CN112930345A - 新型卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物及其用途 - Google Patents
新型卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物及其用途 Download PDFInfo
- Publication number
- CN112930345A CN112930345A CN201980068425.7A CN201980068425A CN112930345A CN 112930345 A CN112930345 A CN 112930345A CN 201980068425 A CN201980068425 A CN 201980068425A CN 112930345 A CN112930345 A CN 112930345A
- Authority
- CN
- China
- Prior art keywords
- compound
- ethenyl
- disease
- pyridine
- reaction
- 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.)
- Pending
Links
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 claims abstract description 80
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 claims abstract description 80
- 230000000694 effects Effects 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 201000010099 disease Diseases 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 239000012190 activator Substances 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 145
- -1 Chloro-6- (2- (2-chlorobenzenesulfonyl) ethenyl) pyrimidine Chemical compound 0.000 claims description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 79
- 238000006243 chemical reaction Methods 0.000 claims description 68
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 15
- 208000018737 Parkinson disease Diseases 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
- 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 10
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 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 8
- 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 8
- 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 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 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 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 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 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 208000004683 Corneal Endothelial Cell Loss Diseases 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 206010014561 Emphysema Diseases 0.000 claims description 4
- 206010019799 Hepatitis viral Diseases 0.000 claims description 4
- 206010055171 Hypertensive nephropathy Diseases 0.000 claims description 4
- 206010067125 Liver injury Diseases 0.000 claims description 4
- 208000004852 Lung Injury Diseases 0.000 claims description 4
- 208000019693 Lung disease Diseases 0.000 claims description 4
- 201000002169 Mitochondrial myopathy Diseases 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010039163 Right ventricular failure Diseases 0.000 claims description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 4
- 206010069363 Traumatic lung injury Diseases 0.000 claims description 4
- 239000003929 acidic solution Substances 0.000 claims description 4
- 206010069351 acute lung injury Diseases 0.000 claims description 4
- 230000001363 autoimmune Effects 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 231100000012 chronic liver injury Toxicity 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 230000000925 erythroid effect Effects 0.000 claims description 4
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 claims description 4
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 claims description 4
- 206010022437 insomnia Diseases 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 208000019423 liver disease Diseases 0.000 claims description 4
- 231100000515 lung injury Toxicity 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 201000008383 nephritis 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
- 201000002793 renal fibrosis Diseases 0.000 claims description 4
- 201000001862 viral hepatitis Diseases 0.000 claims description 4
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-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
- 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 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- LIGNRTLKAGDCRD-UHFFFAOYSA-N CP(=O)(O)OSC1=CC=CC=C1O Chemical compound CP(=O)(O)OSC1=CC=CC=C1O LIGNRTLKAGDCRD-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- RWIGWWBLTJLKMK-UHFFFAOYSA-N diethoxyphosphorylmethanol Chemical compound CCOP(=O)(CO)OCC RWIGWWBLTJLKMK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 238000003756 stirring Methods 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
- 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 claims description 2
- 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 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 206010003591 Ataxia Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 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 2
- 239000003637 basic solution Substances 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 150000002780 morpholines Chemical class 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000009423 ventilation Methods 0.000 claims description 2
- 230000003519 ventilatory effect Effects 0.000 claims description 2
- 239000003365 glass fiber Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 168
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 113
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 103
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 235000019439 ethyl acetate Nutrition 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 41
- 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 30
- 229940125758 compound 15 Drugs 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 239000003814 drug Substances 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- 229940079593 drug Drugs 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 23
- SUVMJBTUFCVSAD-UHFFFAOYSA-N sulforaphane Chemical compound CS(=O)CCCCN=C=S SUVMJBTUFCVSAD-UHFFFAOYSA-N 0.000 description 23
- 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
- 102000004190 Enzymes Human genes 0.000 description 19
- 108090000790 Enzymes Proteins 0.000 description 19
- 230000003078 antioxidant effect Effects 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 239000003963 antioxidant agent Substances 0.000 description 18
- 230000004913 activation Effects 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- SUVMJBTUFCVSAD-JTQLQIEISA-N 4-Methylsulfinylbutyl isothiocyanate Natural products C[S@](=O)CCCCN=C=S SUVMJBTUFCVSAD-JTQLQIEISA-N 0.000 description 11
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 210000005064 dopaminergic neuron Anatomy 0.000 description 11
- 229960005559 sulforaphane Drugs 0.000 description 11
- 235000015487 sulforaphane Nutrition 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 9
- 101150116862 KEAP1 gene Proteins 0.000 description 8
- 230000001939 inductive effect Effects 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 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
- 230000036542 oxidative stress Effects 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 7
- 108010044467 Isoenzymes Proteins 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 230000002503 metabolic effect Effects 0.000 description 7
- 108700032225 Antioxidant Response Elements Proteins 0.000 description 6
- NQLFRVRUTMRGLN-UHFFFAOYSA-N C=O.N1=CC(=CC=C1)Cl Chemical compound C=O.N1=CC(=CC=C1)Cl NQLFRVRUTMRGLN-UHFFFAOYSA-N 0.000 description 6
- 206010048610 Cardiotoxicity Diseases 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000007832 Na2SO4 Substances 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
- 239000002253 acid Substances 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 231100000259 cardiotoxicity Toxicity 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- PHFCAYFTCPEEJP-UHFFFAOYSA-N C=O.FC=1C=NC=CC1 Chemical compound C=O.FC=1C=NC=CC1 PHFCAYFTCPEEJP-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
- 108091023040 Transcription factor Proteins 0.000 description 5
- 102000040945 Transcription factor Human genes 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 210000001853 liver microsome Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 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 4
- 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 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
- 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
- 229940126657 Compound 17 Drugs 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 235000019253 formic acid Nutrition 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000700 radioactive tracer Substances 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 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 3
- 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 3
- 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 3
- 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 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 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 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
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-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
- 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 3
- 230000003213 activating effect Effects 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 235000006708 antioxidants Nutrition 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
- 230000008859 change Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000036267 drug metabolism Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 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 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 210000003523 substantia nigra Anatomy 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 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 2
- 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 2
- 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 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-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
- OZIMPUNGBUYCSP-UHFFFAOYSA-N 3-fluoropyridine-2-carbaldehyde Chemical compound FC1=CC=CN=C1C=O OZIMPUNGBUYCSP-UHFFFAOYSA-N 0.000 description 2
- YXIIXGYUTXRAIY-UHFFFAOYSA-N 3-morpholin-4-ylpropyl methanesulfonate Chemical compound CS(=O)(=O)OCCCN1CCOCC1 YXIIXGYUTXRAIY-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
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 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
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- 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 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
- 102100026517 Lamin-B1 Human genes 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002033 PVDF binder Substances 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
- 239000002202 Polyethylene glycol Substances 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
- 230000002411 adverse Effects 0.000 description 2
- 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 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
- 239000012131 assay buffer Substances 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
- 238000000423 cell based assay Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 235000005513 chalcones Nutrition 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013256 coordination polymer Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000001120 cytoprotective effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000008260 defense mechanism Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229960001985 dextromethorphan Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 238000009472 formulation Methods 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
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 108010052263 lamin B1 Proteins 0.000 description 2
- 239000007788 liquid 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
- 210000004185 liver Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 150000007524 organic acids Chemical class 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
- 239000008363 phosphate buffer Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 238000011160 research 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
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 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
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository 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
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 2
- 229950004616 tribromoethanol Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- YKRHKYFHYBFHEH-ZHACJKMWSA-N (2-methoxyphenyl) (E)-2-(2-chlorophenyl)ethenesulfonate Chemical compound COC1=CC=CC=C1OS(=O)(=O)/C=C/C2=CC=CC=C2Cl YKRHKYFHYBFHEH-ZHACJKMWSA-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
- STGNLGBPLOVYMA-MAZDBSFSSA-N (E)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O STGNLGBPLOVYMA-MAZDBSFSSA-N 0.000 description 1
- STGNLGBPLOVYMA-TZKOHIRVSA-N (z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O STGNLGBPLOVYMA-TZKOHIRVSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 description 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 description 1
- KHPAGGHFIDLUMB-UHFFFAOYSA-N 2-chloropyridine-3-carbaldehyde Chemical compound ClC1=NC=CC=C1C=O KHPAGGHFIDLUMB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 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
- OORRCVPWRPVJEK-UHFFFAOYSA-N 2-oxidanylethanoic acid Chemical compound OCC(O)=O.OCC(O)=O OORRCVPWRPVJEK-UHFFFAOYSA-N 0.000 description 1
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-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
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GMGHYIUKCDRGQR-UHFFFAOYSA-N C=O.ClC1=NC=CC=C1 Chemical compound C=O.ClC1=NC=CC=C1 GMGHYIUKCDRGQR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 208000012661 Dyskinesia Diseases 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
- 241000283073 Equus caballus 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
- 206010051301 Exercise tolerance decreased Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 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
- 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
- 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 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
- 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
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 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
- 206010039705 Scleritis Diseases 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282898 Sus scrofa 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
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 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
- 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
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000003125 aqueous solvent 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
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 1
- 238000009227 behaviour therapy Methods 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid 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
- 230000000903 blocking effect Effects 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- HTRXGEPDTFSKLI-UHFFFAOYSA-N butanoic acid;ethyl acetate Chemical compound CCCC(O)=O.CCOC(C)=O HTRXGEPDTFSKLI-UHFFFAOYSA-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
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 239000000969 carrier Substances 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- 210000004748 cultured cell Anatomy 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
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- RCSDMTWWPNXXPP-UHFFFAOYSA-N diethoxyphosphorylmethylsulfonylbenzene Chemical compound CCOP(=O)(OCC)CS(=O)(=O)C1=CC=CC=C1 RCSDMTWWPNXXPP-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000006739 dopaminergic cell death Effects 0.000 description 1
- 239000002552 dosage form Substances 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
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion 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
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 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
- GTTBQSNGUYHPNK-UHFFFAOYSA-N hydroxymethylphosphonic acid Chemical compound OCP(O)(O)=O GTTBQSNGUYHPNK-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 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
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 235000019860 lauric fat Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 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
- 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
- 230000028161 membrane depolarization 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
- 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
- KIEMOIGXXJFNIX-UHFFFAOYSA-N methyl 2-diethoxyphosphoryl-4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)c1cc(C)ccc1S(=O)(=O)OC KIEMOIGXXJFNIX-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 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
- 230000000813 microbial effect Effects 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
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000016273 neuron death Effects 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
- 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
- 235000005985 organic acids Nutrition 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
- 239000002245 particle Substances 0.000 description 1
- YKEKYBOBVREARV-UHFFFAOYSA-N pentanedioic acid Chemical compound OC(=O)CCCC(O)=O.OC(=O)CCCC(O)=O YKEKYBOBVREARV-UHFFFAOYSA-N 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
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000136 polysorbate 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
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- SXBRULKJHUOQCD-UHFFFAOYSA-N propanoic acid Chemical compound CCC(O)=O.CCC(O)=O SXBRULKJHUOQCD-UHFFFAOYSA-N 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
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 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
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 238000005096 rolling process Methods 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
- 229940001607 sodium bisulfite Drugs 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
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 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
- 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
- 230000001225 therapeutic effect Effects 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
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 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
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 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
-
- 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
- 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
-
- 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
-
- 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 System
- 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, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
Abstract
本发明涉及一种新型卤代‑(3‑(苯磺酰基)丙‑1‑烯)吡啶衍生物或其药学上可接受的盐、其制备方法以及作为有效成分含其的Nrf2活化剂及用于预防或治疗由Nrf2活性降低引起的疾病的药物组合物。
Description
技术领域
本发明涉及新型卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物或其药学上可接受的盐、其制备方法以及作为有效成分含其的Nrf2活化剂及用于预防或治疗由Nrf2活性降低引起的疾病的药物组合物。
背景技术
核因子红系衍生2相关因子2(nuclear factor erythroid-derived 2-relatedfactor 2,Nrf2)是碱性区域亮氨酸拉链的cap‘n’collar(CNC)家族(Cap'n'Collar familybasic region-leuzine zip per)的转录因子,与涉及保护细胞的各种基因表达的区域抗氧化反应元件(Antioxidant Response Element,ARE)序列结合以诱导基因转录。尽管并非所有抗氧化酶的表达都是由ARE诱导物质诱导的,但是通过利用被人为敲除该转录因子的Nrf2缺失小鼠的研究发现,抗氧化酶的表达是由ARE介导Nrf2活化诱导的。
Nrf2被Kelch一样的ECH相关蛋白1(Kelch-like ECH associated protein,Keap1)负调控。在无氧化应激条件下,Nrf2与Keap1结合而泛素化被蛋白酶体分解,但在氧化应激条件下,通过修饰Keap1的半胱氨酸残基,与Nrf2的结合发生分离,Nrf2进入细胞核并与ARE结合,增加了启动子区域中各种抗氧化基因的转录。
在天然产物、食品、代谢物、有机合成化合物等中,已发现通过Nrf2-Keap1途径引起保护基因转录的各种结构的化合物。目前已知的所有化合物都是能与Keap1的半胱氨酸反应的亲电化合物,或者是通过细胞内代谢过程转变为亲电化合物的化合物。此类亲电化合物或活性氧与Keap1的半胱氨酸残基反应以氧化硫醇基团,或形成共价键以引起Keap1的结构改变。由于Keap1半胱氨酸残基的变化而分离出的Nrf2移向细胞核并与ARE结合,从而诱导抗氧化酶的表达。有报道称,Nrf2活化剂通过使用亲电化合物预活化Nrf2-Keap1通路,作为一种抗氧化应激的化学防御机制,可以预防退行性脑疾病的发展。
萝卜硫烷(1-异硫氰酸-4-甲基亚磺酰基丁烷,1-isothiocyanato-4-methylsulfinylbutane)是一种能与Keap1半胱氨酸残基发生反应的药物,主要存在于西兰花、大白菜等十字花科植物中,通过活化Nrf2保护多巴胺能神经细胞免受氧化应激。但是,萝卜硫烷可以通过非选择性地使具有硫醇基团的细胞中的各种蛋白质变性来诱导细胞毒性,并且具有血脑屏障通透性非常低的缺点。另外,由于其在体内给药后在1小时以内消失,因此诱导Nrf2活性的效果无法持续,因此为了显示一定的活性而以高浓度给药时会引起细胞毒性。
因此,有必要开发一种能够克服现有Nrf2活化剂存在的问题的新型Nrf2活化剂。在此背景下,已发现VSC2是一种在一系列查尔酮衍生物中具有优异活性的化合物,已知该类查尔酮衍生物可通过Keap1的结构变化诱导Nrf2的活化(Woo等人,Journal ofMedicinal Chemistry 2014,57,1473–1487)。然而,VSC2在体内给药时生物利用率和药物代谢稳定性较低,在水中的溶解度较低,并且具有药物引起的心脏毒性,因此,仍然需要寻找一种能够克服这些问题的药物。
发明内容
技术问题
本发明的发明人们为了研发用于预防或治疗由氧化应激引起的各种疾病的,活化参与抗氧化应激的防御机制的Nrf2的新型小分子化合物而经过广泛研究努力,证实了在(乙烯基磺酰基)苯结构的乙烯基中卤代吡啶基被取代,并且在苯环中卤素、烷基哌嗪基或吗啉基被取代的衍生物有效地活化了Nrf2,并且在活性浓度下不显示毒性,从而完成了本发明。
技术方案
本发明的第一个方面提供如下化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
在所述化学式1中,
R2是氢或C1-4烷基,
n是1到5的整数,
X是卤素。
本发明的第二方面提供一种制备第一方面的化合物或其药学上可接受的盐的方法,该方法包括使((R1-取代苯基)磺酰基)甲基膦酸二乙酯与卤代吡啶醛反应的步骤。
本发明的第三方面提供一种Nrf2活化剂,包括第一方面的化合物或其药学上可接受的盐作为有效成分。
本发明的第四方面提供一种用于预防或治疗由Nrf2活性降低引起的疾病的药物组合物,包括第一方面的化合物或其药学上可接受的盐作为有效成分。
本发明的第五方面提供一种预防或治疗个体中Nrf2活性降低引起的疾病的方法,包括将第四方面的药物组合物施用于有需要的个体的步骤。
发明效果
本发明的新型卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物可以活化Nrf2,因此可以有效地用于治疗或预防由Nrf2活性降低引起的疾病。
附图说明
图1是示出根据本发明一个实施例的根据化合物的浓度的核中Nrf2的活化的定量分析结果的示意图;
图2是示出根据本发明一个实施例的根据化合物的浓度的Nrf2活化和与之相关的一系列抗氧化酶、GCLC、GCLM和HO-1的和表达的定量分析结果的示意图;
图3是显示MPTP诱导帕金森氏病动物试验模型和使用该模型测量的根据本发明一个实施例的化合物对运动能力的效果的示意图;
图4是示出根据本发明一个实施例的化合物对MPTP诱导的帕金森氏病动物试验模型中的多巴胺能神经细胞的保护效果的示意图。
具体实施方式
本发明的第一方面提供如下化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
在所述化学式1中,
R2是氢或C1-4烷基,
n是1到5的整数,
X是卤素。
例如,本发明的化合物可以是R1为氯或氟且X为氯或氟的化合物。
具体地,所述化合物可以是:
1、(E)-3-氟-2-(2-(2-氟苯磺酰基)乙烯基)吡啶,
2、(E)-3-氟-2-(2-(3-氟苯磺酰基)乙烯基)吡啶,
3、(E)-3-氟-2-(2-(4-氟苯磺酰基)乙烯基)吡啶,
4、(E)-3-氯-2-(2-(2-氟苯磺酰基)乙烯基)吡啶,
5、(E)-3-氯-2-(2-(3-氟苯磺酰基)乙烯基)吡啶,
6、(E)-3-氯-2-(2-(4-氟苯磺酰基)乙烯基)吡啶,
7、(E)-2-(2-(2-氯苯磺酰基)乙烯基)-3-氟吡啶,
8、(E)-2-(2-(3-氯苯磺酰基)乙烯基)-3-氟吡啶,
9、(E)-2-(2-(4-氯苯磺酰基)乙烯基)-3-氟吡啶,
10、(E)-3-氯-2-(2-(2-氯苯磺酰基)乙烯基)吡啶,
11、(E)-3-氯-2-(2-(3-氯苯磺酰基)乙烯基)吡啶,
12、(E)-3-氯-2-(2-(4-氯苯磺酰基)乙烯基)吡啶,
13、(E)-2?氯-6-(2-(2-氯苯磺酰基)乙烯基)嘧啶,
14、(E)-2-氯-3-(2-(2-氯苯磺酰基)乙烯基)嘧啶,
15、(E)-4-(3-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉,
16、(E)-4-(3-(3-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉,
17、(E)-2-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮,或
18、(E)-2-(4-(2-(3-氯吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮。
本发明的化合物可以以药学上可接受的盐的形式存在。由药学上可接受的游离酸(free acid)形成的酸加成盐可用作所述盐。本文所使用的术语“药学上可接受的盐”是指具有对患者相对无毒性无害且起到有效作用的浓度,并且由所述盐引起的副作用不会损害所述化学式1所示化合物的有益作用的所述化合物的任何有机或无机加成盐。
酸加成盐可通过常规方法制备,例如通过将化合物溶解于过量酸水溶液中,然后使用水溶性有机溶剂,例如甲醇、乙醇、丙酮或乙腈来沉淀所述盐。可加热等摩尔量的化合物和水中的酸或醇(例如乙二醇单甲醚),然后可通过蒸发来干燥混合物,或可抽滤析出的盐。
在此,可使用有机酸和无机酸作为游离酸。作为无机酸,可以使用盐酸、磷酸、硫酸、硝酸、酒石酸等,作为有机酸,可以使用甲磺酸、对甲苯磺酸、乙酸、三氟乙酸、马来酸(maleic acid)、琥珀酸、草酸、苯甲酸、酒石酸、富马酸(fumaric acid)、扁桃酸、丙酸(propionic acid)、柠檬酸(citric acid)、乳酸(lactic acid)、乙醇酸(glycollicacid)、葡萄糖酸(gluconic acid)、半乳糖醛酸、谷氨酸、戊二酸(glutaric acid)、葡萄糖醛酸(glucuronic acid)、天冬氨酸、抗坏血酸、碳酸、香草醛酸、氢碘酸(hydroiodic acid)等,但不限于此。
此外,可使用碱制备药学上可接受的金属盐。例如,通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐,然后蒸发并干燥滤液,从而获得碱金属盐或碱土金属盐。在此,在药学方面,优选制备钠盐,钾盐或钙盐作为金属盐,但是不限于此。而且,可以通过使碱金属盐或碱土金属盐与合适的银盐(例如硝酸银)反应来获得对应于金属盐的银盐。
除非另外明确指出,否则本发明化合物的药学上可接受的盐可以包括可以存在于化学式1的化合物中的酸性或碱性基团的盐。例如,药学上可接受的盐可以包括羟基的钠盐、钙盐和钾盐,氨基的其他药学上可接受的盐可以包括氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐(甲磺酸盐)及对甲苯磺酸盐(甲苯磺酸盐)等。此外,这些盐可以通过本领域已知的制备方法来制备。
本发明化学式1的化合物的盐时药学上可接受的盐,只要是表现出与化学式1的化合物相同的药理活性的例如诱导Nrf2的活化的由化学式1所表示的化合物的盐则可以不受限制地被使用。
本发明的第二方面提供了一种用于制备第一方面的化合物或其药学上可接受的盐的方法,该方法包括使((R1-取代苯基)磺酰基)甲基膦酸二乙酯与卤代吡啶醛反应的步骤。
例如,所述本发明的制备方法可通过在无水有机溶剂条件下将((R1-取代苯基)磺酰基)甲基膦酸二乙酯和卤代吡啶醛的混合物冷却至-100℃至-60℃,然后添加丁基锂来实施,但不限于此,可以不受限制地通过本领域已知的方法来执行。
本发明的制备方法可以进一步包括在所述反应后与过量的酸性溶液反应以提供盐形式的化学式1所示的化合物,但不限于此。
例如,在本发明的制备方法中,当R1为时,用作反应物的((R1-取代苯基)磺酰基)甲基膦酸二乙酯可通过使(羟基-C1-5烷基)吗啉与甲磺酰卤化物反应制备吗啉基(C1-5烷基)甲磺酸盐第a-1步骤;以及使吗啉基(C1–5烷基)甲磺酸盐与(羟苯磺酰基)甲基膦酸二乙酯反应的第a-2步骤准备,但不限于此。例如,可以购买使用市售产品,或者可以不受限制地使用和/或使用本领域已知的修改后的方法合成的产品。
在此,所述第a-1步骤可以通过将甲磺酰卤化物和碱在-10℃至10℃下添加至将(羟基-C1-5烷基)吗啉溶解在有机溶剂中的溶液中,然后在10℃至35℃下进行反应来进行,但不限于此,可以不受限制地使用和/或变形本领域已知的反应来进行。
例如,三乙胺等叔胺可用作所述碱。然而,本发明的范围不限于此,并且只要能够提供碱性反应环境,就可以不受限制地使用本领域已知的碱性试剂,例如NaOH。
同时,所述第a-2步骤可以通过在10℃至35℃下混合反应物并在以(羟苯磺酰基)甲基膦酸二乙酯的使用量为基准存在1至2当量的K2CO3的情况下下加热至70℃至90℃来进行,但不限于此,可以不受限制地使用和/或变形本领域已知的反应来进行。
例如,在本发明的制备方法中,当R1为时,用作反应物的((R1-取代苯基)磺酰基)甲基膦酸二乙酯可通过使(羟苯磺酰基)甲基膦酸二乙酯与C1-4卤代乙酸烷基酯反应制备出C1-4烷基(((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸酯的第b-1步骤;通过顺序处理碱性溶液和酸性溶液,将(((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸乙酯转化为((((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸的第b-2步骤;以及在存在2至4当量的羰基二咪唑的情况下,使((((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸与哌嗪或1-(C1–4烷基)哌嗪反应来制备((2-(4-哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯或((2-(4-(C1-4烷基)哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯的第b-3步骤准备,但不限于此。例如,可以购买使用市售产品,或者可以不受限制地使用和/或修改本领域已知的方法合成的产品。
具体地,在本发明的制备方法中,第b-1步骤可以在以(羟苯磺酰基)甲基膦酸二乙酯的使用量为基准存在1至2当量的K2CO3的情况下加热到80℃到100℃来执行,但不限于此,可以不受限制地通过使用本领域已知的方法来进行。
例如,所述第b-2步骤可以在10℃至40℃下进行,但不限于此,并且对于本领域技术人员显而易见的是,可通过将反应温度控制在适当范围内来进行反应以提高反应的效率和/或产率。
此外,第b-3步骤可通过使得在10℃至40℃下与羰基二咪唑反应,然后添加哌嗪或1-(C1–4烷基)哌嗪,使其在10℃至40℃下反应,但不限于此,可以不受限制地通过使用和/或修改本领域已知的反应来进行。
另外,在本发明的制备方法中,第a-2步骤和第b-1步骤中用作反应物的(羟苯磺酰基)甲基膦酸二乙酯可以通过使羟甲基膦酸二乙酯与甲苯磺酰卤反应制备(二乙氧基磷酰基)甲基苯磺酸甲酯的第c-1步骤;使(二乙氧基磷酰基)甲基苯磺酸甲酯与巯基苯酚反应制备(羟基苯硫基)甲基膦酸酯的第c-2步骤;以及在0℃下将间氯过氧苯甲酸(meta-chloroperoxybenzoic acid;mCPBA)加入(羟基苯硫基)甲基膦酸酯,然后在室温搅拌的同时进行反应的第c-2步骤制备,但不限于此。例如,可以购买使用市售产品,或者可以不受限制地使用通过使用和/或修改本领域已知的方法合成的产品。
另外,为了提高反应的效率和/或产率,本发明的制备方法还可以包括在每一步骤之后和进行下一步骤之前,选择性地包括分离所生成的化合物的步骤、纯化步骤或依次执行所述两个步骤的步骤。可考虑前后步骤的反应条件和/或与之相关的物质而选择性地包括或不包括分离和/或纯化的步骤。
例如,在本发明的制备方法中,每一步骤可在利用选自二氯甲烷((methylenechloride;MC或dichloromethane;DCM)、二甲基甲酰胺(dimethylformamide;DMF)、乙腈(acetonitrile;CAN或MeCN)、乙醇及四氢呋喃(tetrahydrofuran;THF)的有机溶剂的溶液中进行,但不限于此。
本发明的第三方面提供了一种Nrf2活化剂,包含第一方面的化合物或其药学上可接受的盐作为有效成分。
本发明的第四方面提供了用于预防或治疗由Nrf2活性降低引起的疾病的药物组合物,包含第一方面的化合物或其药学上可接受的盐作为有效成分。
本发明化合物具有活化Nrf2的效果,Nrf2通过作用于抗氧化防御机制来调节对氧化应激的反应。因此它可以用作Nrf2活化剂,并且可以进一步用于预防或治疗由Nrf2活性降低引起的疾病。
本发明的术语“Nrf2(nuclear factor erythroid-derived 2-related factor2)”,是人类由NFE2L2基因编码的转录因子(transcription factor),是一种调节抗氧化蛋白的表达的碱性亮氨酸拉链蛋白(basic leucine zipper protein;bZIP),所述抗氧化蛋白保护损伤或炎症引起的氧化损伤。因此为了治疗氧化应激引起的疾病而正在研究活化Nrf2途径的药物。
本说明书的术语“预防”是指通过施用本发明组合物来抑制或延迟由Nrf2活性降低引起的疾病的发生、传播和复发的所有行为,“治疗”是指通过施用本发明组合物来减轻或有益地改变上述疾病的症状的所有行为。
如上所述,据报道,本发明化合物靶向的Nrf2通过其活化通过抗氧化剂防御机制参与了各种疾病的预防和治疗(O.Al-Sawaf et al.,Clinical Science,2015,129:989–999)。例如,可通过施用本发明组合物来预防或治疗由Nrf2活性降低引起的疾病的非限制性实例可包括:酒精性肝病(alcoholic liver disease)、非酒精性肝病(non-alcoholicliver disease)、非酒精性脂肪肝(non-alcoholic fatty liver disease;NAFLD)、慢性肝损伤(chronic liver injury)、病毒性肝炎(viral hepatitis)及肝细胞癌(hepatocellular carcinoma)等肝脏疾病(liver diseases);糖尿病性肾病(diabeticnephropathy)、局灶性节段性肾小球硬化症(focal segmental glomerulosclerosis)、肾纤维化(renal fibrosis)、狼疮样自身免疫性肾炎(lupus-like autoimmune nephritis)、慢性肾脏病(chronic kidney disease;CKD)及高血压性肾脏病(hypertensive kidneydisease)等肾脏疾病(kidney diseases);慢性阻塞性肺疾病(chronic obstructivepulmonary disease;COPD)、肺气肿(pulmonary emphysema)、通气相关性肺损伤(ventilation-associated lung injury)、急性肺损伤(acute lung injury;ALI)、急性呼吸窘迫综合征(acute respiratory distress syndrome;ARDS)、肺动脉高压(Pulmonaryartery hypertension;PAH)及由所述肺动脉高压所致右心衰(right heart failure)等肺部疾病(pulmonary diseases);帕金森氏病(Parkinson's disease;PD)、阿尔茨海默病(Alzheimer's disease;AD)、亨廷顿氏病(huntington's disease)、卢伽雷氏(LouGehrig's disease)病、癫痫(epilepsy)、抑郁症(depression)、失眠症(insomnia)、焦虑症(anxiety)和多发性硬化症(Multiple sclerosis;MS)等神经退行性疾病(neurodegenerative diseases);线粒体肌病(Mitochondrial myopathy);弗雷德里希共济失调(Friedreich's ataxia);角膜内皮细胞损失(Corneal endothelial cell loss);及银屑病(Psoriasis)。
本发明的组合物可进一步包括药学上可接受的载体、稀释剂或赋形剂,可根据使用目的按照常规方法剂型化成粉剂、颗粒剂、片剂、胶囊剂、悬浮液、乳剂、糖浆、气雾剂等口服制剂、无菌注射溶液等注射剂等多种形态使用,可以通过包括口服给药或静脉给药、腹腔给药、皮下给药、直肠给药、局部给药等各种途径给药。可包含在这种组合物中的适当载体、赋形剂和稀释剂的实例可以包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物质等。此外,本发明的组合物还可包含填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂、防腐剂等。
用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等。这些固体制剂通过向所述组合物混合至少一种赋形剂例如淀粉、碳酸钙、蔗糖、乳糖、明胶等制备。此外,除简单赋形剂外,还可使用诸如硬脂酸镁、滑石粉之类的润滑剂。
用于口服给药的液体制剂的实例包括悬浮液、内用液剂、乳液、糖浆等。除了通常使用的单纯稀释剂也就是水、液体石蜡之外还可以包括各种赋形剂,例如润湿剂、甜味剂、芳香剂、防腐剂等。
用于非口服给药的制剂可包括灭菌水溶液剂、非水溶剂、悬浮剂、乳剂、冻干制剂、栓剂。作为非水溶剂、悬浮液,可使用丙二醇、聚乙二醇、橄榄油之类的植物油、油酸乙酯之类的可注射酯等。作为栓剂的基质,可以使用威特松、聚乙二醇、吐温61、可可脂、月桂酸脂、甘油明胶等。同时,所述注射剂可包括常规添加剂,例如增溶剂、等渗剂、悬浮液、乳化剂、稳定剂、防腐剂等。
本发明的组合物可以以药物有效量施用。本说明书的术语“药物有效量”是指足以以可适用于医疗的合理益处/风险比率治疗疾病且不会引起不良反应的量,其有效剂量水平可以根据包括患者的健康状况、疾病的类型和严重程度、药物的活性、对药物的敏感性、给药方法、给药时间、给药途径和排泄率、疗程、配合或同时使用的药物在内的要素以及其他医学领域众所周知的要素来确定。本发明的组合物可以作为单独的治疗剂或与其他治疗剂组合施用,并且可以与常规治疗剂顺序施用或同时施用,或者可以单次施用或多次施用。重要的是鉴于上述所有要素以能够通过最小剂量达到最大效果且无不良反应的剂量施用组合物。这可以由本领域技术人员容易地确定。
例如,可以根据给药途径、疾病的严重程度、性别、体重、年龄等增减,因此所述剂量并不旨在以任何方式限制本发明的范围。
此外,本发明的第五方面提供了一种用于预防或治疗个体中Nrf2活性降低引起的疾病的方法,包括将第四方面的药物组合物施用到需要其的个体的步骤。
本说明书的术语“个体”是指患有或可发病由Nrf2活性降低引起的疾病的包括人、猴、牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔子或豚鼠在内的所有动物,可以通过向个体施用本发明的药物组合物有效地预防或治疗疾病。此外,本发明的药物组合物通过Nrf2活化表现出治疗效果,因此可通过与常规治疗剂并行给药以表现出协同效果。
本发明的术语“给药”是指通过任何适当的方法向患者提供所定物质。关于本发明的组合物的给药途径,可以通过能够到达目标组织的任何常规途径来给药。可经由腹腔内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、口服给药、局部给药、鼻内给药、肺内给药或直肠内给药施用,但不限于此。此外,本发明的药物组合物可提供能够将活性物质递送到靶细胞的任何装置给药。优选的给药方式和剂型包括静脉注射剂、皮下注射剂、皮内注射剂、肌肉注射剂、滴注注射剂等。注射剂可以使用生理盐水、林格溶液等水溶液、植物油、高级脂肪酸酯(例如油酸乙酯等)、醇类(例如乙醇、苯甲醇、丙二醇、甘油等)等非水溶液等制备,并且可以包括用于防止变质的稳定剂(例如,抗坏血酸、亚硫酸氢钠、焦亚硫酸钠、BHA、生育酚、EDTA等)、乳化剂、用于调节pH的缓冲剂、用于抑制微生物生长的防腐剂(例如,硝酸苯汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苯甲醇等)等药物载体。
本发明中与有效成分组合使用的术语“治疗有效量”是指在预防或治疗靶疾病中有效的卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物、其互变异构体或其医药上可接受的盐的量。
发明的实施方式
以下通过实施例更详细地描述本发明。然而,这些旨在更具体地进行说明,本发明的范围不限于这些实施例。
制备例1:(羟苯磺酰基)甲基膦酸二乙酯的合成
步骤1-1:由羟甲基膦酸二乙酯合成(二乙氧基磷酰基)4-甲基苯磺酸甲酯
按上述反应式合成了(二乙氧基磷酰基)4-甲基苯磺酸甲酯((diethoxyphosphoryl)methyl4-methylbenzenesulfonate)。具体地,将羟甲基膦酸二乙酯(diethyl hydroxymethylphosphonate,10g,0.06mol)溶解于二氯甲烷(methylenechloride;MC)中,依次加入三乙胺((triethylamine,9.80mL,0.07mmol)和4-甲苯磺酰氯(4-toluenesulfonyl chloride,13.3g,0.07mol),常温搅拌3.5小时。反应完成后,用乙酸乙酯(ethyl acetate;EtOAc)稀释反应液,用水和盐水(brine)洗涤,然后用无水Na2SO4干燥有机层并过滤。通过柱层析法(乙酸乙酯:正己烷=1:3)对减压蒸馏溶剂所得残渣进行纯化得到(二乙氧基磷酰基)4-甲基苯磺酸甲酯(10g),产率为52%。
黄油(yellow oil);
Rf=0.3(己烷:EtOAc=1:2);
1H NMR(400MHz,CDCl3):δ7.80(d,J=7.6Hz,2H),7.37(d,J=8.0Hz,2H),4.19–4.12(m,6H),2.46(s,3H),1.31(t,J=7.4Hz,6H)。
步骤1-2:与巯基苯酚反应合成(羟基苯硫基)甲基膦酸酯
根据上述反应式合成(2-,3-或4-取代苯硫基)甲基膦酸二乙酯(2-,3-or 4-substituted phen ylthio)methylphosphonate)。具体地,在邻位、间位或对位取代氟、氯或羟基的苯硫醇(1.0当量)溶解于二甲基甲酰胺(dimethylformamide;DMF)中,并依次添加碳酸铯(Cs2CO3,1.2eq)和在上述步骤1-1中合成的化合物(1.2eq),并在常温下搅拌3小时。反应完成后,用乙酸乙酯(EtOA c)稀释反应液,用水和盐水洗涤,然后用无水Na2SO4干燥有机层并过滤。通过柱层析法(乙酸乙酯:正己烷=1:3)对减压蒸馏溶剂所得残渣进行纯化得到(2-,3-,或4-取代苯硫基)甲基膦酸二乙酯(1-2a至1-2i)。各化合物的产率及其1H NMR鉴定结果如下所示。取代基的类型和位置如下表1所示。
[表1]
类别 | R | 类别 | R | 类别 | R |
1-2a | 邻位-F | 1-2b | 间位-F | 1-2c | 对位-F |
1-2d | 邻位-Cl | 1-2e | 间位-Cl | 1-2f | 对位-Cl |
1-2g | 邻位-OH | 1-2h | 间位-OH | 1-2i | 对位-OH |
*(2-氟苯硫基)甲基膦酸二乙酯(1-2a)
透明油状(colorless oil);
产率:83%;
Rf=0.30(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.18(t,J=6.9Hz,6H),3.43(d,J=13.8Hz,2H),3.97–4.04(m,4H),7.18–7.59(m,4H)。
*(3-氟苯硫基)甲基膦酸二乙酯(1-2b)
透明油状;
产率:86%;
Rf=0.35(己烷:EtOAc=1:1);
1H NMR(400MHz,DMSO):δ1.20(t,J=7.0Hz,6H),3.52(d,J=14.1Hz,2H),3.99–4.06(m,4H),7.00–7.37(m,4H)。
*(4-氟苯硫基)甲基膦酸二乙酯(1-2c)
产率:62%;
Rf=0.45(己烷:EtOAc=1:2);
1H NMR(400MHz,DMSO):δ1.19(t,J=7.0Hz,6H),3.42(d,J=13.7Hz,2H),3.96–4.03(m,4H),7.16–7.52(m,4H)。
*(2-氯苯硫基)甲基膦酸二乙酯(1-2d)
产率:80%;
Rf=0.37(己烷:EtOAc=1:2);
1H NMR(400MHz,DMSO):δ1.21(t,J=7.0Hz,6H),3.52(d,J=14.7Hz,2H),4.01–4.08(m,4H),7.22(dt,J=1.2Hz,7.6Hz,1H),7.34(dt,J=1.0Hz,7.2Hz,1H),7.46(dd,J=0.9Hz,7.9Hz,1H),7.53(dd,J=1.0Hz,7.9Hz,1H)。
*(3-氯苯硫基)甲基膦酸二乙酯(1-2e)
产率:90%;
Rf=0.30(己烷:EtOAc=1:2);
1H NMR(400MHz,DMSO):δ1.20(t,J=7.0Hz,6H),3.54(d,J=14.0Hz,2H),4.01–4.05(m,4H),7.25–7.53(m,4H)。
*(4-氯苯硫基)甲基膦酸二乙酯(1-2f)
产率:94%;
Rf=0.33(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.20(t,J=7.0Hz,6H),3.47(d,J=13.9Hz,2H),3.99–4.06(m,4H),7.37(d,J=8.6Hz,2H),7.46(d,J=19.6Hz,2H)。
*(2-羟基苯硫基)甲基膦酸二乙酯(1-2g)
产率:58%;
Rf=0.45(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.19(t,J=7.0Hz,6H),3.29(d,J=14.8Hz,2H),3.96–4.03(m,4H),6.75–6.83(m,1H),7.06(t,J=7.6Hz,2H),7.29(d,J=7.8Hz,1H),9.97(s,1H)。
*(3-羟基苯硫基)甲基膦酸二乙酯(1-2h)
产率:87%;
Rf=0.33(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.20(t,J=7.0Hz,6H),3.37(d,J=14.2Hz,2H),3.98–4.05(m,4H),6.60(dd,J=8.1Hz,1.8Hz,1H),6.79–6.80(m,1H),6.82(d,J=7.9Hz,1H),7.11(t,J=7.9Hz,1H),9.58(s,1H)。
*(4-羟基苯硫基)甲基膦酸二乙酯(1-2i)
产率:58%;
Rf=0.22(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.18(t,J=7.0Hz,6H),3.23(d,J=13.5Hz,2H),3.93–4.01(m,4H),6.72(d,J=8.6Hz,2H),7.31(d,J=8.6Hz,2H),9.62(s,1H)。
步骤1-3:使用mCPBA氧化合成(取代苯磺酰基)甲基膦酸二乙酯
按上述反应式合成了(取代苯磺酰基)甲基膦酸二乙酯(diethyl(substitutedphenyl-sulfonyl)methylphosphonate)。具体地,将所述步骤1-2中合成的化合物1-2a至1-2i(1.0eq)溶解于二氯甲烷中,并且在0℃下向其添加间氯过氧苯甲酸((meta-chloroperoxybenzoic acid;mCPBA,2.2eq)并且在室温搅拌2小时。用亚硫酸钠终止反应后用乙酸乙酯稀释反应溶液,用饱和碳酸氢钠水溶液洗涤。有机层经无水Na2SO4干燥并过滤,并且通过柱层析法(乙酸乙酯:正己烷=1:1至1:3)纯化通过减压蒸馏溶剂获得的残余物,得到(2-,3-或4-取代苯磺酰基)甲基膦酸二乙酯(1-3a至1-3i)。各化合物的产率及其1HNMR鉴定结果如下所示。取代基的类型和位置如下表2所示。
[表2]
类别 | R | 类别 | R | 类别 | R |
1-3a | 邻位-F | 1-3b | 间位-F | 1-3c | 对位-F |
1-3d | 邻位-Cl | 1-3e | 间位-Cl | 1-3f | 对位-Cl |
1-3g | 邻位-OH | 1-3h | 间位-OH | 1-3i | 对位-OH |
*(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)
透明油状;
产率:60%;
Rf=0.53(己烷:EtOAc=1:3);
1H NMR(400MHz,CDCl3):δ1.15(t,J=7.0Hz,6H),3.96–4.02(m,4H),4.44(d,J=17.0Hz,2H),7.45–7.88(m,4H)。
*(3-氟苯磺酰基)甲基膦酸二乙酯(1-3b)
透明油状;
产率:98%;
Rf=0.53(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.16(t,J=7.0Hz,6H),3.93–4.06(m,4H),4.55(d,J=17.0Hz,2H),7.52–7.81(m,4H)。
*(4-氟苯磺酰基)甲基膦酸二乙酯(1-3c)
透明油状;
产率:100%;
Rf=0.28(己烷:EtOAc=1:7);
1H NMR(400MHz,DMSO):δ1.16(t,J=7.0Hz,6H),3.94–4.03(m,4H),4.49(d,J=16.9Hz,2H),7.50(t,J=8.8Hz,2H),7.99–8.03(m,4H)。
*(2-氯苯磺酰基)甲基膦酸二乙酯(1-3d)
透明油状;
产率:99%;
Rf=0.34(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.14(t,J=7.0Hz,6H),3.94–4.02(m,4H),4.50(d,J=17.0Hz,2H),7.62–7.76(m,3H),8.03(d,J=7.8Hz,1H)。
*(3-氯苯磺酰基)甲基膦酸二乙酯(1-3e)
透明油状;
产率:90%;
Rf=0.34(己烷:EtOAc=1:3);
1H NMR(400MHz,DMSO):δ1.16(t,J=7.0Hz,6H),3.96–4.04(m,4H),4.56(d,J=17.0Hz,2H),7.69(t,J=7.9Hz,1H),7.83(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.99(s,1H)。
*(4-氯苯磺酰基)甲基膦酸二乙酯(1-3f)
透明油状;
产率:90%;
Rf=0.34(己烷:EtOAc=1:5);
1H NMR(400MHz,DMSO):δ1.17(t,J=6.8Hz,6H),3.98–4.02(m,4H),4.52(d,J=16.9Hz,2H),7.74(d,J=7.4Hz,1H),7.96(d,J=7.4Hz,1H)。
*(2-羟苯磺酰基)甲基膦酸二乙酯(1-3g)
透明油状;
产率:69%;
Rf=0.22(己烷:EtOAc=1:7);
1H NMR(400MHz,DMSO):δ1.14(t,J=7.0Hz,6H),3.89–4.03(m,4H),4.33(d,J=16.7Hz,2H),6.96–7.04(m,2H),7.51(t,J=7.4Hz,1H),7.67(d,J=7.9Hz,1H),11.25(s,1H)。
*(3-羟苯磺酰基)甲基膦酸二乙酯(1-3h)
透明油状;
产率:84%;
Rf=0.22(己烷:EtOAc=1:7);
1H NMR(400MHz,DMSO):δ1.16(t,J=7.0Hz,6H),3.93–4.03(m,4H),4.37(d,J=17.0Hz,2H),7.09(d,J=7.9Hz,1H),7.29–7.45(m,3H),10.25(s,1H)。
*(4-羟苯磺酰基)甲基膦酸二乙酯(1-3i)
透明油状;
产率:95%;
Rf=0.21(己烷:EtOAc=1:7);
1H NMR(400MHz,DMSO):δ1.16(t,J=7.0Hz,6H),3.92–4.04(m,4H),4.28(d,J=16.9Hz,2H),6.93,7.74(d,J=8.7Hz,4H),10.60(s,1H)。
实施例1:合成(E)-3-氟-2-(2-(2-氟苯磺酰基)乙烯基)吡啶(化合物1)
将根据所述制备例1制备的(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a,1eq)溶解在无水THF(0.1M)中后,使用干冰和丙酮将反应混合物冷却至-78℃。将n-BuLi(1.2eq,2.0M环己烷溶液)缓慢滴加到所述溶液中并搅拌1小时,然后添加3-氟吡啶甲醛(3-fluoropicolinaldehyde,1.2eq)并再次反应一个小时。如果通过TLC确认反应未完成,则在常温下再反应30分钟。用少量水终止反应后,用水和10%MeOH/MC萃取反应混合物,用无水Na2SO4从有机层中除去少量水,减压蒸馏除去溶剂并真空干燥。然后,使用EtOAc和10%MeOH/MC通过柱层析法分离和纯化产物以获得(E)-3-氟-2-(2-(2-氟苯磺酰基)乙烯基)吡啶((E)-3-fluoro-2-(2-(2-fluorophenylsulfonyl)vinyl)pyridine)。
产率:71%;
Rf=0.33(2%MeOH/MC);
1H NMR(400MHz,DMSO):δ7.50–8.00(m,6H,2trans H),8.54(d,J=4.1Hz,1H);
13C NMR(100MHz,CDCl3):δ117.2(d,JC–F=20.7Hz),124.2(d,JC–F=18.9Hz),124.8(d,JC–F=3.7Hz),126.9(d,JC–F=4.4Hz),128.2(d,JC–F=13.9Hz),129.9,132.2(d,JC–F=3.3Hz),135.0,136.2(d,JC–F=8.5Hz),139.5(d,JC–F=11.0Hz),146.0(d,JC–F=5.0Hz),158.5(d,JC–F=264.3Hz),159.7(d,JC–F=255.6Hz)。
实施例2:合成(E)-3-氟-2-(2-(3-氟苯磺酰基)乙烯基)吡啶(化合物2)
除了使用(3-氟苯磺酰基)甲基膦酸二乙酯(1-3b)代替(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)以外,以与所述实施例1相同的方式进行反应以获得(E)-3-氟-2-(2-(3-氟苯磺酰基)乙烯基)吡啶((E)-3-fluoro-2-(2-(3-fluorophenylsulfonyl)vinyl)pyridine)。
产率:62%;
Rf=0.41(己烷:EtOAc=1:1);
1H NMR(300MHz,DMSO):δ7.60–7.93(m,8H,2trans H),8.52–8.54(m,1H);
13C NMR(75MHz,DMSO):δ114.7(d,JC–F=24.4Hz),121.2(d,JC–F=21.1Hz),123.8(d,JC–F=3.0Hz),124.8(d,JC–F=18.8Hz),128.0(d,JC–F=4.7Hz),132.1(d,JC–F=13.5Hz),132.1,133.7,138.4(d,JC–F=10.9Hz),141.7(d,JC–F=6.7Hz),146.3(d,JC–F=4.8Hz),158.3(d,JC–F=288.2Hz),161.7(d,JC–F=273.9Hz)。
实施例3:合成(E)-3-氟-2-(2-(4-氟苯磺酰基)乙烯基)吡啶(化合物3)
除了使用(4-氟苯磺酰基)甲基膦酸二乙酯(1-3c)代替(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)之外,以与所述实施例1相同的方式进行反应以获得(E)-3-氟-2-(2-(4-氟苯磺酰基)乙烯基)吡啶((E)-3-fluoro-2-(2-(4-fluorophenylsulfonyl)vinyl)pyridine)。
产率:81%;
Rf=0.42(己烷:EtOAc=1:1);
1H NMR(300MHz,DMSO):δ7.59–7.92(m,8H,2trans H),8.51–8.53(m,1H);
13C NMR(75MHz,DMSO):δ114.7(d,JC–F=24.4Hz),121.2(d,JC–F=21.1Hz),123.8(d,JC–F=3.0Hz),124.8(d,JC–F=18.9Hz),128.0(d,JC–F=4.8Hz),132.1(d,JC–F=13.7Hz),132.1,133.7,138.4(d,JC–F=10.9Hz),141.7(d,JC–F=6.7Hz),146.3(d,JC–F=4.8Hz),158.3(d,JC–F=288.1Hz),161.7(d,JC–F=273.9Hz)。
实施例4:合成(E)-3-氯-2-(2-(2-氟苯磺酰基)乙烯基)吡啶(化合物4)
除了使用3-氯吡啶甲醛(3-chloropicolinaldehyde)代替3-氟吡啶甲醛之外,以与所述实施例1相同的方式进行反应以获得(E)-3-氯-2-(2-(2-氟苯磺酰基)乙烯基)吡啶。
产率:90%;
Rf=0.37(己烷:EtOAc=2:1);
1H NMR(400MHz,DMSO):δ7.50–7.57(m,3H),7.75(d,J=14.7Hz,trans H),7.83–7.98(m,2H),8.02(d,J=15.0Hz,trans H),8.09(d,J=8.2Hz,1H),8.63(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ118.0(d,JC–F=20.6Hz),126.1(d,JC–F=3.5Hz),127.6(d,JC–F=13.8Hz),127.8,130.1,132.8,133.4,137.4,137.8(d,JC–F=8.6Hz),138.9,147.1,149.1,159.2(d,JC–F=253.1Hz)。
实施例5:合成(E)-3-氯-2-(2-(3-氟苯磺酰基)乙烯基)吡啶(化合物5)
除了使用3-氯吡啶甲醛代替3-氟吡啶甲醛之外,以与所述实施例2相同的方式进行反应以获得(E)-3-氯-2-(2-(3-氟苯磺酰基)乙烯基)吡啶((E)-3-chloro-2-(2-(3-fluorophenylsulfonyl)vinyl)pyridine)。
产率:68%;
Rf=0.27(己烷:EtOAc=2:1);
1H NMR(300MHz,DMSO):δ7.53–8.10(m,8H,2trans H),8.61(dd,J=1.2,4.5Hz,1H);
13C NMR(75MHz,DMSO):δ114.7(d,JC–F=24.4Hz),121.3(d,JC–F=21.2Hz),123.8(d,JC–F=3.1Hz),127.1,132.1(d,JC–F=7.9Hz),132.3,133.3,135.9,138.4,141.6(d,JC–F=6.7Hz),146.8,148.5,161.9(d,JC–F=248.0Hz)。
实施例6:合成(E)-3-氯-2-(2-(4-氟苯磺酰基)乙烯基)吡啶(化合物6)
除了使用3-氯吡啶甲醛代替3-氟吡啶甲醛之外,以与所述实施例3相同的方式进行反应以获得(E)-3-氯-2-(2-(4-氟苯磺酰基)乙烯基)吡啶((E)-3-chloro-2-(2-(4-fluorophenylsulfonyl)vinyl)pyridine)。
产率:58%;
Rf=0.36(己烷:EtOAc=2:1);
1H NMR(300MHz,DMSO):δ7.49–7.55(m,3H),7.87(dd,J=14.8Hz,14.8Hz,2transH),8.06–8.11(m,3H),8.60(d,J=4.5Hz,1H);
13C NMR(75MHz,DMSO):δ116.8,117.1,127.0,130.9,131.0,132.2,133.9,135.1,135.8(d,JC–F=2.8Hz),138.36,146.91,148.54,165.17(d,JC–F=251.8Hz).
实施例7:合成(E)-2-(2-(2-氯苯磺酰基)乙烯基)-3-氟吡啶(化合物7)
除了使用(2-氯苯磺酰基)甲基膦酸二乙酯(1-3d)代替(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)之外,以与所述实施例1相同的方式进行反应以获得(E)-2-(2-(2-氯苯磺酰基)乙烯基)-3-氟吡啶((E)-2-(2-(2-chlorophenylsulfonyl)vinyl)-3-fluoropyridine)。
产率:75%;
Rf=0.34(己烷:EtOAc=2:1);
1H NMR(400MHz,DMSO):δ7.62–7.93(m,7H),8.18(dd,J=1.4Hz,7.8Hz,1H),8.55(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ125.4(d,JC–F=18.9Hz),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=10.9Hz),147.0(d,JC–F=4.7Hz),158.7(d,JC–F=262.0Hz)。
实施例8:合成(E)-2-(2-(3-氯苯磺酰基)乙烯基)-3-氟吡啶(化合物8)
除了使用(3-氯苯磺酰基)甲基膦酸二乙酯(1-3e)代替(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)之外,以与所述实施例1相同的方式进行反应以获得(E)-2-(2-(3-氯苯磺酰基)乙烯基)-3-氟吡啶((E)-2-(2-(3-chlorophenylsulfonyl)vinyl)-3-fluoropyridine)。
产率:97%;
Rf=0.38(己烷:EtOAc=2:1);
1H NMR(400MHz,DMSO):δ7.60–7.92(m,7H),7.98(d,J=7.8Hz,1H),8.08–8.09(m,1H),8.52(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ124.8(d,JC–F=18.8Hz),126.3,127.3,128.0(d,JC–F=4.6Hz),131.6,132.2(d,JC–F=4.1Hz),133.9(d,JC–F=12.2Hz),134.2,138.4(d,JC–F=10.9Hz),141.6,146.3(d,JC–F=4.7Hz),158.1(d,JC–F=262.1Hz)。
实施例9:合成(E)-2-(2-(4-氯苯磺酰基)乙烯基)-3-氟吡啶(化合物9)
除了使用(4-氯苯磺酰基)甲基膦酸二乙酯(1-3f)代替(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)之外,以与所述实施例1相同的方式进行反应以获得(E)-2-(2-(4-氯苯磺酰基)乙烯基)-3-氟吡啶((E)-2-(2-(4-chlorophenylsulfonyl)vinyl)-3-fluoropyridine)。
产率:70%;
Rf=0.32(己烷:EtOAc=3:1);
1H NMR(400MHz,DMSO):δ7.59–7.76(m,5H),7.88(t,J=9.2Hz,1H),8.02(d,J=8.6Hz,2H),8.52(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ124.8(d,JC–F=1 8.8Hz),128.0(d,JC–F=4.7Hz),129.6,129.8,132.5(d,JC–F=4.2Hz),133.3,138.4,138.5,139.1,146.4(d,JC–F=4.8Hz),158.1(d,JC–F=262.0Hz)。
实施例10:合成(E)-3-氯-2-(2-(2-氯苯磺酰基)乙烯基)吡啶(化合物10)
除了使用3-氯吡啶甲醛代替3-氟吡啶甲醛之外,以与所述实施例7相同的方式进行反应以获得(E)-3-氯-2-(2-(2-氯苯磺酰基)乙烯基)吡啶((E)-3-chloro-2-(2-(2-chlorophenylsulfonyl)vinyl)pyridine)。
产率:70%;
Rf=0.37(己烷:EtOAc=2:1);
1H NMR(400MHz,DMSO):δ7.54–8.10(m,7H),8.17(d,J=7.8Hz,1H),8.63(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ127.8,128.9,131.3,131.9,132.5,132.6,132.8,136.4,137.1,138.3,138.9,147.2,149.2。
实施例11:合成(E)-3-氯-2-(2-(3-氯苯磺酰基)乙烯基)吡啶(化合物11)
除了使用3-氯吡啶甲醛代替3-氟吡啶甲醛之外,以与所述实施例8相同的方式进行反应以获得(E)-3-氯-2-(2-(3-氯苯磺酰基)乙烯基)吡啶((E)-3-chloro-2-(2-(3-chlorophenylsulfonyl)vinyl)pyridine)。
产率:71%;
Rf=0.50(己烷:EtOAc=2:1);
1H NMR(400MHz,DMSO):δ7.53(m,1H),7.70(t,J=7.9Hz,1H),7.84–8.07(m,6H),8.60(d,J=4.0Hz,1H);
13C NMR(100MHz,DMSO):δ126.8,127.6,127.8,132.2,132.8,133.9,134.5,134.8,136.6,138.9,141.9,147.4,149.0。
实施例12:合成(E)-3-氯-2-(2-(4-氯苯磺酰基)乙烯基)吡啶(化合物12)
除了使用3-氯吡啶甲醛代替3-氟吡啶甲醛之外,以与所述实施例9相同的方式进行反应以获得(E)-3-氯-2-(2-(4-氯苯磺酰基)乙烯基)吡啶((E)-3-chloro-2-(2-(4-chlorophenylsulfonyl)vinyl)pyridine)。
产率:70%;
Rf=0.40(己烷:EtOAc=3:1);
1H NMR(400MHz,DMSO):δ7.53–7.77(m,3H),7.81(t,J=14.8Hz,trans H),7.96(d,J=14.7Hz,trans H),8.02(d,J=7.2Hz,2H),8.07(d,J=8.2Hz,1H),8.61(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ127.6,130.1,130.3,132.8,134.2,136.1,138.8,138.9,139.7,147.4,149.0。
实施例13:合成(E)-2-氯-6-(2-(2-氯苯磺酰基)乙烯基)吡啶(化合物13)
除了使用6-氯吡啶甲醛代替3-氯吡啶甲醛之外,以与所述实施例10相同的方式进行反应以获得(E)-2-氯-6-(2-(2-氯苯磺酰基)乙烯基)吡啶((E)-2-chloro-6-(2-(2-chlorophenylsulfonyl)vinyl)pyridine)。
产率:94%;
Rf=0.30(己烷:EtOAc=1:1);
1H NMR(400MHz,DMSO):δ7.54–7.83(m,5H),7.93(d,J=15.4Hz,trans H),8.18(dd,J=1.4Hz,7.9Hz,1H),8.39(dd,J=1.7Hz,7.8Hz,1H),8.50(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO):δ124.3,127.4,128.9,131.2,131.5,132.0,132.6,136.3,137.2,138.6,139.1,150.8,152.4。
实施例14:合成(E)-2-氯-3-(2-(2-氯苯磺酰基)乙烯基)吡啶(化合物14)
除了使用2-氯烟碱醛代替3-氯吡啶甲醛之外,以与所述实施例10相同的方式进行反应以获得(E)-2-氯-3-(2-(2-氯苯磺酰基)乙烯基)吡啶((E)-2-chloro-3-(2-(2-chlorophenylsulfonyl)vinyl)pyridine)。
产率:96%;
Rf=0.30(己烷:EtOAc=2:1);
1H NMR(400MHz,DMSO):δ7.60(d,J=7.8Hz,1H),7.66–7.82(m,5H),7.89(d,J=7.4Hz,1H),7.99(t,J=7.7Hz,1H),8.16(dd,J=1.4Hz,7.8Hz,1H);
13C NMR(100MHz,DMSO):δ125.5,126.8,128.3,131.1,131.2,132.1,132.6,136.3,137.3,141.6,142.4,151.1,151.6。
制备例2:通过引入哌嗪基部分合成(4-(2-(4-甲基哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯
步骤2-1:合成3-吗啉丙基甲磺酸酯
根据上述反应式合成了3-吗啉丙基甲磺酸酯(3-morpholinopropylmethanesulfonate)。具体地,将市售试剂4-(3-羟丙基)吗啉(1eq,4.76mL,34.43mmol)加入反应器中,并用二氯甲烷(0.12M,280mL)溶解,然后在0℃添加三乙胺(1.2eq,5.76mL,41.32mmol)和甲磺酰氯(1.2eq,3.2mL,41.32mmol),并在室温下反应1小时。反应完成后用水和10%MeOH/MC萃取,用无水MgSO4除去有机层中的少量水,然后减压蒸馏除去溶剂。随后立即真空干燥溶剂,而无需通过柱层析法进行分离和纯化,得到透明棕色油状化合物,即3-吗啉丙基甲磺酸酯(3-morpholinopropyl methanesulfonate,6.47g)。
粗产率(crude yield):84%;
1H NMR(400MHz,CDCl3):δ1.95–1.90(m,2H),2.44(t,J=6.9Hz,6H),3.00(s,3H),3.68(t,J=4.6Hz,4H),4.30(t,J=6.3Hz,2H)。
步骤2-2:合成((3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯
按上述反应式合成了((3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯(diethyl((3-morpholinopropoxy)phenylsulfonyl)methylphosphonate)。具体地,将根据所述制备例1制备的化合物1-3h和1-3i(1eq,1.03g,3.34mmol)溶解于乙腈(0.1m,34mL),然后在常温下添加碳酸钾(1.5eq,0.69g,5.01mmol)和在所述步骤2-1合成的化合物(1.48eq,1.10g,4.95mmol)并在82℃回流搅拌2小时30分钟。反应完成后冷却至室温,用水和10%MeOH/MC萃取,用无水Na2SO4从有机层中除去少量水,然后减压蒸馏除去溶剂并真空干燥。随后通过柱层析法(100%EtOAc和10%MeOH/MC)分离和纯化获得(3-(3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯和(4-(3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯。
[表3]
实施例15:合成(E)-4-(3-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉盐酸盐(化合物15)
除了使用(4-(3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯(2-2a)代替(2-氟苯磺酰基)甲基膦酸二乙酯(1-3a)之外,以与所述实施例1相同的方式进行反应以获得(E)-4-(3-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉((E)-4-(3-(4-(2-(3-fluoropyridin-2-yl)vinylsulfonyl)phenoxy)p ropyl)morpholine)。在将所得化合物溶解于EtOAc中后滴加过量HCl(4.0M 1,4-二恶烷溶液)并在常温反应2小时。随后用正己烷和EtOAc洗涤数次以过滤所形成的沉淀物,并使用EtOAc和10%MeOH/MC通过柱层析法分离和纯化以获得(E)-4-(3-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉盐酸盐((E)-4-(3-(4-(2-(3-fluoropyridin-2-yl)vinylsulfonyl)phenoxy)propyl)morpholinehydrochloride)。
产率:97%;
Rf=0.35(MeOH:EtOAc=1:4);
1H NMR(400MHz,DMSO):δ2.18–3.24(m,6H),3.45(d,J=12.2Hz,2H),3.79(t,J=11.9Hz,2H),3.95(d,J=12.2Hz,2H),4.20(t,J=5.8Hz,2H),7.19(d,J=8.7Hz,2H),7.57–7.62(m,1H),7.66(s,2H),7.87(t,J=9.6Hz,1H),7.93(d,J=8.6Hz,2H),8.50(d,J=3.8Hz,1H),11.00(s,1H);
13C NMR(100MHz,DMSO):δ23.2,51.5,53.7,63.6,66.1,115.9,125.3(d,JC–F=9.6Hz),128.2,130.5,131.7,132.1,134.06(d,JC–F=4.2Hz),139.10(d,JC–F=10.9Hz),146.87(d,JC–F=4.6Hz),158.5(d,JC–F=261.3Hz),163.0。
实施例16:合成(E)-4-(3-(3-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉盐酸盐(化合物16)
除了使用(3-(3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯(2-2b)代替(4-(3-吗啉丙氧基)苯磺酰基)甲基膦酸二乙酯(2-2a)之外,以与所述实施例15相同的方式进行反应以获得(E)-4-(3-(3-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉盐酸盐((E)-4-(3-(3-(2-(3-fluoropyridin-2-yl)vinylsulfonyl)phenoxy)propyl)morpholinehydrochloride)。
产率:97%;
Rf=0.35(MeOH:EtOAc=1:4);
1H NMR(400MHz,CDCl3):δ1.95–3.73(m,12H),4.08(t,J=6.3Hz,2H),7.14(dd,J=8.2Hz,2.1Hz,1H),7.32–7.54(m,6H),7.91(d,J=15.0Hz,1H),8.42(d,J=4.4Hz,1H),11.00(s,1H);
13C NMR(100MHz,CDCl3):δ26.2,53.7,55.3,66.6,66.9,112.8,120.1,120.6,124.1(d,JC–F=19.0Hz),126.67(d,JC–F=4.4Hz),130.5,132.9,133.2(d,JC–F=4.4Hz),141.1,145.94(d,JC–F=5.1Hz),158.4(d,JC–F=264.1Hz),159.6。
制备例3:通过引入哌嗪基部分合成(4-(2-(4-甲基哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯
步骤3-1:通过与卤代乙酸乙酯的反应合成2-(4-((二乙氧基磷酰基)甲磺酰基)苯
氧基)乙酸乙酯
在室温下将K2CO3(1.5eq,2.03g,14.70mmol)和溴乙酸乙酯(1.2eq,1.3mL,11.70mmol)滴加到将根据所述制备例1制备的化合物1-3i(1eq,3.02g,9.80mmol)溶解于乙腈(acetonitrile;ACN,25mL)准备的溶液中,并在90℃加热搅拌反应混合物2小时。反应完成后冷却至室温,用水和10%MeOH/MC萃取,用无水MgSO4从有机层中除去少量水,然后减压蒸馏除去溶剂并真空干燥。随后,通过柱层析法(乙酸乙酯:正己烷=1:1至1:3)分离纯化以获得透明油状化合物,即2-(4-((二乙氧基磷酰基)甲磺酰基)苯氧基)乙酸乙酯(ethyl 2-(4-((diethoxyphosphoryl)methylsulfonyl)phenoxy)acetate,3.88g)。
产率:100%;
Rf=0.30(EtOAc:丙酮=6:1);
1H NMR(400MHz,DMSO):δ1.18(t,J=5.7Hz,6H),1.22(t,J=7.1Hz,6H),3.93–4.03(m,4H),4.18(q,J=7.1Hz,14.2Hz,2H),4.38(d,J=16.9Hz,2H),4.94(s,2H),7.15(d,J=8.9Hz,2H),7.85(d,J=8.9Hz,2H)。
步骤3-2:通过将乙酸盐转化为乙酸合成2-(4-((二乙氧基磷酰基)甲磺酰基)苯氧
基)乙酸
将所述步骤3-1中合成的化合物(1eq,2.0g,5.07mmol)溶解在溶于乙醇(10mL)的NaOH(1.5eq,0.3mg,7.60mmol)溶液后,使反应混合物在常温下反应2小时。反应完成后减压蒸馏去除溶剂。通过加水和HCl酸化化合物并用EtOAc萃取,并且使用无水Na2SO4从有机层去除少量水。此后,通过减压蒸馏除去溶剂,然后真空干燥而不进行进一步分离和纯化,以获得透明的棕色油状化合物,即2-(4-((二乙氧基磷酰基)甲磺酰基)苯氧基)乙酸(2-(4-((diethoxyphos phoryl)methylsulfonyl)phenoxy)acetic acid,1.83g)。
产率:98%;
Rf=0.34(20%MeOH/MC);
1H NMR(400MHz,DMSO):δ1.16(t,J=6.9Hz,6H),3.93–4.01(m,4H),4.37(d,J=16.9Hz,2H),4.83(s,2H),7.13(d,J=8.1Hz,2H),7.85(d,J=8.0Hz,2H),13.20(s,1H)。
步骤3-3:通过哌嗪衍生物取代合成(4-(2-(4-甲基哌嗪-1-基)-2-氧乙氧基)苯磺
酰基)甲基膦酸二乙酯
将所述步骤3-2合成的化合物(1eq,1.82g,4.98mmol)溶于四氢呋喃(tetrahydrofuran;THF)后,缓慢滴加1,1′-羰基二咪唑(1,1'-carbonyldiimidazole;CDI,3eq,2.42g,14.90mmol)并在常温下反应20分钟,然后加入1-甲基哌嗪(1.2eq,0.66mL,5.97mmol)并常温下反应2小时。反应完成后减压蒸馏除去溶剂,然后用EtOAc萃取,并且使用无水Na2SO4从有机层中除去少量水并真空处理。此后,通过使用MeOH和MC的柱层析法获得透明油状化合物,即(4-(2-(4-甲基哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯(diethyl(4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)phenylsulfonyl)methylphosphonate,1.32g)。
产率:60%;
Rf=0.33(10%MeOH/MC);
1H NMR(400MHz,DMSO):δ1.16(t,J=7.0Hz,6H),2.19(s,3H),2.26–2.34(m,4H),3.43–4.01(m,8H),4.10(q,J=5.3Hz,10.5Hz,2H),4.35(d,J=16.9Hz,2H),4.99(s,2H),7.10(d,J=8.9Hz,2H),7.83(d,J=8.9Hz,2H)。
实施例17:合成(E)-2-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐(化合物17)
将根据所述制备例1及3制备的(4-(2-(4-甲基哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯(1eq)溶于无水THF(0.1m)后,使用干冰和丙酮冷却至-78℃。将n-BuLi(1.2eq,2.0M环己烷溶液)缓慢滴加到所述溶液并搅拌1小时,然后添加3-氟吡啶甲醛(3-fluoropicolinaldehyde,1.2eq)并再次反应1小时。如果通过TLC确认到反应未结束,则在常温下再反应30分钟。用少量水终止反应后,用水和10%MeOH/MC萃取,用无水Na2SO4从有机层中除去少量水,减压蒸馏除去溶剂并真空干燥。然后,通过使用EtOAc和10%MeOH/MC的柱层析法分离和纯化以获得(E)-2-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮((E)-2-(4-(2-(3-fluoropyridin-2-yl)vinylsulfonyl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone)。在将获得的化合物溶解于EtOAc中后滴加过量HCl(4.0M 1,4-二恶烷溶液)并在常温反应2小时。随后用正己烷和EtOAc洗涤几次以过滤形成的沉淀物,并使用EtOAc和10%MeOH/MC柱层析法分离纯化以得到(E)-2-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐((E)-2-(4-(2-(3-fluoropyridin-2-yl)vinylsulfonyl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanonehydrochloride)。
产率:60%;
Rf=0.50(10%MeOH/MC);
1H NMR(400MHz,DMSO):δ2.75–3.63(m,10H),4.00(d,J=13.4Hz,1H),4.36(d,J=13.1Hz,1H),4.69(s,2H),5.10(dd,J=14.7Hz,33.6Hz,2H),7.19(d,J=8.6Hz,2H),7.57–7.90(m,6H),8.49(d,J=3.7Hz,1H),11.72(s,1H);
13C NMR(100MHz,DMSO):δ42.4,52.3(d,JC–F=15.6Hz),66.1,66.8,116.1,125.2(d,JC–F=18.8Hz),128.2(d,JC–F=4.4Hz),130.3,131.7,132.1,134.0(d,JC–F=4.0Hz),139.1(d,JC–F=11.0Hz),146.8(d,JC–F=4.8Hz),158.5(d,JC–F=261.4Hz),159.8,162.8。
实施例18:合成(E)-2-(4-(2-(3-氯吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐(化合物18)
除了使用3-氯吡啶甲醛(3-chloropicolinaldehyde)代替3-氟吡啶甲醛之外,以与所述实施例17相同的方式进行反应以获得(E)-2-(4-(2-(3-氯吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐((E)-2-(4-(2-(3-chloropyridin-2-yl)vinylsulfonyl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone hydrochloride)。
产率:66%;
Rf=0.50(10%MeOH/MC);
1H NMR(400MHz,DMSO):δ2.76–3.11(m,6H),3.99(d,J=13.6Hz,1H),4.37(d,J=13.4Hz,1H),5.09(dd,J=14.5Hz,31.4Hz,2H),7.18(d,J=8.7Hz,2H),7.51–7.54(m,1H),7.72(d,J=14.7Hz,1H),7.85–7.91(m,3H),8.06(d,J=8.1Hz,1H),8.59(d,J=4.0Hz,1H),11.28(s,1H);
13C NMR(100MHz,DMSO):δ42.5,52.5,66.0,99.1,116.2,127.4,130.3,131.6,132.5,134.4,135.2,138.8,147.5,149.0,162.8,165.9。
根据所述实施例1至18合成的化合物1至18的取代基的类型和位置如下表4所示。
[表4]
实验例1:诱导Nrf2活性的效果
为了证实根据所述本发明的实施例1至18合成的化合物的药理活性,通过构建基于Nrf2功能性细胞的分析方法(Nrf2 functional cell based assay,DiscoveRx)评估合成的衍生物对诱导Nrf2活性的效果,Nrf2是防御氧化应激的主要调节因子。具体采用U2OS细胞,用CP 0试剂释放细胞颗粒后,以80μL的量装入密度为1.5×104细胞/孔的96孔板中,培养24小时。将根据所述实施例1至18合成的化合物在7种不同浓度的DMSO中稀释3倍以制备储备原液(stock solution)。将10μL各化合物溶液与90μL的CP 0混合,以20μL的量加入96孔板的各孔中,各实验重复3次。作为阳性对照,用5μM的萝卜硫素(sulforaphane)处理,用铝箔包裹培养板并培养6小时。将底物试剂(substrate reagent)1和2添加到细胞分析缓冲液(cell assay buffer)中并混合,然后将50μL底物试剂添加到96孔板的各孔中用箔包裹并培养1小时。此后,使用发光分光光度计(luminescence spectrophotometer,Molecular Devices)在所有波长(all wav elength)和积分时间(integaration time)100ms测量发光值。各化合物的效果都表示为相对于高浓度下显示的最大效果活化50%的浓度。结果如下表5所示,以相当于萝卜硫素处理组的百分比比较了化合物的疗效。使用具有与本发明类似的母体结构且已证实通过Keap1的结构变化诱导Nrf2的活化的查尔酮(Chalcone)衍生物、VSC2((E)-1-(2-((2-methoxyphenyl)sulfonyl)vinyl)-2-chlorobenzene,Woo et al.,J.Med.Chem.,2014,57:1473–1487)作为另一对照组。
[表5]
化合物 | Nrf2 EC<sub>50</sub>(μM) |
化合物1 | 0.176 |
化合物2 | 0.474 |
化合物3 | 0.542 |
化合物4 | 0.030 |
化合物5 | 0.084 |
化合物6 | 0.231 |
化合物7 | 0.122 |
化合物8 | 0.198 |
化合物9 | 0.286 |
化合物10 | 0.026 |
化合物11 | 0.046 |
化合物12 | 0.065 |
化合物13 | 0.147 |
化合物14 | 0.384 |
化合物15 | 0.346 |
化合物16 | 0.908 |
化合物17 | 1.204 |
化合物18 | 0.327 |
VSC2 | 0.530 |
SFN(萝卜硫素) | 0.414 |
如表5所示,可以发现本发明实施例1至18的化合物(化合物1至18)均诱导Nrf2活性,尤其是化合物1、4至15和18表现出比众所周知的Nrf2活化剂(activator)萝卜硫素和VSC2更好的Nrf2活化效果。具体地,可以确定在本发明化合物中表现出最优异的活性的化合物10表现出了比萝卜硫素优异15倍以上的效果。尤其,已知萝卜硫素因为含有异硫氰酸酯基团(NCS),因此尽管它具有很高的活性,但由于非选择性的强烈反应性而在5μM以上的浓度表现出高毒性。本发明的实验例的结果表明已证实即使浓度为10μM也不表现出细胞毒性且诱导Nrf2活性的本发明的化合物可以代替萝卜硫素用作Nrf2活化剂。
另外,为了确认合成的化合物中取代基的位置与Nrf2活性诱导效果之间的关系,分别比较了包括相同的取代基但位置不同的化合物1至3、4至6、7至9和10至12。结果证明,无论取代基的类型如何,与在不同位置具有相同取代基的化合物相比,苯环和吡啶基环均在邻位具有取代基的化合物,化合物1、4、7和10显示出更优异的活性。
实验例2:CYP活性抑制能力的评估
为了确认本发明实施例的化合物作为实质上向身体给药的药物的应用可能性,确认了参与药物代谢大约75%的CYP活性抑制能力。具体地,对于代表性地选择的化合物1、4、13和15至18,对据报道至少占CYP总代谢的90%以上的五种同工酶1A2、2C9、2C19、2D6和3A4为对象评估了活性抑制。以0或10μM的浓度分别添加人肝微粒体(human liver microsomes,0.25mg/mL)与0.1M磷酸盐缓冲液(pH7.4)、所述五种药物代谢酶的底物药物混合物(非那西丁(Phenacetin)50μM、双氯芬酸(Diclofenac)10μM、S-美苯妥英(S-mephenytoin)100μM、右美沙芬(Dextromethorphan)5μM和(Midasolam)咪唑安定2.5μM)和化合物1、4、13和15至18,并在37℃下预培养5分钟,添加NADPH生成系统(NADPH generation system)溶液,并的37℃培养15分钟。此后,通过添加含有内标底物(特非那定(Terfenadine))的乙腈溶液终止反应,然后离心分离(14,000rpm,4℃)5分钟。随后将上清液注入LC-MS/MS系统,同时分析底物药物的代谢物,以评估这些化合物对药物代谢酶的抑制能力。使用ShimadzuNexera XR系统和TSQ vantage(Thermo)分析通过上述反应生成的每种CYP同工酶指示剂药物的代谢物。将Kin etex C18柱用作HPLC柱,将含有0.1%甲酸的蒸馏水和含有0.1%甲酸的乙腈用作流动相。使用多反应监测(multiple reaction monitoring;MRM)定量模式对产生的代谢物进行定量,并使用Xcalibur(版本1.6.1)分析了数据。将实施例17和18以及VSC2对每种CYP同工酶的抑制能力转化为相对于未添加上述化合物的阴性对照的%活性,结果示于下表6。
[表6]
化合物 | 2C19 | 2D6 | 2C9 | 1A2 | 3A4 |
化合物1 | 65.9 | 87.0 | 100.0 | 96.0 | 100.0 |
化合物4 | 47.3 | 86.0 | 62.6 | 96.0 | 100.0 |
化合物13 | 40.0 | 100.0 | 100.0 | 94.0 | 86.0 |
化合物15 | 77.4 | 99.7 | 100.0 | 87.2 | 97.4 |
化合物16 | 63.1 | 96.0 | 100.0 | 98.11 | 80.7 |
化合物17 | 83.9 | 93.0 | 122.0 | 95.6 | 96.2 |
化合物18 | 71.9 | 89.9 | 73.4 | 93.9 | 91.1 |
VSC2 | 16.8 | 54.9 | 100.0 | 37.9 | 55.6 |
如上述表6所示,经评估所述各化合物的药物代谢酶药物相互作用可能性,与VSC2相比,本发明的化合物提高了对大多数CYP同工酶的抑制活性。本发明的化合物对所述五种CYP同工酶没有表现出抑制活性,这表明与VSC2相比,几乎没有药物相互作用可能性。
实验例3:代谢稳定性的评估
代谢稳定性是可影响药物清除率(clearance)、半衰期(half-life)、口服生物利用率(oral bioa vailability)等药代动力学参数(pharmacokinetic parameter;PKparameter;PK参数)的因素,因此是候选药物组应具备的特性之一。因此,为了通过体外实验(in vitro)预测作为药物代谢的主要器官的肝脏的药物代谢程度,利用肝微粒体评价药物的代谢稳定性。具体地,使用微粒体进行稳定性试验,其通过将候选药物、本发明的化合物中化合物1、4、13、15和17以及VSC2处理到微粒体并培养一定时间来确认剩余药物的量。具体地,将化合物以1μM的浓度添加到人肝微粒体(0.5mg/mL)和0.1M磷酸盐缓冲液(pH6.4)中并在37℃下预培养5分钟,然后添加NADPH再生系统(NADPH regeneration system)溶液并在37℃下培养30分钟。此后,通过添加含有内标物(氯丙酰胺(chloropropamide))的乙腈溶液终止反应,然后离心分离5分钟(14,000rpm,4℃),然后将上清液注入LC-MS/MS系统分析底物药物,从而评价这些化合物的代谢稳定性。使用Shimadzu Nexera XR系统和TSQvantage分析所述反应残留的底物量。将Kinetex C18柱用作HPLC柱,将含有0.1%甲酸的蒸馏水和含有0.1%甲酸的乙腈用作流动相。使用Xcalibur(版本1.6.1)分析了数据,结果显示在下表7中。
[表7]
化合物 | 30分钟后未被代谢降解的残留化合物百分比(%) |
化合物1 | 95 |
化合物4 | 86 |
化合物13 | 99 |
化合物15 | 94 |
化合物17 | 94 |
VSC2 | 20 |
如表7所示,通过测量将各化合物与微粒体培养30分钟后剩余的药物量,确认本发明的化合物1、4、13、15和17均保持在85%或以上,最高达到99%。这表明相对于对照组VSC2,本发明的实施例的化合物均对人肝微粒体的稳定性有明显改善。
实验例4:溶解度的评估
在新药开发中,药物的溶解度是影响药物生物吸收率的重要因素之一。例如,在水溶液中具有低溶解度的化合物通常会表现出低生物吸收率。此外,溶解度低的药物可能在组织中结晶或引起严重毒性,因此,FDA要求对溶解度低的口服药物进行额外的研究。此外,低溶解度是开发候选物质方面失败的最大原因。因此,测量了本发明的化合物1至18在水中的溶解度,结果表明含有吗啉基作为取代基的化合物15和16表现出高溶解度。具体地,化合物15表现出10mg/mL以上的高溶解度。结果表明,引入了吗啉基的化合物15的溶解度显著高于对照组,即已知诱导现有Nrf2活化的合成化合物VSC2的溶解度(≤0.01mg/mL)。此外,这表明在开发药物时可通过引入吗啉基提高溶解度。
实验例5:hERG通道结合抑制能力的评估
人类ether-a-go-go相关基因(human ether-a-go-go related gene;hERG)离子通道是心脏复极的重要因素,该通道的抑制剂可引起心律失常和猝死。因此,如果候选物质在新药开发过程中被确定为hERG离子通道的潜在抑制剂,它可能会诱发心脏毒性引起的副作用,因此需要努力将这种副作用降至最低。利用当把荧光hERG通道示踪剂(tracer)结合到含有hERG通道蛋白质的膜时示踪剂的旋转(rotation)受到限制,从而维持高极化(polarization)状态,而当竞争性抑制剂结合到hERG通道时示踪剂从膜上被竞争性地推离而失去方向性去极化的原理确定了本发明的化合物的hERG结合抑制能力。选择本发明的化合物中具有优良药理活性和高溶解度从而有望具有较高生物吸收率的化合物15作为代表性化合物。关于阳性对照组,将E-4031化合物分步稀释三倍,然后与预先制备的含hERG通道的膜和荧光示踪剂混合并反应4h,然后测量浓度对应的极化值,计算IC50值。对于所述化合物15,同样在不同浓度下测量荧光强度,然后与对照组比较计算IC50值,结果表明化合物15具有20μM的IC50值。这表明本发明的化合物在20μM以上的浓度下表现出心脏毒性,是安全的化合物。
实验例6:体外Nrf2活化效果
通过所述实验例1间接证实了本发明的化合物对Nrf2的活化。因此,为了直接证实本发明的化合物对Nrf2活化的作用,进行了免疫印迹(Western blot)。选择通过本发明合成的代表性化合物即化合物15,并对其按不同浓度进行处理,确认了Nrf2是否在细胞核中积累和/或程度。具体地,将BV2细胞以2×106个细胞/瓶的密度各4mL装到25T烧瓶中,并在RPM1640培养基中培养24小时。第二天将化合物15以DMSO 0.1%条件混合到各培养基使得最终浓度为0至10μM,如此准备后添加细胞并培养6小时。回收如上培养的细胞,分离细胞核和细胞质提取物。分离的核提取物用10%SDS-PAGE电泳转移到PVDF膜上,并用牛血清白蛋白(bovine serum albumin;BSA)封闭(blocking)。此后,使用抗Nrf2抗体测量细胞核中Nrf2蛋白质量,结果如图1所示。相对于表示核提取物的相同量的核纤层蛋白B1(Lamin B1)测量了Nrf2量。
如图1所示,未用化合物15处理的细胞的核提取物(0μM)中几乎没有发现Nrf2,但以0.1μM浓度处理的细胞中Nrf2量逐渐增加,从以10μM浓度处理的细胞中检测到了大量的Nrf2。这表明本发明的化合物以浓度依赖方式促进Nrf2的活化。
实验例7:体内Nrf2相关抗氧化蛋白表达的效果
Nrf2作为一种转录因子,通过在细胞核内增加抗氧化酶来起到保护细胞的作用。通过前面的实验例1和6直接、间接地确认了本发明的化合物对Nrf2的活化。因此,通过用免疫印迹(Western blot)测定抗氧化酶的量,确认了活化的Nrf2是否增加了抗氧化酶。选择已知由于Nrf2而表达增加的GCLC、GCLM和HO-1作为待检测的抗氧化酶。具体而言,BV2细胞以5×105细胞/孔的密度以1.5ml的量装载在6孔板中,并在RPM1640培养基中培养24小时。第二天将化合物15以DMSO 0.1%条件混合到各培养基使得最终浓度为0至10μM,如此准备后添加细胞并培养24小时。回收培养的细胞提取全部蛋白,用10%SDS-PAGE电泳。将电泳后的全部提取物转移到PVDF膜上,然后用牛血清白蛋白封闭。此后,使用对应于各抗氧化酶的抗体来测量细胞中抗氧化酶的表达量,结果如图2所示。
如图2所示,相对于表示总提取物的相同量的肌动(actin)蛋白对Nrf2和抗氧化酶,即GCLC、GCLM和HO-1进行定量。具有根据对测试的所有酶处理的化合物15的浓度表达量增加的倾向。具体地,当化合物15未处理及以0.1μM低浓度处理时,抗氧化酶的表达差异并不显著到足以肉眼可鉴,但1μM以后起肉眼可见Nrf2和抗氧化酶显著增加,均在10μM时表达最高。这些结果表明本发明化合物,例如化合物15以浓度依赖性方式通过Nrf2活化增加抗氧化酶的表达,因此可以表现出保护细胞的效果。
实验例8:在帕金森氏病模型MPTP小鼠中的细胞保护效果
在所述实验例6和7中,通过体外实验直接证明了本发明的化合物15活化细胞中的Nrf2并增加抗氧化酶的表达。因此为了证实本发明的化合物是否在动物模型中也具有细胞保护效果,使用了给药神经毒性物质MPTP(1-甲基-4-苯基-1,2,3,6-四氢吡啶)杀死多巴胺能神经元诱导帕金森氏病的小鼠动物模型。具体设计的动物实验时间如图3上端所示。以10周龄C57/BL6小鼠为动物模型,分为腹腔注射生理盐水并口服不含化合物15的溶液的阴性对照组;腹腔注射MPTP并口服不含化合物15的溶液的阳性对照组;腹腔注射MPTP并口服含化合物15的溶液的实验组共三个组准备了动物模型。一天以2h间隔共4次腹腔注射20mg/kg的MPTP制备MPTP诱导帕金森病模型。阴性对照组同时注射不含MPTP的生理盐水。为了确定是否诱发帕金森病,通过垂直网格(vertical grid)试验和衣架(coat-hanger)试验确认了已知是帕金森病的主要症状的由多巴胺能神经元细胞死亡引起的运动障碍。从注射MPTP前一天开始口服化合物15,剂量为20mg/mL,每天一次,连续3天,MPTP注射日后经过6天后进行行为实验,结果分别如图3中间和底部所示。
垂直网格试验是评估实验动物模型放置在垂直梯子上时下来的时间。在本发明中,在本发明中测量了把小鼠放在梯子上时转向地板的时间(time to turn)和从梯子下来的总时间。如图3中间的图表所示,只注射了MPTP的阳性对照组相比于代表正常小鼠的阴性对照组,转动时间和总耗时均增加,这表明MPTP诱导帕金森病模型中运动能力降低。另一方面,在施用本发明化合物15的实验组的情况下,转动时间和总耗时再次减少到与阴性对照组相似的水平,显示出与上述阳性对照组的显著差异。
衣架试验是另一项评估运动能力的行为实验,如图3左下角所示,当小鼠被放置在离地板30厘米的衣架中间时,小鼠在悬挂状态下向衣架顶部的安全位置移动,根据该时间点时的位置进行评分的方式进行试验,时间限制为3分钟。具体的实验方法和结果如图3底部所示。如图3底部的图表所示,大多数阴性对照组移动到对应于5分的衣架的顶部,但对于阳性对照组,主要停在衣架底部的两端,因此记录了2到3分。然而,在施用本发明化合物15的实验组中,相当数量的小鼠移到对应于4或5分的顶部,因此记录平均4分以上的高分。
通过总结上述两项运动能力测试,确定了本发明的化合物将由于MPTP而降低的运动能力恢复到与正常小鼠相似的水平。
实验例9:在帕金森病模型MPTP小鼠中对多巴胺能神经元的效果
根据所述实验实施例8的结果确认了本发明化合物的恢复运动能力的效果。为了确认这种运动能力的恢复是否是由于本发明化合物的神经保护效果所致,切除小鼠大脑并通过使用酪氨酸羟化酶作为多巴胺能神经元标记物的免疫组织化学染色法进行了分析。选择多巴胺能神经元集中的纹状体和黑质作为分析部位。
具体地,将阴性对照组、阳性对照组和实验组的小鼠用三溴乙醇(avertin)麻醉后,分别向其心脏注射生理盐水和4%甲醛,切除大脑,依次用4%甲醛和30%蔗糖浸泡,并分别在冰箱保存1天。此后使用冷冻切片机从储存的所述大脑中获得纹状体和黑质的组织切片。使用多巴胺能神经元中特异性表达的酪氨酸羟化酶抗体通过DAB染色法对脑组织切片进行免疫组织化学染色法,并在显微镜下进行观察,结果如图4所示。含有酪氨酸羟化酶的区域经免疫组织化学染色呈棕色,表明存在活的多巴胺能神经元。如图4的左侧所示,代表正常小鼠的阴性对照组的纹状体和黑质的染色呈深褐色,但通过MPTP诱发疾病的阳性对照组的染色变得相当浅。这可能是由于MPTP处理导致许多多巴胺能神经元死亡所致。另一方面,在用本发明的化合物15处理的实验组中,染色再次变深,这可能是由于基于施用的化合物15的抗氧化作用的细胞保护效果抑制了由MPTP引起的多巴胺能神经元的死亡。表明本发明的化合物具有预防或治疗由多巴胺能神经元死亡引起的神经退行性疾病如帕金森氏病的效果。
比较例1和2:与已知查尔酮化合物的活性进行比较
作为候选药物,为了证实本发明化合物的效果,合成了已知诱导Nrf2活化的已知查尔酮衍生物中具有优异活性的两种化合物,即,(E)-1-氯-2-(2-(2-甲氧基苯磺酰基)乙烯基)苯((E)-1-chloro-2-(2-(2-methoxyphenylsulfonyl)vinyl)benzene,VSC2,比较例1)和(E)-2-氯-3-(2-(2-甲氧基苯磺酰基)乙烯基)吡啶((E)-2-chloro-3-(2-(2-methoxyphenylsulfonyl)vinyl)pyridine,比较例2)用作比较例。这些化合物公开在韩国授权专利第10-1438655和J.Med.Chem.,2014,57:1473–1487。为了证实其作为实际药物的效用,除了诱导Nrf2活性的效果外,还确认了与生物利用率有关的溶解度、代谢稳定性以及与心脏毒性有关的hERG通道结合抑制能力,结果见下表8。
[表8]
如表8所示,尽管比较例1和2的化合物具有诱导Nrf2活性的效果,但该效果约为化合物15的约60%和10%程度。此外,化合物15对五种CYP同工酶未表现出抑制活性,但比较例1和2的化合物对某些CYP同工酶表现出显著的抑制活性。此外,通过与人肝微粒体培养30分钟,比较例1和2的化合物的残留量分别降低至20%和62%,而化合物15在相同条件下保持94%,因此确认了与比较例的化合物相比具有显著更高的代谢稳定性。同时,比较例1和2的化合物均具有小于0.01mg/mL的低溶解度,因此预期生物利用率非常低,而化合物15由于引入吗啉基而具有大于10mg/mL的高溶解度,并且预期表现出高的生物利用率。最后经过确认与心脏毒性有关的hERG通道结合抑制能力,证实了比较例1和2的化合物表现出1μM的低IC50值,表明当施用到身体时存在表现心脏毒性的可能性。而化合物15表现出20μM的高IC50值,这表明它是一种即使以对常规治疗有效的剂量给药也不会表现出心脏毒性的安全的化合物。
Claims (22)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,R1为氯或氟,X为氯或氟。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中,所述化合物为:
1、(E)-3-氟-2-(2-(2-氟苯磺酰基)乙烯基)吡啶,
2、(E)-3-氟-2-(2-(3-氟苯磺酰基)乙烯基)吡啶,
3、(E)-3-氟-2-(2-(4-氟苯磺酰基)乙烯基)吡啶,
4、(E)-3-氯-2-(2-(2-氟苯磺酰基)乙烯基)吡啶,
5、(E)-3-氯-2-(2-(3-氟苯磺酰基)乙烯基)吡啶,
6、(E)-3-氯-2-(2-(4-氟苯磺酰基)乙烯基)吡啶,
7、(E)-2-(2-(2-氯苯磺酰基)乙烯基)-3-氟吡啶,
8、(E)-2-(2-(3-氯苯磺酰基)乙烯基)-3-氟吡啶,
9、(E)-2-(2-(4-氯苯磺酰基)乙烯基)-3-氟吡啶,
10、(E)-3-氯-2-(2-(2-氯苯磺酰基)乙烯基)吡啶,
11、(E)-3-氯-2-(2-(3-氯苯磺酰基)乙烯基)吡啶,
12、(E)-3-氯-2-(2-(4-氯苯磺酰基)乙烯基)吡啶,
13、(E)-2?氯-6-(2-(2-氯苯磺酰基)乙烯基)嘧啶,
14、(E)-2-氯-3-(2-(2-氯苯磺酰基)乙烯基)嘧啶,
15、(E)-4-(3-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉,
16、(E)-4-(3-(3-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)丙基)吗啉,
17、(E)-2-(4-(2-(3-氟吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮,或
18、(E)-2-(4-(2-(3-氯吡啶-2-基)乙烯基磺酰基)苯氧基)-1-(4-甲基哌嗪-1-基)乙酮。
7.根据权利要求6所述的制备方法,其中,通过在无水有机溶剂条件下将所述((R1-取代苯基)磺酰基)甲基膦酸二乙酯和所述卤代吡啶醛的混合物冷却至-100℃至-60℃进行所述反应。
8.根据权利要求6所述的制备方法,其中,还包括在所述反应之后与过量的酸性溶液反应的步骤。
10.根据权利要求9所述的制备方法,其中,所述第a-1步骤通过以下方式进行:将所述甲磺酰卤化物和碱在-10℃至10℃下添加至将(羟基-C1-5烷基)吗啉溶解在有机溶剂中的溶液中,然后在10℃至35℃下进行反应。
11.根据权利要求9所述的制备方法,其中,所述第a-2步骤通过以下方式进行:在10℃至35℃下混合反应物,并在以(羟苯磺酰基)甲基膦酸二乙酯的使用量为基准存在1至2当量的K2CO3的情况下加热至70℃至90℃来进行。
12.根据权利要求6所述的制备方法,其中,
使(羟苯磺酰基)甲基膦酸二乙酯与C1-4卤代乙酸烷基酯反应制备出C1-4烷基(((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸酯的第b-1步骤;
将(((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸乙酯依次用碱性溶液和酸性溶液进行处理以转化为((((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸的第b-2步骤;以及
在2至4当量的羰基二咪唑存在下,使((((二乙氧基磷酰基)甲基磺酰基)苯氧基)乙酸与哌嗪或1-(C1–4烷基)哌嗪反应制备((2-(4-哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯或((2-(4-(C1-4烷基)哌嗪-1-基)-2-氧乙氧基)苯磺酰基)甲基膦酸二乙酯的第b-3步骤。
13.根据权利要求12所述的制备方法,其中,第b-1步骤通过以下方式进行:以(羟苯磺酰基)甲基膦酸二乙酯的使用量为基准存在1至2当量的K2CO3的情况下加热到80℃到100℃。
14.根据权利要求12所述的制备方法,其中,第b-2步骤在10℃至40℃下进行。
15.根据权利要求12所述的制备方法,其中,第b-3步骤通过以下方式进行:在10℃至40℃下与羰基二咪唑反应,然后添加哌嗪或1-(C1–4烷基)哌嗪使得在10℃至40℃下反应。
16.根据权利要求9或12所述的制备方法,其中,所述(羟苯磺酰基)甲基膦酸二乙酯通过以下步骤制备:
使羟甲基膦酸二乙酯与甲苯磺酰卤反应制备(二乙氧基磷酰基)甲基苯磺酸甲酯的第c-1步骤;
使(二乙氧基磷酰基)甲基苯磺酸甲酯与巯基苯酚反应制备(羟基苯硫基)甲基膦酸酯的第c-2步骤;以及
在0℃下将间氯过氧苯甲酸(meta-chloroperoxybenzoic acid;mCPBA)加入(羟基苯硫基)甲基膦酸酯,然后在室温搅拌的同时进行反应的第c-2步骤。
17.根据权利要求6至15中任一项所述的制备方法,其中,在各步骤之后和进行下一步骤之前,还包括选择性地将生成的化合物分离的步骤、纯化的步骤或依次执行所述分离的步骤及纯化的步骤的步骤。
18.根据权利要求6至15中任一项所述的制备方法,其中,各步骤是在溶解于有机溶剂的溶液中进行,所述有机溶剂选自二氯甲烷(methylene chloride;MC或dichloromethane;DCM)、二甲基甲酰胺(dimethylformamide;DMF)、乙腈(acetonitrile;ACN或MeCN)、乙醇及四氢呋喃(tetrahydrofuran;THF)。
19.一种核因子红系衍生2相关因子2(nuclear factor erythroid-derived 2-related factor 2;Nrf2)活化剂,其中,包含权利要求1至5中任一项所述的化合物或其药学上可接受的盐作为有效成分。
20.一种用于预防或治疗由核因子红系衍生2相关因子2活性降低引起的疾病的药物组合物,其中,包含权利要求1至5中任一项所述的化合物或其药学上可接受的盐作为有效成分。
21.根据权利要求20所述的药物组合物,其中,由所述核因子红系衍生2相关因子2活性降低引起的疾病是:选自酒精性肝病(alcoholic liver disease)、非酒精性肝病(non-alcoholic liver disease)、非酒精性脂肪肝(non-alcoholic fatty liver disease;NAFLD)、慢性肝损伤(chronic liver injury)、病毒性肝炎(viral hepatitis)及肝细胞癌(hepatocellular carcinoma)的肝脏疾病(liver diseases);选自糖尿病性肾病(diabetic nephropathy)、局灶性节段性肾小球硬化症(focal segmentalglomerulosclerosis)、肾纤维化(renal fibrosis)、狼疮样自身免疫性肾炎(lupus-likeautoimmune nephritis)、慢性肾脏病(chronic kidney disease;CKD)及高血压性肾脏病(hypertensive kidney disease)的肾脏疾病(kidney diseases);选自慢性阻塞性肺疾病(chronic obstructive pulmonary disease;COPD)、肺气肿(pulmonary emphysema)、通气相关性肺损伤(ventilation-associated lung injury)、急性肺损伤(acute lunginjury;ALI)、急性呼吸窘迫综合征(acute respiratory distress syndrome;ARDS)、肺动脉高压(Pulmonary artery hypertension;PAH)及由所述肺动脉高压所致右心衰(rightheart failure)的肺部疾病(pulmonary diseases);选自帕金森氏病(Parkinson'sdisease;PD)、阿尔茨海默病(Alzheimer's disease;AD)、亨廷顿氏病(huntington'sdisease)、卢伽雷氏(Lou Gehrig's disease)病、癫痫(epilepsy)、抑郁症(depression)、失眠症(insomnia)、焦虑症(anxiety)和多发性硬化症(Multiple sclerosis;MS)的神经退行性疾病(neurodegenerative diseases);线粒体肌病(Mitochondrial myopathy);弗雷德里希共济失调(Friedreich's ataxia);角膜内皮细胞损失(Corneal endothelial cellloss);或银屑病(Psoriasis)。
22.根据权利要求20所述的药物组合物,其中,还包含药学上可接受的载体、稀释剂或赋形剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180096167A KR102127407B1 (ko) | 2018-08-17 | 2018-08-17 | 신규한 할로-(3-(페닐설포닐)프로프-1-에닐)피리딘 유도체 및 이의 용도 |
KR10-2018-0096167 | 2018-08-17 | ||
PCT/KR2019/010513 WO2020036474A1 (ko) | 2018-08-17 | 2019-08-19 | 신규한 할로-(3-(페닐설포닐)프로프-1-에닐)피리딘 유도체 및 이의 용도 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112930345A true CN112930345A (zh) | 2021-06-08 |
Family
ID=69525720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980068425.7A Pending CN112930345A (zh) | 2018-08-17 | 2019-08-19 | 新型卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物及其用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210317083A1 (zh) |
EP (1) | EP3838896A4 (zh) |
JP (1) | JP7163482B2 (zh) |
KR (1) | KR102127407B1 (zh) |
CN (1) | CN112930345A (zh) |
WO (1) | WO2020036474A1 (zh) |
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 |
Citations (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 |
US20020022666A1 (en) * | 1997-10-03 | 2002-02-21 | Reddy E. Premkumar | Styryl sulfone anticancer agents |
KR20030036993A (ko) * | 2001-11-01 | 2003-05-12 | 주식회사 안지오랩 | 칼콘 또는 이의 유도체를 함유하는 매트릭스메탈로프로테아제 활성 억제용 약학 조성물 |
KR20130122420A (ko) * | 2012-04-30 | 2013-11-07 | 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 |
WO2014151682A1 (en) * | 2013-03-14 | 2014-09-25 | Icahn School Of Medicine At Mount Sinai | Pyrimidine compounds as kinase inhibitors |
US20170226073A1 (en) * | 2014-08-07 | 2017-08-10 | 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 WO PCT/KR2019/010513 patent/WO2020036474A1/ko unknown
- 2019-08-19 EP EP19849176.3A patent/EP3838896A4/en active Pending
- 2019-08-19 US US17/268,958 patent/US20210317083A1/en active Pending
- 2019-08-19 JP JP2021508298A patent/JP7163482B2/ja active Active
- 2019-08-19 CN CN201980068425.7A patent/CN112930345A/zh active Pending
Patent Citations (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 |
US20020022666A1 (en) * | 1997-10-03 | 2002-02-21 | Reddy E. Premkumar | Styryl sulfone anticancer agents |
KR20030036993A (ko) * | 2001-11-01 | 2003-05-12 | 주식회사 안지오랩 | 칼콘 또는 이의 유도체를 함유하는 매트릭스메탈로프로테아제 활성 억제용 약학 조성물 |
KR20130122420A (ko) * | 2012-04-30 | 2013-11-07 | 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 |
WO2014151682A1 (en) * | 2013-03-14 | 2014-09-25 | Icahn School Of Medicine At Mount Sinai | Pyrimidine compounds as kinase inhibitors |
US20170226073A1 (en) * | 2014-08-07 | 2017-08-10 | Mayo Foundation For Medical Education And Research | Compounds and methods for treating cancer |
Non-Patent Citations (1)
Title |
---|
SEO YEON WOO等: "Discovery of Vinyl Sulfones as a Novel Class of Neuroprotective Agents toward Parkinson’s Disease Therapy", J. MED. CHEM., vol. 57, pages 1473 - 1487, XP055689041, DOI: 10.1021/jm401788m * |
Also Published As
Publication number | Publication date |
---|---|
KR102127407B1 (ko) | 2020-07-07 |
WO2020036474A1 (ko) | 2020-02-20 |
EP3838896A1 (en) | 2021-06-23 |
KR20200020443A (ko) | 2020-02-26 |
EP3838896A4 (en) | 2022-04-27 |
JP2021534191A (ja) | 2021-12-09 |
US20210317083A1 (en) | 2021-10-14 |
JP7163482B2 (ja) | 2022-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102483876B1 (ko) | 아미노 피리미딘 ssao 억제제 | |
US20220402913A1 (en) | Apoptosis-inducing agents | |
BR112017002811B1 (pt) | Compostos de pirrolopirimidina usados como agonista de tlr7 e seu uso, composição farmacêutica e kit | |
CN107151250B (zh) | 嘧啶类七元环化合物、其制备方法、药用组合物及其应用 | |
EP1099692B1 (en) | N,n-substituted cyclic amine derivatives | |
CN112930345A (zh) | 新型卤代-(3-(苯磺酰基)丙-1-烯)吡啶衍生物及其用途 | |
WO2020161623A1 (en) | N-(pyridin-2-yl)pyridine-sulfonamide derivatives and their use in the treatment of disease | |
KR20240007137A (ko) | 소르틸린 활성 조절제 | |
US10442818B2 (en) | Chromone oxime derivative and its use as allosteric modulator of metabotropic glutamate receptors | |
EP4053108A1 (en) | Compound containing benzene ring and application thereof | |
CN110357833B (zh) | 芳杂乙酰胺类衍生物及其制备和应用 | |
EP3105207B1 (en) | Gpr142 agonist compounds | |
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 | |
CA2726270A1 (en) | Small molecule leptin receptor modulators | |
EP3481801B1 (en) | Indoline derivatives and method for using and producing the same | |
CA2715527A1 (en) | New compounds iv | |
CN106810532A (zh) | 一类胺烷氧基噻吨酮类化合物、其制备方法和用途 | |
KR20210126975A (ko) | 신규한 우레아 유도체 및 이의 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |