CN115916766A - 新型吡唑衍生物 - Google Patents
新型吡唑衍生物 Download PDFInfo
- Publication number
- CN115916766A CN115916766A CN202280005464.4A CN202280005464A CN115916766A CN 115916766 A CN115916766 A CN 115916766A CN 202280005464 A CN202280005464 A CN 202280005464A CN 115916766 A CN115916766 A CN 115916766A
- Authority
- CN
- China
- Prior art keywords
- tetrahydro
- indazol
- pyridin
- substituted
- unsubstituted
- 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
- 150000003217 pyrazoles Chemical class 0.000 title description 8
- -1 pyrazole derivative compound Chemical class 0.000 claims abstract description 208
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 239000012453 solvate Substances 0.000 claims abstract description 38
- 230000000155 isotopic effect Effects 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 279
- 238000002360 preparation method Methods 0.000 claims description 133
- 125000003118 aryl group Chemical group 0.000 claims description 82
- 125000001072 heteroaryl group Chemical group 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 125000001424 substituent group Chemical group 0.000 claims description 54
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 52
- 229910052805 deuterium Inorganic materials 0.000 claims description 52
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
- 229910052760 oxygen Inorganic materials 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 44
- 150000002367 halogens Chemical group 0.000 claims description 44
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 44
- 229910052717 sulfur Inorganic materials 0.000 claims description 43
- 201000010099 disease Diseases 0.000 claims description 42
- 206010016654 Fibrosis Diseases 0.000 claims description 40
- 230000004761 fibrosis Effects 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 150000005840 aryl radicals Chemical class 0.000 claims description 33
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 26
- 230000036542 oxidative stress Effects 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 21
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 20
- 208000018737 Parkinson disease Diseases 0.000 claims description 19
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 238000006467 substitution reaction Methods 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 210000001519 tissue Anatomy 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 14
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 14
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 206010061218 Inflammation Diseases 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 230000004054 inflammatory process Effects 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 208000019423 liver disease Diseases 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 230000004770 neurodegeneration Effects 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 230000003176 fibrotic effect Effects 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- UVZGAAAZEQIXDV-UHFFFAOYSA-N OC1=C(CC(CC2)NC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 UVZGAAAZEQIXDV-UHFFFAOYSA-N 0.000 claims description 6
- 208000017442 Retinal disease Diseases 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 208000012268 mitochondrial disease Diseases 0.000 claims description 6
- 208000017520 skin disease Diseases 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- PSVPHYGXHHDALW-UHFFFAOYSA-N CN(CC1=CC=C(C(F)(F)F)C=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC=C(C(F)(F)F)C=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O PSVPHYGXHHDALW-UHFFFAOYSA-N 0.000 claims description 5
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- UMZWVWPERIYWLY-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC(C=C3)=CC=C3F)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC(C=C3)=CC=C3F)C2=NN1C1=NC=CC=C1 UMZWVWPERIYWLY-UHFFFAOYSA-N 0.000 claims description 5
- UHOBABDVLVTQLF-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC(C=CC=C3)=C3Cl)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC(C=CC=C3)=C3Cl)C2=NN1C1=NC=CC=C1 UHOBABDVLVTQLF-UHFFFAOYSA-N 0.000 claims description 5
- GUODKCDZFHVQPK-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC(Cl)=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC3=CC(Cl)=CC=C3)C2=NN1C1=NC=CC=C1 GUODKCDZFHVQPK-UHFFFAOYSA-N 0.000 claims description 5
- XMCWKJMFTUZSHB-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 XMCWKJMFTUZSHB-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 150000003973 alkyl amines Chemical class 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000002458 infectious effect Effects 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 208000002780 macular degeneration Diseases 0.000 claims description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 4
- WNKVRECPINUOPW-UHFFFAOYSA-N CCCN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CCCN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O WNKVRECPINUOPW-UHFFFAOYSA-N 0.000 claims description 4
- FELJPOUHUCOOHI-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=CC4=C3C=CS4)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=CC4=C3C=CS4)CC1=C2O FELJPOUHUCOOHI-UHFFFAOYSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- OVYDQPKVMFRRRT-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CC4CCCCC4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CC4CCCCC4)CC3)C2=NN1C1=NC=CC=C1 OVYDQPKVMFRRRT-UHFFFAOYSA-N 0.000 claims description 4
- VZJNAFMJZWDAMN-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CC4CCN(CC5=CC=CC=C5)CC4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CC4CCN(CC5=CC=CC=C5)CC4)CC3)C2=NN1C1=NC=CC=C1 VZJNAFMJZWDAMN-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 208000031472 Retinal fibrosis Diseases 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 4
- 238000009825 accumulation Methods 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 210000003205 muscle Anatomy 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 208000007848 Alcoholism Diseases 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 208000036640 Asperger disease Diseases 0.000 claims description 3
- 201000006062 Asperger syndrome Diseases 0.000 claims description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
- 206010003805 Autism Diseases 0.000 claims description 3
- 208000020706 Autistic disease Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- BGLYFWPOVUZINJ-UHFFFAOYSA-N CC1=CC(C(F)(F)F)=CC(N2N=C(CCC(C3)N4CCN(C)CC4)C3=C2O)=N1 Chemical compound CC1=CC(C(F)(F)F)=CC(N2N=C(CCC(C3)N4CCN(C)CC4)C3=C2O)=N1 BGLYFWPOVUZINJ-UHFFFAOYSA-N 0.000 claims description 3
- DKMWFBPBIRPYSN-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=C(C(F)(F)F)C=C3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=C(C(F)(F)F)C=C3)CC1=C2O DKMWFBPBIRPYSN-UHFFFAOYSA-N 0.000 claims description 3
- ULPRJRKLBPHLQK-UHFFFAOYSA-N COC1=CC=CC(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1 Chemical compound COC1=CC=CC(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1 ULPRJRKLBPHLQK-UHFFFAOYSA-N 0.000 claims description 3
- 206010012442 Dermatitis contact Diseases 0.000 claims description 3
- 208000012239 Developmental disease Diseases 0.000 claims description 3
- 201000010374 Down Syndrome Diseases 0.000 claims description 3
- 208000007882 Gastritis Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 208000019022 Mood disease Diseases 0.000 claims description 3
- 208000021642 Muscular disease Diseases 0.000 claims description 3
- 208000009525 Myocarditis Diseases 0.000 claims description 3
- 201000009623 Myopathy Diseases 0.000 claims description 3
- FNYQWDDOIDJIIW-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCCCC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCCCC3)C2=NN1C1=NC=CC=C1 FNYQWDDOIDJIIW-UHFFFAOYSA-N 0.000 claims description 3
- ZVAYEZYOTSLJRE-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CC4=NC=CC=C4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CC4=NC=CC=C4)CC3)C2=NN1C1=NC=CC=C1 ZVAYEZYOTSLJRE-UHFFFAOYSA-N 0.000 claims description 3
- JZRYSBGANMWAPQ-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC(C=C3)=CC=C3Cl)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC(C=C3)=CC=C3Cl)C2=NN1C1=NC=CC=C1 JZRYSBGANMWAPQ-UHFFFAOYSA-N 0.000 claims description 3
- SSYBRWOYLWHLEO-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC(C=CC(F)=C3)=C3F)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC(C=CC(F)=C3)=C3F)C2=NN1C1=NC=CC=C1 SSYBRWOYLWHLEO-UHFFFAOYSA-N 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 206010061323 Optic neuropathy Diseases 0.000 claims description 3
- 206010033645 Pancreatitis Diseases 0.000 claims description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 208000006289 Rett Syndrome Diseases 0.000 claims description 3
- 206010050207 Skin fibrosis Diseases 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 3
- 208000016620 Tourette disease Diseases 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 206010047115 Vasculitis Diseases 0.000 claims description 3
- 230000032683 aging Effects 0.000 claims description 3
- 208000002029 allergic contact dermatitis Diseases 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 230000009787 cardiac fibrosis Effects 0.000 claims description 3
- 210000000170 cell membrane Anatomy 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 3
- 206010014599 encephalitis Diseases 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 206010016256 fatigue Diseases 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 208000037906 ischaemic injury Diseases 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 201000006938 muscular dystrophy Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 201000003142 neovascular glaucoma Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 208000020911 optic nerve disease Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 238000012261 overproduction Methods 0.000 claims description 3
- 230000010412 perfusion Effects 0.000 claims description 3
- 206010034674 peritonitis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 210000000813 small intestine Anatomy 0.000 claims description 3
- 210000000130 stem cell Anatomy 0.000 claims description 3
- 210000002784 stomach Anatomy 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- 208000029257 vision disease Diseases 0.000 claims description 3
- 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 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- KGPHSECMMPUQGT-UHFFFAOYSA-N C=CC(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound C=CC(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O KGPHSECMMPUQGT-UHFFFAOYSA-N 0.000 claims description 2
- MGHSKJVGPXXORA-UHFFFAOYSA-N CC(C(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound CC(C(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O MGHSKJVGPXXORA-UHFFFAOYSA-N 0.000 claims description 2
- LVLBWCDKOAMXDV-UHFFFAOYSA-N CC(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CC(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O LVLBWCDKOAMXDV-UHFFFAOYSA-N 0.000 claims description 2
- XEVNYLSAECIMTP-UHFFFAOYSA-N CC(N1CCC(CN(CC2)CCN2C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)CC1)=O Chemical compound CC(N1CCC(CN(CC2)CCN2C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)CC1)=O XEVNYLSAECIMTP-UHFFFAOYSA-N 0.000 claims description 2
- FSVIPTSYEPTYTK-UHFFFAOYSA-N CC(NC1=NC(N2N=C(CCC(C3)N(C)CC4=CC=CC=C4)C3=C2O)=CC=C1)=O Chemical compound CC(NC1=NC(N2N=C(CCC(C3)N(C)CC4=CC=CC=C4)C3=C2O)=CC=C1)=O FSVIPTSYEPTYTK-UHFFFAOYSA-N 0.000 claims description 2
- JBOZJUSVOQZGCT-UHFFFAOYSA-N CC1=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=CC=C1 Chemical compound CC1=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=CC=C1 JBOZJUSVOQZGCT-UHFFFAOYSA-N 0.000 claims description 2
- RLNBGBZLUGWGFL-UHFFFAOYSA-N CC1=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)N=C2N1C(N1CCN(C)CC1)=CC=C2 Chemical compound CC1=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)N=C2N1C(N1CCN(C)CC1)=CC=C2 RLNBGBZLUGWGFL-UHFFFAOYSA-N 0.000 claims description 2
- YWLJQCPJMCTNMO-UHFFFAOYSA-N CC1=CC(C(F)(F)F)=CC(N2N=C(CCC(C3)NCCC4=CC=CC=C4)C3=C2O)=N1 Chemical compound CC1=CC(C(F)(F)F)=CC(N2N=C(CCC(C3)NCCC4=CC=CC=C4)C3=C2O)=N1 YWLJQCPJMCTNMO-UHFFFAOYSA-N 0.000 claims description 2
- HVADRNWMUPFCIO-UHFFFAOYSA-N CC1=CC(NC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C(C)C=C1 Chemical compound CC1=CC(NC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C(C)C=C1 HVADRNWMUPFCIO-UHFFFAOYSA-N 0.000 claims description 2
- CTUPFYHVHYEFRS-UHFFFAOYSA-N CC1=CC=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 Chemical compound CC1=CC=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 CTUPFYHVHYEFRS-UHFFFAOYSA-N 0.000 claims description 2
- GOKVSOJMSCMMRK-UHFFFAOYSA-N CC1=CC=CC(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1 Chemical compound CC1=CC=CC(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1 GOKVSOJMSCMMRK-UHFFFAOYSA-N 0.000 claims description 2
- PVPPZWPLJOJMKS-UHFFFAOYSA-N CC1=CC=CC(N2N=C(CCC(C3)NCCC4=CC=CC=C4)C3=C2O)=N1 Chemical compound CC1=CC=CC(N2N=C(CCC(C3)NCCC4=CC=CC=C4)C3=C2O)=N1 PVPPZWPLJOJMKS-UHFFFAOYSA-N 0.000 claims description 2
- NWMSYRWMGIHIEK-UHFFFAOYSA-N CCN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CCN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O NWMSYRWMGIHIEK-UHFFFAOYSA-N 0.000 claims description 2
- HFYDSTLHCDRQOZ-UHFFFAOYSA-N CCN(CC1=CC=NC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CCN(CC1=CC=NC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O HFYDSTLHCDRQOZ-UHFFFAOYSA-N 0.000 claims description 2
- TUTZJKCMCKMGIH-UHFFFAOYSA-N CN(C)C(C1=CC=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1)=O Chemical compound CN(C)C(C1=CC=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1)=O TUTZJKCMCKMGIH-UHFFFAOYSA-N 0.000 claims description 2
- BSZZEKUVTJRWHH-SOFGYWHQSA-N CN(C)C/C=C/C(N(C)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound CN(C)C/C=C/C(N(C)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O BSZZEKUVTJRWHH-SOFGYWHQSA-N 0.000 claims description 2
- BFEQFWHECRZOEE-UHFFFAOYSA-N CN(C)C1=CC=CC(CCNC(CCC2=NN3C(C=CC=C4)=C4Cl)CC2=C3O)=C1 Chemical compound CN(C)C1=CC=CC(CCNC(CCC2=NN3C(C=CC=C4)=C4Cl)CC2=C3O)=C1 BFEQFWHECRZOEE-UHFFFAOYSA-N 0.000 claims description 2
- BRDDNTGJCLDVOW-UHFFFAOYSA-N CN(C)C1=CC=CC(CNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1 Chemical compound CN(C)C1=CC=CC(CNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1 BRDDNTGJCLDVOW-UHFFFAOYSA-N 0.000 claims description 2
- HULNSYRSYIQBNX-UHFFFAOYSA-N CN(CC(C=C1)=CC=C1O)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC(C=C1)=CC=C1O)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O HULNSYRSYIQBNX-UHFFFAOYSA-N 0.000 claims description 2
- BYAIINVNBTYYRA-UHFFFAOYSA-N CN(CC(C=C1)=CC=C1[N+]([O-])=O)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC(C=C1)=CC=C1[N+]([O-])=O)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O BYAIINVNBTYYRA-UHFFFAOYSA-N 0.000 claims description 2
- UPICMDPPYXQFRY-UHFFFAOYSA-N CN(CC(C=CC=C1)=C1OC)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC(C=CC=C1)=C1OC)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O UPICMDPPYXQFRY-UHFFFAOYSA-N 0.000 claims description 2
- JPNRZQOHBUSAER-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3Br)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3Br)CC1=C2O JPNRZQOHBUSAER-UHFFFAOYSA-N 0.000 claims description 2
- JZAFEGOPNOTLOE-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3C#N)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3C#N)CC1=C2O JZAFEGOPNOTLOE-UHFFFAOYSA-N 0.000 claims description 2
- TWEULWFJKZKABK-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3Cl)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3Cl)CC1=C2O TWEULWFJKZKABK-UHFFFAOYSA-N 0.000 claims description 2
- LWGJUMLTOYECOC-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3F)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C(C=C3)=CC=C3F)CC1=C2O LWGJUMLTOYECOC-UHFFFAOYSA-N 0.000 claims description 2
- FCPCBEBWRQOROT-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C(N=C3N4CCOCC4)=NC=C3F)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C(N=C3N4CCOCC4)=NC=C3F)CC1=C2O FCPCBEBWRQOROT-UHFFFAOYSA-N 0.000 claims description 2
- KTSYCHPAJACKBA-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=CC(Cl)=CN=N3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=CC(Cl)=CN=N3)CC1=C2O KTSYCHPAJACKBA-UHFFFAOYSA-N 0.000 claims description 2
- DGBDYPLYEYRJLY-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=CC=C(C(F)(F)F)C=C3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=CC=C(C(F)(F)F)C=C3)CC1=C2O DGBDYPLYEYRJLY-UHFFFAOYSA-N 0.000 claims description 2
- NMRHUYRMNMUDSY-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC(Cl)=CC=C3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC(Cl)=CC=C3)CC1=C2O NMRHUYRMNMUDSY-UHFFFAOYSA-N 0.000 claims description 2
- GVMKQLFWBITFEW-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O GVMKQLFWBITFEW-UHFFFAOYSA-N 0.000 claims description 2
- OOIMDFPHRSIJGH-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3F)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3F)CC1=C2O OOIMDFPHRSIJGH-UHFFFAOYSA-N 0.000 claims description 2
- IIMDQGSMVNPEOU-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=CC=N3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=CC=N3)CC1=C2O IIMDQGSMVNPEOU-UHFFFAOYSA-N 0.000 claims description 2
- PXLPOMCPGXOHRV-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=CS3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=CS3)CC1=C2O PXLPOMCPGXOHRV-UHFFFAOYSA-N 0.000 claims description 2
- GARSSVFIGFSQQN-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=NC=C3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=NC=C3)CC1=C2O GARSSVFIGFSQQN-UHFFFAOYSA-N 0.000 claims description 2
- DPDKZIUVKZVONB-UHFFFAOYSA-N CN(CC1=C(C(F)(F)F)C=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=C(C(F)(F)F)C=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O DPDKZIUVKZVONB-UHFFFAOYSA-N 0.000 claims description 2
- HPKVHTDHTZZOMJ-UHFFFAOYSA-N CN(CC1=CC(C(F)(F)F)=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC(C(F)(F)F)=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O HPKVHTDHTZZOMJ-UHFFFAOYSA-N 0.000 claims description 2
- XDCMGYDBNNEZBX-UHFFFAOYSA-N CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O XDCMGYDBNNEZBX-UHFFFAOYSA-N 0.000 claims description 2
- JAXMVLCATGFKKM-UHFFFAOYSA-N CN(CC1=CC2=CC=CC=C2C=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC2=CC=CC=C2C=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O JAXMVLCATGFKKM-UHFFFAOYSA-N 0.000 claims description 2
- YAIAWSZKQCURQD-UHFFFAOYSA-N CN(CC1=CC2=CC=CC=C2C=N1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC2=CC=CC=C2C=N1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O YAIAWSZKQCURQD-UHFFFAOYSA-N 0.000 claims description 2
- PSEWXPURRASCBQ-UHFFFAOYSA-N CN(CC1=CC=C2N=CC=CC2=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC=C2N=CC=CC2=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O PSEWXPURRASCBQ-UHFFFAOYSA-N 0.000 claims description 2
- GFOPXHLXOWUVJC-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C(N=C3)=NC=C3C(O)=O)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C(N=C3)=NC=C3C(O)=O)CC1=C2O GFOPXHLXOWUVJC-UHFFFAOYSA-N 0.000 claims description 2
- CMIDWJZJJRWPTJ-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C(N=C3)=NC=C3[N+]([O-])=O)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C(N=C3)=NC=C3[N+]([O-])=O)CC1=C2O CMIDWJZJJRWPTJ-UHFFFAOYSA-N 0.000 claims description 2
- QYRUVFHXXQTVBQ-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C(N=CC=C3)=C3C(OC)=O)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C(N=CC=C3)=C3C(OC)=O)CC1=C2O QYRUVFHXXQTVBQ-UHFFFAOYSA-N 0.000 claims description 2
- JEOVWLISKVDXGX-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=CC=CN3C)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=CC=CN3C)CC1=C2O JEOVWLISKVDXGX-UHFFFAOYSA-N 0.000 claims description 2
- JMXWHRPGLZUVML-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=CC=NN3C)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=CC=NN3C)CC1=C2O JMXWHRPGLZUVML-UHFFFAOYSA-N 0.000 claims description 2
- GVCSDZJNRKYIKO-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=CN=CN3C)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=CN=CN3C)CC1=C2O GVCSDZJNRKYIKO-UHFFFAOYSA-N 0.000 claims description 2
- OJHFKFSKTRKDKY-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2OC Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2OC OJHFKFSKTRKDKY-UHFFFAOYSA-N 0.000 claims description 2
- XVMAUPOKYIWIJA-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2OC(C=C)=O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2OC(C=C)=O XVMAUPOKYIWIJA-UHFFFAOYSA-N 0.000 claims description 2
- YQTKCQUPDSLCFP-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2OCC1CC1 Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2OCC1CC1 YQTKCQUPDSLCFP-UHFFFAOYSA-N 0.000 claims description 2
- FUMLCBDMIYQDNO-UHFFFAOYSA-N CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=N3)CC1=C2O Chemical compound CN(CC1=CC=CC=C1)C(CCC1=NN2C3=NC=CC=N3)CC1=C2O FUMLCBDMIYQDNO-UHFFFAOYSA-N 0.000 claims description 2
- AXDSFKSKIAALHW-UHFFFAOYSA-N CN(CC1=CC=NC=C1)C(CCC1=NN2C(C=C3)=NC=C3Cl)CC1=C2O Chemical compound CN(CC1=CC=NC=C1)C(CCC1=NN2C(C=C3)=NC=C3Cl)CC1=C2O AXDSFKSKIAALHW-UHFFFAOYSA-N 0.000 claims description 2
- AJMNIAHXUNAVIP-UHFFFAOYSA-N CN(CC1=CC=NC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CC=NC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O AJMNIAHXUNAVIP-UHFFFAOYSA-N 0.000 claims description 2
- KKHPDYDCWVFRTE-UHFFFAOYSA-N CN(CC1=CN2C(N3CCN(C)CC3)=CC=CC2=N1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=CN2C(N3CCN(C)CC3)=CC=CC2=N1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O KKHPDYDCWVFRTE-UHFFFAOYSA-N 0.000 claims description 2
- LBWLPNHIIUPQQI-UHFFFAOYSA-N CN(CC1=NC=CC=C1)C(CCC1=NN2C3=CC=CC=C3)CC1=C2O Chemical compound CN(CC1=NC=CC=C1)C(CCC1=NN2C3=CC=CC=C3)CC1=C2O LBWLPNHIIUPQQI-UHFFFAOYSA-N 0.000 claims description 2
- JEXWWLLCPISUJO-UHFFFAOYSA-N CN(CC1=NC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=NC=CC=C1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O JEXWWLLCPISUJO-UHFFFAOYSA-N 0.000 claims description 2
- ARLBOLWJIOLXLR-UHFFFAOYSA-N CN1CCC(CN(CC2)CCN2C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)CC1 Chemical compound CN1CCC(CN(CC2)CCN2C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)CC1 ARLBOLWJIOLXLR-UHFFFAOYSA-N 0.000 claims description 2
- CGOMAGJHHLIJGB-UHFFFAOYSA-N CNC(C1=CC=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1)=O Chemical compound CNC(C1=CC=C(CN(C)C(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1)=O CGOMAGJHHLIJGB-UHFFFAOYSA-N 0.000 claims description 2
- VOIASDSLSPFSAY-UHFFFAOYSA-N COC(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound COC(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O VOIASDSLSPFSAY-UHFFFAOYSA-N 0.000 claims description 2
- GSWHBMMKRNBENO-UHFFFAOYSA-N COC(C=C1)=CC=C1NC(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound COC(C=C1)=CC=C1NC(CCC1=NN2C3=NC=CC=C3)CC1=C2O GSWHBMMKRNBENO-UHFFFAOYSA-N 0.000 claims description 2
- UCRMFNLDVCTMEW-UHFFFAOYSA-N COC(C=CC=C1)=C1N1N=C(CCC(C2)NCCC3=CC=CC=C3)C2=C1O Chemical compound COC(C=CC=C1)=C1N1N=C(CCC(C2)NCCC3=CC=CC=C3)C2=C1O UCRMFNLDVCTMEW-UHFFFAOYSA-N 0.000 claims description 2
- WRIZFPNUQPKVTR-UHFFFAOYSA-N COC1=CC=C(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 Chemical compound COC1=CC=C(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 WRIZFPNUQPKVTR-UHFFFAOYSA-N 0.000 claims description 2
- ABYWHCQYMYBGIR-UHFFFAOYSA-N COC1=CC=C(CNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 Chemical compound COC1=CC=C(CNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 ABYWHCQYMYBGIR-UHFFFAOYSA-N 0.000 claims description 2
- AGKQNAFWJSULJN-UHFFFAOYSA-N CS(C1=CC=C(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1)(=O)=O Chemical compound CS(C1=CC=C(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1)(=O)=O AGKQNAFWJSULJN-UHFFFAOYSA-N 0.000 claims description 2
- SSDCXGXCMPQEEU-UHFFFAOYSA-N CS(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)(=O)=O Chemical compound CS(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)(=O)=O SSDCXGXCMPQEEU-UHFFFAOYSA-N 0.000 claims description 2
- 206010007749 Cataract diabetic Diseases 0.000 claims description 2
- 208000004232 Enteritis Diseases 0.000 claims description 2
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 2
- 206010028289 Muscle atrophy Diseases 0.000 claims description 2
- AXOCWBYAPSDAPY-UHFFFAOYSA-N N#CC1=CC(CNCC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=CC=C1 Chemical compound N#CC1=CC(CNCC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=CC=C1 AXOCWBYAPSDAPY-UHFFFAOYSA-N 0.000 claims description 2
- XTRFJGKGGVPLBK-UHFFFAOYSA-N N#CC1=CC=C(CNCC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 Chemical compound N#CC1=CC=C(CNCC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)C=C1 XTRFJGKGGVPLBK-UHFFFAOYSA-N 0.000 claims description 2
- FOCUVOKXBBLXEV-UHFFFAOYSA-N NC1=CC=CC(N2N=C(CCC(C3)NCCC4=CC=CC=C4)C3=C2O)=N1 Chemical compound NC1=CC=CC(N2N=C(CCC(C3)NCCC4=CC=CC=C4)C3=C2O)=N1 FOCUVOKXBBLXEV-UHFFFAOYSA-N 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- BMASCBOEFWNURA-UHFFFAOYSA-N OC1=C(CC(CC2)N(CC3)CCN3C(C=C3)=CC(F)=C3F)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N(CC3)CCN3C(C=C3)=CC(F)=C3F)C2=NN1C1=NC=CC=C1 BMASCBOEFWNURA-UHFFFAOYSA-N 0.000 claims description 2
- NOIDSTOTIZTQQU-UHFFFAOYSA-N OC1=C(CC(CC2)N(CC3)CCN3C(OCC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N(CC3)CCN3C(OCC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 NOIDSTOTIZTQQU-UHFFFAOYSA-N 0.000 claims description 2
- ZWATYBGGCBFXMH-UHFFFAOYSA-N OC1=C(CC(CC2)N(CC3)CCN3S(C3=CC=CC=C3)(=O)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N(CC3)CCN3S(C3=CC=CC=C3)(=O)=O)C2=NN1C1=NC=CC=C1 ZWATYBGGCBFXMH-UHFFFAOYSA-N 0.000 claims description 2
- LHUKTLJTKNVOHA-UHFFFAOYSA-N OC1=C(CC(CC2)N(CC3=CC=CC=C3)C3CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N(CC3=CC=CC=C3)C3CC3)C2=NN1C1=NC=CC=C1 LHUKTLJTKNVOHA-UHFFFAOYSA-N 0.000 claims description 2
- BOIWVZSAPDSDGY-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCCC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCCC3)C2=NN1C1=NC=CC=C1 BOIWVZSAPDSDGY-UHFFFAOYSA-N 0.000 claims description 2
- GUFCLVARNVVPQU-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CC4=CC=C5N=CC=CC5=C4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CC4=CC=C5N=CC=CC5=C4)CC3)C2=NN1C1=NC=CC=C1 GUFCLVARNVVPQU-UHFFFAOYSA-N 0.000 claims description 2
- NUYUGNZNMUEUQX-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CC4=CC=CC=C4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CC4=CC=CC=C4)CC3)C2=NN1C1=NC=CC=C1 NUYUGNZNMUEUQX-UHFFFAOYSA-N 0.000 claims description 2
- LYLYINPJWJCELY-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CC4CCNCC4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CC4CCNCC4)CC3)C2=NN1C1=NC=CC=C1 LYLYINPJWJCELY-UHFFFAOYSA-N 0.000 claims description 2
- ORHQSOKVZZVIEZ-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCN(CCCC4=CC=CC=C4)CC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCN(CCCC4=CC=CC=C4)CC3)C2=NN1C1=NC=CC=C1 ORHQSOKVZZVIEZ-UHFFFAOYSA-N 0.000 claims description 2
- QXNHLFUQHJMBNH-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCNCC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCNCC3)C2=NN1C1=NC=CC=C1 QXNHLFUQHJMBNH-UHFFFAOYSA-N 0.000 claims description 2
- WLWOIVHWJBTGCH-UHFFFAOYSA-N OC1=C(CC(CC2)N3CCOCC3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N3CCOCC3)C2=NN1C1=NC=CC=C1 WLWOIVHWJBTGCH-UHFFFAOYSA-N 0.000 claims description 2
- BRVDLBAWGLCBIS-UHFFFAOYSA-N OC1=C(CC(CC2)NC(C3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC(C3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 BRVDLBAWGLCBIS-UHFFFAOYSA-N 0.000 claims description 2
- UVEYLRXBLPHTNJ-UHFFFAOYSA-N OC1=C(CC(CC2)NC(C=C3)=CC(F)=C3F)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC(C=C3)=CC(F)=C3F)C2=NN1C1=NC=CC=C1 UVEYLRXBLPHTNJ-UHFFFAOYSA-N 0.000 claims description 2
- IWZBBXHJNQBVIG-UHFFFAOYSA-N OC1=C(CC(CC2)NC(NC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC(NC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 IWZBBXHJNQBVIG-UHFFFAOYSA-N 0.000 claims description 2
- HKQZARCPHFXLRA-UHFFFAOYSA-N OC1=C(CC(CC2)NC(NCC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC(NCC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 HKQZARCPHFXLRA-UHFFFAOYSA-N 0.000 claims description 2
- RGGDNQVGQOCDEB-UHFFFAOYSA-N OC1=C(CC(CC2)NC3=CC4=CC=CC=C4N=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC3=CC4=CC=CC=C4N=C3)C2=NN1C1=NC=CC=C1 RGGDNQVGQOCDEB-UHFFFAOYSA-N 0.000 claims description 2
- WRFLSQWMQTYCNT-UHFFFAOYSA-N OC1=C(CC(CC2)NCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 WRFLSQWMQTYCNT-UHFFFAOYSA-N 0.000 claims description 2
- NXFUPJCFHYAIKE-UHFFFAOYSA-N OC1=C(CC(CC2)NCC3=NC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCC3=NC=CC=C3)C2=NN1C1=NC=CC=C1 NXFUPJCFHYAIKE-UHFFFAOYSA-N 0.000 claims description 2
- MHZXUOAETXYFHZ-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC(C=C3)=CC(Cl)=C3Cl)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC(C=C3)=CC(Cl)=C3Cl)C2=NN1C1=NC=CC=C1 MHZXUOAETXYFHZ-UHFFFAOYSA-N 0.000 claims description 2
- HFKOMHFTYNDDQP-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC(C=CC(Cl)=C3)=C3Cl)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC(C=CC(Cl)=C3)=C3Cl)C2=NN1C1=NC=CC=C1 HFKOMHFTYNDDQP-UHFFFAOYSA-N 0.000 claims description 2
- RXOGCHPXLSVHGJ-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC(F)=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC3=CC(F)=CC=C3)C2=NN1C1=NC=CC=C1 RXOGCHPXLSVHGJ-UHFFFAOYSA-N 0.000 claims description 2
- CDIMWZVYNZFZBG-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C(C=C1)=CC=C1Br Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C(C=C1)=CC=C1Br CDIMWZVYNZFZBG-UHFFFAOYSA-N 0.000 claims description 2
- WWDIKXXPHZZEER-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C(C=C1)=NC=C1Cl Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C(C=C1)=NC=C1Cl WWDIKXXPHZZEER-UHFFFAOYSA-N 0.000 claims description 2
- MXNDWOSQXNCAQD-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C(C=CC=C1)=C1Cl Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C(C=CC=C1)=C1Cl MXNDWOSQXNCAQD-UHFFFAOYSA-N 0.000 claims description 2
- RXLWOZKGYNOTLA-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=CC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=CC=CC=C1 RXLWOZKGYNOTLA-UHFFFAOYSA-N 0.000 claims description 2
- ZZPBSEIKSLLKMX-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC(C(F)(F)F)=CC=C1 Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC(C(F)(F)F)=CC=C1 ZZPBSEIKSLLKMX-UHFFFAOYSA-N 0.000 claims description 2
- QRNREEIDDRKBPX-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=C(C(F)(F)F)C=C1 Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=C(C(F)(F)F)C=C1 QRNREEIDDRKBPX-UHFFFAOYSA-N 0.000 claims description 2
- PXWVXKHDNRDINM-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=CC2=C1C=CS2 Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=CC2=C1C=CS2 PXWVXKHDNRDINM-UHFFFAOYSA-N 0.000 claims description 2
- KQJKOJGAUKPZKG-UHFFFAOYSA-N OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1F Chemical compound OC1=C(CC(CC2)NCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1F KQJKOJGAUKPZKG-UHFFFAOYSA-N 0.000 claims description 2
- DCTPHNIGBLNVGG-UHFFFAOYSA-N OC1=C(CC(CC2)NCCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 DCTPHNIGBLNVGG-UHFFFAOYSA-N 0.000 claims description 2
- RYIFNPUGOROWOF-UHFFFAOYSA-N OC1=C(CC(CC2)NCCCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 RYIFNPUGOROWOF-UHFFFAOYSA-N 0.000 claims description 2
- RGHUFPBCRBBADQ-UHFFFAOYSA-N OC1=C(CC(CC2)NCCCCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCCCCCC3=CC=CC=C3)C2=NN1C1=NC=CC=C1 RGHUFPBCRBBADQ-UHFFFAOYSA-N 0.000 claims description 2
- DNJSVCZTXSVNOY-UHFFFAOYSA-N OC1=C(CC(CC2)NS(C3=CC=CC=C3)(=O)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NS(C3=CC=CC=C3)(=O)=O)C2=NN1C1=NC=CC=C1 DNJSVCZTXSVNOY-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- UNDPGMGLURLEPP-UHFFFAOYSA-N [O-][N+](C(C=C1)=CC=C1NC(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound [O-][N+](C(C=C1)=CC=C1NC(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O UNDPGMGLURLEPP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 claims description 2
- 201000007025 diabetic cataract Diseases 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 208000030175 lameness Diseases 0.000 claims description 2
- 210000002429 large intestine Anatomy 0.000 claims description 2
- 201000010901 lateral sclerosis Diseases 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 208000005264 motor neuron disease Diseases 0.000 claims description 2
- 230000020763 muscle atrophy Effects 0.000 claims description 2
- 201000000585 muscular atrophy Diseases 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 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
- 239000000375 suspending agent Substances 0.000 claims description 2
- 150000003254 radicals Chemical group 0.000 claims 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims 2
- GJHJUQHPHMOCDD-UHFFFAOYSA-N CN(CC1=C(CO)N2C(N3CCN(C)CC3)=CC=CC2=N1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CN(CC1=C(CO)N2C(N3CCN(C)CC3)=CC=CC2=N1)C(CCC1=NN2C3=NC=CC=C3)CC1=C2O GJHJUQHPHMOCDD-UHFFFAOYSA-N 0.000 claims 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- HLMFVUNVHOZVLZ-UHFFFAOYSA-N CN(CC1)CCN1C(CCC1=NN2C3=NC=CO3)CC1=C2O Chemical compound CN(CC1)CCN1C(CCC1=NN2C3=NC=CO3)CC1=C2O HLMFVUNVHOZVLZ-UHFFFAOYSA-N 0.000 claims 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims 1
- SRUAMRSBNPSUPK-UHFFFAOYSA-N OC1=C(CC(CC2)NC(CC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NC(CC3=CC=CC=C3)=O)C2=NN1C1=NC=CC=C1 SRUAMRSBNPSUPK-UHFFFAOYSA-N 0.000 claims 1
- 235000021314 Palmitic acid Nutrition 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229940092714 benzenesulfonic acid Drugs 0.000 claims 1
- 229930016911 cinnamic acid Natural products 0.000 claims 1
- 235000013985 cinnamic acid Nutrition 0.000 claims 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 229940107700 pyruvic acid Drugs 0.000 claims 1
- 229960004889 salicylic acid Drugs 0.000 claims 1
- 239000004094 surface-active agent Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- 239000007787 solid Substances 0.000 description 80
- 238000003786 synthesis reaction Methods 0.000 description 76
- 230000015572 biosynthetic process Effects 0.000 description 75
- 239000011541 reaction mixture Substances 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 210000004027 cell Anatomy 0.000 description 53
- 239000003642 reactive oxygen metabolite Substances 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000004519 manufacturing process Methods 0.000 description 37
- 230000002829 reductive effect Effects 0.000 description 32
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 210000002950 fibroblast Anatomy 0.000 description 27
- 230000014509 gene expression Effects 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 230000000694 effects Effects 0.000 description 21
- 229920001577 copolymer Polymers 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 229920000147 Styrene maleic anhydride Polymers 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000007882 cirrhosis Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 14
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 11
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 10
- 229920002678 cellulose Polymers 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000002260 Keloid Diseases 0.000 description 9
- 206010023330 Keloid scar Diseases 0.000 description 9
- ROYNTENWULAUDK-UHFFFAOYSA-N OC1=C(CC(CC2)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)=O)C2=NN1C1=NC=CC=C1 ROYNTENWULAUDK-UHFFFAOYSA-N 0.000 description 9
- 235000010980 cellulose Nutrition 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 210000001117 keloid Anatomy 0.000 description 9
- XJLDYKIEURAVBW-UHFFFAOYSA-N Aethyl-heptyl-keton Natural products CCCCCCCC(=O)CC XJLDYKIEURAVBW-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 102000003802 alpha-Synuclein Human genes 0.000 description 8
- 108090000185 alpha-Synuclein Proteins 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000001913 cellulose Substances 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- PHEDXBVPIONUQT-UHFFFAOYSA-N Cocarcinogen A1 Natural products CCCCCCCCCCCCCC(=O)OC1C(C)C2(O)C3C=C(C)C(=O)C3(O)CC(CO)=CC2C2C1(OC(C)=O)C2(C)C PHEDXBVPIONUQT-UHFFFAOYSA-N 0.000 description 7
- 102000004889 Interleukin-6 Human genes 0.000 description 7
- 108090001005 Interleukin-6 Proteins 0.000 description 7
- 102000004890 Interleukin-8 Human genes 0.000 description 7
- 108090001007 Interleukin-8 Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- 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 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 206010003591 Ataxia Diseases 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940126142 compound 16 Drugs 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 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 5
- 208000014644 Brain disease Diseases 0.000 description 5
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 5
- 208000009829 Lewy Body Disease Diseases 0.000 description 5
- 229940125797 compound 12 Drugs 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000004677 hydrates Chemical class 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- HDBHPQJOSZBECI-UHFFFAOYSA-N methyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate Chemical compound C1CC(=O)C(C(=O)OC)CC21OCCO2 HDBHPQJOSZBECI-UHFFFAOYSA-N 0.000 description 5
- 210000000651 myofibroblast Anatomy 0.000 description 5
- 210000000440 neutrophil Anatomy 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 230000002441 reversible effect Effects 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229940126639 Compound 33 Drugs 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 4
- 102000003777 Interleukin-1 beta Human genes 0.000 description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 description 4
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 4
- 201000002832 Lewy body dementia Diseases 0.000 description 4
- 108700006159 Long-chain acyl-CoA dehydrogenase deficiency Proteins 0.000 description 4
- 201000009035 MERRF syndrome Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000001089 Multiple system atrophy Diseases 0.000 description 4
- 206010069825 Myoclonic epilepsy and ragged-red fibres Diseases 0.000 description 4
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 4
- WMUJUWOELRAUNU-UHFFFAOYSA-N OC1=C(CC2(CC3)OCCO2)C3=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC2(CC3)OCCO2)C3=NN1C1=NC=CC=C1 WMUJUWOELRAUNU-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 208000004687 long chain acyl-CoA dehydrogenase deficiency Diseases 0.000 description 4
- 201000002697 mitochondrial DNA depletion syndrome Diseases 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229920000193 polymethacrylate Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- NWELCUKYUCBVKK-UHFFFAOYSA-N pyridin-2-ylhydrazine Chemical compound NNC1=CC=CC=N1 NWELCUKYUCBVKK-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 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 3
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- QKRMWQVTBYQJFS-UHFFFAOYSA-N CNC(CCC1=NN2C3=NC=CC=C3)CC1=C2O Chemical compound CNC(CCC1=NN2C3=NC=CC=C3)CC1=C2O QKRMWQVTBYQJFS-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 108010022452 Collagen Type I Proteins 0.000 description 3
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 3
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 108091058560 IL8 Proteins 0.000 description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 3
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 3
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 229920002301 cellulose acetate Polymers 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940127573 compound 38 Drugs 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 208000033679 diabetic kidney disease Diseases 0.000 description 3
- 210000005064 dopaminergic neuron Anatomy 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 210000003953 foreskin Anatomy 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 210000004024 hepatic stellate cell Anatomy 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 210000004558 lewy body Anatomy 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000004792 oxidative damage Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 210000000844 retinal pigment epithelial cell Anatomy 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 229920003176 water-insoluble polymer Polymers 0.000 description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- 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 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 201000005943 Barth syndrome Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- VYIVOIVBEGJRNE-UHFFFAOYSA-N CN(CC1)CCN1C(CCCC1=NN2C(C=C3)=CC=C3C#N)C1=C2O Chemical compound CN(CC1)CCN1C(CCCC1=NN2C(C=C3)=CC=C3C#N)C1=C2O VYIVOIVBEGJRNE-UHFFFAOYSA-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 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 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 2
- 208000004986 Diffuse Cerebral Sclerosis of Schilder Diseases 0.000 description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 208000037357 HIV infectious disease Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-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
- 208000006136 Leigh Disease Diseases 0.000 description 2
- 208000017507 Leigh syndrome Diseases 0.000 description 2
- 102100021644 Long-chain specific acyl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 2
- 208000009564 MELAS Syndrome Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 201000002169 Mitochondrial myopathy Diseases 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- 208000013234 Pearson syndrome Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 208000032859 Synucleinopathies Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- UGXQOOQUZRUVSS-ZZXKWVIFSA-N [5-[3,5-dihydroxy-2-(1,3,4-trihydroxy-5-oxopentan-2-yl)oxyoxan-4-yl]oxy-3,4-dihydroxyoxolan-2-yl]methyl (e)-3-(4-hydroxyphenyl)prop-2-enoate Chemical compound OC1C(OC(CO)C(O)C(O)C=O)OCC(O)C1OC1C(O)C(O)C(COC(=O)\C=C\C=2C=CC(O)=CC=2)O1 UGXQOOQUZRUVSS-ZZXKWVIFSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229920000617 arabinoxylan Polymers 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 2
- 229940075529 glyceryl stearate Drugs 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 208000006443 lactic acidosis Diseases 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910052901 montmorillonite Inorganic materials 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 206010028537 myelofibrosis Diseases 0.000 description 2
- 201000010256 myopathy, lactic acidosis, and sideroblastic anemia Diseases 0.000 description 2
- ZXTRMHOUGKPHHM-UHFFFAOYSA-N n-methyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1=CN=C2C(NC)CCCC2=C1 ZXTRMHOUGKPHHM-UHFFFAOYSA-N 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000010825 rotarod performance test Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 210000002536 stromal cell Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- NNKPSUBWDUYRMJ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) but-2-enoate Chemical compound CC=CC(=O)ON1C(=O)CCC1=O NNKPSUBWDUYRMJ-UHFFFAOYSA-N 0.000 description 1
- BKNUTQQQAPBRAR-UHFFFAOYSA-N (2-methoxyphenyl)methylurea Chemical compound COC1=CC=CC=C1CNC(N)=O BKNUTQQQAPBRAR-UHFFFAOYSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- UUHNQHFOIVLAQX-BJILWQEISA-N (e)-4-(dimethylamino)but-2-enoic acid;hydrochloride Chemical compound Cl.CN(C)C\C=C\C(O)=O UUHNQHFOIVLAQX-BJILWQEISA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- UFNPJQRQWKZJNL-UHFFFAOYSA-N 1,2,4,5,6,7-hexahydroindazol-3-one Chemical compound C1CCCC2=C1NNC2=O UFNPJQRQWKZJNL-UHFFFAOYSA-N 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical class CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- SGIBOXBBPQRZDM-UHFFFAOYSA-N 1-benzylpiperidine-4-carbaldehyde Chemical compound C1CC(C=O)CCN1CC1=CC=CC=C1 SGIBOXBBPQRZDM-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- BRAJQLYTRXKQAW-UHFFFAOYSA-N 1-methyl-4-phenyl-2h-pyridine Chemical compound C1=CN(C)CC=C1C1=CC=CC=C1 BRAJQLYTRXKQAW-UHFFFAOYSA-N 0.000 description 1
- QHZLMUACJMDIAE-UHFFFAOYSA-N 1-monopalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 description 1
- YTPQLWVHCBATKO-UHFFFAOYSA-N 1-propylpiperazine;dihydrobromide Chemical compound Br.Br.CCCN1CCNCC1 YTPQLWVHCBATKO-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- DGPBVJWCIDNDPN-UHFFFAOYSA-N 2-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=CC=C1C=O DGPBVJWCIDNDPN-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- SSONCJTVDRSLNK-UHFFFAOYSA-N 2-methylprop-2-enoic acid;hydrochloride Chemical compound Cl.CC(=C)C(O)=O SSONCJTVDRSLNK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- PYSRRFNXTXNWCD-UHFFFAOYSA-N 3-(2-phenylethenyl)furan-2,5-dione Chemical compound O=C1OC(=O)C(C=CC=2C=CC=CC=2)=C1 PYSRRFNXTXNWCD-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- SATHPVQTSSUFFW-UHFFFAOYSA-N 4-[6-[(3,5-dihydroxy-4-methoxyoxan-2-yl)oxymethyl]-3,5-dihydroxy-4-methoxyoxan-2-yl]oxy-2-(hydroxymethyl)-6-methyloxane-3,5-diol Chemical class OC1C(OC)C(O)COC1OCC1C(O)C(OC)C(O)C(OC2C(C(CO)OC(C)C2O)O)O1 SATHPVQTSSUFFW-UHFFFAOYSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 1
- BNNMDMGPZUOOOE-UHFFFAOYSA-N 4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1 BNNMDMGPZUOOOE-UHFFFAOYSA-N 0.000 description 1
- 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
- ICFHDYFCVQPVHM-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde Chemical compound C1CN(C)CCN1C1=CC=CC2=NC(C=O)=CN12 ICFHDYFCVQPVHM-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- JIAKIQWNYAZUJD-UHFFFAOYSA-N 6,7-dihydro-5h-quinolin-8-one Chemical compound C1=CN=C2C(=O)CCCC2=C1 JIAKIQWNYAZUJD-UHFFFAOYSA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 208000036022 Alpers' disease Diseases 0.000 description 1
- 208000023434 Alpers-Huttenlocher syndrome Diseases 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920000945 Amylopectin Chemical class 0.000 description 1
- 229920000856 Amylose Chemical class 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 239000001904 Arabinogalactan Chemical class 0.000 description 1
- 229920000189 Arabinogalactan Chemical class 0.000 description 1
- 208000033116 Asbestos intoxication Diseases 0.000 description 1
- 102000007371 Ataxin-3 Human genes 0.000 description 1
- 102000014461 Ataxins Human genes 0.000 description 1
- 108010078286 Ataxins Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000012657 Atopic disease Diseases 0.000 description 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 206010004664 Biliary fibrosis Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- SGXOYPITQRBTBC-UHFFFAOYSA-N C(C(O)CO)C(C(=O)O)CCCCCCCCCCCCCCCCCCCC.C(CCCCCCCCCCCCCCCCCCCCC)(=O)OCC(O)CO Chemical compound C(C(O)CO)C(C(=O)O)CCCCCCCCCCCCCCCCCCCC.C(CCCCCCCCCCCCCCCCCCCCC)(=O)OCC(O)CO SGXOYPITQRBTBC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- HFSUSVDQLYXMLL-UHFFFAOYSA-N CC#CC(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound CC#CC(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O HFSUSVDQLYXMLL-UHFFFAOYSA-N 0.000 description 1
- PNRCINJRNDHSIK-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O PNRCINJRNDHSIK-UHFFFAOYSA-N 0.000 description 1
- KBXSSAYHGULBME-FNORWQNLSA-N CN(C)C/C=C/C(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O Chemical compound CN(C)C/C=C/C(N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)=O KBXSSAYHGULBME-FNORWQNLSA-N 0.000 description 1
- MMXAFEJBKCWGOM-UHFFFAOYSA-N CN(CC1)CCN1C(CC1)CC(C(OC)=O)C1=O Chemical compound CN(CC1)CCN1C(CC1)CC(C(OC)=O)C1=O MMXAFEJBKCWGOM-UHFFFAOYSA-N 0.000 description 1
- QDWNSQAMKLBDCL-UHFFFAOYSA-N CS(C(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)(=O)=O Chemical compound CS(C(C=C1)=CC=C1N(CC1)CCN1C(CCC1=NN2C3=NC=CC=C3)CC1=C2O)(=O)=O QDWNSQAMKLBDCL-UHFFFAOYSA-N 0.000 description 1
- GCUNIMNSCYMTHQ-UHFFFAOYSA-N CS(C1=CC=CC(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1)(=O)=O Chemical compound CS(C1=CC=CC(CCNC(CCC2=NN3C4=NC=CC=C4)CC2=C3O)=C1)(=O)=O GCUNIMNSCYMTHQ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical class [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 229920001747 Cellulose diacetate Polymers 0.000 description 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 206010008025 Cerebellar ataxia Diseases 0.000 description 1
- 206010008027 Cerebellar atrophy Diseases 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 1
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010072268 Drug-induced liver injury Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 229920000896 Ethulose Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 1
- 229920003149 Eudragit® E 100 Polymers 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003163 Eudragit® NE 30 D Polymers 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 229920002148 Gellan gum Polymers 0.000 description 1
- 206010064571 Gene mutation Diseases 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 208000024934 IgG4-related mediastinitis Diseases 0.000 description 1
- 208000014919 IgG4-related retroperitoneal fibrosis Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010022562 Intermittent claudication Diseases 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000002569 Machado-Joseph Disease Diseases 0.000 description 1
- 208000002805 Mediastinal fibrosis Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000014844 Mitochondrial neurogastrointestinal encephalomyopathy Diseases 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 206010048654 Muscle fibrosis Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 125000004633 N-oxo-pyridyl group Chemical group 0.000 description 1
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 description 1
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- XRWDEKBYOYDQRS-UHFFFAOYSA-N OC1=C(CC(CC2)N(CC3)CCN3C(C3CC3)=O)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)N(CC3)CCN3C(C3CC3)=O)C2=NN1C1=NC=CC=C1 XRWDEKBYOYDQRS-UHFFFAOYSA-N 0.000 description 1
- DWGUDXGLTHAOOW-UHFFFAOYSA-N OC1=C(CC(CC2)NCC3=CC4=CC=CC=C4C=N3)C2=NN1C1=NC=CC=C1 Chemical compound OC1=C(CC(CC2)NCC3=CC4=CC=CC=C4C=N3)C2=NN1C1=NC=CC=C1 DWGUDXGLTHAOOW-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000002192 Parkinson disease 3 Diseases 0.000 description 1
- 229920002230 Pectic acid Chemical class 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 208000024571 Pick disease Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010057430 Retinal injury Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 1
- 206010038979 Retroperitoneal fibrosis Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 101150110423 SNCA gene Proteins 0.000 description 1
- 241000207929 Scutellaria Species 0.000 description 1
- 208000009106 Shy-Drager Syndrome Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 1
- 208000036834 Spinocerebellar ataxia type 3 Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- PDRJYGJBOYHPJC-UHFFFAOYSA-N [5-(trifluoromethyl)pyridin-2-yl]hydrazine Chemical compound NNC1=CC=C(C(F)(F)F)C=N1 PDRJYGJBOYHPJC-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006851 antioxidant defense Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000019312 arabinogalactan Nutrition 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 206010003441 asbestosis Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 description 1
- 208000031326 autosomal dominant parkinson disease 3 Diseases 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- VAXVWHDAGLTVRV-UHFFFAOYSA-N benzoic acid;phthalic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1C(O)=O VAXVWHDAGLTVRV-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 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
- VHEMBTYWURNBQQ-UHFFFAOYSA-N butanoic acid;phthalic acid Chemical compound CCCC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O VHEMBTYWURNBQQ-UHFFFAOYSA-N 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 230000001587 cholestatic effect Effects 0.000 description 1
- 208000024980 claudication Diseases 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WIHDAPMHNYYTOA-UHFFFAOYSA-N cyclopropyl(piperazin-1-yl)methanone;hydrochloride Chemical compound Cl.C1CNCCN1C(=O)C1CC1 WIHDAPMHNYYTOA-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 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
- 230000007850 degeneration Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005072 dihydrothiopyranyl group Chemical group S1C(CCC=C1)* 0.000 description 1
- WQABCVAJNWAXTE-UHFFFAOYSA-N dimercaprol Chemical compound OCC(S)CS WQABCVAJNWAXTE-UHFFFAOYSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 231100000594 drug induced liver disease Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- XPNLOZNCOBKRNJ-UHFFFAOYSA-N ethyl prop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C=C.COC(=O)C(C)=C XPNLOZNCOBKRNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 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
- 239000011737 fluorine Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940096898 glyceryl palmitate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 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
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 239000001341 hydroxy propyl starch Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005237 imidazopyrimidines Chemical class 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 208000026919 intracranial meningioma Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 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 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 208000018637 late onset Parkinson disease Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 230000036210 malignancy Effects 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
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- OPGQKSHKFCOBGF-UHFFFAOYSA-N methanesulfonic acid;methanol Chemical compound OC.CS(O)(=O)=O OPGQKSHKFCOBGF-UHFFFAOYSA-N 0.000 description 1
- DYHGYAOSFBZYRW-UHFFFAOYSA-N methyl 1,4-dioxaspiro[4.5]decane-7-carboxylate Chemical compound C1C(C(=O)OC)CCCC21OCCO2 DYHGYAOSFBZYRW-UHFFFAOYSA-N 0.000 description 1
- IWVKTOUOPHGZRX-UHFFFAOYSA-M methyl 2-methylprop-2-enoate;2-methylprop-2-enoate Chemical compound CC(=C)C([O-])=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 201000011540 mitochondrial DNA depletion syndrome 4a Diseases 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- DUIPUNLJRBPNMK-UHFFFAOYSA-N n,n-dimethyl-4-(methylaminomethyl)aniline Chemical compound CNCC1=CC=C(N(C)C)C=C1 DUIPUNLJRBPNMK-UHFFFAOYSA-N 0.000 description 1
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 1
- OUMBFMLKPJUWDQ-UHFFFAOYSA-N n-benzylpropan-1-amine Chemical compound CCCNCC1=CC=CC=C1 OUMBFMLKPJUWDQ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- XGQJMRWYNBLYQQ-UHFFFAOYSA-N oxolane-2,2,3,3-tetrol Chemical compound OC1(O)CCOC1(O)O XGQJMRWYNBLYQQ-UHFFFAOYSA-N 0.000 description 1
- 125000005475 oxolanyl group Chemical group 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000036281 parasite infection Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 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
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 206010035653 pneumoconiosis Diseases 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 239000010318 polygalacturonic acid Chemical class 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 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
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- VUAOIXANWIFYCU-UHFFFAOYSA-N quinoline-6-carbaldehyde Chemical compound N1=CC=CC2=CC(C=O)=CC=C21 VUAOIXANWIFYCU-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000007845 reactive nitrogen species Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000011571 secondary malignant neoplasm Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- SMZMHUCIDGHERP-UHFFFAOYSA-N thieno[2,3-b]pyridine Chemical compound C1=CN=C2SC=CC2=C1 SMZMHUCIDGHERP-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- PKIDNTKRVKSLDB-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PKIDNTKRVKSLDB-UHFFFAOYSA-K 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000004291 uterus Anatomy 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
- 239000003981 vehicle Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229920001221 xylan Chemical class 0.000 description 1
- 150000004823 xylans Chemical class 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
技术领域
本发明涉及一种具有优异氧化应激抑制活性的新型吡唑衍生物,更具体地,涉及一种由于优异的氧化应激抑制能力而显示出预防、改善或治疗各种相关疾病的能力的新型吡唑衍生物、其光学异构体、立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,制备它们的方法以及包含它们的药物组合物。
背景技术
氧化应激是指体内生物分子、细胞和组织中活性氧物质或活性氮物质的产生和抗氧化防御机制失衡,活性氧物质或活性氮物质的产生相对过量,在这种情况下通常导致细胞损伤和组织损伤的现象。
活性氧物质(ROS)统称为由于氧及由其衍生的氧化合物的化学性质而产生的氧自由基,例如超氧阴离子(O2-·)、过氧化氢(H2O2)、羟基(OH·)、烷氧基(RO·)、过氧基(ROO·)等。
由于这些活性氧物质在化学上非常不稳定且具有高度活性,它们通过对体内的生物分子、细胞、组织等造成广泛的氧化损伤引起酶催化反应、线粒体中的电子转移、细胞信号传导系统和基因表达、转录因子的激活和周围的炎症,并充当组织纤维化的主要因素。这种氧化损伤会导致人体所有组织中的各种疾病。具体而言,已知其参与诸如皮肤、肾脏、心脏、关节、肺、脑、血管、肠道和眼部等组织中癌症的发生以及所产生癌症的进展,并且已知其在包括心血管疾病、炎症、纤维化疾病、糖尿病等的几乎所有疾病中发挥重要作用
近年来,肿瘤微环境与癌细胞之间的相互作用在肿瘤生长、转移和抗肿瘤药物耐药性表达中起着重要作用,而在这种情况下,癌症相关成纤维细胞(CAF)起着重要作用。已知癌相关成纤维细胞被ROS激活,促进肿瘤免疫逃避,从而作用于肿瘤的恶性和转移。因此,近年来,癌症相关成纤维细胞正在成为癌症治疗的新靶标。
据报道,在经历肝纤维化的患者的肝组织中,肝细胞中ROS生成的增加是由TGF-β1刺激引起的,从而增加胶原和αSMA的表达,这对纤维化很重要。据报道,ROS可加重特发性肺纤维化患者的肺组织中的肺纤维化。
脑是一个高度代谢的组织,因此非常容易受到氧化损伤。因此,已经进行了许多研究,以有效去除ROS来治疗各种神经退行性疾病(帕金森病、亨廷顿病、肌萎缩侧索硬化症、阿尔茨海默病、多发性硬化症、缺血性和创伤性脑损伤等),但没有成功。最近,由于发现ROS是这些脑疾病中的一个重要因素,因此报道了通过ROS抑制来治疗这些脑疾病的可能性。
瘢痕疙瘩是一种良性肿瘤疾病,其中皮肤结缔组织在病理上增生,形成硬块,表皮变薄、发亮、微红。据报道,瘢痕疙瘩发生和恶化的原因之一是TGF-β1刺激产生的ROS过度表达结缔组织生长因子(CTGF)。
在糖尿病情况下,如糖尿病肾病和糖尿病视网膜病变等并发症可能伴随长期高血糖,已知ROS在并发症的发生中起重要作用。换言之,高血糖导致ROS生成增加,此时产生的ROS可以通过一系列包括肾细胞和视网膜细胞死亡的过程引起糖尿病肾病和糖尿病视网膜病变。
此外,据报道,当CTGF基因在眼睛视网膜中过度表达时,瘢痕疙瘩病会导致视网膜纤维化和黄斑变性等。
因此,本发明人重点研究了可通过使用抑制氧化应激产生的分子机制开发由氧化应激引起的癌症、炎症性疾病、纤维化疾病、神经退行性疾病、肝脏疾病、皮肤病或视网膜疾病的治疗剂,结果发现本发明的新型吡唑衍生物具有优异的ROS生成的抑制活性,并已证实其可用于治疗与氧化应激相关的各种疾病,从而完成本发明。
现有技术
(专利文献1)WO 2016-207785
发明内容
技术问题
本发明的一个目的是提供一种化学式I的吡唑基化合物,其光学异构体、立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐。
本发明的一个目的是提供一种药物组合物,包含化学式I的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐和药学上可接受的载体。
本发明的一个目的是提供一种使用化学式I的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐控制ROS生成的方法。
本发明的一个目的是提供一种通过向受试者给药化学式I的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐来治疗氧化应激相关疾病的方法。
本发明的一个目的是提供一种制备化学式I的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐的方法。
本发明的一个目的是提供化学式I的化合物,其溶剂化物、立体异构体或药学上可接受的盐在制备用于预防、改善或治疗氧化应激相关疾病的药物组合物中的用途。
技术方案
为了实现上述目的,作为本发明的一个方面,可以提供一种新型吡唑衍生物,即以下化学式1表示的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐。
[化学式1]
在上式中,A、B和R的定义如下。
作为本发明的一个方面,本发明提供了由化学式1表示的化合物、溶剂化物、立体异构体或药学上可接受的盐,用于预防、改善或治疗氧化应激相关疾病。
作为本发明的一个方面,本发明提供了一种用于治疗氧化应激相关疾病的药物组合物,其包含作为活性成分的由化学式1表示的化合物、溶剂化物、立体异构体或药学上可接受的盐和可接受的载体。
此外,本发明提供了一种治疗氧化应激相关疾病的方法,包括向需要治疗的受试者给药有效剂量的由化学式1表示的化合物、溶剂化物、立体异构体或药学上可接受的盐。
此外,本发明提供了由化学式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐在制备用于预防或治疗氧化应激相关疾病的药物组合物中的用途。
有益效果
本发明的新型吡唑衍生物和包含该新型吡唑衍生物的药物组合物为氧化应激相关疾病提供了优异的疗效。
此外,新型吡唑衍生物有效抑制各种细胞中的氧化应激和αSMA的产生,尤其具有有效改善由氧化应激引起的癌症、炎症性疾病、纤维疾病、神经退行性疾病、肝病、皮肤病或视网膜疾病等的作用。
附图简要说明
图1示出了合成例化合物抑制LX-2和NHLF细胞中由PMA诱导的ROS生成的效果。
图2示出了合成例3化合物抑制N27细胞中由α-突触核蛋白预制原纤维(PFF)诱导的ROS生成的效果。
图3a和3b示出了合成例化合物(图3a:化合物1、23和12,图3b:化合物5、14和33)抑制HFF细胞中由TGFβ1诱导的αSMA表达的效果。
图4示出了合成例化合物1抑制各种细胞中由TGFβ1诱导的αSMA表达的效果。
图5示出了合成例化合物抑制P.CAF细胞中IL6表达的效果。
图6示出了合成例化合物抑制P.CAF细胞中IL8表达的效果。
图7示出了合成例化合物抑制HFF细胞中由TGFβ1诱导的胶原凝胶收缩的效果。
图8示出了合成例化合物在LX2、NHLF、ARPE19和KEL-Fib细胞中抑制由LPS诱导的IL1β表达的效果。
具体实施方式
在下文中,将更详细地描述本发明。
除非另有定义,否则本文使用的所有技术术语具有与本发明所属领域的技术人员通常理解的相同含义。此外,除非另有明确说明,否则本文公开的数值旨在包括“约”的含义。本文提及的所有出版物和其他参考文献通过引用全部并入本文。
本文使用的残基的定义如下。此外,除非存在残基的单独定义,否则其以本领域技术人员通常理解的含义使用。
本文中使用的术语“独立地”是指当从多个可能的取代基中选择一个以上的取代基时,这些取代基可以彼此相同或不同。
本文中使用的术语“烷基”指脂族烃基团,并指直链、支链单价饱和烃基团。除非另有规定,烷基通常包括1~10、1~8、1~6、1~4或1~3个碳原子。烷基的实例包括甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基和叔丁基)、戊基(例如正戊基、异戊基和新戊基)、正己基、正庚基、正辛基、正壬基和正癸基。
本文中使用的术语“烯基”是指包含一个或多个碳-碳双键的脂肪族烃基团,并且包括直链和支链烃基团。例如,“烯基”是乙烯基、烯丙基、丁-1-烯基或丁-2-烯基。
本文中使用的术语“炔基”是指包含一个或多个碳-碳三键的脂肪族烃基团,并且包括所有直链和支链烃基团。例如,“炔基”是乙炔基、炔基或丁炔基。
本文使用的术语“卤代烷基”是指具有一个或多个卤素取代基的烷基。卤代烷基包括-CF3、-C2F5、-CHF2、-CCl3、-CHCl2和-C2Cl5。除非另有定义,卤代烷基通常包含1~6、1~5、1~4或1~3个碳原子,并且可以进一步被其他取代基取代。
本文中使用的术语“烷氧基”可以是直链、支链或环链。烷氧基的碳数量不受特别限制,但碳数优选为1~10、1~8、1~6、1~4或1~3。具体地,它可以是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、新戊氧基、异戊氧基等,但不限于此。
本文中使用的术语“羟基(hydroxy)”或“羟基(hydroxyl)”是指单独或与其他术语组合的-HO。
本文中使用的术语“氨基”是指-NH2。
本文中使用的术语“卤素(halo)”、“卤素(halogen)”和“卤化物”表示氟、氯、溴和碘。
本文中,术语“环烷基”表示包含环化烷基、烯基和炔基的非芳香族碳环。环烷基可包含单环或多环。多环具有例如2、3或4个稠环。除非另有定义,否则环烷基通常包含3至10个或3至7个环碳原子。环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环己二烯基、环庚三烯基等,并且可进一步被其他取代基取代。
本文中,术语“芳基”是指具有单环或多环的芳香烃基团,并且可以进一步被其他取代基取代。本文中,多环是指其中芳基直接连接到另一个环基或与另一个环基稠合。本文中,另一个环基可以是芳基,但可以是其他种类的环基,例如环烷基、杂芳基等。多环可以具有例如2、3或4个环。除非另有规定,芳基通常具有5至20、6至15、6至12或6至10个碳环原子。芳基包括例如苯基、萘基(例如萘基-1-基和萘基-2-基)、非苯基、蒽基(anthracenyl)、菲基(phenanthreneyl)等。
本文中使用的“杂环”表示包含指定数量的环状原子的芳香族、饱和或部分不饱和的单、双、二或多环系统,并包括选自N、O和S的一个或多个杂原子。环成员,本文中的杂环通过环状原子(可以是C或N)连接到基础分子。双环系统可以通过1,1-稠合(螺环)、1,2-稠合(稠合的)或1,>2-稠合(桥接)连接。
本文中,术语“杂芳基”是指具有一个或多个选自N、O和S的杂原子作为环成员的单价芳族基团。杂芳基包括单环或多环结构。多环可以具有例如2、3或4个稠环。除非另有定义,杂芳基通常包含3至10、3至7或3至5个环原子。杂芳基可包含1、2或3个杂原子。所述杂芳基包括例如呋喃基、吡啶基、N-氧吡啶基、嘧啶基、吡嗪基(pirazinyl)、哒嗪基(piridazinyl)、三嗪基、呋喃基(furyl)、喹啉基、异喹啉基、二氢异喹啉基、噻吩基、咪唑基、呋喃基(furanyl)、噻唑基、吲哚基、吡咯基(pyrryl)、唑基(oxazolyl)、苯并呋喃基、苯并噻吩基、苯并噻唑基、异唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、苯并噻吩基、呋喃基(furinyl)、苯并咪唑基、吲哚啉基等,并且可以进一步被其他取代基取代。
本文中使用的“杂环烷基”是指具有3至10个碳环成员的单环、双环、三环或多环烷基,所述碳环成员包含一个或多个,例如1至4个、1至3个或1至2个选自N、O和S的杂原子。此外,根据本发明的杂环也可以是稠合或交联的杂环烷基。非芳香环的实例可以是氮杂环丁烷基、氧杂环戊烷基、四氢基、四氢呋喃、吡咯基、吡咯烷基、咪唑啉基、咪唑烷基、唑啉基、唑烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢吡啶基、二氢吡啶基,二氢硫代吡喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢硫代吡喃基、四氢吡唑并吡啶基、吗啉基、吲哚基、氮杂硫代吗啉基等。
杂环烷基取代基的连接可以通过碳原子或杂原子发生。杂环烷基可以被一个或多个上述基团随机地取代为一个或更多个合适的基团。除非另有定义,杂环烷基指4至12元杂环烷基,优选4至10元杂环烷基、更优选4至7元杂环烷基。
在本文中,术语“芳烷基”表示被芳基取代的烷基。“芳基”和“烷基”的定义与如上所定义的相同。
在本文中,术语“杂芳烷基”表示被杂芳基取代的烷基。“杂芳基”和“烷基”的定义与如上所定义的相同。
在本文中,术语“烷基杂环烷基”表示被烷基取代的杂环烷基。“烷基”和“杂环烷基”的定义与如上所定义的相同。
在本文中,“被取代或未取代的胺基”可选自由单烷基胺基、-NH2和二烷基胺基组成的组,且“烷基”的定义与如上所定义的相同。被取代或未取代的胺基的具体实例包括NH2、甲胺基、二甲胺基、乙胺基、二乙胺基等,但不限于此。
在本文中,“亚烷基”是指具有两个结合位点的烷基,即二价基团。前述烷基的描述可以适用于它们,除了它们中的每一个都是二价基团之外。
在本文中,术语“取代”是指结合到化合物的碳原子的氢原子被另一个取代基取代,并且被取代的位置不受限制,只要氢原子被取代的位置,即取代基可被取代的位置不受限制,并且当两个或更多个取代基被取代时,两个或更多个取代基可以彼此相同或不同,并且两个或更多个相同或不同的取代基可以被连接和取代。
在本文中,术语“被取代的烷基”是指C1-C10直链或支链烷基的碳原子处以下取代基被取代的形式。具体地,它是一种其中选自重氢、卤素、氰基、硝基、羧基、取代或未取代的胺、取代或未取代的C5-C20芳基或C5-C20杂芳基、C1-C5烷氧基和C1-C5卤代烷基中的一个或多个取代基,或相同或不同的2个或更多个取代基被连接和取代的形式。作为示例性取代基,可以使用三氟甲基、卤素、氰基、甲氧基、羧基、甲基、氨基、硝基、二甲氨基、环丙基取代的咪唑、吡啶、取代或未取代的磺酰基等,但不限于此。
本文中的术语“被取代的环烷基”是一种其中选自重氢、卤素、氰基、硝基、羧基、被取代或未被取代的胺、被取代或未被取代的C5-C20芳基或C5-C20杂芳基、C1-C5烷氧基和C1-C5卤代烷基中的一个或多个取代基,或相同或不同的2个或更多个取代基被连接并取代为C3-C8环烷基的形式。作为示例性取代基,可使用三氟甲基、卤素、氰基、甲氧基、羧基、甲基、氨基、硝基、二甲胺基、环丙基、取代的咪唑、取代的或未取代的磺酰基等,但不限于此。
本文中的术语“取代的芳基”或“取代的杂芳基”是一种其中选自重氢、卤素、氰基、硝基、羧基、被取代或未被取代的胺、C1-C5烷氧基、C1-C5卤代烷基、C1-C10烷基、C3-C8环烷基或C3-C8杂环烷基、C3-C8环烷基C1-C10烷基、C5-C20芳基C1-C10烷基中的一个或多个取代基,或相同或不同的2个或更多个取代基被连接并取代为C5-C20芳基或C5-C50杂芳基的形式。作为示例性取代基,可使用三氟甲基、卤素、氰基、甲氧基、羧基、甲基、氨基、硝基、二甲胺基、环丙基取代的咪唑、甲基哌嗪、取代的咪唑并嘧啶、取代的或未取代的磺酰基等,但不限于此。
在本文中,“相邻”基团可以是指在直接连接到其中相应取代基被取代的原子上取代的取代基、空间上最接近相应取代基的取代基或在其中相应取代基被取代的原子上被取代的另一取代基。例如,在苯环的邻位被取代的两个取代基和在脂肪族环的相同碳上被取代的两个取代基可以被解释为彼此“相邻”的基团。
当用于化合物时,“有效剂量”是指如本文所述有效治疗或预防受试者疾病的量。
化合物
为了实现上述目的,本发明提供以下化学式I的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐:
在式中,
A是取代或未取代的5元至20元杂芳基或取代或未取代的C5-C20芳基;和
其中,5元至20元杂芳基或C5-C20芳基可以是未取代的,或者可以被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至20元杂芳基和取代或未取代的5元至20元杂环烷基组成的取代基中的1、2、3或4种取代,其中,R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至10元杂芳环或C5-C10芳环;和
R是氢、重氢、氰基、卤素、硝基、卤代烷基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的C5-C20芳基、取代或未取代的5元至20元杂芳基或-C(=O)R2,其中,R2是C3-C8环烷基、C1-C10烷基、C2-C10烯基或C6-C10芳基;和
B是-NKM或取代或未取代的5元至20元杂芳基或取代或未取代的5元至20元杂环烷基;和
K和M各自独立地为氢、重氢、氰基、卤素、硝基、卤代烷基、取代或未取代的C1-C10烷基、取代或未取代的C1-C10烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C5-C20芳基、取代或未取代的C5-C20芳基C1-C10烷基、取代或未取代的5元至20元杂芳基或取代或未取代的5元至20元杂芳基C1-C10烷基;
其中,C1-C10烷基可以是未取代的,或被选自由重氢、卤素、羟基、氰基、硝基、羧基、取代或未取代的氨基、取代或未取代的C1-C10烷基、取代或未取代的C1-C10卤代烷基、取代或未取代的C1-C10羟烷基、取代或未取代的C3-C8环烷基、C1-C10烷氧基、C1-C10烷基磺酰基、C5-C20芳基磺酰基、C5-C20芳氧基、取代或未取代的C5-C20芳基、取代或未取代的5元至20元杂芳基和取代或未取代的5元至20元杂环烷基组成的组中的1、2、3或4种取代基取代;和
C3-C8环烷基可以是未取代的,或被选自由重氢、卤素、氰基、硝基、羧基、取代或未取代的胺、取代或未取代的C5-C20芳基或5元至20元杂芳基、C1-C10烷氧基和C1-C10卤代烷基组成的组中的1、2、3或4种取代基取代;和
5元至20元杂芳基、5元至20元杂环烷基或C5-C20芳基可以是未取代的,或被选自由重氢、卤素、氰基、硝基、-C(=O)R’、-C(=O)OR’、-NH-C(=O)R”、取代或未取代的氨基、取代或未取代的C1-C10烷基、取代的或未取代的C1-C10烷氧基、取代或未取代的C1-C10卤代烷基、取代或未取代的C1-C10羟烷基、取代或未取代的C1-C10烷基磺酰基、取代或未取代的C5-C20芳基磺酰基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10芳基、取代或未取代的C5-C20芳基、取代或未取代的C5-C20芳基C1-C10烷基、取代或未取代的5元至12元杂环烷基、取代或未取代的C1-C10烷基C3-C8环烷基和取代或未取代的C1-C10烷基5元至20元杂环烷基组成的组中的1、2、3或4种取代基取代;和
其中,R’和R”各自独立地为氢、重氢、取代或未取代的胺、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基或取代或者未取代的C6-C10芳基或C1-C6烷基;和
取代的氨基可以被1种或2种C1-C10烷基取代;和
杂环烷基或杂芳环的杂原子可以是选自N、S和O的一种或多种。
作为一个具体方面,
A是未取代的或被取代的5元至12元杂芳基或C6-C10芳基,其中,5元至12元杂芳基或C6-C10芳基可以被选自由氰基、卤素、C1-C6卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C6烷基、C1-C-6烷氧基、C3-C6环烷基、氨基、C6-C10芳基、5元至12元杂芳基和5元至12元杂环烷基组成的组中的1、2、3或4种取代基取代,其中R1是氢、重氢或C1-C6烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至7元杂芳环或C6-C9芳环。
作为一个具体方面,A可以是具有1、2、3或4个选自N、O和S的杂原子的5元至10元杂芳基或C6-C9芳基。
作为一个具体方面,A可以是吡啶基、嘧啶基、吡唑基、三唑基、噻唑基、苯基或噻吩并[3,2]吡啶。
作为一个具体方面,A可以被C1-C6烷基、C1-C6烷氧基、F、Cl、Br、I、氰基、氨基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、5元至12元杂环烷基中的1种、2种、3种或4种取代,其中Ra可以是氢、重氢、C1-C6烷基。
作为一个具体方面,A可以被甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、F、Cl、Br、I、氰基、氨基、硝基、-C(=O)OH、-C(=O)CH3、-NH-C(=O)CH3、吗啉基或哌啶基中的1种、2种、3种或4种取代。
作为一个具体方面,R是氢、重氢、氰基、卤素、硝基、未取代的或C3-C6环烷基取代的C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C6-C10芳基、5元至12元杂芳基、-C(=O)R2,其中,R2是C3-C6环烷基、C1-C6烷基、C2-C6烯基或C6-C10芳基。
作为一个具体方面,R2可以是环丙基、甲基、乙基、丙基、乙烯基、丙烯基或苯基。
作为一个具体方面,R可以是氢、重氢、氰基、卤素、硝基、甲基、乙基、丙基、丁基、环丙基甲基、CF3、-C(=O)-环丙基、-C(=O)-乙烯基或苯甲酰基。
作为一个具体方面,B是-NKM或5元至12元杂芳基或5元至12元杂环烷基,其中,5元至12中元杂芳基或5元至12元杂环烷基是未取代的,或被重氢、卤素、氰基、硝基、-NR3R4、C1-C6烷基、C1-C6烷氧基、C6-C10芳基、-C(=O)R5、-SO2-R6中的1、2、3或4种取代,和
其中,C1-C6烷基、C1-C6烷氧基或C6-C10芳基可以是未取代的,或被羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳氧基中的1、2、3或4种取代,或未取代的或C1-C6烷基、C6-C10芳基C1-C6烷基或C1-C6烷基羰基取代的4元至12元杂环烷基,和
R3和R4各自独立地为氢、重氢、-C(=O)-Ra、C1-C6烷基或C6-C10芳基,并且C1-C6烷基或C6-C10芳基是未取代的,或被卤素、羟基、C1-C6烷基、C1-C6烷氧基或者C6-C10芳氧基中的1、2、3或4种取代,其中Ra为氢、重氢、C1-C6烷基或C1-C6卤代烷基;和
R5是-ORb、-NRcRd、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基,其中,C1-C6烷基、C2-C6烯基或C2-C6炔基可以是未取代的,或者被单C1-C6烷基胺或二C1-C6烷基胺中的1、2、3或4种取代,其中Rb、Rc和Rd各自独立地为氢、重氢、C6-C10芳基或C6-C10芳基C1-C6烷基,和
R6是未取代的C1-C6烷基或C1-C6烷基取代的C6-C10芳基中的1、2、3或4种,和
K和M各自独立地为氢、重氢、氰基、卤素、硝基、C1-C6卤代烷基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、5元至12元杂芳基、5元至12元杂芳基C1-C6烷基,其中,C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基或5元至12元杂芳基可以被氰基、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6烷基磺酰基、C6-C10芳基磺酰基、-NR7R8、-C(=O)R9、5元至12元杂环基、羟基、硝基、C6-C10芳基中的1、2、3或4种取代,其中5元至12元杂环基或C6-C10芳基可以是未取代的或被C1-C6烷基取代的,和
R9是-ORe、-NReRf、未取代的或-NReRf-取代的C2-C6烯基或C6-C10芳基中的1、2、3或4种,其中,Re和Rf各自独立地为氢、重氢、C1-C6烷基、C6-C10芳基或C1-C6烷基。
作为一个具体方面,B可以是具有选自由N、O和S组成的组中的1种至3种杂原子的5元至10元杂芳基或5元至10元杂环烷基,并且它们可以被前述取代基取代或为未取代的。
作为一个具体方面,B可以是吡咯烷、哌嗪、二氢异喹啉、吗啉或哌啶,并且它们可以被前述取代基取代或为未取代的。
作为一个具体方面,化学式I的化合物可以是以下化学式I-1的化合物:
[化学式I-1]
在式中,
K、M和R的定义与化学式I相同;和
D是CR10、N、O或S,或E是CR11、N、O或S,或F是CR12、N、O或S,或G是CR13、N、O或S,或J是CR14、N、O或S,但N、O和S是一个或多个;和
R10至R14相同或不同,并且可以独立地被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至12元杂芳基和取代或未取代的5元至12元杂环烷基组成的取代基中的1、2、3或4种取代,其中R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至10元杂芳环或C6-C10芳环。
作为一个具体方面,化学式I的化合物可以是以下化学式I-2的化合物:
[化学式I-2]
在式中,
R、D、E、F、G和J的定义与化学式I-1相同;和
n是0、1或2的整数;和
L是CH2、NH或O;和
其中,C1-C6烷基、C1-C6烷氧基或C6-C10芳基可以是未取代的,或被羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳氧基中的1、2、3或4种取代,或未取代的或C1-C6烷基、C6-C10芳基C1-C6烷基或C1-C6烷基羰基取代的4元至12元杂环烷基,和
R3和R4各自独立地为氢、重氢、-C(=O)-Ra、C1-C6烷基或C6-C10芳基,并且C1-C6烷基或C6-C10芳基可以是未取代的,或被卤素、羟基、C1-C6烷基、C1-C6烷氧基或C6-C10芳氧基中的1、2、3或4种取代,其中Ra为氢、重氢、C1-C6烷基或C1-C6卤代烷基;和
R5是-ORb、-NRcRd、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基,其中,C1-C6烷基、C2-C6烯基或C2-C6炔基可以是未取代的,或者被单C1-C6烷基胺或二C1-C6烷基胺中的1、2、3或4种取代,并且Rb、Rc和Rd各自独立地是氢、重氢、C6-C10芳基或C6-C10芳基C1-C6烷基,和
R6是未取代的C1-C6烷基,或C1-C6烷基取代的C6-C10芳基中的1、2、3或4种。
作为一个具体方面,化学式I的化合物可以是以下化学式I-3的化合物:
[化学式I-3]
在式中,
K、M、R、D、E、F和G的定义与化学式I-1相同。
作为一个具体方面,化学式I的化合物可以是以下化学式I-4的化合物:
[化学式I-4]
在式中,
L、n、R、D、E、F和G的定义与化学式I-2相同。
作为一个方面,根据本发明的化学式I的化合物可以是选自由以下化合物1)至161)组成的组中的一种或多种,但不限于此。
1)5-(苄基甲基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
2)5-(苄基环丙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
3)4-{[(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)甲基氨基]甲基}苯甲腈;
4)5-[(4-氟苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
5)5-[(2,4-二氟苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
6)5-[(2-氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
7)5-[(3-氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
8)5-[甲基-(4-三氟甲基苄基)氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇;
9)5-[甲基-(3-甲基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
10)5-[甲基-(3-三氟甲基苄基)-氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇;
11)5-[甲基-(2-三氟甲基苄基)-氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇;
12)5-[(4-甲基磺酰基苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
13)5-[(3-甲氧基苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
14)5-哌啶-1-基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
15)5-吗啉-4-基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
16)5-(4-甲基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
17)5-(4-(2-(2-羟基甲氧基)乙基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
18)5-(3,4-二氢-1H-异喹啉-2-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
19)5-[(4-氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
20)5-(苄基乙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
21)5-(苄基丙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
22)5-(苄基丁基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
23)5-[甲基(3-甲基磺酰基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
24)5-[甲基-(4-甲基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
25)3-{[(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)甲基氨基]甲基}苯甲腈;
26)5-[(2-甲氧基苄基)-甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
27)5-[(3-氟苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
28)5-[(4-甲氧基苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
29)5-[甲基-(2-甲基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
30)5-[(2,4-二氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
31)5-[(3,4-二氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
32)5-(3,4-二氟苯基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
33)5-[甲基(5,6,7,8-四氢喹啉-8-基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
34)5-((((3-(羟甲基)-5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基)甲基)(甲基)氨基)-2-(吡啶2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
35)5-{[(3-(羟甲基)-5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基)甲基]甲基氨基}-2-(吡啶-2-基,4,5,6,7-四氢-2H-吲唑-3-醇;
36)5-{甲基[3-甲基-5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基]甲基氨基}-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
37)5-{甲基[5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基]甲基氨基}-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
38)[4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2-吲唑-5-基)哌嗪-1-基]环丙基甲酮;
39)5-(苄基甲基氨基)-2-(5-三氟甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
40)5-(苄基甲基氨基)-2-(5-氯吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
41)5-(苄基甲基氨基)-2-(6-(三氟甲基)吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
42)5-(苄基甲基氨基)-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
43)5-(苄基甲基氨基)-2-(3-氟吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
44)6-(5-(苄基甲基氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)烟碱甲腈;
45)5-(苄基甲基氨基)-2-(6-甲基-4-三氟甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
46)5-(苄基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
47)2-(吡啶-2-基)-5-[(吡啶-2-基甲基)氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
48)5-[甲基(吡啶-2-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
49)5-[甲基(吡啶-4-基甲基)氨基]-2-(5-三氟甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
50)2-(5-氯吡啶-2-基)-5-[甲基(吡啶-4-基甲基)氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
51)5-[甲基(吡啶-4-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
52)2-(4-溴苯基)-5-[甲基(吡啶-4-基甲基)氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
53)5-(苄基甲基氨基)-2-(噻吩并[3,2-c]吡啶-4-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
54)2-(6-氨基吡啶-2-基)-5-(苄基甲基氨基)-4,5,6,7-四氢-2H-吲唑-3-醇;
55)5-苯基氨基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
56)5-[(2,5-二甲基苯基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
57)5-[(4-硝基苯基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
58)5-[(4-甲氧基苯基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
59)5-(苯基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
60)2-(吡啶-2-基)-5-(喹啉-3-基氨基)-4,5,6,7-四氢-2H-吲唑-3-醇;
61)5-[甲基(萘-2-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
62)5-[(异喹啉-3-基甲基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
63)5-[甲基(喹啉-6-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
64)5-[(异喹啉-3-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
65)5-[甲基(吡啶-2-基甲基)氨基]-2-苯基-4,5,6,7-四氢-2H-吲唑-3-醇;
66)5-[乙基(吡啶-4-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
67)5-[(3-二甲氨基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
68)5-[(4-二甲氨基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-2-醇;
69)5-[(3-二甲基氨基苄基)甲基氨基)]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
70)5-[(4-二甲基氨基)苄基甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
71)5-[(2-二甲基氨基)苄基甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
72)5-(苄基甲基氨基)-2-苯基-4,5,6,7-四氢-2H-吲唑-3-醇;
73)4-[(5-苄基甲基氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基]苯甲酸;
74)5-(苄基甲基氨基)-2-(4-溴苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
75)5-(苄基甲基氨基)-2-(2-氯苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
76)5-(苄基甲基氨基)-2-(2-甲氧基苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
77)2-(2-氯苯基)-5-[(3-二甲基氨基苄基)甲基氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
78)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)苯甲酸;
79)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)苯甲酰胺;
80)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)-N-甲基苯甲酰胺;
81)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)-N,N-二甲基苯甲酰胺;
82)5-(4-甲基哌嗪-1-基)-2-(5-(三氟甲基)吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
83)2-(6-氯吡啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
84)2-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
85)5-(4-甲基哌嗪-1-基)-2-(噻吩并[3,2-c]吡啶-4-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
86)2-(3-氟吡啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
87)2-(吡啶-2-基)-5-(4-(吡啶-2-基甲基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
88)5-((4-甲氧基苄基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
89)1-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)丁-2-烯-1-酮;
90)2-(吡啶-2-基)-5-(4-(喹啉-6-基甲基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
91)5-(4-乙基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
92)5-(苯基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
93)5-(五乙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
94)2-(4-氯苯基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
95)5-(4-甲基哌嗪-1-基)-2-(4-(三氟甲基)苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
96)2-(吡啶-2-基)-5-(吡咯烷-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
97)1-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)丙-2-烯-1-酮;
98)(E)-4-(二甲氨基)-1-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)丁-2-烯-1-酮;
99)(E)-4-(二甲氨基)-N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-N-甲基丁-2-烯酰胺;
100)5-(4-丙基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
101)2-(4-溴苯基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
102)2-(4-氟苯基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
103)4-(3-羟基-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-2-基)苯甲腈;
104)5-(4-五乙基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
105)5-(4-苄基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
106)5-(4-(环己基甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
107)5-(4-(3-苯基丙基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
108)5-(4-甲基哌嗪-1-基)-2-(嘧啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
109)5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
110)5-(4-(甲基磺酰基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
111)5-(4-(苯基磺酰基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
112)2-(吡啶-2-基)-5-(4-甲苯基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
113)4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-N-苯基哌嗪-1-甲酰胺;
114)4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-甲酸苄酯;
115)2-(1-甲基-1H-吡咯-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
116)5-(4-甲基哌嗪-1-基)-2-(噻唑-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
118)2-(1-甲基-1H-吡唑-5-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
119)2-(1-甲基-1H-咪唑-5-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
120)2-(1-甲基-1H-咪唑-5-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
121)5-(苄基(甲基)氨基)-2-(嘧啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
122)5-(苄基(甲基)氨基)-2-(1-甲基-1H-吡咯-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
123)5-(苄基(甲基)氨基)-2-(1-甲基-1H-吡唑-5-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
124)5-(苄基(甲基)氨基)-2-(1-甲基-1H-咪唑-5-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
126)2-(吡啶-2-基)-5-(4-(对甲苯基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
127)5-(4-(4-羟基苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
128)5-(4-(3,4-二氟苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
129)5-(4-(4-甲氧基苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
130)1-(4-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)苯基)乙-1-酮;
131)5-(4-(4-(甲基磺酰基)苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
132)5-(4-(4-苯氧基苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
133)5-(4-(哌啶-4-基甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
134)5-(4-((1-甲基哌啶-4-基)甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
135)5-(4-((1-苄基哌啶-4-基)甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
136)1-(4-((4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)甲基)哌啶-1-基)乙烷-1-酮;
137)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)苯甲酰胺;
138)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-2-苯基乙酰胺;
139)1-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-3-苯基脲;
140)1-苄基-3-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)脲;
141)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)苯磺酰胺;
142)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-4-甲基苯磺酰胺;
143)(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)氨基甲酸苄基酯;
144)2-(5-氟-4-吗啉基嘧啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
145)N-苄基-3-甲氧基-N-甲基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-胺;
146)N-苄基-3-(环丙基甲氧基)-N-甲基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-胺;
147)5-(苄基(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-基环丙甲酸酯;
148)5-(苄基(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-基丙烯酸酯;
149)5-(苄基(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-基苯甲酸酯;
150)2-(5-(苄基(甲基)氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)嘧啶-5-甲酸;
151)2-(5-(苄基(甲基)氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)烟酸甲酯;
152)N-(6-(5-(苄基(甲基)氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)吡啶-2-基)乙酰胺;
153)5-(苄基(甲基)氨基)-2-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
154)5-(4-甲基哌嗪-1-基)-2-(嘧啶-4-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
155)2-(5-氯哒嗪-3-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
156)2-(吡啶-2-基)-5-(4-(嘧啶-2-基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
157)5-(苄基(甲基)氨基)-2-(5-硝基嘧啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
158)5-((4-羟基苄基)(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
159)5-(甲基(4-硝基苄基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
160)5-(3-(乙基(甲基)氨基)吡咯烷-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;和
161)2,2,2-三氟-N-(1-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)吡咯烷-3-基)乙酰胺。
除非另有规定,本说明书和权利要求中给出的化学式或命名是指互变异构体和所有立体、光学和几何异构体(例如,对映体、非对映体和E/Z异构体等)及其外消旋体,以及不同比例的不同对映体的混合物、非对映体混合物,或其中存在异构体和对映体的任何上述形式的混合物,以及其药学上可接受的盐和溶剂化物,例如水合物(包含例如游离化合物的溶剂化物和水合物,或相应化合物的盐的溶剂化物和水合物)。
在一个实施方式中,本发明的化合物可以药学上可接受的盐形式存在。盐是指本发明所属的医学领域中常用的盐,由药学上可接受的游离酸形成的酸加成盐是有用的。本发明的术语“药学上可接受的盐”是指化合物的任何有机或无机加成盐,其中由该盐引起的副作用不会降低根据本发明的化合物的有益功效,其浓度具有对患者相对无毒和无害的有效作用。
酸加成盐通过常用方法制备,例如,通过将化合物溶解在过量的酸水溶液中,并使用水混溶性有机溶剂(例如甲醇、乙醇、丙酮或乙腈)沉淀该盐。可在水中加热等摩尔量的化合物和酸或醇(例如乙二醇单乙醚),然后蒸发混合物使其干燥,或抽吸过滤沉淀的盐。
其中,可以使用有机酸和无机酸作为游离酸,可以使用盐酸、磷酸、硫酸、硝酸、酒石酸等作为无机酸,并且可以使用甲磺酸、对甲苯磺酸、乙酸、三氟乙酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、柠檬酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸等作为有机酸,但不限于此。
此外,使用碱可以制备药学上可接受的金属盐。碱金属盐或碱土金属盐例如通过将化合物溶解在过量的碱金属氢氧化物或碱土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而获得。其中,作为金属盐,药学上适合制备钠、钾或钙盐,但不限于此。此外,相应的银盐可通过碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应而获得。
除非另有说明,否则本发明化合物的药学上可接受的盐包括可以存在于上述化学式I所述化合物中的酸性或碱性基团的盐。例如,作为药学上可接受的盐,可以包括羟基的钠盐、钙盐和钾盐,而其他的氨基的药学上可接受的盐包括氢溴酸盐、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(甲醇盐)和对甲苯磺酸盐(p-甲苯磺酸盐),其可以通过本领域已知的盐的制备方法来制备。
作为本发明的上述化学式I中所述化合物的盐,可以无限制地使用任何药学上可接受的盐,其是上述化学式I中所述化合物的显示出与表1中所示化合物相同药理活性的盐。
此外,本发明的化合物也可以是其立体异构体的形式。立体异构体包括所有立体异构体,如对映体和非对映体。该化合物可以是立体异构纯形式或一种或多种立体异构体的混合物,例如外消旋混合物。特定立体异构体的分离可通过本领域已知的常用方法之一进行。本发明化合物的一些实例可对特定立体异构物的氧化应激具有更大的抑制作用。在这种情况下,通过使用特定的立体异构体,可以减少剂量。因此,可以分离对氧化应激具有很大抑制作用的特定立体异构体,例如对映体或非对映体,从而有效地治疗氧化应激相关疾病。
本发明的化合物可以是其溶剂化物的形式。“溶剂化物”是指一种或多种溶质分子(即化学式I的化合物或其药学上可接受的盐)与一种或多种溶剂分子的复合物或集合体。溶剂化物可以是例如由各种溶剂分子如水、甲醇、乙醇、异丙醇或乙酸盐等形成的复合物或聚集体。
水作为溶剂分子的溶剂化物称为水合物。水合物包括含有化学计量量的水的组合物以及含有变化量的水的组合物。
本发明的化合物也可以是其互变异构体的形式。
术语“互变异构体”或“互变异构体形式”是指不同能量的不同组成异构体,它们可以通过低能量势垒相互转化。质子互变异构体(也称为质子互变异构体)的一些非限制性实例包括通过质子转移的相互转化,如酮烯醇和亚胺烯胺异构化。价互变异构体包括通过一些键合电子的重组而发生的相互转化。
本发明的化合物也可以是其同位素变体的形式。
术语“同位素变体”是指至少一个原子具有与任何化合物相同的原子数,但被另一个原子量与自然界中通常或正常存在的原子量不同原子取代的化合物。
上述化学式I的化合物的溶剂化物、立体异构体、互变异构体和同位素变体可使用本领域已知的方法由该化合物制备。
在本发明的制备方法中,作为上述反应式中使用的反应物,可按原样购买和使用市售化合物,或通过按原样进行一种或多种本领域已知的反应或通过适当改变它们并使用它们来合成它们。例如,考虑到框架结构中包括的反应性官能团和/或杂元素的存在、类型和/或位置,可以通过以串联顺序进行一个或多个反应来合成它们,但不限于此。
在一种实施方式中,与对照组相比,本发明合成例的化合物通过处理HL-60细胞(人白血病细胞)中PMA产生的ROS,显示出30%、50%、70%或更多的ROS产生抑制作用,并且还表现出浓度依赖性抑制能力,因此,本发明的化合物可用于预防或治疗氧化应激相关疾病。
据报道,随着成纤维细胞向肌成纤维细胞分化,癌相关成纤维细胞(CAF)形成或诱导各种组织纤维化。作为用本发明的合成例化合物处理HFF-1(人包皮成纤维细胞)细胞的结果(其中通过TGF-β1处理诱导纤维化),显示了抑制αSMA(是纤维化的指标)的表达效果。因此,本发明的化合物可用于预防或治疗纤维化相关疾病,并可通过调节癌相关成纤维细胞用于治疗癌症,癌相关成纤维细胞是肿瘤微环境相互作用的重要指标。
当神经细胞中的ROS水平升高时,脂质氧化被诱导,这被认为是神经细胞死亡的一个重要因素。当诱导ROS的MPP+(1-甲基-4-苯基吡啶(1-methyl-4-phenylptridinium))和合成例化合物同时处理N27细胞(大鼠多巴胺能神经细胞)时,示出了有效抑制ROS生成的效果。因此,本发明的化合物可用于预防或治疗由氧化应激引起的神经细胞死亡相关疾病。
皮肤纤维化疾病的主要原因之一是瘢痕疙瘩成纤维细胞的CTGF产生细胞外基质,如I型胶原等。当合成例化合物处理KEL-FIB(瘢痕疙瘩成纤维细胞)细胞,然后TGF-β1处理以诱导纤维化时,CTGF基因和I型胶原基因的表达被有效抑制。因此,本发明的化合物可用于预防或治疗皮肤瘢痕疙瘩疾病。
药物组合物和医疗用途
本发明的化合物、其光学异构体、其立体异构体、其溶剂化物、其同位素变体、其互变异构体或其药学上可接受的盐由于其生物学特性而适用于预防、改善或治疗由氧化应激引起的各种疾病。
本发明的药物组合物可用于治疗氧化应激相关疾病。该疾病可以是癌症、炎症性疾病、纤维化疾病、神经退行性疾病、神经系统疾病、肝病、皮肤病、线粒体疾病、衰老、慢性酒精中毒、干细胞功能障碍、跛行、代谢综合征、唐氏综合征、不育、组织中过氧化脂质的过量产生、肌肉相关疾病、细胞膜中过氧化脂的积聚、慢性疲劳或视网膜疾病。
癌症可选自由肝癌、肝细胞癌、胃肠道癌、胃癌、神经纤维瘤相关颅内脑膜瘤、胰腺癌、白血病、骨髓及外骨髓增生/骨髓增生异常疾病、皮肤纤维肉瘤、乳腺癌、肺癌、甲状腺癌、结直肠癌、前列腺癌、乳腺癌、卵巢癌、脑瘤、头颈癌、胶质母细胞瘤等组成的组。此外,癌症可以是已从各种类型的癌症转移到另一器官的继发性癌症。
代谢综合征可以是肥胖症、糖尿病、高血压、高脂血症、动脉硬化、外周血管疾病、缺血灌注、心肌梗塞或中风等。
炎症性疾病可为炎症伴随性风湿性关节炎、骨关节炎、肺炎、肝炎、炎症性结直肠疾病、肠道肠炎、肾小球肾炎、胃炎、血管炎、胰腺炎、腹膜炎、支气管炎、心肌炎、脑炎、缺血后再灌注损伤中的炎症和组织器官移植后免疫排斥引起的炎症、皮肤上发生的各种炎症(如烧伤、过敏性接触性皮炎等)、多器官疾病引起的炎症、包括糖尿病肾病在内的糖尿病炎症、病毒或细菌感染引起的感染性炎症,或自身免疫性疾病(如特应性疾病、狼疮、银屑病、动脉粥样硬化等)。
纤维化疾病可以是代谢性疾病诱导的肝纤维化或肝硬化、NAFLD诱导的纤维化或肝硬化、NASH诱导的纤维化或肝硬化、酒精诱导的肝纤维化或肝硬化、药物诱导的肝纤维化或肝硬化、感染性病原体诱导的肝纤维化或肝硬化、寄生虫感染诱导的肝纤维化或肝硬化、细菌感染诱导的肝纤维化或肝硬化、病毒感染诱导的肝纤维化或肝硬化、HBV感染诱导的肝纤维化或肝硬化、HCV感染诱导的肝纤维化或肝硬化、HIV感染诱导的肝纤维化或肝硬化、双重HCV和HIV感染诱导的肝纤维化或肝硬化、放疗或化疗诱导的纤维化或肝硬化、胆道纤维化、任何慢性胆汁淤积性疾病引起的肝纤维化或肝硬化、任何病因引起的消化道纤维化、克罗恩病诱导的纤维化、溃疡性结肠炎诱导的纤维化、小肠纤维化、结肠纤维化、胃纤维化、肺纤维化、皮肤纤维化、表皮纤维化、内皮纤维化、皮肤硬化/系统性硬化引起的皮肤纤维化、慢性阻塞性肺病(COPD)、哮喘、肺气肿、吸烟者的肺、肺结核、肺纤维化,继发于肺纤维化的特发性肺纤维化(IPF)、心脏纤维化、肾纤维化、肾源性系统纤维化、肌肉纤维化、软组织纤维化、骨髓纤维化、关节纤维化、腱纤维化、软骨纤维化、胰腺纤维化、子宫纤维化、神经系统纤维化、睾丸纤维化、卵巢纤维化、肾上腺纤维化、动脉纤维化、静脉纤维化、眼纤维化、内膜心肌纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、作为尘肺并发症的进行性大规模纤维化、增殖性纤维化、肿瘤纤维化、移植物周围纤维化、石棉肺、关节纤维化或粘连性包膜炎。
神经退行性疾病可以是阿尔茨海默病(包括轻度或早期阿尔茨海默病、轻度至中度阿尔茨海默病、中度至中期阿尔茨海默病、中度至重度阿尔茨海默病、中重度阿尔茨海默病、重度阿尔茨海默病和阿尔茨海默病伴路易体)、帕金森病(包括因暴露于环境因素如杀虫剂、杀昆虫剂或除草剂,和/或金属如锰、铝、镉、铜或锌而化学诱导的帕金森病;SNCA基因相关帕金森病;散发性或特发性帕金森病或帕金森病相关或LRRK2相关帕金森病)、常染色体显性帕金森病、弥漫性路易体病(DLBD)(也称路易体痴呆(DLB))、纯自主神经失衡、路易体吞咽困难、随机LBD、遗传LBD(例如,α-突触核蛋白基因突变、PARK3和PARK4)、多系统萎缩症(包括橄榄体脑桥小脑萎缩、纹状体黑质变性、Shy-Drager综合征(MSA)),复杂阿尔茨海默病和帕金森病和/或MSA、亨廷顿病、突触核蛋白病、以路易体存在为特征的紊乱或病症、多发性硬化、肌萎缩侧索硬化(ALS)、痴呆(包括血管性痴呆、路易小体痴呆、帕金森痴呆和额颞叶痴呆)、精神病(包括由神经变性疾病引起或与多巴胺治疗相关的焦虑,例如帕金森氏精神病、阿尔茨海默氏精神病、路易体痴呆精神病(不限于此))、运动障碍(包括由神经变性疾病引起或与多巴胺治疗相关的焦虑)、焦虑(由神经退行性疾病引起或与多巴胺治疗相关的焦虑)、与多巴胺治疗相关的病症(包括肌张力障碍、肌阵挛或颤动)、突触核蛋白病、与α突触核蛋白异常表达相关的疾病、缺血性脑疾病、克雅氏病(Creutzfeldt-Jakobdisease)、马查多-约瑟夫病(Machado Joseph disease)或脊髓小脑共济失调或皮克病(Pick disease)。
肝病可以是代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物诱导的肝病、酒精诱导的肝病、传染性病原体诱导的肝病、炎症性肝病、免疫系统功能障碍介导的肝病或血脂异常。
皮肤病可以是瘢痕疙瘩病、银屑病或牛皮癣,视网膜病可以是视网膜纤维化、黄斑变性、糖尿病视网膜病变、糖尿病黄斑变性、早产儿视网膜病变、缺血再灌注相关视网膜损伤、色素性视网膜炎、白内障或新生血管性青光眼。
线粒体疾病可以是遗传性线粒体疾病、Alpers病、Barth综合征、慢性进行性眼外肌麻痹(CPEO)、长链酰基CoA脱氢酶缺乏症(LCAD)、melas综合征、Leber遗传性视神经病变(LHON)、Leigh病、Leigh样综合征、Luft病、Pearson综合征、神经病变、共济失调和色素性视网膜炎(NARP),Co-Q10缺乏、MERRF综合征(MERRF)、线粒体DNA耗竭综合征(MDS)、致死性婴儿心肌病(LIC)、线粒体神经胃肠系统脑肌病、β氧化缺陷、弗里德里希共济失调(弗里德里希共济共济失调FA)、卡恩斯-塞尔综合征(KSS)或乳酸性酸中毒。
神经疾病可以是双相情感障碍、发育障碍、自闭症、阿斯伯格综合征、Rett综合征、视力障碍、视神经病变、注意力缺陷多动障碍(ADHD)、癫痫、情绪障碍、Tourette综合征或精神分裂症等。肌肉相关疾病可以是肌病、肌营养不良、心肌病、脑肌病或脊髓性肌萎缩等。
本发明的另一方面提供了一种药物组合物,其包含治疗有效剂量的上述限定的化学式I的化合物,或其药学上可接受的盐或其溶剂化物或立体异构体和药学上可接受的载体。
在本发明的组合物中,化合物或其药学上可接受的盐或溶剂化物或立体异构体如上文所定义。
在本发明的组合物中,“药学上可接受的载体”表示与活性成分组合使用以帮助应用活性成分的物质,通常为惰性物质。该载体包括常见的药学上可接受的赋形剂、添加剂或稀释剂。载体可以包括选自例如填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧化剂、醛类(glydent)、调味剂、增稠剂、着色剂、乳化剂、悬浮剂、稳定剂、pH调节剂和等渗剂中的一种或多种。
作为稀释剂,可使用糖、淀粉、微晶纤维素、乳糖(水合乳糖)、葡萄糖、二甘露醇、海藻酸盐、碱土金属盐、粘土、聚乙二醇、无水磷酸氢钙或其混合物等;作为粘合剂,可使用淀粉、微晶纤维素、高分散性二氧化硅、甘露醇、二甘露醇、蔗糖、乳糖水合物、聚乙二醇、聚乙烯吡咯烷酮(聚维酮)、聚乙烯吡咯烷酮共聚物(共聚维酮)、羟丙甲纤维素、羟丙基纤维素、天然胶、合成胶、明胶或其混合物等。
作为崩解剂,可使用淀粉或改性淀粉,如淀粉乙醇酸钠、玉米淀粉、马铃薯淀粉、预糊化淀粉等;粘土,如膨润土、蒙脱石或硅酸镁铝等;纤维素,如微晶纤维素、羟丙基纤维素或羧甲基纤维素等;海藻酸,如海藻酸钠或海藻酸等;交联纤维素,如交联羧甲基纤维素等;树胶,如瓜尔豆胶、黄原胶等;交联聚合物,如交联聚乙烯吡咯烷酮(交联聚维酮)等;起泡剂(effervescent agent),如碳酸氢钠、柠檬酸等,或其混合物。
作为润滑剂,可使用滑石、硬脂酸盐、硬脂酸镁、硬脂酸钙、十二烷基硫酸钠、氢化植物油、苯甲酸钠、硬脂富马酸钠、单硬脂酸甘油酯、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、胶体二氧化硅或其混合物等。
作为pH调节剂,可使用酸化剂,如乙酸盐、抗坏血酸、抗坏血酸钠、乙酸钠、苹果酸、琥珀酸、酒石酸、富马酸和柠檬酸(柠檬酸盐)等,以及碱性剂,如沉淀碳酸钙、氨水、葡甲胺、碳酸钠、氧化镁、碳酸镁、柠檬酸钠和三碱式磷酸钙等。
作为抗氧化剂,可使用二丁基羟基甲苯、丁基羟基茴香醇、生育酚醋酸酯、生育酚、没食子酸丙酯、亚硫酸氢钠、焦亚硫酸钠等。在本发明的预释放室中,作为增溶剂,可使用十二烷基硫酸钠、聚氧乙烯山梨醇酐脂肪酸酯(如聚山梨醇酯)、多库酯钠、泊洛沙姆等。
此外,为了制备缓释剂,可包括肠道聚合物、水不溶性聚合物、疏水性化合物和亲水性聚合物。
肠道聚合物是指在pH小于5的酸性条件下不溶或稳定,在pH 5以上的特定pH条件下溶解或降解的聚合物,例如,包括肠道纤维素衍生物,如醋酸琥珀酸羟丙甲纤维素、邻苯二甲酸羟丙甲纤维素(邻苯二甲酸羟丙基甲基纤维素)、邻苯二甲酸羟甲基乙基纤维素、邻苯二甲酸醋酸纤维素、醋酸琥珀酸纤维素、醋酸苹果酸纤维素、苯甲酸邻苯二甲酸纤维素、丙酸邻苯二甲酸纤维素、邻苯二甲酸甲基纤维素、羧甲基乙基纤维素和邻苯二甲酸乙基羟乙基纤维素、甲基羟乙基纤维素;肠溶型丙烯酸酯类共聚物,如苯乙烯-丙烯酸酯共聚物、丙烯酸甲酯-丙烯酸酯共聚物、丙烯酸酯-甲基丙烯酸甲酯共聚物(例如,acryl-is)、丙烯酸丁酯-苯乙烯-丙烯酸酯共聚物和丙烯酸酯-甲基丙烯酸甲酯-丙烯酸辛酯共聚物;肠道聚甲基丙烯酸酯共聚物,如聚(甲基丙烯酸酯甲基丙烯酸甲酯)共聚物(例如,Eudragit L,Eudragit S,Evonik,Germany)和聚(甲基丙烯酸酯乙基丙烯酸酯)共聚物(例如,EudragitL100-55);肠溶马来酸基共聚物,如乙酸乙烯酯-马来酸酐共聚物、苯乙烯-马来酸酐共聚物、苯乙烯-马来酸酐单酯共聚物、乙烯基甲醚-马来酸酐共聚物、乙烯-马来酸酐共聚物、乙烯基丁基醚-马来酸酐共聚物、丙烯腈-丙烯酸甲酯·马来酸酐共聚物和丙烯酸丁酯-苯乙烯-马来酸酐共聚物;和肠溶聚乙烯衍生物,如聚乙烯醇邻苯二甲酸酯、聚乙烯醇缩醛邻苯二甲酸酯(polyvinylacetalphthalate)、聚乙烯丁酸邻苯二甲酸酯(polyvinylbutylatephthalate)和聚乙烯醇缩醛邻苯二甲酸酯(polyvinylacetacetalphthalate)。
水不溶性聚合物是指不溶于水的药学上可接受的聚合物,其控制药物的释放。例如,水不溶性聚合物包括聚醋酸乙烯酯(例如Kollicoat SR30D)、水不溶性聚甲基丙烯酸酯共聚物[例如,聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物(例如,Eudragit NE30D,聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸三甲氨基乙酯)共聚物(例如,Eudragit RSPO等)、乙基纤维素、纤维素酯、纤维素醚、酰化纤维素、二酰化纤维素、三酰化纤维素、醋酸纤维素、二醋酸纤维素和三醋酸纤维素等。
疏水化合物是指不溶于水的药学上可接受的物质,其控制药物的释放。例如,包括脂肪酸和脂肪酸酯,如棕榈硬脂酸甘油酯(glyceryl palmitostearate)、硬脂酸甘油酯、山嵛酸甘油酯(glyceryl behenate)、棕榈酸十六酯、单油酸甘油酯和硬脂酸甘油酯;脂肪酸醇,如鲸蜡硬脂醇、鲸蜡醇和硬脂醇;蜡,如巴西棕榈蜡、蜂蜡和微晶蜡;和矿物质,如滑石、沉淀碳酸钙、磷酸一氢钙、氧化锌、氧化钛、高岭土、膨润土、蒙脱石和硅酸镁铝等。
亲水性聚合物是指溶于水的药学上可接受的聚合物物质,其控制药物的释放。例如,它包括糖类,如糊精、聚糊精、葡聚糖、果胶和果胶衍生物、海藻酸盐、聚半乳糖醛酸、木聚糖、阿拉伯糖基木聚糖(arabinoxylan)、阿拉伯半乳聚糖、淀粉、羟丙基淀粉、直链淀粉和支链淀粉;纤维素衍生物,如羟丙甲纤维素、羟丙基纤维素、羟甲基纤维素、羟乙基纤维素、甲基纤维素和羧甲基纤维素钠;树胶,如瓜尔豆胶、刺槐豆胶、黄芩胶、卡拉胶、相思胶、阿拉伯胶、结冷胶和黄原胶;蛋白质,如明胶、酪蛋白和玉米醇溶蛋白;聚乙烯醇衍生物,如聚乙烯醇、聚乙烯吡咯烷酮和聚乙烯醇缩醛二乙胺醋酸酯;亲水性聚甲基丙烯酸酯共聚物,例如聚(甲基丙烯酸丁酯-(2-二甲氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)共聚物(例如,Eudragit E100,Evonik,Germany),聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸三乙基氨基乙酯氯化物)共聚物(例如,Eudragit RL,RS,Evonik,Germany);聚乙烯衍生物,如聚乙二醇和聚氧化乙烯;和卡波姆等。
此外,作为选自着色剂和调味剂的各种添加剂,本发明的制剂可以通过选择和使用药学上可接受的添加剂来配制。
在本说明书中,添加剂的范围不限于使用上述添加剂,其可通过选择上述添加剂将剂量控制在常规范围内来进行配制。
本发明的药物组合物可以以口服制剂的形式配制,如粉末、颗粒、片剂、胶囊、悬浮液、乳液、糖浆和气溶胶,以及外部制剂、栓剂或灭菌注射溶液。
本发明的组合物可口服给药,或包括静脉、腹腔内、皮下、直肠内和局部给药的肠外给药。
本发明的其他方面提供了一种治疗受试者的疾病的方法,包括向受试者给药治疗有效剂量的化学式I的化合物或其药学上可接受的盐或溶剂化物或立体异构体。
在该方法中,本领域技术人员可以根据患者的病症在给药时适当地选择给药途径。可以口服或肠外给药。肠外给药包括静脉、腹腔、皮下、直肠和局部给药。
在该方法中,剂量可根据各种因素(如患者的病症、给药途径、家庭医生的判断等)进行各种调整,如上所述。可根据从体外实验或动物模型试验获得的剂量-反应曲线估计有效剂量。可根据化学性质、给药途径、治疗剂量等确定存在于待给药组合物中的本发明化合物的比例和浓度。可以约1μg/kg至约1g/kg/天或约0.1mg/kg至约500mg/kg/天的有效剂量向受试者给药该剂量。剂量可根据受试者的年龄、体重、敏感性或症状进行调整。
此外,包含本发明化合物或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐作为活性成分的药物组合物可用于预防或治疗选自由以下组成的组中的疾病的方法中:癌症;选自类风湿性关节炎、骨关节炎、肺炎、肝炎、炎性结直肠疾病、肠道肠炎、肾小球肾炎、胃炎、血管炎、胰腺炎、腹膜炎、支气管炎、心肌炎、脑炎、过敏性接触性皮炎、糖尿病炎症、感染性炎症和自身免疫性疾病的炎性疾病;选自肝纤维化、肝硬化、小肠纤维化、大肠纤维化、胃纤维化、肺纤维化、皮肤纤维化、表皮纤维化、真皮硬化/系统性硬化、心脏纤维化和肾纤维化的纤维化疾病;选自帕金森病、亨廷顿病、淀粉营养性侧索硬化症、阿尔茨海默病、多发性硬化症、缺血性和创伤性脑损伤的神经退行性疾病;选自双相情感障碍、发育障碍、自闭症障碍、阿斯伯格综合征、Rett综合征、视力障碍、视神经病变、注意力缺陷多动障碍(ADHD)、癫痫、情绪障碍、Tourette综合征和精神分裂症的神经疾病;肝病;皮肤病;选自遗传性线粒体疾病、Alpers病、Barth综合征、慢性进行性眼外肌麻痹(CPEO)、长链酰基CoA脱氢酶缺乏症(LCAD)、melas综合征、Leber遗传性视神经病变(LHON)、Leigh病、Leigh样综合征、Luft病、Pearson综合征、神经病变、共济失调和色素性视网膜炎(NARP),Co-Q10缺乏、MERRF综合征(MERRF)、线粒体DNA耗竭综合征(MDS)、致死性婴儿心肌病(LIC)、线粒体神经胃肠系统脑肌病、β氧化缺陷、弗里德里希共济失调(弗里德里希共济失调FA)、卡恩斯-塞尔综合征(KSS)或乳酸性酸中毒的线粒体疾病;衰老;慢性酒精中毒;干细胞功能障碍;跛行;选自肥胖、糖尿病、高血压、高脂血症、动脉硬化、外周血管疾病、缺血灌注、心肌梗死和中风的代谢综合征;唐氏综合征;不育;组织中过氧化脂质的过量产生;选自肌病、肌营养不良、心肌病、脑肌病和背部肌肉萎缩的肌肉相关疾病;细胞膜脂质过氧化物积累;慢性疲劳;以及选自视网膜纤维化、黄斑变性、糖尿病视网膜病变、白内障和新生血管性青光眼的视网膜疾病,
所述方法包括将其给药于需要其的受试者中。
实施方式
[实施例]
在下文中,将通过实施例更详细地描述本发明。这些实施例旨在更具体地说明本发明,并且对于本领域技术人员来说显而易见的是,本发明的范围不受这些实施例的限制。
<参考例-制备中间体1至3>
中间体1:8-氧代-1,4-二氧杂螺[4,5]癸烷-7-甲酸甲酯的制备
将4-二氧杂螺[4.5]癸烷-8-酮(10.0g,64mmol)溶于250mL四氢呋喃中,然后在室温下加入氢化钠(1.84g,77mmol,1.2eq)。将反应混合物在室温下搅拌30分钟,然后加入碳酸二甲酯(11.5g,128mmol,2eq)。在室温下搅拌12小时后,加入200mL饱和氯化铵水溶液以终止反应。用乙酸乙酯(100mL×3)和盐水萃取反应混合物,用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯=18/1)纯化,得到无色油的标题化合物(6.94g,56%)。
1H NMR(400MHz,CDCl3):δ12.19(s,1H),4.04(s,4H),3.79(s,3H),2.60-2.50(m,4H),2.30-2.05(m,1H),1.88(t,J=4.8Hz,2H).
将4-二氧杂螺[4.5]癸烷-8-酮(15.0g,96.04mmol)溶于250mL无水四氢呋喃中,然后在室温下加入氢化钠(9.22g,192.08mmol,2eq)。将反应混合物在50℃回流30分钟,然后加入碳酸二甲酯(17.3g,192.08mmol,2eq)。将反应混合物回流4小时,然后冷却至室温,然后在0℃下用2M盐酸水溶液中和。用乙酸乙酯(100mL×3)和盐水萃取反应混合物,用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(己烷/乙酸乙酯=3/1)纯化,得到白色固体的标题化合物(18.10g,88%)。
中间体2:2'-(吡啶-2-基)-2',4',6',7'-四氢螺[[1,3]二氧戊环-2,5'-吲唑]-3'-醇的制备
将8-氧代-1,4-二氧杂螺[4,5]癸烷-7-甲酸甲酯(2.0g,10.3mmol)溶于20mL乙醇中,然后加入2-肼基吡啶(1.1g,10.3mol,1.0eq)。将反应混合物回流12小时,然后在减压下浓缩。残余物用乙酸乙酯重结晶,得到黄色固体的标题化合物(1.5g,54%)。
1H NMR(400MHz,DMSO-d6):δ11.56(s,1H),8.41(t,J=4.8Hz,2H),7.88(t,J=8.0Hz,1H),7.19(t,J=6.0Hz,1H),3.95-3.90(m,4H),2.60-2.52(m,2H),2.38-2.33(m,2H),1.89-1.84(m,2H).
将8-氧代-1,4-二氧杂螺[4,5]癸烷-7-甲酸甲酯(18.1g,84.53mmol)溶于120mL乙醇中,然后加入2-肼基吡啶(9.22g,84.5mmol,1.0eq)。反应混合物在100℃下回流4小时,然后减压浓缩。残余物用乙酸乙酯重结晶,得到黄色固体的标题化合物(16.39g,71%)。
中间体3:3-羟基-2-吡啶-2-基-2,4,6,7-四氢吲唑-5-酮的制备
将2'-(吡啶-2-基)-2',4',6',7'-四氢螺[[1,3]二氧戊环-2,5'-吲唑]-3'-醇(5.0g,18.3mmol,1.0eq)溶解在40mL二氯甲烷中,然后加入三氟乙酸盐(80mL)。反应混合物在50℃下回流12小时,然后减压浓缩。用二氯甲烷稀释反应混合物,然后用碳酸氢钠将其调节至pH 6。用二氯甲烷和水萃取反应混合物,然后用硫酸钠干燥,过滤,减压浓缩。残余物通过硅胶柱色谱法(溶剂:二氯甲烷/甲醇=20/1)纯化,得到棕色固体的标题化合物(2.3g,54.9%)。
1H NMR(400MHz,DMSO-d6):δ8.48-8.40(m,1H),8.31(d,J=8.4Hz,1H),8.00-7.90(m,1H),7.25-7.22(m,1H),3.09(s,2H),2.93(t,J=6.8Hz,2H),2.62(t,J=6.8Hz,2H).MS计算值:229.2;MS实际值:230.2([M+H]+).
将2'-(吡啶-2-基)-2',4',6',7'-四氢螺[[1,3]二氧戊环-2,5'-吲唑]-3'-醇(12,99g,47,56mmol)溶于120mL二氯甲烷中,然后加入三氟乙酸盐(240mL)。将反应混合物在60℃下回流12小时,然后在减压下浓缩。用乙醚重结晶反应混合物,得到浅棕色固体的标题化合物(10.88g,99%)。
<合成例>
合成例1.8-氧代-1,4-二氧杂螺[4,5]癸-7-甲酸甲酯的制备
将4-二氧杂螺[4.5]癸烷-8-酮(10.0g,64mmol)溶于250mL四氢呋喃中,然后在室温下加入氢化钠(1.84g,77mmol,1.2eq)。将反应混合物在室温下搅拌30分钟,然后加入碳酸二甲酯(11.5g,128mmol,2eq)。在室温下搅拌12小时后,加入200mL饱和氯化铵水溶液以终止反应。用乙酸乙酯(100mL×3)和盐水萃取反应混合物,用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯=18/1)纯化,得到无色油的标题化合物(6.94g,56%)。
1H NMR(400MHz,CDCl3):δ12.19(s,1H),4.04(s,4H),3.79(s,3H),2.60-2.50(m,4H),2.30-2.05(m,1H),1.88(t,J=4.8Hz,2H).
将4-二氧杂螺[4.5]癸烷-8-酮(15.0g,96.04mmol)溶于250mL无水四氢呋喃中,然后在室温下加入氢化钠(9.22g,192.08mmol,2eq)。将反应混合物在50℃下回流30分钟,然后加入碳酸二甲酯(17.3g,192.08mmol,2eq)。将反应混合物回流4小时,然后冷却至室温,然后在0℃下用2M盐酸水溶液中和。用乙酸乙酯(100mL×3)和盐水萃取反应混合物,用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(己烷/乙酸乙酯=3/1)纯化,得到白色固体的标题化合物(18.10g,88%)。
合成例2.2'-(吡啶-2-基)-2',4',6',7'-四氢螺[[1,3]二氧戊环-2,5'-吲唑]-3'-醇的制备
将8-氧代-1,4-二氧杂螺[4,5]癸烷-7-甲酸甲酯(2.0g,10.3mmol)溶于20mL乙醇中,然后加入2-肼基吡啶(1.1g,10.3mol,1.0eq)。将反应混合物回流12小时,然后在减压下浓缩。残余物用乙酸乙酯重结晶,得到黄色固体的标题化合物(1.5g,54%)。
1H NMR(400MHz,DMSO-d6):δ11.56(s,1H),8.41(t,J=4.8Hz,2H),7.88(t,J=8.0Hz,1H),7.19(t,J=6.0Hz,1H),3.95-3.90(m,4H),2.60-2.52(m,2H),2.38-2.33(m,2H),1.89-1.84(m,2H).
将8-氧代-1,4-二氧杂螺[4,5]癸烷-7-甲酸甲酯(18.1g,84.53mmol)溶于120mL乙醇中,然后加入2-肼基吡啶(9.22g,84.5mmol,1.0eq)。将反应混合物在100℃下回流4小时。残余物用乙酸乙酯重结晶,得到黄色固体的标题化合物(16.39g,71%)。
合成例3.3-羟基-2-吡啶-2-基-2,4,6,7-四氢吲唑-5-酮的制备
将2'-(吡啶-2-基)-2',4',6',7'-四氢螺[[1,3]二氧戊环-2,5'-吲唑]-3'-醇(5.0g,18.3mmol,1.0eq)溶解在40mL二氯甲烷中,然后加入三氟乙酸盐(80mL)。反应混合物在50℃下回流12小时,然后减压浓缩。用二氯甲烷稀释反应混合物,然后用二氯甲烷和水将其调节至pH 6。用二氯甲烷和水萃取反应混合物,然后用硫酸钠干燥,过滤并减压浓缩。残余物通过硅胶柱色谱法(溶剂:二氯甲烷/甲醇=20/1)纯化,得到黄色固体的标题化合物(2.3g,54.9%)。
1H NMR(400MHz,DMSO-d6):δ8.48-8.40(m,1H),8.31(d,J=8.4Hz,1H),8.00-7.90(m,1H),7.25-7.22(m,1H),3.09(s,2H),2.93(t,J=6.8Hz,2H),2.62(t,J=6.8Hz,2H).MS计算值:229.2;MS实际值:230.2([M+H]+).
将2'-(吡啶-2-基)-2',4',6',7'-四氢螺[[1,3]二氧戊环-2,5'-吲唑]-3'-醇(12,99g,47,56mmol)溶于120mL二氯甲烷中,然后加入三氟乙酸盐(240mL)。用乙醚重结晶反应混合物,得到浅棕色固体的标题化合物(10.88g,99%)。
合成例4.5-(苄基丙基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物21)的制备
将3-羟基-2-吡啶-2-基-2,4,6,7-四氢吲唑-5-酮(500mg,2.18mmol,1.0eq)溶解于30mL二氯甲烷中,然后在氮气流下缓慢加入叔丁基二甲基甲硅烷氯化物(494mg,3.27mmol,1.5eq)和三乙胺(0.6mL,4.36mmol,2.0eq)。将反应混合物在室温下搅拌12小时,然后用水和盐水萃取。用无水硫酸钠干燥有机层,然后将该混合物用于下一步骤而无需额外纯化。
向反应中获得的化合物中加入N-苄基丙烷-1-胺(649mg,4.36mmol,2.0eq)、三乙酰氧基硼氢化钠(1.39g,6.54mmol,3.0eq)和乙酸盐(4滴),然后在室温下搅拌12小时。向反应混合物中加入饱和碳酸氢钠水溶液(50mL)以调节pH至约8,然后用二氯甲烷(30mL×3)萃取。有机层用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱(溶剂:二氯甲烷/甲醇=20/1)进行一次纯化,得到混合物6(400mg)。通过分选高效液相色谱法对一次纯化的混合物进行二次纯化,得到黄色固体的标题化合物(104mg,13.1%)。
1H NMR(400MHz,CD3OD):δ8.40(s,1H),8.15-8.11(m,1H),8.08-8.01(m,1H),7.56-7.53(m,2H),7.41(s,3H),7.34(t,J=6.4Hz,1H),4.58-4.51(m,1H),4.38-4.31(m,1H),3.72-3.68(m,1H),3.25-3.18(m,1H),3.15-2.83(m,3H),2.80-2.70(m,2H),2.50-2.42(m,1H),2.20-2.08(m,1H),1.75-1.60(m,1H),1.60-1.57(m,1H),0.90-0.81(m,3H).MS计算值:362.2;MS实际值:363.3([M+H]+).
合成例5.5-(苄基乙基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物20)的制备
根据化合物21的制备方法,得到黄色固体的标题化合物(120mg,15.8%)。
1H NMR(400MHz,CD3OD):δ9.55-9.40(m,1H),8.42(d,J=4.0Hz,1H),8.40-8.30(br,1H),7.92(t,J=8.0Hz,1H),7.60-7.45(m,4H),7.23(t,J=6.8Hz,1H),4.68(t,J=13.6Hz,1H),4.50-4.44(m,1H),3.90-3.86(m,1H),3.47-3.37(m,2H),3.20-3.02(m,2H),2.95-2.90(m,2H),2.60-2.50(m,1H),2.35-2.25(m,1H),1.47-1.37(m,3H).MS计算值:347.5;MS实际值:349.2([M+H]+).
合成例6.5-(苄基丁基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物22)的制备
根据化合物21的制备方法,得到黄色固体的标题化合物(100mg,12.1%)。
1H NMR(400MHz,CD3OD):δ9.55-9.40(m,1H),8.42(d,J=4.0Hz,1H),8.40-8.30(br,1H),7.92(t,J=8.0Hz,1H),7.60-7.45(m,5H),7.23(t,J=6.8Hz,1H),4.61-4.50(m,1H),4.40-4.35(m,1H),3.66-3.50(m,2H),3.30-3.15(m,2H),3.10-2.90(m,1H),2.80-2.55(m,4H),2.45-2.30(m,1H),2.15-1.80(m,1H),1.75-1.60(m,1H),1.60-1.40(m,1H),1.35-1.22(m,3H).MS计算值:376.2;MS实际值:377.2([M+H]+).
合成例7.5-[(2-甲氧基苄基)-甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物26)的制备
将3-羟基-2-吡啶-2-基-2,4,6,7-四氢吲唑-5-酮(500mg,2.18mmol,1.0eq)溶于30mL二氯甲烷中,然后加入1-(2-甲氧基苯基)-N-甲基甲烷胺(658mg,4.36mmol,2.0eq)和三乙酰氧基硼氢化钠(1.39g,6.54mmol,3.0eq),并加入乙酸盐4滴。将反应混合物在室温下搅拌12小时。向反应混合物中加入饱和碳酸氢钠水溶液(50mL),然后用二氯甲烷(50mL×2)萃取。用盐水洗涤有机层后,用无水硫酸钠干燥并减压浓缩。通过分选高效液相色谱法纯化残余物,得到黄色固体的标题化合物(200mg,34.0%)。化合物39至60、64至68、72至76、78至81、121至125、146至153和157至159也通过上述方法制备。
1H NMR(400MHz,CD3OD):δ8.56(d,J=5.2Hz,1H),8.30-8.22(m,2H),7.59-7.52(m,3H),7.19(d,J=8.4Hz,1H),7.10(t,J=7.6Hz,1H),4.78(dd,J1=12.8Hz,J2=19.2Hz,1H),4.20(dd,J1=12.8Hz,J2=27.6Hz,1H),4.00(s,3H),3.90-3.85(m,1H),3.15-3.08(m,2H),3.00-2.85(m,5H),2.60-2.50(m,1H),2.40-2.10(m,1H).MS计算值:364.2;MS实际值:365.3([M+H]+).
合成例8.5-(苄基甲基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物1)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(200mg,27.4%)。
1H NMR(400MHz,DMSO-d6):δ10.8-10.50(br,1H),8.45-8.38(m,2H),7.88(t,J=11.2Hz,1H),7.40-7.15(m,6H),3.63(q,J1=18.4Hz,J2=34.4Hz,2H),2.80-2.70(m,1H),2.65-2.55(m,1H),2.52-2.50(m,1H),2.48-2.30(m,1H),2.31-2.25(m,1H),2.16(s,3H),2.05-1.85(m,1H),1.71-1.65(m,1H).MS计算值:334.2;MS实际值:335.2([M+H]+).
合成例9.5-(苄基环丙基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物2)的制备
根据化合物26的制备方法,得到黄色固体的标题化合物(94mg,11.9%)。
1H NMR(400MHz,DMSO-d6):δ11.39(s,1H),8.42-8.37(m,2H),7.92-7.85(m,1H),7.31-7.15(m,6H),3.82(s,2H),2.80-2.70(m,1H),2.60-2.52(m,1H),2.50-2.35(m,2H),2.13-2.00(m,2H),1.77-1.72(m,1H),0.48-0.43(m,2H),0.30-0.26(m,2H).MS计算值:360.2;MS实际值:361.0([M+H]+).
合成例10.4-{[(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)甲基氨基]甲基}苯甲腈(化合物3)的制备
根据化合物26的制备方法,得到黄色固体的标题化合物(103mg,16.4%)。
1H NMR(400MHz,DMSO-d6):δ8.40(s,1H),7.96-7.60(m,4H),7.60-7.55(m,2H),7.22-7.18(m,0.5H),6.95-6.90(m,0.5H),3.80-3.62(m,2H),2.90-2.75(m,1H),2.75-2.60(m,2H),2.50-2.22(m,2H),2.21-2.04(m,3H),2.05-1.92(m,1H),1.75-1.62(m,1H).MS计算值:359.4;MS实际值:360.2([M+H]+).
合成例11.5-[(4-氟苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物4)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(189mg,30.8%)。
1H NMR(400MHz,DMSO-d6):δ8.40-8.33(m,2H),7.90-7.83(m,1H),7.40-7.30(m,2H),7.22-7.10(m,3H),3.58(q,J1=13.6Hz,J2=30.0Hz,2H),2.75-2.60(m,2H),2.50-2.22(m,1H),2.21-2.04(m,1H),2.15(s,3H),2.03-1.96(m,1H),1.68-1.52(m,1H).MS计算值:352.2;MS实际值:353.1([M+H]+).
合成例12.5-[(2,4-二氟苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物5)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(150mg,23.3%)。
1H NMR(400MHz,DMSO-d6):δ11.60-11.45(br,1H),8.50-8.36(m,2H),7.96-7.92(m,1H),7.46(q,J1=11.2Hz,J2=20.4Hz,2H),7.22-7.16(m,2H),7.10-7.05(m,1H),3.63(q,J1=9.6Hz,J2=28.0Hz,2H),2.75-2.60(m,2H),2.60-2.50(m,1H),2.50-2.42(m,1H),2.42-2.20(m,1H),2.20(s,3H),2.03-1.96(m,1H),1.72-1.68(m,1H).MS计算值:370.2;MS实际值:371.1([M+H]+)
合成例13.5-[(2-氯苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物6)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(270mg,42.0%)。
1H NMR(400MHz,DMSO-d6):δ11.60-11.45(br,1H),8.50-8.38(m,2H),7.92-7.90(m,1H),7.53(d,J=7.2Hz,1H),7.42(d,J=7.6Hz,1H),7.40-7.35(m,1H),7.35-7.30(m,1H),7.20-7.17(m,1H),3.76-3.68(m,2H),2.85-2.70(m,2H),2.65-2.55(m,1H),2.55-2.50(m,1H),2.42-2.20(m,2H),2.20(s,3H),2.03-1.96(m,1H),1.72-1.68(m,1H).MS计算值:368.9;MS实际值:369.1([M+H]+)
合成例14.5-[(3-氯苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物7)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(150mg,23.4%)。
1H NMR(400MHz,DMSO-d6):δ11.50-11.42(br,1H),8.50-8.38(m,2H),7.90-7.80(m,1H),7.40-7.23(m,4H),7.30-7.23(m,1H),3.65(q,J1=14.0Hz,J2=32.0Hz,2H),2.85-2.70(m,1H),2.65-2.55(m,1H),2.55-2.50(m,1H),2.42-2.20(m,1H),2.20(s,3H),2.03-1.96(m,1H),1.68-1.60(m,1H).MS计算值:368.1;MS实际值:369.1([M+H]+)
合成例15.5-[甲基-(4-三氟甲基苄基)氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物8)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(304mg,43.5%)。
1H NMR(400MHz,DMSO-d6):δ11.43(s,1H),8.44-8.38(m,2H),7.92-7.90(m,1H)7.67(d,J=8.0Hz,2H),7.58(d,J=8.0Hz,2H),7.17(t,J=5.6Hz,1H),3.70(q,J1=14.4Hz,J2=31.2Hz,2H),2.85-2.70(m,1H),2.65-2.55(m,1H),2.55-2.50(m,1H),2.42-2.30(m,1H),2.30-2.20(m,1H),2.20(s,3H),2.03-1.96(m,1H),1.72-1.68(m,1H).MS计算值:402.4;MS实际值:403.1([M+H]+)
合成例16.5-[甲基-(3-甲基苄基)氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物9)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(103mg,17.0%)。
1H NMR(400MHz,DMSO-d6):δ11.43(s,1H),8.44-8.38(m,2H),7.92-7.90(m,1H),7.21-7.04(m,4H),7.04-7.02(m,1H),3.60-3.48(m,2H),2.80-2.72(m,1H),2.70-2.66(m,1H),2.48-2.40(m,1H),2.29(s,3H),2.20-2.16(m,1H),2.19(s,3H),2.03-1.96(m,2H),1.70-1.62(m,1H).MS计算值:348.4;MS实际值:349.2([M+H]+)
合成例17.5-[甲基-(3-三氟甲基苄基)-氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物10)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(292mg,57.5%)。
1H NMR(400MHz,DMSO-d6):δ11.43(s,1H),8.44-8.38(m,2H),7.92-7.90(m,1H),7.71-7.52(m,4H),7.19-7.16(m,1H),3.70(q,J1=12.0Hz,J2=30.4Hz,2H),2.85-2.70(m,1H),2.65-2.55(m,1H),2.55-2.50(m,1H),2.45-2.20(m,2H),2.20(s,3H),2.03-1.96(m,1H),1.73-1.68(m,1H).MS计算值:402.4;MS实际值:403.2([M+H]+)
合成例18.5-[甲基-(2-三氟甲基苄基)-氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物11)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(117mg,16.7%)。
1H NMR(400MHz,DMSO-d6):δ11.52-11.47(br,1H),8.50-8.38(m,2H),7.89-7.83(m,2H),7.70-7.65(m,2H),7.45(t,J=7.6Hz,1H),7.18(br,1H),3.80(q,J1=10.0Hz,J2=25.0Hz,2H),2.86-2.70(m,1H),2.65-2.55(m,1H),2.53-2.50(m,1H),2.42-2.31(m,1H),2.29-2.20(m,1H),2.20(s,3H),2.05-1.96(m,1H),1.72-1.68(m,1H).MS计算值:402.4;MS实际值:403.1([M+H]+)
合成例19.5-[(4-甲磺酰基苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物12)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(100mg,11.1%)。
1H NMR(400MHz,DMSO-d6):δ11.45(s,1H),8.44-8.38(m,2H),7.89(d,J=8.0Hz,3H),7.60(d,J=8.0Hz,2H),7.19-7.16(m,1H),3.72(q,J1=14.8Hz,J2=31.2Hz,2H),3.19(s,3H),2.84-2.80(m,1H),2.65-2.55(m,1H),2.55-2.50(m,1H),2.42-2.32(m,1H),2.28-2.20(m,1H),2.20(s,3H),2.05-1.98(m,1H),1.72-1.68(m,1H).MS计算值:412.1;MS实际值:413.1([M+H]+)
合成例20.5-[(3-甲磺酰基苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物23)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(50mg,5.5%)。
1H NMR(400MHz,DMSO-d6):δ8.51-8.30(m,2H),7.95-7.85(m,2H),7.81(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.60(t,J=8.0Hz,1H),7.25-7.15(m,1H),3.76(dd,J1=14.0Hz,J2=31.6Hz,2H),3.21(s,3H),2.90-2.80(m,1H),2.70-2.60(m,1H),2.60-2.50(m,1H),2.50-2.40(m,1H),2.30-2.15(m,4H),2.10-2.00(m,1H),1.70-1.60(m,1H).MS计算值:412.5;MS实际值:413.1([M+H]+).
合成例21.5-[甲基-(4-甲基苄基)氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物24)的制备
根据化合物26的制备方法,得到亮黄色固体的标题化合物(50mg,5.5%)。
1H NMR(400MHz,CD3OD):δ8.51-8.50(m,1H),8.35-8.20(m,2H),7.65-7.47(m,3H),7.34(d,J=8.0Hz,2H),4.63(t,J=13.2Hz,1H),4.34(t,J=13.6Hz,1H),3.90-3.70(m,1H),3.20-3.00(m,2H),3.00-2.75(m,5H),2.65-2.52(m,1H),2.41(s,3H),2.25-2.10(m,1H).MS计算值:348.2;MS实际值:349.2([M+H]+).
合成例22.5-[(3-甲氧基苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物13)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(105mg,13.2%)。
1H NMR(400MHz,CDCl3)δ8.24(br,1H),7.82(m,2H),7.26-7.22(m,1H),7.14-7.02(m,1H),7.00-6.90(m,2H),6.80-6.75(m,1H),3.85-3.80(m,3H),3.65(s,2H),2.95-2.78(m,2H),2.65-2.52(m,2H),2.50-2.40(m,1H),2.32-2.28(m,3H),2.27-2.16(m,1H),1.72-1.58(m,1H).MS计算值:364.2;MS实际值:365.1([M+H]+)
合成例23.5-哌啶-1-基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物14)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(70mg,10.7%)。
1H NMR(400MHz,DMSO-d6):δ9.74(br,1H),8.42(d,J=4.4Hz,1H),8.35(d,J=8.0Hz,1H),7.92(t,J=8.4Hz,1H),7.23(t,J=6.8Hz,1H),3.60-3.40(m,3H),3.12-3.02(m,2H),2.75-2.60(m,3H),2.55-2.48(m,1H),2.30-2.27(m,1H),1.90-1.70(m,6H),1.50-1.42(m,1H).MS计算值:298.2;MS实际值:299.2([M+H]+)
合成例24.5-吗啉-4-基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物15)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(80mg,11.3%)。
1H NMR(400MHz,DMSO-d6):δ11.65-11.47(br,1H),8.39-8.33(m,2H),7.89(t,J=7.2Hz,1H),7.18(t,J=5.6Hz,1H),3.59-3.53(m,4H),2.60-2.55(m,2H),2.55-2.45(m,4H),2.45-2.40(m,1H),2.20-2.05(m,1H),2.01-1.98(m,1H),1.62-1.50(m,1H).MS计算值:300.4;MS实际值:301.2([M+H]+)
合成例25.5-(4-甲基哌嗪-1-基)-2-吡啶-2-基4,5,6,7-四氢-2H-吲唑-3-醇(化合物16)的制备
根据化合物26的制备方法,得到呈灰色固体的标题化合物(195mg,28.5%)。
1H NMR(400MHz,DMSO-d6):δ8.42(d,J=4.4Hz,1H),8.35(d,J=8.4Hz,1H),7.91(t,J=7.6Hz,1H),7.22(t,J=5.6Hz,1H),3.70-3.20(br,9H),2.88(s,3H),2.74-2.51(m,3H),2.42-2.37(m,1H),2.26-2.23(m,1H),1.82-1.72(m,1H).MS计算值:313.4;MS实际值:314.2([M+H]+)
合成例26.5-(3,4-二氢-1H-异喹啉-2-基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物18)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(120mg,16.0%)。
1H NMR(400MHz,DMSO-d6):δ11.47(s,1H),8.44-8.38(m,2H),7.91-7.88(m,1H),7.19-7.16(m,1H),7.10-7.04(m,4H),3.76(s,2H),2.91-2.50(m,7H),2.50-2.40(m,1H),2.40-2.25(m,1H),2.20-2.02(m,1H),1.78-1.70(m,1H).MS计算值:346.2;MS实际值:347.2([M+H]+)
合成例27.3-{[(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)甲基氨基]甲基}苯甲腈盐酸盐(化合物25)的制备
根据化合物26的制备方法,得到黄色固体的标题化合物(104mg,13.3%)。
1H NMR(400MHz,CD3OD):δ8.5(d,J=6.0Hz,1H),8.40-8.32(m,1H),8.21(d,J=8.4Hz,1H),8.16-8.10(m,1H),8.08-8.00(m,1H),7.90(d,J=8.0Hz,1H),7.72(t,J=8.0Hz,1H),7.66-7.56(m,1H),4.80-4.75(m,1H),4.62-4.45(m,1H),4.00-3.80(m,1H),3.25-3.00(m,2H),3.00-2.80(m,5H),2.70-2.60(m,1H),2.30-2.15(m,1H).MS计算值:359.1,MS实际值:360.1([M+H]+).
合成例28.5-[(4-氯苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物19)的制备
根据化合物26的制备方法,得到棕色固体的标题化合物(144mg,22.5%)。
1H NMR(400MHz,DMSO-d6):δ11.42(s,1H),8.44-8.38(m,2H),7.87(m,1H),7.39-7.33(m,4H),7.19-7.16(m,1H),3.72(q,J1=13.6Hz,J2=30.4Hz,2H),2.83-2.80(m,1H),2.65-2.55(m,1H),2.55-2.50(m,1H),2.42-2.32(m,1H),2.28-2.20(m,1H),2.16(s,3H),2.05-1.98(m,1H),1.72-1.68(m,1H).MS计算值:368.1;MS实际值:369.1([M+H]+)
合成例29.5-[(3-氟苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物27)的制备
根据化合物26的制备方法,得到黄色固体的标题化合物(95mg,12.3%)。
1H NMR(400MHz,CD3OD):δ8.44(d,J=5.6Hz,1H),8.25-8.15(m,1H),8.15-8.10(m,1H),7.50-7.45(m,2H),7.39(d,J=8.4Hz,2H),7.25-7.10(m,1H),4.65-4.55(m,1H),4.40-4.28(m,1H),3.80-3.65(m,1H),3.10-2.90(m,2H),2.85-2.65(m,5H),2.50-2.40(m,1H),2.15-2.00(m,1H).MS计算值:352.2;MS实际值:353.1([M+H]+).
合成例30.5-[(4-甲氧基苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物28)的制备
根据化合物26的制备方法,得到黄色油的标题化合物(80mg,10.7%)。
1H NMR(400MHz,CD3OD):δ8.44(d,J=5.2Hz,1H),8.30-8.20(m,1H),8.15-8.05(m,1H),7.55-7.40(m,3H),6.94(d,J=8.4Hz,2H),4.50(t,J=12.8Hz,1H),4.22(t,J=14.0Hz,1H),3.76-3.64(m,4H),3.10-2.93(m,2H),2.92-2.70(m,5H),2.50-2.42(m,1H),2.10-2.00(m,1H).MS计算值:364.2;MS实际值:365.2([M+H]+).
合成例31.5-[甲基-(2-甲基苄基)氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物29)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(300mg,39.5%)。
1H NMR(400MHz,CD3OD):δ8.43(d,J=5.2Hz,1H),8.20-8.10(m,2H),7.50-7.37(m,2H),7.35-7.20(m,3H),4.68(dd,J1=13.6Hz,J2=23.6Hz,1H),4.21(dd,J1=13.2Hz,J2=32.8Hz,1H),3.90-3.73(m,1H),3.10-2.85(m,2H),2.84-2.65(m,5H),2.51-2.45(m,1H),2.43(s,3H),2.30-2.00(m,1H).MS计算值:348.2;MS实际值:349.2([M+H]+).
合成例32.5-[(2,4-二氯苄基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物30)的制备
根据化合物26的制备方法,得到白色固体的标题化合物(127mg,13.3%)。
1H NMR(400MHz,CD3OD):δ8.42(d,J=5.2Hz,1H),8.20-8.07(m,2H),7.71(d,J=8.0Hz,1H),7.61(d,J=2.0Hz,1H),7.49-7.35(m,2H),4.78-4.68(m,1H),4.50-4.30(m,1H),3.90-3.70(m,1H),3.10-2.90(m,2H),2.90-2.65(m,5H),2.55-2.45(m,1H),2.30-2.05(m,1H).MS计算值:402.1;MS实际值:403.1([M+H]+).
合成例33.5-[(3,4-二氯苯基)甲基氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物31)的制备
根据化合物26的制备方法,得到黄色固体的标题化合物(144mg,16.4%)。
1H NMR(400MHz,CD3OD):δ8.54(d,J=5.2Hz,1H),8.30-8.20(m,2H),7.93(d,J=1.6Hz,1H),7.75-7.60(m,2H),7.58-7.50(m,1H),4.75-4.60(m,1H),4.50-4.35(m,1H),3.95-3.76(m,1H),3.20-3.00(m,2H),3.00-2.77(m,5H),2.62-2.55(m,1H),2.23-2.15(m,1H).MS计算值:402.1;MS实际值:403.1([M+H]+).
合成例34.5-(甲基(5,6,7,8-四氢喹啉-8-基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物33)的制备
1)N-甲基-5,6,7,8-四氢喹啉-8-胺的制备
将6,7-二氢喹啉-8(5H)-酮(2.0g,13.59mmol)溶于40mL二氯乙烷中,然后加入甲胺(3.39mL,27.18mmol,2.0eq)和乙酸盐7滴。将反应混合物在室温下搅拌1小时,然后加入三乙酰氧基硼氢化钠(5.7g,27.18mmol,2.0eq)。将反应混合物在室温下搅拌12小时,然后加入10%氯化铵水溶液以将pH调节至约8.0。用二氯甲烷(60mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层,然后在减压下浓缩,得到标题化合物(1.98g,90.0%)。
1H NMR(600MHz,CDCl3):δ8.33(d,J=4.1Hz,1H),7.25-7.32(m,1H),7.01(q,J=4.1Hz,1H),3.66(m,1H),2.73-2.78(m,1H),2.66-2.70(m,1H),2.49(s,3H),2.07-2.11(m,1H),1.91-1.96(m,1H),1.66-1.76(m,2H).
2)5-(甲基(5,6,7,8-四氢喹啉-8-基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇的制备
将3-羟基-2-(吡啶-2-基)-2,4,6,7-四氢-5H-吲唑-5-酮(0.03g,0.13mmol)溶于8mL二氯乙烷中,然后加入N-甲基-5,6,7,8-四氢喹啉-8-胺(0.02g,0.13mmol,1.0eq)和乙酸盐2滴。将反应混合物在室温下搅拌1小时,然后加入氰基硼氢化钠(0.01g,0.16mmol,1.2eq)。将反应混合物在室温下搅拌12小时,然后加入10%氯化铵水溶液以将pH调节至约8.0。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶色谱法(二氯甲烷/甲醇=5/1+0.1%三乙胺)纯化,得到棕色固体的标题化合物(0.05g,11.0%)。
1H NMR(600MHz,CDCl3):δ8.50–8.44(m,1H),8.23–8.17(m,1H),7.90–7.70(m,2H),7.33(d,J=7.4Hz,1H),7.10–6.97(m,2H),4.20–4.12(m,1H),3.15–2.95(m,1H),2.85–2.77(m,3H),2.71–2.65(m,1H),2.60–2.42(m,2H),2.29(s,3H),2.27–2.20(m,1H),2.05–1.95(m,2H),1.83–1.67(m,3H).MS计算值:375.2;MS实际值:376.1([M+H]+).
合成例35.环丙基(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)甲酮(化合物38)的制备
将3-羟基-2-(吡啶-2-基)-2,4,6,7-四氢-5H-吲唑-5-酮(2.5g,10.9mmol)溶于100mL二氯甲烷/二氯乙烷(1/1)中,然后加入环丙基(哌嗪-1-基)甲酮盐酸盐(3.1g,16.4mmol,1.5eq)、二异丙基乙胺(2.8mL,16.4mmol,1.5摩尔)、乙酸盐(1.0mL,16.4mmol,1.5eq)。将反应混合物在室温下搅拌3小时,然后加入三乙酰氧基硼氢化钠(4.6g,21.8mmol,2.0eq)。将反应混合物在室温下搅拌48小时,然后加入2M氢氧化钠水溶液以将pH调节至约8.0。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1)初步纯化,然后用乙醚重结晶,得到浅棕色固体的标题化合物(2.8g,70.0%)。
1H NMR(600MHz,CDCl3):δ8.23(d,J=5.5Hz,1H),7.82(t,J=3.4Hz,2H),7.10(q,J=4.1Hz,1H),3.74-3.61(m,4H),2.91-2.81(m,1H),2.81 -2.52(m,8H),2.44-2.35(m,1H),2.15-2.07(m,1H),1.76-1.70(m,1H),1.04-0.95(m,2H),0.79-0.70(m,2H).MS计算值:367.2;MS实际值:368.1([M+H]+).
合成例36.5-((4-(二甲氨基)苄基)(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物70)的制备
将3-羟基-2-(吡啶-2-基)-2,4,6,7-四氢-5H-吲唑-5-酮(0.70g,3.04mmol)溶于40mL二氯甲烷/二氯乙烷(1/1)中,然后加入N,N-二甲基-4-((甲基氨基)甲基)苯胺(0.50g,3.03mmol,1.0eq)和乙酸盐(0.19mL,3.04mmol,1.0eq)。将反应混合物在室温下搅拌1小时,然后加入三乙酰氧基硼氢化钠(0.64g,3.04mmol,1.0eq)。将反应混合物在室温下搅拌18小时,然后加入2M氢氧化钠水溶液以将pH调节至约8.0。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1)纯化,得到黑色固体的标题化合物(0.094g,8.0%)。
1H NMR(600MHz,CD3OD):δ8.42–8.34(m,1H),8.25(d,J=8.8Hz,1H),7.90–7.79(m,1H),7.27(d,J=9.0Hz,2H),7.18(dd,J=8.0,5.4Hz,1H),6.77(d,J=9.1Hz,2H),4.11(dd,J=23.9,13.5Hz,2H),3.55-3.37(m,1H),2.93(s,6H),2.87–2.72(m,2H),2.63(s,3H),2.58–2.47(m,2H),2.34–2.25(m,1H),2.02–1.92(m,1H).
MS计算值:377.2;MS实际值:378.3([M+H]+).
合成例37.2-吡啶-2-基-5-吡咯烷-1-基4,5,6,7-四氢-2H-吲唑-3-醇(化合物96)的制备
将3-羟基-2-(吡啶-2-基)-2,4,6,7-四氢-5H-吲唑-5-酮(0.30g,1.30mmol)溶于10mL二氯甲烷中,然后加入吡咯烷(0.32mL,3.91mmol,3.0eq)和乙酸盐(0.16mL,2.61mmol、2.0eq)。将反应混合物在室温下搅拌12小时,然后加入三乙酰氧基硼氢化钠(0.35g,1.65mmol,1.3eq)。将反应混合物在室温下搅拌12小时,然后加入10%碳酸氢钠水溶液以将pH调节至约8.0。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1)纯化,得到棕色凝胶的标题化合物(0.085g,23.0%)。通过与上述相同的方法制备化合物17、160和161。
1H NMR(600MHz,CDCl3):δ10.45(brs,1H),8.23(s,1H),7.98–7.75(m,2H),7.21-7.05(m,1H),3.51–3.20(m,5H),3.00-2.80(m,2H),2.77–2.59(m,2H),2.45-2.30(m,1H),2.15-2.00(m,5H).MS计算值:284.2;MS实际值:285.4([M+H]+).
合成例38.5-(4-甲氧基苄基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物88)的制备
根据化合物96的制备方法,得到深灰色固体的标题化合物(0.30g,39.3%)。
1H NMR(600MHz,CDCl3):δ8.23(d,J=4.8Hz,1H),7.93–7.85(m,1H),7.83–7.77(m,1H),7.36(d,J=8.6Hz,2H),7.09(dd,J=7.5,5.3Hz,1H),6.86(d,J=8.7Hz,2H),3.93(dd,J=50.4,13.1Hz,2H),3.06(ddd,J=12.3,5.1,2.6Hz,1H),2.90(dd,J=14.7,5.0Hz,1H),2.78(ddd,J=16.7,4.9,3.9Hz,1H),2.58(ddd,J=16.8,11.1,5.7Hz,1H),2.50(dd,J=14.6,9.6Hz,1H),2.26–2.14(m,1H),1.91–1.81(m,1H).MS计算值:350.2;MS实际值:351.3([M+H]+).
合成例39.5-苯乙氨基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物93)的制备
根据化合物96的制备方法,得到深灰色固体的标题化合物(0.30g,39.3%)。
1H NMR(600MHz,DMSO-d6):δ8.44–8.23(m,2H),7.85(t,J=7.1Hz,1H),7.27–7.23(m,2H),7.21–7.18(m,2H),7.15-7.12(m,2H),2.90-2.75(m,3H),2.72–2.65(m,2H),2.60-2.50(m,1H),2.48–2.35(m,2H),1.95-1.89(m,2H),1.56–1.44(m,1H).MS计算值:334.2;MS实际值:335.3([M+H]+).
合成例40.5-苯基氨基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物92)的制备
根据化合物96的制备方法,得到棕色固体的标题化合物(0.21g,53.2%)。
1H NMR(600MHz,CDCl3OD):δ8.27–8.21(m,1H),7.87–7.79(m,2H),7.20–7.13(m,2H),7.13–7.03(m,1H),6.74–6.66(m,1H),6.66–6.58(m,2H),3.90–3.73(m,1H),2.95(ddd,J=16.0,9.0,4.5Hz,1H),2.85–2.69(m,2H),2.45–2.33(m,1H),2.23–2.07(m,1H),1.95–1.79(m,1H).MS计算值:306.2;MS实际值:307.3([M+H]+).
合成例41.5-(3,4-二氟苯基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物32)的制备
根据化合物96的制备方法,得到深灰色固体的标题化合物(0.22g,74.2%)。
1H NMR(600MHz,DMSO-d6):δ11.50(s,1H),8.39(d,J=8.4Hz,1H),8.36(d,J=4.0Hz,1H),7.84(t,J=7.2Hz,1H),7.14(dd,J=6.9,5.2Hz,1H),7.06(q,J=9.7Hz,1H),6.58(ddd,J=13.7,6.8,2.4Hz,1H),6.37(d,J=9.1Hz,1H),5.80(d,J=8.1Hz,1H),3.62-3.50(m,1H),2.64–2.55(m,2H),2.51(dd,J=15.1,5.1Hz,1H),2.06–2.00(m,1H),2.00–1.93(m,1H),1.64–1.53(m,1H).MS计算值:342.1;MS实际值:343.2([M+H]+).
合成例42.5-(4-乙基哌嗪-1-基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物91)的制备
根据化合物96的制备方法,得到棕色凝胶的标题化合物(0.20g,47.0%)。
1H NMR(600MHz,CDCl3):δ8.28–8.00(m,1H),7.95–7.80(m,1H),7.80–7.65(m,1H),7.10–6.95(m,1H),2.85–2.50(m,12H),2.35–2.25(m,1H),2.15–2.05(m,1H),2.05–1.95(m,2H),1.70–1.55(m,1H),1.50–1.15(m,3H).MS计算值:327.2;MS实际值:328.4([M+H]+).
合成例43.5-(4-丙基哌嗪-1-基)-2-吡啶-2-基4,5,6,7-四氢-2H-吲唑-3-醇(化合物100)的制备
将3-羟基-2-(吡啶-2-基)-2,4,6,7-四氢-5H-吲唑-5-酮(0.25g,1.09mmol)溶于14mL二氯甲烷/二氯乙烷(1/1)中,然后加入1-丙基哌嗪二氢溴化物(0.41g,1.42mmol,1.3eq)和二异丙基乙胺(0.50mL,2.84mmol,2.6eq)。将反应混合物在室温下搅拌1小时,然后加入三乙酰氧基硼氢化钠(0.30g,1.42mmol,1.3eq)。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1)纯化,得到棕色固体的标题化合物(0.11g,29.0%)。通过与上述相同的方法还制备了化合物127和128。
1H NMR(600MHz,CDCl3OD):δ8.28–8.16(m,1H),8.00–7.58(m,2H),7.17–6.97(m,1H),3.05-2.87(m,8H),2.85-2.75(m,2H),2.71(dd,J=14.5,4.7Hz,1H),2.68–2.57(m,3H),2.39(dd,J=14.3,10.8Hz,1H),2.21–2.12(m,1H),1.75–1.65(m,3H),0.93(t,J=7.4Hz,3H).MS计算值:341.2;MS实际值:342.4([M+H]+).
合成例44.5-(4-环己基甲基哌嗪-1-基)-2-吡啶-2-基4,5,6,7-四氢-2H-吲唑-3-醇(化合物106)的制备
根据化合物100的制备方法,得到棕色固体的标题化合物(0.14g,33.1%)。
1H NMR(600MHz,CD3OD):δ8.45-8.20(m,2H),7.87(dd,J=12.7,5.3Hz,1H),7.19(dd,J=7.1,5.3Hz,1H),3.55-3.35(m,1H),3.09–2.53(m,10H),2.40-2.25(m,1H),2.25–2.07(m 1H),1.92–1.61(m,8H),1.37–1.28(m,4H),1.26–1.19(m,1H),1.10-0.90(m,2H).MS计算值:395.3;MS实际值:396.3([M+H]+).
合成例45.5-(4-苄基哌嗪-1-基)-2-吡啶-2-基4,5,6,7-四氢-2H-吲唑-3-醇(化合物105)的制备
根据化合物100的制备方法,得到棕色固体的标题化合物(0.20g,47.1%)。
1H NMR(600MHz,CDCl3):δ8.22(d,J=5.1Hz,1H),7.90-7.70(m,2H),7.39–7.27(m,5H),7.11(dd,J=7.5,5.4Hz,1H),3.75(brs,2H),3.31–2.75(m,10H),2.74–2.61(m,2H),2.60–2.42(m,1H),2.41–2.24(m,1H),1.89–1.67(m,1H).MS计算值:389.2;MS实际值:390.3([M+H]+).
合成例46.5-(4-苯乙基哌嗪-1-基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物104)的制备
根据化合物100的制备方法,得到棕色固体的标题化合物(0.18g,40.9%)。
1H NMR(600MHz,CDCl3):δ10.24(brs,1H),8.24–8.11(m,1H),8.04–7.81(m,1H),7.81–7.69(m,1H),7.27–7.22(m,2H),7.18–7.14(m,3H),7.07–7.02(m,1H),3.70(ddd,J=6.6,4.2,2.5Hz,1H),2.88–2.64(m,12H),2.63–2.52(m,2H),2.36(dd,J=14.3,10.7Hz,1H),2.19–2.10(m,1H),1.84–1.76(m,1H),1.68(ddd,J=23.9,12.2,5.2Hz,1H).MS计算值:403.2;MS实际值:404.3([M+H]+).
合成例47.5-[4-(3-苯基丙基)-哌嗪-1-基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物107)的制备
根据化合物100的制备方法,得到棕色固体的标题化合物(0.11g,24.2%)。
1H NMR(600MHz,CD3OD):δ8.36(ddd,J=5.0,1.9,0.9Hz,1H),8.27(d,J=8.4Hz,1H),7.83(ddd,J=8.4,7.4,1.9Hz,1H),7.28–7.22(m,2H),7.21–7.12(m,4H),3.05–2.78(m,8H),2.75(ddd,J=16.1,5.3,3.2Hz,3H),2.67–2.55(m,4H),2.31–2.23(m,1H),2.13(ddtdd,J=8.1,5.4,2.7,1.3,0.6Hz,1H),1.96–1.88(m,3H),1.76–1.66(m,1H).MS计算值:417.3;MS实际值:418.3([M+H]+).
合成例48.5-((2-(二甲氨基)苄基)(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物71)的制备
将5-(甲氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(0.20g,0.82mmol)溶于15mL二氯乙烷中,然后加入2-(二甲氨基)苯甲醛(0.18g,1.23mmol,1.5eq)和乙酸盐2滴。将反应混合物在室温下搅拌1小时,然后加入三乙酰氧基硼氢化钠(0.35g,1.63mmol,2.0eq)。将反应混合物在室温下搅拌16小时,然后加入2M氢氧化钠水溶液。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1)纯化,得到浅棕色固体的标题化合物(0.09g,29%)。通过与上述相同的方法还制备了化合物69和77。
1H NMR(600MHz,CD3OD):δ8.38–8.35(m,1H),8.23(d,J=8.4Hz,1H),7.86–7.81(m,1H),7.44–7.37(m,2H),7.34(d,J=7.4Hz,1H),7.20–7.14(m,2H),4.31(s,2H),3.38(tdd,J=5.2,4.5,2.7Hz,1H),2.83(ddd,J=16.8,5.3,2.5Hz,1H),2.80–2.74(m,1H),2.71(s,6H),2.69–2.64(m,1H),2.65(s,3H)2.61(dd,J=13.8,11.1Hz,1H),2.29(ddd,J=7.0,5.2,2.7Hz,1H),2.02(qd,J=11.9,5.5Hz,1H).MS计算值:377.2;MS实际值:378.3([M+H]+).
合成例49.5-(甲基喹啉-6-基甲基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物63)的制备
将5-甲氨基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(0.25g,1.02mmol)溶于20mL二氯甲烷/二氯乙烷(1/1)中,然后加入喹啉-6-甲醛(0.24g,1.5mmol,1.5eq)和乙酸盐(0.06mL,1.0mmol,1eq)。将反应混合物在室温下搅拌1小时,然后加入三乙酰氧基硼氢化钠(0.09g,1.5mmol,1.5eq)。将反应混合物在室温下搅拌12小时,然后加入10%氢氧化钠水溶液以将pH调节至约8.0。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1+0.1%三乙胺)纯化,得到棕色固体的标题化合物(0.058g,14.7%)。通过与上述相同的方法,也制备了化合物61。
1H NMR(600MHz,DMSO-d6):δ11.42(brs,1H),8.81(dd,J=4.2,1.8Hz,1H),8.42–8.33(m,2H),8.30(d,J=7.7Hz,1H),7.94(d,J=8.6Hz,1H),7.84(s,2H),7.72(dd,J=8.6,1.7Hz,1H),7.46(dt,J=4.1,3.0Hz,1H),7.10-7.20(m,1H),3.78(dd,J=43.2,13.9Hz,2H),2.84(ddd,J=10.8,5.0,2.7Hz,1H),2.72–2.61(m,1H),2.57–2.47(m,1H),2.40(tddd,J=7.9,6.7,3.5,2.1Hz,1H),2.30–2.14(m,1H),2.19(s,3H),2.09–1.99(m,1H),1.70(qd,J=12.0,5.4Hz,1H).MS计算值:385.2;MS实际值:386.2([M+H]+).
合成例50.5-(异喹啉-3-基甲基-甲基氨基)-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物62)的制备
根据化合物63的制备方法,得到棕色固体的标题化合物(0.02g,6.1%)。
1H NMR(600MHz,DMSO-d6):δ11.45(brs,1H),9.21(s,1H),8.47–8.31(m,2H),8.05(d,J=8.2Hz,1H),7.92(d,J=8.2Hz,1H),7.89–7.79(m,2H),7.70(t,J=7.5Hz,1H),7.58(t,J=7.4Hz,1H),7.10-7.20(m,1H),3.88(dd,J=41.3,14.7Hz,2H),2.93–2.81(m,1H),2.71–2.59(m,1H),2.56–2.36(m,2H),2.27(s,3H),2.25–2.14(m,1H),2.09–1.99(m,1H),1.75–1.64(m,1H).MS计算值:385.2;MS实际值:386.2([M+H]+).
合成例51.5-(甲基((5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基)甲基)氨基)-2-(吡啶-2-基]-4,5,6,7-四氢-2H-吲唑-3-醇(化合物37)的制备
将5-(甲基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(0.13g,0.55mmol)溶解在6mL二氯甲烷/二氯乙烷(1/1)中,然后加入5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-甲醛(0.20g,0.82mmol,1.5eq),并加入乙酸盐3滴。将反应混合物在45℃下搅拌16小时,然后加入氰基硼氢化钠(0.07g,1.09mmol,2.0eq)。将反应混合物在45℃下搅拌24小时,然后加入2M氢氧化钠水溶液。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(溶剂:二氯甲烷/甲醇=5/1)纯化,得到浅棕色固体的标题化合物(0.059g,15%)。通过与上述相同的方法还制备了化合物35和36。
1H NMR(600MHz,CD3OD):δ8.39–8.33(m,1H),8.27(d,J=8.8Hz,1H),7.88–7.78(m,1H),7.67(s,1H),7.28(ddd,J=31.9,16.9,6.7Hz,2H),7.15(dd,J=8.1,5.3Hz,1H),6.52–6.40(m,1H),3.94(dd,J=26.0,14.0Hz,2H),3.24–3.01(m,4H),3.02–2.93(m,1H),2.82–2.56(m,7H),2.43(s,3H),2.37(s,3H),2.41–2.35(m,1H),2.26–2.19(m,1H),1.80(qd,J=11.9,5.4Hz,1H).MS计算值:472.2;MS实际值:473.4([M+H]+).
合成例52.5-{甲基-[6-(4-甲基-哌嗪-1-基)-嘧啶-4-基甲基]-氨基}-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物34)的制备
根据化合物37的制备方法,得到棕色固体的标题化合物(0.03g,12.7%)。
1H NMR(600MHz,CD3OD):δ8.40–8.32(m,2H),8.27(d,J=8.4Hz,1H),7.87–7.79(m,1H),7.16(dd,J=7.2,5.0Hz,1H),6.87(s,1H),3.76–3.54(m,6H),2.94–2.87(m,1H),2.80–2.70(m,1H),2.65–2.53(m,2H),2.53–2.42(m,5H),2.35(s,3H),2.29(s,3H),2.15–2.08(m,1H),1.81(dtd,J=22.2,11.0,5.4Hz,1H).MS计算值:434.3;MS实际值:435.5([M+H]+).
合成例53.1-[4-(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)-哌嗪-1-基]-2-丁炔-1-酮(化合物89)的制备
1)4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-甲酸叔丁酯的制备
将3-羟基-2-吡啶-2-基-2,4,6,7-四氢吲唑-5-酮(1.55g,6.78mmol,1.0eq)溶于80mL二氯甲烷/二氯乙烷(1/1)中,然后在氮气流下加入哌嗪-1-甲酸叔丁酯(3.65g,16.97mmol,2.5eq)和乙酸盐(0.4mL,6.77mmol、1.0eq)。将反应混合物在室温下搅拌2小时,然后在0℃下加入三乙酰氧基硼氢化钠(4.31g,20.3mmol,3.0eq),然后在室温下搅拌3小时。向反应混合物中加入饱和碳酸氢钠水溶液(20mL)以调节pH至约7,然后用二氯甲烷(30mL×3)萃取。有机层用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱(溶剂:二氯甲烷/甲醇=10/1)纯化,得到黄色固体的标题化合物(1.59g,58.8%)。通过与上述相同的方法还制备了化合物109。
1H NMR(600MHz,CDCl3)δ8.23(dt,J=5.0,1.2Hz,1H),7.81(dd,J=11.0,4.4Hz,2H),7.09(dd,J=8.3,5.1Hz,1H),3.49(brt,4H),2.88–2.78(m,2H),2.73–2.61(m,6H),2.42–2.31(m,1H),2.15(dd,J=8.4,5.1Hz,1H),1.77–1.64(m,1H),1.46(s,9H).
2)5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇二盐酸盐的制备
将4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-甲酸叔丁酯(1.59g,3.98mmol,1.0eq)溶解在30mL甲醇中,然后在氮气流下加入10mL 4.6N盐酸异丙醇溶液。将反应混合物在室温下搅拌1天,并在减压下浓缩。残余物用乙醇和乙醚重结晶,得到黄色固体的标题化合物(1.31g,87.8%)。
1H NMR(600MHz,CD3OD)δ8.51–8.44(m,1H),8.26(dd,J=8.5,0.8Hz,1H),8.17–8.11(m,1H),7.47–7.35(m,1H),4.01–3.61(m,9H),3.08(dd,J=14.2,5.1Hz,1H),3.01(ddd,J=17.4,5.4,2.3Hz,1H),2.89(ddd,J=17.4,11.6,5.7Hz,1H),2.78–2.70(m,1H),2.61–2.53(m,1H),2.13(qd,J=12.1,5.5Hz,1H).
3)1-[4-(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)-哌嗪-1-基]-2-丁炔-1-酮的制备
将2-丁烯酸2,5-二氧代吡咯烷-1-基酯(0.12g,0.65mmol)、5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇二盐酸盐(0.24g,0.65mmol,1.0eq)溶于5mL乙腈中,然后加入N,N-二异丙基乙胺(0.6mL,3.25mmol,5.0eq)。将反应混合物在室温下搅拌1天,然后用水和盐水萃取。用二氯甲烷(20mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1)纯化,得到绿色固体的标题化合物(0.25g,92.6%)。
1H NMR(600MHz,CDCl3):δ8.22(d,J=3.3Hz,1H),7.80(s,2H),7.08(s,1H),3.74(dd,J=10.3,5.8Hz,2H),3.70–3.58(m,2H),2.89–2.69(m,2H),2.69–2.51(m,6H),2.40–2.27(m,1H),2.07(d,J=10.4Hz,1H),2.01–1.92(m,3H),1.69(dt,J=11.4,7.0Hz,1H).MS计算值:365.2;MS实际值:367.2([M+H]+).
合成例57a.1-[4-(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)-哌嗪-1-基]-丙烯酮(化合物97)的制备
将5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇二盐酸盐(0.038g,0.10mmol)溶于3mL二氯甲烷中,然后加入三乙胺(0.04mL,0.30mmol,3.0eq)。将反应混合物在0℃下搅拌10分钟。加入丙烯酰氯(0.01mL,0.10mmol,1.0eq)并在0℃下搅拌30分钟,然后使用碳酸氢钠水溶液调节中和。用二氯甲烷(10mL×2)萃取反应混合物,然后用无水硫酸钠干燥有机层并在减压下浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1+1%氨水)纯化,得到棕色固体的标题化合物(19mg,53.7%)。
1H NMR(600MHz,CDCl3):δ8.23(s,1H),7.82(s,2H),7.10(s,1H),6.64–6.48(m,1H),6.28(dd,J=16.8,1.6Hz,1H),5.76–5.59(m,1H),3.85–3.40(m,4H),2.95–2.50(m,7H),2.44–2.28(m,1H),2.09(s,1H),1.84–1.61(m,1H),0.86(dd,J=17.6,10.5Hz,1H).MS计算值:353.2;MS实际值:354.3([M+H]+).
合成例57b.反应酰胺、碳酸酯、尿素和磺酰胺衍生物的合成反应将5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇二盐酸盐(0.038g,0.10mmol)溶解在5mL乙腈和1mL水的混合溶液中,并加入NaHCO3饱和溶液(200uL)。为了合成每种衍生物,在室温下加入羧基氯化物、氯甲酸盐、异氰酸酯和磺酰氯中的一种。将反应混合物溶液在室温下搅拌1小时,通过LC-MS确认反应完成,然后加入乙酸乙酯50mL并稀释,用盐水和NaHCO3的混合饱和溶液洗涤。分离产物并通过TLC纯化以进行纯化,收率在10~70%范围内。此外,描述了根据一般合成方法和使用特定材料的合成方法制备的合成例的数据。通过与上述相同的方法制备了化合物110至114。
合成例54.4-二甲氨基-1-[4-(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)-哌嗪-1-基]-2-丁烯-1-酮(化合物98)的制备
将5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇二盐酸盐(0.37g,1.00mmol)溶解于15mL二氯甲烷中,然后加入(E)-4-(二甲氨基)-2-丁烯酸盐酸盐(0.20g,1.20mmol,1.2eq)、羟基苯并三唑(0.18g,1.30mmol,1.3eq)和N,N-二异丙基乙胺(1.74mL,10.0mmol,10.0eq)。将反应混合物在0℃下搅拌10分钟,然后加入1,3-二异丙基碳二亚胺(0.19mL,1.20mmol,1.2eq),并在室温下搅拌8小时。对于反应混合物,使用碳酸氢钠水溶液调节中和,然后用二氯甲烷(10mL×2)萃取。有机层用无水硫酸钠干燥并减压浓缩。残余物通过硅胶柱色谱法(二氯甲烷/甲醇=5/1+0.1%氨水)纯化,得到棕色固体的标题化合物(0.27g,65.8%)。通过与上述相同的方法,还制备了化合物99。
1H NMR(600MHz,CDCl3):δ8.25(d,J=5.0Hz,1H),7.83(dt,J=14.3,7.8Hz,2H),7.13–7.07(m,1H),6.84(dt,J=15.2,6.3Hz,1H),6.50–6.43(m,1H),3.70(d,J=0.9Hz,2H),3.52(s,2H),3.30–3.22(m,2H),2.84(d,J=16.5Hz,1H),2.77–2.69(m,1H),2.69–2.60(m,4H),2.57(s,2H),2.41–2.33(m,7H),2.11–2.04(m,1H),1.70(qd,J=12.1,5.3Hz,1H).MS计算值:410.2;MS实际值:411.3([M+H]+).
合成例55.5-(4-甲基哌嗪-1-基)-2-(5-(三氟甲基)吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物82)的制备
将5-(4-甲基哌嗪-1-基)-2-氧代环己烷-1-甲酸甲酯(0.19g,0.75mmol)溶于15mL乙醇中,然后加入5滴乙酸盐和2-肼基-5-(三氟甲基)吡啶(0.13g,0.75mmol,1.0eq)。将反应混合物在室温下搅拌1小时,在100℃下搅拌4小时,并在减压下浓缩。残余物用乙酸乙酯/二乙醚重结晶,得到浅棕色固体的标题化合物(0.092g,32%)。通过与上述相同的方法还制备了化合物115至120、132、137至145、154至156。
1H NMR(600MHz,CD3OD):δ8.69(s,1H),8.57(d,J=8.5Hz,1H),8.15(dd,J=8.9,2.4Hz,1H),3.55–2.86(m,8H),2.84(s,3H),2.76(dd,J=5.1,3.3Hz,1H),2.70–2.61(m,2H),2.59–2.51(m,1H),2.31(dd,J=14.5,10.1Hz,1H),2.16–2.09(m,1H),1.80(qd,J=11.2,5.5Hz,1H).MS计算值:381.2;MS实际值:382.3([M+H]+).
合成例56.2-(6-氯-吡啶-2-基)-5-(4-甲基-哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物83)的制备
根据化合物82的制备方法,得到亮灰色固体的标题化合物(0.11g,59.8%)。
1H NMR(600MHz,D2O):δ7.91(d,J=8.2Hz,1H),7.80(t,J=7.9Hz,1H),7.23(d,J=7.9Hz,1H),3.82–3.30(m,8H),2.97–2.87(m,1H),2.93(s,3H),2.84–2.75(m,2H),2.74–2.65(m,1H),2.48–2.40(m,1H),2.33(dd,J=8.4,3.3Hz,1H),1.93(qd,J=11.9,5.6Hz,1H).MS计算值:347.1;MS实际值:348.2([M+H]+).
合成例57.5-(4-甲基-哌嗪-1-基)-2-(6-甲基-4-三氟甲基-吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物84)的制备
根据化合物82的制备方法,得到灰色固体的标题化合物(0.12g,73.8%)。
1H NMR(600MHz,CD3OD):δ8.41(s,1H),7.73(s,1H),4.16–3.59(m,9H),3.30(s,3H),3.33–3.24(m,2H),3.19(ddd,J=18.6,10.1,3.7Hz,1H),2.84(s,3H),2.91–2.77(m,1H),2.74–2.67(m,1H),2.30(qd,J=12.0,5.6Hz,1H).MS计算值:395.2;MS实际值:396.3([M+H]+).
合成例58.5-(4-甲基-哌嗪-1-基)-2-噻吩并[3,2-c]吡啶-4-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物85)的制备
根据化合物82的制备方法,得到灰色固体的标题化合物(0.11g,43.0%)。
1H NMR(600MHz,CD3OD):δ8.22(d,J=5.6Hz,1H),8.03(d,J=5.3Hz,1H),7.90(d,J=5.6Hz,1H),7.74(d,J=5.7Hz,1H),3.22–2.86(m,9H),2.81(ddd,J=16.9,5.0,3.2Hz,1H),2.76(s,3H),2.73–2.62(m,2H),2.42–2.34(m,1H),2.19–2.12(m,1H),1.79(qd,J=11.6,5.4Hz,1H).MS计算值:369.1;MS实际值:370.2([M+H]+).
合成例59.2-(3-氟-吡啶-2-基)-5-(4-甲基-哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物86)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.41g,86.3%)。
1H NMR(600MHz,CD3OD):δ8.34(d,J=4.6Hz,1H),7.81–7.76(m,1H),7.51–7.43(m,1H),3.00–2.69(m,9H),2.68–2.59(m,2H),2.52(s,3H),2.32(dd,J=14.8,10.7Hz,1H),2.20–2.13(m,1H),1.83–1.70(m,1H),0.92–0.79(m,1H).MS计算值:331.2;MS实际值:332.3([M+H]+).
合成例60.2-吡啶-2-基-5-(4-吡啶-2-基甲基-哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物87)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.064g,23.6%)。
1H NMR(600MHz,CD3OD):δ8.47(d,J=4.4Hz,1H),8.36(d,J=4.6Hz,1H),8.26(d,J=8.4Hz,1H),7.87–7.77(m,2H),7.52(d,J=7.8Hz,1H),7.31(dd,J=7.3,5.2Hz,1H),7.16(dd,J=7.1,5.1Hz,1H),3.69(s,2H),2.90–2.69(m,6H),2.69-2.50(m,6H),2.34–2.23(m,1H),2.22–2.14(m,1H),1.76–1.64(m,1H).MS计算值:390.2;MS实际值:391.3([M+H]+).
合成例61.2-吡啶-2-基-5-(4-喹啉-6-基甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物90)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.064g,23.6%)。
1H NMR(600MHz,DMSO-d6):δ11.40(s,1H),8.83(dd,J=4.2,1.8Hz,1H),8.38(d,J=8.5Hz,1H),8.36–8.34(m,1H),8.31(d,J=8.2Hz,1H),7.94(d,J=8.6Hz,1H),7.83(d,J=10.9Hz,2H),7.69(dd,J=8.6,1.6Hz,1H),7.47(dd,J=8.3,4.1Hz,1H),7.17–7.11(m,1H),3.62(s,2H),2.67–2.23(m,12H),2.14–2.01(m,1H),2.00-1.90(m,1H),1.60-1.45(m,1H).MS计算值:440.2;MS实际值:441.4([M+H]+).
合成例62.2-(4-氯苯基)-5-(4-甲基-哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇盐酸盐(化合物94)的制备
根据化合物82的制备方法,得到米色固体的标题化合物(0.048g,39.8%)。
1H NMR(600MHz,DMSO-d6):δ12.47–11.52(brd,1H),7.72(d,J=9.0Hz,2H),7.45(d,J=8.9Hz,2H),3.79–3.24(m,10H),2.80(s,3H),2.75-2.65(m,1H),2.60-2.55(m,1H),2.47-2.40(m,1H),2.38–2.21(m,1H),1.90-1.75(m,1H).MS计算值:382.1(Free Base:346.2);MS实际值:347.3([M+H]+).
合成例63.5-(4-甲基-哌嗪-1-基)-2-(4-三氟甲基苯基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物95)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.072g,68.8%)。
1H NMR(600MHz,CD3OD):δ7.97(d,J=8.3Hz,2H),7.70(d,J=7.8Hz,2H),3.00–2.61(m,8H),2.77–2.66(m,4H),2.55(s,3H),2.41–2.11(m,2H),1.75–1.65(m,1H).MS计算值:380.2;MS实际值:381.2([M+H]+).
合成例64.2-(4-溴苯基)-5-(4-甲基-哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物101)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.005g,6%)。
1H NMR(600MHz,CD3OD):δ7.65(d,J=8.9Hz,2H),7.50(d,J=8.9Hz,2H),2.89–2.46(m,11Hz),2.34(s,3H),2.2-2.30(m,1H),2.19–2.11(m,1H),2.05-1.95(m,1H),1.67(qd,J=11.8,5.4Hz,1H).MS计算值:390.1;MS实际值:391.2([M+H]+).
合成例65.2-(4-甲基-哌嗪-1-基)-2-(4-三氟甲基苯基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物102)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.10g,55.8%)。
1H NMR(600MHz,CD3OD):δ8.53(dd,J=9.1,4.8Hz,2H),8.06–8.00(m,2H),3.76–3.61(m,4H),3.61–3.42(m,8H),3.26(s,3H),3.19–3.13(m,1H),3.08–3.02(m,1H),2.59(ddd,J=24.0,11.5,5.4Hz,1H).MS计算值:330.2;MS实际值:331.4([M+H]+).
合成例66.4-[3-羟基-(4-甲基哌嗪-1-基)-4,5,6,7-四氢吲唑-2-基]-苯甲腈(化合物103)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.035g,17.6%)。
1H NMR(600MHz,CD3OD):δ8.04(d,J=8.9Hz,2H),7.68(d,J=8.9Hz,2H),2.78-3.00(m,5H),2.77–2.66(m,4H),2.66–2.52(m,3H),2.44(s,3H),2.34–2.22(m,1H),2.11-2.17(m,1H),1.69(ddd,J=24.0,11.8,5.3Hz,1H).MS计算值:337.2;MS实际值:338.2([M+H]+).
合成例67.5-(4-甲基哌嗪-1-基)-2-嘧啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物108)的制备
根据化合物82的制备方法,得到棕色固体的标题化合物(0.10g,40.5%)。
1H NMR(600MHz,CD3OD):δ8.71(d,J=4.9Hz,2H),7.23(t,J=4.9Hz,1H),2.79–2.68(m,6H),2.67–2.52(m,5H),2.36(s,3H),2.34–2.23(m,2H),2.18–2.11(m,1H),1.68(ddd,J=23.9,11.8,5.3Hz,1H).MS计算值:314.2;MS实际值:315.3([M+H]+).
合成例68.2-吡啶-2-基-5-(4-对甲苯基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇(化合物126)的制备
根据化合物96的制备方法,得到米色固体的标题化合物(0.14g,32.9%)。
1H NMR(600MHz,CDCl3):δ8.40–8.34(m,1H),8.32–8.26(m,1H),7.85(ddd,J=8.6,7.4,1.9Hz,1H),7.17(ddd,J=7.3,5.0,0.8Hz,1H),7.04(d,J=8.3Hz,2H),6.87(d,J=8.6Hz,2H),3.16(t,J=5.0Hz,4H),2.94–2.73(m,6H),2.70–2.59(m,2H),2.32(dd,J=13.9,10.9Hz,1H),2.27-2.22(m,1H),2.22(s,3H),1.75(qd,J=11.8,5.4Hz,1H).MS计算值:389.2;MS实际值:390.3([M+H]+).
合成例69.5-[4-(4-甲氧基苯基)-哌嗪-1-基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物129)的制备
根据化合物96的制备方法,得到棕色固体的标题化合物(0.10g,23.7%)。
1H NMR(600MHz,CDCl3):δ8.28–8.19(m,1H),7.90–7.70(m,2H),7.10(ddd,J=8.4,4.3,3.2Hz,1H),6.91(d,J=9.1Hz,2H),6.83(d,J=9.1Hz,2H),3.76(s,3H),3.20-3.10(m,4H),3.01–2.72(m,7H),2.73–2.60(m,1H),2.52–2.36(m,1H),2.32–2.19(m,1H),1.76(qd,J=12.2,5.1Hz,1H).MS计算值:405.2;MS实际值:406.3([M+H]+).
合成例70.1-{4-[4-(3-羟基-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-5-基)-哌嗪-1-基]-苯基}-乙酮(化合物130)的制备
根据化合物96的制备方法,得到灰色固体的标题化合物(0.14g,30.1%)。
1H NMR(600MHz,CDCl3):δ8.30-8.22(m,1H),7.89–7.75(m,4H),7.12-7.05(m,1H),6.91–6.80(m,2H),3.40-3.30(m,4H),2.92–2.59(m,8H),2.50(s,3H),2.45–2.33(m,1H),2.19–2.07(m,1H),1.80-1.65(m,1H).MS计算值:417.2;MS实际值:418.3([M+H]+).
合成例71.5-[4-(4-甲基磺酰基苯基)-哌嗪-1-基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物131)的制备
根据化合物96的制备方法,得到浅灰色固体的标题化合物(0.09g,18.1%)。
1H NMR(600MHz,CDCl3):δ8.25–8.20(m,1H),7.86–7.79(m,2H),7.76(d,J=9.0Hz,2H),7.11(ddd,J=6.8,5.2,2.0Hz,1H),6.93(d,J=9.0Hz,2H),3.43–3.27(m,4H),3.00(s,3H),2.91–2.83(m,1H),2.82-2.75(m,6H),2.70–2.59(m,1H),2.47–2.37(m,1H),2.19–2.10(m,1H),1.74(dddd,J=12.6,7.1,3.3,0.7Hz,1H).MS计算值:453.2;MS实际值:454.2([M+H]+).
合成例72.5-[4-(1-苄基哌啶-4-基甲基)-哌嗪-1-基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物135)的制备
将5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇二盐酸盐(0.70g,1.88mmol)溶解在30mL二氯甲烷/二氯乙烷(1/1)中,然后在氮气流下加入1-苄基哌啶-4-甲醛(0.35mL,1.88mmol,1.0eq)和三乙胺(0.77mL,5.64mmol,3.0eq)。在0℃下加入三乙酰氧基硼氢化钠(0.79g,3.76mmol,2.0eq)后,将反应混合物在室温下搅拌2小时。向反应混合物中加入饱和碳酸氢钠水溶液(20mL)以调节pH至约7,然后用二氯甲烷(30mL×3)萃取。有机层用无水硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱(溶剂:氯仿/甲醇=5/1+1%氨水)纯化,得到棕色固体的标题化合物(0.65g,70.3%)。通过与上述相同的方法还制备了化合物133、134和136。
1H NMR(600MHz,CDCl3):δ8.26–8.19(m,1H),7.90-7.80(m,2H),7.27–7.17(m,5H),7.10-7.00(m,1H),3.51(s,2H),2.96–2.80(m,2H),2.80–2.27(m,11H),2.17(d,J=7.1Hz,2H),2.00-1.90(m,3H),1.75–1.64(m,2H),1.55-1.40(m,1H),1.34–1.16(m,5H).MS计算值:486.3;MS实际值:487.4([M+H]+).
合成例73.5-{4-[2-(2-羟基乙氧基)-乙基]-哌嗪-1-基}-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇(化合物17)的制备
根据化合物96的制备方法,得到黄色固体的标题化合物(0.15g,29.5%)。
1H NMR(600MHz,CDCl3):δ8.25–8.19(m,1H),7.99–7.73(m,2H),7.11–7.02(m,1H),3.76–3.50(m,6H),2.89–2.55(m,14H),2.39–2.30(m,1H),2.16–2.09(m,1H),1.72–1.60(m,1H).MS计算值:387.2;MS实际值:388.3([M+H]+).
制备的合成例化合物1-161的结构、MS结果和IUPAC命名示于下表1中。
[表1]
<实施例1>在通过DMSO处理分化为中性粒细胞的HL-60细胞中,分析PMA处理诱导的ROS生成的变化
为了证实合成例化合物对成纤维细胞和特定基质细胞的ROS生成的影响,对通过DMSO处理分化为中性粒细胞的HL-60细胞、NHLF(正常人肺成纤维细胞(normal human lungfibroblast,Lonza)、LX-2(人肝星状细胞,Sigma)、ARPE19(人视网膜色素上皮细胞,ATCC)和KEL-FIB(瘢痕疙瘩成纤维细胞(Keloid fibroblast),ATCC)通过刺激PMA(佛波醇12-肉豆蔻酸13-醋酸酯)、TGF-β1、棕榈酸酯或高浓度葡萄糖等来诱导ROS生成,并在此条件下观察到合成例化合物的ROS生成的抑制作用。
HL-60细胞(人白血病细胞,ATCC)悬浮于含有1.25% DMSO(RPMI+10%FBS)的培养基中,在5% CO2、37℃条件下培养6天,从而诱导分化为中性粒细胞。将分化为中性粒细胞的HL-60细胞以2×104细胞/孔的浓度在96孔板中等分,并将合成例化合物以0.5mM的浓度处理细胞30分钟。然后,在每个含有细胞和药物的孔中处理200mM的PMA以诱导ROS生成,并通过使用100μM L-012观察每个孔的发光水平来测量这种ROS生成。
将NHLF(正常人肺成纤维细胞,Lonza)、LX-2(人肝星状细胞,Sigma)、ARPE19(人视网膜色素上皮细胞,ATCC)、KEL-FIB(瘢痕疙瘩成纤维细胞,ATCC)细胞悬浮在含有10%FBS的培养基中,于96孔板中等分,然后在5% CO2、37℃条件下培养24小时。将以10、20、30、40、60和80μM浓度的合成例化合物预处理30分钟至1小时后,对每个包含细胞和药物的孔进行ROS刺激。在额外培养48小时后,使用L-012或DCF-DA确认ROS生成水平。
实验结果表明,在所有NHLF、LX-2、ARPE19、KEL-FIB细胞中,合成例化合物通过ROS刺激抑制ROS生成。表2的结果示出了当合成例化合物(0.5μm)处理诱导为中性粒细胞的HL-60细胞时通过PMA诱导的ROS生成被抑制的结果。图1示出了合成例化合物1和17处理LX-2和NHLF细胞时通过PMA诱导的ROS生成全部被抑制的结果。
因此,证实当用合成例化合物处理分化的HL-60细胞或诱导ROS生成的各种成纤维细胞或特定基质细胞时,ROS生成被有效抑制。
[表2]
[在分化的HL-60细胞中ROS生成抑制作用]
<*:<30%,**:30<<50%,***:50<<70%,****:>70%>
<实施例2>TGF-β1诱导的αSMA表达变化分析
据报道,当成纤维细胞分化为肌成纤维细胞时,形成癌相关成纤维细胞(CAF)或引起各种组织的纤维化。
为了证实本发明的合成例化合物是否影响成纤维细胞分化为肌成纤维细胞,观察了合成例化合物对HFF-1(人类包皮成纤维细胞,ATCC)、NHLF(正常人肺成纤维细胞,Lonza)、LX-2(人肝星状细胞,Sigma)、ARPE19(人视网膜色素上皮细胞,ATCC)和KEL-FIB(瘢痕疙瘩成纤维细胞,ATCC)细胞中由TGF-β1诱导的αSMA(确认分化为肌成纤维细胞的生物标记物)表达增加的抑制作用。
将每个细胞悬浮在含有10%FBS的DMEM培养基中,并以1×104-1.5×105个细胞/孔的浓度在4孔室载玻片(Nunc)上等分,合成例化合物和TGF-β1(TGF-β1和TGF-β具有相同含义)处理以制备用于确认αSMA表达的细胞。用免疫细胞化学方法确认αSMA在制备的细胞中的表达,如下所示。对于细胞,在使用4%多聚甲醛固定10分钟并使用0.1%Triton x-100对细胞进行透化后,依次进行用针对αSMA的一级抗体(抗αSMA抗体,1:200,在4℃下持续16小时)和二级抗体(缀合Alexa-594的抗体,1:800,在室温下持续1小时)处理的过程,然后用荧光显微镜观察αSMA的表达水平。
图3观察了通过TGF-β1(10ng/mL)处理HFF细胞诱导αSMA表达后,用10、20和40μM各合成例化合物处理的效果。合成例中的化合物1、化合物23、化合物12、化合物5、化合物14和化合物33均示出了抑制35%~70%的αSMA表达的效果,尽管程度不同。
此外,同样在LX-2、NHLF、ARPE19、KEL-FIB细胞中,证实了由TGF-β1(10ng/mL)诱导的αSMA表达的增加被10μM合成例化合物1的处理显著抑制,如图4中所证实。
<实施例3>TGF-β1诱导的凝胶收缩变化分析
为了证实合成例化合物对成纤维细胞分化为肌成纤维细胞的效果,观察了合成例化合物对由人包皮成纤维细胞(HFF-1,ATCC)和胶原相互作用诱导的凝胶收缩现象的抑制效果。
将以3×106个细胞/mL浓度制备的HFF-1细胞和胶原(牛I型胶原)的混合溶液分别等分于24孔板中,然后在5%CO2、37℃的条件下培养1小时以诱导凝胶聚合。然后,使用勺子将附着在板上的凝胶从板上悬浮后,将包含TGF-β1和合成例化合物的培养基添加到每个孔中。培养72小时后,用10、20、30、40、60和80μM合成例化合物处理以测量凝胶的大小,从而确认通过药物处理的凝胶收缩程度。
作为实验的结果,如图7中所证实,观察到通过合成例化合物1、化合物5、化合物12、化合物13、化合物14、化合物16、化合物23、化合物33、化合物38、化合物63和化合物62的处理有效地抑制了由TGF-β1(10ng/mL)诱导的凝胶收缩。
<实施例4>多巴胺能神经细胞的ROS生成变化分析
为了证实合成例化合物对多巴胺能神经细胞的ROS生成的影响,通过α-突触核蛋白预制原纤维(PFF)刺激N27(大鼠多巴胺能神经神经细胞,Sigma)细胞来诱导ROS生成,并且在此条件下,观察到合成例化合物对ROS生成的抑制效果。
N27细胞在含有10%FBS、1μM血管紧张素II的RPMI培养基中培养,制备的细胞在6孔板上以4×103个细胞/孔的浓度等分。用ROS生成刺激物、PFF(预制原纤维)和合成例化合物处理细胞。在合成例化合物处理24小时后,使用CellROX深红试剂测量每个孔的荧光,从而确认ROS生成的程度。
作为实验结果,如图2所示,证实了通过0.001μM合成例化合物12、化合物16、化合物32和化合物82的处理可有效抑制PFF诱导的ROS生成。
<实施例5>LPS诱导的IL-1β表达的变化分析
为了证实本发明合成例化合物对人源性成纤维细胞中的炎症反应的影响,观察了LPS处理增加的IL-1β表达是否在来自各种组织的成纤维细胞中被合成例化合物抑制。
在6孔板中接种2×105个细胞并培养24小时后,将其在无血清培养液中进一步培养16小时,然后根据每种条件将合成例化合物1预处理20分钟,并用LPS(1μg/mL)诱导炎症反应6小时。使用RT-PCR证实IL-1β的表达。使用RNeasy迷你试剂盒(Qiagen)从细胞中分离总RNA,对于分离的RNA 2ug,使用PrimeScriptTM II第一链cDNA合成试剂盒(TaKaRa)合成cDNA,然后使用PCR PreMix(Bioneer)进行PCR以扩增基因。靶引物的核苷酸序列如下。IL-1β(正向:5’-CCCACAGACCTTCCAGGAGAGATG-3’(SEQ ID NO:1),反向:5’-GGCAGTTCAGTGATCGTACAGG-3’);GAPDH(正向:5’-GTGGGCTGGCTCAGAAAAAGG-3’(SEQ ID NO:3),反向:5’-GGTGGTCCAGGGGTCTTACT-3’(SEQ ID NO:4));β-肌动蛋白(正向:5’-CCACCATTGGCAATGAGCGGTTC-3’(SEQ ID NO:5),反向:5’-AGGTCTTTGCGGATGTCCACGT-3’(SEQID NO:6))。在1.5%琼脂糖凝胶中通过电泳确认PCR产物。
作为实验结果,如图8中所证实,观察到通过10μM合成例化合物1的处理以浓度依赖性方式有效抑制了LPS诱导的IL-1β。
<实施例6>IL-6和IL8癌症相关成纤维细胞表达变化的分析
为了确认本发明合成例化合物对癌症相关成纤维细胞中的炎症反应的影响,观察了IL6和IL8的表达是否在胰腺癌相关成纤维细胞(P.CAF)中被合成例化合物所抑制。
在6孔板中接种1.5×105个细胞,然后在P.CAF完全培养基中培养48小时后,根据每种条件用10、20、30、40、60和80μM合成例化合物处理48小时,然后通过使用QuantkineELISA试剂盒(R&D systems)进行ELISA确认IL-6和IL-8的表达,如下所示。
将100μl合成例化合物处理48小时后的培养液添加到包括100μl测定稀释液的微孔板条中进行分析,并在室温下放置2小时,然后去除内容物,然后用400μl洗涤缓冲液洗涤4次。加入200μl人IL-6或IL-8缀合物,并在室温下放置2小时,然后去除内容物,然后用400μl洗涤缓冲液洗涤4次。加入200μl底物溶液并在室温下放置20分钟,然后在室温下放置20分钟,再加入50μl终止溶液,并在30分钟内测量450nm波长下的吸光度,以确认IL-6和IL-8的表达水平。
作为实验结果,如图5和6所证实,观察到通过合成例的化合物1、化合物5、化合物12至化合物16、化合物23、化合物33、化合物38、化合物63和化合物62的处理可有效抑制P.CAF中表达的IL-6和IL-8。
<实施例7>确认脑损伤治疗效果
为了测试合成例化合物预防或治疗脑疾病或障碍的效果,使用α-突触核蛋白预制原纤维(PFF)注射帕金森病小鼠模型对其进行评估。
使用C57Bl/6小鼠,并将所有小鼠均维持在标准条件下。该实验通过将实验动物分为口服蒸馏水的正常对照组(阴性对照)、α-突触核蛋白预制原纤维(PFF)注射帕金森病诱导组(载体对照)和实验组(每天口服给药25mg/kg的合成例化合物16至α-突触核蛋白预制原纤维(PFF)注射帕金森病诱导组),每组8只动物。正常对照组给予生理盐水,合成例化合物每天口服给药一次,持续7周,然后进行行为改变实验和组织病理学实验。
通过转棒试验(Rota rod)、爬杆试验(pole test)和后肢紧握(hindlimbclasping)分析行为变化,并测量每只动物三次试验的平均值。
完成试验后,将动物麻醉以提取每个动物的脑组织,并将组织固定在4%缓冲中性福尔马林溶液(10%缓冲中性福尔马林)中。将固定的组织切割至一定厚度后,通过常规组织处理工艺将其埋入石蜡中,以制备4~5μm的组织切片。然后,为了证实帕金森病的病理指数是否根据纹状体中的蛋白质聚集水平得到改善,首先用磷酸化的丝氨酸129α突触核蛋白标记,然后进行硫黄素T染色以观察组织病理学结果。
作为实验的结果,作为对合成例化合物16给药组的行为变化(如爬升时间、转棒试验、后肢紧握等)分析结果,观察到帕金森样行为症状改善了50%或更多,帕金森病的重要病理指标a-突触核蛋白的聚集和积累改善了50%或更多。
总之,证实了本发明合成例化合物有效地改善了帕金森病。
<110> 阿普塔生物治疗公司(APTABIO THERAPEUTICS INC.)
<120> 新型吡唑衍生物
<130> OPP20220759KR
<150> KR 10-2021-0025694
<151> 2021-02-25
<160> 6
<170> KoPatentIn 3.0
<210> 1
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IL-1 β 正向引物
<400> 1
ccacagacct tccaggagaa tg 22
<210> 2
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IL-1 β 反向引物
<400> 2
gtgcagttca gtgatcgtac agg 23
<210> 3
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> GAPDH 正向引物
<400> 3
gtggctggct cagaaaaagg 20
<210> 4
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> GAPDH反向引物
<400> 4
ggtggtccag gggtcttact 20
<210> 5
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> β肌动蛋白正向引物
<400> 5
caccattggc aatgagcggt tc 22
<210> 6
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> β肌动蛋白反向引物
<400> 6
aggtctttgc ggatgtccac gt 22
Claims (15)
1.一种以下化学式I的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐:
在式中,
A是取代或未取代的5元至20元杂芳基或取代或未取代的C5-C20芳基;和
其中,5元至20元杂芳基或C5-C20芳基可以是未取代的,或者可以被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至20元杂芳基和取代或未取代的5元至20元杂环烷基组成的取代基中的1、2、3或4种取代,其中,R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至10元杂芳环或C5-C10芳环;和
R是氢、重氢、氰基、卤素、硝基、卤代烷基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的C5-C20芳基、取代或未取代的5元至20元杂芳基或-C(=O)R2,其中,R2是C3-C8环烷基、C1-C10烷基、C2-C10烯基或C6-C10芳基;和
B是-NKM或取代或未取代的5元至20元杂芳基或取代或未取代的5元至20元杂环烷基;和
K和M各自独立地为氢、重氢、氰基、卤素、硝基、卤代烷基、取代或未取代的C1-C10烷基、取代或未取代的C1-C10烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C5-C20芳基、取代或未取代的C5-C20芳基C1-C10烷基、取代或未取代的5元至20元杂芳基或取代或未取代的5元至20元杂芳基C1-C10烷基;
其中,C1-C10烷基是未取代的,或被选自由重氢、卤素、羟基、氰基、硝基、羧基、取代或未取代的氨基、取代或未取代的C1-C10烷基、取代或未取代的C1-C10卤代烷基、取代或未取代的C1-C10羟烷基、取代或未取代的C3-C8环烷基、C1-C10烷氧基、C1-C10烷基磺酰基、C5-C20芳基磺酰基、C5-C20芳氧基、取代或未取代的C5-C20芳基、取代或未取代的5元至20元杂芳基和取代或未取代的5元至20元杂环烷基组成的组中的1、2、3或4种取代基取代;和
C3-C8环烷基可以是未取代的,或被选自由重氢、卤素、氰基、硝基、羧基、取代或未取代的胺、取代或未取代的C5-C20芳基或5元至20元杂芳基、C1-C10烷氧基和C1-C10卤代烷基组成的组中的1、2、3或4种取代基取代;和
5元至20元杂芳基、5元至20元杂环烷基或C5-C20芳基可以是未取代的,或被选自由重氢、卤素、氰基、硝基、-C(=O)R’、-C(=O)OR’、-NH-C(=O)R”、取代或未取代的氨基、取代或未取代的C1-C10烷基、取代的或未取代的C1-C10烷氧基、取代或未取代的C1-C10卤代烷基、取代或未取代的C1-C10羟烷基、取代或未取代的C1-C10烷基磺酰基、取代或未取代的C5-C20芳基磺酰基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10芳基、取代或未取代的C5-C20芳基、取代或未取代的C5-C20芳基C1-C10烷基、取代或未取代的5元至12元杂环烷基、取代或未取代的C1-C10烷基C3-C8环烷基和取代或未取代的C1-C10烷基5元至20元杂环烷基组成的组中的1、2、3或4种取代基取代;和
其中,R’和R”各自独立地为氢、重氢、取代或未取代的胺、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基或取代或者未取代的C6-C10芳基C1-C6烷基;和
取代的氨基被1种或2种C1-C10烷基取代;和
杂环烷基或杂芳环的杂原子是选自N、S和O的一种或多种。
2.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中A是未取代的或被取代的5元至12元杂芳基或C6-C10芳基,其中,5元至12元杂芳基或C6-C10芳基可以被选自由氰基、卤素、C1-C6卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C6烷基、C1-C-6烷氧基、C3-C6环烷基、氨基、C6-C10芳基、5元至12元杂芳基和5元至12元杂环烷基组成的组中的1、2、3或4种取代基取代,其中R1是氢、重氢或C1-C6烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至7元杂芳环或C6-C9芳环。
3.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中R是氢、重氢、氰基、卤素、硝基、未取代的或C3-C6环烷基取代的C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C6-C10芳基、5元至12元杂芳基、-C(=O)R2,其中,R2是C3-C6环烷基、C1-C6烷基、C2-C6烯基或C6-C10芳基。
4.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中B是-NKM或5元至12元杂芳基或5元至12元杂环烷基,其中,5元至12元杂芳基或5元至12元杂环烷基是未取代的,或被重氢、卤素、氰基、硝基、-NR3R4、C1-C6烷基、C1-C6烷氧基、C6-C10芳基、-C(=O)R5、-SO2-R6中的1、2、3或4种取代,和
其中,C1-C6烷基、C1-C6烷氧基或C6-C10芳基可以是未取代的,或被羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳氧基中的1、2、3或4种取代,或未取代的或被C1-C6烷基、C6-C10芳基C1-C6烷基或C1-C6烷基羰基取代的4元至12元杂环烷基,和
R3和R4各自独立地为氢、重氢、-C(=O)-Ra、C1-C6烷基或C6-C10芳基,并且C1-C6烷基或C6-C10芳基是未取代的,或被卤素、羟基、C1-C6烷基、C1-C6烷氧基或者C6-C10芳氧基中的1、2、3或4种取代,其中Ra为氢、重氢、C1-C6烷基或C1-C6卤代烷基;和
R5是-ORb、-NRcRd、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基,其中,C1-C6烷基、C2-C6烯基或C2-C6炔基可以是未取代的,或者被单C1-C6烷基胺或二C1-C6烷基胺中的1、2、3或4种取代,其中Rb、Rc和Rd各自独立地为氢、重氢、C6-C10芳基或C6-C10芳基C1-C6烷基,和
R6是未取代的C1-C6烷基或C1-C6烷基取代的C6-C10芳基中的1、2、3或4种,和
K和M各自独立地为氢、重氢、氰基、卤素、硝基、C1-C6卤代烷基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、5元至12元杂芳基、5元至12元杂芳基C1-C6烷基,其中,C1-C6烷基、C1-C6烷氧基、C6-C10芳基、C3-C8环烷基或5元至12元杂芳基可以被氰基、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6烷基磺酰基、C6-C10芳基磺酰基、-NR7R8、-C(=O)R9、5元至12元杂环基、羟基、硝基、C6-C10芳基中的1、2、3或4种取代,其中5元至12元杂环基或C6-C10芳基可以是未取代的或被C1-C6烷基取代的,和
R9是-ORe、-NReRf、未取代的或-NReRf-取代的C2-C6烯基或C6-C10芳基中的1、2、3或4种,其中,Re和Rf各自独立地为氢、重氢、C1-C6烷基、C6-C10芳基或C1-C6烷基。
5.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中化学式I的化合物是以下化学式I-1的化合物:
[化学式I-1]
在式中,
K、M和R的定义与化学式I相同;和
D是CR10、N、O或S,或E是CR11、N、O或S,或F是CR12、N、O或S,或G是CR13、N、O或S,或J是CR14、N、O或S,但N、O和S是一个或多个;和
R10至R14相同或不同,并且可以独立地被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至12元杂芳基和取代或未取代的5元至12元杂环烷基组成的取代基中的1、2、3或4种取代,其中R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的C6-C10芳环或5元至10元杂芳环。
6.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中化学式I的化合物是以下化学式I-2的化合物:
[化学式I-2]
在式中,
R的定义与化学式I相同;和
D是CR10、N、O或S,或E是CR11、N、O或S,或F是CR12、N、O或S,或G是CR13、N、O或S,或J是CR14、N、O或S,但N、O和S是一个或多个;和
R10至R14相同或不同,并且可以独立地被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至12元杂芳基和取代或未取代的5元至12元杂环烷基组成的取代基中的1、2、3或4种取代,其中R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至10元杂芳环或C6-C10芳环,和
n是0、1或2的整数;和
L是CH2、NH或O;和
可以是未取代的,或被重氢、卤素、氰基、硝基、-NR3R4、C1-C6烷基、C1-C6烷氧基、C6-C10芳基、-C(=O)R5、-SO2-R6中的1、2、3或4种取代,其中,当取代基为2个或更多个时,两个或更多个相邻基团可以彼此结合以形成具有的取代或未取代的5元至20元杂芳基或取代或未取代的5元至20元杂环烷基;和
其中,C1-C6烷基、C1-C6烷氧基或C6-C10芳基可以是未取代的,或被羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳氧基中的1、2、3或4种取代,或未取代的或C1-C6烷基、C6-C10芳基C1-C6烷基或C1-C6烷基羰基取代的4元至12元杂环烷基,和
R3和R4各自独立地为氢、重氢、-C(=O)-Ra、C1-C6烷基或C6-C10芳基,并且C1-C6烷基或C6-C10芳基可以是未取代的,或被卤素、羟基、C1-C6烷基、C1-C6烷氧基或C6-C10芳氧基中的1、2、3或4种取代,其中Ra为氢、重氢、C1-C6烷基或C1-C6卤代烷基;和
R5是-ORb、-NRcRd、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基,其中,C1-C6烷基、C2-C6烯基或C2-C6炔基可以是未取代的,或者被单C1-C6烷基胺或二C1-C6烷基胺中的1、2、3或4种取代,并且Rb、Rc和Rd各自独立地是氢、重氢、C6-C10芳基或C6-C10芳基C1-C6烷基,和
R6是未取代的C1-C6烷基,或C1-C6烷基取代的C6-C10芳基中的1、2、3或4种。
7.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中化学式I的化合物是以下化学式I-3的化合物:
[化学式I-3]
在式中,
K、M和R的定义与化学式I相同;和
D是CR10、N、O或S,或E是CR11、N、O或S,或F是CR12、N、O或S,或G是CR13、N、O或S,但N、O和S是一个或多个;和
R10至R13相同或不同,并且可以独立地被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至12元杂芳基和取代或未取代的5元至12元杂环烷基组成的取代基中的1、2、3或4种取代,其中R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至10元杂芳环或C6-C10芳环。
8.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中化学式I的化合物是以下化学式I-4的化合物:
[化学式I-4]
在式中,
R的定义与化学式I相同;和
D是CR10、N、O或S,或E是CR11、N、O或S,或F是CR12、N、O或S,或G是CR13、N、O或S,但N、O和S是一个或多个;和
R10至R13相同或不同,并且可以独立地被由氰基、卤素、卤代烷基、硝基、-C(=O)R1、-C(=O)OR1、-NH-C(=O)R1、C1-C10烷氧基、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的胺、取代或未取代的C5-C20芳基、取代或未取代的5元至12元杂芳基和取代或未取代的5元至12元杂环烷基组成的取代基中的1、2、3或4种取代,其中R1可以是氢、重氢、C1-C10烷基;和
两个或更多个相邻基团可彼此结合以形成取代或未取代的芳香族烃环,其中芳香族烃环可形成包含0、1、2或3个选自N、O和S的杂原子的5元至10元杂芳环或C6-C10芳环,和
n是0、1或2的整数;和
L是CH2、NH或O;和
可以是未取代的,或被重氢、卤素、氰基、硝基、-NR3R4、C1-C6烷基、C1-C6烷氧基、C6-C10芳基、-C(=O)R5、-SO2-R6中的1、2、3或4种取代,其中,当取代基为2个或更多个时,两个或更多个相邻基团可以彼此结合以形成具有的取代或未取代的5元至20元杂芳基或取代或未取代的5元至20元杂环烷基;和
其中,C1-C6烷基、C1-C6烷氧基或C6-C10芳基可以是未取代的,或被羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳氧基中的1、2、3或4种取代,或未取代的或被C1-C6烷基、C6-C10芳基C1-C6烷基或C1-C6烷基羰基取代的4元至12元杂环烷基,和
R3和R4各自独立地为氢、重氢、-C(=O)-Ra、C1-C6烷基或C6-C10芳基,并且C1-C6烷基或C6-C10芳基可以是未取代的,或被卤素、羟基、C1-C6烷基、C1-C6烷氧基或C6-C10芳氧基中的1、2、3或4种取代,其中Ra为氢、重氢、C1-C6烷基或C1-C6卤代烷基;和
R5是-ORb、-NRcRd、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基,其中,C1-C6烷基、C2-C6烯基或C2-C6炔基可以是未取代的,或者被单C1-C6烷基胺或二C1-C6烷基胺中的1、2、3或4种取代,并且Rb、Rc和Rd各自独立地是氢、重氢、C6-C10芳基或C6-C10芳基C1-C6烷基,和
R6是未取代的C1-C6烷基,或1、2、3或4种C1-C6烷基取代的C6-C10芳基。
9.根据权利要求1所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐,
其中由化学式I表示的化合物选自以下化合物1)至161):
1)5-(苄基甲基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
2)5-(苄基环丙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
3)4-{[(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)甲基氨基]甲基}苯甲腈;
4)5-[(4-氟苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
5)5-[(2,4-二氟苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
6)5-[(2-氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
7)5-[(3-氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
8)5-[甲基-(4-三氟甲基苄基)氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇;
9)5-[甲基-(3-甲基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
10)5-[甲基-(3-三氟甲基苄基)-氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇;
11)5-[甲基-(2-三氟甲基苄基)-氨基]-2-吡啶-2-基-4,5,6,7-四氢-2H-吲唑-3-醇;
12)5-[(4-甲基磺酰基苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
13)5-[(3-甲氧基苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
14)5-哌啶-1-基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
15)5-吗啉-4-基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
16)5-(4-甲基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
17)5-(4-(2-(2-羟基甲氧基)乙基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
18)5-(3,4-二氢-1H-异喹啉-2-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
19)5-[(4-氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
20)5-(苄基乙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
21)5-(苄基丙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
22)5-(苄基丁基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
23)5-[甲基(3-甲基磺酰基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
24)5-[甲基-(4-甲基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
25)3-{[(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)甲基氨基]甲基}苯甲腈;
26)5-[(2-甲氧基苄基)-甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
27)5-[(3-氟苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
28)5-[(4-甲氧基苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
29)5-[甲基-(2-甲基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
30)5-[(2,4-二氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
31)5-[(3,4-二氯苄基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
32)5-(3,4-二氟苯基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
33)5-[甲基(5,6,7,8-四氢喹啉-8-基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
34)5-(((3-(羟甲基)-5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基)甲基)(甲基)氨基)-2-(吡啶2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
35)5-{[(3-(羟甲基)-5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基)甲基]甲基氨基}-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
36)5-{甲基[3-甲基-5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基]甲基氨基}-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
37)5-{甲基[5-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶-2-基]甲基氨基}-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
38)[4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2-吲唑-5-基)哌嗪-1-基]环丙基甲酮;
39)5-(苄基甲基氨基)-2-(5-三氟甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
40)5-(苄基甲基氨基)-2-(5-氯吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
41)5-(苄基甲基氨基)-2-(6-(三氟甲基)吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
42)5-(苄基甲基氨基)-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
43)5-(苄基甲基氨基)-2-(3-氟吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
44)6-(5-(苄基甲基氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)烟碱甲腈;
45)5-(苄基甲基氨基)-2-(6-甲基-4-三氟甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
46)5-(苄基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
47)2-(吡啶-2-基)-5-[(吡啶-2-基甲基)氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
48)5-[甲基(吡啶-2-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
49)5-[甲基(吡啶-4-基甲基)氨基]-2-(5-三氟甲基吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
50)2-(5-氯吡啶-2-基)-5-[甲基(吡啶-4-基甲基)氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
51)5-[甲基(吡啶-4-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
52)2-(4-溴苯基)-5-[甲基(吡啶-4-基甲基)氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
53)5-(苄基甲基氨基)-2-(噻吩并[3,2-c]吡啶-4-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
54)2-(6-氨基吡啶-2-基)-5-(苄基甲基氨基)-4,5,6,7-四氢-2H-吲唑-3-醇;
55)5-苯基氨基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
56)5-[(2,5-二甲基苯基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
57)5-[(4-硝基苯基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
58)5-[(4-甲氧基苯基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
59)5-(苯基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
60)2-(吡啶-2-基)-5-(喹啉-3-基氨基)-4,5,6,7-四氢-2H-吲唑-3-醇;
61)5-[甲基(萘-2-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
62)5-[(异喹啉-3-基甲基)甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
63)5-[甲基(喹啉-6-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
64)5-[(异喹啉-3-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
65)5-[甲基(吡啶-2-基甲基)氨基]-2-苯基-4,5,6,7-四氢-2H-吲唑-3-醇;
66)5-[乙基(吡啶-4-基甲基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
67)5-[(3-二甲氨基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
68)5-[(4-二甲氨基苄基)氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-2-醇;
69)5-[(3-二甲基氨基苄基)甲基氨基)]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
70)5-[(4-二甲基氨基)苄基甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
71)5-[(2-二甲基氨基)苄基甲基氨基]-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
72)5-(苄基甲基氨基)-2-苯基-4,5,6,7-四氢-2H-吲唑-3-醇;
73)4-[(5-苄基甲基氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基]苯甲酸;
74)5-(苄基甲基氨基)-2-(4-溴苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
75)5-(苄基甲基氨基)-2-(2-氯苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
76)5-(苄基甲基氨基)-2-(2-甲氧基苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
77)2-(2-氯苯基)-5-[(3-二甲基氨基苄基)甲基氨基]-4,5,6,7-四氢-2H-吲唑-3-醇;
78)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)苯甲酸;
79)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)苯甲酰胺;
80)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)-N-甲基苯甲酰胺;
81)4-(((3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)(甲基)氨基)甲基)-N,N-二甲基苯甲酰胺;
82)5-(4-甲基哌嗪-1-基)-2-(5-(三氟甲基)吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
83)2-(6-氯吡啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
84)2-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
85)5-(4-甲基哌嗪-1-基)-2-(噻吩并[3,2-c]吡啶-4-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
86)2-(3-氟吡啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
87)2-(吡啶-2-基)-5-(4-(吡啶-2-基甲基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
88)5-((4-甲氧基苄基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
89)1-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)丁-2-烯-1-酮;
90)2-(吡啶-2-基)-5-(4-(喹啉-6-基甲基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
91)5-(4-乙基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
92)5-(苯基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
93)5-(五乙基氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
94)2-(4-氯苯基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
95)5-(4-甲基哌嗪-1-基)-2-(4-(三氟甲基)苯基)-4,5,6,7-四氢-2H-吲唑-3-醇;
96)2-(吡啶-2-基)-5-(吡咯烷-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
97)1-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)丙-2-烯-1-酮;
98)(E)-4-(二甲氨基)-1-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)丁-2-烯-1-酮;
99)(E)-4-(二甲氨基)-N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-N-甲基丁-2-烯酰胺;
100)5-(4-丙基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
101)2-(4-溴苯基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
102)2-(4-氟苯基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
103)4-(3-羟基-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-2-基)苯甲腈;
104)5-(4-五乙基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
105)5-(4-苄基哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
106)5-(4-(环己基甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
107)5-(4-(3-苯基丙基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
108)5-(4-甲基哌嗪-1-基)-2-(嘧啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
109)5-(哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
110)5-(4-(甲基磺酰基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
111)5-(4-(苯基磺酰基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
112)2-(吡啶-2-基)-5-(4-甲苯基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
113)4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-N-苯基哌嗪-1-甲酰胺;
114)4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-甲酸苄酯;
115)2-(1-甲基-1H-吡咯-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
116)5-(4-甲基哌嗪-1-基)-2-(噻唑-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
118)2-(1-甲基-1H-吡唑-5-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
119)2-(1-甲基-1H-咪唑-5-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
120)2-(1-甲基-1H-咪唑-5-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
121)5-(苄基(甲基)氨基)-2-(嘧啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
122)5-(苄基(甲基)氨基)-2-(1-甲基-1H-吡咯-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
123)5-(苄基(甲基)氨基)-2-(1-甲基-1H-吡唑-5-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
124)5-(苄基(甲基)氨基)-2-(1-甲基-1H-咪唑-5-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
126)2-(吡啶-2-基)-5-(4-(对甲苯基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
127)5-(4-(4-羟基苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
128)5-(4-(3,4-二氟苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
129)5-(4-(4-甲氧基苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
130)1-(4-(4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)苯基)乙-1-酮;
131)5-(4-(4-(甲基磺酰基)苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
132)5-(4-(4-苯氧基苯基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
133)5-(4-(哌啶-4-基甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
134)5-(4-((1-甲基哌啶-4-基)甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
135)5-(4-((1-苄基哌啶-4-基)甲基)哌嗪-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
136)1-(4-((4-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮;
137)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)苯甲酰胺;
138)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-2-苯基乙酰胺;
139)1-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-3-苯基脲;
140)1-苄基-3-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)脲;
141)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)苯磺酰胺;
142)N-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)-4-甲基苯磺酰胺;
143)(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)氨基甲酸苄基酯;
144)2-(5-氟-4-吗啉基嘧啶-2-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
145)N-苄基-3-甲氧基-N-甲基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-胺;
146)N-苄基-3-(环丙基甲氧基)-N-甲基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-胺;
147)5-(苄基(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-基环丙甲酸酯;
148)5-(苄基(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-基丙烯酸酯;
149)5-(苄基(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-基苯甲酸酯;
150)2-(5-(苄基(甲基)氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)嘧啶-5-甲酸;
151)2-(5-(苄基(甲基)氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)烟酸甲酯;
152)N-(6-(5-(苄基(甲基)氨基)-3-羟基-4,5,6,7-四氢-2H-吲唑-2-基)吡啶-2-基)乙酰胺;
153)5-(苄基(甲基)氨基)-2-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
154)5-(4-甲基哌嗪-1-基)-2-(嘧啶-4-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
155)2-(5-氯哒嗪-3-基)-5-(4-甲基哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
156)2-(吡啶-2-基)-5-(4-(嘧啶-2-基)哌嗪-1-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
157)5-(苄基(甲基)氨基)-2-(5-硝基嘧啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
158)5-((4-羟基苄基)(甲基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
159)5-(甲基(4-硝基苄基)氨基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;
160)5-(3-(乙基(甲基)氨基)吡咯烷-1-基)-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-3-醇;和
161)2,2,2-三氟-N-(1-(3-羟基-2-(吡啶-2-基)-4,5,6,7-四氢-2H-吲唑-5-基)吡咯烷-3-基)乙酰胺。
10.根据权利要求1所述的化合物或其盐,
其中所述盐是由选自由盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、乙磺酸、苯磺酸和甲苯磺酸等组成的组中的一种或多种酸诱导的盐的形式。
11.一种用于预防、改善或治疗氧化应激相关疾病的药物组合物,包含作为活性成分的根据权利要求1-9中任一项权利要求所述的化合物或其药学上接受的盐和药学上可接受的载体。
12.根据权利要求11所述的药物组合物,
其中药学上可接受的载体是选自由赋形剂、稀释剂、崩解剂、粘合剂、醛类、表面活性剂、乳化剂、悬浮剂和稀释剂组成的组中的一种或多种。
13.根据权利要求11所述的药物组合物,
其中氧化应激相关疾病选自由以下组成的组:癌症;选自类风湿性关节炎、骨关节炎、肺炎、肝炎、炎性结直肠疾病、肠道肠炎、肾小球肾炎、胃炎、血管炎、胰腺炎、腹膜炎、支气管炎、心肌炎、脑炎、过敏性接触性皮炎、糖尿病炎症、感染性炎症和自身免疫性疾病的炎性疾病;选自肝纤维化、肝硬化、小肠纤维化、大肠纤维化、胃纤维化、肺纤维化、皮肤纤维化、表皮纤维化、真皮硬化/系统性硬化、心脏纤维化和肾纤维化的纤维化疾病;选自帕金森病、亨廷顿病、淀粉营养性侧索硬化症、阿尔茨海默病、多发性硬化症、缺血性和创伤性脑损伤的神经退行性疾病;选自双相情感障碍、发育障碍、自闭症障碍、阿斯伯格综合征、Rett综合征、视力障碍、视神经病变、注意力缺陷多动障碍(ADHD)、癫痫、情绪障碍、Tourette综合征和精神分裂症的神经疾病;肝病;皮肤病;线粒体疾病;衰老;慢性酒精中毒;干细胞功能障碍;跛行;选自肥胖、糖尿病、高血压、高脂血症、动脉硬化、外周血管疾病、缺血灌注、心肌梗死和中风的代谢综合征;唐氏综合征;不育;组织中过氧化脂质的过量产生;选自肌病、肌营养不良、心肌病、脑肌病和背部肌肉萎缩的肌肉相关疾病;细胞膜脂质过氧化物积累;慢性疲劳;以及选自视网膜纤维化、黄斑变性、糖尿病视网膜病变、白内障和新生血管性青光眼的视网膜疾病。
14.一种用于预防、改善或治疗氧化应激相关疾病的方法,包括向受试者给药权利要求1-9中任一项权利要求所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐。
15.一种权利要求1-9中任一项权利要求所述的化合物,或其立体异构体、溶剂化物、同位素变体、互变异构体或药学上可接受的盐在制备用于预防、改善或治疗氧化应激相关疾病的药物组合物中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20210025694 | 2021-02-25 | ||
KR10-2021-0025694 | 2021-02-25 | ||
PCT/KR2022/002802 WO2022182205A1 (ko) | 2021-02-25 | 2022-02-25 | 신규한 피라졸 유도체 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115916766A true CN115916766A (zh) | 2023-04-04 |
Family
ID=83048373
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280005464.4A Pending CN115916766A (zh) | 2021-02-25 | 2022-02-25 | 新型吡唑衍生物 |
Country Status (13)
Country | Link |
---|---|
US (1) | US20230234940A1 (zh) |
EP (1) | EP4163277A1 (zh) |
JP (1) | JP2023536764A (zh) |
KR (1) | KR102473680B1 (zh) |
CN (1) | CN115916766A (zh) |
AU (1) | AU2022224918B2 (zh) |
BR (1) | BR112023002485A2 (zh) |
CA (1) | CA3189497A1 (zh) |
CL (1) | CL2023000200A1 (zh) |
CO (1) | CO2023000854A2 (zh) |
IL (1) | IL299303A (zh) |
MX (1) | MX2023000926A (zh) |
WO (1) | WO2022182205A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023191201A1 (ko) * | 2022-03-31 | 2023-10-05 | 압타바이오 주식회사 | 신규한 피라졸 유도체 |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2701467A1 (de) * | 1976-01-16 | 1977-07-28 | Du Pont | Substituierte cycloalkanapyrazole, sie enthaltende herbizide und verfahren zur kontrolle von unerwuenschter vegetation |
CN1071424A (zh) * | 1991-10-08 | 1993-04-28 | 日本曹达株式会社 | 吡唑衍生物及其农业园艺用杀菌剂 |
JP2004123700A (ja) * | 2002-05-22 | 2004-04-22 | Mitsubishi Pharma Corp | パーオキシナイトライト消去剤 |
JP2005029573A (ja) * | 2003-06-18 | 2005-02-03 | Mitsubishi Pharma Corp | 腫瘍転移抑制剤 |
KR20050114606A (ko) * | 2003-01-10 | 2005-12-06 | 미츠비시 웰파마 가부시키가이샤 | 혈액뇌관문 파탄 억제제 |
CN101484425A (zh) * | 2006-07-01 | 2009-07-15 | 默克专利有限公司 | 用于治疗hsp90诱导的疾病的吲唑衍生物 |
WO2010015657A2 (en) * | 2008-08-05 | 2010-02-11 | Institut Pasteur | New alkoxypyrazoles |
WO2011101804A1 (en) * | 2010-02-18 | 2011-08-25 | Genkyotex Sa | Pyrazolo piperidine derivatives as nadph oxidase inhibitors |
CN102939087A (zh) * | 2010-05-27 | 2013-02-20 | 宇部兴产株式会社 | 新型吲唑衍生物或其盐、其制造中间体,以及使用其的抗氧化剂、吲唑衍生物或其盐的用途 |
WO2013158644A2 (en) * | 2012-04-16 | 2013-10-24 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
CN110023311A (zh) * | 2016-11-15 | 2019-07-16 | 生物电子技术有限公司 | 2-取代的氨基-萘并[1,2-d]咪唑-5-酮类化合物或其药学上可接受的盐 |
WO2021145655A1 (ko) * | 2020-01-13 | 2021-07-22 | 압타바이오 주식회사 | 신규한 피라졸 유도체 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06287187A (ja) * | 1993-04-02 | 1994-10-11 | Nippon Soda Co Ltd | 新規なピラゾ−ル誘導体及びその農園芸用殺菌剤 |
JP2005162639A (ja) | 2003-12-01 | 2005-06-23 | Sumitomo Pharmaceut Co Ltd | 複素環化合物 |
JP2011026305A (ja) | 2009-06-24 | 2011-02-10 | Daiichi Sankyo Co Ltd | イミダゾールカルボニル化合物を含有する医薬組成物 |
ES2824450T3 (es) | 2015-06-22 | 2021-05-12 | Actelion Pharmaceuticals Ltd | Compuestos de benzoxazol y de benzotiazol 2,5-disustituidos como inhibidores de la NADPH oxidasa 4 |
-
2022
- 2022-02-25 BR BR112023002485A patent/BR112023002485A2/pt unknown
- 2022-02-25 CN CN202280005464.4A patent/CN115916766A/zh active Pending
- 2022-02-25 JP JP2023512372A patent/JP2023536764A/ja active Pending
- 2022-02-25 IL IL299303A patent/IL299303A/en unknown
- 2022-02-25 CA CA3189497A patent/CA3189497A1/en active Pending
- 2022-02-25 AU AU2022224918A patent/AU2022224918B2/en active Active
- 2022-02-25 WO PCT/KR2022/002802 patent/WO2022182205A1/ko unknown
- 2022-02-25 MX MX2023000926A patent/MX2023000926A/es unknown
- 2022-02-25 KR KR1020220025313A patent/KR102473680B1/ko active IP Right Grant
- 2022-02-25 EP EP22760121.8A patent/EP4163277A1/en active Pending
-
2023
- 2023-01-06 US US18/150,955 patent/US20230234940A1/en active Pending
- 2023-01-20 CL CL2023000200A patent/CL2023000200A1/es unknown
- 2023-01-26 CO CONC2023/0000854A patent/CO2023000854A2/es unknown
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2701467A1 (de) * | 1976-01-16 | 1977-07-28 | Du Pont | Substituierte cycloalkanapyrazole, sie enthaltende herbizide und verfahren zur kontrolle von unerwuenschter vegetation |
CN1071424A (zh) * | 1991-10-08 | 1993-04-28 | 日本曹达株式会社 | 吡唑衍生物及其农业园艺用杀菌剂 |
JP2004123700A (ja) * | 2002-05-22 | 2004-04-22 | Mitsubishi Pharma Corp | パーオキシナイトライト消去剤 |
KR20050114606A (ko) * | 2003-01-10 | 2005-12-06 | 미츠비시 웰파마 가부시키가이샤 | 혈액뇌관문 파탄 억제제 |
JP2005029573A (ja) * | 2003-06-18 | 2005-02-03 | Mitsubishi Pharma Corp | 腫瘍転移抑制剤 |
CN101484425A (zh) * | 2006-07-01 | 2009-07-15 | 默克专利有限公司 | 用于治疗hsp90诱导的疾病的吲唑衍生物 |
WO2010015657A2 (en) * | 2008-08-05 | 2010-02-11 | Institut Pasteur | New alkoxypyrazoles |
WO2011101804A1 (en) * | 2010-02-18 | 2011-08-25 | Genkyotex Sa | Pyrazolo piperidine derivatives as nadph oxidase inhibitors |
CN102939087A (zh) * | 2010-05-27 | 2013-02-20 | 宇部兴产株式会社 | 新型吲唑衍生物或其盐、其制造中间体,以及使用其的抗氧化剂、吲唑衍生物或其盐的用途 |
WO2013158644A2 (en) * | 2012-04-16 | 2013-10-24 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
CN110023311A (zh) * | 2016-11-15 | 2019-07-16 | 生物电子技术有限公司 | 2-取代的氨基-萘并[1,2-d]咪唑-5-酮类化合物或其药学上可接受的盐 |
WO2021145655A1 (ko) * | 2020-01-13 | 2021-07-22 | 압타바이오 주식회사 | 신규한 피라졸 유도체 |
Also Published As
Publication number | Publication date |
---|---|
AU2022224918A1 (en) | 2023-02-09 |
IL299303A (en) | 2023-02-01 |
EP4163277A1 (en) | 2023-04-12 |
US20230234940A1 (en) | 2023-07-27 |
WO2022182205A1 (ko) | 2022-09-01 |
KR102473680B1 (ko) | 2022-12-06 |
MX2023000926A (es) | 2023-02-22 |
CO2023000854A2 (es) | 2023-02-16 |
BR112023002485A2 (pt) | 2023-04-04 |
KR20220122931A (ko) | 2022-09-05 |
CA3189497A1 (en) | 2022-09-01 |
JP2023536764A (ja) | 2023-08-29 |
CL2023000200A1 (es) | 2023-09-08 |
AU2022224918B2 (en) | 2023-04-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106458934B (zh) | 喹喔啉化合物及其用途 | |
WO2014134774A1 (en) | Compounds inhibiting leucine-rich repeat kinase enzyme activity | |
TW201625586A (zh) | 環己烯-1-基-吡啶-2-基-1h-吡唑-4-羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 | |
TW201625584A (zh) | 茚滿及吲哚啉衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 | |
JP2017519025A (ja) | チオフェン−2−イル−ピリジン−2−イル−1h−ピラゾール−4−カルボン酸誘導体、および可溶性グアニル酸シクラーゼ活性化剤としてのその使用 | |
WO2021078135A1 (zh) | 吡咯酰胺类化合物及其用途 | |
EA035406B1 (ru) | Соединения пиридиния | |
KR102333863B1 (ko) | 신규한 피라졸 유도체 | |
CN115916766A (zh) | 新型吡唑衍生物 | |
TWI424998B (zh) | 作為腺苷A3受體配體的三唑并[1,5-a]喹啉類 | |
AU2018305223A1 (en) | New propanamine derivatives for treating pain and pain related conditions | |
JP7249428B2 (ja) | 疼痛に対して活性があるピペラジニル及びピペリジニルキナゾリン-4(3h)-オン誘導体 | |
JP6518692B2 (ja) | 多環式herg活性化剤 | |
WO2002006249A1 (fr) | Procede de fabrication d'un derive de 1,2,3 triasol substitue en position 1 | |
WO2023030685A1 (en) | Novel ras inhibitors | |
RU2816835C1 (ru) | Новые производные пиразола | |
TW200900408A (en) | Fused pyridine derivative | |
TW202334109A (zh) | 新穎吡唑衍生物 | |
WO2017008681A1 (zh) | 酰胺类衍生物、其制备方法及其在医药上的用途 | |
EP3697766A1 (en) | New alkoxyamino compounds for treating pain and pain related conditions | |
CN114787143A (zh) | Zeste增强子同源物2抑制剂及其用途 |
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 |