びこの用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210317083A1 (ja) |
EP (1) | EP3838896A4 (ja) |
JP (1) | JP7163482B2 (ja) |
KR (1) | KR102127407B1 (ja) |
CN (1) | CN112930345A (ja) |
WO (1) | WO2020036474A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102588612B1 (ko) | 2021-01-25 | 2023-10-16 | 한국과학기술연구원 | 인지 장애 예방 또는 개선용 조성물 |
KR20230168233A (ko) * | 2022-06-03 | 2023-12-13 | 한국과학기술연구원 | 신규한 설파논 유도체 또는 이의 약학적으로 허용가능한 염 및 이의 용도 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5510490A (en) * | 1994-01-11 | 1996-04-23 | Council Of Scientific & Industrial Research | Process for the preparation of epibatidine |
US6548553B2 (en) * | 1997-10-03 | 2003-04-15 | Temple University-Of The Commonwealth System Of Higher Education | Styryl sulfone anticancer agents |
KR100567125B1 (ko) * | 2001-11-01 | 2006-03-31 | 주식회사 안지오랩 | 칼콘 또는 이의 유도체를 함유하는 매트릭스메탈로프로테아제 활성 억제용 약학 조성물 |
KR101438655B1 (ko) * | 2012-04-30 | 2014-09-17 | 한국과학기술연구원 | 산화질소 생성 억제 효과와 Nrf2 활성 효과를 통해 뇌신경 질환 예방 및 치료용으로 사용 가능한 활성화된 비닐기를 포함하는 벤질 유도체 화합물 및 이의 약학조성물 |
EP2968331B1 (en) * | 2013-03-14 | 2020-07-01 | Icahn School of Medicine at Mount Sinai | Pyrimidine compounds as kinase inhibitors |
EP4180041A1 (en) * | 2014-08-07 | 2023-05-17 | Mayo Foundation for Medical Education and Research | Compounds and methods for treating cancer |
-
2018
- 2018-08-17 KR KR1020180096167A patent/KR102127407B1/ko active IP Right Grant
-
2019
- 2019-08-19 EP EP19849176.3A patent/EP3838896A4/en active Pending
- 2019-08-19 WO PCT/KR2019/010513 patent/WO2020036474A1/ko unknown
- 2019-08-19 US US17/268,958 patent/US20210317083A1/en active Pending
- 2019-08-19 CN CN201980068425.7A patent/CN112930345A/zh active Pending
- 2019-08-19 JP JP2021508298A patent/JP7163482B2/ja active Active
Non-Patent Citations (1)
Title |
---|
Journal of Medicinal Chemistry,2018年12月12日,Vol.62,pp.811-830 |
Also Published As
Publication number | Publication date |
---|---|
EP3838896A1 (en) | 2021-06-23 |
KR102127407B1 (ko) | 2020-07-07 |
JP2021534191A (ja) | 2021-12-09 |
KR20200020443A (ko) | 2020-02-26 |
CN112930345A (zh) | 2021-06-08 |
US20210317083A1 (en) | 2021-10-14 |
WO2020036474A1 (ko) | 2020-02-20 |
EP3838896A4 (en) | 2022-04-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11091478B2 (en) | Apoptosis-inducing agents | |
JP6517827B2 (ja) | イソインドリン組成物および神経変性疾患の治療方法 | |
JP6121339B2 (ja) | 芳香環化合物 | |
EP1527048B1 (fr) | Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique | |
KR101123178B1 (ko) | 2-아릴벤조싸이오펜 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 진단 또는 치료용 약학적 조성물 | |
TW201738226A (zh) | 雜環化合物 | |
IL187881A (en) | Sphingosine kinase-inhibiting compounds, containing pharmaceuticals and their use in the preparation of a drug to treat diseases characterized by abnormal sphingosine kinase activity | |
JP7163482B2 (ja) | 新規なハロ-(3-(フェニルスルホニル)プロプ-1-エニル)ピリジン誘導体及びこの用途 | |
JP2003528046A (ja) | フェノキシプロパノールアミン類、それらの製造および治療的使用 | |
EA020320B1 (ru) | Акриламидопроизводные, применимые как ингибиторы перехода митохондриальной проницаемости | |
TWI250152B (en) | N,N-substituted cyclic amine compounds used as calcium antagonizer | |
US20230122912A1 (en) | Methods and Compositions of 4-Substituted Benzoylpiperazine-1-Substituted Carbonyls as Beta-Catenin/B-Cell Lymphoma 9 Imhibitors | |
DK2207776T3 (en) | Drug active in neuropathic pain | |
EP0360685B1 (fr) | "[(diarylméthoxy) alcoyl] - 1 pyrrolidines et piperidines, procédés de préparation et médicaments les contenant" | |
TW401417B (en) | 4-Aryloxy- and 4-arylthiopiperidine derivatives | |
JP2019523256A (ja) | ボルチオキサチン類似化合物、その用途及びその製造 | |
EA022043B1 (ru) | Сульфоновые соединения в качестве лигандов 5-htрецептора | |
CN110770209B (zh) | 用作p2x1及p2x3受体拮抗剂的新型5-羟基吡啶类化合物及包含其的药物组合物 | |
JP5302214B2 (ja) | Trpv1受容体拮抗薬としてのo−置換ジベンジル尿素誘導体 | |
RU2422447C2 (ru) | Предшественники антиаритмических соединений, способы синтеза и способы применения | |
US20190135746A1 (en) | Indoline derivatives and method for using and producing the same | |
KR20130082453A (ko) | 아밀로이드 병리의 치료 및 예방을 위한 플루페녹신 유도체 | |
CN106810532A (zh) | 一类胺烷氧基噻吨酮类化合物、其制备方法和用途 | |
RU2774618C2 (ru) | Соединение гризеофульвина и его фармацевтическое применение | |
CN108203439A (zh) | 苯乙烯吡啶类化合物、其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210217 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220308 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220608 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220805 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220927 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221019 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7163482 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |